Cryptogenic West Syndrome Research Articles

Developmental Outcome of West Syndrome

Medical records of 32 patients with cryptogenic West syndrome were reviewed for factors correlating with developmental outcome in a study at Saitama Children’s Medical Center, and the Jikei University School of Medicine, Tokyo, Japan.

Developmental Outcomes of Cryptogenic West Syndrome

To elucidate factors affecting the developmental outcome of cryptogenic West syndrome. Medical records of 32 patients, who were followed-up regularly for more than 1 year, were reviewed for clinical features: treatment lag, electroencephalography findings, and seizure evolution. Those features were compared between the normal outcome group (12 patients) and the delayed outcome group (20 patients). The outcomes were determined at the average age of 8.6 +/- 4.7 years. The duration from onset to any treatment of the delayed group was longer than that of the normal group (P < .05). Evolution of electroencephalographic findings showed that paroxysmal discharges reappeared in frontal regions more frequently in the delayed group than in the normal group (P < .05). In the delayed group, other types of seizure except for spasms occurred more commonly than in the normal group (P < .05). More patients of the delayed group evolved to focal epilepsy than those of the normal group (P < .05). Shorter treatment lag might be associated with a favorable outcome in cryptogenic West syndrome. Reappearance of paroxysmal discharges in the frontal regions and evolution to other types of seizure may be associated with undetectable lesions in the frontal regions.

The course of West syndrome

West syndrome (infantile spasms) is an unusual but generally devastating epileptic syndrome presenting in infancy. Although occasionally one component of an underlying disorder (such as chromosomal derangements or metabolic diseases), the disorder is idiopathic (“cryptogenic”) in a number of children. Much of our contemporary knowledge of West syndrome comes from work by Hamano et al in Japan. In the current issue of The Journal, this group addresses the question of factors that might predict the developmental outcome of children with cryptogenic West syndrome. These workers reviewed the records of 32 patients with an average age of over 8 years. Specifically, they looked for differences between children with a normal developmental outcome and those with delays. Children with normal developmental outcome had a shorter lag between the onset of spasms and the institution of treatment (a variety of agents, including anticonvulsants, intravenous gamma globulin, and ACTH). Delayed children were also more likely to have other seizures types associated with their infantile spasms, and to have EEGs that evolved to show frontal lobe activity. Given the size of the group studied, as well as the careful data collection by this group, this should be a valuable paper for the clinician who is counseling a family with a child in whom this frightening diagnosis is made. Although it is not clear from this study whether the “short interval” observation is a surrogate for something else or a direct effect of early treatment, the study also suggests that this is a diagnosis that should be pursued vigorously once suspected. Developmental Outcomes of Cryptogenic West SyndromeThe Journal of PediatricsVol. 150Issue 3PreviewTo elucidate factors affecting the developmental outcome of cryptogenic West syndrome. Full-Text PDF

Regional Cerebral Blood Flow and Developmental Outcome in Cryptogenic West Syndrome

To elucidate the relation between alterations of regional cerebral blood flow (rCBF) by adrenocorticotropic hormone (ACTH) therapy and developmental outcomes of cryptogenic West syndrome. Quantitative measurement of rCBF, with autoradiography method using N-isopropyl-((123)I) p-iodoamphetamine single photon emission computed tomography before and after ACTH therapy, was performed on 17 infants with cryptogenic West syndrome. Regions of interest for rCBF were placed bilaterally in the cerebellum, the thalamus, the caudate nucleus, and the frontal, temporal, and occipital cortices. RCBFs and the alteration ratios calculated from rCBFs before and after ACTH therapy were compared between two groups: the normal and delayed groups, which were divided by developmental outcome at 2 years old. RCBFs before the therapy were not different statistically between the normal and delayed groups, and between those groups and the control group also. RCBFs after ACTH therapy of the occipital, thalamic and cerebellar regions were different between the normal and delayed groups (p < 0.05). Alteration ratios were different between the normal and delayed groups, in all of the regions but the frontal region (p < 0.05). This study showed the differences of rCBF response by ACTH therapy between the normal and delayed groups of cryptogenic West syndrome. The difference of rCBF alteration might be associated with maturation of the cerebrovascular system, or influence of corticotropin-releasing hormone regarding the brain-adrenal-axis.

Short-Duration ACTH Therapy for West Syndrome

Short-term developmental and seizure outcomes were assessed in 7 children, aged <12 months, with cryptogenic West syndrome treated with a short-duration (7-12 days) and low-dose synthetic ACTH at Nagoya City Hospital, Japan.

Short-Duration ACTH Therapy for Cryptogenic West Syndrome With Better Outcome

In this study, seven patients with cryptogenic West syndrome were subjected to short-duration adrenocorticotrophic hormone (ACTH) therapy. ACTH was administered daily for 7 to 12 days (mean 10 days), and then was withdrawn. Daily single dose was 0.022 to 0.027 mg/kg/day (0.024 mg/kg/day, 0.96 IU/kg), total dose was 0.17 to 0.28 mg/kg (0.23 mg/kg, 9.0 IU/kg), and treatment lag was 12 to 105 days (median 14 days). ACTH therapy controlled tonic spasms with no serious side effects in all patients, but two patients still had electroencephalographic abnormality. The intelligence quotients or developmental quotients of six patients with short treatment lag were 79 to 110 at the age of 2 to 6 years; only one patient with long treatment lag had a developmental quotient of 60. This new short-duration ACTH therapy could yield better cognitive outcomes for cryptogenic West syndrome.

Pharmacokinetics of Intravenous Immunoglobulin: A Systematic Review

Intravenous immunoglobulin (IGIV) is used in the treatment of a wide variety of immune disorders. To our knowledge, no comprehensive or systematic review on the pharmacokinetics of IGIV has been published despite the availability of many published individual studies. To systematically review published studies of the pharmacokinetics of IGIV. We conducted a search of PubMed/MEDLINE from January 1966-September 2005 and EMBASE from January 1980-September 2005 for English-language articles on the pharmacokinetics of IGIV. This search was supplemented by a bibliographic review of all relevant articles. Data elements extracted from these articles included study design, number of study subjects, indication for IGIV therapy, IGIV treatment regimen (formulation, dosage, and duration), pharmacokinetic parameters (clearance, volume of distribution, elimination rate constant, and half-life), analytic methodology, pharmacokinetic model, and blood sampling times. The United States Preventive Services Task Force rating scale was used to categorize the 50 pertinent citations identified in our literature search. According to the rating scale, 12 studies were level I (prospective, randomized, controlled studies), 3 were level II-1 (prospective, nonrandomized, controlled studies), 30 were level II-2 (prospective, nonrandomized, uncontrolled [cohort] studies), and 5 were level III (case reports or descriptive studies). The pharmacokinetics of IGIV shows considerable intra- and interpopulation variability among patients with normal immunoglobulin levels, patients with primary immunodeficiency diseases, bone marrow transplant recipients, patients with immune deficiency due to chronic lymphocytic leukemia or multiple myeloma, very low birth weight neonates, neonates with suspected sepsis, high-risk infants in the neonatal intensive care unit, high-risk infants with cardiopulmonary disease, children with cryptogenic West or Lennox-Gastaut syndrome, women and infants with fetal alloimmune thrombocytopenia, and women with recurrent spontaneous abortions. Despite the large number of studies characterizing the pharmacokinetics of IGIV, major literature gaps include lack of information on IGIV clearance or area under the curve parameters and target serum immunoglobulin G concentrations. Further study is needed to rigorously characterize the pharmacokinetic properties of IGIV in a range of patient populations.

Cerebrospinal fluid interleukin-6 levels in patients with west syndrome

Elevated cytokine response has been reported in patients with epileptic seizures. The objective of this study was to investigate the possible role of interleukin-6 (IL-6) in the pathogenesis of infantile spasms in West syndrome (WS). We measured IL-6 levels in cerebrospinal fluid (CSF) obtained from the newly diagnosed patients with WS. Twelve patients with WS (Group I) were classified as symptomatic WS (Group IA) in eight and as cryptogenic WS (Group IB) in four. The results were compared with control groups including patients with tonic–clonic seizures associated with two different kind of inflammation of central nervous system; Group IIA (infection): bacterial meningitis/encephalitis and Group IIB (trauma): post-traumatic seizures. There was no statistically significant difference between the mean values of CSF IL-6 levels in patients with WS (2.95±2.31 pg/ml) and those of subgroups of WS (Group IA: 2.26±2.01 pg/ml and Group IB: 4.33±2.52 pg/ml). Both control groups had highly increased IL-6 levels in CSF (Group IIA: 193.05±185.52 pg/ml and Group IIB: 112.74±167.44 pg/ml) than those of the patients with WS. Elevated IL-6 response in patients with tonic–clonic seizures associated with inflammation of central nervous system might be due to the seizures themselves or related to the underling etiology (infection or trauma). However, no elevated IL-6 response was found in patients with infantile spasms.

Extremely low-dose ACTH step-up protocol for West syndrome: Maximum therapeutic effect with minimal side effects

We studied the effectiveness of our new ACTH treatment strategy for West syndrome (WS), which was based on the results of our previous extremely low-dose ACTH study. The subjects were 31 infants with WS (cryptogenic WS in nine; symptomatic WS in 22). Synthetic ACTH-Z in a dose of 0.005 mg (=0.2 IU)/kg/day was injected once every morning for at least 2 weeks, up to a maximum of 3 weeks. When this first treatment course achieved full seizure and EEG control, ACTH was tapered to zero over the subsequent 1 or 2 weeks. In the absence of a documented response, the dosage was increased to 0.025 mg (=1.0 IU)/kg/day for the next 2 weeks (second treatment course). We analyzed the short-term as well as long-term effects, and the incidence of side effects. The first treatment course successfully controlled both spasms and hypsarrhythmia in 17 patients (55%), only spasms in one, and hypsarrhythmia in two. The second treatment course was then introduced in eight of the remaining 14 patients, providing complete suppression of WS in an additional two patients. Regarding the long-term effects, 13 patients (48%), with excellent short-term results and a longer than 1-year follow-up, remained seizure-free. Side effects of a mild degree were seen in 13 patients during ACTH treatment. Our new ACTH step-up method brought 61 and 48% of the patients into short-term and long-term remission, respectively, without significant side effects. The dose of ACTH required to control WS appears to be unexpectedly smaller than the dose we previously used.

Comparison of two low dose ACTH therapies for West syndrome: their efficacy and side effect

In order to clarify the appropriate usage of adrenocorticotropic hormone (ACTH), the efficacy and side effects of two different regimens of low dose ACTH therapy were compared. Thirty-four patients with West syndrome (WS) were treated with ACTH. The dose of synthetic ACTH-Z was 0.015 mg/kg/dose in 18 patients who were treated between 1996 and 1998 (regimen A), and 0.010 mg/kg/dose in 16 patients who were treated between 1999 and 2001 (regimen B). Patients were classified into cryptogenic and symptomatic groups. Efficacy and adverse effects of ACTH were compared between regimens A and B. Similar analyses were performed after stratification into cryptogenic and symptomatic groups. The efficacy of ACTH was not different between regimens A and B. However, among patients with symptomatic WS, the number of ACTH injections and the dose of ACTH until cessation of spasms were significantly smaller in regimen A than in regimen B. There was no significant difference in these variables between the regimens among those with cryptogenic WS. Adverse effects were not different between regimens A and B. 0.010 mg/kg per day of ACTH will be adequate for cryptogenic WS, but 0.015 mg/kg per day of ACTH is recommended for symptomatic WS.

Very Fast Rhythmic Activity on Scalp EEG Associated with Epileptic Spasms

Very fast activity was investigated on the ictal EEGs of epileptic spasms to elucidate the pathophysiology of West syndrome (WS) and related disorders from a novel point of view. The traces of scalp ictal EEG of spasms temporally were expanded in 11 patients whose clinical diagnosis was symptomatic WS in six, cryptogenic WS in two, Aicardi syndrome in one, and symptomatic generalized epilepsy after WS in the remaining two. Time evolution of averaged power spectra of the ictal fast activity also was analyzed in each patient. Rhythmic gamma activity with frequency ranging from 50 to 100 Hz was detected in a total of 345 of 537 spasms. Fast activity was seen bilaterally in nine patients, was lateralized to one hemisphere in another, and appeared independently on each hemisphere in the remaining infant with Aicardi syndrome. Power spectra showed a clear peak corresponding to spasm-associated gamma rhythm, with frequency centering approximately 65 Hz and ranging from 51 to 98 Hz. The morphology and spectral characteristics of ictal gamma rhythm were completely different from those of muscle activity or alternating current (AC) artifacts. Spasm-associated gamma activity was clearly detected on the scalp. This observation may provide a clue to the pathophysiology of spasms.

Prognostic value of positron emission tomography in cryptogenic West syndrome.

The relationship between positron emission tomography (PET) findings and developmental or seizure outcome was examined in 17 infants (11 males, six females; mean age at onset of spasms 7 months, range 3 to 26 months) with newly diagnosed cryptogenic West syndrome. The predictive value of PET in these infants was assessed. PET was performed in the infants at the onset of spasms and 3 months after initial therapy using 18F-labelled 2-deoxy-2-fluoro-D-glucose. A third PET was performed at 18 months of age if the second scan was abnormal. All infants were followed up until at least 3 years of age. Cortical hypometabolism was detected in 11 infants on the first PET and in five infants on the second. Rate of developmental delay at the last follow-up was significantly higher in infants with hypometabolism on the second PET than in those without PET abnormalities (p<0.05). Rate of seizure occurrence after initial treatment was higher in infants with cortical hypometabolism on the second PET, but the difference was not statistically significant. Results suggest that when PET after the initial treatment shows no abnormalities, even though the first PET shows hypometabolism, infants with cryptogenic West syndrome may have a favourable developmental or seizure outcome. PET may be a useful tool in evaluating the prognosis in infants with cryptogenic West syndrome.

Prognostic value of positron emission tomography in cryptogenic West syndrome

The relationship between positron emission tomography (PET) findings and developmental or seizure outcome was examined in 17 infants (11 males, six females; mean age at onset of spasms 7 months, range 3 to 26 months) with newly diagnosed cryptogenic West syndrome. The predictive value of PET in these infants was assessed. PET was performed in the infants at the onset of spasms and 3 months after initial therapy using 18F‐labelled 2‐deoxy‐2‐fluoro‐D‐glucose. A third PET was performed at 18 months of age if the second scan was abnormal. All infants were followed up until at least 3 years of age. Cortical hypometabolism was detected in 11 infants on the first PET and in five infants on the second. Rate of developmental delay at the last follow‐up was significantly higher in infants with hypometabolism on the second PET than in those without PET abnormalities (p&lt;0.05). Rate of seizure occurrence after initial treatment was higher in infants with cortical hypometabolism on the second PET, but the difference was not statistically significant. Results suggest that when PET after the initial treatment shows no abnormalities, even though the first PET shows hypometabolism, infants with cryptogenic West syndrome may have a favourable developmental or seizure outcome. PET may be a useful tool in evaluating the prognosis in infants with cryptogenic West syndrome.

Serum cytokine levels are altered in patients with West syndrome

The objective of this study is to explore the neuroimmunomodulator effect of interleukin (IL)-2, tumor necrosis factor (TNF)-alpha and interferon (IFN)-alpha in West syndrome (WS). Twenty-three cases of WS (13 males and 10 females, aged 4–14 months old) who first visited and consisted from 10 cryptogenic and 13 symptomatic, were enrolled in this study. Double-antibody sandwich enzyme-linked immunosorbent assay was used to measure serum IL-2, TNF-alpha and IFN-alpha levels in 23 patients with WS and the data were compared to those of 15 healthy infants who were matched with regard to age and sex. Levels of all three cytokines were significantly higher in both cryptogenic and symptomatic WS groups than the control group. Serum IL-2 levels in symptomatic WS were significantly higher than that in cryptogenic WS. There was a positive correlation between IL-2 and TNF-alpha in both cryptogenic and symptomatic WS groups. The immune systems of patients with WS are in an activated state. An imbalance in cytokine levels may be involved in the immunopathology of WS.

Epidemiological and clinical studies of West syndrome in Nagasaki Prefecture, Japan

Recent advances in diagnostic and therapeutic techniques may have changed incidence and etiologies of West syndrome (WS). We performed a retrospective epidemiological study of WS that occurred in 47 children in Nagasaki Prefecture during a recent 10-year period from 1989 to 1998. The incidence of WS was 3.1/10,000 live births. Thirty-nine patients (83%) had symptomatic WS, in which the prenatal causes were most frequent, followed by low-birth weight (LBW) infants, perinatal and postnatal. Such high frequency of LBW may have been due to a relative increase in survivors of premature babies because of recent advances in perinatal care. The brain computerized tomography/magnetic resonance imaging performed in 41 patients revealed congenital brain malformation (10 patients), destructive brain disorders (13 patients), and no structural abnormalities (18 patients). The seizure outcome was worse in the symptomatic WS than in the cryptogenic WS. The developmental outcome was very poor in both symptomatic and cryptogenic WS. The mean developmental quotient (DQ) in all patients was 25, and only four patients (11%) had a normal DQ (>70). DQ was lower in patients with developmental delay before the onset of WS, symptomatic group, relapse and/or persistence of seizure. Developmental delay seen in WS patients seems to be related to the two major factors, that is, underlying brain abnormalities and the persistent seizures as a result of the former. Therefore, every effort should be made to control seizures, including medical and early surgical treatment, as well as prevention of brain damage through perinatal care.

Neurophysiological study of secondary synchronous occipito-frontopolar spikes in childhood

Objectives: We conducted this latency study to clarify the neurophysiological mechanism underlying the synchronous appearance of independent occipital and frontopolar spike discharges in childhood epilepsies. Methods: The subjects were 13 children with localization-related epilepsies (LRE) who showed apparently synchronous occipital and frontopolar EEG spike discharges. There was idiopathic LRE in 7 children, symptomatic LRE in 4, and cryptogenic LRE and a history of cryptogenic West syndrome in one patient each. Patient ages at the time of the study ranged from 4 years 3 months to 14 years 0 month with a mean of 9 years 4 months. The EEGs were digitized at 1024 samples/s. The latency was measured between the peak of the occipital and frontopolar spike discharges. The conduction velocity was calculated by dividing the distance between the occipital and frontopolar electrodes by the latencies. Results: We studied 19 EEGs including 6 serial EEGs recorded longitudinally in 5 patients. The number of occipito-frontal spike discharges available for the study ranged from 12 to 70 with an average of 36±17 in each EEG record. Occipital spikes always preceded the frontopolar spikes by 11.1–31.6 ms (average 19.3±5.4 ms). The estimated conduction velocity ranged from 6.7 to 19.2 m/s with a mean of 12.2±3.7 m/s. Conclusions: The synchronizing spike phenomenon we showed in this study was in the posterior to anterior direction (intrahemispheric synchrony) in contrast to that of secondary bilateral interhemispheric synchrony through the corpus callosum. It is suggested that the long occipito-frontal association fibers play a role in synchronizing both spike discharges. This secondary occipito-frontopolar synchrony should be one of the developmental EEG phenomena related to the maturation of brain, and contribute to the multiplication or diffusion of the pre-existing localized spike discharges often seen in pediatric LRE regardless of etiology.

Propuestas para el tratamiento de los niños con síndrome de West

The justification of guidelines for the treatment of children with infantile spasms and West's syndrome. We review, by means of prospective studies of suitable methodology, the efficacy and side-effects of adrenocorticotropin, sodium valproate, vigabatrin and other drugs used in the treatment of children with West's syndrome. In view of the information obtained from these studies, we suggest that in children with idiopathic or cryptogenic West's syndrome, treatment should be started with oral prednisone up to a dose of 8 mg/kg/day which should be changed to vigabatrin in the case of inefficacy or side effects. In children with secondary or symptomatic West's syndrome, treatment should be started with vigabatrin, up to a maximum dose of 200 mg/kg/day and if this is ineffective or there are side-effects it should be replaced by prednisone. If neither of these forms of treatment are successful, topiramate (up to 24 mg/kg/day) or valproate (up to 200 mg/kg/day) should be given.

Casuística de epilepsias idiopáticas y criptogénicas en una unidad de neuropediatría de referencia regional

Advances in genetics, techniques for diagnosis and treatment, and increasing concern for the quality of life and neuropsychological aspects of epileptic children and the possible repercussions of treatment lead to changes in the approach to epilepsy and require continual adaptation. In this study we analysed a series of cases of idiopathic and cryptogenic epilepsy attended by the Neuropaediatric Department of the Hospital Miguel Servet in Zaragoza (Spain). We studied the cases diagnosed as having idiopathic or cryptogenic epilepsy between May 1990 and December 1999. We assessed 4,507 children. In 1,794 (39.8%) consultation was for a paroxystic disorder. Epilepsy was diagnosed in 466 children (10.3%) and 103 cases were considered possibly or probably epilepsy but the diagnosis remains in doubt (2.3%). In 111 cases (23.8%) the epilepsy was considered idiopathic, in 122 (26.2%) cryptogenic and in 233 cases (50%) symptomatic. The following epileptic syndromes were identified: epilepsy-absence attacks in 28 cases (6%), benign myoclonic infantile epilepsy in 4 cases, other idiopathic generalized epilepsies in 61 cases (13%), benign Rolandic epilepsy in 18 cases (3.9%), 2 cases of cryptogenic Ohtahara syndrome, 6 cases of cryptogenic West syndrome, 1 severe case of infantile myoclonic epilepsy, 1 case of continuous wave epilepsy during slow eye movement sleep and 1 case of Landau-Kleffner syndrome. Current requirements and the rate of advances in epilepsy make it essential for neuropaediatric teams to include experts in epilepsy.

Low-Dose ACTH Therapy for Infantile Spasms

The lowest effective ACTH dose, with fewest adverse effects, for the treatment of West syndrome (WS) was determined in a comparative, randomly assigned, controlled study involving 25 patients with cryptogenic (CWS, n=9) or symptomatic (SWS, n=16) WS, at the Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan.

Resonancia magnética cerebral en el estudio del síndrome de West

West's syndrome (WS) is an epileptic encephalopathy of the first year of life, associated with different aetiologies. MRI of the brain allows precise determination of the type and extent of the lesions. The aetiology must be recognised in order to establish the prognosis and a suitable therapeutic approach. The objective of this study is to analyse the aetiologies of a population of children with WS and compare the results of cases diagnosed before and after using MRI. We analyzed the clinical histories of 448 patients fulfilling the diagnostic criteria for WS (infantile spasms and a EEG with a pattern of hypsarrhythmia), 217 in pre-MRI era (group 1) and 231 in the post-MRI era (group 2). The following parameters were analyzed: type of WS, sex, duration of follow-up, age of onset of infantile spasms and particularly the neuroradiological studies. Group 1: symptomatic WS, 157 patients; cryptogenic WS, 60 patients. Group 2: symptomatic WS, 169 patients; cryptogenic WS, 62 patients. The aetiologies of symptomatic WS were: cortical dysplasias, neurocutaneous disorders, cerebral malformation and prenatal clastic lesions, hypoxic ischaemia, post-infection, metabolic, tumors, Down's syndrome, others and unknown cause. It is known that cerebral MRI gives better definition of these types of cerebral lesions than cerebral CT does. We emphasize the importance of MRI in patients with symptomatic WS for precise determination of the aetiology, and speculate as to whether some of the 21 cases of unknown aetiology of group 1 could have been diagnosed if studied nowadays.