Approach

The goal of management is to reduce tremor, improve functional ability, and reduce social embarrassment. However, patients' response to medications is unpredictable, and a large proportion of patients (25% to 55%) have no response. This may be related to the fact that essential tremor (ET) is not a homogeneous condition and there are different clinical subtypes (e.g., with and without head tremor), which may differ in pathogenesis and response to treatment.[6] Complete suppression of tremor is unlikely. For patients refractory to medical management, surgical approaches may be appropriate.

Mild disease without dysfunction or embarrassment

Medications are not indicated for mild cases that do not cause dysfunction or embarrassment.[6] For these patients, observation is all that is required.

Medical treatment

Medications are not indicated for mild cases that do not cause dysfunction or embarrassment.[6] For these patients, observation is all that is required.

Medical therapy may be used to improve function (e.g., using a smartphone, performing work-related tasks) or reduce embarrassment (e.g., the inability to eat or drink in public without making a mess) associated with the disorder. First-line agents include propranolol and primidone. These should be offered to patients who desire medical treatment for ET. Their choice depends on concurrent medical conditions and potential adverse effects.[81]

Propranolol has been shown to be more effective than placebo at doses of 120 mg/day or greater.[82] A metabolite of primidone, phenylethylmalonamide (PEMA), has anticonvulsant properties and may be responsible for the antitremor effects of this drug. An acute toxic reaction of ataxia, nausea, and vomiting is not uncommon when beginning primidone, and these adverse effects cannot be circumvented even with low starting doses or a slow titration schedule.[83] Despite this fact, patients have been shown to prefer primidone to propranolol.[84]

There are several second-line agents that can be used to treat ET if primidone and propranolol are either ineffective or not tolerated. Gabapentin, an anticonvulsant, is also used.[85][86][87] Benzodiazepines potentiate gamma-aminobutyric acid (GABA), and alprazolam is another second-line choice; however, sedative effects can limit its use. Topiramate, another anticonvulsant drug, is also used.[81][88][89][90]

Surgical treatment

Deep brain stimulation (DBS) of the nucleus ventralis intermedius (VIM) of the thalamus is a highly effective surgical treatment for medication-refractory patients with impairment in daily life as a result of tremor (e.g., patients who are unable to write or pick up a cup using just one hand).[91] A multidisciplinary team that includes a movement disorders-specialized neurologist, a neurosurgeon, and a neuropsychologist should be involved. For centers where such specialists are not readily available, simpler screens have been designed to help identify potential candidates for DBS.[92][93][94][95][96] As this is an elective procedure, determining a favorable risk-to-benefit ratio is paramount. This includes accurately diagnosing the patient's tremor, establishing that appropriate medical therapy was not successful, estimating the improvement in the patient's functional capacity and quality of life that would result with tremor control, and assessing the patient's suitability for surgery (i.e., age, cognitive function, and medical comorbidities).

Several studies with short- and long-term follow-up have documented the efficacy of VIM DBS for tremor. Rates of tremor reduction have been reported to range from 50% to 90%, with the majority falling in the 70% to 80% range.[97][98][99][100][101][102][103][104][105][106][107][108][109] Although deterioration of effective tremor suppression has been reported in 18.5% to 21% of patients over time, other reports with up to 6 years' follow-up document sustained tremor reductions of 46% to 86%.[98][107][109][110][111] The loss of efficacy is thought to be most commonly due to disease progression; the development of tolerance to therapy is likely to be over-reported in the literature.[112] The incidence of adverse events ranges from 9% to 65%.[111][113] Patients with and without adverse events have been reported to fare equally well in terms of motor outcomes, quality-of-life measures, and subjective patient-oriented impression scales. Thalamic stimulation is adjustable so, if the stimulation causes an adverse effect, the stimulation parameters can be modified or stimulation can be discontinued. Adverse effects related to stimulation, including paresthesia, dysarthria, and gait disorders, are relatively common but are reversible with setting adjustments. One study suggests that the incidence of increased walking difficulties after DBS surgery for ET has been widely underestimated, and that it may occur in as many as 58% of patients. This adverse effect appears to be more common among patients with higher Fahn-Tolosa-Marin tremor rating scale scores, which typically correlate with more advanced disease and a higher tendency toward gait instability at baseline.[114] Long-term efficacy and adverse events have yet to be defined fully, but a consensus statement notes the superiority of DBS over lesional thalamotomy, with DBS providing better functional outcome and fewer adverse effects.[115]

An alternative target for DBS is the caudal zona incerta (cZi), also known as the posterior subthalamic area. A new strategy whereby the DBS lead is implanted through the VIM thalamic nucleus into the cZi has been proposed, which allows stimulation in either or both targets. This new target shows substantial promise as an effective target for suppressing contralateral tremor in these patients, with a long-lasting effect.[116][117][118]

Focused ultrasound thalamotomy with magnetic resonance imaging guidance has been proven to be effective in medically refractory ET, and the improvement can last for more than 12 months.[119] Long-term follow-up data showed a subset of patients may have gradual tremor return. One meta-analysis of ET patients receiving focused ultrasound thalamotomy showed consistent tremor reduction; however, 32.8% of patients had ataxia and 25.1% of patients had paresthesia 3 months after the procedure.[120] Ataxia symptoms tended to resolve by 12 months but paresthesia persisted.[121][122]

The American Society for Stereotactic and Functional Neurosurgery (ASSFN) recommends transcranial magnetic resonance-guided focused ultrasound (TcMRgFUS) thalamotomy as a treatment option for patients with refractory ET, who have an appendicular tremor that interferes with quality of life, and that are expected to have a significant improvement with unilateral treatment.[123]

Another surgical option for refractory ET therapy is gamma knife thalamotomy, which is especially suitable for older patients or those with high surgical risk for DBS or radiofrequency thalamotomy.[124]

Adjunctive therapies

Various nonpharmacologic and nonsurgical interventions have been advocated as beneficial for tremor management, including neuromuscular physical therapy, strength training, and tremor-suppressing orthoses based on viscous materials, weighted splints, and vibration therapies. While these modalities are commonly employed by occupational therapists in an effort to improve activities of daily living for patients with tremor, the evidence to support their efficacy is poor.[125]

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