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Diagnosis, Pathophysiology, Diagnosis, Pathophysiology, and Treatment of and Treatment of Essential TremorEssential Tremor

Theresa A. Zesiewicz, MD FAANProfessor of Neurology

University of South Florida

Essential TremorEssential Tremor

Essential tremor is characterized by a Essential tremor is characterized by a postural and/or kinetic tremor and is one of postural and/or kinetic tremor and is one of the most common tremor disorders in the the most common tremor disorders in the world.world.

There is currently only one FDA approved There is currently only one FDA approved medication, propranol, for its treatment.medication, propranol, for its treatment.

DiagnosisDiagnosis

There currently are no lab test or There currently are no lab test or radiological scans to aid in the diagnosis.radiological scans to aid in the diagnosis.

It is estimated that 30 % to 50 % of cases It is estimated that 30 % to 50 % of cases are misdiagnosed. are misdiagnosed.

Clinical criteria is used in the diagnosis. Clinical criteria is used in the diagnosis.

Clinical CriteriaClinical Criteria1.1. Bilateral action (postural or kinetic) tremor of the hands and forearms (not Bilateral action (postural or kinetic) tremor of the hands and forearms (not

a rest tremor) or an isolated head tremor without signs of dystonia.a rest tremor) or an isolated head tremor without signs of dystonia.

2.2. The absence of other neurologic signs, with the exception of the The absence of other neurologic signs, with the exception of the cogwheel phenomenon (an oscillation of resistance during passive cogwheel phenomenon (an oscillation of resistance during passive movement that is thought to be secondary to the tremor).movement that is thought to be secondary to the tremor).

3.3. Secondary diagnostic criteria include long duration of disease (usually Secondary diagnostic criteria include long duration of disease (usually greater than 3 years), positive family history, and beneficial response to greater than 3 years), positive family history, and beneficial response to alcohol. The diagnosis of ET is made clinically, and there are no alcohol. The diagnosis of ET is made clinically, and there are no biomarkers or neuroimaging tools available to assist in the diagnosis.biomarkers or neuroimaging tools available to assist in the diagnosis.

4.4. Exclusion criteria for ET include a unilateral rest tremor, rigidity, Exclusion criteria for ET include a unilateral rest tremor, rigidity, bradykinesia, a focal tremor with abnormal posture, or a sudden onset of bradykinesia, a focal tremor with abnormal posture, or a sudden onset of

tremor.tremor.

Non-motor SymptomsNon-motor Symptoms

Mild cognitive changesMild cognitive changesDepressionDepressionAnxietyAnxietySocial phobiasSocial phobiasOlfactory and hearing deficienciesOlfactory and hearing deficiencies

Treatment of Essential TremorTreatment of Essential Tremor

Make correct diagnosis and exclude other Make correct diagnosis and exclude other possible causes of tremor.possible causes of tremor.

Treatment is not a cure but may offer Treatment is not a cure but may offer tremor improvement.tremor improvement.

It is estimated that there is a 50 % It is estimated that there is a 50 % improvement in tremor magnitude. improvement in tremor magnitude.

There still remains 30 % to 50 % of ET There still remains 30 % to 50 % of ET patients that will not respond to medical patients that will not respond to medical therapy. therapy.

Antihypertensive MedicationsAntihypertensive Medications

These include beta blockers and calcium These include beta blockers and calcium channel blockers and are used to treat channel blockers and are used to treat hypertension and other cardiovascular hypertension and other cardiovascular conditions.conditions.

Two clinical studies suggests that Two clinical studies suggests that propranolol (Inderal) reduces tremor in propranolol (Inderal) reduces tremor in patients with ET.patients with ET.

Others include atenolol (Tenormin) and Others include atenolol (Tenormin) and sotalol (Sotacor).sotalol (Sotacor).

AntiepileticsAntiepiletics

Primidone (Mysoline) is an anticonvulsant Primidone (Mysoline) is an anticonvulsant that effectively treats ET.that effectively treats ET.

Topiramate (Topamax) another Topiramate (Topamax) another anticonvulsant that has been shown to anticonvulsant that has been shown to effectively reduce ET. effectively reduce ET.

Zonisamide (Zonegram) may have anti-Zonisamide (Zonegram) may have anti-tremor efficacy, although study results are tremor efficacy, although study results are mixedmixed

AntiepilepticsAntiepileptics

Levetiracetam (Keppra), failed to show Levetiracetam (Keppra), failed to show significant tremor reduction when tested significant tremor reduction when tested several weeks compared to placebo in several weeks compared to placebo in several controlled trials.several controlled trials.

Pregabalin (Lyrica), the effect on ET is Pregabalin (Lyrica), the effect on ET is unclear. unclear.

AntibioticsAntibiotics

Isoniazid, an antituberculosis medication, Isoniazid, an antituberculosis medication, was evaluated in a double blind, was evaluated in a double blind, randomized placebo-controlled study of 11 randomized placebo-controlled study of 11 patients with ET. patients with ET.

At the end of the 4 week treatment period, At the end of the 4 week treatment period, only two patients experienced objective or only two patients experienced objective or subjective change in tremor.subjective change in tremor.

AntidepressantsAntidepressants

Antidepressants have been used to treat Antidepressants have been used to treat ET without much success. ET without much success.

Mirtazapine (Remeron) and trazodone Mirtazapine (Remeron) and trazodone (Desyrel) have been studied but failed to (Desyrel) have been studied but failed to find an improvement in tremor evaluations find an improvement in tremor evaluations based on clinical rating scales.based on clinical rating scales.

AntipsychoticsAntipsychotics

Clozapine (Clozaril) ) is an atypical neuroleptic Clozapine (Clozaril) ) is an atypical neuroleptic with minimal extrapyramidal side effects that has with minimal extrapyramidal side effects that has been shown to reduce tremor by 45-50% in two been shown to reduce tremor by 45-50% in two controlled studies controlled studies

However, clozapine use has a 1% risk of However, clozapine use has a 1% risk of agranulocytosis, a serious side effect, and its agranulocytosis, a serious side effect, and its use should be reserved for refractory cases. use should be reserved for refractory cases.

AntiviralsAntivirals

Amantadine (Symmetrel) is an antiviral Amantadine (Symmetrel) is an antiviral medication that is used to treat PD. medication that is used to treat PD.

One small open-label study evaluated the One small open-label study evaluated the use of amantadine, an antiviral and use of amantadine, an antiviral and antiparkinsonian agent, in 6 patients with antiparkinsonian agent, in 6 patients with ET. After a 1-month period there was no ET. After a 1-month period there was no difference in accelerometric parameters difference in accelerometric parameters compared to baseline. compared to baseline.

BarbituratesBarbiturates

Two double-blind, randomized, placebo-Two double-blind, randomized, placebo-controlled crossover studies evaluated the controlled crossover studies evaluated the effects of phenobarbital, an anticonvulsant effects of phenobarbital, an anticonvulsant and sedative, on tremor. and sedative, on tremor.

One study found a significant improvement One study found a significant improvement in accelerometry parameters, compared to in accelerometry parameters, compared to placebo, but no change in clinical rating placebo, but no change in clinical rating scales. The other study failed to find a scales. The other study failed to find a difference compared to placebo.difference compared to placebo.

BenzodiazepinesBenzodiazepines

Alprazolam (Xanax) has been shown to reduce Alprazolam (Xanax) has been shown to reduce clinical ratings of tremor in two double-blind, clinical ratings of tremor in two double-blind, randomized, controlled studies.randomized, controlled studies.

Although alprazolam has demonstrated effect in Although alprazolam has demonstrated effect in some patients with ET, it should be used some patients with ET, it should be used cautiously as it has a high potential for abuse.cautiously as it has a high potential for abuse.

Clonazepam (Klonopin) improved tremor Clonazepam (Klonopin) improved tremor compared to baseline in a blinded, controlled compared to baseline in a blinded, controlled study. Another study failed to show any study. Another study failed to show any improvement in tremor, but had a 60% dropout improvement in tremor, but had a 60% dropout rate due to side effects rate due to side effects

BronchodilatorsBronchodilators

Studies of theophylline (Theo-dur), a Studies of theophylline (Theo-dur), a xanthine derivative bronchodilator on ET, xanthine derivative bronchodilator on ET, have found conflicting results. have found conflicting results.

Carbonic anhydrase inhibitorsCarbonic anhydrase inhibitors

Controlled studies of two carbonic Controlled studies of two carbonic anhydrase inhibitors, acetazolamide anhydrase inhibitors, acetazolamide (Diamox) and methazolamide (Glauctabs, (Diamox) and methazolamide (Glauctabs, Neptazane), failed to find a significant Neptazane), failed to find a significant difference in tremor evaluations compared difference in tremor evaluations compared to placebo to placebo

Botulinum ToxinBotulinum Toxin

Chemodenervation using botulinum toxin Chemodenervation using botulinum toxin A (BTX) has been demonstrated to reduce A (BTX) has been demonstrated to reduce hand tremor in patients with ET.hand tremor in patients with ET.

Its use is hampered by side effects Its use is hampered by side effects including hand weakness.including hand weakness.

Two controlled studies and 4 uncontrolled Two controlled studies and 4 uncontrolled studies demo started improvement in limb studies demo started improvement in limb tremor with BTX.tremor with BTX.

Surgical TreatmentSurgical Treatment

Thalamotomy is a stereotactic procedure Thalamotomy is a stereotactic procedure that creates a lesion in the ventral that creates a lesion in the ventral intermediate nuclear (VIM) of the intermediate nuclear (VIM) of the thalamus. thalamus.

Studies have typically reported an 80–90%Studies have typically reported an 80–90%

improvement in tremor symptoms improvement in tremor symptoms compared to baseline. compared to baseline.

Surgical TreatmentSurgical Treatment

Deep brain stimulation (DBS) uses high Deep brain stimulation (DBS) uses high frequency electrical stimulation from an frequency electrical stimulation from an implanted electrode to modify activity in implanted electrode to modify activity in the target area, usually the VIM thalamus. the target area, usually the VIM thalamus.

The electrode are connected to a pulse The electrode are connected to a pulse generator which is implanted in the chest generator which is implanted in the chest wall.wall.

DBS is usually reserved for patients who DBS is usually reserved for patients who are refractory to pharmacotherapy. are refractory to pharmacotherapy.