Hypokinetic Movement Disorders

Parkinson's Disease

Pathogenesis and Pathophysiology. Pathological findings of Parkinson's disease (PD) include depigmentation and neuronal loss in the substantia nigra (SN) and the presence of Lewy bodies and pale bodies( Fig 34-1). Because the degenerating cells in the SN normally synthesize the neurochemical dopamine, the pathophysiological hallmark of PD is dopaminergic underactivity at the site of these cells' axonal projection--that is, the striatum (caudate nucleus and putamen). Lewy bodies are eosinophilic inclusions composed of neurofilament, tubulin components,

-synuclein and ubiquitin. Pale bodies are composed of neurofilament interspersed with vacuolar granules. Besides the substantia nigra, they are also present in the basal ganglia, cortex, brain stem, and spinal cord. Although characteristic of PD, Lewy bodies are also seen in Alzheimer's disease, Hallervorden-Spatz disease (HSD), ataxia-telangiectasia, and, rarely, in patients without clinical neurological disease. y

The mechanism of Lewy body formation and cell death in PD is not known, but the degenerative process is highly localized at the beginning of the illness. Anatomical studies have found that the area first affected in the disorder is the pars compacta in the ventrolateral SN (SNpc) with its fibers projecting to the putamen. y Neurochemical changes resulting from this selective neurodegeneration consist mainly of loss of dopamine (DA), and it is estimated that 60 to 85 percent of nigral neurons and striatal Da is lost prior to the development of PD symptoms.

The most actively studied hypothesis of the origin of PD has focused on selective oxidative stress. Metabolic pathways for DA generate numerous byproducts that include

Figure 34-1 A and B, An isolated Lewy body, a distinctive eosinophilic cytoplasmic inclusion body found in the substantia nigra of Parkinson's disease.

hydrogen peroxide, superoxide anions, and hydroxyradicals. Interaction between these chemicals and membrane lipids leads to lipid peroxidation, membrane disruption, and, potentially, cell death. In support of this hypothesis, several observations are pertinent: (1) glutathione peroxidase, a tripeptide normally present in brain that is reduced with oxidative stress, is markedly reduced in the SN of patients with PD; (2) elemental iron, which can facilitate the formation of free radicals in the nervous system, is increased in the brains of PD patients; (3) the iron-chelating protein ferritin is decreased or of normal concentration in PD, so that compensatory increases to handle elemental iron do not occur; and (4) specific enzymatic activity defects in complex 1 of the mitochondrial respiratory chain appear to occur in the SN of the brains of patients with PD. Whereas all these events develop and probably reflect or provoke oxidative stress in the SN, the actual precipitant, whether genetic, environmental, dietary, or multifactorial, remains to be determined.

Whereas the primary lesion involves dopamine, other neurotransmitter systems are also affected. At the level of the striatum, muscarinic cholinergic function competes with dopaminergic activity, and hence in PD, there is a relative overactivity of acetylcholine. Also, other pigmented nuclei besides the substantia nigra degenerate, and changes in norepinephrine and serotonin result from changes in the locus ceruleus and dorsal raphe, respectively.

Epidemiology and Risk Factors. Population-based surveys in the United States, Portugal, and Italy have reported that the prevalence of PD ranges from 107 to 187 per 100,000 population.1?1 A recent community study of the elderly in a suburb of Boston, however, found parkinsonian features in 159 of 467 (34 percent) individuals aged 65 years or older.[4 This study suggests that at least one third of the elderly exhibit some evidence of PD or other parkinsonian disorders.

Although both environmental and inherited factors have been implicated in the pathogenesis of PD, no specific cause has been found. Case-controlled studies have documented an increase in risk for PD associated with a family history of PD, insecticide exposure, herbicide exposure, rural residency at the time of diagnosis, well water exposure, and nut or seed eating 10 years prior to diagnosis. [5 Numerous reports suggest the possibility that the frequency of PD is decreased in patients with a history of cigarette smoking, but these data remain controversial. [10] The best studied model of parkinsonism is that produced by

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a meperidine analog first developed during the production of an illicit drug. This compound, when injected intravenously, produces parkinsonism in humans and animals. y

Twin studies suggest that genetic predisposition may play a role in the development of PD, M and a number of parkinsonian pedigrees have been reported. y y y y The gene locus in one autosomal dominant pedigree was isolated to chromosome 4q21.23 and was later found to involve Ala53thr substitution in the -synuclein gene.y Jankovic and colleagues^1 and others have found that PD and essential tremor (ET) coexist relatively frequently, and ET has been considered by some a risk factor for PD. Further studies, however, are needed to confirm this observation.

Clinical Findings and Associated Disorders. The cardinal features of PD include resting tremor, rigidity, bradykinesia, and postural instability. Many movement disorder specialists consider a good response to levodopa or dopamine agonists useful in clinically supporting the diagnosis. y The rest tremor usually consists of an oscillatory movement of 4- to 7-Hz frequency that involves the limbs, jaw, face, and tongue but almost never involves the head itself. The tremor of the forearm is often pronating and supinating, while the hand tremor has been described as "pill-rolling." Early in the course of the disease, the tremors and other signs are usually asymmetrical but eventually become bilateral. In addition to the rest tremor that is so distinctive of PD, most patients also have a postural tremor, which is evident with the hands extended or in action. This postural tremor probably represents re-emergence of rest tremor or coexistent ET (see later discussion). Tremor in patients with ET, in contrast to PD, often involves not only the hands but also the head and voice, rarely affects the legs, and improves frequently with alcohol, propranolol, or primidone. Some PD patients or their relatives have an associated postural tremor that appears as ET and precedes the onset of PD symptoms by several years or decades, suggesting a possible link between the two conditions, at least in some families.

Bradykinesia (slowness of movement) or hypokinesia (poverty of movement) is manifested by slowing of activities of daily living such as dressing, feeding, brushing teeth, and bathing. Other features of bradykinesia or hypokinesia include masked facies (hypomimia), hypokinetic dysarthria, drooling, and slow and small handwriting (micrographia).

On examination, rapid alternating movements are performed slowly and with decreasing amplitude. In more advanced stages, frequent arrests of movement, called "freezing" or "motor blocks," may be seen. These are manifested by an interruption in finger tapping or hand clasping, start hesitation such as an inability to initiate gait or other movements, and freezing when turning or walking through narrow passages.

Postural instability also often occurs in the more advanced stages of the disease. This gait and postural difficulty are frequently accompanied by small steps and festination, a tendency when standing or walking to propulse involuntarily or to retropulse and fall. In the distinctive "pull test" the examiner stands behind the patient and tugs briskly on the shoulders; the PD subject takes several small steps backward, possibly falling into the examiner's arms.

Most of the other signs of PD represent variations of these cardinal characteristics: sialorrhea, dysphagia, difficulty in turning in bed, and ambulatory problems that become progressively worse. Sleep disruption is common in PD patients, who demonstrate fragmented sleep and frequent awakenings. Recent studies suggest that a distinctive sleep aberration, REM behavioral disorder (see Chapt.e.L.54 ), may be a frequent early element of PD. Additionally, akathisia, an uncomfortable feeling that drives the patient to move, can be a prominent and poorly appreciated aspect of untreated PD, and this behavior may be related to dopaminergic dysfunction. Besides motor symptoms, PD patients may also exhibit several behavioral changes, including depression in at least one third of patients, and dementia in an equal proportion. Frontal release, or "cortical disinhibition" signs, may be seen, but they are not specific for PD. Pain, burning, coldness, numbness, and other sensory symptoms, often wrongly attributed to bursitis or arthritis, are reported by about half of patients. Seborrhea, particularly that involving the face, is an example of systemic involvement in PD.

The mean age of clinical onset of PD is the mid fifties, but the range is very wide, and some patients present in their twenties and thirties, while others show no signs until their eighties. Although there are many exceptions, young patients often present with tremor-predominant disease and elderly patients with gait dysfunction and akinesia. Juvenile PD is a childhood and adolescent disease, presenting with parkinsonism and dystonia, and has a different histological appearance than PD.

Differential Diagnosis. Besides PD, there are many other causes of parkinsonism (.Table34:1 ). The second most common group is the parkinsonism-plus syndromes (12 percent), a conglomerate term for a large number of degenerative disorders in which parkinsonism is one of several neurological features. Drug-induced parkinsonism (8 percent), and heredodegenerative conditions, such as juvenile Huntington's disease (HD), are less frequent. Cyanide intoxication and carbon monoxide poisoning associated with bilateral pallidal necrosis are examples of an acute cause of parkinsonism, [io] and other toxins like carbon disulfide and manganese can also produce parkinsonism, the latter often preceded by psychiatric difficulties ("manganese madness"). Reversible parkinsonism is caused by drugs, especially neuroleptics and metoclopramide, and lesser known agents such as alpha-methyldopa, reserpine, amiodarone, and certain calcium channel blockers must also be considered in the differential diagnosis. Finally, patients in whom PD is suspected should be screened for potential illicit narcotic exposure, a travel history, or an underlying medical illness such as the acquired immune deficiency syndrome (AIDS) that would predispose them to opportunistic infections including abscesses, and a family history of neurological disorders should be obtained as well. A past medical history of stroke or hypertension may suggest a subcortical vascular encephalopathy presenting with parkinsonian features, and old meningitis or head trauma could suggest normal pressure hydrocephalus presenting with freezing, festination, and a gait disorder sometimes confused with parkinsonism.

Evaluation. When all four cardinal characteristic signs are present, and the patient shows a brisk response to dopaminergic therapy, the diagnosis is straightforward. Part of the workup usually includes a magnetic resonance (MR) scan, looking for evidence of alternate diagnoses like stroke, intoxications, or other degenerative disorders.^] Although it is not yet firmly established, cerebrospinal fluid (CSF) homovanillic acid (HVA), the final metabolite of dopamine, especially when expressed as a ratio to CSF xanthine, may become a future marker of disease activity.

Management. The large array of drugs used in the treatment of PD is outlined in T§.ble.,34.:2 with standard doses and side effects. Treatment of symptomatic PD is based primarily on restoring a deficiency of dopamine (DA) due to a loss of dopamine-producing cells in the SN. [ii] This neurotransmitter is synthesized from the amino acid tyrosine. The conversion of tyrosine to levodopa is facilitated by the rate-limiting enzyme tyrosine hydroxylase; levodopa is in turn converted into dopamine by the nonspecific enzyme dopa-decarboxylase. These dopaminergic neurons synapse with cholinergic interneurons and gamma-aminobutyric acid (GABA)-ergic outflow neurons in the striatum.

Five subtypes of DA receptors have been identified; the D1 and D2 receptors are most prominent in the striatum, and the D3 , D4 , and D5 receptors are present in the limbic system and other dopaminergic pathways. The D1 receptor is linked to adenylate cyclase. In contrast, the D 2 receptor is activated by DA and DA agonists. The different roles of D1 and D2 receptors in regulation of striatal function have not been fully defined, but the D 2 receptor appears to be more important in mediating the parkinsonian symptoms. In the brain in PD, the D1 receptors in the striatum appear to be reduced (downregulated), whereas the D 2 receptors are increased (upregulated).y As a result of nigrostriatal deficiency, activation of the indirect D 2 -mediated, inhibitory (GABA) striatopallidal pathway is increased, resulting in disinhibition of the subthalamic nucleus and the globus pallidus internum (GPi), the main output nucleus from the basal ganglia. The increased activation of the GPi is further enhanced by disinhibition of the decreased activity of the direct D 1 -mediated, inhibitory (GABA) striatopallidal pathway ( Fig.,34z2 ).

The most effective treatment for the symptoms of PD is levodopa, but the chronic use of levodopa is complicated by the development of two motor problems, namely, fluctuations and dyskinesias in about half the patients after 5 years of therapy. Fluctuations are irregular and clinically

_TABLE 34-1 -- CLASSIFICATION OF PARKINSONISM_

I. Primary Parkinsonism Parkinson's disease Juvenile parkinsonism

II. Multiple System Degenerations (Parkinsonism-Plus Syndromes) Progressive supranuclear palsy (PSP)

Multiple system atrophy (MSA) Striatonigral degeneration (SND) Olivopontocerebellar atrophy (OPCA) Shy-Drager syndrome (SDS)

Lytico-Bodig or parkinsonism-dementia-ALS complex of Guam (PDACG) Cortical-basal ganglionic degeneration (CBGD) Progressive pallidal atrophy

III.Hereditary Parkinsonism Hereditary juvenile dystonia-parkinsonism Autosomal dominant Lewy body disease Huntington's disease (HD)

Wilson's disease (WD) Hereditary ceruloplasmin deficiency Hallervorden-Spatz disease (HSD)

Olivopontocerebellar and spinocerebellar degenerations (OPCA and SCA)

Familial amyotrophy-dementia-parkinsonism

Disinhibition-dementia-parkinsonism-amyotrophy complex

Gerstmann-Strausler-Scheinker disease

Familial progressive subcortical gliosis

Lubag (X-linked dystonia-parkinsonism)

Familial basal ganglia calcification

Mitochondrial cytopathies with striatal necrosis

Ceroid lipofuscinosis

Familial parkinsonism with peripheral neuropathy Parkinsonian-pyramidal syndrome Neuroacanthocytosis (NA) Hereditary hemochromatosis

IV. Secondary (Acquired, Symptomatic) Parkinsonism

Infectious: postencephalitic, AIDS, SSPE, Creutzfeldt-Jakob disease, prior diseases

Drugs: dopamine receptor-blocking drugs (antipsychotic, antiemetic drugs), reserpine, tetrabenazine, alpha-methyldopa, lithium, flunarizine, cinnarizine Toxins: MPTP, CO, Mn, Hg, CS2 , cyanide, methanol, ethanol

Vascular: multi-infarct, Binswanger's disease Trauma: pugilistic encephalopathy

Other: parathyroid abnormalities, hypothyroidism, hepatocerebral degeneration, brain tumor, paraneoplastic diseases, normal pressure hydrocephalus, noncommunicating hydrocephalus, syringomesencephalia, hemiatrophy-hemiparkinsonism, peripherally induced tremor and Parkinsonism, and psychogenic disorders

Modified from Fahn S, Marsden CD, Jankovic J: Principles and Practice of Movements Disorders. New York, Churchill Livingstone, 1996.

unpredictable responses to medications, and dyskinesias are involuntary, usually choreic, but sometimes dystonic movements that are drug induced. Levodopa is absorbed in the small intestine via a large neutral amino acid (LNAA) transporter system and is then converted to DA by the ubiquitous enzyme dopa-decarboxylase. Conversion to DA outside the blood-brain barrier activates the area postrema and is largely responsible for some of the early side effects of levodopa, particularly nausea and vomiting. The addition of dopa-decarboxylase inhibitors that do not cross the blood-brain barrier (e.g., carbidopa or benserazide) minimizes DA formation in the periphery and greatly improves patient tolerance to therapy. This is the concept behind the use of the carbidopa-levodopa combination (e.g., Sinemet), which is prescribed as a ratio of carbidopa to levodopa (25/ 100, 25/250, or 10/100) and more recently has become available in a controlled-release formulation (CR 50/200 or CR 25/100). Approximately 100 mg of carbidopa per day is needed for effective peripheral blockade. Although carbidopa is useful in preventing the "peripheral" side effects of levodopa, the motor side effects of fluctuations and dyskinesia as well as psychiatric reactions such as confusion, delusions, and visual hallucinations are not prevented or ameliorated by its addition to levodopa.

In the early stages of levodopa therapy, motor fluctuations correlate well with plasma levodopa levels. Initially, patients may report a "wearing-off" or end-of-dose deterioration in mobility, which is thought to result from a reduced duration of therapeutic plasma and brain levels of levodopa. A typical patient may also notice dyskinesias or involuntary movements related to peak plasma levodopa levels ("peak dose dyskinesia"). Most patients have this pattern of response characterized by improvement-dyskinesia-improvement (IDI). About 15 percent of patients who are treated chronically with levodopa experience initial dyskinesia within a few minutes after ingestion of levodopa; this is followed by an improvement in parkinsonian symptoms for 2 to 4 hours and then by subsequent recurrence of dyskinesia, usually in the form of dystonia. This diphasic dyskinesia pattern of dyskinesia-improvement-dyskinesia is referred to as the DID response. Treatment of these motor fluctuations is based on "smoothing out" the plasma concentration curves either by giving more frequent smaller doses of levodopa, converting to the controlled-release

TABLE 34-2 -- MEDICATIONS

FOR PARKINSON'S DISEASE

Medications

Dosage

Side Effects

Dopaminergic Drugs

Precursor amino acid: Levodopa

Nausea, hypotension, confusion, hallucinations, dyskinesia

Carbiodopa/levodopa

10/100, 25/100, 25/250, 100-1000 mg/24 hr

Controlled release

25/100, 50/200, 200-1400 mg/24 hr

Dopamine agonists

Somnolence, confusion, hallucinations, hypotension

Bromocriptine

2.5-60 mg/24 hr

Pergolide

0.25-6 mg/24 hr

Pramipexole

0.125-4.5 mg/24 hr

Ropinirole

0.25-24 mg 24 hr

Monoamine oxidase B inhibitor

Sleep disturbance, lightheadedness, hallucinations

Selegiline (Deprenyl)

5--10 mg/24 hr

Indirect agonist Amantadine

100-300 mg/24 hr

Hallucinations, dry mouth, livedo reticularis, ankle swelling, myoclonic encephalopathy in setting of renal failure

Catecholamine-O-methyl transferase inhibitor

Used in conjunction with levodopa: dyskinesia, lightheadedness

Tolcopone

300-600 mg/24 hr

Entacopone

Other Drug Classes

Anticholinergics

Confusion, sleepiness, blurred vision, constipation

Trihexiphenidyl

2-15 mg/24 hr

Biperiden

1-8 mg/24 hr

Novel neuroleptics: used for psychosis and unusual tremors

Fatal neutropenia, somnolenee

Clozapine

12.5-100 mg/24 hr

Miscellaneous

Amitriptyline: used for sleep fragmentation

10-50 mg 24 hr at bedtime

Dry mouth, forgetfulness, blurred vision, constipation

Baclofen: used for dystonic cramps

10-80 mg 24 hr

Sleepiness, dizziness

form of levodopa, or, in the patient with markedly advanced disease, titrating the medication by having the patient sip very small quantities of Sinemet dissolved in water or juice every 30 or 60 minutes throughout the waking day. d In patients with advancing disease who have had prolonged levodopa therapy, more complex and less predictable ("on-off") motor fluctuations occur. For instance, patients may change from relatively normal function to a frozen akinetic state in as little as 15 seconds (sudden on-off), or they may develop severe dyskinesia at both the peak effect of the levodopa dose and at the end of the dose (biphasic dyskinesia). The mechanism of these motor fluctuations and dyskinesias is not well understood, but there is a growing body of evidence supporting the notion that some of these problems arise from the combination of loss of presynaptic DA storage capacity and postsynaptic receptor alterations. y

Figure 34-2 Basal ganglia circuitry relevant to pathogenesis of PD. GABA, Gamma-aminobutyric acid; SMA, supplementary motor area.

In the 1980s, the monoamine oxidase-B inhibitor (MAO-B) deprenyl (selegiline) was reported to delay the clinical progression of PD. In a large multicentered trial, the Deprenyl and Tocopherol ^ntioxidative Trial of Parkinson's Disease (DATATOP), deprenyl but not tocopherol delayed the need for levodopa by approximately 9 months.^ Whether this is due to deprenyl's beneficial effect on the parkinsonian symptoms or to a putative neuroprotective action is a subject of continued debate. Other MAO-B inhibitors, such as lazabemide, have been evaluated in PD as well, but long-term protocols aimed at defining neuroprotective mechanisms have not been carried out.

In the early stages of PD, anticholinergic (e.g., trihexyphenidyl) therapy may provide moderate improvement. This strategy is based on the neurochemical competition between DA and acetylcholine in the striatum. Amantadine, an antiviral agent, has mild dopaminergic activity and possibly anticholinergic action as well. Amantadine and anticholinergic agents may produce dry mouth, nausea, vomiting, blurring of vision, visual hallucinations, and other mental changes. Because of the anticholinergic side effects, patients with glaucoma, prostatic hypertrophy, and dementia may experience exacerbations of these conditions with these agents.

Amantadine may also cause pitting edema and livedo reticularis, a purplish-reddish mottling of the skin, particularly the skin below the knees; it should be avoided in patients with impaired renal function.

Since the introduction of bromocriptine and pergolide, DA agonists, which are agents that stimulate dopamine receptors themselves, have played an increasingly important role in the treatment of PD. Because these medications have a relatively long half-life, they are used most frequently to prolong the effects of levodopa and thus smooth out motor fluctuations. While some movement disorder

specialists advocate the use of DA agonists in the early phases of pharmacological therapy, others introduce DA agonists after the dose of levodopa has reached 300 to 600 mg/day or when levodopa-related fluctuations emerge. Side effects associated with DA agonists include nausea, drowsiness, confusion, hallucinations, orthostatic hypotension, exacerbation of dyskinesias, erythromelalgia, and, rarely, pulmonary fibrosis. Ihe latter two side effects have been attributed to the ergot structure of pergolide and bromocriptine, and they should not occur with the recently approved non-ergoline DA agonists pramipexol and ropinirole. y , y

All agonists used in PD activate D2 receptors, although the profiles for other dopamine receptor classes and other neurotransmitter systems differ. Pramipexole, ropinirole, and cabergoline are some of the newer promising DA agonists currently being evaluated in clinical trials in the United States and abroad. y , y Among DA agonists, apomorphine is the only short-acting compound. As an injectable DA agonist, it can be useful in "rescuing" some PD patients from unpredictable off-periods. Because of the strong emetic response with this agent, however, coadministration of the peripheral DA receptor blocking drug domperidone is usually necessary.

Another new class of drugs is the catechol- O-methyltransferase (COMI) inhibitors such as entacapone and tolcapone. By limiting DA metabolism, they increase levodopa bioavailability, prolong the "on" response to levodopa, reduce motor fluctuations effectively, and allow a reduction in daily levodopa dosage. y

Of particular interest in PD during the last several years has been the use of various surgical procedures, which have capitalized on a growing knowledge of basal ganglia anatomy and physiology(see Fig 34-.2 ). Two basic models have been studied, constructive and destructive surgery. In the former, attempts are made to provide a new cell source of dopamine at the level of the denervated striatum. Ihe most notable of these efforts is the use of human fetal mesencephalic transplantation, and early reports of success with this procedure have led to U.S. government-sponsored controlled trials of this therapy in patients with advanced PD.y In addition, growth factors or neurotrophins may be infused into the ventricular CSF or brain tissue itself. In the area of destructive surgery, attempts to ablate overactive pallidal or thalamic function have led to pallidotomies and thalamotomies as well as deep brain stimulation procedures that reversibly inactivate function by the use of high-frequency overstimulation (depolarization blockade). Ihese studies have shown that dyskinesia is improved with pallidal procedures, and severe tremor is reduced or even ablated with thalamic surgery.y , y Potential side effects of all surgical procedures involving the basal ganglia include hematomas, ischemic cerebrovascular accidents, and damage related to needle passage through the cortex.

Because of the remarkable array of options in the treatment of PD, it is reasonable to approach the treatment of each patient with a basic algorithm y (.i.Ia,bIe 34-3 ). For all patients, education, exercise, and good nutrition are considered useful. If patients have no significant functional impairment in terms of independent living, consideration of a mild dopaminergic drug with a putatively neuroprotective strategy in the form of deprenyl can be considered. If

_TABLE 34-3 -- AN ALGORITHM FOR MANAGING PARKINSON'S DISEASE AT DIFFERENT PHASES_

For all patients: Education, physical or exercise therapy, good nutrition For patients with no clinically significant disability:

Consider selegiline

Consider referral to study centers for trials of new neuroprotective strategies For patients with clinically significant disability:

Job security threatened or health endangered:

Levodopa, usually controlled-release formulation

Job security NOT threatened and health NOT endangered:

Young and tremor-predominant disease: Anticholinergic drugs or amantadine

Older patients: Amantadine, dopamine agonists

Very elderly patients (80 or older): Levodopa

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