Cerebrospinal fluid corticotropin and cortisol are reduced in infantile spasms

Baram, Tallie Z.; Mitchell, Wendy G.; Hanson, Rebecca A.; Snead, O. Carter; Horton, E. J.

doi:10.1016/0887-8994(95)00121-u

Cited by 30 publications

(13 citation statements)

References 8 publications

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“…It can effectively suppress the seizures and normalize the EEG in the short-term treatment for infantile spasms [38] . In addition, there is considerable evidence supporting disturbances of neuropeptide metabolism in some infantile spasms and reduced CSF levels of ACTH and cortisol in these patients have been observed [4,41] . Such fi ndings, together with the known effi cacy of ACTH and corticosteroids in controlling spasms, clearly suggest that brain-adrenal dysfunctions play an important role in the pathogenesis of infantile spasms [4,24,41] .…”

Section: Introductionmentioning

confidence: 92%

Analysis of Single Nucleotide Polymorphisms in the Melanocortin-4 Receptor Promoter in Infantile Spasms

Liu¹,

He²,

Fang³

et al. 2007

Neuropediatrics

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Section: Introductionmentioning

confidence: 92%

Analysis of Single Nucleotide Polymorphisms in the Melanocortin-4 Receptor Promoter in Infantile Spasms

Liu¹,

He²,

Fang³

et al. 2007

Neuropediatrics

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“…Endogenous corticosteroid levels are chronically elevated after treatment with the ketogenic diet, a clinically efficacious therapy for a variety of childhood intractable epilepsies (48). Exogenous corticosteroids have been used both in the treatment of infantile spasms (albeit less effectively than ACTH) (49,50) and as empiric treatment for a variety of childhood epilepsies (51,52).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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Systemic adrenocorticotropic hormone (ACTH) administration is a first-line therapy for the treatment of infantile spasms, an age-specific seizure disorder of infancy. It is proposed that exogenous ACTH acts via negative feedback to suppress the synthesis of corticotropin-releasing hormone (CRH), a possible endogenous convulsant in infant brain tissue. The aim of this study was to determine whether systemic ACTH treatment in infant rats down-regulates the hippocampal CRH system, including CRH, CRH-binding protein (CRH-BP), and CRH receptors (CRH-R1 and CRH-R2). Daily i.p. injection of ACTH for 7 consecutive days (postnatal days 3-9) elevated serum corticosterone levels 20-fold measured on postnatal day 10, indicating systemic absorption and circulation of the ACTH. Semiquantitative reverse transcriptase-PCR demonstrated that both CRH and CRH-BP mRNA obtained from the hippocampi of ACTHinjected infant rats was significantly depressed relative to salineinjected animals. Comparable reductions in both CRH and CRH-BP synthesis were further demonstrated with radioimmunoassay. In contrast, neither CRH-R1 nor CRH-R2 mRNA was altered by ACTH treatment, relative to saline-injected rats. This latter finding was confirmed electrophysiologically by measuring the enhancement of hippocampal population spikes by exogenous CRH, also showing no differences between ACTH-and saline-injected rats. The results of this study support the proposal that systemic ACTH treatment down-regulates CRH expression in infant brain, perhaps contributing to the therapeutic efficacy observed during treatment of infantile spasms. 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). In neonates, the adrenal glands are relatively insensitive to ACTH stimulation, and corticosterone release occurs primarily via constitutive secretion (3). 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).Infantile spasms are an age-dependent epileptic syndrome associated with developmental delay and hypsarrhythmia (7). Received February 21, 2003; accepted November 20, 2003

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“…Based on the hypothesis that infants with IS may exhibit malfunction of the hypothalamus–pituitary–adrenal (HPA) axis—supported by clinical findings of decreased ACTH and cortisol in the cerebrospinal fluid (CSF) as well as by ACTH efficacy (Baram et al., 1995; Nagamitsu et al., 2001)—we developed a new model of IS using postnatal NMDA administration in rats with preexisting compromised HPA‐axis function (Velíšek et al., 2007). Indeed, prenatal exposure to synthetic corticosteroids (dexamethasone or betamethasone) during the last week of rat pregnancy is associated with altered expression of glucocorticoid receptors in the brain (Welberg et al., 2001; Velíšek, 2005).…”

Section: Corticosteroid Treatmentmentioning

confidence: 99%

Model of cryptogenic infantile spasms after prenatal corticosteroid priming

Velı́šek

Chachua²,

Yum³

et al. 2010

Epilepsia

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SUMMARYInfantile spasms (IS) is a devastating epilepsy syndrome of childhood. IS occurs in 3-12-month-old infants and is characterized by spasms, interictal electroencephalography (EEG) hypsarrhythmia, and profound mental retardation. Hormonal therapy [adrenocorticotropic hormone (ACTH), corticosteroids] is frequently used, but its efficacy is tainted by severe side effects. For research of novel therapies, a validated animal model of IS is required. We propose the model of spastic seizures triggered by N-methyl-D-aspartate (NMDA) in infant rats prenatally exposed to betamethasone. The spasms have remarkable similarity to human IS, including motor flexion spasms, ictal EEG electrodecrement, and responsiveness to ACTH. Interestingly, the spasms do not involve the hippocampus. Autoradiographic metabolic mapping as well as tagging of the areas of neuronal excitation with c-fos indicates a strong involvement of hypothalamic structures such as the arcuate nucleus, which has significant bilateral connections with other hypothalamic nuclei as well as with the brainstem.

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Cerebrospinal fluid corticotropin and cortisol are reduced in infantile spasms

Cited by 30 publications

References 8 publications

Analysis of Single Nucleotide Polymorphisms in the Melanocortin-4 Receptor Promoter in Infantile Spasms

Analysis of Single Nucleotide Polymorphisms in the Melanocortin-4 Receptor Promoter in Infantile Spasms

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

Model of cryptogenic infantile spasms after prenatal corticosteroid priming

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