Congenital and Perinatal Cytomegalovirus Infection

85.1 Clinical Features

and Laboratory Investigations Cytomegalovirus (CMV) is a member of the Her- pesviridae family of large DNA viruses, along with herpes simplex virus types 1 and 2, Epstein–Barr virus, varicella-zoster virus, and human herpes virus- es 6 and 7. These viruses share the biological proper- ties of latency and potential reactivation. Infection with one member of the family does not confer im- munity against infection or disease with the other members of the herpes family. Naturally acquired CMV infection induces cross-reactive immunity to infection with new strains of CMV, but this protection is not complete, because reinfection with a second strain of CMV has been documented.

Infection with CMV occurs in several ways: first, by close or intimate contact of either a sexual or nonsex- ual nature with another person who is shedding the virus in bodily secretions; secondly, vertically from mother to infant by transplacental infection; thirdly, by blood product transmission from a CMV-seropos- itive donor. In congenital and neonatal CMV infec- tion, the mother plays a dominant role. Infection of the mother with CMV can be either a primary infec- tion or a reactivation of an earlier infection. The risk of congenital CMV infection in the infant is much higher in the case of a primary infection in the moth- er than in the case of reactivation of an old infection.

The transmission rate in a primary infection is 40–50%, whereas it is approximately 1–2% in recur- rent infection. Infants may also be infected during de- livery from CMV-infected maternal vaginal secre- tions or, postnatally, by infected breast milk. Children not congenitally or perinatally infected may acquire the disease during the toddler or preschool years by contact with family members or other children. Blood transfusions can also be a source of CMV infection;

donor-to-recipient transmission of CMV has been documented. CMV may also be transmitted and pro- duce a congenital infection if a pregnant woman or her fetus receives a blood product transfusion from a CMV-seropositive donor.

Approximately 1% of all newborns are congenital- ly infected with CMV, making CMV the most com- mon congenital infection. Of the neonates infected with CMV, approximately 10% will have symptoms at birth that are commonly associated with congenital CMV disease, including intrauterine growth retarda-

tion, jaundice, hepatosplenomegaly, petechiae or pur- pura, and pneumonia. Hepatomegaly, splenomegaly, and petechiae are the most common. The liver is usu- ally smooth and nontender and commonly measures 5 cm or more below the right costal margin. Ascites may be present prenatally and persist postnatally for 1–2 weeks. The hepatomegaly usually resolves by 3 months of age, and persistence beyond 1 year is high- ly unusual. Mild hepatitis is usually present. Hyper- bilirubinemia, on the other hand, may be quite strik- ing, with very high conjugated (direct) bilirubin lev- els. The abnormal results of liver function tests grad- ually resolve during the first few weeks of life. Chronic hepatitis due to congenital infection with CMV is un- usual but may occur. Enlargement of the spleen is very common in congenital CMV infection, and in some cases it may be the only abnormality detectable at birth. Petechiae in congenital CMV disease are usu- ally pinpoint and generalized over the infant’s trunk and extremities. If present at birth, they can be tran- sient and resolve within 48–72 h. They can be the only apparent manifestation of CMV infection. How- ever, more commonly, the triad of hepatomegaly, splenomegaly, and petechiae is seen. Petechiae are usually, but not always, accompanied by thrombo- cytopenia, and platelet counts in the first few weeks of life range from 2,000/mm

to 125,000/mm

. Hemolyt- ic anemia may also be present. Pneumonitis is unusu- al but, if present, it is usually a severe, interstitial pneumonitis occurring in the context of a diffuse, multisystem infection. Post-transfusion CMV infec- tion in neonates, especially premature infants, may cause a syndrome of shock, lymphocytosis, and pneu- monitis. The mortality rate of neonatally sympto- matic CMV infection is 10–30%.

CNS manifestations are common in neonates with a symptomatic CMV infection and include lethargy, poor feeding, seizures, hypertonia or hypotonia, microcephaly, chorioretinitis, and sensorineural deafness. Ocular involvement with CMV occurs in 10–20% of symptomatic infants. Most commonly it produces a chorioretinitis that is usually old and inac- tive at birth. The retinitis is usually unilateral but can produce blindness if the macula is involved, as well as strabismus and optic atrophy. Congenital CMV and congenital toxoplasmosis produce similar lesions;

however, congenital CMV characteristically does not produce microphthalmia or cataracts, and alternative diagnoses, such as congenital rubella or toxoplasmo-

Congenital and Perinatal Cytomegalovirus Infection

Chapter 85

sis or metabolic disorders, should be considered if these eye findings are present. Microcephaly may be present at birth. It may be part of the overall small size of a growth-retarded infant or may be disproportion- ate and accompanied by normal weight, length, and chest circumference. Infants may also have septal de- fects, biliary atresia, inguinal hernias, hip dislocation, and other musculoskeletal abnormalities. In addition, infants with toxoplasmosis, herpes simplex, syphilis, and HIV infections may be coinfected with CMV, and infants with metabolic disorders may have congenital CMV infection as well.

About 90% of the infants with an intrauterine CMV infection are asymptomatic at birth. Ten to fifteen per- cent of the infants with a congenital CMV infection that is clinically silent in the neonatal period, and al- most all neonates with a neonatally symptomatic in- fection, develop persistent problems, most commonly neurological impairment, sensorineural hearing deficits, and decreased vision related to chorioretinitis or optic atrophy. Approximately half of the infants with symptomatic and 15% of infants with asympto- matic congenital CMV infection will have or develop an associated hearing loss. The hearing loss may still develop many years after the initial infection and may fluctuate in severity. The vision loss, too, may be pro- gressive or of late onset. The severity of the neurolog- ical impairment is highly variable.At the severe end of the spectrum are profound mental deficiency and mo- tor handicap, often with serious spasticity; at the mild end are learning, behavioral, and motor coordination problems. Epilepsy may occur, in particular in patients with more severe handicap. The encephalopathy has never been observed to be progressive.

These numbers indicate that congenital CMV is one of the leading causes of mental deficiency. The numbers also indicate that most infants with a con- genital CMV infection have no sequelae at all.

The diagnostic time frame for congenital or peri- natal CMV infection is only the first 3 weeks after birth. CMV infection is very common and a postnatal infection may readily occur. It is therefore important that the test is performed soon after birth. Positive tests after the age of 3 weeks can indicate either a con- genital, perinatal, or postnatal infection.

An important test for the diagnosis of congenital CMV infection in neonates is the isolation of the virus from urine, saliva, or tissue obtained during the first 3 weeks of life. All infants in whom the diagnosis is sus- pected should have a viral culture performed. The virus is usually present in a very high titer, and cul- tures are commonly positive within 2–3 days of incu- bation. Excretion of the virus in the urine may persist for years.

Standard serological tests, such as detection of CMV IgG and IgM antibodies, alone or as part of a TORCH titer panel, are commonly used to diagnose

congenital CMV infection, but this approach has sev- eral drawbacks.Although the absence of IgG antibod- ies to CMV in cord or infant blood probably rules out congenital CMV infection in an immune-competent mother–infant pair, the presence of IgG antibodies has limited value, because 50–80% of women of childbearing age will have anti-CMV IgG antibodies that will be transplacentally transferred to their in- fant. A significantly higher titer of IgG antibodies to CMV in the infant than in the mother may imply an active congenital infection, but in practice this differ- ence is usually difficult to ascertain. Serological sam- ples obtained serially at 1, 3, and 6 months may rule out congenital infection if the level of CMV antibod- ies gradually declines, but if the levels persist, serolog- ical test results alone cannot determine whether the infection was of congenital or postnatal origin. The presence of IgM antibodies at birth, however, is high- ly suggestive of a congenital CMV infection, provided the test was performed properly, but confirmatory urine culture for CMV is recommended for a defini- tive diagnosis. It is important to realize that a negative CMV IgM antibody test does not exclude the diagno- sis of congenital infection. Anti-CMV IgM antibodies are found in only 70–80% of the congenitally infected infants. More recently, the PCR technique has been in- troduced to demonstrate the presence of the virus in tissue or body fluids. CMV DNA has been detected by PCR in urine, saliva, and CSF.

The biggest problem with establishing the diagno-

sis of congenital CMV has been that it cannot be con-

firmed after the neonatal period. In the absence of

overt neonatal signs, infants with congenital or peri-

natal CMV infection are not tested for the presence of

the virus, viral DNA, or antibodies within the appro-

priate time frame of 3 weeks. The infants with a

neonatally asymptomatic congenital CMV infection

who develop neurological sequelae usually come to

medical attention after the age of 6–9 months because

of developmental delay or hearing loss, and at that

time it is no longer possible to confirm the diagnosis

with conventional techniques. However, the PCR

technique allows a delayed diagnosis if neonatal body

fluids are still available. The Guthrie card is usually

the only source of neonatal blood kept beyond the

neonatal period. The Guthrie card is the filter paper

used to collect blood spots in the neonatal period for

neonatal screening tests. These cards are stored for a

variable number of months to years. The introduction

of PCR on Guthrie cards for the diagnosis of congen-

ital CMV creates the opportunity for correct diagno-

sis beyond the neonatal period. The sensitivity of the

PCR for CMV DNA on Guthrie cards is 100% and the

specificity is 99%. The only disadvantage of the test is

that the PCR is negative if the neonate no longer had

viremia. The chance that a neonate with a congenital

CMV infection no longer has viremia is very small but

may exist, especially if the CMV infection occurred long before birth.

In the neonate with congenital infection, the differ- ential diagnosis includes any of the TORCH (toxo- plasmosis, rubella, CMV, herpes simplex) agents. Con- genital toxoplasmosis may mimic congenital CMV in- fection. In parts of Europe, particularly France and Belgium, congenital toxoplasmosis is a common and significant problem. It is less common in the USA.

Other congenital infections to be considered include lymphocytic choriomeningitis virus (LCMV) infec- tion, syphilis, enteroviral disease, and human immun- odeficiency virus (HIV) infection.

85.2 Pathology

Pathological data in congenital and neonatal CMV in- fections stem from lethal infections and are therefore highly biased towards the severe end of the clinical spectrum. Some of these infants were stillborn; others survived for several days or weeks. Microcephaly was present in most of the patients. Other findings includ- ed meningoencephalitis, periventricular necrosis with associated calcifications, more diffuse calcifica- tions, extensive cortical necrosis with calcifications frequently involving the convexity of the gyri, distur- bance of neuronal migration (ranging from lissence- phaly to polymicrogyria), ventriculomegaly, cerebel- lar hypoplasia, and marked disruption of the cerebel- lar architecture. In about half of the cases intranu- clear inclusion bodies are found, while systemic inclusion bodies are found in nearly all cases, in par- ticular in the kidney, lungs and liver.

In clinical specimens, one of the classic hallmarks of CMV infection is the cytomegalic inclusion cell.

These massively enlarged cells (the property of cyto- megaly gave CMV its name) contain intranuclear inclusions, which histopathologically have the ap- pearance of owl’s eyes. The presence of these cells indicates productive infection, although they may be lacking even in actively infected tissues. In most cell lines, CMV is difficult to culture in the laboratory, but in vivo infection seems to involve chiefly epithe- lial cells, and, with severe disseminated CMV disease, involvement can be observed in nearly all organ sys- tems.

There are no pathology data on the nature of the white matter abnormalities observed in children with a mild neurological handicap.

85.3 Pathogenetic Considerations

CMV is a member of the family of eight human her- pes viruses, and is designated human herpes virus 5 (HHV-5). It is the largest member of the herpes virus

family, with a double-stranded DNA genome of more than 240 kilobase pairs, capable of encoding more than 200 proteins. The function of most of these pro- teins remains unclear. As with the other herpes virus- es, the structure of the viral particle is that of an icosahedral capsid, surrounded by a lipid bilayer out- er envelope.

Better understanding of the process of viral repli- cation provides insights into molecular mechanisms of immunity and opens therapeutic windows. CMV replicates very slowly in cell culture, reflecting its very slow pattern of growth in vivo (in contrast to herpes simplex virus infection, which progresses very rapid- ly). The replication cycle of CMV is divided temporal- ly into three regulated classes: immediate early, early, and late.

Immediate early gene transcription occurs in the first 4 h following viral infection, and key regulatory proteins are made which allow the virus to take con- trol of cellular machinery. The major immediate ear- ly promoter of the CMV genome involved in this part of the process is one of the most powerful eukaryotic promoters described in nature, and has been exploit- ed in modern biotechnology as a useful promoter for driving gene expression in gene therapy and vaccina- tion studies.

Following synthesis of immediate early genes, the early gene products are transcribed. Early gene prod- ucts include DNA replication proteins and some structural proteins.

Finally, the late gene products are made approxi- mately 24 h after infection, and these proteins are chiefly structural proteins that are involved in virion assembly and egress. Synthesis of late proteins is high- ly dependent on viral DNA replication and can be blocked by inhibitors of viral DNA polymerase, such as ganciclovir. The lipid bilayer outer envelope con- tains the virally encoded glycoproteins, which are the major targets of host neutralizing antibody responses.

These glycoproteins are candidates for human vaccine design. The proteinaceous layer between the envelope and the inner capsid, the viral tegument, contains pro- teins that are major targets of host cell-mediated im- mune responses. Of these tegument proteins, the most important is the so-called major tegument protein, UL83 (phosphoprotein 65 [pp65]). Another clinically important protein, the UL97 gene product, is a phos- photransferase. Although the function of this protein in the viral life cycle is unknown, this protein is clini- cally important because a substrate of the kinase is the antiviral drug, ganciclovir, which, once phosphorylat- ed, becomes an effective anti-CMV drug.

Immunity to CMV is complex and involves hu- moral and cell-mediated responses. Several CMV gene products are of particular importance in CMV immunity. The outer envelope of the virus, which is derived from the host cell nuclear membrane, con-

85.3 Pathogenetic Considerations 647

tains multiple virally encoded glycoproteins. Glyco- protein B (gB) and glycoprotein H (gH) appear to be the major determinants of protective humoral immu- nity. Antibodies to these proteins are capable of neu- tralizing the virus, and gB and gH are targets of inves- tigational CMV subunit vaccines. However, although humoral responses are important in control of severe disease, they clearly are inadequate in preventing transplacental infection, which can occur even in women who have anti-CMV antibodies.

The generation of cytotoxic T cell responses against CMV may be a more important host immune response in the control of infection. In general, these cytotoxic T cells involve major histocompatibility complex (MHC) class I restricted CD8+ responses.

Although many viral gene products are important in generating these responses, most CMV-specific cyto- toxic T cells target pp65, an abundant phosphoprotein in the viral tegument, the product of the CMV UL83 gene.

Recent investigations into the molecular biology of CMV have revealed the presence of many viral gene products which appear to modulate host inflammato- ry and immune responses. Several CMV genes inter- fere with normal antigen processing and generation of cell-mediated immune responses. To date, three vi- ral gene products have been identified that inhibit MHC class I antigen presentation. One is the US11 gene product, which exports the class I heavy chain from the endoplasmic reticulum to the cytosol, thus rendering it nonfunctional. Another is the US3 gene product, which retains MHC molecules in the endo- plasmic reticulum, preventing them from traveling to the plasma membrane. Finally, the US6 protein in- hibits peptide translocation by transporters associat- ed with antigen processing. Other viral gene prod- ucts, encoded by the UL33, US27, and US28 genes, are functional homologues of cellular G-protein-coupled receptors. They may, via molecular mimicry, subvert normal inflammatory responses, and in the process promote tissue dissemination of virus and interfere with host immune response. The CMV genome also encodes a homologue of the cellular MHC class I gene, which appears to contribute to the ability of CMV to evade host defense. The UL144 gene encodes a structural homologue of the tumor necrosis factor receptor superfamily, which may contribute to the ability of CMV to escape immune clearance.

Little is known about the molecular mechanisms responsible for the pathogenesis of tissue damage caused by CMV, particularly for congenital CMV in- fection. Although the CNS is the major target organ for tissue damage in the developing fetus, culturing CMV from the CSF of symptomatic congenitally infected infants is difficult. Because CMV can infect endothelial cells, it has been postulated that a viral angiitis may be responsible for perfusion failure of

developing brain. Others have postulated a direct teratogenic effect of CMV on the developing fetus.

Observation of CMV-induced alternations in the cell cycle and CMV-induced damage to chromosomes supports this speculation; however, this hypothesis has been difficult to verify experimentally.

It has been hypothesized that the nature and extent of the cerebral abnormalities is related to the gesta- tional age at the time of the infection. Infection of the fetus early in pregnancy would lead to abnormalities in migration with cortical dysplasia, whereas infec- tions late in pregnancy would lead to white matter ab- normalities only. This hypothesis is probably general- ly correct. However, we have seen patients in whom a primary CMV infection was documented in the mother shortly before conception, and in whom only a mild encephalopathy with multifocal white matter lesions without gyral abnormalities was found. It is, of course, possible that the transplacental transfer of the virus occurred late in pregnancy.

85.4 Therapy

Four antiviral chemotherapeutic agents – ganciclovir, foscarnet, cidofovir, and formivirsen – are licensed specifically for treatment of serious, life-threatening or sight-threatening CMV in immunocompromised patients. Currently a randomized, controlled multi- center clinical trial evaluating the use of ganciclovir for the treatment of infants with symptomatic con- genital CMV infection and evidence of CNS involve-

Fig. 85.1. Boy with congenital CMV infection (diagnosis con- firmed by a positive PCR for CMV DNA on the Guthrie card), who presented in the course of the first year of life because of serious developmental delay, spasticity, and microcephaly. A CT scan was performed at 9 months of age (first row) and showed many small calcifications, especially at the cortico- subcortical junction. Some small calcium deposits are seen in the basal ganglia and deep white matter. In addition, the CT suggests a diffuse cortical dysplasia. MRI was performed at the age of 16 months. The T

-weighted images (second and third rows) reveal extensive cortical dysplasia, most seriously affect- ing the lateral sides of the brain.The cortex is too thick, the out- side folding is too coarse, whereas the inner border of the cor- tex is irregular, compatible with polymicrogyric pachygyria. In addition, the images show ventriculomegaly, dilated inferior horns, and multifocal white matter abnormalities, the largest lesions being present in the deep parietal white matter. The T

-weighted images (fourth row) confirm the cortical dysplasia (left), the dilated inferior horn (middle), and tiny high-signal- intensity spots in the white matter (right), probably related to calcium deposits

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85.4 Therapy 649

Fig. 85.1.

ment is in progress. It is unknown whether this early and intensive administration of ganciclovir will has- ten resolution of acute disease, beneficially influence growth and development, decrease auditory and visu- al impairments, or improve intellectual outcome in these infants. There is evidence that with ganciclovir treatment the incidence of delayed hearing loss is lower. However, because of the potential bone marrow suppression, the possibility of as yet unforeseen long- term effects, and the as yet unproven benefit on long- term neurodevelopmental outcome, it is recommend- ed that ganciclovir should not be routinely used to treat infants with congenital CMV disease until the results of ongoing clinical trials establish its safety and efficacy. Anecdotal evidence suggests that criti- cally ill newborns, especially those who are premature and have CMV pneumonia, may benefit from ganci- clovir treatment. Because of the side effects of thera- py with currently available antiviral agents, treatment of newborns with an asymptomatic congenital CMV infection is presently not advocated, even though these infants are particularly at some risk for devel- oping hearing loss.

The antiviral drugs that are now in use for the treatment of CMV either directly or indirectly inhibit viral polymerase or are able to reduce viral prolifera- tion in patients with signs of CMV disease. These drugs, however, do not clear the virus completely and have serious side effects. Strains of CMV with re- duced susceptibility to these antiviral drugs have been reported. There are, fortunately, newer therapies on their way, based upon better knowledge of the physiology and life cycle of the virus. Attempts are being made to improve the efficacy of orally taken drugs. Research is also going on in purine and pyrim- idine nucleoside analogues, as well as in nonnucleo- side CMV inhibitors and CMV protease inhibitors.

The ultimate goal is the development of a vaccine that prevents congenital CMV disease.

85.5 Magnetic Resonance Imaging

Most published neuroimaging reports concern CT scans obtained during the follow-up of patients with a neonatal symptomatic congenital CMV infection.

Frequent findings are intracranial calcifications (33–

54%), unilateral or bilateral ventriculomegaly (10–

37%), white matter abnormalities (0–22%), neuronal migration abnormalities with cortical dysplasia (0–10%), and an extensive, destructive encephalo- pathy (5–13%). Occasionally, subdural effusions or hemorrhage are seen. In 20–30% of the children no abnormalities are found.

In patients with a neonatal confirmed but asymp- tomatic congenital CMV infection, CT scans show milder abnormalities, and shows them less frequent-

ly. White matter abnormalities are reported in 14% of the children, whereas no abnormalities were demon- strated in 86% of the children. Few children have cal- cifications or mild ventriculomegaly (Fig. 85.1).

Characteristically the calcifications in congenital CMV are distributed in a linear, periventricular pat- tern ranging from tiny, punctate lesions to large de- posits of calcium that appear to line the entire ven- tricular system. Calcifications also may involve the cortical and subcortical regions or involve the basal ganglia (Fig. 85.1). Infants with intracranial calcifica- tions are more likely to display cognitive and audio- logical deficits later in life than those infants who do not have detectable abnormalities.

With respect to MRI, conventional MR sequences, including T

- and T

-weighted images, are useful to show morphological and structural details. Gradient echo sequences should be added to better show calci- fications. Either an inversion recovery technique or a T

-weighted 3D gradient echo sequence can help to assess the presence and extent of the cortical gyral abnormalities.

Studies reporting MRI findings in patients with neonatal symptomatic congenital CMV infection are restricted to small numbers. The findings include di- lated ventricles, enlarged subarachnoid spaces, cere- bral gyral abnormalities, cerebellar hypoplasia, cere- bellar cortical dysplasia, delayed myelination, and white matter lesions. The ventricular dilatation may be extreme with serious thinning of the cerebral mantle. In the early stages, subependymal germi- nolytic cysts and intraparenchymal, intraventricular, and subdural hemorrhages may be present.

In patients with proven but neonatally asympto- matic congenital CMV, white matter abnormalities are frequently observed. The occurrence of anterior temporal cysts, often in combination with dilated in- ferior horns has been described repeatedly.

The gyral abnormalities in congenital CMV main- ly involve the lateral aspects of the cerebrum (Figs.

85.1 and 85.2), although they may also be diffuse (Fig. 85.3). In patients with diffuse gyral abnormali- ties, the cortex may be thin and almost agyric. In ad- dition, the lateral ventricles are often dilated in these patients. If the abnormalities are more limited, they most often consist of polymicrogyria (polymicro- gyric pachygyria). The cortex is slightly thickened and folded in abnormally broad and shallow gyri (Figs. 85.1 and 85.2). The inner border of the cortex is irregular, indicative of underlying polymicrogyria.

The gyral abnormalities may be unilateral or asym- metrical (Figs. 85.4 and 85.5). They may also present in the form of schizencephaly.

The pattern of white matter abnormalities ob-

served in congenital CMV infection is distinct. Most

often, the white matter abnormalities consist of mul-

tifocal lesions with the largest lesions in the parietal

area and with predominant involvement of deep white matter, relatively sparing the immediately periventricular and subcortical white matter (Figs.

85.6–85.8). Numerous small additional lesions are usually seen in the frontal white matter (Figs. 85.6 and 85.8). The white matter abnormalities are as a rule bi-

85.5 Magnetic Resonance Imaging 651

lateral but not always symmetrical. In patients with gyral abnormalities, both diffuse (Fig. 85.3) and mul- tifocal (Figs. 85.1, 85.2, 85.4 and 85.5) white matter ab- normalities may occur. The white matter abnormali- ties may be limited in extent (Figs. 85.2 and 85.4), but may also be extensive (Figs. 85.3 and 85.5). In partic-

Fig. 85.2. Images of a 3-year-old girl with congenital CMV (di- agnosis confirmed by a positive PCR for CMV DNA on the Guthrie card). The T

-weighted images (first and second rows) show polymicrogyric pachygyria, more severe on the right than on the left, and dilated ventricles, larger on the right side.

The inferior horns of the lateral ventricles are dilated. Along

the border of the left ventricle, in the parietal region, white

matter lesions are seen.The FLAIR images (third row) show the

white matter lesions more clearly

ular when the abnormalities are extensive, they are often mistaken for a genetic leukoencephalopathy and extensive laboratory tests are performed in that direction.

In addition, anterior temporal abnormalities, in- cluding abnormal and swollen white matter, subcorti- cal cysts, and focal enlargement of the anterior part of the inferior horn, either alone or more often in com- bination, have been demonstrated to be particularly suggestive of congenital CMV (Figs. 85.1–85.8). The enlarged inferior horns are related to an abnormal configuration of the hippocampi, which have a verti- cal orientation instead of the normal horizontal ori- entation, and are abnormally small (Fig. 85.7).

The MRI pattern suggestive of congenital CMV does not resemble the pattern of any of the known leukoencephalopathies with the exception of some of the congenital muscular dystrophies. A combination of cortical dysgyria and diffuse or multifocal white matter abnormalities is also seen in Walker–Warburg

syndrome, muscle–eye–brain disease, and the Fuku- yama type of congenital muscular dystrophy. Howev- er, in addition to muscle weakness, patients with these latter conditions have other MRI abnormalities, such as pontine hypoplasia and subcortical cerebellar cysts. None of these are seen in congenital CMV. A combination of multifocal white matter abnormali- ties and anterior temporal cysts has been reported previously in a few children with a clinically static en- cephalopathy (Olivier et al. 1998). It has been suggest- ed that this might be a novel, genetically determined leukoencephalopathy. Considering our findings, con- genital CMV should also be considered.

A CT scan showing calcification could raise the suspicion of congenital toxoplasmosis. In contrast to congenital CMV, the intracranial calcifications ob- served in congenital toxoplasmosis are usually scat- tered diffusely throughout the brain and not in the classic periventricular distribution of CMV, which may be an important clue.

Fig. 85.3. A 11-month-old boy with CMV (diagnosis con- firmed by a positive PCR for CMV DNA on the Guthrie card).

The T

-weighted images show polymicrogyria of both hemi- spheres, but also of the cerebellar cortex. Only the posterior part of the brain has better gyral development. There is a rim

of low signal intensity around the ventricles, probably a rim of

ectopic neurons. The lateral ventricles are dilated. The inferior

horns are markedly dilated and the hippocampus has an ab-

normal shape. Note the diffusely abnormal cerebral white

matter

85.5 Magnetic Resonance Imaging 653

Fig. 85.4. A 6-year-old boy with con- genital CMV infection, diagnosed at birth. Note the unilateral left-sided gyral abnormalities. The abnormalities in the deep parietal white matter are most pronounced on the right. The inferior horn is dilated on the left

Fig. 85.5.

Fig. 85.5. (continued). A 17-month-old boy with congenital CMV (diagnosis confirmed by a positive PCR for CMV DNA on the Guthrie card). The T

-weighted images (first and second rows) depict extensive, partly confluent, partly multifocal white matter abnormalities. On the left side of the brain, corti- cal dysplasia is present, best visible on the higher sections.The inferior horns of the lateral ventricles are dilated and the ante- rior temporal white matter is abnormal and swollen. The

T

-weighted axial image (third row, left) shows the left-sided gyral abnormalities. The sagittal T

-weighted images (third row, middle and right) demonstrate the presence of multiple intraparenchymal and intraventricular cysts. Note the cysts in the anterior temporal white matter and the enlarged inferior horn. Courtesy of Dr. A. Clarke, Department of Pediatric Neurol- ogy, St. George’s Hospital, London, UK

Fig. 85.6. The boy presented with neonatal signs of a congen- ital CMV infection and was diagnosed in the neonatal period.

The first MRI was obtained at the age of 1 month (first and sec- ond rows). The T

-weighted images show that the cerebral white matter has an abnormally high signal intensity and is slightly swollen. The abnormalities are most pronounced in the posterior region. It is difficult to identify lesions within the high signal intensity of unmyelinated white matter. The sagittal T

-weighted images (first row, left and middle) show swelling of the anterior temporal white matter, a small cyst in the inferior horn, and a subependymal cyst in the thalamocau- date notch. The follow-up MRI was obtained at the age of 1.5 years (third and fourth rows).The T

-weighted images show the typical multifocal white matter abnormalities with the largest lesions in the deep parietal white matter. Note the signal abnormality in the anterior temporal white matter.

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85.5 Magnetic Resonance Imaging 655

Fig. 85.6.

Fig. 85.7.

85.5 Magnetic Resonance Imaging 657

Fig. 85.8. A 1.5-year-old boy, diagnosed with congenital CMV in the neonatal period. Note the multifocal white matter ab- normalities with the largest lesions in the deep parietal white matter. The inferior horn is dilated and the anterior temporal

white matter is highly abnormal in signal and has a somewhat swollen appearance. The FLAIR images (third row, middle and right) suggest that the anterior temporal white matter is almost cystic

Fig. 85.7. A baby girl presented soon after birth with an en- cephalopathy. She was diagnosed with a congenital CMV in- fection on the basis of a positive PCR for CMV DNA on the Guthrie card. The first MRI was obtained at 6 weeks (first row), which showed diffusely mildly abnormal cerebral white mat- ter but no well-delineated lesions. There are subependymal cysts in the left thalamocaudate notch and in the left inferior horn. The hippocampus has an abnormal shape. Follow-up MRI at the age of 4 months (second row) shows that the pari- etal white matter is now evidently more abnormal than the re-

mainder of the cerebral white matter.The subependymal cysts have disappeared. MRI obtained at the age of 2.5 years (third and fourth rows) shows that the cerebral white matter looks much better myelinated.There are some remaining multifocal white matter abnormalities, most prominent in the deep pari- etal region. The inferior horns are highly dilated. The coronal FLAIR image (fourth row, middle) shows the abnormal shape of the hippocampus. The sagittal T

-weighted image (fourth row, right) shows a cystic lesion anterior to the highly dilated inferi- or horn.

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