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Chronic encephalitis epilepsy and cerebrovascular immune complex deposits.

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BRIEF COMMUNICATIONS
Chronic Encephahtis,
Epilepsy, and
Cerebrovascular Immune
Complex Deposits
John M. Andrews, MD,* Joel A. Thompson, MD,?‘
Theodore J. Pysher, MD,”Sn Marian L. Walker, MD,t§I
and M. Elizabeth Hammond, MD’
Refractory epilepsy, electroencephalographic abnormalities, progressive hemiplegia, and contralateral
hemicerebral atrophy developed in a previously healthy
%year, 9-month-old girl. Extensive laboratory testing
showed elevated serum antinuclear antibody titers, cerebrospinal fluid oIigoclonal bands, and elevated immunoglobulin G (IgG): albumin ratio, IgG index, and
IgG synthesis rate. Pathological study of a subtotal
hemispherectomy specimen revealed widespread cerebral vasculitis with immunofluorescence staining for
IgG, IgM, IgA, C3, and C l q , and ultrastructural evidence of vascular injury in addition to severe cortical
atrophy with marked neuronal loss. Cerebrospinal fluid
abnormalities in other reported patients suggest that immunological abnormalities may not be unique to this
girl. These data suggest possible immunopathogenetic
mechanisms in these patients.
Andrews JM, Thompson JA, Pysher TJ, Walker ML,
Hammond ME. Chronic encephahtis, epilepsy,
and cerebrovascular immune complex deposits.
Ann Neurol 1990;28:88-90
In 1958, Rasmussen and colleagues El} reported 3 patients with an unusual combination of slowly progressive hemiparesis, frequent seizures, and “chronic encephalitis” on the basis of pathological findings of
cerebral perivascular cuffing with chronic inflammatory
cells, glial nodules, widespread gliosis, and other abnormalities in surgical and autopsy specimens. Subsequent reports from the same group and others have
further described clinical and pathological features of
this syndrome, recently referred to as “Rasmussen’s
syndrome,” but its pathogenesis remains unknown 1261. We describe a patient with clinical and pathological
findings similar to those previously reported in whom
From the *Depatment of Pathology, University of Utah School of
Medicine, and the Departments of tNeurology, $Pathology, SNeurosurgery, and ”Pediatrics, Primary Childrens’ Medical Center, Salt
Lake City, LJT.
Received May 23, 1989, and in revised form Oct 24, 1989, andJan
12, 1990. Accepted for publication Jan 15, 1990.
Address correspondence to Dr Andrews, Department of Pathology,
St Mark‘s Hospital, 1200 East 3900 South, Salt Lake City, UT
84124.
we also found evidence of immune complex disease.
This is, to our knowledge, the first report describing
immunopathological changes in brain tissue from a patient with this syndrome.
Case Report
A previously healthy white girl, at age 3 years, 9 months,
spontaneously developed simple partial seizures involving
the left face, arm, and leg with associated aphasia and postictal paralysis lasting 1 to 2 minutes. Family history was unremarkable. Initial neurological examination and magnetic resonance imaging head scan were normal. Phenobarbital and
methsuximide caused a rash. Valproic acid, carbarnazepine,
clorazepate dipotassium, ethosuximide, phenytoin, and paraldehyde were also used during the course of seizure therapy.
Serial electroencephalograms demonstrated bilateral epileptiform activity with right hemispheric preponderance. Serial
head scans over a 2-year period demonstrated progressive
right cortical and subcortical atrophy, and a severe spastic left
hemiparesis developed. Cerebral angiography was noncontributory . Normal laboratory results, in addition to routine
blood and urine studies, included cerebrospinal fluid (CSF)
(demonstrating 2-7 lymphocytes per cubic millimeter; 0- 1
red blood cells per cubic millimeter; glucose, 5 1-60 mg idl;
protein, 19-21 mgidl), serum copper and ceruloplasmin,
serum amino acid screening, urine organic acid screen,
leukocyte lysosomal enzymes, serum long chain fatty acids,
leukocyte electron microscopy, prothrombin time, partial
thromboplastin time, protein S, protein C, and antithrombin
111. Serum viral antibody titers and lupus erythematosus
preps were negative, but antinuclear antibody (ANA) titer
was repeatedly elevated, the highest value being 1:10,240
with a speckled pattern (normal, less than 1:40). Rheumatoid factor, centromere, double-stranded DNA, SSA, SSB,
SM, RNP, and SCL-70 antibodies were all negative, as were
serum immunoglobulin (Ig)G, IgA, IgM, complement, anticardiolipin, and lupus anticoagulant studies.
The CSF was positive for oligoclonal bands and revealed
an IgG/albumin ratio of 46% (normal, 6-25%), a serum
albumidglobulin ratio of 3.6 (normal, 3.5-6.5), a bloodbrain barrier of 3.3 (normal, 1.6-8.8), an IgG index of 1.68
(normal, 0.35-0.65), and an IgG synthesis rate of +18.8
(normal, -5.0 to +5.0 mglday). CSF viral titers were not
elevated.
A right subtotal hemispherectomy was performed for intractable seizures. Seizures have not recurred during the subsequent 8 months.
Materials and Methods
Formalin-fixed representative tissue was processed by
routine methods and stained with H&E, and Karnovsky’s
fixed tissue was used for transmission electron microscopy.
Quick-frozen tissue was processed by standard methods
and incubated with fluorescein-conjugated monoclonal or
polyclonal antibodies against human IgG, IgM, IRA, C3,
Clq, fibrinogen, albumin, cytomegalovirus, and herpes I
antigen. Slides were cover-slipped using polyvinyl alcohol
after postincubation washing in phosphate-buffered solution
(pH 7.41, and examined immediately in a microscope
equipped for epifluorescence. All slides showing positive
staining were photographed.
88 Copyright 0 1990 by the American Neurological Association
Immunofluorescence controls included normal human
kidney and kidney from patients with systemic lupus
erythematosus, liver tissue from a case of cytomegalovirus
hepatitis in a child, brain tissue from a case of herpes simplex
viral encephalitis in an adult, and brain tissue from a 12-yearold white girl with systemic lupus erythematosus.
Pathological Findings
Mild diffuse cortical atrophy and increased firmness of both
gray and white matter were present. Histological findings
were qualitatively similar in all areas studied but varied in
severity without a clear lobar emphasis. The leptomeninges
contained a patchy mild increase in lymphocytes and macrophages, while the cerebral tissue showed moderate to severe diffuse atrophy of gray greater than white matter with
gliosis, occasional glial-mesodermal nodules, and cortical
neuronal loss. There was patchy but widespread infiltration
of meningeal and cerebral vessels (mainly, but not exclusively, venules) by lymphocytes and lesser numbers of histiocytes and plasma cells (Fig 1) wit-hout fibrinoid necrosis.
Immunofluorescence microscopy revealed that all vessels
demonstrated granular accumulation of IgG, IgM, IgA, C3,
and C l q within vessel walls (Fig 2). There was no staining for
albumin, cytomegalovirus, or herpes I antigen. Staining for
fibrinogen was observed in a few leptomeningeal vessels. All
controls gave appropriate results. Electron microscopy revealed endothelial swelling, fibrillar material adjacent to endothelial cells, discontinuities in cell attachments and granular thickening, and reduplication of basal lamina in some
small vessels. No amyloid deposits or viral particles were
seen.
Intraoperatively obtained CSF and cerebral tissue cultures
for bacteria, fungi, and viruses were negative.
A
Discussion
Clinical and light microscopic features of our patient
correspond well to the condition that has lately been
described by the term Rasmussen’s syndrome, although the true vasculitis component of the pathological findings have not been emphasized previously
{ 1-61. Viral studies in other than tick-borne encephalitis cases have been consistently unremarkable I5-8).
A first-zone or mid-zone colloidal gold curve elevation
{9} has been described in some cases of Rasmussen’s
syndrome c5, 61, suggesting that other such patients
might have had spinal fluid immunoglobulin (and tissue immunofluorescence) results analogous to the results seen in our patient, if ,all the patients had been
examined by similar techniques. Immunosuppressant
therapy has been tried in a few patients with Rasmussen’s syndrome with only “moderate and temporary
benefit,” but protocol details are not specified 16, 101,
~ l ~ many
h ~anrironvdsants
~ ~ h may
a druginduced lupus syndrome or elevated ANA titer, or
both, w e do not believe the relevant literature supports a role for this mechanism in our patient [l 1- 14).
Immunofluorescence techniques are a more sensitive
indicator of allograft rejection and presumably other
Brief Communication: Andrews et
Fig 1 Intracerebral vessels with perivascular and intramural
chronic infEammatolycdL infiltrutes. Gliosis is present umund
the vessel in (A). (A, x 415; B, x 560.)
I
al:
Chronic Encephalitis with Immune Complex Deposits
89
forms of vasculitis related to immune mechanisms than
are routine histological techniques {lS, 161. Further
application of such methods to patients with Rasmussen’s syndrome and, possibly, to selected patients
with conditions such as hypsarrhythmia and infantile
spasms, the syndrome of multiple independent spike
foci with seizures and intellectual impairment, the Lennox-Gastaut syndrome, Landau’s syndrome, the syndrome of alternating hemiplegia in infants, and particularly, myoclonic encephalopathy of infants 117-181
might reveal that our findings in this patient are less
unique than available reports indicate.
References
1. Rasmussen T, OlszewskiJ, Lloyd-Smith D. Focal seizures due to
chronic localized encephahtis. Neurology 1958;8:435-445
2. Aguilar MJ, Rasmussen T. Role of encephalitis in pathogenesis
of epilepsy. Arch Neurol 1960;2:663-676
3. Rasmussen T, McCann W. Clinical studies of patients with focal
epilepsy due to “chronic encephalitis.” Trans Am Neurol Assoc
1968;93:89-94
4. Gupta PC, Roy S, Tandon PN. Progressive epilepsy due to
chronic persistent encephalitis. Report of four cases. J Neurol
Sci 1974;22:105-120
5. Rasmussen T. Further observations on the syndrome of chronic
encephalitis and epilepsy. Appl Neurophysiol 1978;42:1- 12
6. Rasmussen T, Andermann F. Update on the syndrome of
“chronic encephalitis” and epilepsy. Cleve Clin J Med 1989;
56:S-181-S-184
7. Johnson RT, Herndon RM.Virologic scudies of multiple sclerosis and other chronic and relapsing neurological diseases. Prog
Med Virol 1974;18:214-228
8. Asher DM. Persistent tick-borne encephalitis infection in man
and monkeys: relation to chronic neurologic disease. In: Kurstak E, ed. Arctic and tropical arborviruses. Proceedings of the
2nd international symposium on arctic arborviruses. New York:
Academic Press, 1979:179-195
9. Brumback RA. Collecting cerebrospinal fluid. In: Herndon
RM, Brumback RA, eds. The cerebrospinal fluid. Hingham,
MA: Kluwer Academic Publishers, 1989:97-130
10. Andermann F. Panel discussion. Cleve Clin J Med 1989;56:
s-83
B
Fig 2. Representatioe immunofluorescencefinding.i.Positive
granular staining for immunoglobulin A (A) and C3 (B) i n
cerebral parenchymatous vessels is pment. IvtmunofEuorescent
stain. (A,X 490;B, X 490.)
90 Annals of Neurology Vol 28 No 1 July 1990
11. Alexander EL, Lijewski JE, Jerdan MS, et al. Evidence of an
immunopathogenic basis for central nervous system disease in
primary Sjogren’s syndrome. Arthritis Rheum 1986;29:12231231
12. Golombek SJ, Graus F, Elkon KB. Autoantibodies in the cerebrospinal fluid of patients with syscemic lupus erythematosus.
Arthritis Rheum 1986;29:1090-1097
13. Weinstein A. Drug-induced systemic lupus erythematosus. Prog
Clin Immunol 1980;4:1-2 1
14. Signsen BH, Fishman L, Hanson V. Antinuclear antibodies and
lupus-like syndromes in children receiving anticonvulsants. Pediatrics 1976;57:529-534
15. Yowell RL, Hammond EH, Bristow MR, et al. Acute vascular
rejection involving the major coronary arteries of a cardiac allograft. J Heart Transplant 1988;7:191-197
16. Hammond EH, Yowell FU,
Nunoda S, et al. Vascular (humoral)
rejection in cardiac transplantation. I: Pathologic observations
and clinical implications. J Heart Transplant 1989;8:430-443
17. Christoff N. Myoclonic encephdopathy of infants: report of two
cases and observations on related disorders. Arch Neurol
1969;21:229-234
18. Kragelow I, Aicardi J. Alternating hemiplegia in infants: report
of five cases. Dev Med Child Neurol 1980;22:784-791
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deposits, cerebrovascular, complex, encephalitis, immune, chronic, epilepsy
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