Current Geriatric Diagnosis & Treatment, 1st Edition

Section III - Common Disorders in the Elderly

13. Parkinson's Disease & Essential Tremor

Elise Carey MD

Josh Adler MD

PARKINSON'S DISEASE

ESSENTIALS OF DIAGNOSIS

  • Any combination of resting tremor, bradykinesia, rigidity, and postural instability.
  • Asymmetric onset is the norm.
  • Responds well to levodopa in most cases.
  • Diagnostic accuracy improves with observation over time.

General Considerations

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.

Pathogenesis

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).

Clinical Findings

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.

  1. SYMPTOMS & SIGNS

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

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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.

Parkinsonism

Tremor

Antipsychotic medication
Lithium
Metoclopramide

Amphetamines
Antidepressants
Antipsychotic medication
β-agonist medications
Corticosteroids
Lithium
Methylxanthines (including coffee and tea)
Thyroid hormone
Valproic acid

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.

Stage

Description

I

Unilateral involvement only; little or no functional impairment

II

Bilateral or midline involvement, no balance impairment

III

Impaired postural reflexes and difficulty with balance, still able to walk independently, mild to moderate disability, still physically capable of leading independent lives in most cases

IV

Severely disabling disease; patient cannot get out of bed or chair unassisted but is able to walk independently, however unsteadily, once up

V

Bedridden or wheelchair-bound; cannot ambulate independently

Based on Hoehn MM, Yahr MD: Parkinsonism:Onset, progression, and mortality. Neurology 1967;17:427.

  1. PATIENT EXAMINATION

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

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backward to regain balance after the pull, indicating impaired postural reflexes.

Table 13-3. Definitions.

Symptom

Definition

Bradykinesia

Motor slowing resulting from difficulty executing movements

Bradyphrenia

Slowness of thought

Cogwheeling

Occurs when an extremity rigid from parkinsonism is passively manipulated. A ratcheting motion is felt by the examiner as the extremity is moved along its course, as if caught on the cogs of a wheel

Masked facies

Decreased facial muscle movement and consequent loss of facial expression

Hypophonia

Slowed speech that is low in volume and with reduced inflection

Micrographia

Small handwriting

Festination

Gait impairment, marked by the patient's center of gravity being shifted. The patient will take increasingly rapid short steps in an effort to bring the feet under the center of gravity, leading to an accelerated, forward flexed gait, often resulting in a fall.

En bloc turn

Turn characteristic of PD gait in which the patient takes several small steps to turn the body around as a unit, with the body aligned with the feet throughout the turn. Patients with PD are often unable to make a fluid turn in one step, as with normal gait.

Dyskinesia

Involuntary, abnormal writhing and jerking movements, distinct from tremor, which usually occur with the peak effect of the levodopa dose.

Wearing off effect

Phenomenon in which the response to levodopa therapy becomes progressively shorter over time, leading to loss of mobility and function before the next dosage.

On-off effect

Unpredictable, sudden shift between periods of mobility and immobility not related to the timing of levodopa therapy.

  1. LABORATORY FINDINGS

There are no laboratory tests that assist in the diagnosis of PD.

  1. IMAGING TESTS

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]

Differential Diagnosis

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.

Cardinal clinical features

Frequency (%)

Resting tremor

76–100

Bradykinesia

89–99

Rigidity

77–98

Asymmetric onset

72–75

Diagnostic guidelines

Possible Parkinson's Disease
   Two of 4 cardinal features present
   No features suggestive of an alternative diagnosis to date, including hallucinations unrelated to medication, dementia, supranuclear gaze palsy, or severe dysautonomia.
   Beneficial response to levodopa or dopamine agonist or the patient has not received an adequate trial of one of these medications.
Probable Parkinson's Disease
   Three of 4 cardinal features present
   No features suggestive of an alternative diagnosis in the first 3 years of parkinsonian symptoms, including hallucinations unrelated to medication, dementia, supranuclear gaze palsy, or severe dysautonomia.
   A definite clinical response to levodopa or a dopamine agonist.

Adapted from Gelb DJ et al: Diagnostic criteria for Parkinson's disease. Arch Neurol 1999;56:33. Used with permission.

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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

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.

Treatment

  1. NONPHARMACOLOGICAL THERAPY

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.

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  1. PHARMACOTHERAPY

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.

  1. Levodopa—Levodopa is the most effective drug in the treatment of PD. By providing dopamine replacement, levodopa ameliorates all of the major motor symptoms of Parkinson's disease, including tremor, bradykinesia, and rigidity. In so doing, it reduces morbidity and disability, and it is effective in most patients with PD. It does not, however, stop progression of the disorder. Later features of the disease are not responsive to levodopa, namely postural instability, autonomic dysfunction, freezing, speech difficulties, psychiatric problems, and dementia.

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.

  1. Dopamine agonists—Dopamine agonists directly stimulate dopamine receptors. Two of the older agents, bromocriptine and pergolide, are ergot derivatives. The newer agents, ropinirole and pramipexole, are both nonergot dopamine agonists. They have been more extensively studied and are more currently commonly used. Dopamine agonists are approved for use as monotherapy in Parkinson's disease, although they are more commonly used as adjunctive therapy to levodopa. As monotherapy, these agents improve many of the motor symptoms of PD and reduce disability. As adjunctive therapy, dopamine agonists decrease motor fluctuations and dyskinesias by allowing for Sinemet dose reduction. When used as initial therapy for PD, the newer dopamine agonists have been found to be similar in effectiveness to levodopa for symptom control and disability reduction. In addition, the dopamine agonists have been associated with fewer motor complications than levodopa alone at 2-5 years. Dopamine agonists are considered a first-line therapy in the treatment of PD, especially in younger patients, who will likely experience motor complications from levodopa therapy during the course of their treatment. However, adverse effects appear to be more common with dopamine agonists than with carbidopa-levodopa.

Table 13-5. Pharmacological treatment of Parkinson's disease.

Medication

Recommended starting dosage

Usual dosage

Cost/mo

Comments

Carbidopa/levodopa

Sinemet

25-mg/100-mg tablet qod.
Gradually increase to the lowest dose that provides satisfactory benefit.

200-400 mg levodopa qd, divided into tid dosing

$$

Once > 600 mg levodopa per day is required, consider adding a second agent rather than further escalating the dose.
Take on an empty stomach if possible. If nausea develops, take with soda crackers or other simple carbohydrate.

Sinemet CR

50 mg/200 mg bid

Titrate to effect

$$$

Sinemet CR has only 70% of the bioavailability of the shorter acting agent, so higher doses may be required.

Dopamine agonists

Pramipexole

0.125 mg tid

0.5-1.5 mg tid

$$$

Double dose weekly during the second and third weeks of therapy. After the third week, dose can be increased at a weekly interval by 0.75 mg/day, depending on response and tolerance.

Ropinirole

0.25 mg tid

2-8 mg tid

$$-$$$

Increase daily dose by 0.75 mg each week until adequate dose response.

Amantadine

100 mg qod × 1 week

100 mg bid-tid

$

Modest therapeutic benefit and numerous side effects.

Anticholinergics

Benztropine

0.5 mg bid

0.5-2.0 mg bid

$

Modest therapeutic benefit and numerous side effects.

Trihexyphenidyl

0.5-1.0 mg bid

2 mg tid

$

COMT inhibitors

Entacapone

200 mg administered with each levodopa dose

Max dose 1600 mg/day

$$-$$$

Reducing levodopa by approximately 30% after initiating COMT inhibitors can help reduce dopaminergic side effects.

Tolcapone

100 mg tid

200 mg tid

$$$

Selegiline

5 mg qod

5 mg with breakfast and 5 mg with lunch

$

No neuroprotective effect demonstrated.
Modest therapeutic benefit and numerous side effects.

$ = ≤ $30; $$ = $30-$100; $$$ = > $100. COMT, catecholamine-O-methytransferase.

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  3. Adverse effects of dopamine agonists include nausea, vomiting, orthostatic hypotension, flushing, sweating, somnolence, dizziness, and psychiatric symptoms. Psychiatric symptoms, including psychosis, may be more common in older patients. Most adverse effects occur with the initiation of the medication and will dissipate over days to weeks as tolerance develops. Starting at low doses and titrating up slowly reduces the severity of adverse effects. The ergot-derived dopamine agonists bromocriptine and pergolide are associated uncommonly with erythromelalgia, pulmonary or retroperitoneal fibrosis, and Raynaud's phenomenon.
  4. Initiating pharmacotherapy with dopamine agonist and/or levodopa—Many physicians advocate initiating treatment with a dopamine agonist as a first-line agent and supplementing with levodopa as needed. Others advocate starting with levodopa and supplementing with a dopamine agonist after a dose of 600 mg or more of levodopa is required. It seems reasonable to start pharmacotherapy with a dopamine agonist in patients with a longer life expectancy because they are at a higher risk for experiencing dyskinesias during the course of their illness. Dopamine agonist therapy can then be supplemented with levodopa to achieve the desired symptomatic benefit. On the other hand, levodopa may be the preferred agent in physiologically older patients, who have a lower risk of experiencing levodopa-related motor complications and who are at higher risk for dopamine agonist-induced psychiatric symptoms. Patients of any age with cognitive impairment are likely to tolerate levodopa better than a dopamine agonist.

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.

  1. Other agents—Other medications used in the treatment of PD include selegiline, amantadine, anticholinergic agents, and catecholamine-O-methyltransferase inhibitors (COMT inhibitors). Selegiline, amantadine, and the anticholinergic agents provide only a modest therapeutic benefit and are associated with numerous side effects, especially in the elderly population. These agents should generally be used in consultation with a neurologist.

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.

  1. SURGICAL THERAPIES

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.

  1. Pallidotomy—Pallidotomy is the surgical destruction of the globus pallidus. Pallidotomy relieves contralateral drug-induced dyskinesias in up to 90% of patients and decreases off-state symptoms in approximately 30% of patients. Pallidotomy is associated with a 10-15% incidence of persistent adverse outcomes, including intracerebral hematoma, visual changes, and cognitive decline.
  2. Deep brain stimulation—Deep brain stimulation (DBS) is nondestructive and reversible. In DBS, a 4-contact lead is placed into the brain and connected to a programmable generator that is implanted in the chest, similar to a cardiac pacemaker. The frequency and amplitude of stimulation are adjusted to deliver maximum symptomatic benefit.

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.

  1. TREATMENT OF COMPLICATIONS
  2. Dyskinesias—Dyskinesias are a motor complication of dopaminergic therapy and can manifest as dystonia or choreiform movements. When severe, dyskinesias can be more disabling than the features of PD itself.

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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.

  1. Dementia—Dementia may occur in up to 30% of patients, depending on age, disease duration, and illness severity. It is usually a late development in PD and increases the likelihood of nursing home placement. If dementia is an early feature of the illness, another parkinsonian syndrome, such as LBD, should be suspected. Patients with cognitive impairment or dementia are at increased risk for delirium and psychosis and may tolerate antiparkinsonian medications poorly. Sedatives, anticholinergic medications, and amantadine should be avoided. In patients with cognitive impairment and parkinsonism, medications need to be prescribed with great care, balancing improvement of motor symptoms against adverse neuropsychiatric effects.
  2. Delirium, hallucinations, & psychosis—Hallucinations are common in patients with PD. These occur both as a result of the disease itself and secondary to dopaminergic therapy. It is estimated that up to 20% of PD patients treated with dopaminergic drugs develop drug-induced hallucinations. These hallucinations are usually visual and are often not disturbing to the patient. If they are not disturbing the patient or causing behavioral problems, no specific change in pharmacotherapy is warranted. However, reassurance and education should be given to patients and their families. If the hallucinations begin to cause the patient distress, become frightening, or cause behavioral problems, dose reductions in dopaminergic medications should be attempted. If unsuccessful, antipsychotic medications may be beneficial. Typical antipsychotics, like haloperidol, should be avoided because they are likely to worsen parkinsonism. Atypical antipsychotics, however, are effective and are less likely to aggravate parkinsonism. Clozapine and quetiapine appear to be the most beneficial of the atypical antipsychotic medications in this situation. The main side effect of concern in clozapine is rare, but life-threatening, agranulocytosis (1-2%). Weekly blood count monitoring is, therefore, required in patients taking clozapine. Clozapine should be started at a low dose and titrated slowly to effect. The other atypical antipsychotics, risperidone and olanzapine, are effective against psychosis but do occasionally worsen parkinsonism.

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.

  1. Depression—Depression is common in PD, occurring in up to 40% of patients at some point during their illness. Parkinsonian features such as bradykinesia, bradyphrenia, and masked facies can make it difficult to distinguish between depression and parkinsonism. PD patients with depression should be treated with antidepressant therapy and psychotherapy when appropriate. Selective serotonin reuptake inhibitors (SSRIs) are recommended as first-line therapies because they avoid the anticholinergic effects of the tricyclic antidepressants. Of the SSRIs, citalopram is associated with the fewest drug interactions. Coadministration of SSRIs with selegiline should be avoided because of the theoretical risk of inducing the serotonin syndrome.
  2. Orthostatic hypotension—Orthostatic hypotension is common in late-stage PD and is thought to result from decreased intravascular volume. Medications that contribute to orthostatic hypotension, including antihypertensives and diuretics, should be reduced in dosage or discontinued. Levodopa and dopamine agonists can exacerbate postural hypotension; thus dose reduction, if feasible, may be of benefit. Sodium intake should be increased. The head of the bed should be elevated to approximately 35°. Eating small, frequent meals can help avoid exacerbation of symptoms mediated by splanchnic vasodilatation. Caffeine in the morning may be beneficial. Waist-high stockings might also provide some symptomatic relief but can be difficult for patients to tolerate. Hot weather, hot liquids, and hot showers should be avoided.

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.

  1. Falls—Falls are of multifactorial etiology in patients with PD and are related to postural instability, impaired balance, muscle weakness, freezing, festinating

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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.

  1. Gastrointestinal complications—Dysphagia, disordered salivation, constipation, and defecatory dysfunction occur much more commonly in patients with PD than in age-matched controls. The presence of these complications corresponds with the severity and duration of the disease but not with age, gender, antiparkinson therapy, activity, or diet.

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.

  1. Dysphagia—The dysphagia of parkinsonism does not respond to dopaminergic therapy or to standard promotility agents, such as metoclopramide. Consequently, treatment of dysphagia focuses on efforts to avoid aspiration. Speech therapy is invaluable in identifying the presence of moderate to severe dysphagia and in teaching maneuvers to assist in bolus transfer. When patients progress to a point at which they are unable to reliably take in proper nutrition or medications, enteral feeding may be considered if the patient so desires.
  2. Constipation & defecatory dysfunction—Like dysphagia, constipation and defecatory dysfunction do not respond to dopaminergic therapies. Stool softeners, prokinetic agents, laxatives, fiber, and fluids are first-line agents, just as they are in patients without PD. Prokinetics may be particularly helpful in counteracting slowed colonic transport in parkinsonism, but this has not been well studied.

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.

  1. REFERRAL GUIDELINES

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.

  1. ADVANCE PLANNING

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]

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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]

Prognosis

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

  • Long-acting carbidopa-levodopa has not been found to reduce dyskinesias compared with short-acting carbidopa-levodopa.
  • When used as initial therapy for PD, the newer dopamine agonists have been found to be similar in effectiveness to levodopa for symptom control and disability reduction. In addition, the dopamine agonists have been associated with fewer motor complications than levodopa alone at 2-5 years.
  • Low-dose clozapine has been found to be more effective than placebo against drug-induced psychosis and has not been found to worsen parkinsonism. It also had a positive effect on tremor.

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)

ESSENTIAL TREMOR

ESSENTIALS OF DIAGNOSIS

  • Characterized by a bilateral action tremor of the hands and forearms and possibly the head, voice, trunk, and legs.
  • Other neurological signs are absent.
  • Positive family history.
  • Beneficial response to alcohol.

General Considerations

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.

Differential Diagnosis

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

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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.

Complications

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.

Treatment

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.

  1. PHARMACOTHERAPY
  2. First-line agents—Primidone and propranolol are the most effective medications for treating ET. Primidone is an anticonvulsant medication that has been found to be 40-50% effective in reducing the tremor of ET. It is most effective in treating hand tremor and has little or no efficacy in treating head or voice tremor. It can be administered as single nighttime dose or as multiple daily doses, but the former is recommended to improve compliance. The usual therapeutic dosage ranges from 50-350 mg/day. Adverse effects occur in 20-30% of patients, including vertigo, nausea, and unsteadiness. These side effects are temporary and will abate with continued use of the drug. Chronic use is rarely associated with side effects.

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.

  1. Second-line agents—Gabapentin is well tolerated and has been found to be more effective than placebo (usual therapeutic dosage: 1200-3600 mg/day). Alprazolam is the only benzodiazepine that has been found to be effective in ET, and it caused sedation in half of the patients in the doses required to improve tremor (usual therapeutic dosage: 0.75-2.5 mg/day). The risk of dependence, in addition to the sedation, makes alprazolam an undesirable chronic treatment. Calcium-channel blockers and theophylline have been used but have not been adequately studied in ET and are not recommended for routine use.
  2. OTHER THERAPIES
  3. Interventional therapies—ET patients with severe, disabling, medication-resistant tremor may be candidates for interventional therapies. Unilateral thalamotomy and continuous deep brain stimulation (DBS) improve contralateral tremor and disability scores in > 70% of those treated. Dysarthria, dysequilibrium, cognitive impairment, and weakness occur in < 10% of patients after thalamotomy. DBS may be associated with fewer adverse events.
  4. Botulinum toxin A—Intramuscular injections of botulinum toxin A into the intrinsic muscles of the dominant hand have been found to reduce tremor amplitude but not improve function.

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]

EVIDENCE-BASED POINTS

  • Both primidone and propranolol are more effective than placebo, but neither is conclusively better than the other.
  • Thalamotomy and DBS are equally as effective in reducing tremor, but DBS is associated with fewer adverse events.