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Journal of Neurology Jul 2024To report the effects of adjunctive cenobamate and concomitant antiseizure medications (ASMs) on weight from two double-blind, placebo-controlled, phase 2 studies...
OBJECTIVE
To report the effects of adjunctive cenobamate and concomitant antiseizure medications (ASMs) on weight from two double-blind, placebo-controlled, phase 2 studies (YKP3089C013 [C013] and YKP3089C017 [C017]) and their open-label extensions (OLEs) and from a long-term, open-label phase 3 safety study, YKP3089C021 (C021).
BACKGROUND
Cenobamate is an ASM approved in the US and EU for treatment of focal seizures in adults. Some ASMs are associated with weight gain (e.g., valproate, gabapentin, pregabalin), which can negatively affect patient health.
DESIGN/METHODS
Patients with uncontrolled focal seizures taking stable doses of 1-3 ASMs were enrolled in each study. In C013, cenobamate was titrated to a target dose of 200 mg/day (max OLE dose 400 mg/day). In C017, patients were randomized to cenobamate 100, 200, or 400 mg/day (max OLE dose 400 mg/day). In C021, cenobamate was titrated to a target dose of 200 mg/day (max dose 400 mg/day). Median weight changes at 1 and 2 years from baseline were analyzed post hoc.
RESULTS
Analyses included 39, 206, and 1054 patients from C013, C017 (dose groups combined), and C021, respectively. Median weight changes from baseline ranged from -0.2 to -0.9 kg at 1 year and from -1.0 to +1.0 kg at 2 years. Some numerical reductions in weight were noted in patients who discontinued valproate by 1 (-13.0 kg, C013, n=1) or 2 years (-24.5 kg, C017, n=2) and in patients who discontinued gabapentin by 1 (-7.1 kg, C017, n=2) or 2 years (-7.0 kg, C017, n=2). Otherwise, median weight changes from baseline for patients receiving concomitant valproate, gabapentin, or pregabalin ranged from -3.1 to +2.6 kg at 1 year and from -1.6 to +2.7 kg at 2 years.
CONCLUSIONS
Adjunctive cenobamate was not associated with clinically significant changes in weight from baseline in patients treated for 1 and 2 years, including those receiving concomitant valproate, gabapentin, or pregabalin.
PubMed: 38954033
DOI: 10.1007/s00415-024-12510-1 -
European Journal of Pediatrics Jul 2024The purpose of this study is to investigate the diagnostic and prognostic role of cerebrospinal fluid (CSF) biomarkers in the diagnostic work-up of glucose transporter 1... (Review)
Review
The purpose of this study is to investigate the diagnostic and prognostic role of cerebrospinal fluid (CSF) biomarkers in the diagnostic work-up of glucose transporter 1 (GLUT1) deficiency. Reported here is a systematic review according to PRISMA guidelines collecting clinical and biochemical data about all published patients who underwent CSF analysis. Clinical phenotypes were compared between groups defined by the levels of CSF glucose (≤ 2.2 mmol/L versus > 2.2 mmol/L), CSF/blood glucose ratio (≤ 0.45 versus > 0.45), and CSF lactate (≤ 1 mmol/L versus > 1 mmol/L). Five hundred sixty-two patients fulfilled the inclusion criteria with a mean age at the diagnosis of 8.6 ± 6.7 years. Patients with CSF glucose ≤ 2.2 mmol/L and CSF/blood glucose ratio ≤ 0.45 presented with an earlier onset of symptoms (16.4 ± 22.0 versus 54.4 ± 45.9 months, p < 0.01; 15.7 ± 23.8 versus 40.9 ± 38.0 months, p < 0.01) and received an earlier molecular genetic confirmation (92.1 ± 72.8 versus 157.1 ± 106.2 months, p < 0.01). CSF glucose ≤ 2.2 mmol/L was consistently associated with response to ketogenic diet (p = 0.018) and antiseizure medications (p = 0.025). CSF/blood glucose ratio ≤ 0.45 was significantly associated with absence seizures (p = 0.048), paroxysmal exercise-induced dyskinesia (p = 0.046), and intellectual disability (p = 0.016) while CSF lactate > 1 mmol/L was associated with a response to antiseizure medications (p = 0.026) but not to ketogenic diet.Conclusions:This systematic review supported the diagnostic usefulness of lumbar puncture for the early identification of patients with GLUT1 deficiency responsive to treatments especially if they present with co-occurring epilepsy, movement, and neurodevelopmental disorders. What is Known: • Phenotypes of GLUT1 deficiency syndrome range between early epileptic and developmental encephalopathy to paroxysmal movement disorders and developmental impairment What is New: • CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with early onset absences • CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with paroxysmal exercise induced dyskinesia and intellectual disability. • CSF glucose may predict better than CSF blood/glucose and lactate the response to ketogenic diet and antiseizure medications.
PubMed: 38954008
DOI: 10.1007/s00431-024-05657-6 -
Der Nervenarzt Jul 2024While the neuronal mechanisms of epileptic hyperexcitability (HE) have been studied in detail, recent findings suggest that extraneuronal, mainly immune-mediated... (Review)
Review
OBJECTIVE
While the neuronal mechanisms of epileptic hyperexcitability (HE) have been studied in detail, recent findings suggest that extraneuronal, mainly immune-mediated inflammatory and vascular mechanisms play an important role in the development and progression of HE in epilepsy and the cognitive and behavioral comorbidities.
MATERIAL AND METHODS
Narrative review.
RESULTS
As in autoimmune (limbic) encephalitis (ALE/AIE) or Rasmussen's encephalitis (RE), the primary adaptive and innate immune responses and associated changes in the blood-brain barrier (BBB) and neurovascular unit (NVU) can cause acute cortical hyperexcitability (HE) and the development of hippocampal sclerosis (HS) and other structural cortical lesions with chronic HE. Cortical HE, which is associated with malformation of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT), for example, can be accompanied by secondary adaptive and innate immune responses and alterations in the BBB and NVU, potentially modulating the ictogenicity and epileptogenicity. These associations illustrate the influence of adaptive and innate immune mechanisms and associated changes in the BBB and NVU on cortical excitability and vice versa, suggesting a dynamic and complex interplay of these factors in the development and progression of epilepsy in general.
DISCUSSION
The described concept of a neuro-immune-vascular interaction in focal epilepsy opens up new possibilities for the pathogenetic understanding and thus also for the selective therapeutic intervention.
PubMed: 38953922
DOI: 10.1007/s00115-024-01695-5 -
Epileptic Disorders : International... Jul 2024Mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE) is a recently described, histopathologically and molecularly defined...
OBJECTIVE
Mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE) is a recently described, histopathologically and molecularly defined (SLC35A2-mutated) type of cortical malformation. Although increasingly recognized, the diagnosis of MOGHE remains a challenge. We present the characteristics of the first six patients diagnosed in Bulgaria, with the aim to facilitate identification, proper presurgical evaluation, and surgical treatment approach in this disease.
METHODS
Revision of histopathological specimens of 202 patients operated on for drug-resistant focal epilepsy identified four cases with MOGHE. Another two were suggested, based on clinical characteristics and subsequently, were histologically confirmed. Sanger SLC35A2 sequencing on paraffin-embedded or fresh-frozen brain tissue was performed. Analysis of seizure types, neuropsychological profiles, electroencephalographic (EEG), imaging features and epilepsy surgery outcomes was done.
RESULTS
Three out of the six cases (50%) harbored pathogenic SLC35A2 mutations. One patient had a heterozygous somatic variant with uncertain significance. Clinical characteristics included epilepsy onset in infancy (in 100% under 3 years of age), multiple seizure types, and moderate or severe intellectual/developmental delay. Epileptic spasms with hypsarrhythmia on EEG were the initial seizure type in five patients. The subsequent seizure types resembled those in Lennox-Gastaut syndrome. The majority of the patients (n = 4) presented prominent and persisting autistic features. Magnetic resonance imaging (MRI) showed multilobar (n = 6) and bilateral (n = 3) lesions, affecting the frontal lobes (n = 5; bilaterally in three) and characterized by increased signal on T2/fluid-attenuated inversion recovery (FLAIR). Voxel-based morphometric MRI post-processing and positron emission tomography helped determining the localization and extent of the lesions and presumed epileptogenic zones. After surgery, four patients (66.7%) were seizure-free ≥2 years. Interestingly, all seizure-free patients carried somatic SLC35A2-alterations.
SIGNIFICANCE
Epileptic spasms, early prominent neuropsychological disturbances, MRI-T2/FLAIR hyperintense lesions with cortico-subcortical blurring, frequently multilobar and especially frontal, can preoperatively help to suspect MOGHE. Epilepsy surgery is still the only successful treatment option in MOGHE.
PubMed: 38953904
DOI: 10.1002/epd2.20261 -
Epilepsia Open Jul 2024To conduct a systematic review of the literature regarding rates and predictors of favorable seizure outcome after resective surgery for epileptic spasms (ES) in... (Review)
Review
To conduct a systematic review of the literature regarding rates and predictors of favorable seizure outcome after resective surgery for epileptic spasms (ES) in pediatric patients. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed. We searched PubMed, EMBASE, and Cochrane CENTRAL for articles published on the prevalence or incidence of epileptic spasm since 1985. Abstract, full-text review, and data extraction were conducted by two independent reviewers. Meta-analysis was performed to assess overall seizure freedom rate. Subject-level analysis was performed on a subset of studies to identify prognostic indicators. A total of 21 retrospective studies (n = 531) were included. Meta-analysis of all studies demonstrated a pooled seizure freedom rate of 68.8%. Subject-level analysis on 18 studies (n = 360) demonstrated a significant association between duration of spasms and recurrence of spasms after surgery, with an estimated increased risk of 7% per additional year of spasms prior to operation. Patients who underwent resective surgery that was not a hemispherectomy (i.e., lobectomy, lesionectomy, etc.) had an increased recurrence risk of 57% compared to patients who had undergone hemispherectomy. Resective surgery results in seizure freedom for the majority of pediatric patients with epileptic spasms. Patients who undergo hemispherectomy have lower risk of recurrence than patients who undergo other types of surgical resection. Increased duration of spasms prior to surgery is associated with increased recurrence risk after surgery. PLAIN LANGUAGE SUMMARY: Children with epileptic spasms (ES) that do not respond to medications may benefit from surgical treatment. Our study reviewed existing research to understand how effective surgery is in treating ES in children and what factors predict better outcomes. Researchers followed strict guidelines to search for and analyze studies published since 1985, finding 21 studies with a total of 531 patients. They found that, on average, nearly 70% of children became seizure-free after surgery. Further individual analysis of 360 patients showed that longer duration of spasms before surgery increased the risk of spasms returning by 7% per year. Additionally, children who had less extensive surgeries, such as removal of only a specific part of the brain, had a 57% higher risk of seizure recurrence compared to those who had a hemispherectomy, which removed or disconnected half of the brain. Overall, the study concludes that surgery can often stop seizures, especially when more extensive surgery is performed and when the surgery is done sooner rather than later.
PubMed: 38953892
DOI: 10.1002/epi4.13007 -
Epilepsia Jul 2024DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small...
OBJECTIVE
DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature.
METHODS
Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains.
RESULTS
DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum.
SIGNIFICANCE
We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.
PubMed: 38953796
DOI: 10.1111/epi.18054 -
Journal of Clinical Research in... Jul 2024Secondary osteoporosis is a condition when the underlying disease or its treatment causes the bone mass to decrease and the bone structure to deteriorate, increasing the...
OBJECTIVE
Secondary osteoporosis is a condition when the underlying disease or its treatment causes the bone mass to decrease and the bone structure to deteriorate, increasing the risk of fracture. The importance of diagnosis and treatment during childhood and adolescence is due to its long-term negative effects. In this study, our objectives were to determine the diagnostic findings, treatment efficacy, and follow-up characteristics of childhood with secondary osteoporosis.
METHODS
61 patients diagnosed with secondary osteoporosis between January 2000 and January 2021 were included in the study. The research is a cross-sectional and descriptive study. Study participants had to be under 18 years of age when the primary underlying disease was diagnosed and received treatment for secondary osteoporosis. Patient data were collected from patient files. Patient data were obtained from patient files in hospitals and were interpreted through the IBM SPSS Statistics for Windows version 20.0 (IBM Corp, Armonk, NY, USA).
RESULTS
61 patients (28 women/33 men) were evaluated. The most common underlying primary diseases in patients with secondary osteoporosis were inflammatory diseases (57.7%), neuromuscular diseases (26.2%), immunodeficiency (13.1%), acute lymphoblastic leukemia (8.2%), metabolic diseases (8.2%), and solid organ transplantation. (8.2%), bone marrow transplantation (6.6%) and epilepsy (6.6%). The average chronological age when secondary osteoporosis was diagnosed was 11.89±4.88 years. They were evaluated for osteoporosis 6.39±5.13 years after the onset of the underlying primary chronic diseases. 78.7% of the patients had one or more chronic drug use. Systemic steroid use was 59%, chemotherapeutics 23%, immunomodulatory drugs 19.7%, antiepileptic drugs 8.2%, inhaled steroids 4.9%, IVIG 1.6%, and antituberculosis drugs 1.6%. Additionally, 1.6% of the patients were using testosterone as replacement, 3.3% L-Thyroxine, 1.6% estrogen, and 1.6% growth hormone. Bone pain was detected in 49.2% of the patients. All patients had vertebral fractures before treatment. Bisphosphonate treatment was given to 45 patients with secondary osteoporosis. There was a statistically significant increase in mean bone mineral density (BMD) and bone mineral content values six months after treatment, (p<0.001). There was a significant increase in BMD Z-score values for chronological and height age (p<0.001). The patients' BMD values increased on average by 31.15% with treatment. Following bisphosphonate treatment, there was a significant reduction in both fracture number and bone pain in patients (p<0.01). When patients who received and did not receive steroid treatment were compared, both groups received similar benefits from bisphosphonate treatment.
CONCLUSION
Secondary osteoporosis is a condition that is influenced by many factors, such as the primary disease causing osteoporosis, chronic medication use, especially steroids. If left untreated, osteoporosis leads to important diseases such as bone pain, bone fractures, immobilization, and reduced linear growth of bone. When used to treat childhood secondary osteoporosis, Bisphosphonates significantly improve BMD and reduce fracture risk.
PubMed: 38953735
DOI: 10.4274/jcrpe.galenos.2024.2024-4-4 -
Transpalpebral Transorbital Approach for Pediatric Temporal Epilepsy: 2-Dimensional Operative Video.Operative Neurosurgery (Hagerstown, Md.) Jul 2024The transpalpebral approach provides a minimally invasive corridor to the anterior skull base and temporal lobe. It has been described for anterior circulation aneurysms...
The transpalpebral approach provides a minimally invasive corridor to the anterior skull base and temporal lobe. It has been described for anterior circulation aneurysms and skull base tumors as well as more recently for resection of epileptogenic pathology in the adult population. We describe our experience using this approach in a 13-year-old adolescent boy suffering from epilepsy secondary to concomitant left temporal focal cortical dysplasia and pleomorphic xanthoastrocytoma extending throughout the amygdala with excellent results.1-5 To the best of our knowledge, this is the first published case using the transpalpebral approach for this pathology, as well for epilepsy in the pediatric population. The patient consented to the procedure and to the publication of his image.
PubMed: 38953672
DOI: 10.1227/ons.0000000000001243 -
Neurosurgery Jul 2024The influence of the age at which complete corpus callosotomy (CC) surgery is performed on seizure outcomes remains unclear. This study aimed to evaluate the...
BACKGROUND AND OBJECTIVES
The influence of the age at which complete corpus callosotomy (CC) surgery is performed on seizure outcomes remains unclear. This study aimed to evaluate the age-dependent aspects of long-term seizure outcomes after complete CC.
METHODS
We reviewed 41 patients who underwent one-stage complete CC. Seizure outcomes were analyzed for age at epilepsy onset and at complete CC, focal MRI abnormality, and etiology.
RESULTS
The median age was 7 months at epilepsy onset and 93 months at complete CC. The median follow-up duration was 67 months. Sixteen patients had focal MRI lesions and 4 had only general atrophy. Etiology was identified in 20 patients. For overall seizure outcomes (N = 41), complete seizure freedom was achieved in 5 patients, excellent seizure reduction (>80%) in 11, good (50%-80%) in 5, and poor (<50%) in 20. Freedom was correlated with younger age at complete CC and unknown etiology (P ≤ .05). Freedom was only achieved in patients aged younger than 7 years. Worthwhile (≥50%, freedom, excellent, and good) and not worthwhile (<50%, poor) overall seizure reduction showed no statistical difference in age at complete CC. No related factor was found for worthwhile overall seizure reduction. For drop attack outcomes (N = 31), freedom was achieved in 22 cases, excellent in 5, and poor in 4. Freedom was correlated with younger age at complete CC (P < .05) although freedom was achieved in 4 of 7 patients older than 20 years. Age at complete CC showed no statistical difference between worthwhile (≥50%) and not worthwhile (<50%) drop attack reduction. Worthwhile drop attack reduction was correlated with unknown etiology (P < .05). Complications were mild and transient.
CONCLUSION
Complete CC is an excellent surgical option based on favorable seizure outcomes and acceptable complications in our present study.
PubMed: 38953628
DOI: 10.1227/neu.0000000000003092 -
European Journal of Neurology Jul 2024Cognitive complaints are common in functional neurological disorder (FND), but it is unclear whether objective neurocognitive deficits are present. This systematic... (Review)
Review
BACKGROUND AND PURPOSE
Cognitive complaints are common in functional neurological disorder (FND), but it is unclear whether objective neurocognitive deficits are present. This systematic review summarized validated/standardized cognitive test performance in FND samples across cognitive domains.
METHODS
Embase, PsycInfo and MEDLINE were searched from inception to 15 May 2023, combining terms for FND and cognitive domains (e.g., attention, memory, executive functioning). Studies included a range of FND phenotypes (seizures, motor, cognitive disorder, mixed), compared to healthy or clinical controls. Risk of bias was assessed with the modified Newcastle-Ottawa Scale and a qualitative synthesis/narrative review of cognitive performance in FND was conducted. Test performance scores were extracted, and random effects meta-analyses were run where appropriate. This review was registered on PROSPERO, CRD42023423139.
RESULTS
Fifty-six studies including 2260 individuals with FND were eligible. Although evidence for some impairments emerged across domains of executive functioning, attention, memory and psychomotor/processing speed, this was inconsistent across studies and FND phenotypes. Common confounds included group differences in demographics, medication and intellectual functioning. Only 24% of studies objectively assessed performance validity. Meta-analyses revealed higher scores on tests of naming (g = 0.67, 95% confidence interval [CI] 0.50, 0.84) and long-term memory (g = 0.43, 95% CI 0.13, 0.74) in functional seizures versus epilepsy, but no significant differences in working (g = -0.08, 95% CI -0.44, 0.29) or immediate (g = 0.25, 95% CI -0.02, 0.53) memory and cognitive flexibility (g = -0.01, 95% CI -0.29, 0.28).
CONCLUSIONS
There is mixed evidence for objective cognitive deficits in FND. Future research should control for confounds, include tests of performance validity, and assess relationships between objective and subjective neurocognitive functioning.
PubMed: 38953473
DOI: 10.1111/ene.16386