Movement Disorders


16	Movement Disorders

PARKINSON DISEASE

Idiopathic Parkinson disease (PD) is the most common neurodegenerative movement disorder and is the most important form of parkinsonism, the clinical syndrome characterized principally by bradykinesia and rigidity. Features of other parkinsonian syndromes are reviewed in Table 16-1.

EPIDEMIOLOGY

PD is most common in middle-aged and older patients, affecting approximately 1% of people over 60 years. It is typically a sporadic disorder, but hereditary forms of PD due to mutations in genes such as PRKN, PINK1, LRRK2, and GBA may affect younger patients.

PATHOLOGY

The precise source of PD is not known, but the essential motor manifestations of the disease are due to degeneration of dopaminergic neurons in the substantia nigra pars compacta. The key histopathologic finding of PD is the Lewy body, which is an alpha-synuclein containing eosinophilic cytoplasmic inclusion that accumulates in neurons of the brainstem, cerebral cortex, and sympathetic autonomic ganglia.

CLINICAL MANIFESTATIONS

The four cardinal motor manifestations of PD are tremor, rigidity, bradykinesia, and postural instability. Approximately 80% of patients with PD have a resting tremor, which is characteristically asymmetric, involves the hands, recurs about 4 times per second (4 Hz), and is worse with distraction. A “pill-rolling” tremor involving the thumb and forefinger is classic. Bradykinesia or slowness of movement is often the most disabling feature of PD and involves both axial and appendicular muscles. Speech and swallowing difficulties in PD are manifestations of bradykinesia. Rigidity is an increase in muscle tone, which is equal in both flexion and extension of a body part. In patients with PD, rigidity tends to be greater in the limbs than in the trunk. Postural instability is the final cardinal motor manifestation of PD: Patients with advanced PD have difficulty with postural control and tend to fall backward when pulled from behind.

TABLE 16-1. Parkinsonian Syndromes
Parkinsonian Syndrome	Distinguishing Clinical Features
Progressive supranuclear palsy	Supranuclear ophthalmoplegia, with greatest limitation of downward gaze; axial rigidity; early falls due to rigidity, impaired postural reflexes, neck hyperextension, and inability to look down
Corticobasal ganglionic degeneration	Limb apraxia; cortical sensory impairment; alien-limb phenomenon; asymmetric rigidity; dementia
Diffuse Lewy body disease	Early dementia; prominent visual hallucinations; cognitive fluctuations; extreme sensitivity to extrapyramidal side effects of antidopaminergic neuroleptic drugs
Vascular parkinsonism	“Lower-half” parkinsonism in which rigidity in the legs is greater than in the arms, resulting in slow, shuffling gait
Multiple system atrophy	Early and prominent features of autonomic dysfunction (MSA-A); cerebellar dysfunction (MSA-C); parkinsonism refractory to levodopa (MSA-P); high-pitched, quivering dysarthria

PD also has important “nonmotor” features. Rapid eye movement (REM) sleep behavior disorder is characterized by violent enacting of dreams: The patient’s bed partner will describe them as fighting, kicking, or running while asleep. This phenomenon is due to the failure to induce muscle atonia in REM sleep and often predates overt PD by many years. Autonomic dysfunction, especially orthostatic hypotension, is common in patients with PD. Constipation due to gastrointestinal hypomotility is another nonmotor feature of PD. Dementia, often accompanied by psychotic features, occurs in 25% to 30% of PD patients and is more common with advanced disease.

TREATMENT

The most effective medical treatment for PD is replacement of deficient endogenous dopamine with levodopa. (Indeed, if this does not help, one should consider the possibility of illnesses other than idiopathic PD.) Levodopa is combined with carbidopa, an inhibitor of peripheral dopamine decarboxylase, which allows the levodopa to cross the blood–brain barrier and reach its target, while also reducing peripheral dopaminergic side effects including nausea, vomiting, and hypotension. Initially, levodopa is quite effective for most patients with PD, but over time it loses its effectiveness, and disabling dyskinesias develop. The long-term treatment of PD is complicated (Table 16-2).

The monoamine oxidase B inhibitors rasagiline and selegiline may provide slight benefit to patients with PD and are often used in early stages of the disease as monotherapy or as a supplement to levodopa.

The dopamine agonists pramipexole and ropinirole are also options for the treatment of mild or early PD. These medications may improve symptoms and reduce levodopa requirement, thereby minimizing the long-term probability of dopamine-related dyskinesias. Rotigotine is a dopamine agonist available in patch form and is designed to prevent excessive fluctuation in drug levels.

Other medications are used for specific applications in PD. Anticholinergics including benztropine and trihexyphenidyl are used to treat tremor but generally have little effect on other PD symptoms. Amantadine is helpful in the management of dyskinesias and dystonia associated with PD. The catechol-O-methyl transferase inhibitor entacapone inhibits levodopa metabolism, thereby extending the duration of levodopa action in patients who experience “wearing off.” Drug treatments are summarized in Table 16-3.

TABLE 16-2. Therapeutic Strategies in Parkinson Disease
Scenario/Problem	Therapeutic Approach
Initial treatment	Levodopa, dopamine agonist, or MAO inhibitor
Poor or no response to initial treatment	Increase levodopa dose and consider alternative diagnoses
Tremor-predominant disease	Anticholinergic or amantadine
Overnight or early morning bradykinesia	Consider overnight controlled-release preparation of levodopa
Levodopa-induced hallucinations	Discontinue concurrent therapy with anticholinergics, amantadine, selegiline, or dopamine agonists Decrease dose of levodopa Low-dose atypical antipsychotic (with quetiapine, clozapine, or pimavanserin)
“Wearing off”	More frequent dosing Extended release formulation of levodopa Add COMT inhibitor
Dyskinesia	Reduce dose of levodopa Add or increase dose of dopamine agonist Change dopamine agonist Add amantadine Consider deep brain stimulation
COMT, catechol O-methyl transferase; MAO, monoamine oxidase.

Deep brain stimulation of the subthalamic nucleus (STN) and globus pallidus internus may be helpful for patients with advanced disease.

KEY POINTS

●Idiopathic PD is the most common form of parkinsonism and results from loss of dopaminergic neurons in the substantia nigra.

●Tremor, rigidity, bradykinesia, and postural instability are the four cardinal motor features of PD.

●There are many nonmotor features of PD, including REM behavior disorder and autonomic dysfunction.

●A wide variety of medical and surgical treatment options are available for PD.

DRUG-INDUCED MOVEMENT DISORDERS

Medications which block dopamine receptors including antipsychotic medications (both traditional dopamine blockers and newer, atypical agents) and the promotility agent metoclopramide may produce a variety of movement disorders:

Acute dystonic reactions occur when patients are introduced to dopamine-blocking medications or given high doses of dopamine blockers to which they are not accustomed. Intermittent or sustained contraction in any of the muscles in the face, limbs, or trunk may occur. Forced contraction of the extraocular muscles and tonic deviation of the eyes may occur. Acute dystonic reactions are best treated with anticholinergic agents and benzodiazepines. The reaction is short-lived and does not produce any long-term consequences.

Parkinsonism may occur as the result of long-term use of any neuroleptic agent. The symptoms are similar to those seen in PD, but tremor is less common and patients tend to be less responsive to levodopa.

TABLE 16-3. Pharmacologic Treatment of Parkinson Disease
Drug	Mechanism of Action	Dosing	Side Effects
Levodopa/carbidopa	Dopamine precursor/dopa decarboxylase inhibitor	Start with a half of a 25/100 tablet bid; increase dose as needed; typically dosed 3–5 times a day	Anorexia, nausea, psychosis, hallucinations, orthostatic hypotension, dyskinesia
Trihexyphenidyl	Anticholinergic	Start with 1 mg bid–tid; increase to 4 mg tid as needed	Dry mouth, constipation, urinary retention, confusion, hallucinations, narrow-angle glaucoma
Benztropine	Anticholinergic	Start with 0.5–1 mg at bedtime; increase to 2 mg qid as needed	As above
Amantadine	NMDA antagonist	100 mg bid	Hallucinations, leg edema, livedo reticularis
Pramipexole	Dopamine agonist	Start with 0.125 mg tid; titrate gradually to 1.5 mg tid as needed	Lightheadedness, sleep attacks, pathologic gambling, and other impulse control disorders
Ropinirole	Dopamine agonist	Start with 0. 25 mg tid; titrate gradually to 1 mg tid as needed	As above
Rotigotine patch	Dopamine agonist	2 mg qd; titrate to 6 mg qd	As above, patch site reactions
Entacapone	COMT inhibitor	200 mg with each l-dopa dose	Nausea, diaphoresis, lightheadedness
Rasagiline	MAO-B inhibitor	1 mg qd	Dizziness, flulike syndrome
Selegiline	MAO-B inhibitor	5 mg bid	Confusion, orthostatic hypotension, nausea
COMT, catechol O-methyl transferase; MAO-B, monoamine oxidase B; NMDA, N-methyl d-aspartate.

Neuroleptic malignant syndrome occurs when patients are exposed to high doses of dopamine-blocking medications or when levodopa or dopamine agonists are withdrawn abruptly. The syndrome includes fever, autonomic instability, encephalopathy, and muscular rigidity. The offending agent must be stopped, but a combination of bromocriptine, dantrolene, and benzodiazepines is usually required to control the muscle rigidity.

Tardive dyskinesia (TD) is a disorder that occurs after chronic exposure to dopamine-blocking agents. Commonly observed movements include chewing, grimacing, lip smacking, and tongue thrusting. The limbs, trunk, and even diaphragm may be affected. Treatment of TD is challenging: Withdrawal of the offending agent often makes the movements worse. The dopamine-depleting agent tetrabenazine may be helpful.

KEY POINTS