Diagnosis and Treatment of Tremors

By Administrator

By Holly Shill, MD–Director, Muhammad Ali Parkinson Center–Movement Disorder Section, Barrow Neurological Institute

Introduction
Tremor is an involuntary, rhythmic, shaking movement of a part or parts of the body (usually hands, lower arms or head). It is produced by alternating contractions of muscles that would normally work against each other (See Figure 1). Although tremor is more often associated with Parkinson’s Disease (PD), it can also be one of the symptoms experienced during the clinical course of multiple sclerosis (MS), typically in the form of action tremor. A total of 76% of the 10,069 NARCOMS MS Patient Registry participants responding to the spring 2002 update survey reported sometimes experiencing at least minimal tremor or loss of coordination, although only 13% reported that tremor affected their daily activities. The purpose of this paper is to briefly review the essential elements of tremor and its treatment as it relates to MS.

Classification Based on Clinical Phenomenology

Tremor can be observed at rest or/and during movement. More specifically, the following classification is useful in discussing tremors typically encountered in clinical practice:

-Resting tremor-”Tremor in the absence of voluntary movement and with body part fully supported.
-Postural tremor-Tremor while voluntarily maintaining posture against gravity.
-Kinetic/Action tremor-Tremor during voluntary movement.
-Task-Specific tremor-Kinetic tremor during specific, skilled movement.
-Orthostatic tremor-Tremor of lower extremities or trunk while standing in place.

Clinical Diagnosis
In order to correctly diagnose and treat a tremor, a clinician first conducts several functional tests to establish the type of tremor in question.

For cranial (head) tremor, observations include establishing the tremoring structures, such as head, jaw, tongue or palate. The frequency of tremor is also noted. Direction of tremor is also noteworthy, with the typical “no-no” shaking of the head seen most frequently. The clinician also looks for presence of abnormal postures and postures that bring out tremor. Muscle hypertrophy (overgrowth) and neck rigidity are additional signs to consider.

Tremor in the limbs is observed in three different situations: 1) resting tremor is assessed while the patient is focused on a mental activity, such as counting; 2) postural tremor is assessed while the limb is extended against gravity (e.g., holding arms out while sitting or standing); 3) action tremor is assessed with activities such as finger-nose-finger test, writing or drawing a spiral.

Laboratory investigation may be ordered to identify potential causes and treatment options for the tremor observed. The tests typically include thyroid function tests, ceruloplasmin and 24-hour urine test for copper, and CT or MRI brain scan. It is important, however, to keep in mind that laboratory testing is not needed in patients whose symptoms are not consistent with idiopathic PD or Essential Tremor (ET). These and other types of tremor are explained below.

Essential Tremor
Primary criteria for ET include bilateral action tremor of the hand and forearms without resting tremor, absence of other neurological signs (except cogwheel, tandem gait, hearing loss, and maybe dystonia), and isolated head tremor without signs of dystonia. Secondary criteria for ET include a long duration (over 3 years), positive family history, and beneficial response to alcohol (e.g., decrease in tremor).

Epidemiological research has shown that in the United States ET affects approximately 1% of the total population. In the general population over 40 years of age, ET is diagnosed in 2% to 4% and with increasing age ET becomes more prevalent, affecting approximately 10% of those over 70 years of age. ET is as common in men as in women and 60% of those with ET also have at least one 1st degree relative (parent, sibling or a child) with ET. It is estimated that in 15% of the cases tremor leads to disability (Rautakorpi, Takala, Marttila, Sievers, & Rinne, 1982; Lou & Jankovic, 1991). Pure ET is rare with MS, but since it is the most well-studied tremor condition, and the treatments for MS tremors are similar, we will review it in more detail.

Several treatment options for ET are available, but not all of them are considered effective. Table 1 provides a classification of commonly used therapies by their effectiveness as published by American Academy of Neurology in 2005. The following sections describe in more detail the recommended use of some of the therapies deemed effective.

Propranolol is a non-selective beta blocker primarily prescribed for hypertension. In treating tremor the optimal daily dose range is 240 mg to 320 mg. Approximately 40% to 50% of tremor patients benefit from this therapy, although it rarely eliminates tremor completely. Reduction in tremor amplitude is 50% to 60% with no effect on frequency of the tremor. Propranolol is most effective against hand tremor, but it also has some effect on head, voice, and tongue tremor. Long-acting formulation has proven to be equal to or better than standard formulation. Patients with heart failure, second- or thirddegree atrioventricular block, asthma, bronchoasthmatic conditions, or diabetes should not use propranolol. Central nervous system (CNS) side-effects may occur during treatment or following withdrawal, including fatigue, sleep disturbances, depression, impotency, cognitive impairment, and mania. Cardiovascular (CV) side-effects may follow sudden withdrawal. It is also important to keep in mind that beta blockers may mask the progression of an underlying CV disease.

Primidone is an anticonvulsive drug typically used to treat epilepsy. In treating tremor the optimum response is usually at 250 mg per day or less. Currently, 50 mg tablets are currently only available under the Mysoline brand name. Acute initial reactions are common with primidone. Up to 25% of patients experience flu-like syndrome (nausea, vomiting) or ataxia. These acute reactions, however, usually last only several days. A starting dose of 12.5 mg or 25 mg at bedtime (1-4 or 1-2 of 50 mg tab or suspension) can be used to minimize the side-effects. Daily dose is then increased slowly over several months.

Other drug therapies to consider include Gabapentin (1200-1800 mg/day), Topamax (100–400/day), and Clozapine (12.5-50 mg/day). Deep Brain Stimulation (DBS) of Ventromediol (VM) nucleus of thalamus is a relatively new but well researched treatment option. One study found a major benefit in 68% of the study population (Benabid et al., 1993) and another reported major improvement in 23 out of 29 patients (Hubble et al., 1997). A study documenting an 83% reduction in tremor (Ondo, Jankovic, Schwartz, Almaguer, & Simpson, 1998) finally led the Food and Drug Administration (FDA) to approve the Medtronic device used for DBS in 1997.

Cerebellar Tremor
This type of tremor is probably the most common seen in patients with MS. It resembles the tremor seen with Essential Tremor with some exceptions. First, it can be more severe and progressive compared with ET (which can take 10-20 years to become disabling). Second, it tends to affect movement more than posture (so-called action tremor). This is manifested in difficulty using the limbs for fine motor skills such as handwriting, drinking liquids, eating soup, putting on make-up or contact lenses. The treatment is very much the same as essential tremor, although it tends to be less responsive to these medications. DBS is auseful option for patients with intractable tremor in whom tremor is a primary and disabling symptom, but who otherwise have good neurological function. Referral to a specialized center is necessary for DBS.

Differential Diagnosis–Other Tremors

Parkinsonian Tremor: Diagnosis of Parkinson tremor is still primarily based on clinical observations. Characteristics of PT include asymmetry, rigidity (but not cogwheel), reemergent tremor, arm swing, handwriting, and possibly smell test. Dopamine imaging can assist in some cases. Tremor treatment options for PD consist of Amantadine or artane, levodopa/dopamine agonists, ET meds, DBS. It is very rare that patients with MS have a parkinsonian tremor, unless it is drug induced. Drugs that cause parkinsonian tremor include promethazine or metoclopramide.

Enhanced Physiological Tremor: The frequency of enhanced physiological tremor is 8 to12 Hz (cycles per second) which is much higher than the typical frequency of PD tremor. Enhanced physiological tremor is linked to the mechanical-reflex properties of limb and more evident with posture than with action. Stress and caffeine are typical causes of enhanced physiological tremor.

Psychogenic Tremor: Psychogenic tremor is characterized by an abrupt onset, associated pain and other false neurological signs. Other observations include distractibility, co-activation sign, and absent finger tremor. In some cases a secondary gain, such as attention from a loved one or disability status, may be involved.

Drug-induced Tremor: Certain drugs are known to induce or worsen tremor in some patients. Table 2 provides a list of some of the most common agents in this category. For example, levetiracetam (Keppra), typically used to treat epilepsy, was reported to worsen ET in 5 out of 10 patients in an open label study (Ondo, Jimenez, Vuong, & Jankovic, 2004). In patients with MS, drugs such as prednisone or antidepressants are common causes of tremor.

Orthostatic Tremor: Orthostatic tremor is observed in lower extremities and trunk during upright posture.


Task-specific Tremor:
This type of tremor appears with goal-oriented tasks, such as speaking or writing. A common form of task-specific tremor is primary writing tremor, a variant of focal hand dystonia (Writer’s cramp). Unlike ET, this form of tremor is not evident in other tasks requiring coordination, only during writing.

Summary and Conclusion
If you are experiencing tremor related to MS, please be sure to bring it to the attention of your physician. The first strategy would be to define the type of tremor seen. If the tremor turns out to be drug-induced, removing or reducing the offending agents should be the first approach. Second, medication to specifically treat tremor can be tried along the guidelines reviewed above. Finally, DBS might be considered for drug-resistant tremor.

References
Benabid, A. L., Pollak, P., Seigneuret, E., Hoffmann, D., Gay, E., & Perret, J. (1993). Chronic VIM thalamic stimulation in Parkinson’s Disease, essential tremor and extra-pyramidal dyskinesias. Acta Neurochirurgica. Supplementum, 58, 39-44.

Hubble, J. P., Busenbark, K. L., Wilkinson, S., Pahwa, R., Paulson, G.W., Lyons, K., et al. (1997). Effects of thalamic deep brain stimulation based on tremor type and diagnosis. Movement Disorders: Official Journal of the Movement Disorder Society, 12(3), 337-41.

Lou, J. S. & Jancovic, J. (1991). Essential Tremor: Clinical correlates in 350 patients. Neurology, 41 (2[pt 1]), 234-8. Ondo, W., Jankovic, J., Schwartz, K., Almaguer, M., & Simpson, R.K. (1998). Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson’s disease tremor. Neurology, 51(4),1063-9.

Ondo, W. G., Jimenez, J. E., Vuong, K. D., & Jankovic, J. (2004). An open-label pilot Study of Levetiracetam for essential tremor. Clinical Neuropharmacology, 27(6), 274-7.

Rautakorpi, I., Takala, J., Marttila, R. J., Sievers, K., & Rinne, U. K. (1982). Essential tremor in a Finnish population. Acta Neurologica Scandinavica, 66(1), 58-67.

Zesiewicz, T. A., Elble, R., Louis, E. D., Hause, R. A., Sullivan, K. L., Dewey, R. B., et al. (2005). Practice parameter: Therapies for essential tremor: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 64(12), 2008-20.

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