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FISIOPATOLOGIA DEI TREMORI

Enrico Alfonsi

Neurofisiopatologia

IRCCS-Istituto Neurologico Nazionale

«Casimiro Mondino»

Pavia

TREMORTREMORTREMORTREMORA 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.

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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

Psychogenic (functional) tremor Hereditary geniospasm

Action tremor Jaw tremor

Postural tremor Parkinson’s disease

Physiologic tremor and enhanced physiologic tremor Dystonia

Essential tremor Palatal tremor

Dystonic tremor Idiopathic (essential)

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

Commontremordisordersclassifiedaccordingto two maincriteria

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Essential tremor

• A resting tremor can appear only in advanced

stages. Other neurological signs (with the

exception of cog-wheel phenomenon and

difficulties with tandem gait) are typically

absent. Isolated head tremor without evidence

of abnormal posture may occur. The aetiology

and clinical definition of essential tremor is

currently under debate. The potential

distinction between late-onset essential tremor

(≥ 65 years old) and postural tremor of old age

(‘’senile tremor’’) remains unclear.

• No causative gene has been identified to date.

Recently, genetic variants in the gene for

LINGO1 have been identified as risk factors for

ET.

• Importance of cerebello-thalamo-cortical

projections, with the primary role of the

cerebellum.

Features considered typical of the essential tremor syndromeFeature Description

Tremor 4–12 Hz action tremor that occurs

when patients voluntarily attempt

to maintain a steady posture

against gravity (postural tremor) or

move (kinetic tremor)

Tremor may be suppressed by

performing skilled manual tasks

Tremor resolves when the body

part relaxes as well as during sleep

Tremor at rest is not uncommon

and observed in approximately

20% of patients

Age at onset Adolescence (15–20 years) or late

adulthood (50–70 years)

Distribution Bilateral with minimal asymmetry

Affected body sites Upper limbs >> head >> voice >>

face/jaw >> tongue >> trunk >>

lower limbs

Progression Tremor may initially be

intermittent, occurring during

periods of emotional activation,

and then becomes persistent over

time

Response to alcohol Beneficial alcohol response

present in 50–75% of patients

Family history Positive family history present in

30–60% of patients

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Clinical heterogeneity of ET is reflected in

heterogeneous pathophysiological findings

Three mutually nonexclusive hypotheses:

• The neurodegeneration hypothesis

• The oscillating network hypothesis

• The GABA hypothesis

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NEURODEGENERATION HYPOTHESISArgouments 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

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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

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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

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Essential tremor: pharmacotherapyCLASS NAME OF DRUG (BRAND NAME) INITIATING TREATMENT (DAILY DOSE) MAINTENANCE DAILY DOSAGE RANGE

(DOSING REGIMEN)

MOST COMMON ADVERSE EFFECTS

I. Anticonvulsants

Primidone (Mysoline) (most effective in this class) 25 to 31.5 mg at night for 1 week and then weekly

increase as necessary and tolerated

25 mg to 750 mg/day Once daily or up to 3 times

daily. Available tablet size varies in different

countries. Available in liquid suspension.

Sedation, dizziness, fatigue drowsiness, ataxia,

confusion, nausea, vomiting

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

control of tremor)

Usual 0.5 mg to 6 mg/day (1 to 3 divided doses) Sleepiness, confusion, risk of drug dependency

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

tremor

Approximately one every 3 months 50 units to 400 units (usually 1/3 months) Muscle weakness, dysphagia

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

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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.

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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

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PathophysiologyPathophysiologyPathophysiologyPathophysiology of of of of Parkinson’sParkinson’sParkinson’sParkinson’s diseasediseasediseasedisease restingrestingrestingresting tremortremortremortremor::::

the the the the ThalamicThalamicThalamicThalamic Pacemaker Pacemaker Pacemaker Pacemaker HypothesisHypothesisHypothesisHypothesisSingle 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 toserve as relay systems and as single cell oscillators at two distinct frequencies, 9–10 Hz and 5–6 Hz. Slightlydepolarized thalamic cells tend to oscillate at 10 Hz, whereas hyperpolarized cells oscillate at 6Hz. These twofrequencies coincide with the frequency of physiological tremor and PD tremor, respectively

• Any mechanism that engenders membrane hyperpolarization, whether through reduction of excitatory drive orexcess inhibition, will trigger low-frequency rhythmicity of thalamic neurons

• The GPi sends increased (inhibitory) output to the thalamus, which may hyperpolarize thalamic neurons andthus 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 interferencewith the cerebellar thalamus (VLp) is superior for treating tremor, or with the finding that there are more tremorcells 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 itdoes not explain why DBS of the basal ganglia can also suppress tremor


the the the the Basal Ganglia Pacemaker HypothesisBasal Ganglia Pacemaker HypothesisBasal Ganglia Pacemaker HypothesisBasal Ganglia Pacemaker HypothesisThe basal ganglia circuitry, not the thalamus, forms the tremor pacemaker

• In normal primates, the activity of neighboring pallidal neurons is completely uncorrelated, whereasparkinsonian primates develop markedly increased correlations between remotely situated pallidalneurons. 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 thepallidum of non-tremor PD patients

• The STN–GPe pacemaker hypothesis proposes that the STN and GPe constitute a central pacemaker thatis modulated by striatal inhibition of GPe neurons. However, these oscillations occurred at frequenciesbetween 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. Itwas found that the firing was dependent on feedback to the STN and GPe, which was modeled as asingle unit. Dopamine depletion makes the elements of the basal ganglia circuitry more functionallyconnected, there by increasing feedback and thus enhancing tremor bursting

• Advantage: it is firmly linked to the primary pathological substrate in PD, which is dopaminergicdysfunction of the basal ganglia

• Disadvantage: it does not explain the causal involvement of the cerebellothalamocortical circuit in PDresting tremor, as evidenced by the strong tremor reduction after DBS of the VLp

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???


the the the the DimmerDimmerDimmerDimmer----Switch Switch Switch Switch HypothesisHypothesisHypothesisHypothesis

Basal ganglia trigger tremor episodes (analogous to a light switch), whereas the cerebellothalamocorticalcircuit 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 foundthat:

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 thebasal ganglia and the cerebellothalamocortical circuit, whereas tremor amplitude-related activity waslocalized only to the cerebellothalamocortical circuit, but not the basal ganglia;

3. tremor-dominant PD patients had increased functional connectivity between the basal ganglia and thecerebellothalamocortical 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 cerebellothalamocorticalcircuit (VLp) can treat tremor. In contrast to the other models, which emphasize single oscillators, thedimmer-switch model emphasizes network parameters such as between-circuit coupling, whileattributing specific contributions to different network nodes

• Further studies are necessary to investigate the role of pallidal dopamine depletion in tremor. Furtherresearch is necessary to explain why dopaminergic drugs fail to adequately treat resting tremor in a largeproportion of PD patients, although other patients may experience a gratifying response of tremor tolevodopa

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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’

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Tremor Mechanisms Shared Between PD and ET:Tremor Mechanisms Shared Between PD and ET:Tremor Mechanisms Shared Between PD and ET:Tremor Mechanisms Shared Between PD and ET:

PD Action TremorPD Action TremorPD Action TremorPD Action Tremor� 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 asreemergent resting tremor: it occurs after a delay of 2 s or more after the limb affected by tremor has assumeda 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 voluntaryactions. It ranges from incomplete to complete suppression, and occurs only in PD patients and not in ETpatients with resting tremor

• In PD, resting tremor suppression by voluntary actions may be caused by interference between tremor-relatedand action-related activity in the basal ganglia or the cerebello-thalamo-cortical circuit: it is plausible thatreemergent tremor is caused by the same mechanisms as resting tremor

� Action tremor that is not reemergent tremor occurs at a higher frequency (6–15 Hz) and it does not respond tolevodopa: it resembles both ET and PD resting tremor, and therefore forms an interesting overlap between thetwo disorders

• PD resting tremor and action tremor share a common pathological substrate: the severity of both tremor typesis 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 thefrequency and moment of occurrence:

1. a transcranial magnetic stimulation study in PD showed that the cerebellum drives postural tremor but notresting tremor;

2. by use of DBS electrodes in the STN of PD patients, distinct tremor clusters for resting and postural tremor werefound;

3. although approximately 50 % of patients with resting tremor show an adequate response to dopaminergicmedication, 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, andserotonin binding in the caudate and putamen. In contrast, the severity of both action tremor and restingtremor correlates with serotonin binding in the raphe nuclei

� Recent findings suggest that DBS of the posterior subthalamic zone is an effective treatment not only in PD, butalso in ET. Although subthalamic DBS may influence cerebello-thalamic fibers to the ventral intermediatenucleus, another possibility is that the STN is involved in both tremor types, given its anatomical connectivitywith 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.

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Orthostatic tremor

Pharmacological agents

Medication Dosage Clinical Efficacy Comment

Clonazepam 0.5–6 mg/day +++ Documented

effect

Gabapentin 300–2400 mg/day ++ Documented

effect

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

immunoglobulin1

2 g/kg over 3 days + Anecdotal effect

Propanolol 120 mg/day – Without effect

Levetiracetam 3000 mg/day – Without effect

Botulinum toxin 200 mU in the

tibialis anterior

bilaterally

– Without effect

Alcohol – – Without effect

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

Surgical treatment• Generally bilateral but also

unilateral Vim DBS

• Chronic spinal cord stimulation

has demonstrated a benificial

effect with long-term follow-up

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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.

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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.

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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

spontaneous rhytmic discharges from the inferior olive.

• HT generally arising a few months after the acute event. It generally has a wide

amplitude and makes the affected limb(s) practically unusuable.

• HT can be associated with athetosis, dystonia, chorea, ataxia, ocular-palatal

tremor or other neurological signs.

Guillain–Mollaret Triangle. (a) Dentate-rubral tract; (b) Dentate-rubral-olivary tract; (c) Olivo-dentate tract.

• 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.

21

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.

30

The treatment of tremor (evidence classes in parentheses)

1st

choice Additional (optional) 2nd

choice 3rd

choice Surgical treatment in

case of inadequate

improvement from

drug treatment alone

Tremor in

Parkinson’s disease

dopamine agonists (Ia) levodopa (Ia),

anticholinergic drugs (III)

(biperidene, bornaprine),

budipine (II)

clozapine, propranolol deep brain stimulation

(preferably in the

subthalamic nucleus; in

exceptional cases,

nucleus

ventrointermedius [Vim]

of the thalamus)

Essential tremor propranolol (Ia),

primidone (Ia), these two

combined

gabapentin (I),

topiramate (I), atenolol,

sotalol

clonazepam, clozapine deep brain stimulation in

the Vim nucleus of the

thalamus

Cerebellar tremor low chance of success

with carbamazepine,

ondansetron

experimental: 4-

aminopyridine (approved

under the name Fampyra

for gait ataxia in MS)

of possible benefit for

selected patients: deep

brain stimulation in the

Vim nucleus of the

thalamus

Dystonic tremor local injection of

botulinum toxin

as in the treatment of

dystonia: trihexyphenidyl,

biperidene,

benzodiazepines

Intensified

physiological tremor

diagnosis and treatment

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

surgery

Deep brain

stimulation


(tremor-dominant)

Vim/STN thalamotomy

radiosurgery

Vim stimulation

STN stimulation


(with both tremor

and

rigidity/akinesia)

STN

pallidum

subthalamotomy

pallidotomy

radiosurgery

STN stimulation

GPi stimulation

Essential tremor Vim

zona incerta

STN

thalamotomy

subthalamotomy

radiosurgery

Vim stimulation

STN stimulation

Tremor in multiple

sclerosis

Vim thalamotomy

radiosurgery

Vim stimulation

Holmes’ tremor Vim – Vim stimulation

Orthostatic tremor Vim – Vim stimulation

Dystonic tremor Vim, pallidum thalamotomy GPi stimulation

Vim stimulation

possibly,

combination of

targets

• Medical treatment of complex

tremors is usually disappointing and

DBS should be considered in select

refractory cases.

• GPi DBS can be considered in HT if

thalamic Vim nucleus anatomy is

grossly disrupted by intracranial

pathology and in patients with

associated movement disorders like

chorea, parkinsonism, and dystonia.

• GPi should be viewed as the

preferred target for stimulation in DT

patients with generalized and

segmental dystonia, but thalamic

stimulation may be added in cases

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.

fisiopatologia dei tremori - fondazione mondino · 1 fisiopatologia dei tremori enrico alfonsi...

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