West Syndrome Cases Research Articles

KABUKI SYNDROME AND EPILEPSY

Background: Kabuki syndrome is a rare disease. In 2018, a global consensus on diagnostic criteria for Kabuki syndrome (KS) was published, diagnosing KS both with and without molecular genetic confirmation. Neurological symptoms are a major clinical problem in more than 80% of cases. Seizures occur with a frequency of 10% to 40% in Kabuki syndrome. Various degrees of severity of epilepsy in KS have been reported. There are isolated cases of West syndrome in KS worldwide. Objective: To investigate the frequency of epilepsy in KS and the features of West syndrome comorbid with KS, using evidence from reviews and describing the clinical presentation based on the history of a patient with molecularly positive KS. Methods: The study design was a two-centre retrospective observational study. Study subjects were paediatric patients with genetically verified KS. We conducted our own observation of 4 patients with KS and detailed a clinical case of a male patient with West syndrome in KS. Results: Epilepsy was found in 2 patients. Onset of epilepsy at 1.5 and 20 months of age. Both cases were characterised by a severe course of epilepsy. A rare form of epilepsy in KS, West syndrome, was described in patient M. Initial complaints included first seizures and delay in psychomotor development from 1.5 months of age. The clinical features of West syndrome, an electroencephalographic image, MRI of the brain, and the patient's seizure management were presented. Conclusion: Epilepsy in KS is not an uncommon clinical symptom that exacerbates the underlying disease. KS in combination with West syndrome exacerbates neurological deficits and leads to a significant delay in psycholinguistic and psychomotor development against a background of low efficacy of medication and differential effects of hormones and ketogenic diet.

Clinical and Laboratory Profiles of Children with West Syndrome: Experience of 50 Cases in a Tertiary Hospital in Bangladesh

Background: West Syndrome (WS) consists of epileptic spasms, hypsarrhythmia on EEG and psychomotor delay or regression in children.
 Objective: To observe the clinical and laboratory profiles of children with west syndrome.
 Materials & Methods: This was a cross sectional study and done from July 2017 to June 2018 in Pediatric Neurology OPD, NINS among total 50 cases of WS (age of > 2 month to 2 years). WS was diagnosed by direct observation or video recording of spasm, along with history of developmental delay or regression and EEG change. Collected data regarding demography, detailed of spasm, clinical examination, radiological and EEG findings were analyzed.
 Results: Mean age of the patients was 12.61 ± 7.11 months. Males (58.0%) were predominant than females (42.0%). Mean age of onset of spasm was 5.88 ± 3.73 months. Type of spasm: Flexor in 88.0% cases, extensor in 6.0% cases, mixed in 4.0% and asymmetric in 2.0%. Microcephaly was present in 90.0% cases and in 64% cases H/o perinatal asphyxia (PNA) was present. In EEG, Hypsarrhythmia was found in 62.0% cases and modified hypsarrhythmia in 38.0% cases. In CT scan of brain, cerebral atrophy was found in 62.5.0% cases, stroke in 6.0% cases. Out of all WS patients 82% were symptomatic and 18% were either cryptogenic or idiopathic.
 Conclusion: Flexor type spasm was found more commonly in West syndrome. History of perinatal asphyxia (PNA) was present in majority of cases. In EEG findings, hypsarrhythmia was found more than modified hypsarrhythmia.
 Bangladesh J Child Health 2020; VOL 44 (3) :139-142

Intravenous immunoglobulin therapy is rarely effective as the initial treatment in West syndrome: A retrospective study of 70 patients

PurposeTo evaluate factors influencing the efficacy and safety of intravenous immunoglobulins (IVIG) therapy for West syndrome. MethodsWe investigated seizure outcomes in 70 patients who received IVIG treatment for West Syndrome during the first 3months after the onset of epileptic spasms. IVIG was administered for 3 consecutive days (initial IVIG treatment) at dosages ranging from 100 to 500mg/kg/day. If spasms disappeared within 2weeks of the initial treatment, maintenance IVIG treatment was commenced. We evaluated seizure outcomes at 2weeks (initial evaluation), at 2years (long-term evaluation), and the last visit (last follow-up evaluation) after the initial IVIG treatment. We analyzed dosages of IVIG, age at onset of spasms, treatment lag, and etiologies between responders and non-responders. ResultsAmong the patients, 7/70 (10.0%) had cessation of spasms and resolution of hypsarrhythmia at the initial evaluation. Another 6/70 patients (8.6%) were found to have cessation of spasms at the long-term evaluations. The treatment lag in responders was shorter than that in non-responders (P<0.01). There were no significant differences between responders and non-responders in IVIG dosages, age at onset of spasms, and etiologies. Two patients had relapse of partial seizures after cessation of spasms at the last follow-up evaluation. Adverse effects occurred in 2/70 patients. ConclusionsThe efficacy of IVIG was so low that it should not be considered as first-line treatment in West syndrome. IVIG therapy has a good safety profile and we would recommend it for West syndrome cases with drug resistance, severe complications associated with profound brain damage, severe brain atrophy, and in immunocompromised patients.

Treatment of infantile spasms, a Venezuelan experience

We analyzed the treatment of 25 children with infantile spasm, 52% were males and 48% females. Of the cases studied 80% were symptomatic and 20% cryptogenic. Twenty-three children were treated with synthetic adrenocorticotropic hormone (ACTH), in 15 children the ACTH was administered with antiepileptic drugs and two children received vigabatrin. In the symptomatic cases of West syndrome, we found hypoxic-ischemic encephalopathy, tuberous sclerosis, brain malformations and Down syndrome. ACTH was efficacious in symptomatic infantile spasms and in cryptogenic spasms. The side effects most frequently found were: irritability, edema, Cushingoid obesity (moon face), hypertension and hypokalemia. Vigabatrin was used in patients with tuberous sclerosis and was efficacious in the control of infantile spasms. Infantile spasms should be treated as soon as the diagnosis is made. ACTH is still first-choice treatment in patients with West syndrome. The drug of choice of the treatment of infantile spasms in children with tuberous sclerosis is vigabatrin.

De novo KCNT1 mutations in early-onset epileptic encephalopathy.

KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1-targeted next-generation sequencing (207 samples) and/or whole-exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K(+) conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1-4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS.

PP07.14 – 2617: 10-year-review of West syndrome cases: Descriptive analysis and outcome prognostic factors

Objectives To describe the clinical characteristics of children diagnosed of West Syndrome (WS) during the last 10 years in our center. To analyse treatment options, clinical response and influential variables in the subsequent evolution. Methods A descriptive observational study with retrospective follow-up of WS patients in our center between years 2000 and 2010. Results 24 cases of WS were identified. The mean age at diagnosis was 6 months, most of them classified as symptomatic (63%, hypoxic-ischemic encephalopathy was the main etiology). Vigabatrin and oral prednisone were used as first-line treatments, achieving complete remission of spasms in monotherapy in 18% and 54% of cases, respectively. We analysed the evolution of each patient and variables related to it, taking into account the development of a chronic epilepsy (68% of all patients) and the degree of psychomotor retardation (moderate or severe in 63% of them). We found that the most significant factors related to the development of a chronic epilepsy were the total time with spasms and hypsarritmia (p=0.006 and 0.012, respectively) during the acute phase of WS, and the initial response to treatment (p=0.047) classified as favorable or not, independently of the treatment received. When evaluating psychomotor retardation we found that the most determining factors were those related to personal antecedents (birth type p=0.04, Apgar score Conclusion Our experience is similar to what reported previously in literature about etiology and response to treatment of WS. We furthermore provide data about significant prognostic outcome factors in WS, evaluating the risk of developing a chronic epilepsy (which is directly related to an early and favourable response in the acute phase) and the evolution to a moderate-severe psychomotor retardation (which is mostly related to the personal antecedents and underlying etiology).

Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome

We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs). We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing. We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay. Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.

Lesions of acetylcholine neurons in refractory epilepsy.

We have examined brainstem lesions in patients with refractory epilepsy disorders, including West syndrome (WS), Lennox-Gastaut syndrome (LGS), and dentatorubral-pallidoluysian atrophy (DRPLA). Acetylcholinergic neurons (AchNs) in the pedunculopontine tegmental nucleus (PPN) are involved in mental development, and disruption of neuronal nicotinic acetylcholine receptors can lead to epilepsy. In order to investigate the involvement of lesions of AchNs in refractory epilepsy, we performed immunohistochemical analyses of AchNs in the PPN in autopsy cases who had a past history of WS and/or LGS and in DRPLA cases who showed progressive myoclonic epilepsy. In addition, we performed a preliminary quantification of the levels of acetylcholine, neuropeptides, and monoamine metabolites in the cerebrospinal fluid (CSF) of patients with WS and benign convulsions associated with mild gastroenteritis (CwG). In the PPN analysis, the total number of neurons and the number of AchNs were reduced in WS/LGS and WS cases, while DRPLA cases showed a decrease in the number and percentage of AchNs. In the CSF analysis, WS patients demonstrated a reduction in the levels of inhibitory neuropeptides, while CwG patients showed increased levels of acetylcholine and decreased levels of serotonin metabolites. These data suggest the possible involvement of lesions of AchNs in WS and DRPLA.

Early infantile epileptic encephalopathy with unusual favourable outcome

The authors report the case of an infant suffered from early infantile epileptic encephalopathy with suppression–burst, or Ohtahara syndrome, a severe form of epilepsy in early childhood. The patient was treated with vigabatrin causing a favourable response. This unusual outcome may be related with the normality of neuroimaging and metabolic studies, as happens with idiopathic West syndrome cases.

Multicenter long‐term follow‐up of children with idiopathic West syndrome: ACTH versus vigabatrin

Long-term follow-up of children with idiopathic West syndrome (WS) treated with adrenocorticotropic hormone (ACTH) or vigabatrin. Records of 28 normal magnetic resonance imaging (MRI) WS cases were reviewed for seizure development and cognitive outcome in relation to treatment type and lag. Average age at disease onset was 5.5 months, and average lag time to treatment was 25 days. Fourteen patients were treated with ACTH (eight early and six late), and 14 with vigabatrin (without delay). Response rates were 88% for ACTH and 80% for vigabatrin. Short-term outcomes for seizure cessation and electroencephalography normalization were identical between the groups. In the long-term, early ACTH treatment was better than the rest combined. Average follow-up time was 9 years. A normal cognitive outcome was achieved in 100% of the early-ACTH group, 67% of the late-ACTH group and 54% of the vigabatrin group (P = 0.03). Seizures subsequently developed in 54% of the vigabatrin group, in 33% of the late ACTH group, and 0% of the early ACTH group (P < 0.05). Idiopathic WS with normal MRI is associated with a good cognitive outcome. Early ACTH treatment, administered within 1 month, yields a better cognitive and seizure outcome than vigabatrin or late ACTH.

Utility of subtraction ictal SPECT images in detecting focal leading activity and understanding the pathophysiology of spasms in patients with West syndrome

The aims of the study were to evaluate the detectability of focal leading activity in three cases of West syndrome having focal abnormal activity on EEG by comparing subtraction ictal images and raw ictal images, and to interpret the results in 16 cases. Subtraction images were constructed using iNeurostat (revision 2). In three cases with focal abnormal activity on EEG, subtraction ictal images reflected the EEG findings; in contrast, raw ictal images did not. Diverse degrees of cortical hyperperfusion, ranging from zero to 10 sites, seen in the other 13 cases seemed to reflect spasm pathophysiology and rapid spasm propagation. Subtraction ictal images also allowed the ready detection of hyperperfusion of subcortical structures and of a tight cortico-subcortical relationship in a subset of cases. We showed the superiority of subtraction ictal images in detecting the focal epileptic region and in showing propagation pathways from the cortex to subcortical structures. A subset of spasms in WS may be focal cortical-onset secondarily generalized seizures. We believe that subtraction analysis is valuable in patients with complex WS who have partial seizures and spasms simultaneously along with focal epileptic EEG activity, as they will likely be candidates for epilepsy surgery.

ESP012 Normal MRI West syndrome cases: therapy type and diagnostic delay as prognostic factors

ESP012 Normal MRI West syndrome cases: therapy type and diagnostic delay as prognostic factors

Remission Associated With Human Herpesvirus Infection in West Syndrome

Generally, West syndrome is an intractable epileptic syndrome in infancy, although spontaneous remission has been reported in some cases. An immunologic response to infection might be one of the factors involved in the remission of West syndrome, but the mechanisms remain unknown. On the other hand, exanthema subitum is a common disease occurring in infancy with the characteristics of fever and rash. Two kinds of human herpesvirus, 6 and 7, have been isolated as causal agents of exanthema subitum. We experienced one symptomatic case and three cryptogenic cases of West syndrome that showed spontaneous remission. In the symptomatic case, the subject showed a temporary remission; however, in the other cases, the remissions were long term. In the present study, we report the patients' improvement and electroencephalographic (EEG) findings. In all of our cases, hypsarrythmia disappeared on the EEG findings, the human herpesvirus 6 IgG antibodies increased in all four cases, and the herpesvirus 7 IgG antibodies increased in two cases. We postulate that the remission of the four cases proceeded from infection by exanthema subitum. The changes in serum antibody values suggest that the spontaneous remission of West syndrome was related to human herpesvirus 6 and 7 infections.

Pediatric intractable epilepsy syndromes: Reason for early surgical intervention

Drug-resistance in several childhood epilepsy syndromes is common, and these patients may tolerate epilepsy surgery. In this study, the surgical outcomes of 24 pediatric patients with various intractable epilepsy syndromes and three patients with tuberous sclerosis were examined at Xinqiao hospital between 1997 and 2004. The study included nine cases of Lennox–Gastaut syndrome, two cases of Rasmussen‘s syndrome, one case of Sturge–Weber syndrome, three cases of West syndrome, three cases of tuberous sclerosis and nine cases of mesial temporal lobe epilepsy syndrome. In each case, different surgical procedures were performed according to preoperative evaluation and ECoG. At an average of 4.5 years after surgery, 14 out of 27 patients (51.9%) had an Engel Class I outcome after surgery, and an additional eight patients (29.6%) had rare seizure (Engel ClassII). Three patients showed a significant decrease in seizure frequency (Engel Class III). The mean IQ increased from 61.4 ± 12.2 to 75.0 ± 11.0, and greater IQ increase was seen in patients with shorter seizure history and drug-resistance. Temporary complications were observed in four patients and there were no deaths. In conclusion, early surgical intervention in pediatric intractable epilepsy syndromes may results in a favorable outcome in a high percentage of cases and may provides an important opportunity to prevent irreversible decline in intelligence and disability.

Profile of West syndrome in North Indian children

To study the profile of West syndrome (WS) in North Indian Children, 165 cases of WS were analyzed. Details of seizure semiology, prenatal and perinatal events, developmental milestones, treatment received, physical and neurological examination and investigations were recorded. The response of seizures to various therapeutic modalities and the final developmental status were taken as primary outcome variables. Analysis was done to find the factors influencing these outcome variables. The age of onset of infantile spasms ranged from 1 to 19 (mean 6.1±3.4) months. Age at presentation ranged from 1.5 months to 4.5 years (mean 14.7±11.4 months); 74% had flexor spasms. Other types of seizures were associated in 31 children. Antenatal problems and adverse perinatal events were reported in 26.7 and 59.4%, respectively. Developmental delay was recognized in 69.7% prior to and in 27.9% after onset of spasms. Microcephaly was seen in 72.7%. Interictal EEG showed hypsarrhythmia in 44; generalized spike and slow waves in 31% and burst suppression in 7%. Computed tomography scan done in 94 cases showed cerebral atrophy in 15%, infarcts in 8%, tubers in 7%, developmental malformations in 5%. Magnetic resonance imaging done in 77 cases showed periventricular T2WI white matter hyper intensities in 33.8% and cerebral atrophy in 21%. Prednisolone and ACTH were used in 57 and 35 cases, respectively. Complete control of seizures was seen in 49 and 46% cases. No significant difference in seizure control or developmental outcome was found in the two groups. Overall, 42.4, 30.9 and 16% children showed complete, partial and no control of seizures. After therapy, developmental improvement was seen in 55.8% and no change in 23.6% cases. The type of spasms had no correlation with the other parameters including etiology, seizure or developmental outcome. An early age of onset correlated with presence of antenatal problems ( P<0.05). Seizure control and developmental improvement correlated significantly ( P<0.005). Developmental outcome was better in cryptogenic as compared to symptomatic cases ( P<0.05). No other significant correlations were found. In India WS is often diagnosed late because of lack of awareness. Adverse perinatal events are important etiological factors. Nonaffordability of ACTH and Vigabatrin prompts the use of prednisolone in most cases.

Spontaneous improvement of intractable epileptic seizures following acute viral infections

In general, epileptic seizures become more serious following infections. However, transient and permanent improvement of epileptic seizures has been observed following acute viral infections, without a recent change in anti-epileptic therapy. Questionnaires were sent to 73 institutions, throughout Japan, where pediatric neurologists care for children with epilepsy to characterize this phenomenon through clinician survey. Completed surveys were received from 11 institutions, and 21 cases were selected for the study. The age of the patients were 6 months to 17 years. The West syndrome or epilepsy subsequent to West syndrome cases were 16 out of 21. Two cases of symptomatic generalized epilepsy and one case each of symptomatic partial epilepsy, continuous spike-waves of slow sleep and severe myoclonic epilepsy in infancy were also reported. These seizures disappeared within 2 weeks subsequent to viral infections such as, exanthema subitum, rotavirus colitis, measles and mumps. The disappearance of intractable epileptic seizures following acute viral infections might be related to the inflammatory processes or the increased levels of antibodies after viral infections.

A population-based neuroepidemiological survey of West syndrome in Okayama Prefecture, Japan

It is important for the fields of child neurology and child public health to clarify the prevalence and incidence rates of West syndrome because this syndrome is a major cause of developmental disorders. However, there have been few reports in Japan on the prevalence rate of West syndrome in the general population. We carried out a population-based survey in Okayama Prefecture, in western Japan in 1994. The population under 2 years of age in Okayama Prefecture in 1994 was 37,085. Six cases of West syndrome were identified. The prevalence rate was 0.16 per 1000.

Epidemiology of West syndrome in Singapore

The incidence of West syndrome (WS) was determined by a search of reports of electroencephalograms (EEG) recorded in 1998 and 1999 in all public hospitals in Singapore. Amongst records of patients born in 1998, nine were found with EEG features of hypsarrhythmia or modified hypsarrhythmia with onset of seizures between January 1,1998 and December 31, 1999. The medical records of these patients were reviewed. The population of children born in 1998 was 43,664. In 1998 and 1999, 67% of all hospital admissions for patients 2 years or younger in Singapore were in public hospitals. The cumulative incidence of WS in Singapore corrected for the percentage of hospital admissions to public hospitals was 3.1/10,000 live births. The corrected cumulative incidences in Chinese, Malays and Indians were 2.7, 3.1 and 3.3 per 10,000, respectively. Three cases were idiopathic; three were due to congenital structural lesions of the brain; one each had periventricular leucomalacia, intracranial hemorrhage and severe intrauterine growth retardation. None of the patients were normal at follow up. The three patients with idiopathic WS had mild global developmental delay and the other six cases had cerebral palsy and severe mental retardation. With the best modern medical treatment, possibly only two of the nine cases of WS may have been prevented.

Clinical and pedigree study on familial cases of West syndrome in Japan

Nationwide survey on familial cases of West syndrome (WS) in first- and second-degree relatives was conducted by mailing a questionnaire to 64 major university hospitals, children's hospitals, and epilepsy centers in Japan, and by review of the Japanese cases in the literatures. Thirty-four familial cases, 20 males and 14 females, were obtained in 15 families including one with five affected members in two generations and another with three affected male siblings including a half brother by a different father (X-linked WS). A mother and the child or children were involved in three families. Nine families had 21 cryptogenic cases and six families had 13 symptomatic cases, and the etiologies were same among the affected members in each family. Familial cases of WS have characteristic clinical features and genetic mechanisms. Age of onset, seizure types, electroencephalographic abnormalities, early seizure outcome, effective treatment, long-term seizure prognosis, and long-term developmental prognosis were concordant among the affected members in each family. Long-term seizure and developmental prognoses were far better than those in WS in general, with seizure-free rate of 82% and normal mental development rate of 44%. Poor prognosis was limited to specific symptomatic cases. Adrenocorticotropic hormone (ACTH) was a treatment of choice, and even in relapse of WS after ACTH therapy, the patients well responded to antiepileptic drugs. Specific inheritance pattern was difficult to imagine in the majority of the present cases, except for one family with X-linked WS and another family with five patients of maternal inheritance. These results are helpful for the treatment choice and prognostication of clinical course for familial cases of WS.

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.