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What must we know to develop better therapies?
WHAT MUST WE KNOW TO DEVELOP BE'I-I'ERTHERAPIES?
Jean Aicardi Department of Child Neurology Hospital Robert Debre Paris 75019, France
I. II. III. IV.
Introduction T h e Need for Better Clinical Data T h e Need for I m p r o v e m e n t of Pathophysiological Knowledge W h a t Can D r u g Effects Tell Us about the Mechanisms of Epileptogenesis in Infantile Spasms? V. Conclusion References
h Introduction
Infantile spasms (IS) are notoriously difficult to treat. They are resistant to most conventional antiepileptic agents and, until 1958, no effective therapy was available (Sorel and Dusaucy-Bauloye, 1958, Snead and Chiron, 1994). Following the initial report of the remarkable activity of ACTH in the syndrome, a vast literature has become available not only on ACTH and corticosteroid therapy, but also on other drugs, as it was progressively realized that some new antiepileptic agents were also effective in some cases. Good reviews of the treatment of IS are available (Snead and Chiron, 1994; Jeavons and Bower, 1994; Riikonen and Donner, 1980). Overall, ACTH a n d / o r corticosteroid therapy is still regarded as most efficacious against the seizures. However, the effect of these agents on the cognitive and behavioral abnormalities that constitute the most important consequence of IS is less spectacular and, indeed, has never been conclusively demonstrated (Snead and Chiron, 1994; Lacy and Penry, 1976). Conflicting results have been and are still being published, and decisions about the choice and modalities of treatment are still largely determined on the basis of fragile evidence and personal preferences. The aim of this chapter is to review the contentious points of therapy and to try to define the possible manners of improving it. T h r e e points are considered successively: (1) The need for better clinical data on the various therapies available and the m a n n e r of assessing them; (2) the n e e d for improvement of our pathophysiological knowledge; and (3) what drug INTERNATIONAL REVIEW OF NEUROBIOLOGY, VOL. 49
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effects can tell us about the intimate mechanisms of IS and thus lead to other possibly more rational treatments.
Ih The Need for Better Clinical Data
Proper evaluation of available therapeutic agents is a prerequisite to any attempt at improving treatment. Thus far, this has been only rarely, if ever, achieved. ACTH and corticosteroids have been generally considered as the most effective treatment of IS since 1958 (Snead and Chiron, 1994;Jeavons and Bower, 1974; Lacy and Penry, 1976). The overall rate of control of spasms with hormonal therapy varies between 33 and 90% with an average of 50 to 60%. However, the significance of such figures is not clear because of the use of two different agents, ACTH and corticosteroids, of the innumerable modalities of treatment, and of the fact that IS are a syndrome of multiple causes, which obviously influences considerably their response to therapy (Snead and Chiron, 1994; Lacy and Penry, 1976). Therefore, a considerable effort is necessary to form reasonably h o m o g e n e o u s series. Important factors of prognosis must be taken into account: the results are very different in symptomatic IS, in which the percentage of control varies between 0 and 20% (Jeavons etal., 1973; Snyder, 1967) and in cryptogenic cases in which it reaches between 60 and 80% (Lombroso, 1983; Favata et al., 1987) or even 90% (Schlumberger and Dulac, 1994). Moreover, the proportion of symptomatic cases can vary considerably according to the completeness of diagnostic investigations. With the use of m o d e r n magnetic resonance (MR) techniques, cryptogenic cases b e c o m e increasingly infrequent as they demonstrate types of lesions, especially cortical dysplasias, that were previously undectable and are one of the most frequent cause of IS. Thus, a preestablished protocol of investigations should be a prerequisite to studies on therapeutic results. One major issue about h o r m o n a l treatment is the lack of comparability of many studies that results from the use of highly individual therapeutic protocols in terms of the agent used and of the modalities of treatment. A majority of investigators have used ACTH, but others have preferred oral corticosteroids in order to avoid the necessity of injections (and thus of hospitalization with its attending infectious risks) (Snead and Chiron, 1994; Favata et al., 1987; Schlumberger and Dulac, 1994). Only a few prospective, controlled studies comparing ACTH and corticosteroids (usually prednisone) are available. Glaze et al. (1988) and Hrachovy et al. (1983) found no significant difference between natural ACTH and prednisone in children with cryptogenic IS who had a normal development up to the onset
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of the seizures. In a large prospective study of 72 patients with cryptogenic spasms, Lombroso (1983) found no difference in short-term effects between the two treatments. He observed that ACTH was superior with regard to developmental outcome in the long term. However, Baram et al. (1996) obtained a significantly better short-term outcome with high-dose ACTH than prednisone. Thirteen of 15 infants receiving ACTH went into remission versus only 4 of 14 of those receiving prednisone. Recent work (Snead and Chiron, 1994) thus seems to favor high doses of ACTH. However, the numbers of infants studied are still small, and further studies with special attention to dosages, duration, and type of product (natural vs synthetic ACTH) have to be continued. W h e t h e r ACTH or corticosteroids give superior results in terms of cognitive/behavioral development, an essential consideration, is even more difficult to determine. Only one study (Lombroso, 1983) favored ACTH in this regard and its methodology was not perfect. Such long-term evaluation demands difficult studies, requiring large numbers of participants, and therefore needs to be multicentric and to include a long follow-up with attending major problems to maintain all children in the studies. The m a n n e r of assessing the results is a critical factor in comparisons of results and every effort should be made to make it as objective and standardized as possible. For short-term results, disappearance of the spasms is the usual criterion. However, a decrease in the n u m b e r of spasms has been used in some studies [e.g., that of Dreifuss et al. (1986)], making direct comparison impossible. Nevertheless, the h o r m o n a l treatment result is usually all or n o n e so complete control is probably the best criterion. Spasms should be separated from other types, especially partial seizures, whose signification is different with regard to prognosis and therapy. However, mild spasms have been shown to escape easily to parents (Kellaway et al., 1979), and not all studies include sleep electroencephalogram (EEG) recordings. These are necessary to confirm the clinical impression of disappearance of seizures. They should include sleep tracings as abnormalities, in the case of recurrence, occur first and most prominently in sleep (Lacy and Penry, 1976; Gastaut et al., 1984; Hrachory and Frost, 1986). EEGs certainly should be included among assessment criteria. An EEG should be obtained within 2 weeks of discontinuation of treatment and a repeat one 2 months later. Long-term developmental assessment requires rigorous methodology to ensure uniformity of results and must take into account a study of other fields of cognitive and behavior in addition to I Q determination. This issue is discussed later with surgical treatment. Clearly, the duration of follow-up should be of the same order or magnitude both for control of seizures and for developmental progress. Overall, the long-term outcome of IS is rather
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poor with a proportion of normal development that does not appear to be strongly linked with the m o d e of treatment used. Some n o n h o r m o n a l treatments have been used extensively in the past few years. They include nitrazepam, valproate, vigabatrin (VGB), lamotrigine, and topiramate. The latter two have received only preliminary trials. O t h e r agents have also been used but not submitted to critical trials. They include pyridoxine, which is reported to have given control in 10 to 30% of cases (Ohtsuka et aL, 1987; Pietz et al., 1993); thyrotropin-releasing h o r m o n e (TRH) (Matsumoto et al., 1987), with a surprisingly high reported control rate of up to 53%, as compared to 75% for ACTH; and immunoglobulins for which only anecdotal data are available. Valproate in large doses (80 to up to 300 m g / k g ) has been reported in uncontrolled studies to stop IS in 20 to 45% of cases (Siemes et al., 1988; Dykey et al., 1985; Prats et al., 1991). A double-blind study has compared nitrazepam with corticotrophin in 52 infants (Dreifuss et al., 1986). Both treatments resulted in a significant reduction in spasm frequency from the baseline, but the difference between treatments was not significant. However, the impression prevails a m o n g investigators that ACTH is more effective, and no further comparison has been since published since, again indicating that clinicians do not easily accept results of comparative studies, even double-blind ones, when they contradict their everyday experience. Although this is a regrettable trend, it should be recognized that results of comparative studies are often difficult to apply to clinical practice as differences inevitably exist in some of the parameters, such as selection of patients, doses, and duration, and, strictly speaking, they apply rigorously only when all of these factors are identical, which is seldom, if ever, the case. Vigabatrin has proved effective in uncontrolled studies with a control rate varying from 26 to 68% (Aicardi et al., 1996; Chiron et al., 1990) and even up to 90% in patients with tuberous sclerosis (TS). Prospective, controlled studies have compared this drug to hormonal therapy. Vigevano et al. (1997) found VGB slightly less effective than ACTH in the control of IS; however, because relapses were less frequent in this study with VGB, the ultimate efficacy was similar in both groups. Chiron et al. (1997) found the efficacy ofvigabatrin in tuberous sclerosis greater than that of corticosteroids although problems of retinal toxicity are currently limiting the use of VGB, this agent is certainly of considerable interest, especially in view of its possible selective efficacy on IS associated with tuberous sclerosis (Chiron et al., 1990; Vigevano and Cilio, 1997; Lortie et al., 1993). Several studies confirmed its special efficacy (Aicardi et al., 1996; Chiron including a controlled one (Chiron et al., 1997). However, some investigators were less impressed with the superiority of vigabatrin in TS (Granstr6m et al., 1999). This possible selectiveness raises an additional
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difficulty for comparative studies: the etiologic diagnosis may have to be taken into consideration in such studies, imposing further constraints on future trials. Additionally, other subgroups might have different sensitivity to various agents, thus posing the practical problem of specific drug indications for subgroups of IS. Currently, however, this problem seems limited to tuberous sclerosis, but other etiologic subgroups with different responses to individual agents may exist. All problems involved in comparisons of medical therapies of IS underline the practical difficulties of such studies. Clearly, efforts to obtain homogeneous groups with regard to age, known prognostic factors, protocols of treatment employed, methods of assessment, and standardization of pretreatment evaluation [certainly including MR imaging studies and possibly other techniques, such as positron emission tomography (PET) in selected cases] are warranted if comparisons are to be valid. Ethical considerations may complicate the issue and possible relational problems with families may also arise, given the severity of the prognosis. Careful clinical study of selected cases remains of interest even though its reliability is questionable. Evaluation of surgical therapy is even more difficult, as no doublebind studies are ethically possible. It is, however, possible to compare the outcome of operated children with those of similar historical controls or of children not operated on for "nonmedical" reasons. Asarnow et al. (1988) have studied the developmental outcomes in 24 children with IS who had received resection surgery and compared it with that of unoperated children (presumably because of lesions not amenable to resection). They used an extensive battery of psychological tests exploring multiple cognitive and behavioral domains (Vineland adaptive behavior, communication skills, socialization, and daily living skills) that were performed just before operation and about 2 years later. Development had progressed in all children following their operation and the level they reached compared favorably to that in literature series of medically treated cases that probably included less severe cases. However, the velocity of development of these operated children was clearly below that of normal children, thus indicating that any "catch up" observed was only relative, in comparison with medically treated IS children, rather than absolute. The authors considered this improvement significant and of practical value for patients and families. Although criticisms may be directed at this study (e.g., unoperated patients might have been rejected because of greater severity), it represents a valiant effort to deal with the type of problems raised by the impossibility of randomized surgical series and a serious attempt at standardization, which is particularly hard to apply to surgical results. The results of this study also suggested that early surgery and the shortest active period, as judged
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by the duration of persistence of spasms, were associated with the best outcomes, even though very few patients actually reached satisfactory levels of central nervous system (CNS) function. Some theoretical considerations (see later) that indicate the involvement of the brain stem, especially of the reticular substance, in the mechanisms of IS suggest a possible role for agents modifying the levels, distribution, or action of monoamines, such as serotonin and dopamine. To the author's knowledge, no trial of such agents has been p e r f o r m e d so far. In summary, clinical therapeutic data are absolutely essential, as IS are a purely h u m a n disorder whose treatment can only be evaluated clinically. Further studies, satisfying the conditions discussed earlier, are clearly in order, despite their difficulties.
IIh The Need for Improvement of Pathophysiological Knowledge
Little is known about the pathophysiology and mechanisms of IS, although many hypotheses have been proposed to account for the delayed occurrence of the seizures, their peculiar responsiveness to corticotrophin and corticosteroids, the multiplicity of their causes with or without CNS lesions, and the frequent persistence of mental retardation after disappearance of the seizures and of the paroxysmal EEG abnormalities (Mosh6 et al., 1994; Baram, 1993; Riikonen, 1983). The proposed hypotheses include that of a developmental defect with delayed and abnormal brain maturation with resulting changes in neuronal connectivity responsible for both the heighte n e d excitability and later cognitive deficits (Mosh6 et al., 1994); that of an abnormal immunologic reactivity to u n d e t e r m i n e d antigens (Riikonen, 1983) or that of abnormal regulation of the h y p o t h a l a m o - a d r e n a l axis (Baram, 1993). The occurrence oflS with hypsarrhythmia and cognitive decline requires involvement of the cortex as also indicated by the finding of cortical pathology in a large majority of cases (Robain and Vinters, 1994). However, there are also some clinical and physiological arguments in favor of subcorfical, especially brain stem, involvement (Riikonen, 1983; Robain and Vinters, 1994; Neville, 1972; Chugani et al., 1992; Fukuyama, 1960; Hrachovy and Frost, 1989). Spasms have been reported in an infant with hydranencephaly (Neville, 1972) and have been observed in cases of anencephaly). PET studies have revealed hypermetabolism in the brain stem in 48% (21 of 44), of cases and in the lenticular nuclei in 73% (32 of 44), suggesting their participation in the generation of IS (Chugani et al., 1992). Cortical lesions associated with IS are most often of developmental origin, but no
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c o m m o n pattern of lesions is apparent. Both diffuse (e.g., lissencephaly or pachygyia) and focal or unilateral lesions are possible, even though focalization may not be absolute, as minimal developmental anomalies can be associated and not be detected by imaging or at operation. Spasms can be similar even with widely different localization and nature of lesions. Except for rare instances, no pathology has been f o u n d in the brain stem. In fact, a structurally normal brain stem may be necessary for the production of IS. Studies o f m o n o a m i n e neurotransmitters in the brain stem have reported contradictory findings. Some investigators f o u n d high levels of serotonin and dopamine, whereas others were unable to demonstrate similar changes (Hrachory and Frost, 1989). Reduced rapid eye movement (REM) sleep and decreased total sleep time as compared with normal infants have been d o c u m e n t e d (Fukuyama, 1960), and only those infants who responded to ACTH or prednisone showed a reversal of REM sleep abnormalities. These findings suggest that neural structures close to centers that regulate sleep cycles in the pons may be involved in the generation or propagation of spasms. A reasonable hypothesis suggests that IS directly result from subcortical mechanisms, triggered by discharges from the cortex (Chugani et al., 1992; Dulac and Plouin, 1993). Such discharges may often be focal, even though the spasms in such cases are sometimes bilaterally symmetrical (Shewmon, 1994). However, lateralized spasms frequently occur with cortical lesions and are generally contralateral to the hemisphere involved, arguing against a purely brain stem origin. Focal discharges may manifest initially as focal seizures preceding the appearance of IS for variable periods T h e r e may thus be a time window during which cortical discharges can trigger the brain stem, accounting for the age-related d e p e n d e n c y of IS. In fact, spasms can occur after the age of 2 years and up to adulthood in rare instances. Such cases could be particularly important to study in terms of their circumstances of occurrence and type of cortical lesions. T h e r e is a suggestion that late-occurring spasms tend to be associated with extensive cortical lesions, e.g. diffuse lissencephaly or Aicardi syndrome (Chevrie Aicardi, 1986), but whether this is really significant remains to be seen. T h e absence of an animal model of IS is a major limitation to understanding the mechanisms and performance of animal therapeutic trials. No model satisfies the conditions described elsewhere by Holmes. In some (e.g., the NMDA model), the seizures may resemble IS with ventral flexion (Mosh6 et al., 1994), but most other conditions, such as spontaneous occurrence, response to drugs, and presence of EEG abnormalties, are not fulfilled. In some attempted models, even though the criterion of age relation (at least as far as age of onset is concerned) is satisfied, the type of seizure
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is different from IS and these models look more like models of infantile seizures in general than specifically of infantile spasms. This can be said of the kindling models suggested by Mosh6 et al. (1994), as well as the adrenocortical model of Baram (1993). Indeed, if rats 2 to 3 weeks old are particularly sensitive to kindling and may exhibit seizures dramatically more violent than kindled adult animals after a shorter kindling period, the seizures are not like IS. The same applies to the kindling model in kittens even though animals u n d e r 6 months of age may exhibit multifocal EEG abnormalities after kindling and occasionally seizures with a '`jackknife" character (Mosh6 et al., 1994). Such p h e n o m e n a emphasize the propensity of the immature CNS to express multifocal seizures that may be a factor in the generation of IS, but do not reproduce the p h e n o m e n o l o g y of IS. Likewise, although an excess of corticotrophin-releasing factor may have a proconvulsant activity that could be suppressed by both ACTH and corticosteroids, the seizures do not have the characteristics and course of infantile spasms (Baram, 1993). Given the absence of a satisfactory model accounting for most of the features of the h u m a n disease, it might be worthwhile to limit our ambitions to the realization of partial models in an effort to reproduce only some of the characteristics of h u m a n IS, e.g., the very disorganized EEG, the "jackknife" seizures, or the neurological and developmental regression, and to try to determine the mechanism(s) of these more limited abnormalities. Another important issue is the understanding of the cognitive/behavioral changes in IS. During the " a c u t e " phase of the disorder, it can be accepted that the continuous EEG paroxysmal activity represents one form of nonconvulsive status epilepticus, responsible for the stagnation or deterioration of performances (Aicardi, 1994). This sort of explanation is also generally accepted in other epileptic conditions of later life, such as continuous spike-waves of slow sleep or the L a n d a u - K l e f f n e r syndrome (Morrell et al., 1989). The persistence of cognitive/behavioral disturbances after the acute phase and the disappearance of EEG abnormalities d e m a n d a n o t h e r explanation. It has been suggested that lasting deficits may be due to changes resulting from plastic modifications of connectivity induced by massive, continuous paroxysmal activity. This nonselective paroxysmal activity could maintain synaptic connections that would normally be " p r u n e d . " Persistence of excess synapses could prevent the establishment of neuronal circuits normally determined and maintained by the facilitation of only those synapses that participate in physiological activities. The resulting abnormal circuitry could account for the lasting cognitive and behavioral problems (Morrell et al., 1989). This hypothesis is partially testable by clinical studies: suppression of spasms and diffuse, paroxysmal EEG
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abnormalities, if accomplished early enough, whether by drug treatment or by surgery, should result in an improvement of cognitive functions. In addition to the requirements mentioned earlier, strict and repeated verification of the normality of the EEG, including sleep tracings, would be necessary. The possible contribution of experiments studying the molecular genetics and neurotransmitters and of the combinations and topographic distribution of their various subunits at the single cell level (White et aL, 2001) may prove to be of great importance for the understanding of the origin of tuberous sclerosis and cortical dysplasia. Such studies have already shown that different alterations of genes encoding glutamatergic and 0t-aminobutyric acid GABAergic receptors and uptake sites may occur selectively in dysplastic neurons and giant cells of brain samples from patients with tuberous sclerosis and may contribute to the increased excitability of abnormal tissue and thus to seizure initiation. Such cell-specific changes in gene transcription argue for distinct molecular phenotypes of dysplastic neurons and giant cells and suggest that dysplastic neurons and giant cells make different contributions to epileptogenesis in TS. Such fine molecular dissection ultimately could be combined with direct recording from individual cells, dendrites, or synapses, thus giving a comprehensive picture of the balance of excitation and inhibition in developmental defects, thereby offering opportunities to correct or to neutralize their epileptogenic effects.
IV. What Can Drug Effects Tell Us about the Mechanisms of Epileptogenesis in Infantile Spasms?
The peculiarities of response to drugs of IS, especially their resistance to conventional anticonvulsants and their sensitivity to ACTH and corticosteroids, have suggested that these agents might be in some way implicated in the mechanisms involved in their generation or propagation. However, the same agents are not specific for IS but may also produce satisfactory results in other epilepsy syndromes (Snead and Chiron, 1994), and the same certainly applies to vigabatrin (Aicardi et al., 1996). In general, drug effects represent at best indirect indications, as their site and modalities of action are poorly known and are often very different from what would be theoretically expected according to current knowledge. Multiple hypotheses have been put forward to account for the therapeutic effects of ACTH and corticosteroids. A direct action of hormonal therapy is possible. Corticosteroids have been shown to reduce
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the excitability of hippocampal pyramidal cells in vitro, perhaps through the mediation of steroid receptors in the central nervous system. Alternatively, they could be selectively toxic to glutamatergic neurons, especially numerous, in the developing brain (Moshfi etal., 1994). ACTH might also exert its action through an extraadrenal mechanism. Previously described clinical experience would favor this possibility, as would reports of its effectiveness in some cases of IS in patients with adrenal suppression (Farwell et aL, 1984). Substantial pharmacological and physiological evidence supports a direct effort of ACTH on the development and activity of the brain (Snead and Chiron, 1994). ACTH may play a role in the regulation and synthesis of several neurotransmitters and may affect various categories of receptors. This activity may reside in fragments of the peptide devoid of corticotropic activity. More recent work suggests that ACTH directly influences limbic neurons independently of corticosteroid secretion, although previous trials of such fragments in a few patients with IS have not shown any therapeutic effect (Pentella et al., 1982). Brunson et al. (2001) r e p r o d u c e d the effect of ACTH with a fragment devoid of corticotropic activity, an effect abolished by a specific antagonist of the receptors. This suggests that ACTH has a direct action on the brain unrelated to corticosteroids. The positive effect of both corticosteroids and corticotrophin can be accounted for by the hypothesis that a fundamental pathogenic role is played by the corticotrophin-releasing h o r m o n e (CRH). This hypothalamic neuropeptide normally acts to promote the release of ACTH, which in turn enhances glucocorticoids synthesis. ACTH and corticosteroids exert an inhibitory action on the synthesis and secretion of CRH, a negative feedback mechanisms. CRH has excitant properties on a wide variety of neurons, increases neuronal excitability, and can produce seizures in animals (Baram, 1993). This convulsant action is more potent in infant rats than in adult animals (Baram and Schulz, 1992). This hypothesis could explain that both ACTH and corticosteroids have a therapeutic effect, as both can suppress CRH secretion, although the action of corticosteroids would be only indirect through inhibition of ACTH release. In the absence of a p r o p e r animal model, no verification of this hypothesis is currently possible and the only verified conclusion is that CRH is indeed a convulsant agent, but a specific relation to IS remains to be demonstrated. As indicated earlier, several other mechanisms can account for the therapeutic properties of ACTH and perhaps ofcorticosteroids, such as an acceleration of the CNS maturational process, and altered expression of many genes that could result in changes in connectivity and excitability. Because VGB has proved an effective agent in the treatment of IS, elucidation of its mode of action could shed some light on the mechanisms involved in their generation. VGB, an irreversible inhibitor of the enzyme
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GABA transaminase, considerably increases the content of GABA in the CNS. This GABAergic action could be an important mechanism in its therapeutic effect on IS, although no direct evidence is available for a specific mechanism, and other GABAergic agents could have a similar action. However, tiagabine, an inhibitor of GABA reuptake, does not seem to be active. T h e r e are important differences between infants and adult animals in the effects of GABA that may be significant in a syndrome such as infantile spasms, which is rather narrowly age limited. Early in life, GABA has excitatory effects through GABAA receptors in several structures (hippocampus, cerebral cortex, cerebellum, and spinal cord) and thus enhances rather than antagonizes glutamate excitatory action. Thus, GABAergic inhibition in young infants may be mediated solely by GABAB receptors (Ben-Ari et al., 1997). In the developing brain, the GABAB inhibition may therefore be strengthened. This appears to be the case in the substantia nigra pars reticulata, a site critical for the control of generalized seizures (Mosh6 et al., 1994). VGB seems to act on both GABAA and GABAB inhibition (Mosh6 et al., 1994) and thus might be active through the increase in GABA content that it produces. The differences in the mechanisms of action of GABA with age might be of particular interest in neural structures such as substantia nigra as this structure is critically located between the cerebral cortex and the pontine reticular formation, whose role in the propagation and elaboration of IS is probably important. The differences in GABA action in the course of development may thus be critical for the occurrence, and possibly in antagonization, of IS. Changes in the effect of various GABAA and GABAB agonists and antagonists and in receptor subtypes may ultimately be relevant for therapy. Mosh6 and colleagues (1994) has suggested that possible new directions in the treatment of IS may include the use of drugs that act on the substantia n i g r a - p o n t i n e reticular formation circuit and that GABAB receptor agonists such as baclofen should be tested clinically. Levetiracetam might also be of interest, as it specifically acts on the substantia nigra (L6scher et al., 1996). Such highly hypothetical suggestions maywell deserve to be pursued and various GABAB agonists could be screened. Another interesting point about vigabatrin concerns its possible specificity against IS caused by tuberous sclerosis. Chugani et al. (1998) indicates that there is an excess of tryptophan and 5-hydroxytryptamine (serotonin) in epileptogenic tubers from patients with tuberous sclerosis, as shown by PET after the administration ofa-methyl-L-tryptophan marked with radioactive carbon 11 C. Resection of the fixating tubers was associated with control of the seizures in some cases (Chugani et al., 1998). Nonepileptogenic tubers do not demonstrate excess fixation. A similarly increased serotonin content
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may also be present in some cases of cortical dysplasias not associated with tuberous sclerosis (Trottier et al., 1996). W h e t h e r there may be possible specific effects of vigabatrin in IS due to tuberous sclerosis is completely unknown but perhaps worth investigating. A possible role of serotonergic mechanisms in epileptogenesis has already b e e n suggested. Genetically epilepsy-prone rats have a decreased concentration of brain serotonin (Dailey et al., 1989), and lowering of brain 5-hydroxytryptamine concentration leads to an increase in seizure susceptibility in animal models of epilepsy (Wenger et al., 1973), as well as in h u m a n s (Pallister, 1982). Levels of 5-hydroxyindole acetic acid, a metabolite of serotonin, were f o u n d to be higher in samples of actively spiking temporal cortex f r o m patients with epilepsy c o m p a r e d to normal controls (Trottier et al., 1996). A m o r e specific relationship of IS to serotonin was suggested by Coleman (1971), who f o u n d that administration of 5-hydroxytryptophan to infants with Down's syndrome was associated with the a p p e a r a n c e of IS. However, the diagnosis of IS may not have b e e n correct as no hypsarrythmia was present. Nevertheless, there are reasons for further study of serotonin metabolism in IS and for possible attempts to find whether antagonists could be of any therapeutic benefit.
V. Conclusion
Despite m a n y years of practice with multiple treatments of IS, the therapeutic results remain unsatisfactory. This is due to two m a j o r defects. T h e first is the fact that various agents and protocols have b e e n used by different physicians, rendering comparisons of results impossible. Only rare comparative studies with a correct m e t h o d o l o g y have b e e n p e r f o r m e d and there is still a n e e d for m o r e good studies, especially inasmuch as long-term cognitive and behavioral o u t c o m e is concerned. T h e second defect is the absence of real animal models of the h u m a n condition, which precludes e x p e r i m e n t a t i o n of new agents. Although most new antiepileptic drugs have not proved of greater value than those used thus far, there is clearly a place for o t h e r categories of agents, provided they are submitted to critical, well-planned studies.
References
Aicardi,J. (1994). "Epilepsy in Children," 2nd Ed., pp. 207-216. Raven Press, New York. Aicardi, J., Sabril Investigator Group, Dumas, C., and Mumford,J. (1996). Vigabatrin as initial therapy for infantile spasms. Epilepsia 37, 638-642.
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Asarnow, R. F., LaPresti, C., Guthrie, D., et aL (1988). Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms. Dev. Med. Child. Neurol. 39, 430-440. Baram, T. Z. (1993). Pathophysiology of massive infantile spasms: Perspective on the putative role of the brain adrenal axis. Ann. Neurol. 33, 231-236. Baram, T. Z., Mitchell, W. G., Tournay, A., Snead, O. C., III et al. (1996). High-dose corticotropin (ACTH) versus prednisone for infantile spasms: A prospective randomized, blinded study. Pediatrics 97, 375-379. Baram, T. Z., and Schulz, L. (1992). CRH is a rapid and potent convulsant in the infant rat. Brain Res. 61, 97-101. Ben-Ari, Y., Khazipov, R., Leinekugel, X., et al. (1997). GABAA, NMDA and AMPA receptors: A developmentally regulated " m t n a g e fi trois." Trends Neurosci. 20, 523-529. Brunson, K. L., Khan, N., Eghbaal-Ahmadi, M., and Baram, T. Z. 2001, ACTH acts directly on amygdala neurons to downregulate corticotropin releasing hormone gene expression. Ann. Neurol. 49, 304-312. Chevrie, J. J., and Aicardi, J. (1986). The Aicardi syndrome. I n " R e c e n t Advances in Epilepsy," (T.A. Pedley and B.S. Meldrum, eds.), Vol. 3, pp. 189-210. Churchill Livingstone, Edinburgh. Chiron, C., Dulac, O., and Luna, D. (1990). Vigabatrin in infantile spasms. Lancet 1,363-364. Chiron, C., Dumas, C., Jambaqut, I., Mumford,J., and Dulac, O. (1997). Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res. 26, 389-395. Chugani, D., Chugani, H. T., Muzik, O., et al. (1998). Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[ll C] methyl-L-tryptophan positron emission tomography. Ann. Neurol. 44, 858-866. Chugani, H., Shewmon, D. A., Sankar, R., et aL (1992). Infantile spasms. II. Lenticular nuclei and brainstem activation on positron emission tomography. Ann. Neurol. $1,212-219. Coleman, M. (1971). Infantile spasms associated with 5-hydroxytryptophan in patients with Down's syndrome. Neurology 21, 911-914. Dailey, J. W., Reigel, C. E., Mishra, P. K., andJobe,J. C. (1989). Neurobiology of seizure predisposition in the genetically epilepsy-prone rat. Epilepsy Res. $, 317-320. Dreifuss, F., Farwell,J., Holmes, G., etal. (1986). Infantile spasms: Comparative trial of nitrazepam and corticotropin. Arch. Neurol. 43, 1107-1110. Dulac, O., and Plouin, P. (1993). Infantile spasms and West syndrome. In "The Treatment of Epilepsy" (E. Wyllie, ed.), pp. 464-491. Lea and Febiger, Philadelphia. Dykey, P. R., Dukant, R. H., Mindon, D. B., and King, D.W. (1985). Short-term effects of valproate on infantile spasms. Pediatr. Neurol. 1, 34-37. Farwell,J., Milstein,J., Opheim, K., Smith, E., and Glass, S. (1984). Adrenocorticotropic hormone controls infantile spasms independently of cortical stimulation. Epilepsia 25, 605-608. Favata, I., Leuzzi, V., and Curratolo, M. (1987). Mental outcome in West syndrome: Prognostic value of some clinical factors.J. Ment. Defic. Res. 31, 9-15. Fukuyama, Y. (1960). Studies on the etiology and pathogenesis of flexor spasms in infancy. Adv. Neurol. Sci. (Tokyo) 4, 861-865. Garant, D. S., Sperber, E. F., and Mosht, S. L. (1992). The density of GABAB binding sites in the substantia nigra is greater in rat pups than in adults. Eur.J. Pharmacol. 214, 75-78. Gastaut, H., Roger, J., Rtgis, H., and Ouhachi, S. (1984). Semeiologie electrographique. In "L'enctphalopathie Myoclonique Avec Hypsarythmie (Syndrome de West)" (H. Gastaut, et al. eds.). Masson, Paris.
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Glaze, D. G., Hrachovy, R.A., Frost, J. D., Kellaway, P., and Zion, T. E. (1988). Prospective study of outcome of infants with infantile spasms treated during controlled studies of ACTH and prednisone.J. Pediatr. 112, 389-396. Granstr6m, M. L., Gaily, E., and Liukkonen, E. (1999). Treatment of infantile spasms: Results of a population-based study with vigabatrin as the first drug for spasms. Epilepsia 40, 950-957. Hrachovy, R.A., and Frost, J. D.,Jr. (1986). Intensive monitoring of infantile spasms. In "Intractable Epilepsy" (D. Schmidt and P.L. Morselli eds.), pp. 87-97. NewYork, Raven Press. Hrachovy, R. A., and Frost, J. D.Jr. (1989). Infantile spasms: A disorder of the developing nervous system. In "Problems and Concepts in Developmental Neurophysiology" (P. Kellaway andJ.L. Noebels, eds.), pp. 131-147.Johns Hopkins Univ. Press, Baltimore. Hrachovy, R. P., Frost, J. D., Kellaway, P. R., and Ziion, T. E. (1983). Double-blind study of ACTH vs prednisone therapy in infantile spasms.J. Pediatr. 103, 641-645. Hrachovy, R. A., Glaze, D. G., and Frost, J. D. (1991). A retrospective study of spontaneous remission and long-term outcome in patients with infantile spasms. Epilepsia 32, 212-214. Jeavons, P., Bower, B., and Dimitrakoudi, M. (1973). Long-term prognosis of 150 cases of West syndrome. Epilepsia 14, 153-164. Jeavons, P.M., and Bower, B.D. (1974). Infantile spasms. In "Handbook of Clinical Neurology" (P.J. Vinken and G.W. Bruyn, eds.), Vol. 15, pp. 219-234. Elsevier Amsterdam. Kellaway, P. R., Hrachovy, R. A., Frost, J. D., and Zion, T. (1979). Precise characterization and quantification of infantile spasms. Ann. Neurol. 6, 214-218. Lacy, J. K., and Penry, J. K. (1976). "Infantile spasms," Raven Press, NewYork. Lombroso, C. T. (1983). A prospective study of infantile spasms: Clinical and therapeutic correlations. Epilepsia 24, 135-158. Lortie, A., Plouin, P., Pinard,J. M., and Dulac, O. (1993). The potential for increasing seizure frequency, relapse, and appearance of seizure types with vigabatrin. Neurology 43, $24-$27. L6scher, W., Honack, D., and Bloms-Funke, P. (1996). The novel antiepileptic drug levetiracetam (UCB L059) induces alteration in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in the substantia nigra pars reticulata. Brain Res. 735, 208-216. Matsumoto, A., Kumagai, T., Takeuchi, T., Miyazaki, S., and Watanabe, K. (1987). Clinical effects of thyrotropin-releasing hormone therapy for severe epilepsy in childhood: A comparative study with ACTH therapy. Epilepsia 28, 49-55. Morrell, F., Whisler, W. W., Smith, M. C., et al., (1989). Landau-Kleffner syndrome: Treatment with subpial intracortical transection. Brain, 118, 1529-1546. Mosh6, S. L., Garant, D. S., Sperber, E. F., Xu, S. G., and Brown, L. L. (1994). Basic mechanisms. In "Infantile Spasms and West Syndrome" (O. Dulac, H. T. Chugani, and B. Dalla Bernardina, eds.), pp. 23-35. Saunders, London. Neville, B. G. R. (1972). The origin of infantile spasms: Evidence from a case of hydranencephaly. Dev. Med. Child. Neurol. 14, 644-656. Ohtsuka, Y., Matsuda, M., Ogino, T., Kobayashi, K., and Ohtahara, S. (1987). Treatment of the West syndrome with high dose pyridoxal phosphate. Brain Dev. 9, 418-421. Pallister, P. D. (1982). Aggravation of epilepsy by reserpine associated with possible bleeding and clotting disturbances. Rocky Mt. Med.J. 56, 46-50. Pentella, K., Bachman, D. S., and Sandman, C. A. (1982). Trial of an ACTH 4-9 analog (ORG 2766) in children with intractable seizures. Neuropediatrics 13, 59-62. Pietz,J., Benninger, C., Schaefer, H., et aL (1993). Treatment of infantile spasms with high dosage vitamin B6. Epilepsia 34, 757-763.
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Prats, J. M., Garaizar, C., Rua, M.J., Garcia-Nieto, M. L., and Madez, P. (1991). Infantile spasms treated with high doses of sodium valproate: Initial response and follow-up. Dev. Med. Child. Neurol. 33, 617-625. Riikonen, R. (1983). Infantile spasms: Some new theoretical aspects. Epilepsia 24, 159-168. Riikonen, R., and Donner, M. (1980). ACTH therapy of infantile spasms: Side effects. Arch. Dis. Childh. 61,671-676. Robain, O., and Vinters, H.V. (1994). Neuropathological studies. In "Infantile Spasms and West Syndrome" (O. Dulac, H.T. Chugani, and B. Dalla Bernardina, eds.), pp. 99-117. Saunders, London. Schlumberger, E., and Dulac, O. (1994). A simple effective and well-tolerated treatment regime for West syndrome. Dev. Med. Child. NeuroL 36, 863-872. Shewmon, D. A. (1994). Ictal aspects with emphasis on unusual variants. In "Infantile Spasms and West Syndrome" (O. Dulac, et aL eds.), pp. 36-51. Saunders, London. Siemes, H., Spohr, H. L., Michael, T., and Nau, H. (1988). Therapy of infantile spasms with valproate: Results of a prospective study. Epilepsia 29, 553-560. Snead, O. C., and Chiron, C. (1994). Medical treatment. In "Infantile Spasms and West Syndrome, (O. Dulac, H.T. Chugani, and B. Dalla Bernardina, eds.), pp. 244-264. Saunders, London. Snyder, C. H. (1967). Infantile spasms: Favorable response to steroid therapy. JAMA 201, I98-201. Sorel, L., and Dusaucy-Bauloye, A. (1958). Apropos de l'hypsarythmie de Gibbs: Son traitement spectaculaire par I'ACTH. Acta Neurol. Belg. 58, 130-141. Trottier, S., Evrard, B., Vignal,J. P., et al. (1996). The serotonergic innervation of the cerebral cortex in man and its changes in focal cortical dysplasia. Epilepsy Res. 25, 79-106. Vigevano, F., and Cilio, M. R. (1997). Vigabatrin versus ACTH as first-line treatment for infantile spasms: A randomized, prospective study. Epilepsia 38, 1270-1274. Wenger, G. R., Stitzel, R. E., and Craig, C. R. (1973). The role of biogenic amines in the reserpine-induced alteration of minimal electroshock seizure threshold in the mouse. Neuropharmacology 12, 693-703. White, R., Hua, Y., Scheihauer, B., et al. (2001). Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers. Ann. Neurol. 49, 67-78.
Jean Aicardi Department of Child Neurology Hospital Robert Debre Paris 75019, France
I. II. III. IV.
Introduction T h e Need for Better Clinical Data T h e Need for I m p r o v e m e n t of Pathophysiological Knowledge W h a t Can D r u g Effects Tell Us about the Mechanisms of Epileptogenesis in Infantile Spasms? V. Conclusion References
h Introduction
Infantile spasms (IS) are notoriously difficult to treat. They are resistant to most conventional antiepileptic agents and, until 1958, no effective therapy was available (Sorel and Dusaucy-Bauloye, 1958, Snead and Chiron, 1994). Following the initial report of the remarkable activity of ACTH in the syndrome, a vast literature has become available not only on ACTH and corticosteroid therapy, but also on other drugs, as it was progressively realized that some new antiepileptic agents were also effective in some cases. Good reviews of the treatment of IS are available (Snead and Chiron, 1994; Jeavons and Bower, 1994; Riikonen and Donner, 1980). Overall, ACTH a n d / o r corticosteroid therapy is still regarded as most efficacious against the seizures. However, the effect of these agents on the cognitive and behavioral abnormalities that constitute the most important consequence of IS is less spectacular and, indeed, has never been conclusively demonstrated (Snead and Chiron, 1994; Lacy and Penry, 1976). Conflicting results have been and are still being published, and decisions about the choice and modalities of treatment are still largely determined on the basis of fragile evidence and personal preferences. The aim of this chapter is to review the contentious points of therapy and to try to define the possible manners of improving it. T h r e e points are considered successively: (1) The need for better clinical data on the various therapies available and the m a n n e r of assessing them; (2) the n e e d for improvement of our pathophysiological knowledge; and (3) what drug INTERNATIONAL REVIEW OF NEUROBIOLOGY, VOL. 49
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effects can tell us about the intimate mechanisms of IS and thus lead to other possibly more rational treatments.
Ih The Need for Better Clinical Data
Proper evaluation of available therapeutic agents is a prerequisite to any attempt at improving treatment. Thus far, this has been only rarely, if ever, achieved. ACTH and corticosteroids have been generally considered as the most effective treatment of IS since 1958 (Snead and Chiron, 1994;Jeavons and Bower, 1974; Lacy and Penry, 1976). The overall rate of control of spasms with hormonal therapy varies between 33 and 90% with an average of 50 to 60%. However, the significance of such figures is not clear because of the use of two different agents, ACTH and corticosteroids, of the innumerable modalities of treatment, and of the fact that IS are a syndrome of multiple causes, which obviously influences considerably their response to therapy (Snead and Chiron, 1994; Lacy and Penry, 1976). Therefore, a considerable effort is necessary to form reasonably h o m o g e n e o u s series. Important factors of prognosis must be taken into account: the results are very different in symptomatic IS, in which the percentage of control varies between 0 and 20% (Jeavons etal., 1973; Snyder, 1967) and in cryptogenic cases in which it reaches between 60 and 80% (Lombroso, 1983; Favata et al., 1987) or even 90% (Schlumberger and Dulac, 1994). Moreover, the proportion of symptomatic cases can vary considerably according to the completeness of diagnostic investigations. With the use of m o d e r n magnetic resonance (MR) techniques, cryptogenic cases b e c o m e increasingly infrequent as they demonstrate types of lesions, especially cortical dysplasias, that were previously undectable and are one of the most frequent cause of IS. Thus, a preestablished protocol of investigations should be a prerequisite to studies on therapeutic results. One major issue about h o r m o n a l treatment is the lack of comparability of many studies that results from the use of highly individual therapeutic protocols in terms of the agent used and of the modalities of treatment. A majority of investigators have used ACTH, but others have preferred oral corticosteroids in order to avoid the necessity of injections (and thus of hospitalization with its attending infectious risks) (Snead and Chiron, 1994; Favata et al., 1987; Schlumberger and Dulac, 1994). Only a few prospective, controlled studies comparing ACTH and corticosteroids (usually prednisone) are available. Glaze et al. (1988) and Hrachovy et al. (1983) found no significant difference between natural ACTH and prednisone in children with cryptogenic IS who had a normal development up to the onset
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of the seizures. In a large prospective study of 72 patients with cryptogenic spasms, Lombroso (1983) found no difference in short-term effects between the two treatments. He observed that ACTH was superior with regard to developmental outcome in the long term. However, Baram et al. (1996) obtained a significantly better short-term outcome with high-dose ACTH than prednisone. Thirteen of 15 infants receiving ACTH went into remission versus only 4 of 14 of those receiving prednisone. Recent work (Snead and Chiron, 1994) thus seems to favor high doses of ACTH. However, the numbers of infants studied are still small, and further studies with special attention to dosages, duration, and type of product (natural vs synthetic ACTH) have to be continued. W h e t h e r ACTH or corticosteroids give superior results in terms of cognitive/behavioral development, an essential consideration, is even more difficult to determine. Only one study (Lombroso, 1983) favored ACTH in this regard and its methodology was not perfect. Such long-term evaluation demands difficult studies, requiring large numbers of participants, and therefore needs to be multicentric and to include a long follow-up with attending major problems to maintain all children in the studies. The m a n n e r of assessing the results is a critical factor in comparisons of results and every effort should be made to make it as objective and standardized as possible. For short-term results, disappearance of the spasms is the usual criterion. However, a decrease in the n u m b e r of spasms has been used in some studies [e.g., that of Dreifuss et al. (1986)], making direct comparison impossible. Nevertheless, the h o r m o n a l treatment result is usually all or n o n e so complete control is probably the best criterion. Spasms should be separated from other types, especially partial seizures, whose signification is different with regard to prognosis and therapy. However, mild spasms have been shown to escape easily to parents (Kellaway et al., 1979), and not all studies include sleep electroencephalogram (EEG) recordings. These are necessary to confirm the clinical impression of disappearance of seizures. They should include sleep tracings as abnormalities, in the case of recurrence, occur first and most prominently in sleep (Lacy and Penry, 1976; Gastaut et al., 1984; Hrachory and Frost, 1986). EEGs certainly should be included among assessment criteria. An EEG should be obtained within 2 weeks of discontinuation of treatment and a repeat one 2 months later. Long-term developmental assessment requires rigorous methodology to ensure uniformity of results and must take into account a study of other fields of cognitive and behavior in addition to I Q determination. This issue is discussed later with surgical treatment. Clearly, the duration of follow-up should be of the same order or magnitude both for control of seizures and for developmental progress. Overall, the long-term outcome of IS is rather
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poor with a proportion of normal development that does not appear to be strongly linked with the m o d e of treatment used. Some n o n h o r m o n a l treatments have been used extensively in the past few years. They include nitrazepam, valproate, vigabatrin (VGB), lamotrigine, and topiramate. The latter two have received only preliminary trials. O t h e r agents have also been used but not submitted to critical trials. They include pyridoxine, which is reported to have given control in 10 to 30% of cases (Ohtsuka et aL, 1987; Pietz et al., 1993); thyrotropin-releasing h o r m o n e (TRH) (Matsumoto et al., 1987), with a surprisingly high reported control rate of up to 53%, as compared to 75% for ACTH; and immunoglobulins for which only anecdotal data are available. Valproate in large doses (80 to up to 300 m g / k g ) has been reported in uncontrolled studies to stop IS in 20 to 45% of cases (Siemes et al., 1988; Dykey et al., 1985; Prats et al., 1991). A double-blind study has compared nitrazepam with corticotrophin in 52 infants (Dreifuss et al., 1986). Both treatments resulted in a significant reduction in spasm frequency from the baseline, but the difference between treatments was not significant. However, the impression prevails a m o n g investigators that ACTH is more effective, and no further comparison has been since published since, again indicating that clinicians do not easily accept results of comparative studies, even double-blind ones, when they contradict their everyday experience. Although this is a regrettable trend, it should be recognized that results of comparative studies are often difficult to apply to clinical practice as differences inevitably exist in some of the parameters, such as selection of patients, doses, and duration, and, strictly speaking, they apply rigorously only when all of these factors are identical, which is seldom, if ever, the case. Vigabatrin has proved effective in uncontrolled studies with a control rate varying from 26 to 68% (Aicardi et al., 1996; Chiron et al., 1990) and even up to 90% in patients with tuberous sclerosis (TS). Prospective, controlled studies have compared this drug to hormonal therapy. Vigevano et al. (1997) found VGB slightly less effective than ACTH in the control of IS; however, because relapses were less frequent in this study with VGB, the ultimate efficacy was similar in both groups. Chiron et al. (1997) found the efficacy ofvigabatrin in tuberous sclerosis greater than that of corticosteroids although problems of retinal toxicity are currently limiting the use of VGB, this agent is certainly of considerable interest, especially in view of its possible selective efficacy on IS associated with tuberous sclerosis (Chiron et al., 1990; Vigevano and Cilio, 1997; Lortie et al., 1993). Several studies confirmed its special efficacy (Aicardi et al., 1996; Chiron including a controlled one (Chiron et al., 1997). However, some investigators were less impressed with the superiority of vigabatrin in TS (Granstr6m et al., 1999). This possible selectiveness raises an additional
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difficulty for comparative studies: the etiologic diagnosis may have to be taken into consideration in such studies, imposing further constraints on future trials. Additionally, other subgroups might have different sensitivity to various agents, thus posing the practical problem of specific drug indications for subgroups of IS. Currently, however, this problem seems limited to tuberous sclerosis, but other etiologic subgroups with different responses to individual agents may exist. All problems involved in comparisons of medical therapies of IS underline the practical difficulties of such studies. Clearly, efforts to obtain homogeneous groups with regard to age, known prognostic factors, protocols of treatment employed, methods of assessment, and standardization of pretreatment evaluation [certainly including MR imaging studies and possibly other techniques, such as positron emission tomography (PET) in selected cases] are warranted if comparisons are to be valid. Ethical considerations may complicate the issue and possible relational problems with families may also arise, given the severity of the prognosis. Careful clinical study of selected cases remains of interest even though its reliability is questionable. Evaluation of surgical therapy is even more difficult, as no doublebind studies are ethically possible. It is, however, possible to compare the outcome of operated children with those of similar historical controls or of children not operated on for "nonmedical" reasons. Asarnow et al. (1988) have studied the developmental outcomes in 24 children with IS who had received resection surgery and compared it with that of unoperated children (presumably because of lesions not amenable to resection). They used an extensive battery of psychological tests exploring multiple cognitive and behavioral domains (Vineland adaptive behavior, communication skills, socialization, and daily living skills) that were performed just before operation and about 2 years later. Development had progressed in all children following their operation and the level they reached compared favorably to that in literature series of medically treated cases that probably included less severe cases. However, the velocity of development of these operated children was clearly below that of normal children, thus indicating that any "catch up" observed was only relative, in comparison with medically treated IS children, rather than absolute. The authors considered this improvement significant and of practical value for patients and families. Although criticisms may be directed at this study (e.g., unoperated patients might have been rejected because of greater severity), it represents a valiant effort to deal with the type of problems raised by the impossibility of randomized surgical series and a serious attempt at standardization, which is particularly hard to apply to surgical results. The results of this study also suggested that early surgery and the shortest active period, as judged
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by the duration of persistence of spasms, were associated with the best outcomes, even though very few patients actually reached satisfactory levels of central nervous system (CNS) function. Some theoretical considerations (see later) that indicate the involvement of the brain stem, especially of the reticular substance, in the mechanisms of IS suggest a possible role for agents modifying the levels, distribution, or action of monoamines, such as serotonin and dopamine. To the author's knowledge, no trial of such agents has been p e r f o r m e d so far. In summary, clinical therapeutic data are absolutely essential, as IS are a purely h u m a n disorder whose treatment can only be evaluated clinically. Further studies, satisfying the conditions discussed earlier, are clearly in order, despite their difficulties.
IIh The Need for Improvement of Pathophysiological Knowledge
Little is known about the pathophysiology and mechanisms of IS, although many hypotheses have been proposed to account for the delayed occurrence of the seizures, their peculiar responsiveness to corticotrophin and corticosteroids, the multiplicity of their causes with or without CNS lesions, and the frequent persistence of mental retardation after disappearance of the seizures and of the paroxysmal EEG abnormalities (Mosh6 et al., 1994; Baram, 1993; Riikonen, 1983). The proposed hypotheses include that of a developmental defect with delayed and abnormal brain maturation with resulting changes in neuronal connectivity responsible for both the heighte n e d excitability and later cognitive deficits (Mosh6 et al., 1994); that of an abnormal immunologic reactivity to u n d e t e r m i n e d antigens (Riikonen, 1983) or that of abnormal regulation of the h y p o t h a l a m o - a d r e n a l axis (Baram, 1993). The occurrence oflS with hypsarrhythmia and cognitive decline requires involvement of the cortex as also indicated by the finding of cortical pathology in a large majority of cases (Robain and Vinters, 1994). However, there are also some clinical and physiological arguments in favor of subcorfical, especially brain stem, involvement (Riikonen, 1983; Robain and Vinters, 1994; Neville, 1972; Chugani et al., 1992; Fukuyama, 1960; Hrachovy and Frost, 1989). Spasms have been reported in an infant with hydranencephaly (Neville, 1972) and have been observed in cases of anencephaly). PET studies have revealed hypermetabolism in the brain stem in 48% (21 of 44), of cases and in the lenticular nuclei in 73% (32 of 44), suggesting their participation in the generation of IS (Chugani et al., 1992). Cortical lesions associated with IS are most often of developmental origin, but no
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c o m m o n pattern of lesions is apparent. Both diffuse (e.g., lissencephaly or pachygyia) and focal or unilateral lesions are possible, even though focalization may not be absolute, as minimal developmental anomalies can be associated and not be detected by imaging or at operation. Spasms can be similar even with widely different localization and nature of lesions. Except for rare instances, no pathology has been f o u n d in the brain stem. In fact, a structurally normal brain stem may be necessary for the production of IS. Studies o f m o n o a m i n e neurotransmitters in the brain stem have reported contradictory findings. Some investigators f o u n d high levels of serotonin and dopamine, whereas others were unable to demonstrate similar changes (Hrachory and Frost, 1989). Reduced rapid eye movement (REM) sleep and decreased total sleep time as compared with normal infants have been d o c u m e n t e d (Fukuyama, 1960), and only those infants who responded to ACTH or prednisone showed a reversal of REM sleep abnormalities. These findings suggest that neural structures close to centers that regulate sleep cycles in the pons may be involved in the generation or propagation of spasms. A reasonable hypothesis suggests that IS directly result from subcortical mechanisms, triggered by discharges from the cortex (Chugani et al., 1992; Dulac and Plouin, 1993). Such discharges may often be focal, even though the spasms in such cases are sometimes bilaterally symmetrical (Shewmon, 1994). However, lateralized spasms frequently occur with cortical lesions and are generally contralateral to the hemisphere involved, arguing against a purely brain stem origin. Focal discharges may manifest initially as focal seizures preceding the appearance of IS for variable periods T h e r e may thus be a time window during which cortical discharges can trigger the brain stem, accounting for the age-related d e p e n d e n c y of IS. In fact, spasms can occur after the age of 2 years and up to adulthood in rare instances. Such cases could be particularly important to study in terms of their circumstances of occurrence and type of cortical lesions. T h e r e is a suggestion that late-occurring spasms tend to be associated with extensive cortical lesions, e.g. diffuse lissencephaly or Aicardi syndrome (Chevrie Aicardi, 1986), but whether this is really significant remains to be seen. T h e absence of an animal model of IS is a major limitation to understanding the mechanisms and performance of animal therapeutic trials. No model satisfies the conditions described elsewhere by Holmes. In some (e.g., the NMDA model), the seizures may resemble IS with ventral flexion (Mosh6 et al., 1994), but most other conditions, such as spontaneous occurrence, response to drugs, and presence of EEG abnormalties, are not fulfilled. In some attempted models, even though the criterion of age relation (at least as far as age of onset is concerned) is satisfied, the type of seizure
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is different from IS and these models look more like models of infantile seizures in general than specifically of infantile spasms. This can be said of the kindling models suggested by Mosh6 et al. (1994), as well as the adrenocortical model of Baram (1993). Indeed, if rats 2 to 3 weeks old are particularly sensitive to kindling and may exhibit seizures dramatically more violent than kindled adult animals after a shorter kindling period, the seizures are not like IS. The same applies to the kindling model in kittens even though animals u n d e r 6 months of age may exhibit multifocal EEG abnormalities after kindling and occasionally seizures with a '`jackknife" character (Mosh6 et al., 1994). Such p h e n o m e n a emphasize the propensity of the immature CNS to express multifocal seizures that may be a factor in the generation of IS, but do not reproduce the p h e n o m e n o l o g y of IS. Likewise, although an excess of corticotrophin-releasing factor may have a proconvulsant activity that could be suppressed by both ACTH and corticosteroids, the seizures do not have the characteristics and course of infantile spasms (Baram, 1993). Given the absence of a satisfactory model accounting for most of the features of the h u m a n disease, it might be worthwhile to limit our ambitions to the realization of partial models in an effort to reproduce only some of the characteristics of h u m a n IS, e.g., the very disorganized EEG, the "jackknife" seizures, or the neurological and developmental regression, and to try to determine the mechanism(s) of these more limited abnormalities. Another important issue is the understanding of the cognitive/behavioral changes in IS. During the " a c u t e " phase of the disorder, it can be accepted that the continuous EEG paroxysmal activity represents one form of nonconvulsive status epilepticus, responsible for the stagnation or deterioration of performances (Aicardi, 1994). This sort of explanation is also generally accepted in other epileptic conditions of later life, such as continuous spike-waves of slow sleep or the L a n d a u - K l e f f n e r syndrome (Morrell et al., 1989). The persistence of cognitive/behavioral disturbances after the acute phase and the disappearance of EEG abnormalities d e m a n d a n o t h e r explanation. It has been suggested that lasting deficits may be due to changes resulting from plastic modifications of connectivity induced by massive, continuous paroxysmal activity. This nonselective paroxysmal activity could maintain synaptic connections that would normally be " p r u n e d . " Persistence of excess synapses could prevent the establishment of neuronal circuits normally determined and maintained by the facilitation of only those synapses that participate in physiological activities. The resulting abnormal circuitry could account for the lasting cognitive and behavioral problems (Morrell et al., 1989). This hypothesis is partially testable by clinical studies: suppression of spasms and diffuse, paroxysmal EEG
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abnormalities, if accomplished early enough, whether by drug treatment or by surgery, should result in an improvement of cognitive functions. In addition to the requirements mentioned earlier, strict and repeated verification of the normality of the EEG, including sleep tracings, would be necessary. The possible contribution of experiments studying the molecular genetics and neurotransmitters and of the combinations and topographic distribution of their various subunits at the single cell level (White et aL, 2001) may prove to be of great importance for the understanding of the origin of tuberous sclerosis and cortical dysplasia. Such studies have already shown that different alterations of genes encoding glutamatergic and 0t-aminobutyric acid GABAergic receptors and uptake sites may occur selectively in dysplastic neurons and giant cells of brain samples from patients with tuberous sclerosis and may contribute to the increased excitability of abnormal tissue and thus to seizure initiation. Such cell-specific changes in gene transcription argue for distinct molecular phenotypes of dysplastic neurons and giant cells and suggest that dysplastic neurons and giant cells make different contributions to epileptogenesis in TS. Such fine molecular dissection ultimately could be combined with direct recording from individual cells, dendrites, or synapses, thus giving a comprehensive picture of the balance of excitation and inhibition in developmental defects, thereby offering opportunities to correct or to neutralize their epileptogenic effects.
IV. What Can Drug Effects Tell Us about the Mechanisms of Epileptogenesis in Infantile Spasms?
The peculiarities of response to drugs of IS, especially their resistance to conventional anticonvulsants and their sensitivity to ACTH and corticosteroids, have suggested that these agents might be in some way implicated in the mechanisms involved in their generation or propagation. However, the same agents are not specific for IS but may also produce satisfactory results in other epilepsy syndromes (Snead and Chiron, 1994), and the same certainly applies to vigabatrin (Aicardi et al., 1996). In general, drug effects represent at best indirect indications, as their site and modalities of action are poorly known and are often very different from what would be theoretically expected according to current knowledge. Multiple hypotheses have been put forward to account for the therapeutic effects of ACTH and corticosteroids. A direct action of hormonal therapy is possible. Corticosteroids have been shown to reduce
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the excitability of hippocampal pyramidal cells in vitro, perhaps through the mediation of steroid receptors in the central nervous system. Alternatively, they could be selectively toxic to glutamatergic neurons, especially numerous, in the developing brain (Moshfi etal., 1994). ACTH might also exert its action through an extraadrenal mechanism. Previously described clinical experience would favor this possibility, as would reports of its effectiveness in some cases of IS in patients with adrenal suppression (Farwell et aL, 1984). Substantial pharmacological and physiological evidence supports a direct effort of ACTH on the development and activity of the brain (Snead and Chiron, 1994). ACTH may play a role in the regulation and synthesis of several neurotransmitters and may affect various categories of receptors. This activity may reside in fragments of the peptide devoid of corticotropic activity. More recent work suggests that ACTH directly influences limbic neurons independently of corticosteroid secretion, although previous trials of such fragments in a few patients with IS have not shown any therapeutic effect (Pentella et al., 1982). Brunson et al. (2001) r e p r o d u c e d the effect of ACTH with a fragment devoid of corticotropic activity, an effect abolished by a specific antagonist of the receptors. This suggests that ACTH has a direct action on the brain unrelated to corticosteroids. The positive effect of both corticosteroids and corticotrophin can be accounted for by the hypothesis that a fundamental pathogenic role is played by the corticotrophin-releasing h o r m o n e (CRH). This hypothalamic neuropeptide normally acts to promote the release of ACTH, which in turn enhances glucocorticoids synthesis. ACTH and corticosteroids exert an inhibitory action on the synthesis and secretion of CRH, a negative feedback mechanisms. CRH has excitant properties on a wide variety of neurons, increases neuronal excitability, and can produce seizures in animals (Baram, 1993). This convulsant action is more potent in infant rats than in adult animals (Baram and Schulz, 1992). This hypothesis could explain that both ACTH and corticosteroids have a therapeutic effect, as both can suppress CRH secretion, although the action of corticosteroids would be only indirect through inhibition of ACTH release. In the absence of a p r o p e r animal model, no verification of this hypothesis is currently possible and the only verified conclusion is that CRH is indeed a convulsant agent, but a specific relation to IS remains to be demonstrated. As indicated earlier, several other mechanisms can account for the therapeutic properties of ACTH and perhaps ofcorticosteroids, such as an acceleration of the CNS maturational process, and altered expression of many genes that could result in changes in connectivity and excitability. Because VGB has proved an effective agent in the treatment of IS, elucidation of its mode of action could shed some light on the mechanisms involved in their generation. VGB, an irreversible inhibitor of the enzyme
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GABA transaminase, considerably increases the content of GABA in the CNS. This GABAergic action could be an important mechanism in its therapeutic effect on IS, although no direct evidence is available for a specific mechanism, and other GABAergic agents could have a similar action. However, tiagabine, an inhibitor of GABA reuptake, does not seem to be active. T h e r e are important differences between infants and adult animals in the effects of GABA that may be significant in a syndrome such as infantile spasms, which is rather narrowly age limited. Early in life, GABA has excitatory effects through GABAA receptors in several structures (hippocampus, cerebral cortex, cerebellum, and spinal cord) and thus enhances rather than antagonizes glutamate excitatory action. Thus, GABAergic inhibition in young infants may be mediated solely by GABAB receptors (Ben-Ari et al., 1997). In the developing brain, the GABAB inhibition may therefore be strengthened. This appears to be the case in the substantia nigra pars reticulata, a site critical for the control of generalized seizures (Mosh6 et al., 1994). VGB seems to act on both GABAA and GABAB inhibition (Mosh6 et al., 1994) and thus might be active through the increase in GABA content that it produces. The differences in the mechanisms of action of GABA with age might be of particular interest in neural structures such as substantia nigra as this structure is critically located between the cerebral cortex and the pontine reticular formation, whose role in the propagation and elaboration of IS is probably important. The differences in GABA action in the course of development may thus be critical for the occurrence, and possibly in antagonization, of IS. Changes in the effect of various GABAA and GABAB agonists and antagonists and in receptor subtypes may ultimately be relevant for therapy. Mosh6 and colleagues (1994) has suggested that possible new directions in the treatment of IS may include the use of drugs that act on the substantia n i g r a - p o n t i n e reticular formation circuit and that GABAB receptor agonists such as baclofen should be tested clinically. Levetiracetam might also be of interest, as it specifically acts on the substantia nigra (L6scher et al., 1996). Such highly hypothetical suggestions maywell deserve to be pursued and various GABAB agonists could be screened. Another interesting point about vigabatrin concerns its possible specificity against IS caused by tuberous sclerosis. Chugani et al. (1998) indicates that there is an excess of tryptophan and 5-hydroxytryptamine (serotonin) in epileptogenic tubers from patients with tuberous sclerosis, as shown by PET after the administration ofa-methyl-L-tryptophan marked with radioactive carbon 11 C. Resection of the fixating tubers was associated with control of the seizures in some cases (Chugani et al., 1998). Nonepileptogenic tubers do not demonstrate excess fixation. A similarly increased serotonin content
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may also be present in some cases of cortical dysplasias not associated with tuberous sclerosis (Trottier et al., 1996). W h e t h e r there may be possible specific effects of vigabatrin in IS due to tuberous sclerosis is completely unknown but perhaps worth investigating. A possible role of serotonergic mechanisms in epileptogenesis has already b e e n suggested. Genetically epilepsy-prone rats have a decreased concentration of brain serotonin (Dailey et al., 1989), and lowering of brain 5-hydroxytryptamine concentration leads to an increase in seizure susceptibility in animal models of epilepsy (Wenger et al., 1973), as well as in h u m a n s (Pallister, 1982). Levels of 5-hydroxyindole acetic acid, a metabolite of serotonin, were f o u n d to be higher in samples of actively spiking temporal cortex f r o m patients with epilepsy c o m p a r e d to normal controls (Trottier et al., 1996). A m o r e specific relationship of IS to serotonin was suggested by Coleman (1971), who f o u n d that administration of 5-hydroxytryptophan to infants with Down's syndrome was associated with the a p p e a r a n c e of IS. However, the diagnosis of IS may not have b e e n correct as no hypsarrythmia was present. Nevertheless, there are reasons for further study of serotonin metabolism in IS and for possible attempts to find whether antagonists could be of any therapeutic benefit.
V. Conclusion
Despite m a n y years of practice with multiple treatments of IS, the therapeutic results remain unsatisfactory. This is due to two m a j o r defects. T h e first is the fact that various agents and protocols have b e e n used by different physicians, rendering comparisons of results impossible. Only rare comparative studies with a correct m e t h o d o l o g y have b e e n p e r f o r m e d and there is still a n e e d for m o r e good studies, especially inasmuch as long-term cognitive and behavioral o u t c o m e is concerned. T h e second defect is the absence of real animal models of the h u m a n condition, which precludes e x p e r i m e n t a t i o n of new agents. Although most new antiepileptic drugs have not proved of greater value than those used thus far, there is clearly a place for o t h e r categories of agents, provided they are submitted to critical, well-planned studies.
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