Risk factors associated with new-onset epilepsy in young adults: Population-based study.

OBJECTIVE: Risk factors for childhood and late-onset epilepsy are thoroughly described in existing literature, while they are less defined and ambiguous for young adults. We aimed to evaluate the prevalence of various risk factors associated with new-onset epilepsy in adults aged 20-49 years. We included all incident cases in North Macedonia between 2015 and 2018. METHODS: Study participants were ascertained through the nationwide healthcare platform. We performed a retrospective analysis of their Electronic Health Records and identified associated conditions which are considered putative risk factors for epilepsy. RESULTS: Of 1691 included patients, 694 (41%) had at least one putative risk factor. The most common were neoplasms and cerebrovascular diseases (8% of cases, respectively), followed by intellectual disability (6%), alcohol/substance abuse (5%), and traumatic brain injury (4%). Infective and inflammatory diseases were infrequent in our cohort (1%). Other very rare risk factors included degenerative and metabolic disorders and malformations of cortical development (2%). Idiopathic (genetic) generalized epilepsies accounted for 7% of incident cases. Chronic alcoholism and illicit drugs abuse (dominantly opioids) were significantly more frequent in males than in females (p < 0.00001). CONCLUSION: Brain neoplasms and stroke were the most prevalent risk factors associated with new-onset epilepsy in young adults. Furthermore, adult-onset IGE were common in our cohort. The majority of patients did not have any of conventional risk factors and probably specific genetic causes might become increasingly recognized in adult-onset epilepsies in the future.

Patients' attitude toward AED withdrawal: A survey among individuals who had been seizure-free for over 2 years.

OBJECTIVE: The study aimed to evaluate the attitudes of seizure-free patients toward the antiepileptic drug (AED) withdrawal and to highlight the factors that affect their perspectives. METHODS: The study participants were recruited among the individuals attending the epilepsy outpatient clinic of a university hospital in Skopje between January 2018 and April 2019. Patients with epilepsy who had been seizure-free for at least 2 years on stable monotherapy were included. RESULTS: Among the 90 participants, 43 were female, and the mean age was 36.3 years. The mean duration of active epilepsy before remission was 7.9 years, and the length of the seizure-free period at the time of evaluation was 2-20 years. Forty-four percent of participants aimed to taper their antiseizure medications because of concerns about the potential long-term side effects and teratogenicity, the burden of taking medication daily, stigma, as well as the impression of no longer having a chronic disease after withdrawal. The majority of them preferred slow versus rapid withdrawal. On the other side, 55% of patients choose to continue AED treatment, mainly feeling well-adjusted to it and being concern about possible seizure recurrence after withdrawal and subsequent loss of driving license or even their jobs. Previous unsuccessful attempts to discontinue AED together with previously uncontrolled seizures were additional motives against withdrawal. The patients' views toward stopping or withholding AED were significantly associated with their gender and marital status (male patients as well as single ones favored medication withdrawal). Patients' age to some extent, though not significantly, affected their viewpoints (younger participants tended to question the further necessity of AEDs and were more concerned about the potential adverse consequences). No other demographic or epilepsy-related data considerably predisposed the decisions. CONCLUSIONS: More than half of the patients with epilepsy preferred to continue their AED after 2 years of seizure freedom. Male gender, being single, and somewhat younger age were associated preferences to withdraw AED.

Rhabdomyolysis in Critically Ill Surgical Patients.

INTRODUCTION: Rhabdomyolysis is a syndrome of injury of skeletal muscles associated with myoglobinuria, muscle weakness, electrolyte imbalance and often, acute kidney injury as severe complication. THE AIM: of this study is to detect the incidence of rhabdomyolysis in critically ill patients in the surgical intensive care unit (ICU), and to raise awareness of this medical condition and its treatment among the clinicians. MATERIAL AND METHODS: A retrospective review of all surgical and trauma patients admitted to surgical ICU of the University Surgical Clinic "Mother Teresa" in Skopje, Macedonia, from January 1st till December 31st 2015 was performed. Patients medical records were screened for available serum creatine kinase (CK) with levels > 200 U/l, presence of myoglobin in the serum in levels > 80 ng/ml, or if they had a clinical diagnosis of rhabdomyolysis by an attending doctor. Descriptive statistical methods were used to analyze the collected data. RESULTS: Out of totally 1084 patients hospitalized in the ICU, 93 were diagnosed with rhabdomyolysis during the course of one year. 82(88%) patients were trauma patients, while 11(12%) were surgical non trauma patients. 7(7.5%) patients diagnosed with rhabdomyolysis developed acute kidney injury (AKI) that required dialysis. Average values of serum myoglobin levels were 230 ng/ml, with highest values of > 5000 ng/ml. Patients who developed AKI had serum myoglobin levels above 2000 ng/ml. Average values of serum CK levels were 400 U/l, with highest value of 21600 U/l. Patients who developed AKI had serum CK levels above 3000 U/l. CONCLUSION: Regular monitoring and early detection of elevated serum CK and myoglobin levels in critically ill surgical and trauma patients is recommended in order to recognize and treat rhabdomyolysis in timely manner and thus prevent development of AKI.

Fractures in people with epilepsy: A nationwide population-based cohort study.

OBJECTIVE: The objective of this study was to determine the age, gender, and site-specific prevalence of fractures in people with epilepsy (PWE) and matched general population comparators in a nationwide study in North Macedonia between 2015 and 2018. METHODS: PWE and matched controls were selected through a systematic search of the electronic National Health System (eNHS). We determined the period prevalence (PP) of all site-specific fractures. We also calculated gender and age-specific incidence rate ratios (IRR) for various fractures. Odds ratios (ORs) and risk ratios (RR) were estimated for the number and type of ASM as well as comorbid conditions. RESULTS: Out of 13 818 prevalent epilepsy cases, 6383 (46.2%) were females, and 7435 (53.8%) were males. 109 PWE out of 1000 had at least one fracture during the study period and ~8 people out of 1000 in the general population. The most frequent sites in terms of PP both in PWE and controls, were fractures of the lower arm, hip and femur, and lower leg. Significant differences in PP for all fracture locations were observed between PWE and controls (P < 0.001). The noticeable differences of ∼100 times higher PP were observed for fractures of the skull and jaw in PWE. IRR of any fracture in PWE was 272.84/10 000 person-years; higher in the older age groups and among people who received >2 ASM. Fracture risk was increased with the use of >2 ASM (OR: 1.56; 95% CI: 1.32-1.84 and RR: RR: 1.32). The presence of comorbidities also increased fractures risk (OR: 1.24; 95% CI: 1.10-1.38). SIGNIFICANCE: This population-based study depicts a higher fracture prevalence in PWE compared to the general population. A higher number of ASM and the presence of comorbidities increase the risk of fractures and targeted prevention might be needed in those subgroups of PWE.

Prevalence of various risk factors associated with new-onset epilepsy after the age of 50: a retrospective population-based study.

Population-based studies of epilepsy risk factors are rare. We aimed to evaluate the prevalence of various risk factors associated with new-onset epilepsy after the age of 50 years. We included all incident cases in North Macedonia between 2015 and 2018. Study participants were ascertained from the national healthcare platform. We performed a retrospective analysis of Electronic Health Records of 2,367 patients (1,017 females and 1,350 males) whose epileptic seizures started after the age of 50 years. Patients were stratified into 10-year age groups. The most common risk factor for new-onset epilepsy in our cohort was stroke, which was associated with new-onset epilepsy in 20% of patients aged 50-59 years and almost 50% of patients aged 70-79 years. The second most frequent risk factor was neoplasm in patients aged 50-69 years and dementia in patients older than 70 years. The other pre-existing conditions included: metabolic disorders, traumatic brain injury, and postencephalitic and inflammatory diseases. Chronic alcoholism was the most common metabolic risk factor associated with new-onset epilepsy and accounted for 84% of cases in this subgroup. Only metabolic disorders were significantly more frequent in males than in females (p<0.00001). We did not identify any epilepsy risk factor in 967 patients (41%). Systemic vascular risk factors were frequent in our cohort: 1,574 patients had hypertension (66%) and 449 patients had diabetes (19%), and 339 had both conditions (14%). We found that structural lesions were the most prevalent risk factor associated with new-onset epilepsy in middle-aged and elderly patients. Recognition of possibly modifiable factors associated with late-onset epilepsy could have a positive impact on reducing the risk of developing epilepsy.

Possible genetic anticipation in families with idiopathic generalised epilepsy.

Idiopathic generalised epilepsies (IGE) constitute nearly one third of all epilepsies. IGEs manifest with absences, myoclonic jerks and generalised tonic-clonic seizures (GTCS), either alone or in varying combinations, and have a strong genetic background. We present two three-generation families with juvenile myoclonic epilepsy (JME) probands and other affected family members with different forms of IGE in whom genetic anticipation was possible, i.e. the progressive decrease in age at onset with each successive generation. In the first family, the proband presented with JME with all three seizure types with an age at onset of eight years. Her cousin presented with both absence seizures and myoclonic jerks simultaneously at age 14 years, and GTCS occurred one year later. The proband's mother had her first seizures at the age of 39 years (brief myoclonic jerks and subtle absences predated GTCS by a few months). In the second family, the proband and his younger brother presented with JME at the age of 13 years, their mother experienced a single GTCS at the age of 38 years, while the grand-mother died during de novo generalised status at the age of 62 years. To our knowledge, this is one of the few reports to describe the occurrence of possible genetic anticipation in IGE which should be further investigated in larger cohorts of patients.

Association of rs211037 GABRG2 gene polymorphism with susceptibility to idiopathic generalized epilepsy.

Aim This case-control study aimed to determine a possible association of single nucleotide polymorphism rs211037 of the gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2) gene with the susceptibility to idiopathic generalized epilepsy (IGE) in the Macedonian population. Methods It enrolled 96 patients with clinically verified IGE and 51 healthy individuals without personal and family history of epilepsy or other neurological disorders as controls. A determination of the GABRG2 rs211037 polymorphism was performed using the TaqMan-based genotyping assay. Results A significant dominant association of the CC genotype (odds ratio - OR=2.100, 95% CI=1.018-4.332; p=0.043) and allelic association of C allele (OR=1.902, CI=1.040-3.477; p=0.035) with susceptibility to IGE was found. Carriers of CC genotype had approximately a 2-fold higher probability of developing IGE than the carriers of CT and TT genotypes. Carriers of the C allele had a 1.9-folds higher probability for IGE than the carriers of the T allele. Conclusion The polymorphism rs211037 of the GABRG2 gene increases the risk of the development of idiopathic generalized epilepsy in the Macedonian population.

Incidence and prevalence of epilepsy in the Republic of North Macedonia: Data from nationwide integrated health care platform.

PURPOSE: This study aimed to evaluate the incidence and period prevalence of epilepsy in the Republic of North Macedonia, an upper-middle-income country with universal access to healthcare, based on a nationwide healthcare platform (NHP). METHODS: NHP contains reports from all inpatient and outpatient medical encounters and procedures, and all electronic medical records are linked together with a unique patient number. We performed the analysis of the data maintained at the Macedonian Ministry of Health, concerning the five years of the study (2014 through 2018). Population and demographic data for each year were obtained from the State Statistical Office. RESULTS: The period prevalence was 6.67 per 1,000 inhabitants. There were 6383 (46.2%) females and 7435 (53.8%) males; the gender difference was significant: 6.17 per 1,000 females and 7.16 per 1,000 males (p = 0.0000). Between 2015 and 2018 the median annual incidence of epilepsy was 68 new epilepsy patients per 100,000, with an upward trend over time. The age-specific incidence was high in childhood and adolescence, was constant (and low) in the adult years, and gradually increased in each successive age group after the age of 50 years. The greatest incidence was found in group 70-79 years of age. The incidence in childhood and adolescence tends to gradually decrease from 2015 to 2018, while it progressively increased in population over 50 years of age, which may explain a rise in overall incidence. We found a statistically significant higher incidence in males than in females, a ratio consistently being 1.2: 1. CONCLUSION: The data from the study provides accurate findings on the prevalence and incidence of epilepsy in the upper-middle-income Southeastern European country.

Widespread frontal lobe cortical dysplasia or partial hemimegalencephaly: a continuum of the spectrum.

Focal cortical dysplasia (FCD) type II and hemimegalencephaly (HME) are currently considered as a continuum of pathology, the most important distinction being the extent or the size/volume of the lesion. While partial HME involving the posterior cortex has been well described, we present an unusual case with a dysplastic lesion of the whole frontal lobe. A 17-year-old boy had focal seizures from the age of nine years. Apart from diminished right-hand dexterity, his neurological and cognitive status were unremarkable. The course of his epilepsy exhibited a relapsing-remitting pattern, with prolonged periods of remission. Imaging showed dysplastic left frontal lobe (including paracentral lobule) thickened cortex with an abnormal gyration pattern resembling polymicrogyria, as well as dystrophic calcifications and hypodensity scattered throughout the white matter. This patient represents an intermediate case within the FCD type II/HME spectrum. Localization of the lesion in the frontal lobe as well as clinical characteristics (childhood onset, relapsing-remitting epilepsy, without hemiparesis and overt cognitive impairment) are more consistent with FCD type II, while a range of MRI features is shared between HME and FCD type II.

Hypernatremia-induced Neurologic Complications After Hepatic Hydatid Cyst Surgery: Pretreat to Prevent.

INTRODUCTION: Surgery is effective treatment for echinococcosis; however, there is a risk of hypertonic saline resorption and acute hypernatremia. AIM: We report two cases of severe hypernatremia following hydatid cyst removal. CASE REPORTS: A 17-year-old girl underwent surgical removal of hepatic hydatid cyst. Following the surgery, she developed seizures evolving to status epilepticus, and was sedated and mechanically ventilated. Blood chemistry showed hypernatremia. Fluid resuscitation with 5% dextrose infusions was started in combination with furosemide. Electrolytes were monitored frequently until plasma sodium levels normalized, 30 hours later. The patient was seizure free 48 hours later. The second patient is a 70-year-old man with hepatic hydatid cyst. After the surgery he became somnolent and confused due to severe hypernatremia. Intravenous administration of five percentage dextrose was initiated and high doses of furosemide. Sodium level normalized within 38 hours. The patient's mental status improved. CONCLUSION: A hospital protocol was established aiming to prevent hypernatremia and neurological complications.

Heterotopia or overlaying cortex: What about in-between?

We describe a patient with unilateral periventricular nodular heterotopia (PNH) and drug-resistant epilepsy, whose SEEG revealed that seizures were arising from the PNH, with the almost simultaneous involvement of heterotopic neurons ("micronodules") scattered within the white matter, and subsequently the overlying cortex. Laser ablation of heterotopic nodules and the adjacent white matter rendered the patient seizure free. This case elucidates that "micronodules" scattered in white matter between heterotopic nodules and overlying cortex might be another contributor in complex epileptogenicity of heterotopia. Detecting patient-specific targets in the epileptic network of heterotopia creates the possibility to disrupt the pathological circuit by minimally invasive procedures.

Levetiracetam-Induced Seizure Aggravation in Patients With Focal Cortical Dysplasia.

OBJECTIVES: The choice of antiepileptic drug is typically based on seizure type, and there is no evidence for superior effectiveness or potential deterioration of particular antiepileptic drug in specific etiologic subgroups. The aim of the study was to identify etiological factor(s) associated with increased risk of seizure aggravation with levetiracetam (LEV). METHODS: A retrospective analysis of 139 patients treated with LEV was performed. Seizure aggravation was defined as a 100% or greater increase in seizures frequency, which occurred within 1 month of drug introduction. RESULTS: Five patients who fulfilled the selection criteria were identified. Seizure aggravation occurred with low doses (500-1000 mg) of LEV. In addition to increased frequency and duration, 2 patients developed new seizure types. Withdrawal of LEV resulted in seizure return to background frequency in all patients. Four of 5 patients have distinctive magnetic resonance imaging finding of focal cortical dysplasia. No patients with paradoxical effect of LEV were detected in the idiopathic epilepsy group or other types of symptomatic epilepsies. CONCLUSIONS: Our results suggest that LEV may possibly induce seizure exacerbation in a subset of patients with focal cortical dysplasia-related epilepsy, although large studies are needed to establish the relation. Underlying causes of epilepsy could impact the treatment choice because electroclinical semiology might be the "final common pathway" of different epileptogenic mechanisms in diverse etiologies.

Phenotypic spectrum in families with mesial temporal lobe epilepsy probands.

PURPOSE: The traditional perception of mesial temporal lobe epilepsy (MTLE) as a predominantly acquired disorder is challenged due to emerging evidence of familial aggregation. In this study, we ascertained the extent of familial occurrence of epilepsy in MTLE patients, as well as phenotypic heterogeneity in affected relatives. METHODS: We identified and reevaluated patients with MTLE, treated at Epilepsy Department for a period of two years. All eligible putatively affected relatives were asked to participate in the study. In addition to comprehensive epilepsy interview, they underwent EEG and MRI studies. RESULTS: 52 patients with MTLE were included; nine of them (17%) had at least one family member with epilepsy. Subsequently, we analyzed nine probands with MTLE and a total of 15 relatives with seizures. Among affected relatives, spectrums of clinical manifestations were observed. Typical MTL seizures were described in five individuals, while other types of focal or generalized tonic-clonic seizures were reported in other ten relatives. A total of seven individuals had febrile seizures. Hippocampal sclerosis was found in three probands and none of the relatives. Two of affected family members had a traumatic brain injury in addition to febrile seizures, prior to the occurrence of their epilepsy. CONCLUSION: We demonstrate that familiar occurrence of epilepsy and subsequently putative genetic background, accounts for a substantial proportion MTLE patients. In addition, we foreground the remarkable intra- and interfamilial phenotypic heterogeneity than usually described, displaying the complexity of the genotype-phenotype correlations.

Seizure outcome following medical treatment of mesial temporal lobe epilepsy: Clinical phenotypes and prognostic factors.

OBJECTIVE: Surveys on mesial temporal lobe epilepsy (MTLE) repeatedly demonstrate that seizures are commonly resistant to antiepileptic drugs (AED), but patients usually came from third-level epilepsy centers, making the medically refractory population larger. The aim of our study is to evaluate patterns of seizure control and prognostic factors of general population of MTLE patients observed in clinical practice. METHODS: Sixty five MTLE patients were evaluated for demographic data, family history, febrile convulsions, detailed descriptions of auras and seizures, presence of secondarily generalized seizures, age at seizure onset, duration of epilepsy, epileptiform discharges in EEG, neuroradiological findings and AED schedules with therapeutic response. According to seizure frequency, patients were divided into three groups: (1) seizure-free (SF) patients at the time of evaluation, (2) patients considered as having infrequent seizures (IS) if they presented only auras or up to three dyscognitive (complex partial) seizures per year and (3) patients with higher rate were regarded as having frequent seizures i.e. being drug-resistant (DR). For each clinical parameter, the three groups were compared statistically. In addition, following the patterns of evolution over time, patients were categorized into two groups: continuous pattern, with no period of remission, and intermittent pattern, in which patients had at least one period of remission. RESULTS: Ten patients (15.4%) were seizure free, 19 (29.2%) had infrequent seizures, while 36 patients (55.4%) had frequent uncontrolled seizures. Ten (52.6%) IS patients and ten (27.7%) DR patients had a intermittent i.e. relapse-remitting pattern with at least one period of two years without seizures. Female patients dominated SF group and the gender difference with other groups reached statistical significance (p=0.02). Comparing the groups, DR group had longer seizure duration than IS group (12.6±10.9years vs. 22.8±10.6years, p=0.006). Number of tried AEDs (p<0.00006) was significantly lower in the seizure-free patients. Other variables are not related to course of the epilepsy. CONCLUSION: MTLE is a heterogeneous syndrome, 45% of patients in our series were having either rare auras or seizures or were seizure-free. The factors associated with drug resistance were longer duration of epilepsy, higher number of previously tried AED and male gender.

Brief communication of assessment of clinical practice regarding pharmacological treatment of epilepsy: a survey of neurologists in Republic of Macedonia.

A questionnaire of 15 items was developed in order to evaluate clinical practice regarding pharmacological treatment of epilepsy among adult neurologists in R. Macedonia. It was mailed to 30 practising neurologists, 24 answered (80%). Half of them administer AED after a first unprovoked seizure considering EEG and MRI, while others usually wait for a second one before introducing treatment. Discontinuation of treatment should be individualized. Carbamazepine and lamotrigine are the most frequently prescribed first-line drugs for partial seizures; second choices include a number of older and new generation AEDs. For generalized tonic-clonic seizures, absences, myoclonic, mixed or undetermined seizures, valproate is by far the most commonly used AED. The survey showed that prescription patterns are in accordance with current evidence about the spectrum of efficacy of individual AEDs in different types of seizures. Yet some results are a cause of concern and continuous education of the neurological community on AED treatment of epilepsy is needed.

Clinical genetic study in juvenile myoclonic epilepsy.

PURPOSE: To evaluate clinical features of probands with juvenile myoclonic epilepsy (JME) and affected members of their families in order to study clinical genetics of JME. METHOD: Thirteen unrelated families with at least two members with history of seizures were identified; clinical and genealogic data were collected from JME probands and family members. RESULTS: All probands had myoclonic and generalized tonic-clonic seizures (GTCS), while absences occurred in 25% of them. The average age of seizure onset was 13 years. Totally 22 members from 13 families had history of seizures with average age of seizure onset at 18 years. Ten family members had JME, three had epilepsy with GTCS, two had juvenile absence epilepsy, one had adult onset myoclonic epilepsy and six of the affected individuals had unclassified type of epilepsy. In five families, JME was the solely clinical feature. JME dominated among siblings, while phenotypic heterogeneity was observed in second and third degree relatives. In three multi-generation families, members with adult onset genetic generalized epilepsies (GGE) were identified. CONCLUSION: We found phenotypic heterogeneity regarding epilepsy type and age of seizure onset. Using pedigree analysis, we found no evidence for preferential maternal or any other distinctive inheritance pattern. Further study is needed to confirm and clarify the results.

The association of C3435T single-nucleotide polymorphism, Pgp-glycoprotein gene expression levels and carbamazepine maintenance dose in patients with epilepsy.

The ABCB1 gene encodes the P-glycoprotein (Pgp) protein, which is thought to transport various antiepileptic drugs. The single nucleotide polymorphism (SNP) (C3435T) in exon 26 of this gene correlates with the altered expression levels of P-glycoprotein, range of drug response and clinical conditions. In order to investigate the influence of this polymorphism on the susceptibility to and efficacy of carbamazepine therapy, we evaluated the allelic frequency and genotype distribution of this variant in 162 epilepsy patients from the Republic of Macedonia. Statistically significant differences were detected neither in the allelic frequency and genotype distribution between carbamazepine-resistant and carbamazepine-responsive epilepsy patients nor between the subgroups of carbamazepine (CBZ)-responsive patients treated with different CBZ doses. However, the T-allele was enriched in CBZ-responsive patients who required higher maintenance CBZ doses, This observation was substantiated by the findings that the median total plasma levels were the lowest in patients with CC (20 µmol/L) followed by CT (23 µmol/L) and TT (29 µmol/L) genotypes. Patients with a CC genotype also had a higher likelihood of response compared to patients with CT or TT genotypes over a wide range (400-1000 mg/day) of initial doses of CBZ. The T allele showed a reduced expression of ~5% compared to the C allele in peripheral blood mononuclear cells in heterozygotes for the variant. This difference might be translated into ~10% difference in homozygotes for the variant, which would explain the trend towards a dose-dependent efficacy of the CBZ treatment in patients with different genotypes. A larger prospective study is warranted to clarify the clinical utility of a genotypespecific individualized CBZ therapy.