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Parkinsn Current Topics
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 (between 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 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).
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
--------------------------------------------------------------------------
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.
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
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}
Neurodiagnostic Studies
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 (MRl) 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} (See article on Magnetic Resonance Imaging in Parkin-
sonism in this issue.) 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.
Neuropathology and Neurochemistry
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 atruphy.{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 contrnst to patients with Parkinson's
disease, glutathione was found to be increased in the substantia nigra
of patients with PSP.{89}
Treatment
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 douNe-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}
MULTIPLE SYSTEM ATROPHY
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.
Shy-Drager Syndrome
Clinical Aspects
ln 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 leatures, 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 lightheadedness
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 instabil-
ity, 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}
Neurodiagnostic Studies
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} MRl in patients with SDS often reveals areas of
decreased signal bilaterally in the posterolateral putamen on T2-weigted
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}
Neuropathology and Neurochemistry
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}
Treatment
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 ortho-
static 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}
Striatonigral Degeneration
Clinical Aspects
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.
Neurodiagnostic Studies
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}
Neuropathology
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}
Olivopontocerebellar Atrophy
Clinical Aspects
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}
Neurodiagnostic Studies
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}
Neuropathology and Neurochemistry
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}
CORTICOBASAL GANGLIONIC DEGENERATION
Clinical Aspects
ln 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.
Neurodiagnostic Studies
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}
Neuropathology and Neurochemistry
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.
ALZHEIMER'S DISEASE WITH PARKINSONISM
Clinical Aspects
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 at' overlap between
Alzheimer's disease and l2arkinson'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}
Neurodiagnostlc Studies
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}
Neuropathology and Neurochemistry
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.
PARKINSONISM-DEMENTIA COMPLEX OF GUAM (PDCG)
Clinical Aspects
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.
Neurodiagnostic Studies
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}
Neuropathology and Neurochemistry
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.
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Address reprint requests to Joseph jankovic, MD Department of Neurology Baylor College of Medicine 6550 Fannin, 1801 Smith Tower Houston, TX 77054
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