Unifying the Motor & Non-motor Features of Parkinson’s Disease
Ali Shalash Professor of Neurology Chair of Ain Shams Movement Disorders Group Department of Neurology, Ain Shams Univeristy Cairo, Egypt AGENDA
1. Motor and non-motor Symptoms
2. Pathophysiology of Motor & NMS
3. Relation To Disease Course
4. NMS in motor subtypes
5. Motor & NMS fluctuation
6. Treatment of Motor & NMS: links Parkinson’s Disease
• PD prevalence 1 % of populations older than 65 years (Abbas et al., 2018)
• From 1990 to 2015, the number of with PD patients doubled to over 6 million, and double again to over 12 million by 2040 (Dorsey et al, 2018)
• Aging populations, increasing longevity, decreasing smoking rates, and the by- products of industrialization MDS Clinical Diagnostic Criteria for PD
Postuma et al 2015 MDS Clinical Diagnostic Criteria for PD
Postuma et al 2015 Non-motor Symptoms of PD
• Neuropsychiatric symptoms • Autonomic dysfunction • Depression up to 50-70 % • Drooling • Anxiety up to 60 % • Orthostatic hypotension 30–58% • Apathy 60 % • Urinary dysfunction • Psychosis up to 40% • Erectile dysfunction • Impulse control and related disorders • Gastrointestinal dysfunction 25–67% • Dementia, 24% to 40%. • Excessive sweating • Cognitive impairment 20-25% (other • Others than dementia mainly mild cognitive impairment) • Pain 30–85% • Fatigue 50% • Disorders of sleep and wakefulness • Olfactory dysfunction 90% • • Sleep fragmentation and insomnia Ophthalmologic dysfunction • Rapid eye movement sleep behavior disorder 65 % • Excessive daytime sleepiness Pathophysiology of Motor & NMS Neuropathology of PD: Motor Symptoms
Two major pathologic processes: (a) premature selective loss of dopamine neurons: 30–70% cell loss ⇢ motor symptoms. (b) the accumulation of Lewy bodies, composed of α-synuclein
Poewe, W. et al. (2017) Parkinson disease Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.13 Neuropathological staging of Lewy body disease Jellinger Neural Transmission 2019
Kosaka LBD Braak PD stage Anatomical distribution of Lewy bodies stage Medulla oblongata: lesions in the dorsal IX/X motor nucleus and/or 1 intermediate reticular zone, enteric and peripheral autonomic nervous system, spinal cord, and anterior olfactory nucleus. Brain stem– predomine Medulla oblongata and pontine tegmentum: pathology of stage 1 plus lesions nt type 2 in the caudal raphe nuclei, gigantocellular reticular nucleus, and ceruleus- subceruleus complex; involvement of the olfactory bulb. Midbrain: pathology of stage 2 plus midbrain lesions, particularly in the pars 3 compacta of the substantia nigra.
Transitional Basal prosencephalon and mesocortex: pathology of stage 3 plus (limbic) 4 prosencephalic lesions. Cortical involvement confined to temporal mesocortex type (transentorhinal region) and allocortex (CA2 plexus).
Neocortex: pathology of stage 4 plus lesions in high-order sensory association 5 areas of the neocortex and prefrontal neocortex. Diffuse Advanced neocortex: pathology of stage 5 plus lesions in first-order sensory cortical association areas of the neocortex and premotor areas; occasionally, mild type 6 changes in primary sensory areas and the primary motor field. Metabolic and functional abnormalities already occur in brain regions in early stages of PD that are not accompanied by Lewy pathology. Motor cortex circuitry activity changes in Parkinson disease
Poewe, W. et al. (2017) Parkinson disease Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.13 Macpherson & Hikida et al 2019 Regions and neurotransmitters implicated in NMSs of PD
NMS Implicated Regions Neurotransmitter Hyposmia Olfactory bulb and amygdale, perirhinal cortex Substance P. Ach colour vision retina Dopamine (DA) Hallucinations Cortex, Amygdala, hippocampus DA Pain Basal Ganglia, locus coeruleus, raphe nucleus amygdale DA 5-HT , NA and thalamus, spinal cord,epidermal nerves Anxiety LC, Basal ganglia DA, NA Depression LC, Limbic and cortical areas DA, NA Cognitive dysfunction Frontal cortex, Nucleus basalis Meynert DA Dementia Temporal, parietal and Occipital lobes, Nucleus basalis Ach Meynert Sleep Disturbance Hypothalamus and reticular formation, Diencephalon, Hypocretin, DA, 5-HT PPN, gigantocellular reticular and lateral dorsal tegmental nuclei, coeruleus–subcoeruleus complex, and DRN Bladder hyper- basal ganglia, DMV, prefrontal anterior cingulate and DA, Ach reflexia, sexual insular cortex, and the sacral spinal dorsal horn, pelvic dysfunction plexus Orthostatic Adrenal glands, DVN, nucleus ambiguus, caudal raphe NA Hypotension nuclei, ventromedial medulla, cardiac sympathetic nerves GIT, constipation DMV, Intermediate column of spinal cord, dorsal root, Sympathetic and parasympathetic ganglia (paravertebral, celiac), Gastroesophagial/enteric plexus Dysphagia Brainstem (PPN) and /or the esophageal myenteric plexus, Cholinergic SMA Titova et al 2017 Conclusion: PD is associated with BAEP and VEMP abnormalities that are correlated to the motor and some non- motor clinical characteristics. These abnormalities could be considered as potential electrophysiological biomarkers for brainstem dysfunction and its associated motor and non-motor features.
Shalash et al Front Neurol 2017 Motor & Nonmotor Features Relation To Disease Course Clinical symptoms associated with PD Course
Poewe, W. et al. (2017) Parkinson disease Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.13 Schapira et al 2018 Goldman et al 2020 Motor & NMS as biomarkers tackling for PD pathological changes
Picillo et al 2017 Non-motor symptoms in the premotor PD Todorova et al 2013
Commonly associated—with reasonable evidence base Hyposmia (usually of late onset 10 times increase in risk of developing PD;+abnormal and idiopathic) DATScan—43% develop motor PD in 4 years Rapid eye movement sleep 25–40% risk of developing a synucleinopathy at 5 years; behaviour disorder 40–65% risk of developing a synucleinopathy at 10 years
Constipation 2.7–4.5 times increased risk of PD Depression 2.4 times increased risk of developing PD Described associations Excessive daytime sleepiness 3.3 times increased risk of PD Fatigue (a sense of exhaustion as In 45%—a premotor symptom opposed to sleepiness) Pain (often unilateral and in 34% increased risk of PD affected limb)
Erectile dysfunction 3.8 times increased risk of PD Postuma et al 2015 MDS Clinical Diagnostic Criteria for Prodromal PD • Frequency of NMS increased along with the disease duration and severity
• NMS are correlated with motor severity
• Motor and NMSs are correlated to patients QoL
Barone et al PRIAMO 2009 Shalash et al 2017 Martinez-Martin MDJ 2011 Leonardi et al PRD 2012 Marinus et al, Lancet neurology 2018 Motor & NMS Subtypes Motor & NMS Subtypes
Motor Types:
1. Tremor dominant type
2. Non-tremor dominant type
1. Akinetic rigid type
2. Postural instability Gait disorder type
3. Mixed or indeterminate phenotype
Tremor-dominant PD is often associated with a slower rate of progression and less functional disability than non-tremor-dominant PD.
Kalia, & Lang 2015 Non-motor Subtypes of PD a) Cognitive subtype in PD. b) Apathy subtype in drug naïve PD . c) Depression/Anxiety subtypes in PD.
1. Anxious depressed subtype
2. Depressed subtype
3. Anxious subtype d) REM sleep behavior disorder subtype in PD. e) Lower limb pain subtype in PD. f) Park weight subtype (combined with olfactory dysfunction & dyskinesia)
1. Phenotype A - More severe loss of olfaction (anosmia)
2. Phenotype B - Less loss of olfaction (hyposmia) Sauerbier et al, 2015 Clinical description of NMS-dominant phenotypic variants Marras & Chaudhuri MDJ 2016
Nonmotor Defining features of Ancillary features domain subtype Cognitive Early and dominant Older age (≥72 years) cognitive dysfunction Non-tremor-dominant motor phenotype associated with falls Poor semantic fluency score (<20) Lower pentagon copying score (0 < 1 < 2) Microtubule-associated protein tau (MAPT) H1/H1 genotype possibly a biomarker Neuro- Anxiety/depression: psychiatric A. Anxious-depressed B. Depressed Postural instability gait disturbance C. Anxious Younger age Marked motor fluctuations Apathetic Relatively severe motor symptoms (out of proportion to disease duration) Concomitant depression Lower cognitive status Fatigue Good response to dopaminergic drugs Sleep REM sleep behavior Symmetric disease onset disorder Increased periods of freezing Autonomic dysfunction Prone to higher prevalence and severity of orthostatic symptoms Higher rate of depression Visual hallucinations, Impairment of color vision Increased frequency of falls Olfactory A. Severe loss of Dyskinesias olfaction (anosmia) Progressive weight loss B. Moderate hyposmia No further weight loss with disease progression Autonomic Urinary dysfunction Early noradrenergic deficit- Postural hypotension NMS in Motor subtypes
• Non-tremor-dominant subtypes have consistently been shown to have a broader array of NMS, more early autonomic features, Later more cognitive disturbance.
• Motor aspects of PD such as falls may also be intricately linked to specific NMSs of PD such as cognition.
• PIGD & ART may be more prone to mood disorders.
• Non-tremor-dominant PD represents a more advanced and diffuse neurodegeneration than tremor-dominant PD, encompassing dopaminergic and nondopaminergic as well as synuclein and nonsynuclein (Abeta) pathologies.
• NMS as biomarker for disease progression. Patients with the diffuse/malignant phenotype were more likely to have mild cognitive impairment, orthostatic hypotension, and RBD at baseline (Fereshtehnejad et al 2015)/
Marras & Chaudhuri MDJ 2016 Marras & Chaudhuri MDJ 2016 NMS in Genetic Parkinson’s Disease Jellinger Neural Transmission 2019 Kasten, Arch Neurol. 2010 Treatment of Motor & NMS: links TREATMENT OF PARKINSON’S DISEASE
• Medical • Dopaminergic agents; levodopa, DA agonists • Anticholinergics • MAO-B inhibitors • Therapies of NMSs • Others • Surgical • Ablative • Advanced therapies; DBS, Duodopa, apomorphine infusion. • Restorative • Physical therapies • Others: botulinum toxin, TMS Don’t miss NMSs of your patient.
Patients education, leaflets.
Management Advices for the patients. of Nonmotor Symptoms Clinical practice.
Botulinum toxin: drooling, overactive bladder, constipation, pain, hyperhidrosis (Slawek and Medalinski, 2017)
Evidence based recommendations. Treatment of Nonmotor Symptoms of PD
• Depression:
– Clinically useful: Prampexole, venlafaxine – Possibly useful: other SSRIs, TCA, rTMS, CBT
• Apathy: Possibly useful; Piribidil, rivastigmine
• Fatigue: Possibly useful; rasagiline
• ICD: Possibly useful; CBT • PDD: Rivastigmine (Clinically useful), donepezil, galantamine (Possibly useful)
• Psychosis: Pimavaserine, clozapine (Clinically useful), quetiapine(Possibly useful). • Autonomic: Fludrocortisone, midodrine, sildenafil, macrogol, Lubiprostone, botulinium toxin • Exercise Seppi et al MD 2019 Nonmotor complications of Dopamiergic treatments
• NMSs fluctuation with motor fluctuations, usually being more frequent and severe in off- compared to on-state. • Antiparkinsonian treatment can cause or worsen these and other NMSs (hallucinations, compulsive behavior, binge eating, fluctuations, hypersexuality, punding, etc.)
• A higher dose of levodopa was associated with future development of depression, whereas a high combined dose of levodopa and dopamine agonists was associated with future development of hallucinations. • Use of dopamine agonists was specifically associated with a risk of excessive daytime sleepiness, impulse-control disorders, hallucinations, and insomnia.
• Dopamine withdrawal Syndrome.
Ossig et al., 2017 Storch et al., 2013 Marinus et al, 2018 Motor and Nonmotor Complications of Levodopa
Movement Disorders, Volume: 33, Issue: 6, Pages: 909-919, First published: 23 July 2018, DOI: (10.1002/mds.27386)
Chaudhuri et al MDJ 2018 Motor Complications of NMS Medications
• TCAs: prolong QT, narrow angle-closure glaucoma, orthosta c hypotension, with the concomitant risk of falls and injuries, cons pa on, and urinary reten on, confusion and delirium. Benefit; treat insomnia, tremor, sialorrhea.
• SSRIs may produce nausea, seda on, a fast ac on tremor, and sexual dysfunc on, hyponatremia, prolong QTc interval
• SSRIs may be associated with movement disorders, including akathisia, dyskinesia, dystonia, parkinsonism, tremor, tardive dyskinesia; and bruxism.
• It is believed that this risk is rela vely low because, at the dosages typically used for PD (5 mg or 10 mg daily), there is dopamine selec vity, and it becomes nonselec ve only at higher dosages.
• Rasagiline should be used cau ously together with other SSRIs because of the risk of producing a serotonergic syndrome.
• An psycho cs: dopamine blocking agents ☠☠ Sertonin Syndrome
• Life threating emergency • Triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities • Clinical features: anxiety, agitation, delirium, diaphoresis, tachycardia, hypertension, hyperthermia, gastrointestinal distress, tremor, muscle rigidity, dilated pupils, myoclonus, and hyperreflexia. • Examination: hyperthermia, agitation, ocular clonus, tremor, akathisia, deep tendon hyperreflexia, inducible or spontaneous clonus, muscle rigidity, dilated pupils, dry mucus membranes, increased bowel sounds, flushed skin, and diaphoresis. Neuromuscular findings are typically more pronounced in the lower extremities. Relation & responsiveness to dopaminergic drugs (Kim & Joen, 2017)
Responsive to DRT Unresponsive to DRT Exacerbated by DRT Neuro- Depression Dementia Psychosis, Dopamine psychiatric Off period-related anxiety Confusion Dysregulation syndrome, symptoms Apathy Punding, Impulse control Cognitive impairment disorders Autonomic Urgency (detrusor Frequency Orthostatic hypotension dysfunction \overactivity) Sweating Parkinson hyperpyrexia Nocturia syndrome Erectile dysfunction Serotonin syndrome Gastro- Constipation Ageusia, Dysphagia Diarrhea intestinal Unsatisfactory voiding of Reflux, vomiting Nausea dysfunction bowel Fecal incontinence Sleep Restless legs Syndrome NREM sleep movement Excessive daytime sleepiness disorders Periodic limb movement disorders disorder, REM behavior Vivid dreaming disorder, Insomnia Sleep-disordered breathing Sensory Musculoskeletal pain Radiculo-neuropathic pain symptoms Akathitic pain Paresthesia Central pain Olfactory dysfunction Off -related dystonic pain Visual dysfunction Other Fatigue Peripheral edema symptoms Fibrotic reactions Blurred vision -Weight gain Neurobehavioral effects of DBS Hogg et al, 2017
Target Possible Beneficial Possible Side Effect STN Improved depression depression Improved anxiety Anxiety Improved cognition (i.e Apathy visuospatial functioning) Hypomania Psychosis Hyperesexuality Dopamine dysregulation syndrome Suicidality Reduced cognition (word fluency : executive control; learning and memory) GPi Improved depression Depression Improved anxiety Anxiety Improved cognition (i.e milld Hypomania memory Improvement; visuospatial functioning Reduced cognition (word fluency : executive control; learning and memory) Motor & Nonmotor Fluctuations Motor Fluctua ons
• Chronic exposure to Levodopa is associated with the development of motor complications
in ∼30% of patients with PD after 2–3 years of exposure and >50% after >5 years.
• Motor response fluctuations; on–off oscillations in Levodopa response; symptom control
(‘on’ state) VS symptoms recur (‘off’ state).
• Major risk factors are high Levodopa dose, longer disease duration and younger age.
• Mechanisms: ⇢ different patterns of variation in motor response.
1. The short half-life of levodopa,
2. Variations in gastrointestinal absorption and blood–brain barrier transport
3. Striatal pharmacodynamic changes also have a role.
Poewe et al 2017 Non-motor fluctuation in PD Todorova et al 2013
Non-motor symptoms that worsen during ‘off’ periods
• Fatigue
• Depression
• Anxiety
• Inner restlessness MDJ 2016
• Impaired concentration/attention.
Non-motor symptoms occurring only/exclusively during ‘off’ periods
• Fatigue
• Depression
• Anxiety
• Impaired concentration
• Inner restlessness. Nonmotor Fluctuations
• 17% up to 100% in patients with motor fluctuation
• Up to two thirds of motor fluctuating PD patients also presented mood swings.
• 86% of patients with NMF also report motor fluctuations, indicating that NMF may occur independent of motor fluctuations in a relevant proportion of patients
• Higher motor scores and levodopa dosage, younger age at onset, disease duration, and female gender are major risk factors for the development of motor fluctuations
• The predictive factors for NMF are very similar to those for motor fluctuations, but additionally include the presence of motor fluctuations, levodopa treatment duration
• Combination of the oscillation of dopaminergic stimulation and nondopaminergic mechanisms, which specifically mediate the respective fluctuating NMS, is responsible for the occurrence of NMF.
• Dopaminergic modulation of other neurotransmitter systems (serotoninergic, adrenergic, glutamatergic) Franke & Alexander Storch 2017 The hidden sister of motor fluctuations in Parkinson's disease: A review on nonmotor fluctuations
Martınez-Fernandez et al MDJ 2016 Motor & Nonmotor Fluctuation
• NMS fluctuation: neuropsychiatric, autonomic and sensory.
• A multicenter study of 320 patients reported significant early morning off (EMO) in 59.7%, and 88% reported severe NMS on awakening, such as urinary frequency, anxiety, depression, pain, and dribbling of saliva
• The anxious-depressed phenotype showed the most consistent association with off periods and dyskinesias.
• NMS such as anxiety, paresthesae, pain, and fatigue can also complicate dyskinesias, particularly peak dose and diphasic dyskinesias.
• Apathy or panic attacks can be disabling aspects of severe NMFs (Chaudhuri et al 2018).
• Dopamine stimulation hypothesis is supported by correlations for some neuropsychiatric NMF such as anxiety, depression, inner restlessness, lack of concentration and fatigue with motor OFF states (Classen et al 2017). The effect of advanced treatments on fluctuating NMS in PD Martınez-Fernandez et al MDJ 2016
Fluctuating NMS STN-DBS GPi-DBS Apomorphine l-dopa-Carbido Pump pa Pump Neuropsychiatric Depression Improvement/ Worsening Improvement Improvement Improvement Anxiety Improvement/ Worsening NA NA Improvement Fatigue Improvement NA Improvement Improvement Apathy Improvement/ Worsening NA Improvement Improvement Attention/cognition Improvement NA Improvement Improvement ICD/hyperdopaminergic Improvement/Worsening/onset NA Improvement Improvement behaviors Hallucination Improvement//Worsening NA Improvement Improvement Autonomic Cardiovascular Improvement NA NA Improvement Worsening Constipation Improvement NA Improvement Improvement Worsening Worsening Drenching sweats Improvement NA Improvement Improvement Bladder dysfunction Improvement NA Improvement Improvement Swallowing Improvement NA NA NA Worsening Sexual disorders Improvement NA NA Improvement Sensory/pain Pain Improvement Improvement NA Improvement Dysesthesia NA Improvement NA NA Restless legs Improvement Worsening NA NA NA Todorova et al 2013 Nonmotor Symptoms (summary)
• Related to the disease process or pathophysiology
– Dopaminergic origin
– Non-dopaminergic origin • Related to a partial non-motor origin (usually brainstem autonomic impairment with motor end result, such as constipation or diplopia)
• Related to non-motor fluctuations (cognitive, autonomic and sensory subtypes)
– Fluctuating
– Constant
• Related to PD drug therapy
– Specific symptoms (e.g., hallucinations, delirium)
– Syndromes—impulse control disorders, dopamine agonist withdrawal syndrome, Parkinson's hyperpyrexia syndrome (thermoregulatory failure, delirium)
• Possibly genetically determined
– Dementia in cases with glucocerebrosidase mutation
– Depression and sleep disorders in cases with leucine-rich repeat kinase-2 mutation Upcoming MDS-AS Regional Online Courses
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