Freezing of Gait in Parkinson's Disease

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in Parkinson’s diseasein Parkinson’s in Parkinson’s diseasein Parkinson’s Tackling freezing freezingTackling Tackling of of gait gait

Tackling freezing of gait in Parkinson’s disease ANKE H. SNIJDERS

90 978-94-91027-33-8 ISBN

Tackling freezing of gait in Parkinson’s disease

Anke H. Snijders

‘like the wheels of a locomotive failing to bite the rails when they are slippery with frost and making, in consequence, ineffective revolutions’

William W describing his gait disorder, according to Thomas Buzzard, neurologist National Hospital Queen Square, London, 1882 The studies presented in this thesis were carried out at the Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience and Centre for Cognitive Neuroimaging, Radboud University Medical Centre, Nijmegen, the Netherlands, with financial support of the Prinses Beatrix Fonds, the Radboud University Medical Centre and the Netherlands Organization for Scientific Research (NWO), grant numbers 92003490 (A.H.Snijders) and 016076352 (B.R.Bloem).

Cover design and layout by: In Zicht Grafisch Ontwerp, Arnhem Printed by: Ipskamp Drukkers, Enschede DVD layout and production by: Mimumedia, Nijmegen

ISBN: 978-94-91027-33-8

Proefschrift

ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. mr. S.C.J.J.Kortmann, volgens besluit van het college van decanen in het openbaar te verdedigen op maandag 4 juni 2012 om 13.30 uur precies

door

Anke Helene Snijders geboren op 9 juni 1979 te Groningen Promotor: Prof. dr B.R. Bloem

Copromotor: Dr I. Toni

Manuscriptcommissie: Prof. dr G. Fernandez Prof. dr A.C.H. Geurts Prof. dr A. Nieuwboer (KU Leuven) Tackling freezing of gait in Parkinson’s disease

Doctoral thesis

To obtain the degree of doctor from Radboud Universiteit Nijmegen on the authority of the Rector Magnificus, prof. dr. S.C.J.J.Kortmann, according to the decision of the Council of Deans to be defended in public on Monday, June 4, 2012 at 13.30 hours

Anke Helene Snijders Born on June 9, 1979 Groningen, Netherlands Supervisor: Prof.dr B.R. Bloem

Co-supervisor: Dr I. Toni

Doctoral Thesis Committee: Prof. dr G. Fernandez Prof. dr A.C.H. Geurts Prof. dr A. Nieuwboer (KU Leuven) Contents

1 | Outline of the thesis 9 2 | General introduction to gait disorders and freezing of gait 19 2.1 Neurological gait disorders in the elderly 21 2.2 Freezing of gait: general overview 45 3 | Provoking freezing of gait 59 3.1 Clinimetrics of freezing of gait 61 3.2 To freeze or not to freeze: clinical provocation of freezing of gait 75 3.3 Obstacle avoidance to provoke freezing of gait on a treadmilll 89 3.4 Objective detection of subtle freezing of gait in Parkinson’s disease 103 4 | Understanding freezing of gait 119 4.1 Gait-related cerebral changes in freezing of gait 121 5 | Cycling and freezing of gait 155 5.1 Cycling breaks the ice for freezing of gait 157 5.2 Cycling is less affected then walking in freezers of gait 167 6 | Treating freezing of gait 173 6.1 Cueing for freezing of gait: a need for 3D cues? 175 6.2 ‘ON-state’ freezing of gait in Parkinson’s disease: 181 A paradoxical levodopa-induced complication 7 | Summary & discussion 193 8 | Nederlands 209 8.1 Loopstoornissen 211 8.2 Wankel op de benen en vallen 225 8.3 Nederlandse samenvatting 235 8.4 Overzicht van de behandeling van bevriezen van lopen 243 A | 251 Appendix 1: Freezing of gait Scoring Form 253 Appendix 2: Abbreviations 256 Appendix 3: Reference list 257 Appendix 4: Video contents 273 Appendix 5: Video legends 274 Dankwoord 279 CV 283 List of publications 285 Donders Graduate School for Cognitive Neuroscience Series 287 Dissertations of the Parkinson Centre Nijmegen (ParC) 291

Outline of the thesis

OUTLINE OF THE THESIS 1

Outline of the thesis

Gait disorders and freezing of gait Gait disorders are common and often devastating companions of ageing, leading to reductions in quality of life and increased mortality.328;375;387 A curious feature of some gait disturbances is their fluctuating or frank episodic nature. An example of an incapacitating episodic gait disorder is freezing of gait (FOG), where patients feel like their feet are ‘glued to the floor’. FOG is frequently seen in patients with Parkinson’s disease (PD: Box 1), with unexpected episodes during which patients experience an inability to start walking or to continue moving forward.150 Because of this sudden and unpredictable nature, FOG is an important cause of falls and injuries.201;219

Vignettes A remarkable observation in a single patient can sometimes help to advance the field, by generating new ideas for further research. Therefore, each chapter of this thesis starts with a short vignette presenting an intriguing video, as a source of inspiration and contemplation. This thesis will start with a general introduction of gait disorders in Chapter 2.1, discussing its pathophysiology, core clinical features and assessment. We propose a

Box 1 Parkinson’s disease Parkinson’s disease (PD) is a degenerative disorder with abnormalities of movement, behaviour, learning and emotions, mainly due to dopaminergic deficiency of the striatum (caudate nucleus and putamen in the basal ganglia). The pathognomonic pathological feature of PD is the presence of intraneuronal inclusions (pale bodies and Lewy bodies), mainly containing α-synuclein. This pathology affects not only the dopaminergic neurons, but also noradrenergic, cholinergic, serotonergic and other central neurotransmitter systems. The main motor features of PD result from dopaminergic deficiency in the striatum (caudate nucleus and putamen): tremor, rigidity, bradykinesia (slowing down of movements) and hypokinesia/akinesia (scarcity/absence of movements). However, non-motor signs and symptoms are increasingly recognized in PD, including fatigue, hyposmia, pain, autonomic dysfunctions, mood disorders, sleep disorders and cognitive deficits. Mainstay of treatment are levodopa, dopamine agonists and deep brain stimulation. All these therapies are symptomatic treatments: they do not stop the neurodegeneration itself. To date, there is no treatment that cures the disease. Also, there is no evidence for neuroprotective medications to slow down the disease.1;53;322

13 CHAPTER 1

Box 1 Continued

(From: Bear, M. F., Connors, B.W. & Paradiso M. A., Neuroscience: Exploring the Brain, Second Edition, Lippincott Williams & Wilkins, 2001, pp 473-482.) practical three-step approach to categorise gait disorders and we present a simplified classification system based on clinical signs and symptoms. Then, I will give a general overview of freezing of gait in Chapter 2.2.

Provoking freezing of gait FOG is an unusual gait disorder because of its “episodic” character: the gait problem is sometimes there, but often it is not. This makes FOG a challenge for clinicians. Many patients inadvertently deny having FOG gait because they do not properly know what actual freezing looks like. Even when patients report having FOG at home, the phenomenon is notoriously difficult to elicit in the clinical setting.288 Apparently, excitement associated with the doctor’s visit or the patient’s extra attention to gait during physical examination can temporarily suppress FOG (a form of “kinesia paradoxa”). Another explanation is that FOG, which is typically provoked while walking in tight quarters,329 is less likely to occur in a widely spaced hospital corridor than at home in a crammed living room. This failure to demonstrate the problem that hinders

14 OUTLINE OF THE THESIS 1

them so much at home is very frustrating for patients and carers. It is also inconvenient for doctors who need to base their clinical management decisions based on observations in the examination room. Besides, it hinders patient inclusion in research studies. Hence, we have tried to find ways to provoke FOG. In the section “Provoking freezing of gait” we start with Chapter 3.1, a review on the clinimetry of FOG. Then Chapter 3.2 deals with the best way to clinically provoke FOG, followed by Chapter 3.3 and 3.4 on the provocation and detection of FOG on a treadmill.

Understanding freezing of gait The mechanisms leading to FOG remain poorly understood, and this hampers development of improved treatment strategies. In Chapter 4, we used motor imagery of gait in combination with fMRI (Box 2) to study the cerebral correlates of gait planning in patients with and without FOG.

Box 2 fMRI and motor imagery fMRI: functional Magnetic Resonance Imaging is a type of specialized MRI scan. It measures the hemodynamic response (change in blood flow) related to neural activity in the brain. To do so, it measures the blood-oxygen-level dependence (BOLD), the MRI contrast of blood deoxyhemoglobin. Advantages are its relatively low invasiveness, absence of radiation exposure, wide availability and high spatial resolution. Still, images must be interpreted carefully, as correlation does not imply causality. Rigorous statistical analyses are needed to avoid false positives. In addition, temporal resolution in poor.

Motor imagery: During motor imagery a particular movement is imagined but not executed.193 There is a large functional and neural overlap between motor planning and motor imagery.77;193;251 Several issues are important when using motor imagery to study real movement in PD: - Motor imagery relies on the current physical configuration of a subject. For example, motor imagery in patients with amputated limb is delayed,282 and hand position influences the ability to mentally rotate hands.89 - Motor imagery is sensitive to motor control variables. For example, performing an imagined arm movement with an added mass (4kg) attached to the wrist increases duration of imagined movements.138 - Motor imagery relies on similar neural processes as performance and planning of the same movement. This is not only true for hand movements352 but also for walking.213

15 CHAPTER 1

Box 2 Continued - There is a tight behavioural association between imagined and actual gait.29 When imagining to walk along a narrow path, it takes longer to reach your goal compared to walking along a broad path: just as would be expected during real walking. Also, when more time is needed to reach a certain goal in real life, also imagining to get to the goal takes more time (high temporal correspondence between imagined and actual walking). Hence, the internal simulation of an action - as during motor imagery - probably represents the core element of a motor plan. Although motor imagery of gait is likely to engage only a portion of the cerebral circuits controlling walking, it has several advantages for investigating FOG. - Motor imagery specifically provides opportunities for studying alterations in the planning of gait, which may be a crucial element in FOG pathophysiology.76;187 Meaningful cerebral comparisons between patients and controls require matched behavioural performance.311 During real motor performance it will be difficult to match behavioural performance between patients with PD and controls. However, with motor imagery of gait there can be a matched performance of the test between groups - If cerebral responses are measured during a real FOG episode, there is different motor performance (namely FOG instead of walking) and the patients feels his body moving differently. In addition, the FOG may provoke emotions in the patient. With motor imagery of gait cerebral responses related to walking can be isolated, distinct from alterations in motor performance and somatosensory feedback produced by actual FOG episodes.12

16 OUTLINE OF THE THESIS 1

Cycling and freezing of gait The section “Cycling and freezing of gait” starts with the presentation of a fascinating case: a patient with longstanding PD and severe FOG, who showed a remarkably preserved ability to ride a bicycle. In Chapter 5.1, the scientific and clinical implications of this single case observation are discussed, and the video of a similar case is shown. Chapter 5.2 shows that these cases do not stand alone, but ‘abasia sine abicyclia’ is a more widespread phenomenon in PD patient with FOG.

Treatment of freezing of gait Levodopa (Box 3) generally alleviates FOG, both with respect to severity and frequency. However, freezing is sometimes resistant to dopaminergic therapy.153 This does not necessarily exclude a role for dopamine deficiency in the underlying pathophysiology, because the threshold for therapeutic relief may simply be higher for freezing than for other symptoms, falsely creating the impression of ‘levodopa-resistance’. More puzzling is the observation that dopaminergic therapy can paradoxically cause or aggravate FOG. We deal with this FOG during ‘ON-state’ in the case description in Chapter 6.1.

Another hallmark of the current treatment of FOG is cueing (Box 1.4). However, determining the right cue parameters is important for obtaining the best effect on FOG. Chapter 6.2 deals with a patient with severe FOG who responded well to three- dimensional cues, but not to two-dimensional visual cues.

In chapter 7 we give a general summary of this thesis and discuss the results. This chapter ends with a short review on the current state-of-art treatment of FOG. Finally, Chapter 8 is in Dutch, with a Dutch review on gait disorders (Chapter 8.1) and a clinical lesson on patients who fall -due to FOG- (Chapter 8.2). Chapter 8.3 gives a Dutch summary of the results of this thesis in Chapter 8.3, written to also be understandable for ‘lay’ people. The final Dutch chapter (8.4) is a short review on the current state-of-art treatment of FOG.

17 CHAPTER 1

Box 3 Levodopa53 Levodopa or LEVODOPA (L-3,4-di-hydroxy-phenylalanine) is the cornerstone of treatment in Parkinson’s disease. Levodopa is a precursor of dopamine and is able to pass the blood-brain barrier (unlike dopamine itself). Therefore, it can be used to treat dopamine-depletion as seen in Parkinson’s disease. It was developed in the 1960s, and still successfully relieves symptoms and dramatically improves quality of life. At first, very high doses of levodopa were needed to treat Parkinson’s disease, due to peripheral breakdown of levodopa by the enzyme dopa-decarboxylase. This lead to peripheral side effects such as nausea and vomiting. The addition of a peripheral dopa-decarboxylase inhibitor to levodopa made it possible to reduce the dosage and decrease peripheral side-effects. Unfortunately, long-term use of levodopa is associated with motor complications (motor fluctuations and dyskinesias). Natural progression of the disease leads to narrowing of the therapeutic window. In addition, the short half-life of the drug leads to pulsatile stimulation, and the absorption of levodopa may be a problem.

http://epda.eu.com/medinfo/levodopa/

18 OUTLINE OF THE THESIS 1

Box 4 Cueing284;312 Movement in parkinsonism has been long known to improve on cues. A cue is an external stimulus that helps improving movement. This cue can aimed to improve the timing of steps (temporal cue) or to improve the amplitude of steps (spatial cue). There are three different cue modalities: - Visual cues (e.g. stripes on the floor) - Auditory cues (e.g. rhythmical tones, for example from metronome) - Tactile cues (e.g. rhythmical small vibrations) Internal stimuli may also improve walking. Examples are: - Attention to regular and big stepping - Singing a rhythmical song or counting without speaking aloud The specific information a cue provides (cue parameter) partly defines the effect of a cue. For example, when the frequency of auditory cueing is too high, patients with FOG do not improve their walking. This effect of the cue parameters was already described by Martin in 1967: He described transverse lines were helpful to improve gait. However, zigzag lines or lines without contrast of color were somewhat less effective. Very narrow lines closely together or lines parallel to the line of movement did not have any effect.

General introduction to gait disorders and freezing of gait

2.1

Neurological gait disorders in the elderly

Published as: Snijders AH, van de Warrenburg BP, Giladi N, Bloem BR. Neurological gait disorders in elderly people; clinical approach and classification.Lancet neurology. 2007; 6(1); 63-74. CHAPTER 2

Summary

Gait disorders are common and often devastating companions of ageing, leading to reductions in quality of life and increased mortality. Here, we present a clinically oriented approach to neurological gait disorders in the elderly population. We also draw attention to several exciting scientific developments in this specialty. Our first focus is on the complex and typically multifactorial pathophysiology underlying geriatric gait disorders. An important new insight is the recognition of gait as a complex higher order form of motor behaviour, with prominent and varied effects of mental processes. Another relevant message is that gait disorders are not an unpreventable consequence of ageing, but implicate the presence of underlying diseases that warrant specific diagnostic tests. We next discuss the core clinical features of common geriatric gait disorders and review some bedside tests to assess gait and balance. We conclude by proposing a practical three-step approach to categorise gait disorders and we present a simplified classification system based on clinical signs and symptoms.

24 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

Introduction Gait disorders are common in elderly populations and their prevalence increases with 2 age. At the age of 60 years, 85% of people have a normal gait, but at the age of 85 years or older this proportion has dropped to 18%.48;355 Gait disorders have devastating consequences. Perhaps the most notorious corollary is falling, which is often caused by an underlying gait problem. Injuries caused by accidental falls range from relatively innocent bruises to major fractures or head trauma. Another important consequence is reduced mobility, which leads to loss of independence. This immobility is often compounded by a fear of falling, which further immobilises patients and affects their quality of life.195 Importantly, gait disturbances are also a marker for future development of cardiovascular disease and dementia.47;241;376 These associations suggest that gait disturbances—even when they present in isolation - can reflect an early, preclinical, underlying cerebrovascular or neurodegenerative disease. Finally, gait disorders are associated with reduced survival, which can be attributed to a combination of fatal falls, reduced cardiovascular fitness, and death from underlying disease.328;375;387 Elderly patients regularly present with complex gait disorders, with concurrent contributions from multiple causal factors.8 To describe specific gait disorders accurately is often difficult. Here, we provide a practical approach that may support clinicians in their everyday management of neurological gait disorders in elderly people. We briefly address the pathophysiology of gait disorders and discuss the effects of mental function and normal ageing on gait. We conclude by describing a practical clinical approach and simplified classification system to differentiate gait disorders in everyday practice, based on clinically discernable gait patterns. Treatments for geriatric gait disorders are not reviewed.

Pathophysiology of gait disorders

Normal gait requires a delicate balance between various interacting neuronal systems (figure 1) and consists of three primary components: locomotion, including initiation and maintenance of rhythmic stepping; balance; and ability to adapt to the environment. Dysfunction in any of these systems can disturb gait. Most ambulatory problems in elderly people are caused by concurrent dysfunction of multiple systems. Virtually all levels of the nervous system are needed for normal gait.264;267;283;299

Recent studies have drawn attention to pattern generators in the spinal cord that generate rhythmic stepping.100 Neuroimaging studies point to the role of the frontal cortex in controlling gait and in coordinating automatic and voluntary movements.327 One interesting study used functional MRI to identify patterns of brain activity while

25 CHAPTER 2

Figure 1 Levels of the central and peripheral nervous system required for normal gait

Feedback: Vestibular system Visual system Sensory nerves

Execution: Frontal cortex planning Basal ganglia initiation, automatisation Brainstem integration Cerebellum coordination, adaptation Spinal cord Support: spinal pattern generators Cardiovascular system Nerve roots Bones Peripheral nerves Joints (both motor and sensory) Ligaments Muscles Feet

participants imagined standing, walking, or running while lying in the scanner.189 With running (automated locomotion), spinal pattern generators and the cerebellum were involved, whereas slow walking evoked activity in the parahippocampal region, presumably because spatial navigation becomes more important.

26 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

Gait and mental function Walking is traditionally seen as an automatic motor task that requires little, if any, 2 higher mental functions. In the past decade, new insights have drawn attention to the importance of cognition in daily walking.391 Normal walking requires strategic planning of the best route, as well as continuous interaction with the environment and with internal factors. Failing to understand the significance of an obstacle, choosing an inappropriate route, or misinterpreting one’s own physical abilities can all lead to falls. The safety and efficacy of normal walking rely not only on sensorimotor systems, but also critically depend on the interaction between the executive control dimension (integration and decision of action) with the cognitive dimension (eg, navigation, visuospatial perception, or attention) and the affective dimension (mood, cautiousness, and risk-taking). A common situation where such an integration is challenged is when people must walk while performing one or more secondary tasks. Lundin-Olsson and colleagues233 were the first to note the significance of a failure to maintain a conversation while walking (“stop walking while talking”) as a marker for future falls. The ability to maintain normal walking while performing a secondary task (dual task paradigm) has become the classic way to assess the interaction between cognition and gait.52 In elderly people, this dual task ability deteriorates because central resources decline, secondary to subclinical disease processes or medication. This deterioration leads to a mismatch between the limited personal resources of elderly people and the complexity of the demand (the combined walking and secondary task). As a consequence, elderly people slow down or have an increased stride variability (suggesting reduced automaticity) while performing a secondary task during walking.105 Gait becomes less secure and the risk of falling increases. In patients with overt disease, such as stroke or Parkinson’s disease (PD), gait deteriorates even more during dual tasking.51;56;393 Another form of dual task impairment is when elderly people fail to get their priorities right.46 Under complex circumstances, young healthy people begin to neglect the secondary task and lend more priority to walking safely. This prudent posture-first strategy is diminished in elderly people,52 and failure to prioritise gait under difficult circumstances is weakly associated with falls.46 Research has shown that frontal executive functions are especially important for maintaining walking stability. Dysexecutive functions can be the primary cause of falls in a group of idiopathic elderly fallers.169;349 The involvement of cognitive control in normal gait could explain why falls are so common in patients with dementia and why demented patients are so vulnerable to dual task performance while walking.68;335 Interestingly, patients with PD whose phenotype is dominated by postural instability and gait disorder have a much greater risk of cognitive decline and dementia than do patients with tremor- dominant PD.15;64 Additionally, adverse effects on cognitive gait control might explain

27 CHAPTER 2

the high incidence of falls and injuries in individuals taking psychoactive medication.223 Affective disorders are also associated with gait problems in elderly people. For example, depression, anxiety, and particularly fear of falling are common consequences of unsecured gait and falls among elderly people.145;166;174 In view of these complex interactions between walking, cognition, and mood, new interventional strategies should be developed to promote secured mobility of elderly people by improving attention, dual task performance, mood, and executive functions.203

Effect of normal ageing on locomotion and gait

Ageing is typically equated with abnormalities, and this association certainly applies to gait. Many older people accept their gait difficulty as being normal for their age and their doctors often support them in this view. But are gait disorders truly an inevitable consequence of ageing itself? This question is illustrated by the evolving concepts around the so-called senile gait disorder: the slow, shuffling, and cautious walking pattern commonly seen in older age. Because clinical examination reveals no apparent cause, normal ageing was long held responsible for this disorder. However, recent findings have challenged this concept. Up to 20% of very old individuals walk normally, hence gait disorders are certainly not an inevitable feature of old age.48 This finding indirectly implies that those who have gait impairment in fact suffer from underlying disease. This assumption is lent support by the fact that individuals with a senile gait disorder have an increased risk of becoming demented376 and have reduced survival compared with age-matched individuals who walk normally at a high age (figure 2).47 These findings suggest that senile gait disorders are an early manifestation of underlying pathology, most notably subtle white-matter changes, vestibular dysfunction, visual changes, or oculomotor changes.32;40;126;199;202;383;389 Such disorders might alter gait directly, but may also act in an indirect way by causing a subjective sensation of instability and insecurity, forcing individuals to purposely adopt a more cautious gait. The message for clinicians is that gait disorders in elderly people are not merely the unpreventable consequence of ageing. Instead, these gait disturbances more likely result from the increased prevalence and severity of (clinical or subclinical) diseases with increasing age (figure 3). For this reason, we suggest abandoning the term senile gait as a specific gait category.

28 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

Figure 2 Kaplan-Meier curves showing cumulative survival due to all causes of death Results are shown for patients with a completely normal gait (n=25), those with senile gait disorders 2 (n=14), and those with gait disorders due to known disease (n=87). Mean age was 90 years in all groups (range 87–97 years). Survival was different between the groups (log-rank p=0.01). All-cause-mortality risk was increased in people with senile gait disorders compared with those with a normal gait (RR=2.8; 95% CI 1.1–7.3, p = 0·03) and was similar to those with gait disorders due to known disease (RR=1.2; 95% CI 0.6–2.5, p=0.6). Mortality due to cardiovascular disease also diff ered among the three groups, with a two-fold increased risk of cardiovascular death in people with senile gait disorders compared with those with normal gait (data not shown). Reproduced with permission from Blackwell Publishing.47

1·0

0·8

0·6

0·4 Cumulative survival Normal gait Senile gait disorder 0·2 Gait disorder due to disease

0·0 0 1 2 3 4 5 6 Survival (years)

Differentiation of gait disorders

Only few studies describe the distribution of geriatric gait disorders. Obviously, the spectrum of underlying illnesses will depend on the population under consideration and the assessment technique. Within a relatively healthy subgroup of 153 community residents aged 88 years and older, about 61% reported distinct diseases as a cause of gait impairment.48 Non-neurological disorders were the leading causes of gait impairment, in particular joint pain (52 of 87 people), whereas many others had multiple causes for their gait impairment. Stroke was the most common neurological

29 CHAPTER 2

Figure 3 Indirect association between ageing and geriatric gait disorders

This association occurs mainly, if not exclusively, via the intermediate of age-related pathology. Adverse consequences of gait disorders in elderly people include reduced quality of life and, eventually, reduced survival.

Gait disorders Falls Mortality Injuries

Age-related Fear of ? pathology falling

Morbidity (cardiovascular disease, cognitive decline) Reduced quality Ageing Immobility of life

cause. In another study of 120 elderly outpatients seen in a neurological reference practice, the most common causes for gait disorders were sensory ataxia (18%), myelopathy (17%), multiple strokes (15%), and parkinsonism (12%).355 Largely the same causes dominated in a series of 493 neurological inpatients, 60% of whom had a gait disorder.353

Recognition of specific gait disorders

Table 1 summarises the main features of the weak, spastic, and ataxic gait disorders (for reviews, see references33;100;142;267). Because these categories usually cause little difficulty in clinical practice, we focus next on the remaining gait disorders.

Hypokinetic-rigid gait disorders Diseases of the basal ganglia and the frontal lobe mostly present with a hypokinetic- rigid gait. However, frontal pathology can also cause a higher level gait disorder in which truncal imbalance and frequent falls are a key feature. Other associated features of this higher level gait disorder are depression, frontal release signs, and impaired executive function.19 Specific features of gait, posture, or balance can assist in the differential diagnosis of these different disorders (table 2). A characteristic feature of hypokinetic-rigid gait is shuffling with a reduced step height, often with a reduced stride length, leading to slowness of gait. The base of support is typically normal in PD, but is often widened in patients with atypical parkinsonism. Other characteristic

30 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

Table 1 Main features of specific gait syndromes

Gait Main features of gait Specific clinical Associated syndrome diagnostic test symptoms & signs 2 Antalgic gait Reduced stance phase on Pain affected limb Limited range of Limping movement Paretic / High-steppage Trendelenburg’s sign Lower motor neuron hypotonic Dropping foot features (e.g. weakness; gait Waddling atrophy; low to absent tendon reflexes) Spastic gait Circumduction Intermittent Pyramidal syndrome abduction of ipsilateral arm Anterior-medial side of with each step Foot dragging: the shoe sole worn out audible “scuffing toe” Scissoring; bilateral circumduction Vestibular Deviation to Aggravated by eye Vestibular features (e.g. gait one side closure nystagmus; abnormal Positive Unterberger tilting test) test Sensory Staggering, Aggravated by eye Disturbed ataxic gait wide based closure proprioception Cerebellar Staggering, Not aggravated by Cerebellar ataxia ataxic gait wide based eye closure Dyskinetic Extra Can be task-specific Features of dystonia, gait movements that (e.g. dystonic gait) chorea, myoclonus affect gait or tics Hypokinetic- Shuffling (slow speed, short Improves with Hypokinetic-rigid rigid gait stride, rigidity, reduced step external cues features (e.g. height) Aggravation by bradykinesia, resting secondary task tremor) Cautious gait “Walking on ice”; slow, wide None or only minimal base, short steps Excessive fear of falling Striking improvement by external support Higher level Severe balance impairment (no Abnormal Frontal executive gait disorder rescue reactions; “falling like a interaction with dysfunction log”) environment (e.g. Inadequate trouble adapting synergies with walking aids; o Inappropriate or bizarre foot no benefit from placement cues) o Crossing of the legs (Sometimes) o Leaning into wrong direction better able to when turning or standing perform cycling leg Variable performance movements while (influenced by environment recumbent (gait and emotion) “apraxia”) Hesitation and freezing (“ignition failure”)

31 CHAPTER 2

Table 2 Differential diagnosis of parkinsonian disorders, based on specific features of gait, balance, or posture Main Disease Characteristic Associated anatomical process features features substrate Parkinson’s Substantia nigra Neuro- Narrow-based gait Good response disease degenerative Asymmetrical to levodopa Stooped posture Resting tremor Early freezing and falls hand(s) rare Multiple Basal ganglia Neuro- Early phase like PD gait Cerebellar system atrophy, Cerebellum degenerative Later phase more wide- ataxia parkinsonian Pyramidal tracts based Autonomic type Autonomic Pisa syndrome features nervous system Antecollis Pyramidal signs Vertical falls (due to syncope) Progressive Diffuse brainstem Neuro- Wide-based gait Vertical gaze supranuclear pathology degenerative Freezing common palsy palsy Erect posture, Pseudobulbar retrocollis palsy Early/ spontaneous/ Frontal backward falls dementia Motor reckleckness Applause sign Frequent and severe injuries Corticobasal Basal ganglia Neuro- Asymmetrical Apraxia degeneration Cortex degenerative presentation – eg, Alien limb unilateral leg apraxia, Cortical sensory dystonia or myoclonus loss Later: wide-based gait, freezing, shuffling Dementia with Basal ganglia Neuro- Like PD gait Dementia Lewy bodies Cortex degenerative More symmetric Fluctuations Visual hallucinations Subcortical Subcortical white Vascular Small steps Urinary arteriosclerotic matter Wide-based gait incontinence encephalopathy Start hesitation Cognitive Variable timing and decline amplitude of steps Stepwise progression Vascular Diffuse white Vascular Lower body Urinary parkinsonism matter parkinsonism incontinence Basal ganglia More wide based Cognitive Less stooped decline Relatively preserved Stepwise arm swing progression

32 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

Table 2 Continued Main Disease Characteristic Associated anatomical process features features substrate 2 Strategic Putamen Vascular Lower body vascular lesion Globus pallidus parkinsonism Thalamus Freezing/severe gait Dorsal akinesia mesencephalon Severe disequilibrium Drifting to one side Normal pressure Frontrostriatal Ventricular Wide-based gait, Urinary hydrocephalus (peri-ventricular) widening freezing, gait apraxia incontinence Truncal imbalance Cognitive Preserved arm swing decline Drug-induced Basal ganglia Mild gait impairment, Upper limb parkinsonism (postsynaptic) rarely freezing tremor Preserved postural Symmetrical reflexes presentation Pisa syndrome

features include reduced arm swing (asymmetrical in PD, but more symmetrical in atypical parkinsonism), which can present in isolation and precede the onset of other hypokinetic-rigid features by many years. Turning movements become slow and are executed en bloc. Festination is a feature of more advanced disease, where patients take rapid small steps in an attempt to maintain the feet beneath the forward moving trunk. Poorly mobile patients with advanced disease can sometimes respond quickly to environmental events - typically emotional or threatening circumstances - and move unexpectedly well (kinesia paradoxica). Apparently, patients with PD can use such external triggers to engage alternative motor circuits and thereby bypass the defective basal ganglia circuitry.392 Hypokinetic-rigid gait disorders can be classified according to the underlying anatomical substrate. One main group involves lesions within the basal ganglia and their connections to the frontal cortex, brainstem, or both. Pathological changes in the frontal lobe itself can also contribute to a hypokinetic-rigid gait. There are no well-defined clinical markers for frontal-lobe contribution, but suggestive features include a wide-based or variable stance and truncal imbalance. Some would also include gait apraxia here, often defi ned as a marked discrepancy between the severity of the gait disorder and the ability to perform other leg movements, such as cycling in the air while lying down. Associated features include urinary urgency and cognitive changes and a poor response to external cues. Hypokinetic-rigid gait disorders can also be classified according to the underlying disease process. One important group includes neurodegenerative disorders such as

33 CHAPTER 2

PD and various forms of atypical parkinsonism (eg, multiple system atrophy or progressive supranuclear palsy). Another common group includes underlying cerebrovascular disease. Gait disorders with a mixed hypokinetic-rigid and ataxic character are a common occurrence in patients with subcortical arteriosclerotic encephalopathy.107 A less common feature of cerebrovascular disease is lower body parkinsonism, a predominance of symptoms and signs in the legs, with a relatively preserved arm swing and little bradykinesia of the hands.388;400 The term lower body parkinsonism is a useful descriptive term in clinical practice because it refers to a recognisable phenotype that is often associated with underlying cerebrovascular disease, including white-matter changes and lacunar infarcts in the basal ganglia. However, lower-body parkinsonism is not synonymous with vascular parkinsonism. Occasional patients can present with a clinical presentation resembling PD (with upper-limb involvement) or even progressive supranuclear palsy. Hypokinetic-rigid gait disorders due to cerebrovascular disease can develop acutely or with an insidious onset.388 The acute syndrome mainly involves infarcts in the putamen, globus pallidus, or thalamus, whereas the gradual form is associated with diffuse white-matter changes. A third type of underlying disease process is ventricular widening, as occurs in patients with normal pressure hydrocephalus. Whether normal pressure hydrocephalus truly exists as a separate entity with its own unique pathophysiology is unknown. Typically, the disorder presents with a recognisable triad of hypokinetic-rigid gait impairment, urinary incontinence, and (frontal) dementia. Gait is characterised by marked slowing and small shuffling steps and regular freezing, but usually with largely preserved arm movements.153;354 Ataxic elements are also seen, including a broad stance width and an increased variability in timing and amplitude of the steps. The pathophysiology has not been clarified, but may relate to an excessive volume of intraventricular cerebrospinal fluid that is not explained by cerebral atrophy. The classic radiological appearance includes widened lateral ventricles (especially affecting the anterior horns), often accompanied by periventricular white-matter lesions. An unresolved question (yet one with direct implications for treatment) is whether these periventricular white-matter lesions are the cause or consequence of ventricular widening.364 Clinical examination alone cannot always disentangle these different anatomical and pathophysiological causes of hypokinetic-rigid gait disorders, especially in early stages where overlap is substantial. In such patients, it is best to refrain from confusing terminology. It initially suffices to classify the patient as having a hypokinetic rigid gait disorder and to base a more definitive anatomical or aetiological diagnosis on ancillary investigations (MRI) and sometimes the response to treatment (eg, a trial of levodopa).

Cautious and careless gaits Typically, people with a cautious gait move slowly, with a wide base and short strides, with little movement of the trunk, while the knees and elbows are bent. Cautious gait

34 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

is common in elderly people and originates in part from fear of falling, which is sometimes present to the degree of panic.145 There are two main subgroups. In the first, fear of falling is excessive relative to the degree of actual instability. In fact, 2 balance can be fully normal, as in people with a pathological fear of falling (fall phobia) caused by a single fall. In these individuals, the remaining neurological examination is completely normal, and provision of external support or reassurance can substantially improve gait. In the second subgroup, fear of falling is justified by a recent history of recurrent falls or by a self-perceived instability due to overt or sometimes otherwise subclinical underlying disease. These individuals might show mild freezing of gait, occurring mainly with gait initiation and while turning.145 Neurological examination can further reveal mild hypokinetic-rigid signs, disturbed postural responses, and frontal release signs. With time, these patients may develop other subcortical or frontal disturbances, or progress to having a more disabling gait impairment. A therapeutic levodopa trial is justifiable, but it has been our clinical impression that after a short positive response that could represent a placebo effect, patients with cautious gait no longer improve. Fear has to be treated medically or behaviourally. Careless gait is the counterpart of the cautious gait. Some patients seem overly confident and walk inappropriately fast, perhaps because of lack of insight or frontal-lobe disinhibition. Notorious examples are patients with progressive supranuclear palsy and Huntington’s disease who typically move too abruptly despite a severe balance deficit and who seem unable to properly judge the risk of their actions. This motor recklessness probably underlies the high incidence of fall-related injuries in these disorders.50;155 A similar recklessness contributes to falls and injuries in ageing disorders such as Alzheimer’s disease. Confusion and delirium can also contribute to a careless gait. A recent study showed that gait velocity should be judged in the context of the patient’s physical capabilities. Thus, although frail elderly patients with dementia walked slowly, they still walked relatively too fast, given their overall degree of physical impairment, which should have warranted an even much slower gait.367 For some cognitively impaired patients, restriction of unsupervised physical activities is an ultimate measure to prevent wandering behaviour and to reduce injurious falls.69

Fluctuating or episodic gait disorders A curious feature of some gait disturbances is their fluctuating or frank episodic nature. The specific provoking factor can differentiate these gait disturbances. Some gait disorders fluctuate more or less predictably because of exercise intolerance or pain. In elderly people, walking difficulties after exercise are often due to fatigue (car- diopulmonary or neuromuscular disease), but might also indicate vascular or neurogenic claudication. Psychogenic gait disorders can also present with an episodic character, for example an aggravation when bystanders are present.

35 CHAPTER 2

Other gait disorders are truly episodic. The sudden and largely unpredictable nature of these episodes is incapacitating, commonly leading to falls because patients are caught unprepared.49 An example is freezing of gait, where patients suddenly experience a characteristic feeling “as if the feet become glued to the floor”. Various terms have been used in different contexts, including gait ignition failure or slipping clutch phenomenon. We propose to use the term freezing of gait to describe all gait initiation disturbances. Although freezing of gait is most often observed when initiating gait, it also occurs when walking through a narrow passage, during turning, while executing a secondary task (eg, responding to a question), or upon reaching a destination. In severely affected patients, it can occur seemingly spontaneously while walking in open terrain. Three different clinical presentations are recognised: shuffling with small steps; trembling in place, while attempting to overcome the block; or being fully unable to start or continue walking, which is relatively rare.329 Freezing of gait can present largely in isolation, as occurs in primary progressive freezing gait. This usually results from frontal lobe damage, irrespective of the specific disease process.116 However, freezing of gait is mostly seen as part of a hypokinetic-rigid syndrome, including PD and various forms of atypical parkinsonism.147;269

Dyskinetic gait disorders The term dyskinesias includes all involuntary movements or postures—eg, chorea or dystonia. Presence of such involuntary movements during walking suggests a dyskinetic gait. A well-known example is the gait in patients with postanoxic encephalopathy, in which the positive and negative action myoclonus (Lance-Adams syndrome) produces a bouncing gait and stance. Dyskinesias can contribute to falls by causing excessive trunk movements beyond the limits of stability, as occurs in patients with PD with medication-induced dyskinesias45 or in patients with Huntington’s disease.155 Note that dyskinesias might be absent during clinical examination because of their fluctuating character or because patients suppress them intentionally. Cognitive distractions can help to elicit the involuntary movements during examination. Patients with dystonia require specific attention because their gait or balance impairment can be task-specific.229 For example, patients may have severe gait impairment due to leg dystonia, but can easily walk backwards or even run. This is easily misinterpreted as a psychogenic sign. Examples of gait dystonia include early onset PD presenting with a foot dystonia while walking, or patients with idiopathic torsion dystonia who can present with unusual gait patterns. Other forms of gait dystonia include retrocollis in patients with progressive supranuclear palsy, antecollis or a Pisa syndrome (severe and persistent lateroflexion of the trunk) in patients with multiple system atrophy, and an asymmetrical arm or leg dystonia during walking in patients with corticobasal degeneration. Many dystonic patients tend to walk on their

36 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

toes (cock walk). Axial forms of dystonia, including dystonic scoliosis, hyperlordosis, or torticollis can also interfere with walking and standing. This is particularly true if extensor or flexor spasms are present. 2

Psychogenic gait disorders Although suspicion of psychogenic gait disorders is highest in younger patients, they can occur in elderly patients. Psychogenic gait is often not compatible with known gait patterns and they can take unusual forms (panel).41;356;379 Falls and injuries are thought to be rare in patients with a psychogenic gait, but we encountered one such patient who sustained severe injuries (epidural haematomas and a skull base fracture).379 Care must be taken not to miss underlying organic disease, in particular frontal-lobe dysfunction. The differential diagnosis includes organic gait disorders that can mimic psychogenic gait disturbances; examples include choreatic gait in Huntington’s disease, task-specific dystonic gait, episodic weakness in myasthenia gravis, and cataplexy. Gait in stiff person syndrome can also look strange; gait abnormalities typically aggravate when patients are instructed to hurry up.248

Panel 1 Suggestive features of a psychogenic gait disturbance Incongruous with known gait disorders Bizarre presentation Variable, inconsistent pattern Non-physiological pattern Rarely falls / injuries Abrupt onset Extreme slowness Unusual / uneconomic postures Exaggerated effort Associated features: · Incongruous affect (belle indifference) · Secondary gain · Prior history of psychiatric disease

Gait disorders and falls caused by medication Gait disorders and falls in elderly people are commonly associated with adverse effects of drugs (table 3).7;9;44;111;127;132;175;211;222;222;223;380 The precise underlying pathophysiological mechanism is unclear in many cases. Commonly implicated factors include sedation, orthostatic hypotension, behavioural abnormalities, extrapyramidal side-eff ects, or ataxia. However, there can also be confouding by indication - ie, falls that are

37 CHAPTER 2

caused by the underlying disorder for which the drugs were prescribed in the first place. Thus, falls or a disturbed gait in patients taking anti-diabetic medication might simply be caused by an underlying diabetic polyneuropathy. Polypharmacy is particularly associated with falls, but only if a patient daily takes at least one drug with an established risk of increasing falls.399 A critical review of medication is therefore important in elderly people. For example, a recent randomised controlled trial showed that when a pharmacist reduced the number of drugs in elderly care-home residents, the number of falls was reduced by 40%.397

Table 3 Drugs with adverse effects on gait, posture and balance

Medication group Comments Antipsychotics 175;132 Occurs with both typical and atypical antipsychotics. Antidepressants 111;132 Occurs with both selective serotonin reuptake inhibitors (SSRI’s) and tricyclic antidepressants. Anticonvulsants 127;132 Occurs with both older anti-epileptic drugs (e.g. phenobarbital) and newer anti-epileptic drugs (e.g. lamotrigine), but possibly less in the newer drugs. Antiparkinson drugs 44 Occurs with all classes of antiparkinson drugs. Underlying mechanism is complex, but mainly includes excessive dyskinesias, orthostatic hypotension and behavioural abnormalities. Benzodiazepines / other hypnotics 9;132 Occurs with both short and long-acting benzodiazepines. Newer ‘Z’-compound hypnotics such as zopiclone are considered safer. Analgetics 132;222;380 Occurs with opiates, NSAIDs and paracetamol. Some studies find stronger effects of opiates, others of NSAID’s Antihypertensive 7;222 Diuretics, beta-blockers, ACE inhibitors and nitrates. Evidence is stronger for inpatients then for outpatients, probably due to a stronger impact of orthostatic hypotension after prolonged bed-rest. Anticholinergics 7;132 Anti-diabetics 211 Perhaps via underlying pathology, e.g. diabetic polyneuropathy or cerebrovascular disease. Anti-arrhythmics 222 Quinine 132 Quinine and derivates

Assessment of gait disorders

Assessment includes a full physical and neurological examination and a systematic gait assessment. Use of standard rating scales, such as the Tinetti mobility index362 or gait and balance scale,360 help to score all different elements of gait and balance. Most examination rooms are too small, so it is often necessary to examine the patients

38 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

while walking in the corridor. Simple undisturbed gait can be informative, but additional abnormalities come to light when gait is challenged. For example, walking with eyes closed might provoke or aggravate ataxia in patients with a sensory 2 neuropathy, or cause a consistent deviation to one side in patients with unilateral vestibular loss. Patients suspected of having freezing of gait often walk normally in the examination room because excitement associated with the doctor’s visit can suppress this sign. In such patients, careful questioning supported by validated questionnaires152 is important. Additionally, walking in tight quarters, while turning or when doing secondary tasks may provoke freezing of gait. Next to challenging gait, observation of whether patients can improve their gait - eg, by benefiting from walking aids or provision of external support - is equally instructive. Seemingly incapacitated patients with a cautious gait can show striking improvements in gait when provided with external support while walking. Similarly, providing individuals with external visual, auditory, or mental cues can help to reduce freezing of gait.203 By contrast, patients with a higher-level gait disorder typically do not benefit from external cues and have troubles adapting with walking aids. Such patients are sometimes better able to perform cycling leg movements while lying recumbent, suggesting that their loss of control over leg movements is task-specific (gait apraxia). As mentioned earlier, this task-specificity can also be seen in patients with dystonia.229 The pull test (or retropulsion test) is commonly used to probe the reactive and defensive balance reactions.43;179 Many variants exist, but most commonly the investigator, standing behind the patient, suddenly pulls the patient’s shoulders. The test is typically used to score the severity of postural instability. However, failure to initiate a corrective step - due to freezing of gait - also produces an abnormal test result. We usually deliver one shoulder pull without specific prior warning, as this best mimics daily life circumstances where falls are usually unexpected events. We then repeat the test several times and regard failure to habituate to the test as another sign of balance impairment. A recently introduced variant is the push and release test, which rates the postural response to a sudden release of a patient pressing backward on an examiner’s hands placed on the subject’s back. An advantage is that this test allows examiners to apply more consistent perturbation forces to the patients than with the conventional pull test, and the outcome seems to correlate better with self-reported falls.185 Timed tests can be used to quantify gait velocity (eg, to assess the effect of treatment), but these do not accommodate the quality of gait. A commonly used test is the timed up and go test, where patients are observed and timed while rising from a high chair with arms, walking 3 meters, turning around, walking back, and sitting down again.308 Cognition and affect should be routinely examined in elderly patients with gait problems, with emphasis on frontal cognitive dysfunction. Fear of falling can be assessed directly or, preferably, by using a validated questionnaire.195 Finally, it is

39 CHAPTER 2

important to assess footwear and vision (with and without correction), as these contribute to gait disorders and falls in the elderly.231;249 A relatively new method is physiological analysis of gait, by use of a treadmill and quantitative outcome measures: kinematics (joint motion), kinetics (reactive forces), and dynamic electromyography. An important disadvantage is that gait is assessed under constrained and highly unnatural circumstances, leading to lack of ecological validity.54 Less complex systems can be applied in freely moving individuals. Common tools are ambulatory goniometers or accelerometers, to quantify movement of the limbs or trunk,11 and shoes with pressure-sensitive insoles167;306 or a carpet with pressure-sensitive sensors280 to measure subtle changes in locomotion rhythmicity, variability, or left–right synchronisation. Although this type of gait analysis better approaches real-life situations, whether the currently available equipment provides any clinically relevant extra information is unknown. We therefore feel that it is currently not worth sending elderly patients for a quantitative study of gait in a sophisticated gait laboratory. Possible exceptions include a preoperative assessment to guide the surgeon before an orthopaedic intervention, detailed electromyography studies in spastic or dystonic patients to fine-tune subsequent treatments with botulinum toxin or selective surgical denervation, and kinematic gait analyses to assist rehabilitation specialists in their choice for specific segmental orthoses or adjusted footwear.66;71;95;252;337 Physiological gait analysis is a very useful technique for scientific purposes.

Clinical approach and classification of gait disorders

We conclude our contribution by discussing a new, practically oriented approach to gait disorders, as well as a simplified modification of the classification originally proposed by Nutt and colleagues.296 A broadly accepted classification system would assist health professionals when they communicate about patients with gait disorders. Research will also benefit from a good classification system, for example to ascertain that properly diagnosed patients and homogeneous groups are included in trials or gait experiments. Different types of gait classifications currently exist, with different and partly overlapping starting points (hierarchical, anatomical, aetiological, or phenomenological). Every classification system has inconsistencies (table 4). We propose a practical three-step approach that begins with a gait classification based on clinical phenomenology, as observed in the consultation room (step 1 in figure 4). This first step includes three elements: the core features of a patient’s gait; additional clinically based gait and balance tests; and associated neurological or physical abnormalities. These three elements are all listed systematically in table 1 for each of the main

40 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

clinically discernable gait patterns. For example, patients with an ataxic gait typically have a wide-based, staggering gait (core clinical feature). By itself, this core feature can implicate either sensory ataxia or cerebellar ataxia, and this distinction can be 2 made with additional gait and balance tests, such as the effect of eye closure (aggravates the gait impairment much more in sensory ataxia compared with cerebellar ataxia). The distinction between both types of ataxic gait disorders can be corroborated by a search for associated neurological or physical abnormalities: hypermetria, nystagmus, and cerebellar dysarthria suggest that the wide-based gait was in fact caused by cerebellar ataxia, whereas disturbed proprioception would suggest sensory ataxia. Taken together, the three elements of this first step thus lead to a clinically based classification, determined by recognisable gait features (syndromes or possible gait disorders), as listed in the left column of table 1. Note that this first step of the classification avoids anatomical, pathophysiological, and aetiological terminology because it is solely based on clinical impressions obtained in the examination room. For that reason, our clinical classification also avoids a distinct categorisation of low level and middle level gait disorders as proposed in the original Nutt classification296 because this hierarchical distinction formally requires ancillary studies to demonstrate the site of the lesion. Also, symptoms can overlap between middle level and higher level gait disorders. We propose to abandon the anatomically based term frontal gait disorders, as these may present with at least three different phenotypes: a shuffling hypokinetic-rigid gait; a wide-based ataxic pattern; and an episodic gait disorder, dominated by freezing episodes. Furthermore, the frontal phenotype can be seen in a wide variety of disorders, including PD, various forms of atypical parkinsonism, or frontal mass lesions. How can we classify the gait disorders collectively grouped under the original term higher level gait disorders? These cannot be captured by a single, dominant, and consistently present gait feature, but do share a recognisable phenotype19;110 that can be identified using the first step of our approach (table 1). We propose to maintain the original term higher level gait disorders until better insights arrive from pathophysiology. There is a growing consensus to avoid, for the time being, any further subdivisions of the higher level gait disorders, as these have little value in clinical practice.297 A more certain clinical diagnosis (which we would define as a probable gait disorder) often requires an additional diagnostic step (step 2 in figure 4). This second diagnostic step again involves three elements. First, for some patients, the clinical diagnosis will serve as a guide for tailored ancillary investigations, such as structural neuroimaging to detect, for example, underlying cerebrovascular disease. Second, the response to treatment will further assist in making a definitive diagnosis. For example, a substantial improvement of a shuffling gait disorder with levodopa suggests involvement of a presynaptic dopaminergic lesion, possibly due to PD. Third, the factor time may provide additional clues about the disease course, or reveal newly emerging

41 CHAPTER 2

neurological abnormalities. For example, prolonged follow-up (up to 16 years) of patients with a cryptogenic primary progressive freezing gait showed a progression to recognisable clinical diagnoses, including pallido nigroluysian degeneration, diffuse Lewy body disease, progressive supranuclear palsy, and corticobasal degeneration.116 The third and final step of our diagnostic approach will lead to a definitive, aetiology- based diagnosis (step 3 in figure 4). This step often depends on post-mortem examination. Further enhancement of our understanding of particular gait disorders by increasing the number of clinicopathological correlations will be a major challenge. Our classification does not include gait disorders that are secondary to a clear and overriding balance problem. We feel that these should be classified as primary balance disorders and managed as such. An example is the astasia-abasia syndrome due to thalamic stroke, where gait is severely hampered not due to a defect in the neural machinery that is responsible for maintaining gait, but to a severe balance deficit.244

Table 4 Drawbacks to currently available gait classification systems

Classification Examples Drawbacks Hierarchical Lower level Term ‘higher level’ often abused as ‘basket’ term Intermediate level for any poorly understood gait disorder Higher level Subdivisions of ‘higher level’ gait disorders difficult to use in clinical practice Overlap in symptoms between middle and higher level gait disorders Anatomical Frontal gait Different anatomical lesions may present with Cerebellar gait similar gait patterns Any given anatomical lesion may present with different gait patterns Etiological Vascular Ancillary studies or post-mortem examination Neurodegenerative often required to make definitive diagnosis

Phenomenological See table 1 Pathophysiology not taken into account

Panel 2 Suggestive features of a psychogenic gait disturbance References for this review were identified by searches of PubMed up to August 2006. Papers were also identified from the authors’ own files and from references given in relevant articles. Search terms “gait”, “gait disorder”, “locomotion”, “elderly”, “geriatric”, and “ageing” were used.

42 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

Figure 4 Practical three-step approach for the classification of geriatric gait disorders The first level yields a temporary, clinically based diagnosis, according to phenotype (possible gait 2 disorder). Further refinement of the diagnosis can be based on tailored ancillary studies (eg, structural neuroimaging, nuclear imaging, or genetics), the response to treatment (eg, response to levodopa, or the effect of stopping sedative drugs), and the factor time (disease course). This second level yields a probable gait disorder. A definite aetiological diagnosis will often depend on post-mortem examination.

Core gait features Speci c gait or balance tests Associated symptoms and signs Step 1

Possible gait disorder (clinically based gait syndrome)

Ancillary investigations Therapeutic investigations Disease progression Step 2

Probable gait disorder

Post-mortem examination Step 3

De nite (aetiology-based) gait disorder

Conclusions

This review shows that the field of gait disorders is very much on the move, with exciting new insights in the underlying pathophysiology. There is an increasing awareness that gait disorders in old people are often not due to merely ageing, but rather are associated with diseases that are more common in elderly people and which are potentially amenable to therapeutic intervention. Clinical assessment of geriatric gait disorders may seem difficult, but is facilitated by the practical approach proposed here. Modern neuroscience methods such as functional MRI and virtual

43 CHAPTER 2

reality are now increasingly engaged in gait research, and there is good reason to believe that this will enhance our fundamental understanding of geriatric gait disorders, thereby opening new avenues to improve the management of this common and disabling problem.

44 NEUROLOGICAL GAIT DISORDERS IN THE ELDERLY

2.2

Freezing of Gait: general overview

Parts of this chapter are based on: Mahabier W, Snijders AH, Delval A, Bloem BR. Freezing of gait. In: Kompoliti K, and Verhagen Metman L (eds.) Encyclopedia of Movement Disorders. Oxford: Academic Press. 2010; 486-491.

FREEZING OF GAIT: GENERAL OVERVIEW

Definition Freezing of gait (FOG) is a common and disabling feature of Parkinson’s disease(PD). It 2 is a remarkable gait disorder, because of its episodic character. Patients with FOG experience sudden and often unexpected episodes during which their feet subjectively are ‘being glued to the floor’, while their trunk continues to move forward. A FOG episode is thus defined as a brief episode during which patients find it impossible to generate effective forward stepping movements, in the absence of another cause than parkinsonism or higher cortical deficits. It is most commonly experienced during turning and step initiation, but also when faced with spatial constraint, stress and distraction. Focused attention and external stimuli (cues) can overcome the episode. Because of the sudden and unpredictable nature, FOG often leads to falls and injuries.150

History

Already in 1817, James Parkinson described in his classical essay ‘The Shaking Palsy’ the typical ’propensity to bend the trunk forwards, and to pass from a walking to a running pace’.300 This phenomenon is currently known as ‘festination’: taking increasingly rapid and small sequential steps during walking, in an attempt to maintain the center of gravity above the feet while the trunk leans progressively forward.151 Although festination and FOG appear to be closely related, James Parkinson did not specifically describe FOG. The first description of a FOG episode presumably stems from Charcot, who in 1877 described gait initiation failure, followed by forward propulsion with festination. “… elle ne part pas ; il semble, qu’auparavant, elle ait besoin de s’equilibrer: elle est en quelque sorte incertaine, ayant le tronc incliné en avant ; enfin elle se décide. Lente tout d’abord, la marche progressivement s’accélère…”73 Since then, several terms have been used to describe FOG (Box 1). In 1882, the phenomenon was already linked to ‘frost’, although with a different meaning: Thomas Buzzard, a neurologist of National Hospital Queen Square in London, said in 1882: “William W – an engine-driver- remains for a time unable to start when attempting to walk, his feet beating the ground rapidly as he marks time before setting off at a fair pace - the patient likening his condition to ‘the wheels of a locomotive failing to bite the rails when they are slippery with frost and making, in consequence, ineffective revolutions’.78 In his 1921 essay on kinesia paradoxicale, Souques described a patient who was glued to the floor: ‘Un parkinsonien que j’ai observe, malade depuis dix ans, ne pouvait marcher que très péniblement, les pieds collés au sol. Or, parfois, il pouvait courir et même soulever les pieds assez haut pour sauter un obstacle.’346

49 CHAPTER 2

In 1967, Martin described the remarkable effect of cues in patients with postencephalitic parkinsonism. He described patients being ‘stuck to the ground’, whose gait improved remarkably with transverse visual cues or when being ‘rocked from side to side’.312 The first time the phenomenon was really termed ‘freezing’ was in 1972 by Barbeau, where he described that adding a peripheral decarboxylase inhibitor to Levodopa lead to less frequent freezing.34 Barbeau compared the episodic freezing of gait to the kinesia paradoxica as described by Souques. The classic story presentation of kinesia paradoxica is that of a rigid, wheelchair-confined patient who suddenly gets up and runs out of the house upon hearing the warning cry of ‘fire’, only to ‘freeze’ again on the lawn outside. In contrast, he referred to FOG as ‘akinesia paradoxica’, as patients who are suddenly unable to move while they could do so beforehand (“in a clear blue sky”).35 However, these two phenomena may not be different really, but just two ends of a spectrum, reflecting disease severity and the effect of medication. The literature then remained more or less silent for some time, but particularly during the last 10 years, interest in the clinical impact, the underlying pathophysiology and the various treatment methods of FOG has increased rapidly.

Box 1 Terms used which are (partly) synonymous to freezing of gait Frozen gait Akinesia paradoxica Start hesitation Marche a petit pas Piétinement Magnetic gait Ignition failure Gait apraxia Arrhythmokinesia

Epidemiology / Risk factors

Epidemiology as related to different etiologies FOG is common in idiopathic PD; it occurs in 6 - 80% of PD patients, depending on disease severity, disease duration and treatment status. Interestingly, some patients experience FOG in early stages of their disease, while other patients never develop FOG. It is also seen in some 25-60% of patients with atypical parkinsonism caused by vascular parkinsonism, normal-pressure hydrocephalus or neurodegenerative diseases such as progressive supranuclear palsy or multiple system atrophy147;157;269. FOG is less often seen in patients with corticobasal degeneration (8-25%)269 and rarely

50 FREEZING OF GAIT: GENERAL OVERVIEW

occurs in neuroleptic-induced parkinsonism.162 Primary progressive freezing of gait is an uncommon condition starting with FOG, often with frequent falls. Patients initially do not experience bradykinesia, rigidity or tremor and usually do not respond to 2 treatment with levodopa. With extended follow-up, this condition may clinically progress to progressive supranuclear palsy or corticobasal degeneration.79;116 Post- mortem examination in these patients may reveal pallidonigroluysian degeneration or diffuse Lewy body disease, underscoring how heterogenic the underlying etiology can be. Table 1 shows the frequency of FOG in different disorders, with references that describe the phenomenon. Earlier studies are not included, but FOG was not structurally investigated at the time. The wide range of frequencies probably reflect the different assessment methods (questionnaires, different questions) and different severities / disease durations of the included patient populations.

Table 1 Prevalence of freezing of gait in Parkinson’s disease and other disorders

Disorder Frequency of FOG References Focal lesions Dorsal mesencephalon Case reports only. Frequency unknown · Single case: haemorrhage in pontomesencephalic 243 junction and right PPN · Three cases: unilateral midbrain tegmentum stroke · Single case with bilateral PPN strokes 163 · Case of patient with brain lymphoma in dorsal mesencephalon, cerebellum and periventricular 212 white matter 184 Frontal lobe lesions Frequency unknown.

There are reports on akinetic mutism in bilateral 209;220;281 ACA stroke, or in left-sided ACA in combination with bilateral lacunar infarcts of the caudate nucleus. In a series of 100 patients with ACA stroke, 91 had 197 motor dysfunction, but only paresis is reported. Three had ‘parkinsonian symptoms such as bradykinesia’, but FOG is not reported. Probably they didn’t look. Frontal lobe deficits, such as infarcts or tumors. 115 Stroke involving the supplementary motor regions of 91 both hemispheres. The gait deficit was termed ‘gait apraxia’, in the absence of apraxia for other functions. Hemiparetic stroke 33% (26 of 79 patients) self-reported ‘freezing’. 65 Symptoms of hemiparesis not further localized. Questionnaire not totally reliable. No difference between right or left sided stroke. No CT images available.

51 CHAPTER 2

Table 1 Continued

Disorder Frequency of FOG References More diffuse lesions PD

Mild 10-20% 234 52% 315 6% <7 years 117 7.1% early PD, 148

Moderate 25% 1.5 years later 148 32% 149 40-70% 234 83% H&Y 2-3 315 60% (in general) 215 19% 7-12 years 117

Severe 35% after >12 years 117 Advanced disease: 53% 153 71% 230 70-80% 234 76% H&Y 4-5 315 81% after 20 years 173 Delayed adverse Gait deterioration during the OFF-state occurred in 368 effect of bilateral STN 42% of subjects. stimulation. Atypical 46% 147 parkinsonism Start 24% last 47% 269

MSA 75% (50% MSA-C, 82% MSA-P 157 40-54% 269

PSP 25-53% 269

DLB 21-54% 269

CBD 8-25% 269

Vascular 57% 147 parkinsonism 30% (13 of 37 stroke patients with parkinsonism, but 10 372 had lacunar infarcts) 38% (6 of 16) 94

NPH 56% 147

See 115; earlier studies do not cite FOG as a symptom, but did not structurally search for this.

52 FREEZING OF GAIT: GENERAL OVERVIEW

Table 1 Continued

Disorder Frequency of FOG References More diffuse lesions 2 Primary progressive 100% (by definition) 115;182 freezing of gait When called pure akinesia: 70% FOG Drug induced ‘very low risk’ OR 0.1 147;162 parkinsonism Higher level gait 20% at baseline; 40% after 3 years 145;146 disorders Cerebral radiotherapy Case report 98 Carbon monoxide Case report 221 intoxication

FOG = freezing of gait; PD = Parkinson’s disease; PPN = pedunculopontine nucleus; ACA = anterior cerebral artery; CT = computed tomography; H&Y = Hoehn and Yahr stage; STN = subthalamic nucleus; MSA = Multiple system atrophy; MSA-P = MSA, parkinsonian subtype; MSA-C = MSA, cerebellar dysfunction subtype; PSP = progressive supranuclear palsy; DLB = diffuse Lewy body disease; CBD = corticobasal degeneration; NPH = normal pressure hydrocephalus

Risk factors In idiopathic PD the most important risk factors for developing FOG include a more advanced disease and a longer disease duration.140 A longer duration of levodopa treatment is also seen as a risk factor for FOG, although it is difficult to uncouple this from disease duration and disease severity. Also, medicated patients may show more FOG simply because they can walk for a longer period, increasing the likelihood of witnessing FOG episodes. Other risk factors include disturbances in gait, posture, and speech, but bradykinesia and rigidity are not related to the occurrence of FOG.36;140 Remarkably, the presence of tremor is associated with a lower risk of developing FOG.36 FOG is further associated with frontal cognitive (executive) deficits, including even overt dementia and urinary incontinence (which may also reflect frontal dysfunction).18 FOG is itself a strong risk factor for falls and ensuing injuries.201;219

Clinical features / diagnostic criteria

Circumstances of freezing FOG episodes most commonly occur in complex environments that necessitate integration of multiple sensory stimuli. Therefore, they are typically seen during a shift of attention or a circumstantial or directional change. Thus, in daily life FOG particularly occurs under specific conditions such as starting, turning, walking in tight quarters (e.g. passing a narrow doorway) or upon reaching a destination, but it may occasionally

53 CHAPTER 2

also occur during straight walking in open space.150 Turning around appears to be the strongest provoking factor.329 Dual tasks or stressful demands may also increase the occurrence of FOG. Furthermore, the majority of FOG episodes occur when the response to dopaminergic treatment has vanished (i.e. during an OFF-state), when FOG is both lengthier and more severe (see also the section on Treatment).329 See chapter 3 for an extensive elaboration on the circumstances that provoke FOG.

Characterization The main characteristic of FOG is a loss of efficient forward movement generation, which can manifest itself as three different subtypes. The least severe subtype consists of taking very small shuffling steps, with only minimal forward movement. A more severe subtype includes trembling of the leg, without any effective forward motion, known as ‘trembling in place’. The most severe subtype is a complete akinesia, without any observable motion of the legs. The duration of a FOG episode is usually very brief, typically ranging from less than a second to up to 10 seconds. Episodes longer than 10 seconds are very rare and only occur during the OFF-state, when FOG episodes last longer compared to the ON-state.329

Diagnosis The current ‘gold standard’ of diagnosis of FOG is the observation of FOG by an experienced examiner. However, FOG is notoriously difficult to elicit in the examination room, so the patient’s subjective feeling of periodically being ‘glued to the floor’ often serves as surrogate marker to establish the diagnosis. FOG is currently only classified as being either ‘present’ or ‘absent’, and reliable gradations of severity are not yet available. Assessment of FOG will be discussed in more detail in chapter 3.

FOG should be differentiated from a voluntary stop or hesitation (for example, because the patient feels unsafe), overall akinesia, or festination.151 Overall akinesia differs from FOG because the episodic character is absent: patients with overall akinesia have the feeling of being glued all the time, while patients with FOG experience the glued feeling only episodically. Festination should also be differentiated from real FOG episodes. During festination, the feeling of being glued to the floor is lacking. Festination typically occurs during gait, while FOG mainly occurs during gait initiation and turning. Moreover, festination leads to a fastening instead of slowing of walking velocity. Finally, FOG should also be differentiated from central nervous system overloading that occurs during complex multitasking, as may occur when patients undertake a secondary task during walking (e.g. carrying a tray). A classical example is the ‘stops walking when talking’ phenomenon, where patients stop walking because the task of maintaining a simultaneous conversation is too demanding.46;233 Such multitasking can provoke real FOG, but some stops simply

54 FREEZING OF GAIT: GENERAL OVERVIEW

reflect a conscious adaptive strategy: it is better to temporarily stop walking when the overall task has become too complex. Voluntary stops lack the typical trembling of the legs, the preceding sequence effect and the flexed posture seen in FOG. 2

Pathophysiology

The precise pathophysiology underlying FOG remains unknown, but the following hypotheses are commonly heard.

Neuroanatomical substrate FOG appears to be an independent motor symptom, caused by a pathology different from tremor, bradykinesia or rigidity. Dopaminergic cell implants into the putamen of PD patients improve bradykinesia and rigidity of the legs, but do not improve FOG,81 whereas levodopa can decrease FOG in PD patients that do not improve in rigidity or bradykinesia.36 Hence, FOG might be related to dopamine deficiency outside the putamen. Case reports of freezing after stroke and after misplaced deep brain stimulation electrodes suggest a role for the pedunculopontine nucleus and the supplementary motor area.37;140;212;363 Furthermore, studies using neuroimaging techniques have implicated the caudate nucleus, the orbitofrontal cortex and central noradrenergic systems as being possibly involved generating the freezing phenomenon.246;298 It is most likely that FOG does not result from localized pathology within a specific locus in the brain, but rather reflects dysfunction in an organized network that involves the frontal cortex, the basal ganglia (perhaps mainly the caudate nucleus) and the connections between these areas. For at least some of the patients, non-dopaminergic circuitries (possibly involving noradrenergic pathways) may be additionally involved. Chapter 4 sheds some light on the cerebral substrate of freezing of gait.

Neurophysiology Basal ganglia dysfunction in patients with PD leads to a faulty production of adequate amplitude and timing of movements. The basal ganglia play two important roles in the performance of learned automatic movement sequences.181 The first role is to match and maintain the movement amplitude of a cortically selected movement plan (motor set), and the second role is to run each component of the plan in a timely manner (motor cue production). In patients with FOG, basal ganglia dysfunction leads to failure in generating adequate movement amplitudes (reflected by a progressive decrease in step length), combined with a disturbed timing of steps, a phenomenon known as the ‘sequence effect’.181 Movement timing difficulties in freezers are reflected by a disturbed timing of stepping movements during gait. This becomes

55 CHAPTER 2

apparent as an increased variability of gait (even outside overt FOG episodes)164;168 and a premature timing of muscle activations immediately prior to FOG episodes.288 More recent work specifically pointed to disturbances in the fine regulation of interlimb coordination, as reflected by a marked temporal gait asymmetry in patients with FOG.306 This indicates an impairment in controlling the simultaneous timing and pacing of stepping movements of both legs, rather than an inability to regulate steps per se. Finally, a newly emerging concept is that failure to initiate compensatory stepping could be due to impairment of anticipatory postural adjustments (a lateral weight shift is normally required to allow for a contralateral limb swing).206 Apparently, a walking problem (gait akinesia) may be caused by a deficit in the integration of balance and gait programs, or by a primary balance deficit, i.e. the inability to shift weight. This notion is supported by the finding that PD patients, when provided with an assistive (externally imposed) anticipatory postural adjustment, can step faster.250

Neuropharmacology Levodopa generally alleviates FOG, both with respect to severity and frequency, which implies that dopamine depletion in the striatum is the main neurochemical substrate of FOG.49 Methylphenidate may improve gait and reduce FOG in PD, conceivably by increasing the availability of striatal dopamine or by improving attention. Furthermore, increasing striatal dopamine using monoamine oxidase type B inhibitors (selegiline, rasagiline) is also associated with reduced FOG, although the effects in clinical practice are rarely convincing.141 However, FOG is sometimes resistant to dopaminergic therapy. This does not necessarily exclude a role for dopamine deficiency in the underlying pathophysiology, because the threshold for therapeutic relief may simply be higher for FOG than for other symptoms, falsely creating the impression of ‘levodopa-resistance’. More puzzling is the observation that dopaminergic therapy can also paradoxically cause or aggravate FOG (see Chapter 6.2). This might point to a role for excessive dopaminergic stimulation in extra-nigrostriatal circuitries (much like the dopamine dysregulation syndrome), or alternatively, to a role for lesions within non-dopaminergic circuitries. The latter assumption is supported by the fact that FOG rarely occurs in patients with neuroleptic-induced parkinsonism. Further support could be derived from therapeutic trials with non-dopaminergic compounds, such as the noradrenaline precursor L-threo DOPS, but this has only been tested in small series and with crude outcome measures.278

56 FREEZING OF GAIT: GENERAL OVERVIEW

Management Medication 2 Most patients have “off” FOG, with more frequent and severe episodes during the ‘OFF-state’ when the effect of medication has worn off. However, a minority of the patients experience FOG in the ‘ON-state’. Paradoxically, dopaminergic medication (especially dopamine receptor agonists) can sometimes cause FOG. In patients with mainly OFF-state FOG, increasing the dose of antiparkinson medication often leads to improvement, while true “on” FOG may be alleviated by tapering the antiparkinson medication. Selegiline may prevent the development of FOG – possibly by improvement of the visuomotor system – but is less effective once the symptoms are fully developed. Another MAO-B inhibitor, rasagiline, improved FOG in a double-blind, placebo-controlled study. However, the small improvement seen in this study is unlikely to be clinically relevant. Other pharmacological approaches focus on improving attention and executive function, but only small case series have been published. Small open label studies suggested methylphenidate may improve ‘OFF-state’ FOG in PD,24;309 but this effect was not confirmed in a recent double blind trial.113 L-threo DOPS, an immediate precursor of noradrenaline, was effective in Japanese patients with primary progressive FOG, but subsequent studies failed to confirm this.141;279 Small studies using donezepil, an acetylcholinesterase inhibitor specifically used to enhance attention, had beneficial effects in patients with pure FOG. Further placebo-controlled blinded studies with adequate numbers of patients and proper outcome measures remain much needed.141

Physiotherapy Specific cueing techniques using rhythmic auditory cues can reduce the severity of FOG by improving step length and walking speed.284 (see Box 3 in the Introduction). Furthermore, physiotherapists can teach patients to avoid or better deal with dual tasks, as FOG typically occurs during a shift of attention. Avoiding stress might also be beneficial to prevent FOG episodes. Using a wide arc while turning, instead of making an axial turn ‘in place’, is also effective in preventing FOG episodes (see chapter 3.2).

Deep brain stimulation A relatively new method for the treatment of FOG is deep brain stimulation. Currently the preferred target for deep brain stimulation in advanced PD is the subthalamic nucleus, but the globus pallidus remains a good alternative according to some. There is evidence that subthalamic nucleus stimulation improves FOG, but only when it occurs in the ‘OFF-state’.86;210 The general rule of thumb is that FOG that fails to improve

57 CHAPTER 2

with dopaminergic treatment will neither respond to deep brain stimulation. Moreover, there are concerns about the development of secondary gait worsening or postural deficits postoperatively, not immediately after surgery but only after several years, even in the face of a persistent beneficial effect on ‘appendicular’ motor control.368 Possibly, reducing the frequency of deep brain stimulation (to frequencies more typically used to stimulate the pedunculopontine nucleus) can be used to optimize deep brain stimulation treatment. 258 A new area of interest is deep brain stimulation of the dorsal mesencephalon where the pedunculopontine nucleus is situated, because the pedunculopontine nucleus has extensive connections with the basal ganglia, as well as with descending spinal pathways.270 Furthermore, the pedunculopontine nucleus has been suggested to play an important role in the initiation and maintenance of locomotion.212 Open label studies in small groups showed promising results of pedunculopontine nucleus stimulation for patients with FOG.351 However, more recent studies were less hopeful.31;122 Moreover, the precise localization of the pedunculopontine nucleus for deep brain stimulation remains difficult.401

Prognosis

FOG will worsen with advancing disease. Most treatment methods fail to provide a lasting effect and may even paradoxically aggravate FOG. Patients with gait disorders such as FOG have an increased mortality risk, mainly due to a direct result of falling. In addition, the ensuing immobility results in secondary cardiovascular disease and cognitive decline. The mobility problems related to FOG are among the most distressing symptoms of PD. Hence, there is an urgent need for further understanding and management of this intriguing phenomenon.

Acknowledgments

Wandana Mahabier was supported by a research grant of Mr. Akkerman. Bastiaan R. Bloem was supported by a VIDI research grant of the Netherlands Organisation for Health Research and Development (016.076.352) and a research grant of the Prinses Beatrix Fonds. Anke H. Snijders was supported by an ‘MD-medical research trainee’ grant of the Netherlands Organisation for Health Research and Development (92003490). Arnaud Delval was supported by a grant from France Parkinson.

58 FREEZING OF GAIT: GENERAL OVERVIEW

Provoking freezing of gait

Video vignette 1

Freezing is a frustrating phenomenon for patients, family, physicians and researchers, as ‘sometimes it’s there, sometimes it isn’t.’ As an example, video vignette 1 shows a patient with Parkinson’s disease. He reported to have marked freezing of gait at home, interfering with his daily activities. Yet, when he walked through the corridor of the outpatients department, no freezing of gait was seen at all. When he turned to come back, very slight freezing of gait was elicited. Asking the patient to turn to the other direction indeed provoked marked freezing of gait. (Greatly to relieve of his spouse, who kept telling us that he really did have marked freezing at home.)

3.1

Clinimetrics of freezing of gait

Published as: Snijders AH, Nijkrake M, Bakker M, Munneke M, Wind C, Bloem BR. Clinimetrics of freezing of gait. Movement Disorders. 2008; 23:S468-474. CHAPTER 3

Summary

The clinical assessment of freezing of gait (FOG) provides great challenges. Patients often do not realise what FOG really is. Assessing FOG is further complicated by the episodic, unpredictable and variable presentation, as well as the complex relationship with medication. Here, we provide some practical recommendations for a standardised clinical approach. During history taking, presence of FOG is best ascertained by asking about the characteristic feeling of “being glued to the floor”. Detection of FOG is greatly facilitated by demonstrating what FOG actually looks like, not only to the patient but also to the spouse or other carer. History taking further focuses on the specific circumstances that provoke FOG and on its severity, preferably using standardised questionnaires. Physical examination should be done both during the ON and OFF-state, to judge the influence of treatment. Evaluation includes a dedicated “gait trajectory” that features specific triggers to elicit FOG (gait initiation; a narrow passage; dual tasking; and rapid 360 degree axial turns in both directions). Evaluating the response to external cues has diagnostic importance, and helps to determine possible therapeutic interventions. Because of the tight interplay between FOG and mental functions, the evaluation must include cognitive testing (mainly frontal executive functions) and judgement of mood. Neuroimaging is required for most patients in order to detect underlying pathology, in particular lesions of the frontal lobe or their connections to the basal ganglia. Various quantitative gait assessments have been proposed, but these methods have not proven value for clinical practice.

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Introduction

Freezing of gait (FOG) is a curious type of gait disorder. It is unusual because of its “episodic” character: the gait problem is sometimes there, but often it is not. Patients with FOG can experience debilitating episodes during which they are unable to start walking or, while walking, suddenly fail to continue moving forward. Because of this sudden and unpredictable nature, FOG is an important cause of falls and injuries.49

FOG is a challenge for clinicians. Many patients inadvertently deny having FOG 3 because they do not properly know what actual freezing looks like. Even when patients report having FOG at home, the phenomenon is notoriously difficult to elicit in the clinical setting. Apparently, excitement associated with the doctor’s visit or the patient’s extra attention to gait during physical examination can temporarily suppress FOG (a form of “kinesia paradoxa”). Another explanation is that FOG, which is typically provoked while walking in tight quarters,329 is less likely to occur in a widely spaced hospital corridor than at home in a crammed living room. This failure to demonstrate the problem that hinders them so much at home is very frustrating for patients and carers. It is also inconvenient for doctors who need to base their clinical management decisions based on observations in the examination room.

FOG provides equally great challenges for researchers. In a formal testing environment (e.g. a gait laboratory), it is even more difficult to elicit FOG.288 This makes it hard to evaluate the underlying pathophysiology. Also, because of the aforementioned problems, it is not easy to reliably classify a patient as being either a “freezer” or a “non-freezer”, yet many research studies are typically focused on a between-group comparison of freezers versus no-freezers (e.g. in neuroimaging studies). Just as in linkage analyses in the field of genetics, misclassifications can have a great impact on the statistical reliability of such studies.

In this review, we will present the available methods to assess FOG, including history taking, physical examination, quantitative gait analysis and neuroimaging (Table 1).

History taking

Presence of FOG It is usually insufficient to simply ask about “freezing”, because not all patients interpret this correctly. Instead, ask if patients experience the characteristic feeling of “being glued to the floor”. Another helpful suggestion is to ascertain whether patients understand what you mean, by demonstrating a typical FOG episode. The examiner

65 CHAPTER 3

Table 1 Several useful “tips and tricks” for the assessment of FOG History Ask about being ‘glued to the floor’ Provide demonstration of FOG, including different subtypes: - Shuffling forward with small steps - Trembling in place - Total akinesia Interview spouse / other carer Ask patient / carer to maintain a FOG diary Ask about triggering circumstances: turning, starting, tight quarters, dual tasking, reaching destination. Ask about attenuating circumstances (e.g. external or internal cues) Differentiate between ON vs. OFF period FOG: - ask about FOG immediately after waking up - ask about recent changes in medication Falls that point to FOG: - Forward falls - Falls during turning - ‘Spontaneous’ falls Use the standardised FOG Questionnaire Physical ON and OFF (before first morning dose of medication or at ‘end-of-dose’) examination Gait trajectory, including (Figure 2): - Gait ignition - Crossing narrow passage (Doorway / Two chairs) - (>) 360º axial turns in both directions - Voluntary stop The trajectory should be repeated as quickly as possible and while performing a dual task (mental arithmic task) Videotape for objective assessment and future comparison Physiotherapist to make home visit and assess effect of cues Focus attention by cues: - Auditory: metronome - Visual: stripes on the floor - Mental: counting Guideline available via http://www.rescueproject.org / https://www.kngfrichtlijnen.nl/654/KNGF-Guidelines-in-English.htm Divert attention using dual tasks Differentiate FOG episode from normal stop - Preceded by decreased step length and increased cadence - Trembling / shuffling forward - Increased flexed posture with fixed flexion hip, knee, ankle - Ask about concurrent feeling of being ‘glued to the floor’ Simple quantification - Timed up and Go test - Parkinson Activity Scale Ancillary Structural neuroimaging to detect underlying pathology investigations No place yet for functional neuroimaging or elaborate quantitative measures

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may imitate FOG, or show videos of typical FOG episodes. This should be presented not just to the patient, but also to the spouse or other immediate carer who provide a valuable resource of information because they regularly observe FOG in the domestic situation.291

Sometimes, the presence of falls may point to the presence of FOG.49 Three types of falls are particularly associated with FOG: forward falls (which are the inevitable result when the feet suddenly become stuck while walking); lateral falls during turning, sometimes resulting in hip fractures (which are typically caused by a fall sideways 3 onto the trochanter of the hip); and “unexplained” and seemingly spontaneous falls. In our experience, when patients with unexplained falls (but subjectively no FOG) are carefully examined in both the ON and OFF-state (and using specific tricks to provoke FOG – see Physical Examination), FOG can often be identified as the likely cause of the falls. Interestingly, even though FOG is an important source of falls in Parkinson’s disease (PD), there is no difference in frequency or duration of FOG episodes between falling and non-falling freezers.152 Apparently, even a brief FOG episode can be sufficient to make people fall, so clinicians should do their utmost to detect even these mild forms of FOG.

A phenomenon that is closely related to FOG is “festination”, where patients take increasingly rapid and small sequential steps during walking. This festination phenomenon is common in severely affected patients. Like FOG, it is an episodic gait disturbance, and one may speculate that festination in fact reflects a form of FOG (the “shuffling forward” type). Indeed, patients who experience festination are also more likely to experience FOG.151 However, an important difference between festination and the shuffling type of FOG is that the characteristic “magnetic feeling” under the feet is not present in festination. Moreover, festination occurs typically while walking, whereas FOG occurs most often while initiating gait or during turning. More research is needed to unambiguously differentiate these two types of episodic gait disturbances.

Freezing circumstances FOG typically occurs during a shift of attention or a circumstantial or directional change. Specific questions should be tailored to FOG while starting to walk, turning around, moving in tight quarters, when dual tasking (e.g. walking and talking at the same time) or when reaching a destination. Turning around appears to be the strongest provoking factor (Figure 1).323;329 Stress associated with the need to move under time constraints, for example when the telephone or doorbell suddenly rings, may also provoke FOG.140;153 Specific environments can either provoke FOG (e.g. a busy living room with thick carpets) or help to overcome FOG (e.g. crossing a street at a zebra).

67 CHAPTER 3

Figure 1 Characteristics of FOG episodes

A. Circumstances under which freezing of gait (FOG) occurs. B. Duration of FOG episodes. Data for this figure have been distilled from a study of 19 patients with Parkinson’s disease and OFF period FOG.329

100

A 90 Oﬀ medication 80 On medication 70 60 50 40 30 20

Percentage of freezers of Percentage 10 0 Turning Start walking Tight Reaching Open space around quarters destination B

Oﬀ medication On medication Number episodes of

Duration (s)

Influence of medication Most patients – possibly up to 90% of freezers, but this is not precisely known – suffer from ‘OFF-state FOG’, with more frequent and severe freezing episodes when medication effects have worn off. A minority of patients has more severe FOG during the ‘ON-state’, apparently because dopaminergic drugs can sometimes cause freezing. In studies comparing dopamine receptor agonists to levodopa, agonists were more frequently associated with FOG,153 but this may also be explained by their lower therapeutic efficacy on OFF-state FOG. Differentiating between OFF versus ON-state FOG has obvious therapeutic implications. When in doubt, a useful trick is to ask patients whether they experience any FOG immediately after waking up, before

68 CLINIMETRICS OF FREEZING OF GAIT

intake of the first morning dose of antiparkinson medication. When FOG is present at this time, the patient is likely to have OFF period FOG, and the first morning dose will then typically alleviate the complaints. Conversely, when FOG is absent or minimal upon awakening, but aggravated by taking antiparkinson medication, ON period FOG is most likely. It also helps to ask about recent changes in antiparkinson medication. For example, if FOG developed shortly after the start of a new or a higher dose of a dopaminergic drug, ON period FOG should be considered.

Differentiating between OFF and ON-state FOG has consequences for drug therapy: 3 OFF-state FOG usually improves with higher doses of antiparkinson medication, while patients with predominantly ON period FOG may improve with tapering of antiparkinson medication. Interestingly, the effect of external cues (as a means to improve FOG) is also different between ON and OFF-state FOG.82;207;385 Several cueing modalities – visual, auditory, tactile and mental – can improve FOG,25;290;369 but these effects appear to be greatest for patients with OFF period FOG.207

The medication effects may provide information about the underlying aetiology. Patients with ON period FOG that do not respond to cues may suffer from frontal pathology, rather than idiopathic PD, especially when they have a wide-based gait.207

Severity of FOG The distress caused by FOG is related to the frequency, intensity and duration of FOG episodes.27 Most FOG episodes are actually brief, certainly during the ON-state, typically lasting only several seconds and rarely more than 30 seconds.329There are three subtypes of FOG: shuffling forward with small steps (the least severe form); trembling in place; and total akinesia (the severest form). FOG during the ON-state is less severe compared to OFF period FOG, with less frequent and briefer episodes, and presenting less often as total akinesia (Figure 1B).329

Standardized questionnaires Several attempts have been made to develop rating scales for a standardised history taking of FOG. The current Unified Parkinson’s Disease Rating Scale (UPDRS) merely features a single question concerning the presence of freezing (item 14 of Part II, ADL section).216 The scoring system for this question (Table 2) places much emphasis on falling as a result of FOG while, as noted earlier, falling is not related to the frequency and duration of FOG.152

A specific set of questions has been bundled into the Freezing of Gait Questionnaire (FOGQ).152 The FOGQ can help clinicians screen for the presence of FOG, and also to assess the subjective severity. A second version of the FOGQ (NFOGQ), which is

69 CHAPTER 3

accompanied by a video to demonstrate FOG episodes to patients and their carers, has been developed to more specifically assess FOG.291 The NFOGQ also incorporates the impact of freezing on daily life, for example fear of falling. However, these questionnaires only assess FOG during turning and gait ignition, and no other circumstances that commonly cause FOG, such as negotiating narrow passages or performing a dual task. In addition, they do not document the effect of treatment interventions or the environment in which FOG occurs. Finally, the treatment effect (ON or OFF-state) in which FOG predominantly occurs is not scored. As patients are asked to score the overall presence of FOG during the entire day (including well- controlled ON periods), the outcome of the FOGQ may not be strongly related to the presence of FOG during the OFF-state.

Table 2 Scoring of FOG in the ADL section of the UPDRS

0 No freezing when walking 1 Rare freezing when walking; may have start hesitation 2 Occasional freezing when walking 3 Frequent freezing. Occasionally falls from freezing 4 Frequent falls from freezing

Physical examination

The next step in the diagnostic process involves the physical examination. Whenever possible, patients should be examined during both the ‘OFF-state’ (preferably following withdrawal of antiparkinson medication for at least 12 hours) and the subjective “best ON” state. Presence of FOG should ideally be examined using a standardised gait trajectory that features all possible circumstances that may provoke FOG: gait initiation; undisturbed walking in an open space; and walking under challenging situations (crossing a door or other narrow space), turning around and while performing a dual task (Figure 2). Performance can be videotaped in order to objectively evaluate the type of freezing, the duration of each episode and the frequency of FOG.329 Interestingly, many patients only experience FOG during full turns (360 to 540º) and not during partial turns (180º), so a standardised gait trajectory should include such full turns.329 We observed that wider turns seem to be easier for patients than turns “on the spot”, and slow turns are easier than rapid turns. Also, the examination must include turning in both directions because FOG often shows a directional sensitivity, being much worse and sometimes even exclusively present for turns in either a rightward or leftward direction. Preliminary evidence in our laboratory shows that this directional sensitivity has no consistent relationship with the most affected side of the body. Others have included obstacles in their trajectory to provoke FOG.288

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Figure 2 Essential elements of a dedicated FOG trajectory

Gait Narrow Turning Dual initiation passage around tasking

Performance on a gait trajectory can also be timed. An example is the Timed Up and Go test, where patients are observed and timed while rising from a chair, walking three meters, turning around, walking back and sitting down again.308 Regular FOG will obviously increase the timed needed to complete the test, but slowed performance can have many other causes as well. A test that also scores the quality of gait – in addition to timing – is the Parkinson Activity Scale. This scale also includes a Timed up and Go test, but is more specific for FOG because patients have to turn in a tight square.287 Apart from the timing, the examiner scores the severity of FOG for both gait initiation and while turning (using an ordinal five-point scale). The Parkinson Activity Scale has recently been modified and now also includes a cognitive dual task (counting backwards) and a motor dual task (carrying a full glass of water) to provoke FOG.203 In contrast to the original Parkinson Activity Scale, the modified Parkinson Activity Scale has not yet been investigated with respect to its psychometric properties. A disadvantage of the Parkinson Activity Scale is that it only includes a 180-degree turn.

We find it helpful to refer patients to a physiotherapist with expertise in movement disorders. Because the physiotherapist can spend more time with patients, they become familiarised with the environment, which makes FOG more likely to occur. Moreover, the physiotherapist can evaluate the effect of cueing strategies or cognitive movement strategies.203 Furthermore, the physiotherapist can give tailored advice,

71 CHAPTER 3

such as making larger turns to avoid FOG, to increase attention to gait and to avoid dual tasking. Finally, the physiotherapist (or occupational therapist) can assess and train patients in their own home environment, where FOG occurs most commonly and where assessment in the OFF phase is more feasible.

Patients with FOG should receive a cognitive examination, especially testing the frontal executive functions and attention. Frontal executive dysfunction is related to gait impairment in Parkinson patients394 and is associated with an increased risk of falls.165 Moreover, frontal executive dysfunction and FOG frequently co-occur, but there is as yet no proof of a direct causal interrelationship.146 Recklessness, decreased ability to learn cues and an increased sensitivity to cognitive overload (for example when dual tasking) may explain why patients with frontal executive dysfunction are more prone to falls. Moreover, the presence of frontal executive dysfunction may give a clue to the underlying aetiology, as it is more prominently present in atypical parkinsonism then in idiopathic PD.

Attention has a dual influence on FOG. On the one hand, attention to gait – with or without additional external cues – helps to relieve FOG, presumably by switching from automatic to more conscious walking. Judging the effect of different types of cues (visual, auditory, tactile and mental) should be part of the examination, because not all patients improve with the same cueing modality. Moreover, an individual tailoring of cueing parameters is critical: when the cueing frequency is too high, patients will react with smaller steps that can in fact induce FOG.385 Guidelines are available to implement the correct cueing therapy for individual freezers.203 (http://www.kngf.nl/index.html?dossier_id=81&dossiers=1; http://www.rescueproject.org/)

On the other hand, diverting attention with a secondary task while walking makes patients more prone to develop FOG. Note that not all cessations of motor activity while performing a dual task should be seen as FOG, because very complex multiple tasks can also cause hesitations and motor “blocks” in a substantial proportion of healthy subjects controls.52 At least some of these blocks reflect a purposeful behavioural adaptation to prioritize certain specific actions in a complex situation, at the expense of others that are deemed less important. To differentiate such voluntary stops from FOG, the examiner should pay attention to the characteristics of the stop itself and the steps preceding the stop. First, a gait stop caused by FOG is accompanied by a flexed posture with fixed flexion in the hip, knee and ankle joints.285 Second, the FOG stop is often not complete, with some residual trembling in place or forward shuffling.329 Third, FOG episodes are often preceded by a progressive decrease in step length and increase in cadence.181;288 Finally, it can be useful to ask patients whether they experienced the feeling of “being glued to the floor”.

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Other mental functions should also be examined. Depression is possibly associated with increased FOG severity.148;227 FOG is also associated with anxiety: 62% of Parkinson patients with FOG were found to be moderately to markedly anxious, as compared to only 18% of patients without FOG.144 Patients with FOG had more panic attacks (32% compared to 9%), with panic attacks often preceding, co-occurring or following an episode of FOG.

Neuroimaging 3

Structural neuroimaging can be important to detect pathology underlying FOG, such as frontal atrophy, frontal lesions, hydrocephalus, cerebrovascular lesions or abnormalities suggestive of atypical parkinsonian syndromes. Novel MRI techniques such as magnetization transfer imaging, diffusion-weighted imaging and magnetic resonance volumetry may gain significance in the future, as these are more sensitive in detecting abnormal features of atypical parkinsonism.334 Other studies have used functional neuroimaging to gain better insights into the underlying pathophysiology and neural substrate of FOG.37;114;246 Such techniques are currently only relevant for research purposes and are therefore not discussed in more detail here.

Quantitative gait analysis

It would be helpful to have a reliable, objective and quantitative outcome measure for FOG, for example to detect FOG episodes in the home setting, or in clinical trials to evaluate the effect of new therapeutic interventions. Several approaches are available, mainly for research purposes (to clarify the pathophysiology of FOG), but some have a potential clinical utility. One example is a device using angular velocity sensors that can measure trunk motion in different planes while subjects move about freely.11 This has, for example, been used to quantify the “stops walking while talking” test88 and to record trunk motion while making axial turns.378 A theoretically interesting application would be to detect FOG episodes, although trunk sway measures are only an indirect derivative of possible FOG episodes in the legs. A more direct method to detect FOG consists of a goniometer and angular velocity sensor attached to the shank of one of the legs.256

Another approach to study FOG more directly is an ambulatory gait analysis system with pressure sensitive insoles that continuously record walking in freely moving subjects. The results of a study in Parkinson patients showed markedly increased stride-to stride variability in freezers compared to non-freezers.329 Another study

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using this approach showed a marked asymmetry and variability of swing time during gait in patients with FOG.306

More elaborate approaches are also available in specific gait laboratories, their advantage being the more detailed and comprehensive set of outcome measures, but with several clear disadvantages as well (costs; burden to the patient; and reduced likelihood of observing real FOG under these experimental conditions). These techniques are discussed in more detail in other contributions in this supplement.

Towards a new definition of “freezers”

As outlined in the Introduction, it is crucial to have a reliable definition of freezers versus non-freezers, as misclassification can greatly affect the outcome of research studies. Currently, there is no such classification system that can unambiguously separate freezers from non-freezers. The main reason is that neither history taking nor physical examination is infallible, and gold standard laboratory measures are missing. We envision two possible approaches. The first would be an ordinal “black or white” classification, where patients would be defined as being a freezer when FOG is present according to at least one of the following assessments: (a) subjectively (using a FOG questionnaire); (b) according to the carer (using video demonstrations of FOG episodes); (c) during physical examination (using a standardized gait trajectory as defined in Table 1); (d) “objectively” at home (using ambulatory gait assessment techniques); or (e) during formal experimental testing in a laboratory setting (e.g. kinematic gait analyses during treadmill walking). An alternative, and perhaps more reasonable approach, would acknowledge the inherent difficulties in making an absolute distinction between freezers and non-freezers, and rather attempt to classify the severity of FOG, ranging from either absent to marked. Such a continuous rating scale should accommodate the frequency, severity and specific provoking circumstances of FOG, and could be used as a covariate in statistical analyses. Future studies are needed to develop and validate such classification systems, as these are an essential requirement to gain more insights into this curious gait abnormality.

Acknowledgements

This work was supported by NWO VIDI research grant #91776352, a research grant of the Prinses Beatrix Fonds and a research grant from the Stichting Internationaal Parkinson Fonds.

74 CLINIMETRICS OF FREEZING OF GAIT

3.2

To freeze or not to freeze: clinical provocation of freezing of gait

Published as: Snijders AH, Haaxma CA, Hagen YJ, Munneke M, Bloem BR. Freezer or Non-freezer: Clinical assessment of freezing of gait. Parkinsonism and Related Disorders. Parkinsonism Relat Disord. 2012; 18:149-54. CHAPTER 3

Summary

Freezing of gait (FOG) is both common and debilitating in patients with Parkinson’s disease (PD). Future pathophysiology studies will depend critically upon adequate classification of patients as being either ‘freezers’ or ‘non-freezers’. This classification should be based ideally upon objective confirmation by an experienced observer during clinical assessment. Given the known difficulties to elicit FOG when examining patients, we aimed to investigate which simple clinical test would be the most sensitive to provoke FOG objectively. We examined 50 patients with PD, including 32 off-state freezers (defined as experiencing subjective ‘glueing of the feet to the floor’). Assessment including a FOG trajectory (three trials: normal speed, fast speed, and with dual tasking) and several turning variants (180° vs. 360° turns; leftward vs. rightward turns; wide vs. narrow turning; and slow vs. fast turns). Sensitivity of the entire assessment to provoke FOG in subjective freezers was 0.74, specificity was 0.94. The most effective test to provoke FOG was rapid 360° turns in both directions and, if negative, combined with a gait trajectory with dual tasking. Repeated testing improved the diagnostic yield. The least informative tests included wide turns, 180° turns or normal speed full turns. Sensitivity to provoke objective FOG in subjective freezers was 0.65 for the rapid full turns in both directions and 0.63 for the FOG trajectory. The most efficient way to objectively ascertain FOG is asking patients to repeatedly make rapid 360° narrow turns from standstill, on the spot and in both directions.

78 TO FREEZE OR NOT TO FREEZE: CLINICAL PROVOCATION OF FREEZING OF GAIT

Introduction

Freezing of gait (FOG) is an episodic gait disorder characterized by an inability to generate effective forward stepping movements.150 FOG is common in Parkinson’s disease (PD) and in many forms of atypical parkinsonism.269 It is a distressing symptom27;27;255 which, due to the unexpected nature of FOG events, commonly leads to falls.201;219

Both clinical decision making and future research depend critically upon adequate 3 classification of patients as being either ‘freezers’ or ‘non-freezers’. Currently, there is no gold standard for this classification. Most earlier studies used the subjective experience of the patient (‘feet being glued to the floor´), as part of the freezing of gait questionnaire (FOGQ).152;291 However, some patients who deny subjective gluing may nevertheless demonstrate FOG when being examined in a profound OFF-state (at least 12 hours after the last intake of medication).344;348 In such cases, FOG will simply remain unnoticed in daily life where dopaminergic treatment suppresses the phenomenon.149 Conversely, some patients may misunderstand the question and interpret ‘being glued’ as representing their overall akinesia which they can experience during a profound OFF-state (but which lacks the typical episodic nature of freezing of gait). Demonstrating the phenomenon to patients or showing a video with typical examples of FOG may be helpful in such cases.291

Figure 1 shows an algorithm which combines the subjective experience of patients with the objective judgment by an examiner, allowing for a classification of subjects as being either a ´non-freezer´, a ´probable freezer´ or a ´definite freezer´.235 The need to adequately identify and classify freezers as such depends on the setting. In clinical practice, no freezers should be missed and, consequently, be withheld from effective treatment (e.g. optimizing medication, or offering cueing strategies). In other words, a high sensitivity of a test to identify freezers is most important in the clinical setting, even if this goes at the expense of specificity. Hence, in the clinic, it is satisfactory to define a patient as being a ‘probable freezer’, and for this purpose, use of the FOGQ or a question about ‘feeling glued’ suffices.

However, in research studies aiming to study the underlying pathophysiology, it is vital to have a high specificity, in order not to include false-positive freezers, especially when performing between-group comparisons. Ideally, in a research setting patients are classified more strictly as being either ‘definite freezers’ or ‘non-freezers’. For this purpose, objective measures (observer-based) are also required. However, objective confirmation is challenging, because it is generally difficult to elicit FOG during a clinical assessment, and even more so in an experimental environment.286 This would

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hinder research, because patient inclusion would be more difficult. An objective test with a high sensitivity to elicit FOG will make it easier to match patients with and without FOG for disease severity, because patients who do not show FOG during clinical assessment are usually less severely affected.191 More complex tasks and combinations of tests appear to offer a greater diagnostic yield.329 In a recent study, full turns in combination with a dual task elicited most FOG episodes, and this provoked FOG in 50% of subjective freezers.348 Preferably, more sensitive methods to elicit FOG will become available.

Figure 1 Freezer classification algorithm

Assessment of freezing of gait future perspective

Does the patient feel intermittently glued to the oor? Use freezing of gait questionnaire + –

Has the caregiver seen the patient freezing? Educate caregiver about freezing, e.g. videodemonstration + –

Freezing certied by an Freezing certied by an Use repeated full narrow turns and, experienced examiner? experienced examiner? if negative, freezing of gait trajectory – + + –

Probable De nite No FOG FOG FOG

Markers of freezing present during Use quantitative analysis, e.g. quantitative gait analysis? ambulatory monitoring

Here, we examined which objective clinical tests are most sensitive to elicit FOG. Our aim was to determine which clinical tests are most sensitive to classify ‘definite’ freezers. Based on our own clinical experience and on previous research,329;386 we hypothesized that several specific factors might influence our ability to classify freezers. This included the following specific hypotheses and predictions: turning range (narrow versus wide turn, narrow turns expected to be most provocative), turning speed (slow versus fast, fast turns expected to be most provocative), turning direction (most-affected versus less affected side, turning towards the most affected expected to be most provocative) and turn extent (180 versus 360 degree turns, full turns expected to be most provocative). To minimize strain on patients and researchers

80 TO FREEZE OR NOT TO FREEZE: CLINICAL PROVOCATION OF FREEZING OF GAIT

in future practice, we aimed to arrive at the minimum amount of tests needed to get a maximum diagnostic yield. Hence, we also hypothesized that rapid axial turns would be as sensitive in classifying freezers as a more elaborate and more time-consuming FOG trajectory.

Table 1 Clinical characteristics

N Age Gender UPDRS H&Y Disease N-FOGQ duration Objective freezers# 25 64 88% male 36.8 2.5 10.7 16.6 3 Only subjective freezers* 8 61 63% male 29.9 2.3 6.5 8.1 Non-freezers 17 62 65% male 26.9 2.1 7 0 All patients 50 62 76% male 32.3 2.3 8.7 9.6

# Objective freezers: Patients that showed freezing upon examination (definite freezers). * Only subjective freezers: Patients that told they were freezing on history, but did not show freezing upon extensive examination. H&Y = Hoehn and Yahr Rating Scale; UPDRS = Unified Parkinson’s Disease Rating Scale part 3; N-FOGQ = New Freezing of Gait Questionnaire. H&Y and UPDRS values are measured during ‘OFF’ state.

Methods

Patients We included 50 patients (Table 1) that were recruited by telephone from the total database of our large outpatients clinic of the Parkinson Centre Nijmegen. Inclusion criteria were idiopathic PD, defined according to the UK PD Brain bank criteria,178 Hoehn and Yahr stage 2-3, the ability to come to the department for research studies, and to perform the experiment in an OFF-state (because these subjects represent the patients that are typically used for research studies). To assess patient-rated (subjective) FOG, we used the new Freezing of Gait Questionnaire (NFOG-Q).291 We included thirty-two subjects with a subjective history of FOG (i.e. they answered ‘yes’ to the question: ‘Do you sometimes feel as if your feet are being glued to the floor?’). We only included patients whose FOG was most prominent during an OFF-state. In addition, we included 18 patients without a history of subjective FOG. Exclusion criteria included other causes for gait impairment (such as severe arthrosis or neuropathy) and Mini Mental State Examination <25. The study was conducted in accordance with the declaration of Helsinki. All subjects gave informed consent, as approved by the local medical ethics committee.

We examined 46 patients during a practically defined OFF condition (in the morning, >12 hours after intake of the last dose of dopaminergic medication).217 The four remaining patients could not withhold their medication for 12 hours and were tested

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in the morning during a subjective OFF-state (‘end of dose’ effect of the first morning dose), just prior to intake of the second medication dose.

Clinical test battery To assess the effect of turning range (narrow versus wide turn), turning speed, turning direction and turn extent (180 versus 360° turns), patients performed the following tests (Figure 2): • Narrow half turns. Patients arose from a chair, walked 2.5 meters, and then made a 180° turn in a narrow quarter. The turning direction was self-selected. This was repeated twice, once at preferred speed, and once as rapidly as possible. • Wide half turns. Same as above, but now using a wide turn around a chair. This test was performed by only 33 patients (20 subjective freezers)). • Normal speed full turns. Patients performed 360° turns from standstill in narrow quarters, at self-selected speed, with two leftward turns to and two rightward turns, in random order. • Rapid full turns. Same as above, but now as rapidly as possible.

In addition, to be able to compare the turning with the FOG trajectory, patients performed the following trajectories (Figure 2): • Normal speed gait trajectory. Patients performed a 15-meter walking trajectory 329 at self-selected speed. The trajectory consisted of rising from a chair, walking through a narrow passage (created by two chairs placed 50 cm apart), stopping and starting again, a full narrow turn (360°) in one self-selected direction, followed by one and a half turn (540°) in the opposite direction, and walking straight back to the chair. • Dual task gait trajectory. Same as above, with a cognitive dual task (subtracting serial sevens from 100). • Rapid speed gait trajectory. Same as above, but now as rapidly as possible.

The tasks were administered in semi counter balanced fashion. We always started with the 180° turns. Half of the patients then first performed the 360° turns and subsequently the gait trajectory, the other half performed these tests the other way round. During the 360° turns the normal speed turns were always performed first, but the direction of turns was counter balanced (randomly). The gait trajectory always started at normal speed, was repeated as rapidly as possible, and then with dual task.

Outcome The entire experiment was videotaped for offline visual analysis. Two independent and experienced raters (AS & CH) scored the videos for presence of FOG. The definition used to score FOG was an obvious episode with ineffective stepping.150 If the two

82 TO FREEZE OR NOT TO FREEZE: CLINICAL PROVOCATION OF FREEZING OF GAIT

Figure 2 Clinical test battery

A: Half turns. Narrow turns, repeated at normal speed and as rapidly as possible. In addition, performed with wide turn around obstacle. B: Axial full turns. From standstill. Two turns to both directions, normal speed and as rapidly as possible. Each condition repeated twice: total of 8 turns. C: Gait trajectory. Repeated three times: Normal speed, as rapidly as possible and with dual task (100-7).

A 3 Sit in chair Axial 180º turn Sit in chair Wide 180º turn Walk 2,5 m Walk 2,5 m Get up and go in U-shape Get up and go around obstacle

Walk 2,5 m Walk 2,5 m Walk 2,5 m

Sit in chair Walk through Stop walking Axial 360º turn Get up and go obstacles and start Then turn 540º in (50 cm apart) walking again opposite direction

Same way back without stopping (total walking distance 15 m)

raters disagreed, consensus was reached in discussion with a third rater (BRB). Inter-rater reliability was assessed using Cohen’s kappa, both for all trials separately as for the classification as a freezer.

Best way to provoke FOG To assess our hypothesis that rapid axial turns would be as effective in classifying freezers as a more elaborate FOG trajectory, we assessed specificity and sensitivity of the rapid turns (4 turns) and the FOG trajectory (normal speed, rapid speed and dual tasks combined). For this analysis, as a gold standard we set the answer ‘yes’ to the question: ‘Do you sometimes feel as if your feet are being glued to the floor?’ of the NFOG-Q. In addition, we evaluated which components of the FOG trajectory provoked FOG, to see whether other components then turning were of added value.

83 CHAPTER 3

Next, we assessed the ability of the separate tests to classify freezers as ‘definite freezers’, and investigated which combination of tests would have found all ‘definite freezers’ in our sample.

Provoking factors during turning We made several specific comparisons to explore the effect of the different provoking factors during turning (using Wilcoxon’s signed rank test for related samples). Each time, the outcome was a binary classification: the test elicited FOG in a patient (1) or not (0). Hence, we did not intend to provide a severity score to assess FOG, as described recently.398 We specifically examined the following predefined contrasts:

• Space : wide vs. narrow 180o turns (one turn for each condition). • Range : 180o vs. 360o turns (one slow and one rapid 180o turn were compared to one slow and one rapid 360o turn). • Speed : rapid versus self-selected speed (two turns each). • Laterality: turn to the most affected side vs. turn to the least affected side (four turns each). • Uni- or bilateral: turns into one direction only versus turns into both directions (four compared to eight turns). • Repetition : four vs. eight turns to both sides (four turns were compared to eight turns).

SPSS 16.0 was used for statistic testing, with α-value set at 0.0083 to correct for six multiple comparisons (Bonferroni).

Results

Classification of freezers Clinical assessment revealed objective FOG in 24 of the 32 patients with a subjective history of FOG. The patients with definite FOG had a higher NFOG-Q score then the patients with only subjective FOG (Table 1). In addition, FOG was elicited during clinical assessment in one of the 18 patients without history of freezing. Hence, 25 subjects with objective ‘definite’ FOG were available to evaluate the diagnostic yield of the various tests. The combination of all objective tests thus showed a sensitivity for FOG of 0.74 (95% confidence interval (CI) 0.55 – 0.88) and a specificity of 0.94 (CI 0.73-1.0). Inter-rater reliability was excellent for the classification as a freezer (agreement 97%, Cohen’s kappa 0.93), and very high for all trials rated separately (agreement 96%, Cohen’s kappa 0.89).

84 TO FREEZE OR NOT TO FREEZE: CLINICAL PROVOCATION OF FREEZING OF GAIT

Best way to provoke FOG Taking as a gold standard the NFOG-Q, rapid full turns (four turns) had a sensitivity of 0.65 (CI 0.45-0.81) and a specificity of 1.00 (CI 0.81-1.0). The gait trajectory (three times) had a sensitivity of 0.63 (CI 0.44-0.80) and a specificity of 0.94 (CI 0.73-1.0) (1 patient without feeling glued on history was rated to experience FOG during the gait trajectory upon gait initiation). The elements of the gait trajectory differed in their ability to provoke FOG (Figure 3). The element that provoked most FOG was turning, where FOG occurred in all but two of the 21 patients that froze during the gait trajectory (90%). These two remaining 3 patients only showed FOG upon gait initiation.

Figure 3 Provocation of FOG by the different elements of the gait trajectory

Percentage of definite (objective) freezers that show FOG upon each different element of the gait trajectory.

Provocation of FOG in % of de nite freezers

100 90 Open space 80 Narrow passage 70 Reaching destination 60 Gait initiation 50 Turns 40 30 20 10 0

A combination of ‘Rapid full turns’, ‘Dual task gait trajectory’ and ‘Normal speed gait trajectory’ provoked FOG in all definite freezers (Table 2 shows FOG provocation of separate and combined tests). This remained true when the rapid turns were performed only into the least affected direction. Performing rapid turns is easier and less time-consuming than performing the gait trajectory. Indeed, including only the full narrow turns (four at normal speed, and four rapidly) already elicited FOG in 88% of the definite freezers.

Provoking factors during turning Comparisons between the different conditions are shown in Figure 4 and Table 2. Turning space (wide vs. narrow turn), turning range (full versus half) and turning

85 CHAPTER 3

Table 2 Ability of the different tasks to classify patients as ‘definite freezers’ (freezing of gait episode(s) seen on examination)

ONE task provoking at least one FOG episode (% of definite freezers) Task 1 Rapid full turns 84% Task 2 Dual task gait trajectory 68% Task 3 Normal speed gait trajectory 60% Task 4 Normal speed full turns 48% Task 5 Rapid speed gait trajectory 48% Task 6 Narrow half turns 40% Task 7 Wide half turns 0% TWO tasks provoking at least one FOG episode Task 1 and 2 Rapid full turns, dual task gait trajectory 96% Task 1 and 4 Rapid full turns, normal gait trajectory 92% Task 1 and 3 Rapid full turns, normal speed full turns 88% Task 2 and 3 Normal gait trajectory, dual task gait trajectory 84% THREE tasks provoking at least one FOG episode Task 1, 2, 3 Rapid full turns, dual task gait trajectory, normal gait 100% trajectory speed all influenced the percentage of freezers that showed objective FOG (Figure 4A-C) with an α-value of <0.05, but these effect was not significant anymore when corrected for multiple comparisons. Whether patients turned to their most or least affected side did not affect the diagnostic yield (65% of definite freezers showed FOG when turning to the most affected side, and 74% to least affected side, Wilcoxon’s Z = -0.6, p = 0.53). However, nine patients (43% of definite freezers) exclusively froze when turning to one specific side, and not when they turned to the other side. Turning to both sides tended to yield more freezers than turning to one side (p = 0.026, figure 3D). However, this could reflect a repetition effect, because comparing four turns to eight turns gave a significant difference (figure 4D).

Discussion

Our goal was to define the most sensitive, simple clinical test to classify ‘definite’ freezers. Using various scenarios combined, we found 0.74 sensitivity to elicit definite FOG in patients with PD and a subjective history of freezing (‘probable’ FOG). Moreover, unambiguous FOG was observed during this assessment in 5% of patients who firmly denied the characteristic gluing experience of FOG in daily life. The most

86 TO FREEZE OR NOT TO FREEZE: CLINICAL PROVOCATION OF FREEZING OF GAIT

Figure 4 Provocation of FOG by different testing tests

Provocation of FOG by different testing tests. Percentage of definite (objective) freezers that show FOG upon the different turning tests. Between brackets: number of turns. * = p value between 0.05 and 0.0083. ** = p-value < 0.0083 (Bonferroni corrected for performing 6 comparisons). A: Turning range (Wide vs narrow half turn, z = -2, p = 0.046) B: Turning extent (Half vs full turn, z = -0.6, p = 0.56) C: Turning speed (Normal vs rapid turns, z = -2.5, p = 0.011) D: Side or repetition. Turns to first versus to both sides (Z = -2.2, p = 0.025), one turn each condition (right, left, normal, rapid) versus two turns each condition (Z = -2.6, p = 0.008).

Provocation of FOG in % of % of de nite freezers de nite freezers A 100 B 100 3 90 90 80 80 70 70 60 60 50 50 40 * 40 30 30 20 20 10 10 0 0 Wide half turn (1) Narrow half turn (1) Half turns (2) Full turns (2) % of % of de nite freezers de nite freezers

C 100 D 100 90 90 80 * 80 * ** 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Slow turns (4) Rapid turns (4) First side (4) Both sides (8) All once (4) All twice (8) effective test to provoke FOG was rapid 360° turns in both directions and, if negative, combined with a gait trajectory with dual tasking. Repeated testing improved the diagnostic yield. The least informative tests included wide turns, 180° turns or normal speed full turns. Rapid full turns (four turns) were as sensitive to objectively provoke FOG in subjective freezers as FOG trajectories (three trajectories, including six turns).

This study confirms the challenge of provoking FOG in patients who complain of ‘feeling glued to the floor’. It is especially difficult to elicit FOG in patients with less severe subjective FOG, as measured by the NFOG-Q. In addition, similar to another study,348 we found that one of the 18 subjective ‘non-freezers’ did actually show clear FOG during our extensive clinical assessment. Two factors may explain this. First, the

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examination took place during a practically defined OFF-state, and this may unveil FOG that remains unnoticed in daily life where dopaminergic treatment suppresses the phenomenon.141 This is why research studies into FOG should preferably examine patients during the OFF-state. Second, our extensive test battery exposed patients to situations which they have ‘learned’ – either consciously or subconsciously – to avoid in daily life. For example, the spontaneous behavior of many patients is to take wide and careful turns, while our present results suggest that rapid turns in tight quarters are the best way to provoke FOG. We therefore recommend using such rapid, narrow turns as part of the test battery to classify patients as either freezers or non-freezers.

Our findings confirm that turning is the best way to provoke FOG in PD.329;348;398 We also showed that repeated full turns in both direction (four turns) are as effective - and more efficient- in provoking FOG as an elaborative gait trajectory (three times, including a total of six turns). Indeed, when FOG occurred during the gait trajectory, this was usually during turning.

Narrow turns identified more freezers than wide turns. This is probably because a narrow turn imposes a greater amount of temporal and spatial asymmetry of steps compared to wider turns.307 The step length of particularly the leg on the inner side of the turn decreases during a narrow turn, and such a decreasing step length can provoke FOG.76 The observed effect of repetition underscores that examiners should not stop when the first test is normal. It may be speculated that the effect of repetition is caused by the suppression of FOG by initial anxiety of being examined or the attention given to a task when performed for the first time.265 However, a closer look at our data does not support this: 10 patients showed FOG in the first turns of the conditions, but not in the second, while 6 patients showed FOG in the second turn of the condition, but not in the first. Probably the effect of repetition just highlights the episodic quality of FOG: sometimes it is there and sometimes it is not.

A recent study showed that a combination of full turns with dual tasking elicited most FOG episodes.348 In this study, 24 turns (of which 12 were full turns) elicited FOG in 50% of 14 subjective freezers. Using eight full turns, we elicited FOG in 66% of a comparable sample of 32 subjective freezers. The ‘full turns’ used in both studies were different: Spildooren and colleagues used turns around a small marker after walking towards this marker,348 whereas we used turns ‘on the spot’ from standstill. Another potentially relevant difference is that we requested subjects to turn ‘as rapidly as possible’ during four of the eight turns, and this may explain the slightly higher diagnostic yield in our study. Importantly, Spildooren and colleagues found that adding a dual task to the turning tasks further improved the diagnostic yield for

88 TO FREEZE OR NOT TO FREEZE: CLINICAL PROVOCATION OF FREEZING OF GAIT

FOG.348 This dual tasking benefit was less prominent in our study, likely because their dual task difficulty was better selected and more challenging (specifically, Spildooren and colleagues used a color classification task, for which the load could be varied without increasing the level of difficulty). Indeed, more complex multitask conditions show great sensitivity to balance deficits in PD and correlate better to falls in daily life than simple dual task conditions.46 A small disadvantage to using dual tasks is the risk of increasing the false-positive classification rate, because it can be difficult to differentiate the akinetic form of FOG from more purposeful stops, as in the ‘stops walking when talking’ phenomenon.233 3

Rapid full turns (four turns) were as sensitive to objectively provoke FOG in subjective freezers as FOG trajectories (three trajectories, including six turns). We propose as an objective test for the classification of freezers in research studies to perform at least eight rapid full turns (four into each direction, ‘on the spot’, each time from standstill). If negative, a gait trajectory involving dual tasking may be added. Future work now needs to validate this approach. An additional question is whether adding straight walking with short steps (25% of step length) adds something to this classification of freezers.76;76 Such careful objective testing should be part of future research, thus reducing misclassification in pathophysiology studies.

Acknowledgements

This research was supported by the Netherlands Organization for Scientific Research (NWO) [016076352 to B.B., 92003490 to A.S.] and by the Prinses Beatrix Fonds. We are thankful to prof. George Borm for help with the statistical analyses.

3.3

Obstacle avoidance to provoke freezing of gait on a treadmilll

Published as: Snijders AH, Weerdesteyn V, Hagen YJ, Duysens J, Giladi N, Bloem BR. Obstacle avoidance to elicit freezing of gait during treadmill walking. Mov Dis 2010; 25(1):57-63. CHAPTER 3

Summary

Freezing of gait (FOG) is a common and disabling feature of Parkinson’s disease (PD). Detailed pathophysiological studies are hampered by the fact that FOG episodes are difficult to elicit in a gait laboratory. We evaluated whether the need to avoid sudden obstacles could be used to experimentally provoke FOG. We included 21 PD patients (15 with self-reported ‘OFF-state’ FOG). Patients were tested in the OFF-state. FOG during over-ground walking was assessed using a standardised gait trajectory and axial 360 degree turns. Subsequently, patients walked on a motorised treadmill with suddenly appearing obstacles that necessitated compensatory stepping. The available time to respond was varied by dropping the obstacle either immediately in front of the patients or at 1 meter distance in front of them. Performance was videotaped, and presence of FOG was scored visually by two independent raters. Thirteen patients showed FOG during over-ground walking. During treadmill walking, obstacle avoidance was associated with 13 unequivocal FOG episodes in eight patients (all of whom also showed over-ground FOG), whereas only one patient froze during undisturbed treadmill walking (Wilcoxon z = -2.0, p = 0.046). FOG episodes elicited by obstacle avoidance were brief (typically < 1 s). Almost all episodes were provoked when subjects had a longer available response time. Suddenly appearing obstacles on a treadmill can elicit FOG, permitting detailed pathophysiological studies of FOG in a controlled laboratory setting. However, the moving treadmill and the obstacle both act as cues that apparently help to immediately overcome the provoked FOG episode. This may limit the ecological validity of this new approach.

92 OBSTACLE AVOIDANCE TO PROVOKE FREEZING OF GAIT ON A TREADMILLL

Introduction

Freezing of gait (FOG) is a common and disabling feature of Parkinson’s disease (PD).343 A FOG episode is defined as an episodic inability to generate effective forward stepping movements, in the absence of any known cause other than parkinsonism or higher cortical deficits.150 It is most commonly experienced during turning and step initiation, but also when faced with spatial constraint, stress or distraction. Focused attention and external stimuli (cues) can help to overcome the episode.150 Because of its sudden and unpredictable nature, FOG often leads to falls and injuries.49 3

Several therapies are used to treat FOG, including pharmacotherapy, stereotactic deep brain surgery and the use of visual, auditory or mental cueing techniques.124;141;284 Unfortunately, these therapies generally fail to provide a gratifying and lasting improvement in FOG. Improved treatment strategies are needed, tailored to the specific underlying pathophysiology. However, the mechanisms leading to FOG remain insufficiently understood. To further clarify the pathophysiology of FOG, there is a need for detailed gait analyses under carefully controlled experimental conditions, for example while patients walk on a treadmill in a gait laboratory. However, evaluating FOG proves extremely difficult in such a research environment, because even patients with clear FOG typically fail to demonstrate the phenomenon during formal experimental testing.288;341

In this study, we aimed to evaluate a new procedure that would evoke FOG in an experimental gait laboratory. Inspired by pilot observations,90 we investigated whether suddenly appearing obstacles could be used to provoke FOG in patients with PD, walking on a motorised treadmill. In addition, we investigated the effect of the available time to negotiate the obstacle. More preparation time may facilitate obstacle avoidance, but may also challenge a more complex neural circuitry103 and thereby promote FOG episodes.

Methods

Subjects Twenty-one patients were randomly recruited from the outpatient clinic of Parkinson Centre Nijmegen. Inclusion criteria were idiopathic PD (diagnosed according to the UK Brain Bank criteria ),178 Hoehn and Yahr stage 2-3 and ability to walk on a treadmill during an OFF-state. Exclusion criteria were other neurological disorders, severe co-morbidity, other clinically relevant causes of gait impairment or severe cognitive impairment (Mini Mental State Examination (MMSE) < 25 or Frontal Assessment

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Battery (FAB) < 12).104 Fifteen patients were included with subjective FOG (answer ‘yes’ to item #3 of the FOG Questionnaire: ‘Do you sometimes feel as if your feet get ‘glued to the floor’),152 mainly occurring during OFF periods. We did not include patients with mainly ‘On period’ freezing. In addition, six patients without a history of FOG were included. Sixteen patients were examined in the morning during a practically defined OFF period at least 12 hours after intake of the last dose of antiparkinson medication. Because this was impossible for the five remaining patients (all freezers), they were measured during an end-of-dose OFF-state. There were no differences in freezing outcomes (overground or treadmill FOG, described below) between these five patients and the other patients. All subjects gave informed written consent and the study was approved by the local ethics committee.

Clinical assessment during over-ground walking Prior to the treadmill experiment, Unified Parkinson’s Disease Rating Scale (UPDRS) motor score and Hoehn and Yahr stage (H&Y) were obtained. In addition, cognitive status was assessed using the MMSE and the FAB.104

To grade patient-rated FOG severity, the FOG Questionnaire and the new FOG Questionnaire (N-FOGQ) were used.152;291 To examine observer-rated FOG, a standardized gait trajectory was used containing specific elements to provoke FOG: starting walking, walking through a narrow passage (created by two chairs placed 50 cm apart), temporarily stop walking and start walking again. Patients also had to turn in a tight square of 1 by 1 m. First, they turned 360 degrees in a self-selected direction, followed by a 540 degree turn in the opposite direction. Finally, patients walked 7.5 m back to the chair. This gait trajectory was repeated three times: at normal speed, as rapidly as possible, and while performing a dual task (mental arithmetic). In addition, patients were asked to make eight 360 degree axial turns from standstill in both directions, and both at normal and at high speed.158;341

Treadmill experiment Subjects walked on a motorised treadmill at a speed of 2 km/h. In two subjects 1.5 km/h was used, as 2 km/h was not feasible. Patients wore a safety harness attached to the ceiling to prevent falling, without interfering with natural walking. In addition, one of the examiners constantly watched the patient with an emergency brake at hand. Patients did not have a handrail.

First, patients were familiarised with treadmill walking for 5 minutes, and practiced obstacle avoidance with 5-7 obstacles. Patients were instructed to avoid the obstacle and not to step alongside or onto the obstacle. The obstacles were sized 40 cm by 30 cm with a height of 1.5 cm and were attached by a magnet to a bridge placed over

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Figure 1 Experimental set-up

The obstacle is attached by a magnet to a bridge placed over the treadmill.

the treadmill, as described earlier (Figure 1).331 Using remote control, the obstacles were unexpectedly released in front of one of the legs at random intervals (30-60 seconds apart). The patients could see the obstacle being attached to the magnet, but had no possibility to predict when the obstacle would fall. We manipulated the available time to negotiate the obstacle. For this purpose, subjects were positioned at either a short distance from the appearing obstacle (10 cm) or a long distance (1 m). This was repeated for both the left and right leg. During the Short Distance conditions, 15 obstacles fell in front of each leg at three different moments in the step cycle (mid stance, early swing and mid swing). For the Long Distance conditions, 10 obstacles fell in front of each leg. Hence, the whole experiment consisted of 50 obstacles. The order of the test conditions (Short Distance – Most affected leg, Short Distance – Less affected leg, Long Distance – Most affected leg, Long Distance – Less affected leg), was randomly alternated for each subject.

The period between obstacle release until the obstacle left the treadmill was defined as ‘obstacle avoidance’, while the period from the moment the obstacle left the treadmill until eight strides later was defined as ‘baseline treadmill walking’.

Outcome measures The primary outcome measure was the presence of FOG according to the current gold standard: visual assessment of digitally videotaped gait performance.341

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Performance during baseline assessment (over-ground walking) and the treadmill experiment was digitally videotaped for later objective evaluation. The presence of FOG during baseline over-ground assessment was scored by a single rater with considerable clinical experience with FOG. To guarantee valid rating of the ‘new’ treadmill FOG, the treadmill performance was independently rated by two other raters with considerable clinical experience with FOG. Only unequivocal FOG in the eyes of both raters was classified as a FOG episode to ensure high specificity. An additional third independent rater with extensive knowledge of obstacle avoidance ascertained that no variants of normal obstacle avoidance were inadvertently rated as FOG episodes. All four raters were not present during the experiments and were blinded to the clinical status (prior FOG yes or no) and to the other rater’s score.

For each video fragment with FOG, the circumstances of FOG were determined: which leg (most/least affected), which distance to the obstacle (10 or 100 cm), before or after crossing the obstacle. Furthermore, the duration of the FOG episode and the need to stop the treadmill were determined visually.

Data analysis The proportion of subjects that showed at least one unequivocal FOG episode during over-ground clinical assessment, baseline treadmill walking and during obstacle avoidance on the treadmill was compared using a Friedman test with a significance level of p = 0.05. If this test was significant, a Wilcoxon’s signed rank test was used to assess differences between these conditions. Patient characteristic differences between groups were analysed using a Kruskal-Wallis test. Agreement between raters was assessed using Cohen’s Kappa. Data were analysed using SPSS 14.0 for windows, using a significance level of p = 0.05.

Results

FOG during over-ground walking Twelve of the 15 freezers (80%) showed at least one FOG episode during over-ground assessment (mean number of FOG episodes 5.6, range 0-16). Only two freezers (13%) also showed FOG during straight walking (one freezer during gait initiation, while crossing a narrow passage and upon reaching the destination; the other freezer only during gait initiation and upon reaching the destination. All other FOG episodes were associated with turning). One subjective ‘non-freezer’ (17%) unexpectedly showed a FOG episode during the OFF-state over-ground assessment, although it was very brief (<1 s). This patient was therefore classified as a freezer for the remainder of the experiment.

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FOG during treadmill walking Characteristics of the patients and occurrence of FOG are summarized in Table 1. During treadmill walking, obstacle avoidance was associated with 13 unequivocal FOG episodes in eight patients (all of whom also showed over-ground FOG), whereas only one patient (patient 6 in Table 1) froze during undisturbed treadmill walking (Friedman Chi square = 16.9, p < 0.001, baseline treadmill walking vs. obstacle avoidance Wilcoxon z = -2.0, p = 0.046). The patients with unequivocal FOG episodes on the treadmill experienced these with 6% of obstacles that had to be avoided. 3 More patients froze during over-ground walking (n = 13) compared to obstacle avoidance on the treadmill (n = 8, Wilcoxon z = -2.6, p = 0.008) or baseline treadmill walking (n = 1, Wilcoxon z = -3.3, p = 0.001). However, only two patients showed FOG episodes during over-ground straight walking, as almost all FOG episodes occurred during turning. If only FOG episodes during straight walking were taken into account, obstacle avoidance on the treadmill provoked more FOG than overground walking (n = 2, Wilcoxon z = -2.4, p = 0.014). There was no difference in age, UPDRS score, Hoehn and Yahr stage, or cognitive status between patients with or without FOG on the treadmill. In addition, there was no difference in the number of overground FOG episodes between freezers with or without FOG on the treadmill.

Characteristics of FOG episodes on the treadmill Table 2 states which conditions provoked FOG, and whether FOG occurred before or after obstacle crossing. Video 1 shows an example of FOG during the Long Distance condition, directly after the obstacle crossing. Video 2 shows an example of FOG during the Short Distance condition, between obstacle release and obstacle crossing. Video 3 shows one patient (patient 5 in table 1 and 2) where FOG already occurred when the obstacle was placed but not yet released, so this was apparently provoked by the mere anticipation of the upcoming obstacle. Two patients only showed a clear FOG episode during the practice trials. In the other patients the FOG episodes were distributed equally over the experiment.

Duration of the FOG episodes during obstacle avoidance was always less than 1 second, and the treadmill never needed to be stopped because of these episodes. The FOG episodes that occurred ‘spontaneously’ during undisturbed treadmill walking without the need to actually avoid an obstacle did sometimes force an emergency stop (video 3).

Agreement among raters The rating of separate trials as containing either ‘FOG’ or ‘no FOG’ had an acceptable agreement between both clinical raters (Kappa = 0.70, p < 0.001). There was perfect

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Table 1 Clinical characteristics of all participants in relation to the occurrence of freezing of gait (FOG)

Patients Age Gender UPDRS H&Y FOGQ FOGQ-II Over-ground FOG score score FOG* during OA on treadmill* 1 73 M 31 3 9 18 2 2 2 52 M 45 2.5 7 5 2 1 3 59 M 46 2.5 10 14 16 1 4 61 M 27 2 12 21 2 1 5 62 M 32 2 15 26 9 5 6 64 M 31 2.5 10 13 11 1 7 53 M 22 2 8 14 1 1 8 68 M 24 2 11 19 13 1 9 75 F 46 3 11 17 4 0 10 66 M 45 2.5 13 21 1 0 11 66 M 18 2 16 24 15 0 12 66 M 20 2.5 8 17 8 0 13 65 M 34 2 1 0 1 0 14 55 M 35 2.5 6 7 0 0 15 62 M 29 2.5 16 11 0 0 16 71 M 49 3 9 19 0 0 17 68 M 32 2 2 0 0 0 18 54 F 24 2 3 0 0 0 19 44 F 21 2 1 0 0 0 20 54 M 19 2.5 2 0 0 0 21 69 M 53 2.5 4 0 0 0

Overground 64 32 2.3 10 16 100% 67% freezers

Freezers only 63 38 2.7 10 12 0% 0% on history

Non-freezers 58 30 2.2 2 0 0% 0%

UPDRS = Unified Parkinson’s Disease Rating Scale. H&Y = Hoehn and Yahr stage. FOGQ-score is FOG Questionnaire score152, FOGQ II = new FOG Questionnaire score291. OA = obstacle avoidance * = Number of episodes

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Table 2

Patients Short Long Obstacle Obstacle FOG before FOG after distance distance before MA before LA obstacle cross obstacle cross condition condition leg leg 1 0 1 0 1 0 1 2 NAP 1 0 1 1 0 3 1 0 1 0 1 0 4 0 1 1 0 0 1 5 NAP 1 1 0 1 0 3 6 1 0 1 0 0 1 7 0 1 0 1 1 0 8 NAP 1 1 0 1 0 Total (%) 40% 75% 63% 38% 63% 38%

0 = No FOG, 1 = at least one unequivocal FOG episode occurred. MA leg = most affected leg, LA leg = less affected leg, FOG = Freezing of gait, NAP = Not able to perform due to festination when walking close to the obstacle

inter-rater agreement for the classification of individual patients as ‘treadmill freezer’ or ‘treadmill non-freezer’ (Kappa = 1.0, p < 0.001). Also, all trials that were rated as ‘FOG’ by the clinical raters, were also rated as ‘abnormal’ by the obstacle avoidance rater.

Discussion

Our findings show that suddenly appearing obstacles during treadmill walking can provoke unequivocal FOG episodes. This observation opens a new avenue to study FOG in a controlled laboratory setting. However, these FOG episodes were less common and much briefer compared to episodes during over-ground walking.

The ability of sudden obstacles to provoke FOG, even while walking in an experimental environment, may be interpreted in several ways. A first explanation is that upcoming obstacles force subjects to adjust their gait, necessitating a rapid planning and execution of adaptive movements. During normal walking, PD patients partially rely upon cortical compensation to bypass their defect basal ganglia.181 The need to combine consciously controlled walking with a deliberate obstacle avoidance may well outweigh the available resources.46;62 In support of this notion, we observed that more FOG episodes were provoked when the obstacle fell in front of the most

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affected leg. Probably, movement adaptation with the most affected leg needs more resources than adaptation with the least affected leg. In addition, the Long Distance condition produced even more FOG episodes than the Short Distance condition, even though the task of obstacle avoidance is presumably easier when subjects have more time to prepare. We suspect that obstacle avoidance in the Short Distance condition engages a fast pathway that runs largely over subcortical structures, releasing motor programs stored in the reticular formation.70;313;318;319 Hence, this “cued” fast response could bypass the defective basal ganglia and mesencephalic pedunculopontine nucleus. In contrast, the Long Distance condition likely involves a longer and more complex circuitry, involving the parietal and motor cortex, the lateral cerebellum and pontine gray nuclei, as was demonstrated in the cat.103 This complex circuitry may be more susceptible to sudden interference, leading to relatively more FOG episodes during the Long Distance condition.

Second, sudden obstacle avoidance calls for a switch in motor tasks, requiring subjects to make corrective steps instead of walking straight. PD patients have great difficulties switching between motor tasks,14;38;62 and this also applies to gait.46;236 These switching difficulties may be related to deficits in frontal executive functions, which are increasingly implicated in the pathophysiology of FOG.144;146 Third, increased anxiety may have contributed to the occurrence of FOG. In everyday life, patients report that FOG episodes may be elicited by anxiety and panic.227;316 The upcoming obstacle during treadmill walking may well increase anxiety. Indeed, one patient froze while merely anticipating the upcoming obstacle and two other patients only showed FOG during the practice trials. However, moderate stress, such as visiting a doctor, may also suppress FOG, which may partly explain the difficulty to elicit FOG in clinical practice.140;341 In this study, fear of falling, being harnessed and being forced to keep moving by the treadmill may all have contributed to the state of mind of our patients.

Fourth, obstacle avoidance may have caused FOG by interfering with the mechanically required motor output. Obstacles interfere with step amplitude, forcing the patient to take smaller steps, either to avoid the obstacle, or to regain stability after obstacle crossing (when an extra long step with a more forward movement was used to avoid the obstacle). A decrease in step length could provoke FOG via the presumed ‘sequence effect’, where a successive step-to-step amplitude reduction ultimately culminates in a motor block.76 In addition, gait rhythm is disturbed by the obstacle. Patients with FOG have a disturbed timing of gait, manifesting as an increased stride variability and phase fluctuations in between FOG episodes,4;168;306 as well as an uncontrolled timing of steps just before a FOG episode.288 Our finding that FOG can be provoked by interrupting step length and gait rhythm by a sudden obstacle

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suggests that these motor deficits might provoke FOG, and represent more than just ‘coincidental’ features of advanced disease.

A final explanation is supported by interesting recent work, showing that FOG may be regarded as a consequence of defective integration between preparatory balance adjustments and stepping movements.187;206 Obstacle avoidance likely requires extra balance adjustments (including lateral weight shifts) while the subject is forced to keep moving. This may particularly explain the FOG episodes occurring immediately after obstacle avoidance. 3 We should note that while we used sudden obstacles to provoke FOG, a small obstacle on the floor (such as an inverted walking stick) is commonly used by patients as an external cue to overcome FOG.207;316 One explanation for this apparent contradiction is the unpredictability and perceived consequence of the appearing obstacles. Unlike therapeutic cues, a sudden and unpredictable event needs more attentional resources, and may also lead to increased arousal or stress.

Several limitations of this study need to be mentioned. First, the current ‘gold standard’ of FOG, visual assessment of digitally videotaped gait performance, does not accommodate the crucial but subjective feeling of the feet becoming glued to the floor. Only the more severe FOG episodes on the treadmill indeed generated the feeling of ‘getting glued’. Hence, we cannot be sure whether we really observed FOG, or merely episodes that looked to experienced eyes very similar to FOG.

Second, we used a fixed speed of the treadmill of 2 km/h. As PD patients display abnormalities in the stride length-cadence relationship depending on the velocity,263 a variable treadmill velocity might have yielded more reliable results. However, to vary treadmill velocity depending on the overground individual velocity is not always feasible. For example, we noticed that the preferred overground individual velocity is often much higher than the preferred treadmill individual velocity. In addition, the optimal ‘individual speed’ in relation to preferred speed for eliciting FOG would still have to be determined. Introducing more experimental conditions might have caused more fatigue, and this could have affected the results. It would be interesting for future studies to evaluate which treadmill velocities are best able to provoke FOG in individual patients.

Third, the duration of FOG episodes was less on the treadmill compared to over-ground walking. This may be expected as the treadmill does not allow a major slowing since speed is constant. Obstacles and the treadmill itself could have acted as cues to overcome FOG and quickly ‘abort’ the episode.133 This may limit the ecological validity of this approach, as FOG is often defined as lasting at least one second.14 However,

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there is probably a spectrum of ‘ineffective stepping’ before this truly develops into a FOG episode that is recognisable for both patients and observers. Future detailed electrophysiological assessment of FOG may help to detect such subtle FOG episodes that currently escape the clinical eye.

We showed that the appearance of sudden obstacles can provoke brief FOG episodes during treadmill walking. This ability to provoke brief FOG episodes in a standardized environment, where it can be combined with e.g. kinematic measures, accelerometry, forceplates or electromyography, offers new opportunities to study the pathophysiology of FOG. Eventually, this may allow for development of an electrophysiological definition of FOG that could support clinicians in diagnosing or evaluating FOG.

Acknowledgements

This research was supported by the Prinses Beatrix Fonds and the Netherlands Organisation for Health Research and Development (Bastiaan R. Bloem by a VIDI research grant nr 016.076.352, Anke H. Snijders by an ‘MD-medical research trainee’ grant nr 92.003.490). We thank Roland Loeffen, Cristel van Wezenbeek and Charlotte Haaxma for their assistance.

Legend to the video’s

Video 1: A typical FOG episode evoked just after obstacle crossing Video 2: A typical FOG episode evoked between obstacle release and obstacle cross Video 3: A more severe FOG episode evoked by the threat of a coming obstacle, needing an emergency stop. Hereafter, the patient shows a very subtle FOG episode just before obstacle cross.

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103

3.4

Objective detection of subtle freezing of gait in Parkinson’s disease

Published as: Delval A, Snijders AH, Weerdesteyn V, Duysens JE, Defebre L, Giladi N, Bloem BR. Objective detection of subtle freezing of gait episodes in Parkinson’s disease. Mov Dis 2010; 25(11):1684-93. CHAPTER 3

Summary

Freezing of gait (FOG) is a clinically defined phenomenon of Parkinson’s disease (PD). Recent evidence suggests that subtle FOG episodes can be elicited in a gait laboratory using suddenly appearing obstacles during treadmill walking. We evaluated which quantitative gait parameters identify such subtle FOG episodes. We included 10 PD patients with FOG, 10 PD patients without FOG and 10 controls. Subjects walked on a motorised treadmill while avoiding unexpectedly appearing obstacles. Treadmill walking was videotaped, and FOG episodes were identified by two independent experts. Gait was also analysed using detailed kinematics. Knee joint signals were processed using time-frequency analysis with combinations of sliding Fast Fourier transform and wavelets transform. Twenty FOG episodes occurred during treadmill walking in five patients (all with clinically certified FOG), predominantly in relation to obstacle avoidance. FOG was brief when it occurred just before or after obstacle crossing and was characterised by short, rapid steps. Frequency analysis showed a typical qualitative pattern: before the FOG episode an increase in dominant frequency in the 0-3 Hz band (festination), followed by decreased power in 0-3 Hz band and an increased power in the 3-8 Hz band during the FOG episode. This pattern led to an increased FOG index as a qualitative measure. These approaches detected even very brief FOG with acceptable sensitivity (75-83%) and specificity (>95%). We conclude that time frequency analysis is an appropriate approach to detect brief and subtle FOG episodes. Future work will need to decide whether this approach can support or even replace expert clinical opinion.

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Introduction

Freezing of gait (FOG) is defined as an episodic inability to generate effective stepping.150 Typically, FOG episodes are brief (1–2 seconds) and are associated with a subjective feeling of “the feet being glued to the ground”.153 The ‘shuffling’ phenotype of FOG is frequently associated with festinating gait.151;181;329 Festination is often described as taking increasingly rapid and small steps during walking, but without the subjective feeling of “glueing”.44;61;151 Festination and FOG may represent complementary phenotypes along the same pathophysiological spectrum. 3 Several studies have attempted to characterize FOG. One approach concentrates on characterizing FOG using spatiotemporal kinematic parameters of gait. The period just before a FOG episode is characterised by an increased cadence, decreased stride length, decreased angular excursion of leg joints.285;288;366 Another approach is based on frequency analysis of leg movement. Normal gait is characterized by a narrow peak around 1 Hz (which corresponds to the frequency of stepping).164 Several studies found an abnormal peak in the 3-6 Hz band during FOG.118;164;366 This extra peak could be easily differentiated from increases in cadence during or before the FOG episode. In addition, evident FOG episodes of long duration show an increase in the 3-8 Hz band, as well a decrease in the 0.5-3 Hz band.256 Despite these promising findings, the question remains which of the previously identified factors (increased cadence, decreased step length, high frequency oscillations of the legs) are most relevant to detect FOG. A particular challenge is to identify very brief FOG episodes. It is often difficult to provoke FOG in either an experimental or clinical setting, and when FOG does occur it is often subtle.289;306 Freezing is a common cause of falls in PD.49;219 Detection of subtle FOG in patients would be relevant for daily life, not because the subtle freezing itself would necessarily lead to falls, but rather because these laboratory-evoked brief episodes might serve as a marker for more severe FOG. We have recently demonstrated that patients with clinically certified FOG can experience brief freezing episodes while walking on a motorised treadmill when subjects need to avoid suddenly appearing obstacles.345 In the present study, we have used this paradigm to provoke FOG. We investigated the use of an elaborate set of quantitative outcome measures to optimally detect even subtle signs of FOG.

Methods

Patients We included 10 patients with PD (according to the UK Brain Bank criteria) and an unambiguous previous history of FOG (Freezer group, mean age ± SD: 62.5 ± 6.5 years), 10 PD patients without any clinical evidence of FOG (Non-freezer group, mean

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age ± SD: 59.5 ± 7.5 years) and 10 healthy age-matched control subjects (Controls, mean age ± SD: 60.1 ± 6.0 years). All experiments were done in a practically defined ‘OFF-state’.217 Patients of the freezer group were defined as having at least subjective freezing, according to the FOG questionnaire item #3 (n=10) (median 10, 1st quartile (Q1) 8, 3rd quartile (Q3) 14)152; Eight patients also had overt FOG episodes while walking on a specific gait trajectory that included all known triggers for FOG.341 Disease severity according to the Hoehn and Yahr stage ranged between 2 and 3 (median 2.5, Q1 2, Q3 2.5) for freezers, and between 2 and 3 (median 2, Q1 2, Q3 2.4) for non-freezers. Median (Q1, Q3) UPDRS motor score in ‘OFF-state’ was 30 (22, 31.75) for freezers, 24 (21, 27.5) for non-freezers. Patients with cognitive impairment (MMSE score <24), other causes for gait disorders, major psychiatric disorders or severe co-morbidity were excluded.

Procedure Participants walked on a motorised treadmill used in previous experiments187 at a fixed speed of 2 km/h. To prevent subjects from falling, they wore a safety harness. A bridge with an electromagnet was placed over the front of the treadmill. The electromagnet suspended the obstacle (length 40 cm, width 30 cm, height 1.5 cm). Participants walked at a fixed and predetermined position on the treadmill, such that the most anterior position of the toes had a distance of approximately 100-150 cm (depending on the phase of the step cycle) to the obstacle prior to its release. Before the experimental procedure, a training phase of 10 min allowed subjects to become familiar with treadmill walking and with obstacle avoidance. The experimental procedure itself consisted of a maximum of 10-20 obstacle avoidance trials. The obstacle was dropped randomly after at least 10 strides. Subjects were specifically instructed not to touch the obstacle or step besides the obstacle with the crossing foot. A trial consisted of at least 5 strides before obstacle release, obstacle crossing and at least 5 strides after obstacle crossing.

Data analysis The entire experiment was recorded on videotape. The presence of FOG episodes (defined as an episodic inability to generate effective stepping150) was scored off-line by two independent experts in FOG (BR Bloem and N Giladi) who were blinded with respect to group allocation. Raters were asked to score gait before, during and after each obstacle clearance as either “definite FOG”, “possible (very brief) FOG” or “no FOG”. If only one expert identified an episode as “definite” FOG but the other expert scored this as “possible” FOG, or if both experts identified “possible FOG”, we asked a third rater (V Weerdesteyn) with expertise in obstacle avoidance to determine if the trial showed normal obstacle avoidance or not. If the trial was also considered as abnormal by this third observer, we then scored the event as a FOG episode.

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Detailed gait analyses was performed using 10 reflective markers that were attached to the heels, toes, ankles, shoulders, over vertebra T10, and to the obstacle. A 3D motion analysis system (VICON® video System, Oxford Metrics, Oxford, England)) recorded the marker positions at a sample rate of 100 Hz. In addition, knee angle trajectories were recorded using goniometers at a sample rate of 1000 Hz. This joint seemed particularly involved in freezing phenomenons.293 The analog signals were filtered by a low-pass filter of 10 Hz and differentiated. All measurements were determined using a MATLAB® (The Mathworks, Inc.) program. Spatio-temporal characteristics of gait are influenced by obstacle crossing. Therefore, 3 we separated FOG episodes that occurred without obstacle appearance, just before obstacle crossing (after release of the obstacle, defined as the pre-cross time window) or immediately after obstacle crossing (the first five steps after crossing, defined as post-cross time window) for the analysis. As kinematic parameters, we calculated the mean and minimum step amplitude and step duration for all time windows. We also computed decrease in step duration which is the maximum decrease in step duration in %: 100 - (100 * minimum step duration / mean step duration). Spectral analysis of the knee signal on the side of obstacle release (as both sides showed similar results) was first performed using Fast Fourier Transform for both the pre-cross and post-cross time windows (Figure 1). From this time frequency analysis we calculated the frequency ratio which is the ratio of the maximum power peak in the 3-8 Hz band, divided by maximum power peak in 0-3 Hz band, for the time interval in question (Figure 1). Second, we wanted to describe the temporal course of the changes in frequency, in order to better understand the relationship between festination and FOG. In secondary qualitative analyses, in order to detect very brief, transient event-related spectral perturbations, we used open source software, namely EEGlab.237 For this purpose we performed time/frequency analyses using sliding windowed Fast Fourier Transform. The window size was 4.1 s at all frequencies between 0 and 8 Hz.92 We also performed the sinusoidal wavelet transform in which the data window length depends inversely on the frequency in order to obtain a better compromise between time changes and frequency changes.333 Indeed, resolution in time to detect changes in frequency power was improved with this latter method. We used visual evaluation on these trials to describe the temporal course of the changes in power for the different frequencies that occurred before or after obstacle. We compared them to the frequency pattern found in unequivocal FOG episodes of longer duration during unobstructed gait on the treadmill. (see Figure 2 for description).

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Figure 1 Fast Fourier Transform (FFT) in the post-cross time window

Trial without freezing of gait (FOG) episode. See the main dominant frequency at 1.2 Hz that corresponds to the stride frequency. The ratio 3-8 Hz/0-3 Hz corresponds to the ratio of the maximum power peak in 3-8 Hz band, divided by the maximum power peak in 0-3 Hz band. Trial with a clear FOG episode. See the decrease in power frequencies in the 0-3 Hz band and the increase in the 3-8 Hz band.

Figure 2 Sliding Fast Fourier transform (FFT) and wavelets transform of:

A. Normal obstacle crossing in a PD patient. OR: obstacle release, cross: moment when the toe marker of the crossing leg reaches the obstacle. 1. Increase in power of the very low frequencies due to the crossing. ERSP: event-related spectral perturbation, corresponding to event-related shifts in the power spectrum.

110 OBJECTIVE DETECTION OF SUBTLE FREEZING OF GAIT IN PARKINSON’S DISEASE

Figure 2 Sliding Fast Fourier transform (FFT) and wavelets transform of:

B. FOG episode occurring before obstacle release in a PD patient. The pattern of increased power of the dominant frequencies in the 0-3 Hz band (stride and step frequencies) corresponds to festinating gait (1), which precedes the increased power in the 3-8 Hz band (2) (associated with the decrease in power in the 0-3 Hz band (3)) during the actual FOG episode.

Statistical analyses The blinded clinical judgement of the videotapes by the two independent raters was considered as the gold standard for presence of FOG episodes. First, ROC curves were drawn, to differentiate trials with FOG from other trials. We then calculated the threshold for each relevant parameter to determine its ability in identifying FOG episodes. Correlations between relevant parameters and the FOG Questionnaire were also calculated (Spearman test). In addition, we compared trials with FOG and trials without FOG using ANOVA with one factor, accepting p < 0.05 as significance level for all groups. Comparisons between four groups were then assessed using Tukey’s test with correction for multiple comparisons (p < 0.01). For the detection of the ultimate parameter, we were interested in those parameters that showed a difference between FOG trials in freezers and all other groups, including trials of freezers that did not show FOG. In other words, we wished to identify variables that were capable of detecting strictly FOG episodes, and not just the differences in baseline hypokinesia or bradykinesia that might be present between freezers, non-freezers and controls. Statistical analyses were performed using SPSS 13 (©SPSS Inc.) software.

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Results

We recorded 90 trials in controls and 96 trials in non-freezers, none of which were clinically rated as showing FOG. We recorded 130 trials in PD patients of the freezer group. In this group, 20 FOG episodes occurred according to the raters. Eight of the episodes occurred in the pre-cross time window, eight immediately after obstacle crossing and four during unobstructed gait (in anticipation of obstacle release). The duration of the FOG episodes during obstacle avoidance (pre and post OR) was brief, less than 1 second and did not necessitate emergency stops. The ROC curves revealed that Fast Fourier Transform and decrease in step duration or amplitude were good predictors of the occurrence of a FOG with an area under the curve (AUC) or 1-AUC > 0.8 (Figure 3; Table 1). A threshold was determined for all variables (Table 1, Figure 4).The group results are graphically illustrated in Figure 4 for the pre-cross window. There was no difference in outcome of gait parameters between FOG episodes rated as ‘possible (very brief)’ or as ‘clear’ FOG by the raters. Post-hoc analyses showed there was a clear difference between trials with FOG and trials without FOG of all three groups (trials of freezers where no FOG occurred, non-freezer trials, control trials) for decrease in step duration (% baseline), minimum step length and ratio 3-8/0-3 Hz (Table 1). In addition, there were no differences between the trials of the freezers where no FOG occurred, the non-freezer trials or control trials for these 3 variables. That makes them more interesting than other variables in detecting strictly FOG episodes and not differences in baseline hypokinesia or bradykinesia between freezers, non-freezers and controls. Ratio in the pre cross time window in all trials was weakly correlated with the FOG Questionnaire (r = 0.17, p < 0.05) in the freezer group.

Qualitative time-frequency transforms of the knee joint angles Sliding Fast Fourier Transform and wavelet analysis showed significant changes in frequency with an increase in frequency power in the 3-8 Hz band during the four clear FOG episodes during unobstructed gait. The FOG phenomenon is associated with a typical Frequency pattern, with initially an increased main frequency in the 0-3 Hz band, corresponding to an increase in stepping frequency (what would be called festinating gait), and subsequently with a decreased power in the 0-3 Hz band (the motor block) with an increase in frequencies in the 3-8 Hz band (probably reflecting the attempt to overcome the block) (Figure 2). Festination could occur either in isolation or in association with FOG (as defined by the clinical observers). This is illustrated in Figure 5. We next examined whether this typical Frequency pattern would help in identifying less obvious FOG periods (duration < 1 second) just before or after obstacle avoidance. The pattern was seen in all trials with FOG episodes. However, this pattern was also present in 5.4% of trials of freezers where no FOG

112 OBJECTIVE DETECTION OF SUBTLE FREEZING OF GAIT IN PARKINSON’S DISEASE

episode occurred, although only in patients who did present clear FOG episodes during other trials of the experiment. It was present in none of the trials of non-freezers, but in one trial of the control subjects.

Table 1 Validity of the parameters

PRE CROSS variabels Mean SD AUC Cut-off Sens Spec ANOVA: Post-Hoc F, p Tukey, p 3 Decrease in step duration (%) Freezer-FOG 55.4 31.8 0.87 48 0.75 0.95 11.8*** 1≠2***,3***,4*** Freezer-no FOG 16.2 25.1 2≠1***

Non-freezer 10.0 16.6 3≠1***

Controls 11.1 20.2 4≠1***

Ratio 3-8/0-3 Hz Freezer-FOG 0.77 0.84 0.96 0.21 0.88 0.97 35.3*** 1≠2***,3***,4*** Freezer-no FOG 0.12 0.24 2≠1*** Non-freezer 0.04 0.04 3≠1*** Controls 0.04 0.04 4≠1***

Mean step duration (cs) before OR (at least 5 unperturbed strides) Freezer-FOG 45 16 0.07 65 0.79 0.87 50.7*** 1≠2***,3***,4*** Freezer-no FOG 66 13 (1-AUC=0,93) 2≠1***,3***,4***

Non-freezer 72 10 3≠1***,2***,4***

Controls 82 6 4≠1***,2***,3***

Mean step duration (cs) between OR and OC Freezer-FOG 39 15 0.05 65 0.75 0.87 35.1*** 1≠2***,3***,4*** Freezer-no FOG 66 16 (1-AUC= 0,95) 2≠1***,3*,4***

Non-freezer 72 11 3≠1***,2*,4***

Controls 80 10 4≠1***,2***,3***

Minimum step duration (cs) between OR and OC Freezer-FOG 24 20 0.08 42 0.9 0.87 24.7*** 1≠2***,3***,4*** Freezer-no FOG 58 19 (1-AUC= 0.92) 2≠1***,3*,4***

Non-freezer 65 16 3≠1***,2*,4*

Controls 73 17 4≠1***,2***,3*

113 CHAPTER 3

Table 1 Continued

PRE CROSS variabels Mean SD AUC Cut-off Sens Spec ANOVA: Post-Hoc F, p Tukey, p Mean step distance (mm) before OR Freezer-FOG 230 106 0.09 357 0.75 0.87 50.6*** 1≠2***,3***,4*** Freezer-no FOG 352 78 (1-AUC= 0.91) 2≠1***,3***,4***

Non-freezer 395 54 3≠1***,2***,4***

Controls 443 34 4≠1***,2***,3***

Mean step distance (mm) between OR and OC Freezer-FOG 187 70 0.03 276 0.9 1 27.1*** 1≠2***,3***,4*** Freezer-no FOG 358 94 (1-AUC= 0,97) 2≠1***,4*** Non-freezer 384 84 3≠1***,4*** Controls 435 74 4≠1***,2***,3** Minimum step distance (mm) between OR and OC (at least five unperturbed strides) Freezer-FOG 12 125 0.09 141 0.82 0.87 7.5*** 1≠2**,3**,4*** Freezer-no FOG 266 153 (1-AUC= 0.91) 2≠1**

Non-freezer 283 172 3≠1**

Controls 325 223 4≠1***

POST CROSS variables Decrease in step duration (%) Freezer-FOG 51.5 22.9 0.86 43 0.83 0.95 9.1*** 1≠2***,3***,4*** Freezer-no FOG 9.1 25.2 2≠1*** Non-freezer 12.4 11.8 3≠1*** Controls 10.9 19.7 4≠1***

Ratio 3-8/0-3 Hz Freezer-FOG 1.15 1.97 0.98 0.39 0.83 0.98 26.8*** 1≠2***,3***,4*** Freezer-no FOG 0.12 0.17 2≠1***

Non-freezer 0.05 0.04 3≠1*** Controls 0.05 0.03 4≠1***

Minimum step duration (cs) 5 steps after OC Freezer-FOG 15 12 0.02 40 0.95 1 42.5*** 1≠2***,3***,4*** Freezer-no FOG 58 15 (1-AUC= 0.98) 2≠1***,4***

Non-freezer 62 10 3≠1***,4***

Controls 72 14 4≠1***,2***,3***

114 OBJECTIVE DETECTION OF SUBTLE FREEZING OF GAIT IN PARKINSON’S DISEASE

Table 1 Continued

POST CROSS variables Mean SD AUC Cut-off Sens Spec ANOVA: Post-Hoc F, p Tukey, p Minimum step distance (mm) 5 steps after OC Freezer-FOG -86 141 0.05 120 0.89 1 7.0*** 1≠2**,3**,4*** Freezer-no FOG 249 107 (1-AUC= 0.95) 2≠1**

Non-freezer 236 156 3≠1** 3 Controls 289 286 4≠1***

OR: obstacle release; OC: obstacle cross. * <0.05, **<0.01, ***<0.001. SD = Standard deviation; AUC = area under the curve. Sens = Sensitivity; Spec = Specificity; Freezer-FOG = Freezer group, trials with FOG; Freezer-no FOG = Freezer group, trials without FOG.

Figure 3 ROC curve representing the sensitivity and 1-specificity in detecting FOG episodes for decrease in step time (% baseline), ratio 3-8/0-3 Hz, mean and minimum value of step duration and distance between obstacle release (OR) and obstacle cross (OC), mean value of step duration and distance before OR in the pre-cross window (similar results in the post-cross time window).

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Figure 4 Decrease in step duration (% of baseline) and ratio 3-8 Hz/0-3 Hz in the four populations (8 trials with FOG in the Freezer group; 122 trials without FOG in the Freezer group, 96 trials of Non freezer group; and 90 trials of controls) in the pre-cross time window (results similar in the post-cross time-window)

Top Figure, right: for decrease in step duration, rate of false positives in the ‘Freezer group, trials without FOG group’ was 5.7%; rate of false positives in the ‘Non freezer group’ was 2.1%, rate of false positives in the ‘Controls’ group was 3.3%. Top Figure, left: for Ratio 3-8/0-3 Hz, rate of false positives in the ‘Freezer group, trials without FOG group’ was 5.7%; rate of false positives in the ‘Non freezer group’ was 0%, rate of false positives in the ‘Controls’ group was 0%. Bottom Figure, Y axis: Mean ± 1.96 standard error. See the more important decrease in step duration and increase in frequency ratio in case of trials with FOG.

116 OBJECTIVE DETECTION OF SUBTLE FREEZING OF GAIT IN PARKINSON’S DISEASE

Figure 5 Sliding FFT and wavelets transform of a FOG episode. A pattern of increase in the dominant frequency in the 0-3 Hz band (at 6 s) corresponding to festinating gait (FSG) precedes another similar pattern (at 9 s) that leads to a FOG episode

It is difficult to differentiate the first pattern of changes in frequency corresponding to festination alone with the second (festination + FOG episode). 3

Discussion

We have demonstrated that the occurrence of high frequencies in a biomechanical gait signal or a marked reduction in step duration and amplitude can detect even very brief FOG episodes, with acceptable sensitivity (75-88%) and specificity (>95%). The link between a decrease in step length and FOG is in keeping with recent work.76 Qualitative frequency analysis showed a decreased power in the 0-3 Hz band and an increased power in the 3-8 Hz band (representing the actual FOG episode with the motor block and the attempt to overcome the block). We were able to predict more than 83% of all subtle FOG periods using knee goniometer data. A study using accelerometer data, had a similar prediction percentage of 78.256 These patients experienced long, severe FOG episodes (mean around 20 seconds),256 while our study focused on much subtler episodes of < 1 second duration. This difference is likely explained by the fact that the PD patients in

117 CHAPTER 3

our study were less severely impaired compared to previous studies.164;256;288 In addition, the treadmill and the obstacles may have acted as cues to overcome the episode.133 The detection of a FOG episode was quite specific. None of the controls or PD patients without FOG history had a ratio up to the threshold for neither time interval. The first question that arises is whether the current methods detected FOG episodes or merely festinating steps. We found the occurrence of abnormal frequencies in the 3-8 Hz band to be highly sensitive and specific for detection FOG. However, such high frequencies are not completely specific because these may also occur during festinating gait without FOG.256 Moore et al differentiated festination from FOG, noting a clear decrease in frequencies < 3 Hz before a FOG episode that was not present during festination without FOG. Our data suggest that it is possible to visualize festination, both with and without FOG (Figure 5). However, it is often difficult to distinguish festinating steps that occur before FOG from pure festination without subsequent FOG. For example, Nieuwboer and colleagues288 found no differences in spatiotemporal parameters of pre-freezing and festinating steps. We should note that some of our non-freezers present a clear decrease in step duration (false positives) without any change in frequency ratio. This may correspond to isolated festination. Iansek and colleagues181 have postulated that FOG is the consequence of a “sequence effect” (inability to maintain a predefined movement amplitude and movement timing) that is superimposed on gait hypokinesia, and consequently that FOG will not occur in the absence of festination. Our current qualitative analyses using sliding Fast Fourier Transform and wavelet analysis clearly describe a characteristic frequency pattern. These findings would suggest that festination and FOG phenomenon are linked phenomena. Indeed, our Frequency Pattern was observed in both festination that does not lead to a recognisable FOG episode and in FOG. Possibly, these high frequencies in freezers without an overt FOG episode do reflect pathology and perhaps even herald FOG that currently escapes both the clinical eye and the sensation of the patient. A spectrum may exist from festination leading to FOG, all characterised by the same characteristic Frequency Pattern. Sometimes, the patient will be able to overcome the FOG episode before it even becomes recognisable. Our findings support the hypothesis that FOG is not an isolated phenomenon that appears randomly.181 Indeed, the appearance of an obstacle induces a need to adjust the step in order to facilitate an optimal crossing,381 and in case of PD patients, this process of step adjustment may culminate in festination or even overt FOG. This is in agreement with a recent study76 that provoked FOG by asking the patients to walk with increasingly shorter steps. Moreover, FOG can also be elicited when patients are placed under considerable strain like extreme imposed step duration by a metronome.257 It would also fit with another hypothesis,187 that it is the inability to

118 OBJECTIVE DETECTION OF SUBTLE FREEZING OF GAIT IN PARKINSON’S DISEASE

generate correct anticipatory postural adjustments prior to the step that is responsible for provocation of FOG. Another explanation could be withdrawing of attention because of the noise of the obstacle. However, this cannot explain the FOG episodes that occur just after the crossing of the obstacle. A limitation of this study is that we did not study “real life” FOG, but instead focused on an admittedly artificial form of “freezing” that occurred while subjects were walking on a motorised treadmill with a similar speed for all subjects. However, controls still showed a regular gait pattern and were still able to use big steps, in comparison to the small steps seen in PD. We should point out that treadmill walking 3 also presents obvious advantages (better control of speed; possibility to introduce FOG-eliciting methods; and availability of detailed electrophysiological gait analysis). The phenotype on the treadmill looked remarkably like “real” FOG. and there was a high rate of agreement.344 In addition, the longer FOG episodes that occurred during unobstructed gait on the treadmill showed the same Frequency Pattern. Hence, we assume that the subtle episodes we provoked are indeed similar to subtle episodes that frequently occur in daily life.

Future perspectives This study provides ‘proof of concept’ that even subtle FOG episodes can be detected using frequency analysis, and thereby opens several new perspectives. More work is now needed in larger groups of ambulatory patients to determine if this approach can be used as a screening test for “real life” FOG and for risk of falls.. Future work will also need to establish whether these new methods are a valuable addition to clinical screening. Indeed, the ‘gold standard’ of clinical rating is possibly not sensitive enough, as very brief and subtle FOG episodes may well escape even an experienced clinical eye, particularly in a clinical setting when FOG is often paradoxically suppressed.

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Understanding freezing of gait

Video vignette 2

Based on animal studies and open label studies, the pedunculopontine nucleus has been proposed as a promising new target for deep brain stimulation, specifically directed at improving gait.299 However, double blind studies have failed to live up to these expectations.122;261 Video vignette 2A and 2B show two patients with Parkinson’s disease who received pedunculopontine nucleus stimulation (4 years after subthalamic nucleus stimulation).122 In video vignette 2A, surgery did not have any effect on FOG (woman, age 68 years, disease duration 18 years, location contact relative to pontomesencephalic line: 6.7, 9.5, 0.8). In contrast, video vignette 2B shows a patient with a remarkable response of his FOG on pedunculopontine nucleus stimulation (man, age 68 years, disease duration 13 years, location contact 5.3, 8.7, 1.5). Interestingly, the electrodes of both patients were located posterior to the pedunculopontine nucleus.122

I’m thankful to Muriel Ferraye and Bettina Debu for the use these videos.

4.1

Gait-related cerebral changes in freezing of gait

Published as: Snijders AH, Leunissen HP, Bakker M, Helmich RCG, Bloem BR, Toni I. Gait-related cerebral alterations in Parkinson patients with freezing of gait. Brain 2011. 134:59-72. CHAPTER 4

Summary

Freezing of gait is a common, debilitating feature of Parkinson’s disease. We have studied gait planning in patients with freezing of gait, using motor imagery of walking in combination with fMRI. This approach exploits the large neural overlap that exists between planning and imagining a movement. In addition, it avoids the confounds introduced by brain responses to altered motor performance and somatosensory feedback during actual freezing episodes. We included 24 patients with Parkinson’s disease [12 patients with freezing of gait (‘freezers’), 12 matched patients without freezing of gait (‘non-freezers’)] and 21 matched healthy controls. Subjects performed two previously validated tasks: motor imagery of gait, and a visual imagery control task. During fMRI scanning, we quantified imagery performance by measuring the time required to imagine walking on paths of different width and length. In addition, we used voxel-based morphometry to test whether between-group differences in imagery-related activity were related to structural differences. Imagery times indicated that freezers, non-freezers, and controls engaged in motor imagery of gait, with matched task performance. During motor imagery of gait, freezers showed more activity than non-freezers in the mesencephalic locomotor region. Freezers also tended to have decreased responses in mesial frontal and posterior parietal regions. Furthermore, freezers had grey matter atrophy in a small portion of the mesencephalic locomotor region. The gait-related hyperactivity of the mesencephalic locomotor region correlated with clinical parameters (freezing of gait severity and disease duration), but not with the degree of atrophy. These results indicate that Parkinson’s disease patients with freezing of gait have structural and functional alterations in the mesencephalic locomotor region. We suggest that freezing of gait might emerge when altered cortical control of gait is combined with a limited ability of the mesencephalic locomotor region to react to that alteration. These limitations might become particularly evident during challenging events that require precise regulation of step length and gait timing, such as turning or initiating walking, which are known triggers for freezing of gait.

124 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

Introduction

Freezing of gait (FOG) is an episodic gait disorder during which the feet appear ‘glued to the floor’.49 The pathophysiology underlying FOG remains largely unknown. Behavioural studies have identified several gait alterations in Parkinson’s disease (PD) patients with FOG (“freezers”), even when the patient is not experiencing an actual FOG episode. Alterations include premature timing of muscle activations,289 increased variability of gait,168 increased temporal gait asymmetry,307 and faulty generation of postural adjustments before step initiation.186 A recent paper suggested that FOG may be caused by a failure to generate adequate amplitudes for the intended movement. This will lead to a progressive reduction of step size that may culminate into a FOG event.76 This so-called sequence effect could result from defective stride length amplitude setting by the supplementary motor area and its maintenance by the basal ganglia, leading to a mismatch between intention and automation.76 However, empirical tests of this hypothesis are difficult, because most non-invasive 4 neuroimaging methods are not suitable for assessing gait.30 Some experimental approaches can bypass these difficulties, allowing researchers to study the cerebral correlates of FOG.37;114;213;246 One possibility is to focus on the planning phase of walking movements, rather than the manifestation of actual FOG episodes. Motor imagery (asking subjects to imagine a particular movement) exploits the large functional and neural overlap between motor planning and imagery of a movement.77;193;251 Imagining a movement is sensitive to motor control variables,138 it is contingent on the current physical configuration of the subject,89;282 and it relies on neural processes similar to those evoked during performance and planning of the same movement.213;352 We have recently shown that motor imagery of gait follows similar motor constraints as actual walking.29 Accordingly, motor imagery of gait has been used repeatedly to study human walking using fMRI28;213 or PET.239 Although motor imagery of gait is likely to engage only a portion of the cerebral circuits controlling walking, it has several advantages for investigating FOG. First, motor imagery provides opportunities for studying alterations in the planning of gait, which may be a crucial element in FOG pathophysiology.76;187 Second, meaningful cerebral comparisons between patients and controls require matched behavioural performance.311 This condition can be met with motor imagery of gait, whereas real motor performance will often differ between patients and controls. Third, motor imagery of gait allows us to isolate cerebral responses related to walking, distinct from alterations in motor performance and somatosensory feedback produced by actual FOG episodes.12 Accordingly, we used motor imagery of gait in combination with fMRI to study the cerebral correlates of gait planning in patients with and without FOG. Stimulated by current hypotheses concerning FOG pathophysiology – which mainly deal with

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deficits in regulating step length and gait timing76;307 – we also included a behavioural control experiment where actual gait was electrophysiologically quantified. Finally, we used voxel-based morphometry to assess whether between-group differences in imagery-related activity were related to structural differences.

Methods

Subjects We included 25 patients with PD, 13 freezers and 12 non-freezers who were matched for disease severity and duration (Table 1 – one freezer was excluded from the analyses due to his inability to engage in imagery, see below). Patients were diagnosed according to the UK Brain Bank criteria.178 All patients except one used dopaminergic medication (levodopa or dopamine-agonists). Patients were examined in the morning, at least 12 hours after intake of the last dose of antiparkinson medication. Disease severity was assessed using the Hoehn & Yahr stages and Unified Parkinson’s Disease Rating Scale (UPDRS). Patients with marked resting tremor were excluded. In the remaining patients, we carefully controlled for tremor influences on scanning results by recording electromyography (see below). Twenty-one healthy volunteers, matched for age and gender, served as controls (Table 1). Freezers were identified based on three criteria: (1) convincing subjective reports of FOG, based on consistent and characteristic accounts of the phenomenon (including the typical feeling of the feet being glued to the floor); (2) patient’s recognition of typical phenotype when this was demonstrated to them by an experienced clinician, or using the New Freezing of Gait Questionnaire (NFOG-Q) video.291 In addition, a standardized and videotaped gait trajectory was performed containing specific elements known to provoke FOG.341 These videos were rated off-line for the presence of FOG by two different experts. Nine of the 12 freezers (75%) also showed FOG during physical examination. None of the non-freezers experienced subjective freezing, recognized the phenotype when this was demonstrated to them, or manifested freezing during physical examination. The median NFOG-Q score291 for freezers was 12.4, range 5-27. The score for non-freezers was 0.

All subjects were right-handed according to the Edinburg Handedness Inventory, had no cognitive dysfunction (Mini-Mental State Examination > 24, Frontal Assessment Battery > 13), and no vestibular, orthopaedic, neurological or psychiatric diseases. Before participation, subjects received the (unrevised) Vividness of Motor Imagery Questionnaire (VIMQ)183 to screen for ability to perform motor imagery. When a subject was unable to perform motor imagery (VIMQ score >200), the subject was excluded (one freezer with a score of 240). Patients and controls were equally able to

126 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

Table 1 Clinical characteristics

Parameter Group N Mean SD P-value Gender Patients 24 9F / 15M 0.18 Controls 21 9F / 12M Freezers 12 4F / 8M 0.22 Non-Freezers 12 5F / 7M Age (years) Patients 24 60.2 8.9 0.25 Controls 21 57.0 9.1 Freezers 12 58.7 9.0 0.20 Non-Freezers 12 62.6 7.1 Disease duration Freezers 12 9.8 4.6 0.10 Non-Freezers 12 7.1 3.0 UPDRS III Freezers 12 34.6 9.6 0.20 Non-Freezers 12 28.6 12.2 FAB Freezers 12 16.5 1.4 0.22 Non-Freezers 12 17.1 0.8 4 H&Y = Hoehn and Yahr Rating Scale; UPDRS III = Unified Parkinson’s Disease Rating Scale part 3; FAB = Frontal Assessment Battery; M = Male; F = Female. Statistical inferences are based on independent samples t-test (Chi-squared test for Gender).

perform motor imagery (one-way ANOVA, effect of group: F(2,41) = 1.4, p = 0.24), with scores comparable to age-matched healthy subjects.268 The study was approved by the local ethics committee, and written informed consent was obtained from all subjects prior to the experiment according to the Declaration of Helsinki.

Tasks We used a behaviourally validated protocol29 used in a previous fMRI study in young healthy subjects.28 Briefly, subjects performed two tasks: motor imagery of gait (MI), during which they had to imagine walking along a path, and a matched visual imagery control task (VI), during which they imagined seeing a disc moving along the path (Figure 1). Subjects were presented with a picture of a path with a target placed on it. They were asked to either imagine themselves walking towards the target (MI), or to imagine a disc moving towards the target (VI). During both tasks, the motion-relevant portion of the path could have two different widths (narrow, broad) and five different distances (2, 4, 6, 8, and 10 m). These manipulations allowed us to monitor the subject’s ability to perform motor imagery in the scanner.28 Specifically, imagery times for both MI and VI should vary with alterations in path length. Furthermore, only MI times should be susceptible to path width alterations, because a narrow path requires precision gait. Conversely, the VI task (a moving disc) should not be influenced by path width.28 The MI and VI tasks were performed in two successive sessions of 25

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minutes each, separated by a break outside the scanner. The order of the sessions was counterbalanced across subjects. To control for actual movements related to tremor or overt leg movements, muscle activity from the forearm and lower leg was measured during the fMRI experiment. For further details, see the supplementary material directly after this chapter. After the imagery sessions, we tested subjects’ actual walking along the same paths as displayed during the imagery session. Performance on each of the 10 experimental conditions (2 different path widths over 5 different distances) was sampled once, recording the actual walking time with a stopwatch. These measurements served to confirm the relationship between imagined and actual walking performance.29

Figure 1 Task setup

A) Examples of photographs of walking trajectories presented to the subjects during motor imagery (MI), and visual imagery (VI) experiments. The photographs show a corridor with a white path in the middle and a green pillar positioned on the path. During MI trials, a green square is present at the beginning of the path. During VI trials, a black disc is present at the beginning of the path. During both tasks, the path width can be either broad, or narrow. In addition, the green pillar can be positioned at 2, 4, 6, 8 or 10 m from the start marker (2 m is presented in the photos of this figure). B) Time course of motor imagery trials. During each trial, after a short inspection of the photo on display, the subjects closed their eyes and imagined standing on the left side of the path, next to the green square. The subjects were asked to press a button with the index finger of their left or right hand to signal that they had started imagining stepping onto the path and walking along the path. The subjects were also asked to press the button again when they imagined having reached the end of the walking trajectory. Following the second button press, a fixation cross was presented on the screen and the subjects could open their eyes. The duration of the inter-trial interval (ITI) was 4-12 s. A Visual Imagery Motor Imagery

Stimulus

Task 1) Inspect picture 2) Close eyes Imagine walking Open eyes 3) Imagine standing

trial n trial n+1 Time Imagery time ITI (4-12 s)

128 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

Behavioural analysis We objectively monitored task performance by testing whether imagery times were modulated by the width and length of the path presented to the subjects. For each trial, imagery time was defined as the time between the button presses indicating the onset and offset of imagery. Trials in which subjects failed to press the button (either at the onset or offset of the imagery phase) were excluded from analyses (freezers mean [range]: 1.1 [0 to 4] trials; non-freezers: 0.5 [0 to 3] trials; controls: 0.5 [0 to 5] trials). Afterwards, the standard deviation (SD) of the mean picture inspection duration and imagery time was computed. Trials outside the mean ± 3 SD range were considered outliers and removed (freezers mean [range]: 1.2 [0 to 3] trials; non-freezers: 0.6 [0 to 2] trials; controls: 0.8 [0 to 2] trials). We considered the effect of “Group” (analysis 1: patients versus controls; analysis 2: freezers versus non-freezers), “Task” (MI, VI), “Path Width” (narrow, broad) and “Path Length” (2, 4, 6, 8, 10 m) on imagery time. The significance of the experimental factors was tested within the framework of the General Linear Model using two 2x2x2x5 4 mixed-effects ANOVAs. When interactions were significant, the simple main effects were investigated by additional ANOVA’s. The alpha-level of all behavioural analyses was set at p < 0.05. In a separate analysis, we used Spearman’s correlation to assess the relationship between actual walking times and mean imagery times across the different experimental conditions for patients and controls.

Pre-processing of imaging data Functional data were pre-processed and analyzed with SPM5 (Statistical Parametric Mapping, www.fil.ion.ucl.ac.uk/spm). Details on MR images pre-processing can be found in the supplementary material directly after this chapter.

Statistical analysis of imaging data – first level The ensuing pre-processed fMRI time series were analyzed on a subject-by-subject basis using an event-related approach in the context of the General Linear Model.136 The model was aimed at finding regions in which the cerebral response changed as a function of “Task” (MI, VI) and/or “Path Width”. “Path Length” was also considered in the analysis, which gave rise to a model with twenty different regressors of interest. The model also included separate regressors of no interest, modelling BOLD activity evoked by picture inspection, button presses, and incorrect trials, separately for each session. Further details can be found in the supplementary material.

Statistical analysis of imaging data – second level We report the results of a random effects analysis. The statistical significance of the estimated evoked haemodynamic response was assessed using t-statistics in the context of the General Linear Model. For each subject, four contrast images (MI-broad,

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MI-narrow, VI-broad and VI-narrow) were calculated and entered into a second level random effects analysis. Analogously to the analysis of the behavioural data, we considered two analyses: Analysis 1 compared controls (c) with patients (p); analysis 2 compared freezers (f) with non-freezers (nf). First, we identified the cerebral correlates of motor imagery of gait within each group, searching for brain responses that were larger for MI than for VI [analysis 1: cMI>cVI, pMI>pVI; analysis 2: nfMI>nfVI, fMI>fVI ]. Second, we identified regions where task-related activity differed between groups, assessing the “Group*Task” interaction [analysis 1: (cMI>cVI) > (pMI>pVI), (pMI>pVI) > (cMI>cVI); analysis 2: (fMI>fVI) > (nfMI>nfVI) , (nfMI>nfVI) > (fMI>fVI)]. Third, we looked for the shared effects (across groups) of environmental constraints (i.e. “Path Width”) on MI-related activity, searching for brain responses that were larger during imagined walking on a narrow path than during imagined walking on a broad path [analysis 1: cMI-narrow>cMI- broad, pMI-narrow>pMI-broad; analysis 2: nfMI-narrow>nfMI-broad, fMI-narrow>fMI- broad]. Fourth, we assessed differential effects of “Path Width” between groups, looking at the “Group*Path Width” interaction. Statistical inference (p < 0.05) was performed at the cluster-level, correcting for multiple comparisons over the search volume (i.e. the whole brain) using family-wise error, given an intensity threshold of t > 3.4.135

Region of interest analysis Besides whole brain analyses, statistical inference was also performed on regions of interest that were based on our previous study in healthy controls28 (see supplementary material for nomenclature and stereotactic coordinates of regions of interest). More precisely, we considered the local maxima of the clusters that were previously found to be significantly activated in the following contrasts: 1) “MI>VI” for the analyses considering the effects of “Task” and “Group” described above; and 2) “MI-narrow>MI- broad” for the analyses considering the effects of “Path Width” and “Group”. More specifically, we drew spherical region of interests centred at these coordinates with a radius of 8 mm. Statistical inference was performed at the voxel-level, with a family-wise error correction for multiple comparisons (p < 0.05).

Gait assessment In a separate behavioural experiment, gait characteristics were measured with an electronic pressure-sensitive walkway (GAITRite, CIR Systems Inc, USA). This system consists of a 4.6 m long walkway, containing six sensor pads encapsulated in a roll-up carpet to produce an active area 61 cm wide and 366 cm long. This system captures the geometry and relative arrangement of each footfall as a function of time, and can detect gait alterations that are typical for PD.12 Subjects were asked to walk at their normal speed. This procedure was repeated three times. We compared normalized

130 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

step length (step length/leg length) and gait asymmetry (natural logarithm (LN) of the difference in the swing time of the slowest and swing time of fastest foot) between freezers, non-freezers and controls using univariate ANOVA and post-hoc independent sample t-tests.

Brain-disease, brain-behaviour, and structural-functional relationships We tested whether the activity related to motor imagery of gait was correlated with clinical characteristics (disease severity, disease duration, and freezing severity). We considered the significant between-groups effects obtained in the second level analysis of the imaging data, and correlated subject-specific beta values (relative to the contrast motor imagery minus visual imagery) with the UPDRS score, disease duration, and NFOG-Q score, using Pearson’s correlation with an alpha-level set at p<0.05. We took part 2 of the NFOG-Q score, looking at severity of FOG. We also examined whether the activity in motor-imagery related areas was correlated to the kinematic characteristics of gait movements, and whether this effect was 4 different between the three groups. We only considered effects that were robust to the removal of potential outliers (Z-score above/below 2.5 units). We considered the significant between-groups effects obtained in the second level analysis of the imaging data, and we used a generalized linear model with subject-specific beta values (relative to the contrast motor imagery minus visual imagery) as a dependent variable, fixed factor of ‘group’ and the gait parameters as covariates. The generalized linear model uses the Wald statistic with chi-square distribution, to be able to compute the individual contribution of predictors.125 If a significant effect (p < 0.05) was found, post hoc univariate ANOVA was performed on the different groups with the gait parameter as a covariate. In addition, we evaluated whether the between-group differences in imagery-related activity was associated with structural differences, performing a voxel-based morphometry analysis.22 We tested whether there were between-groups differences in grey matter, white matter, or cerebral spinal fluid volume (CSF) (analysis 1: Controls versus patients; analysis 2: Freezers versus non-freezers). We assessed regional differences, as well as differences over regions of interest based on the results of the whole brain fMRI analyses (mesencephalic locomotor region, Table 3), testing for the relevance of structural differences by correlating them to the magnitude of the functional differences (i.e., beta weigths for the MI vs VI contrast). Statistical inference was performed at the voxel level, with a family-wise error correction for multiple comparisons (p < 0.05). For further details on the voxel-based morphometry analysis, see the supplementary material.

Anatomical inference Anatomical details of significant signal changes were obtained by superimposing the statistical parametric maps (SPMs) on the anatomical sections of a representative

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subject of the MNI series. The atlas of Duvernoy was used to identify relevant anatomical landmarks.106 The SPM Anatomy Toolbox was used for regions where cytoarchitectonic maps were available.108;330 We used the WFU PickAtlas Tool version 2.4 to translate MNI into Talairach coordinates (where necessary for relating our findings to existing literature). To define coordinates of mesencephalic locomotor regions, we used maps and coordinates.109;200;402 The functional labelling of premotor cortical areas was based on Mayka et al 2006247 and Picard et al 1996.304

Results

During electrophysiological gait testing patients had a smaller step length and an increased temporal gait asymmetry compared to controls (Table 2).

Table 2 Gait data

Parameter Group Mean SD P-value Normalized Patients 0.71 0.08 0.009 step-length Controls 0.78 0.08 Freezers 0.66 0.15 0.17 Non-Freezers 0.73 0.07 Gait asymmetry Patients 0.036 0.027 0.003 Controls 0.015 0.011 Freezers 0.040 0.027 0.5 Non-Freezers 0.033 0.029

Normalized step length: Step length / leg length Gait asymmetry: Natural logarithm (ln) of the difference in swingtime between the feet Statistical test: independent samples t-tests.

Behavioural results Imagery times are shown in Figure 2; statistical values in Table 3. During the motor imagery experiment, none of the freezers experienced ‘imagined’ FOG. Although non-freezers were numerically slower than freezers (and controls) across both imagery tasks, imagery times for VI and MI were not statistically different between groups (no effect of “Group”, Table 3, Figure 2). In addition, there was no difference between MI and VI (no effect of “Task”, Table 3). The effect of task on imagery times did not differ between groups (no “Task*Group” interaction, Table 3, figure 2B) and showed that all groups performed the imagery adequately. First, there was an effect of increasing path length in both tasks, and this effect was not different between groups (significant effect “Path Length” and no interaction “Group*Path Length”, Table 3, Figure 2A).

132 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

Second, the effect of path width on imagery times differed for the different tasks, which was not different between groups (significant “Task*Path Width” interaction, no interaction “Task*Path Width*Group, Table 3, Figure 2B). A smaller path width resulted in longer imagery times in the MI task (F(1,42) = 17.7, p < 0.001), but had no effect on imagery times in the VI task (F(1,42) = 0.4, p = 0.52). Actual and imagined walking times were significantly correlated, both in controls (Spearman’s rho = 0.78, p < 0.001) and in patients (rho = 0.54, p<0.001). The correlation was also significant for the freezer and non-freezers subtype separately (freezers: rho = 0.77, p < 0.001, non-freezers: rho = 0.53, p < 0.001).

Table 3 Behavioural performance (between-groups comparisons on imagery times)

Effect: Patients versus Controls Freezers versus Non-freezers F (df) p-value F (df) p-value Group < 1 (1,43) 0.35 3.7 (1,22) 0.07 4 Task (MI vs VI) 1.3 (1,43) 0.26 2.5 (1,22) 0.13 Task*Group 2.3 (1,43) 0.13 < 1 (1,22) 0.44 Path length 69.8 (4,172) < 0.001 62.1 (4,88) < 0.001 Path length * Group 1.5 (4,172) 0.23 2.8 (4,88) 0.61 Task*Path width 17.5 (1,43) < 0.001 8.8 (1,22) 0.007 Task*Path width*Group < 1 (1,43) 0.734 < 1 (1,22) 0.80

MI = motor imagery; VI = visual imagery

Electromyography There were no differences in EMG activity between VI and MI (effect “Task” F(1,43) = 1.7, p = 0.20). Patients showed more EMG activity than controls (effect “Group” F (1,43) = 5.4, p = 0.03). Crucially, there were no differences in EMG activity between the two groups (controls, patients) across tasks (analysis 1: “Task*Group” interaction: F(1,43) = 1.3, p = 0.26), nor between freezers and non-freezers across task (analysis 2: “Task*Group” interaction: F(1,22) < 1, p = 0.50). Hence, differences in actual movements (related to tremor or overt leg movements during motor imagery of gait) did not account for changes in differential (MI compared to VI) cerebral activity between groups.

Cerebral activity during motor imagery of gait for each group Controls and patients (analysis 1) We could confirm the presence of significant motor imagery effects in controls (cMI>cVI) in those areas previously reported in young healthy controls28 [cMI>cVI;

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Figure 2 Behavioural performance during scanning

Average imagery times (±SEM) measured in freezers, non-freezers and controls. MI = motor imagery, VI = visual imagery. A) Imagery times for trials with different path lengths [2, 4, 6, 8, and 10 m] and B) for trials with different path widths [broad, narrow].

Controls Non-Freezers Freezers A Imagery time (s) Imagery time (s) Imagery time (s)

14 14 14 12 12 12 10 10 10 10 10 10 8 8 8 6 6 6 4 4 4 2 2 2 0 0 0 MI VI MI VI MI VI

2m 4m 6m 8m 10m B

Imagery time (s) Imagery time (s) Imagery time (s)

12 12 12 10 10 10 8 8 8 6 6 6 4 4 4 2 2 2 0 0 0 MI VI MI VI MI VI Broad Narrow

region of interest analysis; left and right supplementary motor area, left and right superior parietal lobule, right anterior cingulate lobule, left putamen; for statistical data see supplementary material]. In the patient group, there was a significant effect of motor imagery in the right supplementary motor area [pMI>pVI; region of interest analysis, see supplementary material – Table 1]. Furthermore, a post-hoc analysis assessing the cerebral effects evoked during MI of walking (as compared to the baseline provided by the inter-trial epochs) revealed clear responses in other portions of the known locomotor network,188 in particular cerebellar and striatal regions, in both patients and controls (Supplementary material - section 8, Table 2, Figure 2).

Non-freezers and freezers (analysis 2) In non-freezers, activity in both the right and the left supplementary motor area was larger during motor imagery than during visual imagery [nfMI>nfVI; region of interest

134 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

analysis; see supplementary material]. In freezers, none of the areas previously reported were significantly activated during motor imagery [fMI>fVI; region of interest analysis], but whole-brain analysis revealed a strong effect in the posterior mid-mesencephalon (mesencephalic locomotor region, local maximum [2 -30 -18], cluster-size = 330, Z = 5.2, p (cluster-level corrected) = 0.004).

Differential cerebral activity during motor imagery of gait across groups Controls and patients (analysis 1) ROI analysis of the differential motor imagery-related activity of controls compared to patients [(cMI>cVI) > (pMI>pVI)], revealed a reduced activity in patients compared to controls in the superior parietal lobule (Brodmann areas 5L and 7) and in the anterior cingulate cortex (caudal cingulate motor area, Brodmann area 24) (Figure 3; Table 4).304;330

Non-freezers and freezers (analysis 2) Comparing non-freezers to freezers [(nfMI>nfVI) > (fMI>fVI); region of interest analysis], 4 there was no above-threshold between-group difference, although there was a statistical trend towards increased activity in non-freezers compared to freezers in the left supplementary motor area (Brodmann area 6) and the right superior parietal lobule (Figure 3 and 4; Table 4). Comparing freezers to non-freezers [(fMI>fVI) > (nfMI>nfVI); whole brain analysis], there was increased imagery-related activity in the posterior mid-mesencephalon of freezers (Figure 4; Table 4). The maximum of the cluster was located dorsomedial to the pedunculopontine nucleus, just including the pedunculopontine nucleus.402 The cuneiform nucleus and the periaqueductal grey were included in the cluster.109;200 The locus coeruleus is located on the lower-dorsal border of our cluster.200 The mesencephalic locomotor region is a neurophysiologically defined region which includes the pedunculopontine nucleus, cuneiform nucleus, periaqueductal grey and locus coeruleus.194 The activity we found most likely includes several nuclei of the mesencephalic locomotor region, especially the cuneiform nucleus and the periaqueductal grey.

Specific effects of environmental constraints on cerebral activity during motor imagery We found no significant differential activity for motor imagery of gait along a narrow compared to a broad path, nor was there a “Group*Task” interaction for Path width.

Brain-disease, brain-behaviour, and structural-functional relationships Differential mesencephalic locomotor region activity in freezers (MI minus VI) correlated to FOG severity as measured by part 2 of the NFOG-Q (Figure 5A, r = 0.60, p = 0.041). Mesencephalic locomotor region activity correlated to disease duration, only significantly when taking both patient groups into account (Figure 5B, freezers r

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Figure 3 Imagery-related brain activity

Brain areas in which the relative increase in activity for motor imagery (MI) versus visual imagery (VI) was greater in controls than patients (region of interest analysis, p < 0.05 corrected for multiple comparisons using family-wise inference on voxel level). A) Statistical parametric maps of increased activity in the right superior parietal lobule and right anterior cingulate cortex (cingulated motor area), superimposed on a sagittal brain section (top: cingulate motor area, bottom: superior parietal lobule) B) Beta weights of the contrast between motor imagery and visual imagery (mean ± SEM) from right caudal cingulate motor area cluster (top) and the right superior parietal lobule cluster (bottom) in controls, non-freezers and freezers. PD = Parkinson’s disease; F = freezers; NF = non-freezers; * = p < 0.05.

A B Right anterior cingulate cortex

MI > VI 1 (β-value) 0,8 *

0,6

0,4

0,2

-0,2 x = 4 -0,4 NF F Controls Patients PD patients < Controls Right superior parietal lobule

MI > VI 1,4 (β-value) 1,2 * 1 0,8 0,6 0,4 0,2 x = 14 0 -0,2 -0,4 NF F Controls Patients

= 0.53, p = 0.08, all patients r = 0.58, p = 0.003). Motor imagery-related activity (MI>VI) in the supplementary motor area was associated with greater step length (General linear model effect STEP LENGTH Wald χ2 = 41.0, p < 0.001, Post-hoc ANOVA showed a significant relation between supplementary motor area activity and step length in controls (F(1,14) = 9.6, r2 = 0.38, p = 0.01) but not in freezers (F(1,8) < 1, r2 = 0.10, p = 0.71 after removal of outlier) or non-freezers (F(1,9) = 2.9, r2 = 0.26, p = 0.12. Motor imagery- related activity (MI>VI) in the mesencephalic locomotor region, superior parietal lobule or cingulate motor area was not associated with step length or gait asymmetry. There were no differences in global grey matter (GM), white matter (WM), or CSF

136 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

Figure 4 Imagery-related brain activity

Brain areas in which the relative increase in activity for motor imagery (MI) versus visual imagery (VI) differed between freezers and non-freezers (Supplementary motor area: region of interest analysis, p = 0.06 corrected for multiple comparisons using family-wise inference on voxel level; Mesencephalic locomotor region: whole brain search, p < 0.05 corrected for multiple comparisons using family-wise error (cluster-level). A) Statistical parametric map of decreased activity in the supplementary motor area and increased activity in the mesencephalic locomotor region, superimposed on a sagittal brain section (top-left: supplementary motor area, middle-left: mesencephalic locomotor region) and a transversal brain section (top-right: supplementary motor area, middle-left: mesencephalic locomotor region). The bottom brain sections include the small cluster with significant difference in grey matter between freezers and non-freezers in the mesencephalic locomotor region B) Beta weights of the contrast between motor imagery and visual imagery (mean ± SEM) from the supplementary motor area cluster (top panel) and the mesencephalic locomotor region cluster (bottom panel) in controls, non-freezers (NF) and freezers (F).

A B Left Supplementary motor area MI > VI 4 L R 2,5 (β-value) 2

1,5

0,5

x = -8 z = 68 0 -0,5 Freezers < Non-freezers -1 NF F (functional) L R Controls Patients

Mesencephalic locomotor region

MI > VI 3,5 (β-value) 3 * 2,5 2 1,5 x = 2 z = -18 1 Freezers > Non-freezers (functional) 0,5 0 Freezers < Non-freezers (grey matter) -0,5 NF F -1 Controls Patients

volume between groups (patients versus controls; freezers versus non-freezers) (VBM Analysis 1: GM: F(1,41) = 0.753, p = 0.391; WM: F(1,41) = 0.215, p = 0.645; CSF: F(1,41) = 0.329, p = 0.569; Analysis 2: GM: F(1,20) = 0.401, p = 0.534; WM: F(1,20) = 0.321, p = 0.577; CSF: F(1,20) = 0.406, p = 0.531). The analysis of regional volume differences between groups did not show any differences in local grey matter, white matter or CSF between groups at a whole-brain corrected threshold of p < 0.05. When focusing on the mesencephalic locomotor region cluster found in the comparison between

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Table 4 Stereotactic coordinates of local maxima with differential cerebral activity during motor imagery of gait across groups

Contrast Search Anatomical Functional Cluster Hemi- Z-value p-value x y z volume label label size sphere

Analysis 1: Controls versus Patients (cMI>cVI ) Superior parietal Area 5L 144 R 3.1 0.019 14 -58 66 > lobule (pMI>pVI) ROI Ant. cingulate Area 24 65 R 3.0 0.025 2 2 40 cortex Analysis 2: Non-freezers versus Freezers (nfMI>nfVI) Superior parietal Area 5L 93 R 2.6 0.074 22 -50 72 > lobule (fMI>fVI) ROI Superior frontal SMA 64 L 2.6 0.061 -10 -16 72 gyrus (fMI>fVI) Posterior Mes- 170 4.5 0.049 0 -28 -20 > Whole- mid- encephalic (nfMI>nfVI) brain mesencephalon locomotor region

Results of whole-brain analysis are corrected for multiple comparisons for search over the whole brain using cluster-level family-wise inference (p<0.05). Results of ROI analysis are corrected for multiple comparisons over the ROI volume using voxel-level family-wise inference (p<0.05). Stereotactic coordinates are reported in Montreal Neurological Institute (MNI) space. Details on the anatomical and functional labelling can be found in the Methods and Results sections. c = controls; f = freezers; nf = non-freezers; MI = motor imagery; VI = visual imagery; R = right; L = left; SMA = supplementary motor area

freezers and non-freezers [(fMI>fVI)>(nfMI>nfVI)], there was a significantly larger grey matter volume in the latter group [2, -33, -18; Z = 2.89, p (voxel-level corrected) = 0.028, Figure 4, Figure 1 Supplementary Material]. The magnitude of this structural difference did not correlate to FOG severity (r = 0.28, p = 0.37). Crucially, the gait-related difference found in the mesencephalic locomotor region did not correlate to the proportion of grey matter in this same region (MI vs VI; r = 0.17, p = 0.60, Figure 5C). This indicates that differential brain atrophy between the freezers and non-freezers groups cannot account for the gait-related differences we observed in this region.

138 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

Figure 5 Brain-disease and structural-functional relationships

Relation between differential cerebral activity and clinical/structural parameters in freezers. A) Scatterplot of beta weights of the contrast between motor imagery (MI) and visual imagery (VI) from the mesencephalic locomotor region (MLR) cluster (y-axis) against score on the New Freezing of Gait Questionnaire part 2 (N-FOGQ; x-axis; Pearson’s correlation r = 0.60, p = 0.04) B) Scatterplot of beta weights of the contrast between motor imagery and visual imagery from the mesencephalic locomotor region cluster (y-axis) against disease duration (in years; x-axis; r = 0.53, p = 0.08) C) Scatterplot of beta weights of the contrast between motor imagery and visual imagery from the mesencephalic locomotor region cluster (y-axis) against grey matter volume (in millilitre) of the same cluster (x-axis; r = -0.17, p = 0.44).

Mesencephalic locomotor region A MI > VI (β-value at MLR cluster)

NFOG-Q B MI > VI (β-value at MLR cluster)

Disease duration C MI > VI (β-value at MLR cluster)

MLR grey matter (ml)

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Discussion

We used motor imagery to investigate alterations in cerebral activity related to planning of walking in PD patients with or without FOG. We showed that the mesencephalic locomotor region, just dorsomedial to the pedunculopontine nucleus, contributed to motor imagery of gait in freezers but not in non-freezers or controls. This altered cerebral activity was not confounded by the effects of altered motor execution, somatosensory processing, task performance or brain atrophy, and it was related to subjective FOG severity. In addition, controls and non-freezers recruited the supplementary motor area during motor imagery of gait, while freezers did not. Freezers and non-freezers, taken together, showed less motor imagery-related activity in the superior parietal lobule (Brodmann areas 5L and 7) and in the anterior cingulate cortex (Brodmann area 24) than controls.

Increased gait-related activity Mesencephalic locomotor region PD patients with FOG solved the motor imagery task by evoking additional activity in the posterior mid-mesencephalon. This region includes several components of the mesencephalic locomotor region, namely the pedunculopontine nucleus, the cuneiform nucleus and the periaqueductal grey. The pedunculopontine nucleus has been implied in the pathophysiology of akinesia and gait disorders in PD, based on several observations. In animal experiments and human case studies, lesions of the pedunculopontine nucleus yield akinesia, while stimulation or disinhibition of the pedunculopontine nucleus alleviates akinesia.243;299;305;351 Direct electrical stimulation of the pedunculopontine nucleus in humans has so-far resulted in only modest and non-significant effects on gait.122 Analysis of electrode positions among the few patients that received the greatest benefit from pedunculopontine nucleus stimulation suggested that a more posterior stimulation may afford greater beneficial effects on gait.122;310 In another study, this more posterior part of the mesencephalon was activated by mimicked gait in PD patients.303 Those findings suggest that either the pedunculopontine nucleus lies more posterior than previously suspected, or that the subcuneiform/cuneiform nucleus was stimulated. The cluster found in the present study included the pedunculopontine nucleus, with the local maximum located in the cuneiform nucleus, and reaching the periaqueductal grey, a structure severely affected by PD.57;404 We also found grey matter atrophy in the mesencephalic locomotor region in freezers compared to non-freezers, although this did not account for the differences in gait-related mesencephalic locomotor region activity. Taken together, these observations suggest that the mesencephalic locomotor region, and in particular the cuneiform nucleus and the periaqueductal grey, may be involved in FOG.

140 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

Compensation or pathology? The mesencephalic locomotor region is recruited during actual gait in humans.161 Output from this structure is likely inhibited during motor imagery of gait, to prevent the mesencephalic locomotor region from driving the actual walking generators.196 Accordingly, the increased gait-related mesencephalic locomotor region activity we observed in PD patients with FOG may be pathological, reflecting a decreased inhibition from the basal ganglia. Other findings support this interpretation. First, increased mesencephalic locomotor region activity was associated with higher subjective FOG severity scores. Second, the magnitude of mesencephalic locomotor region activity evoked during motor imagery of gait was correlated to disease duration. This finding fits with the observation that longer disease duration increases the likelihood of developing FOG,234 with the mesencephalic locomotor region becoming more affected as PD progresses.57 Third, ischemic lesions in the dorsomedial mesencephalic locomotor region cause gait ataxia, but not a hypokinetic-rigid gait.163 However, if gait-related activity in the mesencephalic locomotor region of freezers were 4 exclusively pathological in nature, then how could freezers have solved the task as adequately as non-freezers and controls, despite their altered cortical responses during imagery of gait? This could point to a possible compensatory role of the mesencephalic locomotor region. This possibility is supported by recent findings,showing increased mesencephalic locomotor region activity when healthy controls perform motor imagery of gait involving frequently repeated periods of gait initiation and termination, but less prominent activation during stable gait.213 The latter finding fits with the absence of gait-related mesencephalic locomotor region activity in our controls, who also imagined a stable gait. Crucially, we showed that patients with FOG deviate from this pattern, showing strong mesencephalic locomotor region activity even during imagery of stable gait. This observation also fits with the increased mesencephalic locomotor region electrophysiological activity observed in freezers during mimicked stepping movements.303 Taken together, these findings suggest that the mesencephalic locomotor region might play both a compensatory and a pathological role, dependent on the computational demands imposed on this structure and on disease progression. We speculate that early in the disease, possibly even at a pre-symptomatic stage,63 medial frontal areas (supplementary motor area) of prospective freezers fail to regulate step length. At such early stages, increased mesencephalic locomotor region activity could play a compensatory role, supporting gait planning and execution. However, the mesencephalic locomotor region ability to control gait may be limited, especially when the structure becomes more severely affected with disease progression. Additional requirements to finely adapt gait parameters to time-varying demands, as during turning and step initiation, might then lead to a collapse of this compensatory system. This scenario would reconcile a compensatory role of the mesencephalic locomotor region during stable gait, with a pathological contribution under more demanding circumstances.

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Decreased gait-related cortical activity Cingulate and supplementary motor areas Gait-related activity in the caudal cingulate motor area was decreased in PD patients compared to controls. The caudal cingulate motor area is involved in updating and switching action plans.170;324 We suggest that alteration of gait-related cingulate motor area activity might create a pre-condition for the manifestation of FOG, limiting the ability of PD patients to switch between motor programs. This is especially required by situations that require rapid gait adjustments like turning and step initiation. Failures in additional gait-related cerebral structures may be necessary to actually evoke FOG. One example is the supplementary motor area. Differently from controls and non-freezers, PD patients with FOG solved the motor imagery task without evoking additional activity in the supplementary motor area, as compared to a visual imagery control task. The observed cluster falls within the portion of the supplementary motor area concerned with leg movements.128 Hypoactivity in the supplementary motor area is associated with hypokinesia in PD,271;325 and movement amplitude in PD patients improves when supplementary motor area activity is normalized (e.g. after medication, motor cortex stimulation, or deep brain stimulation).31;120;271;358 Furthermore, decreased supplementary motor area activity is related to higher cadence and decreased step length in PD patients.161 Accordingly, in this study we show a relation between brain activity in the supplementary motor area (during motor imagery) and step length (during actual walking outside the scanner). These findings suggest that the decreased supplementary motor area activity observed in freezers may be related to altered regulation of step amplitude. The emphasis here is on abnormal regulation, since freezers could produce step amplitudes largely overlapping with those of non-freezers and controls. As such, this finding qualifies the hypothesis that a failure to generate steps of adequate amplitude could lead to a progressive decrease in step amplitude, and ultimately produce FOG.76

Superior parietal lobule During motor imagery of gait, cerebral activity in the right superior parietal lobule was reduced in patients compared to controls. This confirms previous SPECT findings related to gait execution in PD.161 We suggest that the reduced activity in the superior parietal lobule of PD patients during imagery of gait underlies their difficulty in predicting the somatosensory consequences of a motor plan.42;390 This interpretation fits with the known impairments of PD patients in integrating proprioceptive information into a motor plan.12;198;225

Interpretational issues Patients were classified as ‘freezers’ when there was an evident history of FOG. All freezers reported the characteristic gluing of the feet, and recognised the typical

142 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

phenotype when this was demonstrated to them. Most patients also showed FOG during neurological examination. We included patients with relatively mild FOG, as this facilitated a proper match between freezers and non-freezers with respect to disease severity and duration. This may explain why three patients with mild freezing did not demonstrate FOG during clinical examination, despite convincing subjective accounts of FOG. Post-hoc exploratory analyses suggested that the mesencephalic locomotor region activation in these patients without objective FOG was intermediate between fully overt freezers and non-freezers, perhaps reflecting a spectrum of severity (data not shown). All three groups performed the task proficiently, without overall differences in imagery times between groups. Non-freezers showed a trend towards slower imagery times, but this included both the motor imagery and visual imagery task. Hence, this tendency for different imagery times cannot explain the differential (MI>VI) functional brain activity. Moreover, in all groups imagery times were equally sensitive to the length and width of the path and correlated to actual walking times. These findings 4 indicate that both patients and controls were equally effective in solving the motor imagery task. This excludes task difficulty as an explanation for between-group cerebral differences during motor imagery. The basal ganglia are affected in PD, and are involved in motor imagery of gait in young healthy subjects.28 Moreover, other studies have suggested that failure of the caudate nucleus may contribute to FOG.37 However, we found no differences in cerebral activity in the basal ganglia between patients and controls. This is likely a sign of the extreme selectivity of our functional comparison (MI vs. VI), rather than a lack of sensitivity (see Supplementary Table 2, Figure 2).

Conclusions We have shown that PD patients with FOG performing motor imagery of gait use different cerebral structures than matched PD patients without FOG or healthy controls. These cerebral differences were observed in the context of matched behavioural performance across groups, and could not be explained by brain atrophy. During imagined walking, patients with FOG showed increased activity in the mesencephalic locomotor region, which was related to subjective FOG severity. In addition, patients with FOG tended to have reduced activity in mesial frontal and posterior parietal regions. These findings provide new insights into the pathophysiology of FOG: the cause of FOG may be altered cortical regulation of movement execution, together with a progressively impaired ability of mesencephalic structures to flexibly compensate for that alteration. This may explain the manifestation of FOG during changes in motor behaviour, such as turning or initiating walking. These gait adaptations not only require a switch of motor program, but also more precise regulation of step length and gait timing.

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Acknowledgements

This research was supported by the Netherlands Organization for Scientific Research (NWO) [016076352 to B.B., 45203339 to I.T., 92003490 to A.S., 91656103 and 016116371 to S.O.] and by the Stichting Internationaal Parkinson Fonds. R.H. was supported by a grant from the Alkemade-Keuls foundation. We would like to thank Paul Gaalman for his expert assistance during scanning, Lennart Verhagen for his SPM assistance and Charlotte Haaxma for rating the video’s on FOG. In addition, we would like to thank Alan Pieterse for assistance using the GaitRite.

144 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

Supplementary material to chapter 4.1

Supplementary material

Here we describe in detail: 1. Tasks 2. Experimental procedure 3. Data collection 4. EMG recordings, preprocessing and subsequent analyses 5. Preprocessing of imaging data 6. First level statistical analysis of imaging data 7. Details on region of interest analysis 8. Details on a post-hoc analysis assessing the cerebral effects evoked during MI of walking as compared to the baseline 4 9. Details on voxel-based morphometry 10. Supplementary Table 1: Stereotactic coordinates of the local maxima showing cerebral activity during motor imagery of gait for each group 11. Supplementary Table 2: Stereotactic coordinates of the local maxima showing cerebral activity during motor imagery of gait versus baseline for controls and patients 12. Supplementary Figure 1: Average tissue type volume within MLR 13. Supplementary Figure 2: Motor imagery related brain activity: motor imagery versus baseline

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1. Tasks

Subjects performed two tasks: motor imagery of gait, and a matched visual imagery control task. Both tasks started with the presentation of a photograph showing a corridor with a path in the middle (Fig. 1). During the motor imagery task (MI), subjects were asked to imagine walking along this path. During the visual imagery task (VI), subjects were asked to imagine seeing a disc moving along the path. A MI trial started with the presentation of a photograph with a green square as a start marker (Fig. 1a). Subjects were asked to briefly inspect the picture, close their eyes, imagine walking along the path (starting from the green square and stopping at the green pillar) and open their eyes when they imagined having reached the green pillar (see Fig. 1b for trial time course). Subjects were instructed to vividly imagine the walking movement, in a first person perspective, as if their legs were moving, but without making any actual movements. A VI trial started with the presentation of a photograph with a black disc as start marker (Fig. 1a). Subjects were asked to briefly inspect the picture, close their eyes, imagine standing on the left side of the beginning of the path and seeing the disc moving towards the green pillar, and to open their eyes when they imagined the disc reaching the green pillar. During both tasks, the path could have two different widths (narrow, broad). In addition, the green pillar could be placed at five different distances from the green square or the black disc (2, 4, 6, 8, and 10 m). During each trial, subjects signalled that they had started and stopped the imagery by pressing a button. Patients pressed the button with their least affected hand (17 left, 8 right). Controls were matched to the patients: i.e. 14 controls pressed the button with their left hand and 7 with their right hand. Also the freezer and non-freezer groups were matched (freezers: 9 left, 4 right ; non-freezers: 8 left, 4 right). We explicitly instructed subjects not to count during the imagery tasks.

2. Experimental procedure

During the experiment, subjects were lying supine in the MR scanner. Visual stimuli were presented by means of a PC running Presentation software (Neurobehavioural systems, Albany, USA), and were projected onto a screen at the back of the scanner. Subjects could see the screen via a mirror above their heads. The MI and VI tasks were performed in two successive sessions of 25 minutes each, separated by a break outside the scanner. Task order was counter-balanced across subjects. For each session, the trial order was pseudo-randomized across the experimental factors (i.e. path width (2 levels) and path length (5 levels)). We used two fixed pseudo-randomized orders that were counterbalanced across the two tasks. In between trials a fixation cross was presented (inter-trial interval, ITI: 4-12 sec).

146 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

Before each session, subjects were given written and verbal instruction about the task they were going to perform, followed by training in the relevant task outside the scanner (15 trials) and inside the MR-scanner (first session only, 7 trials). Prior to the MI task, subjects were asked to walk along short versions (three meters) of the same broad and narrow paths used in the MI task (3 times for each path width), at a comfortable pace, avoiding to place their feet outside the path. We instructed subjects to pay attention to the feeling of walking along the different path widths, and to imagine walking in a similar way along the two different paths during the imagery trials. To familiarize subjects with the movement of the disc, prior to the VI task, they saw a video of the disc moving through the same corridor as in the photographs. The disc moved for 6 m, in a straight line, at a uniform speed of about 0.8 m/s. We instructed subjects to imagine seeing the disc moving in a similar way along the two different paths during the imagery trials. 4 3. Data collection

Button presses were recorded with an MR-compatible keypad (MRI Devices, Waukesha, WI) positioned on the subjects’ abdomen. MR images were acquired on a Siemens 3T Trio system (Siemens, Erlangen, Germany), using an 8 channel head coil for signal reception and a body coil for radio-frequency transmission. Blood oxygenation level-dependent (BOLD) sensitive functional images were acquired using a single shot gradient EPI sequence (TR/TE = 2380 ms/30 ms; 50 ms gap between successive volumes; 35 transversal slices; ascending acquisition; voxel size 3.5 x 3.5 x 3 mm; FOV = 224 mm). High-resolution anatomical images were acquired using an MP-RAGE sequence (TR/TE = 2300/2.92 ms, 192 sagittal slices, voxel size 1.0 x 1.0 x 1.0 mm, FOV = 256 mm). Eye movements were measured with a video-based infrared eyetracker (Sensomotoric Instruments, Berlin, Germany). These measures allowed us to have online visual inspection of task performance.

4. EMG recordings, preprocessing and subsequent analyses

A concern that arises when comparing cerebral activity during motor imagery of gait in patients versus controls is that differences in actual movements (related to tremor or overt leg movements during motor imagery of gait) might result in changes in cerebral activity between patients and controls. To control for these factors, muscle activity from the forearm and lower leg was measured during the fMRI experiment. Muscle activity was recorded with an MR compatible EMG (electromyography) system

147 CHAPTER 4

(Brain Products GmBH, Gilching, Germany). Silver/silver-chloride electrodes were placed three cm apart on the tibialis anterior and extensor carpi radialis in a belly tendon montage. Ground electrodes were placed on the lateral malleolus and on the head of the radius. For patients this was done at the side which displayed the most severe tremor (13 right, 6 left). The side of recording in control subjects was matched to the patients (14 right, 7 left). Offline MR artefact correction followed the method described earlier10;370 including low-pass filtering (400 Hz), and down-sampling (1000 Hz). Subsequently, we applied high-pass filtering (25 Hz, to remove possible movement artefacts) and rectification. We used the EMG recordings from the leg muscle to control for overt leg muscle movements. We considered the root mean square (rms) of the EMG signals measured during the imagery time (imagery epoch) and during the ITI (inter trial epoch) for each trial of the imagery experiment. For each subject, the average rms value of the EMG measured during the imagery time epoch was normalized to the average rms value of the ITI epoch, testing for an effect of GROUP (PD, controls) and TASK (MI, VI) with a repeated measures ANOVA. We used the EMG recording of the forearm muscle to correct for tremor related cerebral activity in the fMRI data. First, the whole EMG time series was segmented (one segment for each EPI volume). Subsequently a time frequency analysis was performed. That is, we calculated (for each segment) EMG power between 0 – 20 Hz. The peak frequency between 4 and 6 Hz. (i.e. the frequency corresponding to the rest tremor) was determined for each individual subject after visual inspection of the average power spectrum. Subsequently, the EMG power at this frequency was extracted in Matlab (MathWorks, Natick, MA) using the FieldTrip toolbox for EEG/MEG analysis (www.ru.nl/neuroimaging/fieldtrip). We also calculated the EMG amplitude and we log-transformed the EMG power to minimize outliers, leading to three tremor-related EMG regressors (power, amplitude and log of power). Last, we applied a z-transformation to each of these three regressors and convolved them with the hemodynamic response function (hrf), before adding them to our statistical model.

5. Preprocessing of imaging data

Functional data were pre-processed and analyzed with SPM5 (Statistical Parametric Mapping, www.fil.ion.ucl.ac.uk/spm). The first four volumes of each patient’s data set were discarded to allow for T1 equilibration. The remaining functional volumes were spatially realigned using a least squares approach and a 6 parameter (rigid body) spatial transformation.136 Subsequently, the time-series for each voxel was temporally realigned to the acquisition of the first slice. Images were normalized to a standard EPI template centered in MNI (Montreal Neurological Institute) space 21 and resampled at

148 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

an isotropic voxel size of 2 mm. The normalized images were smoothed with an isotropic 10 mm full-width-at-half-maximum Gaussian kernel. Anatomical images were spatially coregistered to the mean of the functional images,21 spatially normalized by using the same transformation matrix applied to the functional images and finally segmented into grey matter, white matter, CSF and other nonbrain partitions.23

6. First level statistical analysis of imaging data

The ensuing pre-processed fMRI time series were analyzed on a subject-by-subject basis using an event-related approach in the context of the General Linear Model.136 The model was aimed at finding regions in which the cerebral response changed as a function of TASK (MI, VI) and/or PATH WIDTH. PATH LENGTH was also considered in the analysis, which gave rise to a model with twenty different regressors of interest. The 4 model also included separate regressors of no interest, modelling BOLD activity evoked by picture inspection, button presses, and incorrect trials, separately for each session. Each effect was modelled on a trial by trial basis as a concatenation of square-wave functions convolved with a canonical haemodynamic response function, down sampled at each scan, generating a total of 26 task-related regressors.134 For the regressors of interest, onsets of the square-wave functions were time-locked to the button press marking the onset of imagery, and durations corresponded to the imagery time of each separate trial (eg. time between the two button presses). For the picture inspection regressors, onsets were time locked to the onset of picture presentation, and offsets were time-locked to the button press marking the onset of imagery. For the button press regressor, onsets were time locked to the button press marking the offset of imagery, and duration was set to zero. For the incorrect trials regressor, onsets were time locked to the onset of picture presentation, and offsets were time-locked to the button press marking the offset of imagery. The potential confounding effects of residual head movement-related effects were modelled using the time series of the estimated head movements during scanning. We included the original time series, the squared, the first-order derivatives of the originals and the first-order derivatives of the squared.232 The intensity changes attributable to the tremor-related movements through the magnetic field were accounted for by using the time series of the mean signal from the white matter, cerebral spinal fluid and out of brain voxels.377 Finally, the three EMG regressors of the arm muscle (power, amplitude and log transformation of the power) were modelled,171 and the data was high-pass filtered (cut-off 128 s) to remove low-frequency confounds such as scanner drifts.

149 CHAPTER 4

7. Details on region of interest analysis

Besides the whole brain analysis, statistical inference was also performed on regions of interest that were based on our previous study in healthy controls.28 More precisely, we considered the maximum coordinates of the clusters that were previously found to be significantly activated in the following contrasts: 1) MI>VI; and 2) MI-narrow>MI- broad, masked with (MI-narrow>MI-broad) > (VI-narrow>VI-broad).

This concerned the following coordinates [x y z]: 1) MI>VI: i. Superior frontal gyrus left: [-12 -10 68] ii. Superior frontal gyrus right; [16 -12 74] iii. Anterior cingulated gyrus: [6 0 46] iv. Superior parietal lobule left [-16 -58 60] v. Superior parietal lobule right [20 -56 68] vi. Putamen [-24 -4 8] 2) MI-narrow>MI-broad i. Superior parietal lobule left [-16 -50 64] ii. Superior parietal lobule right [16 -54 64] iii. Middle occipital gyrus [56 -70 -12]

The set of coordinates obtained from contrast 1) were used for the analyses considering the effects of TASK and GROUP, the set of coordinates obtained from contrast 2) were used for the analyses considering the effects of PATH WIDTH and GROUP. More specifically, we drew spherical ROIs centred at these coordinates with a radius of 8 mm, using WFU Pickatlas. Statistical inference was performed at the voxel level, with a family-wise error correction for multiple comparisons (p < 0.05).

8. Details on a post-hoc analysis assessing the cerebral effects evoked during MI of walking as compared to the baseline

The whole-brain and ROI analysis on differential imagery-related effects did not reveal activation of the whole known locomotor network in either patients or controls. However, this network was not defined using a comparison similar to that used in this study (i.e. MI vs. VI). Accordingly, we performed a new analysis more closely matched to that used in the studies defining the locomotor network.189;213 More precisely, in order to better approximate the comparison between imagining to walk and imagining to lie in a horizontal position (as used in previous papers defining the

150 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

locomotor network ,189;213 we considered the cerebral effects evoked during motor imagery of walking as compared to the inter-trial epochs. Whole-brain statistical inference was based on the same threshold used in the rest of the paper (FWE 0.05 cluster-level, on the basis of a >3.4 intensity). When using this approach we could clearly observe significant cerebellar and striatal activity in both controls and patients. We have added this information to the main text (Results section) and to the Supplementary material (Table 2, Figure 2).

9. Details on voxel-based morphometry

Voxel-based morphometry (VBM) analyses were done in SPM8. We segmented the anatomical MRI scan of each subject into grey matter, white matter, cerebrospinal fluid (CSF), and extra-cerebral compartments (e.g. out-of-brain, skull, skin). We used the DARTEL toolbox20 to create a group-specific anatomical template and register all 4 individual images to this template. All images were subsequently normalized to MNI space, while correcting for volume changes induced by normalization (ie. modulation). Last, we smoothed all images using a kernel of 8 mm FWHM. Global (differences) in grey matter volume and white matter volume were quantified by integrating the tissue probabilities over all voxels. In order to avoid possible edge effects around the border between grey and white matter, we used an absolute grey and white matter threshold of p < 0.15. Global differences in volume between groups were assessed using a two-tailed multivariate linear regression analysis that considered age as a covariate. Regional (i.e. voxel-by-voxel) differences in volume between groups were assessed with t-tests using the general linear model. We considered age and gender as confounding covariates in addition to total grey matter, white matter or CSF volume for the different test respectively.154;301 The results were corrected for search volume by using family-wise error (FWE) correction (p < 0.05). We also considered the fMRI cluster in the mesencephalic locomotor region (MLR, see main results and Table 4) as a region of interests for additional analysis.

151 CHAPTER 4

Supplementary Table 1 Stereotactic coordinates of the local maxima showing cerebral activity during motor imagery of gait for each group

Contrast Anatomical label Cluster Hemi- Z-value p-value x y z size sphere cMI>cVI Superior frontal gyrus 236 L 4.0 0.001 -8 -16 70 Superior frontal gyrus 83 R 3.5 0.006 10 -16 72 Superior parietal lobule 163 L 3.7 0.003 -10 -56 64 Superior parietal lobule 159 R 4.3 < 0.001 12 -56 68 Anterior cingulate gyrus 175 R 3.4 0.008 4 -4 40 Putamen 193 L 3.0 0.023 -16 -4 8 pMI>pVI Superior frontal gyrus 184 R 3.3 0.011 12 -18 74 nfMI>nfVI Superior frontal gyrus 241 R 3.6 0.005 10 -16 72 Superior frontal gyrus 150 L 3.5 0.005 -8 -16 68 fMI>fVI * Posterior 330 R 5.2 0.004 2 -30 -18 mid-mesencephalon

The results are based on ROI coordinates derived from 28, using voxel-level family-wise inference (p < 0.05). * This result is based on whole-brain analysis, using cluster-level family-wise inference. Stereotactic coordinates are reported in Montreal Neurological Institute (MNI) space. c = controls; p = patients; nf = non-freezers; f = freezers; MI = motor imagery; VI = visual imagery; R = right; L = left

Supplementary Table 2 Stereotactic coordinates of the local maxima showing cerebral activity during motor imagery of gait versus baseline for controls and patients

Contrast Anatomical label Cluster Hemi- Z-value p-value x y z size sphere cMI > Superior frontal gyrus 6982 L Inf <0.001 0 0 60 baseline L 7.74 -24 -8 54 R 7.04 30 -6 60 Inferior parietal lobule 5301 L Inf <0.001 -12 -70 60 L 7.51 -44 -46 54 L 7.25 -50 -38 50 Supra marginal gyrus 1306 R 7.81 <0.001 48 -36 44 R 3.36 58 -42 40 Inferior frontal gyrus 2333 L 7.68 <0.001 -52 10 2 L 5.99 -52 6 34 Putamen L 5.82 <0.001 -28 18 8 Inferior frontal gyrus 1927 R 6.62 <0.001 54 10 10 R 6.38 58 10 20 R 5.55 30 22 6 Cerebellum (VI, Cr1) 1177 R 6.31 <0.001 34 -54 -32

152 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

Supplementary Table 2 Continued

Contrast Anatomical label Cluster Hemi- Z-value p-value x y z size sphere R 5.84 46 60 -30 R 5.85 34 -50 -30 Middle frontal gyrus 591 L 6.29 <0.001 -36 36 32 Middle frontal gyrus 220 R 4.90 0.029 38 40 32 Cerebellum (VI, Cr1) 232 L 4.65 0.024 -34 -54 -34 pMI > Superior frontal gyrus 27984 L Inf <0.001 -2 4 58 baseline R Inf 4 -2 66 L Inf -4 -4 68 Cerebellum (V1, Cr1, VIIIA) 1097 L 6.57 <0.001 -48 -60 -28 L 4.57 -34 -56 -34 L 4.32 -36 -50 -50 Cerebellum (VI, CR1, VIIIA) 1098 R 5.14 <0.001 44 -62 -30 R 5.08 32 -60 -30 R 4.96 32 -34 -50 4 The results are based on whole-brain analysis, using cluster-level family-wise inference (p < 0.05). Stereotactic coordinates are reported in Montreal Neurological Institute (MNI) space. c = controls; p = patients; MI = motor imagery; R = right; L = left

Supplementary Figure 1 Average tissue type volume within MLR

Average volume (± SEM) of different tissue classes within the MLR activation blob, determined for freezers and non-freezers.

1.4 Non-freezers 1.2 Freezers

0.8

0.6 * Volume (ml) Volume 0.4

0.2

GM WM CSF Tissue type

153 CHAPTER 4

Supplementary Figure 2 Motor imagery related brain activity

SPM(t) maps of increase in activity for motor imagery (MI) versus baseline for patients and controls separately. The results are based on whole-brain analysis, using cluster-level family-wise inference (p < 0.05).

MI > baseline

Controls

Patients

154 GAIT-RELATED CEREBRAL CHANGES IN FREEZING OF GAIT

155

Cycling and freezing of gait

Video vignette 3

A 58-year old man with a 10-year history of idiopathic Parkinson’s disease presented with an incapacitating freezing of gait (video vignette 3). The patient had severe difficulties initiating gait and was merely able to take a few shuffling steps when provided with a visual cue (the examiner’s foot placed in front of the patient). Attempts to walk evolved rapidly into forward festination, and a fall towards the ground. Axial turning was impossible. However, his ability to ride a bicycle was remarkably preserved (video vignette 3). Gait freezing re-occurred instantaneously after dismounting the bicycle. This striking ‘kinesia paradoxica’ may be explained by the rotating pedals that possibly acted as an external pacing cue. Alternatively, the motor control mechanisms involved in gait and cycling could be affected differentially in Parkinson’s disease. Regardless of the explanation, cycling offers a useful approach for rehabilitation and exercise training in Parkinson patients grounded by severe freezing of gait.

Published as: Snijders AH, Bloem BR. Images in clinical medicine: Cycling for freezing of gait. NEJM. 2010; 362(13):e46.

5.1

Cycling breaks the ice for freezing of gait

Published as: Snijders AH, Toni I, Ruzicka E, Bloem BR. Bicycling breaks the ice for freezers of gait. Movement Disorders 2011; 26(3):367-71. CHAPTER 5

Summary

Patients with freezing of gait have episodic problems with generating adequate steps. This phenomenon is both common and debilitating in patients with Parkinson’s disease or atypical parkinsonism. We recently presented a video case of a patient with longstanding Parkinson’s disease and severe freezing of gait, who showed a remarkably preserved ability to ride a bicycle. Here, we comment on the scientific and clinical implications of this single case observation, and show the video of a similar case. We first consider several pathophysiological explanations for this striking discrepancy between walking and cycling in Parkinson’s disease. We then discuss the merits and shortcomings of cycling as a potential new avenue for rehabilitation and exercise training in patients grounded by freezing of gait. Finally, we provide some directions for future research stimulated by this fascinating observation.

160 CYCLING BREAKS THE ICE FOR FREEZING OF GAIT

Background

Patients with freezing of gait (FOG) have episodic problems with generating adequate steps.150 FOG is common in patients with Parkinson’s disease (PD) and in the various forms of atypical parkinsonism.153;269 The presence of FOG often has great clinical implications, with a marked impact on the quality of life.49 Affected patients lose their mobility, leading to loss of independence, and also to reduced fitness. In addition, FOG frequently leads to falls and injuries,219 because the feet become suddenly and unpredictably “glued” to the floor while the trunk continues to move forward. Falls are particularly common as patients cannot anticipate the impending falls because of the unpredictable nature of the freezing events. There are several therapeutic options, but generally treating FOG remains difficult for most patients (for recent reviews, see:141;235. The mechanisms leading to FOG remain poorly understood, and this hampers development of improved treatment strategies.

Case report

Single case observations provide the lowest class of scientific evidence. Yet, a remarkable observation in a single patient can sometimes help to advance the field, by generating new ideas for further research.373 We recently published a case report of a 58-year old 5 man with longstanding PD who was grounded by severe freezing of gait.338 To our surprise, this patient manifested a strikingly preserved ability to ride his bicycle, as was demonstrated on a video that accompanied our publication. This phenomenon could aptly be referred to as “abasia sine abicyclia” (inability to walk, without inability to cycle). Our observation has since attracted widespread media attention, because of the potential implications for research, for delivering exercise therapy to patients who are physically inactive because of walking difficulties, and perhaps also because of the hope it offers to patients. In the video accompanying this chapter, we present another patient with a similarly preserved ability to ride a bicycle, despite marked freezing of gait. It concerns a 57-year-old man who had been treated with bilateral subthalamic nucleus stimulation for severe motor fluctuations, 12 years after onset of PD. The home video shows the patient’s severe gait disorder, mainly caused by freezing of gait. However, he can immediately generate smooth cycling movements as soon as he mounts his bicycle. Here, we comment in more detail on the possible implications of these intriguing case observations.

161 CHAPTER 5

Pathophysiological implications

The preserved cycling ability is perhaps a trivial mechanical consequence of the regularly rotating pedals: the patient’s legs are passively pushed forward, irrespective of the ability to actively initiate each pedalling movement. It is also possible that the forces transferred from the rotating pedals to the patient’s feet might provide tactile cues that triggered appropriate rhythmic cycling movements. In this perspective, cycling could provide external pacing cues that are less prominent during gait. It is well-known that external sensory cues are effective in overcoming the defective basal ganglia circuitry of PD patients, perhaps by activating the motor cortex via alternative circuitries.25;203;284 An example that is famous even to the layman’s audience is that of auditory cueing in patients with postencephalitic parkinsonism who were unable to move, but could dance ‘out of the frame’ when music was played.326 Visual and auditory cues are best known, but tactile cues are also effective.369 More precisely, the afferent feedback provided by the symmetrically moving pedals may regulate the timing and amplitude of limb movements during cycling. This way, the pedals could restore two mechanisms that have been implied in the pathophysiology of FOG: the inability of PD patients to generate and maintain appropriate movement amplitudes;76;181 and the abnormal temporal coordination between both legs.4;307 In contrast to gait, cycling provides the patient with a mechanical constraint that keeps “step” length constant. In addition, it corrects the coupling between central commands and the biomechanical constraints of the legs.214 We recently speculated that the cause of FOG might relate to an altered cortical regulation of movement execution, together with a progressively impaired ability of mesencephalic structures to flexibly compensate for that alteration.340 The fixed amplitude and timing of leg movements during cycling may decrease the regulatory load on the defective cortical areas. Hence, the mesencephalic locomotor region may retain its ability to support a central rhythm generator during cycling, resulting in adequate cyclic movements. This hypothesis could also explain why sudden gait adaptations (such as turning while walking) that provide greater challenges to these cortical areas may elicit FOG more frequently than simple straight walking.329 Yet, these mechanisms do not explain how patients can self-initiate pedalling movements without problems, but not walking movements. Moreover, one study reported that some PD patients could experience sudden cessations of pedalling while cycling on a stationary ergometer, and this actually correlated with freezing episodes during walking.4 We therefore need to consider alternative possibilities. One further explanation is that FOG involves a pathological alteration of motor control mechanisms specifically dedicated to gait movements, while sparing other complex motor acts. It may be even hypothesized that FOG involves the most common gait routines and spares more complex walking programs, e.g. walking upstairs that is often preserved

162 CYCLING BREAKS THE ICE FOR FREEZING OF GAIT

in patients with FOG. Analogous phenomena can be observed in task-specific dystonia, where movement impairments are bound to performing a particular action, rather than the use of a specific muscle or “effector”.160 In this perspective, it is conceivable that an action different from walking (i.e., cycling) but involving the same “effector” (i.e., the legs) could be spared. Indeed, there are similar anecdotes of disabled patients with PD who are still able to ice-skate, ski, or play badminton. It is necessary to also examine specific differences between walking and cycling. Both acts evoke similar modulations of cutaneous reflexes,396 but compared to walking, cycling may require much less unloading of the weight-bearing leg. Indeed, unlike cycling, walking requires a delicate integration between gait commands (generating a forward stepping movement) and anticipatory postural adjustments (lateral weight shifts, in order to shift the body’s centre of mass laterally towards the weight-bearing leg, allowing the contralateral leg to initiate the swing phase.245 PD patients with FOG have specific difficulties in generating these preparatory lateral weight shifts, and this impairs their step initiation.187;320 Such an integration of anticipatory adjustments with rhythmic leg movements would seem less critical for cycling. Dynamic balance control is also different during cycling and walking. Specifically, cycling mainly requires lateral weight shifts, while gait mainly requires dynamic balance control in the forward-backward direction. Various studies have shown that balance deficits in PD are directionally dependent, being greatest in the backward direction, and much less so in the medio-lateral direction.72;177 This relatively preserved 5 medio-lateral stability could also explain why PD patients typically walk with a narrow-based gait,75;273 and why tandem gait is preserved in most patients.3 Effects of the rapidly changing visual scene during cycling should also be considered. In this respect, it is relevant to discuss two recent studies that studied why FOG commonly occurs when Parkinson patients walk through narrow doorways. Both studies showed that step length decreases to a greater extent in PD patients than healthy controls when they try to walk through a door. This phenomenon worsens as the size of the doorway decreases.13;80 Almeida and colleagues suggested that visual perceptive deficits could explain the propensity for FOG to occur while crossing a narrow doorway. However, these authors provided no direct perceptual evidence for this.13 This issue was addressed by Cowie and colleagues, who demonstrated that explicit perception of door width was no different in freezers than in healthy controls.80 Instead, they raised the interesting suggestion that freezers might over-react to visual information, which is normally needed to inform the next motor actions. For example, the visual information from doors indicates that subjects should slow down, and Parkinson patients do so extremely. Similarly, PD patients over-react to optic flow for maintaining balance.59 These findings may have direct relevance for our observations, because during cycling subjects receive a lot of optic flow information which might act as a powerful cue to motion.

163 CHAPTER 5

Other incidental factors could underlie the discrepancy between walking and cycling abilities, but they appear unlikely. For example, it could be argued that cycling – having a faster rhythm and greater ground speed than walking – might better capture the patient’s attention, for example via the rapidly changing features in the environment. Moreover, the task-focused nature of cycling will lead to a more consistently goal directed behaviour.226 Indeed, voluntary attention to the task at hand can improve motor performance in PD.84 Emotional factors could theoretically play a role. Strong emotions may produce kinesia paradoxa in PD,81 and emotions and motor control are regulated in tight conjunction by the subthalamic nucleus.238 Yet, it seems unlikely that emotional factors could account for such a sustained kinesia paradoxa (several patients were able to make 10 km bicycle rides, without any problems). Hence, the preservation of cycling is probably more related to cueing than to kinesia paradoxa. Anxiety may also play a role, as this is one of the triggers for FOG. Many patients with PD are afraid to fall while walking.5;45 Cycling cannot cause trips or slips, and some of our patients anecdotally reported having greater confidence during cycling, which may in turn lead to fewer freezing episodes.

Implications for rehabilitation

Our findings may have therapeutic importance. FOG commonly leads to a decreased mobility and loss of independence.49 The resultant reduction in physical activities can lead to secondary cardiovascular disease, osteoporosis, depression, cognitive decline, obesity and a heightened mortality.2;274;382 Promoting physical activity might alleviate or prevent these complications, and also offer PD-specific merits. For example, increasing the level of physical activity could have a positive influence on sleep disturbances and constipation, which are common symptoms in PD. Finally, animal work in rodents with experimental parkinsonism suggests that aerobic exercise may arrest neurodegeneration by inducing adaptive changes in dopaminergic transmission.129;302;361 Such findings raise the fascinating possibility that physical activity might slow down disease progression in PD. However, to date no study has examined whether exercise can induce structural or functional brain alterations in PD, and how such neuroplasticity might occur. We are currently taking this to the test in the ParkFit study, a large randomised clinical trial currently involving 580 patients, where we use behavioural change strategies to induce a sustained increase in physical activity levels.371 Another implication of our observation may be the possibility of using the preserved cycling behaviour for devising alternative walking procedures that are less affected by FOG. An example could be the use of insoles that give tactile cues to the posterior

164 CYCLING BREAKS THE ICE FOR FREEZING OF GAIT

stance leg when the swing leg touches the ground (mimicking the mechanical coupling and cueing of pedals). The greatest challenge is to find safe and palatable ways to exercise patients with PD for sustained periods of time. Cycling is certainly an interesting option, even for patients with marked FOG, but safety issues need to be considered. Our patients felt secure while cycling, but reported difficulties – and occasionally falls – during mounting or dismounting the bicycle, particularly when this was unexpected (for example, while approaching a traffic light turning suddenly red). Cycling on a normal bicycle is therefore not ideal for all patients, but a tricycle can be a good alternative. Additional concerns relate to busy traffic and the need for dual tasking, which is problematic in PD.46;321 The safety of driving a car is also challenged when PD patients are distracted.365 Other aspects that merit attention include recklessness and impulsivity (which could increase the risk of accidents) or dementia (patients getting lost). For such patients, a stationary bicycle at home could provide an effective way to remain mobile. A final concern relates to the cardiovascular complications of exercise, which may be increased in PD.274 Patients should therefore be recommended to undergo a health fitness check before embarking upon any exercise program.

Directions for future research 5 Two lines of research may follow from this observation. The first approach involves fundamental work, trying to understand why cycling in PD is preserved better than walking. We will illustrate several possibilities. It would be interesting to quantitatively assess foot kinetics during cycling in PD patients, to test whether their apparently fluent performance contains subtle alterations related to FOG. This could be done using ergometers – with or without phase lock4 – and combined with electrophysiological or kinematic assessment. Equally relevant would be to take the idea of hyper- reactivity to visual information80 to the test, for example by having participants cycle in natural conditions (lots of visual flow) or on an exercise bicycle facing a wall or with eyes closed (no forwards flow or lateral flow). Another attractive research approach would involve mimicked cycling movements (for example, while lying recumbent), to assess the consequences of removing the tactile cues from the rotating pedals. This might further clarify whether the motor control program is really different for gait and cycling. Alternatively, subjects can be asked to mentally imagine making the cycling movements, as this creates the possibility to scan subjects using functional magnetic resonance imaging.190;340 A disadvantage is that mental imagery is only relevant for the preparatory phase of movements. This shortcoming can now be circumvented by asking subjects to make repetitive hand movements while being scanned, as this may elicit upper limb

165 CHAPTER 5

freezing that bears remarkable similarity to leg freezing and that is correlated to FOG.272;292 Functional imaging while making bilateral hand movements can reveal the cerebral substrate underlying freezing, and perhaps unveil why external influences such as rotating pedals may alleviate this. Finally, it may also be relevant to examine cycling in patients with a wider spectrum of freezing behaviours, for example subjects with unilateral freezing149 as this may offer new insights into the bilateral coordination of leg movements in PD. The second approach is more clinically oriented, aiming to evaluate strategies to implement cycling into clinical practice in a safe and enjoyable way, thus offering patients new possibilities to increase their physical activity levels.

Legend to the video

This home video shows the patient’s severe gait disorder, caused mainly by freezing of gait of the akinetic type, although some leg trembling is occasionally seen. The patient is only able to move forward by letting himself fall forward on his knees. However, he is able to generate smooth cycling movements with the legs as soon as he mounts his bicycle.

166 CYCLING BREAKS THE ICE FOR FREEZING OF GAIT

167

5.2

Cycling is less affected then walking in freezers of gait

Published as: Snijders AH, van Kesteren M, Bloem BR. Cycling is less affected then walking in freezers of gait. J Neurol Neurosurg Psychiatry. 2011 sep 20: J Neurol Neurosurg Psychiatry 2012; 83:575-576.

CYCLING IS LESS AFFECTED THEN WALKING IN FREEZERS OF GAIT

We recently described two patients with Parkinson’s disease (PD) who presented with severe freezing of gait (FOG), but who also manifested a remarkably preserved ability to ride a bicycle.338;342 Following these publications, we have been approached by many patients who reported a similar discrepancy between severe gait difficulties and an often striking ability to ride their bicycle.

Stimulated by these anecdotes, we performed a structured interview in 53 consecutive outpatients with PD (diagnosed according the UK Brain Bank Criteria). This structured interview consisted of predefined multiple choice questions about FOG, the ability to cycle, and any subjective experience of ‘freezing’ during cycling (operationally defined as intermittent blockades of one or both legs during cycling). The precise question was ‘Have you ever experienced the feeling of being glued, or experienced freezing or blocks of the legs, while you were riding your bicycle?’ This question was asked by an interviewer with considerable experience with FOG, and more clarification was given if necessary. Also, when a subject answered positively, additional detailed questions were asked to decide with more certainty that this was truly freezing. We excluded eight patients who had never cycled or stopped cycling years earlier for reasons unrelated to PD. Data of 45 remaining patients are shown in Table 1. We classified patients as having FOG when they expressed the characteristic feeling of the feet being glued to the floor.152 Twenty-five patients indicated having FOG. Twenty-one patients had more FOG during the OFF-state compared to the ON-state, 5 although 19 patients also experienced less severe FOG during the ON-state. Four patients were unable to answer which state was worse, but they had only mild FOG. None of the 25 freezers reported that freezing was more evident during the ON-state. Four patients (all freezers) had cognitive impairment.

Only one patient (a woman in her seventies, disease duration of 14 years, without dyskinesias or cognitive impairment) experienced comparable episodes of ‘freezing’ while cycling. She specified this as episodic blocking of her legs, which briefly kept her from actively pushing onto the pedals. These freezing episodes on the bicycle were much less frequent and less severe than her freezing episodes during walking. She experienced the freezing during cycling as a phenomenon comparable to her FOG. We therefore interpreted this as freezing episodes during cycling. We considered asterixis or negative myoclonus as an alternative explanation,224 but neurological examination revealed no asterixis or negative myoclonus. Eight other patients with FOG (i.e. 32% of the 25 freezers, without cognitive impairment) reported that the feet sometimes exerted an irregular pressure on the pedals, but without overt blockades. We considered it unlikely that choreiform dyskinesias could explain this phenomenon, as only one of these eight patients had manifest dyskinesias. Fourteen freezers (61%) cycled without any difficulties, including a normal ability to start the cycling motion.

171 CHAPTER 5

Table 1 Results of the structured interview in 45 consecutive patients with Parkinson’s disease who had been regularly riding a bicycle

FREEZERS NON-FREEZERS Number of patients 25 20 Still cycling 19 18 Gender (men) 19 (76%) 9 (45%) Age (years) 62.6 (SD 11.3) 62.4 (SD 6.6) Hoehn and Yahr (On medication) Stage 1 0 2 Stage 1.5 1 2 Stage 2 14 10 Stage 2.5 3 4 Stage 3 5 2 Stage 4 2 0 Disease duration (years) 8.7 (SD 5.3) 4.2 (SD 3.3) Difficulty cycling 18 7 Freezing (blockades) of the legs 1 0 Irregular pressure on the pedals 8 0 Unable to mount a bicycle 3 0 Unable to maintain balance 6 2 Fitness 3 3 Other (e.g. muscle cramp, deviation) 5 4

Data are expressed as absolute numbers (percentage between brackets), or as means and standard deviations.

In addition to these subjective accounts, we observed cycling in three patients with marked FOG, and did not observe any freezing during cycling on a real or stationary bicycle. None of the 20 patients without FOG ever experienced freezing or blockades of the legs while cycling, nor any irregular pressure on the pedals.

This questionnaire provides new evidence that preservation of cycling abilities is not a rare phenomenon in PD. Many patients can ride a bicycle without difficulties, even when walking has become problematic. Indeed, when cycling becomes impossible early in the course of a parkinsonian syndrome, the patient is unlikely to have PD, but rather has a form of atypical parkinsonism.6 And if freezing does occur during cycling in a patient with PD, the episodes seem less frequent and less severe compared to the freezing episodes during walking. The precise mechanisms underlying the preserved cycling ability remain to be determined, but several explanations can be considered (reviewed in chapter 5.1342). Specifically, the moving pedals could generate external tactile cues, maintaining the legs within a fixed amplitude and phase. The angular momentum of the pedals, gear and chain would carry the feet along, even if muscular

172 CYCLING IS LESS AFFECTED THEN WALKING IN FREEZERS OF GAIT

effort was momentarily interrupted. This does not explain why patients can start cycling without initiation failure. Therefore, cycling may involve a different, better retained motor program compared to walking. In addition, as both feet are mechanically coupled, the less affected side may help the more affected side to move. Another explanation is that compared to walking, cycling does not require postural adjustments (lateral weight shift) to unload the swing leg to initiate a step. Compared to walking, cycling may also involve greater amounts of visual input, or place different attentional demands. In addition, compared to cycling, walking is more likely to be performed during an OFF-state, although only two of our patients experienced exclusive OFF-state FOG. Indeed, various patients explicitly indicated that cycling was normal even during a profound OFF-state, when gait was severely impaired. Finally, preserved cycling abilities may be regarded as a form of kinesia paradoxica. However, kinesia paradoxica classically refers to movements that are markedly affected most of the time, but which can be performed sporadically in an almost normal manner (e.g. when elicited by strong emotions). In contrast, cycling is always retained, not only during specific moments, and it is not elicited by strong emotions. Future research will have to take these different hypotheses to the test.

The observed discrepancy between cycling and walking may also have implications for clinical practice, and in particular for rehabilitation. Cycling may offer an attractive way to promote physical activity in PD, as long as postural stability is intact. Safety is 5 obviously an issue, because patients can have difficulty mounting or dismounting their bicycle. We recommend patients to cycle on an ordinary bicycle in daily life only when they can safely mount and dismount, and otherwise to use a tricycle or stationary bicycle at home. For various reasons (including motor impairment, cognitive decline, depression, apathy, and fatigue), PD patients are heavily inclined to lead a sedentary lifestyle. Our results suggest that cycling can be offered to the majority of these patients to prevent the many complications of immobility.

Acknowledgements

This study was supported by the Prinses Beatrix Fonds, and by a research grant of The Netherlands Organisation for Health Research and Development (BRB: VIDI research grant #016.076.352; AHS: AGIKO research grant #92.003.490).

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Treating freezing of gait

Video vignette 4

The most common form of FOG occurs most frequently during the ‘OFF-state’ (“off” freezing). Hence, freezing is often alleviated by taking an adequate dose of dopaminergic medication. An illustration is seen in video vignette 4A and 4B. These videos show a woman with Parkinson’s disease while walking and turning. On video vignette 4A she has not taken her morning medication of levodopa, leading to severe freezing of gait. After taking 200 mg levodopa/50 mg benserazide, she is able to walk and turn without freezing of gait (video vignette 4B).

I’m thankful to Martin Amarell, Michael Barbe and Lars Timmermann for the use of these videos.

6.1

Cueing for freezing of gait: a need for 3D cues?

Accepted for publication: pending minor revisions Snijders AH, Jeene P, Nijkrake MJ, Abdo WF, Bloem BR. Cueing for freezing of gait: a need for 3D cues? The neurologist. CHAPTER 6

Summary

Visual cues can ameliorate freezing of gait, an incapacitating symptom frequently seen in patients with parkinsonism. Here, we describe a patient with severe freezing of gait who responded well to three-dimensional cues, but not to two-dimensional visual cues. We discuss the potential implications of this phenomenon.

178 CUEING FOR FREEZING OF GAIT: A NEED FOR 3D CUES?

Introduction

Freezing of gait (FOG) is an incapacitating symptom frequently seen in patients with parkinsonism. Visual cues are well known to improve walking in parkinsonism.312 Here, we describe a patient with severe FOG who responded well to three-dimensional (3D) cues, but not to two-dimensional (2D) visual cues. We also discuss the potential implications of this interesting phenomenon.

Case report

An 82-year-old retired engineer presented with a 8-year history of rapidly progressive and symmetrical parkinsonism, without response to levodopa, and with early urinary incontinence and brisk tendon reflexes. Cognition was normal. Cerebral MRI was normal except minor aspecific white matter lesions (Fazekas I). IBZM-SPECT showed bilateral D2 receptor loss. Blood pressure was 160/80 mmHg supine, 140/70 mmHg after 5 minutes standing. Our diagnosis was probable multiple system atrophy. His main problem was severe FOG (video 1). To overcome his FOG episodes, he initially used auditory cues, such as whistling. With disease progression, these auditory cueing lost their efficacy, but being an engineer, he self-developed two treatment devices. First, he adjusted his walking tripod by attaching a foam obstacle, allowing him to deliberately step over it (video 2). Second, to reach the pond in his spacious garden, he created a ‘walking ladder’ consisting of parallel bars attached to the grass (video 3). Interestingly, he said not to improve with flat stripes taped to the floor, but only to 3D cues. This created difficulties at home, as his wife would frequently stumble over the bars he had attached in the hallway. In addition, he showed marked improvement when climbing stairs, which he did several times each day to remain active (video 4). 6 To document this selective reaction to 3D cues, we videotaped him in the hospital. 3D bars improved his FOG considerably (video 5), but he did not react at all to 2D visual cueing (video 6).

Discussion

This patient selectively improved with 3D visual cues, but not with 2D cues. This 3D improvement was the case for the visual cues on the floor, which only alleviated FOG when these had a certain height, and to a large extent also for the modified tripod and for the retained ability to climb stairs. The observation that flat stripes on the floor were ineffective, while 3D obstacles were, has not been described earlier. The modified tripod used by our patient resembles the inverted walking stick, which

179 CHAPTER 6

occasionally improves gait in a subset of Parkinson patients with FOG.99;207 The kinesia paradoxa when climbing stairs was noted already in 1921 by Souques, who described a patient with PD who was unable to walk on an even surface, but who could run upstairs with two flights at a time.346 Indeed, 43% of PD patients with FOG indicate that going upstairs improved their walking.316

Why did our patient show a differential response to 2D and 3D visual cues? First, this observation suggests that the effect of visual cues is not mediated solely by focusing attention to the stepping process or by the requirement of generating larger stepping amplitudes.25 A second explanation may be enhanced visual feedback of the 3D cues on the floor.25 Decreased spatial contrast sensitivity is associated with a propensity to develop FOG, even when corrected for disease duration, perhaps because such patients are deprived from visual compensation for their compromised basal ganglia- supplementary motor area axis.85 The addition of an extra (third) dimension to the visual cue could enhance visual feedback, resulting in more powerful activation of visual cortical areas. With disease progression, this improvement with visual cues may eventually become lost when cortical areas become involved in the disease process. We did not test contrast sensitivity in our patient.

Third, the differential effect of 3D cues may be discussed in light of current theories about the pathophysiology of FOG. When crossing 3D obstacles (and also when climbing stairs), the feet need to be lifted higher, with more marked knee flexion. This type of walking could represent a different motor program compared to normal ‘automatic’ walking. Parkinson patients can have a remarkable preservation of specific motor programs involving repetitive leg movements, such as cycling,338 even in the face of severe FOG. Perhaps the exaggerated and more conscious ‘cock walk’ - with bent knees and the feet lifted higher - is better preserved in parkinsonism than ordinary walking.

Fourth, walking with lifted feet and flexed knees demands larger lateral weight shifts compared to crossing flat stripes on the floor. Defects in these automatic postural adjustments before a step have been suggested to contribute to development of FOG, because inability to make a lateral weight shift will lead to clearance problems at the onset of the swing phase, resulting in the foot being ‘glued to the floor’.187 Our current observation would therefore appear to argue against this hypothesis, because the need to make larger lateral weight shifts when negotiating 3D obstacles should lead to greater gait difficulties. However, we cannot exclude that the larger lateral weight shifts need to be performed more consciously, and thereby help to overcome the clearance problem of the swing leg.

180 CUEING FOR FREEZING OF GAIT: A NEED FOR 3D CUES?

A final hypothesis relates to the so-called action relevance of objects (also referred to as ‘affordances’). The affordance of an object points to the “action possibilities” that are implied by an object. For example, a cord affords pulling and a ball affords throwing. This affordance is dependent on the actor and his capability: thus, a bicycle will not afford the act of cycling if the actor is a crawling infant. Parkinson patients seem to have an exaggerated response to affordances.80 3D cues may have another action relevance than 2D cues, because an increased step height is required to step over them. Indeed, 3D cues can be regarded as obstacles that need to be negotiated, in order to avoid stumbling and even falling. Regularly appearing obstacles may act as cues and thus improve walking, but a suddenly appearing obstacle can actually induce FOG.344 The sudden appearance of a single obstacle introduces time pressure, which makes patients more prone to develop FOG. The perceived consequence of the appearing obstacle may then influence the outcome: for patients expecting 3D cues to be helpful, the 3D object will serve as a cue to improve gait. For other patients the 3D object may be perceived as an obstacle that threatens gait and leads to FOG.

This case report is also a tribute to the inventiveness of patients in developing ‘self made’ cues. Clinicians can learn from this experience, and in turn extend this knowledge about beneficial inventions to other patients. Finally, this report underscores the need for an individually tailored approach in each patient with FOG, considering their specific domestic circumstances, any self-invented cues, safety, and every patient’s individual response to specific cueing modalities. If 2D visual cues prove insufficient, adding an extra dimension may be successful for some patients.

Legend to the videos

Video 1: Severe freezing of gait (FOG) in the absence of cues (videotaped at home), 6 during straight walking and when making turns. Video 2: Marked improvement with a self-modified walking tripod (videotaped at home), during straight walking and when making turns. Video 3: Marked improvement when stepping over 3D bars attached at regular distances on the grass. Note the reoccurrence of FOG when the patient tries to negotiate the turn; apparently, the turning cycle is too tight. Walking immediately improves once the turn has been completed. Video 4: Marked improvement when walking up and down stairs. Video 5: Severe FOG in the absence of cues, but marked improvement with 3D bars placed on the floor (videotaped in the hospital). Video 6: Severe FOG, with hardly any improvement with 2D cues, namely stripes taped to the floor (videotaped in the hospital).

181

6.2

‘ON-state’ freezing of gait in Parkinson’s disease: A paradoxical levodopa-induced complication

Published as: “On” state freezing of gait in Parkinson’s disease: A paradoxical levodopa-induced complication. Espay AJ, Fasano A, van Nuenen BFL, Payne MM, Snijders AH, Bloem BR. Neurology 2012; 78:454-7. CHAPTER 6

Summary

Our objective is to describe the phenotype of levodopa-induced “on” freezing of gait (FOG) in Parkinson’s disease (PD). We present a diagnostic approach to separate “on” FOG (deterioration during the ‘ON-state’) from other FOG forms. Four PD patients with suspected “on” FOG were examined in the ‘OFF-state’ (>12 hours after last medication intake), ‘ON-state’ (peak effect of usual medication) and ‘supra-ON-state’ (after intake of at least twice the usual dose). Patients showed clear “on” FOG, which worsened in a dose-dependent fashion from the ‘ON-‘ to the ‘supra-ON-state’. Two patients also demonstrated FOG during the ‘OFF-state’, of lesser magnitude than during ‘ON-state’. In addition, levodopa produced motor blocks in hand and feet movements, while other parkinsonian features improved. None of the patients had cognitive impairment or a predating “off” FOG. True “on” FOG exists as a rare phenotype in PD, unassociated with cognitive impairment or a predating “off” FOG. Distinguishing the different FOG subtypes requires a comprehensive motor assessment in at least three medication states.

184 ‘ON-STATE’ FREEZING OF GAIT IN PARKINSON’S DISEASE: A PARADOXICAL LEVODOPA-INDUCED COMPLICATION

Introduction

Freezing of gait (FOG) is common in Parkinson’s disease (PD). FOG refers to sudden, relatively brief episodes of gait arrest, experienced subjectively by patients as their feet being “glued to the floor”.329 The relationship between FOG and dopaminergic medication is complex. Most common is “off” FOG, which is relieved by dopaminergic medication.329 Less well recognized types include “unresponsive FOG”, which is indifferent to changes in dopaminergic medication;49;276 “pseudo-on” FOG, seen during a seemingly optimal ‘ON-state’, but which nevertheless improves with stronger dopaminergic stimulation; and “on” FOG, induced by dopaminergic medication.16

Here, we describe the phenotype of “on” FOG, illustrated by four patients with PD. We also present a diagnostic approach to separate the various FOG subtypes, as a basis for understanding pathophysiology and for tailored therapeutic intervention.

Methods

Four patients (ages 59-82, disease duration 6-20 years) with a history of deteriorating FOG during “on” are described in the Supplementary Material at the end of this chapter. Subjects were tested in three states: (1) ‘practically defined OFF-state’, after 12 hours without medication;217 (2) ‘ON-state’, 45-60 minutes after intake of regular levodopa doses; and (3) ‘supra-ON-state’, after at least twice the regular dose. Institutional Review Board approved the study protocol and written informed consent was obtained. These tests were done on one day, in a fixed order, without blinding. Subject 3 was also tested one month later in the “supra-off” state, after 72 hours without any medication. Motor evaluations included the UPDRS-III subscale 6 (supplementary table 1) and timed gait tasks (gait initiation, straight walking with two 180-degree turns, and one 360-degree turn in each direction). Determination of FOG appearance was based on patient and investigator judgment.

Standard Protocol Approvals and Patient Consents: Subjects provided informed consent to participate in this Institutional Review Board-approved study protocol, according to the recommendations of the Declaration of Helsinki.

185 CHAPTER 6

Results

Effect of levodopa All subjects had gait worsening in the ‘ON-state’, which deteriorated further in the ‘supra-ON-state (Figure 1). Overall motor UPDRS scores either did not improve or worsen in three of four patients due to the appearance of severe FOG and associated postural impairment , in the absence of substantial improvements in bradykinesia or rigidity to compensate for such deterioration. In the ‘OFF-state’, only subject 1 and 3 showed FOG, although substantially less compared to the ‘ON-state’. The other subjects exhibited mainly hypokinetic gait, with small steps and shuffling, but no FOG. Timed gait tests are available in supplementary table 2. After 3 days without medication subject 3 experienced gait ignition problems, but without associated trembling or subjective gluing, which were typical for his FOG in the ‘ON-state’. Probably, this represented profound general akinesia, instead of episodic FOG. In the ‘ON-state’, all subjects developed FOG. In the ‘supra-ON-state’, subjects showed severely disabling FOG, being almost completely unable to walk. Consequently, timed tasks took longer to complete from ‘OFF’ to ‘ON’ to ‘supra-ON-state’. Video documentation of gait for Subject 2 and 3 is shown in the videos, described at the end of this chapter in the ‘supplementary material’.

Other levodopa side-effects Subject 2 and 3 showed peak-dose dyskinesias. Subjects 2 and 4 experienced nausea, yawning and orthostatic hypotension during the ‘supra-ON-state’. None of these side effects interfered with gait.

Phenotype of ‘ON’ FOG Periods of FOG were sudden and never preceded by “festination” (rapid increase in cadence at the expense of shortening stride length), and were more common during gait ignition and turns. Subject 1, 3 and 4 also displayed marked FOG during straight walking. FOG was almost as severe during straight walking as during 180-degree turns in all subjects, and during 360-degree turns in subject 4 (Figure 1). Most episodes had the trembling-in-place phenotype, although there were some akinetic episodes, especially in the supra-on phase. During the “on” phase, FOG sometimes led to near-falls (subjects 1, 3 and 4). Concurrently with progressive FOG in the ‘ON-’ and ‘supra-ON-states’, there was corresponding deterioration of rapid alternating pro- and supination of the hands resembling freezing. These movements were relatively fast, with low amplitude. In contrast, other parkinsonian features (speech, handwriting, rigidity) improved with levodopa.

186 ‘ON-STATE’ FREEZING OF GAIT IN PARKINSON’S DISEASE: A PARADOXICAL LEVODOPA-INDUCED COMPLICATION

Figure 1 The 360-degree turn task

Subjects performed a 360-degree turn into each direction in each medication state. The figure shows the time normalized with respect to baseline performance (OFF). For each subject, only the worst performance (with regard to the right/left direction) is displayed; Case 1 was unable to complete the 360-degree-turn task and therefore the straight walking task is shown (the same subject was unable to complete the task in the supra-ON condition).

Discussion 6

This paper addresses two issues. First, we propose a test protocol to unveil the complex relationship between medication effects and FOG, using both supratherapeutic medication doses and a practically defined OFF-state. Second, we preselected four PD patients with self-reported levodopa-induced worsening of gait, to report the phenotype of “on” FOG. Several common characteristics emerged: 1) a trembling FOG type which worsened with increasing levodopa doses; 2) debut of “on” FOG without predating “off” FOG, after a short disease duration and brief dopaminergic treatment; 3) concurrent worsening (freezing) of repetitive alternating hand movements in the ‘ON-state’; 4) good levodopa-responsiveness of other parkinsonian features; and 5) preserved cognition, unlike the frontal cognitive impairment associated with “off” FOG during the ‘ON-state’.17 In three patients FOG affected open space walking as much as turning and gait initiation, unlike classical “off” FOG, where turning is much

187 CHAPTER 6

more affected compared to straight walking.329 These features point to a different pathophysiology underlying “on” and “off” FOG, and suggest that “on” FOG does not result from an effect of dopaminergic drugs on alertness, from orthostatic hypotension or from isolated D2 agonism in the absence of D1 stimulation. Perhaps “on” FOG is related to dopaminergic disruption in rhythm generation of alternating hand and feet movements.292 Alternatively, dopamine regulation or non-dopaminergic neurotransmitter systems may be changed by levodopa use, as occurs in levodopa-induced dyskinesias.67

Based on prior evidence and the observations reported here, four FOG types can be recognized (Figure 2): (1) the most common, “off” FOG, which diminishes or disappears in the ‘ON-state’; (2) “pseudo-on” FOG, due to insufficient dopaminergic stimulation (probably representing “off” FOG); (3) “unresponsive” FOG, where FOG is present in

Figure 2 Types of freezing of gait

The theoretical ‘threshold’ (or rather, the dose range) for motor improvement (and also the threshold for improvement of “off” FOG) may be lower for appendicular manifestations of Parkinson’s disease (PD) (A) versus freezing of gait (B). “Off” FOG occurs below the threshold for motor benefits. In this case a dose increase above such threshold is expected to eliminate the FOG. “Pseudo-on” FOG is an intermediate FOG level, occurring at doses where patients appear to otherwise respond well to medication. Although counterintuitive, a tolerable increase in the dose of antiparkinsonian medication in these patients is also expected to eliminate the FOG. Finally, “on” FOG reported here may develop or worsen with higher Levodopa doses. For these patients, gait only improves after Levodopa dose reduction (adapted from Grimbergen et al156).

Appendicular A symptoms & signs B Freezing of gait

ON state freezing

Threshold to treat freezing of gait

ON state Pseudo ON state freezing

Dose of antiparkinson medication Threshold for Dose of antiparkinson medication Threshold for treatment response treatment response

OFF state OFF state freezing

188 ‘ON-STATE’ FREEZING OF GAIT IN PARKINSON’S DISEASE: A PARADOXICAL LEVODOPA-INDUCED COMPLICATION

‘OFF-‘ and ‘ON-states’, and which is not influenced by medication; and (4) “on” FOG, reported here, where FOG is absent during ‘OFF-state’ (e.g. immediately after waking up) and emerges after the first medication dose.

Table 1 OFF and ON FOG behavior according to medication state

Medication State “off” period FOG “on” period FOG Supra-OFF +++ - OFF ++ +/- ON + ++ Supra-ON - +++

FOG: Freezing of gait; OFF: after an overnight withdrawal, with testing about 12 hours after the last dose of dopaminergic medication; ON: approximately 45 minutes after a dose of Levodopa, once a subject recognizes his/her best response; supra-OFF: after more than 70 hours without any medication; supra-ON: 45 to 60 minutes after intake of 200% of the regular or “therapeutic” Levodopa dose.

Appropriate distinction between “on” and “off” FOG may be difficult during routine clinical visits, where patients typically present in their usual “wearing off” or “subjectively good on” state (Table 1). To identify the FOG subtypes with more certainty, we recommend testing patients after supra-therapeutic doses of dopaminergic agents and, in selected cases, after medication withdrawal for >12 hours (“practically defined off” state). Using these two extreme medication conditions, we showed that our patients worsened in a dose-dependent fashion, from ‘OFF-’ to ‘ON-‘ to ‘supra-ON-state’. This protocol thus eliminated the possibility of “pseudo-on” FOG and “off” FOG. 6 Most FOG during the ‘ON-state’ may actually represent patients who are relatively undertreated, because the ‘threshold’ (dose range) to improve FOG is higher than the threshold to improve appendicular motor signs.156 The term “on” FOG should be reserved for FOG that is truly levodopa-induced, as in our cases. They did not have “unresponsive” (or non-dopaminergic) FOG, because their gait improved and FOG disappeared when levodopa doses were reduced, and did not even return during a profound OFF-state.

“On” FOG was first observed at the time when levodopa was introduced.16 Symptoms disappeared when levodopa dosage was reduced. Further studies will be needed to determine whether supra-therapeutic levodopa doses have similarly deleterious effects in patients without overt “on” freezing. Also, the prevalence of true “on” FOG with the current medication regime remains to be determined.

189 CHAPTER 6

“On” FOG presents a serious therapeutic dilemma. Dopaminergic treatment should be reduced to alleviate FOG, but this may lead to unacceptable worsening of other parkinsonian features. Subthalamic deep brain stimulation is not a good option, because this is generally reserved for levodopa-responsive features, and not for medication-resistant features. However, its dopa-sparing effect may alleviate “on” FOG. Finally, external cueing may be considered, which was indeed effective in three of our subjects. However, others have reported less favorable results of visual cueing for PD patients with “on” FOG.207

190 ‘ON-STATE’ FREEZING OF GAIT IN PARKINSON’S DISEASE: A PARADOXICAL LEVODOPA-INDUCED COMPLICATION

Supplementary material for chapter 6.2: Case Reports

Case 1. A 77-year-old man developed slowly progressive asymmetric hypokinesia and bradykinesia (disease duration 20 years, left-dominant). His brain MRI showed no vascular lesions or other abnormalities. His cognitive function was preserved (MMSE = 28/30; Frontal Assessment Battery = 16/18). A comprehensive neuropsychological evaluation showed only mild executive impairment but no other difficulties. After a disease duration of 5 years, he started walking with short steps but without FOG. Levodopa improved his speech and handwriting, but worsened his gait. Initially, FOG episodes were restricted to turning and crossing doorframes. Subsequently, FOG began to affect straight walking. From the outset, his FOG only improved with visual cueing or when levodopa was discontinued (which led to self-imposed drug ‘holidays’). He used a laser-cued walker or a motorized scooter for longer ambulation. His FOG was mainly the ‘trembling in place’ phenotype. His Freezing of Gait Questionnaire (FOGQ) score was 24/24. Throughout the disease, he only used a dose of 150 mg of levodopa in the morning. Any dose increases elicited severe FOG. He did not improve after therapeutic trials with pramipexole, ropinirole, and rotigotine. He reported improvement in gait with methylphenidate 5 mg three times daily, but developed seizures after three months, prompting discontinuation.

Case 2. This 82-year-old woman presented with an asymmetric hypokinetic-rigid syndrome with marked hypophonia (disease duration 9 years, left-dominant). Cognition was normal (MMSE = 30/30; Frontal Assessment Battery = 18/18; Montreal Cognitive Assessment = 30/30). Although there was marked improvement in speech and handwriting with levodopa, she experienced FOG, falls, and gait disturbance when “on” after 4 years of disease duration, with progressive worsening in severity 6 and frequency. In addition, levodopa caused postural lightheadedness and mild leg chorea, interpreted as diphasic dyskinesia. Several earlier trials of levodopa increase led to severe peak-dose dyskinesias and FOG worsening, which only improved upon dose reductions. Her currently preferred dose of levodopa was 150 mg five times each day. However, severe FOG (FOGQ score 24/24) prevented her from playing tennis or even driving, as she would freeze trying to get out of the car, greatly limiting her socially. She demonstrated FOG when turning and while crossing a doorframe, which was overcome with visual cueing.

Legend to the videos Turns of case 2: Video 1: ‘OFF-state’ gait (task completion = 32 seconds) shows no freezing.

191 CHAPTER 6

Video 2: ‘ON-state’ gait, after 150 mg of levodopa (task completion = 47 seconds) shows moderate FOG. Video 3: ‘Supra-ON-state’, after 300 mg of levodopa (task completion = 94 seconds) shows severe FOG with motor blocks during turns.

Case 3. This 59-year-old man without cognitive complains developed dopa-responsive rest tremor, hypokinesia, bradykinesia, and rigidity in the right arm, 17 years prior to this assessment. The left side slowly became involved over several years. Five years after disease onset, he developed gait initiation problems and FOG episodes, which were initially restricted to turning and crossing narrow passages, resulting in falls. Moving over longer distances could only be accomplished by sitting on a wheeled walker, pushing himself backwards. However, he was able to walk from his bed to the toilet in the early morning (before intake of any medication) with virtually no FOG, although he experienced severe FOG without any fluctuations during the rest of the day (FOGQ 20/24). There was no improvement of FOG with increasing levodopa dosages, although tremor, rigidity and speech did improve. Visual or auditory cues were not successful. Current treatment consisted of levodopa 125 mg 12 to 14 times each day and 1 mg pergolide each day.

Legend to the videos: Case 3: Video 4: Walking while in ‘OFF-state’ shows a hypokinetic gait with small steps and shuffling, but no real FOG episodes. Video 5: Walking in the ‘ON-state’ shows moderately severe freezing. Video 6: Severe freezing with almost complete inability to walk during ‘supra-ON- state’ (after 1250 mg of levodopa in 3 hours).

Case 4. This 74-year-old man suffered from an asymmetric hypokinetic-rigid syndrome (left-dominant, disease duration 6 years) with postural impairment. Cognitive function was normal (MMSE = 28/30; Frontal Assessment Battery = 18/18; comprehensive neuropsychological evaluation revealed only mild short-term memory difficulties). His symptoms were dopa-responsive, although he did notice left foot dyskinesias as well as sweating and hypotension one hour after each levodopa dose. He experienced slowness of walking since disease onset, but suddenly developed FOG 5 years after disease onset. This led to frequent falls (3-4 monthly) and a FOGQ of 22/24. He suffered from FOG when initiating gait, during turning and when walking in open space. FOG could be overcome by using a cane. His current medication was levodopa 125 mg plus entacapone 200 mg q.i.d.

192 ‘ON-STATE’ FREEZING OF GAIT IN PARKINSON’S DISEASE: A PARADOXICAL LEVODOPA-INDUCED COMPLICATION

Supplementary Table 1 Motor UPDRS and levodopa doses per state

Subject UPDRS ‘off’ UPDRS ‘on’ UPDRS Levodopa Levodopa /108) (/108) ‘supra- on’ (/108) ‘on’ (mg) ‘supra-on’ (mg) 1 34.5 36 36.5 200 400 (600 in 2 hr) 2 42.5 42 45 150 300 (450 in 2 hr) 3* 61 43 40 375 1250 4 32 31 30 200 300 (500 in 2 hr)

* Subject 3 ‘supra-OFF-state’ UPDRS = 59. Overall motor UPDRS scores either did not improve or worsen in three of four patients due to the appearance of severe FOG and associated postural impairment , in the absence of substantial improvements in bradykinesia or rigidity to compensate for such deterioration (Hoehn & Yahr scores were 3 when ‘off’ and 4 when ‘on’ and ‘supra-on’).

Supplementary Table 2 Timed gait per task Subject / Task OFF (sec) ON (sec) Supra-ON (sec) 1 / Initiation 32 33 51 1 / Walking 143 242 Unable 1*/ 360° turns Unable to complete 2 / Initiation 18 50 84 2 / Walking 32 47 94 2 / 360° turns R 11 101 64 2 / 360° turns L 20 38 100 3 / Initiation 1 2 8 3 / Walking 8 32 51 3/ 360° turns R 7 11 13 6 3/ 360° turns L 11 17 Not tested 4 / Initiation 1 9 9 4 / Walking 22 128 125 4 / 360° turns R 4 12 14 4 / 360° turns L 4 9 11

* Subject 1 was unable to complete the 360°-turn task.

193

Summary & discussion

SUMMARY & DISCUSSION

This work presented in this thesis aimed to tackle various complementary elements of freezing of gait (FOG) in patients with Parkinson’s disease (PD). The first two sections offer an outline of this thesis and a review of the available literature on gait disorders and freezing of gait. The remaining sections describe our original work, specifically tuning into the following issues: 1. A diagnostic question: what is the best way to provoke the episodic phenomenon of FOG? First, how can we provoke it in clinic, as a basis for use in clinical practice, as well as for optimal inclusion in further research studies. Second, can FOG be provoked in the controlled environment of treadmill walking, to aid further pathophysiological studies (Section 3). 2. A neuroanatomical question: what is the cerebral correlate of gait planning in patients with FOG (Section 4). 3. A pathophysiological question, aiming to clarify the remarkable ‘kinesia paradoxa’ that allows patients with severe FOG to engage seemingly normal in cycling activities, despite marked gait difficulties (Section 5). 4. A treatment question, specifically the effect of cueing on FOG and the complex relationship between levodopa and FOG (Section 6).

Here, we will discuss the main findings of this thesis, and argue directions for future research for each of these issues. In addition, a short review of ‘state-of-the-art treatment’ of FOG in PD will be presented.

Provocation of FOG

FOG is an episodic phenomenon, its sudden appearance causing discomfort and falls.201;219 However, when assessing patients with FOG in clinic or in the gait laboratory, it appears to be very difficult to elicit a freezing episode.288;341 In clinic, a simple test to elicit FOG would be useful. In a research setting, it is mandatory to have a test to classify ‘definite’ freezers, where unambiguous FOG is observed by an experienced observer (see Figure 1, which is elaborated upon in Chapter 3.2). The goal of Chapter 3.2 was to define the most sensitive, simple clinical test to classify ‘definite’ freezers. 7 We evaluated various turning scenarios, including wide and axial 180° turns and axial 360° turns (slow and rapid, in both directions). In addition, we tested a gait trajectory that included turns, a voluntary stop and a narrow passage. This trajectory was repeated three times: at normal speed, as rapidly as possible, and with dual tasking. The combination of all tests offered a sensitivity of 74% to elicit definite FOG in PD patients with a subjective history of freezing (‘probable’ FOG). Moreover, unambiguous FOG was observed using this assessment in 5% of patients who firmly denied the characteristic gluing experience of FOG in daily life. The most effective individual test

197 CHAPTER 7

to provoke FOG was rapid 360° turns in both directions. If this turning test was negative, it could be combined with a gait trajectory that included dual tasking. Repeated testing improved the diagnostic yield. The least informative tests included wide turns, 180° turns or normal speed full turns. We showed that repeated rapid full turns in both direction were equally effective – and more efficient – in provoking FOG compared to the elaborative gait trajectory. Interestingly, when FOG occurred during the more elaborative gait trajectory, this was usually during turning, again highlighting the importance of this particular test as the diagnostic procedure of first choice for the work-up of possible FOG. Other researchers also found that turning is a particularly difficult procedure for patients with FOG.316;329;348;350;398 This is probably because a turn imposes increased asymmetry as well as a decreased amplitude of steps.180 Both increased asymmetry and decreasing step length are known to provoke FOG.76;307

Figure 1 Flowchart to define ‘definite’ freezers (based on the flowchart in Chapter 3.2)

Assessment of freezing of gait future perspective

Use freezing of gait Does the patient feel intermittently glued to the oor? questionnaire + –

Has the caregiver seen the patient freezing? Educate caregiver about freezing, e.g. videodemonstration + –

Use repeated rapid full narrow turns Freezing certied by an Freezing certied by an and, if negative, FOG trajectory with dual experienced examiner? experienced examiner? tasking or walking with small steps – + + –

Probable De nite No FOG FOG FOG

Use quantitative analysis, Markers of freezing present during showing e.g. an increased Freezing Index quantitative gait analysis? (power 3-8Hz/power 0-3 Hz)

Based on these findings, we propose a practical diagnostic paradigm to assess FOG, both in a clinical setting and in a research environment (see Appendix 1: FOG Scoring Form). In this paradigm, we use not only the full rapid turns, but also the instruction to walk with small steps, based on the study by Chee et al.76 In this latter study,

198 SUMMARY & DISCUSSION

subjects were instructed to walk with smaller than usual steps, and this proved to elicit FOG in 11 out of 16 assessed patients (69%). This specific test was motivated by pathophysiological considerations, specifically the hypothesis that the basal ganglia in PD are unable to maintain a preset stride length.181 Forcing patients to walk with extra small steps should then worsen this problem and provoke FOG, which indeed proved to be the case. This study aimed to clarify the pathophysiology of FOG and was not designed as a diagnostic study, so this “small step paradigm” is not yet validated for use as a diagnostic test. However, our own unpublished clinical experience supports the observations made by Chee and colleagues: we observed a high proportion of FOG events when subjects with subjective FOG are forced to walk with small steps, especially when asked to walk as rapidly as possible. An advantage is that this test takes little time to complete. A disadvantage is that the phenomenon of FOG may be difficult to see with the naked clinical eye, because the purposeful small steps conceal the underlying freezing event. This can be solved by asking patients about the subjective experience of gluing during this test procedure. Therefore, we feel inclusion of this test may further improve the diagnostic yield of FOG provocation. Future work now needs to validate this combined approach. Pending such further evidence, we recommend the use of these objective tests as part of the inclusion procedure of test subjects for future research, to reduce misclassification in pathophysiology studies.

A further unmet need is the lack of a continuous rating scale to grade the severity of FOG, taking various factors into account such as the frequency, severity and specific provoking circumstances of FOG. A recent study showed that the current scores on Freezing of Gait Questionnaires do not correlate with the duration and frequency of FOG during extensive objective assessment.336 This makes the development of such a continuous severity scale even more important.

Box 1 Take home message FOG provocation - To provoke FOG, ask patients to make full (360°) turns from standstill, both leftward and rightward, instructing them to turn as rapidly as possible. Repeat the test once or twice if needed. 7 - In addition, instruct patients to walk rapidly with small steps, and ask about the subjective experience of glueing during this test procedure. - Appendix 1 proposes a provocation protocol for use in research studies.

We showed in Chapter 3.3 that the sudden appearance of obstacles during treadmill walking can provoke brief FOG episodes. We discussed various possible explanations

199 CHAPTER 7

why obstacles can induce FOG, even though the treadmill itself may have acted as an external cue to facilitate gait. First, obstacle avoidance forces subjects to suddenly adjust their gait, necessitating rapid planning and execution of adaptive movements.62;181 Second, it calls for a switch in motor tasks, requiring subjects to make corrective steps.170;236 Third, the knowledge of an upcoming obstacle may increase anxiety.227;316 In addition, the obstacle may force the patient to take smaller steps to avoid stepping on it, the smaller steps in turn provoking FOG.76 Lastly, extra balance adjustments are needed to step over the obstacle, and patients with FOG are known to have difficulties integrating postural weight shifts with their stepping commands.187;206(See also Box 3) However, the FOG episodes that were provoked on the treadmill were less common and certainly much briefer compared to the typical FOG episodes evoked during normal over-ground walking, presumably because the moving treadmill may have acted as an external cue to facilitate gait. This may limit the ecological validity of this new approach. However, an advantage is that we now have a validated paradigm to provoke FOG episodes in a laboratory environment where very detailed assessments are possible under well-controlled circumstances, allowing for future studies of the underlying pathophysiology. An example of such a new pathophysiology study is presented below.

In Chapter 3.4, we used the subtle FOG episodes provoked during obstacle avoidance on the treadmill, to investigate which quantitative gait parameters identify such subtle FOG episodes. We demonstrated that the occurrence of high frequencies in a biomechanical gait signal or a marked reduction in step duration and amplitude can detect even very brief FOG episodes, with acceptable sensitivity (75-88%) and specificity (>95%). Qualitative frequency analysis showed a characteristic frequency pattern. A decreased power in the 0-3 Hz band was seen, representing the actual FOG episode (a decrease in normal frequency of stepping). In addition, increased power in the 3-8 Hz band was noted, probably representing the trembling in the legs, which may be seen as an attempt to overcome the block. This finding corresponded with work of others, who also found tremulous leg activity during FOG episodes within a similar frequency band.118;164;366 Earlier work showed this same increased ‘Freezing Index’ (power 3-8Hz band / 0.5-3 Hz band) during clear FOG episodes of long duration.256 We now show that also very brief FOG episodes can be detected using the Freezing Index.

The ability to provoke and detect even subtle FOG episodes in a standardized environment, where it can be combined with e.g. kinematic measures, accelerometry, forceplates or electromyography, offers new opportunities to study the pathophysiology of FOG. Eventually, this may allow for possible development of an electrophysiological definition of FOG that could support clinicians in diagnosing or evaluation of

200 SUMMARY & DISCUSSION

FOG. Indeed, the current ‘gold standard’ of clinically based rating is possibly not sensitive enough, as very brief and subtle FOG episodes may well escape even an experienced clinical eye, particularly in a clinical setting when FOG is often paradoxically suppressed.286;341 Adding electrophysiological measures such as frequency analysis of biomechanical or electromyographic signals may help in detecting even subtle FOG episodes. Our experiments demonstrate the possibility of implementing such techniques during treadmill walking, but others are now also moving to ambulatory assessments,76;187;256 which is likely more ecologically valid. In addition, recording a video of the examination may further improve the sensitivity and specificity of FOG rating, by allowing the examiner to observe the episode again. However, off-line video rating has the disadvantage that the patient cannot be ‘debriefed’, by asking whether he or she felt as if the feet were ‘glued’ to the floor. Interestingly, the electrophysiological background of ‘feeling glued’ remains to be determined.

The main electrophysiological features of FOG – based on work in this thesis, as well as the literature93;168;181;187;256;288 – are shown in Box 2. The freezing index is defined as the power in the 3-8 Hz frequency band, divided by the power in the 0-3 Hz frequency band. Based on our current work, this is probably the most sensitive and specific measure to detect even subtle freezing episodes, and this index can be calculated using simple accelerometry measures. More work is needed in larger groups of ambulatory patients to determine if this approach can be used as a screening test for “real life” FOG, and to see whether this is truly related to the risk of falls that occur under everyday circumstances. The combination of detection devices for FOG coupled with online cueing techniques (i.e. that start cueing immediately after a FOG episodes is detected, rather than offering a continuously present cue) is currently being piloted.26;112 If proven to be effective, such approaches may offer interesting new treatment options.

Box 2 Electrophysiological definition of FOG Freezing episodes are characterised by: - Increased freezing index: Decreased power in the 0-3 Hz band, increased 7 power in 3-8 Hz band - Sequence effect: (Progressive) reduction in step duration and amplitude - Multiple anticipatory postural adjustments during trembling of the legs

201 CHAPTER 7

Understanding the pathophysiology of freezing of gait

The cerebral substrate causing FOG is largely unknown. To unravel what happens in the brain during gait planning in patients with FOG, we used motor imagery of walking in combination with fMRI (described in Chapter 4.1). During motor imagery a particular movement is imagined but not executed.193 This approach exploits the large neural overlap that exists between planning and imagining a movement.77;193;251 In addition, it avoids the confounds introduced by brain responses to altered motor performance and somatosensory feedback during actual freezing episodes.12;311 We included 24 patients with PD (12 patients with FOG, 12 matched patients without FOG) and 21 matched healthy controls. Subjects performed two previously validated tasks: motor imagery of gait, and a visual imagery control task. During fMRI scanning, we quantified imagery performance by measuring the time required to imagine walking on paths of different width and length. In addition, we used voxel-based morphometry to test whether between-group differences in imagery-related activity were related to structural differences. We showed that PD patients with FOG performing motor imagery of gait use different cerebral structures than matched PD patients without FOG or healthy controls. These cerebral differences were observed in the context of matched behavioural performance across groups, and could not be explained by brain atrophy. During imagined walking, patients with FOG showed increased activity in the mesencephalic locomotor region, which was related to subjective FOG severity. In addition, patients with FOG tended to have reduced activity in mesial frontal and posterior parietal regions. These findings provide new insights into the pathophysiology of FOG: the cause of FOG may be altered cortical regulation of movement execution, together with a progressively impaired ability of mesencephalic structures to flexibly compensate for that alteration. This may explain the manifestation of FOG during changes in motor behaviour, such as turning or initiating walking. These gait adaptations not only require a switch of motor program, but also more precise regulation of step length, gait timing and postural adjustments.

Box 3 shows the take-home message concerning the cerebral substrate of FOG, as identified in this thesis. Obviously, the evidence supporting this hypothesis is far from complete. To further understand the cerebral substrate of freezing of gait, several approaches can be employed. For example, it is possible to extend the motor imagery paradigm to other types of relevant movements, such as turning, walking with small steps, or cycling, and to use such imagined movements inside an fMRI or MEG scanner. Moreover, combining these imagined movements with different levels of urgency may help to pinpoint the relation between anxiety and FOG.

202 SUMMARY & DISCUSSION

Box 3 Understanding FOG The cerebral substrate involved in planning of gait in patients with FOG includes: - Decreased cortical activity in mesial frontal and posterior parietal regions - Increased activity in the mesencephalic locomotor region

Mechanisms probably playing a role: - Impaired ability to compensate for altered regulation of movement execution - Difficulties when more complex motor regulation is needed: o Switching motor program / preparing another movement o Changes in symmetry, amplitude or timing of stepping o The need for postural adjustments, such as unloading one of the legs to prepare for the swing phase of gait o Changing optic flow, such as when approaching a doorway o Distracting attention from gait o Increasing emotional stress

A disadvantage to the former approach is that mental imagery is only relevant for the preparatory phase of movements. To complement motor imagery, it would be helpful to study ‘real freezing’ inside an fMRI scanner. However, the simple fact that real walking is not possible inside an fMRI scanner complicates this approach. This shortcoming can now be circumvented by asking subjects to make repetitive hand movements while being scanned, as this may elicit upper limb freezing that bears remarkable similarity to leg freezing, and that is correlated to FOG.272;292;374 Functional imaging while making bilateral hand movements (thus allowing study of interlimb coordination) can reveal the cerebral substrate underlying freezing (and perhaps unveil why external influences such as rotating pedals may alleviate this.) One group has successfully studied rhythmic stepping leg movements in the scanner in a patient with FOG.272 They used this stepping paradigm in combination with a virtual reality environment to provoke freezing episodes in a single patient. The leg movements simulating ‘walking’ activated a pattern of bilateral sensorimotor cortex, similar to prior neuroimaging studies of walking. During freezing episodes, there was a marked 7 bilateral activation in the pre-supplementary motor cortex, motor cortices, prefrontal cortex and posterior parietal regions. In contrast, there was bilateral deactivation of the frontopolar cortices, as well as the precuneus.272 This approach may be a promising approach in a larger patient sample. An alternative approach would be to use other imaging techniques that do allow for real walking and freezing to occur, such as near- infrared-spectroscopy or nuclear imaging.30 Near-infrared-spectroscopy can be applied during actual gait, and uses near infrared light to measure neural activity in superficial cortical areas.254 Nuclear imaging can be applied immediately after a

203 CHAPTER 7

period of walking, and assesses cerebral activation by e.g. measuring glucose uptake (fludeoxyglucose positron emission tomography; FDG-PET, see for an example mapping gait213) or cerebral blood flow (e.g. single-photon emission computed tomography with technetium-99m-hexamethyl-propyleneamine oxime; SPECT with 99mTc-HMPAO, see for an example mapping gait137). Alternatively, resting state activity can be compared between freezing and non- freezing groups, using e.g. nuclear imaging directed at specific neurotransmitter activity,55 or resting state connectivity using fMRI.172 Interfering with the defective circuitry of freezers, either using deep brain stimulation or transcranial magnetic stimulation,39 also offers an interesting opportunity to study the cerebral substrate of FOG (and, ultimately, treat FOG which is dealt with below). For example, an interesting recent study showed a block to pre-prepared movement in PD patients with severe FOG.359 This phenomenon could be restored using deep brain stimulation to the pedunculopontine nucleus.359 Another study combined deep brain stimulation with nuclear imaging to study cerebral blood flow changes induced by pedunculopontine nucleus stimulation.31

Cycling and freezing of gait

In this thesis, we presented two patients with PD with an incapacitating FOG, who had a remarkably preserved ability to ride a bicycle. In Chapter 5.2, we provide evidence that preservation of cycling abilities is not a rare phenomenon in PD. Many PD patients can still ride a bicycle without difficulties, even when walking has become problematic. If freezing does occur during cycling in a patient with PD, the episodes seem less frequent and less severe compared to the freezing episodes during walking.

In Chapter 5.1, we discuss various mechanisms via which cycling may cause this striking ‘kinesia paradoxica’: 1. The rotating pedals acting as external pacing cues.25;203;284 Cerebrally, the fixed amplitude and timing of leg movement during cycling may decrease the regulatory load on defective cortical areas. Then, the mesencephalic locomotor region may retain its ability to support a central rhythm generator during cycling. 2. Involvement of a different and better retained motor plans.160;242 3. Much less dependence on unloading of the weight-bearing leg. This unloading can be seen as a lateral anticipatory balance adjustment, which is impaired in FOG.187;320 4. Provision of extra optic flow information from the environment, which may act as a cue to promote motion. Freezers might over-react to visual information, which is normally needed to inform the next motor actions.13;59;80 Why the changing optic flow of a doorway elicits FOG, while the rapid optic flow during cycling prevents FOG, remains to be determined.

204 SUMMARY & DISCUSSION

5. Capturing the attention of the patient better, because cycling is more task- directed, has a faster rhythm and greater ground speed, within a more rapidly changing environment.265

Regardless of the explanation, cycling offers a useful approach for rehabilitation and exercise training in patients with PD grounded by severe FOG. When balance is a problem, a tricycle or a stationary bicycle can be good alternatives, allowing patients to mount, dismount and keep balance more easily.

As already stated in chapter 5.1, two lines of research may follow from our observation of preserved cycling ability. The first approach involves fundamental work, trying to understand why cycling in PD is preserved better than walking. For example, it would be interesting to quantitatively assess foot kinetics during cycling in PD patients, to test whether their apparently fluent performance contains subtle alterations related to FOG. This could be done using ergometers – with or without phase lock4 – and combined with electrophysiological or kinematic assessment. Equally relevant would be to take the idea of hyper-reactivity to visual information80 to the test, for example by having participants cycle in natural conditions (lots of visual flow) or on an exercise bicycle facing a wall or with eyes closed (no forwards flow or lateral flow). Another attractive fundamental research approach would involve mimicked cycling movements (for example, while lying recumbent), to assess the consequences of removing the tactile cues from the rotating pedals. This might further clarify whether the motor control program is really different for gait and cycling. Imaging studies using mental imagery of cycling movements or real hand movements were already discussed on the previous page.

The second approach is more clinically oriented, aiming to evaluate strategies to implement cycling into clinical practice in a safe and enjoyable way, thus offering patients new possibilities to increase their physical activity levels. This is much needed, because PD patients have a strong tendency to become physically less active,371 which in turn may negatively affect their symptoms and possibly even their disease course.347 7 Treating freezing of gait

In section 6, we touched upon two pillars of FOG treatment: cueing and medication. Visual cues can ameliorate FOG. In Chapter 6.1, we described a patient with severe FOG who responded well to three-dimensional (3D) cues, but not to two-dimensional (2D) visual cues. We also discussed the potential implications of this interesting phenomenon. The main take-home message was that the effect of visual cues is not

205 CHAPTER 7

mediated solely by focusing attention onto the stepping process, nor by the requirement to generate larger stepping amplitudes.25 The addition of an extra (third) dimension to the visual cue could enhance visual feedback, resulting in more powerful activation of visual cortical areas. Another explanation would be that the added third dimension requires patients to really unload their leg, compensating for faulty anticipatory postural adjustments.187 Besides, the third dimension changes a simple line into an obstacle. Thereby, it may change the action relevance (‘affordance’) of the cue. PD patients seem to have an exaggerated response to affordances.80 The perceived affordance of the 3D cue may then influence the outcome: for patients expecting 3D cues to be helpful, the 3D object will serve as a cue to improve gait. For other patients the 3D object may be perceived as an obstacle that threatens gait and leads to FOG.

In chapter 6.2 we introduced a new test protocol to unveil the complex relationship between dopaminergic medication effects and FOG, using both supratherapeutic medication doses and a ‘practically defined OFF-state’217 to clarify which type of FOG the patient is experiencing. Specifically, four different FOG types can be recognized: 1. “Off” period FOG, which is the most common type, and which diminishes or disappears in the ‘ON-state’ (provided that dopaminergic medication is dosed sufficiently high).329 2. “Pseudo-on” FOG, which probably represents “off” period FOG, but which nevertheless also presents during the ‘ON-state’, due to relatively insufficient dopaminergic stimulation. 3. “Unresponsive” FOG, where FOG is present in both the ‘OFF-’ and ‘ON’-states, and which is not influenced by dopaminergic medication.49;276 4. True “on” FOG, where FOG is absent during real ‘OFF-state’, but emerges after intake of dopaminergic medication and further worsens after successive dose increases.16 In chapter 6.2, we also offered one of the first detailed accounts of the phenotype of “on” FOG, and discussed the underlying pathophysiology. In the current literature, the term “on state FOG” is often used for all FOG occurring during the ‘ON-state’, but when used as such, this term in fact combines “pseudo-on”, “unresponsive” and true “on” FOG.259 However, “off” FOG and “pseudo-on” FOG are probably reflections of the same pathology. This probably develops to “unresponsive” FOG with increasing disease severity and involvement of non-dopaminergic pathology. In contrast, the pathophysiology of true “on” FOG seems to be different. Hence, we propose to avoid confusion by reserving the term “on FOG” only for those episodes of FOG that are minimal or absent in a practically defined OFF-state, and that progressively worsens when successively higher doses of dopaminergic medication are being administered, up to the extent where patients may become dyskinetic. In contrast, the term “on” FOG should explicitly not be used for those FOG episodes that also occur during the

206 SUMMARY & DISCUSSION

‘ON-state’, but which are even worse in a practically defined OFF-state, and which improve when dopaminergic medication is pushed to supramaximal doses. Note that all other research studies in this thesis concern the more classical “off” type of FOG.

The two issues described in Section 6 (exclusive improvement of FOG with 3-dimensional cues, and FOG caused by levodopa) are, although interesting conceptually, not representative of the “usual” FOG patient. Therefore, the last part of this ‘Summary & Discussion’ summarizes some general take-home messages on treatment-relates issues, based on this thesis and on recent research studies.

Short review on treatment of freezing of gait

Medication • Most FOG episodes will improve after initiation (or a dose increase) of dopaminergic medication.140;329 • A relatively higher dose of dopaminergic medication is generally needed to treat FOG symptoms, compared to more appendicular symptoms such as hand bradykinesia and tremor (Chapter 6.2, figure 2).156 • True “on” freezing (FOG which is caused or deteriorated by dopaminergic medication) is rare, and should be treated by reducing dopaminergic medication as much as possible (Chapter 6.2). • Although dopamine agonists are associated with a higher prevalence of FOG compared to levodopa, stopping the agonist rarely improves FOG. Most patients who manifest FOG while on agonist monotherapy are in a suboptimal on-state when receiving dopamine agonists, and require a higher dose of dopaminergic medication. Some patients develop FOG shortly after start of an agonist, and in those selected cases, replacement of the agonist with levodopa should be considered.294 • A large controlled study showed that MAO-B inhibitors such as rasagiline and selegiline may decrease the likelihood of developing FOG.148 However, once FOG has developed, there is only a very small effect of MAO-B inhibitors on FOG.294;317 • Case reports and open label studies have reported that amantadine, L-threo DOPS, 7 methylphenidate, botulinum toxin injections in calf muscles, SSRI’s and SNRI’s can reduce FOG.96;97;121;139;141;143;143;191;205;208;260;277;278;295;309;314;384;403 However, there are conflicting results and no level A evidence exists. The huge placebo response in FOG should certainly be considered. For example, in a recent double-blind study into the effect of methylphenidate on FOG, both groups (methylphenidate and placebo) showed a marked reduction in self-reported FOG when using a gait diary.113 Double-blind controlled studies using objective outcome measures are therefore urgently needed.

207 CHAPTER 7

Box Level of evidence A1 = Meta-analysis containing at least some trials of level A2 and of which the results of the trials are consistent. A2 = Randomized comparative clinical trials of good quality (randomized double- blind controlled trials) of sufficient size and consistency. B = Randomized clinical trials of moderate (weak) quality or insufficient size or other comparative trials (non-randomized, cohort studies, patient-control studies) C = Non-comparative trials D = Expert opinion

Physiotherapy • Rhythmic auditory cues and visual cues can reduce FOG.203;204;266;284 (Level B evidence for cues in Parkinson’s disease, and one level B study for auditory cues for FOG290, other studies level C) • The effectiveness of cueing depends on selecting the correct cueing parameters, otherwise FOG may be paradoxically worsened.76;257;284 Increasing step amplitude (bigger steps), retaining rhythm (prevent progressively increasing cadence), making lateral weight shifts and directing attention to gait seem to be most important.266;284 Adding treadmill training on a normal or rotating treadmill may increases effectivity of training.131;176;228 (Level C evidence) • The effect of different cueing modalities differs between patients. Hence, an individually tailored approach should be used in each patient with FOG, considering the specific domestic circumstances, existence of any self-invented cues, the cognitive abilities, and every patient’s individual response to specific cueing modalities (Chapter 6.1). (Level D evidence) • Using a wide arc while turning, instead of making an axial turn ‘in place’, is effective in preventing FOG episodes (Chapter 3.2).339;386 Hence, in the domestic environments of the patients, a wide walking space should be created. (Level D evidence) • Ambulatory aids such as walkers are not that useful in freezers. Standard walkers may even increase the number of freezes (probably due to an increased attentional load, as well as increased asymmetry of gait). If a walker is necessary, a wheeled walkers is preferred as it has no effect of FOG.83 Freezers may profit from a rollator with ‘compression brakes’ which are activated when a patient leans on the rollator. A recent open-label study (n=26) showed adding a laser-light cue to a walker may modestly improve FOG and decrease the number of falls.101 (Level C evidence) • Dual tasking leads to more FOG episodes (Chapter 3.2; 348). However, it remains an open question whether this means that patients should avoid dual tasking, or in contrast, be trained to better deal with dual tasking. Increasing evidence now points to the residual training capacities of elderly and parkinsonian populations.332;395 Thus,

208 SUMMARY & DISCUSSION

a randomized controlled trial in elderly patients with dementia showed that dual-task based exercise training improves dual-task performance.332 In PD, instructing patients to pay specific attention to taking big steps during dual tasking, improves walking during dual tasking.58 Recent work from our own group has shown that PD patients can safely integrate cueing techniques into complex everyday circumstances, such as walking while having to avoid obstacles.275 This again showed that PD patients can safely perform complex dual tasks. A recent pilot study in seven PD patients showed a dual task training can improve gait speed and gait variability during dual tasking.395 Taken together (and pending further evidence), patients should probably be instructed to be careful while dual tasking, but nonetheless try to practice dual tasking under safe circumstances. In this respect, virtual reality gait training may offer possibilities in the future.253 (Level C evidence) • Use of a bicycle may help to maintain a sufficient level of physical activity for patients grounded by FOG. Note that using a stationary bicycle or a tricycle is recommended if balance is affected (Section 5). (Level D evidence) • See also the dutch guideline for physiotherapy in Parkinson’s disease: https://www. kngfrichtlijnen.nl/654/KNGF-Guidelines-in-English.htm

Deep brain stimulation • Subthalamic nucleus stimulation: (Level C evidence for FOG) o improves FOG, especially FOG that occurs during the OFF-state;86 o generally does not alleviate FOG that previously failed to improve with adequately dosed dopaminergic treatment;60;74 o may improve true ‘ON-state’ freezing, by allowing tempering of the levodopa dosage;123 o has been associated with worsening of gait and balance deficits, not only in the immediate postoperative phase, but also several years after follow-up.123;210;262;368 Adjusting the stimulation parameters (e.g. markedly lowering the stimulation frequency, or adjusting the asymmetry of bilateral stimulation) may be helpful in such patients.119;258 • Internal globus pallidus stimulation may offer a better long-term perspective for gait and balance deficits compared to subthalamic nucleus stimulation,130;262 but further 7 work remains needed to substantiate this assumption. (Level C evidence) • Pedunculopontine nucleus stimulation has hitherto failed to live up to its promises as a novel, effective target for gait and balance deficits.122;261 Further work is necessary to define the best possible treatment candidates and stimulation site. (Classification C studies positive, classification B studies negative) • Adjusting the stimulation parameters (frequency, and perhaps also voltage), optimizing the electrode position and better defining patient selection will be important factors for improving the outcome after deep brain stimulation.119;258;359

209

Nederlands

8.1

Loopstoornissen

Gepubliceerd als: van de Warrenburg BPC, Snijders AH, Munneke M, Bloem BR. Loopstoornissen door neurologische aandoeningen. Ned Tijdschr Geneeskd. 2007;151:395-400. CHAPTER 8

Samenvatting

Loopstoornissen komen veel voor en hebben vaak een neurologische oorzaak. De klinische aanpak bij een patient met een loopstoornis is lasting doordat er een groot aantal oorzakelijke aandoeningen is en doordat het moeilijk is om een loopstoornis te interpreteren. Bovendien zijn de beschikbare classificatiesystemen verwarrend. Loopstoornissen kunnen worden ingedeeld in de categorieën: antalgisch, paretisch- hypotonisch, spastisch, vestibulair, atactisch, hypokinetisch-rigide, voorzichtig en funcitoneel. Een juiste interpretative van een loopstoornis is belangrijk, omdat de te overwegen onderliggende aandoeningen, het uit te voeren aanvullend onderzoek en de in te stellen therapie hier direct van afhangen.

214 LOOPSTOORNISSEN

Loopstoornissen komen frequent voor. De prevalentie ervan neemt toe met de leeftijd: van 15% bij 60-jarigen tot maar liefst 82% bij 85-jarigen.48;192;375 Loopstoornis- sen kunnen aanzienlijke gevolgen hebben, zoals een verminderde mobiliteit, toegenomen hulpbehoevendheid en een verhoogd risico om te vallen, met alle consequenties van dien.357;375 Velerlei aandoeningen van zowel het centrale als het perifere zenuwstelsel kunnen tot een gestoord looppatroon leiden. Het herkennen van karakteristieke neurologische loopstoornissen is belangrijk omdat dit een directe aanwijzing kan geven voor de onderliggende aandoening in het zenuwstelsel. In dit artikel belichten wij de neurologische loopstoornissen vanuit een praktisch, algemeen perspectief.

Classificatie van neurologische loopstoornissen

Bij de classificatie van neurologische loopstoornissen die wij hanteren volgen wij een praktijkgerichte benadering die bestaat uit 3 opeenvolgende stappen. De cruciale eerste stap gaat uit van het klinisch geobserveerde hoofdkenmerk van de gestoorde gang. De tweede stap behelst de herkenning van een aantal nevenkenmerken van het looppatroon, al dan niet in combinatie met het effect van een bepaalde provocatie, zoals oogsluiting. De derde stap omvat het zoeken naar essentiële aanvullende gegevens uit het lichamelijk onderzoek. Tezamen leidt dit tot een voorlopige, klinische classificatie van de loopstoornis. Om vervolgens tot een etiologische diagnose te komen is meestal, maar niet altijd, aanvullend onderzoek nodig. In het navolgende bespreken wij kort enkele veel voorkomende of illustratieve loopstoornissen.

Antalgische gang. Kenmerkend van de antalgische gang is de verkorte duur van de standfase van het aangedane, pijnlijke been (‘manken’). Dit kan gepaard gaan met een verminderde knie- en heupflexie tijdens de zwaaifase (‘stijf houden’). Vaak liggen hier aandoeningen van het bewegingsapparaat aan ten grondslag, zoals coxartrose. Neurologische oorzaken zijn lumbosacrale radiculopathieën of kleine neuromen van de Nn. plantares onder de voet (morton-neuralgie). Daarom noopt dit looppatroon tot een gedegen onderzoek van het bewegingsapparaat van de benen, tot het zoeken naar afwijkingen aan de voeten en tot het uitsluiten van een radiculair syndroom.

Paretische gang. Een paretische of hypotonische gang komt voor bij mensen met slappe (synoniem: hypotone) spieren. Er bestaan twee vormen: een distale en een proximale variant. 8 De distale variant van de hypotone gang treedt op bij zwakte van spieren in de onderbenen. Bij geringe zwakte van de voetheffers komt de voet na de zwaaifase van

215 CHAPTER 8

het been met een doffe klap op de grond terecht: ‘klapvoet’ (figuur 1a). Als de zwakte van de voetheffers verder toeneemt, moet het been hoog worden opgetild tijdens de zwaaifase en wordt het onderbeen als het ware vooruit geschopt om te voorkomen dat de tenen over de grond slepen: ‘hanentred’ (zie figuur 1b). Als deze loopstoornis éénzijdig aanwezig is, moet men bekijken of de voethefferszwakte berust op een neuropathie van de N. peroneus of op een radiculair syndroom van de wortel L5. In zeldzame gevallen is deze loopstoornis een eerste uiting van amyotrofe laterale sclerose, een ziekte van de motorische voorhoorncellen. Men moet dan verder letten op handspieratrofie, fasciculaties, een piramidaal reflexpatroon en regressiereflexen. Bij een dubbelzijdige voethefferszwakte kan er polyneuropathie in het spel zijn. De proximale variant van de paretische of hypotonische gang wordt gekenmerkt door een waggelende gang, hetgeen duidt op bilaterale zwakte van de bekkengordelspieren. Hierbij kantelt het bekken tijdens het lopen naar de zijde van het standbeen. Deze manier van lopen is karakteristiek voor de meeste spierziekten, zoals de ziekte van Duchenne. Bij een waggelende gang moet men bij het lichamelijk onderzoek letten op proximale spierzwakte bij weerstandtests en bij het opkomen uit een stoel, proximale spieratrofie, eventueel lage spierrekkingsreflexen, en een positieve uitslag van de proef van Trendelenburg: bij staan op één been ziet men aan de andere kant het bekken afzakken (figuur 2). Zwakte van de bekkengordelspieren kan ook éénzijdig voorkomen, zoals bij postoperatieve zwakte van vooral de M. gluteus medius na een totale heupvervanging, direct door spierletsel of indirect door een letsel van de N. gluteus inferior.102 Overigens kan ook een spastische gang een waggelend aspect hebben, waarbij de patiënt probeert om de circumductie te compenseren (zie hierna).

Spastische gang. Hierbij wordt onderscheid gemaakt tussen de één- en de twee- zijdige spastische gang. De oorzaak voor de spastische gang is een laesie in de tractus corticospinalis, dat is de piramidebaan, ergens in het traject tussen de motorische hersenschors en de motorische voorhoorncellen in het ruggenmerg. Een laesie van de piramidebaan gaat in de benen vooral gepaard met zwakte van de buigspieren en in de armen van de strekspieren. De spastische gang wordt vooral gekenmerkt door zogenaamde circumductie: het aangedane been is stijf en beschrijft tijdens de zwaaifase een soort halve cirkel buiten de looprichting (figuur 3). Wanneer dit tweezijdig voorkomt, krijgt de gang een scharend aspect. De unilaterale spastische gang wordt vooral gezien bij cerebrale laesies, met name na een herseninfarct of een hersenbloeding, waarbij er tijdens het lopen tevens ‘vleugelen’ van de aangedane arm kan zijn, dat wil zeggen abductie van de bovenarm bij elke stap, met flexie in de elleboog (zie figuur 3). Een bilaterale spastische gang komt voor bij patiënten met een cervicale of thoracale myelopathie, maar kan ook worden veroorzaakt door een erfelijke spastische paraplegie of een infantiele encefalopathie; dan spreken wij van diplegia spastica.

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Figure 1 Distale variant van de paretische of hypotonische gang

(a) Bij een klapvoet komt de voet tijdens de afwikkelfase met een doffe klap op de grond terecht door zwakte van de voetheffers; (b) Bij de hanentred heeft de voet door ernstiger zwakte van de voetheffers tijdens de zwaaifase een plantaire in plaats van een dorsale flexie, waardoor de patiënt het zwaaibeen hoger optilt om struikelen te voorkomen.

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Figure 2 Proef van Trendelenburg

Proef van Trendelenburg bij de proximale variant van de paretische of hypotonische gang: wanneer de patiënt één been optilt, zakt het bekken naar de kant van dat been als gevolg van zwakte van de M. gluteus medius die aan het standbeen zou moeten zorgen voor approximatie van de bekkenkam en de trochanter major.

Bij de spastische gang is het belangrijk om klinisch de plaats van de laesie in de tractus corticospinalis vast te stellen, omdat dit richting kan geven aan de diagnose en bovendien bepalend is voor de keuze van het aanvullend onderzoek. Verworven aandoeningen van het ruggenmerg geven vaak een mengbeeld met elementen van zowel een spastische gang als een sensore ataxie.

Vestibulaire loopstoornis. Aandoeningen van het vestibulolabyrintaire systeem veroorzaken meestal een ernstige balansstoornis met verandering van het looppatroon. Patiënten hebben een verbreed gangspoor met deviatie naar één zijde en zoeken naar steun om vallen te voorkomen. Bij acute, eenzijdige uitval is de deviatie naar de aangedane zijde, terwijl bij prikkeling de deviatie juist optreedt naar de contralaterale zijde. In de chronische fase kan de loopstoornis minder uitgesproken of zelfs verdwenen zijn. Dit kan wijzen op herstel van de afwijking, maar ook op compensatie, met name door visuele correctie. Als men de patiënt vraagt met de ogen dicht te lopen, komt die correctie aan het licht. Patiënten met een vestibulaire loopstoornis hebben vaak ook last van misselijkheid en braken en bij het lichamelijk onderzoek moet men letten op nystagmus. Tot de oorzaken horen neuritis vestibularis, ziekte van Ménière, infarcering en traumatische contusie van het labyrint.

Atactische gang. Bij de atactische gang (‘dronkenmansgang’) ziet men een wisselend verbreed gangspoor, een variabele staplengte en het afwisselend naar links en rechts

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Figure 3 Spastische gang

Weergegeven is een eenzijdig spastisch beeld met zogenaamd ‘vleugelen’ van de arm, dat wil zeggen flexie van de arm in elleboog en pols, en stijf houden van het homolaterale been dat tijdens het zwaaien een halve cirkel beschrijft.

deviëren van de looprichting (figuur 4). Voor de etiologische differentiaaldiagnose onderscheidt men de sensorische, de cerebellaire en de frontale atactische gang. Bij de sensorische ataxie wordt de loopstoornis veroorzaakt door een gebrekkige propri- oceptieve terugkoppeling als gevolg van een laesie ergens in het sensibele systeem, meestal de perifere zenuw of de achterstrengen in het ruggenmerg. Patiënten kunnen deze loopstoornis gedeeltelijk compenseren door goed naar de benen te kijken tijdens het lopen: visuele compensatie. Typerend is dan ook dat de loopproblemen toenemen in het donker of als men de patiënt vraagt met gesloten ogen te lopen. 8 Aanvullend lichamelijk onderzoek toont een gestoorde uitslag van de proef van Romberg, dat wil zeggen dat de patiënt omvalt bij staan met gesloten ogen, alsmede

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Figure 4 Atactische gang

De voetstappen vormen een brede basis met een variabele staplengte en -breedte en deviatie van de rechte lijn.

stoornissen in de gnostische sensibiliteit aan de benen, dat wil zeggen verminderde fijne tastzin, vibratiezin en bewegingszin. Eventueel zijn de knie- en achillespeesre- flexen nauwelijks tot niet opwekbaar.

Bij de cerebellaire atactische gang is het effect van oogsluiting veel minder uitgesproken. Bovendien zijn er hierbij andere verschijnselen van cerebellaire disfunctie te vinden, zoals oogbewegingsstoornissen, dysartrie of ataxie van de armen: dysmetrie en intentietremor bij de wijsproeven. De frontale atactische gang wordt ingedeeld bij de hypokinetische gang.

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Hypokinetische gang. Hypokinetische of hypokinetisch-rigide gang is waarschijnlijk de moeilijkste categorie van de neurologische loopstoornissen doordat velerlei aandoeningen met dit type loopstoornis gepaard kunnen gaan.44 Bovendien is de klinische uitdaging juist hierbij groot, omdat de nevenkarakteristieken in het looppatroon essentiële aanwijzingen geven over de mogelijke onderliggende neurologische ziekte. Het hoofdkenmerk van de hypokinetische gang is het trage, schuifelende looppatroon met kleine passen, een verminderde staphoogte en het weinig meebewegen van de armen (figuur 5). De bekendste ziekte in deze categorie is de idiopathische ziekte van Parkinson. Bij deze aandoening is de romp voorovergebogen, zowel tijdens staan als lopen. De verminderde armzwaai vertoont een opvallende asymmetrie. Opvallend genoeg is de basis van de gang vrijwel nooit verbreed. Als de basis van de gang daarentegen wel breed – en variabel – is, moet betrokkenheid van de frontaalkwabben overwogen worden, bijvoorbeeld bij frontale tumoren of uitgebreide ischemische veranderingen van de witte stof, maar ook bij de zogenaamde parkinson-plussyndromen. Onder deze laatste vallen onder andere: multipele systeematrofie, corticobasale degeneratie en vasculair parkinsonisme. De ‘frontale’ loopstoornis heeft een nogal variabele manifestatie, die veelal afhankelijk is van de ziekteduur. Vaak is een ernstige balansstoornis naar achteren waarneembaar, bijvoorbeeld bij het uitvoeren van de retropulsietest; daarbij geeft de onderzoeker, terwijl deze achter de patiënt staat, een ruk aan zijn of haar schouders. Ook vertonen patiënten vaak de neiging spontaan naar achteren te ‘deinzen’. Patiënten met frontale stoornissen kunnen soms een zekere mate van roekeloosheid vertonen, hetgeen in combinatie met de loopstoornis resulteert in frequente valincidenten met ernstige letsels.50 In uitgesproken situaties kan er zelfs gangapraxie bestaan, waarbij de patiënten als het ware niet meer weten hoe zij moeten lopen. Hierbij treedt een opvallende discrepantie op tussen de ernst van de loopstoornis en het intacte vermogen tot normale beenbewegingen in liggende of zittende houding. Ernstig aangedane patiënten kunnen zonder hulp zelfs helemaal niet meer staan; dit noemt men astasia-abasia. Soms wijzen specifieke kenmerken van de loopstoornis al in de richting van de juiste diagnose. Zo is een bekend verschijnsel bij vasculair parkinsonisme het relatieve sparen van de armen, die zelfs bij patiënten met een ernstige loopstoornis vaak nog vrij goed meebewegen tijdens het lopen; men spreekt daarom wel van onderli- chaamparkinsonisme (‘lower body parkinsonism’). Een bijzonder fenomeen in deze categorie van loopstoornissen is het optreden van ‘bevriezen’: het plotseling blokkeren van de benen, waarbij de patiënt zelf het karakteristieke gevoel heeft ‘alsof de voeten aan de vloer vastgekleefd raken’.49 Het plotse 8 karakter van dit bevriezen is bijzonder invaliderend, omdat de patiënt zich niet goed kan aanpassen. Een volledige blokkade van alle bewegingen kan op treden, maar is

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Figure 5 Hypokinetische gang

Bij de hypokinetische gang is het looppatroon schuifelend, met een smalle basis en kleine stapjes, met verminderde of afwezige zwaaibeweging van de armen.

relatief zeldzaam. Veel vaker ziet men de patiënt als het ware ritmische kleine passen maken op de plaats. Typische momenten waarop het bevriezen vaker voorkomt, zijn tijdens pogingen tot starten met lopen, tijdens het draaien om de lengteas, wanneer de patiënt door een nauwe passage wil lopen zoals een deur, of tijdens het uitvoeren van één of meer dubbeltaken tijdens het lopen, bijvoorbeeld praten of iets dragen in de handen. Voorovervallen is een berucht gevolg. Bevriezen treedt vaak op bij de ziekte van Parkinson, vooral in meer gevorderde stadia van de ziekte, maar wordt ook gezien bij vrijwel alle andere vormen van parkinsonisme. De enige uitzondering hierop is parkinsonisme dat is veroorzaakt door blootstelling aan medicatie.

Voorzichtige gang. De voorzichtige gang, soms ook seniele loopstoornis genoemd, heeft veel overeenkomsten met de hypokinetische gang: de voortbeweging is langzaam, met een kleine paslengte, een stijve romp en vaak met een verbreed gangspoor. Dit looppatroon is vergelijkbaar met de manier waarop gezonde personen over een glad oppervlak of langs een afgrond lopen.48 Bij het neurologisch onderzoek worden weinig tot geen afwijkingen gevonden. De oorzaak is voornamelijk gelegen in een angst om te vallen, die soms reëel is, bijvoorbeeld na een recente val of bij een daadwerkelijke onderliggende balansstoornis. De voorzichtige gang kan dan ook een eerste uiting zijn van onderliggende neuro-

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logische stoornissen, vaak cerebrovasculaire schade, en gaat samen met een hogere sterfte aan cardiovasculaire aandoeningen.47 Het voorzichtige looppatroon is weliswaar een redelijk adequate strategie om het vallen te voorkomen, maar leidt weer tot een verminderde mobiliteit. Deze is een risicofactor voor secundaire cardiovasculaire ziekten, vallen, cognitieve achteruitgang en sterfte.2;87;159;218;240 Bij patiënten met een voorzichtige gang is dus specifieke aandacht gewenst voor enerzijds de mogelijkheid van onderliggende pathologische afwijkingen en anderzijds het voorkómen van immobiliteit.

Functionele loopstoornis. Functionele loopstoornissen zijn niet zeldzaam, zelfs niet bij oudere patiënten. De belangrijkste aanwijzing voor een functionele of psychogene loopstoornis is een looppatroon dat niet compatibel is met een bekende, organisch bepaalde loopstoornis. Opvallend is de vaak ernstig gestoorde gang, echter zonder dat de patiënt daadwerkelijk valt, hetgeen op een juist zeer adequate balans wijst (figuur 6). Bij het neurologisch onderzoek is het beeld vaak inconsistent. Afleiden van de patiënt kan de verschijnselen doen veranderen of verminderen. Bij de beoordeling kan men een functionele loopstoornis verwarren met bijvoorbeeld loopstoornissen bij frontaalkwabaandoeningen.41

Figure 5 Psychogene gang

De patiënt neemt oneconomische en bizarre houdingen aan waarvoor zeer goede controle van beweging en evenwicht nodig is.

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Praktische benadering bij een patiënt met een loopstoornis

Voor een adequate beoordeling van het looppatroon moet de loopafstand voldoende zijn. Een eerste indruk kan men krijgen als men de patiënt observeert als deze uit de wachtkamer wordt opgehaald. Het is belangrijk om niet alleen het spontane looppatroon te beoordelen, maar ook te kijken naar het effect van ‘interventies’, zoals een rollator, waarmee het lopen moet verbeteren, of het opleggen van een dubbeltaak tijdens het lopen, waardoor de loopstoornis kan verergeren. Andere voorbeelden van provocaties zijn de patiënt met de ogen dicht of achteruit laten lopen. De loop- en balansfunctie kan ook op semikwantitatieve wijze in kaart gebracht worden. Een bekend voorbeeld is het meten van de tijdsduur tussen het opstaan uit een stoel, 3 m lopen, omdraaien, teruglopen en weer gaan zitten.308 Volgens de klassieke neurologische benadering kan op grond van anamnese en lichamelijk onderzoek een goede inschatting gemaakt worden waar de laesie in het zenuwstelsel gelokaliseerd moet worden. Voor een uiteindelijke etiologische diagnose is echter vaak aanvullend onderzoek noodzakelijk. Bij de voorzichtige en psychogene gangstoornis is, naast het uitsluiten van een mogelijke somatische oorzaak, aandacht nodig voor de psychische en emotionele context.

Conclusie

Loopstoornissen komen veel voor in de dagelijkse neurologische praktijk. Het aantal onderliggende aandoeningen is groot. Toch kan men met een systematische benadering en zorgvuldige determinatie van de loopstoornis vaak een anatomische of functionele diagnose stellen. Aanvullende gegevens uit de anamnese en het gerichte lichamelijke onderzoek sturen de verdere differentiaaldiagnose en daarmee het in te zetten aanvullend onderzoek. De behandeling, die wij hier niet bespraken, heeft algemene pijlers, zoals lichaamsbeweging, fysiotherapie en een revalidatietra- ject; daarnaast kunnen, afhankelijk van de onderliggende aandoening, ziektespeci- fieke interventies nodig zijn.

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225

8.2

Wankel op de benen en vallen

Gepubliceerd als: Snijders AH, Visser JE, Bloem BR. Wankel op de benen en vallen. In: Probleemgeoriënteerd denken in de neurologie. Een praktijkboek voor de opleiding en de kliniek. Ed: van Gijn J, van Dijk G. De Tijdstroom, Utrecht. 2009

WANKEL OP DE BENEN EN VALLEN

Casus

Een man van 68 jaar belt de huisarts omdat hij is gevallen en nu in huis niet goed meer durft te lopen.

Vraag 1. Wat kan in deze fase, met zo weinig informatie, al door uw hoofd gaan?

Antwoord A: Ten eerste dient gedifferentieerd te worden tussen het al dan niet aanwezig zijn van kortdurend bewustzijnsverlies voorafgaand aan de val. De benadering van vallen met of zonder bewustzijnsverlies is namelijk compleet anders. Kortdurende bewustzijnsverlies kan wijzen op epilepsie of syncope. Bij een val zonder bewustzijnsverlies moet onderscheid gemaakt worden tussen twee hoofdgroepen van vallen. Enerzijds kan vallen het gevolg zijn van extrinsieke oorzaken, d.w.z. veroorzaakt door een externe factor, zoals struikelen over een drempel of omgeduwd worden. Anderzijds kan vallen het gevolg zijn intrinsieke oorzaken, waarbij de patiënt zelf de val veroorzaakt. Voorbeelden van intrinsieke (binnen de patiënt zelf gelegen) oorzaken zijn stoornissen van het evenwicht of een afwijkend looppatroon.

Anamnese

Door de telefoon lijkt er geen acute situatie te bestaan, zoals bijvoorbeeld een gebroken heup. Patiënt is zelf weer opgestaan en loopt ondersteund door zijn echtgenote weer door de kamer. U besluit aan het eind van uw spreekuur een huisvisite te maken. De patiënt is bekend met de ziekte van Parkinson. Deze diagnose is acht jaar geleden gesteld door de huisarts. Het begon met trillen en stijfheid van de rechterarm. Later ontstond ook traagheid van het rechterbeen. Na drie jaar breidden de verschijnselen zich uit naar de linkerzijde van het lichaam. Momenteel is vooral het lopen lastig, en heeft patiënt veel moeite om uit stilstand weer op gang te komen. Hij gebruikt 5 maal daags anderhalve tablet levodopa/carbidopa (125/25 mg).

De oorzaak van de val kan de patiënt niet vertellen. Het gebeurde in de woonkamer toen hij met een kop koffie in de handen liep. Er lagen geen obstakels op de grond. De patiënt is voorover gevallen en – voor zover hij kan nagaan – is hij tevoren niet bewusteloos geweest. Hij is op zijn knieën gevallen, en heeft zich bewust opgevangen met de handen. Er zijn geen andere nieuwe klachten. Er waren geen ooggetuigen.

Vraag 2: Wat zijn uw overwegingen op basis van de anamnese? 8 Vraag 3: Is de valrichting van belang? Vraag 4: Waar zou u bij het lichamelijk onderzoek vooral aandacht aan besteden? Waarom?

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Antwoord 2: De patiënt ontkent dat er voorafgaand bewustzijnsverlies was. Het blijkt echter dat dit antwoord niet altijd volledig betrouwbaar is, omdat kortdurend bewustzijnsverlies vooral door ouderen gemakkelijk gemist wordt. Oorzaken van kortdurend bewustzijnsverlies zijn onder andere orthostatische hypotensie, cardiale syncope en sinus caroticus overgevoeligheid. Zeker orthostatische hypotensie valt te overwegen; dit kan veroorzaakt worden door de ziekte van Parkinson zelf of door een bijwerking van de dopaminerge medicatie. Het ontbreken van postictale verwardheid maakt epilepsie veel minder waarschijnlijk. Drie methoden zijn behulpzaam om te beoordelen of er toch voorafgaand bewustzijnsverlies was. Ten eerste helpt het om te vragen of patiënt zich bewust was van het moment waarop het lichaam de grond raakte. Ten tweede is het goed om te kijken naar de zogenaamde opvangreacties: als een patiënt de armen uitstrekte om de val op te vangen was hij vermoedelijk niet bewusteloos ten tijde van de val. Ten derde is het belangrijk om ooggetuigen te interviewen. Helaas zijn deze vaak, net als bij onze patiënt, niet voorhanden.

Al met al lijkt er bij deze patiënt geen voorafgaand bewustzijnsverlies te zijn geweest. Er zijn evenmin aanwijzingen voor een extrinsieke oorzaak van het vallen. Een intrinsieke oorzaak is daarom het meest waarschijnlijk, vermoedelijk een stoornis van het lopen of het evenwicht als gevolg van de ziekte van Parkinson. Deze treden regelmatig op bij de ziekte van Parkinson, en kunnen vooral in de meer gevorderde ziektestadia bijzonder invaliderend zijn. Opmerkelijk is dat de val optrad toen de patiënt kennelijk meerdere dingen tegelijk deed (lopen en een kop koffie dragen). Dit ondersteunt de gedachte dat het hier gaat om een intrinsieke val, omdat het vermogen om meerdere activiteiten tegelijk uit te voeren (het zogenaamde “multi- tasken”) is verminderd bij de ziekte van Parkinson. Als patiënten dit toch proberen neemt de loopstoornis of het balansprobleem verder toe, resulterend in valincidenten.

Antwoord 3: De valrichting kan belangrijke aanwijzingen geven voor de onderliggende oorzaken. Patiënten met de ziekte van Parkinson vallen meestal naar voren. Dit wordt veroorzaakt door een combinatie van de voorovergebogen houding, en met name door het fenomeen “bevriezen”: plotselinge episodes waarbij de voeten als het ware aan de grond vastgeplakt zitten. Als dit optreedt tijdens het lopen ontstaat een voorwaartse val omdat de romp nog doorgaat met de voorwaartse beweging. Als patiënten juist naar achteren vallen (en vooral als dit bijna spontaan lijkt te gebeuren) vormt dit een aanwijzing voor het bestaan van de ziekte progressieve supranucleaire parese (PSP), één van de vormen van atypisch parkinsonisme (zie hoofdstuk 26). “Verticaal” naar beneden vallen treedt op bij zogenaamde “drop attacks”, een nog goeddeels onbegrepen aandoening van vooral vrouwen op middelbare leeftijd die plotseling door de knieën zakken zonder bewustzijnsverlies.

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Antwoord 4: Algemeen lichamelijk onderzoek: De bloeddruk liggend en staand (orthostatische hypotensie?), auscultatie van het hart (ritmestoornis?). Kijk ook naar de verwondingen, niet alleen om deze zo nodig te behandelen, maar ook omdat de aard van de verwondingen een aanwijzing kan vormen voor de oorzaak van de val. Fracturen van de pols of clavicula suggereren dat de patiënt zich had opgevangen, hetgeen een voorafgaand bewustzijnsverlies onwaarschijnlijk maakt. Neurologisch onderzoek: Een indruk van de cognitie, onder andere ter beoordeling van de be- trouwbaarheid van de anamnese, maar ook omdat cognitieve stoornissen een sterke associatie met val incidenten vertonen. Kracht, in het bijzonder in de benen (krachtsverlies bijdragend aan de valneiging?). Bij het sensibiliteitsonderzoek is de proef van Romberg belangrijk, evenals de gnostische sensibiliteit (polyneuropathie of achterstrengstoornis?). Natuurlijk ook een beoordeling van de ernst van de Parkinson symptomen. Het lopen moet uitgebreid onderzocht worden, met het oog op de veiligheid van bewegen. Daarnaast gericht onderzoek naar het bevriezen als mogelijke oorzaak voor het vallen; de beste methode hiervoor is om de patiënt zo snel mogelijk volledig om zijn as te laten draaien, zowel linksom als rechtsom. Tenslotte balanson- derzoek middels de “retropulsietest”, waarbij de onderzoeker achter de patiënt staat en een korte ruk geeft aan de schouders van de patiënt. Hierbij wordt beoordeeld of de patiënt zelfstandig de balans kan bewaren.

Onderzoek

U meet een liggende bloeddruk van 120/85, staand 110/65, zonder begeleidende klachten van duizeligheid. Daarnaast ziet u een schaafwond op de linkerknie en op de linkerhand. Bij neurologisch onderzoek vindt u geen paresen of sensibiliteitsstoornis- sen. Wel is er een “geldtel” rusttremor van de rechterhand, met matige rigiditeit aan alle ledematen, rechts meer dan links. Het lopen gaat wat hinkend (waarschijnlijk antalgisch, als gevolg van het knieletsel). Tevens vallen de kleine, langzame pasjes op, waarbij de voeten niet hoog worden opgetild. Patiënt loopt voorovergebogen en met een verminderde armzwaai, vooral rechts. Als u de patiënt zo snel mogelijk om de as laat draaien haperen de voeten, wiebelt hij met zijn knieën alsof hij probeert alsnog passen te maken, en valt hij bijna opzij. Bij de retropulsietest maakt hij vijf kleine, langzame achterwaartse stappen, maar hij handhaaft wel zelfstandig zijn balans.

Vragen: Vraag 5: Wat is nu de meest waarschijnlijke oorzaak van het vallen? 8 Vraag6: Zijn er andere opties, en waarom zijn die minder waarschijnlijk?

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Antwoord 5: De werkhypothese is nu dat de patiënt tijdens een episode van bevriezen voorover gevallen is. Het bevriezen is een beruchte oorzaak van vallen bij de ziekte van Parkinson, vooral als patiënten zeggen voorover te vallen. U moet zich realiseren dat veel patiënten het bevriezen als zodanig niet herkennen! Net als onze patiënt denken zij zelf dat ze spontaan zijn gevallen, en het bevriezen komt vaak pas aan het licht als u vraagt naar het karakteristieke subjectieve gevoel “alsof de voeten aan de grond blijven plakken”. Dit kan alleen opgespoord worden door hier gericht naar te vragen. Ook is het behulpzaam om te vragen naar specifieke momenten waarop het bevriezen meestal optreedt. Het doet zich vooral voor bij bewegen in nauwe ruimtes zoals een toilet, bij het passeren van deuropeningen of bij het draaien om de lengteas. Ook het uitvoeren van dubbeltaken tijdens het lopen is een beruchte oorzaak voor bevriezen, net zoals dit bij onze patiënt het geval was. Een zorgvuldige anamnese is in dit geval extra belangrijk, omdat de kans groot is dat het bevriezen niet optreedt tijdens het neurologisch onderzoek. Kennelijk wordt het bevriezen onderdrukt in de ‘spannende’ setting van een doktersbezoek, mogelijk omdat de patiënt specifiek de aandacht richt op goed lopen. De meest gevoelige manier om bevriezen op te wekken tijdens het neurologisch onderzoek is om patiënten een snelle en nauwe draai om de as laten maken (het maken van een ruimere draai geeft vaak veel minder moeilijkheden). Hierbij moet u goed kijken naar verschillende verschijningsvormen van bevriezen. Het meest kenmerkend is een onvermogen om effectief voorwaarts te stappen, waarbij de voeten snelle en bijna ritmische pasjes op de plaats maken. Vaak staat de voorvoet aan de grond genageld, en wijst de hiel omhoog. Ook wiebelt de patiënt vaak met de knieën, in een poging alsnog passen te maken. Een minder frequente verschijningsvorm is het geheel ontbreken van stappen of andere bewegingen. Onze patiënt vertoonde inderdaad het kenmerkende bevriezen tijdens het draaien.

Antwoord 6: Een andere optie is een val als gevolg van de balansproblemen bij de ziekte van Parkinson. Meestal is hierbij echter ook een extrinsieke oorzaak van de ba- lansverstoring aanwezig, zoals het struikelen over een los vloerkleed. En natuurlijk kan het vallen ook multifactorieel bepaald zijn, vooral bij oudere mensen. Hierbij kunnen meerdere factoren samen resulteren in een val, of kan het vallen op verschillende momenten door andere factoren veroorzaakt worden. Vooral medicatiegebruik moet altijd als uitlokkende factor overwogen worden (Tabel 1). In ons geval kan de patiënt bijvoorbeeld door een bevriezingsepisode uit balans geraakt zijn, en was hij door zijn balansprobleem onvoldoende in staat dit weer te corrigeren.

Vraag 7: Wat zijn medicamenteuze opties om het bevriezen te verminderen?

Antwoord 7: Er is geen specifieke medicatie voor het bevriezen. Meestal helpt het om

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Table 1 Medicatie met een negatief effect op lopen en balans

Type medicatie Commentaar Neuroleptica Treedt op bij zowel typische als atypische neuroleptica. Antidepressiva Treedt op bij selectieve serotonine reuptake inhibitors (SSRI’s) en tricyclische antidepressiva (TCA’s). Anti-epileptica Treedt op bij zowel oudere (bijvoorbeeld fenobarbital) als nieuwere (bijvoorbeeld lamotrigine) anti-epileptica, maar mogelijk minder frequent bij de nieuwe anti-epileptica. Medicatie tegen ziekte van Parkinson Treedt op bij alle klassen Parkinson medicatie. Onderliggend mechanisme is complex, met o.a. excessieve dyskinesieën, orthostatische hypotensie en gedragsstoornissen. Benzodiazepines / andere hypnotica Zowel kort als lang werkende benzodiazepines. Nieuwere medicatie als zopiclon wordt veiliger geacht. Analgetica Opiaten, NSAIDs en paracetamol. Antihypertensiva Diuretica, beta-blokkers, ACE remmers en nitraten. Meest sterke effect bij opgenomen patiënten, waarschijnlijk door grotere ernst orthostase na bedrust. Anticholinergica Via een effect op de cognitie, of via orthostase. Anti-diabetica Mogelijk door onderliggende aandoening (polyneuropathie, retinopathie, cerebrovasculaire ziekte). Anti-arrhythmica Mogelijk door onderliggende pathologie (cardiale syncope).

Voor alle medicamenten geldt dat het niet altijd duidelijk is of de medicatie zelf de oorzaak is van het vallen, of slechts een “marker” is van onderliggende aandoening die zelf verantwoordelijk is.

de dosering van de Parkinson medicatie te verhogen, omdat veruit de meeste vormen van bevriezen een uiting zijn van een tekort aan dopamine in de hersenen. Voor het verbeteren van het bevriezen zijn vaak hogere doseringen medicatie nodig dan voor het corrigeren van de andere Parkinson symptomen, dus geef niet te snel op! Bij een minderheid van de patiënten wordt het bevriezen echter juist veroorzaakt door de medicatie. Kennelijk kan overmatige stimulatie van het dopaminerge systeem soms leiden tot de typerende blokkades tijdens het lopen. Het mechanisme hierachter is nog niet goed bekend. Wel is duidelijk dat dit zich kan voordoen bij het gebruik van zowel levodopa als dopamine agonisten. Het is dus belangrijk om zorgvuldig na te vragen wat de relatie is tussen het bevriezen en het tijdstip van inname van de medicatie. Het is hierbij behulpzaam om goed uit te vragen of de patiënt al in de vroege ochtend last heeft van bevriezen (nog vóór inname van de eerste medicatie gift), of dat dit juist pas optreedt ná inname van de ochtendmedicatie (in dit laatste 8 geval is de medicatie vermoedelijk als schuldige aan te wijzen). Niet-medicamenteuze middelen kunnen ook helpen tegen bevriezen (zie hieronder).

233 CHAPTER 8

Huisbezoek

Om te kijken hoe het verder gaat bezoekt u patiënt twee weken later opnieuw thuis. Het valt u op dat in de woonkamer een schuivend vloerkleed ligt. De patiënt is echter nooit meer gevallen. Hij zit voornamelijk in zijn stoel, en laat zich volledig door zijn echtgenote verzorgen. Bij navragen blijkt hij zo bang te zijn om weer te vallen dat hij nauwelijks nog ergens komt. Hij gaat niet meer naar zijn wekelijkse biljartuitje, en heeft ook zijn dagelijkse ‘blokje om’ opgegeven.

Vraag 8: Wat kan dit huisbezoek bijdragen aan uw beleid? Vraag 9: Wat stelt u voor aan verdere maatregelen?

Antwoord 8: Middels dit huisbezoek krijgt u een beter inzicht in de omgevingsfactoren die vallen in de thuissituatie kunnen veroorzaken. Voorbeelden zijn niet alleen het losse vloerkleedje of slechte verlichting, maar ook bijvoorbeeld factoren die bevriezen kunnen veroorzaken, zoals een volgestouwde huiskamer. Daarnaast levert dit huisbezoek bijzonder waardevolle inzichten op in een nieuwe complicatie die is opgetreden als gevolg van het vallen: de patiënt heeft een pathologische valangst ontwikkeld, en heeft hierdoor zijn activiteiten drastisch beperkt, met alle nadelige gevolgen van dien voor zijn sociale leven en zijn fysieke en geestelijke gezondheid. Het louter stellen van de vraag ‘Bent u nog gevallen?’ is in dit geval misleidend, omdat de afname van de valneiging in dit geval verklaard wordt door de valangst, die ertoe heeft geleid dat de patiënt volledig is geïmmobiliseerd. En wie niet beweegt valt ook niet meer!

Antwoord 9: U wilt patiënt stimuleren om meer te bewegen, om zo zijn sociaal isolement te doorbreken. Ook leidt immobiliteit op langere termijn tot cognitieve achteruitgang, cardiovasculaire ziekten en uiteindelijk tot vroeger overlijden. Maar het is natuurlijk wel essentieel dat patiënt op een veilige manier gaat bewegen. Fietsen is bijvoorbeeld een manier om meer te bewegen; veel Parkinson patiënten kunnen dit vaak beter dan lopen. Als veilig fietsen niet meer mogelijk is het gebruik van een hometrainer een goed alternatief. Ook het lopen op een loopband gaat vaak beter dan gewoon lopen. Fysiotherapeuten kunnen goed bijdragen aan het stimuleren tot bewegen. Ook kunnen zij gerichte behandelstrategieën toepassen die helpen om het bevriezen te voorkomen, en zo nieuwe valincidenten te voorkomen. Een voorbeeld hiervan is het aanleren van het gebruik van externe prikkels (de zogenaamde “cues”) die het loopritme kunnen ondersteunen, zoals ritmische geluidsprikkels (via een draagbaar metronoom) of visuele prikkels (het plakken van strepen op de huiskamervloer). Daarnaast kan de patiënt worden aangeleerd om in ruime bochten te draaien, omdat dan minder vaak bevriezen optreedt dan bij een draaien in een krappe

234 WANKEL OP DE BENEN EN VALLEN

ruimte. Ook het leren om minder haastig willen bewegen helpt om het bevriezen te voorkomen. Dergelijke specifieke behandelmethoden vergen wel een grote mate van ervaring met de ziekte van Parkinson. U kunt uw patiënt hiervoor het beste verwijzen naar een gespecialiseerde ParkinsonNet fysiotherapeut (de adressen in uw regio vindt u via www.parkinsonnet.nl). In het ParkinsonNet werken ook gespecialiseerde ergo- therapeuten, die kunnen helpen om de thuissituatie aan te passen. Dit kan bijvoorbeeld door de ruimtes minder vol te maken, of door in huis visuele “cues” aan te brengen op drempels of andere obstakels.

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8.3

Nederlandse samenvatting

NEDERLANDSE SAMENVATTING

Dit hoofdstuk geeft een Nederlandse samenvatting van dit proefschrift, waarbij we ons in lekentaal primair richten op lezers zonder uitgebreide ervaring met de ziekte van Parkinson. De Engelse ‘Summary & Discussion’ bediscussieert de resultaten in meer detail voor de professioneel geïnteresseerde lezer.

Dit proefschrift gaat over loopstoornissen, en in het bijzonder over ‘bevriezen’ van het lopen, bij patiënten met de ziekte van Parkinson. Loopstoornissen komen veel voor, met name bij ouderen. Het herkennen van karakteristieke neurologische loopstoornissen is belangrijk omdat dit een directe aanwijzing kan geven over de aard van de onderliggende aandoening in het zenuwstelsel (zie hoofdstuk 2.1 ‘Gait disorders’ en hoofdstuk 7.1 ‘Loopstoornissen’). Neurologische loopstoornissen kunnen aanzienlijke gevolgen hebben op de gezondheid, zoals een verminderde mobiliteit, een toegenomen hulpbehoevendheid en een verhoogd risico om te vallen, met alle consequenties van dien.

Box 1 Ziekte van Parkinson De ziekte van Parkinson is een degeneratieve hersenziekte met zowel motorische verschijnselen als een breed scala aan non-motorische verschijnselen. De belangrijkste motorische kenmerken van de zieke van Parkinson zijn trillen (tremor), stijfheid (rigiditeit), vertragen van bewegingen (bradykinesie) en verminderd aanwezig zijn van bewegingen (hypokinesie). Niet- motorische symptomen van de ziekte van Parkinson worden ook steeds meer onderkend: onder andere vermoeidheid, minder reukvermogen, pijn, problemen met plassen en bloeddruk regulatie, stemmings- stoornissen, slaapstoornissen en cognitieve problemen (onder andere moeite met logisch overzicht en dubbeltaken). Deze verschijnselen komen aanvankelijk vooral door dopamine gebrek in de substantia nigra (een onderdeel van de basale kernen, die diep in de hersenen zijn gelegen). Met het voortschrijden van de ziekte raken steeds meer additionele ‘non-dopaminerge’ en ‘extranigrale’ structuren betrokken bij het neurodegenerative proces. Voor de behandeling van de ziekte van Parkinson zijn vooral medicamenten (onder andere levodopa en dopamine agonisten) en her- senoperaties (diepe hersenstimulatie) belangrijk. Deze behandelingen zijn allen symptomatisch: ze onderdrukken de klachten, maar stoppen de neurodegeneratie (afbraak van neuronen) en dus de progressie van de ziekte zelf niet. Er is tot nu toe geen behandeling die de ziekte afremt of stilzet.1;53;322

Sommige loopstoornissen zijn niet consistent aanwezig, maar treden plots en ‘episodisch’ op (als het ware in aanvallen). Een voorbeeld van dergelijke episodische 8 loopstoornissen is het bevriezen tijdens het lopen, een veelvoorkomend symptoom bij de ziekte van Parkinson (Box 1). Hierbij hebben patiënten het gevoel alsof hun

239 CHAPTER 8

voeten plotseling ‘aan de grond geplakt’ raken. De patiënt kan hierdoor niet meer vooruit stappen, en daarbij maken de voeten vaak snelle en bijna ritmische pasjes op de plaats. Ook wiebelt de patiënt vaak met de knieën, in een poging alsnog passen te maken. Een minder frequente verschijningsvorm is het geheel ontbreken van stappen of andere bewegingen. Doordat bevriezen opeens en onvoorspelbaar optreedt, leidt het vaak tot vallen. Bevriezen is dan ook een zeer invaliderend symptoom van de ziekte van Parkinson. In hoofdstuk 8.2 ‘Wankel op de benen en vallen’ bespreken we in het Nederlands de ziektegeschiedenis van een patiënt die viel ten gevolge van dit bevriezen tijdens het lopen. In hoofdstuk 2.2 wordt een Engels algemeen overzicht van bevriezen tijdens het lopen gegeven. Daarnaast geeft hoofdstuk 8.4 een Nederlands overzicht van de huidige behandelingsmogelijkheden van bevriezen.

Dit proefschrift behandelt verder de volgende vragen betreffende bevriezen van lopen: • Wat is de beste manier om het episodische fenomeen ‘bevriezen van lopen’ te provoceren, zowel in de kliniek als in een experimentele onderzoekssetting? • Kunnen we bevriezen van lopen beter begrijpen door te kijken naar de hersen activiteit tijdens motorische verbeelding van lopen? • Hoe kan het dat sommige patiënten met bevriezen van lopen niet meer kunnen lopen maar nog wel kunnen fietsen? • Hoe kunnen we bevriezen van lopen het beste behandelen?

Provocatie van bevriezen van lopen

Om bevriezen van lopen goed te kunnen herkennen en behandelen, is het nodig dit te kunnen opwekken in een experimentele setting of in de kliniek (zie hoofdstuk 3.1 voor een overzicht). We hebben onderzocht wat de beste manier is om klinisch bevriezen van lopen op te wekken (hoofdstuk 3.2). De meest effectieve manier om bevriezen op te wekken bleek het verrichten van simpele snelle draaien om de as (‘360 graden test’). Wij hebben daarnaast gekeken of het vermijden van obstakels op een loopband het bevriezen van lopen kan opwekken (hoofdstuk 3.3). Onze resultaten laten zien dat de noodzaak om plotse obstakels op een loopband te vermijden inderdaad bevriezen kan opwekken in een looplaboratorium. De bewegende loopband en het vallende obstakel werken echter ook als een ‘cue’ (een uitwendige prikkel) die de optredende bevriezingsepisode meteen weer doorbreekt. Hierdoor waren de opgewekte episodes erg kort. Om zulke korte episodes kwantitatief te detecteren bleek frequentie analyse van de beenbewegingen de juiste benadering (hoofdstuk 3.4). Normaal lopen gaat vaak met een frequentie van ongeveer 1 tot 2 stappen per seconde (1 tot 2 Hz). Bij bevriezen neemt de hoeveelheid normale stappen echter af, waardoor er minder langzame bewegingen van <3 Hz zijn. De hoeveelheid bewegingen met een abnormaal snelle frequentie (3-8 Hz) neemt echter toe, mogelijk omdat de patiënt snelle (doch

240 NEDERLANDSE SAMENVATTING

ineffectieve) bewegingen maakt in een poging om uit de blokkade te komen. Hierdoor stijgt de ‘freezing index’ (hoeveelheid bewegingen 3-8 Hz/hoeveelheid bewegingen 0-3 Hz). Deze ‘freezing index’ bleek in staat korte episodes te detecteren. Dit kan in de toekomst belangrijk zijn om bijvoorbeeld in de thuissituatie korte episodes (die zouden kunnen leiden tot vallen) op te sporen en eventueel zelfs te doorbreken.

Begrijpen van bevriezen van lopen

Wat gaat er nu mis de hersenen bij patiënten met bevriezen van lopen? Gebruiken zij andere hersenstructuren als ze het plan maken om te gaan lopen? We hebben in hoofdstuk 4.1 gebruik gemaakt van functionele MRI om hersenactiviteit tijdens motorische verbeelding van lopen te bestuderen. Tijdens motorische verbeelding verbeeldt een persoon zich dat hij een bepaalde beweging maakt, zonder hem daadwerkelijk uit te voeren. Er zit een grote overlap in functie en hersenactiviteit tussen motorische planning van een daadwerkelijke actie en motorische verbeelding. Wij onderzochten drie groepen: Parkinson patiënten met bevriezen, Parkinson patiënten zonder bevriezen, en gezonde controles.

Er werd bij bevriezers een combinatie gevonden van twee verschillende veranderingen in de hersenen. Om te beginnen ontstaat in de hersenschors een probleem in het gedeelte dat betrokken is bij het selecteren van de juiste beweging (hier werd te weinig activiteit gezien bij Parkinson patiënten). Daarnaast treden haperingen op in een specifiek gebied in de hersenstam (en wel teveel activiteit in het zogenaamde ‘mesencefale locomotorische gebied’), dat wellicht de problemen van de hersenschors probeert te compenseren. Dit zou kunnen verklaren waarom bevriezen vooral optreedt tijdens situaties waar snelle aanpassingen van het looppatroon verwacht worden, zoals draaien of tijdens het vermijden van obstakels; tijdens dat soort complexe omstandigheden schiet de compensatie vanuit de hersenstam mogelijk tekort. Deze twee gebieden zijn mogelijk nieuwe doelwitten voor diepe hersenstimulatie of voor transcraniële magnetische stimulatie, als nieuwe behandeling om het bevriezen beter te gaan behandelen.

Fietsen en bevriezen van lopen

We beschrijven twee interessante ‘case reports’ over patiënten met de ziekte van Parkinson, die enerzijds nauwelijks zelfstandig konden lopen, maar anderzijds zonder problemen een fietstocht konden maken. Ook toen we gestructureerd bij 53 patiënten met de ziekte van Parkinson vroegen naar problemen tijdens het fietsen, bleek dat 8 bevriezen van de beenbewegingen nauwelijks voorkomt bij fietsen – in tegenstelling tot bij lopen.

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Deze observatie heeft verschillende wetenschappelijke en klinische betekenissen. Eén mogelijke verklaring voor dit opmerkelijke verschijnsel zou kunnen zijn, dat de draaiende beweging van de pedalen fungeert als extern feedbackmechanisme. De fiets geeft als het ware het ritme terug aan de patiënt. Een andere verklaringsmoge- lijkheid is dat voor lopen en fietsen in het brein verschillende controlemechanismen bestaan. Daarbij is het bij fietsen minder nodig om het gewicht zijwaarts te verplaatsen, van het ene been naar het andere been. Patiënten met bevriezen van lopen hebben juist moeite om hun gewicht zijwaarts te verplaatsen voordat ze een stap kunnen zetten. Ook geeft fietsen veel visuele informatie, wat een krachtige stimulans voor beweging is. Bevriezers zouden anders op deze visuele informatie kunnen reageren, wat invloed heeft op het voorbereiden van de volgende beweging. Tenslotte zou fietsen de aandacht van de patiënt beter kunnen vasthouden, gezien er meer focus op een bepaalde taak is, er een sneller ritme en grotere snelheid bestaat, met een sneller veranderende omgeving.

Onafhankelijk van de verklaring, kunnen patiënten met bevriezen van lopen dus prima gebruik maken van de fiets. Dit kan onder andere bij wijze van therapie, bijvoorbeeld om in conditie en in beweging te blijven. Voor Parkinsonpatiënten die (ook) balansproblemen hebben, is fietsen op een gewone tweewieler uiteraard geen veilige optie. Dan kan een home-trainer of driewieler echter uitkomst bieden.

Behandelen van bevriezen van lopen (zie voor een uitgebreider overzicht het volgende hoofdstuk 8.4)

Er is geen specifieke medicatie voor het bevriezen. Meestal helpt het om de dosering van de Parkinson medicatie te verhogen, omdat veruit de meeste vormen van bevriezen een uiting zijn van een tekort aan dopamine in de hersenen. Voor het verbeteren van het bevriezen zijn vaak hogere doseringen medicatie nodig dan voor het corrigeren van de andere Parkinson symptomen. Hierdoor kan het lijken alsof het bevriezen medicatie-resistent is, terwijl er simpelweg hoger gedoseerd moet worden. Bij een minderheid van de patiënten wordt het bevriezen echter juist veroorzaakt door de medicatie. Dit beschrijven we in hoofdstuk 6.2. Kennelijk kan overmatige stimulatie van het dopaminerge systeem soms leiden tot de typerende blokkades tijdens het lopen. Het mechanisme hierachter is nog niet goed bekend. Het is dus belangrijk om zorgvuldig na te gaan wat de relatie is tussen het bevriezen en het tijdstip van inname van de medicatie.

Daarnaast zijn er een aantal niet-medicamenteuze behandelingsopties. De patiënt kan worden aangeleerd om in ruime bochten te draaien, omdat dan minder vaak

242 NEDERLANDSE SAMENVATTING

bevriezen optreedt dan bij een draaien in een krappe ruimte. Ook het leren om minder haastig te willen bewegen helpt om het bevriezen te voorkomen. (Hoofdstuk 3.2)

Een andere pijler van de huidige behandeling van bevriezen is het aanleren van gebruik van externe prikkels (zogenaamde ‘cues’). Dit kunnen ritmische geluidsprikkels zijn (via een draagbare metronoom) of visuele prikkels (het plakken van strepen op de huiskamervloer). In hoofdstuk 6.1 beschrijven we een patiënt met ernstig bevriezen van lopen die goed reageerde op driedimensionale –en niet op tweedi- mensionale - visuele cues. Dit laat zien dat niet alleen het focussen van de aandacht op het lopen of het laten zetten van grotere stappen belangrijk is voor de werkzaamheid van cues. De derde dimensie van de visuele cue zou de visuele feedback kunnen vergroten, waardoor de visuele cortex sterker geactiveerd wordt. Een andere verklaring is dat de derde dimensie ervoor zorgt dat de patiënten met aandacht echt hun gewicht moeten verplaatsen voor ze een stap zetten. In ieder geval bepalen de specifieke eigenschappen van een cue of deze werkzaam is, wat per patiënt en afhankelijk van de ernst van de ziekte kan verschillen. Een individuele aanpak is dus noodzakelijk.

243

8.4

Overzicht van de behandeling van bevriezen van lopen

OVERZICHT VAN DE BEHANDELING VAN BEVRIEZEN VAN LOPEN

Hier vatten we de behandeling van bevriezen van lopen samen, gebaseerd op de bevindingen van dit proefschrift en op recente literatuur.

Medicatie • De meeste episodes van bevriezen zullen verbeteren na het beginnen met (of verhogen van de dosis van) dopaminerge medicatie.140;329 • Om symptomen van bevriezen te behandelen, is over het algemeen een relatief hogere dosis dopaminerge medicatie nodig, vergeleken met klassieke symptomen als hand bradykinesie en tremor (hoofdstuk 6.2, figuur 2).156 • Echt “on” bevriezen (bevriezen dat veroorzaakt wordt of verslechtert door dopaminerge medicatie) is zeldzaam, en moet behandeld worden door de dopaminerge medicatie zoveel mogelijk te verminderen (Hoofdstuk 6.2). • Alhoewel dopamine agonisten geassocieerd zijn met een hogere prevalentie van bevriezen vergeleken met levodopa, heeft het stoppen van dopamine agonisten zelden effect.294 De meeste patiënten die bevriezen ontwikkelen terwijl ze monotherapie met een dopamine agonist krijgen, zijn onderbehandeld en hebben een hogere dosis dopaminerge medicatie nodig. Sommige patiënten ontwikkelen bevriezen kort na de start van een agonist, en in deze specifieke gevallen dient vervanging van de agonist door levodopa overwogen te worden. • Een grote gecontroleerde studie liet zien dat MAO-B remmers zoals rasagiline en selegiline de kans om bevriezen van lopen te ontwikkelen mogelijk vermindert.148 Als er echter eenmaal bevriezen van lopen optreedt, is er slechts een minimaal effect van het toevoegen van een MAO-B remmer op bevriezen.294;317 • Case reports en open label studies hebben beschreven dat amantadine, L-threo DOPS, methylfenidaat, botuline toxine injecties, SSRI’s and SNRI’s bevriezen kunnen verminderen.96;97;121;139;141;143;143;191;205;208;260;278;279;295;309;314;384;403 Er zijn echter tegenstrijdige bevindingen en er is geen level A bewijs (zie Box 1). Daarbij moet een grote reactie op placebo bij bevriezen van lopen zeker in het achterhoofd gehouden worden. Een recente dubbel blinde studie naar het effect van methylfenidaat op bevriezen liet bijvoorbeeld voor beide groepen (methylfenidaat en placebo) een behoorlijke vermindering in zelfgerapporteerd bevriezen zien aan de hand van een ‘loopdagboek’.113 Dubbelblinde gecontroleerde studies met objectieve uitkomstmaten zijn dus hard nodig.

Fysiotherapie • Ritmische auditieve en visuele cues kunnen bevriezen verminderen.203;204;266;284 (Bewijsniveau 2 voor effect op lopen, bewijsniveau 3 voor effect op bevriezen) • De effectiviteit van de cues hangt af van de keuze van de juiste parameters, anders 8 kan bevriezen paradoxaal zelfs verergeren.76;257;284 Het vergroten van de stap amplitude (grotere passen), het behouden van ritme (progressief versnellen van

247 CHAPTER 8

Box 1 Bewijsniveau Classificatie studies: A1 = Systematische reviews (meta-analysis) A2 = Gerandomiseerd vergelijkend onderzoek B = Gerandomiseerd vergelijkend onderzoek van matige kwaliteit of onvoldoende omvang C = Niet-vergelijkend onderzoek D = Mening van deskundigen

Bewijsniveaus in Nederlandse richtlijnen: Niveau 1 = gebaseerd op A1 of ten minste twee onafhankelijk van elkaar uitgevoerde onderzoeken op niveau A2 Niveau 2 = gebaseerd op ten minste twee onafhankelijk van elkaar uitgevoerde onderzoeken van niveau B Niveau 3 = gebaseerd op een onderzoek van niveau A2 of B, of op onderzoek van niveau C Niveau 4 = mening van deskundigen

stappen vermijden), het verplaatsen van het gewicht naar opzij en het richten van de aandacht op het lopen lijken de belangrijkste interventies. 266;284 Training op een loopband of zelfs een roterende loopband zou de effectiviteit van cue training kunnen verbeteren.131;176;228 (Bewijsniveau 3) • Het effect van verschillende cueing vormen is verschillend per patiënt. Een individuele aanpak is dus noodzakelijk, met aandacht voor de thuissituatie, aanwezigheid van zelf bedachte cues, de cognitieve capaciteiten en de individuele respons op verschillende cue vormen (Hoofdstuk 6.1). (Bewijsniveau 4) • Draaien met een wijde boog in plaats van ‘om de as / op de plaats’ is effectief om bevriezen te voorkomen (Hoofdstuk 3.2).339;386 Zorg dus ook in de thuissituatie voor een brede draai-ruimte. (Bewijsniveau 4) • Alhoewel we in hoofdstuk 6.2 een man presenteren met een geweldige respons op een looprek, zijn over het algemeen hulpmiddelen bij het lopen niet altijd behulpzaam bij bevriezen van lopen. Gebruik van een stok of looprek kan de frequentie van bevriezen zelfs doen toenemen83 (waarschijnlijk doordat meer aandacht vereist wordt, en door het vergroten van asymmetrie van lopen). Een rollator heeft geen effect of bevriezen.83 Bevriezers hebben dan waarschijnlijk het meeste baat bij een rollator met ‘drukremmen’ die geactiveerd worden wanneer de patiënt op de rollator leunt. Een recente open-label studie laat zien dat gebruik van een laserlicht bij een rollator of stok een kleine verbetering van bevriezen zou kunnen geven.101 (Bewijsniveau 3)

248 OVERZICHT VAN DE BEHANDELING VAN BEVRIEZEN VAN LOPEN

• Dubbeltaken zorgen voor meer bevriezingsepisodes (Hoofdstuk 3.2; 339;348). Het is echter onduidelijk of dat betekent dat patiënten dubbeltaken moeten vermijden, of juist oefenen. Er lijkt sprake van een residu training capaciteit van ouderen en PD patiënten.332;395 Een gerandomiseerde gecontroleerde studie bij oudere patiënten met dementie liet zien dat oefeningen met dubbeltaken het uitvoeren van dubbeltaken verbetert.332 Parkinson patiënten lopen beter tijdens dubbeltaken als ze de instructie krijgen om grote stappen te nemen tijdens de dubbeltaken.58 Een recente studie van onze groep liet zien dat Parkinson patiënten veilig cueing technieken kunnen integreren in complexe alledaagse handelingen zoals het vermijden van obstakels.275 Een recente pilot studie bij 7 Parkinson patiënten liet zien dat dubbeltaak training de snelheid en variabiliteit van lopen verbetert.395 Tot hier meer over bekend wordt, zullen patiënten waarschijnlijk geïnstrueerd moeten worden voorzichtig te zijn tijdens het uitvoeren van dubbeltaken, maar ze tegelijkertijd in veilige omstandigheden te oefenen. In de toekomst zou virtuele realiteitstraining daarbij kunnen helpen.253 (Bewijsniveau C) • Fietsen kan bevriezers helpen mobiel te blijven (Hoofdstuk 5). Als de balans gestoord is, kan een ergometer fiets of een driewieler uitkomst bieden. (Bewijsniveau 4) • Zie ook richtlijn fysiotherapie Parkinson 2006: https://www.kngfrichtlijnen.nl/index.php?NODE=2004&richtlijn=2 of http://www.parkinsonnet.nl/media/5357/rlparkinson_vtencover_151206.pdf

Diepe hersenstimulatie • Stimulatie van de subthalame nucleus (specifiek voor bevriezen: Bewijsniveau 3) o verbetert bevriezen, met name bevriezen tijdens “Off”.86 o verbetert over het algemeen bevriezen niet als dat ook niet verbetert met dopaminerge medicatie.60;74 o zou ook “On state” bevriezen kunnen verbeteren, met name doordat het mogelijk is de levodopa dosering te verlagen.123 o is soms geassocieerd met verslechtering van lopen en balans, niet alleen direct post-operatief, maar ook pas na enkele jaren.123;210;262;368 Aanpassen van de stimulatie parameters (bijvoorbeeld sterk verlagen van de frequentie van stimulatie of het aanpassen van de asymmetrie van bilaterale stimulatie) kan in zulke gevallen helpen.119;258 • Interne globus pallidus stimulatie zou betere lange termijn resultaten kunnen bieden voor loop- en balansstoornissen,130;262 maar vervolgstudies zijn nodig om dit te bewijzen. (Bewijsniveau 3) • De resultaten van pedunculopontine nucleus stimulatie zijn tot nu niet wat er van gehoopt werd als nieuw effectief target voor loop en balans stoornissen.122;261 8 Vervolgstudies zijn nodig naar selectie van de beste kandidaten en de beste plaats van stimulatie. (Classificatie C studies: positief, classificatie B studies: negatief)

249 CHAPTER 8

• Het aanpassen van stimulatie parameters (frequentie en wellicht ook voltage), optimale electrode plaatsing en betere patiënt selectie zijn belangrijke factoren om de resultaten van diepe hersenstimulatie in de toekomst te verbeteren.119;258;359

250 OVERZICHT VAN DE BEHANDELING VAN BEVRIEZEN VAN LOPEN

251

Appendices

FREEZING OF GAIT SCORING FORM

Appendix 1: Freezing of Gait Scoring Form

Patient number / Code: ______Birthday: ______Probable diagnosis: ______Most affected side: ______Disease duration (years): ______Date examination: ______Examiner: ______------Freezing on history: Yes / No Start freezing (year): ______FOG during: OFF / ON / both FOG more often during: OFF / ON / both

Severity of FOG according to patient (0-10):

Freezing of Gait Questionnaire score: FOGQ / NFOGQ

------Freezing during examination: Yes / No

Last intake of medication (hours ago): ______State during examination: OFF / ON

FOG during walking 4 m back and forth: +/– during: start / straight walking / turn

FOG during 360° turns from standstill, as rapidly as possible: To the left 1: +/– To the right 1: +/– To the left 3: +/– To the right 3: +/– To the left 2: +/– To the right 2: +/– To the left 4: +/– To the right 4: +/–

FOG during walking with small steps (4 m back and forth): Preferred speed, 25% step length: 1st time: +/– 2nd time: +/– during: start / straight walking / turn As rapidly as possible, 25% step length: 1st time: +/– 2nd time: +/– during: start / straight walking / turn

Clear FOG seen, other than during above examination + / - Being FOG during ______

Severity of FOG according to examiner (0-10):

Assessment not possible, due to other reason than FOG: Yes / No Comments: 255 A APPENDIX 1

Freezing of Gait Score Form: Explanation

Complete right answers and fill in score in squares.

History: Explanation to patient: Freezing is the feeling that your feet are transiently glued to the floor while trying to initiate walking, making a turn or when walking through narrow spaces or in crowded places. Sometimes it can be accompanied with trembling of the legs and small shuffling steps. (demonstrate if necessary)

Fill in year in which FOG occurred the first time (e.g. 2008).

State during FOG: Complete which states patients are freezing and also when most FOG appears (‘OFF’: mainly in the morning before medications are working/ mainly when patient is undermedicated; ‘ON’: mainly when medications are working well. May be together with dyskinesias. Increasing medication dose will lead to more FOG. Complete ‘BOTH’ when there is truly no difference between OFF and ON, with adequate dopaminergic medication.

Severity FOG according to patient (0-10): Let patients indicate severity of FOG, from 0 = no FOG to 10: worst FOG they can imagine. Fill in score van FOG questionnaire (if known). Complete whether this is Giladi version of 2000 (FOGQ) or Nieuwboer version of 2009 (NFOG).

Examination: Preferably during OFF (> 12 hour after last intake of medication)

Definition of FOG: Episodic inability to generate effective forward stepping. Can take different forms: ineffective ‘shuffling’, ‘trembling in place’ to try to move forward, or episodic akinesia. Often preceded by reductions of amplitude or increased/ irregular cadence, in contrast to a voluntary stop. NB: (non-episodic) generalised akinesia due to deep OFF is NOT freezing of gait! If something happens that is not clear freezing, comment on this. Only complete as ‘FOG’ when it is unequivocal FOG.

Walking back and forth: Without further instruction have patients walk 4 meter back and forth. Complete ‘+’ if FOG occurs, ‘-’ when there is no FOG. If ‘+’, indicate when FOG occurs: during initiation of gait, straight walking or turning.

256 FREEZING OF GAIT SCORING FORM

360° turns: Have patients turn from standstill 360° axial turns as rapidly as possible. Repeat four times to the right, four times to the left. EVERY time from standstill! Watch out for losing balance. Every time 2 turns from standstill to one side, then 2 to the other side, to prevent dizziness. Complete ‘+’ if FOG occurs, ‘-’ when there is no FOG.

Walking with short steps: Let the patients walk 4 meter back and forth with instruction to make short steps of 25% of normal step length. Repeat this twice. Repeat again twice, with instruction to make short steps of 25% of normal step length, but walk as rapidly as possible. Complete ‘+’ if FOG occurs, ‘-’ when there is no FOG. If ‘+’, indicate when FOG occurs: during initiation of gait, straight walking or turning.

Please also indicate when there was clear FOG but outside the formal examination, with a comment (e.g. in dooropening, when initiating walking).

Severity FOG as seen by examiner (0-10): Indicate severity of FOG as SEEN by examiner, so not according to history. 0 = no FOG seen, 10 = examination not possible at all due to severe FOG

257 A APPENDIX 2

Appendix 2: Abbreviations

2D = Two-dimensional 3D = Three-dimensional ACA = Anterior cerebral artery ADL = Activities of Daily Living ANOVA = Analysis of variance C = Controls CBD = Corticobasal degeneration CT = Computed tomography DBS = Deep brain stimulation DLB = Diffuse Lewy body disease EMG = Electromyography fMRI = Functional magnetic resonance imaging F = Freezers (Patients with Parkinson’s disease and freezing of gait) FAB = Frontal Assessment Battery FOG = Freezing of gait H&Y = Hoehn and Yahr stage L-threo DOPS = L-threo-dihydroxyphenylserine MAO-B = Monoamine oxidase B MI = Motor imagery MMSE = Mini Mental State Examination MLR = Mesencephalic locomotor region MSA = Multiple system atrophy MSA-P = MSA, parkinsonian subtype MSA-C = MSA, cerebellar dysfunction subtype NFOG-Q = New Freezing of Gait Questionnaire NF = Non-freezers (Patients with Parkinson’s disease without freezing of gait) NPH = Normal pressure hydrocephalus P = Patients (with Parkinson’s disease) PD = Parkinson’s disease PPN = Pedunculopontine nucleus PSP = Progressive supranuclear palsy SD = Standard deviation SEM = Standard error of the mean SSRI = Selective seretonine reuptake inhibitor STN = Subthalamic nucleus SNRI = Seretonine noradrenaline reuptake inhibitor VI = Visual imagery UPDRS = Unified Parkinson’s Disease Rating Scale

258 REFERENCE LIST

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274 VIDEO CONTENTS

Appendix 4: Video contents

3| Provocation of freezing of gait Video vignette 1: The challenge of provoking FOG Chapter 3.3 Video 1: FOG evoked just after obstacle crossing Video 2: FOG between just before obstacle crossing Video 3: FOG evoked by the threat of a coming obstacle

4| Understanding of freezing of gait Video vignette 2A: No effect of PPN stimulation Video vignette 2B: Good effect of PPN stimulation

5| Cycling and freezing of gait Video vignette 3: Case 1: marked FOG but preserved cycling abilities Chapter 5.1 Video 1: Case 2: marked FOG but preserved cycling abilities

6| Treatment of freezing of gait Video vignette 4A: Marked FOG in ‘OFF-state’ Video vignette 4B: No FOG after intake of levodopa/benserazide Chapter 6.1 Video 1: At home: Severe FOG in the absence of cues Video 2: At home: Improvement of FOG with walking tripod Video 3: At home: Improvement of FOG with 3D bars Video 4: At home: Improvement of FOG with walking stairs Video 5: In hospital: Severe FOG, improvement on 3D bars Video 6: In hospital: Hardly any improvement with 2D cues Chapter 6.2 Video 1: Case 2: ‘OFF-state’ without FOG Video 2: Case 2: ‘ON-state’ with moderate FOG Video 3: Case 2: ‘Supra-ON-state’ with severe FOG Video 4: Case 3: ‘OFF-state’ without FOG Video 5: Case 3: ‘ON-state’ with moderate FOG Video 6: Case 3: ‘Supra-ON-state’ with severe FOG

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Appendix 5: Video legends

3| Provocation of freezing of gait Video vignette 1: The challenge of provoking FOG Freezing is a frustrating phenomenon for patients, family, physicians and researchers, as ‘sometimes it’s there, sometimes it isn’t.’ As an example, video vignette 1 shows a patient with Parkinson’s disease. He reported to have marked freezing of gait at home, interfering with his daily activities. Yet, when he walked through the corridor of the outpatients department, no freezing of gait was seen at all. When he turned to come back, very slight freezing of gait was elicited. Asking the patient to turn to the other direction indeed provoked marked freezing of gait. (Greatly to relieve of his spouse, who kept telling us that he really did have marked freezing at home.)

Chapter 3.3 Obstacle avoidance to provoke freezing of gait on a treadmill Video 1: A typical FOG episode evoked just after obstacle crossing Video 2: A typical FOG episode evoked between obstacle release and obstacle cross Video 3: A more severe FOG episode evoked by the threat of a coming obstacle, needing an emergency stop. Hereafter, the patient shows a very subtle FOG episode just before obstacle cross.

4| Understanding of freezing of gait Video vignette 2A and 2B: Dual effect of pedunculopontine nucleus stimulation Based on animal studies and open label studies, the pedunculopontine nucleus has been proposed as a promising new target for deep brain stimulation, specifically directed at improving gait.299 However, double blind studies have failed to live up to these expectations.122;261 Video vignette 2A and 2B show two patients with Parkinson’s disease who received pedunculopontine nucleus stimulation (4 years after subthalamic nucleus stimulation).122 In video vignette 2A, surgery did not have any effect on FOG (woman, age 68 years, disease duration 18 years, location contact relative to pontomesencephalic line: 6.7, 9.5, 0.8). In contrast, video vignette 2B shows a patient with a remarkable response of his FOG on pedunculopontine nucleus stimulation (man, age 68 years, disease duration 13 years, location contact 5.3, 8.7, 1.5). Interestingly, the electrodes of both patients were located posterior to the pedunculopontine nucleus.122 I’m thankful to Muriel Ferraye and Bettina Debu for the use these videos.

5| Cycling and freezing of gait Video vignette 3: Case 1: marked FOG but preserved cycling abilities A 58-year old man with a 10-year history of idiopathic Parkinson’s disease presented with an incapacitating freezing of gait (video vignette 3). The patient had severe

276 VIDEO LEGENDS

difficulties initiating gait and was merely able to take a few shuffling steps when provided with a visual cue (the examiner’s foot placed in front of the patient). Attempts to walk evolved rapidly into forward festination, and a fall towards the ground. Axial turning was impossible. However, his ability to ride a bicycle was remarkably preserved (video vignette 3). Gait freezing re-occurred instantaneously after dismounting the bicycle. This striking ‘kinesia paradoxica’ may be explained by the rotating pedals that possibly acted as an external pacing cue. Alternatively, the motor control mechanisms involved in gait and cycling could be affected differentially in Parkinson’s disease. Regardless of the explanation, cycling offers a useful approach for rehabilitation and exercise training in Parkinson patients grounded by severe freezing of gait.

Chapter 5.1 Cycling breaks the ice for freezing of gait Video 1: This home video shows the patient’s severe gait disorder, caused mainly by freezing of gait of the akinetic type, although some leg trembling is occasionally seen. The patient is only able to move forward by letting himself fall forward on his knees. However, he is able to generate smooth cycling movements with the legs as soon as he mounts his bicycle.

6| Treatment of freezing of gait Video vignette 4A and 4B: Effect of levodopa on ‘off’ freezing of gait The most common form of FOG occurs most frequently during the ‘OFF-state’ (“off” freezing). Hence, freezing is often alleviated by taking an adequate dose of dopaminergic medication. An illustration is seen in video vignette 4A and 4B. These videos show a woman with Parkinson’s disease while walking and turning. On video vignette 4A she has not taken her morning medication of levodopa, leading to severe freezing of gait. After taking 200 mg levodopa/50 mg benserazide, she is able to walk and turn without freezing of gait (video vignette 4B). I’m thankful to Martin Amarell, Michael Barbe and Lars Timmermann for the use of these videos.

Chapter 6.1: Cueing for freezing of gait: a need for 3D cues? Video 1: Severe freezing of gait (FOG) in the absence of cues (videotaped at home), during straight walking and when making turns. Video 2: Marked improvement with a self-modified walking tripod (videotaped at home), during straight walking and when making turns. Video 3: Marked improvement when stepping over 3D bars attached at regular distances on the grass. Note the reoccurrence of FOG when the patient tries to negotiate the turn; apparently, the turning cycle is too tight. Walking immediately improves once the turn has been completed.

277 A APPENDIX 5

Video 4: Marked improvement when walking up and down stairs. Video 5: Severe FOG in the absence of cues, but marked improvement with 3D bars placed on the floor (videotaped in the hospital). Video 6: Severe FOG, with hardly any improvement with 2D cues, namely stripes taped to the floor (videotaped in the hospital).

Chapter 6.2: ‘ON-state’ freezing of gait in Parkinson’s disease Video 1: Case 2: ‘OFF-state’ gait (task completion = 32 seconds) shows no freezing. Video 2: Case 2: ‘ON-state’ gait, after 150 mg of levodopa (task completion = 47 seconds) shows moderate FOG. Video 3: Case 2: ‘Supra-ON-state’, after 300 mg of levodopa (task completion = 94 seconds) shows severe FOG with motor blocks during turns. Video 4: Case 3: Walking while in ‘OFF-state’ shows a hypokinetic gait with small steps and shuffling, but no real FOG episodes. Video 5: Case 3: Walking in the ‘ON-state’ (after 375 mg levodopa) shows moderately severe freezing. Video 6: Case 3: Severe freezing with almost complete inability to walk during ‘supra-ON-state’ (after 1250 mg of levodopa in 3 hours).

278 VIDEO LEGENDS

279 A

DANKWOORD

Dankwoord

“Ne marche pas devant moi, je ne suivrai peut-être pas. Ne marche pas derrière moi, je ne te guiderai peut-être pas. Marche juste à côté de moi et sois mon ami.” (Albert Camus)

Allereerst gaat mijn grote dank uit naar alle patiënten die aan dit proefschrift hebben meegewerkt. Fantastisch hoe jullie je best hebben gedaan, en steeds volhielden om obstakels te vermijden of in de MRI te blijven liggen, denkend aan lopen. Ook veel dank voor het meedenken over hoe het nu precies zit en het delen van jullie ervaringen, met of zonder video. Als ervaringsdeskundigen zijn jullie onmisbaar is het verder ontrafelen van bevriezen. Sorry dat ik juist wilde opwekken wat jullie het liefst wilden vergeten…

En dan natuurlijk Bas. Jij bent echt dé promotor van dit proefschrift. Toen ik laatst in de trein over de schouder van een gelikte bedrijfskundige meelas in een boekje over wat een onderneming succesvol maakt, las ik over ‘de superpromoter’: “De superpromoter is de personificatie van de kracht van het enthousiasme. Het aanstekelijk enthousiasme van de superpromoter is voor bedrijven van levensbelang omdat het zorgt voor aanwas van nieuwe klanten en omzetgroei. Bovendien zijn superpromoters ideale co-creators en motiveren ze het personeel.” (uit ‘de Superpromoter’ van Rijn Vogelaar) Nou Bas, jij bent absoluut een superpromotor, en niet alleen wat betreft onderzoek. Ik heb ontzettend veel van je geleerd, variërend van het opzetten van onderzoek, schrijven en aan de man brengen van artikelen tot klinisch omgaan met patiënten en met bewegingsstoornissen. Ondanks (of dankzij?) dat we twee best verschillende persoonlijkheden zijn, kunnen we heel goed met elkaar samenwerken. Ik hoop nog veel van je te blijven leren.

Ivan, many thanks for your help and effort, especially for the fMRI study but also for the bicycling paper. Your critical vision and expertise were invaluable. And your emails always let me smile (or sigh if they involved more analysis ;-) Thank you for giving me the impression that you valued my opinion –notwithstanding my rudimentary fMRI expertise.

Dank aan de manuscript commissie, Guillen Fernandez, Sander Geurts en Alice Nieuwboer voor het lezen van mijn manuscript. Een speciaal woord van dank voor Alice voor de goede samenwerking en uitwisseling van ideeën, ook met Joke en Sarah.

281 DANKWOORD

Professor Padberg, dank voor de plek als neuroloog in opleiding, en de steun in de rug bij het afbakenen van onderzoek. ‘Je kan er ook nu al een nietje doorheen doen’, toen ik nog nauwelijks begonnen was, en ‘maar wat is freezing nu eigenlijk’, zijn twee uitspraken die me goed zijn bijgebleven. Ook verder dank aan stafleden, (oud)-AIOS en onderzoekers van de afdeling neurologie: In het kader van dit proefschrift met name voor de inspirerende opmerkingen tijdens de researchbespreking, en voor het aanleveren van patiënten. Medebewoners van de vele verschillende onderzoekerska- mers waar ik verbleven heb (met name te noemen Ilse, Bram, Bart, Karlijn, Charlotte, Catherine, Willemijn, Loes en Femke, maar zeker ook de anderen!): dank voor ‘samen goed werken’, de kruisbestuiving, voor de peptalk, voor de afleiding en vele lunch, thee en GFT momenten. BANK-ers, ver zijn we niet gekomen in V&A, maar gezellig was het wel! Het secretariaat dank voor de ondersteuning. Met name dank aan Noortje voor alle hulp, wellicht het meest nog met het inplannen van afspraken met Bas..

The Intention and Action Group, thanks for allowing me as a ‘ghost-clinician’ into your midst, for fruitful discussions and help with analysis (with a special thanks to Rick and Lennart). ‘Donders’ itself, thanks for the inviting and inspiring environment. And of course many thanks to Paul Gaalman for his assistance with scanning.

Dan dank aan de mensen van de revalidatiegeneeskunde, voor de prettige samenwerking. Jacques, dank voor de aanzet van het obstakel experiment, het meedenken en genereren van hypotheses. Vivian, dank voor het ‘sparren’ en de praktische hulp: niet alleen met analyses maar ook met het sturen van het onderzoek naar meer haalbare hoogte. Roland natuurlijk heel veel dank voor je technische ondersteuning!

Arnaud, many thanks for your help with the obstacle analysis paper and the ongoing split belt paper. You have done a lot of analyses (and gave me some work deciphering it ;-), and are a star in suddenly handing in a rough draft of a manuscript. Thank you for all your work!

Maaike, zonder jou bestond het fMRI stuk überhaupt niet. Dank voor je ontzettend gestructureerde opzet, waardoor het voor mij erg makkelijk was het over te nemen. Daarnaast dank voor al je werk, van het opzetten van onderzoek en analyse, het mensen scannen tot het eerste gait-stuk schrijven. Geweldig! En daarnaast ben je gewoon heel fijn om mee samen te werken!

282 DANKWOORD

Er waren een aantal studenten betrokken bij dit onderzoek. Christel, dank voor je hulp bij de start van het obstakel experiment. Yolien, ook dank voor de hulp bij het obstakel experiment, daarnaast voor het enthousiast meedenken over het draaien. Wandana, jij begon als student maar bent inmiddels zelf ook al bijna klaar met je boekje. Ik vond het erg leuk deze ontwikkeling van dichtbij mee te maken. Dank voor de goede samenwerking, niet in de laatste plaats recent bij de e-learning! Inge, jij bent onmisbaar geweest voor het fMRI stuk. Als student ben je bij Maaike begonnen, en daarna heb je ook mij goed geholpen met het scannen en analyseren. Super dat je, toen ik net met verlof was en jij al in Leuven zat, nog zoveel gedaan hebt voor de Brain revisie.

Dank aan alle andere mede-auteurs voor het commentaar en het meedenken of het kijken van vele videos, met name Nir Giladi (thanks for sharing your expertise in gait disorders, and especially for watching all those videos together!), Marten (de epidemiologische-blik), Maarten (de fysiotherapie-blik) en Charlotte (de heel-veel- videos blik). Dank aan Michel Verbruggen voor het bewerken van de videos.

Rick, jij bent niet zomaar paranimf. Dank voor je goede vriendschap, voor de discussies over onderzoek en Parkinson maar vooral over van-alles en het leven. Super dat je zo dichtbij staat in het leven, in onderzoek (van bedenken van wilde ideeën, hulp bij analyses tot als mede-auteur) en nu ook als collega-AIOS. Op nog vele goede momenten samen, en niet te vergeten op nog veel gezellige etentjes, borrels en reisjes - ook met Tom!

Tineke, in de buik, op school, studeren, Groningen, Nijmegen, hersenen, onderzoek, twijfelen, zwanger, mamma, paranimf, promoveren begin juni. Gelukkig mogen we inmiddels lekker op elkaar lijken, ik vind het heerlijk zo’n dierbaar vriendinnetje dichtbij te hebben!

Lieve vrienden en (schoon)familie, dank voor alle belangstelling en nog belangrijker, alle afleiding. Dank voor alle gezelligheid, alle leuke kleine en grote uitjes, maar vooral voor jullie vriendschap. Ik spreek de meesten van jullie niet zo vaak als ik wel zou willen, maar gelukkig gaan we dan gewoon weer verder waar we gebleven waren! In het bijzonder wil ik noemen: Guusje, wat zit je ver weg maar je blijft dichtbij! Rianne en Floor, onderzoek kan jullie gestolen worden, maar vriendschap zeker niet. En natuurlijk lieve vriendinnetjes Brigit, Barbara, Anke, ‘huisgenootjes’ en FIC (hebben we al een date?). Paul, dank voor jouw heerlijk verfrissende ‘wat-maakt-het-uit’ kijk op de wereld. Marga dank voor de warme belangstelling en natuurlijk de super-omi die je bent.

283 DANKWOORD

Lieve Tom en Lieve Lonnie, dank voor het warme nest waaruit ik mocht groeien en me nog steeds in mag nestelen. Van jullie leerde ik mezelf zijn, empathisch zijn, na te denken over de wereld, en wellicht ook om heel veel ballen tegelijk in de lucht te houden. Ik vind het heel leuk ook af en toe ‘professioneel’ met jullie te kunnen praten als dokter of onderzoeker! (of als fietser cq fotograaf..) En dat jullie als echte papa en mama - wat ik ook doe- het altijd prachtig vinden..

Arjen, mijn lief, vriendje, papa van mijn kinderen, steun en afleider in al heel wat tropen- jaren; wat ben ik blij met jou! Nora en Max, jullie zijn de liefsten! Ik geniet van jullie ontdekken van de wereld, jullie kunstwerken, geklets, dansen, zingen, klimmen en lachen. Dikke knuffel!

284 CURRICULUM VITAE

Curriculum Vitae

Anke Helene Snijders was born on June 9th 1979 in Groningen, the Netherlands. She finished her secondary education at Maartenscollege, Haren in 1997 (cum laude). After learning Spanish, travelling and doing voluntary work in Guatemala, she started medical school at the Radboud University Nijmegen in 1998. Anke performed a scientific elective at the Institute of Neurology, Queen’s square in London in 2002. Here she worked with dr Mike Orth, prof Mary Robertson and prof John Rothwell, performing studies on Gilles de la Tourette syndrome and repetitive transcranial magnetic stimulation. She obtained her doctoral degree in 2003 (cum laude). After a clinical elective in Mansoera, Egypt, she continued regular clerkships in the Netherlands. She finished her final clerkships in Paramaribo, Suriname. After graduating in 2005, Anke started as a research assistant in the department of Neurology of the Radboud University Nijmegen Medical Centre, under supervision of prof. Bas Bloem, working on gait disorders and motor imagery. Shortly afterwards, she started her training as a neurological resident. Funded by a grant of the Prinses Beatrix Fonds, she studied eliciting freezing of gait using obstacle avoidance. In 2008, she obtained an ‘AGIKO’ grant of the Netherlands Organization for Scientific Research (NWO) named ‘Tackling freezing of gait in Parkinson’s disease’ to study freezing of gait using gait analysis, motor imagery and functional MRI. These studies resulted in this thesis, and were performed together with prof. Bas Bloem and dr Ivan Toni (Nijmegen), prof. Jacques Duysens (Leuven) and prof. Nir Giladi (Tel-Aviv). In 2011 she obtained a knowledge exchange grant of the NWO to make an e-learning module concerning freezing of gait. She will finish her neurological training in early 2016. Anke is married to Arjen and mother of Nora and Max.

285 CURRICULUM VITAE

Anke Helene Snijders is geboren op 9 juni 1979 in Groningen. Ze volgde voortgezet wetenschappelijk onderwijs aan het Maartenscollege in Haren. Na een periode van Spaans leren, reizen en vrijwilligerswerk in Guatemala, begon ze in 1998 met de studie Geneeskunde aan de Radboud Universiteit Nijmegen. Anke verrichte haar wetenschappelijke stage bij het Institute of Neurology, Queen’s square in London. Daar bestudeerde ze het Gilles de la Tourette syndroom en repetitieve transcraniele magnetische stimulatie, onder supervisie van dr Mike Orth, prof. Mary Robertson en prof. John Rothwell. Ze verkreeg haar doctoraal in 2003 (cum laude). Na een keuze- coschap in Mansoera, Egypte, volgde ze haar reguliere coschappen in Nederland. Haar laatste coschappen deed ze in Paramaribo, Suriname. In 2005 kreeg Anke haar artsenbul, waarna ze startte als junior onderzoeker bij de afdeling Neurologie van het Universitair Medisch Centrum St Radboud, onder supervisie van prof. Bas Bloem. Kort daarna startte ze met haar opleiding tot neuroloog. Gesubsidieerd door het Prinses Beatrix Fonds begon ze met onderzoek naar het opwekken van bevriezen van lopen bij Parkinson patiënten. In 2008 kreeg ze een ‘AGIKO subsidie’ van het NWO om bevriezen van lopen te bestuderen middels loopanalyse, inbeelden van lopen en functionele MRI. Deze studies werden verricht met prof. Bas Bloem, prof. Jacques Duysens, prof. Nir Giladi en dr Ivan Toni en resulteerden in dit proefschrift. In 2011 verkreeg ze een kennisbenuttings subsidie van het NWO, om een e-learning betreffende bevriezen van lopen te maken. Begin 2016 zal ze de opleiding tot neuroloog afronden. Anke is getrouwd met Arjen, en moeder van Nora en Max.

286 LIST OF PUBLICATIONS

List of publications

1. Orth M, Snijders AH, Rothwell JC. The variability of intracortical inhibition and facilitation. Clin Neurophysiol. 2003;114:2362-9. 2. Helmich RCG, Snijders AH, Verkes RJ, Bloem BR. Transcraniële Magnetische Stimulatie: het brein stimuleren om de geest te genezen? Ned Tijdschr Geneeskd. 2004: 148:410-5. 3. Orth M, Kirby R, Snijders AH, Rothwell JC, Trimble MT, Robertson MM, Münchau A. Repetitive transcranial magnetic stimulation has no effect on tics in patients with Gilles de la Tourette syndrome. Clin Neurophysiol. 2005; 116: 764-8. 4. Snijders AH, Münchau A, Bloem BR, Rothwell JC, Robertson MM. Video-analysis of rTMS in Tourette patients. J Neurol Neurosurg Psychiatry. 2005;76:1743-4. 5. Snijders AH, Robertson MM, Orth M. Beck depression inventory is a useful screening tool for major depressive disorder in Gilles de la Tourette syndrome. J Neurol Neurosurg Psychiatry. 2006; 77: 787-9. 6. Snijders AH, van de Warrenburg BP, Giladi N, Bloem BR. Neurological gait disorders in the elderly; clinical approach and classification. Lancet neurol. 2007;6: 63-74. 7. Van de Warrenburg BP, Snijders AH, Munneke M, Bloem BR. Loopstoornissen door neurologische aandoeningen. Ned Tijdschr Geneeskd. 2007; 151:395-400. 8. Snijders AH, Bloem BR. Balance and gait problems in Parkinson’s disease. In: P. W. Overstall (Editor), Falls and bone disease - CD ROM. Hereford: Kiss of Life Multimedia Ltd., 2007. 9. Voermans NC, Snijders AH, Schoon Y, Bloem BR. Why old people fall (and how to stop them). Pract Neurol. 2007; 7:158-71. 10. Snijders AH, Verstappen CCP, Munneke M, Bloem BR. Assessment of gait and balance in the clinical setting. Journal of Neural Transmission, 2007; 114:1315:21. 11. Snijders AH, Nijkrake M, Bakker M, Munneke M, Wind C, Bloem BR. Clinimetrics of freezing of gait. Movement Disorders, 2008; 23:S468-474. 12. Bakker M, Overeem S, Snijders AH, van Elswijk G, Toni I, Bloem BR. Motor imagery of gait and foot movements: effects on cortico-spinal excitability.Clin Neurophysiol. 2008; 119:2519-2527. 13. Snijders AH, Visser JE, Bloem BR. Wankel op de benen en vallen. In: Probleemgeoriënteerd denken in de neurologie. Een praktijkboek voor de opleiding en de kliniek. Ed: van Gijn J, van Dijk G. De Tijdstroom, Utrecht. 2009. 14. Snijders AH, Weerdesteyn V, Haven YJ, Duysens J, Giladi N, Bloem BR. Obstacle avoidance to elicit freezing of gait during treadmill walking. Mov Disord. 2010; 25:57-63. 15. Snijders AH, Bloem BR. Cycling for freezing of gait. New Engl J Med. 2010; 362:e46. 16. Mahabier W, Snijders AH, Delval A, Bloem BR. Freezing of gait. In: Kompoliti K, and Verhagen Metman L (eds.) Encyclopedia of Movement Disorders. Oxford: Academic Press. 2010; 486-491. 17. Delval A, Snijders AH, Duysens JE, Weerdesteyn V, Giladi N, Defebvre L, Bloem BR. Objective detection of subtle freezing of gait episodes in Parkinson’s disease. Mov Disord. 2010; 25(11):1684-93. 18. Snijders AH, Nonnekes J, Bloem BR. Recent advances in the assessment and treatment of falls in Parkinson’s disease. F1000 Medicine Reports. 2010; 2:76. 19. Snijders AH, Leunissen HP, Bakker M, Helmich RCG, Bloem BR, Toni I. Gait-related cerebral alterations in Parkinson patients with freezing of gait. Brain. 2011; 134:59-72. 20. Nanhoe-Mababier W, Snijders AH, Delval A, Weerdesteyn V, Duysens J, Overeem S, Bloem BR. Walking patterns in Parkinson’s disease with and without freezing of gait. Neuroscience. 2011; 182:217-24. 21. Snijders AH, Toni I, Ruzicka E, Bloem BR. Bicycling breaks the ice for freezers of gait. Mov Disord. 2011; 26(3):367-71. 22. Espay AJ, Fasano A, van Nuenen BF, Payne MM, Snijders AH, Bloem BR. “On” state freezing of gait in Parkinson’s disease: A paradoxical levodopa-induced complication. Neurology. 2012, 78(7):454-7 23. Snijders AH, van Kesteren M, Bloem BR. Cycling is less affected then walking in freezers of gait. J Neurol Neurosurg Psychiatry 2012; 83:575-576. 24. Nanhoe-Mahabier W, Delval A, Snijders AH, Weerdesteyn V, Overeem S, Bloem BR. The possible price of auditory cueing: Influence on obstacle avoidance in Parkinson’s disease. Mov Disord 2012. Doi 10.1002/ mds.24935 epub ahead of print. 25. Snijders AH, Jeene P, Nijkrake MJ, Abdo WF, Bloem BR. Cueing for freezing of gait: a need for 3D cues? The neurologist. Provisionally accepted. 26. Snijders AH, Haaxma CA, Hagen YJ, Munneke M, Bloem BR. Freezer or Non-freezer: Clinical assessment of freezing of gait. Parkinsonism Relat Disord. 2012; 18:149-54.

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DONDERS GRADUATE SCHOOL FOR COGNITIVE NEUROSCIENCE SERIES

Donders Graduate School for Cognitive Neuroscience Series

1. van Aalderen-Smeets, S.I. (2007). Neural dynamics of visual selection. Maastricht University, Maastricht, the Netherlands. 2. Schoffelen, J.M. (2007). Neuronal communication through coherence in the human motor system. Radboud University Nijmegen, Nijmegen, the Netherlands. 3. de Lange, F.P. (2008). Neural mechanisms of motor imagery. Radboud University Nijmegen, Nijmegen, the Netherlands. 4. Grol, M.J. (2008). Parieto-frontal circuitry in visuomotor control. Utrecht University, Utrecht, the Netherlands. 5. Bauer, M. (2008). Functional roles of rhythmic neuronal activity in the human visual and somatosensory system. Radboud University Nijmegen, Nijmegen, the Netherlands. 6. Mazaheri, A. (2008). The Influence of Ongoing Oscillatory Brain Activity on Evoked Responses and Behaviour. Radboud University Nijmegen, Nijmegen, the Netherlands. 7. Hooijmans, C.R. (2008). Impact of nutritional lipids and vascular factors in Alzheimer’s Disease. Radboud University Nijmegen, Nijmegen, the Netherlands. 8. Gaszner, B. (2008). Plastic responses to stress by the rodent urocortinergic Edinger-Westphal nucleus. Radboud University Nijmegen, Nijmegen, the Netherlands. 9. Willems, R.M. (2009). Neural reflections of meaning in gesture, language and action. Radboud University Nijmegen, Nijmegen, the Netherlands. 10. van Pelt, S. (2009). Dynamic neural representations of human visuomotor space. Radboud University Nijmegen, Nijmegen, the Netherlands. 11. Lommertzen, J. (2009). Visuomotor coupling at different levels of complexity. Radboud University Nijmegen, Nijmegen, the Netherlands. 12. Poljac, E. (2009). Dynamics of cognitive control in task switching: Looking beyond the switch cost. Radboud University Nijmegen, Nijmegen, the Netherlands. 13. Poser, B.A. (2009). Techniques for BOLD and blood volume weighted fMRI. Radboud University Nijmegen, Nijmegen, the Netherlands. 14. Baggio, G. (2009). Semantics and the electrophysiology of meaning. Tense, aspect, event structure. Radboud University Nijmegen, Nijmegen, the Netherlands. 15. van Wingen, G.A. (2009). Biological determinants of amygdala functioning. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 16. Bakker, M. (2009). Supraspinal control of walking: lessons from motor imagery. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 17. Aarts, E. (2009). Resisting temptation: the role of the anterior cingulate cortex in adjusting cognitive control. Radboud University Nijmegen, Nijmegen, the Netherlands. 18. Prinz, S. (2009). Waterbath stunning of chickens – Effects of electrical parameters on the electroencephalogram and physical reflexes of broilers. Radboud University Nijmegen, Nijmegen, the Netherlands. 19. Knippenberg, J.M.J. (2009). The N150 of the Auditory Evoked Potential from the rat amygdala: In search for its functional significance. Radboud University Nijmegen, Nijmegen, the Netherlands. 20. Dumont, G.J.H. (2009). Cognitive and physiological effects of 3,4-methylenedioxymethamphetamine (MDMA or ’ecstasy’) in combination with alcohol or cannabis in humans Radboud University Nijmegen, Nijmegen, the Netherlands. 21. Pijnacker, J. (2010). Defeasible inference in autism: a behavioral and electrophysiogical approach. Radboud University Nijmegen, Nijmegen, the Netherlands. 22. de Vrijer, M. (2010). Multisensory integration in spatial orientation. Radboud University Nijmegen, Nijmegen, the Netherlands. 23. Vergeer, M. (2010). Perceptual visibility and appearance: Effects of color and form. Radboud University Nijmegen, Nijmegen, the Netherlands. 24. Levy, J. (2010). In Cerebro Unveiling Unconscious Mechanisms during Reading. Radboud University Nijmegen, Nijmegen, the Netherlands. 25. Treder, M. S. (2010). Symmetry in (inter)action. Radboud University Nijmegen, Nijmegen, the Netherlands.

289 DONDERS GRADUATE SCHOOL FOR COGNITIVE NEUROSCIENCE SERIES

26. Horlings C.G.C. (2010). A Weak balance; balance and falls in patients with neuromuscular disorders. Radboud University Nijmegen, Nijmegen, the Netherlands. 27. Snaphaan, L.J.A.E. (2010). Epidemiology of post-stroke behavioural consequences. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 28. Dado – Van Beek, H.E.A. (2010). The regulation of cerebral perfusion in patients with Alzheimer’s disease. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 29. Derks, N.M. (2010). The role of the non-preganglionic Edinger-Westphal nucleus in sex-dependent stress adaptation in rodents. Radboud University Nijmegen, Nijmegen, the Netherlands. 30. Wyczesany, M. (2010). Covariation of mood and brain activity. Integration of subjective self-report data with quantitative EEG measures. Radboud University Nijmegen, Nijmegen, the Netherlands. 31. Beurze S.M. (2010). Cortical mechanisms for reach planning. Radboud University Nijmegen, Nijmegen, the Netherlands. 32. van Dijk, J.P. (2010). On the Number of Motor Units. Radboud University Nijmegen, Nijmegen, the Netherlands. 33. Lapatki, B.G. (2010). The Facial Musculature – Characterization at a Motor Unit Level. Radboud University Nijmegen, Nijmegen, the Netherlands. 34. Kok, P. (2010). Word Order and Verb Inflection in Agrammatic Sentence Production.Radboud University Nijmegen, Nijmegen, the Netherlands. 35. van Elk, M. (2010). Action semantics: Functional and neural dynamics. Radboud University Nijmegen, Nijmegen, the Netherlands. 36. Majdandzic, J. (2010). Cerebral mechanisms of processing action goals in self and others. Radboud University Nijmegen, Nijmegen, the Netherlands. 37. Snijders, T.M. (2010). More than words – neural and genetic dynamics of syntactic unification.Radboud University Nijmegen, Nijmegen, the Netherlands. 38. Grootens, K.P. (2010). Cognitive dysfunction and effects of antipsychotics in schizophrenia and borderline personality disorder. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 39. Nieuwenhuis, I.L.C. (2010). Memory consolidation: A process of integration – Converging evidence from MEG, fMRI and behavior. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 40. Menenti, L.M.E. (2010). The right language: differential hemispheric contributions to language production and comprehension in context. Radboud University Nijmegen, Nijmegen, the Netherlands. 41. van Dijk, H.P. (2010). The state of the brain, how alpha oscillations shape behaviour and event related responses. Radboud University Nijmegen, Nijmegen, the Netherlands. 42. Meulenbroek, O.V. (2010). Neural correlates of episodic memory in healthy aging and Alzheimer’s disease. Radboud University Nijmegen, Nijmegen, the Netherlands. 43. Oude Nijhuis, L.B. (2010). Modulation of human balance reactions. Radboud University Nijmegen, Nijmegen, the Netherlands. 44. Qin, S. (2010). Adaptive memory: imaging medial temporal and prefrontal memory systems. Radboud University Nijmegen, Nijmegen, the Netherlands. 45. Timmer, N.M. (2011). The interaction of heparan sulfate proteoglycans with the amyloid ß protein. Radboud University Nijmegen, Nijmegen, the Netherlands. 46. Crajé, C. (2011). (A)typical motor planning and motor imagery. Radboud University Nijmegen, Nijmegen, the Netherlands. 47. van Grootel, T.J. (2011). On the role of eye and head position in spatial localisation behaviour. Radboud University Nijmegen, Nijmegen, the Netherlands. 48. Lamers, M.J.M. (2011). Levels of selective attention in action planning. Radboud University Nijmegen, Nijmegen, the Netherlands. 49. Van der Werf, J. (2011). Cortical oscillatory activity in human visuomotor integration. Radboud University Nijmegen, Nijmegen, the Netherlands. 50. Scheeringa, R. (2011). On the relation between oscillatory EEG activity and the BOLD signal. Radboud University Nijmegen, Nijmegen, the Netherlands. 51. Bögels, S. (2011). The role of prosody in language comprehension: when prosodic breaks and pitch accents come into play. Radboud University Nijmegen, Nijmegen, the Netherlands. 52. Ossewaarde, L. (2011). The mood cycle: hormonal influences on the female brain. Radboud University Nijmegen, Nijmegen, the Netherlands.

290 DONDERS GRADUATE SCHOOL FOR COGNITIVE NEUROSCIENCE SERIES

53. Kuribara, M. (2011). Environment-induced activation and growth of pituitary melanotrope cells of Xenopus laevis. Radboud University Nijmegen, Nijmegen, the Netherlands. 54. Helmich, R.C.G. (2011). Cerebral reorganization in Parkinson’s disease. Radboud University Nijmegen, Nijmegen, the Netherlands. 55. Boelen, D. (2011). Order out of chaos? Assessment and treatment of executive disorders in brain-injured patients. Radboud University Nijmegen, Nijmegen, the Netherlands. 56. Koopmans, P.J. (2011). fMRI of cortical layers. Radboud University Nijmegen, Nijmegen, the Netherlands. 57. van der Linden, M.H. (2011). Experience-based cortical plasticity in object category representation. Radboud University Nijmegen, Nijmegen, the Netherlands. 58. Kleine, B.U. (2011). Motor unit discharges - Physiological and diagnostic studies in ALS. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 59. Paulus, M. (2011). Development of action perception: Neurocognitive mechanisms underlying children’s processing of others’ actions. Radboud University Nijmegen, Nijmegen, the Netherlands. 60. Tieleman, A.A. (2011). Myotonic dystrophy type 2. A newly diagnosed disease in the Netherlands. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 61. van Leeuwen, T.M. (2011). ‘How one can see what is not there’: Neural mechanisms of grapheme-colour synaesthesia. Radboud University Nijmegen, Nijmegen, the Netherlands. 62. van Tilborg, I.A.D.A. (2011). Procedural learning in cognitively impaired patients and its application in clinical practice. Radboud University Nijmegen, Nijmegen, the Netherlands. 63. Bruinsma, I.B. (2011). Amyloidogenic proteins in Alzheimer’s disease and Parkinson’s disease: interaction with chaperones and inflammation. Radboud University Nijmegen, Nijmegen, the Netherlands. 64. Voermans, N. (2011). Neuromuscular features of Ehlers-Danlos syndrome and Marfan syndrome; expanding the phenotype of inherited connective tissue disorders and investigating the role of the extracellular matrix in muscle. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 65. Reelick, M. (2011). One step at a time. Disentangling the complexity of preventing falls in frail older persons. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 66. Buur, P.F. (2011). Imaging in motion. Applications of multi-echo fMRI. Radboud University Nijmegen, Nijmegen, the Netherlands. 67. Schaefer, R.S. (2011). Measuring the mind’s ear: EEG of music imagery. Radboud University Nijmegen, Nijmegen, the Netherlands. 68. Xu, L. (2011). The non-preganglionic Edinger-Westphal nucleus: an integration center for energy balance and stress adaptation. Radboud University Nijmegen, Nijmegen, the Netherlands. 69. Schellekens, A.F.A. (2011). Gene-environment interaction and intermediate phenotypes in alcohol dependence. Radboud University Nijmegen, Nijmegen, the Netherlands. 70. van Marle, H.J.F. (2011). The amygdala on alert: A neuroimaging investigation into amygdala function during acute stress and its aftermath. Radboud University Nijmegen, Nijmegen, the Netherlands. 71. De Laat, K.F. (2011). Motor performance in individuals with cerebral small vessel disease: an MRI study. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 72. Mädebach, A. (2011). Lexical access in speaking: Studies on lexical selection and cascading activation. Radboud University Nijmegen, Nijmegen, the Netherlands. 73. Poelmans, G.J.V. (2011). Genes and protein networks for neurodevelopmental disorders. Radboud University Nijmegen, Nijmegen, the Netherlands. 74. van Norden, A.G.W. (2011). Cognitive function in elderly individuals with cerebral small vessel disease. An MRI study. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 75. Jansen, E.J.R. (2011). New insights into V-ATPase functioning: the role of its accessory subunit Ac45 and a novel brain-specific Ac45 paralog. Radboud University Nijmegen, Nijmegen, the Netherlands. 76. Haaxma, C.A. (2011). New perspectives on preclinical and early stage Parkinson’s disease. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 77. Haegens, S. (2012). On the functional role of oscillatory neuronal activity in the somatosensory system. Radboud University Nijmegen, Nijmegen, the Netherlands. 78. van Barneveld, D.C.P.B.M. (2012). Integration of exteroceptive and interoceptive cues in spatial localization. Radboud University Nijmegen, Nijmegen, the Netherlands. 79. Spies, P.E. (2012). The reflection of Alzheimer disease in CSF. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

291 DONDERS GRADUATE SCHOOL FOR COGNITIVE NEUROSCIENCE SERIES

80. Helle, M. (2012). Artery-specific perfusion measurements in the cerebral vasculature by magnetic resonance imaging. Radboud University Nijmegen, Nijmegen, the Netherlands. 81. Egetemeir, J. (2012). Neural correlates of real-life joint action. Radboud University Nijmegen, Nijmegen, the Netherlands. 82. Janssen, L. (2012). Planning and execution of (bi)manual grasping. Radboud University Nijmegen, Nijmegen, the Netherlands. 83. Vermeer, S. (2012). Clinical and genetic characterisation of Autosomal Recessive Cerebellar Ataxias. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 84. Vrins, S. (2012). Shaping object boundaries: contextual effects in infants and adults. Radboud University Nijmegen, Nijmegen, the Netherlands. 85. Weber, K.M. (2012). The language learning brain: Evidence from second language and bilingual studies of syntactic processing. Radboud University Nijmegen, Nijmegen, the Netherlands. 86. Verhagen, L. (2012). How to grasp a ripe tomato. Utrecht University, Utrecht, the Netherlands. 87. Nonkes, L.J.P. (2012). Serotonin transporter gene variance causes individual differences in rat behaviour: for better and for worse. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. 88. Joosten-Weyn Banningh, L.W.A. (2012). Learning to live with Mild Cognitive Impairment: development and evaluation of a psychological intervention for patients with Mild Cognitive Impairment and their significant others. Radboud University Nijmegen, Nijmegen, the Netherlands. 89. Xiang, HD. (2012). The language networks of the brain. Radboud University Nijmegen, Nijmegen, the Netherlands 90. Snijders, A.H. (2012). Tackling freezing of gait in Parkinson’s disease. Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

292 DISSERTATIONS OF THE PARKINSON CENTRE NIJMEGEN (PARC)

Dissertations of the Parkinson Centre Nijmegen (ParC)

1. Jasper E. Visser. The basal ganglia and postural control. Radboud University Nijmegen, 17 June 2008. 2. Maaike Bakker. Supraspinal control of walking: lessons from motor imagery. Radboud University Nijmegen, 27 May 2009. 3. W. Farid Abdo. Parkinsonism: possible solutions to a diagnostic challenge. Radboud University Nijmegen, 7 October 2009. 4. Corinne G.C. Horlings. A weak balance: balance and falls in patients with neuromuscular disorders. Radboud University Nijmegen, 1 April 2010. 5. Samyra H.J. Keus. Physiotherapy in Parkinson’s disease: towards evidence-based practice. Leiden University, 29 April 2010. 6. Lars B. Oude Nijhuis. Modulation of human balance reactions. Radboud University Nijmegen, 29 November 2010. 7. Maarten J. Nijkrake. Improving the quality of allied health care in Parkinson’s disease through community- based networks: the ParkinsonNet health care concept. Radboud University Nijmegen, 29 November 2010. 8. Rick C.G. Helmich. Cerebral reorganization in Parkinson’s disease. Radboud University Nijmegen, 24 May 2011. 9. Karlijn F. de Laat. Motor performance in individuals with cerebral small vessel disease: an MRI study. Radboud University Nijmegen, 29 November 2011. 10. Anouk G.W. van Norden. Cognitive function in elderly individuals with cerebral small vessel disease. An MRI study. Radboud University Nijmegen, 30 November 2011. 11. Charlotte A. Haaxma. New perspectives on preclinical and early stage Parkinson’s disease. Radboud University Nijmegen, 6 December 2011. 12. Johanna G. Kalf. Drooling and dysphagia in Parkinson’s disease. Radboud University Nijmegen, 22 December 2011. 13. Anke H. Snijders. Tackling freezing of gait in Parkinson’s disease. Radboud University Nijmegen, 4 June 2012.

293 Anke H. Snijders in Parkinson’s diseasein Parkinson’s in Parkinson’s diseasein Parkinson’s Tackling freezing freezingTackling Tackling of of gait gait

Tackling freezing of gait in Parkinson’s disease ANKE H. SNIJDERS

90 978-94-91027-33-8 ISBN