Elise Carey MD
Josh Adler MD
ESSENTIALS OF DIAGNOSIS
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects men and women equally. The prevalence is approximately 1% in the general population, with the rate rising from 0.6% for ages 60-64 to 3.5% for ages 85-89. Although PD is more frequent in older age groups, 5-10% of patients with PD acquire the disease before age 40. First-degree relatives of patients with PD are at approximately twice the risk for the disorder compared with the general population.
PD is caused by the death of dopaminergic neurons in the substantia nigra of the midbrain, which results in marked striatal dopamine deficiency. It is estimated that by the time a patient is sufficiently symptomatic to seek care 70% of the dopaminergic neurons have already died. In most patients, the specific cause of PD is unknown.
Several potential and actual genetic, environmental, and infectious causes have been identified. Genes at 3 different loci have been implicated in PD, including the alpha-synuclein gene on chromosome 4, the parkin gene on chromosome 6, and a third gene on chromosome 2. The compound, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), a by-product of methamphetamine production, is thought to have caused several cases in young adults in the early 1980s. Pesticides and herbicides have been associated with the development of parkinsonism as well. In the early 20th century, the von Economo encephalitis outbreak was followed by a high rate of postencephalitic parkinsonism. No other infectious agents have been clearly identified as predisposing one to parkinsonism. In addition, several medications, most notably antipsychotic agents, can cause or exacerbate parkinsonism (Table 13-1).
PD is a steadily progressive illness of insidious onset that leads to increasing disability over time (Table 13-2). The decline is not necessarily linear, and the rate of progression is variable. Many patients are first seen with stage II disease and bilateral involvement, which can make diagnosis challenging.
The key feature of the illness is the triad of resting tremor, bradykinesia, and rigidity. Most patients will have at least 2 of these 3 features when they are first seen. Although the resting tremor is often considered the hallmark of PD, approximately 20% of patients with PD will lack tremor. Impaired postural reflexes and postural instability become evident with progression of the disease.
Several other symptoms are commonly associated with PD (Table 13-3). Masked facies, in which the patient has decreased facial expression and facial muscle movement, develops in most patients. The loss of facial expression often causes patients to appear depressed when they are not. Reduced blinking of the eye is also often noted. Slowing of speech with a decrease in volume and inflection, known as hypophonia, is a common late-stage finding. Micrographia, a reduction in the size of the written word, may become so severe that patients lose the ability to write altogether. The posture becomes stooped with generalized flexion at the trunk, hips, knees, and elbows. Postural instability is the hallmark of stage III disease, which makes patients more prone to falls when standing and often causes balance
difficulties of the trunk, even when the patient is seated. Gait impairment develops, marked by the loss of arm swing on the affected side and, eventually, festination. With festination, the patient's center of gravity is shifted forward by the flexed posture, and the patient's steps are too short to bring the feet back under the trunk. As a result, patients take increasingly fast but short steps in an effort to position their lower limbs under their flexed trunk.
Table 13-1. Medications associated with Parkinsonism & tremor.
As PD progresses, it can potentially affect many systems. Respiratory dysfunction of some degree occurs commonly; pulmonary infection is an unfortunate and frequent consequence. Gastrointestinal dysfunction, including dysphagia and constipation, is common. Autonomic dysfunction can result in postural hypotension, bladder dysfunction, sexual dysfunction, and sweating abnormalities.
Table 13-2. Hoehn & Yahr's staging of Parkinsonism.
The diagnosis of PD is based on the history and physical examination and often reveals itself over time. No laboratory or imaging studies exist that are diagnostic of PD, although some imaging tests are under investigation.
The physical examination should include a complete neurological examination. In addition, the patient should be carefully observed for the cardinal motor features of PD: tremor, bradykinesia, and rigidity. The characteristic tremor is a 3- to 6-Hz resting tremor of the distal extremities, commonly called a “pill-rolling” tremor because the patient appears to be rolling a pill in his fingers as the wrist cycles between pronation and supination. The tremor is most pronounced at rest and often disappears with use of the affected extremity.
Bradykinesia, or motor slowing, is not caused by weakness but by difficulty with the execution of movements. It is most prominent with repetitive activities, especially those involving change in direction, such as alternately pronating and supinating the hand. Movements become not only slower with repetition but also smaller, much like in micrographia. To elicit a decrease in movement size, the examiner asks the patient to tap the first finger and thumb together in wide taps, extending the fingers as widely as possible. Over time, the movement will become progressively smaller in a patient with PD. Another way to elicit this is to have the patient draw a series of large circles on a piece of paper, never lifting the pen from the paper. Again, the circles will become progressively smaller as the patient's efforts continue.
Rigidity can be elicited by passively moving the patient's extremities, resulting in a ratcheting motion of the extremity being manipulated, almost as though it is catching on something repeatedly as it is being moved along its course (“cogwheeling”).
Gait should also be carefully observed. The gait of PD is shuffling and festinating. Loss of arm swing on the affected side is a characteristic feature of a parkinsonian gait, as is the “en bloc turn,” in which the patient takes several small steps to turn him- or herself around as a unit, with the trunk and feet aligned throughout the turn.
Impaired postural reflexes can be assessed with the “pull test.” The patient is asked to stand with the feet shoulder-width apart and to resist any effort at displacement. The examiner should warn the patient that he or she will be pulled from behind and should stand behind the patient to prevent falling. The examiner then pulls the patient from behind with modest effort. A positive pull test occurs when the patient takes more than 1 step
backward to regain balance after the pull, indicating impaired postural reflexes.
Table 13-3. Definitions.
There are no laboratory tests that assist in the diagnosis of PD.
A number of imaging studies are currently being investigated in PD, including magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission tomography (SPECT), and proton magnetic resonance spectroscopy (MRS). MRI is most useful in distinguishing PD from other parkinsonian syndromes, but it is not used currently for monitoring disease progression. PET and SPECT may prove useful in monitoring disease progression but are still considered investigational.
Gelb DJ et al: Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56:33. [PMID: 9923759]
Hely MA et al: The Sydney multicentre study of Parkinson's disease: Progression and mortality at 10 years. J Neurol Neurosurg Psychiatry 1999;67:300. [PMID: 10449550]
Hoehn MM, Yahr MD: Parkinsonism: Onset, progression, mortality. Neurology 1967;17:427. [PMID: 11775596]
Müller J et al: Progression of Hoehn and Yahr stages in parkinsonian disorders: A clinicopathologic study. Neurology 2000;55: 888. [PMID: 10994019]
Commonly used, although not yet validated, diagnostic criteria that may aid in the diagnosis are presented in Table 13-4. Drug-induced parkinsonism, multiple system atrophy, progressive supranuclear palsy, and Lewy body dementia (LBD) should be considered in the differential diagnosis. These are considered Parkinson's plus syndromes because there is involvement of central nervous system structures outside the basal ganglia. Parkinson's plus syndromes tend to be less responsive to levodopa than PD and often progress to disability more rapidly.
Drug-induced parkinsonism is associated with medications that deplete dopamine storage or block postsynaptic dopamine receptors. Neuroleptic agents are most commonly associated with parkinsonism, although other medications have also been implicated (see Table 13-1). Drug-induced parkinsonism is indistinguishable from naturally occurring PD, except for the symmetric onset of symptoms. Recognition of drug-induced parkinsonism is extremely important because it may be partially or completely reversible with the discontinuation of the offending agent.
In multiple-system atrophy (Shy-Drager syndrome), parkinsonism is accompanied by autonomic insufficiency, leading to postural hypotension, erectile dysfunction, incontinence, and anhidrosis. There may be lower motor neuron or cerebellar abnormalities as well.
Table 13-4. Diagnostic guidelines for Parkinson's disease.
Progressive supranuclear palsy (PSP) presents with gait unsteadiness, bradykinesia, and rigidity, which is more severe in the axial structures than the limbs. The hallmark feature of PSP is supranuclear gaze paresis, which initially affects vertical eye movements, leading to impairment of downward gaze. Horizontal eye movements are eventually affected as well. Because of these difficulties with downward gaze, patients suffering from this illness often develop sloppiness in dress, urinating, and eating. Cognitive impairment often occurs as the illness progresses.
LBD is marked by parkinsonism, fluctuating cognitive function, and visual hallucinations. Patients with LBD will have marked visuospatial impairment and psychotic features in the setting of a relatively preserved memory initially. It can be distinguished from PD early on by the presence of cognitive dysfunction and hallucinations while the patient still has mild parkinsonism.
Other illnesses sometimes confused with PD include depression, normal pressure hydrocephalus (NPH), and essential tremor. Depression, with its associated flat affect, poorly modulated voice, and psychomotor retardation can sometimes be mistaken for parkinsonism. Indeed, the 2 illnesses may sometimes coexist, making the distinction particularly difficult. A trial of antidepressant therapy may be helpful in making the distinction. NPH is marked by the triad of urinary incontinence, gait impairment, and cognitive impairment. Symmetric bradykinesia and bradyphrenia may also be present. The gait impairment of NPH is often called a “magnetic gait,” in which the patient's feet seem to cling to the floor while walking. This can be distinguished from the parkinsonian gait, which is more shuffling or festinating.
Complications in PD develop from both progression of the disease itself and medication therapy. Potential complications related to disease progression include dysphagia, defecation dysfunction, respiratory dysfunction, gait impairment, postural hypotension, sexual dysfunction, bladder dysfunction, dementia, and depression. Potential complications related to medications include drug-induced dyskinesias, hallucinations, and delirium.
Patient education, addressing the support needs of the patient and caregiver, exercise, and nutrition are the most important nonpharmacological therapies (see Figure 13-1 for management algorithm). Patients and families should understand the natural history of the disease and be educated on the availability of community resources. Although exercise has not been found to diminish the cardinal symptoms of the disease, it does help to reduce the negative effects of these symptoms on mobility and functional status. Exercise has been found to improve mood, strength, flexibility, and mobility. A good program will have a blend of aerobic, strengthening, and stretching exercises and emphasizes building the extensor muscles to counteract the flexor posture that develops.
Most patients will experience constipation. Emphasizing a high-fiber diet and sufficient fluid intake will help to diminish its severity. Maintaining bone health with calcium and vitamin D supplementation is crucial in this population, which is prone to falls as a result of gait abnormalities and postural instability. In later stages of the illness and with more complicated medication regimens, some protein restriction may be necessary to reduce amino acid competition with levodopa for absorption. A consultation with a nutritionist can be helpful in addressing these issues.
Figure 13-1. Algorithm for the management of Parkinson's disease.
Parkinson's disease is a treatable but incurable illness. Goals of pharmacotherapy are to reduce symptoms and manifestations of the illness by replacing or compensating for lost dopaminergic neuron activity. For specific dosing recommendations for each regimen, see Table 13-5.
Because none of the available medications have been shown to delay disease progression, the decision to initiate treatment is based on the severity of symptoms and the presence of functional impairment. In the case of mild disease without functional impairment, it is reasonable to delay therapy until symptomatic relief is needed. If, however, a patient is threatened with loss of employment, decrease in functional status, loss of independence, or social impairment because of symptoms, it is prudent to initiate pharmacotherapy.
Although levodopa is clearly the most effective therapy for PD, it is associated with the eventual development of adverse symptoms in the majority of patients. As many as 50-90% of patients will experience motor complications associated with levodopa therapy after 5-10 years of treatment. These motor complications include dyskinesias and motor fluctuations. The dyskinesias may take many forms but generally manifest as abnormal twisting, turning, and jerking movements. Motor fluctuations include the “wearing-off effect” and the “on-off effect.” In the wearing-off effect, the response to individual levodopa doses becomes progressively shorter, requiring increasing frequency of the dosing regimen. The on-off effect is usually a late-stage event and involves the sudden and unpredictable shift between “on” periods of mobility and “off” periods of immobility that do not seem to be related to the timing of medication therapy. The use of a long-acting carbidopa-levodopa formulation (Sinemet CR) has not been found to reduce dyskinesias compared with Sinemet. The neuropsychiatric complications of Parkinson's disease, such as psychosis, dementia, and confusion, can also be exacerbated by levodopa therapy. In addition to the adverse side effects that develop with long-term levodopa therapy, there is some concern, based on animal data, that levodopa may be neurotoxic. However, data with humans are lacking. Given its efficacy in treating the symptoms of parkinsonism, it is not reasonable to withhold levodopa based on this potential concern.
Levodopa is generally administered in combination with the dopamine decarboxylase inhibitor, carbidopa, in the form of Sinemet. Carbidopa prevents the peripheral conversion of levodopa to dopamine, which can result in nausea, vomiting, hypotension, and, rarely, cardiac irregularities. It takes approximately 75-150 mg of carbidopa per day to adequately inhibit peripheral decarboxylase activity. Thus, when lower doses of Sinemet are being given, additional carbidopa is sometimes needed to avoid peripheral side effects. Levodopa therapy should be started slowly and gradually increased to the lowest dose that provides a satisfactory clinical response. Levodopa should be taken on an empty stomach. Patients who experience nausea when taking levodopa on an empty stomach can take it with soda crackers or a similar simple carbohydrate to help diminish nausea without interfering with absorption.
The long-acting carbidopa-levodopa preparation Sinemet CR may be easier for some patients to take because less frequent dosing is required. Its bioavailability is approximately 70% of that of the regular preparation, so a higher dose is needed to achieve the same effect. The onset of action of Sinemet CR is slower, so a small amount of the immediate-release form can be coadministered if necessary.
Table 13-5. Pharmacological treatment of Parkinson's disease.
When symptoms progress on monotherapy with either levodopa or a dopamine agonist, most neurologists advocate combining lower doses of the 2 agents rather than increasing a single agent to its maximal dose. This approach is thought to reduce the incidence and severity of medication side effects. Referral to a neurologist should be considered when symptoms cannot be adequately controlled using 2 agents.
COMT inhibitors, on the other hand, can be quite useful as adjunctive therapies in the treatment of PD. They increase the bioavailability of levodopa, thereby prolonging its duration of action. The result is often more stable symptom control. Unfortunately, COMT inhibitors can worsen the dopaminergic side effects of levodopa, including dyskinesias and neuropsychiatric problems. To help diminish this side effect, the levodopa dose should be reduced by approximately 30% when initiating COMT inhibitors. Patients who require COMT inhibitors usually have advanced disease; therefore, it is prudent to consult a neurologist before initiating these agents.
In many patients, medications become progressively less effective in relieving parkinsonian symptoms while medication side effects become more severe. Some of these patients may benefit from interventional therapies. The ideal candidate for an interventional procedure is a patient with progressive motor symptoms who still has a response to dopaminergic medications, has progressive dopaminergic side effects, and has normal cognition.
DBS of the globus pallidus appears to improve all motor aspects of PD, including bradykinesia, speech, gait, rigidity, dyskinesia, and tremor. DBS of the subthalamic nucleus also seems to improve virtually all of the motor symptoms of PD, decreasing dyskinesias, and even reducing medication requirements.
Complications with DBS are less common than with ablative procedures and include infections, bleeding, and stimulation of neighboring structures in the brain. Infections and bleeding are rare, occurring in < 10% of patients, and they usually do not result in serious permanent problems. Readjusting the stimulation parameters alleviates side effects resulting from stimulation of neighboring brain structures.
Dyskinesias often correspond in time with the peak blood level of levodopa. In such cases, a slight reduction in the levodopa dosage should be attempted. If a patient is on the sustained-release formulation of levodopa, changing to the short-acting formulation may allow for more predictable control over these symptoms. Adding a dopamine agonist to levodopa therapy to smooth out stimulation of dopamine receptors while simultaneously reducing the levodopa dose may also provide some relief. If the patient does not respond to the conservative measure listed previously or if the dyskinesias do not correspond to the peak dose of levodopa, referral to a neurologist is advisable.
If delirium develops, medical problems such as infection or metabolic abnormalities should be sought and treated. Unnecessary medications, including sedatives, anxiolytics, and anticholinergics, should be stopped when possible. If delirium persists, the dose of levodopa or dopamine agonists, or both, should be reduced as tolerated. Ultimately, a choice may need to be made between optimal control of parkinsonian symptoms and delirium. Sometimes, a low-dose atypical antipsychotic can be helpful in controlling delirium, but careful monitoring for worsening parkinsonism is required.
Pharmacotherapy is appropriate for symptomatic patients only when nonpharmacological interventions have not proven useful. Fludrocortisone, a mineralocorticoid, and midodrine, an α1-agonist, are sometimes used, but both should be used with caution in medically complicated patients. Both can have adverse cardiovascular effects, and midodrine may cause urinary retention in men with benign prostatic hypertrophy.
gait, and orthostatic hypotension among other causes. Falls in any patient may have multiple causes, so taking a careful history is important. Postural instability may be improved with dopaminergic therapy early on, but in later stages it tends to respond less well. People who fall from freezing tend to fall forward onto their hands and knees, so wrist and knee guards may help prevent injury. Gait training and strength exercises, supervised by a physical therapist, may be the most useful fall prevention interventions available regardless of the specific cause. In addition, most patients with PD who fall will benefit from ambulatory assist devices such as front-wheeled walkers. Front-wheeled walkers are more useful than canes or walkers without wheels because patients with PD have difficulty initiating movement, which makes repeatedly lifting the assist device with each step burdensome. Moreover, providing education to patients and caregivers about the removal of throw rugs, extension cords, and other obstacles in the home may reduce the risk of falls. A home safety evaluation can be helpful in identifying factors in the home that may place a patient at increased risk for falling.
Dysphagia affects more than half of patients with parkinsonism. It primarily affects the oropharyngeal phase of swallowing, although esophageal transport may be involved as well. Oropharyngeal dysphagia is a result of the effects of PD on the skeletal muscles of the oropharynx, leading to impaired pharyngeal bolus transport. Drooling occurs as a result of the inability to transfer saliva to the pharynx. Dysphagia is associated with respiratory symptoms, including coughing, choking, nocturnal dyspnea, and aspiration.
Constipation and difficult defecation affect 30-60% of patients. Constipation is the result of slowed colonic transport and can, in severe cases, lead to megacolon or volvulus. Defecatory dysfunction seems to be a result of the effects of PD on the skeletal muscles of the rectum and pelvic floor, leading to a “paradoxical” rectosphincteric reflex, in which the internal anal sphincter responds to rectal fullness with hypercontractility instead of relaxation.
Anticholinergic medications should be discontinued whenever possible once constipation develops. In severe defecatory dysfunction, enemas and manual disimpaction may be necessary. It is important to make sure that these patients move their bowels regularly (at least once every 3 days) to avoid impaction and megacolon.
In general, one should consider referring patients to a neurologist or movement disorders specialist in the following circumstances: (1) when the diagnosis of Parkinson's disease is in question; (2) when a patient is not responding to standard therapies or has unacceptable side effects; (3) when complications of PD and its treatments, such as dyskinesias and hallucinations, are a prominent feature of the disease; and (4) when surgical interventions are being considered.
Advanced planning for long-term care needs can often give patients and their families a sense of control over their fate. An early referral to attorneys or estate planners who specialize in elder law and who are skilled in the financial and legal issues of chronic illness and disability can be crucial in relieving some of the anxieties brought on by progressive disability. It is also important to establish a power of attorney for health care and finances early on, while the patient is still able to discuss concerns and desires. Organizations such as the Caregiver Alliance can be helpful with these issues.
Hallett M et al: Evaluation of surgery for Parkinson's disease: A report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1999;53:1910. [PMID: 10599758]
Koller WC et al: Immediate-release and controlled-release carbidopa/levodopa in PD. Neurology 1999;53:1012. [PMID: 10496260]
Kubu CS et al: Cognitive outcome following pallidotomy: The influence of side of surgery and age of patient at disease onset. J Neurosurg 2000;92:384. [PMID: 10701523]
Olanow CW, Koller WC: An algorithm (decision tree) for the management of Parkinson's disease. Neurology 1998;50 (suppl 3):S1. [PMID: 9524552]
Parkinson Study Group: Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. N Engl J Med 1999;340:757. [PMID: 10072410]
Parkinson Study Group: Pramipexole vs levodopa as initial treatment for Parkinson disease. JAMA 2000;284:1931. [PMID: 11035889]
Rascol O et al: A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. N Engl J Med 2000;342:1484. [PMID: 10816186]
Targum SD, Abbott JL: Efficacy of quetiapine in Parkinson's patients with psychosis. J Clin Psychopharmacol 2000;20:54. [PMID: 10653209]
PD is associated with an increase in mortality; the relative risk of death ranges from 1.6-3 times that of the general population. The mean duration of illness from symptom onset to death is approximately 9 years, although there are occasional patients with slow progression who can live 20 years or more. Once patients reach Hoehn and Yahr's stage V of PD and are bed or wheelchair bound, the mean life expectancy is 9-12 months. Pneumonia is the most common cause of death in patients with PD, followed by cardiovascular disease.
EVIDENCE-BASED MEDICINE POINTS
RELEVANT WORLD WIDE WEB SITES
American Parkinson Disease Association, Inc.: http://www.apdaparkinson.com (Provides information on educational programs, support groups, treatment options, and publications)
Family Caregiver Alliance: http://www.caregiver.org (Provides information on support groups, hiring caregivers, and issues of long-term care.)
National Parkinson Foundation, Inc.: http://www.parkinson.org (Provides information on educational programs, support groups, treatment options, and publications)
ESSENTIALS OF DIAGNOSIS
Essential tremor (ET) is a common movement disorder with an estimated prevalence of 0.4-6%. It occurs most commonly in people older than 65. Approximately 30-50% of cases are familial with an autosomal dominant inheritance pattern. It is a progressive condition.
ET is a 4- to 12-Hz action tremor of the hands and forearms, with its greatest amplitude distally. It can also affect the voice, trunk, and legs, and occasionally presents as an isolated head tremor. ET tends to be most obvious during sustained extension of an extremity or during voluntary movements such as drinking or writing. It can be distinguished from an intention tremor, which is coarser and occurs as a limb approaches a target, such as in the finger-nose-finger maneuver. ET often improves with alcohol intake and is not associated with other neurological symptoms or signs.
The diagnosis of ET is made by history and physical examination. Particular emphasis is placed on an assessment of neurological symptoms and on the neurological examination. Other conditions that may be associated with tremor, including Parkinson's disease, dystonia, and Wilson's disease, should be considered. Furthermore, tobacco and caffeine use, as well as certain medications (see Table 13-1), may result in an enhanced physiological tremor that can mimic ET.
ET is usually slightly asymmetric. Having a patient bring a cup of water from an outstretched arm to the
mouth to drink will demonstrate worsening of the tremor in most cases. In contrast, enhanced physiological tremor is symmetric and should not be worsened by a voluntary task. The tremor of PD is usually a resting tremor, and the neurological exam will often show other signs of parkinsonism in addition to the tremor. Action tremors are also found in dystonia and Wilson's disease, but these conditions generally are associated with other neurological abnormalities and occur in a younger population.
ET can result in significant functional impairment and social embarrassment. The tremor can render patients unable to feed themselves, drink without spilling, apply makeup, or brush their teeth. Some patients are unable to write, type, or perform other fine motor movements. This can result in early retirement, social isolation, and enhanced care needs.
The goal of treatment is to improve function and reduce social embarrassment associated with the tremor. If the tremor is mild, treatment may not be required.
Propranolol is the best studied and most effective of the β-adrenergic blocking agents in the treatment of ET. Approximately 40-50% of patient with ET treated with propranolol will experience symptomatic relief. Like primidone, it is more effective in treating hand tremor than voice or head tremor. The optimal dosage ranges from 240-320 mg/day. The sustained-release preparation is equally as effective as the short-acting preparation. Potential side effects include bradycardia, hypotension, fatigue, rash, erectile dysfunction, and diarrhea.
Primidone and propranolol are both more effective than placebo; neither have a clear advantage over the other. Primidone may be better tolerated over the long term than propranolol, so some experts favor starting with primidone.
Gorman WP et al: A comparison of primidone, propranolol, and placebo in essential tremor, using quantitative analysis. J Neurol Neurosurg Psychiatry 1986;49:64. [PMID: 3514797]
Koller WC et al: Pharmacologic treatment of essential tremor. Neurology 2000;54(suppl 4):S30. [PMID: 10854350]
Louis ED: Essential tremor. N Engl J Med 2001;345:887. [PMID: 11565522]
Pahwa R et al: Surgical treatment of essential tremor. Neurology 2000;54(suppl 4):S39. [PMID: 10854351]
Schuurman PR et al: A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 2000;342:461. [PMID: 10675426]