ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 22, No. 5 Copyright © 1992, Institute for Clinical Science, Inc.

Cerebral Malakoplakia Associated with Neonatal Herpes Virus Infection* EM ILY VOLK, M.S., JO SE PH C. PARKER, JR., M.D., and SH ELLEY T E P PE R , M.D. Department o f Pathology, University o f Missouri-Kansas City School o f Medicine, Truman Medical Center, Kansas City, MO 64108

ABSTRACT C erebral m alakoplakia has b een recognized as a com plication of proba­ ble neonatal herpes encephalitis and may b e associated w ith p ersistent neurologic deficits including seizures. At autopsy, an eight-m onth-old boy had a discrete cystic gliotic lesion in his left inferior frontal lobe w ith malakoplakia. Perinatal herpetic cutaneous lesions w ere seen and w ere successfully treated w ith m edication at two weeks of age. Subsequent dis­ continuation of his anti-epileptic drugs was followed by sudden unex­ pected death. Im m unohistochem ical stains and electron microscopy o f his brain failed to reveal herpes sim plex virus.

to exist solely in the urinary tract, b u t in 1958 the first case of m alakoplakia was M alakoplakia was first d escrib ed by d e s c r ib e d o u ts id e th e u rin a ry tra c t. M ichaelis and G utm ann in 1902.10 T he E x tra v e sic u lar o c c u rre n ce is in c re a s ­ term , coined a year later by Von Hanse- ing.15,16 The m ost common sites include, mann, was derived from the G reek words in order of decreasing frequency, the uri­ ‘m alakos’ (soft) and ‘plakos’ (plaque). It is nary bladder, genital tract, gastrointesti­ a rare, m orphologically unique, chronic nal tract, and retroperitoneum .15,16 C ere­ inflam m atory process characterized by bral malakoplakia, how ever, is extrem ely the accum ulation of large m ononuclear rare and has b e e n d e s c rib e d in five phagocytes term ed Von H ansem ann his­ infants, including neonates.1,5,7,11 M alakoplakia in the urinary b lad d e r tiocytes, surrounded by and containing d ia sta se -re sista n t p e rio d ic acid Schiff has b een linked to coliform infections, (PAS) positive inclusions and calcified, and bacteria have b een dem onstrated in lam inated, target-shaped bodies term ed some diseased bladders.10 O ther possible M ichaelis-G utm ann bodies.1 W hen origi­ agents have in c lu d e d stap h y lo co cci,13 nally described, malakoplakia was thought e x t r a v a s a t e d e r y t h r o c y t e s , 14 a n d viruses.15 To date, no virus has b e e n iso­ lated or identified from m alakoplakic tis­ * Send reprint requests to Joseph C. Parker Jr., M.D., Department of Pathology, University of Lou­ sues. The process may result from im m u­ isville School of Medicine, Louisville, KY 40292. n o lo g ic d y s f u n c tio n a n d h a s b e e n 300

Introduction

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CEREBRAL MALAKOPLAKIA WITH NEONATAL HERPES VIRUS INFECTION

associated w ith tuberculosis, sarcoidosis, m alignancy, cachexia, and im m une defi­ ciency sta te s.15 T he distinctive m acro­ phage pattern of the Von H ansem ann his­ tiocytes suggests an altered m acrophage response, secondary to an altered T-cell response. Lou and T eplitz9 suggested a d e fe c t in th e m ac ro p h a g ic lysosom e w hich could lead to incom plete cell deg­ radation, resulting in deposition of prod­ ucts in co m p le te ly d ig este d p roducing m a la k o p la k ia . H e rp e s sim p le x v iru s (HSV) infecting the brain could lead to necrosis and histiocytic phagocytosis of cellu lar d ebris, w hich w ith an altered im m une state, could cause malakoplakia. Case R eport This 13-day-old black male weighing 3.9 kg (75th percentile) was bom after a gestation of 40 weeks. He was delivered vaginally by forceps without com­ plications and admitted to Children’s Mercy Hospi­ tal in Kansas City, Missouri, for uncontrollable gen­ eralized myoclonic seizures. At birth, a small blister was noted on his scalp. At 11-days-old, his mother noted two small blisters on the baby’s subscapular region. Neurological exam revealed a lethargic infant with equal motion in all extremities and bilat­ eral upgoing plantar reflexes. Moro and suck reflexes were intact. His neck was normal. The infant had tonic-clonic seizures beginning in his right arm becoming secondarily generalized in the Emergency Room. These seizures lasted only a few minutes, but occurred several times. The patient was treated with dilantin and hospitalized. On his first day of hospitalization, he had recur­ rent seizures which began on the right side and became generalized. The baby was given more dilantin and had another seizure that day. Phéno­ barbital was added and was given intravenously until his 10th hospital day when it was adminis­ tered orally. An electroencephalogram (EEG) and computerized tomographic scan of his head were normal. Laboratory studies on admission included white blood cell count of 10.2 thousand per mm3 with 38 percent segmented neutrophils, three per­ cent bands, 44 percent lymphocytes, 11 percent monocytes, one percent eosinophil and one percent basophil. Hemoglobin was 13.1 g per dl with 756,000 per mm3 platelets. Serum electrolytes were normal. Cerebrospinal fluid showed no red blood cells, 66 per mm3 white blood cells with three seg­ mented neutrophils, 28 lymphocytes, and 35 mono­ cytes. Cerebrospinal fluid (CSF) protein was 64 mg per dl and glucose was 38 mg per dl. Urine analysis was normal. Blood cultures showed no growth after ten days.

301

During the first week of his hospital stay, the baby was irritable with periods of somnolence. He remained in a flexed posture and was given intra­ venous acyclovir for 14 days. Cultures of his skin lesions grew HSV 2. His cerebrospinal fluid (CSF) remained sterile. New skin lesions never devel­ oped, and his scalp and back lesions healed. An EEG prior to discharge was normal. About four months later, his mother brought him to the Emer­ gency Room at Children’s Mercy Hospital for “sei­ zures”, though no seizure activity was witnessed. The baby’s vital signs included 7.21 kg, 62 cm length, 37.8°C, pulse of 140 per sec, and respira­ tions of 44 per sec. He was pink with capillary refill of less than two seconds. He was moving all extremities. At six-months-old, CSF studies were repeated and failed to reveal HSV 1 and 2. His mother reported no recent seizures and stated that the baby’s doctor had discontinued seizure medication. At eight months old, without further seizures, according to the mother, he was found dead four hours following a feeding of diluted Coca-Cola. His death was attributed to chronic meningoencephali­ tis owing to HSV.

Postm ortem Findings T oxicologic te s tin g o f p o st-m o rtem blood was negative for opiates, am pheta­ m ines, cocaine, and phenobarbital. C on­ gestion and edem a of the lungs w ere o b serv ed , b u t no o th e r a b n o rm a litie s w ere observed in the general autopsy. T h e n e u ro p a th o lo g ic e x a m in a tio n re v e a le d a fixed b ra in w e ig h in g 800 grams (normal 850 grams). T he circle of W illis was intact. T he right and left lat­ eral ventricles w ere m ildly dilated w ith the left lateral ventricle bein g slightly larger than the right. A discrete subcortical cyst was seen in the left m id posterior inferior frontal gyrus and m easured 2 x 2 x 0.8 cm (figure 1). T he corpus callosum was m arkedly th in n ed and varied from one to three mm in the maximal thick­ n e s s . T h e c e n tr u m s e m io v a le w as re d u c e d in th e left frontal lo b e , b u t appeared normal in the right frontal lobe. T h e d e e p basal n u c le i an d tem p o ral lobes w ere intact. T h e brain stem and cerebellum w ere normal. M icro sco p ically , focal p e riv a s c u la r lym phoid cell infiltrates w ere seen in the m idbrain, cerebellum , and frontal cortex

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VOLK, PARKER, AND T E P P E R

FIGURE 1. (Coronal section)-A discrete 2 x 2 x 0.8 cm subcortical cyst was found in the left m id posterior-inferior frontal gyrus.

with astrogliosis. Cystic gliotic changes in left m id posterior inferior frontal gyrus w ere associated with diffuse astrogliosis in th e c e n tru m sem iovale, m icroglial n o d u le s , g ra n u lo m a to id le sio n s w ith m ultinucleated giant cells, and focal calcospherites. Some calcospherites w ere seen in m ultinucleated giant cells (figure 2). A djacent dem yelination in the cen­ trum sem iovale and corpus callosum with chronic vasculitis was seen in the left frontal lobe adjacent to the cystic gliotic lesion. R educed m yelin w ith astrogliosis was p resent in the left pyram id consis­ tent w ith secondary dem yelination. Acidfast, m e th e n a m in e silv e r, a n d G ram stains show ed no microbes. Im m unoperoxidase stains for herpes sim plex virus 1

and herpes simplex virus 2 w ere nega­ tive. U ltrastructural studies of the cere­ bral lesion revealed no viral particles. Com m ent Cerebral malakoplakia has b een asso­ ciated with encephalitis owing to herpes sim plex virus (HSV), a cq u ired by the neonate from the m aternal birth canal (table I) and includes five infants. A onem onth-old infant girl w ith rising HSV titers suggestive of infection had a left frontal lobe cortical cystic lesion consis­ tent w ith m alakoplakia.1 A two-year-old girl w ith right frontal lobe malakoplakia also had existing HSV

CEREBRAL MALAKOPLAKIA W ITH NEONATAL HERPES VIRUS IN F E C T IO N

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e n c e p h a litis .1 A th re e -m o n th -o ld boy with m alakoplakia of the brain and aorti­ tis was o b se rv e d w ith n eo n atal HSV infection.11 A three-m onth-old infant boy with cerebral malakoplakia of the brain had herpes sim plex m eningoencephalitis diagnosed at two w eeks.5 A three-w eekold girl with right tem poral lobe mala­ koplakia had rising serum HSV titers

, 5

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and a m other w ith p o st-p a rtu m HSV 2 infection.7 T hree m ajor features in the c u rre n t baby included (a) neonatal herpes sim ­ plex virus 2 infection, (b) cerebral m ala­ koplakia, and (c) seizures. T he HSV 2 infection seem s to have dam aged cere­ bral tissue leading to epilepsy. This virus is transm itted from person to person by

304

VOLK, PARKER, AND T E P P E R

TABLE I Cerebral Malakoplakia Associated with Probable Herpes Virus (HSV) Encephalitis Reference

Sex

Chandra, & Kapur: Arch. Pathol. Lab. Med. .122:688-692, 1979.

Age

Location

Course

F 1 month

Left frontal lobe

2 Week hospital stay

Rising HSV titer

Chandra & Kapur: Arch. Pathol. Lab. Med. 103: 688-692,1979.

F

Right frontal lobe

Encephalitis

Severe neurological impairment

Mirra: Am. J. Clin. Pathol. 56:104-110,1971.

M 3 months

Cerebral cortex

Died at 1.5 years

Associated aortitis

Gorde, Borit, et al: M 2 weeks Bull. Los Angeles Neurol. Soc. 42:6-11, 1978.

Right frontal lobe

Recovery over 5 months

Siezures

Ho-Chang, Nigro, et al: Arch. Pathol. Lab. Med. 104:494-495. 1980.

F

Right temporal lobe

Severe psychomotor delay

Rising HSV titer

Current:

M 13 days

Left frontal lobe

Died at 8 months

Seizures with scalp lesion which yielded HSV

2 years

3 weeks

contact w ith infected cutaneous vesicles and can occur during the second stage of lab o r w ith fetal c o n ta c t w ith g e n ita l herpes. Perinatal infectious risk is high­ est w hen the prim ary genital infection has occurred w ithin w eeks of delivery.4 N eonatal death is usually due to dissem i­ nated infection w ith HSV-2 w hich infects the liver, adrenals, and any other organs. D eath occurs from infection of the brain, heart, and/or lu n g s.12 N eonatal herpes can in fe c t th e c e re b ra l h e m isp h e re s, basal ganglia, b rain stem , c e re b e llu m , spinal cord, or any com bination. Microg­ lial proliferation and intra-nuclear inclu­ sion bodies in neurons and glial cells are seen. Perivascular inflam m ation occurs, b u t it is not as striking as in other affected organs. W idespread necrosis of the cere­ b ru m can ca u se m u ltic y stic c e re b ra l d e g e n era tio n ,6 as seen in our patient.

Comment

According to Nahmias e t al,12 67 percent of symptom atic neonates have dissem i­ nated disease and 33 percent have local­ ized involvem ent to the brain, eye, skin, or m outh. Approximately 50 percent of symptom atic neonates w ith herpes virus show cen tral nervous system in v o lv e­ m ent. M ortality rate is 62 percent. Among survivors, 50 p e rc e n t have p e rm a n en t sequelae.12 C hildren w ith HSV encepha­ litis rarely survive w ithout neurological deficits.3,4 M ost neonates w ith dissem i­ n a te d HSV infection are sym ptom atic w ithin the first w eek after delivery, but they may show clinical m anifestations as m uch as th ree w eeks later.6 V esicular cutaneous lesions usually appear on the scalp or buttocks in 30 p ercent.12 H erpes encephalitis is m anifested by irritability and seizures, w hich m ay be focal or generalized and often refractory

CEREBRA L MALAKOPLAKIA W ITH NEONATAL H E R PES VIRUS IN F E C T IO N

to therapy. T he E E G is usually abnorm al w ith slow waves or spike discharges. The CSF shows a leukocytosis w ith lym pho­ cytic p redom inance. E rythrocytes may b e s e e n w h e n h e m o rrh a g ic n e c ro sis develops. T he C S F protein concentration is elevated.12 Patients w ith HSV-2 may d e v e lo p s e v e re n e u ro lo g ic d am ag e. According to Corey e t al,2 50 percent of infants w ith HSV-2 encephalitis treated w ith acyclovir w ere m icrocephalic; 57 p e rc e n t had e p ile p sy ; 64 p e rc e n t had ophthalm ic disease; 64 percent had cere­ bral palsy; and 57 p e rc e n t w ere m en­ tally retarded. Since cerebral m alakoplakia is rare, its sequelae are not w ell defined. Mortality, in this condition, m ay exceed 50 p e r­ cent.15 T he extra-genitourinary involve­ m ent has b een linked w ith im m unosup­ p ressio n , in c lu d in g A ID S. A specific d e fe c t in in tra c e llu la r k illin g m ec h a ­ nisms m ay be the underlying cause.9 The HSV infection could cause incom plete histiocytic phagocytosis of necrotic cellu­ lar debris, resulting in subsequent m in­ e ra liz a tio n a n d m a la k o p la k ia .16 T his m echanism , w hich has b e e n described w ith bacterial products, has not b een rec­ ognized w ith viruses. E pilepsy in our patien t w ith chronic m eningoencephalitis was associated with sudden unexpected death (SUD), which varies from one in 500 to 1000 epileptic persons.8 T he m echanism deals w ith con­ nections b e tw e e n th e c ereb ral cortex, lim bic system , and hypothalam us w ith the heart via the sym pathetic autonom ic nervous system. Abnormal cerebral dis­ charges in seizures occur w ith potentially fatal c ard iac d y srh y th m ia s, in c lu d in g v e n tric u la r fib rilla tio n a n d a sy sto le.8 Although anticonvulsant m edication can ab o lish th e s e a sso c ia te d cardiac d y s­ rhythm ias, m ost victim s of SUD show s u b th e ra p e u tic or no b lo o d lev els of a n tic o n v u lsa n t m ed icatio n at autopsy. Transition from late sleep stage to wakeful­ ness can also induce epileptic discharges.8

305

O ur p atien t was infected w ith HSV 2 e ith e r th ro u g h in tra u te rin e ro u te s or d u rin g labor. T h e virus colonized the baby’s skin, entered his blood stream and seem s to have settled in the left frontal lobe follow ing virem ia. Necrosis in ter­ fere d w ith norm al c e re b ra l e le c tric a l d is c h a r g e s , c r e a tin g e p ile p s y . T h e a lte re d im m u n e reactio n in th e b ab y resulted in malakoplakia. M onths later, anticonvulsant m edication was discontin­ ued. T h e baby ex p e rien c e d abnorm al electrical discharges from his dam aged left frontal lobe, w hich stim ulated the sym pathetic nervous system, resulting in a fatal cardiac dysrhythm ia. Acknowledgment Thanks are extended to John J. Kepes, M.D. of the Department of Pathology at the University of Kansas Medical Center in Kansas City, Kansas, for his assistance in identifying and classifying the lesion in the current case report.

R eferences 1. C h a n d r a , R. S. and K a p u r S.: Malakoplakia of the Brain. Arch. Pathol. Lab. Med. 103:688— 692, 1979. 2. C o r e y , L., W h i t l e y , R. J ., and S t o n e , T.: Dif­ ference between HSV 1 and HSV 2 neonatal encephalitis in neurological outcome. Lancet I : 1-4, 1988. 3. F r e n t z , J. M., G o h d , R. S., and W o o d y , N. C.: Untreated neonatal herpes simplex men­ ingitis without apparent neurological damage. J. Pediat. 85:77-79, 1974. 4. G e r s h o n , A. A., F i s h , I., and B r u n e l l , P. A.: Herpes simplex infection of the newborn. Am. J. Dis. Child. 224:739-741, 1972. 5. G r o d e , M. L., B o r i t , A., V a n D e V e l d e , R. L., W e i n e r , L., and C a r t o n , C . A.: Cere­ bral Malakoplakia. Bull. Los Angeles Neuro­ logical Soc. 43:6-11, 1978. 6. Haynes, R. E.: The spectrum of herpes sim­ plex virus infections in children. Southern Med. J. 69:1069-1078, 1976. 7. H o - C h a n g C ., N i g r o , M. A., and P e r r i n , E. V.: Cerebral malakoplakia and neonatal herpes simplex infection. Arch. Pathol. Lab. Med. 204:494-495, 1980. 8. J a y , G . and L e e s t m a , J.: Sudden death in epi­ lepsy, a comprehensive review of literature and

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proposed m echanism s. Acta N eurologica Scand. 63 Suppl 82:5-59, 1981. 9. LOU, T. Y. and T e P L IT Z , C.: Malakoplakia: pathogenesis and ultrastructural morphogene­ sis, a problem of altered macrophage response. Human Pathol. 5:191-207, 1974. 10. MlCHAELIS L. a n d GUTMANN C.: U e b e r e in s c h lu s s e in b la s e n tu m o r e n . Z . K lin ic h e M e d .

47:208—215, 1902. 11. M lRRA, J. M .: Aoritis and malakoplakia-like lesion of the brain in association with neonatal herpes simplex infection. Am. J. Clin. Pathol. 56:104-110, 1971. 12. N a h m i a s , A. J., A l f o r d , C. A ., and K o r o n e s , S. B.: Infections of newborn with herpesvirus hominus. Adv. Pediat. 27:185—226, 1970.

13. P r i c e , H. M., H a m r a h a n , J. B., and F i l i r i d a , R. G.: Morphogenesis of calcium laden cyto­ plasmic bodies in malakoplakia of the skin: an electron microscopic study. Human Pathol. 4: 381-394, 1973. 14. S m i t h -S i n c l a i r , C ., Ka h n , L. B., and C y r v e s , C .: Malakoplakia in childhood; A case report with ultrastructural observation and review of literature. Arch. Pathol. 99:198-203, 1975. 15. S t a n t o n , M . J. a n d M a x t e d M .: M a la k o ­ p la k ia , a s tu d y o f t h e li te r a tu r e a n d c u r r e n t c o n ­ c e p ts o f p a th o g e n e s is , d ia g n o s is a n d t r e a tm e n t. J. U ro l. 225:129-146, 1981.

16.

J. Y. and L A T T E S , R.: Malakoplakia of colon and retroperitoneum. Am. J. Clin. Pathol. 44:20-31, 1965.

TERNER