Essential Tremor

Tremor, an oscillatory movement produced by rhythmic contractions of muscles, is the most common form of involuntary movement disorder encountered in the clinic, but only a small fraction of those with tremor seek medical attention. Essential tremor (ET) is the most common form of tremor, affecting about five percent of people over the age of 60 years. Although ET is more common in the elderly and is often wrongly labeled as "senile tremor" it may start at any age, including in childhood. In contrast to tremor at rest, which is most frequently encountered in patients with Parkinson's disease, essential tremor is typically an action-postural tremor. Patients usually first become aware of the tremor when they are holding newspapers or utensils or when reaching for objects. ET can also affect the neck muscles and produce either "yes-yes" or "no-no" oscillation of the head, and the vocal cords, noted as a tremulous voice while talking or singing.

A review of the clinical features in 300 patients diagnosed with essential tremor referred to the Movement Disorders Clinic at Baylor Medicine has shown that besides hand tremor noted in all, tremors involved head in 47 percent, voice in 25 percent, and legs in 23 percent of patients. Stress, overactive thyroid, certain drugs and may other conditions can exacerbate the tremor. Despite the frequently used prefix, "benign" ET can produce significant physical and psychosocial disability. In addition to social embarrassment, ET can interfere with writing, typing, texting, eating, speaking, singing, and various other activities of daily living. Although the tremor frequency tends to decrease with age, the amplitude usually increases making the tremor more and more troublesome.

In some cases, tremors occur only during a particular task, such as writing, or while holding limbs in a certain position such as when bringing a glass to the mouth or putting on makeup. These task- and position-specific tremors are considered variants of ET, but in some cases, the clinical features overlap with another movement disorder called dystonia. In some patients, dystonia produces rhythmical movements resembling ET, but in contrast to ET, dystonic tremor is more irregular, “jerkier”, and may worsen when body parts are placed in certain positions or resolve in other positions, the so-called “null-point”.

Some studies have suggested that there is an association between ET and dystonia, and between ET and Parkinson's disease. This is supported by the reports of well-studied families in which some members have typical ET, while others have dystonia, parkinsonism, or a combination of all three disorders. Furthermore, some patients start with typical ET and several years or decades later develop parkinsonism, dystonia, or both. Subtler dystonic features can often be seen in ET patients. Although it should not be difficult to differentiate tremor of ET and tremor typically seen in patients with PD, the occasional co-existence of the two disorders in the same individual may present a diagnostic challenge. The frequent presence of ET before the onset of PD has led to the proposal that ET may be considered a form of prodromal PD.

In addition to dystonia and parkinsonism, patients with ET seem to have a higher frequency of deafness, hereditary neuropathy, cognitive problems, mild incoordination, and loss of balance.

Cause

Frequently misdiagnosed as a stress-related condition or a natural consequence of aging, ET is actually a manifestation of a genetic neurological disorder as most patients with ET have a family history of tremor. Although one of the most common genetic disorders, the causative genes of ET have not yet been identified. This is partly due to the marked heterogeneity of ET, suggesting that there may be different subtypes of ET.

Currently, ET is considered the result of a dysfunction in the network that coordinates movements, which involves the cortex and deeper areas of the brain such as the thalamus, cerebellum, and olivary nucleus. Loss and swelling of specialized cells called Purkinje cells in the cerebellum and changes in the production of GABA were reported, but no clear mechanism was defined. 

Treatment

Medications

The treatment of tremor depends largely on its severity; many patients require nothing more than simple reassurance. Most patients who are referred to a neurologist, however, have troublesome tremors that require medication or surgical treatments. The large volume and slow frequency postural tremors usually do not respond well to pharmacologic therapy.

Since alcohol reduces ET in about two-thirds of patients, some use alcohol its "calming" effect which could potential lead to alcohol abuse (alcoholism). Very small amounts of alcohol before an important engagement or potentially stressful or embarrassing situation, when used judiciously and only sporadically, may be a reasonable approach for some patients.  Regular use of alcohol to treat ET, however, is not recommended.

Propranolol and primidone are the most effective medications to treat ET. Propranolol (Inderal) a beta-adrenergic blocker, is often considered the treatment of choice. It is often initially prescribed in a small dose (20 mg) and if the patient finds it effective and well tolerated it may be changed to an extended-release formulation. While usually well-tolerated, some patients experience side effects, such as fatigability, sedation, depression, and erectile dysfunction. Propranolol is contraindicated in the presence of asthma and insulin-dependent diabetes. The anti-tremor effect of primidone (Mysoline) has been confirmed by several clinical trials. By starting primidone at a very low dose at bedtime, the occasional side effects (nausea, vomiting, sedation, confusion, and loss of balance) can be prevented. A combination of the two drugs, propranolol and primidone, may be more efficacious than either drug alone.

In addition to propranolol and primidone, other beta-blockers such as pindolol and nadolol, benzodiazepine drugs, such as lorazepam (Ativan), and clonazepam (Klonopin) also may also improve essential tremor and its variants. Gabapentin (Neurontin), topiramate (Topamax), and pregabalin (Lyrica), drugs approved for the treatment of epilepsy, may be also useful in the treatment of tremors.

Hand, head and voice tremor may also respond to local injections with botulinum toxin (BTX). Usually well-tolerated, the effects of BTX can be observed withing a few days and last 3-4 months. Rarely, BTX injections may be associated with transient weakness of the injected muscles.

Procedures and Surgery

Deep Brain Stimulation

Neurosurgical treatments, such as deep brain stimulation (DBS), are generally reserved for patients whose tremors continue to interfere with work or activities of daily living despite optimal medical therapy. DBS involves an incision in the scalp and drilling a hole in the skull. The surgeon then uses a "probe," a wire electrode, and advances the electrode into the portion of the brain that is thought to be functioning abnormally. The DBS lead, which contains four electrodes, is surgically inserted into the desired target and fixed to the skull with a ring and cap. An extension wire passes from the scalp area under the skin to the chest and is connected to a totally implantable pulse generator (IPG), a pacemaker-like device, which can deliver pulses with a variety of parameters, modes, and polarities into the target brain area. The IPG is placed under the skin in the upper chest area near the collar bone. The patient can activate, deactivate, and possibly adjust other settings for the DBS system using a patient controller. The major advantage of DBS over the traditional ablative procedures is that the stimulating electrodes and parameters (frequency of stimulation, pulse width, and current amplitude) can be adjusted to the needs of the individual patients. Potential risks, such as hemorrhage, stroke or infection, are rare but should be considered when making a final decision about this treatment option. Side effects, if they occur, are usually related to stimulation and thus reversible with settings changes, but may include weakness, speech and swallowing difficulties, and abnormal sensations. Most patients continue to have improved tremor for more than 7 to 10 years. See article on DBS at www.jankovic.org.

MR-Guided Focused Ultrasound

Focused ultrasound thalamotomy (FUS) reduces the abnormal brain activity that is responsible for the tremor, providing meaningful clinical benefits. FUS therapy is applied on a deep brain structure called the thalamus, with the goal of creating a tiny ablation or lesion reducing the abnormal brain activity responsible for the tremor. FUS is indicated when medications or local botulinum toxin injections do not provide adequate tremor control and/or there is poor tolerance to their side effects. FUS is not a cure for ET and does not necessarily improve any associated symptoms such as balance difficulties. FUS is performed on one side initially, with the option of adding the other side in the future. If performed bilaterally at the same procedure it could cause problems with speech and balance. See article on FUS at www.jankovic.org.

When considering surgical therapies for tremor, it is important to discuss clearly the goals, expectations, benefits, and risks of each procedure, so that the best therapy can be chosen on a patient-by-patient basis.

References

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