Novel Homozygous Variants of SLC13A5 Expand the Functional Heterogeneity of a Homogeneous Syndrome of Early Infantile Epileptic Encephalopathy.

BACKGROUND: Early infantile epileptic encephalopathy 25 (EIEE25) is a distinct type of neonatal epileptic encephalopathy caused by autosomal recessive mutations in the SLC13A5 gene. SLC13A5 encodes a transmembrane sodium/citrate cotransporter required for regulating citrate entry into cells. METHODS: Four families with recessively inherited epileptic encephalopathy were sequenced by clinically accredited laboratories using commercially available epilepsy gene panels. Patients were examined by a neurologist and were clinically diagnosed with infantile epileptic encephalopathy. RESULTS: We present four families with global developmental delay, intellectual disability, and defective tooth development with four novel homozygous mutations in SLC13A5. The neurological examination showed spastic quadriplegia with increased deep tendon reflexes. Brain magnetic resonance imaging showed nonspecific signal abnormality of the bilateral hemispheric white matter. Despite similar clinical features, the conditions were based on different molecular mechanisms acting on SLC13A5 (abnormal splicing, large-scale deletions, and tandem-residue insertion). CONCLUSIONS: Our results extend the landscape of autosomal recessive inherited homozygous mutations in SLC13A5 that cause a distinctive syndrome of severe neonatal epileptic encephalopathy. Our observations confirm the homogeneity of epileptic encephalopathy and dental abnormalities as a distinct clinical marker for EIEE25 despite the heterogeneous functional and mutational background.

Moyamoya syndrome secondary to mitochondrial disease in a patient with partial trisomy 13q14 and 13q31: A novel case report and literature review.

Moyamoya syndrome (MMS) is a cerebrovascular disease characterized by stenosis of the internal carotid arteries and the formation of an abnormal vascular network at the base of the brain. MMS usually occurs secondary to various conditions, particularly Down syndrome, and sickle cell anemia, and presents with motor deficits, sensory symptoms, recurrent ischemic strokes, hemodynamic transient ischemic attacks, recurrent seizures, and hemorrhage. Trisomy 13 (Patau Syndrome) is a chromosomal abnormality that may be characterized by full or partial trisomy of chromosome 13. Phenotypic features of partial trisomy 13 include leukoencephalopathy, hippocampal hypoplasia, intellectual disability, facial anomalies, and others. Herein, we report a case of a 19-year-old female diagnosed with partial trisomy 13q, characterized by two large duplications in the 13q14 and 13q31 regions, with trisomy-induced bilateral MMS - the first known case to be discussed in literature. Particularly, our patient was identified to have a gain of 22Mb within the 13q14.11q21.31 region - a duplication that has not been described previously. Our patient suffered four strokes between the ages of 5 and 7, later developing intractable seizures, hemiplegia, spasticity in all limbs, global delay, and regression. Despite bilateral encephaloduroarteriosynangiosis and being on several antiepileptic medications, the MMS continued to progress, confounded by the partial trisomy 13. Studies must elucidate the association between mitochondrial damage and MMS, as well as mechanisms of epilepsy associated with chromosomal abnormalities, particularly in the context of underlying mitochondrial diseases.

Patterns of antiseizure medication prescription in pregnancy and maternal complications in women with epilepsy: A retrospective study in Saudi Arabia.

Aim: To evaluate patterns of antiseizure medication (ASM) prescription in pregnancy and changes over a 16-year period: 2005-2020, and to investigate maternal complications in pregnant women with epilepsy (WWE). Method: Data of pregnant WWE was retrospectively reviewed at the King Faisal Specialist Hospital and Research Centre, Riyadh and Jeddah, Saudi Arabia. Results: Out of 162 pregnancies, 81.5% were prescribed ASMs. During the study period, the prescription rate increased from 68.8% to 93.5%. Between 2005 and 2020, the use of new ASMs increased from 15.4% to 75.5% (p < 0.0001). Furthermore, valproate use markedly decreased from 23.08% to 2.04%. The rate of maternal and delivery complications was 29.6%; the most frequent was gestational diabetes (5.6%), followed by bleeding during pregnancy (4.9%). Furthermore, preeclampsia and eclampsia were documented in 3.7% and 1.8%, respectively. ASMs use and other factors were not found to be associated with maternal complications (p > 0.05). However, first generation ASMs, i.e. carbamazepine (38.71%) and valproate (41.67%), were associated with higher maternal complication rates than new ASMs, i.e. levetiracetam (25%) and lamotrigine (20%), but the difference was not statistically significant (p = 0.4403). Conclusion: ASM prescription in pregnancy is increasing as is the use of new ASMs. The rate of maternal and delivery complications was relatively low, particularly preeclampsia and eclampsia. ASMs use was not found to associated with these complications. However, exposure to first generation ASMs seemed to be a predictor of adverse pregnancy outcomes.

Marital status among patients with epilepsy in Saudi Arabia.

There are no adequate studies on Saudi Arabia regarding the effect of the social environment on marriage among people with epilepsy (PWE). To fill this gap in the literature, we investigated the marital status of PWE to determine the factors affecting their marital prospects. The subjects of the study included PWE aged 18 years or above, recruited between 1998 and 2019 from the Epilepsy Registry of King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. We collected a wide range of socio-demographic data on age, gender, location, education level, employment status, and marital status. In total, 1857 PWE, comprising 1086 men (58.48%) and 771 women (41.52%), were enrolled in the study. The data analysis showed that those 'married' and those who 'had been married' comprised 46.96% of the sample, while those 'never married' comprised 53.04%; 65.37% of the sample held a 'high school diploma or less' or had 'no education', 26.85% reported ongoing university education or had already obtained a bachelor's or higher degree; 50.08% of the respondents were employed, while 47.98% were not. Of the sample, 40.28% resided in Riyadh, whereas 13.14% were from the Asir region. We found that socio-demographic factors, especially employment status, had a major influence on the marital prospects of PWE.

Antiseizure medications use during pregnancy and congenital malformations: A retrospective study in Saudi Arabia.

AIM: To evaluate the incidence of congenital malformations in children exposed prenatally to antiseizure medications (ASMs), to assess other perinatal and fetal complications, and to determine the potential predictors for these complications. METHOD: A retrospective review of pregnancy outcomes of women with epilepsy. Patients were followed up at the King Faisal Specialist Hospital and Research Centre, Riyadh and Jeddah, Saudi Arabia, between Dec 1993 and Oct 2020. RESULTS: Of 162 pregnancies included, 10 (6.17%) congenital malformations were observed, 6.82% in ASM-exposed babies versus 3.33% in babies of epilepsy-untreated mothers (P = 0.69). The overall incidence of perinatal and fetal complications was 53%; most frequent were low birth weight (24%), preterm birth (19%), transfer to neonatal intensive care unit (18%) and abortion (8%). These complications were higher in the untreated group (66.67%) than in the ASM group (50%). The use of other non-antiseizure medications during pregnancy was the only factor that significantly increased the risk of complications. CONCLUSION: Prenatal exposure to ASMs was associated with increased risk of congenital malformations. However, overall perinatal and fetal complications were higher in the untreated group than in the ASM group, which could be explained by maternal seizures. Therefore, taking ASMs to control epilepsy and prevent perinatal complications may outweigh the risks of teratogenicity.

The Risk Of Seizure-Related Hospitalization Among Older Adults On Levetiracetam Monotherapy: A Retrospective Comparative Cohort Study.

BACKGROUND: Antiepileptic drug monotherapy is the mainstay of treatment for epilepsy; however, the efficacy of different antiepileptic drugs in reducing the incidence of seizure-related hospitalization among older adults, who are at higher risk of developing epilepsy compared to their younger counterparts, has not been examined. PURPOSE: The objective of the present study was to compare the rate of seizure-related hospitalization among older adults on levetiracetam compared to different antiepileptic drugs (AEDs). PATIENTS AND METHODS: This was a retrospective cohort study of older adults (≥60 years) in two tertiary care hospitals. Patients who are 60 years of age and older, have a confirmed diagnosis of epilepsy, and are taking a single and the same antiepileptic drug for at least 36 months were included. The patients were followed up for 24 months after 12 months of treatment with no incidence of seizure-related hospitalization via their health records. Multiple Poisson regression with robust error variance was used to estimate the relative risk of hospitalization for patients on levetiracetam compared to different antiepileptic drugs controlling for age, gender, number of prescription medications, dosage strengths, and Charlson Comorbidity Index (CCI) score. RESULTS: One hundred and thirty-six patients met the inclusion criteria and were included in the study. The recruited patients were on one of the following four antiepileptic drugs: carbamazepine (n=44), levetiracetam (n=39), phenytoin (n=31), and valproic acid (n=22). Patients on levetiracetam were more than twice as likely to be hospitalized due to seizures within the 24 months of follow-up compared to their counterparts on other AEDs (RR=2.76, 95% CI=1.16-6.53, P=0.021). CONCLUSION: This study suggests that older adults on old generation AEDs such as phenytoin, carbamazepine, and valproic acid appear to have a lower risk of seizure-related hospitalization compared to their counterparts on levetiracetam.

Potential oligogenic disease of mental retardation, short stature, spastic paraparesis, and osteopetrosis.

The interaction of multiple genetic factors, as opposed to monogenic inheritance, has been suspected to play a role in many diseases. This interaction has been described as an oligogenic inheritance model, which may be a useful tool in explaining certain clinical observations. The purpose of this study was to search for novel genetic defects among members of a family with traits that include mental retardation, short stature, osteopetrosis, calcification of basal ganglia, and thinning of the corpus callosum. In the index case (111-4), we identified four homozygous mutations: chromosome 8, intron2 (c.232+1G>A) at CA2 gene; chromosome 15, exon 32 (c.6100C>T) at the SPG11; chromosome 5, exon 11 (c.1015G>A) at the MCCC2; and chromosome 9, exon 9 (C.1193g>t) at the LARP gene. The mutations were confirmed by Sanger sequencing, and both parents were observed to be heterozygous for the four mutations. A moderately affected sister of the index case was homozygous for only three mutations in CA2, LARP, and Mccc2, while a nonaffected sister was heterozygous for three mutations in CA2, LARP, and MCCC2 and negative for SPG11. The clinical features of the two affected sisters can be explained distinctively by each homozygous mutation in an oligogenic pattern of inheritance. This family represents an example of an oligogenic pattern of inheritance of mental retardation, short stature, spastic paraparesis, and osteopetrosis.

The impact of old versus new antiepileptic drugs on costs and patient reported outcomes among older adults.

The aim of this prospective questionnaire-based cross-sectional study was to examine whether the new generation of Antiepileptic drugs (AEDs) with higher acquisition cost generate lower adverse effects than the old AEDs among a sample of 102 Arabic-speaking older adults (60 years of age or older) with seizure disorders. The mean scores of the Arabic version of the Liverpool Adverse Events Profile (LAEP), which assessed the adverse effects of the AEDs, did not differ between patients taking the old and new generations of AEDs. Despite their 4-fold higher cost, the new generation of AEDs were not characterized by lower LAEP scores of adverse effects. However, higher LAEP scores were associated with better health literacy. In conclusion, the use of new AEDs was not associated with lower self-reported adverse effects scores among Arabic-speaking older adults with seizure disorders despite their higher acquisition costs.

Correction to: Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism.

CORRECTION: After publication of the article [1], it has been brought to our attention that there is a nomenclature issue with this article. At the time of acceptance, the VARS2 mutation was considered equivalent to the VARS2 mutation. However, this has changed so that VARS now only refers to shorter mitochondrial sequence of valyl-tRNA synthesase containing 1093 amino acids. "Therefore, in the context of this article, every usage of "VARS2" should be replaced with "VARS" when referring to the causative variant".

Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism.

BACKGROUND: Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency. RESULTS: A G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic. CONCLUSIONS: These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.

Intraoperative direct cortical stimulation motor evoked potentials: Stimulus parameter recommendations based on rheobase and chronaxie.

OBJECTIVE: To determine optimal interstimulus interval (ISI) and pulse duration (D) for direct cortical stimulation (DCS) motor evoked potentials (MEPs) based on rheobase and chronaxie derived with two techniques. METHODS: In 20 patients under propofol/remifentanil anesthesia, 5-pulse DCS thenar MEP rheobase and chronaxie with 2, 3, 4 and 5ms ISI were measured by linear regression of five charge thresholds at 0.05, 0.1, 0.2, 0.5 and 1msD, and estimated from two charge thresholds at 0.1 and 1msD using simple arithmetic. Optimal parameters were defined by minimum threshold energy: the ISI with lowest rheobase2×chronaxie, and D at its chronaxie. Near-optimal was defined as threshold energy <25% above minimum. RESULTS: The optimal ISI was 3 or 4 (n=7 each), 2 (n=4), or 5ms (n=2), but only 4ms was always either optimal or near-optimal. The optimal D was ∼0.2 (n=12), ∼0.1 (n=7) or ∼0.3ms (n=1). Two-point estimates closely approximated five-point measurements. CONCLUSIONS: Optimal ISI/D varies, with 4ms/0.2ms being most consistently optimal or near-optimal. Two-point estimation is sufficiently accurate. SIGNIFICANCE: The results endorse 4ms ISI and 0.2msD for general use. Two-point estimation could enable quick individual optimization.

Large-scale mitochondrial DNA deletion underlying familial multiple system atrophy of the cerebellar subtype.

A family with mitochondrial inheritance of multiple system atrophy of the cerebellar subtype. MRI brain shows significant cerebellar atrophy with mild pontine atrophy and the classical hot cross bun sign in Pons. The muscle biopsy was indicative of mitochondrial myopathy. Mitochondrial DNA analysis revealed a low-level large mtDNA deletion, m.3264_1607del12806 bp.

The selective cytotoxic anti-cancer properties and proteomic analysis of Trigonella Foenum-Graecum.

BACKGROUND: There are a number of dietary components that may prove useful in the prevention and treatment of cancer. In some cultures, fenugreek seeds are used to treat cancer. The current study focuses on the anticancer properties and proteomic profiles of fenugreek seeds, and is prompted by the clinical profile of a case of primary CNS T cell lymphoma that responded to fenugreek treatment and resulted in tumor regression. METHOD: Various normal and cancer cell lines were exposed to fenugreek extract at differing concentrations (100 µg/ml, 200 µg/ml and 300 µg/ml) and at different time points (0, 24, 48, 72 and 96 hrs). Protein fingerprints of fenugreek grain/seed types, obtained from four different geographical regions, were analyzed by proteomic expression profiles. RESULTS: We observed selective cytotoxic effects of fenugreek extract in vitro to a panel of cancer cell lines, including T-cell lymphoma. Additionally, the cluster analysis of proteomics data showed that the protein profile of the particular fenugreek used by the patient is significantly different from three other regional subtypes of fenugreek extract. CONCLUSION: The in vitro effect of fenugreek as a substance with significant cytotoxicity to cancer cells points to the potential usefulness of fenugreek in the prevention and treatment of cancer.

Epilepsy surgery series: a study of 502 consecutive patients from a developing country.

Purpose. To review the postoperative seizure outcomes of patients that underwent surgery for epilepsy at King Faisal Specialist Hospital & Research Centre (KFSHRC). Methods. A descriptive retrospective study for 502 patients operated on for medically intractable epilepsy between 1998 and 2012. The surgical outcome was measured using the ILAE criteria. Results. The epilepsy surgery outcome for temporal lobe epilepsy surgery (ILAE classes 1, 2, and 3) at 12, 36, and 60 months is 79.6%, 74.2%, and 67%, respectively. The favorable 12- and 36-month outcomes for frontal lobe epilepsy surgery are 62% and 52%, respectively. For both parietal and occipital epilepsy lobe surgeries the 12- and 36-month outcomes are 67%. For multilobar epilepsy surgery, the 12- and 36-month outcomes are 65% and 50%, respectively. The 12- and 36-month outcomes for functional hemispherectomy epilepsy surgery are 64.2% and 63%, respectively. According to histopathology diagnosis, mesiotemporal sclerosis (MTS) and benign CNS tumors had the best favorable outcome after surgery at 1 year (77.27% and 84.3%, resp.,) and 3 years (76% and 75%, resp.,). The least favorable seizure-free outcome after 3 years occurred in cases with dual pathology (66.6%). Thirty-four epilepsy patients with normal magnetic resonance imaging (MRI) brain scans were surgically treated. The first- and third-year epilepsy surgery outcome of 17 temporal lobe surgeries were (53%) and (47%) seizure-free, respectively. The first- and third-year epilepsy surgery outcomes of 15 extratemporal epilepsy surgeries were (47%) and (33%) seizure-free. Conclusion. The best outcomes are achieved with temporal epilepsy surgery, mesial temporal sclerosis, and benign CNS tumor. The worst outcomes are from multilobar surgery, dual pathology, and normal MRI.

Hypogonadism and neurological diseases.

Affected patients with hypogonadism have unnaturally low amounts of sex hormones that produce male and female sex characteristics. Males who suffer from this condition lack testosterone, while females fail to produce enough estrogen. Hypogonadism may be present at birth, or it may take effect years later following injury or illness to the sex glands. Hypogonadism has remarkable associations with variable medical disorders; however, it is characterized by a distinctive association with variable neurological disorders: such as epilepsy, ataxia, dysmyelination, nerve muscle disease, movement disorders, mental retardation and deafness. The remarkable neurological diseases with hypogonadism should not basically be regarded as coincidental findings, but possibly related to an intrinsic pathophysiological association.

Ictal kissing with subdural EEG recording.

PURPOSE: Ictal kissing has been described in the literature. Five cases were reported and associated with temporal lobe epilepsy lateralizing to the nondominant hemisphere. METHODS: A case of ictal kissing was identified. The aim was to demonstrate the clinical, clinical and electrophysiological features (as recorded by subdural electrodes). The surgical procedure, histopathology, and imaging data were reviewed and correlated with the literature. RESULTS: A 29-year-old right-handed female, who presented with ictal right hand left arm dystonic posturing, and lip smacking, was studied. The automatism was usually followed by prolonged emotional gestures and by hugging and kissing her relative and/or attendant nurse. Magnetic resonance imaging of the brain showed right small cortical and subcortical lesions of the right inferior frontal lobe with gliosis but without mass effect and normal-sized hippocampi. The PET scan showed hypometabolism of the right temporal lobe. Neuropsychological evaluation showed deficit in her nonverbal memory. The subdural electrodes showed high amplitude spikes over right mesial temporal lobe strips. The offsite of the ictal discharges was usually at the right frontal strips. Right standard temporal lobectomy with amygdalohippocampectomy and right inferior frontal lesionectomy were performed. The patient continued to be seizure-free for one year postoperatively. CONCLUSION: Our case report supports with subdural EEG recording the findings of the few reported cases of ictal kissing behavior lateralized to the nondominant hemisphere. However, the affectionate kissing behavior was associated with spread of the epileptic discharges to the right frontal lobe.

Natural course of epilepsy concomitant with CNS tuberculomas.

BACKGROUND: Epilepsy is relatively common in CNS tuberculomas, but its natural course is unclear. AIM: To determine the prevalence and prognosis of epilepsy in patients with seizures related to CNS tuberculomas. METHODS: We retrospectively reviewed the charts of patients with CNS tuberculomas who presented at our institution between 1983 and 2001. RESULTS: Seizures occurred in 22 of 93 (23.6%) of the patients with CNS tuberculomas. These patients were treated with standard antituberculous therapy for a period varying between 6 and 20 months. Sixty-three out of 93 patients were cured of tuberculosis, and 21 of the 63 (33%) who had concomitant epilepsy became seizure-free. TB recurred in 3 patients, and 1 out of 22 who had concomitant epilepsy continued to have seizures; 3 died and 24 were lost to follow-up. Anti-epileptic medications were discontinued after completion of the anti-TB course. CONCLUSION: Seizures are commonly associated with CNS tuberculomas and most often resolve after successful treatment of the underlying CNS tuberculosis.

Primary Sjogren's syndrome with central nervous system involvement.

OBJECTIVE: To describe the clinical, laboratory, and radiological features of Primary Sjogren's syndrome (PSS) with central nervous system (CNS) involvement. METHODS: A retrospective case series of 12 female patients with PSS and CNS involvement at King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia from 1991-2009. The diagnosis of PSS is defined by the American-European Diagnostic Criteria. We analyzed the clinical, radiological, and immunological features. RESULTS: The mean age was 40 years (range 16-58 years); all patient were females and presented with active neurological symptoms. The neurological involvement preceded the classic sicca symptoms (33%). Eight patients (66%) presented with myelopathy, 9 patients (75%) had optic neuritis, and the rest had variable neurological signs. Immunological tests (anti-Sjogren's syndrome A and anti-Sjogren's syndrome B) were high in 7 patients (58%). Minor salivary gland biopsy revealed inflammatory cell infiltrate in 11 patients (92%). Brain MRI showed scattered white matter changes in 7 patients (58%). Spine MRI showed multiple foci of hyperintensity in T2-weighted image in 6 patients (50%), and long segment of hyperintensity at the cervical spinal cord in 2 patients (16%). CONCLUSION: Our findings demonstrate that CNS involvements in PSS have great clinical variability and could precede the classic sicca symptoms by years. Primary Sjogren's syndrome can mimic multiple sclerosis (primary progressive multiple sclerosis or relapsing remitting multiple sclerosis), therefore a screening test for PSS should be considered in suspected cases. A well-defined management protocol awaits studies with larger case numbers.