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}
John Cottingham [log in to unmask]
