FISIOPATOLOGIA DEI TREMORI

Enrico Alfonsi Neurofisiopatologia IRCCS-Istituto Neurologico Nazionale «Casimiro Mondino» Pavia

TREMOR A rhythmic involuntary movement of one or several regions of the body. It represents the most common neurological sign, as everyone has a ‘’physiological’’ tremor, which can only be measured with instrumental tools.

1 BACKGROUND

Relation to Voluntary Movement Relation to Body Part Rest tremor Head tremor Parkinson’s disease Cerebellar disease Other parkinsonian syndromes Dystonia Tardive (drug-induced) parkinsonism Essential tremor (rarely when isolated)

Vascular parkinsonism Chin tremor Hydrocephalus Parkinson’s disease Common Psychogenic (functional) tremor Hereditary geniospasm tremor Action tremor Jaw tremor disorders Postural tremor Parkinson’s disease classified Physiologic tremor and enhanced physiologic tremor Dystonia according Essential tremor Palatal tremor to two main Dystonic tremor Idiopathic (essential) criteria Parkinsonism Owing to brainstem lesions (secondary) Fragile X premutation (fragile X tremor–ataxia syndrome) Owing to degenerative disease (adult-onset Alexander’s disease) Neuropathies Arm tremor Tardive tremor Cerebellar disease Toxins (e.g., mercury) Dystonia Metabolic disorder (e.g., hyperthyroidism, hypoglycemia) Essential tremor

Psychogenic (functional) tremor Parkinson’s disease Kinetic tremor Leg tremor Cerebellar disease Parkinson’s disease Holmes’ tremor Orthostatic tremor Wilson’s disease Psychogenic (functional) tremor

2 Essential tremor

Features considered typical of the essential tremor syndrome Feature Description Tremor 4–12 Hz action tremor that occurs when patients voluntarily attempt • A resting tremor can appear only in advanced to maintain a steady posture stages. Other neurological signs (with the against gravity (postural tremor) or move (kinetic tremor) exception of cog-wheel phenomenon and Tremor may be suppressed by difficulties with tandem gait) are typically performing skilled manual tasks absent. Isolated head tremor without evidence Tremor resolves when the body of abnormal posture may occur. The aetiology part relaxes as well as during sleep and clinical definition of essential tremor is Tremor at rest is not uncommon and observed in approximately currently under debate. The potential 20% of patients distinction between late-onset essential tremor Age at onset Adolescence (15–20 years) or late (≥ 65 years old) and postural tremor of old age adulthood (50–70 years) (‘’senile tremor’’) remains unclear. Distribution Bilateral with minimal asymmetry • No causative gene has been identified to date. Affected body sites Upper limbs >> head >> voice >> face/jaw >> tongue >> trunk >> Recently, genetic variants in the gene for lower limbs LINGO1 have been identified as risk factors for Progression Tremor may initially be ET. intermittent, occurring during • Importance of cerebello-thalamo-cortical periods of emotional activation, and then becomes persistent over projections, with the primary role of the time cerebellum. Response to alcohol Beneficial alcohol response present in 50–75% of patients Family history Positive family history present in 30–60% of patients

3 Clinical heterogeneity of ET is reflected in heterogeneous pathophysiological findings

Three mutually nonexclusive hypotheses:

• The neurodegeneration hypothesis

• The oscillating network hypothesis

• The GABA hypothesis

4 NEURODEGENERATION HYPOTHESIS Argouments put forward:

• ET begins insidiously, follows a progressive course, and is associated with age

• In some studies ET is associated with increased risk of PD and Alzheimer disease

Argouments against this hypothesis:

• Many pathologial abnormalities fall in the normal range

• These abnormalities do not correlate with the duration of ET

There is evidence for neurodegeneration of the cerebellum in ET (Voxel- based mophometry studies), although more indipendent samples are necessary to confirm this.

There is some evidence for neurodegeneration of the locus coeruleus and there is no evidence for inferior olive disease.

The Oscillating Network Hypothesis for ET

5 The Oscillating Network Hypothesis for ET

• In physiological tremor , during movement, inhibitory nucleo-olivary cells increase their activity, activating climbing fibers of the inhibitory Purkinje cells with a strong and synchronous inhibition onto the cerebellar nuclear neurons. This generates an oscillatory rebound potentials in these cells which are relayed to the motor cortex via the thalamus resulting in a physiological tremor of about 10 Hz

• Recenltly, the idea that single oscillators can produce the tremor has been questioned: many group of neurons are only intermittently coherent with tremulous muscle activity: 1. cortico-muscular coherence in ET was lost intermittently without observable changes in peripheral tremor activity; similar findings for pallidomuscular coherence in PD tremors. 2. DBS in ET and tremor-dominant PD have showed that multiple, spatially separated tremor clusters within the VLp are capable of driving the tremor

• These findings have shifted the attention to network properties such as strength and directionality of interregional connettivity. This contrasts with the single oscillator hypotheses which take into account the neural network in which the oscillator is embedded but not the interaction between the elements of the network and its connettivity structure. This hypothesis may explain why ET disappears after cerebellar stroke in some patients, whereas other patients develop ET after ipsilateral cerebellectomy. This also fits with the fact that lesions at several different localization within the cerebello-thalamocortical circuits can remove ET, which argues against a single oscillator.

THE GABA HYPOTHESIS

Several lines of evidence support the idea that ET is associated with abnormal function of the inhibitory neurotrasmitter GABA

• Drugs that increase GABAergic transmission like primidone , topiramate , gabapentin , and ethanol are effective in ET treatment

• Reduced levels of GABA in the CSF of patients with ET are observed

• Experimental interference with GABAergic transmission in animals can evoke an ET-like postural tremor (hamaline evokes postural tremor by ihnibiting GABA-A receptors: enhancement of electrical coupling of cerebellar afferents in the inferior olive)

• GABA-A receptors α1for knockout mice exhibit postural and kinetic tremor resembling ET

• Nuclear imaging studies found altered binding to GABA receptors in ET

• Using PET in ET, 11C-Flumazenil binding to GABA-A receptors increased in the ventrolateral thalamus, the dentate nucleus of the cerebellum, and the premotor cortex

• Using PET in ET, Flumazenil binding increases with tremor severity

• In post-mortem biopies GABA-A and GABA-B receptors in the dentate nucleus of the cerebellum of ET patients are less than those of PD patients and normals : the reduction of the levels of dentate GABA receptors may be a primary deficit in ET, restricting the post- synaptic action of GABA released from Purkinje cell axons, and thereby disinhibiting deep cerebellar nuclei neurons which spead up their ensuing overactivity through the cerebellar- thalamo-cortical circuits possibly resulting in tremor

6 THE GABA HYPOTHESIS

The GABAergic abnormalities in ET do not have a know genetic basis: several studies have failed to find a relationship between GABA receptor and transporter polymorphisms and ET

There is firm evidence for a reduction of GABAergic tone in ET, which, interestingly, is located in the same areas ( cerebellum and Locus coeruleus) where neurodegenerative changes have been found

7 8 9 Essential tremor: pharmacotherapy

CLASS NAME OF DRUG (BRAND NAME) INITIATING TREATMENT (DAILY DOSE) MAINTENANCE DAILY DOSAGE RANGE MOST COMMON ADVERSE EFFECTS (DOSING REGIMEN)

I. Anticonvulsants Primidone (Mysoline) (most effective in this class) 25 to 31.5 mg at night for 1 week and then weekly 25 mg to 750 mg/day Once daily or up to 3 times Sedation, dizziness, fatigue drowsiness, ataxia, increase as necessary and tolerated daily. Available tablet size varies in different confusion, nausea, vomiting countries. Available in liquid suspension.

Topiramate (Topamax) 50 mg (2 divided doses) 50 mg to 325 mg/day (2 divided doses) Anorexia, weight loss, memory decline, cognitive difficulty, paresthesias, kidney stone

II. Beta adrenergic receptor antagonists Propranolol IR (Inderal) (most effective in this class) 10 mg 1 dose gradually increase to 2 or 3 doses 10 mg to 320 mg/day (1 to 3 divided doses) Bradycardia, bronchospasm, fatigue, depression, decline in sexual function, hypotension

Propranolol LA (long acting) (Inderal LA) 60 or 80 mg (1 dose) 60 mg 320 mg/day (1 or 2 divided doses) Similar to Propranolol IR Atenolol (Tenormin) 12.5 mg (1 dose) 50 mg to 150 mg/day (1 or 2 divided doses) Bradycardia, dry mouth, sleepiness

Nadolol (Corgard) 20 mg (1 dose) 120 mg to 240 mg/day (1 dose) Bradycardia, dizziness, lightheadedness, hypotension III. Benzodiazepines/GABAergic agents Clonazepam (Klonopin) 0.25 mg (1 dose) (preferred use is for occasional Usual 0.5 mg to 6 mg/day (1 to 3 divided doses) Sleepiness, confusion, risk of drug dependency control of tremor) therefore to use with caution

Alprazolam (Xanax) 0.125 mg (1 dose) 0.125 mg to 3 mg/day (1 to 3 divided doses) Sedation, fatigue. Caution for risk of drug dependency. Best used for occasional control of tremor.

Gabapentin (Neurontin) 50 mg (1 dose, increase as necessary and tolerated) 50 mg to 1800 mg/day (1 to 3 divided doses) Lethargy, decreased libido, dizziness, shortness of breath, nervousness

Pregabalin (Lyrica) 25 mg (1 dose and gradual increase as necessary) 50 mg to 600 mg/day (2 divided doses) Sedation

IV. Calcium channel blockers Nimodipine (Nimotop) 30 mg (1 dose and adjust as necessary 30 to 120 mg/day (3 divided doses) Mild heart burn, headache V. Atypical neuroleptic agents Clozapine (Clozaril) 12.5 mg (1 dose) 12.5 mg to 75 mg/day (1 to 3 divided doses) Sedation, agranulocytosis This drug needs continuous monitoring with blood counts.

Olanzapine (Zyprexa) 5 mg (1 dose) 5 mg to 20 mg/day (1 or 2 divided doses) Weight gain, sedation VI. Botulinum toxin A (Botox, Xeomin) for head Approximately one every 3 months 50 units to 400 units (usually 1/3 months) Muscle weakness, dysphagia tremor Botulinum toxin A (Botox, Xeomin) for voice tremor Approximately one every 3 months. 0.6 to 14 units (usually 1/3–6 months) Swallowing difficulty, weak voice, breathlessness

10 Essential tremor: pharmacotherapy

A summary of medical treatment options in patients with different severity of ET.

Essential tremor: non-pharmacotherapy

• Alcohol : relieved the amplitude but not the frequency of the tremor. Typically, the tremor improved at 10 min after alcohol consumption. This benefit diminished after 60-90 min, and after 3 h the tremor rebounded. Due to the short duration of symptomatic benefit, the rebound of tremor and adverse effects of long-term alcohol consumption, alcohol has been occasionally recommended. • DBS : Vim, ventrolateral talamus or posterior subthalamic area area targeted in ET, with significant disability reduction. Compared with unilateral implants, bilateral ones significantly reduce tremor. • Thalamotomy : gamma-knife thalamotomy is effective for the suppression of refractory ET and other tremors. It is capable of inactivating larger regions than electrical stimulation and is an option for patients who are not candidates for DBS. DBS is generally preferable to thalamotomy because it can be reversed by removing the electrodes, it leaves little or no residual damage, and it is adjustable with the use of a programmable stimulator. Nevertheless, DBS is associated with risks, which include intracranial bleeding and infection, as well as malpositioned electrodes, the need to replace the battery periodically, and hardware issues as lead breakage. • MRI-guided focused ultrasoud thalamotomy : creating a unilateral thalamic ablation, it significantly improves tremor scores. The results are promising, since this procedure does not require entering the cranium with a probe. There are some limitis such as the limited follow-up period examined (12 months), loss of efficacy with time (progression or tolerance?), individual-level responses, and the nature of the procedure, which is a thalamotomy, hence it creates a fixed brain lesion. • rTMS and tDCS : in some studies, stimulating cerebellum, rTMS had significant effects at low frequencies (1 Hz or lower) after 5 min up to 60 min (acute anti-tremor effect). The effect persists for 3 weeks after the last session of rTMS applicated daily for 5 consecutive sessions. However, cerebellar cTBS doesn’t ameliorate tremor. Thus, additional studies are needed to further comment on the issue of the effectiveness of rTMS.

11 Parkinsonian tremor

• The diagnosis of Parkinson’s disease is based on the clinical observation of its cardinal manifestations - tremor, rigidity, and bradykinesia – and the exclusion of other signs that would indicate an atypical parkinsonian syndrome. • Frequence: 4-6 Hz. Unlike ET, it is often characterized by an alternating activation of agonists/antagonists. • Type I: unilateral (or asymmetric) resting tremor that increases in amplitude under mental stress and is suppressed during initiation of a movement and often during the course of a movement. ‘’Re- emergent tremor’’ is a resting tremor re-emerging while the patient holds a posture. • Type II: bilateral (usually asymmetric) action tremor coexisting with type I tremor. • Type III: action tremor of the hands without a resting component. • Pharmacological replacement of the deficient neurotrasmitter dopamine alleviates tremor effectively, even if postural tremor is present in addition. Clinical experience indicates that the tremor can actually increase in amplitude when treatment is begun, because rigidity responds first to dopaminergic treatment and tremor only improves at higher doses. • The classic dopaminergic drugs include levodopa and a variety of dopamine agonists. If tremor persists, anticholinergic drugs (bornaprine, biperidene) can be used. Their efficacy has not been documented in modern clinical trials, but it was concluded in a systematic review that they work better than placebo. Budipine is an effective drug that can be held in reserve. • Drug-resistant parkinsonian tremor can be treated with DBS.

REST TREMOR IN PD HYPOTHESES

• The thalamic pace-maker hypothesis

• The basal ganglia pake-maker hypothesis

• The dimmer-switch hypothesis

• The finger-switch-dimmer hypothesis

12 Pathophysiology of Parkinson’s disease resting tremortremor: ::: the Thalamic Pacemaker Hypothesis Single thalamic neurons, not the basal ganglia circuitry, form the tremor pacemaker • In vitro preparations, it was found that the intrinsic biophysical properties of thalamic neurons allow them to serve as relay systems and as single cell oscillators at two distinct frequencies, 9–10 Hz and 5–6 Hz. Slightly depolarized thalamic cells tend to oscillate at 10 Hz, whereas hyperpolarized cells oscillate at 6Hz. These two frequencies coincide with the frequency of physiological tremor and PD tremor, respectively • Any mechanism that engenders membrane hyperpolarization, whether through reduction of excitatory drive or excess inhibition, will trigger low-frequency rhythmicity of thalamic neurons • The GPi sends increased (inhibitory) output to the thalamus, which may hyperpolarize thalamic neurons and thus trigger oscillations at 5– 6 Hz. This mechanism would predict a predominant role for the pallidal thalamus (VLa) in tremor genesis. This does not fit with findings from deep brain surgery, which show that interference with the cerebellar thalamus (VLp) is superior for treating tremor, or with the finding that there are more tremor cells in the VLp than in the VLa • Other possible brain regions that may hyperpolarize thalamic neurons are: 1. the zona incerta, which is connected to the basal ganglia and sends GABAergic projections to the VLp; 2. the cerebellar nuclei, which receive input from the STN through the pons and cerebellar cortex; 3. dopaminergic projections from the midbrain to the VLp • Advantage : it explains the causal role of the cerebellar thalamus (VLp) in PD tremor. • Disadvantage : it remains to be tested how the cerebellothalamic circuit becomes entrained in tremor, and it does not explain why DBS of the basal ganglia can also suppress tremor

Pathophysiology of Parkinson’s disease resting tremortremor: ::: the Basal Ganglia Pacemaker Hypothesis The basal ganglia circuitry, not the thalamus, forms the tremor pacemaker • In normal primates, the activity of neighboring pallidal neurons is completely uncorrelated, whereas parkinsonian primates develop markedly increased correlations between remotely situated pallidal neurons. This could lead to excessive synchronization in the basal ganglia, resulting in tremor • These changes were found to be larger in the pallidum of tremor-dominant PD patients than in the pallidum of non-tremor PD patients • The STN–GPe pacemaker hypothesis proposes that the STN and GPe constitute a central pacemaker that is modulated by striatal inhibition of GPe neurons. However, these oscillations occurred at frequencies between 0.4 and 1.8 Hz, and it is unclear whether they have any relationship with parkinsonian tremor • Basal ganglia–thalamocortical circuit, and in particular STN-GPe, is prone to tremor-like burst firing. It was found that the firing was dependent on feedback to the STN and GPe, which was modeled as a single unit. Dopamine depletion makes the elements of the basal ganglia circuitry more functionally connected, there by increasing feedback and thus enhancing tremor bursting • Advantage : it is firmly linked to the primary pathological substrate in PD, which is dopaminergic dysfunction of the basal ganglia • Disadvantage : it does not explain the causal involvement of the cerebellothalamocortical circuit in PD resting tremor, as evidenced by the strong tremor reduction after DBS of the VLp

13 ???

Pathophysiology of Parkinson’s disease resting tremortremor: ::: the DimmerDimmer----SwitchSwitch Hypothesis

Basal ganglia trigger tremor episodes (analogous to a light switch), whereas the cerebellothalamocortical circuit modulates tremor amplitude (analogous to a light dimmer) • On SPECT and EMG–functional MRI study in tremor-dominant and non-tremor PD patients, it was found that: 1. dopamine depletion in the pallidum, but not the striatum, correlated with tremor severity; 2. cerebral activity time-locked to the onset of high-amplitude tremor episodes was localized to both the basal ganglia and the cerebellothalamocortical circuit, whereas tremor amplitude-related activity was localized only to the cerebellothalamocortical circuit, but not the basal ganglia; 3. tremor-dominant PD patients had increased functional connectivity between the basal ganglia and the cerebellothalamocortical circuit, as compared with non-tremor PD patients and healthy controls • This model explains why DBS in either the basal ganglia (STN or GPi) or the cerebellothalamocortical circuit (VLp) can treat tremor. In contrast to the other models, which emphasize single oscillators, the dimmer-switch model emphasizes network parameters such as between-circuit coupling, while attributing specific contributions to different network nodes • Further studies are necessary to investigate the role of pallidal dopamine depletion in tremor. Further research is necessary to explain why dopaminergic drugs fail to adequately treat resting tremor in a large proportion of PD patients, although other patients may experience a gratifying response of tremor to levodopa

14 BG activity induces tremor: ’the finger’

The Thalamus generates PD- tremor oscillations: ‘the switch’

The Cerebellum considers PD- tremor as it would a voluntary movement: ‘the dimmer’

15 Tremor Mechanisms Shared Between PD and ET: PD Action Tremor V Most studies have focused on PD resting tremor. However, many PD patients also have action tremor, which is probably an inherent symptom of the disease. In 34–60 % of PD patients, action tremor can be classified as reemergent resting tremor: it occurs after a delay of 2 s or more after the limb affected by tremor has assumed a new posture, at the same frequency as the resting tremor, and it responds to levodopa • The most interesting phenomenon is actually the transient suppression of resting tremor during voluntary actions. It ranges from incomplete to complete suppression, and occurs only in PD patients and not in ET patients with resting tremor • In PD, resting tremor suppression by voluntary actions may be caused by interference between tremor-related and action-related activity in the basal ganglia or the cerebello-thalamo-cortical circuit: it is plausible that reemergent tremor is caused by the same mechanisms as resting tremor V Action tremor that is not reemergent tremor occurs at a higher frequency (6–15 Hz) and it does not respond to levodopa: it resembles both ET and PD resting tremor, and therefore forms an interesting overlap between the two disorders • PD resting tremor and action tremor share a common pathological substrate: the severity of both tremor types is correlated, and DBS of the STN is effective in treating both PD resting tremor and PD action tremor • There are also important differences between PD resting tremor and PD action tremor, other than the frequency and moment of occurrence: 1. a transcranial magnetic stimulation study in PD showed that the cerebellum drives postural tremor but not resting tremor; 2. by use of DBS electrodes in the STNof PD patients, distinct tremor clusters for resting and postural tremor were found; 3. although approximately 50 % of patients with resting tremor show an adequate response to dopaminergic medication, postural tremor often responds better to drugs that are also used for treating ET; 4. a PET study in PD reported a correlation between the severity of action tremor, but not resting tremor, and serotonin binding in the caudate and putamen. In contrast, the severity of both action tremor and resting tremor correlates with serotonin binding in the raphe nuclei V Recent findings suggest that DBS of the posterior subthalamic zone is an effective treatment not only in PD, but also in ET. Although subthalamic DBS may influence cerebello-thalamic fibers to the ventral intermediate nucleus, another possibility is that the STN is involved in both tremor types, given its anatomical connectivity with both the basal ganglia and the cerebellar circuits

Orthostatic tremor

• High-frequency (13-18 Hz) in the legs, trunk, and, sometimes, the arms, which is coherent in all muscles studied, characterized by unsteadiness when standing that is relieved when sitting or walking. In more advanced stages, patients may demonstrate abnormalities in tandem gait, indistinguishable from abnormalities seen in cerebellar diseases. A clear proximal spread of OT may be confirmed. • It might be primary with/without postural arm tremor (idiopathic ) or associated with other primary neurological disorders, mainly parkinsonism, (plus forms ) or secondary to structural lesions/other causes (symptomatic forms ). • Although most patients first develop orthostatic tremor (OT) around 60 years old, the age range at onset is wide, from 13 to 85 years, even depending on whether OT is primary or plus form. • Two reports of molecular defects: C10orf2 Twinkle and REEP1 (formerly SPG31 ) mutation. • OT might be generated by a central oscillator and/or be neurodegenerative. • A ‘’ slow ’’ OT has been rarely reported in the literature. • Differential diagnosis with essential tremor , parkinsonian tremor and orthostatic myoclonus . • ‘’ Pseudo-OT ’’: levodopa-responsive, 6-7 Hz standing tremor preceding a parkinsonian syndrome.

16 Orthostatic tremor

Pharmacological agents Surgical treatment • Generally bilateral but also Medication Dosage Clinical Efficacy Comment unilateral Vim DBS Clonazepam 0.5–6 mg/day +++ Documented effect • Chronic spinal cord stimulation has demonstrated a benificial Gabapentin 300–2400 mg/day ++ Documented effect effect with long-term follow-up Levodopa 300–800 mg/day ++ Only short-term benefit Pramipexole 0.75 mg/day + Anecdotal effect Primidone 125–250 mg/day + Anecdotal effect Valproic acid 500–1000 mg/day +/– Anecdotal effect Carbamazepine 400 mg/day +/– Anecdotal effect Phenobarbital 100 mg/day +/– Anecdotal effect Intravenous 2 g/kg over 3 days + Anecdotal effect 1 immunoglobulin Propanolol 120 mg/day – Without effect Levetiracetam 3000 mg/day – Without effect Botulinum toxin 200 mU in the – Without effect tibialis anterior bilaterally Alcohol – – Without effect

1It was used in a case of slow orthostatic tremor associated with a novel antineuronal antibody.

17 Dystonic tremor

• Dystonic tremor (DT) : postural/kinetic tremor, rarely at rest, occurring in the body region affected by dystonia. It is usually focal with irregular amplitudes and variable frequencies (mostly below 7 Hz); antagonistic gestures lead to a reduction of the tremor amplitude. DT usually worsens when the patient voluntarily moves the affected body part against the major direction of pulling caused by dystonia and vice versa. Some patients exhibit focal tremors even without overt signs of dystonia, that can later develop. • Tremor associated with dystonia (TAD) (or with the ‘’dystonia gene’’) is an ‘’essential tremor-like’’ tremor in a body region not affected by dystonia but dystonia is present elsewhere in the same partecipant or in some of the relatives. This is a relatively symmetric, postural and kinetic tremor usually showing higher frequencies than typical DT. • Head tremor in the context of cervical dystonia is the most common form of DT. • Task-specific tremors as primary writing tremor (PWT) : focal and irregular task-specific tremor that predominantly occurs during specific motor task (type A) or position (type B). Although there is some resemblance to essential tremor (ET), its focal task-specific nature, the lack of response to propranolol and a well-documented effect of central cholinergic drugs have suggested more closely relation with focal dystonia than ET. • Different drugs in variable combination were used. No controlled or randomised studies are available and detailed information is generally missing. Data on carbamazepine, acetazolamide, baclofen, amitriptyline, imipramine, fluvoxamine and sulpiride are too scanty to draw any useful conclusions as these drugs were anecdotally employed in single cases. • Given their consolidated use in the treatment of dystonia, anticholinergic were found to have slight to moderate effectiveness in reducing tremor amplitude. Trihexyphenidyl 4 to 10 mg has been the most commonly used. • Incostant positive effect of propranolol (in idiopathic focal dystonia with tremor), timolol (in head DT), primidone (in PWT), benzodiazepine (in particular clonazepam 0.5 to 3 mg in DT), tetrabenazine (in PWT and dystonic jaw tremor) only in some studies. • Levodopa is the treatment of choice in dopa-responsive dystonia also for the associated tremor.

18 Dystonic tremor

A possible algorithm for the treatment of dystonic tremor (DT) or primary writing tremor (PWT) on the basis of the limited evidence available to date. Botulinum neurotoxin (BoNT) is the most useful strategy in the management of axial (head or vocal cord) tremors, whereas appendicular tremor-with the exception of PWT-should be first treated with drugs, thus allowing the use of BoNT in a stepwise approach (in order to further improve the regions not adequately improved). By contrast, BoNT might be the first-choice therapy in PWT, followed by drugs or surgery. DBS should be considered only when the disability derived by tremor overcomes the risks of its invasiveness. Unilateral procedures can be tried in case of appendicular tremor, whereas bilateral surgery is indicated for head tremor. As for the target of DBS, Vim and GPi are the most used ones, based on the predominance of tremor (Vim) or dystonic postures (GPi). The combined approach Vim+GPi might be considered in case of failure of the single target procedure. Other targets (VLp, STN and surrounding areas, ie, PSA or cZi) might be considered in very selected cases.

19 Holmes’ tremor

• Holmes’ tremor (HT) : a slow frequency (usually less than 4.5 Hz) and resting tremor combined with an action tremor of the same frequency as the resting component caused by lesion within the Guillain-Mollaret triangle or the talamus. The Guillain-Mollaret triangle is the anatomical description of the connections between the rubral, olivary and dentate nuclei. In the vast majority of patients with Holmes’ tremor, the lesion involves the ascending limb of the Guillain-Mollaret triangle (dentate-thalamic projections), thus the older terms rubral, midbrain, thalamic, cerebellar, or ‘’outflow’’ tremor. Breach in the continuity of the Guillain-Mollaret triangle results in pseudohypertrophy and Guillain–Mollaret Triangle. spontaneous rhytmic discharges from the inferior olive. (a) Dentate-rubral tract; • HT generally arising a few months after the acute event. It generally has a wide (b) Dentate-rubral-olivary tract; amplitude and makes the affected limb(s) practically unusuable. (c) Olivo-dentate tract. • HT can be associated with athetosis, dystonia, chorea, ataxia, ocular-palatal tremor or other neurological signs. • Because HT is very rare, the current recommendation for treatment with high-dose levodopa (up to 750 mg per day) or stereotactic lesional/stimulator surgery is based on single case reports, as higher-level evidence is unavailable. Other drugs such as propranolol, anti-cholinergics, clonazepam, and levetiracetam have also been used, which reflects lack of consensus. • Palatal tremor : Rhythmic movement of the roof of the soft palate due to contractions of the tensor veli palatine muscle (cranial nerve V, isolated form) or of the edge of the soft palate due to contraction of the levator veli palatine muscle (cranial nerves IX and X, symptomatic form). In symptomatic forms (the lesion involves the ascending and descending limbs of the Guillain-Mollaret triangle), other muscles innervated by cranial nerves may be involved (eye, tongue, pharynx) or, more rarely, the diaphragm or upper limbs.

Other tremors • Cerebellar tremor : pure or dominantly an intention tremor, unilateral or bilateral, with a tremor frequency usually below 5 Hz; a postural tremor (> 5 Hz) resembling essential tremor may be present. Titubation is a slow-frequency (3 Hz) tremor involving the axial body parts (head or trunk). It is commonly seen in acquired cerebellar disease, for example, multiple sclerosis, stroke or alcoholic cerebellar degeneration. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited, X-linked, adult-onset neurodegenerative disorder caused by a moderately expanded trinucleotide repeat (CGG block lengths 55-200) in a noncoding region of the fragile X mental retardation 1 (FMR1) gene, causing action tremor, gait and limb ataxia, cognitive and neuropsychiatric dysfunction, parkinsonism, dysautonomia, and peripheral neuropathy. • Neuropathic tremor : a variable postural/kinetic tremor (usually 3-6 Hz) affecting the limbs; two criteria should be fulfilled: confirmed diagnosis of neuropathy (abnormal position sense need not be present) and exclusion of other neurological diseases associated with tremors. It is observed mainly in chronic inflammatory demyelinating polyneuropathies, HMSN, and IgM demyelinating paraprotein-related neuropathy, and is more common with kappa rather lambda light chain disease. Propranolol, primidone, or clonazepam can be considered for the treatment with disappointing results. • Post-traumatic tremors : atypical tremors that occur secondary to traumatic brain injury, characterized by a combination of irregular resting, postural and intention tremor of large amplitude with slow frequency. Tremor is usually unilateral, it predominantly affects the proximal upper extremities, and it is markedly worsened by goal- directed movements. Therapy is difficult, and additional concerns complicate the surgical treatment. • Functional tremor : irregular tremor with variable frequency and amplitude. Decrease of tremor amplitude or frequency during distraction or entrainment and/or presence of the ‘’coactivation sign’’. • Unusual tremor syndromes : SCA 12, tremors caused by autosomal recessive cerebellar ataxias, myorhythmia, isolated tongue tremor, Wilson’s disease, peripheral trauma-induced tremor, tardive tremor and rabbit syndrome, paroxysmal tremors (hereditary chin tremor, bilateral high-frequency synchronous discharges, head tremor, limb- shaking transient ischaemic attack), bobble-head doll syndrome, spasmus nutans, and shuddering attacks. Rare tremors generally present with an action tremor and a variable combination of postural and kinetic components with resting tremors less frequently seen.

20 Other tremors

• Physiological tremor : normally only demonstrable with ancillary testing, as its amplitude is too small to be seen with the naked eye. It reflects the intrinsic frequency of muscle stretch reflexes. Various metabolic disorders, including hypoglicemia, hyperthyroidism, and ethanol withdrawal syndrome, can accentuate physiological tremor to the point of obvious visibility. It is a bilateral, low-amplitude postural tremor of relatively high frequency (about 7 Hz). • Drug-induced and toxic tremor : many drugs or toxins might cause tremor, which is usually present during action (enhanced physiological tremor); resting tremor might be caused by antidopaminergic drugs or dopamine depletors. Tremor can be due to not only current medication but also drugs recently discontinued as part of a withdrawal or tardive phenomenon. It is most commonly induced by antiepileptic drugs, lithium, valproic acid, and cyclosporine A.

21 22 23 24 25 26 27 28 29 The treatment of tremor (evidence classes in parentheses)

st nd rd 1 choice Additional (optional) 2 choice 3 choice Surgical treatment in case of inadequate improvement from drug treatment alone Tremor in dopamine agonists (Ia) levodopa (Ia), clozapine, propranolol deep brain stimulation Parkinson’s disease anticholinergic drugs (III) (preferably in the (biperidene, bornaprine), subthalamic nucleus; in budipine (II) exceptional cases, nucleus ventrointermedius [Vim] of the thalamus)

Essential tremor propranolol (Ia), gabapentin (I), clonazepam, clozapine deep brain stimulation in primidone (Ia), these two topiramate (I), atenolol, the Vim nucleus of the combined sotalol thalamus Cerebellar tremor low chance of success experimental: 4- of possible benefit for with carbamazepine, aminopyridine (approved selected patients: deep ondansetron under the name Fampyra brain stimulation in the for gait ataxia in MS) Vim nucleus of the thalamus

Dystonic tremor local injection of as in the treatment of botulinum toxin dystonia: trihexyphenidyl, biperidene, benzodiazepines

Intensified diagnosis and treatment physiological tremor of cause, e.g., hyperthyroidism, vitamin B12 deficiency, drugs

Orthostatic tremor gabapentin (Ib) clonazepam, primidone (II)

Indications and targets for the stereotactic treatment of tremor

Cause of tremor Target structure Lesion-making Deep brain surgery stimulation • Medical treatment of complex Parkinson’s disease Vim/STN thalamotomy Vim stimulation tremors is usually disappointing and (tremor-dominant) radiosurgery STN stimulation DBS should be considered in select Parkinson’s disease STN subthalamotomy STN stimulation refractory cases. (with both tremor pallidum pallidotomy GPi stimulation and radiosurgery • GPi DBS can be considered in HT if rigidity/akinesia) thalamic Vim nucleus anatomy is Essential tremor Vim thalamotomy Vim stimulation grossly disrupted by intracranial zona incerta subthalamotomy STN stimulation pathology and in patients with STN radiosurgery associated movement disorders like Tremor in multiple Vim thalamotomy Vim stimulation sclerosis radiosurgery chorea, parkinsonism, and dystonia. Holmes’ tremor Vim – Vim stimulation • GPi should be viewed as the Orthostatic tremor Vim – Vim stimulation preferred target for stimulation in DT Dystonic tremor Vim, pallidum thalamotomy GPi stimulation patients with generalized and Vim stimulation segmental dystonia, but thalamic possibly, stimulation may be added in cases combination of targets with incomplete tremor control. • PSA DBS can be considered in patients with refractory tremors with associated cerebellar features and in proximal tremors as it provides theoretical advantages to thalamic DBS. • MS patients with largely kinetic tremor with minor or absent cerebellar dysfunction might benefit from thalamic DBS. PSA DBS can be considered in selected cases. • In post-traumatic tremors, target selections should be based on tremor characterisric and associated neurological features, including cerebellum dysfunction, cognitive, sensory, and motor deficits as well as spasticity, and dystonia. • Closed loop neuromodulation may in the future be an option for complex tremors.

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