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Olivopontocerebellar atrophy and multiple system atrophy Clinical follow-up of 10 patients studied with PET.

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*Emory University, Atlanta, GA; and fFlinders University,
Bedford Park, South Australia, Australia
1. Ellis R, Hsia K, Spector S , et al. Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neuro-
cognitively impaired individuals with acquired immunodeficiency
syndrome. Ann Neurol 1997;42:679-688
2. Epstein LG, Gendelman HE. Human immunodeficiency virus
type 1 infection of the nervous system: pathogenetic mechanisms. Ann Neurol 1993;33:429-436
3. Glass JD, Fedor H, Wesselingh SL, McArthur JC. Immunocytochemical quantitation of human immunodeficiency virus in
the brain: correlations with dementia. Ann Neurol 1995;38:
lar trafficking between the blood and the CSF in some patients before AIDS may result in higher HIV RNA levels in
the CSF compartment. As clearly shown in Figure 2, there
was no direct relationship between C D 4 count and CSF
We agree that the preponderance of data accumulated
thus far suggest that multiple pathophysiological mechanisms
contribute to the development of HIV-associated dementia.
Our findings suggest that the presence of virus in the CSF in
late disease may be a marker of virus in other CNS tissues,
and that appropriate treatment may interrupt the subsequent
cascade of events that leads to neuronal injury and clinical
neurological disease.
Departments of Neurosciences and Medicine, University of
California, San Diego, C 2
Ronald J. Ellis, MD, PhD, and J. Allen McCutchan, MD
W e appreciate the careful reading of our article undertaken
by Drs Glass and Wesselingh. They correctly summarize the
data from our prospective cohort study' but overlook two
important points of emphasis.
The title of the article summarizes one of these points,
which is that among subjects with acquired immunodeficiency syndrome (AIDS), cerebrospinal fluid (CSF) human
immunodeficiency virus type 1 (HIV-1) RNA levels were elevated in those who showed neuropsychological impairment
compared with those who did not. The same was not true
for HIV-infected subjects who did not have AIDS. This is
not a trivial distinction. Individuals with AIDS, defined by
the Centers for Disease Control in 1993 as those with a
CD4+ lymphocyte count of less than 200, have a dramatically increased risk of major medical and neurological morbidities and mortality compared with those without AIDS.
Using data provided in the published study, the calculated
odds ratio for the association between CSF HIV RNA levels
greater than 200 and neuropsychological impairment in
AIDS is 19.
Because the preponderance of severe neurological disease
occurs in patients with AIDS, and because our observations
suggest that elevated CSF HIV RNA levels are strongly associated with neuropsychological impairment (including
HIV-associated dementia and minor cognitive motor disorder) in AIDS, these findings are of considerable potential
clinical importance. If prospective studies demonstrate that
lowering elevated CSF HIV RNA levels with carefully chosen antiretroviral agents can benefit patients' cognitive status,
then a long-sought goal of HIV clinical neurological research
will have been achieved.
The second point deals with a potential explanation for
the lack of association between CSF HIV RNA levels and
neuropsychological impairment in subjects who did not have
AIDS. W e found that CSF pleocytosis (elevated leukocyte
numbers) was common before AIDS, and that subjects with
pleocytosis typically had CSF HIV RNA levels much closer
to those in blood plasma than did subjects without pleocytosis. These data suggest that elevated CSF HIV RNA levels
occur for different reasons before and after AIDS. The findings are consistent with the notion that an increase in cellu-
Olivopontocerebellar Atrophy and Multiple System
Atrophy: Clinical Follow-Up of 10 Patients
Studied with PET
A. Schrag, MD,* J. 0. Rinne, M D , t
D. J. Burn, MD, MRCP,$
C. J. Mathias, DPhil, FRCP,*
C. D. Marsden, MD, FRS, DSc,*
D. J. Brooks, MD, FRCP,$
and N. P. Quinn, MD, FRCP*
Many patients with sporadic olivopontocerebellar atrophy
(sOPCA) develop other symptoms and signs to indicate that
they have multiple system atrophy (MSA).' Three years ago,
in Annals, we reported ['*F]fluorodopa and ["Cldiprenorphine positron emission tomography (PET) data in 10 patients with the cerebellar form of MSA with autonomic
symptoms (8 severe and 2 mild), to clarify what proportion
of these patients also have nigrostriatal dysfunction.2 In 7
patients, striatal tracer uptake was significantly reduced even
in the absence of clinical parkinsonism in 5 of them, indicating that PET can detect subclinical nigrostriatal dysfunction in sOPCA. An eighth patient with mild finger akinesia
had a fluorodopa K, value reduced 1 S D below the control
mean, and the other 2 patients had normal PET scans and
no parkinsonism clinically. However, it remained uncertain
what proportion of patients with normal or abnormal nigrostriatal function on PET scanning would later develop parkinsonism. Here we report clinical follow-up of these 10 patients (Table).
Now, 4 years after the examination, 7 patients have died
(necropsy was, unfortunately, not obtained), 1 has emigrated,
and 2 are still alive. All of the 7 patients with reduced fluorodopa uptake developed additional features (pyramidal
signs [n = 71, urinary incontinence or retention [n = 61,
abnormal sphincter electromyogram (EMG) [n = 6 ] ) ,confirming OPCA-type MSA. In addition to the 2 who already
had definite parkinsonism, a further 4 of these 7 patients
went on to develop it; the seventh rapidly deteriorated to
being wheelchair bound and died 6 months after his PET
scan, but we do not know whether he developed clear signs
of parkinsonism. The patient with slightly reduced fluorodopa uptake later became more parkinsonian. In the remain-
Annals of Neurology
Vol 44
No 1
July 1998
Table. Striatal ['8F]Fluorodopa Uptake and Concurrent and Subsequent Vital Status
Striatal ['8F]F1uor~dopa
Uptake in 1991
in 1991
Died 12/92
Died 1/96
Patient No.
Reduced by 1 SD
Vital Status
Died 2/97
Died 9/95
Died 12/95
Emigrated 3/96
Died 12/95
Died 11/95
Boldface table entries indicate patients with abnormal [18F]fluorodopapositron emission tomographic scans who subsequently developed clinical
ing 2 patients who had normal fluorodopa PET scans, ataxia,
postural hypotension, and urinary incontinence or retention
progressed rapidly. Both developed pyramidal signs and their
sphincter EMGs were abnormal. The first of these 2 required
tracheostomy for stridor and died 5 years after the scan without developing parkinsonism. The second patient had not
developed parkinsonism when she emigrated 4 years after her
PET scan.
We conclude that OPCA patients with abnormal striatal
function on PET are likely to develop parkinsonism within a
few years and that fluorodopa PET is a sensitive marker for
nigrostriatal dysfunction preceding clinical parkinsonism in
OPCA-type MSA. Patients with normal striatal fluorodopa
uptake on PET seem less likely to develop parkinsonism in
life, but normal uptake does not exclude coexistent subclinical nigrostriatal dysfunction in patients with sOPCA. The
proportion of patients with sOPCA who do not have, or do
152 Annals of Neurology Vol 44
No 1 July 1998
not develop, MSA is uncertain but probably constitutes a
minority of cases.
*Institute of Neuroiogy, and $Medical Research Council
Cyclotron Unit, Hammersmith Hospital, London, UK and
?Department of Neurology, University of Turku, Turku,
1. Gilman S, Quinn NP. The relationship of multiple system atrophy to sporadic olivopontocerebellar atrophy and other forms of
idiopathic late-onset cerebellar atrophy. Neurology 1996;46:
1197-1 199
2. Rinne JO, Burn DJ, Mathias CJ, et al. Positron emission tomography studies in the dopaminergic system and striatal opioid
binding in the olivopontocerebellar atrophy variant of multiple
system atrophy. Ann Neurol 1995;37:568-573
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atrophy, patients, clinical, follow, olivopontocerebellar, system, multiple, pet, studies
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