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Encephalopathy associated with cryoprecipitable Australia antigen.

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Encephalopathy Associated with
Cryoprecipitable Australia Antigen
Roger N. R o s e n b e r g , MD, Edward A. N e u w e l t , MD,
Joel Kirkpatrick, MD, a n d Peter Kohler, MD
A 19-year-old white woman w i t h urticaria, a r t h r d g i a s , a n d hepatitis B-associated antigen i n h e r serum developed a
progressive encephalopathy despite only mild hepatic dysfunction. The patient's serum at 4°C produced a cryoprecipitate containing the hepatitis B-associated antigen and its antibody. Serum complement levels were borderline
low. A t autopsy, gross a n d histological examination of t h e b r a i n revealed only mild residual cerebral edema. Indirect
immunofluorescent studies of t h e cerebral cortex and choroid plexus showed no evidence of i m m u n e complex
deposition. T h e patient's progressive encephalopathy may have been related to t h e presence of cryoprecipitable
hepatitis B antigen, a relationship not previously reported.
Rosenberg RN, Neuwelt EA, Kirkpatrick J, et al: Encephalopathy associated with cryoprecipitable Australia
antigen. Ann Neurol 1:298-300, 1977
A 19-year-old white woman who was comatose and bilaterally decerebrate was seen in the emergency room of Parkland Memorial Hospital. Her history, obtained from the
patient's sister, indicated that she had lived with a jaundiced
heroin addict until two months before admission and had
developed arthralgias and urticaria six weeks previously. An
assay for the hepatitis B surface antigen (HBsAg) obtained
at that time was positive [4](Table). Four weeks later the
patient developed anorexia, nausea and vomiting, a mild
headache, and some neck sriffness. She was irritable, slept
most of the day, and continued to have joint pains that
required salicylates for relief. O n the morning of admission
the patient was found comatose o n the floor.
Physical examination in the emergency room revealed
a pulse of 140 per minute, temperature of 4 V C , and
Cheyne-Stokes respirations. She had mild scleral icterus and
a normal-sized liver. Rectal examination revealed guaiacpositive stools. O n neurological examination her disc margins were found to be blurred bilaterally, indicating increased intracranial pressure. She had downbeat nystagmus
and alternated between decorticate and decerebrate poscur-
ing. The hemoglobin concentration was 1I .7gm/dl with a
leukocyte count of 6,800 cells/mm3 and a placelet count of
470,000/mm3. H e r serum chemistry, arterial blood gas, and
clotting studies were normal except for a direct1indirect
bilirubin concentrarion of 7.215 .0 mgidl, serum glutamic
oxaloacetic acid transaminase reading above 500 units, and
alkaline phosphatase of 160 and 244 units (normal, < 80).
T h e prothrombin time was normal. Arterial and cerebrospinal fluid (CSF) ammonia levels were only minimally elevated. H e r HBsAg in serum remained positive. The patient's serum was also positive for anti-HAA antibody by
radioimmunoassay [4-6] (see the Table). The results of
serological tests for collagen vascular disease (antinuclear
antibody titer, lupus erythematosus cell preparations, serum
protein electrophoresis) were negarive. A screen for toxic
substances and a salicylate level were both normal.
Urinalysis revealed trace proteinuria.
Changes observed in a four-vessel intracranial arteriogram were consistent with mild cerebral cdema. There were
no masses nor shift of major vessels. Cerebrospinal fluid
obtained via a frontal twist drill ventriculostomy contained
138 red cells and no white cells per cubic millimeter, a
protein of 6 mgidl, and aglucose of 187 mg/dl, with aplasma
glucose of 207 mg/dl. There was no detectable Australia
antigen in the CSF. A portable electroencephalogram revealed diffuse slowing and absence of any triphasic waves,
suggestive of hepatic coma.
The patient was intubated in the emergency room. She
was treated with dexamethasone, mannitol, and furosemide
to reduce rhe cerebral edema. The patient developed
generalized major motor seizures on the second hospital
day; these were controlled with anticonvulsants. Subsequently she showed gradual but definite neurological
From the Department of Neurology, The University of Texas
Health Science Center at Dallas, Southwestern Medical School,
Dallas, TX, and the Department of Medicine, University of Colorado Medical Center, Denver, CO.
Address reprint requests to Dr Rosenberg, Department of Neurology, The University of Texas Health Science Center at Dallas,
Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX
The hepatitis B-associated antigen (HAA) has been
indirectly implicated in the past as a cause of encephalopathy. T h e patient w i t h Australia antigenpositive hepatitis who develops hepatic encephalopathy is the m o s t c o m m o n a n d i m p o r t a n t
e x a m p l e of this indirect association [ 1-31, We p r e s e n t
a case that more directly implicates, o n an immunological basis, the hepatitis-associated antigen and t h e
development of a n a c u t e encephalopathy.
Case Report
Accepted for publication Sepr 24, 1976.
Szvinzaq of Hepatztzs B SurjCace Antigen iHBsAg) mid Antibodj (Anti-€lB~Ag,~
Serum V a h e s
Supernatant of
Whole serum
Ausria 1
Supernatant of
41 1417 4
Ausria I1
Anti HBs
Ausria 1
Pa tie n t
0-325 cpm
0-325 cpm
1,740 cpm
401 cpm
0-500 cpm
<15 1 %
7,979 rpm
24.1 cf
<15 If;
aThe cryoprecipitate was ohtained by placing 30 ml of the patient’s serum at 4°C for 72 hours and rhen removing any precipitate by
centrifugation at 50,000 x g for 30 minutes. T h e visible pcllet was then resuspended in 1.0 ml of normal saline. The supernatant and
resuspended pellet were assayed for HBsAg using the Ausria I radioimmunoassay [41. Since t’alsc-posirive results have been reported
with Ausria I, the initial sample of the patient’s serum was subsequcntly reassayed using the highly speclfic Ausria I1 radioimmunoassay
[ 5 ] . The presence of antibody to HBsAg in the supernatant and resuspended cryoprecipitate was detected using the radioimmunoassay
(anti-HBs RIA) method of Shorey and Combes [6].
bThe values listed are counts per minute per sample aliquot.
improvement. O n the fourth hospital day she moved all
cxtremities in response to pain without decerebrate posturing, and her nystagmus resolved. Interstitial pneumonia
developed on the fourth hospital day, complicated by partial, intermittent, and frequent airway obstructions, and the
patient died of progressive respiratory failure. Cultures of
tracheal secretions, serum, and CSF did not grow viruses.
The findings at autopsy were minimal cerebral edema,
mild resolving hepatitis, interstitial and bronchial pneumonia, and acute gastric ulcers. There was no evidence of
vasculitis in the brain, spinal cord, meninges, or choroid
plexus by either light or electron microscopy. There was no
evidence of renal glomerulonephritis by light microscopy;
further immunochemical studies with renal tissue were not
carried out.
Further immunological studies showed that the patient’s
serum produced a visible cryoprecipitate after 72 hours at
4°C in which the HBsAg was markedly concentrated as
measured by radioimmunoassay (see the Table). Total
serum hcmolytic complement was borderline low at 33
CH,, Ulml (normal, 33-61 CM50 Ulml). The serum C‘3
value was borderline low at 0.81 mgiml (normal, 0.82-1.7
mg/ml), with C’4, C’5, and C ’ l q normal (0.381, 0.77, and
0.223 mglml, respectively). The CSF hemolytic C‘4 was low
at 13 CHSoUlml (normal, 43-99 CH,,, Ulml), but the CSF
was stored at -20”C, a temperature at which CSF complement, unlike serum complement, is unstablc [ 7 ] .The results
of indirect immunofluorescent studies using fluoresceinconjugated anti-IgM, anti-IRA, anti-IgG, anti-IgC’3, and
antifibrinogen were all negative w h e n incubated with the
cerebral cortex or the choroid plexus.
I n this young woman who developed symptoms of
circulating immune complex disease and subsequently an encephalopathy, the presence of cryoprecipitable H B s A g antibody complexes was demonstrated in the serum at the time of her maximal illness.
No mass was demonstrated by arteriography, and
resolving cerebral e d e m a was the only abnormal
postmortem finding in the brain. A search for a
metabolic o r infectious cause of the encephalopathy
revealed only mild hepatic disease. It is suggested that
this patient’s encephalopathy with marked cerebral
edema was related to her immunological disorder.
Gell and Coombs [8] have outlined four basic immunopathogenic mechanisms: ( 1) anaphylactic (IgE
mediated), (2) antimembrane, (3) immune complex,
and ( 4 ) cell-mediated. Immune complex disease, a
Gell and Coombs type 3 mechanism, may have played
a role in this patient’s neurological disorder. Immune
complex disease is generally divided into two subgroups: the Arthus reaction and serum sickness. A n
Arthus reaction is identifiable histologically as a vasculitis, b u t this was not revealed in a careful examination of o u r patient’s brain. However, there is good
evidence for serum sickness in the present case [9].
T h e patient presented with urticaria and arthralgias,
had a borderline-low serum complement, and had
circulating immune complexes as evidenced by t h e
presence of a cryoprecipitate in which H B s A g and
anti-HBs antibodies were concentrated.
In Mirick and Shank’s [lo] series of 272 patients
who contracted serum hepatitis in an iatrogenic
epidemic, 50% presented with allergic symptoms,
and many had a low serum complement. N o n e of
those patients developed an encephalopathy. More
recent studies have demonstrated the presence of
cryoglobulins containing H B s A g and anti-HBsAg in
patients with acute and chronic hepatitis [ 111.
T h e presence of cryoprecipitable immune complexes in the serum of this patient and t h e associated
encephalopathy with mild cerebral edema is, to o u r
knowledge, unique. Patients with systemic lupus
erythematosus often have clinical and immunological
findings similar to those in our patient and often develop a severe encephalopathy with minimal histological changes [ 121. Recent studies by Lampert and Old-
Case Report: Rosenberg et al: Encephalopathy with Australia Antigen
stone [131 in N Z B mice with a lupus-type syndrome
and by Atkins et a1 [ 141 in patients with central nervous system lupus erythernatosus have demonstrated
immune deposits in the choroid plexus. Immune
complex deposits were not evident in the brain of our
patient, as measured by indirect immunofluorescent
techniques. However, an increase in brain vascular
permeability resulting in cerebral edema could have
been due in part to the titer of serum cryoprecipitable
immune complexes.
Glomerulonephritis and associated glomerular
immune complex formation have been described in
patients with active viral hepatitis [15]. These renal
changes are not uniformly present in all patients during the early phase of circulating immune complex
disease associated with Australia antigen and also
were not present in our patient [91.
It is of note that Hutchinson and Howell [I61 reported a patient with cryoglobulinemia who developed the sudden onset of coma without other focal
neurological signs and which resolved in 24 hours.
In conclusion, we speculate that the cryoprecipitable HBsAg-anti-HBsAg complexes present in this
patient's serum may have played a role in the production of encephalopathy, possibly through a mechanism of the serum sickness type (Gell-Coombs type
3. Denny-Brown D: The cerebral control ofmovement, in No. g 1
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associates, encephalopathy, antigen, australia, cryoprecipitate
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