Goetz: Textbook of Clinical Neurology, 3rd ed.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 projectionthat is, the striatum (caudate nucleus and putamen) ( Fig. 34-2 ). 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, spinal cord, and even in the sympathetic ganglia, myenteric plexus, and cardiac plexus. Although characteristic of PD, Lewy bodies are also seen in Alzheimer's disease, neurodegeneration with brain iron accumulation (Hallervorden-Spatz disease), ataxia-telangiectasia, and, rarely, in patients without clinical neurological disease.

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

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

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. Neurochemical changes resulting from this selective neurodegeneration consist mainly of loss of dopamine (DA), and it is estimated that 60% to 85% of nigral neurons and striatal DA is lost prior to the development of PD symptoms. The traditional view that the pathological process in PD starts with degeneration of dopaminergic neurons in SNpc has been challenged by Braak and colleagues,[1] who proposed a six-stage pathological process. During the presymptomatic stages 1 and 2, the Lewy bodies remain confined to the medulla oblongata and olfactory bulb. In stages 3 and 4, the SN and basal forebrain become involved, and in stages 5 and 6, the pathological process encroaches upon the telencephalic cortex. Although the Braak staging has gained widespread popularity, no cell counts have been done to correlate with the described synuclein pathology.The most actively studied hypothesis of the origin of PD has focused on the possibility that the natural proteasomal activity in the brains of patients with PD may be impaired, thus leading to abnormal protein aggregation. Postmortem studies of brains of patients with PD have provided evidence that proteasomal function is selectively impaired in the SN.[2] Aggresomes, centrosome-associated structures that sequester proteasomal components, normally localize in the perinuclear area presumably to guard the nucleus and protect other organelles from exposure to the potentially toxic proteins, but in PD the normal aggresome formation is impaired and therefore these cells do not benefit from the potentially cytoprotective response. This finding is one piece of growing evidence that inhibition of the ubiquitin-proteasome pathway leads to altered protein handling and Lewy body formation. Thus, as a result of an age-related or disease-related impaired proteasomal system, both normal and abnormal proteins accumulate and aggregate to form Lewy bodies. Although Lewy bodies were once considered to be toxic, they are now thought to actually serve a protective role by absorbing the unwanted proteins. The neuronal loss in PD is presumably due to a failure of ubiquitination and proteasomal degradation resulting in accumulation of aggregated proteins that promote oxidative stress, disrupt intracellular processes, and induce apoptosis. Metabolic pathways for DA generate numerous by-products that include hydrogen peroxide, superoxide anions, and hydroxy radicals. 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. Although 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.Although the cardinal motor signs of PD, such as tremor, bradykinesia, rigidity, and postural instability, are primarily related to dopaminergic deficiency, many of the other motor and nonmotor signs that do not respond to levodopa are probably mediated through other neurotransmitter systems.[3] Thus, norepinephrine and serotonin deficiency resulting from degeneration of the lower brain stem nuclei, locus caeruleus and dorsal raphe, respectively, may be associated with depression and anxiety, whereas cholinergic deficit may lead to cognitive impairment.[4]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.[5] A community study of the elderly in a suburb of Boston, however, found parkinsonian features in 159 of 467 (34%) individuals aged 65 years or older.[6] 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.[7] Study of time trends over 15 years in the incidence of parkinsonism in Olmsted County, Minnesota, found no evidence of major environmental risk factors for PD.[8] Exposure to hydrocarbon solvents has been associated with earlier onset of symptoms and more severe PD and other forms of parkinsonism. [0090] [0100] In one study, welders with PD were found to have their onset of PD an average of 17 years earlier than a control population of PD patients, suggesting that welding, possibly by causing manganese toxicity, is a risk factor for PD.[11] Critical review of the literature, however, provides no evidence that welding is associated with an increased risk of PD.[12] Numerous reports suggest the possibility that the frequency of PD is decreased in patients with a history of cigarette smoking and caffeine consumption. [0130] [0140] [0150] The best studied model of parkinsonism is that produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a meperidine analogue first developed during the production of an illicit drug. This compound, when injected intravenously, produces parkinsonism in humans and animals.[16]Twin studies and other family studies suggest that genetic predisposition plays an important role in the development of some forms of PD.[17] The original 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.[18] It has been hypothesized that this and other mutations cause the natively unfolded -synuclein protein to alter its secondary structure, ubiquitinate, and self-aggregate.[19] The application of quantitative real-time polymerase chain reaction amplification of the -synuclein gene exons showed results consistent with whole gene triplication in a large family with autosomal dominant, young-onset parkinsonism, dysautonomia, cardiac denervation, dementia, with Lewy bodies and glial cytoplasmic inclusions at autopsy.[20]In addition to mutations in the gene coding for -synuclein, there is a growing number of parkinsonian disorders associated with specific genetic defects. For example, one of the most common causes of young-onset parkinsonism is an autosomal recessive form of PD (ARPD) due to mutations in the gene called Parkin (PARK2) on chromosome 6q25.227. This 500-kilobase, 12-exon gene encodes a 465-amino acid protein containing an N-terminal ubiquitin-like motif and C-terminal RING finger motif. Multiple mutations have been identified in this gene among families with this levodopa-responsive form of PD.[21] Parkin, the protein product of the Parkin gene, is expressed in SN and other brain regions as well as in Lewy bodies of patients with PD.[22] Normal parkin is thus involved in ubiquitination and subsequent degradation of certain proteins, but mutated parkin protein loses this activity and thus may lead to an accumulation of proteins yet to be identified. This process could cause a selective neural cell death without formation of Lewy bodies. In contrast to typical PD, patients with ARPD often present with a dystonic gait during early adulthood. The mean age at onset of this variant is 25 years, but the disease may not present until age 58. Parkin gene mutation phenotypes range from dopa-responsive dystonia to young-onset PD with early levodopa-induced dyskinesias and to otherwise typical PD. In one study, 36 of 73 (49%) families with PD onset at 45 or younger had a mutation in the Parkin gene: 10 of 13 (77%) patients with onset at 20 or before and 2 of 64 (3%) patients with onset at 30 or later.[23] Another gene locus for PD has been found on chromosome 2p13.[24] This locus (PARK3) was detected in a group of European families with a mean age at onset of 59 years. Although some members of the kindreds had prominent dementia, the autopsy in some cases confirmed the typical pathological features of PD, including Lewy bodies. An autosomal dominant, levodopa-responsive Lewy body parkinsonism has been mapped to chromosome 4p15.7 (PARK4).[25] The haplotype also occurred in members of the family who did not have any clinical evidence of parkinsonism but, rather, exhibited postural tremor phenomenologically identical to essential tremor (ET). This finding and other data provide further evidence that PD and ET may be associated and genetically related.[26] The finding of a mutation in the deubiquinating enzyme ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene on 4p14 in one German family with autosomal dominant PD (PARK5)[27] further supports the concept that an impairment of normal protein degradation is an important mechanism of neurodegeneration in PD. Two loci on chromosome 1 have been found to be associated with autosomal recessive, early onset parkinsonism: 1p3536 (PARK6)[28] and 1p36 (PARK7).[29] Mutation in the PTEN-induced kinase 1 (PINK1) gene, chromosome 1p36, was identified in three consaguinous, autosomal recessive families with early onset parkinsonism (PARK6).[30] The PINK1 gene codes for a putative serine-threonine kinase, located in the mitochondria, thus providing further support for the role of oxidative stress in the pathogenesis of PD. Patients with PINK1 mutation may be indistinguishable from those with typical PD or from those with Parkin mutations. [0310] [0320] Although located in the same chromosomal region, 1p36, another autosomal recessive form of PD has been identified and found to be caused by a mutation in the DJ-1 gene. This form of PD, designated as PARK7, is manifested by a range from slow progression and mild hypokinesia to severe parkinsonism, dementia, motor neuron disease, and levodopa-induced motor fluctuations and psychiatric disturbances. [0330] [0340]Another locus, mapped to 12p11.23-q13.11 (PARK8), has been identified in a Japanese family with typical PD inherited in an autosomal dominant pattern with incomplete penetrance.[35] This novel gene, called LRRK2 (leucine-rich repeat kinase 2), belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains.[36] The gene product, a protein called dardarin (from the Basque word dardara, meaning tremor), is a novel protein that probably functions as a cytoplasmic kinase involved in phosphorylation of proteins, such as -synuclein and tau. Dardarin protein contains 2527 amino acids (AA) (in contrast to -synuclein protein, which contains only 140 AAs) encoded by 51 exons. The course of the disease is relatively benign, usually presenting with unilateral hand or leg tremor without cognitive deficit; patients respond well to levodopa. Other clinical phenotypes have included parkinsonism with dementia or amyotrophy or both and otherwise typical essential tremor.[37] An autopsy examination of some patients with this mutation demonstrated variable pathology, ranging from Lewy body and neurofibrillary tangle pathology to no pathological changes.[36] Other postmortem findings show brain stem dopaminergic degeneration consistent with Lewy body PD, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, progressive supranuclear palsy-like pathology, and even -amyloid deposits in anterior horn cells. This mutation has been found to be particularly frequent in people with PD of North African origin and in approximately one third of familial PD cases of Ashkenazi Jewish origin. [0370] [0380] [0390] Also known as the Kufor-Rakeb syndrome (PARK9), this levodopa-responsive parkinsonism has also been associated with spasticity, dementia, supranuclear gaze palsy, and globus pallidus atrophy on imaging studies. The disorder has been linked to chromosome 1p36, but no gene has been identified.[40] These genetic discoveries have important implications for genetic counseling.[41]In addition to these parkinsonism-related gene loci, there may be multiple genetic factors important in the pathogenesis of PD and other parkinsonian disorders. In a complete genomic screen of 174 families with multiple individuals diagnosed with PD involving a total of 870 family members (378 with PD), Scott and colleagues[42] found LOD scores ranging from 1.5 to 5.47 indicative of linkage to the following five chromosomal regions: 6 (in the Parkin gene), 17q (in the Tau gene), 8p, 5q, and 9q.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. The rest tremor usually consists of an oscillatory movement of 4 to 7Hz frequency that involves the limbs, jaw, face, and tongue but almost never involves the head (Video 59, Rest Tremor). The tremor of the forearm is often pronating and supinating, whereas the hand tremor has been described as pill-rolling (Video 67, Parkinsonian Rest Tremor). 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 (Video 61, Bradykinesia). 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 (Video 90, Freezing of Gait).Postural instability also often occurs in the more advanced stages of the disease. This gait and postural difficulty is 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 (Video 68, Postural Reflex Impairment).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. Studies suggest that a distinctive sleep aberration, rapid eye movement behavioral disorder (see Chapter 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 approximately half of patients. Joint deformities, known as striatal hand or striatal foot, and other skeletal deformities, such as scoliosis and camptocormia, are also often attributed to arthritic or orthopedic problems ( Fig. 34-3 ). [0430] [0440] Seborrhea, particularly that involving the face, and constipation are examples of systemic involvement in PD.

Figure 34-3 Typical striatal hand deformity in the right hand with marked flexion of fingers in the left hand resulting in severe flexion-contracture. (Reproduced from Ashour R, Tintner R, Jankovic J: Striatal hand and foot deformities in Parkinson's disease. Lancet Neurol 2005;4:423431.)

The mean age of clinical onset of PD is the mid-50s, but the range is very wide, and some patients present in their 20s and 30s, whereas others show no signs until their 80s. 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 In addition to PD, there are many other causes of parkinsonism ( Table 34-1 ). The second most common group is the parkinsonism-plus syndromes (12%), a conglomerate term for a large number of degenerative disorders in which parkinsonism is one of several neurological features (Video 58, High-Amplitude Tremor). Drug-induced parkinsonism (8%) and heredodegenerative conditions, such as juvenile Huntington's disease, are less frequent. Cyanide intoxication and carbon monoxide poisoning associated with bilateral pallidal necrosis are examples of an acute cause of parkinsonism,[13] and other toxins such as carbon disulfide and manganese can also produce parkinsonism, the latter often preceded by psychiatric difficulties (manganese madness) (Video 41, Carbon Monoxide Intoxication Parkinsonism). Reversible parkinsonism is caused by drugs, especially neuroleptics and metoclopramide, and lesser known agents such as -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 acquired immunodeficiency syndrome that would predispose them to opportunistic infections including abscesses. 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 (Video 54, Normal Pressure Hydrocephalus; Video 233, Vascular Parkinsonism).

Table 34-1 --Classification of ParkinsonismI. 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), also known as neurodegeneration with brain iron accumulation type I (NBIA-I)

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 receptorblocking drugs (antipsychotic, antiemetic drugs), reserpine, tetrabenazine, -methyldopa, ithium, 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

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 imaging (MRI) scan searching for evidence of alternate diagnoses such as stroke, intoxications, or other degenerative disorders.[45]Management The large array of drugs used in the treatment of PD is outlined in Table 34-2 with standard doses and side effects. Treatment of symptomatic PD is based primarily on restoring a deficiency of DA due to a loss of dopamine-producing cells in the SN.[45] 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 -aminobutyric acid (GABA)-ergic outflow neurons in the striatum.

Table 34-2 --Medications for Parkinson's DiseaseMedicationDosageSide Effects

Dopaminergic Drugs

Precursor amino acid: levodopaNausea, hypotension, confusion, hallucinations, dyskinesia

Carbidopa/levodopa10/100, 25/100, 25/250, 1001000mg/day

Controlled release25/100, 50/200, 2001400mg/day

Dopamine agonistsSomnolence, confusion, hallucinations, hypotension

Bromocriptine2.560mg/day

Pergolide0.256.0mg/day

Pramipexole0.256.0mg/day

Ropinirole0.256.0mg/day

Monamine oxidase B inhibitorSleep disturbance, lightheadedness, hallucinations

Selegiline (deprenyl)510mg/day

Rasagiline1mg/dayHallucinations, dry mouth, livedo reticularis, ankle swelling, myoclonic encephalopathy in setting of renal failure

Indirect agonist

Amantadine100300mg/day

Catecholamine-O-methyl transferase inhibitor (used in conjunction with levodopa)Dyskinesia, lightheadedness, diarrhea, orange urine

Tolcapone300600mg/day

Entacapone200mg, 28 times/day with each dose of carbidopa/levodopa

Other Drug Classes

AnticholinergicsConfusion, sleepiness, blurred vision, constipation

Trihexyphenidyl215mg/day

Biperidine18mg/day

Novel neuroleptics: used for psychosis and unusual tremor

Clozapine12.5100mg/dayFatal neutropenia, somnolence

Quetiapine12.5100mg/daySomnolence, potential aggravated parkinsonism

Miscellaneous

Amitriptyline: used for sleep fragmentation1050mg/day at bedtimeDry mouth, forgetfulness, blurred vision, constipation

Baclofen: used for dystonic cramps1080mg/daySleepiness, dizziness

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 D2 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 D2 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 D2 receptors are increased (upregulated).[46] As a result of nigrostriatal deficiency, activation of the indirect D2-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 D1-mediated, inhibitory (GABA) striatopallidal pathway (see Fig. 34-2 ).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 approximately half the patients after 5 years of therapy. Fluctuations are irregular and clinically unpredictable responses to medications, and dyskinesias are involuntary, usually choreic but sometimes dystonic movements that are drug induced (Video 250, Levodopa-Induced Dyskinesias). Levodopa is absorbed in the small intestine via a large neutral amino acid 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 has become available in a controlled-release formulation (CR 50/200 or CR 25/100). Approximately 100mg 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. Despite the theoretical concern that dopamine is neurotoxic, this is not supported by a large, multicenter study, the ELLDOPA trial, evaluating the effects of levodopa on progression of PD in 361 patients with no prior anti-PD treatment and not requiring symptomatic therapy. These patients were randomized to placebo or levodopa at 150, 300, or 600mg/day for 40 weeks, followed by a 2-week washout (extended to 4 weeks for a subset of patients).[47] This study is consistent with other in vivo studies that have found no evidence that levodopa is toxic.As patients continue to take levodopa, they often begin to 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.[48] 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). Approximately 15% 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 by giving more frequent smaller doses of levodopa, converting to the controlled-release 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.[49] 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 few as 15 seconds (sudden on-off), or they may develop severe dyskinesia at both the peak effect of the levodopa dose and 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.[50]In the 1980s, the monoamine oxidase-B (MAO-B) inhibitor deprenyl (selegiline) was reported to delay the clinical progression of PD. In a large multicenter trial, the Deprenyl and Tocopherol Antioxidative Trial of Parkinson's Disease (DATATOP), deprenyl but not tocopherol delayed the need for levodopa by approximately 9 months.[51] 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, 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. Whereas 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 600mg/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. The latter two side effects have been attributed to the ergot structure of pergolide and bromocriptine, and they almost never occur with the non-ergoline DA agonists pramipexole and ropinirole. Although gambling and compulsive shopping have been attributed to dopamine agonists, this adverse effect may be a nonspecific dopaminergic effect.[52]As a result of new findings suggesting levodopa sparing and possibly neuroprotective effects of DA agonists, their role in the management of PD has shifted from being primarily used late in the disease in conjunction with levodopa (adjunctive therapy) to being also used as early symptomatic treatment. Several studies have demonstrated that when introduced in early stages of PD, dopamine agonists provide adequate symptomatic benefit and delay the need for levodopa, thus minimizing the risk of levodopa-related dyskinesias and motor fluctuations. [0530] [0540] A 4-year follow-up of patients initially randomized to receive levodopa or pramipexole (the CALM-PD study) found that (1) initial treatment with pramipexole was associated with a significant reduction in the risk of developing dyskinesias (24.5% vs. 54.0%; hazard ratio, 0.37; P < 0.0001) and wearing off (47.0% vs. 62.7%; hazard ratio, 0.68; P = 0.02), but there was no difference between the two groups in disabling dyskinesias; (2) initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs. 37.1%; hazard ratio, 1.70; P = 0.01); (3) the improvement in mean total UPDRS was greater with levodopa than with pramipexole (2.0 &pm; 15.4 vs. -3.2 &pm; 17.3 points, P = 0.003); (4) pramipexole treatment was associated with a higher risk of somnolence (36% vs. 21%, P = 0.005) and edema (42% vs. 15%, P = 0.001); and (5) there was no difference in quality of life.[55] This study, coupled with the ELLDOPA study, has resulted in some modification of the strategy to delay the use of levodopa as long as possible and many clinicians are now using levodopa in early treatment of PD, particularly in elderly patients or in patients who may be slightly cognitively impaired and may be at a high risk for levodopa-induced hallucinations and other psychiatric side effects.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 sudden, 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 (COMT) 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.[56]Of particular interest in PD during the past 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 ).[57] The traditional ablative procedures have given way to newer strategies, particularly deep brain stimulation (DBS); this procedure has markedly improved the function and quality of life of many patients with advanced PD.[58] Besides lower risks associated with surgery, DBS has the advantage of customizing the stimulating parameters to the needs of the individual patient. In a multicenter, prospective, double-blind, cross-over study in 143 patients with advanced PD who received bilateral high-frequency stimulation of SN or GPi, the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores improved by 49% (P < 0.001) and 37% (P < 0.001), respectively, in comparison to the nonstimulated state.[59] Furthermore, 6 months following implantation compared to baseline, the percentage of time on without dyskinesias increased from 27 to 74 (P < 0.001) and 28 to 64 (P < 0.001) with SN and GPi DBS, respectively. Adverse events included intracranial hemorrhage in seven and lead displacement in two. Although the levodopa dosage remained unchanged in the GPi group, the daily levodopa dose equivalents were reduced by 37% in the SN DBS group (P < 0.001). Two double-blind trials of fetal graft transplantation for advanced PD showed no lasting benefit and approximately half of the implanted patients experience off dyskinesias even without levodopa, requiring DBS. [0600] [0610]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 ( Table 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 additional symptomatic relief is needed, most movement disorder specialists add a DA agonist and later, when symptoms need urgent treatment to protect the patient's safety or job security, levodopa is introduced. If symptoms can be treated more slowly, the use of anticholinergic drugs in young patients with tremor-predominant PD is often helpful, and amantadine can be used as a mild dopaminergic drug to delay the need to start levodopa in other patients. In patients who are just starting levodopa/carbidopa, the controlled-release form is often selected to minimize the number of doses needed each day. As the disease progresses, combinations of drugs are usually needed, and most patients will require both an agonist and levodopa/carbidopa within the first 7 years of therapy. However, in elderly patients, especially those with hallucinations or dementia, levodopa/carbidopa alone, usually in the regular formulation, is often the most practical regimen because of its relative simplicity.

Table 34-3 --Algorithm for Managing Parkinson's Disease at Different PhasesFor 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, amantadine, selegeline

Older patients: amantadine, dopamine agonists

Elderly patients or cognitively impaired: levodopa

Above Patients with Progressive Disability

Add levodopa either as controlled-release or standard formulation

Once on levodopa, if added prolongation of effect is needed, add selegiline if patient is not currently taking it or, in the future, catechol-O-methyl (COMT) transferase inhibitors may become available.

Patients with Specific Complications

Patients on levodopa who develop motor fluctuations

More frequent, small doses of levodopa or liquid Sinemet

Selegiline agonists (or COMT inhibitors)

Consider deep brain stimulation of the subthalamic nucleus.

Patients with unremitting tremor

Deep brain stimulation

Patients with hallucinations

Reduce medications. Stop all drugs except Sinemet.

Consider Quetiapine, atypical neuroleptic

One particularly difficult problem in managing PD patients is hallucinosis. Patients who are treated chronically with dopaminergic drugs develop visual hallucinations that can become frightening and severely disabling to the patient and caregiver. In this situation, the drug dosage should be reduced, and most patients are best managed on levodopa/carbidopa alone. In some instances, atypical neuroleptics with few extrapyramidal side effects can be used. Clozapine has been successful in abating hallucinations and psychotic behavior in PD patients, but it is an expensive drug and is associated with the potentially lethal side effect of agranulocytosis.[62] Other atypical antipsychotic drugs, particularly quetiapine, are often used to control drug-induced psychosis without aggravating underlying parkinsonism. Whenever a neuroleptic agent is introduced, however, careful monitoring is needed to ensure that parkinsonism is not exacerbated.Prognosis and Future Perspectives Survival of patients with PD has greatly improved since the development of levodopa. Prior to the advent of levodopa, mortality among PD patients was three times the normally expected rate. However, with the advent of levodopa and other medications, the life span of PD patients is almost the same as that of an age-matched control population without the disease.[63] Some studies have suggested that PD patients are more likely to die from infection than from cancer, compared to an age-matched group of controls. Early, even presymptomatic, detection of disease is paramount to early intervention, and major efforts are currently aimed at identifying biological markers for both the presence of disease (trait marker) and disease activity (state marker).Parkinsonism-Plus Syndromes In addition to PD, parkinsonism is one of the major clinical features in several other primary neurodegenerative conditions. However, because they all have additional features not typical of Parkinson's disease and share an overall worse prognosis and poorer response to antiparkinsonian therapy, they are often grouped together under the conglomerate term parkinsonism-plus syndromes. Within this group, each condition has distinctive characteristics that must be recognized and distinguished from one another and from PD.Progressive Supranuclear Palsy Pathogenesis and Pathophysiology Progressive supranuclear palsy (PSP) is the most common and best recognized entity among the parkinsonism-plus syndromes. PSP is an idiopathic condition with no known precipitant or strong genetic component. Postmortem analysis of the brains of PSP patients shows neuronal loss, gliosis, and neurofibrillary tangles composed of straight and paired helical filaments.[64] The SN, subthalamic nucleus, globus pallidus, superior colliculus, pretectal area, and substantia innominata are the sites of maximum involvement. Dopaminergic, cholinergic, and adrenergic neurotransmitter systems are affected, provoking a far more diffuse degenerative process than that seen in PD.[16] There is a growing body of evidence that PSP is due to an alteration in the gene on chromosome 17 coding for the tau protein.[65] Several studies have provided evidence for an increase in the 4R tau isoform mRNA in PSP, which contributes to overexpression of neurofibrillary tangles in brain stems of patients with PSP. Although a tau gene mutation has been associated with early dementia and PSP-like syndrome,[66] in most cases of PSP no specific tau mutation is present, but the H1 haplotype appears to be associated with PSP.[67]Epidemiology and Risk Factors A medically based survey in central New Jersey found that the age-adjusted prevalence of PSP was 1.38 per 100,000 population, and men appeared to be slightly more frequently affected than women.[68] Most patients experience the initial symptoms during their sixth and seventh decades. No clear geographic, occupational, or temporal clusters of PSP have been found. Although PSP is not considered a genetic disorder, rare familial clusters have been reported.Clinical Features and Associated Disorders PSP shares some clinical features with PD, such as bradykinesia, rigidity, dysarthria, dysphagia, and dementia. However, PSP patients rarely exhibit tremor and usually have much more profound postural instability. In addition, axial rigidity is more prominent than limb rigidity. Some patients with PSP also develop severe palilalia, emotional incontinence, and other evidence of bilateral frontal lobe dysfunction.[64] One characteristic sign of frontal lobe dysfunction in PSP the applause sign, manifested by persistence (perseveration) of clapping after the patient has been instructed to clap three times.[69]The best known feature of PSP, vertical ocular gaze paresis, may be overcome by passive head movement, which activates the oculocephalic reflexes (hence the designation supranuclear) (Video 55, Supranuclear Gaze Paresis). Riley and colleagues[70] reported five patients who presented with pure akinesia of gait, speech, and handwriting without rigidity, tremor, dementia, or eye movement abnormalities on clinical examination. None of the patients responded to levodopa, and four demonstrated subtle changes in vertical saccades on eyelid movement recordings (Video 206, Postural Instability).[70] The diagnostic criteria for PSP have been recently refined as a result of careful clinical-pathological correlative studies, and the greatest diagnostic confidence is placed in the combined clinical features of early frequent falls within the first year of clinical disease and vertical downward supranuclear paresis on examination.[71]Differential Diagnosis Whereas PSP is idiopathic, the same clinical syndrome has been associated with Alzheimer's disease, multiple strokes, multiple system atrophy (MSA), posthypoxic encephalopathy, and Whipple's disease. Parkinson's disease and the other parkinsonism-plus syndromes, including corticobasal ganglionic degeneration (CBD), Lewy body dementia (Video 232, Dementia with Lewy Bodies), normal pressure hydrocephalus (Video 54, Normal Pressure Hydrocephalus), and multi-infarct parkinsonism, must also be considered. Rarely, other conditions, such as dentato-rubro-pallido-luysian atrophy, neuroacanthocytosis, progressive external ophthalmoplegia, Whipple's disease, and hydrocephalus, may present with oculomotility disorders that are suggestive of PSP (Video 110, Facial Myokymia).Evaluation MRI should be performed in patients in whom PSP is suspected to rule out a multi-infarct state or hydrocephalus. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) demonstrate prefrontal hypoactivity and show evidence of severe involvement of the dopaminergic terminals as well as the postsynaptic DA receptors in the striatum.[72]Management Although PSP is associated with loss of multiple neurotransmitters, pharmacological therapies remain disappointing. Levodopa ameliorates the bradykinesia and rigidity in approximately one third of cases, but the benefit rarely persists beyond 1 or 2 years. DA agonists rarely provide additional benefit. If, however, the dopaminergic drugs improve the bradykinesia but have no impact on poor balance, the medicated patient may feel more agile and independent, only to fall more frequently, leading to consequently greater disability. Anticholinergic drugs and tricyclic antidepressants with anticholinergic effects (e.g., amitriptyline) may be helpful in treating emotional incontinence. Idazoxan, a noradrenergic drug, produced modest improvement in a small number of patients, but sympathomimetic and other side effects have limited further development of this drug.[73] Blepharospasm, occasionally associated with PSP, responds to botulinum toxin injection, and dry eyes may be treated with topical lubricants. Although physical, occupational, and speech therapy are of limited potential, these options may be beneficial in some patients and their families. Electroconvulsive therapy, adrenal implantation, and pallidotomy have been of no benefit.Prognosis And Future Perspectives The median interval from onset of the initial symptom, regardless of its nature, to onset of gait difficulty is estimated at 0.3 years; to the need for gait assistance, 3.1 years; to confinement to bed or wheelchair, 8.2 years; and to death, 9.7 years.[68] In contrast to the approximately 1.5% annual decline in the Unified Parkinson's Disease Rating Scale Part III noted in patients with PD, the average annual decline in MSA-P is 28.3%.[74] The problems that most frequently cause complications or death are falls and aspiration.Multiple System Atrophy Pathogenesis and Pathophysiology The pathogenic mechanisms of MSA remain unknown, and in contrast to PD, there is no evidence that genetic factors play a role. Recent findings link MSA to PD and related neurodegenerative disorders as -synucleinopathies.[18] Whereas the initial neurodegenerative events are unclear, in well-established cases, the staining characteristics and distribution of oligodendroglial fibrillary cytoplasmic inclusions are distinctively different from the neurofibrillary tangles of Alzheimer's disease, PSP, postencephalitic parkinsonism, and others.[75] Highly variable neuronal loss and gliosis are seen in the substantia nigra, caudate, putamen, cerebellar cortex, pyramidal tract, Edinger-Westphal nucleus, locus caeruleus, inferior olives, dorsal motor nucleus of the vagus, Purkinje cells, intermediolateral cell column of the spinal cord, spinocerebellar tracts, and Onuf's nucleus. Reduced dopamine or norepinephrine levels occur in the nigra, nucleus accumbens, septum, hypothalamus, and locus caeruleus.[75]Epidemiology and Risk Factors In a review of autopsies of parkinsonism, Quinn reported frequencies ranging from 3.6% to 22%, with a mean of 8.2% (68/833 cases).[76] However, no study has been undertaken to determine the population prevalence of MSA. At one large referral center, 100 patients with MSA reported a median age at onset of 53 years (range, 33 to 76 years).[77]Clinical Features and Associated Disorders MSA encompasses three neurodegenerative syndromes, which in the past were considered clinically distinct: striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and Shy-Drager syndrome (SDS). All these conditions share similarities with one another and with PD. The hallmark features of MSA are parkinsonism that is poorly responsive to levodopa therapy and varying degrees of autonomic, cerebellar, and pyramidal dysfunction. SDS is diagnosed clinically when dysautonomia far outweighs the other signs, SND is designated when anterocollis and pyramidal dysfunction are prominent (Video 235, Multiple System Atrophy, Striatal-Nigral Degeneration), and OPCA is used to characterize the patient with prominent cerebellar features of ataxia, limb dyssynergia, and kinetic tremor (Video 234, Multiple System Atrophy, Cerebellar Type). For all MSA patients, autonomic insufficiencies include orthostatic hypotension, postprandial hypotension, anhidrosis with thermoregulatory disturbances, poor lacrimation and salivation, constipation, and impotence. Disturbances in bladder emptying and incontinence may also occur. In addition, emotional lability, pyramidal signs, supranuclear ophthalmoplegia, anterocollis, myoclonus, sleep apnea and other ventilatory dysrhythmias, respiratory stridor, polyneuropathy, amyotrophy, and dementia may be present in any of the forms.[71] The variety of clinical presentations is wide, and pure autonomic failure, sleep apnea syndromes, some forms of peripheral neuropathies, and conditions that clinically resemble amyotrophic lateral sclerosis all may represent forms of underlying MSA.Differential Diagnosis Parkinson's disease, particularly in patients with prominent postural instability and gait disturbance, may be difficult to distinguish from MSA.[78] PSP and other parkinsonism-plus syndromes can be particularly difficult to separate, especially in the first 5 years of clinical illness. Vascular encephalopathies with multiple subcortical strokes may produce a similar constellation of signs, and the condition of pure autonomic failure can be difficult to differentiate from MSA in the early course of illness.Evaluation MRI may be useful to rule out a multi-infarct state, normal pressure hydrocephalus, or other causes of parkinsonism. An MRI scan demonstrating marked hypointensity of the striatum and linear hyperintensity lateral to the putamen on T2-weighted images suggests iron deposition and supports the diagnosis of MSA.[76] PET scans of MSA are similar to those of PSP and usually confirm a decreased density of striatal D2 receptors.[79] External urethral and rectal sphincter electromyography (EMG) is abnormal in almost all patients with MSA. Resting, supine, and standing norepinephrine levels are of questionable value, but supine and standing norepinephrine levels have been found to be slightly elevated in patients with MSA, whereas in those with pure autonomic failure they are usually decreased.[80]Management Levodopa may provide some relief, usually short term, for the rigidity, bradykinesia, and postural instability typical of MSA.[81] Patients with MSA usually require larger doses of levodopa than patients with PD, but side effects such as increased orthostatic hypotension and facial dystonia often limit the usefulness of levodopa. Patients rarely derive any meaningful benefit from DA agonists, anticholinergics, amantadine, or other antiparkinsonian drugs. Symptomatic orthostatic hypotension can be treated with sodium and volume repletion unless the patient is at risk of congestive heart failure or renal insufficiency. Ancillary measures such as wearing elastic stockings to increase central venous volume and elevating the head of the bed 6 inches may also be attempted but often prove uncomfortable. Fludrocortisone, a mineralocorticoid, often improves orthostatic symptoms by increasing vascular volume. Some patients benefit from the inhibition of vasodilator prostaglandin synthesis brought about by indomethacin and from the use of the -adrenergic agonist clonidine and the peripheral vasoconstrictor ephedrine. Midodrine, an -adrenergic agonist, has benefited some patients with moderate and severe orthostatic hypotension of various causes.[82] Urinary frequency or incontinence, if due to detrusor hyper-reflexia, may respond to peripherally acting anticholinergic agents such as oxybutynin or propantheline given at bedtime. Intranasal desmopressin at bedtime may offer relief from nocturnal urinary frequency. Impotence may respond to yohimbine, papaverine, or a penile implant. Constipation can be treated with cisapride, stool softeners, and bulk-forming agents. Hallucinations caused by dopaminergic therapeutic agents usually respond to a lower dose of dopaminergic medications or to clozapine at bedtime.[62] However, this latter therapy must be used cautiously in patients with hypotension. All patients receiving this drug must be monitored for agranulocytosis with weekly white blood cell counts.Prognosis and Future Perspectives Based on autopsy-proven cases of MSA, the average survival time is expected to be less than a decade (mean survival, 8.0 years[76]; median survival, 9.5 years).[77] Future studies may focus on the role of iron and oxidative stress in this disorder and the pathological hallmark of glial cytoplasmic inclusion bodies.Other Parkinsonism-Plus Syndromes Corticobasal Degeneration CBD is a distinctive parkinsonism-plus syndrome because specific cortical signs are associated with it, and it has a particular pathological picture. Autopsy in patients with CBD reveals asymmetrical, focal frontoparietal atrophy, ballooned and enlarged cells in the cortex, depigmentation of the substantia nigra without Lewy bodies, and diffuse neuronal loss.[83] There is no familial predisposition, and no environmental factors increase the risk of disease. Clinically, patients usually develop symptoms after age 60, and neurological signs of CBD include focal or asymmetrical rigidity, bradykinesia, postural and action tremor, and marked dystonia, usually predominantly in one upper extremity (Video 231, Cortical Basal Degeneration). The most characteristic symptom, however, is limb apraxia (Video 40, Apraxia), and the involved extremity can become so dysfunctional that it moves completely by itself and can be considered an alien limb (Video 39, Alien Hand Syndrome).[84] In most instances, the condition starts as an apparent case of PD, but the cortical sensory loss, dystonia, and apraxia are noticed quickly as distinctive. Ideomotor apraxia, possibly secondary to predominant involvement of the supplementary motor area and characterized by not knowing how to do it (as opposed to not knowing what to do with everyday objects in the ideational or conceptual apraxia), and limb-kinetic apraxia (loss of hand and finger dexterity with inability to isolate or connect individual movements) are the most typical forms of apraxia in CBD.[85] The parkinsonism can be treated with modest success in some cases by introducing levodopa or DA agonists, but the marked disability resulting from the limb dyspraxia is progressive, untreatable, and markedly disabling. Botulinum toxin can relieve elements of the dystonia. The condition usually progresses steadily, and death occurs within 10 years of diagnosis.[84]Parkinsonism-Dementia Amyotrophic Lateral Sclerosis Complex (PDALS) This distinctive condition occurs on the island of Guam (locally known as Lytico-Bodig disease) and has been the focus of significant research because of the possibility that genetic and environmental causes may be contributive (Video 236, ALS-Parkinsonism Dementia).[86] A study of more than 2000 affected and nonaffected individuals in Guam showed that the incidence of this disorder peaked in the 1950s and has gradually declined since that time. The rapid decline in incidence of this disorder in Guam strongly supports the role of environmental factors in the pathogenesis of this disorder.[87] Early studies focusing on possible environmental dietary toxins were encouraging, but recent work has failed to identify any agent consistently, and the once-held hypothesis that native flour contains a causative neurotoxin is no longer considered tenable.[87] Pathologically, depigmentation, basophilic inclusion bodies, and cell loss in the substantia nigra are apparent in cases of PDALS. Neurofibrillary tangles without senile plaques are present in the substantia nigra, anterior horn cells, and pyramidal tracts.[87] Clinical findings in PDALS range from motor neuron disease in younger patients to parkinsonism with severe dementia in the older population. The amyotrophic lateral sclerosis (ALS) form is seen predominantly in the Chamorros, whereas the parkinsonism-dementia presentation may be seen in both Chamorro and Filipino residents. The ALS seen in Guam does not differ clinically from the motor neuron disease seen in the remainder of the world. Although no cause has been established, the coexistence of these neurodegenerative conditions in one population with overlapping signs supports the continuation of hypotheses based on a common cause. The differential diagnosis for PDALS includes Alzheimer's disease, diffuse Lewy body disease, postencephalitic parkinsonism, PD, the parkinsonism-plus syndromes, lower body parkinsonism and other causes of parkinsonism, as well as ALS and the various forms of motor neuron disease (Video 232, Dementia with Lewy Bodies; Video 233, Vascular Parkinsonism).[87] Regardless of its form of clinical presentation, the disorder is relentlessly progressive, and death usually occurs within 10 years of diagnosis.Hemiatrophy/Hemiparkinsonism Hemiatrophy/hemiparkinsonism (HA/HP) is an uncommon disorder that involves the onset of parkinsonism on one side of the body in association with a hemiatrophic face, arm, or leg in varying combinations (Video 243, Hemiatrophy). First described by Klawans,[88] the disease presents with unilateral parkinsonism; the hemiatrophy is completely unnoticed by the patient. In a hemiparkinsonian patient, therefore, comparative examination of the size of the hands and feet may be necessary to diagnose the condition. Compared to PD, the parkinsonism of HA/HP usually begins at a younger age and generally remains on the hemiatrophic side for several years before it sometimes becomes bilateral. Unilateral dystonic movements are a common early feature and may respond well to levodopa. The cause is unknown, but early birth injury from hypoxia or trauma has been suggested as a possibility, and there may be some relationship between this syndrome and a distinct form of dystonia termed dopa-responsive dystonia.[89] Hemiatrophy of the contralateral cortex may be seen on MRI in some patients.Stiff-Person Syndrome Pathogenesis and Pathophysiology Stiff-person syndrome (SPS) is believed to be an idiopathic disorder in some patients and an autoimmune disorder with functional impairment of spinal neurons due to antibodies directed against the enzyme glutamic acid decarboxylase (GAD) in others.[90] This enzyme is essential for the conversion of glutamic acid to GABA, an inhibitory neurotransmitter found throughout the central nervous system.[91] In a paraneoplastic form of SPS, amphiphysin, a protein associated with synaptic vesicles, has been implicated, and this product's gene has been mapped to 7p13-14.[92] Neurophysiological studies show continuous excessive firing of the motor unit, suggesting that the disorder is due to disinhibition of the descending pathways to the Renshaw cells or gamma motor system.[93] Autopsy information, albeit limited, has failed to demonstrate any abnormalities in the brain stem, spinal cord, peripheral nerve, or muscle.Epidemiology and Risk Factors The disorder is more common in women and is frequently associated with other autoimmune disorders (diabetes mellitus, thyroiditis, myasthenia gravis, pernicious anemia, and vitiligo).[93]Clinical Features and Associated Disorders Typically, SPS patients present with painful muscle cramps and severe lordosis secondary to chronic spasm of the paraspinal muscles. Although predominantly a disease of the axial muscles, cranial involvement has been reported in 25% of patients, and spread to the proximal limbs occurs. Examination reveals marked lumbar and thoracic muscle spasms. Stress or exertional activity may provoke painful spasms that may last for hours. Because of hypertonicity, the gait may resemble that of a tin soldier (Video 238, Stiff Person Syndrome).Differential Diagnosis Among the primary differential diagnoses are dystonia and orthostatic tremor. In both instances, patients may complain of tight cramping muscles and pain, especially when standing. Other rare conditions resembling SPS include tetanus, progressive encephalomyelitis with rigidity, and Isaac's syndrome. Tetanus secondary to infection with Clostridium tetanii is usually associated with a laceration injury and progresses from focal muscle spasm at the site of inoculation to bulbar and generalized spasms. Progressive encephalomyelitis usually begins with pain and sensory changes, and in these patients, a paraneoplastic disorder is possible. Isaac's syndrome is often familial and is associated with peripheral neuropathy, but most important, it usually causes more symptoms in the appendicular muscles than in the axial ones.Evaluation Electromyographic demonstration of continuous motor unit activity is essential to confirm the diagnosis of SPS. The presence of reduced motor activity after benzodiazepine administration is also important. Diagnostically, spinal fluid analysis may reveal increased immunoglobulin or oligoclonal bands, and the presence of GAD antibodies is helpful in confirming the autoimmune form of this diagnosis.Management Treatment is based on controlling rigidity; diazepam (20 to 300mg/day) is the most effective medication for this purpose. Baclofen, clonazepam, valproic acid, and clonidine have been reported to improve symptoms. The role of treatment for autoimmune conditions, such as plasmapheresis, corticosteroids, or azathioprine, has yet to be defined, but high-dose intravenous immunoglobulin has been found to be an effective, albeit costly, treatment.[94] Intrathecal baclofen and botulinum toxin may also be beneficial, but because of the rarity of this syndrome, controlled clinical trials of these drugs for this purpose have not been undertaken. Although these patients may be in pain, extreme caution must be used in mixing narcotic medications with benzodiazepine derivatives, especially if the patient's spasms induce respiratory acidosis because of the rigidity of the diaphragmatic muscles.Prognosis and Future Perspectives Without treatment, SPS progresses to total disability related to generalized rigidity and secondary musculoskeletal deformities. The pathogenetic autoimmune mechanisms remain to be elucidated.