Lissencephaly-Pachygyria Associated With Congenital Cytomegalovirus Infection C. Hayward, MD; David S. Titelbaum, MD; Robert R. Robert A. Zimmerman, MD

Jean

Clancy, MD;

Abstract We report the presence of major cerebral migrational defects in five severely, multiply handicapped children with congenital cytomegalovirus (CMV) infection. These patients had both computed tomographic (CT) scan and magnetic resonance imaging (MRI) evidence of marked migrational central nervous system defects consistent anatomically with the spectrum of lissencephaly-pachygyria, a disorder commonly idiopathic or associated with chromosomal abnormalities or with unknown early gestational insults. Neuroradiologic features included broad, flat gyri, shallow sulci, incomplete opercularization, ventriculomegaly, periventricular calcifications, and white-matter hypodensity on CT scans or increased signal intensity on long-TR MRI scans. Evidence for congenital CMV infection included prenatal onset of microcephaly, periventricular calcifications, neonatal jaundice, hepatomegaly, elevated CMV-specific immunoglobulin M, or viral isolation from urine. Previous reports of the neurologic sequelae of CMV have emphasized varying degrees of psychomotor retardation, cerebral palsy and epilepsy due to polymicrogyria, periventricular calcification, microcephaly, or rarely, hydrocephalus. Our patients appear to represent extremely severe examples of the effects of CMV on neurologic growth, maturation, and development. Recognition of these severe migrational abnormalities was improved by use of MRI, a technique that affords superior definition of the nature and extent of gyral and white-matter abnormalities. We suggest that these abnormalities may be more common than has previously been recognized. ( J Child Neurol 1991;6:109-114).

infection with cytomegalovirus has been estimated to occur in 0.5% I to 2.4% of newborn infants in the United States. The majority of these infants are asymptomatic at birth, but some may develop subtle cognitive deficits during later childhood. However, a small number of these congenitally infected infants display severe psychomotor retardation, a finding that has been variably attributed to associated neuropathologic findings of porencephaly, micrencephaly, polymicrogyria, periventricular calcifications, and hydrocephalus.2-4 Numerous epidemiologic studies have

ongenital C(CMV)

Received

August 14, 1989. Received revised March 1, 1990. for publication March 12, 1990. From the Division of Neurology, Children’s Hospital of Philadelphia (Drs Hayward and Clancy) and the Departments of Neurology (Drs Hayward and Clancy), Radiology (Drs Titelbaum and Zimmerman), and Pediatrics (Dr Clancy), University of Pennsylvania School of Medicine, Philadelphia, PA. Abstract presented at the Child Neurology Society Meeting

to define the risk factors most predictive of poor outcome, including timing of the infection, maternal immunity, and neurologic abnormalities such as microcephaly and chorioretinitis.I,5-8 We report five children with congenital CMV infection and severe neurodevelopmental delay who had associ-

attempted

ated

findings on magnetic resonance imaging (MRI) changes typical of lissencephaly-pachygyria. We postulate that these changes date their infections to of

before the first three to four months of gestation. Neurodevelopmental assessment of these children revealed a uniformly poor outcome including severe mental retardation, spastic quadriparesis, and seizures.

Accepted

in

Halifax, Nova Scotia, September 15-18, 1988.

Address correspondence to Dr Robert R. Clancy, Division of The Children’s Hospital of Philadelphia, 34th Street & Civic Center Blvd, Philadelphia, PA 19104.

Neurology,

Materials and Methods Children followed in the Pediatric Neurology Clinic of The Children’s Hospital of Philadelphia between January and September 1988 with a history of symptomatic congenital CMV infection were identified from clinic chart review to determine neuroimaging abnormalities. Charts were reviewed for presence of neurologic signs and symptoms in

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Cranial Imaging Studies The CT and MRI scans revealed clear evidence of migrational central nervous system defects characteristic of lissencephaly or changes like those seen in pachygyria (Table 2). These features included a smooth cortical surface or broad gyri, colpocephaly, incomplete opercularization, thickened cortical mantle, and sparse arborization of the white matter (Fig-

the neonatal period. Original birth records were obtained to document congenital infections. All patients were examined by one of the authors (J.H.) to determine present neurologic condition and developmental quotient, defined as the ratio of developmental age to chronologic age. Computed tomography (CT) scans (GE 8800, General Electric Medical Systems, Milwaukee, WI) and MRI scans (GE Signa 1.5 Tesla, General Electric Medical Systems-Signa, Milwaukee, WI) were performed in a routine clinical fashion and reviewed by the Neuroradiology Department and then by the authors (R.Z., D.T.).

through 5). In some cases the complete radiologic spectrum of lissencephaly was present, whereas in others, findings such as those of broad gyri with some sulcal formation were incomplete. In addition, the patients who also had CT scans frequently showed varying degrees of cerebral calci-

ures

CMV infection was determined to be excretion of CMV in the urine during the first week of life or elevated anti-CMV immunoglobulins (Ig) M or G at birth. The general physical examinations were reviewed for presence of other stigmata of congenital infection such as thrombocytopenia, hepatomegaly, and

Congenital

present if there

was

1

jaundice.

Results Patients Five children (four boys and one girl) with a history of symptomatic congenital CMV infection and subsequent severe psychomotor retardation were identified (Table 1). Their ages at the time of this study ranged from 13 months to 6 years. All patients had severe neurodevelopmental delay manifested by spastic quadriparesis and had developmental quotients below 30. All developed seizures in the first year of life.

Documentation of Congenital CMV Infection The diagnosis of congenital CMV infection was established by laboratory evidence of congenital infection (positive anti-CMV IgM or positive culture of urine for CMV) and by clinical signs of systemic infection in the newborn period such as jaundice

(three cases), petechiae (four cases), hepatosplenomegaly (four cases), and microcephaly (five cases). There

were no cases

of chorioretinitis

(Table 1).

FIGURE 1 MRI ened gray matter.

Ti-weighted

scan

of

patient

1 shows

diffusely

thick-

TABLE 1

Neonatal

Signs

and

Laboratory Evidence

of

Congenital

CMV cytomegalovirus; HSM hepatosplenomegaly; CR not done. *Seizures in the first year of life. tAfter 1 year of age. $Persistently positive cultures after 1 year. =

=

=

CMV Infection in Five Patients With

chorioretinitis; MC

=

microcephaly; DQ

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Lissencephaly

=

development quotient;

ND

=

TABLE 2

Comparison of Radiographic Features in CMV Patients Neuropathologic Features of Classic Lissencephaly

CMV

=

absent;

cytomegalovirus; ±

=

CT

=

computed tomography;

incompletely present;

MRI

=

magnetic

ND

=

With Standard

not

resonance

done;

imaging;

+ *

= =

present; - = could not be

determined. _

fication, infection

a common

consequence of congenital CMV and 5).

(Figures 2A, 3A, 4A,



Discussion Since the neuropathologic effects of congenital CMV infection were first described in the early 1900s,3 many investigators have followed congenitally infected children to determine their neurodevelopmental outcome. The majority of asymptomatic infected patients remained overtly well without major neurodevelopmental handicaps.I,6,9,10 Still others may have hearing loss or subtle learning, cognitive, and behavioral disabilities demonstrable in later childhood by formal neuropsychological testing. An

important minority of infants with congenital CMV infection were symptomatic at birth and displayed conspicuous signs of systemic infection such as thrombocytopenia, hepatosplenomegaly, and jaundice. The incidence of later severe neurodevelopmental sequelae in this group ranges from 15% to

75%.~&dquo; A variety of cerebral malformations, but only

of lissencephaly, in association with congenital CMV infection has been described.l2 Lissencephaly is a severe cerebral migrational malformation attributed to dysgenetic or early gestational insults. Dobyns et a113-15 have reported the most extensive collection of these patients. Common genetic syndromes associated with lissencephaly include one case

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FIGURE 2 Unenhanced CT scan of patient 2 (A) shows thickened gray matter, hypodensity of white matter, and focal calcifications. TI-weighted MRI scan of patient 2 (B) shows thickened gray matter.

FIGURE 3 Unenhanced CT scan of patient 3 (A) shows thickened gray matter, hypodensity of white matter, and focal calcifications. Proton-density MRI scan of patient 3 (B) reveals thickened gray matter and marked white-matter hyperin-

tensity.

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FIGURE 5

Sagittal T,-weighted sive atrophy.

MRI

scan

of

patient

5 shows exten-

include a smooth brain surface that lacks the normal patterns of gyri and sulci and displays microscopic anomalies in the architecture of cortical lamination. The expected organization of the cortex into six cell layers is replaced by a more simplified four layers or even a complete lack of distinctive lamination. Associated findings include subcortical, periventricular, and cerebellar heterotopic gray matter. Pachygyria is a related but less extreme example of the same malformation in which the gyri are broad and thick instead of absent.16,1~ Many of these more gross findings can be seen using MRI

cephaly-pachygyria

scans. 18

Norman et al 12 reported one infant with lissencephaly and the neuropathologic findings of cytomegalic inclusion disease. In this case the anatomic findings included micrencephaly with small, smooth, nonsulcated hemispheres; dilated ventricles with periventricular calcifications; and discolored,

FIGURE 4

Unenhanced CT scan of patient 4 (A) shows periventricular calcification, thickened gray matter, and white matter

hypodensity. Tl-weighted

MRI of

patient

4

(B)

shows

thickened gray matter.

Miller-Dieker (karyotype 17p-), Walker-Warburg, and Norman-Roberts syndromes. The causes of the other cases were unknown or were thought to be a variety of potent, early gestational insults. The essential neuropathologic findings in lissen-

thickened leptomeninges. Microscopic examination showed patchy neuronal loss without demarcation of the cortex into layers, diffuse subcortical calcifications, and neuronal loss throughout the cerebellum and brain stem. Our patients clearly represent one extreme in the clinicopathologic spectrum of congenital CMV infection. Their neuroimaging studies show varying

degrees of, changes like those seen in lissencephalypachygyria and implicate cerebral CMV infection 113

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early during gestation, before completion of normal cortical neuronal migration. Although neuropathologic correlates are not available for these patients, in the literature

differences between the microscopic findings in genetically determined lissencephaly and those seen following congenital infection. Another possible cause of the MRI appearance of thickened cortex is polymicrogyria, a migrational abnormality thought to occur dur4 ing the fourth and fifth months of gestation.4 Clinical outcome in all of these patients is similar and presumably reflects the widespread disruption of brain function stemming from the gross pathologic disturbances and migrational abnormalities. The small number of patients in our series cautions against predicting uniformly poor outcomes for all patients with similar findings. We suspect that the more ubiquitous use of MRI scans will identify many additional cases in the future, and these will provide the necessary data from which firmer conclusions might be drawn. one case

suggests

some

Forsgren M, Ivarsson S-A, et al: Congenital cytomegalovirus infection: On the relation between type and time of maternal infection and infant’s symptoms. Scand J Infect Dis

5. Ahlfors K,

1983;15:129-138. 6. Monif GRG, of maternal in

gestation

Egan EA II, Held B, Eitzman DV: The correlation cytomegalovirus infection during varying stages with neonatal

involvement.J Pediatr 1972;80:

17-20. 7.

Pass RF, Stagno S, et al: Early clinical manifestations and intellectual outcome in children with symptomatic

Conboy TJ,

congenital cytomegalovirus infection.J Pediatr 1987;111: 343-348. 8.

9.

10. 11. 12. 13.

Stagno S, Pass RF, Dworsky ME, et al: Congenital cytomegalovirus infection: The relative importance of primary and recurrent maternal infection. N Engl J Med 1982;306:945-949. Saigal S, Lunyk O, Larke RPB, Chernesky MA: The outcome in children with congenital cytomegalovirus infection. Am J Dis Child 1982;136:896-901. Hanshaw JE: Congenital cytomegalovirus infection: A fifteen year perspective. J Infect Dis 1971;123:555-561. Collaborative Study Group: Cytomegalovirus infection in the North West of England. Arch Dis Child 1970;45:513-522. Norman MG, Roberts M, Sirois J, Tremblay LJM: Lissencephaly. CanJ Neurol Sci 1976;3:39-46. Dobyns WB, Gilbert EF, Opitz JM: lissencephaly syndromes, letter.

Further comments on the Am J Med Genet 1985;

22:197-211. 14.

References 1. Pass RF, Stagno S, Myers GJ, Alford CA: Outcome of symptomatic congenital cytomegalovirus infection: Results of long-

15.

longitudinal follow-up. Pediatrics 1980;66:758-66. Hanshaw JB: Cytomegalovirus infections. Pediatr Rev 1981;

16.

term

2.

2:245-251. 3. Navin JJ, Angevine JM: Congenital cytomegalic inclusion disease with porencephaly. Neurology 1968;18:470-472. 4. Bignami A, Appicciutoli L: Micropolygyria and cerebral calcification in cytomegalic inclusion disease. Acta Neuropathol

(Berl) 1964;4:127-137.

Dobyns WB, Stratton RF, Greenberg F: Syndromes with lissencephaly. I. Miller-Dieker and Norman-Roberts syndromes and isolated lissencephaly. Am J Med Genet 1984;18:509-526. Dobyns WB: Developmental aspects of lissencephaly and the lissencephaly syndromes. Birth Defects 1987;23:225-241. Daube JR, Chou SM: Lissencephaly: Two cases. Neurology 1966;16:179-191. RM, Richman DP, Caviness VS Jr: Lissencephaly and

17. Stewart

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pachygyria: An architectonic and topographical analysis. Acta Neuropathol (Berl) 1975;31:1-12. Krawinkel M, Steen H-J, Terwey B: Magnetic resonance imaging in lissencephaly. EurJ Pediatr 1987;146:205-208.

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Lissencephaly-pachygyria associated with congenital cytomegalovirus infection.

We report the presence of major cerebral migrational defects in five severely, multiply handicapped children with congenital cytomegalovirus (CMV) inf...
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