Reduced ACTH Content in Cerebrospinal Fluid of Children Affected by Cryptogenic Infantile Spasms with Hypsarrhythmia

Mitchell²,

Snead³

et al. 1992

Neurology

Massive infantile spasms (MIS), a seizure disorder unique to infants, is considered an agedependent response of the immature brain to various insults and stressors. The seizures improve with ACTH and glucocorticoids, both major components of the brain-adrenal axis. We hypothesized that CNS levels of these hormones are abnormal in infants with MIS and studied CSF from 14 infants with MIS and 13 age-matched controls by analysis for corticotropin-releasing hormone (CRH), ACTH, cortisol, and interleukin-1-beta. ACTH levels in CSF of patients were significantly lower than those of controls, but differences in cortisol levels between patients and controls were not statistically significant. CRH levels in both groups were similar and fluctuated diurnally. These results indicate an alteration of specific CNS components of the brain-adrenal axis in MIS.Massive infantile spasms (MIS), or West syndrome, consists of myoclonic seizures, hypsarrhythmic EEG, and subsequent mental retardation. 1-4 MIS is age-specific: onset of spasms is usually between the third and ninth postnatal month, and rarely after the first year. [1][2][3] Since MIS occurs in one of 2,400 to 4,000 live births and the majority of patients have long-term cognitive sequelae, the entity is an important cause of mental retardation. 1,5 MIS has been associated with structural abnormalities, neurocutaneous syndromes, intrauterine infections, metabolic aberrations, meningitis, encephalitis, and cerebral infarcts. [1][2][3][4] Infants with MIS and other neurologic abnormalities (symptomatic) are distinguished from those with no known etiology for the seizures (cryptogenic). The cryptogenic group is further subdivided by the neurologic examination (normal or delayed).The pathophysiology of MIS is unclear. The common denominator of infants with symptomatic MIS is the past occurrence of a major CNS insult or stress. 6 Thus, MIS has been considered a unique, age-dependent manifestation of stress or injury to the immature brain. 6,7 The therapy of MIS remains unsatisfactory. Conventional anticonvulsants, with the possible exception of benzodiazepines, are generally ineffective. [1][2][3][4] Benzodiazepines, including nitrazepam, may be less effective than corticotropin (ACTH) and glucocorticoids (GC). 1,8 Since the original administration of ACTH by Sorel in the late 1950s, ACTH and steroids have been the mainstay of therapy. 1,9 Numerous uncontrolled studies, as well as a doubleblinded and controlled one, 10 have shown their efficacy to be 60 to 70%. Control of the spasms themselves, moreover, may not affect the overall outcome: mental retardation occurs We hypothesize that ACTH and GC are efficacious in MIS because they counteract an abnormality of the brain-adrenal axis. Such abnormalities might include increased abundance of corticotropin-releasing hormone (CRH) or a reduction of ACTH. Methods Patient populationInfants presenting to the neurology service of Childrens Hospital of Los Angeles (CHLA) between July 1988 and March 1991 with a clinical diagnosis...

Section: Discussionsupporting

confidence: 80%

Brain‐adrenal axis hormones are altered in the CSF of infants with massive infantile spasms

Mitchell²,

Snead³

et al. 1992

Neurology

“…High brain CRH levels are expected to reduce cerebrospinal fluid (CSF) levels of ACTH and of steroids [because chronic activation of CRH receptors leads to their desensitization (Hauger et al, 1993) and decreased ACTH release]. Indeed, several groups have independently reported reduced ACTH levels in IS patients compared with agematched controls (Nalin et al, 1985;Baram et al, 1992b;Heiskala, 1997). Thus, these data are consistent with enhanced levels of endogenous CRH in brains of youngsters with IS.…”

Section: B the Many Etiologies Of Is Activate The Corticotropin-relesupporting

confidence: 76%

Acth treatment of infantile spasms: Mechanisms of its effects in modulation of neuronal excitability

Brunson

Avishai-Eliner

International Review of Neurobiology

2002

The efficacy of ACTH, particularly in high doses, for rapid and complete elimination of infantile spasms (IS) has been demonstrated in prospective controlled studies. However, the mechanisms for this efficacy remain unknown. ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system have been attributed to activation of glucocorticoid receptors. The manner in which activation of these receptors improves IS and the basis for the enhanced therapeutic effects of ACTH -compared with steroids -for this disorder are the focus of this chapter. First, a possible "common excitatory pathway," which is consistent with the many etiologies of IS and explains the confinement of this disorder to infancy, is proposed. This notion is based on the fact that all of the entities provoking IS activate the native "stress system" of the brain. This involves increased synthesis and release of the stress-activated neuropeptide, corticotropin-releasing hormone (CRH), in limbic, seizure-prone brain regions. CRH causes severe seizures in developing experimental animals, as well as limbic neuronal injury. Steroids, given as therapy or secreted from the adrenal gland upon treatment with ACTH, decrease the production and release of CRH in certain brain regions. Second, the hypothesis that ACTH directly influences limbic neurons via the recently characterized melanocortin receptors is considered, focusing on the effects of ACTH on the expression of CRH. Experimental data showing that ACTH potently reduces CRH expression in amygdala neurons is presented. This downregulation was not abolished by experimental elimination of steroids or by blocking their receptors and was reproduced by a centrally administered ACTH fragment that does not promote steroid release. Importantly, selective blocking of melanocortin receptors prevented ACTHinduced downregulation of CRH expression, providing direct evidence for the involvement of these receptors in the mechanisms by which ACTH exerts this effect. Thus, ACTH may reduce neuronal excitability in IS by two mechanisms of action: (1) by inducing steroid release and (2) by a direct, steroid-independent action on melanocortin receptors. These combined effects may explain the robust established clinical effects of ACTH in the therapy of IS. I. How Do the Many Etiologies of Infantile Spasms (IS) Lead to Excitability and Seizures? The Scope of the ProblemIS is an age-specific disorder of brain excitability, with diverse genetic, teratogenic, perinatal, and postnatally acquired etiological factors. Two key elements characteristic of this entity are (1) the remarkable number and variability of the predisposing factors and (2) the fact that regardless of the time of onset of the underlying etiology (i.e., conception, intrauterine, prenatal, perinatal, or postnatal), IS commence at a distinct developmental age (typically the third to seventh postnatal month). These facts have suggested that (a) there must be a "final common pathway" for the etiologies, le...

“…Attempts have been made to measure CSF levels of CRH as well as of ACTH and cortisol, the major human GC. Nalin and colleagues [65] found a reduction in CSF ACTH levels in 15 infants with MIS. We have recently confirmed this finding in 14 patients controlled for age, stress levels, and diurnal hormonal variation [66].…”

Section: Human Evidence For the Crh-excess Theory Of Massive Infantilmentioning

confidence: 99%

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

1993

Annals of Neurology

136

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...