RESEARCH: Olivopontocerebellar Atrophy (OPCA)

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Neurology

Volume 46 . Number 5 . May 1996

Copyright © 1996 American Academy of Neurology

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Views & Reviews

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The relationship of multiple system atrophy to sporadic olivopontocerebellar

atrophy and other forms of idiopathic late-onset cerebellar atrophy

Sid Gilman MD

Niall P. Quinn MD

From the Department of Neurology (Dr. Gilman), University of Michigan, Ann

Arbor, MI; and the University Department of Clinical Neurology (Dr. Quinn),

Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

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Received September 22, 1995. Accepted in final form October 16, 1995.

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Address correspondence and reprint requests to Dr. Sid Gilman, Department of

Neurology, University of Michigan, Taubman Center 1914/0316, 1500 East

Medical Center Drive, Ann Arbor, MI 48109-0316.

Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative

disease of undetermined cause characterized clinically by combinations of

cerebellar, pyramidal, extrapyramidal, and autonomic disorders. [1] [2] Many

patients with MSA initially develop extrapyramidal symptoms and later

experience autonomic disturbance or cerebellar features, or both; others

start with autonomic disturbance, and some first manifest cerebellar

symptoms and later develop autonomic or extrapyramidal features. Many

patients develop only extrapyramidal and autonomic symptoms, but in most of

these cases, subsequent neuropathologic studies also demonstrate

degenerative changes in the cerebellum and brainstem. [3] [4] The term MSA

encompasses striatonigral degeneration (SND), the Shy-Drager syndrome (SDS),

and many cases of sporadic olivopontocerebellar atrophy (sOPCA). Autopsy

examination discloses neuronal loss and gliosis within some or all of the

following structures: inferior olives, pons, cerebellum, substantia nigra,

locus ceruleus, striatum (mainly putamen), and the intermediolateral columns

and Onuf's nucleus of the spinal cord. [5]

Recently there have been descriptions of distinctive neuropathologic

features of MSA consisting of oligodendroglial [6] [7] [8] [9] [10] [11] and

neuronal [12] [13] [14] intracytoplasmic and intranuclear argyrophilic

inclusions containing accumulations of tubular structures. The glial

cytoplasmic inclusions (GCIs) are present in all MSA brains, regardless of

whether the patients were diagnosed in life as having SND, SDS, or

sOPCA-type MSA. [6] [14] [15] In contrast, GCIs were not initially [6] found

in a large number of neurologic controls, including patients with

Parkinson's disease, progressive supranuclear palsy (PSP), and

Machado-ph disease. However, a recent report [16] indicates that,

although characteristic of MSA, the presence of GCIs is not specific to this

disease. Thus, although GCIs were found in all of a series of 56 MSA brains

examined, they were also found in 3 of 7 cases with corticobasal

degeneration and in 2 of 18 with PSP. They were also present in 2 (of 22)

patients with hereditary OPCA [7] [17] (including 1 patient with the SCA-1

mutation [17] ) and in a patient with chromosome 17-linked dementia. [18] In

this context, the analogy with Lewy bodies in idiopathic Parkinson's disease

(IPD) is pertinent. Most authorities consider that the brains of all

patients with IPD contain Lewy bodies in pigmented brainstem nuclei.

Nevertheless, not all patients with Lewy bodies in CNS structures

necessarily had IPD in life. For example, 5 to 10% of elderly control brains

have incidental Lewy bodies (which may, nevertheless, often represent

presymptomatic IPD), and they are also found in about 10% of MSA brains.

[19] As with IPD, therefore, a pathologic diagnosis of MSA has to

incorporate an appropriate clinical history, together with the presence,

nature, and distribution of both cell loss and inclusions. The finding of

numerous GCIs in postmortem CNS tissue of patients with MSA adds a further

element to the pathologic diagnosis of MSA in addition to the previously

accepted findings of neuronal loss and gliosis in a common set of CNS

structures.

The genetic basis of a number of hereditary forms of cerebellar degeneration

has been elucidated recently, and reviewed by Rosenberg. [20] In the absence

of genetic markers, however, the nosology of the conditions that can present

initially as sporadic idiopathic late (i.e., adult)-onset cerebellar ataxia

(ILOCA) [21] remains problematic. A " pure " cerebellar syndrome occurs in

patients who have progressive degeneration restricted to the cerebellum and

olives in the absence of brainstem atrophy elsewhere. Conventionally, and

somewhat misleadingly, this combination has been called cerebellar cortical

atrophy (CCA) when sporadic [22] or when inherited as a dominant trait, [23]

and olivocerebellar atrophy when inherited as a recessive trait. [24]

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OPCA is a collective describing a number of progressive neurologic disorders

that have in common neuronal degeneration and gliosis in the inferior

olives, pons, and cerebellum. [25] [26] [27] [28] [29] The seemingly

universal presence of GCIs in the sporadic (sOPCA) type of MSA, together

with their rarity in inherited OPCA, also provides further justification for

separating sporadic from hereditary OPCA. Thus, sOPCA is distinct from

dOPCA, and many of the former are examples of MSA.

The differentiation of patients with CCA from those with OPCA on clinical

grounds early in their course is difficult. Thus, the finding of signs of

cerebellar dysfunction in the absence of other signs or symptoms may

initially suggest CCA, but does not rule out the possibility of early OPCA.

Similarly, the absence of brainstem atrophy in anatomic imaging studies does

not rule out the possibility that brainstem atrophy will later become

apparent, [30] or that at autopsy examination pathologic changes will be

found in the brainstem compatible with the diagnosis of sOPCA. Similarly,

apparent brainstem (or cerebellar) atrophy on imaging studies is not

uniformly confirmed at autopsy. When such patients develop other clinical

features, this usually indicates that the patient has sOPCA but, contrary to

the title of a recent editorial, [31] we do not know whether all patients

with sOPCA necessarily have MSA. Thus, the additional presence of pyramidal

and even extrapyramidal signs may indicate sOPCA, but autonomic failure or a

pathologic sphincter EMG are currently considered necessary to make a

clinical diagnosis of probable sOPCA-type MSA. [32]

At present it is presumed, but not established, that GCIs are not

characteristic of CCA. It is also currently unclear what proportion of

sporadic patients with cerebellar degeneration plus pyramidal or

extrapyramidal signs, or evidence of brainstem atrophy, have OPCA, and how

many of them will develop autonomic failure, indicating that they in fact

have MSA. If some of these patients are not destined to develop the clinical

features of MSA, it would be helpful if these individuals could be

identified early in the course of their disease, since MSA is a relentlessly

progressive disorder leading to severe incapacity and a limited life

expectancy. [33] It would also be helpful to know whether they

characteristically have GCIs at neuropathologic examination.

Currently we suggest that, in sporadic adult-onset cases, when cerebellar

signs are unaccompanied by evidence of pyramidal, extrapyramidal, or

autonomic features, there is no justification for using the term OPCA.

Instead, we propose that such cases should be labeled ILOCA, a term that

makes no presumptions about the presence or absence of extracerebellar

pathology. Conversely, the development of additional pyramidal and

extrapyramidal features rules out CCA and indicates sOPCA. Those patients

with additional autonomic failure represent a form of MSA and, accordingly,

their brains, in addition to olivopontocerebellar pathology, will also

contain GCIs and usually show degeneration in striatum, nigra, and the

intermediolateral cell columns or Onuf's nucleus in the spinal cord. At

present, the best investigations for supporting a diagnosis of sOPCA-type

MSA are cardiovascular autonomic function tests and the external urethral or

anal sphincter EMG; [34] either test, however, may be normal in MSA, [35] or

may change from normal to abnormal during the course of the disease, and an

abnormal sphincter EMG is also often found in PSP. [36] Finally, it remains

to be determined whether, at the stage at which the only clinical label that

can be attached is ILOCA, structural (MRI) [37] or functional (PET) [38]

[39] [40] imaging evidence of additional extracerebellar involvement can be

used to separate patients with CCA from those with sOPCA, or to distinguish

between sOPCA subjects who have MSA and any who do not.

The preliminary classification and diagnostic predictions presented in this

review are based on currently available evidence. Whether or not they stand

the test of time depends critically upon meticulous clinicopathologic

correlation, which should be secured whenever possible.

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