Changes in CSF neurotransmitters in infantile spasms

Langlais, Philip J.; Wardlow, M.L.; Yamamoto, Hitoshi

doi:10.1016/0887-8994(91)90028-j

Cited by 38 publications

(18 citation statements)

References 31 publications

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“…Alterations of 5-HIAA have been reported in progressive myoclonic epilepsies, infantile spasms, and burst suppression pattern-associated disorders ). However, these results have been controversial (Langlais et al 1991;Airaksinen et al 1992) and an association between biogenic amines and antiepileptic drugs has not been excluded in previous studies (García-Cazorla et al 2007;Assmann et al 2002).…”

Section: Discussionmentioning

confidence: 97%

“…By contrast, and although serotoninergic innervation in the brain is more evenly distributed, its implication in different neurological disorders other than psychiatric diseases has scarcely been described. Previous studies showed secondary low 5-HIAA levels in infants with diverse neurological disorders and cortical brain atrophy (García-Cazorla et al 2007), idiopathic adult-onset dystonia (Naumann et al 1996), malignant epilepsies (Langlais et al 1991), and dopa nonresponsive dystonia (Assmann et al 2002). However, to date and to our knowledge, a large study determining the frequency and reviewing the possible causes of serotoninergic alterations in patients with diverse neurological problems has not been reported.…”

Section: Introductionmentioning

confidence: 92%

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Cerebrospinal fluid alterations of the serotonin product, 5‐hydroxyindolacetic acid, in neurological disorders

Grandis

Serrano

Pérez‐Dueñas

et al. 2010

J of Inher Metab Disea

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Although patients with low cerebrospinal fluid (CSF) serotonin metabolite levels have been reported, inborn errors of the rate-limiting enzyme of serotonin synthesis (tryptophan hydroxylase, TPH) have not been described so far. In this study we aimed to evaluate CSF alterations of the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) in patients with neurological disorders and to explore a possible TPH deficiency in some of them. A total of 606 patients (286 males, 320 females, mean age 4 years and 6 months, SD 5 years and 7 months) underwent CSF analysis of neurotransmitter metabolites by reverse phase high performance liquid chromatography. Results were compared with values established in a control population. Patients' medical records were reviewed to determine diagnosis and clinical features. A primary defect of biogenic amines was genetically investigated in indicated patients. Low 5-HIAA was seen in 19.3%. Of these, 22.2% showed inborn errors of metabolism (mitochondrial disorders being the most frequent at 10.2% of low 5-HIAA patients) and neurogenetic conditions. Other relatively frequent conditions were pontocerebellar hypoplasia (4.3%), Rett syndrome (4.3%), and among congenital nonetiologically determined conditions, epilepsy including epileptic encephalopathies (26.4%), leukodystrophies (6.8%), and neuropsychiatric disturbances (4.2%). Mutational analysis of the TPH2 gene, performed in five candidate patients, was negative. Although frequency of secondary alteration of 5-HIAA was relatively high in patients with neurological disorders, this finding was more frequently associated with some neurometabolic disorders, epileptic encephalopathies, and neuropsychiatric disturbances. No inborn errors of TPH were found. Due to serotonin's neurotrophic role and to ameliorate symptoms, a supplementary treatment with 5-hydroxytriptophan would seem advisable in these patients.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 92%

Cerebrospinal fluid alterations of the serotonin product, 5‐hydroxyindolacetic acid, in neurological disorders

Grandis

Serrano

Pérez‐Dueñas

et al. 2010

J of Inher Metab Disea

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“…Spasms in this model are induced in male Sprague-Dawley rats by acute intracerebral infusion of the cytotoxic agent doxorubicin and TLR-4 agonist lipopolysaccharide (LPS) on postnatal day 3 (PN3) followed by a single intraperitoneal injection of brain serotonin synthesis blocker p-chlorophenylalanine (PCPA) on PN5 (Scantlebury, Galanopoulou, Chudomelova, Raffo, Betancourth & Moshe 2010). PCPA was added due to old reports on abnormal serotonin metabolism in patients with IS (Silverstein & Johnston 1984, Langlais, Wardlow & Yamamoto 1991, Yamamoto 1991, Scantlebury, Galanopoulou, Chudomelova, Raffo, Betancourth & Moshe 2010). LPS is a prototypical inducer of inflammation in both periphery and in the brain, known to lower seizure threshold when added with proconvulsant compounds and worsen seizure sequelae (Sayyah, Javad-Pour & Ghazi-Khansari 2003, Sankar, Auvin, Mazarati & Shin 2007, Galic, Riazi, Heida, Mouihate, Fournier, Spencer et al 2008).…”

Section: Does Activation Of the Inflammatory Pathways In The Brainmentioning

confidence: 99%

Inflammation in Epileptic Encephalopathies

Shandra

Moshé

Galanopoulou

2017

Stress and Inflammation in Disorders

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West syndrome (WS) is an infantile epileptic encephalopathy (EE) that manifests with infantile spasms, hypsarrhythmia (in ~60% of infants) and poor neurodevelopmental outcomes. The etiologies of WS can be structural-metabolic pathologies (~60%), genetic (12–15%) or of unknown origin. The current treatment options include hormonal treatment [adrenocorticotropic hormone (ACTH) and high dose steroids], the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate pro-inflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of West syndrome? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox-Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation?

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“…The induction method utilized in this model included therefore right intracerebroventricular infusions of the cytotoxic agent doxorubicin and right intracortical infusion of the lipopolysaccharide to target white matter, both given on PN3 (Scantlebury et al 2010). A subsequent intraperitoneal injection of the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) was given on PN5 to deplete serotonin, due to old reports that serotonin metabolism may be abnormal in infants with IS (Langlais et al 1991; Silverstein and Johnston 1984; Yamamoto 1991). This protocol resulted in the expression of spasms between PN4-13 indicating that PCPA was not necessary for their expression.…”

Section: West Syndrome and Infantile Spasmsmentioning

confidence: 99%

Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

Galanopoulou

Moshé

2015

Neurobiology of Disease

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Early onset and infantile epileptic encephalopathies (EIEEs) are usually associated with medically intractable or difficult to treat epileptic seizures and prominent cognitive, neurodevelopmental and behavioral consequences. EIEEs have numerous etiologies that contribute to the inter- and intra-syndromic phenotypic variability. Etiologies include structural and metabolic or genetic etiologies although a significant percentage is of unknown cause. The need to better understand their pathogenic mechanisms and identify better therapies has driven the development of animal models of EIEEs. Several rodent models of infantile spasms have emerged that recapitulate various aspects of the disease. The acute models manifest epileptic spasms after induction and include the NMDA rat model, the NMDA model with prior prenatal betamethasone or perinatal stress exposure, and the γ-butyrolactone induced spasms in a mouse model of Down syndrome. The chronic models include the tetrodotoxin rat model, the aristaless related homeobox X-linked (Arx) mouse models and the multiple-hit rat model of infantile spasms. We will discuss the main features and findings from these models on target mechanisms and emerging therapies. Genetic models have also provided interesting data on the pathogenesis of Dravet syndrome and proposed new therapies for testing. The genetic associations of many of the EIEEs have also been tested in rodent models as to their pathogenicity. Finally, several models have tested the impact of subclinical epileptiform discharges on brain function. The impact of these advances in animal modeling for therapy development will be discussed.

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Changes in CSF neurotransmitters in infantile spasms

Cited by 38 publications

References 31 publications

Cerebrospinal fluid alterations of the serotonin product, 5‐hydroxyindolacetic acid, in neurological disorders

Cerebrospinal fluid alterations of the serotonin product, 5‐hydroxyindolacetic acid, in neurological disorders

Inflammation in Epileptic Encephalopathies

Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

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