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Pathogenesis of Infantile Spasms: A Model Based on Developmental Desynchronization

Frost, James D. Jr*†§; Hrachovy, Richard A.*‡§

Journal of Clinical Neurophysiology: January-February 2005 - Volume 22 - Issue 1 - p 25-36
doi: 10.1097/01.WNP.0000149893.12678.44
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Infantile spasms is a severe epileptic encephalopathy of infancy. The fundamental cause is unknown, although a number of predisposing conditions are recognized. In this article, the authors critically review current knowledge concerning the pathophysiologic basis of infantile spasms and propose a new model based on developmental desynchronization. It is suggested that infantile spasms may result from a particular temporal desynchronization of two or more central nervous system developmental processes, resulting in a specific disturbance of brain function. The disturbance of function is postulated to be crucially dependent on an unbalanced maturational pattern, in which certain brain systems become dysfunctional owing to divergent developmental status. An important aspect of this model is the idea that disturbed function of a specific kind can result from multiple causative factors, and so can be associated with a variety of different anatomic and/or biochemical abnormalities. Thus, this concept is compatible with the observed diversity of pathologic findings and multiplicity of etiological associations observed in infantile spasms patients.

*Peter Kellaway Section of Neurophysiology, Department of Neurology and †Department of Neuroscience, Baylor College of Medicine; ‡Michael E. DeBakey Veterans Affairs Medical Center; and §The Methodist Hospital and Texas Children's Hospital; Houston, Texas

Address correspondence and reprint requests to Dr. James D. Frost, Jr., Neurophysiology Department, The Methodist Hospital, 6565 Fannin, M.S. M587, Houston, TX 77030; e-mail: jamesf@bcm.tmc.edu.

Infantile spasms is a distinct epileptic disorder that occurs in infancy and early childhood, and its clinical features are well documented (Frost and Hrachovy, 2003). The incidence is approximately 1 case per 3,225 live births, most cases begin during the first year of life (peak incidence at 6 months), and familial occurrence is rare. Brief, bilaterally symmetric contractions of the muscles of the extremities, neck, and trunk (motor spasms) are the characteristic ictal manifestation, although other phenomena (e.g., attenuated responsiveness, eye deviation, respiratory pauses, autonomic events) may also be present. The spasms typically occur in clusters (70–80%), and the intensity often waxes and wanes with time. This disorder is usually associated with mental and developmental retardation, and approximately half of the cases exhibit major neurologic deficits. Around 20% of patients with infantile spasms are currently classified as cryptogenic (i.e., normal prior development, no known etiologic factors, and normal computed tomography and MRI findings), with the remainder classified as symptomatic. The interictal EEG is almost always abnormal, and the most characteristic pattern is hypsarrhythmia, or one of its variants. Hormonal therapy (adrenocorticotropic hormone and corticosteroids) remains the treatment of choice in most cases, although there is currently no consensus regarding the optimal dosing schedule, and a number of other drugs have been shown to have efficacy. However, although spasms are eventually controlled, or cease spontaneously, in most cases the long-term outcome is poor. Persistent neurologic deficits are common, and a normal mental outcome can be expected in only 16% of the cases. Approximately half develop other resistant seizure types, and about 17% exhibit an evolution to Lennox-Gastaut syndrome.

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ETIOLOGY AND PATHOPHYSIOLOGY

One of the most unusual aspects of infantile spasms is the very large number of conditions that have been identified as etiologic or predisposing factors (including trauma, infections, neoplasms, genetic aberrations, toxins, and hypoxia/ischemia). In a recent review of more than 400 published reports concerned with etiology (Frost and Hrachovy, 2003), 200 associated conditions were identified. Although some of these associations probably represent coincidental relationships, it is clear that a wide range of brain insults definitely increase the likelihood that infantile spasms will occur (e.g., hypoxia/ischemia, tuberous sclerosis, intraventricular hemorrhage, Down syndrome). Although structural abnormalities (e.g., lissencephaly, tubers, malformations) are present in many cases, none are unique to infantile spasms and, conversely, a significant number of cryptogenic cases occurs in the absence of any detectable anatomic abnormalities. Similarly, although biochemical abnormalities (e.g., pyridoxine deficiency, disturbances of tryptophan and catecholamine metabolism, amino acid and neuropeptide abnormalities) are present in many cases, no specific pattern consistent across all patients has been identified. Despite intensive research efforts over the past 50 years, no consistent pathologic feature or process has been identified that can explain the characteristics of this disorder. These facts have led some investigators to conclude that this disorder is nonspecific in terms of its basic underlying neuropathology (e.g., Mischel and Vinters, 1997). Yet, despite the seemingly diverse and nonspecific nature of the predisposing factors, infantile spasms itself appears to be a very well circumscribed disorder, with a unique and readily recognizable seizure type, and a characteristic EEG pattern, hypsarrhythmia, that is highly specific to this disorder. Another characteristic feature of this disorder is its time dependency. Regardless of the timing, or even the existence, of prior brain insult, infantile spasms typically begins around 6 months of age, is infrequent before 4 months, and onset is rare after 1 year.

A number of hypotheses have been proposed over the years to explain the unique features of this disorder, although none have been proven, and, more importantly, none adequately explain the major features of the disorder noted above.

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BRAINSTEM DYSFUNCTION

A brainstem origin for infantile spasms has long been suspected, based on the typical absence of clinical signs of focality and the usual symmetric nature of the seizures (Druckman and Chao, 1955) as well as the electroencephalographic features (Kellaway, 1959). Numerous studies have found evidence for brainstem pathology in this disorder (Frost and Hrachovy, 2003), including a number of cases in which cortical lesions were entirely absent (Kamoshita et al., 1970; Kellaway, 1959; Tominaga et al., 1986), and typical spasms occasionally have been reported in association with hydranencephaly (Neville, 1972). Based on this evidence and on observations documenting abnormal sleep patterns in infantile spasms patients (Hrachovy et al., 1981), we proposed a model of infantile spasms (Hrachovy and Frost, 1989a) suggesting that the primary defect could be a loss of the normal reciprocal relationship existing between the inhibitory noradrenergic and serotonergic neurons of the locus ceruleus and dorsal raphe, respectively, and the excitatory cholinergic neurons in adjacent pontine regions, which is involved in the timing of REM sleep (Hobson et al., 1976). The effect was postulated to result in a decreased output of the cholinergic system. Thus, the epileptic spasms would result from intermittent interference with descending pathways that control spinal reflex activity, whereas abnormal activity in the ascending tracts from these same pontine regions that project widely to the cerebral cortex would lead to the characteristic EEG features, and possibly disturbances of mental function as well. This model is supported by evidence from studies documenting disturbed monoamine metabolism in patients with infantile spasms (Coleman, 1971; Langlais et al., 1991; Klawans et al., 1973; Ross et al., 1983; Silverstein and Johnson, 1984; Yamamoto, 1991; Yamamoto et al., 1992). Also, animal experiments have shown that adrenocorticotropic hormone (ACTH) (Pranzatelli, 1989) and corticosteroids (Nausieda et al., 1982) may suppress serotonergic activity, a finding consistent with the model. However, a serious limitation of this model is the fact that this pontine region receives inputs from widespread brain areas, and so the brainstem dysfunction could possibly be secondary to a primary disturbance located in some other region (Hrachovy and Frost, 1989a). In addition, therapeutic trials of several agents that block the production or reduce the effectiveness of serotonin and/or norepinephrine were effective in only a small fraction of the patients tested (Hrachovy et al., 1988b, 1989). However, Rektor et al. (1987, 1990) reported that injection of a centrally acting cholinesterase inhibitory agent, physostigmine, resulted in an acute improvement of the EEG and a reduction in spasms. Because additional work in this area has not been forthcoming, the possibility that dysfunction of these neurotransmitter systems constitute the “common denominator” underlying infantile spasms remains speculative.

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CORTICAL–SUBCORTICAL INTERACTIONS

There have been a number of reports of infantile spasms cases in which there was evidence for cortical lesions but no demonstrable brainstem pathology (Bignami et al., 1964; Branch and Dyken, 1979; Trojaberg and Plum, 1960; Tucker and Solitare, 1963), and several investigators have postulated that abnormal activity in subcortical regions might reflect primary cortical dysfunction (attributed to Gastaut and Roger, 1953, by Kellaway, 1959; Wright, 1969). There has been an increased interest in this possibility in recent years, following the initial positron emission tomography imaging studies in infantile spasms by Chugani et al. (1990, 1992) that demonstrated focal or regional metabolic changes in the cortex of many patients (even in some patients with normal CT/MRI studies), increased metabolic activity in the lenticular nuclei of most subjects, and increased brainstem metabolic activity in some patients. Based on these findings, Chugani et al. (1992; Chugani, 2002) have proposed an expanded model of infantile spasms in which the primary dysfunction is a focal or diffuse cortical abnormality that, at a critical maturational stage, triggers (through projection pathways to the brainstem) abnormal activity within the serotonergic raphe nuclei. Concurrent raphe-striatal pathway activation is postulated to produce the observed hypermetabolism within the lenticular nuclei, whereas raphe-cortical, and cortico-cortical, projections might underlie the hypsarrhythmic EEG pattern. The epileptic spasms themselves would result from projections from brainstem regions to spinal cord neurons, as well as from the lenticular dysfunction. This model is consistent with evidence supporting the brainstem hypothesis (see above) and also provides an explanation for the finding that seizures may cease, and the EEG improve, after surgical resection of some cortical foci, including certain of those identified by positron emission tomography (Chugani et al., 1990; Uthman et al., 1991; Wyllie et al., 1996b). The observation that partial seizures may sometimes be temporally coupled with epileptic spasms (Bour et al., 1986; Carrazana et al., 1993; Donat and Wright, 1991; Hrachovy et al., 1984; Plouin et al., 1987; Yamamoto et al., 1988) is also supportive of this model. However, this apparent association needs further investigation because a statistically significant coupling of spasms with partial seizures is rare (Hrachovy et al., 1994).

Several other investigators have proposed similar models based on cortical–subcortical interactions. Dulac et al. (1994) postulated that spasms arise in subcortical structures, such as the basal ganglia, as a manifestation of functional deafferentation resulting from continuous abnormal cortical activity, whereas the abnormal EEG pattern more directly reflects the cortical dysfunction. Avanzini et al. (2002) also favor this type of mechanism, and emphasize the similarity of epileptic spasms and the normal Moro reflex. Lado and Moshe (2002) have hypothesized that proconvulsant changes are actually necessary in both cortical and brainstem regions in order for the disorder to develop. In their model, the key requirement is increased epileptogenicity in one area (either cortex or brainstem), with simultaneous failure of the other region (brainstem or cortex) to suppress the epileptic activity.

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HYPOTHALAMIC-PITUITARY-ADRENAL AXIS DYSFUNCTION

There is considerable evidence for disturbances of neuropeptide metabolism in some infantile spasms patients. For example, several studies have documented reduced CSF levels of ACTH (Baram et al., 1992a, 1995; Facchinetti et al., 1985; Nagamitsu et al., 2001; Nalin et al., 1985) and cortisol (Baram et al., 1995) in these patients. Such findings, together with the known efficacy of ACTH and corticosteroids in controlling the seizures associated with this disorder, clearly suggest a role for the hypothalamo-pituitary-adrenal axis in the pathogenesis of infantile spasms. Baram and her colleagues (Baram et al., 1992a; Baram, 1993; Brunson et al., 2002) have hypothesized that the basic abnormality is stress-related excessive production of corticotropin-releasing hormone (CRH) during early life. The presence of elevated CRH levels at a time of high CRH-receptor abundance is proposed to result in permanent epileptogenic changes in brainstem circuits, which then become the site of spasm origin. According to this idea, the efficacy of ACTH and corticosteroids in infantile spasms is related to their ability to downregulate CRH synthesis. However, although animal studies have proven that CRH does have convulsant effects (Baram and Schultz, 1991, CRH-induced seizures in rats were not prevented by ACTH pretreatment (Baram and Schultz, 1995), suggesting that ACTH might instead exert its effect by suppressing synthesis and secretion of endogenous CRH. This latter possibility was subsequently confirmed in studies that demonstrated ACTH activation of melanocortin receptors in the amygdala, with a resultant reduction of CRH production (Brunson et al., 2001a, b, 2002). At present, the applicability of this model to infantile spasms is unclear. The seizures and interictal EEG features seen in these animals are not typical of infantile spasms (Baram et al., 1992b), and elevated CRH levels have not been found in the CSF of patients with this disorder (Baram et al., 1992a). In addition, the treatment of several patients with infantile spasms with α-helical CRH, a competitive antagonist of CRH, did not improve the EEG or change the spasm frequency (Baram et al., 1999).

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IMMUNE SYSTEM DYSFUNCTION

Several investigators have proposed that infantile spasms may result from a defect of the immune system (Hrachovy and Frost., 1989a; Mandel and Schneider, 1964; Martin, 1964). Antibodies to brain tissue have been demonstrated in the sera of infantile spasms patients (Mota et al., 1984; Reinskov, 1963), and increased numbers of activated B and T cells have been found in the peripheral blood of some patients (Hrachovy et al., 1985). In addition, several studies have documented abnormal human leukocyte antigen (HLA) studies in infantile spasms patients (Howitz and Platz, 1978; Hrachovy et al., 1988a; Suastegui et al., 2001). Although these findings indicate that the immune system is altered in some patients with this disorder, a casual relationship has not been established. The possibility remains that these alterations identified in some infantile spasms patients may simply reflect responses to underlying brain damage.

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DEVELOPMENTAL DESYNCHRONIZATION MODEL

None of the hypothetical models proposed to explain the pathogenesis of infantile spasms adequately account for all of the known clinical manifestations of this disorder. There are several crucial characteristics that are not consistent with any of these postulated mechanisms: None of the many conditions that have been causally associated with infantile spasms invariably result in this disorder, no single pathologic factor has been found in all infantile spasms patients, and the response to treatment is inconsistent and unpredictable. In addition, none of the proposed models provide an explanation for the phenomenon of spontaneous remission, which is occasionally observed in this disorder.

Previous hypotheses proposed to explain the pathophysiology of this disorder have been directed toward the search for a single defective process that serves as a “common denominator.” The hypothesis explored here attempts instead to explain these diverse and inconsistent findings by postulating that there is in fact a specific and unique abnormality in this disorder, but that it is manifested not as a particular lesion or unique defective biochemical pathway, but as a particular disturbance of function that results from an impaired maturational process. More specifically, it is suggested that the primary disturbance is related to a failure of one, or several, maturational processes to remain adequately synchronized with the totality of developmental processes that are active within the first year of life. Thus, the disturbance of function is crucially dependent on an unbalanced maturational pattern, in which certain brain systems are not able to interact in the normal manner due to their divergent developmental status. A critical aspect of this model is the concept that disturbed function of a specific kind can result from multiple causative factors (e.g., impaired neuronogenesis, myelination, synaptogenesis, apoptosis, neurotransmitter systems), and so can be associated with a variety of different anatomic and/or biochemical abnormalities. Thus, this concept is compatible with the observed diversity of pathologic findings and multiplicity of etiological associations.

Specifically, it is hypothesized that infantile spasms results from a particular (but, as yet, undetermined) temporal desynchronization of two or more central nervous system developmental processes, resulting in a specific disturbance of brain function. As outlined in Fig. 1, the developmental desynchronization can be produced by one (or a combination) of three different mechanisms (each of which can be manifested at various locations): (1) as an indirect result of mutations or inherited abnormalities affecting the primary genes governing ontogenesis, (2) as an indirect result of mutations or inherited abnormalities affecting the genes specifying transcription factors (or other genetic modulators), or (3) as a direct result of injurious external environmental factors affecting the maturational processes of brain tissues and/or neurochemical systems. As a result of any (or a combination) of these mechanisms, at least one CNS developmental process significantly lags (or leads) other processes, resulting in a situation incompatible with normal integrated brain function. This proposed mechanism is illustrated schematically in Fig. 2. In part A, two different developmental processes are presumed to be normally synchronized in the prenatal period. An insult slowing the development of process 2 occurs at approximately 3 months before birth (Fig. 2B), as indicated by the “X,” and by the time of birth this difference in maturational rate has resulted in slight desynchronization of the two processes. This minimal desynchronization is presumed to be insufficient to disrupt the normal functional interactions at this time. However, by postnatal month 7 (Fig. 2C), the desynchronization has become significant, and a functional deficit now results due to loss of the normal interactions between the two processes.

FIGURE 1.

FIGURE 1.

FIGURE 2.

FIGURE 2.

A theoretic example of how this general concept could be implemented is provided by reconsideration of the brainstem monoaminergic (norepinephrine and serotonin) and cholinergic neurotransmitter systems which are known to function in a reciprocal (i.e., balanced) relationship (Hobson et al., 1976), and which project widely to other brain regions. As discussed above, a number of investigators have thought that these regions are involved in infantile spasms, but conclusive evidence supporting a causative role has not been found. We postulated (Hrachovy and Frost, 1989a) that the disrupted sleep pattern associated with infantile spasms was suggestive of a relatively increased output of the inhibitory monoaminergic systems and/or decreased activity within the associated excitatory pontine cholinergic system. According to this idea, the epileptic spasms would be a result of abnormal activity projected from the pons into descending brainstem pathways controlling spinal reflex activity, whereas ascending pathways from these same pontine centers to the cerebral cortex would result in abnormal cortical function and the characteristic EEG changes. Experimental and clinical support for this scheme was, however, not convincing. Although a number of studies have demonstrated disturbed CNS monoamine metabolism in patients with infantile spasms, the findings have been variable, and, most significantly, none have been present in all patients. As noted before, therapeutic trials of several agents that block the production or reduce the effectiveness of serotonin and/or norepinephrine were effective in only a few of the patients tested, although acute treatment with the cholinesterase inhibitor, physostigmine, did result in transient improvement in a small number of patients. Consequently, it was concluded that dysfunction of these neurotransmitter systems was unlikely to constitute the “common denominator” underlying infantile spasms.

If, however, the data concerning these monoaminergic and cholinergic systems are reexamined within the framework of the developmental desynchronization model, it can be seen that the proposed mechanism may in fact be supported rather than refuted by the available evidence. For example, any pathologic factor that significantly retarded (or accelerated) the development of either of the monoaminergic systems with respect to that of the cholinergic system, or, alternatively, accelerated (or retarded) maturation of the cholinergic system with respect to the monoaminergic systems could produce an imbalance in the overall mutual interactions of the combined reciprocal systems. Such an imbalance would effectively render the combined system nonfunctional in terms of its integrated role in regulating other central nervous system activity. According to this model, such a pathologic factor could be manifested at the primary gene level (i.e., genes directly responsible for production of elements of the neurotransmitter systems), at the level of genes responsible for transcription factors regulating the primary genes, or externally as an adverse environmental influence directly affecting the integrity of the neuronal and support tissues of the neurochemical systems. Any of these influences could result in the crucial alteration of maturational rate ultimately responsible for the imbalance leading to a specific functional deficit. But because the precise nature of the pathologic factor's impact on the system would differ among the various possibilities, it would not be expected that all such influences would be associated with the same structural or biochemical abnormalities. For example, genetic factors could impact any of the multiple metabolic pathways leading to production of any one of the three neurotransmitters involved, potentially resulting in either deficient or increased levels at the involved synapses. Other genetic influences could instead result in altered production or structure of the various neurotransmitter receptors involved. Alternatively, environmental factors could adversely affect the structure of the involved neuronal and/or supportive systems, leading to altered function despite preserved metabolic pathways and receptor systems. The clinical manifestations of the disorder would, however, be the same because the crucial element (in this example the critical reciprocal relationship between monoaminergic and cholinergic systems) necessary for normal function becomes significantly disrupted at some point in time. Consequently, it can be seen that the key aspect of this model is the idea that diverse pathologic impacts on the maturing nervous system can, at some point in time, result in the same functional deficit. This particular example, focusing on brainstem neurotransmitter mechanisms, is provided to illustrate the concepts of the model, and clearly it is not the only possibility.

An important implication of this model is the possibility that significant developmental desynchronization, resulting in the occurrence of infantile spasms, could occur as a result of the chance simultaneous occurrence of several factors or conditions, each of which, by itself, causes an insignificant degree of developmental impairment. Although any one such factor (e.g., a minor genetic variation or subtle environmental influence) by itself might not cause a detectable effect, the random combination of two, or more, such factors could result in a significant developmental desynchronization within a particular CNS system (e.g., a genetic variation might slightly accelerate one process, while an environmental factor might slightly delay a related process). Consequently, before the exact time at which the system becomes critically unbalanced (and therefore dysfunctional) it is possible that no actual abnormality would exist in any of the developmental processes within the nervous system, thus providing a theoretic basis for cryptogenic cases, as well as a mechanism explaining the fact that not all individuals with a particular predisposing insult or condition develop infantile spasms.

This hypothetical model is also consistent with the observed diversity of response to all therapeutic modalities known to have efficacy in infantile spasms. All treatments would not be expected to be effective in all patients because of the different fundamental impairments responsible for the common functional deficit, and efficacy in an individual patient would depend on the exact nature of the pathologic process. Effective therapy would be dependent on an ability of the agent to induce resynchronization of the involved developmental process or processes. For example, a particular agent might act to up or down regulate genes active in controlling the maturation of a specific process, while another therapy might block, or otherwise alter, the response to specific neurotransmitters. Spontaneous remission, seen occasionally in this disorder, may simply reflect the ability of internal control mechanisms to detect, and ultimately respond to, developmental desynchronization by the activation or modulation of other gene regulation systems.

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Evidence Supporting the Model

The essential element of the model proposed here is the concept that a very specific disturbance of central nervous system function may arise from a wide variety of pathologic agents as a result of influences on developmental pathways that eventually produce desynchronization and imbalance within a particular critical system. Although the identity of the critical system(s) responsible for infantile spasms remains unknown, consideration of the proposed model may suggest novel directions for future work in this area. Available data need to be reassessed in terms of the possible disturbances of functional systems that could be reflected by the diverse biochemical and pathologic findings associated with this disorder. New approaches must be developed to search for diverse genetic aberrations that could provide important clues regarding the specific system(s) involved.

If the model proposed here is valid, then the search for the basic pathophysiologic substrate of infantile spasms must focus on the identification of brain systems particularly susceptible to disruption by disturbances of the maturational process. Consequently, this search should be directed in particular at systems that normally undergo major changes in structure and function before 8 (postnatal) months of age, because such dynamic and rapidly evolving systems would be most vulnerable to desynchronizing influences, and because the onset of infantile spasms is very rare after this time. Unfortunately, relatively little precise data exist concerning the temporal aspects of central nervous system maturation in the human infant. While much more extensive information is available for other species, in particular the rat, precise extrapolation of these findings to the human is not straightforward, and correlation factors are often different for different maturational processes (e.g., Avishai-Eliner et al., 2002). However, a few maturational processes have been studied in enough detail in the human to allow a preliminary assessment of the possible role they could play in the pathogenesis of infantile spasms. Several of these processes are discussed below to illustrate the possible mechanisms by which the proposed pathophysiologic model could be implemented. We recognize that many other developmental processes could potentially provide a similar pathophysiologic basis, and chose these particular examples only because the currently existing human data were sufficiently comprehensive, and/or that abnormalities of the specific process previously have been observed in patients with infantile spasms.

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Synaptogenesis

The maturational time course of synaptogenesis in the human brain has been extensively mapped in several cortical regions from its onset in the gestational period through adult life (Huttenlocher and De Courten, 1987; Huttenlocher and Dabholkar, 1997). As summarized in Fig. 3, in all areas evaluated the synaptic density increases progressively during the third trimester of gestation, exhibits an accelerated rate of increase around 2 to 3 months after birth, and reaches a plateau around 3 to 9 months. Figure 3 also shows the age-incidence of infantile spasms (Hrachovy and Frost, 1989b) on the same time scale. Comparison of the normal cortical synaptic density profiles with infantile spasms age-incidence reveals that the rising incidence of infantile spasms during the first 5 months of postnatal life correlates with the period of most rapidly increasing synaptogenesis, whereas the decreasing incidence of infantile spasms after 5 to 6 months is associated with a period of relatively stable levels of synaptic density. This relationship suggests the possibility that infantile spasms could be triggered by factors that delay the normal pattern of synaptogenesis and as a result lead to the desynchronization of a functional system dependent on the maintenance of a critical level of synaptic density in conjunction with other ongoing maturational processes. The process of synaptogenesis is highly complex and still incompletely understood. However, a number of specific genes (at least 41) that are known to determine particular aspects of the process, or to regulate its timing, have been identified (OMIM online database). If some aspect of synaptogenesis is in fact responsible for a specific disturbance of function of the type hypothesized above, then it would be expected that more than one gene could trigger the developmental disturbance leading to the critical desynchronization. To our knowledge, there have been no studies in which the degree of synaptogenesis has been evaluated quantitatively in patients with infantile spasms.

FIGURE 3.

FIGURE 3.

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Myelination

The developmental time course of myelination in the infant brain is complex, and exhibits pronounced regional differences. However, studies based on analysis of T1- and T2-weighted MRI images have demonstrated a relatively consistent qualitative pattern (see review by Paus et al., 2001). Myelination is initially observed in the cerebellar peduncles and pons around the time of birth, and appears sequentially in the posterior limb of the internal capsule, optic radiation, and splenium of the corpus callosum over the next 1 to 3 months. By 6 months, myelination has occurred in the anterior limb of the internal capsule and the genu of the corpus callosum, and myelination of the cortical white matter appears between 8 and 12 months. In the context of the current hypothesis, it is of particular interest that the corpus callosum exhibits significant thickening during the first year of life, achieving an essentially adult configuration by 8 months, with a peak of development occurring between 4 and 6 months of age (Barkovich and Kjos, 1988). Because this rapidly changing period of myelination clearly coincides with the peak incidence of infantile spasms, this process should be considered as a potential factor in the pathogenesis of infantile spasms. Any influence that altered the time course of myelination during this critical period could result in significant desynchronization of the components of a functional system. Studies of infantile spasms patients have in fact frequently documented the presence of delayed myelination (Kasai et al., 1995; Muroi et al., 1996; Natsume et al., 1996; Schropp et al., 1994; Staudt et al., 1994; Zhongshu et al., 2001). In several studies that provided sufficient information, the proportion of subjects with evidence for delayed myelination ranged from 67% to 77%. At least 52 identified genes have been implicated in various aspects of the myelination process (OMIM database).

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Neurotransmitter Systems

Glutamate

The amino acid glutamate is an excitatory neurotransmitter, and its role in the pathogenesis of epilepsy has been extensively studied in animal models. Although there have been reports of elevated glutamate levels in some infantile spasms patients (Spink et al., 1988), this has not been a consistent finding (Ince et al., 1997). However, the pattern of developmental changes in the glutamate receptors in some brain regions suggests that this system should be considered as a potential factor in infantile spasms pathogenesis. For example, Panigrahy et al. (1995) have demonstrated that glutamate receptor activity (as determined by [3H] kainate binding studies) is higher in a number of brainstem regions in the fetal and infantile periods, as compared with the mature brain. In approximately half of the brainstem sites evaluated by Panigrahy et al., mature levels were significantly lower than those of the immature brain, and similar, although nonsignificant, trends were observed in all other areas. Most of these brainstem sites exhibited a progressive decline of kainate binding from the fetal period to maturity. However, three locations (arcuate nucleus, griseum pontis, and the principal inferior olive) are of particular interest with respect to the proposed developmental desynchronization model since they demonstrated a pattern of transiently increased reactivity in the infantile period (mean age 3 months) compared wtih the fetal levels (19–24 weeks postconceptional age), with a marked subsequent decrease to the mature values (4–70 years). This suggests that these regions would be particularly vulnerable to perturbing influences in the first few months of life, and so would be most susceptible to desynchronization with respect to other developmental processes with which they normally interact. This possibility has not been specifically investigated in infantile spasms patients, although brainstem abnormalities are not uncommon. At least 79 identified genes have been implicated in glutamate metabolism and neurotransmission, including those regulating glutamate receptors (OMIM database).

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Serotonin

As noted above, abnormalities of brainstem serotonin metabolism, and related metabolic pathways, have been postulated as possible pathophysiologic factors underlying infantile spasms. In particular, it has been suggested that relative hyperactivity of this neurotransmitter system could account for many of the observed features of this disorder (e.g., Chugani et al., 1992; Hrachovy and Frost, 1989a). Consideration of the developmental aspects of the serotonin system within the framework of the current model provides some support for these suggestions. Zec et al. (1996) have provided quantitative information regarding the developmental course of human serotonin receptor function by measuring brainstem [3H]LSD binding in three age groups: fetal (19–25.5 weeks after conception), infant (42–55.5 weeks after conception), and mature (4–53 years). As illustrated in Fig. 4 (pons and midbrain nuclei), receptor binding in all regions was higher in the fetal period, exhibited a moderate to marked decline in the infantile period, and achieved the lowest level at maturity. As would be expected, the highest binding was observed in the raphe nuclei (dorsal and median), and these two areas exhibited the least degree of decline during infancy as compared to the prenatal period. Panigrahy et al. (1998) observed a similar developmental pattern of serotonin receptor binding in the human interpeduncular nucleus. [3H]LSD binding was greatest in the dorsal region, and values declined significantly with age. The dynamic developmental patterns observed in these studies suggest that the serotonin receptor system may be particularly vulnerable to desynchronization. Significant desynchronization of the serotonin system with respect to the other systems with which it normally interacts (e.g., acetylcholine) could result from even mild impairment of the normal downregulation process during the early postnatal time period. Such impairment at a time when normal function is associated with a very rapid rate of decline would be expected to quickly disturb the critical balance of such related systems. This possibility has not been investigated in patients with infantile spasms. At least 41 identified genes have been implicated in serotonin metabolism and neurotransmission (OMIM database).

FIGURE 4.

FIGURE 4.

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Acetylcholine

As discussed previously, the possibility that a deficit of cholinergic activity within certain brainstem neuronal circuits might be a factor in infantile spasms pathogenesis has been suggested (Hrachovy et al., 1981; Hrachovy and Frost, 1989a). Although this hypothesis has not been adequately tested, the concept is supported in part by the findings of Rektor et al. (1987, 1990), who evaluated the acute effects of physostigmine in several patients with infantile spasms. Administration of the cholinesterase inhibitor reportedly was followed by significantly decreased paroxysmal EEG activity and normalization of the background activity, whereas atropine had an opposite effect, and increased the abnormal activity. Although the developmental aspects of the brainstem cholinergic systems have not been extensively studied, the available information does provide some support for the current hypothesis. Kinney et al. (1993) compared the distribution of [3H]nicotine binding sites in the brainstems of several midgestational fetuses (21–26 weeks) to those associated with early infancy (41–61 weeks post conceptional age). Relatively high nicotinic binding levels were found in many tegmental nuclei in the fetal brainstems, with a very significant decrease (typically 60–70%) occurring by early infancy. Major cerebellar relay nuclei (principal inferior olive and griseum pontis), however, exhibited relative low nicotinic binding levels at both time periods. This group of investigators also assessed the development of the muscarinic cholinergic system (Kinney et al., 1995) by measuring [3H]quinuclidinyl benzilate binding at several ages. As illustrated in Fig. 5, this system exhibited a considerable degree of variability with respect to its developmental characteristics. Although some areas demonstrated a pattern similar to most nicotinic sites, with significant decreases occurring in early infancy (e.g., nucleus pontis oralis and nucleus parabrachialis lateralis), others maintained a high binding level during this time (e.g., interpeduncular nucleus, griseum pontis, and pontine paramedian bands). In all areas, the fetal and early infancy binding values were higher than the subsequent mature levels. These findings provide evidence that the cholinergic system is highly dynamic with respect to its developmental characteristics, and consequently may be particularly vulnerable to developmental desynchronization. At least 47 identified genes have been implicated in acetylcholine metabolism and neurotransmission (OMIM database).

FIGURE 5.

FIGURE 5.

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Neuronal Migration

Disordered neuronal migration patterns (cortical dysplasia) have been a frequent finding in pathologic specimens obtained during surgical procedures done for the treatment of infantile spasms (e.g., Vinters, 2002). Although it is not clear if this finding represents a primary etiological factor involved in the genesis of infantile spasms, or if it is simply another associated finding, its frequent association suggests that neuronal migration must be carefully considered within any proposed model. In contrast to synaptogenesis, neuronal migration begins early in fetal life (before the eighth week), and is essentially complete by the time of birth (see the review by Encga-Razavi and Sonigo, 2003). Consequently, with respect to the present hypothesis, it would be expected that any factor impacting the rate of neuronal migration during early development, and predisposing to the later development of infantile spasms, would not produce significant desynchronization of the critical functional process until after birth (as illustrated in Fig. 2). Other, possibly functionally related, processes (such as those discussed above) that exhibit a normal developmental acceleration after birth might govern the actual time of onset of the resultant developmental desynchronization, even though the primary deficit was based on delayed neuronal migration that began several months previously. In addition, because the neuronal migration process itself is in many ways a prerequisite to normal synaptogenesis and myelination, a factor adversely affecting migration in the prenatal period could potentially alter the normal developmental time courses of synaptogenesis and myelination (described above), and, again, result in a delayed onset of developmental desynchronization several months after birth. A significant number of identified genes (at least 68) are known to be, or are suspected to be, involved in the processes associated with neuronal migration (OMIM database).

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KNOWN GENETIC ASSOCIATIONS

As discussed above, infantile spasms has been reported to occur in association with many other pathologic entities, and among these are more than 100 conditions that are known to have a genetic basis (see Frost and Hrachovy, 2003, Table 9.2). In most of these cases there is insufficient information available in the scientific literature to determine if the reported associations represent a true etiologic relationship between the underlying pathology and the occurrence of infantile spasms, as opposed to a simple coincidence resulting from the fact that many childhood disorders can occur during the same general time period. In general, to establish a causal relationship, it is either necessary to demonstrate that the incidence of infantile spasms is higher in groups of subjects with the potential etiologic factor than it is in the general population, or to demonstrate that the etiologic factor itself is more common in infantile spasms patients than in the general population. If these criteria are applied to the large list of potential genetic associations, only 13 genetically based conditions can be considered as probable etiologic or predisposing factors for infantile spasms: tuberous sclerosis, Aicardi syndrome, Down syndrome, phenylketonuria, PEHO syndrome, lissencephaly, neurofibromatosis type I, Angelman syndrome, pyruvate dehydrogenase complex deficiency, hemimegalencephaly, Ito hypomelanosis, X-linked infantile spasms, and cortical dysplasia (see Frost and Hrachovy, 2003, Table 9.3). Table 1 lists the set of 15 identified human genes that have been implicated in eight of these 13 genetic disorders causally associated with infantile spasms and provides the name of the encoded protein and known functions of potential relevance to infantile spasms pathogenesis. Five of the 13 genetic conditions are not listed in Table 1 because although a genetic basis has been established, the responsible gene or genes have not been identified (PEHO syndrome, hemimegalencephaly, and cortical dysplasia) or the disorder is not associated with specific genes (e.g., Down syndrome results from a chromosomal aberration involving many genes, and Ito hypomelanosis involves different states of chromosomal mosaicism). With respect to the proposed developmental desynchronization model, it is of interest that nine of the 15 genes listed in Table 1 are known to have a role in regulation of neuronal migration. Consequently, more detailed and specific analysis of the genetic basis of this subset of conditions linked to infantile spasms may provide additional information relevant to the current hypothesis.

TABLE 1

TABLE 1

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CONCLUSIONS

Meaningful research directed toward a more comprehensive understanding of the underlying pathophysiology of infantile spasms has been seriously impeded by the lack of an animal model of this disorder. Without such a model, it seems likely that the precise mechanisms responsible for this entity will remain elusive. However, the hypothetical concepts proposed above provide a general framework for future investigations of infantile spasms pathogenesis, and it is hoped that consideration of the ideas explored here will stimulate specific research in this area and eventually lead to the development of an animal model. If the basic tenets of the hypothesis are correct (i.e., that the disorder is a result of temporal desynchronization of two or more central nervous system developmental processes, resulting in a specific disturbance of brain function) then future work should attempt to identify systems that are functionally based on two or more closely interacting processes, rather than seeking a single common denominator. The model also provides an explanation for the wide diversity of associated etiologic factors that have been associated with this disorder, because many different patho-logic impacts can produce the same functional deficit. One possible approach to the detection of the crucial functional system would involve screening of groups of infantile spasms patients for defects in multiple genes within categories known to be involved in developmental processes that normally exhibit pronounced maturational changes before, or during, the time period coincident with the peak incidence of infantile spasms. A clustering of aberrant genes within one category would suggest that some process within that particular developmental category was likely to provide the basis for an underlying disturbed functional process directly responsible for producing the features of infantile spasms. Detailed analysis of the known roles of the specific genes detected would be expected to provide new insights regarding the identity of the underlying functional disturbance leading to the manifestations of infantile spasms.

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Keywords:

Infantile spasms; Epilepsy; Encephalopathy; Pathogenesis

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