RESEARCH: Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy

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Neurology

Volume 55 . Number 4 . August 22, 2000

Copyright © 2000 American Academy of Neurology

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Articles

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Evolution of sporadic olivopontocerebellar atrophy into multiple system

atrophy

S. Gilman MD, R. Little PhD, J. Johanns MS, M. Heumann BA, K. J. Kluin MS,

L. Junck MD, R. A. Koeppe PhD, H. An MS

>>From the Department of Neurology (Drs. Gilman and Junck, M. Heumann, and

K.J. Kluin), Department of Biostatistics (Dr. Little, J. Johanns, and H.

An), Department of Physical Medicine and Rehabilitation (K.J. Kluin), and

Division of Nuclear Medicine, Department of Internal Medicine (Dr. Koeppe),

University of Michigan, Ann Arbor, Michigan.

Received November 10, 1999.

Accepted in final form April 20, 2000.

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Supported in part by the National Institute on Aging, National Institutes of

Health (P50AG08671).

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

Neurology, University of Michigan Health System, 1500 E. Medical Center Dr.,

Ann Arbor, MI 48109-0316

Objective: To determine the percentage of sporadic olivopontocerebellar

atrophy (sOPCA) patients who later develop multiple system atrophy (MSA).

Methods: Observations of the course of 51 sOPCA patients 20 years of age or

older initially evaluated in an ataxia clinic over 14 years and followed at

3- to 6-month intervals for 3 months to 10 years (median 2.5 years,

interquartile range 5 months to 4 years).

Results: Seventeen patients evolved to develop MSA, whereas the remaining 34

manifested only progressively worsening cerebellar ataxia. The features of

the MSA cases included autonomic failure and parkinsonism in 10 patients,

autonomic failure without parkinsonism in six, and parkinsonism without

autonomic failure in one. Using survival analysis methods, the authors

estimated that 24% of subjects in this population will evolve to MSA within

5 years of the onset of sOPCA symptoms (95% CI 10% to 36%). An older age at

onset of symptoms and a shorter time from onset of symptoms to first

presentation in a neurology specialty clinic were both highly predictive of

evolution to MSA. Six of the 17 patients who evolved to MSA died 4 months to

5 years after they had met diagnostic criteria for MSA. The estimated median

survival time from time of transition was 3.5 years. In contrast, death

occurred in only one of the 34 patients with sOPCA who did not evolve to

MSA. Autopsy examination of all six patients with MSA who died confirmed the

diagnosis.

Conclusions: Approximately one-fourth of sporadic olivopontocerebellar

atrophy patients will evolve to multiple system atrophy within 5 years, and

this transition carries a poor prognosis for survival. Older age at onset of

ataxia and earlier presentation in a neurologic specialty clinic predicted

transition to MSA.

Introduction

Sporadic olivopontocerebellar atrophy (sOPCA) is a generic term for a group

of neurodegenerative diseases of unknown cause affecting the brain stem and

cerebellum. The clinical presentation consists of progressive ataxia of gait

and limb movements accompanied by dysarthria, disturbances of extraocular

movements, and in some patients, signs of corticospinal tract disease. [1]

[2] The neuropathologic changes consist of neuronal loss and gliosis in the

brain stem (inferior olives, pontine nuclei, and vestibular nuclei) and

cerebellum (molecular, Purkinje cell, and granular layers). [3] [4] [5] Some

patients with an initial clinical presentation suggesting sOPCA later

develop autonomic failure and parkinsonian features [6] [7] and at

postmortem show degenerative changes in the basal ganglia and spinal cord as

well as the brain stem and cerebellum, indicating transition from sOPCA to

multiple system atrophy (MSA). [8] [9] [10] [11]

MSA is a sporadic neurodegenerative disease characterized by various

combinations of cerebellar ataxia, autonomic insufficiency, and parkinsonian

symptoms of bradykinesia and rigidity that are poorly responsive or

unresponsive to levodopa, often accompanied by signs of corticospinal tract

disease. [12] [13] [14] [15] [16] [17] In some patients with MSA, the

initial symptoms consist of cerebellar ataxia, leading to a diagnosis of

sOPCA, and this is followed later by autonomic dysfunction or parkinsonian

features or both. In others, MSA begins with parkinsonian symptoms followed

by autonomic disorders or cerebellar symptoms or both.

The proportion of patients presenting with sOPCA who later develop MSA is

unknown, and no method is currently available to determine whether

individual sOPCA patients will progress over time to develop MSA. In one

study, genitourinary dysfunction and a narrow-based, unsteady gait were the

only findings thought to be helpful in predicting the transition of sOPCA

into MSA. [6] The diagnosis of MSA carries a more grave prognosis than

sOPCA, so a means of predicting progression from sOPCA into MSA would be

useful for giving patients information about the anticipated course of their

disease. To address these issues, we reviewed the initial clinical

presentation and subsequent evolution of the disorder in the records of all

patients with a diagnosis of sOPCA who were seen in an ataxia clinic from

1983 to 1997 and who were followed longitudinally.

Methods.

Subjects.

We reviewed the medical records of all patients age 20 years or older who

received a diagnosis of sOPCA (or idiopathic sporadic progressive cerebellar

ataxia) in the Ataxia Clinic of the Department of Neurology in the

University of Michigan Hospitals from 1983 through 1997. We excluded

patients with sporadic cerebellar ataxia who were younger than 20 years of

age for the following reasons: 1) this group, classified as early-onset

cerebellar ataxia with retained tendon reflexes, frequently has a genetic

disorder with autosomal recessive inheritance; [18] 2) MSA has not been

described in patients below 30 years of age, [12] [13] [14] hence a cutoff

at age 20 should capture all patients who would evolve by age 30; and 3) a

similar study used this cutoff age as well. [19] Among the records of 91

patients reviewed, 51 were followed clinically at 3- to 6-month intervals,

and 40 were seen only once (table 1). Most of those seen only once had come

from long distances for a diagnosis or for a second opinion concerning the

diagnosis. We limited this study to data from the 51 patients followed over

time in the clinic.

Table 1. Characteristics at time of first clinic visit of 91 patients with a

diagnosis of sporadic olivopontocerebellar atrophy Variable Patient

follow-up status p Value

Followed longitudinally, n = 51: mean (SD) Not followed longitudinally, n =

40: mean (SD)

Age at first visit 53.7 (12.6) 57.4 (9.3) 0.132

Age at onset 48.4 (13.1) 52.3 (10.1) 0.124

Percent M 41 55 0.190

Percent in-state 67 30 0.001

We based the diagnosis of sOPCA on a history of sporadically occurring

progressive deterioration of cerebellar function manifested by at least two

of the following features: limb ataxia, gait ataxia, ocular dysmetria, and

ataxic dysarthria. The diagnosis required the exclusion of other disorders

such as sensory loss adequate to cause ataxia, medications, toxins,

cerebellar neoplasms, paraneoplastic cerebellar degeneration, MS, or other

diseases that can cause progressive cerebellar ataxia. We took a detailed

family history to ensure that the disorder was sporadic. The diagnosis was

assisted by finding cerebellar and brain stem atrophy in MR scans, although

this finding was not required, because OPCA can occur without demonstrable

atrophy in anatomic imaging studies. [20] The patients were evaluated with

complete blood counts; serum profiles of hepatic and renal function; serum

levels of vitamin E, vitamin B12 , and folic acid; a serologic test for

syphilis; tests for anti-Purkinje cell antibodies in patients with ataxia

for less than 2 years; and MR scans to detect white matter lesions

suggesting demyelinating disease. We tested patients to detect the triplet

repeat expansion of SCA-1, 2, and 3 as these tests became commercially

available. We also tested for the triplet repeat expansion of Friedreich's

ataxia when this test became commercially available, because this is the

most frequent expanded triplet found in the sporadic ataxias. [21] Tests for

SCA-6, 7, and 8 were not available during the study. We did not test for

antigliadin antibodies, as the association of these antibodies with

idiopathic sporadic progressive cerebellar ataxia was first reported toward

the end of the study. [22] [23] [24] [25]

We based the diagnosis of MSA on demonstration of a neurologic disorder

meeting criteria described above for sOPCA plus autonomic failure or a

levodopa-unresponsive or poorly responsive parkinsonian syndrome or both.

The diagnosis of autonomic failure required the presence of postural

hypotension or urinary incontinence without either outflow obstruction or

disorders of bladder suspension. Although all men studied had erectile

dysfunction, this was not included in the criteria because of the many

possible causes of the disorder. The criteria for postural hypotension were

an orthostatic drop of 30 mm Hg or more in systolic blood pressure and 20 mm

Hg or more in diastolic blood pressure with an increase in heart rate of no

more than 10 beats per minute [26] in the absence of medication,

dehydration, or medical disorders that might cause this finding. Blood

pressure and pulse were measured after the patient had been supine for 2

minutes and then again 2 minutes after the patient had assumed a standing

position. The diagnosis of a parkinsonian syndrome required at least two of

the following: akinesia, rigidity, tremor, and hypokinetic dysarthria, all

poorly responsive or unresponsive to levodopa. This investigation was

conducted before development of consensus guidelines for the diagnosis of

MSA, [27] but these guidelines were used to categorize the patients in this

group. Among the 17 patients whose disease evolved to MSA, 16 would be

labeled as having probable MSA and one would now be labeled as having

possible MSA because of the combination of cerebellar ataxia and

parkinsonism without autonomic failure.

Autopsy studies.

Seven of the patients died during the observation period, including one with

a clinical diagnosis of sOPCA and six with probable MSA. Postmortem

examinations were conducted in all six MSA cases but not in the sOPCA case.

The examinations included both gross and microscopic examination of the

brain and, in three cases, the spinal cord. Sections were taken from the

cerebral cortex, basal ganglia, amygdala, thalamus, hippocampus, midbrain,

pons, medulla, cerebellar cortex, and dentate nucleus. Sections were taken

from the cervical, thoracic, lumbar, and sacral levels of the spinal cord (2

cases) or from the thoracic level only (1 case). Paraffin sections were

stained with hematoxylin and eosin, luxol fast blue-cresyl violet-eosin,

phosphotungstic acid-hematoxylin, and Bielschowsky silver. Selected sections

were stained with Hirano silver and ubiquitin (1 case).

Statistical analysis.

Descriptive analyses were carried out to compare the characteristics of the

51 patients who were followed longitudinally with those who were seen only

once. For those who were followed, Kaplan-Meier (KM) estimators were used to

study the time to transition to MSA from the date of first presentation.

Data from patients whose illness had not evolved at the date of the last

clinic visit or who died before evolving were treated as censored data.

Although some patients had relatively short periods of follow-up, they were

included because survival analysis adjusts for differential follow-up

periods, and thus inclusion of these cases does not affect the validity of

the conclusions. The impact of evolution on survival was studied

descriptively using KM estimators and analytically using a proportional

hazards model (Statistical Analysis System/STAT Software [28] [29] ) with

transition to MSA as a time-dependent covariate. KM estimators were used to

compare the times of transition to MSA of subgroups defined by age at onset,

age at first presentation, time from age at onset to first presentation,

sex, and whether or not the patient was a resident of Michigan. The log-rank

test statistic was used to determine whether the transition curves were

equal in the different subgroups. Finally, a proportional hazards model was

fitted to estimate the simultaneous effects of the covariates on the time to

transition to MSA. Diagnostic plots did not suggest serious violations of

the proportional-hazards assumption in this analysis.

Results.

The 51 patients studied were evaluated clinically every 3 to 6 months for 3

months to 10 years (median 2.5 years, interquartile range 5 months to 4

years). The group consisted of 30 women and 21 men. They first reported

symptoms of a cerebellar disorder at age 48 ± 13 years (mean ± SD; range 24

to 79 years). Their age at presentation was 54 ± 13 years. In comparison to

the 40 patients who were not followed, the 51 patients studied

longitudinally were younger at the time of first visit, had earlier ages at

onset of OPCA, and were more likely to live in Michigan (see table 1).

Among the 51 patients who were followed, sOPCA evolved to MSA in 17,

including 10 women and seven men. Of these 17 patients, 11 survived and six

died during the period of observation, whereas all but one of the patients

who did not progress to MSA were still alive at the end of the observation

period. For all six patients with MSA who died, death resulted directly from

the neurologic disorder. By contrast, in the one patient with sOPCA who

died, death resulted from an unrelated heart disorder. Figure 1 shows KM

estimates of the survival distribution for the group that evolved to MSA and

for the group that did not evolve, measured from the time of first onset of

symptoms. This classification is not perfect, because some individuals who

had not evolved to MSA might have done so after the end of the study.

Nevertheless, figure 1 clearly shows that patients who develop MSA have a

markedly inferior survival prognosis (p < 0.0003, log-rank test). For those

who evolved to MSA, the median survival time from the time of transition was

3.5 years, and no patient with continuous follow-up survived for more than 5

years.

Figure 1. Estimated distribution of survival for patients with sporadic

olivopontocerebellar atrophy (sOPCA) who evolved to develop multiple system

atrophy (MSA) (dashed line) as compared with patients who did not develop

MSA (dotted lines). Crosses represent patients still surviving at the end of

the study. Survival times are measured from the onset of symptoms of ataxia

to the time of death or the last visit.

In all six patients in the MSA group who died, the diagnosis of MSA was

confirmed by autopsy examination, which showed neuronal loss and gliosis in

the substantia nigra, caudate nucleus, putamen, globus pallidus, pons,

inferior olives, and cerebellum. Large numbers of glial and neuronal

cytoplasmic inclusions were found in the CNS of all six patients. In the

three cases that included examination of the spinal cord, the

intermediolateral columns showed neuronal loss and gliosis.

Figure 2 displays the KM-estimated distribution of time from the onset of

ataxia to the point of transition to MSA, plotted as a dotted line. The

dashed line represents the 95% CI and is terminated after 12 years from

onset, given the small number of subjects followed beyond that time. The

5-year transition rate was 24% (95% CI [CI] = 10% to 36%). The 10-year

transition rate was 36% (95% CI = 19% to 50%). The KM-estimated

distributions of time to transition to MSA were compared according to

characteristics of the patients at time of first presentation. The time to

transition did not differ for men as compared with women (p = 0.79, log-rank

test), but the predictors of transition were older age at onset, shorter

time from onset to first presentation in a neurology specialty clinic, and

older age at first presentation. Figure 3 shows the estimated distributions

of time to transition for two subgroups, late onset and early onset,

classified by median age at onset of the initial symptoms of ataxia for the

entire group (51 years). Figure 4 shows a similar comparison for subgroups

separated by median time from onset to first presentation in a neurology

specialty clinic (4.5 years). Patients in the late onset group (age >51

years) were more likely to evolve to MSA than patients in the early onset

group (age 51 years) (p = 0.02, log-rank test). The estimated probability

that a patient would evolve to MSA within 5 years of first presentation was

0.39 in the late onset group and 0.17 in the early onset group (see figure

3). The time from onset to first presentation in the clinic was an even

stronger predictor of evolution to MSA (p < 0.0001), showing patients below

the median time to be much more likely to progress (see figure 4). The age

at first presentation in the clinic was a less powerful predictor of

transition (p = 0.07), with patients who had late presentation more likely

to evolve to MSA.

Figure 2. Estimated distribution of time from onset of ataxia to transition

to multiple system atrophy (MSA) (dotted line). Crosses represent patients

who had not evolved to develop MSA by the end of the study. Dashed lines

indicate the 95% CI, which are terminated at 12 years because the sample

size of patients more than 12 years from onset is small.

Figure 3. Estimated distribution of time from onset of ataxia to point of

transition to multiple system atrophy (MSA), classified into two groups

based on median age at onset of initial symptoms of ataxia (51 years). Data

for patients with onset younger than 51 years are shown with dotted lines

and for those with onset older than 51 years with dashed lines. Crosses

represent patients who had not evolved to develop MSA by the end of the

study.

Figure 4. Estimated distribution of time from onset of ataxia to point of

transition to multiple system atrophy (MSA), classified into two groups

based on median time from onset of ataxia to presentation in a neurologic

specialty clinic (4.5 years). Data for patients who first presented below

4.5 years are shown with dotted lines and for those above 4.5 years with

dashed lines. Crosses represent patients who had not evolved to MSA by the

end of the study.

Of the 17 patients who evolved to MSA, 10 developed cerebellar dysfunction

followed by autonomic failure and parkinsonian features, six developed

cerebellar dysfunction followed by autonomic failure without parkinsonian

features, and one developed cerebellar ataxia followed by parkinsonian

features without autonomic failure. With this limited sample size, we were

unable to detect any difference in the prognosis for survival among these

subgroups.

To assess the simultaneous effects of the predictors, we fitted a

proportional hazards regression model with time from onset of symptoms to

transition to MSA as the outcome variable, and sex, state (in-state or not),

age at onset of first symptoms, and time from onset to first presentation as

covariates. Diagnostic plots did not suggest serious violations of the

proportional-hazards assumption in this analysis. Only one of the variables,

time from onset to first presentation in a neurology specialty clinic, was

significant (p = 0.0002) in the regression model when all four variables

were included, reinforcing the importance of this variable as a predictor of

evolution.

Discussion.

The evolution of sOPCA into MSA carries a grave prognosis; hence, studies

that elucidate the rate and determinants of evolution are important.

One-third of this sample of 51 sOPCA patients developed MSA during the

14-year observation period. Analysis using KM estimators indicated that

approximately one-fourth of sOPCA patients can be expected to evolve to MSA

within 5 years of the time of first presentation in a neurology specialty

clinic. Patients who evolved to MSA had a high likelihood of death within 5

years, whereas those who continued to show progressive cerebellar

dysfunction without developing autonomic failure or parkinsonism had a much

better prognosis for survival. In a previous study, patients with the

clinical diagnosis of idiopathic late onset cerebellar ataxia were divided

into two groups, one with a pure cerebellar disorder and another with a

cerebellar disorder plus noncerebellar findings, principally parkinsonism.

[19] The median life expectancy from symptom onset was 20.7 years in the

group with a pure cerebellar disorder and 7.7 years in the other group,

indicating that the addition of noncerebellar symptoms to cerebellar

degeneration carries a poor prognosis for survival.

Our analysis demonstrates that the onset of symptoms of cerebellar

degeneration after age 51 years carries a higher risk for development of MSA

than onset before this age. Patients with shorter times from first symptoms

to first presentation in the clinic were also much more likely to develop

MSA. We interpret this to indicate a more rapid initial course of the

disease rather than decreased awareness of the initial symptoms, because the

course continued to be rapid over the subsequent observation period. Hence,

a rapid initial course of disease appears to be prognostic for development

of MSA. The predictive power of this variable is remarkable given

differences among patients in the threshold for perceiving the first

symptoms and the ability to recall them a number of years later. These

differences would be expected to attenuate the relationship with the

transition outcome. Patient referrals to our clinic are tied to an

established referral pattern, and this variable may not have the same

predictive value in other clinics.

The findings of this study reinforce the notion that sOPCA is a

heterogeneous disorder producing at least two groups of patients, those who

evolve to develop MSA and those who continue to show progressive

deterioration of cerebellar function without developing signs of MSA. MSA

also appears to be a heterogeneous disorder, with major variations in both

the rate and the degree of degeneration of the component systems. For

example, in PET studies of ligand inflow and binding, patients with MSA

presenting initially with cerebellar ataxia have markedly decreased

perfusion of the brain stem and cerebellum, reflecting decreased tissue

mass. [30] [31] In contrast, patients with MSA presenting initially with

parkinsonism have essentially normal perfusion of these structures. [30]

[31] Conversely, PET studies of the density of striatal monoaminergic

presynaptic terminals show severe decreases in patients with MSA presenting

with parkinsonism and mild to moderate decreases in patients with MSA

presenting with cerebellar ataxia. [31]

Our survival analyses take into account differential periods of follow-up of

the patients, but a shortcoming is that this study excludes patients seen

just once in the clinic and not followed over time. These patients differed

from those who were followed in being older and having an older age at

symptom onset. Also, the study patients were from a single (albeit large)

ataxia clinic. Other studies are needed to ascertain whether our findings

can be replicated in other study populations. The sample size for the study

was large for these rare diseases, but still rather small from a statistical

perspective. Large samples and longer periods of follow-up are needed to

provide more definitive estimates of the distribution of time to transition

to MSA, particularly in subgroups of the population defined by presenting

characteristics. Our study indicates that a short time from reported onset

to first presentation in a specialty clinic and a late age at onset are

highly prognostic for whether a patient's illness will eventually evolve to

MSA. As our database and period of observation increase, we will be able to

study whether other characteristics at first presentation, such as

particular clinical signs or neuropsychologic test results, are predictive

of the transition from OPCA to MSA.

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