Adverse Skin Reactions with Antiepileptic Drugs Using Korea Adverse Event Reporting System Database, 2008-2017.

BACKGROUND: Severe and life-threatening drug eruptions include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). One class of medications that has been highly associated with such drug eruptions is antiepileptic drugs (AEDs). We attempt to investigate drug eruptions associated with AEDs as a class, as well as with individual AEDs, in Korea. METHODS: We used the Korea Institute of Drug Safety and Risk Management - Korea Adverse Event Reporting System (KIDS-KAERS) database, a nationwide database of adverse events reports, between January 2008 and December 2017 to investigate the reporting count of all drug eruptions and calculated the ratio of DRESS/SJS/TEN reports for each AED. RESULTS: Among a total of 2,942 reports, most were of rash/urticaria (2,702, 91.8%), followed by those of DRESS (109, 3.7%), SJS (106, 3.6%), and TEN (25, 0.85%). The common causative AEDs were lamotrigine (699, 23.8%), valproic acid (677, 23%), carbamazepine (512, 17.4%), oxcarbazepine (320, 10.9%), levetiracetam (181, 6.2%), and phenytoin (158, 5.4%). In limited to severe drug eruptions (DRESS, SJS, and TEN; total 241 reports), the causative AEDs were carbamazepine (117, 48.8%), lamotrigine (57, 23.8%), valproic acid (20, 8.3%), phenytoin (15, 6.3%), and oxcarbazepine (10, 4.2%). When comparing aromatic AED with non-aromatic AED, aromatic AEDs were more likely to be associated with severe drug eruption (aromatic AEDs: 204/1,793 versus non-aromatic AEDs: 37/1,149; OR, 3.86; 95% CI, 2.7-5.5). Death was reported in 7 cases; DRESS was the most commonly reported adverse event (n = 5), and lamotrigine was the most common causative AED (n = 5). CONCLUSION: Although most cutaneous drug eruptions in this study were rash or urticaria, approximately 8% of reports were of severe or life-threatening adverse drug reactions, such as SJS, TEN, or DRESS. When hypersensitivity skin reactions occurred, aromatic AEDs were associated with 4 fold the risk of SJS/TEN/DRESS compared with non-aromatic AEDs. Our findings further emphasize that high risk AEDs should be prescribed under careful monitoring, and early detection and prompt interventions are needed to prevent severe complications.

Sleep Apnea and Early Neurological Deterioration in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Evidence of an association between sleep apnea (SA) and early neurological deterioration (END) in acute phase ischemic stroke is scant. We investigated the prevalence of SA and the impact of SA severity on END in acute ischemic stroke (AIS) patients. METHODS: We prospectively enrolled consecutive AIS patients admitted to our stroke unit within 72 hours of symptom onset. SA severity was assessed with ApneaLink-a validated portable respiratory monitor. SA was defined as an apnea-hypopnea index (AHI) of greater than or equal to 5 per hour. END was defined as an incremental increase in the National Institutes of Health Stroke Scale (NIHSS) score by greater than or equal to 1 point in motor power, or greater than or equal to 2 points in the total score within the first week after admission. RESULTS: Of the 305 patients studied, 254 (83.3%) patients had SA (AHI ≥ 5 per hour), and of these, 114 (37.4%) had mild SA (AHI 5-14 per hour), 59 (19.3%) had moderate SA (AHI 15-29 per hour), and 81 (26.6%) had severe SA (AHI ≥ 30 per hour). Thirty-six (11.8%) patients experienced END: 2 of the 51 (3.9%) patients without SA and 34 of the 254 (14.4%) patients with SA. Multivariable regression analysis showed AHI independently predicted END (odds ratio 1.024; 95% confidence interval 1.006 to 1.042; P = .008). CONCLUSIONS: SA is common in the acute phase of ischemic stroke, and SA severity is associated with the risk of END.

Increased Left Ventricular Filling Pressure and Arterial Occlusion in Stroke Related to Atrial Fibrillation.

BACKGROUND: We investigated whether left ventricular filling pressure is associated with arterial occlusion in patients with ischemic stroke related to atrial fibrillation (AF). METHODS: Ninety-nine patients with AF-related stroke were included. Left ventricular filling pressure was assessed by E (early mitral inflow velocity)/e' (early diastolic velocity of the mitral valve annulus velocity) ratio based on tissue Doppler echocardiography. Arterial occlusion was evaluated by computed tomography or magnetic resonance angiography. In addition, the presence of a hyperdense middle cerebral artery sign (HMCAS) on noncontrast brain computed tomography, a marker of acute thrombus burden, was assessed. Multiple logistic regression was used to evaluate the association of E/e' with arterial occlusion and the HMCAS. RESULTS: The mean age was 73.2 (±10.2), and 56% were men. Thirty-six (36.4%) patients had arterial occlusion on imaging. E/e' ratios were independently associated with arterial occlusion with an odds ratio of 1.24 (per 1 increase, 95% confidence interval 1.11-1.38). The receiver operating characteristics curve demonstrated that E/e' ratios have an excellent discriminatory capacity in predicting arterial occlusion with an area under the curve of .77 (P < .001). In addition, E/e' ratios were higher in patients with HMCAS than in those without (19.1 versus 14.0, P < .001). CONCLUSION: E/e' ratios were associated with arterial occlusion in AF-related stroke and may play a role in identifying patients at high risk of severe stroke.

The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy.

Although long-term therapy with antiepileptic drugs can increase the risk of vascular diseases, there have been little attempts to reduce the increased vascular risk in patients with epilepsy. We conducted a prospective longitudinal study to assess the effects of lifestyle modification and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy on the increased circulatory markers for vascular risk in patients with epilepsy. We recruited patients with increased vascular risk such as a history of vascular events or hypercholesterolemia, and they decided whether to be treated with statin or just to modify their lifestyle. The circulatory markers of vascular risk were measured twice before and after a 3-month intervention. A total of 78 patients completed the study, and 37 of them chose to be treated with statin. A 3-month intervention with statin results in significant decreases in homocysteine (p=0.010) and uric acid (p=0.015) as well as total cholesterol (p<0.001) and low-density lipoprotein (LDL) cholesterol (p<0.001). The lifestyle modification group experienced less prominent decreases in total cholesterol (p=0.010) and LDL cholesterol (p=0.012). There were no reports of serious adverse events or seizure aggravation related to the statin treatment. Our findings suggest that lifestyle education is necessary in patients with epilepsy with increased vascular risk and that treatment with statin would be a well-tolerated and effective option for these patients.

Clinical predictors for delirium tremens in patients with alcohol withdrawal seizures.

BACKGROUND: Delirium tremens (DT) is the severest form of alcohol withdrawal syndrome, frequently after alcohol withdrawal seizures. Delirium tremens occurs in a small proportion of patients with alcohol withdrawal seizures; nevertheless, early identification of high-risk patients is important for intensive preventive management of unexpected episodes due to agitation and its associated increased mortality. However, there are limited studies on clinical predictors of the development of DT in patients with alcohol withdrawal seizures. METHODS: Patients who visited the emergency department with acute seizures were included in the study when alcohol withdrawal was the only or the strongest precipitating factor for seizures. All patients were carefully observed for at least 48 hours in the intensive care unit after the initial assessment to closely monitor vital signs and development of DT. Clinical and laboratory findings were analyzed for predicting the development of DT. RESULTS: Of the 97 patients (82 males; mean age, 48.6 ± 13.3 years) with alcohol withdrawal seizures, 34 (35.1%) developed DT. Low platelet count, high blood level of homocysteine, and low blood level of pyridoxine were associated with the subsequent development of DT. Low platelet count and high blood level of homocysteine were independent risk factors with high diagnostic sensitivity and specificity for the development of DT. CONCLUSIONS: The study indicated that some easily determined parameters are potential clinical predictors for the development of DT in patients with alcohol withdrawal seizures. These findings would be helpful in clinical identification and management patients at high risk for DT.

Effects of surgical weight loss for treating obstructive sleep apnea.

PURPOSE: Weight loss has been reported to reduce the severity of obstructive sleep apnea (OSA), particularly in the obese population. However, prospective studies with polysomnography (PSG) for the precise evaluation of OSA are lacking especially in Asian countries. We evaluated the effects of surgical weight loss for treating OSA using PSG data obtained before and after surgery. METHODS: We performed a prospective study analyzing the clinical and PSG data obtained from our cohort of bariatric surgical candidates with moderate to severe OSA, as confirmed by preoperative PSG. The patients underwent follow-up PSG at least 12 months after bariatric surgery (laparoscopic Roux-en-Y gastric bypass). RESULTS: Of the 47 patients (70.1%) with moderate to severe OSA among 67 patients who underwent preoperative PSG, 10 patients underwent postoperative PSG. The mean apnea-hypopnea index (AHI) of these 10 patients significantly reduced from 51.0±34.2 to 9.3±12.9 events/h, while their mean body mass index (BMI) loss was from 39.9±8.3 to 26.9±4.4 kg/m2. Although the severity of OSA improved considerably, OSA resolution was achieved in only five patients (50%). When compared to the patients who achieved OSA resolution, the patients with residual OSA showed a tendency to have lower minimum arterial oxygen saturation (SaO2) levels and higher supine AHI values in preoperative PSG. CONCLUSIONS: Surgical weight loss resulted in the significant improvement of OSA associated with obesity. However, OSA remained in a considerable proportion of patients even after substantial weight loss. We recommend that postoperative PSG be considered for the evaluation of residual OSA, especially in patients with low minimum SaO2 levels and high supine AHI in preoperative PSG.

Nonaneurysmal subarachnoid hemorrhage after udenafil intake.

We report a 67-year-old man who presented with severe headache after taking 50 mg of udenafil, a new phosphodiesterase 5 inhibitor. Computed tomographic imaging of the brain revealed a small amount of acute subarachnoid hemorrhage localized around basal cisterns (anterior to midbrain and pons). There were no aneurysms in the cerebral arteries, although vein of Galen stenosis was suspected after magnetic resonance venography. This case anecdotally suggests that phosphodiesterase 5 inhibition might trigger perimesencephalic subarachnoid hemorrhage with venous hypertension possibly associated with vein of Galen stenosis.

Withdrawal of antiepileptic drugs after neocortical epilepsy surgery.

OBJECTIVE: This study investigated the prevalence of successful antiepileptic drug withdrawal and identified predictors of seizure recurrence after antiepileptic drug reduction following resectional operation for intractable neocortical epilepsy. METHODS: We retrospectively assessed 223 patients (100 with neocortical temporal lobe epilepsy, 69 with frontal lobe epilepsy, 23 with parietal lobe epilepsy, 25 with occipital lobe epilepsy, and 6 with multifocal epilepsy) who underwent surgery. The mean period of observation was 84.4 months (range, 24-152 months) after surgery and 72.6 months (range, 12-138 months) after initial reduction. Clinical characteristics, magnetic resonance imaging, and surgical parameters were evaluated for their potential to predict recurrence associated with antiepileptic drug withdrawal. RESULTS: Antiepileptic drug reduction was attempted in 147 patients (65.9%), 78 (53.1%) of whom had seizure recurrence after initial reduction. Discontinuation was achieved in 73 patients (32.7%), and 59 (80.8%) of these remained seizure free until final assessment. Multivariate analysis revealed that early drug tapering, normal magnetic resonance imaging results, seizure before reduction, and longer epilepsy duration were associated with recurrence. Finally, 27.4% of patients were seizure free without drugs, and 26.9% were seizure free with drugs. Compared with preoperative status, the number of antiepileptic drugs needed decreased in 50.7% of patients, did not change in 19.3%, and increased in 30.0% after surgery. INTERPRETATION: The complete-cure rate of intractable neocortical epilepsy by resectional surgery was 27.4%. When patients undertake early tapering, and have normal magnetic resonance imaging results, seizure before reduction, and longer disease duration, further withdrawal should be done cautiously because of the high risk of relapse.

Ictal asystole and eating reflex seizures with temporal lobe epilepsy.

Both ictal asystole and eating reflex seizures are rare conditions that are closely related to temporal lobe epilepsy (TLE). Patients exhibiting these two conditions simultaneously have not been previously reported. We describe two unusual cases in which patients with left TLE were confirmed to have ictal asystole and eating epilepsy by video-electroencephalographic monitoring. As the pathophysiological mechanisms underlying these conditions are unknown, the association between ictal asystole and eating reflex seizures may be coincidental or may suggest an elusive common mechanism in association with TLE. In addition, combined electrocardiography monitoring and cardiac evaluation are recommended for patients with TLE and unexplained collapse.

Cardiac effects of rapid intravenous loading of lacosamide in patients with epilepsy.

BACKGROUND: Lacosamide (LCM) is a new antiseizure medication, and intravenous (IV) loading of LCM is recently used against status epilepticus. IV loading of LCM is usually well-tolerated; however, there are concerns about LCM-induced serious adverse cardiac events. This study was aimed at investigating whether rapid IV loading of LCM is associated with adverse cardiac or hemodynamic events in cases of epilepsy emergencies in real-world settings. METHODS: We reviewed medical records of consecutive adult epilepsy patients who received a single loading dose (400 mg) of IV LCM between January 2019 and December 2020 and included patients who exhibited status epilepticus or acute repetitive seizures. Electrocardiography findings, blood pressure, and heart rate before and after the IV infusion of LCM were collected. RESULTS: Of the 85 patients included, 32.9 % (28/85 patients) had experienced at least one cardiac adverse event. The most common adverse events were new-onset first-degree atrioventricular block (19 patients) and hypotension (seven patients). Atrial fibrillation and bradycardia developed in two patients and atrial flutter in one. There were significant increases in the mean PR interval (from 169.3 msec to 184.5 msec, P < 0.01) and decreases in the mean heart rate (from 91.7 to 86.9, P = 0.01) after IV loading of LCM. Older age was significantly associated with a higher magnitude of the PR interval difference between before and after IV loading of LCM. CONCLUSIONS: In cases of epilepsy emergencies, adverse cardiac events commonly developed after IV loading of LCM, although most adverse events were mild in severity or not clinically significant. Elderly patients or patients with underlying cardiac diseases were prone to exhibiting a more prolonged PR interval after IV loading of LCM. Thus, the loading dose of IV LCM should be infused under careful ECG monitoring in these patients.

MicroRNAs induced during ischemic preconditioning.

BACKGROUND AND PURPOSE: MicroRNAs (miRNA) are single-stranded short RNA molecules that regulate gene expression by either degradation or translational repression of mRNA. Although miRNAs control a number of conditions and diseases, few neuroprotective miRNAs have been described. In this study, we investigated neuroprotective miRNAs induced early in ischemic preconditioning. METHODS: Ischemic preconditioning or focal cerebral ischemia was induced in mice by transient occlusion of the middle cerebral artery for 15 or 120 minutes. We prepared RNA samples from the ischemic cortex at 3 or 24 hours after the onset of ischemia. Selective miRNAs then were synthesized and transfected into Neuro-2a cells before oxygen-glucose deprivation. RESULTS: We detected a total of 360 miRNAs. Two miRNA families, miR-200 and miR-182, were selectively upregulated at 3 hours after ischemic preconditioning. Transfections of some of these were neuroprotective in in vitro ischemia. Among them, miR-200b, miR-200c, and miR-429 targeted prolyl hydroxylase 2 and had the best neuroprotective effect. CONCLUSIONS: Two miRNA families, miR-200 and miR-182, were upregulated early after ischemic preconditioning and the miR-200 family was neuroprotective mainly by downregulating prolyl hydroxylase 2 levels. These miRNAs may be useful in future research and therapeutic applications.

Switching from traditional sodium channel blockers to lacosamide in patients with epilepsy.

PURPOSE: Lacosamide (LCM) is a recently developed sodium channel blocker (SCB), which acts mainly on the slow activation state in sodium channels. Although LCM shares a range of dose-dependent adverse effects with traditional SCBs, it has several advantages in that it does not induce hepatic drug metabolizing enzymes and has less risk of drug interactions and idiosyncratic adverse effects. METHODS: We retrospectively analyzed the efficacy and tolerability of switching from traditional SCBs to LCM. The reason for the switch was classified as insufficient efficacy, adverse effects, or concern about metabolic derangement, resulting in conditions such as atherosclerosis and osteoporosis, with long-term use of traditional SCBs. RESULTS: Seventy-five patients were switched to LCM from traditional SCBs. The overall rate of successful switching was high (81.3%, 61/75 patients). However, the success rate was strongly dependent on the reason for the switch; patients with insufficient efficacy on SCBs had less chance of a successful switch (71.8%, 28/39 patients) than those with adverse effects (89.5%, 17/19) or concerns about metabolic derangement (94.1%, 16/17, p = 0.038). Patients with insufficient efficacy were significantly younger (p = 0.004) and had a higher chance of drug-resistant epilepsy (p = 0.004) than those in the other two groups. CONCLUSIONS: Our study shows that switching from traditional SCBs to LCM is usually successful and the likelihood of a successful switch is higher in patients when the reason for the switch is adverse effects or concerns about metabolic derangement on traditional SCBs.

Electroencephalographic Abnormalities in the Screening for Pilot Applicants in Korea.

BACKGROUND AND PURPOSE: Electroencephalography (EEG) is often used as a screening tool for selecting pilots despite controversy regarding its contribution to aviation safety. We investigated EEG abnormalities in Korean commercial pilot applicants in order to identify the usefulness of EEG screening in this population. METHODS: We retrospectively analyzed the EEG results of 740 unselected pilot applicants who underwent waking EEG at Inha University Hospital from January 2013 to May 2017. EEG recording was performed for 30 minutes, which included 3 minutes of hyperventilation and intermittent photic stimulation. RESULTS: The pilot applicants were predominantly male (95.3%) and had a mean age of 27.8 years (range: 16-40 years). Nine of them (1.2%) exhibited EEG abnormalities; the most common abnormality (six applicants) was a small amount of generalized irregular slow activities, while the other three applicants (0.4%) exhibited epileptiform discharges, with two showing generalized spike-and-wave complexes and one showing a few spike-and-wave complexes in the left frontotemporal area. The two applicants with generalized spike-and-wave complexes were found to have experienced clinical seizures by a neurologist during detailed history-taking. CONCLUSIONS: This study found that 2 of 740 pilot applicants (0.3%) were diagnosed with epilepsy by routine EEG screening in an unselected population. Considering the low predictive value of EEG without the relevant clinical history in an unselected healthy young population, our findings raise questions regarding the cost-effectiveness of the current EEG screening protocol applied to pilot applicants. We suggest that a more-targeted and standardized EEG screening approach be applied to pilot applicants with epilepsy risk factors or a seizure history as determined by thorough medical history-taking.

Factors influencing topiramate clearance in adult patients with epilepsy: A population pharmacokinetic analysis.

PURPOSE: To identify the factors influencing topiramate pharmacokinetics (PK) in a large population of adult patients with epilepsy using population PK analysis. METHODS: Clinical data and blood samples were collected from 550 adult patients with epilepsy treated using topiramate. Nonlinear mixed effects modeling software (NONMEM, version 7.2) was used to fit the plasma concentration to a one-compartment PK model. Demographic and clinical variables tested as potential covariates were age, sex, body weight, height, serum creatinine, creatinine clearance (CLcr), total bilirubin, prothrombin time, albumin, aspartate transaminase (AST), alanine transaminase (ALT), daily dose (DOSE), and concomitant medications (phenytoin [PHT], clobazam, carbamazepine [CBZ], valproic acid, lamotrigine, levetiracetam, oxcarbazepine [OXC], pregabalin, clonazepam, and phenobarbital [PB]). RESULTS: The final PK model was CL/F (L/h)=(1.16+1.36 × PHT+1.01 × CBZ+0.643 × OXC+0.476 × PB)×(CLcr/90)(0.310)×(DOSE/100)(0.0929) (1 in patients co-medicated with each drug, 0 in otherwise) and V/F (L)=109 × (WT/62). For a typical patient with CLcr of 90 mL/min and DOSE of 100mg, co-medication with PHT, CBZ, OXC, and PB increased the CL/F to 2.52 (1.16+1.36)L/h, 2.17 (1.16+1.01)L/h, 1.803 (1.16+0.643)L/h, and 1.636 (1.16+0.476)L/h, respectively, which was 117, 87, 55, and 41% higher, respectively, than in patients without co-medication. CONCLUSION: The apparent clearance of topiramate increased with co-medication of PHT, CBZ, OXC, and PB. This population PK model can be applied for optimizing topiramate dosage regimens in actual clinical practice.

A pathophysiologic approach for subacute encephalopathy with seizures in alcoholics (SESA) syndrome.

Subacute encephalopathy with seizures in alcoholics (SESA) syndrome is a unique disease entity characterized by typical clinical and electroencephalographic (EEG) features in the setting of chronic alcoholism. We present two patients with distinctive serial MRI and EEG findings which suggest a clue to the underlying pathophysiologic mechanisms of SESA syndrome. Two patients with chronic alcoholism and alcoholic liver cirrhosis presented with generalized seizures and confused mental status. Brain MRI demonstrated restricted diffusion, increased T2-weighted signal intensity, and hyperperfusion in the presumed seizure focus and nearby posterior regions of the cerebral hemispheres. EEG showed periodic lateralized epileptiform discharges which were prominent in the posterior regions of the cerebral hemispheres ipsilateral to the side of brain MRI abnormalities. Even after patients clinically improved, these brain abnormalities persisted with progressive atrophic changes on follow-up brain MRI. These patients had not only the distinguishing clinical and EEG features of SESA syndrome, but also showed novel brain MRI abnormalities. These changes on MRI displayed characteristics of seizure-related changes. The posterior dominance of abnormalities on MRI and EEG suggests that the pathophysiologic mechanisms of SESA syndrome may share those of posterior reversible encephalopathy syndrome.

Cefepime-induced Aphasic Status Epilepticus Mimicking Acute Stroke.

Cefepime-induced neurotoxicity, including nonconvulsive status epilepticus, has been reported especially in patients with renal impairment. However, focal nonconvulsive status epilepticus is very rare and cefepime-induced aphasic status epilepticus proven by electroencephalography have never been reported to our knowledge. We present an interesting case of aphasic status epilepticus mimicking acute stroke in a patient treated by cefepime.

Neuropathologic and clinical features of human medial temporal lobe epilepsy.

BACKGROUND AND PURPOSE: There is recent evidence of various types of morphological changes in the hippocampus of a rodent model of medial temporal lobe epilepsy (mTLE). However, little is known about such changes in humans. We examined the histological changes [i.e., neuronal loss, cell genesis, and granule cell dispersion (GCD)] in surgical hippocampal specimens taken from patients with mTLE. METHODS: Nissl staining, and nestin and Prox1 immunohistochemistry were performed on human hippocampal specimens obtained from patients with medically intractable mTLE, thus allowing the analysis of neuronal loss, cell genesis, and GCD, respectively. We also assessed the correlations between clinical parameters and the histopathologic findings. RESULTS: The degree of cell genesis in the granule cell layer was significantly correlated with the severity of GCD, history of childhood febrile seizures, and frequent generalized seizures. Cell genesis was not correlated with cell death, age at seizure onset, duration of epilepsy, or the mean frequency of all seizures. CONCLUSIONS: Our results indicate that cell genesis in the dentate gyrus of patients with mTLE is associated with GCD and is influenced by the presence of febrile seizures during childhood and the frequency of episodes of generalized seizures.