Long-term Prognosis of Childhood Absence Epilepsy.

Introduction: We aimed to investigate the long-term prognosis of childhood absence epilepsy (CAE), and identify factors associated with treatment outcomes. Methods: Patients with a definitive diagnosis of CAE according to the International League Against Epilepsy 2021 criteria and with a minimum of 3-year follow-up duration were included. The children were divided according to the time of seizure control. Early seizure remission was defined as seizure freedom within 6 months after the treatment onset. Results: Twenty-four patients with a mean age of 13.7 (9.4-22.0) were included in this study. At the final follow-up, all patients were seizure-free except for one case. Seizure freedom was achieved after initial treatment in a mean of 0.78 years. The treatment was ceased in 19 children (79.2%) after a mean of 3.2 years. Patients having absence seizures without motor components had a higher rate of early seizure remission (p=0.026). In 81.3% of the patients; all of whose repetitive post-treatment EEGs were devoid of any generalized spike-wave discharges and absence seizures; remission was established within 6 months or less (p=0.026). Conclusions: CAE has a favorable prognosis with seizure control obtained in the majority of the cases and more than half of them were obtained within 6 months following the initiation of treatment. Moreover, having an absence seizure without motor components and repetitively normal post-treatment EEGs appear to be associated with a higher rate of early seizure remission.

Serum Levels of Neuropeptides in Epileptic Encephalopathy With Spike-and-Wave Activation in Sleep.

BACKGROUND: Epileptic encephalopathy with spike-and-wave activation in sleep (EE-SWAS) is a syndrome of childhood, characterized by diffuse or generalized spike-wave activity in electroencephalography during non-rapid eye movement sleep. Neuropeptides have been demonstrated in several studies to function in the sleep-wake cycle and display convulsant and anticonvulsant features. In this study, we aimed to investigate the relationship between EE-SWAS and neuropeptides such as dynorphin, galanin, ghrelin, leptin, melatonin, and orexin. METHODS: This multicenter study was conducted from July 2019 to January 2021. There were three groups: Group 1 contained patients with EE-SWAS. Group 2 consisted of patients with self-limited focal epilepsy of childhood (SeLFE), and group 3 was the control group. Levels of neuropeptides were compared in the sera of these three groups. RESULTS: There were 59 children aged between four and 15 years. Group 1 contained 14 children, group 2 contained 24 children, and group 3 contained 21 children. The level of leptin is higher and the level of melatonin is lower in group 1 than in group 3 (P = 0.01 and P = 0.005, respectively). In group 3, the level of orexin was lower than in both groups 2 and 3 (P = 0.01 and P = 0.01). CONCLUSIONS: These data show that the level of leptin was higher and the level of melatonin was lower in patients with EE-SWAS than in the control group. Furthermore, patients with EE-SWAS had lower orexin levels than both the control group and patients with SeLFE. Further research is required to understand the potential role of these neuropeptides in the pathophysiology of EE-SWAS.

Photosensitive occipital lobe epilepsy: Delineation of an under-recognized reflex epilepsy syndrome according to the new ILAE criteria and long-term follow-up.

OBJECTIVE: Photosensitive occipital lobe epilepsy (POLE) should be suspected in patients with occipital lobe seizures triggered by photic stimuli, who have normal motor-mental development and brain imaging. We aimed to examine the clinical, electrophysiological, and prognostic features of POLE, which is a rare and under-investigated syndrome. METHODS: Archives from two tertiary epilepsy centers were retrospectively scanned and patients with normal neurological examination and cranial imaging were identified with POLE if they had: (1) seizures consistently triggered by photic stimuli; (2) non-motor seizures with visual symptoms; and (3) photosensitivity documented on EEG. The clinical and electrophysiological features and prognostic factors were evaluated for patients who had follow-up ≥5 years. RESULTS: We identified 29 patients diagnosed with POLE with a mean age of 20.1 ± 7.6 years. In one-third of the patients, POLE syndrome overlapped with genetic generalized epilepsy (GGE). The overlap group had higher rates of febrile seizure history and self-induction; when compared to pure POLE patients, their EEGs showed more frequent interictal generalized epileptic discharges and posterior multiple spikes during intermittent photic stimulation. During long-term follow-up, the remission rate for POLE was 80%, but EEG photosensitivity persisted in three quarters of patients despite clinical remission, and more than half had relapsed after clinical remission. SIGNIFICANCE: This first long-term follow-up study, utilizing newly suggested criteria of the International League Against Epilepsy, showed that POLE syndrome shows a notable overlap with GGE but also has distinctive features. POLE has a good prognosis; however, relapses are common, and photosensitivity persists as an EEG finding in the majority of patients.

Early Diagnostic Signs and the Natural History of Typical Findings in Cohen Syndrome.

OBJECTIVE: To describe the clinical presentation and long-term clinical features of a molecularly confirmed cohort with Cohen syndrome. STUDY DESIGN: Twelve patients with Cohen syndrome aged 0.2-13.9 years from 8 families with a median follow-up of 7 years were enrolled to the study. Genetic analyses were made by VPS13B and whole-exome sequencing analyses. RESULTS: Biallelic VPS13B variants, including 3 nonsense, 1 frameshift, and 1 splice-site variant, and a multiexon deletion were detected. Prader-Willi syndrome-like features such as hypotonia, small hands, round face with full cheeks, almond-shaped eyes, and micrognathia were observed in all infantile patients. Beginning from age 4 years, it was noticed that the face gradually elongated and became oval. The typical facial features of Cohen syndrome such as a long face, beak-shaped nose, and open-mouth appearance with prominent upper central incisors became evident at age 9. Other Cohen syndrome features including retinopathy (11/11), neutropenia (11/12), truncal obesity (5/12), and myopia (5/11) were detected at the median ages of 7.8, 7, 7.5, and 5 years, respectively. Eleven patients aged older than 5 years at their last examination had severe speech delay. CONCLUSIONS: A differential diagnosis of Cohen syndrome in the infancy should be made with Prader-Willi syndrome, and that the typical facial features for Cohen syndrome is prominent at age 9 years, when retinopathy, neutropenia, and truncal obesity become evident. Moreover, adding the severe speech delay to the diagnostic criteria should be considered.

Four Turkish families with hyperekplexia: A missense mutation and the exon 1-7 deletion in the GLRA1 gene.

BACKGROUND: Hyperekplexia is a disease that progresses with excessive startle attacks and is included in the differential diagnosis of epilepsy and many movement disorders. METHODS: The WES results were validated in available family members by Sanger sequencing, or in the case of deletion, PCR followed by agarose gel electrophoresis was performed. RESULTS: WES analysis revealed the previously reported homozygous c.277C>T p.Arg93Trp variant in the GLRA1 gene (ENST00000455880.2) in Family 1. In all other three families, the previously reported homozygous deletion of exons 1-7 of the GLRA1 gene was identified using CNV analysis based on the WES data. CONCLUSIONS: The homozygous exon1-7 deletion has been described several times in different populations and may be a founder mutation in the Kurdish people in Turkey. The family with Arg93Trp variant stems from the Black Sea region of Turkey where close consanguinity is common. These analyses are important to provide genetic counseling to families and for a better understanding of the pathophysiology of the disease.

Pretreatment electroencephalographic features in patients with childhood absence epilepsy.

OBJECTIVE: To analyze the ictal and interictal electroencephalographic (EEG) features in newly diagnosed childhood absence epilepsy (CAE) and determine the association between seizure onset topography, interictal focal spike-wave discharges (FSWDs) and accompanying clinical features of absence seizures. METHODS: The authors searched the EEG database for a definite diagnosis of CAE according to ILAE 2017 criteria. Video-EEGs of untreated pediatric patients during sleep and wakefulness were evaluated retrospectively. RESULTS: The study included 47 patients (25 males, 22 females). Interictal FSWDs were observed in 49% of patients with CAE during wakefulness and in 85.1% during sleep (p = 0.001). Interictal FSWDs were most frequently observed in the frontal regions (awake: 34%; asleep: 74.5%), followed by the posterior temporoparietooccipital region (awake: 21.2%; asleep: 36.1%), and the centrotemporal region (awake: 6.4%; asleep: 8.5%). Eleven patients (23.4%) had polyspikes during sleep. Both bilateral symmetric and asymmetric seizure onset were noted in 32%, whereas focal seizure onset was observed in 14.9% of the patients. Absence seizures with and without motor components were seen in 72.3% and 61.7% of patients, respectively, and in 33% of patients both occurred. There were no associations between the existence of interictal FSWDs, focal/asymmetric seizure onset, and absence seizures with and/or without motor components. CONCLUSION: Asymmetric and/or focal seizure onset, interictal FSWDs, and absence seizures with motor components are commonly observed in drug-naive CAE. This study found no association between seizure onset topography, interictal FSWDs, and semiological features of absence seizures.

Isolated Unilateral EEG Findings in Juvenile Myoclonic Epilepsy: A Case Report.

Juvenile myoclonic epilepsy (JME) has well-defined clinical and electrophysiological features. On the other hand, large case series have shown that focal and asymmetrical discharges may accompany generalized epileptiform activities in JME. Although it is known that these non-generalized electrophysiological findings do not exclude the diagnosis of this syndrome, some findings may create confusion in the differential diagnosis. In this case report, a case of JME with electroencephalographic findings characterized by isolated unilateral epileptiform activities without typical generalized discharges was discussed. The current case clinically presented with involuntary jerk movements in the bilateral upper extremities. It has been determined that these movements are uni/bilateral myoclonic beats based on home video recordings. Metabolic, toxic and structural problems were excluded in the investigations for the etiology of myoclonus. In the electrophysiological examination performed for epileptic processes, epileptiform discharges localized to the isolated right hemisphere were observed. JME was considered primarily due to clinical findings in the patient, and effective seizure control was achieved in a 4-year follow-up under anti-seizure treatment. The peculiarity of the case is the presence of electrophysiology recordings of isolated unilateral epileptiform activity during the 4-year follow-up period. It should be emphasized that there is no case of JME diagnosed with isolated unilateral epileptiform activity in the absence of generalized spike-slow waves or multiple spike-slow waves in the literature.

Progression of myoclonus subtypes in subacute sclerosing panencephalitis.

OBJECTIVES: Diagnostic criteria of subacute sclerosing panencephalitis (SSPE) include myoclonus, a well-recognized clinical feature. Here, we studied the electrophysiological features of myoclonus with regards to disease staging in SSPE patients. METHODS: We included 10 patients diagnosed with SSPE between 2010 and 2018, along with 21 healthy subjects. All participants had detailed electrophysiological evaluation including polymyographic analysis, blink reflex after trigeminal stimulation, auditory startle response, startle response after somatosensory stimuli, F-waves, and long-loop reflexes. Clinical findings were retrieved from the medical records. RESULTS: Patients were categorized into Gascon stage 2B (n = 5, 50%), 2A (n = 2, 20%), 3B (n = 2, 20%) and 4A (n = 1, 10%) at the time of electrophysiological evaluation. Two patients had cortical myoclonus, four had possible cortico-subcortical myoclonus, and four had brainstem myoclonus. Patients were categorized into Gascon stages 2a and 2b had possible cortico-subcortical myoclonus (85.7%). However, none of the patients with stage 3b or 4a had possible cortico-subcortical subtype but all had the brainstem subtype. CONCLUSION: Association was seen between subtypes of myoclonus and clinical staging in SSPE. This suggests that myoclonus in SSPE may primarily involve the cortex and cortico-subcortical structures such as the thalamus at earlier stages of disease, and then involve more caudal structures as the disease progresses.

Immune alterations in subacute sclerosing panencephalitis reflect an incompetent response to eliminate the measles virus.

In subacute sclerosing panencephalitis (SSPE) the persistence of measles virus (MeV) may be related to the altered immune response. In this study, cytokine responses of lymphocytes and monocytes were evaluated in SSPE compared to controls with non-inflammatory (NICON) and inflammatory (ICON) diseases. Patients with SSPE (n = 120), 78 patients with ICON and 63 patients with NICON were included in this study. Phenotypes of peripheral blood mononuclear cells (PBMC) have been analyzed by flow cytometry. CD3 and CD28, and S. aureus Cowan strain I (SAC) stimulated and unstimulated cells were cultured and IL-2, IL-10, IFN-γ, IL-12p40, IL-12p70 and IL-23 were detected in supernatants by ELISA. MeV peptides were used for MeV-specific stimulation and IFN-γ secretion of PBMC was measured by ELISPOT. Spontaneous and stimulated secretions of IL-10 were lower in SSPE compared to both control groups. T cell stimulation induced lower IFN-γ production than ICON group, but higher IL-2 than NICON group in SSPE. Stimulated PBMC produced lower IL-12p70 in SSPE and had decreased CD46 on the cell surface, suggesting the interaction with the virus. IFN-γ responses against MeV peptides were not prominent and similar to NICON patients. The immune response did not reveal an inflammatory activity to eliminate the virus in SSPE patients. Even IL-10 production was diminished implicating that the response is self-limited in controlling the disease.

Panayiotopoulos syndrome and Gastaut syndrome are distinct entities in terms of neuropsychological findings.

BACKGROUND: Although the courses of self-limited focal epilepsies of childhood are considered as benign, a handful of studies suggested that these children may suffer from cognitive problems. Implementing tailor-made educational strategies would aid these children to reach their full potentials. Therefore, it is crucial to understand and differentiate the complete neuropsychological and behavioral profiles of these rather common syndromes. We aimed to examine the distinct cognitive and behavioral profiles of the Panayiotopoulos syndrome (PS) and the Gastaut syndrome (GS), comparatively. METHOD: Twenty patients with PS, 20 patients with GS, and 20 healthy controls have been recruited. The testing protocol included Wechsler Intelligence Scale for Children-Revised, Conner's Continuous Performance Test, Verbal Fluency Test, Stroop Color and Word Test, Color Trails Test, Tower of London Test, Symbol Digit Modalities Test, California Verbal Learning Test-Children's Version, Rey Complex Figure Test, Benton Face Recognition Test, Benton Judgment of Line Orientation, Peabody Picture Vocabulary Test, Reading and Writing Test, Child Behavior Checklist, Conner's Parent Rating Scale-48, and Behavior Rating Inventory of Executive Function. Demographical, clinical, electrophysiological data, and imaging findings have also been evaluated. RESULTS: With regard to intelligence, the patients with PS scored less in all scales compared to the healthy controls. However, only the performance IQ (intelligence quotient) scores differed significantly between the patient groups, with the patients with PS scoring lower than the patients with GS. Verbal memory problems were eminent in both of the patient groups; whereas, visual memory was impaired only in the group with PS. Psychomotor speed was affected in both groups. Reading problems were prominent only in the patients with PS. Writing and arithmetic skills were defective in both patient groups. There were no noteworthy behavioral problems in comparison to healthy subjects. CONCLUSION: Using neuropsychological profiles, this study demonstrated that the GS and the PS are two distinct entities. Cognitive dysfunction is a more prominent and widespread feature of the patients with PS; whereas, the patients with GS suffer only from milder and isolated cognitive problems.

Chromosome 14q11.2-q21.1 duplication: a rare cause of West syndrome.

Proximal duplication of chromosome 14q, including the FOXG1 gene located on 14q12, is a rare condition characterised by developmental delay, dysmorphic craniofacial features, epilepsy, and severe speech delay. Here, we report a patient with West syndrome whose chromosome analysis revealed 14q11.2-21.1 duplication. The patient was admitted due to infantile epileptic spasms at eight months of age, motor developmental delay, and dysmorphic features. Chromosome and array-CGH analysis revealed de novo 14q11.2-21.1 duplication, spanning ∼20 Mb (minimal interval chr14:20203610_40396835). The patient was followed up to 13 years of age, and at the last examination was shown to have severe speech delay, seizures, and continuous spike-and-wave activity on EEG. The possibility of this chromosomal abnormality should be kept in mind in patients with developmental delay, epilepsy, and hypsarrtyhmia, in the absence of any structural brain lesion or metabolic aetiology.

EEG abnormalities and long term seizure outcome in high functioning autism.

Electroencephalographic abnormalities may occur in autistic spectrum disorders (ASD) even in the absence of clinical seizures. These abnormalities may vary from nonspecific changes to epileptiform abnormalities and are more common compared to the overall population. The level of intelligence is a significant risk factor for epilepsy in ASD. However, the relation between the functionality of the individuals with autism and the electroencephalographic (EEG) abnormalities, and the clinical significance of these abnormalities still remain relatively unclear. In this study we investigated the presence of EEG abnormalities in sixteen children diagnosed with high-functioning ASD. EEG recording was performed for at least 2 h and included at least 90 min of sleep activity. While none of the patients had clinical seizures, 5 patients (31.3%) were detected to have EEG abnormalities. Four of these were epileptiform (25%), and one patient developed seizure during follow-up. Our results support the fact that EEG abnormalities are observed at a higher rate also in ASD with a better functionality. The potential impact of EEG abnormalities on cognition and behavior, and the risk of epilepsy should be considered during long-term follow-up of these patients.

Increased photosensitivity following short sleep in sleep deprived patients.

INTRODUCTION: We aimed to determine the effect of short day-time sleep on photoparoxysmal epileptic activity in sleep-deprived patients. METHODS: We retrospectively reviewed video-EEG recordings performed between 2003 and 2015. All recordings following at least four hours of sleep deprivation, including intermittent photic stimulation (IPS) both before and after sleep with any form of epileptiform activity were included. The study group was divided into four subgroups: (1) no photoparoxysmal response (PPR) group, with epileptiform activities other than PPRs; (2) increment group, with PPR duration increased by ≥200% after vs. before sleep; (3) no significant change group, with PPR duration increased between 50% and 200% after vs. before sleep; (4) decrement group, with PPR duration increased ≤50% after vs. before sleep. RESULTS: A total number of 5805 EEG recordings from 459 patients was analyzed. Photosensitivity was present in 98 patients (21.4%). The PPRs after sleep were increased in 70% of the photosensitive patients, did not change in 23%, and were decreased in 7%. The increase in duration of PPRs was statistically significant (P<0.001). In our cohort, photosensitivity would have been detected in 67 patients if IPS was applied only before sleep and in 91 patients if IPS was applied only after awakening (P<0.05). CONCLUSIONS: This study demonstrates that photosensitivity is enhanced after awakening from a short sleep following sleep deprivation. Thus, we recommend performing IPS after awakening to increase sensitivity to detect photoparoxysmal epileptiform discharges.

Visually evoked startle response in a patient with epilepsy: a case report and review of the literature.

Both symptomatic and genetic, cases with hyperekplexia or startle seizures induced by acoustic stimuli, are previously reported. By contrast, startle response induced by visual stimuli is rare. While visual stimuli are more commonly associated with startle seizures, here we present an 11-year-old girl with epilepsy, motor-mental retardation, and spastic tetraparesis, who had repetitive startle responses by photic stimulation during the electroencephalogram recording, without any spike-and-wave discharges associated with the startles. We report this unique case with startle responses induced both by acoustic and photic stimuli and review the literature related to this exceptionally rare combination of symptoms.

Startle and blink reflex in high functioning autism.

An important clinical feature of autism is the presence of atypical responses to sensory stimuli. In this study, we investigated if high functioning autistic patients had abnormalities in the blink reflex and the startle reaction to auditory or somatosensory stimuli. Fourteen patients aged between 7 and 16 years were included in the study. We found a longer latency of the blink reflex, an increased duration and amplitude of the auditory startle reaction and a lower presence rate of the somatosensorial startle reaction in autistic patients. To better define the sensorial characteristics of the disease could improve the therapeutic management of children with autism spectrum disorder.

Epilepsy Surgery in Children with Lesional Partial Epilepsies.

AIM: Surgery for epilepsy is a significant treatment alternative with favorable outcomes in the pediatric age group. In this study we present the surgical outcomes of pediatric population referred to our center. MATERIAL AND METHODS: The clinical data of 126 patients (≤18 years) with lesional partial epilepsies operated in our center between 1995- 2011 were evaluated retrospectively. Parameters investigated were gender, age at seizure onset, duration of epilepsy, etiology, type and location of operation and outcome. Seizure outcome was classified according to Engel's classification. RESULTS: The study group consisted of 70 males (55,6%) and 56 females (44.4%). The most common etiology was malformation of cortical development followed by tumors and hippocampal sclerosis. Overall 73.8% of patients had Engel I, 13.5% Engel II and 11.9% Engel III+IV postoperative seizure outcome. CONCLUSION: The results of our pediatric patients who underwent surgery were similar to previous reports in the literature. The seriousness of the clinical picture should tempt physicians to refer the patients as soon as possible to avoid long term complications like epileptic encephalopathies and the side effects of antiepileptic drugs during the development of the young brains.

Long-term outcomes in patients with West syndrome: an outpatient clinical study.

PURPOSE: Nearly half of all patients with seizure onset in the first year of life suffer from West syndrome (WS). The prognosis of epilepsy and psychosocial outcomes in children with WS are variable. This study was performed to examine the factors influencing the outcome of this patient population. METHODS: A total of 109 patients with WS followed up regularly for at least 3 years were included in the study. Relevant clinical, laboratory, and imaging data were collected. RESULTS: The male/female ratio was 65/44 (59.6%/40.4%). The mean age at onset of infantile spasm (IS) was 6 ± 6 (1-36) months. With regard to neuro-developmental and social conditions during the final evaluation, 29.4% of the patients were socially dependent on caregivers, 61.8% needed assistance, and 8.8% were normal. Among the patients, 5.9% were free of epilepsy and antiepileptic drugs (AED) for at least 2 years, 49.0% had no seizures with AEDs, and 45.1% had uncontrollable seizures. Parameters with significant negative effects on the long-term outcomes included symptomatic etiology, presence of developmental retardation before the onset of IS, persistence of active epilepsy, and male gender. CONCLUSION: In this study, 37 (33.9%) patients had severe consequences as a result of WS. The majority of the rest could cope with daily life with varying degrees of assistance. Eight percent of the patients had a normal development. These results draw attention to the two-thirds of patients with WS who have the chance of an acceptable quality of life (QoL) with early diagnosis and therapeutic measures.

A decrease of regulatory T cells and altered expression of NK receptors are observed in subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is caused by a persistent measles virus infection. Regulatory mechanisms can be responsible for a failure of immunosurveillance in children with SSPE. In this study, peripheral blood cells of 71 patients with SSPE and 57 children with other diseases were compared phenotypically. The proportions of CD4(+), CD8(+) T, and NK cells were homogenous, whereas total CD3(+) T and Treg (CD4(+)CD25(+)CD152(+)) cells were decreased in patients with SSPE. The proportion of CD8(+) T cells expressing the inhibitory NKG2A(+) receptor was also decreased (1.7% ± 1.7% vs. 2.6% ± 1.9%, p = 0.007) in patients with SSPE, whereas the proportion of NK cells expressing activating NKG2C was increased compared with the control group (30.0% ± 17.3% vs. 22.2% ± 17.0%, p = 0.039). The decrease in the number of cells with regulatory phenotype, the lower presence of the inhibitory NK receptors on CD8(+) cells, and higher activating NK receptors on NK cells in SSPE indicate an upregulation of these cell types that favors their response. This state of active immune response may be caused by chronic stimulation of viral antigens leading to altered regulatory pathways.

Granzyme B gene polymorphism associated with subacute sclerosing panencephalitis.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a late complication of measles infection. Immune dysfunction related to genetic susceptibility has been considered in disease pathogenesis. A functional single nucleotide polymorphism (SNP) of granzyme B gene (GZMB) reported in several pathologies may also be involved in susceptibility to SSPE. PATIENTS AND METHODS: An SNP (rs8192917, G → A, R→Q) was screened in 118 SSPE patients and 221 healthy controls (HC) by polymerase chain reaction-restriction fragment length polymorphism. Frequencies were compared between groups. In vitro production of GZMB was measured in controls with different genotypes. RESULTS: The SNP had a minor allele (G) frequency of 0.22 in patients and 0.31 in controls. GG genotype was significantly less frequent in patients (odds ratio, 0.23). G allele carriers produced relatively higher levels of GZMB, when stimulated in vitro. CONCLUSION: These findings implicate possible effect of this genetic polymorphism in susceptibility to SSPE which needs to be confirmed in bigger populations.