Developmental and epileptic encephalopathies after successful treatment of pediatric ALL: A case series and review of literature.

Successful treatment of acute lymphoblastic leukemia (ALL) requires multiagent chemotherapy regimens and central nervous system prophylaxis, including intrathecal methotrexate. Although acute symptomatic seizures can occur during ALL treatment, epilepsy is less common. Furthermore, drug resistant epilepsy (DRE) is rare, presenting with two phenotypes: focal epilepsy, such as temporal lobe, or epileptic encephalopathies (EE), such as Lennox-Gastaut syndrome (LGS). For ALL survivors, the development of DRE has significant impact on morbidity, mortality, and quality of life. We describe four patients with ALL remission, who developed EEs, of which 3 had LGS. Mean age at ALL diagnosis was 1.9 years; range 1.1-2.5 years. All, but one, had normal development prior to ALL. No patient had CNS leukemic involvement. All patients received CNS prophylaxis with intrathecal methotrexate, without cranial radiotherapy. Three had symptomatic methotrexate neurotoxicity during treatment. The mean age at first seizure was 5.6 years; range 3.9-7.5 years, with a mean latency of 3.7 years from ALL diagnosis. All patients developed drug resistant EEs, moderate intellectual disability, and neuropsychiatric co-morbidities. Two patients had a minimal response to corpus callosotomy (CC), and one did not respond the ketogenic diet. Successful treatment of childhood ALL is rarely associated with the development of DRE and EEs. Young age at ALL diagnosis (<3 years) may be a predisposing factor. Palliative treatments, including ketogenic diet and CC have limited benefit in these patients. Individual genetic susceptibility to MTX toxicity is likely related to epileptogenesis, and further research is required for epilepsy biomarkers.

Novel LAMC3 pathogenic variant enriched in Finnish population causes malformations of cortical development and severe epilepsy.

OBJECTIVE: Recessive LAMC3 mutations are recognized to cause epilepsy with cortical malformations characterized by polymicrogyria and pachygyria. The objective of this study was to describe the clinical picture and epilepsy phenotype of four patients with a previously undescribed LAMC3 variant. METHODS: All epilepsy patients treated in Kuopio Epilepsy Center (located in Kuopio, Finland) are offered the possibility to participate in a scientific study investigating biomarkers in epilepsy (Epibiomarker study). We have collected a comprehensive database of the study population, and are currently re-evaluating our database regarding the patients with developmental and/or epileptic encephalopathy (DEE). If the etiology of epilepsy remains unknown in the clinical setting, we are performing whole exome sequencing to recognize the genetic causes. RESULTS: Among our study population of 323 DEE patients we recognized three patients with similar homozygous LAMC3 c.1866del (p.(Phe623Serfs*10)) frameshift variant and one patient with a compound heterozygous mutation where the same frameshift variant was combined with an intronic LAMC3 c.4231-12C>G variant on another allele. All these patients have severe epilepsy and either bilateral agyria-pachygyria or bilateral polymicrogyria in their clinical MRI scanning. Cortical malformations involve the occipital lobes in all our patients. Epilepsy phenotype is variable as two of our patients have DEE with epileptic spasms progressing to Lennox-Gastaut syndrome and intellectual disability. The other two patients have focal epilepsy without marked cognitive deficit. The four patients are unrelated. LAMC3 c.1866del p.(Phe623Serfs*10) frameshift variant is enriched in the Finnish population. SIGNIFICANCE: Only a few patients with epilepsy caused by LAMC3 homozygous or compound heterozygous mutations have been described in the literature. To our knowledge, the variants discovered in our patients have not previously been published. Clinical phenotype appears to be more varied than previously assumed and patients with a milder phenotype and normal cognition have probably remained unrecognized.

Clinical outcomes of MR-guided laser interstitial thermal therapy corpus callosum ablation in drug-resistant epilepsy: a systematic review and meta-analysis.

OBJECTIVE: The goal of this systematic review and meta-analysis was to provide an updated analysis of studies investigating outcomes, morbidity, and mortality associated with MR-guided laser interstitial thermal therapy (MRgLITT) corpus callosum ablation (CCA). METHODS: Study inclusion criteria for screening required that studies report on human subjects only, including patients aged 1-52 years diagnosed with drug-resistant epilepsy who underwent CCA. Sixteen articles published between 2016 and 2023 were included for the systematic review and analysis, including 4 case reports, 11 case series, and 1 case-control study. Altogether, 85 pediatric and adult patients undergoing CCA were included in the systematic review (46 patients younger and 39 patients older than 21 years). The main outcome of seizure freedom was measured using the decrease in the frequency of atonic seizures following surgery, percentage of atonic seizure freedom following surgery, and percentage of overall seizure freedom following surgery. These measurements were made using data from the last follow-up for patients with at least 6 months of follow-up post-CCA. RESULTS: The extent of CCA differed across the pooled cohorts, including anterior two-thirds CCA (38.89%, n = 35) and posterior one-third CCA for completion of a prior partial CCA (22.22%, n = 20), complete CCA (27.78%, n = 25), or CCA of residual white matter in the case of subtotal initial ablation (5.56%, n = 5). Overall, 12.94% of the patients undergoing CCA experienced operational complications. The most common operative complications across 90 CCA operations were probe malpositioning (n = 6), hemorrhage (n = 5), off-target extension of splenium ablation to the thalamus (n = 1), infection (n = 1), and postoperative CSF leak (n = 1). Neurological deficits following CCA were reported as transient in 18.82% and permanent in 4.71% of patients across all studies. The most common neurological deficits were disconnection syndrome (n = 4) or transient hemiplegia (supplementary motor area-like syndrome; n = 4). The 6-month overall seizure freedom rate was 18.87% of 53 patients, and the atonic seizure freedom rate was 46.28% of 52 patients postoperatively. CCA resulted in an average decrease in atonic seizure rate from 8.30 to 1.65 atonic seizures per day (average decrease 80.12%). CONCLUSIONS: CCA is associated with an acceptable complication profile, and most patients experience a meaningful reduction in target seizure semiologies. Accurate MRgLITT probe placement is likely important for maximizing CCA while avoiding collateral damage. Avoidable complications of CCA include off-target ablation (and associated deficits), hemorrhage, and future surgery for residual CCA to palliate continued seizures.

Case report: Alexander's disease with "head drop" as the main symptom and literature review.

Alexander's disease (AxD) is a rare autosomal dominant hereditary disorder that is caused by the mutations in the GFAP gene, which encodes the glial fibrillary acidic protein (GFAP). This neurogenerative disease has many clinical manifestations, and the onset of disease spans a wide range of ages, from newborns to children, adults, and even the elderly. An overaccumulation of the expression of GFAP has a close causal relationship with the pathogenesis of Alexander's disease. Usually, the disease has severe morbidity and high mortality, and can be divided into three distinct subgroups that are based on the age of clinical presentation: infantile (0-2 years), juvenile (2-13 years), and adult (>13 years). Children often present with epilepsy, macrocephaly, and psychomotor retardation, while adolescents and adults mainly present with muscle weakness, spasticity, and bulbar symptoms. Atonic seizures are a type of epilepsy that often appears in the Lennox-Gastaut syndrome and myoclonic-astatic epilepsy in early childhood; however, the prognosis is often poor. Atonic episodes are characterized by a sudden or frequent reduction in muscle tone that can be local (such as head, neck, or limb) or generalized. Here, we report a 4-year-old girl whose main symptoms were intermittent head drop movements, which could break the frontal frame and even bleed in severe conditions. A video-encephalography (VEEG) showed that the nodding movements were atonic seizures. A head magnetic resonance imaging (MRI) revealed abnormal signals in the bilateral paraventricular and bilateral subfrontal cortex. The gene detection analyses indicated that the GFAP gene exon 1 c.262 C>T was caused by a heterozygous mutation, as both her parents were of the wild-type. The girl had no other abnormal manifestations except atonic seizures. She could communicate normally and go to kindergarten. After an oral administration of sodium valproate, there were no atonic attacks. Although epilepsy is a common symptom of Alexander's disease, atonic seizures have not been reported to date. Therefore, we report a case of Alexander's disease with atonic seizures as the main symptom and provide a review of the literature.

Safety and efficacy of rufinamide in children and adults with Lennox-Gastaut syndrome: A post hoc analysis from Study 022.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with the first symptoms usually appearing during early childhood. Due to the highly variable underlying etiologies, LGS cannot be considered as one disease but as an electro-clinical entity, often challenging to diagnose early and treat accordingly. The anti-seizure medication, rufinamide, is indicated for the adjunctive treatment of patients with LGS aged ≥1 year. This post hoc analysis assessed the safety and efficacy of adjunctive rufinamide for total and tonic-atonic seizures during Study 022 in children (aged <16 years) and adults (aged ≥16 years). METHODS: Randomized, placebo-controlled, phase III Study 022 included patients with a diagnosis of LGS and a history of multiple seizure types (including tonic-atonic or astatic seizures and atypical absence seizures; ≥90 seizures in the month prior to baseline). Assessments included monitoring of treatment-emergent adverse events (TEAEs), percent change in tonic-atonic seizure frequency/28 days during the double-blind phase relative to study baseline (a primary endpoint), and percentage of patients with ≥25%, ≥50%, or ≥75% reduction in seizure frequency relative to baseline. RESULTS: Of 138 enrolled patients, 74 received rufinamide (<16 years, n = 49 [66%]) and 64 received placebo (<16 years, n = 43 [67%]). Incidence of TEAEs was generally similar between age groups. The frequency (per 28 days) of tonic-atonic seizures was reduced with rufinamide (vs. placebo) in both younger and older patients: age <16 years (-41% vs. -6%), age ≥16 years (-55% vs. +16%) (p < 0.025; both age groups). In patients aged <16 years receiving rufinamide, 38% and 17% achieved ≥50% and ≥75% reductions in tonic-atonic seizure frequency vs. 18% and 3% with placebo, respectively. Corresponding responder rates for patients aged ≥16 years were 52% and 32% (rufinamide) vs. 15% and 5% (placebo), respectively. CONCLUSIONS: In this post hoc analysis, adjunctive rufinamide was well tolerated and improved seizure control in patients with LGS, irrespective of age.

Focal atonic seizures originated in the posterior temporoparietal area: A case report.

Atonic seizures are typically observed in younger children with Lennox-Gastaut syndrome and have been rarely described in adults. Herein we present a case of the adolescent-onset drug-resistant focal epilepsy in a 31-year-old woman with focal atonic seizures originating in the left posterior temporoparietal area and manifesting without aura with abrupt impairment of consciousness and slow falling down. According to the video-EEG monitoring, the seizure began with the medium amplitude spikes principally at T5 area evolving onto the left centroparietal area, which was immediately followed by the diffuse suppression of the background EEG activity. The underlying mechanism might be related to high-frequency electrical stimulation of the negative motor areas within the inferior frontal gyrus or anterior to the supplementary sensorimotor area.

[A case of refractory generalized atonic seizure and hemifacial spasm with the possible causative pontocerebellar lesion].

The patient was a 35-year-old woman. At the age of 1, she had undergone resection and radiation therapy for neoplastic lesions in the pons. She had a history of gelastic seizures when she was in elementary school, and brief lapses of the neck and truncal muscular tone and convulsions on the left face occurred at the age of 23. After a generalized sharp wave in the ictal electroencephalogram and electromyogram recording, left orbicularis oris muscle contraction was observed followed by sudden cervical extensor atonia. Seizure propagation was noted in the cerebral cortex, left facial nerve nucleus, and brainstem reticular formation. In a simultaneous electroencephalography with functional MRI, the blood oxygen level-dependent effect related to generalized sharp waves was observed in the vicinity of brainstem lesions in addition to a decrease in bilateral frontal and parietal lobes signals, as detected in generalized seizures. These findings suggest that the lesion could be a part of the epilepsy network. Although most epileptic seizures are derived from the cerebral cortex, it is important to note that brainstem lesions are involved in seizures in the patient presented in this study.

Efficacy and safety of corpus callosotomy after vagal nerve stimulation in patients with drug-resistant epilepsy.

OBJECTIVE Vagal nerve stimulation (VNS) and corpus callosotomy (CC) have both been shown to be of benefit in the treatment of medically refractory epilepsy. Recent case series have reviewed the efficacy of VNS in patients who have undergone CC, with encouraging results. There are few data, however, on the use of CC following VNS therapy. METHODS The records of all patients at the authors' center who underwent CC following VNS between 1998 and 2015 were reviewed. Patient baseline characteristics, operative details, and postoperative outcomes were analyzed. RESULTS Ten patients met inclusion criteria. The median follow-up was 72 months, with a minimum follow-up of 12 months (range 12-109 months). The mean time between VNS and CC was 53.7 months. The most common reason for CC was progression of seizures after VNS. Seven patients had anterior CC, and 3 patients returned to the operating room for a completion of the procedure. All patients had a decrease in the rate of falls and drop seizures; 7 patients experienced elimination of drop seizures. Nine patients had an Engel Class III outcome, and 1 patient had a Class IV outcome. There were 3 immediate postoperative complications and 1 delayed complication. One patient developed pneumonia, 1 developed transient mutism, and 1 had persistent weakness in the nondominant foot. One patient presented with a wound infection. CONCLUSIONS The authors demonstrate that CC can help reduce seizures in patients with medically refractory epilepsy following VNS, particularly with respect to drop attacks.

Atonic seizures in children with surgically remediable epilepsy: a motor system seizure phenotype?

Atonic seizures are common in some epileptic syndromes beginning in infancy or early childhood but they are rarely described in epilepsy with focal seizures of structural aetiology. We aimed to characterize the electroclinical features of atonic seizures in surgically remediable paediatric patients and to study the spatiotemporal organization of the underlying epileptogenic networks. We retrospectively analysed two consecutive, longitudinally evaluated and surgically treated paediatric patients presenting with atonic seizures as a manifestation of pharmacoresistant epilepsy of structural aetiology, evidenced by scalp- and stereotactic intracerebral video-EEG-recordings. A quantitative analysis of the epileptogenic zone organization was performed using the "epileptogenicity index". Long-lasting generalized ictal atonia, occurring in infancy, was a predominant clinical feature in both patients, with some hints of focal origin present in one case. The seizure phenotype evolved at later age into subtle segmental atonia, associated with prominent positive motor signs. The epileptogenic zone was localized within the dorsolateral or mesiolateral premotor region. Its spatial organization was focal, matching the lesional cortex in one and distributed involving several lesional and non-lesional structures in the other case. The emergence of atonic semiology temporally correlated with involvement of both lateral and mesial premotor, as well as primary motor areas. We hypothesize that atonic seizures may be considered as a motor system seizure phenotype in the setting of structural epilepsy. Complete removal of the epileptogenic area provided excellent seizure control.

Diaphragm myoclonus followed by generalised atonia in a patient with trisomy 4p: unusual semiology in an unusual condition.

In this report, we describe a female patient with trisomy 4p, a rare genetic condition, with unusual seizure semiology. The patient is one of the oldest reported survivors with this condition. This semiology was noted while she was being monitored by inpatient video telemetry. We observed a series of myoclonic shoulder jerks, followed by hiccup-like episodes, and finally an atonic head drop. Corresponding ictal EEG showed semi-rhythmic high-amplitude slow waves with spikes superimposed over the frontotemporal areas. This semiology was confirmed as habitual by her parents. Subsequent hiccup-like episodes had no EEG correlate, and the head drop was again associated with semi-rhythmic high-amplitude slow waves and superimposed spikes, more prominent over the right hemisphere. In addition, we review the several cases in which hiccups have been associated with seizures and how this may relate to the neural pathways involved in the pathophysiology of hiccups. We believe the ictal hiccup-like episodes followed by atonia to be a seizure semiology that has not previously been documented. [Published with video sequence].

Relationship of Lennox-Gastaut syndrome with perinatal event: A cross-sectional study.

INTRODUCTION: About one-half of children with Lennox-Gastaut syndrome (LGS) have history of birth hypoxia or other perinatal event but the knowledge about clinical, radiological profile and severity of epilepsy in these children as compared to those without a perinatal event is not known. MATERIALS AND METHODS: Thirty-one children with LGS were enrolled in this study and divided into two groups: One group with the perinatal event and other group without evidence of the perinatal event. We hypothesized that LGS with the perinatal event will have an early age of onset of LGS, more motor deficits and abnormal brain magnetic resonance imaging (MRI) and more severe epilepsy. RESULTS: There were 17 children in the perinatal event group and 14 in the other group. The mean age of onset of illness was significantly earlier in the perinatal event group (P < 0.05). More children in the perinatal event group had delayed milestones (P < 0.05), had higher seizure frequency (P < 0.05) however; there was no significant difference in number of anti-epileptic drugs consumed, motor deficits or MRI abnormalities. CONCLUSION: LGS children with the perinatal event have more severe epilepsy with early onset of disease and delayed milestones. History of perinatal insult in these children may help in predicting prognosis in LGS.

The efficacy and tolerability of pharmacologic treatment options for Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy that appears in childhood. LGS is characterized by a slow spike-wave pattern on electroencephalogram (EEG), cognitive impairment, and multiple seizure types. This mixture of seizure types, along with the need to use more than one type of medication, makes LGS one of the most complicated epilepsies to treat successfully. Recent developments in approved therapies for the treatment of LGS offer physicians more options, but also make developing a treatment strategy that minimizes adverse events more challenging. There are currently 5 treatment options for LGS: felbamate, lamotrigine, topiramate, rufinamide, and clobazam, and several others that are used off-label, each of which has benefits and limitations. There are several factors that must be considered when determining which medication to use when treating patients with LGS, including efficacy, which is assessed by seizure frequency, tolerability, and the anticipated duration of treatment. In this article, data supporting current treatment options are discussed, and important considerations about the treatment of LGS are reviewed.

Atonic Seizure with Hypotonia in a Patient with Parietal Lobe Epilepsy / 대한간질학회지

Atonic seizure shows characteristic features such as head drop because postural muscle tone is suddenly lost. Atonia of the seizure means no muscle tone and loss of electromyographic activities were reported. We report a left parietal lobe epilepsy patient with atonic seizure showing hypotonia on electromyography. A 27 year-old woman had intractable head drop seizures since 6 years old. Her brain MRI demonstrated cortical dysplasia in the left parietal lobe. During the video-EEG monitoring, she had 21 epileptic seizures which were atonic seizures. During her atonic seizures, simultaneous EMG recordings showed decreased muscle activities during the head drop attacks, instead of no muscle tone. This is the first case showing transient hypotonia during the atonic seizure, instead of atonia.

Atonic Seizure with Hypotonia in a Patient with Parietal Lobe Epilepsy

Atonic seizure shows characteristic features such as head drop because postural muscle tone is suddenly lost. Atonia of the seizure means no muscle tone and loss of electromyographic activities were reported. We report a left parietal lobe epilepsy patient with atonic seizure showing hypotonia on electromyography. A 27 year-old woman had intractable head drop seizures since 6 years old. Her brain MRI demonstrated cortical dysplasia in the left parietal lobe. During the video-EEG monitoring, she had 21 epileptic seizures which were atonic seizures. During her atonic seizures, simultaneous EMG recordings showed decreased muscle activities during the head drop attacks, instead of no muscle tone. This is the first case showing transient hypotonia during the atonic seizure, instead of atonia.

A Case of Suspicious Focal Atonic Seizure Characterized by Drop Attack / 대한소아신경학회지

Atonic seizures exhibits loss of postural tone, resulting in head drops or falling. When this event is extremely brief, It has been known as a drop attack. Atonic seizure are firmly placed under the category of generalized seizures. However, a various phenomena satisfying the above description has been recognized in patients with partial seizures. A 13-year-old girl had brief episodes of drop attacks. She complained of weakness of both legs in the absence of consciousness loss. These episodes occurred at a frequency of 4 or 5 time per day for 1 year. Her developmental and physical examinations were normal. Also, the brain MRI was normal. However, her Interictal EEG showed the repetitive spike and wave complexes on C(z) electrode. She was controlled completedly by antiepileptic drungs. We report a patient who suffered from focal atonic seizures characterized by drop attack.

The Results of One stage Total Callosotomy in Pediatric Epilepsy / 대한간질학회지

PURPOSE: In the pediatric patients who have medically intractable epilepsy the callosotomy is useful to prevent the propagation of seizure from one hemisphere to the other. The indications of callosotomy are drop attack, life threatening primarily or secondarily generalized seizure, medically refractory mixed seizure types such as Lennox-Gastaut syndrome. In addition, the retarded children are not contraindicated. The anterior callosotomy is used to perform to control medically intractable epilepsy which is believed to have some advantages to total callosotomy. But, we propose that the anterior callosotomy does not seem to be superior to total callosotomy for the prevention of the propagation of seizure or complication. We describe a series of 21 patients with medically intractable epilepsy who underwent total callosotomy in one stage. METHODS: The diagnoses in these patients included Lennox-Gastaut syndrome, atonic seizure, infantile hemiplegia, and no obvious solitary seizure focus on chronic video/EEG monitoring to characterize seizures, electrographic activity, and postictal behaviors. Preoperatively 16 patients suffered from disabling drop attacks or intense head drop seizures which caused frequent physical injuries. Other types of seizures are 12 generalized tonic-clonic seizures, 7 complex partial seizures, 1 absence seizure, and 7 myoclonic seizures. Male:Female=14:7, Age: 2-22 years (Mean: 9.4 years). The follow-up period ranged from 0.8 to 3.8 years (median 2.4 years). Seizure outcome, parental assessment of daily function, and parental satisfaction with outcome were assessed postoperatively. RESULTS: Drop attacks disappeared completely during the entire follow-up period in 13 patients and decreased to less than 10% of baseline in five. The corpus callosum of the one patient were not completely sectioned in Diffusion Tensor Image, tractography. Other types of seizures resolved completely in 14 patients and decreased in 7. 2 patients experienced a transient disconnection syndrome, but completely resolved within four weeks. Overall daily function improved and parents were satisfied with the surgical outcome in all patients except three who experienced recurrent of drop attacks after operation. There was no sign of significant and persistent neurological deficits in any case. CONCLUSION: Results of total callosotomy in patients with medically intractable epilepsy with diffuse epileptic foci were favorable in most cases. The procedure was particularly effective against drop attacks causing physical injuries and impaired quality of life in these patients.

Efficacy of Deflazacort with Add-on Therapy in Childhood Intractable Atonic Seizure / 대한소아신경학회지

PURPOSE: This is a clinical study to evaluate the efficacy and adverse reactions of deflazacort as adjunctive therapy in childhood intractable atonic seizure including Lennox- Gastaut syndrome. METHODS: This is a clinical prospective, add-on, and open-label study performed for 6 months from Jun. 2000 to Dec. 2000 at the pediatric neurology clinic of Severance Hospital. Subjects were selected according to the following criteria, 1) Patients were diagosed as refractory atonic seizure disorder including Lennox-Gastaut syndrome during more than 6 months, 2) Patients had been on maximal doses of at least 2 anticonvulants including sodium valproate and clonazepam or clobazam. We observed seizure frequency of 4 weeks and 24 week medication period as well as adverse reactions every 4 weeks. Those data were analysed primarily for median seizure frequency reduction rate and other efficacy variables such as responder rate with frequency reduction more than 50% and seizure free rate. We also compared the clinical aspects between responder and non responder group. RESULTS: 48 patients were evaluated for efficacy and adverse reactions. Median seizure frequency reduction rate was 42.7%, responders were 22 patients(45.8%) and seizure free patients were 4(8.3%). In Lennox-Gastaut syndrome, median seizure frequency reduction rate was 48.9% and in atonic seizure only 39.3%. However, there were no statistically significant differences in efficacy. We compared clinical aspects between respoder and non responder groups, but couldn't find any difference. The number of patients manifesting adverse reactions was 20(41.6%) in an descending order of frequency, weight gain in 16 patients(33.3%), and irritability in 4 patients(8.3%). CONCLUSION: Deflazacort is believed to be an effective and safe anticonvulsant when used as adjunctive therapy for atonic seizure including Lennox-Gastaut syndrome. However, long term follow up is required to evaluate relapse rate and its adverse reactions.