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 DOI: 10.1177/08830738040190010705

2004 19: 50J Child NeurolKonstantinos A. Voudris, Eleni A. Vagiakou, Sotiria Mastroyianni, Yboni Dimitriou and Angeliki Skardoutsou

Infantile Spasms in an Infant With Cytomegalovirus Infection Treated With Ganciclovir  

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1997;17:34–36.

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Infantile Spasms in an Infant With Cytomegalovirus

Infection Treated With Ganciclovir

ABSTRACT

A 3-month-old male infant with cytomegalovirus infection andintractable partial seizures was treated with ganciclovir for 6weeks. The drug was well tolerated, and virus shedding in thecerebrospinal fluid and urine was eliminated, although infantilespasms at the age of 6 months appeared. At the age of 12 months,intractable seizures persisted, and the psychomotor developmentof the infant was markedly delayed. To our knowledge, no previ-ous similar case has been reported. These findings suggest that treat-ment with ganciclovir of infants with cytomegalovirus infectionresults only in cessation of virus shedding in the cerebrospinal fluidand urine without having a preventive effect on the future appear-ance of infantile spasms. This may be due to the irreversibility ofprevious brain damage from the cytomegalovirus infection and thevirostatic nature of the drug. (J Child Neurol 2004;19:50–53).

Intrauterine, perinatal, or early postnatal acquisition ofcytomegalovirus characteristically causes more severe diseasethan does infection acquired later in life.1 Immaturity of the immuneresponse of the fetuses and of young infants is believed to be themajor determinant of virulence of congenital and early postnatallyacquired cytomegalovirus infections. The optimal treatment forcytomegalovirus in infants has not yet been established, and it isnot known whether antiviral drugs, including ganciclovir, alterthe prognosis.2–5 It is important to note that, owing to ganciclovir’sknown toxicity, only children at exceedingly high risk of death orsevere neurologic impairment are selected for therapy with this

antiviral drug. In this report, the case of an infant withcytomegalovirus infection and partial seizures, which were treatedwith ganciclovir, is described. The rationale for treating this infantwith ganciclovir was the possibility of aborting a progressiveencephalitis, avoiding future deafness and retinal damage, andobtaining a carrier-free state. However, despite the rapid and effec-tive suppression of the virus from cerebrospinal fluid and urine andtemporary reduction of seizures, infantile spasms appeared in ourcase 3 months later. Serial electroencephalogram (EEG) record-ings and neurologic examinations were performed from the earlyinfantile period through late infancy. The findings of our case donot provide evidence of efficacy of ganciclovir for the treatmentof infants with symptomatic cytomegalovirus infection and seizuresto avoid the future appearance of infantile spasms.

Case Report

A 3-month-old male infant was admitted to our hospital because of partialseizures. He is the second child of healthy nonconsanguineous parentsborn at term after a normal pregnancy without any perinatal complications.At 6 months’ gestation, the mother had an acute illness with fever andmyalgia but no respiratory symptoms. The infant developed normally up tothe onset of the seizures. He suffered from several partial, mostly right-sidedseizures with clonic movements and a preferential turning of the head andeyes to the right side.

After admission to our hospital, he was given intravenous phenytoin,and as the response to this antiepilepsy drug was unsatisfactory, intra-venous phenobarbital was added. On physical examination, the infant hadmild hypotonia, the weight and length were between the 25th and 50th per-centiles, and the head circumference was at the 25th percentile. Mildhepatosplenomegaly was also noted. A lumbar puncture was done, and theinfant had increased cerebrospinal fluid white blood cells (25/�L) and pro-tein content (107 mg/dL). Cytomegalovirus was detected by the shell vialassay in urine and cytomegalovirus DNA by polymerase chain reaction(PCR) in the cerebrospinal fluid. Serum IgG and IgM antibodies tocytomegalovirus determined by enzyme-linked immunosorbent assay andimmunofluorescence assay were found, whereas cerebrospinal fluid IgG andIgM antibodies to cytomegalovirus were not detected. The serum of themother was also positive to anticytomegalovirus IgG antibody determinedby the same assays. Laboratory investigations, including complete bloodcount, platelet count, serum bilirubin, uric acid, creatinine, and urea nitro-gen levels and urinalysis, were normal. The serum glutamic-oxaloacetictransaminase level was 95 IU/L, and the serum glutamic-pyruvic transam-inase level was 120 IU/L. Other congenital infections, such as toxoplasmo-sis, varicella-zoster virus, rubella, herpes simplex virus, syphilis, and certaingenetic and metabolic diseases, were excluded. Hearing assessment bybrain stem–evoked responses and complete ophthalmologic examinationat baseline and at follow-up were normal. The child had a normal immunesystem for his age. Brain ultrasonography, computed tomography, and mag-netic resonance imaging revealed mild brain atrophy with slightly dilatedbrain ventricles. The interictal EEG recording revealed few left parietal-midtemporal spikes and sharp waves, whereas an ictal EEG recordingshowed sequential spikes with intermingled slow waves, which later becamespike-wave discharges, in the left hemisphere (Figure 1).

Because of these findings, cytomegalovirus encephalitis was diag-nosed, and following parental consent, ganciclovir (12 mg/kg/day intra-venously in two doses) was given for 6 weeks. Monitoring of completeblood cell counts, electrolytes, and renal and liver function tests was per-formed every 4 days during the treatment course. The observed adverse effectsduring ganciclovir therapy were moderate elevation above pretreatmentvalues of liver transaminases (serum glutamic-oxaloacetic transaminaselevel 190 IU/L, serum glutamic-pyruvic transaminase level 230 IU/L), whichappeared 1 week after initiation of ganciclovir and persisted for 1 week, anda 4-day episode of diarrhea at the first week of treatment. No adverse eventswere attributed to the infusion of medication. In our case, ganciclovir provedeffective in clearing cytomegalovirus from the cerebrospinal fluid and urine

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within 2 weeks of treatment, and virus shedding in the cerebrospinal fluidor urine did not recur during the follow-up period. Two weeks after startingthe ganciclovir therapy, as the seizures persisted and the response to the aboveantiepilepsy drug treatment was considered to be unsatisfactory, clon-azepam was added. However, following the 6-week period of ganciclovir treat-ment, a reduction in seizures, which was accompanied by an almost normalEEG and an improvement in the patient’s general condition, was observed,and the infant was discharged on phenobarbital and clonazepam.

At the age of 6 months, the EEG recording revealed a chaotic mixtureof high-voltage slow waves and multifocal spikes (Figure 2), and the infantwas readmitted to our hospital. On physical examination, the infant had amoderate hypotonia, the weight and length were between the 25th and 50thpercentiles, and the head circumference was between the 10th and 25th per-centiles. Serum-specific IgG antibody against cytomegalovirus was stillpresent in the patient, the serum glutamic-oxaloacetic transaminase levelwas 85 IU/L, the serum glutamic-pyruvic transaminase level was 92 IU/L,and the cerebrospinal fluid examination revealed increased levels of pro-tein (64 mg/dL) without any increase in cells. The cerebrospinal fluid andurine were negative for cytomegalovirus, so further antiviral treatmentwith ganciclovir was not commenced. A few days later, the infant began topresent subtle episodes with manifestations that were limited to staring, headnodding, slight raising of eyebrows, and minimum contraction of shoulders,without a true spasm-type movement. However, 2 weeks later, typicalspasms characterized by sudden, brief, symmetric, tonic muscular con-tractions producing flexion of the trunk and extremities, with clusters of 3to 20 spasms occurring several times per day, appeared. The spasmsoccurred particularly on awakening of the infant. Because of the appear-ance of spasms, vigabatrin was added. Three weeks later, because theresponse to this combination of antiepilepsy drugs was unsatisfactory,lamotrigine was added, whereas phenobarbital was gradually discontinued.Following this period of time, the head growth slowed further, and the patientappeared to be visually inattentive and to lose already acquired motorskills. Other concomitant types of seizures consisting of brief focal muscularcontraction, lateral eye deviation, or lateral head jerks also developed.

At the age of 12 months, because seizures had not been controlled yetin spite of various anticonvulsants, the infant was readmitted to our hos-pital. On physical examination, the infant had marked neurodevelopmen-tal delay with the head circumference below the 5th percentile.

Cytomegalovirus shedding did not reappear in the cerebrospinal fluid orurine, the cerebrospinal fluid examination and the liver function tests hadreturned to normal, and serum-specific IgG antibody against cytomegaloviruswas still evident. The EEG persisted to be abnormal, with the spikes becom-ing less multifocal and more synchronous.

Discussion

In this report, the diagnosis of cytomegalovirus infection wasbased clinically on the presence of neurologic symptoms and con-firmed by a positive result for cytomegalovirus DNA on cere-brospinal fluid, isolation of cytomegalovirus from urine, andpositive tests for serum IgM and IgG antibodies specific forcytomegalovirus. In this case, the serum IgG antibody tocytomegalovirus was still present at the age of 12 months, indicatingthat this antibody was not transferred passively by his mother. Usu-ally, the serum IgG antibody to cytomegalovirus is gone by 6 to 9months in infants who receive this antibody from their mother dur-ing the gestation period.1 However, although no other cause wasfound for the neurologic manifestations, the spasms may havebeen caused by another unknown factor in our case.

It is impossible to determine whether the severecytomegalovirus infection in our case was congenital or acquired.The fact that the infant had a good general condition and adequateweight at birth, an uneventful pre- and perinatal history, absenceof stigmata of congenital infection, and normal growth of head cir-cumference up to the age of 3 months argues for an acquired infec-tion. However, postnatally infected immunocompetent neonates andolder individuals are at an extremely low risk of disease, whereasinfants with congenital cytomegalovirus infection often present seri-ous clinical manifestations,1 as was observed in our case. Moreover,it is important to note that the acute problems in the term infants

Brief Communications 51

Figure 1. During an episode of seizures, the patient opened his eyesand deviated them rightward, while the ictal electroencephalogramrecording showed spike wave discharges of high amplitude in the lefthemisphere. Calibration: 1 second, 50 �V. Figure 2. At the age of 6 months, the electroencephalogram record-

ing revealed a chaotic mixture of high-voltage slow waves and mul-tifocal spikes. Calibration: 1 second, 50 �V.

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with postnatally acquired cytomegalovirus infections seem to belimited to lower respiratory disease and moderate hepatic ormononucleosis-like disease and are not associated with severeadverse developmental or neurologic sequelae.1 Progressive neu-rologic manifestations can occur in children with symptomaticcongenital cytomegalovirus infection, and this infection may be somild as to remain undetected for months after birth, having onlylater manifestations.1,6 Therefore, infants with congenitalcytomegalovirus infection, regardless of whether they are symp-tomatic at birth, should have serial neurologic examinations. Theoccurrence of partial seizures before the onset of infantile spasmsand the respiratory infection of the infant’s mother during gesta-tion, which may have been due to cytomegalovirus infection, alsosupport the prenatal etiology of infantile spasms in our case.

In cytomegalovirus encephalitis, cerebrospinal fluid findingsare variable and include elevated protein in the majority, occasionalpleocytosis, decreased glucose values, and, rarely, erythrocyto-sis, although normal cerebrospinal fluid results are not rare.6 Ourinfant had initially increased cerebrospinal fluid cells and proteincontent, which had returned to normal at the age of 12 months. Inour case, cytomegalovirus antibodies in the cerebrospinal fluidcould not be detected. However, the specific antibodies are not oftenpresent in high concentrations in cerebrospinal fluid in cases withcytomegalovirus infection.6 Although central nervous system man-ifestations are the most devastating sequelae of symptomaticcytomegalovirus infection, cytomegalovirus is rarely isolated fromthe central nervous system with standard culture assays.6–8 Recently,PCR of cerebrospinal fluid has been used as a noninvasive and rapidmethod to diagnose cytomegalovirus encephalitis and othercytomegalovirus-associated neurologic abnormalities in immuno-compromised or immunocompetent patients.9 CytomegalovirusDNA was also detected by PCR in the cerebrospinal fluid ofneonates with symptomatic congenital cytomegalovirus disease andcentral nervous system manifestations.7 The clinical significanceof the detection of cytomegalovirus DNA seems to be greaterwhen cytomegalovirus DNA is detected in the cerebrospinal fluidthan when it is detected in urine.8 The detection of viral DNA inthe cerebrospinal fluid of neonates with congenital cytomegalovirusinfection and its correlation with poor neurodevelopmental outcomesuggest that virus is present in the cerebrospinal fluid at birth andpostnatal viral replication may contribute to the later neurologiccomplications of congenital cytomegalovirus disease.7 The normalearly infantile life and the appearance of seizures at the age of 3months and microcephaly after the age of 3 months in our casemight be due to this postnatal viral replication in the brain.

Use of an antiviral agent has been suggested in symptomaticcytomegalovirus infection to prevent ongoing neurologic dam-age.1 Ganciclovir is an antiviral agent for use in the treatment ofsevere infections with cytomegalovirus, but recommendations forthe treatment of cytomegalovirus encephalitis in infants are miss-ing. Only a few previous studies of ganciclovir treatment of infantswith cytomegalovirus infection have been reported, and the effectwas difficult to assess.2–5 However, the results of controlled clini-cal trials demonstrating clinical efficacy of ganciclovir in congen-ital symptomatic cytomegalovirus infections are pending.5

Ganciclovir is virostatic and, therefore, suppresses viral replicationbut does not eliminate it.1 Although ganciclovir has documented

efficacy against acquired cytomegalovirus infections in immuno-compromised patients, relapse is common after cessation of ther-apy.1 In fetuses acquiring infection during intrauterine life withconsequent severe brain involvement, the brain damage is proba-bly irreversible, and the most that can be expected from ganciclovirtherapy is a containment of existing damage.1 Preliminary data havereported that although the excretion of virus decreases signifi-cantly during ganciclovir treatment in infants with symptomatic con-genital infection, virus excretion recurs when the drug isdiscontinued.2,5 However, the ganciclovir therapy may have a con-stant effect on virus shedding,3 as was observed in our patient inwhom virus shedding in the cerebrospinal fluid or urine was notdetected again during the follow-up period. It was also suggestedthat in infants whose culture results become negative and who nolonger have cytomegalovirus DNA, clinical improvement is prompt,and subsequent outcome is normal. The findings in our case sug-gest that, even with effective elimination of cytomegalovirus excre-tion in cerebrospinal fluid and urine, serious damage to the centralnervous system may persist. The most common laboratory abnor-malities during ganciclovir therapy include an increase of liverenzyme activity (which is often already present in patients withcytomegalovirus infection before ganciclovir treatment, as wasalso observed in our case), neutropenia, and thrombocytopenia.4,5

All of these adverse effects are often mild and transient and do notlead to the discontinuation of treatment.

Many different disorders causing damage to the brain seemto be causal factors for infantile spasms.10,11 Cytomegalovirus hasbeen reported to be an agent inducing infantile spasms,6,12,13 andcytomegalovirus DNA was detected in the cerebrospinal fluid ofpatients with West’s syndrome on PCR.8 However, it was also sug-gested that cytomegalovirus infection is only a parallel phenome-non to the infantile spasms and not a causal factor.14 Given thediverse etiologies of infantile spasms, a popular but unproven ideais that infantile spasms represent a nonspecific age-dependentreaction of the immature brain to injury.10,11,14 As was observed inour case, infantile spasms in West’s syndrome can occur withother types of seizures, especially partial, and almost exclusivelyin symptomatic cases. It was reported that the existence of asym-metric spasms and/or focal signs or seizures always indicates asymptomatic etiology. A substantial percentage of cases with infan-tile spasms have partial, myoclonic, tonic, and/or tonic-clonicseizures preceding or accompanying the onset of the spasms, aswas also observed in our case. The initial EEGs of patients whoseinfantile spasms were thought to have a prenatal cause are oftennormal or have focal spikes, and it takes some time for the initialEEG to develop into hypsarrythmia,15 as was observed in our case.The initial post-treatment reduction of seizures and the normal EEGin our case may be due to this reason, and probably this was notthe result of ganciclovir therapy. To our knowledge, no previouspublications are concerned with the EEG recordings and clinicalfeatures of West’s syndrome in infants with cytomegalovirus infec-tion treated with ganciclovir before the onset of the spasms. Usu-ally, the development of hypsarrhythmia coincides with the onsetof the spasms, or the interval between the appearance of epilep-tiform discharges and the onset of spasms is short. However, hyp-sarrhythmia may precede infantile spasms for a long period oftime,13 as was also observed in our case, in whom the appearance

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of hypsarrhythmia preceded the onset of infantile spasms by at least3 weeks. The outcome of children with an infectious etiology ofinfantile spasms appears to be particularly poor.13 Because corti-costeroid therapy may cause a fulminant cytomegalovirus infec-tion in infants with a history of cytomegalovirus,13 this treatmentwas not given in our case.

In conclusion, although ganciclovir therapy may lead to asignificant reduction in the overall quantity of virus in the cere-brospinal fluid, urine, and other sites, it may not have a protectiverole in the future appearance of infantile spasms. This may be theresult of the extensive damage suffered in utero or in the early infan-tile period. However, as was suggested, a ganciclovir regimenincluding a higher dose and more prolonged treatment might bemore effective in otherwise immunocompetent infants with symp-tomatic congenital cytomegalovirus infection.4,5 Furthermore, itremains to be seen whether the current controlled studies will finda significant place for ganciclovir in the treatment of congenitalcytomegalovirus, to establish the right time to start treatment withganciclovir and to determine the duration of the maintenancecourse.5

Konstantinos A. Voudris, MDDepartment of Neurology

“P & A Kyriakou” Children’s Hospital

Athens, Greece

Eleni A. Vagiakou, MD Department of Microbiology

“G. Gennimatas” General Hospital

Athens, Greece

Sotiria Mastroyianni, MDDepartment of Neurology

“P & A Kyriakou” Children’s Hospital

Athens, Greece

Yboni Dimitriou, MDThird Department of Internal Medicine

“NINITS” Hospital

Athens, Greece

Angeliki Skardoutsou, MD Second Department of Pediatrics

University of Athens

“P & A Kyriakou” Children’s Hospital

Athens, Greece

Received Jan 28, 2003. Received revised May 20, 2003. Accepted for publi-cation July 25, 2003.

Address correspondence to Dr Konstantinos A. Voudris, Department ofNeurology, "P & A Kyriakou" Children’s Hospital, Thivon and Levadeias St,115 27, Athens, Greece. Tel: +30 210 6211354, +30 210 7793000; fax: +30 2107774383; e-mail: kvoudris@otenet.gr.

References1. Hanshaw JB: Cytomegalovirus infections. Pediatr Rev 1995;16:43–48.

2. Reigstad H, Bjerknes R, Markestad T, Myrmel H: Ganciclovir therapyof congenital cytomegalovirus disease. Acta Paediatr 1992;81:707–708.

3. Attard-Montalto SP, English MC, Stimmler L, Snodgrass GJ: Ganciclovirtreatment of congenital cytomegalovirus infection: A report of twocases. Scand J Infect Dis 1993;25:385–388.

4. Nigro G, Scholz H, Bartmann U: Ganciclovir therapy for symptomaticcytomegalovirus infection in infants: A two regimen experience. J Pedi-

atr 1994;124:318–322.

5. Whitley RJ, Cloud G, Gruber W, et al: Ganciclovir treatment of symp-tomatic congenital cytomegalovirus infection: Result of a phase II study.National Institute of Allergy and Infectious Diseases CollaborativeAntiviral Study Group. J Infect Dis 1997;175:1080–1086.

6. Riikonen R: Cytomegalovirus infection and infantile spasms. Dev Med

Child Neurol 1978;20:570–579.

7. Troendle Atkins J, Demmler GJ, Williamson WD, et al: Polymerase chainreaction to detect cytomegalovirus DNA in the cerebrospinal fluid ofneonates with congenital infection. J Infect Dis 1994;169:1334–1337.

8. Kohyama J, Kajiwara M, Shimohira M, et al: Human cytomegalovirusDNA in cerebrospinal fluid. Arch Dis Child 1994;71:414–418.

9. Studal M, Ricksten A, Sandberg T, et al: Cytomegalovirus encephali-tis in four immunocompetent patients. Lancet 1992;340:1045–1046.

10. Appleton RE: Infantile spasms. Arch Dis Child 1993;69:614–618.

11. Shields WD: West’s syndrome. J Child Neurol 2002;17(Suppl 1):S76–S79.

12. Midulla M, Balducci L, Iannetti P, et al: Infantile spasms andcytomegalovirus infection. Lancet 1976;2:377.

13. Riikonen R: Infantile spasms: Infectious disorders. Neuropediatrics

1993;24:274–280.

14. Cowan LD, Hudson LS: The epidemiology and natural history of infan-tile spasms. J Child Neurol 1991;6:355–364.

15. Watanabe K, Iwase K, Hara K: The evolution of EEG features in infan-tile spasms: A prospective study. Dev Med Child Neurol 1973;15:584–596.

Speech and Language Deterioration in Benign

Rolandic Epilepsy

ABSTRACT

A 5-year-old boy presented with typical clinical and electrophysi-ologic features of benign rolandic epilepsy. His neurodevelop-ment, language, and behavior prior to the onset of epilepsy wereappropriately normal. He demonstrated marked deterioration oflanguage and cognitive function during the course to a mild andthen a moderate disability range. Serial sleep electroencephalo-graphic recordings initially showed continuous and bilateralrolandic discharges with evolution to localized left rolandic spikes.Language and cognitive improvements were subsequently seen.Educational support and evolution of the electroencephalogramto a localized focus could have been contributory. It is anticipated,however, that he will have significant long-term problems in com-plex language. (J Child Neurol 2004;19:53–58).

This report describes a child who presented with typical featuresof benign rolandic epilepsy and demonstrated speech, language,and neuropsychologic deterioration in association with bilateraland continuous spike and wave discharges in sleep, with someimprovement temporally associated with the use of corticosteroids.The uniqueness of the case is the careful documentation of cog-nitive and language function over a prolonged period of time in asso-ciation with quantification of spike frequency and analysis of spikelocation. The case provides further data that children with appar-ent typical benign rolandic epilepsy can show serious speech, lan-guage, and cognitive impairment. Careful electroencephalographic(EEG) analysis has provided some data supporting the hypothe-sis that paroxysmal EEG activity is a significant factor in the patho-genesis of dysfunction.

Brief Communications 53

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