Motion sickness

Tremor types

Pathologic tremors can take several forms; resting tremor, intention tremor, and action tremor (also referred to as kinetic or postural tremor). Resting tremor occurs when the limb is relaxed and fully supported against gravity, not necessitating voluntary movement. Intention tremor can be described as tremor that worsens during goal-orientated actions; for example, during the finger-to-nose manoeuver.

Action tremor is the most prevalent of the three tremors, and its most common form is essential tremor, defined as a tremor of the hands from 4Hz to 12HZ. The trunk, voice, head and legs may also be affected.

This disorder affects millions of people, making it difficult or even impossible for them to perform the simplest of movements. Because the tremor often becomes more pronounced as the hands near the face, eating and drinking can become very difficult. Functional disability can interfere with on-the-job tasks, resulting in job changes or premature retirement. An estimated 60% of patients with essential tremor choose not to apply for a job or promotion because of their condition.

ET and parkinsonism

Estimates of the prevalence of essential tremor in the general population range from 0.4 to 6%, rendering the condition 5 to 10 times more common than Parkinson’s disease. However, studies show than up to 90% of Parkinson’s patients have action tremor and approximately 20% of people with essential tremor also have a resting tremor, a symptom strongly associated with parkinsonism. Clinicians are divided on whether essential tremor is a risk factor for parkinsonism; while some studies suggest the incident of parkinsonism is greater in people with essential tremor, other studies found no association between the two conditions.

Because essential tremor and parkinsonian tremor are both common and chronic forms of pathologic tremor, is it essential to be able to differentiate between the two. While many patients with Parkinson’s disease have a mild postural tremor, a resting ‘pill-rolling’ tremor of the hand affects an estimated 85% of sufferers. This distinctive feature is less frequent in patients with essential tremor. Parkinson’s disease is also characterised by hypokinetic features and rigidity that are not present in essential tremor.

Causes

Medical texts from ancient India and Greece mention tremors. Charles Dana, the 19th- century neurologist, wrote detailed case histories of people with tremors. Yet, despite this long history, the underlying mechanism of essential tremor is still not fully understood although several theories have been proposed.

Functional neuroimaging studies suggest irregularities in the olivo-nucleus and cerebellum may contribute to abnormal oscillatory activity that is expressed peripherally as pathologic tremor.

Neuroimaging studies have also revealed abnormalities in thalamic GABAA receptors, a finding supported by the tremor-relieving properties of agents with GABA-enhancing activity (gabapentin, benzodiazepines etc.).

Essential tremor also runs in families and is sometimes referred to as familial tremor. Hereditary essential tremor appears to follow an autosomal dominant mode of inheritance, and has been linked to genes FET1 or ETM1 on the long arm of chromosome 3 at q13. According to the 1994 Essential Tremor Study Group, a positive family history was reported in more than 60% of 678 patients with ET. In general practice, approximately 50% of patients report a positive family history. Furthermore, studies of identical twins have shown that essential tremor is not completely inherited, suggesting an environmental factor may play a role in some cases.

In families with a positive history, the chance of developing essential tremor decreases with age. If offspring are still asymptomatic at age 10 years, the risk of developing it at a later age is less than 39%. If unaffected by age 25 years, the risk falls to less than 20% and if the offspring remains unaffected by the age of 50 years, the risk is less than 6%.

Diagnosis

The diagnostic approach for essential tremor involves obtaining a history, physical examination and laboratory tests. While at present the diagnosis of essential tremor is based on clinical findings, laboratory tests are required to rule out other causes of tremor (see ‘At a glance: differential diagnosis). A psychosocial evaluation should also be undertaken to assess the impact of the tremor on daily living.

During history taking, the age at tremor onset, the type and progression of tremor and a full family history should be noted. Because caffeine, cigarettes and medications (such as bronchodilators, lithium and prednisone) can result in enhanced physiologic tremor, a complete inventory of medications, in addition to substance use, is required to exclude these as the cause of tremor.

During the physical examination, clinicians should carefully assess the characteristics of the tremor to rule out Parkinson’s disease. Although no clinical criteria is universally accepted, Elan et al (NEJM 345:12) suggested the following guidelines to diagnosis:

Definite essential tremor

• Postural tremor of moderate amplitude is present in at least one arm.

• Tremor of moderate amplitude is present in a least one arm during at least four tasks such as pouring water, using a spoon to drink water, drinking water, finger to nose manoeuver and drawing a spiral.

• Tremor must interfere with at least one activity of daily living.

• Medications, hyperthyroidism, alcohol and other neurological conditions are not the cause of tremor.

Probable essential tremor

• Tremor of moderate amplitude is present in at least one arm during at least four tasks or head tremor is present.

• Medications, hyperthyroidism, alcohol and other neurologic conditions are not the cause of tremor.

Computerised analysis of tremor is available at some tertiary care centers; however, its diagnostic validity has not been established.

Pharmacotherapy

The goals of treatment are to minimise functional disability, reduce social handicap and improve quality of life. Treatment options, including medication, physical therapy, lifestyle changes and surgery, are based largely on the patient’s needs and history. Medication does not cure essential tremor, but can slow the rate of disease progression and reduce the level of embarrassment associated with the condition. Most patients will benefit from drug therapy, however, it is not indicated in patients with mild tremor.

Propranolol and primidone are the first-line agents in the treatment of essential tremor. The use of the beta-blocker propranolol for management of essential tremor dates back over 40 years, and is supported by several placebo-controlled studies that showed, at a dose of at least 120 mg per day, propranolol produced a significant reduction in tremor. Independently, 45% to 75% of patients also reported that the agent was more effective than placebo in reducing their tremor. Relative contraindications include congestive heart failure, diabetes mellitus and asthma.

Primidone is an anticonvulsant and a first-line agent in patients in whom beta-adrenergic blockers are contraindicated or not tolerated. Studies have shown primidone to be about as effective as propranolol, but less well tolerated in the short-term. Even at a low starting dose of 62.5 mg per day, side effects including nausea, vomiting, and ataxia were reported by 23% to 73% of patients. Discontinuation of primidone was required in approximately 20% or patients in some studies. Although initial intolerability is a problem, there is evidence that the long-term tolerability of primidone is superior to that of propranolol. In one study of 25 patients with essential tremor, acute adverse reactions occurred in 8% of the propranolol group, compared to 32% of the primidone group. However, clinically significant long-term effects were reported in 17% of those in the propranolol group compared to none in the primidone group.

It is notable that many sufferers eventually need to take propranolol and primidone together to get adequate relief. In such cases, primidone is usually prescribed at 25 mg at bedtime, and gradually increased to 250 mg/day. Propranolol is then added, usually at 40 mg three times per day. Propranolol dosage may be increased to a maximum of 320 mg/day if the response remains inadequate.

Studies of another anticonvulsant, topiramate, are promising, but a high proportion of patients experience side effects. In one multicenter, placebo-controlled trial, 223 subjects were randomised to a mean topiramate dose of 292 mg/day, while the remaining 50% received one other antitremor medication at a stable dose. Tremor rating scale scores improved by 29% in the topiramate group, as compared with 16% in the placebo group. Tremor control was rated as good or very good by 72% of the topiramate-treated patients, as compared with 15% of the placebo-treated patients. In all, 32% of the topiramate-treated patients and 10% of the placebo-treated patients withdrew because of side effects. The most common side effects were paresthesias, weight loss, taste abnormalities, memory dysfunction, fatigue, nausea, reduced appetite, and somnolence. The authors concluded that topiramate was effective in the treatment of moderate to severe essential tremor, with tremor reduction accompanied by functional improvements, such as in motor tasks, writing, and speaking.

Additional potential second-line therapies include gabapentin, an anticonvulsant medication, benzodiazepines, calcium-channel blockers, clonidine and carbonic anhydrase inhibitors. However, further research is required to determine the value of their long-term use.

Additional therapies

Botulinum toxin has proved to be a useful therapeutic tool in certain hyperkinetic movement disorders.

Several randomised controlled studies support the use of botulinum toxin type A (BTX-A) in selected patients with hand, head, vocal or palatal tremor. In one such trial, 25 patients with moderate to severe essential hand tremor were injected with BTX-A 50 or 100 U into wrist flexors and extensors and followed for 18 weeks. 75% of those treated with BTX-A reported mild to moderate improvement in the amplitude of tremor four weeks after treatment, compared with 27% of placebo-treated patients. However, no significant improvement in functional disability was seen, primarily because of dose-dependent hand weakness.

Surgery is an option for people with severe tremors, but obviously carries risk. Thalamotomy, introduced in the 1950s to help Parkinson’s patients, is an ablative technique that targets the ventralis intermedius nucleus within the thalamus. The efficacy of the procedure is high with an experienced neurosurgical team, but possible side effects include dysarthria, gait abnormality, paresthesia and cognitive deficits.

Deep brain stimulation of the ventral intermediate (Vim) nucleus of the thalamus, is also a viable treatment option. Multiple studies of DBS of the thalamus have shown that it is efficacious in the treatment of ET hand tremor, often with secondary improvement in voice and head tremor. Adverse effects are generally mild and the results are comparative to, or better than, those seen with thalamotomy. For patients with medication-resistant disabling tremor, DBS may be considered an effective means of treatment.

Conclusion

Essential tremor is the most common type of pathologic tremor. There is no definitive test for the condition, and diagnosis is based on history and physical examination. Another commonly described as benign, essential tremor can be very disabling. In the event of functional or psychosocial disability, therapy should be aimed at achieving optimal tremor reduction with minimal side effects.