DIFFERENTIAL DIAGNOSIS OF PARKINSON'S DISEASE AND THE PARKINSONISM PLUS SYNDROMES Authors: Mark Stacy, MD & J. Jankovic, MD Posted here with permission from Mark Stacy, MD April 7, 1995 Parkinson's disease is an idiopathic, relentlessly progressive, neurologic disorder manifested clinically by tremor, bradykinesia, rigidity, and postural instability. In addition to these four cardinal signs, there are many motor and nonmotor manifestations of Parkinson's disease, including cognitive, sensory, and autonomic disturbances. Within Parkinson's disease, there are different subgroups with relatively specific clinical patterns. For example, several studies have now demonstrated that patients with tremor as the dominant parkinsonian symptom generally have less bradykinesia and slower progression of the disease than those with postural instability and gait difficulty (PlGD) as the dominant features.{54} The PIGD group generally is older, is more likely to be cognitively impaired, and has a more rapidly progressive course than the tremor group. One of the intriguing questions is whether the different subgroups represent variations of the same disease, namely Parkinson's disease, or whether they are etiologically distinct entities. Other still unresolved issues regarding the variable expression of Parkinson's disease include the following questions: (1)Do juvenile (onset before age 21), young-onset (betw'een 21 and 39), and the typical form of Parkinson's disease share common etiology', and (2) is the tremor-dominant form of Parkinson's disease etiologically related to essential tremor?{71} Pathologically Parkinson's disease is defined as a neurodegenerative disorder characterized chiefly by depigmentation of the substantia nigra and by the presence of Lewy bodies. These criteria, however, are too restrictive and ---------------------------------------------------------------------------- >From the Department of Neurology (MS), University' of Missouri, School of Medicine, Columbia, Missouri; and Department of Neurology (JJ), Parkinson's Disease Center and Movement Disorders Clinic, Baylor University College of Medicine, Houston,Texas simple, and they do not take into account the heterogeneous clinical and pathologic presentation of Parkinson's disease and the overlap with other parkinsonian disorders, each with presumably distinct etiology. In the absence of a specific biologic marker for Parkinson's disease, the differentiation of Parkinson's disease from other parkinsonian disorders rests on clinicopathologic criteria that have yet to be rigorously tested and validated. Recent studies have shown that certain populations of neurons are more vulnerable than others and the neuronal loss in Parkinson's disease is not uniform. For example, the ventrolateral part of ihe substantia nigra that projects chiefly to the putamen is more affected than the dorsal part.{29} Although pigmented neurons in the substantia nigra degenerate more than the non pigmented neurons,{86} the other brain stem catecholaminergic neurons seem to degenerate regardless of the degree of melanin pigmentation.{99} Lewy bodies, eosinophilic cytoplasmic inclusions with an unstained halo, represent the typical histologic hallmark of Parkinson's disease. Recent pathologic studies have identified another characteristic, although less specific, inclusion frequently found in the substantia nigra and the locus ceruleus of brains of patients with Parkinson's disease termed 'the pale body'.{33} Because these inclusions are typically found in Parkinson's disease and they are usually absent in the other neuronal degenerations, they are useful in differentiating Parkinson's disease from other parkinsonian disorders. In contrast to Parkinson's disease, brains of patients with pathologically proved multiple system atrophy (MSA){94} were found to have distinct glial cytoplasmic inclusions.{58,82,87} It remains to he proved, however, whether these pathologic hallmarks will be sufficiently specific to differentiate PD, MSA, and the other atypical parkinsonian disorders reliably. Until parkinsonian subgroups can be differentiated either by disease-specific histologic criteria or laboratory tests, the most practical method for separating the different parkinsonian disorders still has to depend largely on previously described clinicopathologic correlations. The vast majority (77.7%) of patients referred to the Baylor College of Medicine Movement Disorders Clinic (BCMMDC) with hypokinetic movement disorders have presumed Parkinson's disease (Table 1). Secondary parkinson- Table 1. ETlOLOGIC CATEGORIES OF PARKINSONISM* Number ot PatIents Percentage Parkinson's disease 1595 77.7 Parkinsonism plus 250 12.2 PSP 154 7.5 SDS 35 1.7 OPCA 23 1.1 CBGD 18 0.9 SND 9 0.4 PD/AD 8 0.4 PD/ALS 3 0.1 Secondary parkinsonism 168 8.2 Heredodegenerative parkinsonism 12 0.6 Unknown 27 1.3 *Baylor College of Medicine. Parkinson's Disease Center and Movement Disorders Clinic (N =2052) CBGD = Corticobasal ganglionic degeneration; OPCA = olivopontocerebellar atrophy; PD/AD parkinsonism wilh seveie dementia; PD/ALS = Parkinson's disease with motor neuron disease; PSP = progressive supranuclear palsy; SDS = Shy-Drager syndrome; SND = strialonigral degeneralion ism is thought to represent 8.2% of all our parkinsonian patients. The causes include environmental exposure (e.g., drugs or toxins) and other factors (trauma, metabolic derangement, infection, stroke, brain tumor). 'Lower body' parkinsonism, a condition in which upper body motor function is relatively preserved while gait is markedly impaired, is often associated with multipte lacunar infarctions and may represent one form of vascular parkinsonism.{23} Hemiparkinsonism-hemiatrophy syndrome occurs in a younger population and is associated with early-onset dystonia, slow progression, and poor response to levodopa. Contralateral cortical hemiatrophy is usually present, and there is often a history of perinatal asphyxia.{34} Medications known to cause parkinsonism include dopamine receptor blocking drugs, such as antipsychotics and antiemetics (e.g., meloclopramide); dopamine depleting drugs, such as reserpine, tetrabenazine, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); and alpha-methyldopa. Drug-induced parkinsonism was noted in 4% of all our parkinsonian patients. Rare causes of parkinsonism include hewdodegenerative diseases, such as Huntington's disease, Wilson's disease, Hallervorden-Spatz disease, and familial basal ganglia calcification (Table 2). These heredodegenerations account for 0.6% of our patients. The second largest group of parkinsonian disorders (12% of all parkinsonian patients seen at the BCMMDC) is classified clinically as 'parkinsonism plus syndromes' and pathologically as 'multiple system degenerations'.{49,50} Patients with these hypokinetic movement disorders share some similarities with patients with Parkinson's disease, but besides the parkinsonian findings, these patients exhibit additional neurologic abnormalities, such as supranuclear ophthalmo- Table 2. CLASSIFICATION OF PARKINSONISM -------------------------------------------------------------------------- Primary (idiopathic) parkinsonism Parkinson's disease Juvenile parkinsonism Secondary (acquired,symptomatic) parkinsonism infectious: postencephalitic, slow virus Drugs:dopamine receptor blocking drugs (antipsychotic. antiemetic drugs), reserpine, tetrabenazine, alpha-methyl-dopa, lithium. flunarizine, cinnarizine Toxins:MPTP, CO, Mn, Hg. CS2, methanol, ethanol Vascular:multi-infarct Trauma:pugilistic encephalopathy Other:parathyroid abnormalities, hypothyroidism. hepatocerebral degeneration. brain tumor, normal pressure hydrocephalus. syringomesencephatia Heredodegenerative parkinsonism Huntington's disease Wilson's disease Hallervorden-Spatz disease Olivopontocerebellar and spinocerebellar degenerations Familial basal ganglia calcification Familial parkinsonism with peripheral neuropathy Neuroacanthocytosis Multiple system degenerations (parkinsonism plus) Progressive supranuclear palsy Shy-Drager syndrome Striatonigral degeneration Parkinsonism-dementia-ALS complex Corticobasat ganglionic degeneration Autosomal dominant Lewy body disease Alzheimer's disease paresis (progressive supranuclear palsy); dysautonomia (Shy-Drager syn- drome); ataxia (olivopontocerebellar atrophy); laryngeal stridor (striatonigral degeneration); combination of apraxia, cortical myoclonus, and 'alien hand' (corticobasal ganglionic degeneration (CBGD); dementia (Alzheimer's disease with parkinsonism (ADP) or diffuse Lewy body disease (DLBD); and dementia coupled with motor neuron disease (parkinsonism- dementia-amyotrophic lateral sclerosis complex of Guam) (Tables 2 and 3). Other features useful in differentiating these disorders from Parkinson's disease include absence or paucity of tremor, early gait abnormality such as freezing, postural instability, pyramidal findings, and poor response to levodopa. The lack of improvement with levodopa or dopamine agonists may be partly explained by fundamental differences in the density of postsynaptic dopamine receptors. These receptors are preserved in Parkinson's disease, but they are usually decreased in the other parkinsonian disorders. This article focuses only on the sporadic (non-genetic) forms of multiple system degenerations. PROGRESSIVE SUPRANUCLEAR PALSY Clinical Aspects First described by Steele, Richardson, and Olszewski,{107,108} the diagnosis of progressive supranuclear palsy (PSP) should be considered in any patient with progressive parkinsonism and ocular motility disturbance. {48,52,72} At BCMMDC, 7.5% of patients with parkinsonism fulfill the clinical criteria for PSP. In a Table 3. DIFFERENTIAL DIAGNOSIS OF PARkINSONISM PLUS SYNDROMES PDCG/ PD PSP SDS SND OPCA CBGD ADP ALS Bradykinesia + + + + +- + +- + Rigidity + + + + + + +- + Gait disturbance + + + + + + +- + Tremor + - - - +- +- + + Ataxta - - +- - + - +- +- Dysautonomia +- +- + +- +- - - +- Dementia +- + +- - - +- + + Dysarthria/ dysphagia +- + +- + + + +- + Dystonia +- +- - +- - + - - Eyelid apraxia - + - +- - +- - - Limb apraxia - - - - - + +- - Motor neuron disease - - +- +- - - - + Myoclonus +- - - - - + +- - Neuropathy - - +- - +- - - - Oculomotility disturbance - + +- - + + +- - Orthostatic hypotension +- +- + +- +- - - - Sleep abnormal +- +- + +- +- - - - Asymmetric find + - - - - + - - Levodopa response + +- +- +- - - - - ADP = Alzheimer's disease with parkinsonism; CBGD = corticobasal gangtionlc degeneralion; OPCA = olivopontocerebellar atrophy; PO = Parkinson's disease; PDCG/ALS = parkinsonism-dementia-amyotrophic laleral sclerosis complex of Guam; PSP = progressive supranuclear palsy; SDS = Shy-Drager syndrome; SND = strialonigral degeneration. review of 126 patients with PSP, we found unsteadiness of gait, frequent falling, monotonous speech, loss of eye contact, slowness of movement and of mentation, sloppy eating habits, and nonspecific visual difficulty to be the most typical presenting features.{52} Similar to Parkinson's disease, PSP occurs more often in men, but its mean age of onset of 63 years is about 1O years later than the onset of Parkinson's disease. Although no well-designed epidemiologic studies have been performed in patients with PSP, one case-control study found that patients with PSP were more likely to live in areas of low population.{15} The earliest and most disabling symptom of PSP usually relates to gait and balance impairment, as a result of which patients frequently fall and sustain injuries. The marked instability is a result of visual-vestibular impairment, axial rigidity, and bradykinesia.{52} In contrast to short and shuffling steps, stooped posture, narrow base, and flexed knees, typically seen in patients with Parkinson's disease, patients with PSP tend to have their knees (and trunk) extended; their gait is stiff and broad based; and instead of turning en bloc, they tend to pivot, which further compromises their balance. Although some patients with PSP appear ataxic, they usually do not exhibit prominent cerebellar findings; hence their ataxia is thought to be of vestibular origin. Pseudobulbar symptoms in patients with PSP arc characterized chiefly by dysarthria, dysphagia, and emotional incontinence. Rigidity, bradykinesia, and hypertonicity of the facial muscles produce deep facial folds and typical worried or astonished facial expression.{48} Speech in patients with PSP is characterized by a spastic, hypernasal, monotonous, low-pitched dysarthria. The speech rate may be slow or fast, and some patients have severe palilalia and stuttering. An 'apraxia of phonation' was previously reported in one patient who was aphonic except during periods of excitement or during sleep.{47} In contrast, some patients have almost continuous, involuntary vocalizations, including loud, groaning, moaning, humming, and grunting sounds.{52} Progressive dysphagia causes most patients to modify their diet, and some eventually need a feeding gastrostomy to maintain adequate nutrition. As a result of chewing difficulties, inability to look down, and poor hand coordination, patients with PSP are often described as "sloppy eaters. Supranuclear ophthalmoparesis, typically manifested by paralysis of down-gaze, is the most important distinguishing feature of PSP. About one third of patients with PSP complain of blurred vision, diplopia, and eye discomfort, but most eventually lose their ability to read or maintain eye contact.{52} Involuntary persistence of ocular fixation is a typical, although rarely mentioned, feature of PSP. In early stages of PSP, patients may have only mild limitation of voluntary down-gaze, inability to converge, and impaired vertical optokinetic nystagmus. Later, limitation of vertical and then lateral eye movements develops. The ophthalmoparesis can be overcome by oculocephalic (doll's eye) maneuver, but with disease progression and brain stem involvement, vestibuloocular reflexes may be lost, suggesting additional nuclear involvement.{45} Pathologically documented cases of PSP without ophthalmoparesis have been reported.{14} Other atypical cases of pathologically documented PSP include patients with 'pure akinesia'.{76} In a recent review of dystonia in Parkinson's disease, MSA, and PSP, Rivest et al {98} found limb dystonia in pathologically proved cases of PSP to be an uncommon feature, and they regard the 'dystonic' neck extension, a frequently noted sign in patients with PSP, as a form of axial rigidity. Patients with PSP frequently exhibit blepharospasm, with or without 'apraxia' of eyelid opening. In one study, 29% of patients had involuntary orbicularis oculi contractions John Cottingham [log in to unmask]