Epilepsia , 34(4): 780-787, 1993 Raven Press, Ltd., New York 0 International League Against Epilepsy Callosotomy in West Syndrome Suggests a Cortical Origin of Hyp sarrhythmia *§J. M. Pinard, 9 0 . Delalande, ?$P. Plouin, and "$0.Dulac *Services de Neuroptdiatrie et fd'Explorations Fonctionnelles du Systbme Nerveux, $INSERM U 29, Hapita1 Saint Vincent de Paul, Paris; and §Service de neurochirurgie, Hapita1 Foch, Suresnes, France Summary: Hypsarrhythmia and spasms of West syndrome have been postulated by some investigators to have a brainstem origin. Cortical involvement is also postulated because of the frequent association with cortical lesions. Cortical discharges have been proposed to stimulate subcortical structures (i.e., brainstem) and hypsarrhythmia is a secondarily generalized phenomenon produced by the brainstem. Two children with cryptogenic West syndrome refractory for several years to steroids and conventional antiepileptic drugs underwent total callosotomy. Hypsarrhythmia that was bilateral before operation became unilateral after the procedure and spasms became asymmetrical, suggesting that a corticocortical pathway through the corpus callosum is important in the generalization of hypsarrhythmia. Key Words: West syndrome-Infantile spasms-Epilepsy-Child-Electroencephalography-Neurosurgery-Corpus callosum. West syndrome (WS), a generalized epileptic syndrome of infancy, with spasms and hypsarrhythmia, is divided into two groups. Children with symptomatic WS (85-90% of cases) have a known neurologic disorder or preexisting signs of brain damage such as psychomotor retardation, neurologic signs, previous seizures, or abnormal neuroradiologic imaging. In those with cryptogenic WS (10-15% of cases) the etiology is unknown, and there is no previous sign of neurologic abnormality at seizure onset (Commission, 1989). In some cases, the spasms and hypsarrhythmia persist for several years and then evolve to Lennox-Gastaut syndrome. Spasms may be associated with other seizures such as tonic or drop attacks (Aicardi, 1986). Spasms and hypsarrhythmia have been postulated by some investigators to be of a pure brainstem origin (Hrachovy and Frost, 1989), but resection of focal hemispheric (Branch and Dyken, 1979) or cortical (Mimaki et al., 1983) lesions has cured the disorder in both symptomatic and cryptogenic cases (Chugani et al., 1990). Carrazana et al. (1990) suggested that cortical discharges stimulate the brainstem and set up a chain of events culminating in spasms and hypsarrhythmia. Based on the find- ing of symmetrical increase in metabolic activity in the lenticular nuclei and brainstem evoked by positron emission tomography (PET), Chugani et al. (1992) proposed that spasms are produced by cortical-subcortical interactions, with the hypsarrhythmia originating from brainstem through raphecortical projections. We report 2 cases of cryptogenic WS in which hypsarrhythmia became unilateral after total callosotomy, suggesting involvement of the corpus callosum in generalization of hypsarrhythmia. CASE REPORTS Patient 1 A boy born at 38 weeks of gestation after an uncomplicated pregnancy and delivery had a birth weight of 3.290 g and occipitofrontal circumference of 34 cm. There was no family history of epilepsy. Early psychomotor development was normal until age 4 months, when a first seizure occurred. During seizures, he either cried or smiled, and then exhibited brief flexor or extensor head and limb movements, sometimes associated with upward eye rolling. Spasms occurred in clusters, several times a day. EEG showed bilateral hypsarrhythmia (Fig. la). After a 2-week treatment with a synthetic polypeptide of the active segment of ACTH, tetracosactide (0.3 mg/day), plus valproate (VPA) (40 mg/ Received September 1992; revision accepted April 1993. Address correspondence and requests to Dr. J.-M. Pinard at HBpital Saint Vincent de Paul, Service de Neuropkdiatrie, 82 ave. Denfert-Rochereau, 75614, Paris Cedex 14, France. 780 CORTICAL ORIGIN OF HYPSARRHYTHMIA kg/day), clinical examination showed axial hypertonia and a left pyramidal syndrome. The child did not smile, had no visual tracking or fixation, and failed to reach for objects. Treatment was changed to a combination of hydrocortisone (15 mgikgiday for 2 weeks, then decreased for 2 more weeks) and VPA (40 mglkglday). Spasms disappeared, and psychomotor condition improved during the next 4 months, during which time the EEG showed a more prominent left-sided background delta activity and right posterior quadrant sharp waves and spikes. At age 9 months, developmental quotient (DQ) was 57. Spasms resumed and remained intractable to various antiepileptic drugs (AEDs), including hydrocortisone, VPA, carbamazepine (CBZ), clonazepam (CZP), and phenytoin (PHT). Video-EEG showed interictal hypsarrhythmia with symmetrical generalized mixed high-voltage delta slow waves, sharp waves, spikes, and spike-wave activity during sleep and awakeness. Spasm clusters typically started with arousal and a startle movement. Just before the first spasm, low-voltage delta activity and spikes localized to the right. Spasms were characterized by upper limb extension and leg flexion. Between spasms, the child appeared alert and exhibited chewing movements. During spasm clusters, the EEG hypsarrhythmia disappeared. Each spasm was preceded by a complex of slow and sharp waves predominant in the right frontal quadrant and associated with generalized 15-Hz rhythms followed by brief flattening of the EEG (Fig. lc). After the spasm series, bursts of 15-Hz rhythms, prominent on the right side, were associated with 2-Hz slow waves. After administration of intravenous diazepam (0.5 mg/kg), hypsarrhythmia disappeared and the EEG showed a spike focus remaining in the right posterior quadrant. Magnetic resonance imaging (MRI) and biochemical investigations were normal. Between age 1 and 4 years, psychomotor development was delayed and EEG showed a more discontinuous bilateral hypsarrhythmic pattern (Fig. lb). At age 4 years, the child could walk and reach for objects, but visual contact remained poor. Behavior was hyperkinetic and autistic, DQ was estimated at 35. Series of spasms occurred 10-15 times daily, associated with drop attacks and tonic seizures. Anterior callosotomy was performed at age 4 years, with transient improvement of spasms and behavior. By age 5 , spasms and autistic behavior had recurred, EEG remained hypsarrhythmic with slow waves and spike waves more prominent in the right frontal area (Fig. Id). Then complete callosotomy was performed. 781 One year after the second operation, visual contact, attention abilities, and behavior had improved Spasms and tonic seizures persisted, but were briefer, with rapid postictal recovery of usual behavior. Tonic seizures were asymmetrical and consisted of brief left-sided hypertonia, and the drop attacks ceased. Clusters persisted, with asymmetrical spasms consisting of left leg jerking preceded by chewing and left facial asymmetry. Clusters were associated with asymmetrical right-side beta activity of high amplitude, maximal in the frontal area (Fig. 2a). Interictal EEG was completely different: The right side showed high-amplitude spike and slow wave activity (Fig. 2b) or a discontinuous hypsarrhythmic pattern; the left side showed 6-7Hz background activity but no spikes. MRI was unchanged except for the callosotomy (Fig. 3). Patient 2 A 9-year-old right-handed girl was the product of a normal pregnancy and delivery. Development was considered normal before age 4 months when she experienced symmetrical spasms occurring in series. Psychomotor development was thereafter delayed: She walked at 24 months and spoke at 3 years. Treatment with VPA and tetracosactide or hydrocortisone, and then with phenobarbital (PB), clobazam (CLB), CZP, CBZ, progabide (PGB), PHT or vigabatrin (GVG) in various combinations did not reduce spasm frequency. Spasms persisted in series several times daily until the operation was performed. Generalized atonic seizures and tonicclonic seizures appeared during the third year and occurred >I0 times daily with falls, until age 7. At age 7, she was hyperkinetic, spoke few words, and did not write or draw. Global IQ was <30. The first EEG, at age 4 months, showed a hypsarrhythmic pattern. After corticotherapy , spike and slow wave abnormalities were more prominent over the right hemisphere until age 1 year; bilateral abnormalities then recurred despite treatments. At age 7, before operation, EEG showed generalized hypsarrhythmia, with no physiologic background activity, and high-amplitude theta and delta slow waves associated with generalized bursts of spikes and spikewaves (Fig. 4a). Although the parents reported series of spasms, no spasms or other seizures were recorded on video-EEG. A two-stage callosotomy was performed. At age 9 years, 1 year after callosotomy was completed, she was clinically improved, more attentive, and less hyperkinetic; she spoke more and no longer had drop attacks. Seizures were less severe and frequent (once or twice daily) occurring in series consisting of head drop followed by head- and eye turning to the left. The Epilepsia, Vol. 34, No. 4, 1993 J . M . PINARD ET AL. 782 a b 'ill L... ----- Rlghl shouldmr Len ehoulder Epilepsia, Vol. 34, No. 4, 1993 FIG. 1. Patient 7. EEG during wakefulness before callosotomy (same EEG sensitivity scale in a, b, and c). a: lnterictal activity, hypsarrythmia at age 6 months, before treatment. b: Interictal activity, at age 3.5 years, w i t h discontinuous hypsarrhythmic EEG pattern. c: lctal activity at age 9 months: bilatera1 spasms, with right predominance of slow wave (hypsarrhythmia disappears during the cluster). CORTICAL ORIGIN OF HYPSARRHYTHMIA 783 d FIG. 1. Continued. d: lnterictal activity, at age 5 years before completion of total callosotomy; hypsarrythmia is evident, with predominant slow waves and spike waves over the right frontal region. 1.1 a b FIG. 2. Patient 7. EEG 1 year after total callosotomy (same EEG sensitivity scale in a and b). a: High-amplitude delta slow waves and spikes localized in the right hemisphere, preceding fast activity of subictal discharge, maximal over the frontal area. b: lnterictal EEG recording showing left-sided 6-7-Hz background activity with high-amplitude right-sided spike and slow wave activity. Epilepsiu, Vof.34, N o . 4 , 1993 784 J . M.PINARD ET AL. DISCUSSION FIG. 3. Patient 7. T,-weighted magnetic resonance sagittal image: total callosotomy without visible hemispheric abnormality. EEG improved and became asymmetrical: Right hemisphere, delta slow waves, spikes, and spikewaves persisted (Fig. 4b); left hemisphere had 5-6Hz background activity with rare and short subclinical discharges. No seizure was recorded. Our two very similar cases demonstrate that symmetrical spasms and bilateral hypsarrhythmia can be altered by total callosotomy to become unilateral hypsarrhythmia with asymmetrical spasms, suggesting that generalization of hypsarrhythmia requires the corpus callosum. Hypsarrhythmia and spasms have been considered to originate from brainstem for several reasons (Martin, 1964; Kellaway et al., 1983). Spasms have been reported with hydrocephalous and extensive supratentorial parenchyma destruction (Neville, 1972). Brainstem lesions have rarely been described (Satoh et al. 1986; Tominaga et al., 1986), and are usually associated with cortical damage (Bignami et al., 1964; Palm et al., 1986; Satoh et al., 1986; Jellinger, 1987). One major although indirect argument in favor of brainstem involvement is the disappearance of spasms and the reduction of the hypsarrhythmic pattern during rapid eye movement sleep (Hrachovy et al., 1981; Plouin et al., 1987). Hrachovy et al. (1981, 1989) postulated that a brainstem neurotransmitter imbalance could be responsible for spasms and hypsarrhythmia, either as a result of increased activity of the adrenergic orland serotonergic systems, or decreased activity of the cholinergic sys- b FIG. 4. Patient 2. Same EEG sensitivity scale in a and b. a: At age 7 years: interictal hypsarrythmic EEG pattern before operation. b: One year after total callosotomy: asymmetrical interictal activity with delta slow waves, spikes, and spike waves. Epilepsia, Vol. 34, N o . 4 , 1993 CORTICAL ORIGIN OF HYPSARRH YTHMIA tem. Coleman et al. (1971) produced WS by administration of 5 hydroxytryptophan to Down syndrome patients. A contribution of subcortical structures in the genesis of WS was supported by the PET findings of symmetrically increased metabolic activity in the lenticular nuclei and brainstem (Chugani et al., 1992). Recent evidence suggests that the cerebral cortex is highly involved in the genesis of spasms and hypsarrhythmia. Various cortical lesions have been seen with spasms and hypsarrhythmia, including brain malformations, neurocutaneous syndromes, perinatal anoxic ischemia damage, early meningitis or encephalitis, or porencephaly (Alvarez et al., 1987; Cusmai et al., 1988). The cortical abnormalities may be diffuse, but are often focal or multifocal with variable topography, mostly in the posterior aspects of the cerebral hemispheres (Mimaki et al., 1983). Areas of abnormal cortical perfusion or metabolism have been shown by single photon emission computed tomography (Dulac et al., 1987b) and PET (Chugani et al., 1990). Partial seizures can precede the appearance of spasms by a few weeks or months. In many cases, spasm clusters appear.to be triggered by focal cortical discharges (Bour et al., 1986; Carrazana et al., 1990, 1993; Plouin et al., 1993). In a few cases, the ictal EEG shows both focal discharges and generalized spasms (Dalla Bernardina et al., 1984). Recovery from WS has been reported after excision of a hemispheric focal lesion such as choroid plexus papilloma (Branch and Dyken, 1979), temporal astrocytoma (Mimaki et al., 1983), parietotemporal ependymoma (Ruggieri et al., 1989), or various lesions (Carrazana et al., 1993). Chugani et al. (1990) reported seizure freedom after focal cortical resection in 4 children with cryptogenic WS in which focal dysplasia was demonstrated on neuropathology . The focal dysplasia was believed to have produced the diffuse hypsarrhythmia that disappeared after focal excision of the malformation. Hypotheses involving both the cortex and subcortical structures have been postulated to explain the pathophysiology of WS. Hypsarrhythmia has been postulated to result from corticocortical spread from single or multiple cortical foci. The cerebral cortex exhibits diffuse dysfunction owing to the lesions, and/or the hypsarrhythmia and fails to exert sufficient inhibition over the subcortical structures. These structures would be the generator of the series of spasms, eventually triggered by focal cortical discharges (Dulac et al., 1987a). Based on the finding of ictal hypermetabolism of the raphe and lenticular nuclei, Chugani et al. (1992) proposed that spasms could be triggered by the cerebral cor- 785 tex with involvement of the raphe nuclei of the brainstem and of the lenticular nuclei. Carrazana et al. (1990) supported the hypothesis of a primary cortical discharge, which would stimulate the brainstem, resulting in secondary generalization consisting of both hypsarrhythmia and spasms. They described 1 patient with corpus callosum agenesis and right frontal cortical malformation in whom flexor spasms preceded by left arm tonic movement was associated with asymmetrical hypsarrhythmic EEG pattern. Rapid secondary generalization through the corpus callosum appeared to be excluded. However, partial corpus callosum agenesis remained possible in this case, because sagittal MRI was not performed. Even in callosal agenesis, other interhemispheric connections persist, e.g., the anterior commissure (Ettlinger et al., 1974; Lassonde et al., 1991). Moreover, the hypsarrhythmic pattern in their case was obviously unilateral. In addition, the spasms recorded on the EEG appeared to be more prominent on the right side, the side of the frontal lobe cortical malformation. If the brainstem had been the generator of hypsarrhythmia through ascending projections, a bilateral symmetric, synergic or asynergic, hypsarrhythmic pattern would have been expected even if the corpus callosum had not been present. In Aicardi syndrome, most of the spasms are asymmetrical (Bour et al., 1986), and hypsarrhythmia is very often unilateral or atypical (Chevrie and Aicardi, 1986). This could be explained by the corpus callosum agenesis, and therefore the lack of propagation of hypsarrhythmia through the corpus callosum. After callosotomy , our 2 patients had asymmetrical spasms. Hypsarrhythmia disappeared on the left, and on the right the hypsarrhythmic pattern progressively evolved into a large frontal (patient 1) or frontocentral (patient 2) focus of continuous spike and slow wave activity. These observations suggest that early generalized hypsarrhythmia involved transcallosal propagation. If hypsarrhythmia originated from the brainstem as suggested by Martin (1964), Kellaway et al. (1983), or Carrazana et al. (1990), we would expect it to remain bilateral, although possibly asynchronous. The origin of hypsarrhythmia appears to be hemispheric with transcallosal propagation, at least in these cases. Cortical lesions, sometimes discovered only by anatomic analysis (Palm et al., 1986; Chugani et al., 1990), are most likely the generators of hypsarrhythmia in many cases. If any, the contribution of the brainstem appears to be secondary. The origin of spasms remains uncertain. There are strong arguments for a major contribution of the Epilepsia, Vol. 34, N o . 4 , 1993 J . M . PINARD ET AL. 786 cortex to physiopathologic mechanism of spasms. Focal cortical EEG discharges may precede or be associated with spasms (Bour et al., 1986; Carrazana et al., 1993; Plouin et al., 1993). Hemispheric or cortical lesions are frequently associated with spasms (Jellinger, 1987), and partial hemispheric resection is an effective treatment (Chugani et al., 1990). Other cases have demonstrated a subcortical contribution, as shown by ictal PET scanning (Chugani et al., 1992). Therefore, cortical and subcortical structures may combine to generate the ictal events. These observations support the hypothesis that hypsarrhythmia results from a corticocortical diffusion of interictal epileptogenic phenomena originating from single or multiple cortical foci. The origin of spasms remains unclear, but a combination of cortical and subcortical involvements is not excluded. Intracranial recordings made at operation may help to resolve this controversy. Acknowledgment: This work was supported in part by a grant from the Association Recherche et Partage of the Caisses d’Epargne Ecureuil and by a research grant from CRAMIFhNSERM. We thank Drs. H. Chugani, C. Camfield, and P. Camfield for advice and critical review of the manuscript. REFERENCES Aicardi J . Epilepsy in children. New York: Raven Press, 1986: 17-38. Alvarez LA, Shinnar S, MoshC SL. Infantile spasms due to unilateral cerebral infarcts. Pediatrics 1987;79: 1024-6. Bignami A, Zappella M, Benedetti P. Infantile spasms with hypsarrhythmia. A pathological study. Helv Paediatr Acta 1964; 4:32&42. 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Neuropathology of the brainstem in age-dependent epileptic encephalopathy-especially of cases with infantile spasms. Brain Dev 1986;8:443-9. Tominaga I, Yanai K, Kashima H, et al. Observation anatomoclinique d’une sCquelle d’enckphalopathie aigue. Rev Neurol (Paris) 1986; 142524-9. R~SUME Le tronc cCrCbral est considkrk par certains comme l’origine de I’hypsarythmie et des spasmes observes dans le syndrome de West. Cependant, I’existence de lCsions corticales frCquemment retrouvkes suggere une participation corticale. Dans ces cas, il a CtC proposC comme hypothese que les dtcharges corticales stimulent les structures sous corticales, en particulier le tronc cCrCbra1, et que I’hypsarythmie est un phCnomBne de g6nCralisation secondaire produit par le tronc cCrCbra1. Deux enfants presentant un syndrome de West cryptogenique persistant plusieurs annCes et rksistant a la corticothtrapie et aux autres antikpileptiques ont subit une callosotomie totale. L’hypsarythmie, bilattrale avant l’intervention, est devenue unilatkrale apr&s celle-ci; les spasmes sont devenus asymktriques. Ceci suggere que des voies corticocorticales passant par le corps calleux sont indispensables A la gCnCralisation de l’hypsarythmie. (Translation supplied by authors) 787 CORTICAL ORIGIN OF H YPSARRHYTHMIA RESUMEN ZUSAMMENFASSUNG El tronco cerebral es considerado por algunos el orken de la hypsarritmia Y el sindrome de West. Sin embargo, se sospecha la participaci6n de la corteza cerebral por la frecuente asociaci6n con lesiones corticales. En estos casos, se ha propuesto weviamente que las descargas corticales estimulan estructuras subcorticales (corn0 el tronco cerebral) Y que la hypsarritmia es un fendmeno secundariamente generalizado producido por el tronco cerebral. Dos nifios con sfndrome de West refractario durante varios aAos al tratamiento esteroidal y antiepildptico convencional fueron sometidos a callosotomia total. La hypsarritmia que era bilateral previo a la cirugia se torno unilateral mientras que 10s espasmos se tornaron asimetricos. Esto suguiere que una via corticocortical a travds del cuerpo calloso es importante en la generalizaci6n de la hypsarritmia. Es wird vermutet, dap Hypsarrhythmie und BNS-Krampfe beim West-Syndrom ihren Ursprung im Hirnstamm haben. Aber eine/kortikale Beteiligung wird gefordert, wegen der haf uigen Assoziation kortikaler Llsionen. Man nimmt an, dap kortikate Entladungen subkortikale Sturkturen (z.B. Hirnstamm) stimulieren und dap die Hypsarrhythmie eine sekundare Generalisierung durch den Hirnstamm darstellt.Zwei Kinder mit kryptogenem West-Syndrom und Therapieresistenz gegeniiber Steroiden und iiblichen wurden einer vollstlndigen Gallosotomie unterzogen. Die vor dem Eingriff bilateral zu beobachtende Hypsarrhythmie trat danach nur noch einseitig Die BNS-Krampfe wurden asymmetrisch. Dies kann ein fiir kortiko-kortikale Verbindungen via CorpusCallosum sein, welches fiir die Generlisierung der Hypsarrhythmie wichtig ist. (Translation supplied by authors) (C. G . Lipinski, HeidelberglNeckargemund Epilepsia, Vol. 34, N o . 4 , 1993