Infantile Spasms in Down Syndrome: A Report of 5 -Cases and Review . of the Literature Michael A. Pollack, MD, Gerald S. Golden, MD, Rina Schmidt, MD, Jessica A. Davis, MD, and Norman Leeds, MD ~~
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Five patients with Down syndrome (DS) and infantile spasms were examined in a four-year interval. Previous reports of this association have been infrequent except during experimental treatment with 5-hydroxytryptophan, a precursor of serotonin. Malformations of the brain in DS are associated with an increased incidence of epilepsy, and both gross and cytoarchitectural anomalies have been described. The severity and distribution of these central nervous system anomalies presumably predispose to the infantile spasms. The contribution of altered serotonin metabolism is uncertain. Pollack MA, Golden GS, Schmidt R, et al: Infantile spasms in Down syndrome: a report of 5 cases and review of the literature. Ann Neurol 3:406-408, 1978
Epilepsy was not included in Langdon Down’s description of the syndrome which bears his name [4].Ellingson and his co-workers 15-71 have stated that seizures are less prevalent in patients with Down syndrome (DS) than in most other groups of institutionalized retardates. Veal1 [ 161reported that the prevalence of epilepsy in 1,654 institutionalized DS patients tended to increase with age and was 1.9% in those less than 20 years old; that survey included only 8 patients who were less than 5 years of age. In the absence of large prospective clinical and electroencephalographic surveys, it is not possible t o specify the prevalence of seizures during infancy in patients with DS. Infrequent case reports [13, 171 or brief notations [ 8 , 9 , 111, however, have drawn attention to the occurrence of neonatal seizures and infantile spasms in this group. Coleman and Barnet [2, 31 described the association of seizures with experimental 5-hydroxytryptophan (5-HTP) therapy in infants with DS. Eleven of their patients (17% of the 5-HTP treated group) had infantile spasms. Since 5-HTP is a precursor of serotonin, a putative neurotransmitter, Coleman and Barnet concluded that an alteration in the balance of biogenic amines might underlie spontaneously occurring infantile spasms. Five patients with DS, infantile spasms, and a pattern of hypsarrhythmia on EEG were cared for by the
From Montefiore Hospital and Medical Center and the Rose F. Retardation and Human Development, Albert Einsrein College of Medicine, Bronx, and the Child Development Center, North Shore University Hospital and Cornell University Medical College, Manhasset, NY. Kennedy Center for Research in
authors between 1972 and 1976 (Table 1). A representative patient is described in detail. Case Report Patient 1, a 9-month-old boy with trisomy 2 1, had experienced the apparent onset of seizures at 7% months of age. One seizure type consisted of momentary loss of head control, sometimes followed by stereotyped laughter. Typical jackknife (massive myoclonic) seizures also occurred and seemed more frequent when the patient was supine. Ten to twenty seizures were recognized daily in the week before the initial neurological evaluation. Examination revealed an obese infant with the physical stigmata of DS. The cardiac examination was normal. He sat independently when placed erect but had no other developmental attainments above the 5-month level on the Denver Developmental Screening Test. Marked hypotonia and hyperextensibility were present. There were no lateralizing neurological abnormalities. Several massive myoclonic spasms and head nodding-gelastic seizures were seen in an interval of 45 minutes. Electroencephalogramsobtained during wakefulness and sleep showed the features of hypsarrhythmia. Roentgenograms of the skull and chest were normal. A computerized tomographic brain scan (Figure) showed prominent subarachnoid spaces in the temporal fossae, believed to reflect atrophy or underdevelopment of the temporal lobes. Urinary metabolic screening tests were negative. Therapy with phenobarbital, pyridoxine, and prednisone
Accepted for publication Nov 2, 1977. Address reprint requests to Dr Golden, Department of Pediatrics, Child DevelopmentDivision, University ofTexas Medical Branch, Galveston, TX 7 7 550.
406 0364-5134/78/0003-0507$01.25 @ 1978 by Michael A. Pollack
Table I. Clinical Data on 5 Infants with Down Syndrome and Infantile Spusms Patient 1.
Patient 2
Patient 3
Patient 4
Patient 5
Karyotyw
Trisomy 2 1
Trisomy 2 1
Trisomy 2 1; mosaic (87%)
Tnsomy 2 I
Trisomy 21
Sex
M
F
M
M
Age at onset of seizures
7Yz mo
7 mo
6 mo
51/2
Seizure type
Infantile spasms
Infantile spasms; partial (right hand)
Infantile spasms; parrial
mo Infantile spasms
F 8 mo Infantile spasms
Developmental r e g e s slon Family hstory of epilepsy EEG ( i ~ t i a l ) Therapy
No
No
NO
No
No
NO
Unknown
No
No
No
Hypsarrhythmia Pyridoxine, prednisone, phenobarbital. clonazeparn Reduced seizure frequency with EEG improvement by age 15 mo
Hypsarrhythmia Phenobarbital, diazepam, pred. nisone Seizure free with normalization of EEG by age 15 mo
Hypsarrhythrnia Phenobarbital, primidone, phenytoin No definite improvement by age 3V2 yr
Hypsarrhyrhmia Pyridoxine, prednisone
Hypsarrhythrnia Pyridoxine. prednisone
Seizure free with normalization of EEG by age 10 m o
Seizure free with improvement of EEG by aKe I8 mo
Factor
Follow-up
"Described in case report
was of no benefit. Clonazepam, which was given in gradually increasing doses ranging from 0.05 to 0.33 mg per kilogram of body weight per day, was associated with increased alertness and a reduction in the number of observed seizures; most of the remaining attacks clustered in the few minutes after awakening. An EEG at 15 months of age showed a smaller percentage of paroxysmal activity than did previous tracings but was otherwise unchanged. N o developmental progress was apparent on examination at 19 months of age.
Computerized tomogram ut the buse (Patient 1 ) . There is ecidence of decreased i;olume of the temporal lobes, muntyested by u diluted subururbnoid spuce within the temporalfossa on the right (arrow)and to a lesser degree on the left.
Discussion This report brings to at least 24 the number of patients in whom the combination of DS and infantile spasms has been described (Table 2). T h e association is unlikely to be coincidental. Coleman and Barnet [ 3 ] presented experimental and clinical evidence favoring a disturbance of serotonin metabolism as the precipitant of infantile spasms in their DS patients treated with 5-HTP. They acknowledged, however, that the responsible biochemical mechanism remains to be elucidated. Several arguments suggest that 5-HTP administration was not responsible for infantile
Table 2. Summary of Reports of Infantile Spasms i n 24 Patients with Down Syndrome Authors Levinson et a1 [ 1 13 Gibbs (see Coleman and Barnet [3]) Coleman and Barnct (31
No. of Patients
EEG Findings Hypsarrhythmia Hypsarrhythmia
1 2 1 (spontaneous) 11 (following 5-HTP)
Wolcott and Chun [ 171
3
Gastaut and Gastaut [81 Pollack et a1 (this report)
1 5
Not given Hypsarrhythmia, 4; normal, 7 Multifocal spike and wave N o t given Hypsarrh ythmia
Pollack et al: Infantile Spasms in Trisomy 21 407
spasms in their patients: (1) The 4 infants with both infantile spasms and hypsarrhythmia on EEG failed to show improvement when 5-HTP was discontinued [ 3 ] . (2) Animal studies have generally demonstrated that reduced rather than elevated concentrations of brain serotonin are associated with seizures [3]. ( 3 ) Pyridoxine dependency has been described in 2 DS infants, 1 with neonatal seizures [ 131 and 1with infantile spasms [ 171. Pyridoxine is a cofactor for the conversion of 5-HTP to serotonin by aromatic L-amino acid decarboxylase and presumably increases brain serotonin. It seems unlikely that the clinical manifestation of a relative excess of serotonergic activity in one DS patient should be the same as that of a relative deficiency in another. (4) The relationship between serotonin concentration in blood and brain is incompletely understood, and it remains to be proved that 5-HTP greatly altered serotonin availability in the brains of treated DS patients. (5)The role o f serotonin in human epilepsy remains controversial. The concentration of serotonin and other indoleamines in the cerebrospinal fluid of untreated epileptics may not differ greatly from that of controls [ 11. Although 5-HTP appears to have precipitated myoclonic seizures in DS infants, it has abolished postanoxic intention myoclonus in adults [ 153. Several objections can be offered to each of these arguments, and none of them invalidates Coleman and Barnet's hypothesis that infantile spasms reflect a disturbance in the balance of biogenic amines in the central nervous system. However, only tentative conclusions concerning the role of serotonin and its precursors in infantile spasms seem justified by presently available evidence. infantile spasms and the hypsarrhythmic EEG appear more closely related to the patient's age than to specific metabolic o r neuropathological abnormalities [12]. Patients with malformations of the brain d o have an increased incidence of epilepsy, and neuropathological findings frequently described in DS include hypoplasia of the cerebellum and superior temporal gyms as well as nonspecific cytoarchitectural abnormalities [14]. In our Patient 1, the CAT scan suggested underdevelopment of the temporal lobes. The severity and distribution of the central nervous system anomalies in an individual with DS presumably modify his risk of infantile spasms. Application to DS of the Golgi-Cox technique, which has demonstrated
408
Annals of Neurology
Vol 3
No 5
May 1978
deficient dendritic development in the brains of children with mental retardation and infantile spasms, might further elucidate the pathogenesis of infantile spasms [ 101.
References 1. Chadwick D. Jenner P, Reynolds EH: Serotonin metabolism in human epilepsy: the influence of anriconvulsant drugs. Ann Neurol 1:218-224, 1977 2. Coleman M: Infantile spasms associated with 5-hydroxytryptophan administration in patients with Down's syndrome. Neurology (Minneap) 21:911-919, 1971 3. Coleman M, Barner A: Acute and chronic side effect5 of 5-hydroxytryptophan, in Coleman M (cd): Serotonin in Down's Syndrome. New York. American Elsevier Publishing Company, 1973, chap 7 4. Down JLH: Observations o n an ethnic classification of idiots. London Hosp Clin Lecr Rep 3:259-262, 1866; reprinted in Vollman RF: Down's Syndrome (Mongolism): A Reference Bibliography. Bcthesda, National Institutes of Health, 1069 5. Ellingson RJ: EEG in disorders associated with chromosome anomalies, in Remond A (ed): Handbook of Elecrroencephalography and Clinical Neurophysiology, sect 3, vol 15, pan B. Amsterdam. Elsevier Publishing Company. 1972 6. Ellingson RJ, Eisen JD, Ottersberg C: Clinical-electroencephalographic observations o n institutionalized mongoloids confirmed by karyotype. Elecrrocncephalogr Clin Neurophysiol 34:193- 196, 1073 7. Ellingson RJ, Menolascino FJ, Eisen JD.Clinical-EEG relationships in mongoloids confirmed by karyorypc. Am J Ment Defic 74:645-650, 1974 8. Gastaut H , Gastaut J L Computerized transverse axial tomography in epilepsy. Epilepsia 17:325-336, 19?6 0. Gibbs FA: Personal communication cited by Coleman [2] 10. Huttenlocher PR: Dendritic development in neocortex of children with mental defccr and infantile spasms. Neurology (Minneap) 24:203-210, 1974 I 1. Ixvinson A, Friedman A, Stamps F: Variability of mongolism. Pcdiatrics 16:43--54. 1955 12. Low NI.: Myoclonic seizures in childhood. in Swaiman KF, Wright FS (cds):T h e Practice of Pediatric Neurology. St Louis, The CV Mosby Company, 1975, pp 858-862 13. Mirza AM, Venugopalan K: Vitamin B6 dcpendcnt convulsions manifest in a case of Down's syndrome. J Menr Defic Res 18:35'-358, 1974 14. Norman RM: Malformations of the nervous system, birrh injury and diseases of early lifc, in Greenfield J G (ed): Neuroparhology. London, Edward Arnold, 197 I 15. Van Woert M H , Serhy V H , Coleman M: Treatment of action myoclonus with 5-hydroxytryptophan. Neurology (Minneap) 2 4 3 8 7 , 1974 16. Veal1 RM: The prevalcnce of epilepsy among mongols related to age. J Ment Defic Res 18:99-106, 1974 17. Wolcott GJ, Chun RWM: Myoclonic seizures in Down's syndrome. Dev Mcd Child Neurol 15:805-808, 1973
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Five patients with Down syndrome (DS) and infantile spasms were examined in a four-year interval. Previous reports of this association have been infrequent except during experimental treatment with 5-hydroxytryptophan, a precursor of serotonin. Malformations of the brain in DS are associated with an increased incidence of epilepsy, and both gross and cytoarchitectural anomalies have been described. The severity and distribution of these central nervous system anomalies presumably predispose to the infantile spasms. The contribution of altered serotonin metabolism is uncertain. Pollack MA, Golden GS, Schmidt R, et al: Infantile spasms in Down syndrome: a report of 5 cases and review of the literature. Ann Neurol 3:406-408, 1978
Epilepsy was not included in Langdon Down’s description of the syndrome which bears his name [4].Ellingson and his co-workers 15-71 have stated that seizures are less prevalent in patients with Down syndrome (DS) than in most other groups of institutionalized retardates. Veal1 [ 161reported that the prevalence of epilepsy in 1,654 institutionalized DS patients tended to increase with age and was 1.9% in those less than 20 years old; that survey included only 8 patients who were less than 5 years of age. In the absence of large prospective clinical and electroencephalographic surveys, it is not possible t o specify the prevalence of seizures during infancy in patients with DS. Infrequent case reports [13, 171 or brief notations [ 8 , 9 , 111, however, have drawn attention to the occurrence of neonatal seizures and infantile spasms in this group. Coleman and Barnet [2, 31 described the association of seizures with experimental 5-hydroxytryptophan (5-HTP) therapy in infants with DS. Eleven of their patients (17% of the 5-HTP treated group) had infantile spasms. Since 5-HTP is a precursor of serotonin, a putative neurotransmitter, Coleman and Barnet concluded that an alteration in the balance of biogenic amines might underlie spontaneously occurring infantile spasms. Five patients with DS, infantile spasms, and a pattern of hypsarrhythmia on EEG were cared for by the
From Montefiore Hospital and Medical Center and the Rose F. Retardation and Human Development, Albert Einsrein College of Medicine, Bronx, and the Child Development Center, North Shore University Hospital and Cornell University Medical College, Manhasset, NY. Kennedy Center for Research in
authors between 1972 and 1976 (Table 1). A representative patient is described in detail. Case Report Patient 1, a 9-month-old boy with trisomy 2 1, had experienced the apparent onset of seizures at 7% months of age. One seizure type consisted of momentary loss of head control, sometimes followed by stereotyped laughter. Typical jackknife (massive myoclonic) seizures also occurred and seemed more frequent when the patient was supine. Ten to twenty seizures were recognized daily in the week before the initial neurological evaluation. Examination revealed an obese infant with the physical stigmata of DS. The cardiac examination was normal. He sat independently when placed erect but had no other developmental attainments above the 5-month level on the Denver Developmental Screening Test. Marked hypotonia and hyperextensibility were present. There were no lateralizing neurological abnormalities. Several massive myoclonic spasms and head nodding-gelastic seizures were seen in an interval of 45 minutes. Electroencephalogramsobtained during wakefulness and sleep showed the features of hypsarrhythmia. Roentgenograms of the skull and chest were normal. A computerized tomographic brain scan (Figure) showed prominent subarachnoid spaces in the temporal fossae, believed to reflect atrophy or underdevelopment of the temporal lobes. Urinary metabolic screening tests were negative. Therapy with phenobarbital, pyridoxine, and prednisone
Accepted for publication Nov 2, 1977. Address reprint requests to Dr Golden, Department of Pediatrics, Child DevelopmentDivision, University ofTexas Medical Branch, Galveston, TX 7 7 550.
406 0364-5134/78/0003-0507$01.25 @ 1978 by Michael A. Pollack
Table I. Clinical Data on 5 Infants with Down Syndrome and Infantile Spusms Patient 1.
Patient 2
Patient 3
Patient 4
Patient 5
Karyotyw
Trisomy 2 1
Trisomy 2 1
Trisomy 2 1; mosaic (87%)
Tnsomy 2 I
Trisomy 21
Sex
M
F
M
M
Age at onset of seizures
7Yz mo
7 mo
6 mo
51/2
Seizure type
Infantile spasms
Infantile spasms; partial (right hand)
Infantile spasms; parrial
mo Infantile spasms
F 8 mo Infantile spasms
Developmental r e g e s slon Family hstory of epilepsy EEG ( i ~ t i a l ) Therapy
No
No
NO
No
No
NO
Unknown
No
No
No
Hypsarrhythmia Pyridoxine, prednisone, phenobarbital. clonazeparn Reduced seizure frequency with EEG improvement by age 15 mo
Hypsarrhythmia Phenobarbital, diazepam, pred. nisone Seizure free with normalization of EEG by age 15 mo
Hypsarrhythrnia Phenobarbital, primidone, phenytoin No definite improvement by age 3V2 yr
Hypsarrhyrhmia Pyridoxine, prednisone
Hypsarrhythrnia Pyridoxine. prednisone
Seizure free with normalization of EEG by age 10 m o
Seizure free with improvement of EEG by aKe I8 mo
Factor
Follow-up
"Described in case report
was of no benefit. Clonazepam, which was given in gradually increasing doses ranging from 0.05 to 0.33 mg per kilogram of body weight per day, was associated with increased alertness and a reduction in the number of observed seizures; most of the remaining attacks clustered in the few minutes after awakening. An EEG at 15 months of age showed a smaller percentage of paroxysmal activity than did previous tracings but was otherwise unchanged. N o developmental progress was apparent on examination at 19 months of age.
Computerized tomogram ut the buse (Patient 1 ) . There is ecidence of decreased i;olume of the temporal lobes, muntyested by u diluted subururbnoid spuce within the temporalfossa on the right (arrow)and to a lesser degree on the left.
Discussion This report brings to at least 24 the number of patients in whom the combination of DS and infantile spasms has been described (Table 2). T h e association is unlikely to be coincidental. Coleman and Barnet [ 3 ] presented experimental and clinical evidence favoring a disturbance of serotonin metabolism as the precipitant of infantile spasms in their DS patients treated with 5-HTP. They acknowledged, however, that the responsible biochemical mechanism remains to be elucidated. Several arguments suggest that 5-HTP administration was not responsible for infantile
Table 2. Summary of Reports of Infantile Spasms i n 24 Patients with Down Syndrome Authors Levinson et a1 [ 1 13 Gibbs (see Coleman and Barnet [3]) Coleman and Barnct (31
No. of Patients
EEG Findings Hypsarrhythmia Hypsarrhythmia
1 2 1 (spontaneous) 11 (following 5-HTP)
Wolcott and Chun [ 171
3
Gastaut and Gastaut [81 Pollack et a1 (this report)
1 5
Not given Hypsarrhythmia, 4; normal, 7 Multifocal spike and wave N o t given Hypsarrh ythmia
Pollack et al: Infantile Spasms in Trisomy 21 407
spasms in their patients: (1) The 4 infants with both infantile spasms and hypsarrhythmia on EEG failed to show improvement when 5-HTP was discontinued [ 3 ] . (2) Animal studies have generally demonstrated that reduced rather than elevated concentrations of brain serotonin are associated with seizures [3]. ( 3 ) Pyridoxine dependency has been described in 2 DS infants, 1 with neonatal seizures [ 131 and 1with infantile spasms [ 171. Pyridoxine is a cofactor for the conversion of 5-HTP to serotonin by aromatic L-amino acid decarboxylase and presumably increases brain serotonin. It seems unlikely that the clinical manifestation of a relative excess of serotonergic activity in one DS patient should be the same as that of a relative deficiency in another. (4) The relationship between serotonin concentration in blood and brain is incompletely understood, and it remains to be proved that 5-HTP greatly altered serotonin availability in the brains of treated DS patients. (5)The role o f serotonin in human epilepsy remains controversial. The concentration of serotonin and other indoleamines in the cerebrospinal fluid of untreated epileptics may not differ greatly from that of controls [ 11. Although 5-HTP appears to have precipitated myoclonic seizures in DS infants, it has abolished postanoxic intention myoclonus in adults [ 153. Several objections can be offered to each of these arguments, and none of them invalidates Coleman and Barnet's hypothesis that infantile spasms reflect a disturbance in the balance of biogenic amines in the central nervous system. However, only tentative conclusions concerning the role of serotonin and its precursors in infantile spasms seem justified by presently available evidence. infantile spasms and the hypsarrhythmic EEG appear more closely related to the patient's age than to specific metabolic o r neuropathological abnormalities [12]. Patients with malformations of the brain d o have an increased incidence of epilepsy, and neuropathological findings frequently described in DS include hypoplasia of the cerebellum and superior temporal gyms as well as nonspecific cytoarchitectural abnormalities [14]. In our Patient 1, the CAT scan suggested underdevelopment of the temporal lobes. The severity and distribution of the central nervous system anomalies in an individual with DS presumably modify his risk of infantile spasms. Application to DS of the Golgi-Cox technique, which has demonstrated
408
Annals of Neurology
Vol 3
No 5
May 1978
deficient dendritic development in the brains of children with mental retardation and infantile spasms, might further elucidate the pathogenesis of infantile spasms [ 101.
References 1. Chadwick D. Jenner P, Reynolds EH: Serotonin metabolism in human epilepsy: the influence of anriconvulsant drugs. Ann Neurol 1:218-224, 1977 2. Coleman M: Infantile spasms associated with 5-hydroxytryptophan administration in patients with Down's syndrome. Neurology (Minneap) 21:911-919, 1971 3. Coleman M, Barner A: Acute and chronic side effect5 of 5-hydroxytryptophan, in Coleman M (cd): Serotonin in Down's Syndrome. New York. American Elsevier Publishing Company, 1973, chap 7 4. Down JLH: Observations o n an ethnic classification of idiots. London Hosp Clin Lecr Rep 3:259-262, 1866; reprinted in Vollman RF: Down's Syndrome (Mongolism): A Reference Bibliography. Bcthesda, National Institutes of Health, 1069 5. Ellingson RJ: EEG in disorders associated with chromosome anomalies, in Remond A (ed): Handbook of Elecrroencephalography and Clinical Neurophysiology, sect 3, vol 15, pan B. Amsterdam. Elsevier Publishing Company. 1972 6. Ellingson RJ, Eisen JD, Ottersberg C: Clinical-electroencephalographic observations o n institutionalized mongoloids confirmed by karyotype. Elecrrocncephalogr Clin Neurophysiol 34:193- 196, 1073 7. Ellingson RJ, Menolascino FJ, Eisen JD.Clinical-EEG relationships in mongoloids confirmed by karyorypc. Am J Ment Defic 74:645-650, 1974 8. Gastaut H , Gastaut J L Computerized transverse axial tomography in epilepsy. Epilepsia 17:325-336, 19?6 0. Gibbs FA: Personal communication cited by Coleman [2] 10. Huttenlocher PR: Dendritic development in neocortex of children with mental defccr and infantile spasms. Neurology (Minneap) 24:203-210, 1974 I 1. Ixvinson A, Friedman A, Stamps F: Variability of mongolism. Pcdiatrics 16:43--54. 1955 12. Low NI.: Myoclonic seizures in childhood. in Swaiman KF, Wright FS (cds):T h e Practice of Pediatric Neurology. St Louis, The CV Mosby Company, 1975, pp 858-862 13. Mirza AM, Venugopalan K: Vitamin B6 dcpendcnt convulsions manifest in a case of Down's syndrome. J Menr Defic Res 18:35'-358, 1974 14. Norman RM: Malformations of the nervous system, birrh injury and diseases of early lifc, in Greenfield J G (ed): Neuroparhology. London, Edward Arnold, 197 I 15. Van Woert M H , Serhy V H , Coleman M: Treatment of action myoclonus with 5-hydroxytryptophan. Neurology (Minneap) 2 4 3 8 7 , 1974 16. Veal1 RM: The prevalcnce of epilepsy among mongols related to age. J Ment Defic Res 18:99-106, 1974 17. Wolcott GJ, Chun RWM: Myoclonic seizures in Down's syndrome. Dev Mcd Child Neurol 15:805-808, 1973
