Harrisons Manual of Medicine, 18th Ed.

CHAPTER 195. Parkinson’s Disease

CLINICAL FEATURES

Parkinsonism is a general term used to define a symptom complex manifest by bradykinesia (slowness of voluntary movements) with rigidity and/or tremor; it has a wide differential diagnosis (Table 195-1). Parkinson’s disease(PD) is idiopathic parkinsonism without evidence of more widespread neurologic involvement. PD afflicts >1 million individuals in the United States. Peak age of onset in the 60s; course progressive over 10–25 years. Tremor (“pill rolling” of hands) at rest (4–6 Hz). Presentation with tremor confined to one limb or one side of body is common. Other findings: rigidity (“cogwheeling”—increased ratchet-like resistance to passive limb movements), bradykinesia, fixed expressionless face (facial masking) with reduced frequency of blinking, hypophonic voice, drooling, impaired rapid alternating movements, micrographia (small handwriting), reduced arm swing, and flexed “stooped” posture with walking, shuffling gait, difficulty initiating or stopping walking, en-bloc turning (multiple small steps required to turn), retropulsion (tendency to fall backwards). Nonmotor aspects of PD include depression and anxiety, cognitive impairment, sleep disturbances, sensation of inner restlessness, loss of smell (anosmia), and disturbances of autonomic function. Normal muscular strength, deep tendon reflexes, and sensory exam. Diagnosis based on history and examination; neuroimaging, EEG, and CSF studies usually normal for age.

TABLE 195-1 DIFFERENTIAL DIAGNOSIS OF PARKINSONISM

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PATHOPHYSIOLOGY

Most PD cases occur sporadically and are of unknown cause. Degeneration of pigmented pars compacta neurons of the substantia nigra in the mid-brain resulting in lack of dopaminergic input to striatum; accumulation of cytoplasmic intraneural inclusion granules (Lewy bodies). Cause of cell death is unknown, but it may result from generation of free radicals and oxidative stress; no environmental factor has yet been conclusively determined to cause PD. Rare genetic forms of parkinsonism exist (~5% of cases); most common are mutations in α-synuclein or parkin genes. Early age of onset suggests a possible genetic cause of PD, although one genetic form (LLRK2) causes PD in the same age range as sporadic PD and may be responsible for as much as 1% of all sporadic cases. Mutations in the glucocerebrosidase (GBA) gene are also associated with an increased risk of idiopathic PD.

DIFFERENTIAL DIAGNOSIS

Atypical parkinsonism refers to a group of neurodegenerative conditions that usually are associated with more widespread neurodegeneration than is found in PD including multiple-system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal ganglionic degeneration (CBGD). Secondary parkinsonism can be associated with drugs (neuroleptics as well as GI medications such as metoclopramide, all of which block dopamine), infection, or exposure to toxins such as carbon monoxide or manganese. Some features to suggest that parkinsonism might be due to a condition other than PD are shown in Table 195-2.

TABLE 195-2 FEATURES SUGGESTING DIAGNOSIS OTHER THAN PD

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TREATMENT Parkinson’ Disease (see Fig. 195-1Table 195-3)

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FIGURE 195-1 Treatment options for the management of PD. Decision points include:

a. Introduction of a neuroprotective therapy: No drug has been established to have or is currently approved for neuroprotection or disease modification, but there are several agents that have this potential based on laboratory and preliminary clinical studies (e.g., rasagiline 1 mg/d, coenzyme Q10 1200 mg/d, the dopamine agonists ropinirole and pramipexole).

b. When to initiate symptomatic therapy: There is a trend toward initiating therapy at the time of diagnosis or early in the course of the disease because pts may have some disability even at an early stage, and there is the possibility that early treatment may preserve beneficial compensatory mechanisms; however, some experts recommend waiting until there is functional disability before initiating therapy.

c. What therapy to initiate: Many experts favor starting with an MAO-B inhibitor in mildly affected pts because of the potential for a disease-modifying effect; dopamine agonists for younger pts with functionally significant disability to reduce the risk of motor complications; and levodopa for pts with more advanced disease, the elderly, or those with cognitive impairment.

d. Management of motor complications: Motor complications are typically approached with combination therapy to try and reduce dyskinesia and enhance the “on” time. When medical therapies cannot provide satisfactory control, surgical therapies can be considered.

e. Nonpharmacologic approaches: Interventions such as exercise, education, and support should be considered throughout the course of the disease. (Adapted from CW Olanow et al: Neurology 72:S1, 2009.)

TABLE 195-3 DRUGS COMMONLY USED FOR TREATMENT OF PD*

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Goals are to maintain function and avoid drug-induced complications; start therapy when symptoms interfere with quality of life. Bradykinesia, tremor, rigidity, and abnormal posture respond early in illness; cognitive symptoms, hypophonia, autonomic dysfunction, and balance difficulties respond poorly.

LEVODOPA

• Routinely administered in combination with a decarboxylase inhibitor to prevent its peripheral metabolism to dopamine and the development of nausea and vomiting. In the United States, levodopa is combined with carbidopa (Sinemet).

• Levodopa is also available in controlled-release formulations and in combination (e.g., as Stalevo) with a COMT inhibitor (see below).

• Levodopa remains the most effective symptomatic treatment for PD, and lack of response to the medication despite an adequate trial should cause the diagnosis to be questioned.

• Side effects include nausea, vomiting, and orthostatic hypotension that can be avoided by gradual titration.

• Levodopa-induced motor complications consist of fluctuations in motor response and involuntary movements known as dyskinesias.

• When pts initially take the drug, the benefits are long-lasting; with continued treatment, the duration of benefit following an individual dose becomes progressively shorter (“wearing-off effect”).

DOPAMINE AGONISTS

• A diverse group of drugs that act directly on dopamine receptors. Second-generation non-ergot dopamine agonists are commonly used (e.g., pramipexole, ropinirole, rotigotine).

• Compared with levodopa, dopamine agonists are longer acting and thus provide a more uniform stimulation of dopamine receptors; less prone to induce dyskinesias compared with levodopa.

• They are effective as monotherapeutic agents and as adjuncts to carbidopa/levodopa therapy.

• Side effects include nausea, vomiting, and postural hypotension. Hallucinations and cognitive impairment are more common than with levodopa, so caution is urged in those older than 70.

• Recently, it has become recognized that dopamine agonists are associated with impulse-control disorders including pathologic gambling, hypersexuality, and compulsive eating and shopping.

MAO-B INHIBITORS

• Block central dopamine metabolism and increase synaptic concentrations of the neurotransmitter; generally safe and well tolerated.

• Provide modest antiparkinson benefits when used as monotherapy in early disease.

• Recent work has examined whether these drugs could have a disease-modifying effect; however, long-term significance is uncertain.

COMT INHIBITORS

• When levodopa is administered with a decarboxylase inhibitor, it is primarily metabolized by COMT; inhibitors of COMT increase the elimination half-life of levodopa and enhance its brain availability.

• Combining levodopa with a COMT inhibitor reduces wearing-off time.

OTHER MEDICAL THERAPIES

• Anticholinergics (trihexyphenidyl, benztropine) have their major clinical effect on tremor. Use in the elderly is limited due to propensity for inducing urinary dysfunction, glaucoma, and particularly cognitive impairment.

• The mechanism of action of amantadine is unknown; it has NMDA antagonist properties; it is most commonly used as an antidyskinesia agent in pts with advanced PD. Side effects include livedo reticularis, weight gain, and impaired cognitive function; discontinue slowly as pts can experience withdrawal symptoms.

SURGICAL TREATMENTS

• In refractory cases, surgical treatment of PD should be considered.

• The use of ablation (e.g., pallidotomy or thalamotomy) has decreased greatly since the introduction of deep-brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus interna (GPi).

• DBS is primarily indicated for pts who suffer disability resulting from levodopa-induced motor complications; the procedure is profoundly beneficial to many pts.

• Contraindications to surgery include atypical PD, cognitive impairment, major psychiatric illness, substantial medical comorbidities, and advanced age (a relative factor).

• Experimental surgical procedures including cell-based therapies, gene therapies, and trophic factors are under investigation.

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For a more detailed discussion, see Olanow CW, Schapira AHV: Parkinson’s Disease and Other Extrapyramidal Movement Disorders, Chap. 372, p. 3317, in HPIM-18.

 



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