Pathophysiology of massive infantile spasms: Perpective on the putative role of the brain adrenal axis

Abstract

Massive infantile spasms are an age-specific seizure syndrome of infancy. Uniquely, the spasms respond to hormonal manipulation using adrenocorticotropic hormone (ACTH) or glucocorticoids. A hypothesis explaining the efficacy of hormonal therapy, age-specificity, multiple causative factors, and spontaneous resolution of infantile spasms is presented. Corticotropin-releasing hormone (CRH), an excitant neuropeptide suppressed by ACTH/steroids, is implicated. Evidence for the age-specific convulsant properties of CRH is presented, and a putative scenario in which a stressinduced enhancement of endogenous CRH-mediated seizures is discussed. Clinical testing of the CRH-excess theory and its therapeutic implications are suggested.Massive infantile spasms (MIS) represent a seizure disorder with unique clinical and electrographic features [1][2][3][4]. It is relatively common (1:2,000-4,000 births [5,6]) and has been known to respond to adrenocorticotropic hormone (ACTH), since 1958 [7]. Long-term intellectual outcome of affected infants, however, remains poor, with 76 to 95% of survivors having moderate to severe mental retardation [1,3,6,8]. Therefore, MIS continues to attract research concerning both pathogenesis and therapy. Several large series [1,3,[9][10][11] and recent reviews [6,8,[12][13][14] have focused on clinical and electroencephalographic phenomenology of MIS, and on the therapy and outcome aspects of this entity. Here I introduce an age-specific endogenous-convulsant hypothesis for the pathophysiology of MIS. The hypothesis implicates an endogenous neuropeptide, which is known to cause seizures in infant rats, and is suppressed by ACTH and glucocorticoids (GCs). I shall present evidence for this hypothesis, discuss some of its predictions for treatment options, and place it in the context of current therapeutic controversies. Definition and DescriptionInfantile spasms were first described by West [15] The syndrome of MIS consists of a constellation of myoclonic seizures in an infant, whose EEG pattern is that of hypsarrhythmia or its variants [1-4, 7-11, 14, 17]. The electroencephalographic (EEG) pattern, response to therapy, and poor outcome distinguish MIS from a variety of other myoclonic epilepsies of infancy [1,18]. Furthermore, MIS is a time-locked entity; it arises in infancy after a delay from the time of insult and, in the majority of cases, disappears spontaneously. Even without treatment, 89% of patients are reported to be spasm free by 5 years of age [19]. Proposed PathophysiologyMIS develops in infants with a variety of central nervous system (CNS) pathologies [1][2][3][4]. Structural anomalies, tuberous sclerosis, and other phakomatoses are commonly associated with MIS. Prenatal as well as peri-and postnatal infections, stroke, trauma, and even chromosomal aberrations have all been implicated as causative factors. This multitude of associated factors has suggested that MIS may be a "final common pathway" or an agespecific yet cause-nonspecific response of the brain [1,20,21]. Cor...

Choosing the Correct Antiepileptic Drugs: From Animal Studies to the Clinic

“…However, the pharmacological response of the spasm-like behavior differed from children with infantile spasms in that the rats did not respond to glucocorticoids [103]. Recently, the model was altered by Velisek and colleagues [105], who reasoned that since infantile spasms may be secondary to disorders of the hypothalamic-pituitary-adrenal system [107], alteration of the adrenal brain axis may predispose the immature brain to spasms. Since prenatal administration of a glucocorticoid can impair brain hypothalamic-pituitary-adrenal function [108], the authors administered betamethasone to pregnant rats.…”

Systemic Adrenocorticotropic Hormone Administration Down-Regulates the Expression of Corticotropin-Releasing Hormone (CRH) and CRH-Binding Protein in Infant Rat Hippocampus

“…Adrenocorticotropic hormone (ACTH) is a 39 -amino acid peptide released into circulation by the anterior pituitary in response to corticotropin-releasing hormone (CRH) stimulation from the hypothalamic paraventricular nuclei (1). Among its various physiologic effects, ACTH is known to regulate both stress and immune responses via stimulation of the adrenal glands (2).…”

“…Although this period of adrenal hyporesponsiveness is proposed to be protective under normal circumstances (4), excessive activity of the hypothalamic-pituitary axis (i.e. CRH release) may result in an attempt to elevate circulating levels of adrenal steroids after stressful events (1,5). Excess synthesis and release of CRH during the neonatal period may also have detrimental effects on neuronal excitability and development during infancy (6).…”

“…The cause of infantile spasms has been attributed to a wide variety of brain insults occurring during antenatal/perinatal development (1,8). At present, infantile spasms are treated primarily with systemic ACTH administration.…”

“…At present, infantile spasms are treated primarily with systemic ACTH administration. It is proposed that ACTH suppresses endogenous release of the excitatory neuropeptide CRH via a negative feedback mechanism (1,9). CRH is elevated during periods of physiologic stress [i.e.…”