SEI27URES IN CHILDREN WITH DOWN SYNDROME: ETIOLOGY, CH14RACTERISTICS AND OUTCOME Cart E. Stafstrom Omar F. Patxot Herbert E. Gilmore Krystyna E. Wisniewski
Seizures are a common feature in developmentally disabled people, occurring in 20 t o 50 per cent of persons with mental retardation (reviewed by Corbett et al. 1975). By comparison, seizures are relatively rare in persons with Down syndrome (trisomy 21): earlier reports cite frequencies ranging from 0 to 13 per cent (Table I), but more recent comprehensive surveys place the frequency around 5 per cent. Specific etiologies of seizures in Down syndrome are rarely discussed in these reports; it is usually assumed that the seizures are a consequence of abnormal brain development. We undertook this study to determine whether seizures in children with Down syndrome are associated with identifiable etiologies, and if‘ so, whether any clinical characteristics could distinguish between seizures of known and unknown cause. Our preliminary data have appeared elsewhere in abstract form (Stafstrom et at. 1988).
Method Patients with karyotypically proven trisorny 21 were identified from computerized records at three institutions: Children’s Hospital and Medical Center, Seattle, Washington, The Floating Hospital for Infants and Children, Boston, Massachusetts, and the Institute for Basic Research in Developmental
Disabilities, Staten Island, New York. Our study population consisted of all children with Down syndrome who had been followed in clinic or admitted to hospital during the years 1978 to 1987. Of these, children with a history of at least one documented seizure were identified, and their charts were analysed in detail. Particular attention was paid to the clinical context in which a seizure occurred, in an attempt to ascertain its cause. In addition, seizure characteristics (type, duration, age at first seizure) and evaluation (laboratory and radiological investigations, EEG) were noted. Longterm seizure outcome was analysed on the basis of the rate of seizure recurrence and response to anticonvulsant medication. In many cases it was possible to obtain more up-to-date information by telephone contact with the child’s family or primary-care physician. Since many young adults with Down syndrome continue to receive medical care at pediatric hospitals, several of our patients were in their early twenties. For inclusion in this study, a patient’s first seizure must have occurred at or before 22 years of age.
Results General characteristics The general characteristics of the patients from the three institutions are compared
191
TABLE 1
Seizures in Down syndrome: literature review Authors
N patients
% with seizures
Age-range of patients Population studied with seizures ~
C
3
n
.s
Kirman 1951 Levinson et al. 1955 Walter et al. 1955 Illingworth 1959 Gibbs et al. 1964 Richards et al. 1965 MacGillivray 1967 Seppalainen and Kivalo 1967 Fedotov et al. 1968 Loesch-Mdzewska 1968 Paulson et al. 1969
91 42 200 87 184 225 111 92 82 31 88
8.7 8.6* 6.5 13.0
Ellingson et al. 1973
181
1.0
1 rnth-13 yrs
5.2 5.8** 6.2
1-65 yrs Newborn-74 15-62 yrs
1.0
4.7 2.0 0 10.0
4.4 9.0
8 yrs Newborn--17 yrs Newborn-48 yrs 1-15 yrs Newborn-29 yrs Not stated 1-58 yrs
Institutional Consecutive clinic patients Institutional Consecutive clinic patients Referred for EEGs Institutional Institutional
4-47 yrs 1-34 yrs 3-21 yrs Not stated
Institutional Unselected cases Institutional Institutional; many had febrile seizures only Institutional; proven trisomy 21 karyotype Institutional Institutional Institutional; includes 6-yr follow-up Referred to tertiary-care center Referred to center genetics service Hospital and clinic patients
3
C
. I
Moore 1973 Veal1 1974 Tangye 1979
2148 1654 128
yrs
Tatsuno et al. 1984
844
1.4
Newborn--15 yrs
Le Berre et al. 1986
480
3.5
Newborn-41
yrs
Present study
737
6.4
Newborn-22
yrs
*8.6 per cent of chronically institutionalized patients; 4.5 per cent of patients seen at a ‘psychoneurological dispensary.’ **Varied with age: 1.9 per cent 0-19 yrs, 6 per cent 20-55 yrs, 12.2 per cent >55 yrs.
TABLE I1
Patient characteristics
Patients with Down syndrome Patients with Down syndrome and seizures Male Female Seizures of known etiology Seizures of unknown etiology Age-range (yrs)
CHMC‘
BFH’
IBR’
Total
359
256
122
737
12 6 6 8 4 NB*-17
21 13
14 5 9 9 5 NB-22
47 24 23 29 18
____
8
12 9 NB-22 ~
‘Children’s Hospital and Medical Center, Seattle, WA; *The Floating Hospital for Infants and Children, Boston, MA; ’Institute for Basic Research in Developmental Disabilities, Staten Island, NY. *Newborn.
192
in Table 11. Since their characteristics were similar, they were analysed as a single group. A total of 737 patients with Down syndrome were identified, 47 (6- 4 per cent) of whom had a history of at least one seizure. There were 24 males and 23 females, whose ages ranged from newborn to 22 years. Three lived in an institution; the others lived at home or in a residential group setting.
Seizures of known and unknown etiology For 29 of the 47 patients with seizures, onset could be related to a specific precipitant. We considered a seizure to have a specific etiology if it occurred during an acute illness, such as heart failure, perinatal asphyxia or meningoencephalitis, or if it occurred in a clinically appropriate setting, e.g. following head trauma or chemotherapy. A specific
seizure etiology could not be identified for the other 18 patients. Causes of the majority of seizures with known etiology could be grouped into three categories (Table 111): cardiovascular disease, neonatal complications and infections, all of which are common problems in children with Down syndrome. Cardiovascular compromise, usually a complication of congenital heart disease, formed the largest subgroup. Most patients in this group had hypoxic seizures secondary to congestive heart failure, severt: intracardiac shunts, or infection compromising an already stressed cardiovascular system. All patients in this group had structural congenital heart defects. Two patients had embolic cerebral infarcts following repair of endocardial cushion defects, and two had moyamoya disease, which has an increased incidence in Down syndrome (Pearson et al. 1985). Asphyxiated infants comprised the largest group with seizure onset in the neonatal period. Three of these patients also had congenital heart defects; another was born after a pregnancy complicated by placenta previa. One patient had an intraventricular hemorrhage secondary to thronibocytopenia. Infections affecting the central nervous system comprised the third subgroup. Three patients had had bacterial meningoencephalitis: one Haemophilus influenzae, another Streptococcus pneumoniae and the third group B streptococcus. One patient had a frontal lobe abscess which grew Streptococcus interrnedius on culture of needle aspirate, and another developed a seizure accompanying viral meningo-encephalitis. Two patients had simple febrile seizures. Two teenage patients developed seizures after head trauma. Another, with acute lymphocytic leukemia, had a generalized tonidclonic seizure after receiving intrathecal methotrexate.
Age czt seizure onset Figure 1 compares the ages at which seizures began in patients with known and unknown seizure etiology. For those with known etiology, the age distribution was bimodal: seizures either began at a very young age (less than three years) or after
TABLE 111 Seizure etiologies (N= 29)
N Cardiovascular disease Hypoxia secondary to congenital heart disease Cerebral artery occlusions Unknown etiology Moyamoya disease Perinatal complications Perinatal asphyxia Intracerebral hemorrhage
m
8
2 2
6 1
Infections Meningo-encephalitis Bacterial Viral Brain abscess Febrile seizures Head trauma
2
Intrathecal chemotherapy
1
2r
a
N 2o
1 known etiology
0unknown etiology
0 5
6 10
11-15
15 22
Age ("eats)
Fig. 1. Age distribution of initial seizures: mean age at first seizure two years for patients with known etiology, 6 . 5 years f o r idiopathic group.
age 13. Children with early-onset seizures had neonatal asphyxia (first seizure within the first four months of life), cardiac disease (onset between one month and two years of age), febrile seizures (onset 22 to 36 months of age), or central nervous system infections (onset between one month and two years of age). Seizures beginning after 13 years of age were most often a result of head injury or delayed sequelae of heart disease. In contrast, the ages at initial seizure of patients without an identifiable etiology were more evenly distributed. The median age at initial seizure differed between the two groups (known etiology two years, unknown etiology 6 . 5 years), but this difference was not statistically significant.
193
N 4 -
-e E
known eimlogy
0 unknown etiology
3-
u)
tri c
8
-
2 -
-
1 -
-
Although many patients in both groups had their initial seizure during the first year of life, the age distribution of seizures in the idiopathic group was different from that of patients with known seizure etiology (Fig. 2). Seizures with known etiology occurred significantly earlier than those without (Mann-Whitney u test, p = 0.05). Four of the eight children in the idiopathic group who had their first seizure before two years of age had infantile spasms.
C
g a
0
,
I
0-1
1-2
1
2-3
.5 3 C
2 9
3-4
I
5-6
4-5
6-7
7-0
&e (nonmr)
Fig. 2. Age distribution of initial seizures occurring during first year of life.
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TABLE IV
Seizure type
Known
Unknown
etiology (N= 29)
etiology (N= 18)
Generalized Generalized tonic/clonic Infantile spasms Myoclonic Absence Atonic Atonic plus tonic/clonic
18 2
2 1
0 0
Partial Simple partial Complex partial
0
Mixed (partial and generalized)
0
1
TABLE V
EEG characteristics*
Generalized slowing Focal slowing Focal/multifocal spikes Generalized spikes, spikes and slow waves Hypsarrhythmia Normal
194
Known
Unknown
etiology (20 of 29 patients)
etiology (16 of la patients)
6 2
6
7 0 3
3 2 2
3 4 2
*Several patients had more than one abnormal EEG finding.
Seizure types The types of seizure are shown in Table IV. Generalized tonic/clonic seizures predominate, comprising 69 per cent of those with known etiologies (including mixed seizure types) and 61 per cent of those with unknown etiologies (including mixed tonic/clonic and atonic seizures). Among the other seizure types, certain patterns emerge. First, four patients (22 per cent) in the idiopathic group had atonic seizures, either alone or in addition to generalized tonic/clonic seizures, whereas none in the known etiology group had atonic seizures. Second, six patients in the known etiology group had focal seizures: the etiologies included infarction, moyamoya disease, intracerebral hemorrhage and brain abscess. Both patients with mixed focal and tonic/clonic seizures had previously had bacterial meningitis. Finally, a striking number of patients had infantile spasms: two (7 per cent) of 29 in the known etiology group (both secondary to neonatal asphyxia) and four (22 per cent) of 18 in the idiopathic group; an over-all frequency of 13 per cent. In addition, three other patients developed myoclonic seizures that were not characteristic of infantile spasms and their EEGS did not meet the criteria for hypsarrhythmia. In summary, generalized tonic/clonic seizures predominated in both the known and unknown etiology groups, but myoclonic seizures and infantile spasms were also common. Atonic seizures occurred only in the idiopathic group. Partial seizures usually had an identifiable etiology. EEG characteristics A wide spectrum of EEG abnormalities was observed (Table V). EEGS of patients with seizures of known etiology often reflected
8
TABLE VI Seizure outcome
c;' Seizure-free (> 1 ;ir) Off medication On medication
Known etiology Cardiovascular disease Perinatal complications CNS infection Febrile seizure Post-traumatic Chemotherapy Unknown etiology
Persistent seizures On medication
Monotherapy
2
3
5
1 2 2
3
2
3
7
Died
Lost to follow-up
4 3
s
1 7
the underlying disease process, e.g. lesions that led to partial seizures showed focal spikes or slowing. However, in many cases generalized slowing or combinations of spikes and slowing did not predict a specific etiology. Generalized slowing was the most common EEG abnormality among patients without an identified seizure etiology. All six patients with infantile spasms had hypsarrhythmia. Two patients in each group had normal EEGs; five others, including one with hypsarrhythmia, had normal followup EEGs. In general, EEG findings could not distinguish between seizures of known and unknown etiology, but were useful in the classification of seizures and for following their clinical course.
Other investigations Since this is a 10-year retrospective study involving three institutions, it is not surprising that the extent of diagnostic investigation of seizures varied considerably. In general, a patient presenting with ii seizure in the context of an acute medical problem underwent a more extensive evaluation. Some patients had cranial CT scans, which demonstrated the underlying pathology (abscess, infarct, hemorrhage, etc.). Four patients with seizures of known etiology had normal findings, five had mild atrophy or ventriculomegaly, and one with neonatal hypoxia had periventricular Ieukomalacia. Three: with seizures of unknown etiology had normal findings; two had mild, diffuse atrophy; and one with infantile spasms had slight atrophy and ventriculomegaly (hydrocephalus ex vucuo), possibly a steroid effect.
5 e
4
1
Spinal fluid examination was performed when clinically indicated (e.g. suspected meningitis). No patient in our study had seizures from electrolyte or metabolic derangement. Nine with unknown etiology and five with known etiology had had EEGS, but no additional diagnostic evaluation.
Outcome The prognosis for recurrent seizures in our population of Down syndrome patients varied with seizure etiology (Table VI). Only one patient was lost to follow-up; the others were followed for at least one year after their initial seizure. Of the 12 with seizures related to cardiovascular disease, four died of complications of acute heart failure. Of the three with this etiology who still have seizures, although on anticonvulsants, only one has frequent seizures (two or three per day); the other two have fewer than one seizure per month. Five patients have been seizure-free for the past year. Neonates with hypoxic-ischemic injury had relatively poor outcomes; only one of the four surviving infants has been seizure-free for one year. All those who died had intractable seizures until death, which occurred between one and 10 months of age. None of the seizures arising from CNS infection are persistent, although several patients must be maintained on anticonvulsant therapy. Neither patient with a febrile seizure has had a recurrence, nor has the child who had a seizure following intrathecal chemotherapy. Both patients with post-
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4
ki c
8 B e
TJ
x
v)
S
5
a .f 3
.-C y1
2
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d
traumatic epilepsy have recurrent seizures, averaging two or three per month, despite medication. As a group, the patients with idiopathic seizures had relatively good outcomes. Only seven of the 17 children have persistent seizures on anticonvulsants, averaging one or two per month. Outcome for those with infantile spasms ranged from being seizure-free, with a normal EEG, to several seizures per month, with EEG and clinical features of the Lennox-Gastaut syndrome. For children who required drug therapy, a single anticonvulsant was sufficient for 58 per cent of patients with known etiology and 70 per cent of those with unknown etiology. There was no correlation between the need for polypharmacy and seizure etiology, except for the two patients with post-traumatic epilepsy, who have persistent seizures, despite therapy with two anticonvulsants in one case and three in the other. The patients were on phenobarbital, phenytoin, carbamazepine or valproic acid, or a combination of these. Anticonvulsant choice was guided by seizure type and patient tolerance. The therapeutic serum levels and spectrum of sideeffects were similar to those for patients without Down syndrome.
Discussion
196
The 6.4 per cent frequency of seizures among children with Down syndrome in our retrospective study is consistent with previous reports (see Table I). Since our institutions are tertiary-care referral centers, we may have studied a subpopulation of patients with more serious medical problems, so our 6.4 per cent figure may overestimate the true frequency of seizures in children with Down syndrome. On the other hand, the inaccuracies inherent in a retrospective chart review may underestimate seizure frequency in some patients. All major seizure types occur in children with Down syndrome, although generalized tonic/clonic seizures predominated in both known and unknown etiology groups, as has been noted previously (Loesch-Mdzewska 1968, Tatsuno et al. 1984). Factors predisposing to seizures in
persons with Down syndrome are rarely discussed in the literature. It has been assumed that they have abnormal brain development and that their seizures are to be expected as a consequence of altered neural circuitry. Several reports consider only idiopathic cases and exclude seizures resulting from ‘obvious’ causes such as cardiac disease, hypoglycemia and perinatal asphyxia (Kirman 1951, MacGillivray 1967, Veal1 1974, Tatsuno et al. 1984, Le Berre et al. 1986). If we also exclude ‘obvious’ lesions and consider only idiopathic cases, our seizure frequency would be 2.5 per cent (still greater than the frequency in the general population). Our analysis shows that 62 per cent of Down syndrome patients have an identifiable etiology for their seizures, and that these etiologies are related to common medical complications of Down syndrome (Pueschel and Rynders 1982): perinatal respiratory distress, with subsequent hypoxic damage; hypoxia or cerebral artery occlusion from congenital heart disease; and high rates of infection and cancer as a result of impaired immune function. None of our patients had reflex seizures triggered by sensory stimuli (Guerrini et al. 1990). Are idiopathic seizures in Down syndrome simply a consequence of altered neuronal structure or function, or could this group represent patients whose seizures were not evaluated sufficiently to establish an etiology? Part of the failure to assign specific etiologies could relate to the presumption that patients with ‘abnormal brains’ are ‘predisposed’ to seizures, so need not be rigorously investigated. Indeed, all patients in our study with seizures of unknown etiology were empirically started on anticonvulsants, regardless of EEG findings, and nine received no further diagnostic evaluation. In contrast, patients who had seizures with identifiable etiologies underwent more extensive diagnostic evaluation, with 19 patients having CT scans and nine having lumbar punctures. The age at which a patient’s first seizure occurred differed between those with known and unknown etiology. Children with a known etiology had a bimodal pattern of onset: early in life,
hypoxia-ischemia, CNS infections and congenital heart disease were the primary etiologies. During the teenage years, head injury and late manifestations of cardiac disease were most common. Many patients with idiopathic seizures also had their first seizure during the first year of life, but these occurred significantly later in the first year than infants whose seizures had an identifiable cause. This suggests that children with Down syndrome have an increased susceptibility to seizures early in life, and that superimposed systemic illness increases the likelihood of seizures. Some children's idiopathic seizures also begin later in childhood, suggesting that seizure susceptibility is not limited to early stages of brain development. It is well recognized that persons with Down syndrome develop the neuropathological and cognitive changes of Alzheimer dementia when they reach their thirties (Cutler et a/. 1985). Accompanying such neurological deterioration, many develop a new onset of seizures (Wisniewski el al. 1985, Lai and Williams 1989, Evenhuis 1990). There are no prognostic data for middle-aged Down syndrome patients whose seizures began in childhood. Febrile seizures occurred in only two of our 231 patients (0.9 per cent) in the susceptible age-range. Others have also commented on the relative rarity of febrile seizures in Down syndrome (Tatsuno et a/. 1984, Le Berre et al. 1986) compared with the general population frequency of 3 to 5 per cent (Nelson and Ellenberg 1978). The low frequency of febrile seizures is somewhat surprising, given the tendency of Down syndrome patients to incur frequent infections, but these seizures may be under-reported in the Down syndrome population. Infantile spasms, another age-specific seizure syndrome, are relatively frequent in patients with Down syndrome (Pollack et al. 1!278).
Cortical dysgenesis and the neuronal basis of seizures Recent advances in neurobiology have increased our understanding of the mechanisms of neurological dysfunction in Down syndrome (Scott et al. 1983, Coyle et al. 1986, Epstein 1986). It would seem that abnormal gene products of the
extra chromosome 21 would confer a unique pathophysiology on Down syndrome brains. Any abnormality that enhances net excitation or limits net inhibition would favor the development of a hyperexcitable, seizure-prone state. At the microscopic level, Down syndrome brains from birth are characterized by a 20 to 50 per cent decrease in the number of small granule cells, lower neuronal density and abnormal neuronal distribution, especially in cortical layers I1 and IV (Ross et al. 1984; Wisniewski et al. 1984, 1986; Kemper 1988). These granule cells are inhibitory, gamma-aminobutyric acidcontaining cortical interneurons (Ribak et al. 1979). A decrease in such cells, secondary to a defect in neurogenesis or neuronal migration (Wisniewski et a/. 1984, 1986), would shift the balance in favor of net cortical excitation. Another consistent microscopic finding in Down syndrome is dysgenesis of dendritic spines; besides a reduction in number, those present tend to be longer and to have thinner necks (Marin-Padilla 1976, Suetsugu and Mehraein 1980, Wisniewski et al. 1986). This spine morphology is common in normal brains prenatally, but postnatally spine morphology becomes more varied. However, in Down syndrome, long-necked dendritic spines persist after birth, suggesting a dysgenetic process (Takashima el al. 1981; Wisniewski et al. 1984, 1986; Becker et al. 1986), or undergo transsynaptic degeneration (Marin-Padilla 1976, Suetsugu and Mehraein 1980). Similar spine dysmorphology is seen in other categories of mental retardation (Purpura 1974); functionally, these morphological abnormalities will distort synaptic input so that voltage attenuation is greater in spines with short, thick necks. Neuronal membranes in Down syndrome are abnormally hyperexcitable. Scott et al. (1982) found that cultured dorsal-root ganglion neurons from Down syndrome fetuses displayed several hyperexcitable membrane properties, including decreased action potential afterhyperpolarizations and decreased voltage thresholds for action potential generation. These changes can be explained by alterations in membrane ionic channels.
m
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197
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Similar results were obtained using the trisomy 16 mouse, an experimental model of Down syndrome (Epstein et af. 1985). Cultured neurons from such mice display hyperexcitable active and abnormal passive membrane properties compared with neurons from control mice because of alterations in potassium and/or sodium channels (Caviedes and Rapoport 1987, Orozco et af. 1987). Although the exact neuronal mechanisms for the increased susceptibility to seizures of children with Down syndrome have not yet been established, the available evidence suggests an interplay between pathologically hyperexcitable membrane properties (ionic conductances), altered neuronal structure (dendritic spines, synaptic density) and disproportionately fewer inhibitory interneurons. How these or other neuronal abnormalities are regulated by an extra chromosome 21 remains to be determined. Although children with Down syndrome have dysgenetic brains, with relatively hyperexcitable neurons, it is wrong to assume that their seizures are simply a consequence of abnormal brain development. Indeed, 62 per cent of seizures in our study population were attributable to common medical complications of Down syndrome. These acute stressors (e.g. hypoxia) may be particularly effective in producing seizures in neuronal circuits that are already predisposed to hyperexcitability.
Recommendations We recommend that all Down syndrome children with seizures, regardless of age or seizure type, be thoroughly evaluated to determine the etiology, especially if anticonvulsant therapy is being considered. Minimum evaluation should include EEG, neuro-imaging (CT or MRI scan of brain), careful cardiovascular examination and diligent search for infection. Duration of anticonvulsant therapy should be tailored to the specific etiology, keeping in mind that many seizures in these children are limited to the period of acute illness, and many others can be controlled by a single anticonvulsant . Accepted for publication 2Ist August 1990. Authors’ Appointments *Carl E. Stafstrom, M.D., Ph.D., Fellow in Pediatric Neurology, Floating Hospital for Infants and Children, Boston, MA. Omar F. Patxot, M.D., Fellow in Neurodegenerative Diseases, Institute for Basic Research in Developmental Disabilities, Staten Island, NY. Herbert E. Gilmore, M.D., Assistant Professor of Pediatrics and Neurology, Floating Hospital for Infants and Children, Boston, MA. Krystyna Wisniewski, M.D., Ph.D., Associate Director of Clinical Services, Institute for Basic Research in Developmental Disabilities, Staten Island, NY. *Correspondence to first author at Clinical NeurophysiologyUnit, Hunnewell2, The Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115.
SUMMARY Of 737 patients with Down syndrome, newborn to 22 years of age, 47 had a history of at least one seizure. Of those, 24 children had seizures with an identifiable etiology, usually related to a common medical complication of Down syndrome: neonatal hypoxia-ischemia, hypoxia from congenital heart disease, or infection. These acute medical illnesses may precipitate seizures in brains already predisposed to hyperexcitability because of abnormal neuronal development. It is recommended that all Down syndrome children with seizures undergo investigations to determine the etiology of the seizure. RESUME ComitaIitP et syndrome de Down: dtiologie, caractiristiques et devenir Sur 737 trisomiques 21, du nouveau-ne au sujet de 22 ans, 47 prksentaient une comitialite. Parmi eux 24 avaient des crises qui pouvaient Ctre reliees a une etiologie precise, habituellement une complication commune du syndrome de Down: hypoxie-ischbmie neo-natale, hypoxie par malformation cardiaque congenitale ou infection. Ces affections medicales aigiies peuvent favoriser la comitialite sur un cerveau d6ja prkdispost ii I’hyperexcitabilite en raison d’un developpement neuronique anormal. I1 est recommande que tous les trisomiques prksentant des crises comitiales beneficient d‘examens pour prkciser l‘origine des crises.
198
ZUSAMMENFASSUNG AnfaIIe bei Kindern rnit Down Syndrom: Atiologien, Charakteristika und Outcome Von 737 Patienten mit Down Syndrom, vom Neugeborenenalter bis zu 22 Jahren, hatten 47 mindestens einen Krampfanfall in der Anamnese. Davon hatten 24 Anfalle mit bekannter Atiologie,
meistens im Zusammenhang mit einer gewohnlichen Komplikation beim Down Syndrom: neonatale Hypoxie-Ischamie, Hypoxie durch angeborenen Herzfehler oder Infektion. Diese akuten medizinischen Probleme konnen in Gehirnen, die bereits eine Pradisposition fur Hyperexzitabilitat aufgrurid einer abnormen neuronalen Entwicklung haben, Anfalle auslosen. Es wird empfohlen, da13 bei allen Kindern mit Down Syndrom und Anfallen, die Ursache der Anfalle untersucht wird. RESUME N Convubiones en niiios con sindrome de Down: etiologias, caracteristicas y curso De 737 pacientes con sindrome de Down de edad eritre recien nacido y 22 aiios, 47 tenian una historia de por lo menos una convulsion. De ellos 2.4 tenian convulsiones de etiologia identificable, en general en relacion con una complicacion medica corriente del sindrome de Down: hipoxiaisquemia neonatal, hipoxia por enfermedad congenita cardiaca o infeccion. Estas enfermedades medicas agudas pueden precipitar convulsiones en cerebros ya predispuestos a la hiperexcitabilidad por su anormal desarrollo neurologico. Se recomienida que todo niiio con sindrome de Down con convulsiones sea sometido a investigaciones para determinar la etiologia de la convulsion. Refererrces Becker, L. E., Armstrong, D. L., Chan, F. (1986) ‘Dendritic atroDhv in children with Down’s syndrome.’ Annals of Neurology, 20, 520-526. Caviedes, P., Rapoport, S. I. (1987) ‘Dorsal root ganglion neurons from normal and trisomy 21 human fetal tissue show tetrodotoxin-sensitive and tetrodotoxin-insensitive sodium channels.’ Society f o r Neuroscience Abstracts, 13, 1599. Corbett, J. A,, Harris, R., Robinson, R. (1975) ‘Epilepsy.’ In Wortis, J . (Ed.) Mental Retardation and Developmental Disabilities, Vol. 7. New York: Brunner/Mazel. Coyle, J. T., Oster-Granite, M. L., Gearhart. J . D. (1986) ‘The neurobiologic consequences of Down syndrome.’ Brain Research Bulletin, 16, 773-787. Cutler, N. R., Heston, L. L., Davies, P., Haxby, J. V., Schapiro, M. B. (1985) ‘Alzheimer’s disease and Down syndrome: new insights.’ Annab of Internal Medicine, 103, 566-578. Ellingson, R. J., Eisen, J. D., Ottersberg, G. (1973) ‘Clinical and electroencephalographic o bservations of institutionalized mongoloids confirmed by karyotype.’ Electroencephalography and Clinical Neurophysiology, 34, 193-196. Epstein, C. J. (1986) The Neurobiology of Down Syndrome. New York: Raven Press. R., Epstein, L. B. (1985) ‘Mouse an animFl model of human trisomy 21 (Down syndrome). Annals of the New York Academy of Sciences, 450, 157-168. Evenhuis, H. M. (1990) ‘The natural history of dementia in Down’s syndrome.’ Archive.r of Neurology, 47, 263-267. Fedotov, D. D., Shapiro, Y . L., Vaindrukh, F. A. (1968) ‘Some features of paroxysmal states in Down’s disease (clinico-statistical analysis).’ Zhurnal Nevropatologii i Psikhiatrii, 68, 1521. Gibbs, E. L., Gibbs, F. A., Hirsch, W. (1964) ‘:.ari’.v of 14- and 6-per-second positive spiking amc,, g mongoloids.’ Neurology, 14, 581-583. Guerrini, R., Genton, P., Bureau, M., Dravet, C., Roger, J. (1990) ‘Reflex seizures are frequent i; patients with Down syndrome and epilepsy. Epilepsia, 31, 406-4 17. Illingworth, R. S. (1959) ‘Convulsions in mentally retarded children with or without cerebral palsy.’ Journal of Mental Deficiency Research, 3, 88-93. Kemper, T. L. (1988) ‘Neuropathology of Down syndrome.’ I n Nadel, L. (Ed.) The Psychobiology of Down Syndrome. Cambridge, MA: MIT Press. Kirman, B. H. (1951) ‘Epilepsy in mongolism.’ Archives of Disease in Childhood, 26, 501-503. Lai, F . , Williams, R. S. (1989) ‘A prospective study of Alzheimer disease in Down syndrome.’ Archives of Neurology, 46, 849-853. Le Berre, C., Journel, H., Lucas, J., Le Meei, F., Betremieux, P., Roussey, M., Le Marec, B. (1986)
‘L’epilepsie chez le trisomique 21 .’ Annales de Pediatrie (Paris), 33, 579-585. Levinson, A,, Friedman, A., Stamps, F. (1955) ‘Variability of mongolism. Pediatrics, 16, 43-54. Loesch-Mdzewska, D. (1968) ‘Some aspects of the. neurology of Down’s syndrome.’ Journal of Mental Deficiency Research, 12, 237-246. MacGillivray, R. C. (1967) ‘Epilepsy in Down’s anomaly.’ Journal of Mental Deficiency Research, 11, 43-48. Marin-Padilla, M. (1976) ‘Pyramidal cell abnormalities in the motor cortex in a child with Down’s syndrome: a Golgi study.’ Journal of Comparative Neurology, 167, 63-81. Moore, B. C. (1973) ‘Some characteristics of institutionalized rnongols. Journal of Mental Deficiency Research, 17, 46-5 1. Nelson, K. B., Ellenberg, J. H. (1978) ‘Prognosis in children with febrile seizures.’ Pediatrics, 61, 720-727. Orozco, C. B., Smith, S. A., Epstein, C. J., Rapoport, S. I. (1987) ‘Electrophysiological properties of cultured dorsal root ganglion and spinal cord neurons of normal and trisomy 16 fetal mice.’ Developmental Brain Research, 32, 11 1-122. Paulson, G. W., Son, C. D., Nance, W. E. (1969) ‘Neurologic aspects of typical and atypical Down’s syndrome. Diseases of the Nervous System, 30, 632-636. Pearson, E., Lenn, N. J., Cail, W. S. (1985) ‘Moya moya and other causes of stroke in patients with Down syndrome.’ Pediatric Neurology, 1, 174-179
Poilack, M. A,, Golden, G. S., Schmidt, R., Davis, J. A., Leeds, N. (1978) ‘Infantile spasms in Down syndrome: a report of 5 cases and review of the literature.’ Annals of Neurology, 3, 406-408. Pueschel, S. M., Rynders, J. E. (1982) Down Syndrome: Advances in Biomedicine and the Behavioral Sciences. Cambridge, MA: Ware Press, Purpura, D. P. (1974) ‘Dendriti5 spine “dysgenesis” and mental retardation. Science, 186, 1126-1128. Ribak, C. E., Harris, A. B., Vaughan, J . E., Roberts, E. (1979) ‘Inhibitory GABAergic nervt terminals decrease at sites of focal epilepsy. Science, 205, 2 1 1-2 14. Richards, B. W., Stewart, A,, Sylvester, P. E., Jasiewicz, V. (1965) ‘Cytogenetic survey of 255 patients diagnosed clinically as mongols.’ Journal of Mental Deficiency Research, 9, 245-259. Ross, M. H., Galaburda, A. M., Kemper, T. L. (1984) ‘Down’s syndrome: is there a decreased population of neurons?’ Neurology, 34, 909-916. Scott, B. S., Petit, T. L., Becker, L. E., Edwards,
199
B. A. V. (1982) ‘Abnormal electric membrane properties of Down’s syndrome DRG neurons in cell culture.’ Developmental Brain Research, 2, 257-270.
. rrj
8
.9 5
- Becker, L. E., Petit, T. L. (1983) ‘Neurobiology of Down’s syndrome.’ Progress in Neurobiology, 21, 199-237. Seppalainen, A. M., Kivalo, E. (1967) ‘EEG findings in Down’s syndrome.’ Journal of Mental Deficiency Research, 11, 116-125. Stafstrom, C. E., Gilmore, H. E., Ehrenberg, B. L. (1988) ‘Seizures in persons with Down’s syndrome: cause and prognosis.’ Annals of Neurology, 24, 308-309. (Abstract.) Suetsugu, M., Mehraein, P. (1980) ‘Spine distribution along the apical dendrites of the pyramidal neurons in Down’s syndrome.’ Acta Neuropathololgica, 50, 207-210. Takashima, S., Becker, L. E., Armstrong, D. L., Chan, F. (1981) ‘Abnormal neuronal development in the visual cortex of the human fetus and infant with Down’s syndrome: a quantitative and qualitative Golgi study.’ Brain Research, 225, 1-21.
.-c
200
Tangye, S. R. (1979) ‘The EEG and incidence of epilepsy in Down’s syndrome.’ Journal of Mental
Deficiency Research, 23, 11-24. Tatsuno, M.,Hayashi, M., Iwamoto, H., Suzuki, Y., Kuroki, Y. (1984) ‘Epilepsy in childhood Down syndrome.’ Brain and Development, 6, 37-44. Veall, R. M. (1974) ‘The prevalence of epilepsy among mongols related to age.’ Journal of Mental Deficiency Research, 18, 99-106. Walter, R. D., Yeager, C. L., Rubin, H. K. (1955) ‘Mongolism and convulsive seizures.’ Archives of Neurology and Psychiatry, 74, 559-563. Wisniewski, K. E., Laure-Kamionowska, M., Wisniewski, H. M. (1984) ‘Evidence of arrest of neurogenesis and synaptogenesis in brains of patients with Down’s syndrome.’ New England Journal of Medicine, 311, 1187-1 188. - Dalton, A. J., McLachlan, D. R. C., Wen, G. Y., Wisniewski, H. M. (1985) ‘Alzheimer’s disease in Down’s syndrome: clinicopathologic studies.’ Neurology, 35, 957-961. - Laure-Kamionowska, M., Connell, F., Wen, G. Y. (1986) ‘Neuronal density and synaptogenesis in the postnatal stage of brain maturation in Down syndrome.’ I n Epstein, C. (Ed.) The Neurobiology of Down Syndrome. New York: Raven Press.
Seizures are a common feature in developmentally disabled people, occurring in 20 t o 50 per cent of persons with mental retardation (reviewed by Corbett et al. 1975). By comparison, seizures are relatively rare in persons with Down syndrome (trisomy 21): earlier reports cite frequencies ranging from 0 to 13 per cent (Table I), but more recent comprehensive surveys place the frequency around 5 per cent. Specific etiologies of seizures in Down syndrome are rarely discussed in these reports; it is usually assumed that the seizures are a consequence of abnormal brain development. We undertook this study to determine whether seizures in children with Down syndrome are associated with identifiable etiologies, and if‘ so, whether any clinical characteristics could distinguish between seizures of known and unknown cause. Our preliminary data have appeared elsewhere in abstract form (Stafstrom et at. 1988).
Method Patients with karyotypically proven trisorny 21 were identified from computerized records at three institutions: Children’s Hospital and Medical Center, Seattle, Washington, The Floating Hospital for Infants and Children, Boston, Massachusetts, and the Institute for Basic Research in Developmental
Disabilities, Staten Island, New York. Our study population consisted of all children with Down syndrome who had been followed in clinic or admitted to hospital during the years 1978 to 1987. Of these, children with a history of at least one documented seizure were identified, and their charts were analysed in detail. Particular attention was paid to the clinical context in which a seizure occurred, in an attempt to ascertain its cause. In addition, seizure characteristics (type, duration, age at first seizure) and evaluation (laboratory and radiological investigations, EEG) were noted. Longterm seizure outcome was analysed on the basis of the rate of seizure recurrence and response to anticonvulsant medication. In many cases it was possible to obtain more up-to-date information by telephone contact with the child’s family or primary-care physician. Since many young adults with Down syndrome continue to receive medical care at pediatric hospitals, several of our patients were in their early twenties. For inclusion in this study, a patient’s first seizure must have occurred at or before 22 years of age.
Results General characteristics The general characteristics of the patients from the three institutions are compared
191
TABLE 1
Seizures in Down syndrome: literature review Authors
N patients
% with seizures
Age-range of patients Population studied with seizures ~
C
3
n
.s
Kirman 1951 Levinson et al. 1955 Walter et al. 1955 Illingworth 1959 Gibbs et al. 1964 Richards et al. 1965 MacGillivray 1967 Seppalainen and Kivalo 1967 Fedotov et al. 1968 Loesch-Mdzewska 1968 Paulson et al. 1969
91 42 200 87 184 225 111 92 82 31 88
8.7 8.6* 6.5 13.0
Ellingson et al. 1973
181
1.0
1 rnth-13 yrs
5.2 5.8** 6.2
1-65 yrs Newborn-74 15-62 yrs
1.0
4.7 2.0 0 10.0
4.4 9.0
8 yrs Newborn--17 yrs Newborn-48 yrs 1-15 yrs Newborn-29 yrs Not stated 1-58 yrs
Institutional Consecutive clinic patients Institutional Consecutive clinic patients Referred for EEGs Institutional Institutional
4-47 yrs 1-34 yrs 3-21 yrs Not stated
Institutional Unselected cases Institutional Institutional; many had febrile seizures only Institutional; proven trisomy 21 karyotype Institutional Institutional Institutional; includes 6-yr follow-up Referred to tertiary-care center Referred to center genetics service Hospital and clinic patients
3
C
. I
Moore 1973 Veal1 1974 Tangye 1979
2148 1654 128
yrs
Tatsuno et al. 1984
844
1.4
Newborn--15 yrs
Le Berre et al. 1986
480
3.5
Newborn-41
yrs
Present study
737
6.4
Newborn-22
yrs
*8.6 per cent of chronically institutionalized patients; 4.5 per cent of patients seen at a ‘psychoneurological dispensary.’ **Varied with age: 1.9 per cent 0-19 yrs, 6 per cent 20-55 yrs, 12.2 per cent >55 yrs.
TABLE I1
Patient characteristics
Patients with Down syndrome Patients with Down syndrome and seizures Male Female Seizures of known etiology Seizures of unknown etiology Age-range (yrs)
CHMC‘
BFH’
IBR’
Total
359
256
122
737
12 6 6 8 4 NB*-17
21 13
14 5 9 9 5 NB-22
47 24 23 29 18
____
8
12 9 NB-22 ~
‘Children’s Hospital and Medical Center, Seattle, WA; *The Floating Hospital for Infants and Children, Boston, MA; ’Institute for Basic Research in Developmental Disabilities, Staten Island, NY. *Newborn.
192
in Table 11. Since their characteristics were similar, they were analysed as a single group. A total of 737 patients with Down syndrome were identified, 47 (6- 4 per cent) of whom had a history of at least one seizure. There were 24 males and 23 females, whose ages ranged from newborn to 22 years. Three lived in an institution; the others lived at home or in a residential group setting.
Seizures of known and unknown etiology For 29 of the 47 patients with seizures, onset could be related to a specific precipitant. We considered a seizure to have a specific etiology if it occurred during an acute illness, such as heart failure, perinatal asphyxia or meningoencephalitis, or if it occurred in a clinically appropriate setting, e.g. following head trauma or chemotherapy. A specific
seizure etiology could not be identified for the other 18 patients. Causes of the majority of seizures with known etiology could be grouped into three categories (Table 111): cardiovascular disease, neonatal complications and infections, all of which are common problems in children with Down syndrome. Cardiovascular compromise, usually a complication of congenital heart disease, formed the largest subgroup. Most patients in this group had hypoxic seizures secondary to congestive heart failure, severt: intracardiac shunts, or infection compromising an already stressed cardiovascular system. All patients in this group had structural congenital heart defects. Two patients had embolic cerebral infarcts following repair of endocardial cushion defects, and two had moyamoya disease, which has an increased incidence in Down syndrome (Pearson et al. 1985). Asphyxiated infants comprised the largest group with seizure onset in the neonatal period. Three of these patients also had congenital heart defects; another was born after a pregnancy complicated by placenta previa. One patient had an intraventricular hemorrhage secondary to thronibocytopenia. Infections affecting the central nervous system comprised the third subgroup. Three patients had had bacterial meningoencephalitis: one Haemophilus influenzae, another Streptococcus pneumoniae and the third group B streptococcus. One patient had a frontal lobe abscess which grew Streptococcus interrnedius on culture of needle aspirate, and another developed a seizure accompanying viral meningo-encephalitis. Two patients had simple febrile seizures. Two teenage patients developed seizures after head trauma. Another, with acute lymphocytic leukemia, had a generalized tonidclonic seizure after receiving intrathecal methotrexate.
Age czt seizure onset Figure 1 compares the ages at which seizures began in patients with known and unknown seizure etiology. For those with known etiology, the age distribution was bimodal: seizures either began at a very young age (less than three years) or after
TABLE 111 Seizure etiologies (N= 29)
N Cardiovascular disease Hypoxia secondary to congenital heart disease Cerebral artery occlusions Unknown etiology Moyamoya disease Perinatal complications Perinatal asphyxia Intracerebral hemorrhage
m
8
2 2
6 1
Infections Meningo-encephalitis Bacterial Viral Brain abscess Febrile seizures Head trauma
2
Intrathecal chemotherapy
1
2r
a
N 2o
1 known etiology
0unknown etiology
0 5
6 10
11-15
15 22
Age ("eats)
Fig. 1. Age distribution of initial seizures: mean age at first seizure two years for patients with known etiology, 6 . 5 years f o r idiopathic group.
age 13. Children with early-onset seizures had neonatal asphyxia (first seizure within the first four months of life), cardiac disease (onset between one month and two years of age), febrile seizures (onset 22 to 36 months of age), or central nervous system infections (onset between one month and two years of age). Seizures beginning after 13 years of age were most often a result of head injury or delayed sequelae of heart disease. In contrast, the ages at initial seizure of patients without an identifiable etiology were more evenly distributed. The median age at initial seizure differed between the two groups (known etiology two years, unknown etiology 6 . 5 years), but this difference was not statistically significant.
193
N 4 -
-e E
known eimlogy
0 unknown etiology
3-
u)
tri c
8
-
2 -
-
1 -
-
Although many patients in both groups had their initial seizure during the first year of life, the age distribution of seizures in the idiopathic group was different from that of patients with known seizure etiology (Fig. 2). Seizures with known etiology occurred significantly earlier than those without (Mann-Whitney u test, p = 0.05). Four of the eight children in the idiopathic group who had their first seizure before two years of age had infantile spasms.
C
g a
0
,
I
0-1
1-2
1
2-3
.5 3 C
2 9
3-4
I
5-6
4-5
6-7
7-0
&e (nonmr)
Fig. 2. Age distribution of initial seizures occurring during first year of life.
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v)
TABLE IV
Seizure type
Known
Unknown
etiology (N= 29)
etiology (N= 18)
Generalized Generalized tonic/clonic Infantile spasms Myoclonic Absence Atonic Atonic plus tonic/clonic
18 2
2 1
0 0
Partial Simple partial Complex partial
0
Mixed (partial and generalized)
0
1
TABLE V
EEG characteristics*
Generalized slowing Focal slowing Focal/multifocal spikes Generalized spikes, spikes and slow waves Hypsarrhythmia Normal
194
Known
Unknown
etiology (20 of 29 patients)
etiology (16 of la patients)
6 2
6
7 0 3
3 2 2
3 4 2
*Several patients had more than one abnormal EEG finding.
Seizure types The types of seizure are shown in Table IV. Generalized tonic/clonic seizures predominate, comprising 69 per cent of those with known etiologies (including mixed seizure types) and 61 per cent of those with unknown etiologies (including mixed tonic/clonic and atonic seizures). Among the other seizure types, certain patterns emerge. First, four patients (22 per cent) in the idiopathic group had atonic seizures, either alone or in addition to generalized tonic/clonic seizures, whereas none in the known etiology group had atonic seizures. Second, six patients in the known etiology group had focal seizures: the etiologies included infarction, moyamoya disease, intracerebral hemorrhage and brain abscess. Both patients with mixed focal and tonic/clonic seizures had previously had bacterial meningitis. Finally, a striking number of patients had infantile spasms: two (7 per cent) of 29 in the known etiology group (both secondary to neonatal asphyxia) and four (22 per cent) of 18 in the idiopathic group; an over-all frequency of 13 per cent. In addition, three other patients developed myoclonic seizures that were not characteristic of infantile spasms and their EEGS did not meet the criteria for hypsarrhythmia. In summary, generalized tonic/clonic seizures predominated in both the known and unknown etiology groups, but myoclonic seizures and infantile spasms were also common. Atonic seizures occurred only in the idiopathic group. Partial seizures usually had an identifiable etiology. EEG characteristics A wide spectrum of EEG abnormalities was observed (Table V). EEGS of patients with seizures of known etiology often reflected
8
TABLE VI Seizure outcome
c;' Seizure-free (> 1 ;ir) Off medication On medication
Known etiology Cardiovascular disease Perinatal complications CNS infection Febrile seizure Post-traumatic Chemotherapy Unknown etiology
Persistent seizures On medication
Monotherapy
2
3
5
1 2 2
3
2
3
7
Died
Lost to follow-up
4 3
s
1 7
the underlying disease process, e.g. lesions that led to partial seizures showed focal spikes or slowing. However, in many cases generalized slowing or combinations of spikes and slowing did not predict a specific etiology. Generalized slowing was the most common EEG abnormality among patients without an identified seizure etiology. All six patients with infantile spasms had hypsarrhythmia. Two patients in each group had normal EEGs; five others, including one with hypsarrhythmia, had normal followup EEGs. In general, EEG findings could not distinguish between seizures of known and unknown etiology, but were useful in the classification of seizures and for following their clinical course.
Other investigations Since this is a 10-year retrospective study involving three institutions, it is not surprising that the extent of diagnostic investigation of seizures varied considerably. In general, a patient presenting with ii seizure in the context of an acute medical problem underwent a more extensive evaluation. Some patients had cranial CT scans, which demonstrated the underlying pathology (abscess, infarct, hemorrhage, etc.). Four patients with seizures of known etiology had normal findings, five had mild atrophy or ventriculomegaly, and one with neonatal hypoxia had periventricular Ieukomalacia. Three: with seizures of unknown etiology had normal findings; two had mild, diffuse atrophy; and one with infantile spasms had slight atrophy and ventriculomegaly (hydrocephalus ex vucuo), possibly a steroid effect.
5 e
4
1
Spinal fluid examination was performed when clinically indicated (e.g. suspected meningitis). No patient in our study had seizures from electrolyte or metabolic derangement. Nine with unknown etiology and five with known etiology had had EEGS, but no additional diagnostic evaluation.
Outcome The prognosis for recurrent seizures in our population of Down syndrome patients varied with seizure etiology (Table VI). Only one patient was lost to follow-up; the others were followed for at least one year after their initial seizure. Of the 12 with seizures related to cardiovascular disease, four died of complications of acute heart failure. Of the three with this etiology who still have seizures, although on anticonvulsants, only one has frequent seizures (two or three per day); the other two have fewer than one seizure per month. Five patients have been seizure-free for the past year. Neonates with hypoxic-ischemic injury had relatively poor outcomes; only one of the four surviving infants has been seizure-free for one year. All those who died had intractable seizures until death, which occurred between one and 10 months of age. None of the seizures arising from CNS infection are persistent, although several patients must be maintained on anticonvulsant therapy. Neither patient with a febrile seizure has had a recurrence, nor has the child who had a seizure following intrathecal chemotherapy. Both patients with post-
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4
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8 B e
TJ
x
v)
S
5
a .f 3
.-C y1
2
.-a
d
traumatic epilepsy have recurrent seizures, averaging two or three per month, despite medication. As a group, the patients with idiopathic seizures had relatively good outcomes. Only seven of the 17 children have persistent seizures on anticonvulsants, averaging one or two per month. Outcome for those with infantile spasms ranged from being seizure-free, with a normal EEG, to several seizures per month, with EEG and clinical features of the Lennox-Gastaut syndrome. For children who required drug therapy, a single anticonvulsant was sufficient for 58 per cent of patients with known etiology and 70 per cent of those with unknown etiology. There was no correlation between the need for polypharmacy and seizure etiology, except for the two patients with post-traumatic epilepsy, who have persistent seizures, despite therapy with two anticonvulsants in one case and three in the other. The patients were on phenobarbital, phenytoin, carbamazepine or valproic acid, or a combination of these. Anticonvulsant choice was guided by seizure type and patient tolerance. The therapeutic serum levels and spectrum of sideeffects were similar to those for patients without Down syndrome.
Discussion
196
The 6.4 per cent frequency of seizures among children with Down syndrome in our retrospective study is consistent with previous reports (see Table I). Since our institutions are tertiary-care referral centers, we may have studied a subpopulation of patients with more serious medical problems, so our 6.4 per cent figure may overestimate the true frequency of seizures in children with Down syndrome. On the other hand, the inaccuracies inherent in a retrospective chart review may underestimate seizure frequency in some patients. All major seizure types occur in children with Down syndrome, although generalized tonic/clonic seizures predominated in both known and unknown etiology groups, as has been noted previously (Loesch-Mdzewska 1968, Tatsuno et al. 1984). Factors predisposing to seizures in
persons with Down syndrome are rarely discussed in the literature. It has been assumed that they have abnormal brain development and that their seizures are to be expected as a consequence of altered neural circuitry. Several reports consider only idiopathic cases and exclude seizures resulting from ‘obvious’ causes such as cardiac disease, hypoglycemia and perinatal asphyxia (Kirman 1951, MacGillivray 1967, Veal1 1974, Tatsuno et al. 1984, Le Berre et al. 1986). If we also exclude ‘obvious’ lesions and consider only idiopathic cases, our seizure frequency would be 2.5 per cent (still greater than the frequency in the general population). Our analysis shows that 62 per cent of Down syndrome patients have an identifiable etiology for their seizures, and that these etiologies are related to common medical complications of Down syndrome (Pueschel and Rynders 1982): perinatal respiratory distress, with subsequent hypoxic damage; hypoxia or cerebral artery occlusion from congenital heart disease; and high rates of infection and cancer as a result of impaired immune function. None of our patients had reflex seizures triggered by sensory stimuli (Guerrini et al. 1990). Are idiopathic seizures in Down syndrome simply a consequence of altered neuronal structure or function, or could this group represent patients whose seizures were not evaluated sufficiently to establish an etiology? Part of the failure to assign specific etiologies could relate to the presumption that patients with ‘abnormal brains’ are ‘predisposed’ to seizures, so need not be rigorously investigated. Indeed, all patients in our study with seizures of unknown etiology were empirically started on anticonvulsants, regardless of EEG findings, and nine received no further diagnostic evaluation. In contrast, patients who had seizures with identifiable etiologies underwent more extensive diagnostic evaluation, with 19 patients having CT scans and nine having lumbar punctures. The age at which a patient’s first seizure occurred differed between those with known and unknown etiology. Children with a known etiology had a bimodal pattern of onset: early in life,
hypoxia-ischemia, CNS infections and congenital heart disease were the primary etiologies. During the teenage years, head injury and late manifestations of cardiac disease were most common. Many patients with idiopathic seizures also had their first seizure during the first year of life, but these occurred significantly later in the first year than infants whose seizures had an identifiable cause. This suggests that children with Down syndrome have an increased susceptibility to seizures early in life, and that superimposed systemic illness increases the likelihood of seizures. Some children's idiopathic seizures also begin later in childhood, suggesting that seizure susceptibility is not limited to early stages of brain development. It is well recognized that persons with Down syndrome develop the neuropathological and cognitive changes of Alzheimer dementia when they reach their thirties (Cutler et a/. 1985). Accompanying such neurological deterioration, many develop a new onset of seizures (Wisniewski el al. 1985, Lai and Williams 1989, Evenhuis 1990). There are no prognostic data for middle-aged Down syndrome patients whose seizures began in childhood. Febrile seizures occurred in only two of our 231 patients (0.9 per cent) in the susceptible age-range. Others have also commented on the relative rarity of febrile seizures in Down syndrome (Tatsuno et a/. 1984, Le Berre et al. 1986) compared with the general population frequency of 3 to 5 per cent (Nelson and Ellenberg 1978). The low frequency of febrile seizures is somewhat surprising, given the tendency of Down syndrome patients to incur frequent infections, but these seizures may be under-reported in the Down syndrome population. Infantile spasms, another age-specific seizure syndrome, are relatively frequent in patients with Down syndrome (Pollack et al. 1!278).
Cortical dysgenesis and the neuronal basis of seizures Recent advances in neurobiology have increased our understanding of the mechanisms of neurological dysfunction in Down syndrome (Scott et al. 1983, Coyle et al. 1986, Epstein 1986). It would seem that abnormal gene products of the
extra chromosome 21 would confer a unique pathophysiology on Down syndrome brains. Any abnormality that enhances net excitation or limits net inhibition would favor the development of a hyperexcitable, seizure-prone state. At the microscopic level, Down syndrome brains from birth are characterized by a 20 to 50 per cent decrease in the number of small granule cells, lower neuronal density and abnormal neuronal distribution, especially in cortical layers I1 and IV (Ross et al. 1984; Wisniewski et al. 1984, 1986; Kemper 1988). These granule cells are inhibitory, gamma-aminobutyric acidcontaining cortical interneurons (Ribak et al. 1979). A decrease in such cells, secondary to a defect in neurogenesis or neuronal migration (Wisniewski et a/. 1984, 1986), would shift the balance in favor of net cortical excitation. Another consistent microscopic finding in Down syndrome is dysgenesis of dendritic spines; besides a reduction in number, those present tend to be longer and to have thinner necks (Marin-Padilla 1976, Suetsugu and Mehraein 1980, Wisniewski et al. 1986). This spine morphology is common in normal brains prenatally, but postnatally spine morphology becomes more varied. However, in Down syndrome, long-necked dendritic spines persist after birth, suggesting a dysgenetic process (Takashima el al. 1981; Wisniewski et al. 1984, 1986; Becker et al. 1986), or undergo transsynaptic degeneration (Marin-Padilla 1976, Suetsugu and Mehraein 1980). Similar spine dysmorphology is seen in other categories of mental retardation (Purpura 1974); functionally, these morphological abnormalities will distort synaptic input so that voltage attenuation is greater in spines with short, thick necks. Neuronal membranes in Down syndrome are abnormally hyperexcitable. Scott et al. (1982) found that cultured dorsal-root ganglion neurons from Down syndrome fetuses displayed several hyperexcitable membrane properties, including decreased action potential afterhyperpolarizations and decreased voltage thresholds for action potential generation. These changes can be explained by alterations in membrane ionic channels.
m
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Similar results were obtained using the trisomy 16 mouse, an experimental model of Down syndrome (Epstein et af. 1985). Cultured neurons from such mice display hyperexcitable active and abnormal passive membrane properties compared with neurons from control mice because of alterations in potassium and/or sodium channels (Caviedes and Rapoport 1987, Orozco et af. 1987). Although the exact neuronal mechanisms for the increased susceptibility to seizures of children with Down syndrome have not yet been established, the available evidence suggests an interplay between pathologically hyperexcitable membrane properties (ionic conductances), altered neuronal structure (dendritic spines, synaptic density) and disproportionately fewer inhibitory interneurons. How these or other neuronal abnormalities are regulated by an extra chromosome 21 remains to be determined. Although children with Down syndrome have dysgenetic brains, with relatively hyperexcitable neurons, it is wrong to assume that their seizures are simply a consequence of abnormal brain development. Indeed, 62 per cent of seizures in our study population were attributable to common medical complications of Down syndrome. These acute stressors (e.g. hypoxia) may be particularly effective in producing seizures in neuronal circuits that are already predisposed to hyperexcitability.
Recommendations We recommend that all Down syndrome children with seizures, regardless of age or seizure type, be thoroughly evaluated to determine the etiology, especially if anticonvulsant therapy is being considered. Minimum evaluation should include EEG, neuro-imaging (CT or MRI scan of brain), careful cardiovascular examination and diligent search for infection. Duration of anticonvulsant therapy should be tailored to the specific etiology, keeping in mind that many seizures in these children are limited to the period of acute illness, and many others can be controlled by a single anticonvulsant . Accepted for publication 2Ist August 1990. Authors’ Appointments *Carl E. Stafstrom, M.D., Ph.D., Fellow in Pediatric Neurology, Floating Hospital for Infants and Children, Boston, MA. Omar F. Patxot, M.D., Fellow in Neurodegenerative Diseases, Institute for Basic Research in Developmental Disabilities, Staten Island, NY. Herbert E. Gilmore, M.D., Assistant Professor of Pediatrics and Neurology, Floating Hospital for Infants and Children, Boston, MA. Krystyna Wisniewski, M.D., Ph.D., Associate Director of Clinical Services, Institute for Basic Research in Developmental Disabilities, Staten Island, NY. *Correspondence to first author at Clinical NeurophysiologyUnit, Hunnewell2, The Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115.
SUMMARY Of 737 patients with Down syndrome, newborn to 22 years of age, 47 had a history of at least one seizure. Of those, 24 children had seizures with an identifiable etiology, usually related to a common medical complication of Down syndrome: neonatal hypoxia-ischemia, hypoxia from congenital heart disease, or infection. These acute medical illnesses may precipitate seizures in brains already predisposed to hyperexcitability because of abnormal neuronal development. It is recommended that all Down syndrome children with seizures undergo investigations to determine the etiology of the seizure. RESUME ComitaIitP et syndrome de Down: dtiologie, caractiristiques et devenir Sur 737 trisomiques 21, du nouveau-ne au sujet de 22 ans, 47 prksentaient une comitialite. Parmi eux 24 avaient des crises qui pouvaient Ctre reliees a une etiologie precise, habituellement une complication commune du syndrome de Down: hypoxie-ischbmie neo-natale, hypoxie par malformation cardiaque congenitale ou infection. Ces affections medicales aigiies peuvent favoriser la comitialite sur un cerveau d6ja prkdispost ii I’hyperexcitabilite en raison d’un developpement neuronique anormal. I1 est recommande que tous les trisomiques prksentant des crises comitiales beneficient d‘examens pour prkciser l‘origine des crises.
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ZUSAMMENFASSUNG AnfaIIe bei Kindern rnit Down Syndrom: Atiologien, Charakteristika und Outcome Von 737 Patienten mit Down Syndrom, vom Neugeborenenalter bis zu 22 Jahren, hatten 47 mindestens einen Krampfanfall in der Anamnese. Davon hatten 24 Anfalle mit bekannter Atiologie,
meistens im Zusammenhang mit einer gewohnlichen Komplikation beim Down Syndrom: neonatale Hypoxie-Ischamie, Hypoxie durch angeborenen Herzfehler oder Infektion. Diese akuten medizinischen Probleme konnen in Gehirnen, die bereits eine Pradisposition fur Hyperexzitabilitat aufgrurid einer abnormen neuronalen Entwicklung haben, Anfalle auslosen. Es wird empfohlen, da13 bei allen Kindern mit Down Syndrom und Anfallen, die Ursache der Anfalle untersucht wird. RESUME N Convubiones en niiios con sindrome de Down: etiologias, caracteristicas y curso De 737 pacientes con sindrome de Down de edad eritre recien nacido y 22 aiios, 47 tenian una historia de por lo menos una convulsion. De ellos 2.4 tenian convulsiones de etiologia identificable, en general en relacion con una complicacion medica corriente del sindrome de Down: hipoxiaisquemia neonatal, hipoxia por enfermedad congenita cardiaca o infeccion. Estas enfermedades medicas agudas pueden precipitar convulsiones en cerebros ya predispuestos a la hiperexcitabilidad por su anormal desarrollo neurologico. Se recomienida que todo niiio con sindrome de Down con convulsiones sea sometido a investigaciones para determinar la etiologia de la convulsion. Refererrces Becker, L. E., Armstrong, D. L., Chan, F. (1986) ‘Dendritic atroDhv in children with Down’s syndrome.’ Annals of Neurology, 20, 520-526. Caviedes, P., Rapoport, S. I. (1987) ‘Dorsal root ganglion neurons from normal and trisomy 21 human fetal tissue show tetrodotoxin-sensitive and tetrodotoxin-insensitive sodium channels.’ Society f o r Neuroscience Abstracts, 13, 1599. Corbett, J. A,, Harris, R., Robinson, R. (1975) ‘Epilepsy.’ In Wortis, J . (Ed.) Mental Retardation and Developmental Disabilities, Vol. 7. New York: Brunner/Mazel. Coyle, J. T., Oster-Granite, M. L., Gearhart. J . D. (1986) ‘The neurobiologic consequences of Down syndrome.’ Brain Research Bulletin, 16, 773-787. Cutler, N. R., Heston, L. L., Davies, P., Haxby, J. V., Schapiro, M. B. (1985) ‘Alzheimer’s disease and Down syndrome: new insights.’ Annab of Internal Medicine, 103, 566-578. Ellingson, R. J., Eisen, J. D., Ottersberg, G. (1973) ‘Clinical and electroencephalographic o bservations of institutionalized mongoloids confirmed by karyotype.’ Electroencephalography and Clinical Neurophysiology, 34, 193-196. Epstein, C. J. (1986) The Neurobiology of Down Syndrome. New York: Raven Press. R., Epstein, L. B. (1985) ‘Mouse an animFl model of human trisomy 21 (Down syndrome). Annals of the New York Academy of Sciences, 450, 157-168. Evenhuis, H. M. (1990) ‘The natural history of dementia in Down’s syndrome.’ Archive.r of Neurology, 47, 263-267. Fedotov, D. D., Shapiro, Y . L., Vaindrukh, F. A. (1968) ‘Some features of paroxysmal states in Down’s disease (clinico-statistical analysis).’ Zhurnal Nevropatologii i Psikhiatrii, 68, 1521. Gibbs, E. L., Gibbs, F. A., Hirsch, W. (1964) ‘:.ari’.v of 14- and 6-per-second positive spiking amc,, g mongoloids.’ Neurology, 14, 581-583. Guerrini, R., Genton, P., Bureau, M., Dravet, C., Roger, J. (1990) ‘Reflex seizures are frequent i; patients with Down syndrome and epilepsy. Epilepsia, 31, 406-4 17. Illingworth, R. S. (1959) ‘Convulsions in mentally retarded children with or without cerebral palsy.’ Journal of Mental Deficiency Research, 3, 88-93. Kemper, T. L. (1988) ‘Neuropathology of Down syndrome.’ I n Nadel, L. (Ed.) The Psychobiology of Down Syndrome. Cambridge, MA: MIT Press. Kirman, B. H. (1951) ‘Epilepsy in mongolism.’ Archives of Disease in Childhood, 26, 501-503. Lai, F . , Williams, R. S. (1989) ‘A prospective study of Alzheimer disease in Down syndrome.’ Archives of Neurology, 46, 849-853. Le Berre, C., Journel, H., Lucas, J., Le Meei, F., Betremieux, P., Roussey, M., Le Marec, B. (1986)
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