Develop. Med. Child Neurol. 1978,20,570-579
Cytomegalovirus Infection and Infantile Spasms Raili Riikonen
another study, Stern et al. (1969) isolated CMV from the urine in six of 35 children with infantile spasms, but with such small numbers they could not establish a statistically significant difference from the ratio in age-matched controls. A series of 205 children with infantile spasms has been followed up for between one and 16 years at the Children’s Hospital, University of Helsinki. We decided to make a retrospective study of these patients in a search for CMV infections. For nearly 20 years the therapy of choice for infantile spasms has been ACTH injections (Sore1 and Dusaucy-Bauloye 1958), and in our series this therapy was given to 147 of the 205 children. Immunosuppressive therapy is known to render a patient susceptible to CMV infection (e.g. Cangir et a/. 1967, Barnett 1972, Fiala et nl. 1975). It is becoming increasingly evident that other viruses besides measles may cause slow-virus infections of the central nervous system (e.g. Weil ef al. 1975), but in this respect nothing is yet known about CMV.
Introduction Feldman and Schwarz (1968) were the first to suggest that cqtomegalovirus (CMV) was a causal factor of infantile spasms. In 1976, Midulla et a/. isolated CMV from the urine of three children aged six, seven and eight months a h o had infantile spasms. The previous psychomotor development of these children had been normal, and there had been no complications in the pre- and perinatal periods. As the children had been vaccinated shortly before the spasms began, the authors suggested that a temporary depression of cellular immunity, induced by the vaccination, might have enabled CMV to invade the central nervous system, since infants who have lost maternal antibodies at the end of their first six months of life might be more susceptible to this type of infection. In none of the three cases was it ascertained whether the infection was congenital or acquired. Because CMV can be isolated from a high proportion of age-matched children in the normal population, it appears likely that CMV infection is only a parallel phenomenon to the infantile spasms and not a cau\al factor. For example, a recent study In Finland by Granstrom et al. (1977) of SIX- to eight-month-old children found that 36 to 37 per cent were CMV excretors. In
Sample The 205 children with infantile spasms had been born between 1960 and 1976. Their records were studied in an attempt to elucidate the cause of the spasms in each
Regional Hospital of Porvoo, 06200 Porvoo 20, Finland.
570
RAIL1 IUIKONEN
which there was retardation following meningoencephalitis caused by CMV,argues for an acquired infection.
case. The age at onset was typical: all before two years and mostly between two and eight months of age. The history of each child, especially of labour and delivery had been carefully elicited, and neurological, metabolic and neuroradiological studies had been carried out on each child. In 11 of the 205 children the spasms were suspected to be due to CMV infection, since no other cause was found (except for one child (Case 4) who had neonatal hypoglycaemia and another (Case 7) who had toxoplasmosis). The 11 children had excreted CMV in the urine, and some of them had presented the typical picture of congenital infection, including intracerebral calcifications and microcephaly.
Clinical Findings Two of the four children with known congenital infection were small for dates at birth, probably having acquired the infection in utero. Three of the four mothers had had respiratory infections during gestation, which may have been due to CMV. Case 3 exhibited the classical picture of cytomegalic inclusion disease, with manifestations in several organs. CMV was isolated from the urine when this patient was less than two weeks old. All four children with overt congenital CMV infection had long-lasting tremor, in spite of normal blood sugar and calcium. Two of the four (Cases 1 and 5) had had meningoencephalitis at three weeks and eight weeks of age, respectively. Rubella, toxoplasmosis and listeria were serologically excluded as causes. Table I1 shows the findings in the cerebrospinal fluid. X-ray examinations showed intracerebral calcifications in three of the 11 children. One of the three had toxoplasmosis simultaneously, and we cannot know which infection was the cause of the calcifications. These were scattered, being present in both hemispheres as well as paraventricularly. The other two children had the classical paraventricular calcifications typical of CMV. In all three children the calcifications were already present by the age of two months, when the spasms began. Children who did not have calcification at that age remained without them at followup examinations years later. Seven of the 11 children had small heads : the increase in head circumference failed to follow the normal growth curve and was slow in relation to general growth, especially in height (Fig. 1). In six of these children the head was noted to be small before the age of seven months, and in the
Case Reports (Table I) In four of the 11 children (Cases, 1, 3, 5, 6) the CMV infection was probably congenital and the cause of the spasms. Another child (Case 7) had simultaneous congenital toxoplasmosis, and either of these infections alone, or both together, may have been the cause. Cases 8 to 11 were identical with the cases of Feldman and Schwarz (1968). If CMV was not the cause of their infantile spasms, these can only be classed as idiopathic cases in which the cause is completely obscure. The children had previously been well, with an uneventful preand perinatal history, but of course congenital CMV infection may be so mild as to remain undetected for months after birth. In these cases, therefore, there is no way of deciding whether the infantile spasms were due to a latent or primarily acquired infection, or were merely an accompanying phenomenon without causal connection. It is impossible to decide whether the severe CMV infection in Cases 2 and 4 was congenital or acquired, but the fact that Case 4 had normal growth of head circumference up to the age of 12 months, after 571
-_
7
Meningoencephalitis at 5 wks. Hepatosplenomegaly. After 5 mths rate of head growth decreased. Intracranial calcifications. Congenital toxoplasmosis
4 mths
6 wks 6 Imminent abortion. Petechiae after birth. Long-lasting tremor from birth to 3 - 4 mths. Head normal at birth, but rate of head growth decreased soon after birth
At 6 wks
+ at 6 wks
Congenital
Spastic tetraplegin. Severe mental retardation CF: 5 mths-l : 8 6 mths--1 : 64
-k at 2 mths
Between 3 wks and 3 mths
Prolonged hyperbilirubinaemia. Meningoencephalitis at 3 wks. Typical intracranial calcifications at age 2 mths. Head normal at birth but rate of growth decreased soon after birth
5
Acquired. Slow virus infection '! Spastic tetraplegia. Severe mental retardation. Optic atrophy
CF: 12mths-l : 4 13 mths-l : 32 13) mths-1 : 64 14 mths-1 : 256 15 mths-1 : 256
+ at I,! yrs, not tested earlier
Spastic tetraplegia. Severe mental retardation. Optic atrophy
Spastic tetraplegia. Congenital ? Severe mental retardation. Chorioretinitis. Strabismus. Died of pneumonia at age 10 niths
CF: 3 mths 22 days- 1 : 16 4 mths 22 days-1 : 32
CF: 2 wks-0 3 wks-0 4 mths-l : 8 6niths-I : 8
Congenital
Congenital cyt omega1ic inclusion disease
95-10 mths
4 Small for dates. At 12 mths had long-lasting, severe CMV infection during ACTH therapy : men ingoencepha I i t i s, fever for many months; erythrocyte sedimentation rate > 100. At first normocephalic, after 12 mths growth of head began to decrease. No other causative factor found, except CMV
infection during ACTH trcatment at 4 j niths
Spastic tetraplegia. Severe mental ret artlat i on
Acauired ?
Died of staph. septicaeniia
CF: I day-I : 8 1 mth-l : 8
Congenital. Slow virus infection ?
Spastic tetraplegia. Severe mental retardation. Optic atrophy
i- at less than 2 wks
8 mths
3 Small for dates. Neonatal petechiae, thrombocytopenia, anaemia, hepatosplenomegaly. Long-lasting tremor. Rate of head growth slowed slightly some weeks after birth. Neonatal meningoencephalitis and frequent episodes of pneumonia
infection
Prognosis
C'MV
Tvpe of'
and generalized CMV
Not tested
11 mths
2 During ACTH therapy developed fatal pneumonia. At necropsy, typical C M V inclusion bodies in brain, tubuli of kidneys, and lungs. Multifocal necroses in brain, liver and kidneys
CF: 2 niths I : 128 2 yrs-1 : 16 Mat.? 1 : 64 (2 yrs after birth)
CF* or platelrt
C F : 3 niths-l : 16 Mat. I : 16 ( 5 mths after birth)
Not tested
I
8 mths
Age at onset of
Small for dates. Long-lasting tremor in newborn period. Small head at birth. Typical intracranial calcifications. First CSF (8 wks) showed meningoencephalitis
110.
:(1 'iP
TABLE 1 Details of 11 children with cvtomerralovirus infection and infantile spasms
RAIL1 RIIKONEN
seventh (Case 4) the head ceased to grow normally from the age of 12 months, after CMV infection was diagnosed. All the children with small heads were severely mentally retarded, and six of them had spastic tetraplegia. The four children whose head circumferences were normal were only slightly below average in mental development, and we suspect that their CMV infection was acquired, not congenital. Three children had optic atrophy and were blind at the age of two, seven and eight years. One (the child with toxoplasmosis) had chorioretinitis ; the other two had strabismus. No specific otological disorders were found, but a hearing test (EEGplus sound stimulus) was done on five children before the age of l$ years and showed evoked potentials to acoustic stimuli. As later tests have not been performed, we have no exact evidence of otological function in these severely retarded children (CMVis known to cause a slowly progressive otological disorder). As toddlers, however, these children did react to loud sharp sounds. Eight of the 11 children had severe recurrent respiratory infections, such as pneumonia. ACTH Therapy and CMV Infection Two children in our series had had fulminant CMV infections during ACTH therapy. CASE 2. Initially this child had no symptoms of CMV;at the age of three months the complement-fixing titre was only 8. We made many efforts to identify the cause of the spasms. Labour and delivery had been uneventful, and all the metabolic and neuroradiological studies on the child were normal. The cause remained unknown. ACTH therapy at the age of three months seemed to alleviate the spasms, but in the fifth week the child had diarrhoea and pneumonia. Tests showed a staphylococcal infection, and the child died at B
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
1978, 20
TABLE I1 CSF findings in 11 children with infantile spasms and CMV infection CSF leucocyteslmm3 (Normal value: newborn 0-10, infant 0-8, thereafter 0-3)
CSFprotein g,!l (Normal value: newborn-l mth: 0.20-1'20, thereafter 0.15-0.45) CaseI* 4 wks 9 wks 10.5 yrs
1.40
2
1.10 0.29
0
L
Case2
3 mths 3.5 mths 4 mths
0.38 0.28 0.11
3 2 3
Case3
1 day 5 . 5 wks
1.64 0.54 0.52 0.36 0.23
300
9 wks 5 mths 7 yrs
Case 4* 17 days 12 mths 13 mths 14mths 15 mths 16 mths 6 yrs
0.75 0.10 0.334.454.33 0.334.7 I 1.2-1.442.17-1.16 1.11 0.188
4 7 3 1
0 0 2-18-56
48-500 51 8-138-256-450
113 2 0.82-1.0%of leucocytes were lymphocytes
Case5* 3 wks 7yrs Case6
2*20-3.40-2.50
3 . 5 mths 6.5mths 6 yrs
Case7* 6 wks 7 wks 1 mth 4 mths
I33
0.31
0
0.18 0.11 0.18
8 I
1.30
76 184-31-120-112 28 12-21
Case 8 CSF not studied Case9 3 mths 10 mths
0.26 0.20
Case I0 5.5 mths 8 yrs
0.41
0.32
Case I I CSF not studied
* Tbe$efour children had meningoencephalitis
574
2 4
RAIL1 RIIKONEN HEAD CIRCUMFERENCE, em
=I
.--
I I I 1 1 , , 1 1 1 1 1 , 1 34401 3 6 9 12
/J
MONTHS
,
1
18
1
1
I
I
2
3
4
1
1
5
1
1
6 7 8
YEARS
GfSl&llON WfiKS
AGE
Fig. 1. Head circumferences of seven children with CMV infectionand infantile spasms. 0 = probably congenitalCMV infection; A = probably acquired = acquired or congenital. CMV infection; Arrows indicate onset of infantilespasms.
the age of 43 months. Autopsy findings were surprising : a fulminant, generalised CMV infection was found, with multifocal necroses and typical CMV inclusion bodies in the cells of the brain, kidneys and lungs. CASE 4. This child, born dysmature, had severe neonatal hypoglycaemia and seemed to be retarded from birth. At the age of 93 months the syndrome of infantile spasms was diagnosed and two months later ACTH therapy was started. In the second week of therapy the child began a continuous high fever and the sedimentation rate rose to over 100mm/h. The child also had elevated CSF protein (2-17g/l vs normal
Cytomegalovirus Infection and Infantile Spasms Raili Riikonen
another study, Stern et al. (1969) isolated CMV from the urine in six of 35 children with infantile spasms, but with such small numbers they could not establish a statistically significant difference from the ratio in age-matched controls. A series of 205 children with infantile spasms has been followed up for between one and 16 years at the Children’s Hospital, University of Helsinki. We decided to make a retrospective study of these patients in a search for CMV infections. For nearly 20 years the therapy of choice for infantile spasms has been ACTH injections (Sore1 and Dusaucy-Bauloye 1958), and in our series this therapy was given to 147 of the 205 children. Immunosuppressive therapy is known to render a patient susceptible to CMV infection (e.g. Cangir et a/. 1967, Barnett 1972, Fiala et nl. 1975). It is becoming increasingly evident that other viruses besides measles may cause slow-virus infections of the central nervous system (e.g. Weil ef al. 1975), but in this respect nothing is yet known about CMV.
Introduction Feldman and Schwarz (1968) were the first to suggest that cqtomegalovirus (CMV) was a causal factor of infantile spasms. In 1976, Midulla et a/. isolated CMV from the urine of three children aged six, seven and eight months a h o had infantile spasms. The previous psychomotor development of these children had been normal, and there had been no complications in the pre- and perinatal periods. As the children had been vaccinated shortly before the spasms began, the authors suggested that a temporary depression of cellular immunity, induced by the vaccination, might have enabled CMV to invade the central nervous system, since infants who have lost maternal antibodies at the end of their first six months of life might be more susceptible to this type of infection. In none of the three cases was it ascertained whether the infection was congenital or acquired. Because CMV can be isolated from a high proportion of age-matched children in the normal population, it appears likely that CMV infection is only a parallel phenomenon to the infantile spasms and not a cau\al factor. For example, a recent study In Finland by Granstrom et al. (1977) of SIX- to eight-month-old children found that 36 to 37 per cent were CMV excretors. In
Sample The 205 children with infantile spasms had been born between 1960 and 1976. Their records were studied in an attempt to elucidate the cause of the spasms in each
Regional Hospital of Porvoo, 06200 Porvoo 20, Finland.
570
RAIL1 IUIKONEN
which there was retardation following meningoencephalitis caused by CMV,argues for an acquired infection.
case. The age at onset was typical: all before two years and mostly between two and eight months of age. The history of each child, especially of labour and delivery had been carefully elicited, and neurological, metabolic and neuroradiological studies had been carried out on each child. In 11 of the 205 children the spasms were suspected to be due to CMV infection, since no other cause was found (except for one child (Case 4) who had neonatal hypoglycaemia and another (Case 7) who had toxoplasmosis). The 11 children had excreted CMV in the urine, and some of them had presented the typical picture of congenital infection, including intracerebral calcifications and microcephaly.
Clinical Findings Two of the four children with known congenital infection were small for dates at birth, probably having acquired the infection in utero. Three of the four mothers had had respiratory infections during gestation, which may have been due to CMV. Case 3 exhibited the classical picture of cytomegalic inclusion disease, with manifestations in several organs. CMV was isolated from the urine when this patient was less than two weeks old. All four children with overt congenital CMV infection had long-lasting tremor, in spite of normal blood sugar and calcium. Two of the four (Cases 1 and 5) had had meningoencephalitis at three weeks and eight weeks of age, respectively. Rubella, toxoplasmosis and listeria were serologically excluded as causes. Table I1 shows the findings in the cerebrospinal fluid. X-ray examinations showed intracerebral calcifications in three of the 11 children. One of the three had toxoplasmosis simultaneously, and we cannot know which infection was the cause of the calcifications. These were scattered, being present in both hemispheres as well as paraventricularly. The other two children had the classical paraventricular calcifications typical of CMV. In all three children the calcifications were already present by the age of two months, when the spasms began. Children who did not have calcification at that age remained without them at followup examinations years later. Seven of the 11 children had small heads : the increase in head circumference failed to follow the normal growth curve and was slow in relation to general growth, especially in height (Fig. 1). In six of these children the head was noted to be small before the age of seven months, and in the
Case Reports (Table I) In four of the 11 children (Cases, 1, 3, 5, 6) the CMV infection was probably congenital and the cause of the spasms. Another child (Case 7) had simultaneous congenital toxoplasmosis, and either of these infections alone, or both together, may have been the cause. Cases 8 to 11 were identical with the cases of Feldman and Schwarz (1968). If CMV was not the cause of their infantile spasms, these can only be classed as idiopathic cases in which the cause is completely obscure. The children had previously been well, with an uneventful preand perinatal history, but of course congenital CMV infection may be so mild as to remain undetected for months after birth. In these cases, therefore, there is no way of deciding whether the infantile spasms were due to a latent or primarily acquired infection, or were merely an accompanying phenomenon without causal connection. It is impossible to decide whether the severe CMV infection in Cases 2 and 4 was congenital or acquired, but the fact that Case 4 had normal growth of head circumference up to the age of 12 months, after 571
-_
7
Meningoencephalitis at 5 wks. Hepatosplenomegaly. After 5 mths rate of head growth decreased. Intracranial calcifications. Congenital toxoplasmosis
4 mths
6 wks 6 Imminent abortion. Petechiae after birth. Long-lasting tremor from birth to 3 - 4 mths. Head normal at birth, but rate of head growth decreased soon after birth
At 6 wks
+ at 6 wks
Congenital
Spastic tetraplegin. Severe mental retardation CF: 5 mths-l : 8 6 mths--1 : 64
-k at 2 mths
Between 3 wks and 3 mths
Prolonged hyperbilirubinaemia. Meningoencephalitis at 3 wks. Typical intracranial calcifications at age 2 mths. Head normal at birth but rate of growth decreased soon after birth
5
Acquired. Slow virus infection '! Spastic tetraplegia. Severe mental retardation. Optic atrophy
CF: 12mths-l : 4 13 mths-l : 32 13) mths-1 : 64 14 mths-1 : 256 15 mths-1 : 256
+ at I,! yrs, not tested earlier
Spastic tetraplegia. Severe mental retardation. Optic atrophy
Spastic tetraplegia. Congenital ? Severe mental retardation. Chorioretinitis. Strabismus. Died of pneumonia at age 10 niths
CF: 3 mths 22 days- 1 : 16 4 mths 22 days-1 : 32
CF: 2 wks-0 3 wks-0 4 mths-l : 8 6niths-I : 8
Congenital
Congenital cyt omega1ic inclusion disease
95-10 mths
4 Small for dates. At 12 mths had long-lasting, severe CMV infection during ACTH therapy : men ingoencepha I i t i s, fever for many months; erythrocyte sedimentation rate > 100. At first normocephalic, after 12 mths growth of head began to decrease. No other causative factor found, except CMV
infection during ACTH trcatment at 4 j niths
Spastic tetraplegia. Severe mental ret artlat i on
Acauired ?
Died of staph. septicaeniia
CF: I day-I : 8 1 mth-l : 8
Congenital. Slow virus infection ?
Spastic tetraplegia. Severe mental retardation. Optic atrophy
i- at less than 2 wks
8 mths
3 Small for dates. Neonatal petechiae, thrombocytopenia, anaemia, hepatosplenomegaly. Long-lasting tremor. Rate of head growth slowed slightly some weeks after birth. Neonatal meningoencephalitis and frequent episodes of pneumonia
infection
Prognosis
C'MV
Tvpe of'
and generalized CMV
Not tested
11 mths
2 During ACTH therapy developed fatal pneumonia. At necropsy, typical C M V inclusion bodies in brain, tubuli of kidneys, and lungs. Multifocal necroses in brain, liver and kidneys
CF: 2 niths I : 128 2 yrs-1 : 16 Mat.? 1 : 64 (2 yrs after birth)
CF* or platelrt
C F : 3 niths-l : 16 Mat. I : 16 ( 5 mths after birth)
Not tested
I
8 mths
Age at onset of
Small for dates. Long-lasting tremor in newborn period. Small head at birth. Typical intracranial calcifications. First CSF (8 wks) showed meningoencephalitis
110.
:(1 'iP
TABLE 1 Details of 11 children with cvtomerralovirus infection and infantile spasms
RAIL1 RIIKONEN
seventh (Case 4) the head ceased to grow normally from the age of 12 months, after CMV infection was diagnosed. All the children with small heads were severely mentally retarded, and six of them had spastic tetraplegia. The four children whose head circumferences were normal were only slightly below average in mental development, and we suspect that their CMV infection was acquired, not congenital. Three children had optic atrophy and were blind at the age of two, seven and eight years. One (the child with toxoplasmosis) had chorioretinitis ; the other two had strabismus. No specific otological disorders were found, but a hearing test (EEGplus sound stimulus) was done on five children before the age of l$ years and showed evoked potentials to acoustic stimuli. As later tests have not been performed, we have no exact evidence of otological function in these severely retarded children (CMVis known to cause a slowly progressive otological disorder). As toddlers, however, these children did react to loud sharp sounds. Eight of the 11 children had severe recurrent respiratory infections, such as pneumonia. ACTH Therapy and CMV Infection Two children in our series had had fulminant CMV infections during ACTH therapy. CASE 2. Initially this child had no symptoms of CMV;at the age of three months the complement-fixing titre was only 8. We made many efforts to identify the cause of the spasms. Labour and delivery had been uneventful, and all the metabolic and neuroradiological studies on the child were normal. The cause remained unknown. ACTH therapy at the age of three months seemed to alleviate the spasms, but in the fifth week the child had diarrhoea and pneumonia. Tests showed a staphylococcal infection, and the child died at B
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
1978, 20
TABLE I1 CSF findings in 11 children with infantile spasms and CMV infection CSF leucocyteslmm3 (Normal value: newborn 0-10, infant 0-8, thereafter 0-3)
CSFprotein g,!l (Normal value: newborn-l mth: 0.20-1'20, thereafter 0.15-0.45) CaseI* 4 wks 9 wks 10.5 yrs
1.40
2
1.10 0.29
0
L
Case2
3 mths 3.5 mths 4 mths
0.38 0.28 0.11
3 2 3
Case3
1 day 5 . 5 wks
1.64 0.54 0.52 0.36 0.23
300
9 wks 5 mths 7 yrs
Case 4* 17 days 12 mths 13 mths 14mths 15 mths 16 mths 6 yrs
0.75 0.10 0.334.454.33 0.334.7 I 1.2-1.442.17-1.16 1.11 0.188
4 7 3 1
0 0 2-18-56
48-500 51 8-138-256-450
113 2 0.82-1.0%of leucocytes were lymphocytes
Case5* 3 wks 7yrs Case6
2*20-3.40-2.50
3 . 5 mths 6.5mths 6 yrs
Case7* 6 wks 7 wks 1 mth 4 mths
I33
0.31
0
0.18 0.11 0.18
8 I
1.30
76 184-31-120-112 28 12-21
Case 8 CSF not studied Case9 3 mths 10 mths
0.26 0.20
Case I0 5.5 mths 8 yrs
0.41
0.32
Case I I CSF not studied
* Tbe$efour children had meningoencephalitis
574
2 4
RAIL1 RIIKONEN HEAD CIRCUMFERENCE, em
=I
.--
I I I 1 1 , , 1 1 1 1 1 , 1 34401 3 6 9 12
/J
MONTHS
,
1
18
1
1
I
I
2
3
4
1
1
5
1
1
6 7 8
YEARS
GfSl&llON WfiKS
AGE
Fig. 1. Head circumferences of seven children with CMV infectionand infantile spasms. 0 = probably congenitalCMV infection; A = probably acquired = acquired or congenital. CMV infection; Arrows indicate onset of infantilespasms.
the age of 43 months. Autopsy findings were surprising : a fulminant, generalised CMV infection was found, with multifocal necroses and typical CMV inclusion bodies in the cells of the brain, kidneys and lungs. CASE 4. This child, born dysmature, had severe neonatal hypoglycaemia and seemed to be retarded from birth. At the age of 93 months the syndrome of infantile spasms was diagnosed and two months later ACTH therapy was started. In the second week of therapy the child began a continuous high fever and the sedimentation rate rose to over 100mm/h. The child also had elevated CSF protein (2-17g/l vs normal
