Tremor is one of the most common and debilitating neurologic conditions in the world, affecting more than 10 million people in the US alone. In an era in which the burden of neurologic disease on society is increasing rapidly, diseases with tremors are amongst the leading causes of disability-adjusted life years lost (DALY). Optimal management of patients with tremor hinges on understanding the causes of tremor, making the right diagnosis, prescribing first-line medical therapies, and referring patients for surgical intervention when appropriate.
Tremor is defined as the involuntary, alternating, rhythmic contractions of opposing muscles. It is not a diagnosis in and of itself, but a symptom. While tremor most commonly affects the arms and hands, it can also affect the head, voice, trunk, and legs. Besides location, tremor is classified with respect to amplitude, rate, and position. The position in which a tremor occurs is one of the most important characterizing features, occurring either at rest, with posture, or with action (i.e., kinetic).
Causes and Diagnoses
Essential tremor (ET) is the most common cause of tremor, affecting four to five percent of people over the age of 40 years and up to nine to 10 percent of people over the age of 60 years—a prevalence approximately 10 times that of Parkinson’s disease. A diagnosis of ET is based on the presence of bilateral postural tremor (8-12 Hz) with or without a kinetic (or action) tremor involving the hands and forearms. The tremor usually emerges either in adolescence or after the age of 50, affects men and women equally, should be gradual in onset, and has a variable progression. ET generally has a very strong family history; it is not uncommon to hear of multiple relatives with similar tremor. Although often referred to as “benign” essential tremor, many patients with ET argue the disease is anything but “benign” and that the tremors interfere with even the most basic functions and activities of life, like drinking, eating, and brushing teeth.
Although not the most common cause of tremor, for many, the term “tremor” is synonymous with Parkinson’s disease (PD). The tremor of PD and ET however are vastly different. PD tremor is slow (3-6 Hz), is predominantly at rest, almost always has an asymmetric onset, and is most often associated with other neurologic symptoms of bradykinesia (slowness) and rigidity (stiffness). While Parkinson’s disease is considered a movement disorder, one must be cognizant of a host of other problems these patients have, including depression, anxiety, constipation, sleep disorders, and cognitive problems later in disease. In fact, more than 80 percent of patients who have suffered from PD for 20-plus years will eventually meet diagnostic criteria for dementia, an incidence which is approximately four times that of the general population.
While PD is most often diagnosed after the age of 65, affecting one to two percent of people over 65 and men twice as often as women, it can also be diagnosed in patients under the age of 40 (so called “young onset Parkinson’s disease”) which is associated with a slower rate of disease progression but greater psychosocial complications. Having a relative with PD increases the risk of developing PD by about threefold. Diagnosis is based on the constellation of symptoms described, but also on response to levodopa or dopamine agonists and the absence of atypical parkinsonism (e.g., early cognitive deficits, incontinence, apraxia, autonomic dysfunction, etc.). Challenging diagnostic cases can be facilitated by DOPA PET scans or DaTscan, which can demonstrate decreased dopamine metabolism in the basal ganglia, but such studies are not diagnostic and must be interpreted in a clinical context. Unlike ET, which does not have a clear pathologic etiology, PD is hallmarked by degeneration of the substantia nigra, pars compacta with deposition of Lewy Bodies containing alpha-synuclein.
Before rendering a diagnosis of ET or PD, secondary causes of tremor need to be excluded. Drug-induced tremors, especially in the setting of lithium, valproate, antipsychotic medications, and antidepressants, should be considered, especially when onset of tremor coincides temporally with initiation or changes in dosing of such medications. Medical causes of tremor including hyperthyroidism and exogenous and endogenous stimulants, such as caffeine and hormone producing tumors should be included in the differential diagnosis. Other neurologic causes of tremor include cerebellar disease, multiple sclerosis, and stroke. Abrupt onset may suggest a cerebellar, midbrain, or thalamic stroke and should prompt detailed neuroimaging assessment. Finally, an astute practitioner will consider the possibility of an enhanced physiologic tremor, which is an exaggeration of a normal physiologic tremor that can emerge in stressful situations.
Symptom Directed Therapy
The goals of treatment for patients with tremor are to reduce tremor severity, improve daily functioning, and improve quality of life. Because therapy is symptom directed, the threshold for intervention will vary by patient and by the degree of impairment. In general, but especially in the case of Parkinson’s disease in which medical therapies can result in complications, therapy is delayed until symptoms are clearly interfering with quality of life.
For ET, two medications are considered first-line therapies: propranolol and primidone. In many cases, these medications can reduce tremor by as much as 50 percent and may obviate the need for further intervention. Combining the two therapies may result in an additional 10-15 percent in improvement in tremor control and function. In many cases, these therapies are not tolerated due to dose limiting side effects of low blood pressure and drowsiness. Second line treatment options can include gabapentin, topiramate, atenolol, alprazolam, sotalol, and clonazepam. In addition to medical therapies, occupational therapies are helpful to provide assistance with adaptive devices such as weighted utensils, plate guards, and other specially designed devices for patients with tremor.
First line therapies for patients with PD largely depend on patient age and degree of functional impairment. There is a different threshold for intervention for every patient. While younger patients (less than 70 years) are generally started with dopamine agonists and MAO-B inhibitors (which may provide a neuroprotective effect), older patients are usually treated with levodopa as a first line agent. The goal is to delay levodopa use as much as possible in younger patients because of the possibility of developing levodopa-induced dyskinesia with prolonged use of this drug. While dopamine agonists can delay use of levodopa, an important dose-limited side effect that must be recognized is impulse control disorders (ICD) which can manifest, amongst other possibilities, as impulsive gambling and spending or hypersexuality. Other classes of medications that can be used to prolong the action of dopamine within the synaptic cleft include COMT inhibitors (such as entacapone or tolcapone) or MAO-B inhibitors (such as selegiline and rasagiline). Amantadine can be used to treat motor fluctuations as well, but its benefit is often limited in time and it can be associated with hallucinations. In patients with tremor dominant disease, tremor often does not respond to any of these medications and may be best managed with anticholinergic medications (e.g., trihexyphenidyl). Because of the complexity of managing multiple medications with varying doses and schedules, such complex patients are ideally managed by a movement disorders specialist with extensive experience with such management.
Limitations and Complications of Medical Therapy
While medications and lifestyle modifications can be more than sufficient for most patients with ET to cope with tremor, in some cases, tremor persists or progresses, does not respond to medical therapy, and significantly interferes with function, either at home or at work. In the setting of ET, lack of response to medical therapies does not affect the diagnosis of ET but may warrant consideration of other therapeutic modalities.
In contrast to ET, lack of response to PD medications in a patient suspected of having PD calls into question the diagnosis. In such cases, metabolic imaging, such as DOPA PET or DaTscan should be considered. More often, however, the complications of medical therapy are not a lack of response but the development of motor fluctuations, which include dyskinesia (or excess uncontrolled movements) when taking medication, rapid wearing off of medication effects, and dystonia when medications are subtherapeutic. These motor fluctuations, which usually require patients to take medications every two to four hours, are thought to be due to the pulsatile nature of taking drugs and are therefore considered a complication of medical therapy. It is nearly impossible to predict when patients will develop such complications, with some developing motor fluctuations within just a few years of initiating therapy and others not developing such fluctuations after using medical therapies for over a decade. The onset of motor fluctuations are complicated by the simultaneous progression of the underlying disease, such that patients develop gait problems including shuffling and freezing of gait as well as balance difficulties.
The surgical management of tremor is deeply rooted within neurosurgery and centers on manipulation and modulation of the thalamus (the ventral intermediate nucleus). The indication for surgical intervention is the presence of tremor that is refractory to medication and is impairing quality of life regardless of tremor amplitude. While historically, tremor was treated with invasive lesioning procedures (i.e., thalamotomy), contemporary therapy is based on modulating the thalamus with deep brain stimulation (DBS) therapy. Rather than creating a lesion, a DBS electrode is precisely and stereotactically implanted in the thalamus and connected to a pulse generator that is implanted in the chest. Just like a cardiac pacemaker resets rhythms in the heart, the DBS system resets pathologic brain rhythms to restore a more normal pattern of activity and level of function. The advantage of DBS over thalamotomy is the ability to modulate the therapy over time using a wireless remote device and the ability to reverse the therapy at any time.
For patients who may not be medically fit for, or who may absolutely refuse surgery, consideration can be given to stereotactic radiosurgery (SRS) thalamotomy. SRS is a method by which to deliver a very high dose of focused radiation to a specific target in the brain. SRS can be delivered with one of three technologies, including Gamma Knife, linear accelerator (LINAC), or proton beam therapy. SRS is most often used for the management of cerebral metastases, but was originally designed for functional stereotactic procedures, such as thalamotomies. While this approach is appealing because it is non-invasive and because studies have shown it to be effective (at least 50 percent tremor reduction) in up to 90 percent of patients, it actually has a greater risk profile than DBS (four percent vs. one percent risk of stroke) and is therefore considered second line. The risk is largely attributable to the inability to accurately select the precise target for lesioning based on current imaging technology. Innovations in current imaging strategies and brain mapping techniques, however, may minimize these risks.
Surgical consideration is given to patients with PD who have advanced PD and demonstrate a good response to levodopa, but have motor fluctuations, including wearing off of medications and medication-induced dyskinesia. Response to levodopa is the most critical component of the history. Patients should expect that DBS therapy will allow them “to spend more time in their best on condition.” In fact, several controlled trials have now demonstrated the superiority of DBS therapy compared to best medical therapy in patients with motor fluctuations. In general, patients can expect to spend up 4-6 more hours per day in their best “on condition.” Interestingly, studies now find that DBS targeting the subthalamic nucleus (STN) and globus pallidus internus (GPi) are equally efficacious with respect to controlling the motor complications of PD. While DBS of the STN is associated with greater medication reduction, it is also associated with an increased trend for neurocognitive complications. GPi DBS, on the other hand, is associated with greater control of dyskinesia. STN however may be particularly preferable in patients with tremor-dominant disease. The recent EARLYSTIM trial concluded that patients should be treated with DBS after the diagnosis of motor fluctuations in order to maximize the benefits of DBS and patients’ quality-of-life.
Deep Brain Stimulation: The Process and The Risks
A critical component to DBS therapy is managing patient and provider expectations. DBS is a symptomatic adjunctive treatment that has been shown in multiple clinical trials to improve motor control and quality of life. It is not however disease modifying and it does not eliminate the need for medications. Workup and assessment for DBS in a comprehensive program will require neurosurgical evaluation, formal on- and off-medication videotaped assessment by a movement disorders neurologist, formal neuropsychological assessment, and general medical examination. Stereotactic implantation of the DBS electrodes and generators can be done in as little as one procedure in one day or may be spread out over 4 procedures over a 6-12 month period, depending on the individual patient’s health and specific medical needs. Surgery is most often done with the patient awake to facilitate intraoperative neurophysiological testing to confirm optimal electrode placement that optimizes the therapeutic window for stimulation, including minimization of side effects of stimulation. Programming requires at a minimum a 3-6 month commitment of return visits for both initial programming and adjustments of both stimulation parameters and medications in order to optimize benefits of stimulation. Patients will then need to return on a semi-annual or annual basis for generator interrogations and possible generator replacement every 3-7 years.
While the benefits of DBS are clear, patients must be aware of the most important risks of DBS surgery. The risk patients are most concerned about is risk of hemorrhage or stroke, which is estimated at approximately 0.6 percent chance of permanent neurological deficit per electrode implanted. The greater risk is that of infection, which can occur in up to 5-10 percent of patients undergoing surgery, which in most cases requires removal of the implant and prolonged antibiotic therapy. Because this is major brain surgery, other medical complications can occur as well including heart attack, deep vein or pulmonary thrombosis, and urinary tract or pulmonary infections. These complications are rare, however. Finally, patients must be aware that implanting a device can be associated with discomfort, skin erosion, and other complications. These types of complications have become more rare with improvements in technology.
The most important factor to safeguard patient safety and maximizing outcomes is the development and implementation of evidence-based protocols for patient management, which ensure providers systematically consider all factors that can minimize complications and optimize benefits.
Future Promising Therapies
While DBS is a state-of-the-art proven therapy, recognized limitations include the risk of stroke associated with the surgical procedure (albeit low), the invasive nature of the procedure, and the need for frequent physician visits for programming. To address these shortcomings, several new technologies and approaches are being investigated.
The most promising technology is the non-invasive treatment of magnetic resonance guided focused ultrasound therapy (MRgFUS). MRgFUS is currently beginning a Phase III randomized clinical trial for the treatment of ET and a Phase I safety trial for management of PD. Like SRS, MRgFUS uses very focused energy to create a lesion in a precise area of the brain. Instead of using radiation energy, MRgFUS uses ultrasonic energy that allows the physician to create test lesions to ensure the efficacy and safety of the final target before making a final lesion. This adds a level of safety to current SRS technology, which is critical. Phase I trial results in ET have been reported in conference proceedings, demonstrating greater than 50 percent tremor reduction in almost all patients with few side effects.
Other innovations are occurring in the domain of DBS therapy, with new technologies being investigated and developed to create “closed loop” systems. While current DBS technology requires the physician to assess patients to determine how to modify stimulation, several academic centers are working on intelligent DBS systems that can detect brain signals and modify stimulation parameters based on intrinsic patterns of brain activity. One device manufacturer has developed such a sensing device and is collaborating with multiple centers to develop novel approaches and methods for closed loop neuromodulation.
Finally, in the interest of avoiding brain surgery altogether, duodopa is a method of delivering a continuous infusion of levodopa directly into the gastrointestinal tract to reduce motor fluctuations associated with pulsatile drug delivery. While the concept holds promise, early reports suggest equal efficacy relative to DBS but with increased procedural complications. Further studies and experience are necessary to better define its role in the management of PD patients.
Tremor is prevalent and can be associated with an array of medical and neurologic diagnoses. Characterizing the tremor and associating it with the correct diagnosis is key to guiding medical and surgical therapies. In all instances, therapy is symptom directed and aims to improve function and quality-of-life. When first line medical therapies fail, attention should be given to surgical therapies, which have a proven track record in clinical trials of providing greater benefit than best medical therapy. Surgical therapy, however is not a standalone therapy and is optimally delivered in the context of a comprehensive multidisciplinary program.
Nader Pouratian, MD, PhD, is a UCLA Neurosurgeon, Assistant Professor of Neurosurgery at the David Geffen School of Medicine at UCLA, and Director of the UCLA Neurosurgical Movement Disorders Program and Peripheral Nerve Program.