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Cytomegalovirus infection of the adult nervous system.

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Cytomegalovirus Infection
of the Adult Nervous System
Michael Duchowny, M D , Louis Caplan, M D , and George Siber, M D
In 2 patients, 1 with brachial plexus neuropathy and another with relapsing chronic encephalitis, the acute neurological syndrome was accompanied by fever, tachycardia, abnormal liver function, and atypical lymphocytosis.
Cytomegalovirus (CMV) infection was documented in both patients by viral isolation and a fourfold rise in
complement-fixation titer. CMV may produce peripheral neuropathy, brachial plexus neuropathy, or a n acute or
chronic meningoencephalitis in previously healthy adults without immune deficiency.
Duchowny M, Caplan L, Siber G: Cytomegalovirus infection of the adult nervous system.
Ann Neurol 5:458-461, 1979
T h e cytomegaloviruses (CMV) are members of the
herpesvirus family characterized by their ability to
produce striking cellular enlargement with intracellular inclusion bodies in epithelial cells [27]. Intrauterine infection with CMV has long been known as
a cause of disease in the neonatal period [9-11, 201.
Infection with CMV during adult life was first recognized in debilitated patients with compromised immune mechanisms [ 3 , 6, 27, 281, renal transplant
recipients [ 5 , 6, 231, and patients undergoing extracorporeal perfusion [181 or transfusions [ 11. Recently,
CMV infection has been reported in previously
healthy adults, usually with a predilection for involvement of lungs, liver, spleen, hematopoietic
system, or heart. Nervous system involvement has
been less commonly described, with reports limited
to cases of postinfectious polyneuropathy [7, 12, 17,
191 or acute meningoencephalitis [4, 6, 17, 21, 22,
261. This report describes 2 previously healthy adults
in whom systemic CMV infection was complicated by
neurological syndromes (brachial plexus neuropathy
and chronic encephalitis) not previously described in
relationship to CMV.
Case Reports
Patient I
A corpulent 59-year-old man was hospitalized in August, 1973. Seven days before admission he had noted
nightly fever t o 39°C. frontal headache, and a heavy sensation in his eyelids. A throbbing sensation developed in
both shoulders and progressively localized to the left
shoulder and upper arm. Tetracycline. 500 mg four times
daily, was administered. The shoulder pain had a
From the Department of Neurology, Beth Israel Hospital. and t h e
Division of Clinical Microbiology, Sidney Farber Cancer Institute
and Harvard Medical School, Boston, MA.
Accepted for publication Oct 3 . 1978.
toothache-like quality and became extremely severe, responding only to narcotics. He denied recent trauma, respiratory illness, o r limb weakness.
His temperature was 39°C. General examination was
normal. Findings o n neurological examination of the left
upper extremity included wasting and 315 weakness of the
deltoid muscle with 215 weakness of the left supraspinatus
and infraspinatus muscles and the clavicular head of the
pectoralis major muscle. There was 4 5 weakness o f the
right supraspinatus muscle. Hypesthesia to pinprick was
present over the shoulder and arm, involving the fifth and
sixth cervical dermatomes, and palpation over the left
brachial plexus produced discomfort. Deep tendon reflexes
were present and symmetrical. The remainder of the neurological examination was normal. Peripheral pulses were
normal and were unaffected by AJson's maneuver or
hyperabduction.
The following laboratory and diagnostic tests were
within normal limits: electrolytes, fasting blood glucose,
blood urea nitrogen (BUN), creatinine, alkaline phosphatase, vitamin B,?, folate level, leucine aminopcptidase,
amylase, hepatitis-associated antigen, sedimentation rate,
monospot test, cold agglutinins, stool guaiac. and intermediate-strength purified protein derivative (PPD); cerebrospinal fluid protein, glucose, and cytology; bacterial
cultures of blood, urine, CSF, and stool; upper gastrointestinal series; electrocardiogram; and Hat plate of the abdomen. Roentgenograms of the left shoulder demonstrated
an accessory seventh cervical rib element on the left. Liver
function test results were slightly abnormal, and a peripheral blood smear contained 15 atypical lymphocytes per
100 leukocytes. Hematological profile revealed a normochromic, normocytic anemia. A bone marrow biopsy was
hypercellular with no evidence of tumor cells and suggested resolving marrow suppression secondary to viral
infection.
requests t o Dr Duchowny, Department o f Neurology, Children's Hospital Medical Center, 300 Longwood Ave,
Boston. MA 021 15.
Address reprint
458 0364-5 134l791050458-04$01.25 @ 1978 by Louis Caplan
Laboratorj D a t a in 2 Putie~ts
ri.irh CytottieRalorirus Iiifec~ion
Determination
Complement-fixation
antibody titer
Week 1
Week 2
Week 1
Conval
Late con
Urine culture
Patient 1
Patient 2
1: 6 4
1 : 128
...
1 :64
1 : 128
1 : 256
1 :256
1 : 128
1 :512
+
1:512
+
Performed in the J. F. Enders Research Virology Laboratory of
Children‘s Hospital Medical Center, Boston.
marked by fever, hypersomnia, increased fatigability. and
deficits in concentration, memory, manipulation of knowledge, humor, and emotional expression. Over t h e following year and a half he experienced a gradual lessening of the
systemic features of fever and hepatosplenomegaly, associated with improved vigilance and mental function. H e
was unable to return to work, however, because of fatigue
and lassitude. Intermittently he had a cough and tachycardia, and he led a bed-to-chair existence. H e was
readmitted to the hospital in March, 1975, and had normal
pulmonary function tests and normal tindings o n right
heart catheterization. Examination in November, 1976,
was normal except for an elevated resting pulse rate of 108
and modest postural hypotension. Neurological examination was normal.
Conval = convalesccncc (6 wk);Late con = late convalescence
( > 3 mo).
Discussion
D o r f m a n [6] r e p o r t e d p o s t m o r t e m data o n 4 pa-
During the first week of illness, pain increased in severity
and responded only to frequent doses of morphine. A
fourfold rise in CMV complement-fixation antibodies was
demonstrated (Table). CMV was isolated from the urine,
but viral cultures of CSF, saliva, and buffy coat were negative. His symptoms gradually resolved over the next six
months and he was able to return t o work.
tients i n w h o m serious medical illness with immunosuppression ( 3 renal transplant cases and 1 case
of systemic vasculitis treated with corticosteroids)
was complicated by CMV infection with encephalitis.
Glial n o d u l e encephalitis w i t h o u t meningitis or
perivascular cell infiltration was n o t e d a t p o s t m o r t e m
examination. I n this g r o u p of patients, superinfection
with multiple infective agents a n d t h e lack of neurological correlation d u r i n g life m a d e clinicopathological correlation difficult. Klemola and colleagues
[17] called attention to t h e additional possibility of
central nervous system involvement in i m m u n o logically normal patients with acquired C M V infection. O n e of their patients with “CMV mononucleosis” had aseptic meningitis. S t e r n e r e t a1 [ 2 6 ] briefly
described a single patient with a CSF pleocytosis,
“dysrhythmia” in t h e electroencephalogram. and a
“slight encephalitis” d u e to CMV. C h i n and colleagues [ 4 ] noted a single patient with CMV w h o s e
clinical features included myalgias, mild confusion,
C S F pleocytosis, and transient myelopathy with a
thoracic sensory level. Phillips and colleagues [ 221
r e p o r t e d in detail 2 patients with CMV encephalitis
w h o were n o t immunosuppressed. O n e patient had
headache, slight right limb weakness, and 7 cells in
t h e CSF. T h e s e patients were initially considered t o
have limbic encephalitis, possibly d u e to h e r p e s
simplex, a n d w e r e treated with a d e n i n e arabinoside
intravenously. Spinal fluid a n d brain cultures w e r e
positive f o r C M V . Full recovery occurred o v e r a p e riod of t w o m o n t h s . P e r h a m and co-workers [ 2 1 ]
added a single case of CMV aseptic meningitis with
c o m p l e t e recovery. Patient 2 of the p r e s e n t r e p o r t
differs f r o m prior cases in the protracted, debilitating
clinical course e x t e n d i n g o v e r a period of years. I n
s u m m a r y , t h e m o s t c o m m o n r e p o r t e d CNS manifestation of CMV is a n acute, self-limited clinical
s y n d r o m e of slight confusion associated with less
t h a n 30 cells in t h e CSF. Limbic encephalitis with
Patient 2
A 30-year-old male psychiatry resident was hospitalized in June, 1974, with the abrupt onset of headache,
dizziness. fever. night sweats, photophobia, myalgias, and a
3 kg weight loss. The night prior to admission, he developed an evanescent abdominal maculopapular rash. He
had had two prior episodes in 1970 and 1972 which were
diagnosed as viral syndromes. the latter associated with
hepatomegaly, abnormal liver function tests, and a negative
monospot test. O n admission. temperature was 38.5”C and
pulse was 98. H e had several small, tender axillary lymph
nodes, a 12 cm tender liver, and 6 cm tender spleen. Neurological evaluation revealeJ fluctuations in the level of
consciousness and attention. ranging from mild Jrowsiness
to confusion, but n o abnormalities of cranial nerve, motor,
sensory, or reflex function.
Abnormal laboratory tests included changes in liver
function. anemia. and atypical lymphocytosis. The following laboratory tests were normal: electrolytes. BUN,,
creatinine. calcium, phosphorus. creatine phosphokinase,
and alkaline phosphatase; CSF protein. glucose, and cytology; prothrombin time; intermediate-strength PPD;
monospor test; Rciter protein reaction (for syphilis);
Epstein-Barr titers; bacterial cultures of blood, urine, stool,
and CSF; heterophil agglutination; Weil antigen; serum titers for toxoplasmosis, histoplasmosis, and amebiasis; febrile apglutinins; and hepatitis-associated antigen. The
erythrocyte sedimentation rate was 27 mm per hour. An
alpha-I globulin of 0.12 gmldl and beta globulin of 0.51
gmldl were slightly below normal limits. CMV was isolated
from the urinc o n three occasions (see the Table).
Following hospital discharge he slept 18 t o 20 hours a
day. and during wakeful periods was unable to concentrate
sufticiently to read a book. The subsequent year was
Duchowny et al: Adult CMV Infection
459
seizures, myelopathy, o r a more chronic encephalitis
are unusual manifestations.
Reports of peripheral nervous system disease in
adults with CMV infection are limited to examples of
Guillain-Bar& syndrome. Klemola and co-workers
[17] and Ironside and Tobin [I21 described 1 case
each of Guillain-BarrO syndrome in patients with
"CMV mononucleosis." Leonard and Tobin [ 191 described in more detail 9 patients with CMVassociated neuropathy; the disorder usually began
with an upper respiratory infection followed by distal
paresthesias and rapidly developing proximal limb
weakness, frequently with cranial nerve involvement.
Tendon reflexes were abolished. T h e C S F was acellular but had a high protein content. Dowling,
Menonna, and Cook [7] surveyed patients with
Guillain-Bar& syndrome and found that 30 of 92
(33c4) had a high and rising C M V complementfixation titer reaction in contrast to normal controls
and patients with other neurological illnesses.
Mononeuropathy or brachial plexus neuropathy
similar to that in our Patient 1 has not been recognized previously, but Patient 15 of Silverstein and
colleagues L251, who suffered radicular pain in the
right arm and paresthesias in t h e right hand, had "infectious mononucleosis" with a low heterophil titer
( 1 / 6 4 ) and only minor clinical manifestations of
mononucleosis in other organs. This case could possibly have been an example of CMV mononucleosis
with brachial neuropathy.
Brachial plexus neuropathy and diffuse encephalopathy are both neurological syndromes for which a
viral cause has frequently been presumed but an infective agent rarely identified. Correct identitication
has awaited advances in virological techniques and a
high index of clinical suspicion. Etiological diagnoses in o u r patients were based on the clinical presentation o f a hetcrophil-negative mononucleosis
syndrome and isolation of C M V from t h e urine,
accompanied by a fourfold rise in C M V complement-fixation titer.
Most adults have serological evidence o f C M V infection. Seropositive C M V conversion increases with
advancing age, so that by 50 years an estimated 8 0 9
of the population has antibodies t o C M V [171. For
most, C M V infection protiuces only a mild febrile
illness with few abnormal findings. T h e development
of active disease could result from exogenous exposure, exogenous reinfection, or endogenous reactivation of a previously acquired "latent" virus.
Manifest C M V infection in healthy adults usually
produces a syndrome closely resembling infectious
mononucleosis [ 13- 161. Fever, atypical lymphocytes in the peripheral blood, and liver function
abnormalities were features in both of our patients,
while in Patient 2 , rash, myalgia, lymphadenopathy,
460 Annals of Neurology
Vol 5
No 5
May 1979
and headache were also noted. These findings are
compatible with the syndrome of CMV mononucleosis [ I S , 161; this syndrome differs from infectious
mononucleosis caused by Epstein-Barr virus infection in the lack of pharyngeal involvement, striking
lymphadenopathy, and positive heterophil antibody
titers. Infectious mononucleosis is a documented
cause of diverse neurological disorders such as encephalitis, radiculopathy, myelopathy, and polyneuropathy [2, 8, 24, 251. Nervous system involvement in patients with C M V is uncommon but
appears to be similar to that described in infectious
mononucleosis. Increased awareness that CMV may
occur in otherwise healthy individuals and that it may
produce a wide spectrum of neurological illness
should prompt further efforts to clarify syndromes
suspected of having a viral origin.
Supported in part by National Institutes o f Health Developincntal
Neurology Training Grant 5 POI N S 0 9 7 0 4 and by N l C H D Post
Doctoral Fellowship 1 F32 H D 0 5 3 6 5 . both to Dr Duchowny.
We thank Dr Michael M . Oxinan for performing viral isolation and
C F titers.
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Duchowny et al: Adult CMV Infection
461
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