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

Abstract

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...

Cerebrospinal fluid corticotropin and cortisol are reduced in infantile spasms

“…The "all-ornone" disappearance of spasms often within days, and the persistence of the effect upon hormone withdrawal, is consistent with a neuroendocrine mechanism [3,6]. We have previously found a low cerebrospinal fluid (CSF) level of ACTH in untreated infants with IS compared with age-matched controls [6]. A trend toward decreased Cortisol did not reach statistical significance (P = .08), but Cortisol values were available only from 12 patients and 9 controls.…”

“…CRH is a convulsant, with strong age-specificity to infancy [10]. One may speculate that CRH plays an epileptogenic role in IS and is associated with decreased CSF ACTH and Cortisol [3,6]. As CRH receptors peak in infancy [11], seizures may only occur at that age.…”

“…Further, the unique response pattern of the seizures to hormonal therapy (abrupt, "all-or-none" disappearance within days, without recurrence on discontinuation of therapy) suggests neuroendocrine mechanisms for ACTH/prednisone efficacy. This may involve a negative feedback suppression of the synthesis or secretion of CRH [3,6], which lasts throughout the period of high CRH receptor abundance [11].…”

“…The mechanisms by which these hormones suppress the seizures and normalize the EEG are not fully understood, yet may help clarify the pathophysiology of this disorder [2,3]. The "all-ornone" disappearance of spasms often within days, and the persistence of the effect upon hormone withdrawal, is consistent with a neuroendocrine mechanism [3,6]. We have previously found a low cerebrospinal fluid (CSF) level of ACTH in untreated infants with IS compared with age-matched controls [6].…”

“…The clinical characteristics of both groups of patients are delineated in Tables 1 and 2; five patients and controls were included in a previous report [6]. The study of CSF was approved by the Internal Review Board for human studies of Childrens Hospital Los Angeles, and Kaiser-Permanente.…”