Benign spasms of infancy: a mimicker of infantile epileptic disorders*

Benign spasms of infancy (BSI), previously described as benign non‐epileptic infantile spasms or benign myoclonus of early infancy, are non‐epileptic movements manifesting during the first year of life and spontaneously resolving in the second year of life. BSI are characterized by spasms typically lasting 1–2 seconds, involving, to varying degrees, the head, neck, trunk, shoulders and upper extremities. Ictal and interictal EEG recordings are normal. BSI are not associated with developmental regression and do not require treatment. Distinction between BSI and infantile epileptic disorders, such as epileptic spasms or myoclonic epilepsy of infancy, can be challenging given the clinical similarities. Moreover, interictal EEGs can be normal in all conditions. Epileptic spasms and myoclonic epilepsy require timely treatment to improve neurodevelopmental outcomes. We describe a six‐month‐old infant presenting with spasm‐like movements. His paroxysms as well as a positive family history for epileptic spasms were in keeping with a likely diagnosis of West syndrome. Surprisingly, ictal video‐EEG did not reveal epileptiform activity, and suggested a diagnosis of BSI. We emphasize that ictal video‐EEG is the gold standard for classification of infantile paroxysms as epileptic or non‐epileptic, thereby avoiding over‐treatment for BSI and facilitating timely targeted treatment of infantile epilepsies. [Published with video sequences]     

Serologic HLA typing in infantile spasms

Serologic HLA typing was performed on 29 patients with infantile spasms and hypsarrhythmic patterns in their electroencephalograms (EEGs). There were no significant increases in the frequencies of HLA-A, B, and C antigens in the infantile spasm group as compared with controls. However, there was a significant increase in the frequency of DRw52 in the infantile spasm patients (90%) as compared with controls (72%) (p less than 0.05). In addition, 3 of 12 white infantile spasm patients demonstrated the complete B18,DR3 (DRw52) haplotype; none of 150 control white subjects showed this haplotype. These findings contribute to evidence that immunological mechanisms may be involved in the pathophysiology of infantile spasms.     

Epilepsy and the Electroencephalogram in Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic Atrophy (the PEHO Syndrome)

Summary: Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome) is an apparently autosomal recessive disorder manifested by infantile spasms, severe hypotonia, and early arrest of psychomotor development. Subcutaneous edema in the limbs, typical facial features, and blindness with optic atrophy are also present. Neuropathologic and radiographic studies show progressive brain atrophy, which is accentuated infratentorially. We recorded 85 EEGs from 10 patients between the ages of 3 weeks and 12.7 years; follow-up ranged from 7 months to 12.1 years. The infantile spasms were preceded by other neurological symp- toms in all patients. Seven of nine patients showed focal or generalized epileptiform activity or abnormal EEG background. All patients developed hypsarrhythmia, first recorded between 3 and 11 months of age, that was resistant to therapy with ACTH and antiepileptic drugs. After the hypsarrhythmia disappeared, five patients showed slow spike-wave activity generally seen in the Lennox-Gastaut syndrome, and three patients showed background EEG abnormality with generalized or diffuse paroxysmal activity. There were no specific EEG features that could help in the diagnosis of PEHO. The PEHO syndrome should be borne in mind in the diagnostic work-up of patients with infantile spasms, so that potentially harmful treatment can be avoided, and the parents can be counseled about the inheritability of the disorder.     

Identification of infants at risk for infantile spasms by neonatal polygraphy

Reevaluation of neonatal EEGs and polygraphic tracings of 40 infants with infantile spasms and/or hypsarrhythmia resulted in the constitution of a compound score for the identification of infants at risk for infantile spasms by neonatal EEG. The score comprises 8 distinct items: 2 concern behavioral characteristics, 6 abnormality of EEG background activity and paroxysmal events. A tracing registered at conceptional age 36 to 44 weeks (eventually up to 50 weeks) presenting at least 4 of these 8 items is scored positive for the risk of evolving hypsarrhythmia. In a prospective study the polygraphic tracings of 941 newborn infants were evaluated for risk: 18 infants suffering from perinatal distress and 7 newborns with malformations of the brain were scored positive and all 25 developed infantile spasms and/or hypsarrhythmia. One infant with later infantile spasms was missed by the scoring system. None of the remaining infants scored negative manifested infantile spasms. Thus, correct positive prognostication was 100% and false negative 0.1%. By conventional EEG 5 out of 8 patients with infantile spasms were correctly predicted. The high validity of the risk-score based on polygraphic tracing between conceptional age 36 to 44 weeks may allow pre-onset treatment preventing secondary mental deterioration due to hypsarrhythmia and infantile spasms.     

Clinical imitators of infantile spasms.

We report 53 infants who by clinical history were thought to have infantile spasms but who video-electroencephalograms showed were having other episodes that closely mimicked infantile spasms. Nine patients had other types of seizures. Forty-five patients had episodic symptoms that were not seizures: 11 patients had spasticity, four had gastroesophageal reflux, and the other patients had nonepileptic myoclonus, including 19 patients with benign neonatal sleep myoclonus. Three patients had more than one type of symptom. Infantile spasms imitators occurred in neurologically normal or abnormal infants, in patients with normal or abnormal interictal electroencephalograms, and in patients who also had previous or current infantile spasms. Differentiation of these episodes from infantile spasms prevented the initiation or continuation of anticonvulsant treatment appropriate for infantile spasms but inappropriate for these other behaviors.     

Influence of ACTH therapy on overnight sleep polygrams in infantile spasms

Overnight sleep polygrams were recorded before and during therapy in nine patients with infantile spasms. Results showed that ACTH therapy increased the waking time and decreased rapid eye movement sleep. Thus it caused sleep disturbance in patients with infantile spasms. During ACTH therapy the number of rapid eye movements/min and the pulse rate decreased significantly. Body movements/min also decreased, but not significantly. These results suggest that ACTH therapy may inhibit functions of the central nervous system. The respiratory rate increased during ACTH and clonazepam therapy, probably in association with the decrease or the absence of seizures. These findings indicate the necessity for further studies on whether ACTH therapy is really of value in patients with infantile spasms, and show that if ACTH is given, the period of therapy should be as short as possible.     

Brain connectivity in West syndrome

PurposeHypsarrhythmia, the pathognomonic EEG pattern of West syndrome, is typically characterized by a high amplitude, arrhythmic, and asynchronous pattern. While this severely aberrant pattern would suggest severe abnormalities in connectivity, coherence has not yet been systematically assessed in hypsarrhythmia.MethodsWe evaluated the EEGs of 28 infants, 12 with infantile spasms with hypsarrhythmia and 16 similarly age control infants for coherence and spectral power.ResultsChildren with infantile spasms and hypsarrhythmia EEGs had marked abnormalities in coherence and spectral power compared to normal children of similar ages. During sleep increases in delta, theta, alpha and beta coherences were seen, particularly at long inter-electrode distances while at short inter-electrode distances coherences were decreased in the theta and beta range, particularly in the frontal region. The enhanced coherences at long inter-electrode distances suggest that during sleep in children with infantile spasms widely spread cortical region do not have functional differentiation whereas in the frontal lobe there is reduced functional connectivity and integration of local cortical regions. Children with continued seizures and developmental delay showed persistent abnormalities in coherence.ConclusionThis study demonstrates that hypsarrhythmic EEGs have marked abnormalities in coherence spectral power and such abnormalities may be related to cognitive impairment.     

Tuberous sclerosis: long-term follow-up and longitudinal electroencephalographic study

We analyzed 320 electroencephalograms done on 60 patients having tuberous sclerosis. The main features in EEGs were diffuse slowing in the background activity, slow spike-wave discharges, focal and multifocal spike discharges, and amplitude asymmetries. No significant changes occurred in EEGs during the follow-up. No characteristic pattern was identified for diagnosing TS. Severe abnormalities were seen in patients who had infantile spasms and frequent seizures, and who were mentally retarded. Slow spike-wave abnormality was less frequent in patients who had mild mental retardation and few seizures. The pathological findings did not offer any clue to the frequently recorded EEG abnormalities.     

Successful zonisamide treatment for infants with hypsarrhythmia

We determined that zonisamide was effective in three epileptic infants with hypsarrhythmia. Two patients had the electroencephalographic pattern of hypsarrhythmia associated with developmental delay but lacked the characteristic tonic spasms. A third patient exhibited the typical triad of infantile spasms but had a poor general condition requiring controlled ventilation. We therefore chose zonisamide instead of adrenocorticotropin for these patients. Our data suggest that zonisamide may be a useful treatment in patients falling short of the diagnostic triad of infantile spasms or complicated by a poor overall medical condition.     

Epileptic Spasms in Older Children: Persistence Beyond Infancy

Summary Although infantile spasms (IS) constitute a well-recognized epileptic syndrome, only recently did investigators propose that spasms be classified as a distinct seizure type, characterized by axial flexionlextension jerks in clusters. Five older children (aged 4.5–14.2 years) who underwent video-EEG monitoring in 1992 in our epilepsy program for intractable mixed seizure disorder (cryptogenic 1, symptomatic 4) demonstrated flexor and extensor spasms in clusters. Seizure onset was from birth to 1.33 years. All 5 had spasms during infancy that continued as the children aged. Ictal EEG during spasms showed a brief high-amplitude delta burst followed by diffuse background attenuation or diffuse background decrease with superimposed rhythmic beta or alpha activity. Multiple other seizure types were present. Interictal EEGs were markedly abnormal and demonstrated slowing, multifocal spikes, generalized slow spike-wave, and polyspike-wave. Two children with spasms were unsuccessfully treated with ACTH, and 3 underwent corpus callosotomy. We conclude that spasms occur in older children with intractable mixed seizure disorders and may persist beyond infancy.     

Atonic elements combined or uncombined with epileptic spasms in infantile spasms

Objective

To study the atonic elements combined or uncombined with epileptic spasms in infantile spasms.

Seizures in Series: Similarities Between Seizures of the West and Lennox-Gastaut Syndromes

We observed seizures resembling infantile spasms in patients with Lennox-Gastaut syndrome (LGS). Infantile spasms, the type of seizures that occurs in patients who have West syndrome, have been well characterized by video-EEG studies and typically occur as a series of sudden generalized flexor or extensor jerks. The seizure types that occur in LGS have not been as clearly delineated. Some patients with West syndrome (WS) in early infancy later develop LGS. Using intensive video-EEG monitoring, we evaluated 14 LGS patients who had seizures that occurred in series. Clinically, the seizures greatly resembled infantile spasms, and the ictal EEG changes were identical to those that occur with infantile spasms. These findings expand the number of features known to be shared by these two syndromes and strengthen the hypothesis that the two syndromes represent age-related manifestations of similar epileptogenic processes.     

The Role of Perinatal Brain Injury in the Genesis of Childhood Epilepsy

In order to elucidate the significance of perinatal brain damage in the etiology of epilepsy, 139 full-term neonates considered to have suffered a severe degree of perinatal hypoxia were examined neurologically and electroencephalographically for two-nine years. Thirty-eight (27.3%) of them developed epileptic seizures during the follow-up period. Sixteen infants developed infantile spasms at ages two-13 months, while 10 manifested generalized motor seizures mainly at one-four years. They all had neonatal background EEGs suggesting a severe degree of brain damage, although the infants with infantile spasms and myoclonic seizures showed more abnormal neonatal EEGs than those with other types of fits.
The combination of multiple factors, mainly exogenous and constitutional, is necessary for the development of epileptic seizures, especially in patients with a lesser degree of brain damage.     

Topiramate for the treatment of infantile spasms

Topiramate is a new antiepileptic drug with a broad spectrum of efficacy. Reports on the use of topiramate for treatment of infantile spasms are limited. We prospectively followed 15 children with recently diagnosed infantile spasms treated with topiramate for efficacy and tolerability. Twelve patients had symptomatic infantile spasms, and two patients had cryptogenic infantile spasms. Topiramate was started at a dose of 3 mg/kg/day and titrated up to a dose of 27 mg/kg/day in 2 to 3 weeks. The primary efficacy measure was comparison of the seizure rate during the 2-week baseline with the median seizure rate during the first 2 months of treatment with topiramate. We also compared baseline electroencephalograms (EEGs) with post-treatment EEGs. The median seizure rate reduction during the first 2 months of treatment was 41% (P = .002). Three patients became spasm free (20%), five had > 50% reduction, and three had at least 25% reduction. Four patients did not respond. Three of 15 patients had clearing of hypsarrhythmia. Topiramate was generally well tolerated, with irritability being the most common side effect. Topiramate was efficacious and well tolerated; one patient discontinued the medication because of adverse effects. (J Child Neurol 2006;21:17-19).     

Infantile spasms in patients with neurofibromatosis type 1

The authors report two patients with neurofibromatosis type 1 who were affected by infantile spasms. The infantile spasms were severe and unresponsive to anticonvulsant treatment. The authors maintain that infantile spasms may belong to the clinical features of neurofibromatosis type 1.     

Basic mechanisms of catastrophic epilepsy – Overview from animal models

Infantile spasms are age-specific seizures of infantile epileptic encephalopathies that are usually associated with poor epilepsy and neurodevelopmental outcomes. The current treatments are not always effective and may be associated with significant side effects. Various mechanisms have been proposed as pathogenic for infantile spasms, including cortical or brainstem dysfunction, disruption of normal cortical–subcortical communications, genetic defects, inflammation, stress, developmental abnormalities. Many of these have been recently tested experimentally, resulting into the emergence of several animal models of infantile spasms. The stress theory of spasms yielded the corticotropin releasing hormone (CRH)-induced model, which showed the higher proconvulsant potency of CRH in developing rats, although only limbic seizures were observed. Models of acute induction of infantile spasms in rodents include the N-methyl-d-aspartate (NMDA) model of emprosthotonic seizures, the prenatal betamethasone and prenatal stress variants of the NMDA model, and the γ-butyrolactone induced spasms in a Down’s syndrome mouse model. Chronic rodent models of infantile spasms include the tetrodotoxin model and the multiple-hit models in rats, as well as two genetic mouse models of interneuronopathies with infantile spasms due to loss of function of the aristaless X-linked homeobox-related gene (ARX). This review discusses the emerging mechanisms for generation of infantile spasms and their associated chronic epileptic and dyscognitive phenotype as well as the recent progress in identifying pathways to better treat this epileptic encephalopathy.     

Positron emission tomography with glucose hypermetabolism of a hypothalamic hamartoma in infantile spasms associated with Pallister–Hall syndrome

Although hypothalamic hamartomas (HHs) have been shown to be intrinsically epileptogenic and to participate in the generation of gelastic seizures, no evidence has been reported regarding its contribution to the pathogenesis of infantile spasms. We describe a male infant with Pallister–Hall syndrome who had a large HH presenting with infantile spasms without hypsarrhythmia. [¹⁸F]fluoro-deoxyglucose positron emission tomography scan performed during the period of epileptic spasms demonstrated glucose hypermetabolism of the HH, which resolved after cessation of the spasms with adrenocorticotropin hormone treatment. No concurrent increased metabolic activity in the lenticular nuclei or brainstem was observed in the ictal or interictal states. The present case suggests that HHs may be involved in the pathogenesis of infantile spasms, possibly with propagation of epileptic discharges from the hamartoma to the descending spinal pathway.     

Medical treatment of patients with infantile spasms

Infantile spasms are the main feature in West syndrome, an age-related epilepsy syndrome that affects 1 in every 2,000-4,000 infants. The authors provide a comprehensive review of the literature about infantile spasms and their therapy. In the United States, the drug of choice for infantile spasms, at least the cryptogenic cases, has been adrenocorticotropic hormone (ACTH). It is generally considered to be more effective than corticosteroids. Adrenocorticotropic hormone appears to alter long-term prognosis of cryptogenic infantile spasms, and helps in some cases of symptomatic infantile spasm. Vigabatrin has been considered the drug of choice for infantile spasms secondary to tuberous sclerosis, and possibly, according to many neurologists, for all cases of infantile spasm. Recent concerns regarding retinopathy associated with vigabatrin therapy are, however, limiting the use of this drug. Valproic acid benefits 40%-70% of patients who failed a trial of ACTH. Nitrazepam is as effective as ACTH in acutely controlling infantile spasms; however, its long-term effects on prognosis have not been studied. Pyridoxine, lamotrigine, topiramate, zonisamide, ketogenic diet, immunoglobulin therapy, felbamate, and thyrotropin-releasing hormone have all been used for the treatment of infantile spasms, but are usually reserved for cases refractory to vigabatrin and/or ACTH.