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:
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 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).
Number of
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 with severe dementia;
PD/ALS = Parkinson's disease with motor neuron disease;
PSP = progressive supranuclear palsy;
SDS = Shy-Drager syndrome;
SND = strialonigral degeneralion
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Secondary parkinsonism 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 multiple 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 pseudodegenerative 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.
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
Corticobasal ganglionic degeneration
Autosomal dominant Lewy body disease
Alzheimer's disease
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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 ophthalmoparesis (progressive supranuclear palsy); dysautonomia (Shy-Drager syndrome); 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.
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 + +- +- +- - - - -
+ = Symptom usually associated with this syndrome
- = Symptom not usually associated with this syndrome
+- = Symptom can be either present or not present
ADP = Alzheimer's disease with parkinsonism
CBGD = corticobasal gangtionlc degeneralion
OPCA = olivopontocerebellar atrophy
PD = Parkinson's disease
PDCG/ALS = parkinsonism-dementia-amyotrophic laleral sclerosis complex of Guam
PSP = progressive supranuclear palsy
SDS = Shy-Drager syndrome
SND = strialonigral degeneration
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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 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 are 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 producing blepharospasm, and over one third had apraxia of eyelid opening, eyelid closure, or both.[52] Although some [66] have suggested that these lid abnormalities are due to involuntary supranuclear inhibition of levator palpebrae, the intermittent inability to open the eyes is analogous to the parkinsonian phenomenon of sudden transient freezing; hence we prefer the term 'lid freezing'.
In their original monograph, Steele, Richardson, and Olszewski[108] indicated that mild dementia was present during early stages of the disease. Although some investigators report severe cognitive impairment in this population,[91] others attribute these deficits, at least in part, to poor visual processing.[22,52,95] Despite a relative preservation of short-term memory,[70] subcortical dementia with deficits in tasks requiring sequential movements, conceptual shifts, or rapid retrieval of verbal knowledge may be seen.[41,91]
Electrophysiologic studies were helpful in documenting abnormalities such as sleep difficulties and seizures. Polysomnographic evaluation of 10 patients with moderate to severe PSP revealed marked sleep abnormalities, and all had significant periods (2 to 6 hours) of insomnia.[2] Sleep problems were correlated with worsening dementia. In a review of 62 patients seen over a 9-year period, Nygaard et al [84] noted seizures in seven patients and suggested a higher than expected frequency of seizures in this population. This was not our observation, but the relatively high frequency of seizures reported by Nygaard et al [84] may be secondary to cortical infarcts. Multi-infarct PSP may be difficult to differentiate clinically from the more common idiopathic variety.[19,109] Abnormalities in motor or sensory evoked potentials have been found in eight of l3 patients with the clinical diagnosis of PSP.[1]
The typical findings on computed tomographic (CT) or magnetic resonance imaging (MRI) scans of patients with PSP include generalized and brain stem atrophy.[109] A higher than expected prevalence of stroke risk factors and a multi-infarct state were noted in patients with PSP as compared with Parkinson's disease.[19] One cause for a subgroup of PSP might be small vessel disease producing subcortical ischemia with reduction of regional cerebral blood flow, cerebral hypometabolism, and a multi-infarct state.[24] MRI in patients with PSP, MSA, and other parkinsonian syndromes was associated with putamenal hypointensity on T2 imaging, but this finding is less consistently noted in PSP than in the other parkinsonism plus syndromes.[18,109] PSP is more often associated with midbrain atrophy. Positron emission tomography (PET) scanning has revealed decreased metabolic activity in the caudate, putamen, and frontal cortex. [7,24,37] Uptake of 6-18F-fluorodopa is usually reduced in patients with PSP but may be normal in early stages. [6] This suggests that the parkinsonian findings in early PSP are related more to postsynaptic receptor changes rather than loss of presynaptic dopamine terminals. In another study, 18F-dopa uptake was markedly reduced in the caudate as well as in the anterior and posterior putamen of patients with PSP. [9] In contrast, the uptake was reduced only in the posterior putamen in patients with Parkinson's disease.
The motor, neurobehavioral, and neuro-ophthalmic findings seen in patients with PSP reflect marked neuronal degeneration in the basal nucleus of Meynert, pallidum, subthalamic nucleus, superior colliculi, mesencephalic tegmentum, substantia nigra, locus ceruleus, red nucleus, reticular formation, vestibular nuclei, cerebellum, and spinal cord.[57,107,108,116] Cholinergic neurons were found to degenerate particularly in the Edinger-Westphal nucleus, rostral interstitial nucleus of Cajal (possibly contributing to the extensor nuchal rigidity), medial longitudinal fasciculus (contributing to vertical gaze palsy), superior colliculus, and pedunculopontine nucleus. [57,116] Microscopic examination reveals neurofibrillary tangles, granulovacuolar degeneration, gliosis, and rare Lewy bodies. [107,108] The neurofibrillary tangles in patients with PSP differ from those seen in patients with Alzheimer's disease and other neurodegenerative disorders in that PSP tangles consist of 15 nm staight tubules rather than 20- to 24-nm wide paired helical filaments. [55] Rarely patients with clinical presentation nearly identical to PSP were reported to have the pathologic picture of pallidonigroluysial atrophy.[63]
The most striking neurochemical abnormality found in PSP brains is a marked reduction in the striatal dopamine, dopamine receptor density, and choline acetyl transferase activity and loss of nicotinic, rather than muscarinic, cholinergic receptors in the basal forebrain.[90,114] In addition, glutamate has been found to be increased in the striatum, pallidum, nucleus accumbens, and occipital and temporal cortex. Normal dopamine levels in the nucleus accumbens suggest that the mesolimbic system is relatively spared. In contrast to patients with Parkinson's disease, glutathione was found to be increased in the substantia nigra of patients with PSP.[89]
Although mild improvement in parkinsonian symptoms may be noted with levodopa or dopamine agonists in the early stages, most patients with PSP fail to improve with these drugs.[46] The most likely reason is that in PSP there is a marked loss of the postsynaptic, particularly the D2, receptors, secondary to the loss of the postsynaptic striatal neurons.[90] Idazoxan, an experimental potent and selective alpha2 presynaptic inhibitor that increases norepinephrine transmission, was shown in a double-blind crossover study to improve motor function in nine patients with PSP. [28] In addition, physostigmine was shown to improve cognitive and attention deficits in seven patients with PSP. [60] Other drugs, including the anticholinergics, methysergide, and amitriptyline, although anecdotally reported to be beneficial, were generally disappointing.[83] Blepharospasm, with or without eyelid freezing, can be effectively treated with botulinum toxin injections. [51]
First coined by Graham and Oppenheimer in 1969, [42] the term 'multiple system atrophy' (MSA) describes a syndrome with features overlapping with Shy-Drager syndrome, striatal nigral degeneration, and olivopontocerebellar atrophy.
The less specific term 'multiple system degeneration' refers to any and all of the primary neuronal degenerations.[94]
MSA is characteuzed clinically by the combination of parkinsonian, pyramidal, cerebellar, and autonomic symptoms. In a recent review of 188 pathologically proved cases of MSA, 28% of patients had all four systems involved; 18% had the combination of parkinsonism, pyramidal, and autonomic findings; 11% had parkinsonian, cerebellar, and autonomic findings; another 11% had parkinsonism and dysautonomomia; 10% had only parkinsonism; and parkinsonism was absent in 11% ot all patients.[94]
The age at onset is typically between 40 and 69 years. The spectrum of pathologic changes includes cell loss and gliosis in the striatum (caudate and putamen), substantia nigra, locus ceruleus, inferior olives, pontine nuclei, dorsal vagal nuclei, Purkinje cells of the cerebellum, and the intermediolateral cell columns and Onuf's nucleus of the spinal cord. Involvement of at least three of these areas, including putamen and substantia nigra, is required for the pathologic diagnosis of MSA.[94]
The presence of glial cytoplasmic inclusions, particularly in the oligodendrocytes, in all autopsied brains of patients with Shy-Drager syndrome (SDS), striatonigral degeneration (SND), and olivopontocerebellar atrophy (OPCA) but not in control brains, strongly argues in support of the notion that these three disorders should be regarded as variants of the same disease entity, namely MSA.[58,82,87,94] The variable clinical and pathologic expression, however, suggests that MSA is not necessarily a single etiologic entity. Therefore until a disease-specific marker is identified, the apparent distinction between the different disorders will continue to be blurred and artificial, and one must rely on classic descriptions to attempt to separate these disorders.
Although it is difficult to clearly differentiate the three types of MSA by clinical and even pathologic criteria, it is well accepted that MSA represents a disorder or a group of disorders distinct from Parkinson's disease. In contrast to Parkinson's disease, which is inherited in at least 15% of cases, MSA occurs sporadically. Therefore nongenetic etiology is most likely responsible for MSA and its three major subcategories.
In their initial report. Shy and Drager [103] described two men who presented with symptoms of orthostatic syncope, impotence, and bladder dysfunction. These men later developed parkinsonian features, including gait disturbance, mild tremor, dysarthria, constipation, and bowel and bladder incontinence.
The diagnosis of SDS should be strongly considered when a parkinsonian patient develops symptoms of orthostatic light-headedness incontinence, sexual impotence, and other autonomic symptoms.
This disease appears to be more common in men than in women with symptoms first beginning in the 6th decade; death usualty occurs 7 to 8 years after the initial symptoms and approximately 4 years after onset of neurolugic impairment.[78] Patients with SDS usually die from aspiration, sleep apnea, or cardiac arrhythmia.
In addition to bradykinesia, slow and shuffling gait, and postural instability, patients with SDS otten exhibit cerebellar ataxia, amyotrophy, corticospinal tract signs, and iris atrophy.[103] Emotional lability, respiratory disturbance including severe obstructive sleep apnea, and vocal cord paralysis with stridor are often found in more advanced stages of the disease.[81] Dystonia is rare in patients with SDS.[98]
In addition to certain tests of autonomic function, patterns of plasma levels of catecholamines and their metabotites may be helpful in differentiating the various forms of autonomic failures.[12,38] In a study comparing polysomnograms of seven patients with SDS to seven control patients, significant obstuctive sleep apnea without oxygen desaturation was seen in four of the five nontracheotomized patients with SDS; three of these patients later died suddenly during sleep.[81] MRI in patients with SDS often reveals areas of decreased signal bilaterally in the posterolateral putamen on T2-weighted imaging.[88] ln a study of three patients with SDS, the two with more advanced stages of the disease showed reduced l8F-6-fluorodopa uptake, indicating nigrostriatal dysfunction.[5]
Pathologic changes seen in patients with SDS often overlap with other MSA disorders (olivopontocerebellar atrophy. striatonigral degeneration).[94] In addition to the typical findings of MSA, there is a marked loss of neurons in the lateral horns of the spinal cord, but these pathologic changes correlate poorly with dysautonomia.[41] Substance P-like immunoreactivity was markedly decreased in laminae I plus II of 4th thoracic and 3rd lumbar spinal cord segments in 10 of 11 patients with SDS, and all had a decrease in small and large myelinated fibers in the 4th thoracic ventral roots.[111] Neurochemical changes seen in patients with SDS are similar to those in pure autonomic failure (PAF), and some suggest that SDS represents a progression from PAF.[78,92] Pharmacologically these two conditions may be distinguished by supine and standing plasma norepinephrine levels. In patients with PAF, both standing and supine norepinephrine levels are low, whereas in patients with SDS, only the standing value is diminished. Besides decreased norepinephrine, acetylcholine and cerebrospinal fluid acetylchotinesterase levels are also reduced.[93]
Parkinsonian symptoms accompanying SDS are difficult to treat because dopaminergic drugs frequently exacerbate the already prominent symptoms of orthostatic hypotension. The addition of liberal salt, fludrocortisone, and Jobst stockings may improve standing blood pressures. Because these measures increase the risk of supine hypertension, patients should be instructed to place their beds in the reverse Trendelenburg position. ln a double-blind, placebo-controlled study of 97 patients, with various causes of autonomic failure, including 18 with SDS and 22 with Parkinson's disease, midodrine, a peripheral alpha-adrenergic agonist, was found to be effective in the treatment of orthostatic hypotension.[53] Other measures employed to increase standing blood pressure include indomethacin, ibuprofen, pseudoephedrine and other sympathomemetics, caffeine and dihydroergotomine, yohimbine, and norepinephrine precursors.[79]
In a recent review of 10 patients, ranging in age from 47 to 50 years, with autopsy-proved SND, five were misdiagnosed as Parkinson's disease, largely because of good response to levodopa.[21] Features helpful in differentiating SND from other parkinsonian disorders included early-onset falling, severe dysarthria and dysphonia, excessive snoring and sleep apnea, respiratory stridor, hyperreflexia. and extensor plantar responses. Cerebellar or pyrramidal tract signs were present in two patients each, whereas autonomic symptoms were present in seven. Duration of illness ranged from 3 to 8 years, and no difference in survival was seen in levodopa responders as compared with nonresponders.
Neuroimaging, specifically designed to assess putamenal integrity, may prove helpful in differentiating this disease from Parkinson's disease and in predicting levodopa response.[18,109] PET scanning revealed decreased striatal and frontal lobe metabolism.[10,16]
At autopsy, the putamen is most prominently affected with neuronal cell loss and deposition of iron, producing brownish pigmentation.[85] There is also degeneration of the substantia nigra, and putamenal degeneration correlates with substanlia nigra cell drop-out. Lewy bodies or neurofibrillary tangles are not common. Goto et al [10] noted selective degeneration of the metenkeplialin-containing neurons in the putamen and globus pallidus externa, with relative preservation of the caudate nucleus. Previous studies report low levels of dopamine and increased dopamine beta-hydroxylase activity in the midbrain. Recently vasomotor impairment in patients with SND was attributed to selective loss of tyrosine hydroxylase-immunoreactive neurons in the Al and A2 regions of the medulla oblongata.[74]
The term 'olivopontocerebellar atrophy' was introduced by Dejerine and Thomas in 1900 to describe a group of heterngeneous disorders characterized clinically by the combination of progressive parkinsonism and cerebellar ataxia and pathologically by neuronal loss in the ventral pons, inferior olives, and cerebellar cortex.[4] OPCA may be inherited, usually in an autosomal dominant pattern, but only sporadic OPCA is classified as a form of MSA, along with SDS and SND.[4,94] Berciano[4] recently reviewed 133, 68 familial and 65 sporadic, pathologically proved cases of OPCA. Although there was nearly 2 to 1 male preponderance in the familial OPCA, no gender difference was found in the sporadic form. Age at onset is more variable in this disorder than in the other parkinsonism plus syndromes, ranging from infancy to 66 years. Cerebellar ataxia is the presenting symptom in 73% of all patients; 8.2% begin with parkinsonian symptoms, and the remainder present with nonspecific symptoms. Dementia, gaze impairment, dysarthria, dysphagia, incontinence, and upper and lower motor neuron signs usually become apparent within a few years after onset. In one large Japanese family with OPCA, the oculomotor abnormalities consisted of limitation of up-gaze and convergence, horizontal gaze nystagmus relative sparing of pupil reactivity, and loss of vestibulo-ocular responses.[102] Autopsy of one patient in this series revealed degeneration of the oculumolor nucleus with sparing of the Edinger-Westphal nucleus. Neuropsychologic evaluation in patients with clinically diagnosed OPCA revealed emotionality anxiety and a tendency toward depression without cognitive decline.[14] Other studies. however, noted some degree of dementia in up to 80% of patients.[4]
CT and MRI scans in patients with OPCA typically show pancerebellar and brain stem atrophy, enlarged 4th ventricle and cerebellopontine angle cisterns, and demyelination of transverse pontine fibers on T2-weighted MRl images.[4] PET scans show reduced metabolic rate in the brain stem and cerebellum.[36] In one study, 73% of brain stem auditory evoked responses were abnormal.[104]
Pathologic studies show a wide variation of neuronal damage. The fundamental pathologic change in OPCA is loss of Purkinje cells in the cerebellar cortex, particularly in the vermis.[56] In addition to cerebellar atrophy, substantia nigra degeneration and depigmentation, neuronal loss in other brain stem nuclei, and demyelination of corticospinal tracts and posterior columns are seen.[62] Recently clear, argyrophilic, introcytoplasmic structures that react with antitubulin antibodies were demonstrated in nearly all patients with OPCA.[58,82,87] These glial cytoplasmic inclusions are located prominently in the white matter of the putamen, internal capsule, cerebral peduncles, and substantia nigra. They were found in the brains of all 11 patients diagnosed with MSA but not in any of the other 284 brains from patients with different neurologic diseases.[87] All of Nakazato et al's [82] six patients with sporadic OPCA were found to have 'oligodendroglial cytoplasmic inclusions', whereas one of two brains with the hereditary forms showed similar lesions. The concurrent cellular and myelin destruction was suggested to be caused by generation of oligodendroglial cytoplasmic inclusions in affected cells triggering a complement activated secondary demyelinating response.[4] The observation of oligodendroglial cytoplasmic inclusions in nearly all cases of MSA suggest the possibility that the three forms of MSA are related and that the disease process originates in the myelin or axons.
Detailed morphometric and biochemical studies correlated reductions in aspartic and glutamic acid with Purkinje cell loss in the cerebellar cortex and with neuronal cell loss in the inferior olives (aspartic acid).[1] In addition, quisqualate receptors appear to be decreased, whereas quinolinic acid metabolism is increased.[61,73] The increased quinolinic acid phosphoribosyl-transferase activity in OPCA was interpreted as a compensatory mechanism designed to protect quinolinic acid-sensitive granule cells.[61] In addition, low glutamate dehydrogenase activity was found in most but not all studies; however, this defect probably is not disease-specific.[4,65] Recently mitochondrial DNA abnormalities were postulated to be important in the pathogenesis of OPCA in some patients.[112]
In 1968, Rebeiz et al [96] reported three patients of Irish decent with parkinsonism, myoclonus, supranuclear palsy, and apraxia who were found at autopsy to have 'corticodentatonigral degeneration with neuronal achromasia', Recently this complex neurobehavioral disorder has become increasingly recognized. Its most striking features include marked asymmetry of involvement. apraxia. and parkinsonism. In their review of 15 patients, Riley et al [97] categorized the typical features of what is now termed 'corticobasal ganglionic degeneration' into movement disorders (akinesia, rigidity, p&~stural instability, limb dystonia, cortical myoclonus, and postural/intention tremor), cortical sensory loss, apraxias (ideational and ideomotor), and the 'alien limb' phenomenon. Dementia is a late feature of CBGD. In our experience, limb contractures, often preceded by the alien hand phenomenon, are more common in this condition than in any other parkinsonism plus syndrome.[17]
Neurologic examination often reveals hyperreflexia, Babinski signs, ocular motility disturbance, and bulbar impairment but no ataxia. Of the 15 patients reported by Riley et al,[97] the age at onset ranged from 51 to 71 years, and men were more commonly affected than women (3:2). Two patients died 7 and 10 years after disease onset.
CT scans were abnormal in 14 of the 15 patients in one series; eight had asymmetrical parietal lobe atrophy corresponding to the most affected side, and six had bilateral parielal atrophy.[97] PET scanning reveals reduced fluorodopa uptake in the caudate and putamen and cortical hypometabolism especially in the superior temporal and inferior parietal lobe.[100]
Pathologic features in this disease include neuronal degeneration in the precentral and postcentral cortical areas with achromatic neural inclusions seen not only in the cortex, but also in the thalamus, subthalamic nucleus, red nucleus, and substantia nigra.[31,69] Dopamine concentration throughout the striatum and substantia nigra was reduced when compared with age-matched controls.[97] To date, no effective treatment has been found, although the dystonia may improve with botulinun' toxin.
Dementia occurs in approximately 20% of patients with Parkinson's disease, but this usually develops later in the course of the illness.[91] Cognitive decline seems to be more prominent in patients with the PIGD form of Parkinson's disease as compared with the more typical tremor variety.[25,54] Alternatively extrapyramidal signs were reported in about one third of patients with Alzheimer's disease.[77] Diffuse Lewy body disease (DLBD), considered by some a variant of Alzheimer's disease or an overlap between Alzheimer's disease and Parkinson's disease, is now well recognized, but its clinical and pathologic criteria have not yet been fully defined.[11,13]
Differentiation of Alzheimer's disease and DLBD on clinical findings alone may he difficult. Crystal et al [13] reviewed the course of six DLBD, three Alzheimer's disease and one Parkinson's disease patient with autopsy-confirmed diagnosis and found that patients with DLBD were more likely to have gait impairment, rigidity, and resting tremor early in the course of the illness.
In another study of 30 patients with DLBD, psychosis and dementia were often found to precede parkinsonism.[11] Agitation, hallucinations, delusions, and abnormal electroencephalograms were more common in patients with DLBD than in the patients with Alzheimer's disease.[11] No differences were found with respect to age, gender, or disease progression between autopsy-proved cases of Alzheimer's disease and DLBD.[30] On neurologic examination, rigidity, bradykinesia, and action tremor were more frequent in the patients with DLBD, whereas impairment of up-gaze was surprisingly more common in the Alzheimer's disease group.
The differentiation between DLBD and the other parkinsonism plus syndromes, particularly PSP, can be particularly difficult when a patient with parkinsonism and dementia is also found to have oculomotor disturbance, as noted in some patients with DLBD.[68]
There are no diagnostic studies that call reliably differentiate between Parkinson's dementia, Alzheimer's disease, and DLBD. PET scanning showed no differences between Alzheimer's disease and DLBD.[113] In one series of 37 patients with Alzheimer's disease, however, concentrations of cerebrospinal fluid homovanillic acid and biopterin were noted to be significantly lower in the patients with Alzheimer's disease with extrapyramidal signs as compared with the group without extrapyramidal signs matched for age and dementia severity.[59]
About one third of patients with Alzheimer's disease have Lewy bodies at autopsy, but patients with DLBD, seem to have a greater neuronal loss in the substantia nigra, substantia inominata, and locus ceruleus and have lower cortical choline acetyltransferase levels than the patients with Alzheimer's disease.[30] Besides diffuse distribution of Lewy bodies throughout the basal forebrain, brain stem and hypothalamus, a paucity of neurofibrillary tangles in DLBD helps to diffrentiate DLBD from Alzheimer's disease.[11,30] Although Gibb et al [30] found no Lewy bodies in the hippocampus or cortex, Burkhardt et al [11]reported 'Lewy-like' bodies in the limbic system and neocortex. Others report different antigenic coniponents of the Lewy body in DLBD and Parkinson's disease, with tau protein being present only in the dementing disorder.[22]
Pathologic changes in Alzheimer's disease have been well characterized: Neuritic plaques containing beta-amyloid protein were demonstrated in both sporadic and familial Alzheimer's disease, and neurofibrillary tangles (NFTs) consist of the paired helical filament tau. The abnormal phosphate substitution is thought to interfere with normal neurotubule formation.[64] In patients with Alzheimer's disease, NFTs are found predominantly in the hippocampus, but extrapyramidal signs are more likely associated with increased NFTs in the substantia nigra.[32] Tabaton et at[110] report antigenic similarities between the NFTs of PSP and Alzheimer's disease when derived from neurons of similar populations and postulated that anatomic location rather than disease specificity is the deterinining factor for antigenicity. In a study contrasting Parkinson's dementia and Alzheimer's disease, de Ia Monte et al[80] found similar reductions in the cross sectional areas of the globus pallidus-putamen; greater cell loss was noted in the amygdala of Parkinson's dementia brains, however, whereas Alzheimer's disease was associated with prominent cortical atrophy. The relative frequencies of Lewy bodies, neuritic plaques, and NFTs, however, were not discussed.
The combination of parkinsonisn, dementia, and motor neuron disease was first noted in a population of Guam.[44] In a review of 363 Chammoro and three Filipino immigrants with this disease, men were affected twice as frequently as women, but no differences in age of onset (57 years) or death (62years) were seen between the genders.[115] Besides parkinsonism, supranuclear ocular motility disorder was reported in all 37 patients in one series.[67] Patients with parkinsonism usually present later than those with amytrophic lateral sclerosis, possibly because patients presenting with motor neuron disease do not survive long enough to develop extrapyramidal symptoms.[114] Furthermore basal ganglia signs may be masked by the motor neuron disease.
PET scanning in patients with the parkinsonian form of this disease reveals decreased presynaptic l8F-6-fluorodopa uptake similar to patients with Parkinson's disease, whereas those with amyotrophic lateral sclerosis have an intermediate picture between Parkinson's disease and control populations, suggesting a preclinical lesion.[105]
The finding of increased frequencies of this neurodegenerative disorder on the island of Guam suggest a possible environmental etiology.[44] The neurotoxin beta-N-methylamino-L-alanine (BMAA), a compound found in the cycad plant and believed to be in high concentrations in flour made from this plant, produces a similar spectrum of neurologic decline in monkeys.[106] An analysis of the BMAA content of cycad flour, however, suggests that the quantities of BMAA normally consumed by the inhabitants of the endemic areas were not sufficient to produce neurologic toxicity.[20] Other hypotheses concerning abnormalities in mineral metabolism and hypomagnesemia or hypocalcemia also have been suggested, but supporting evidence is lacking.[27] Pathologically this condition resembles Alzheimer's disease more than Parkinson's disease; tau-containing NFTs are present particularly in the hippocampus[35,101] and other brain and spinal cord areas.[75] Immunohistochemical studies of autopsied brains of patients with PDCG showed marked reduction in the number of dopaminergic neurons in both the lateral and the medial substantia nigra.[39] Despite marked reduction of nigrostriatal dopamine concentration, the striatal output system was well preserved and glutamate, gamma-aminobutyric acid (GABA), choline acetyltransferase, and serotonin were spared.