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Cerebrospinal fluid antibodies to myelin basic protein in acute idiopathic optic neuritis.

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sory evoked potential evoked by tibial nerve stimulation was increased beyond two standard deviations in 2
patients, bpt the differences between control and subject latency means were not statistically significant.
4.
Discussion
6.
The 15 healthy HIV-seropositive subjects of this study
had neither lower limb weakness nor ataxia, but mean
latencies of BAEPs and tibial nerve evoked potentials
at T12 were prolonged compared with controls. In
AIDS also, these electrophysiological abnormalities
are present, but the slowing of conduction is more
severe and the defects are more widespread in the
peripheral and the central nervous systems (see Table).
Therefore, the electrophysiological abnormalities reported here could represent the earliest detectable
neurological attack during HIV infection.
Despite normal hearing and normal latency of peak
I, the mean latency of peak V of the BAEP was prolonged, suggesting an incipient conduction defect in
the brainstem. As the peripheral conduction along the
tibial nerve was normal, the delay of the potential recorded at the twelfth thoracic vertebra might reflect an
incipient defect in conduction in the vicinity of the
dorsal root ganghon.
The mean latency to the cortical response in subjects was not statistically different from that in controls. Similarly, the mean central conduction time from
TI* to cortex in subjects did not differ from that in
normal subjects (11.2 milliseconds in controls versus
11.2 milliseconds in the HIV-seropositive group).
Thus, it is likely that the delayed TI2 response is
caused by a defect between the gluteal region and the
twelfth thoracic vertebra.
A neuropathological study of the spinal cord in 89
AIDS patients revealed a vacuolar myelopathy caused
by swelling within myelin sheaths and affecting the
long tracts of the lumbar and lower thoracic cord in
one-fifth of the patients E7). There are no reports available of the pathology of the spinal root ganglia in
AIDS patients. Alternatively, the lack of a bloodneural tissue barrier in the ganglia enables the retrovirus to gain access to the nerve cell bodies and their
axons, producing edema and axonal damage. Our findings favor a defect of the myelin in the lumbar part of
the spinal cord, rather than a distal axonopathy with
dorsal root ganglion involvement.
5.
7.
8.
9.
experience at UCSF and review of the literature. J Neurosurg
62~475-495, 1985
Navia BA, Cho E-S, Petito CK, Price RW: The AIDS dementia
complex: 11. Neuropathology. Ann Neurol 19:525-535, 1986
Navia BA, Jordan BD, Price RW. The AIDS dementia complex:
I. Clinical features. Ann Neurol 19:517-524, 1986
Petersen L, Trojaborg W: Visual, auditory, and somatosensory
pathway involvement in hereditary cerebellar ataxia, Friedreich's
ataxia and familial spastic paraplegia Electroencephalogr Clin
Neurophysiol 521:283-297, 1981
Petito CK, Navia BA, Cho E-S, et al: Vacuolar myelopathy
pathologically resembling subacute combined degeneration in patients with the acquired immune deficiency syndrome. N Engl J
Med 312:874-879, 1985
Snider WD,Simpson DM, Nielsen S, et al: Neurological complications of acquired immune deficiency syndrome: analysis of 50
patients. Ann N e w 1 14:403-418, 1983
Trojaborg W, Petersen E: Visual and somatosensory evoked potentials in multiple sclerosis. J Neurol Neurosurg Psychiatry
42:323-330, 1975
CerebrosDinal Fluid
Antibodiis to Myelin Basic
Protein in Acute Idiopathic
Optic Neuritis
Kenneth G. Warren, MD, Ingrid Catz, MSc,
and Christopher Bauer
~
~~~
~~~~~~~~
Free and bound levels of anti-myelin basic protein
(anti-MBP) antibodies were measured by radioimmunoassay in the cerebrospinal fluid of 20 patients with
acute idiopathic optic neuritis, 133 patients with rnultiple sclerosis (MS) divided into three clinical subgroups,
and 76 normal control subjects. Patients with idiopathic
optic neuritis had elevated levels of anti-MBP predominantly in free form, resulting in an elevated (above
unity) freehound anti-MBP ratio similar to that of MS
patients with acute relapses. These data suggest that
acute idiopathic optic neuritis, like active MS, is associated with anti-MBP.
Warren KG, Catz I, Bauer C. Cerebrospinal fluid
antibodies to myelin basic protein in
acute idiopathic optic neuritis.
Ann Neurol 1988;23:297-299
Intrathecally produced autoantibodies to myelin basic
protein (anti-MBP) are detected in increased levels in
References
Helweg-Larsen S, Jakobsen J, Boesen F, et al: Myelopathy in
AIDS. A clinical, neuroradiological, and electrophysiological
study of 23 Danish patients with AIDS. Acta Neurol Scand
7764-73, 1988
Koppel BS, Wormser GP, Tuchman AJ, et al: Central nervous
system involvement in patients with acquired immune deficiency
syndrome (AIDS). Acta Neurol Scand 71:337-353, 1985
Levy RM, Bredesen DE, Rosenblum ML: Neurological manifestations of the acquired immune deficiency syndrome (AIDS):
From the Multiple Sclerosis Patient Care and Research Clinic, Division of Neurology, Department of Medicine of the University of
Alberta, Edmonton, Alberta, Canada.
Received May 13, 1987, and in revised form Jul 31 and Sep 8.
Accepted for publication Sep 11, 1987.
Address correspondence to Dr Warren, 9-101 Clinical Sciences
Building, University of Alberta, Edmonton, Alberta, Canada, T6G
2G3.
Copyright 0 1988 by the American Neurological Association 297
both free and bound forms in patients with active multiple sclerosis (MS) [ l , 21, and anti-MBP levels correlate positively with titers of MBP 131, an accepted indicator of disease activity. The purpose of this study was
to determine if anti-MBP levels in the cerebrospinal
fluid (CSF) are elevated with an initial attack of central
nervous system (CNS) demyelination. Patients who
were experiencing their first episode of acute idiopathic optic neuritis were selected for study.
301
Methods
Free and bound levels of MBP and anti-MBP were determined in all CSF samples by recently described methods [3].
CSF MBP and anti-MBP titers of 20 patients with optic
neuritis were compared with those of 76 normal control
subjects with psychoneurosis and degenerative disc disease
and 133 patients with clinically definite MS, divided into 40
patients in clinical remission, 47 with progressing disease,
and 46 with acute relapses of less than 2 weeks' duration.
The patients diagnosed as having acute idiopathic optic neuritis had no evidence of other nervous system involvement.
Matched CSF and serum samples were obtained from all
patients within 1 to 2 weeks of the onset of acute relapses,
except for 2 of 20 patients with optic neuritis whose samples
were obtained several weeks later when they were in the
recovery phase. Intrathecal I& synthesis, estimated by the
IgG index 147 and the daily rate of CNS IgG synthesis IS],
was used to confirm the clinical diagnosis.
Results
Intrathecal IgG synthesis was within normal limits (0.5
+- 0.13 and - 1.75 +- 2.0, respectively) in all 76 normal control subjects, whereas all patients with MS,
whether with active or inactive disease, had increased
levels [2). Similar to patients with MS, the group of 20
patients with optic neuritis showed overall increased
intrathecal IgG levels (I& index = 1.04 ? 0.59, daily
IgG synthesis = 8.6 ? 8.0), with the exception of 3 of
these 20 patients, who had normal values.
Patients with acute optic neuritis had MBP and antiMBP results similar to patients with MS who were
having acute relapses. Free MBP levels (9.0 2 5.3)
were elevated in 13 of these 20 patients, whereas
bound MBP levels (1.5 -C 0.9) were elevated in only 5
(Fig 1). Free anti-MBP levels (8.8 -t- 4.8) were elevated in 17 of 20 patients; bound antibody levels (1.7
? 0.9) were elevated in only 9 (Fig 2). The freeibound
anti-MBP ratio (5.8 2 2.4) was dramatically elevated
in 17 patients (Fig 3). The same 3 patients with optic
neuritis who had normal levels of intrathecal IgG had
undetectable levels of free anti-MBP.
MBP and anti-MBP levels in both free and bound
forms were also elevated in patients with active MS
(see Figs 1, 2). The freebound anti-MBP ratio was
elevated only in patients with acutely active disease
(see Fig 3).
298 Annals of Neurology Vol 23 N o 3 March 1988
.
F B
Controls
F B
F B
F B
Relapses
Remission Pro gressing
-
"
F B
ODtic
Neuritis
-
Multiple Sclerosis
Fig I . Free (F} and bound (B) Levels ofcerebrospinalfluid (CSP)
myelin basic protein (MBP) in a group of patients with acute
idiopathic neuritis, a normal control group (including those with
psychoneurosis and degenerative disc disease),and three clinical
subgroups of pcztients with multz2k sclerosis. Resuh are expressed as the mean 2 2 SD; p = Student's t test versus control
subjects.
Controls
F B
F B
Remission Pro -
F B
Relapses
gressing
F B
Optic
Neuritis
Multiple Sclerosis
Fig 2. Free (P) and bound (B) levels of cerebrospinalfluid(CSF)
anti-myelin basic protein antibodies (anti-MBP) in a group of
Patients with acute idiopathic optic neuritis, a normal control
group (including those with psychoneurosis and degenerative disc
disease), and three clinical subgroups of patients with multiple
sclerosis. Results are expressed as the mean 2 SD; p = Student's t test versus control subjects.
*
rophy that suggests the involvement of the optic
nerves by neuritis.
The number of patients with optic neuritis who subsequently develop MS has been variously estimated at
11.5% {7), 27 to 28% [8,93, and even as high as 85%
{lo, 11). It has been suggested that those patients who
have optic neuritis with oligoclonal banding of CSF
IgG will be more likely to develop MS 112). If antiMBP is involved in the pathogenesis of acute optic
neuritis and MS, it could be predicted that recurrent
optic neuritis or MS will develop when unbound autoantibodies return to the intrathecal compartment 12, 33
and bind to MBP in situ.
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Financial support for this research was provided by MS benefactors,
including Mr and Mrs Philip May and the Friends of MS Patient
Care and Research Clinic; Mr Clifford Giese, Mrs E. Iaforge and the
Tegler Foundation (Edmonton, Canada), Mrs G. Gerth and friends
of Barrhead, Canada, and Mrs J. L. Atkins of Red Deer, Canada
P
MS
Fig 3. Free to bound (FIB) cerebrospinalfluid anti-MPB ratio
in a group of patients with acute idiopathic optic neuritis, a
normal control group (including those with psychoneurosis and
degenerative disc disease), and three clinical subgroups of patients
with multiple sclerosis (MS). Results are expressed as the mean
-+ 2 SD;p = Student’s t test versus control subjects.
Discussion
In this study 17 of 20 patients with classic clinical features of acute optic neuritis had increased levels of free
CSF anti-MBP; the remaining 3 patients did not. All
17 patients with increased CSF anti-MBP also had increased intrathecal IgG synthesis. One of the 3 patients without detectable anti-MBP was a 52-yearold woman who instantaneously developed a central
scotoma in her right eye with no associated pain; her
acute optic neuropathy probably had a vascular origin
rather than being optic neuritis. She recovered no vision whatsoever, and when followed for more than 5
years she showed no f w h e r progression toward MS.
The CSF samples from the other 2 patients without
detectable anti-MBP were obtained several weeks after the onset of symptoms when they were well into
the recovery phase. In these 3 patients with undetectable anti-MBP, CSF MBP levels were also normal.
Investigations of patients with acute optic neuritis,
Uhthoff’s phenomenon, or those with a more insidious loss of vision should include visual evoked responses, magnetic resonance imaging, as well as a detailed CSF analysis including assays to detect MBP and
anti-MBP. The relationship of optic neuritis to MS has
been debated for almost a century, dating back at least
to the discussions on retro-ocular neuritis of Mr Marcus Gunn and Dr Buzzard in 1897 16). They concluded that 50% of patients with MS have optic at-
We would like to thank the patients with optic neuritis and MS from
northern Alberta who participated in this study. Drs T. A. S. Boyd,
H. K Shun, and D. Hassard kindly referred some of the patients
who had optic neuritis to the Multiple Sclerosis Patient Care and
Research Clinic of the University of Alberta. Assistance with patient
care was provided by Dr D. J. Carroll, Mrs J. Christopherson, and
Mrs J. Rodgers. M a Christopherson was supported by the MS Society of Canada (Alberta Division).
References
1. Can I, Warren KG. Intrathecal synthesis of autoantibodies to
myelin basic protein in multiple sclerosis. Can J Neurol Sci
1986;1 3 ~1-24
2
2. Warren KG, Cam I. Diagnostic value of cerebrospinal fluid antimyelin basic protein in patients with multiple sclerosis. Ann
Neurol 1986;20:20-25
3. Warren KG, Can I. A correlation between cerebrospinal fluid
myelin basic protein and anti-myelin basic protein in multiple
sclerosis patients. Ann Neurol 1987;21:183-189
4. Link H, Tibbling G. Principles of albumin and IgG synthesis in
neurological disorders. 11. Evaluation of IgG synthesis within
the central nervous system in multiple sclerosis. Scand J Clin
Lab Invest 1977;37:397-401
5. Tourtellone WW, Ma B. Multiple sclerosis: the blood brain
barrier and the measurement of de novo central nervous system
IgG synthesis. Part 11. Neurology 1978;28:76-83
6. Gunn M, Buzzard DR. Discussion on retro-ocular neuritis.
TMS Ophthalmol SOCUK 1897;17:107-217
7. Kurkland LT, Auth TLB, Beebe GW, et al. Studies of the natural history of multiple sclerosis. Trans Am Neurol Assoc
1963;88:233-235
8. Cohen M, Lessell S, Wolf P. A prospective study of the risk of
developing multiple sclerosis in uncomplicated optic neuritis.
Neurology 1979;29:208-213
9. Sandberg-Wolheim M. Optic neuritis studies on CSF in relation
to clinical course in 61 patients. Acta Neurol Scand 1975;
52:167-178
10. Lynn BH. Retrobulbar neuritis. Trans Ophthalrnol SOCUK
1959;79:701-716
11. McAlpine D. Benign form of multiple sclerosis: results of a long
term study. Br Med J 1964;2:1029-1032
12. Feasby TE, Ebers GC. Risk of multiple sclerosis in isolated optic
neuritis. Can J Neurol Sci 1982;9:269
Brief Communication: Warren et al: CSF Anti-MBP in Optic Neuritis
233
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