Drug-Induced Liver Injury in Critically Ill Children Taking Antiepileptic Drugs: A Retrospective Study.

BACKGROUND: Antiepileptic drugs are among the leading causes of drug-induced liver injury (DILI). Due to critical illness, children admitted to intensive care units are more prone to DILI. OBJECTIVE: We attempted to elucidate the association between antiepileptic drug use and the associated factors resulting in DILI in a pediatric intensive care unit of a tertiary care hospital. METHODS: We carried out an observational retrospective study on children receiving antiepileptic drugs. Details on their demographic characteristics, drugs, serum levels of antiepileptic drugs and liver function tests, and hospital stay were recorded. Council for International Organizations of Medical Sciences definitions were adhered to when defining DILI. LiverTox (https://livertox.nih.gov) and DILIrank were used to assess the risks of hepatotoxicity of the concomitant drugs. Regression models were developed for predicting DILI. RESULTS: Five out of 9 patients taking phenobarbitone (55.6%), 9 out of 12 taking phenytoin monotherapy (75%), 7 out of 10 taking phenytoin/phenobarbitone (70%), all 3 receiving phenytoin/phenobarbitone/valproate sodium, and 1 with phenytoin/carbamazepine developed DILI either in the form of hepatocellular injury or liver biochemical test abnormalities. None of the patients had cholestatic or mixed type of liver injury. All the critically ill children received at least 2 concomitant drugs with hepatotoxic potential. Concomitant category B hepatotoxic drugs and toxic drug levels were significantly associated with increased risk of DILI. Similarly, a trend was observed for less-DILI-concern concomitant drug class and toxic drug levels when the drugs were analyzed by DILIrank classification. CONCLUSIONS: A significant proportion of critically ill children taking antiepileptic drugs experience DILI. Guidelines recommending use of drugs with reduced risk of potential hepatotoxicity for various concomitant disease states in such children admitted to intensive care units receiving antiepileptic drugs are urgently needed.

Diet therapy for narcolepsy.

The effects of a low-carbohydrate, ketogenic diet (LCKD) on sleepiness and other narcolepsy symptoms were studied. Nine patients with narcolepsy were asked to adhere to the Atkins' diet plan, and their symptoms were assessed using the Narcolepsy Symptom Status Questionnaire (NSSQ). The NSSQ-Total score decreased by 18% from 161.9 to 133.5 (p = 0.0019) over 8 weeks. Patients with narcolepsy experienced modest improvements in daytime sleepiness on an LCKD.

Non-convulsive status epilepticus: usefulness of clinical features in selecting patients for urgent EEG.

BACKGROUND: Non-convulsive status epilepticus (NCSE) is status epilepticus without obvious tonic-clonic activity. Patients with NCSE have altered mental state. An EEG is needed to confirm the diagnosis, but obtaining an EEG on every patient with altered mental state is not practical. OBJECTIVE: To determine whether clinical features could be used to predict which patients were more likely to be in NCSE and thus in need of an urgent EEG. METHODS: Over a six month period, all patients for whom an urgent EEG was ordered to identify NCSE were enrolled. Neurology residents examined the patients and filled out a questionnaire without knowledge of the EEG results. The patients were divided into two groups, NCSE and non-NCSE, depending on the EEG result. The clinical features were compared between the two groups. The sensitivity and specificity of the features were calculated. RESULTS: 48 patients were enrolled, 12 in NCSE and 36 not in NCSE. Remote risk factors for seizures, severely impaired mental state, and ocular movement abnormalities were seen significantly more often in the NCSE group. The combined sensitivity of remote risk factors for seizures and ocular movement abnormalities was 100%. CONCLUSIONS: There are certain clinical features that are more likely to be present in patients in NCSE compared with other types of encephalopathy. Either remote risk factors for seizures or ocular movement abnormalities were seen in all patients in NCSE. These features may be used to select which patients should have an urgent EEG.

Intractable epilepsy following radiosurgery for arteriovenous malformation.

Radiosurgery is often used to treat arteriovenous malformations (AVMs) located in deep brain locations. Most of these procedures are successful not only in obliterating the AVM but also in decreasing the frequency and severity of associated seizures. Although radiosurgery is occasionally associated with the development of easy-to-control seizures immediately postoperatively, there have been no reports of intractable epilepsy developing after radiosurgery. In this report, however, a case is presented in which a patient underwent gamma knife surgery (GKS) for an AVM, after which intractable epilepsy and mesial temporal sclerosis (MTS) gradually developed. A 37-year-old right-handed woman underwent GKS for a right mesial parietotemporooccipital AVM. One year later, the AVM had reduced in size, but the patient began to experience complex partial seizures (CPSs). These CPSs initially occurred at a frequency of one per month, but 6 months later they were occurring every other week. She also started having secondarily generalized tonic-clonic seizures (GTCSs) once per month. Over the next year the frequency of her seizures gradually increased to several CPSs per day and two to three GTCSs per week, despite treatment with various combinations of antiepileptic drugs. By this time her AVM had decreased to one half of its original size. Video-electroencephalography monitoring demonstrated that both the CPSs and GTCSs were arising from the right posterior quadrant. Magnetic resonance imaging revealed not only the presence of the right-sided AVM, but also right-sided MTS. The patient underwent surgical resection of the AVM and right temporal lobectomy. She has been free from seizure for longer than 1 year. Radiosurgery may be associated with intractable epilepsy and MTS.

Lateralized seizure termination: relationship to outcome following anterior temporal lobectomy.

Determination of side of seizure onset is critical for a successful outcome following epilepsy surgery. Little is known about the significance of lateralized seizure termination. Sustained seizure activity contralateral to side of seizure onset, following termination of ictal activity ipsilateral to side of onset, may suggest the presence of an independent focus. Such activity, if present, should predict a poor outcome. We studied side of seizure termination in 13 patients undergoing monitoring with bitemporal depth electrodes and correlated this to outcome following anterior temporal lobectomy (ATL). Side of seizure onset was determined for all seizures during that evaluation. Based on side of final cessation of ictal activity, patients were classified as having ipsilateral final termination or simultaneous termination (Group 1; N=6) or contra-lateral or mixed final termination (Group 2; N=7). The Duke outcome classification system was used. At the end of 2 years follow-up, 6/6 patients in Group 1 and 3/7 patients in Group 2 were seizure free. We conclude that lateralized seizure termination during evaluation with depth electrodes may be useful in predicting outcome following ATL. Continued seizure activity contralateral to side of seizure onset (following termination of ictal activity ipsilateral to side of onset) predicts a poor outcome. This may indicate the presence of an independent seizure focus opposite to the side of surgery.

Rem sleep behavior disorder: potential relationship to post-traumatic stress disorder.

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia in which there is enactment, often violent, of dream mentation. Although this syndrome is sometimes associated with neurologic disorders, psychiatric comorbidity is not typical. The authors present a unique series of veterans with RBD. A high incidence of comorbidity with post-traumatic stress disorder is noted. The literature on RBD is reviewed, and the coexistence of RBD and post-traumatic stress disorder is reasoned. The authors suggest that it is possible that similar neuropathologic processes are responsible for both conditions, at times in the same patient.

Slow wave sleep rebound and REM rebound following the first night of treatment with CPAP for sleep apnea: correlation with subjective improvement in sleep quality.

Objective: The purpose of this study was to correlate changes in PSG parameters between the diagnostic polysomnogram (dPSG) and the first night of treatment with continuous positive airway pressure (CPAP) (cpapPSG) to subjective improvement in sleep quality.Background: In patients with obstructive sleep apnea syndrome (OSAS), therapy with CPAP results in reduction of sleep latency, stage 1 sleep, arousal index (Al) and respiratory disturbance index (RDI), and increase in stage 2 sleep, REM sleep and REM density. No data exists on the differences in polysomnographic (PSG) parameters in patients who have subjective improvement in sleep quality and those who do not.Methods: We retrospectively reviewed PSG studies of 44 patients with OSAS who presented to the Sleep Disorders Center at Duke University Medical Center. Patient's qualitative assessment of sleep was noted using a Likert-type scale administered the morning after the dPSG and cpapPSG. PSG indices of patients noting subjective improvement were compared to those with no improvement.Results: Patients noting a subjective improvement in sleep quality showed a decrease in the percentages of stage 1 sleep (P<0.001) and an increase in percentages of stages 3 and 4 sleep (slow wave sleep rebound; P<0.007) and stage REM sleep (REM rebound; P<0.008).

Comparison of MRI and MRA findings in children with a variety of neurologic conditions.

The role of MRA in the evaluation of children is evolving. We compared MRA and MRI in children with a variety of neurologic conditions to determine when MRA provides positive, cost-beneficial information. A total of 114 patients were retrospectively studied. MRA and MRI were performed and compared. MRA was abnormal in 34 (30%) of 114 patients: five (83%) of six with Menkes' disease, four (33%) of 12 with sickle cell disease, 12 (38%) of 32 with vascular malformations, one (6%) of 17 with headaches, seven (24%) of 24 with new focal deficits, one (10%) of 10 with seizures, and four (31%) of 13 with miscellaneous diagnoses. MRA and MRI were concordant in 73 (64%) of 114. Maximum concordance was in patients with Menkes' disease (100%) and minimum in those with new focal deficits (50%). The best MRA cost/benefit ratios were obtained in patients with Menkes' disease, vascular malformations, and sickle cell disease. A normal MRI usually forecasted a normal MRA. However, abnormal MRI findings did not always predict MRA abnormalities. Positive, cost-beneficial information is provided by MRA mostly in conditions known to involve the cerebral vasculature. Indications to perform MRA should be based on the neurologic diagnosis and MRI findings.

West syndrome in tuberous sclerosis complex.

West syndrome occurs commonly in children with tuberous sclerosis complex and is associated with a grave prognosis for cognitive and seizure outcomes. We sought to determine the epilepsy outcome of children with tuberous sclerosis complex and West syndrome and whether EEG, MRI, or steroid therapy duration were different in those whose epilepsy improved compared with those with intractable seizures. Seventeen patients with tuberous sclerosis complex and West syndrome were identified. For each patient, two sets of clinical evaluations, EEG and MRI data, and treatment information separated by at least 12 months were obtained. The patients were divided into two seizure outcome groups. EEG, MRI, and treatment data were compared between the groups. The intellectual deficiency was either severe (76%) or moderate (24%). Seizure control improved in 10 and worsened in seven, without mortality (follow-up range = 12-216 months). No significant differences in EEG background, MRI findings, or steroid treatment duration were evident between the groups. The difference in EEG-sleep approached statistical significance (P = 0.06). Our findings did not confirm reports of high mortality and poor epilepsy outcome in intellectually deficient children with West syndrome and tuberous sclerosis complex. EEG sleep was the best indicator of seizure control and approached statistical significance. The duration of steroid therapy had no influence on seizure control.

Characteristics of valproic acid resistant juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is often exquisitely responsive to treatment with valproic acid (VPA). However, a subset of patients does not respond to this medication and often has intractable seizures. We wanted to identify differences between these two subsets of JME patients. Charts of all JME patients followed at the Duke Epilepsy Center were reviewed. Clinical parameters, electroencephalogram (EEG) findings and magnetic resonance imaging (MRI) data were reviewed. These features were compared between patients with VPA sensitive and VPA resistant JME. Thirty-three patients with JME were identified: 23 (70%) were VPA sensitive (13 females, 10 males; mean age of onset 15.9 years) and 10 (30%) were VPA resistant (5 females, 5 males; mean age of onset 14.1 years). The VPA resistant group had a higher frequency of EEG asymmetries (40% vs. 10%); atypical seizure characteristics including auras and post-ictal confusion (30% vs. 4%); and intellectual deficiency (20% vs. 0%). Clinical characteristics combined with EEG data may help in predicting which JME patients will respond favorably to VPA. This study also raises the issue whether VPA resistant JME is in fact a localization-related epilepsy.

Tuberous sclerosis complex and epilepsy: prognostic significance of electroencephalography and magnetic resonance imaging.

Tuberous sclerosis complex is a disease that affects many organs, including the central nervous system. Nervous system involvement in the form of hamartomas often results in seizures. In this study we wanted to determine the outcome of epilepsy in tuberous sclerosis complex and determine whether interictal electroencephalograms (EEGs) and hamartoma burden as seen with magnetic resonance imaging (MRI) are predictive of degree of seizure control. The study population consisted of 30 patients. For each patient two sets of EEG and MRI data, separated by at least 12 months, and information on seizure frequency at time of data collection were obtained. Sensitivity, specificity, and positive and negative predictive values of various EEG and MRI findings were determined. Seizure control improved in 20 and worsened in 10 patients. In relation to seizure control, the specificity of an abnormal sleep EEG and the positive predictive value of normal sleep EEG were 100%. MRI and EEG background were neither sensitive nor specific for predicting seizure control. A majority of children with tuberous sclerosis complex can achieve good seizure control. The sleep EEG is helpful in predicting eventual seizure control.

Improved sexual function in three men taking lamotrigine for epilepsy.

Little information exists about the effects of newer antiepileptic drugs (AEDs) on sexual function in men with epilepsy. We report a series of three male veterans whose sexual disorders improved with lamotrigine. All three had partial seizures. One patient was taking phenobarbital and gabapentin and complained of decreased potency and anorgasmia. After lamotrigine was added for better seizure control and the dosage of gabapentin was tapered, anorgasmia improved. The second patient complained of impotence after a rash while taking phenytoin and carbamazepine. Impotence persisted with phenobarbital, valproate, and gabapentin. Eight months after gabapentin was replaced with lamotrigine, impotence improved. The third patient complained of long-standing impotence. Treatment with five AEDs had no effect on the dysfunction. Lamotrigine was added to the carbamazepine regimen; impotence improved with decrease in carbamazepine and increase in lamotrigine. The favorable effect of lamotrigine on sexual disorders in these three patients suggests this drug should be considered under appropriate circumstances for men who have sexual dysfunction while taking other antiepileptic agents.

Lamotrigine-induced blepharospasm.

Movement disorders such as tremor and ataxia occur commonly during therapy with antiepileptic drugs (AEDs). Dystonias, however, are rare. Blepharospasm, although reported with neuroleptic agents, has never been reported with AEDs. Our patient developed blepharospasm during therapy with lamotrigine.

Generalized periodic epileptiform discharges: etiologies, relationship to status epilepticus, and prognosis.

Generalized periodic epileptiform discharges (GPEDs) are generalized, synchronous electrographic discharges. This study investigates etiologies, relationship to status epilepticus (SE), and the prognosis for patients with GPEDs. All EEGs with GPEDs performed at Duke University Medical Center between January 1994 and October 1995 were identified. Clinical histories and EEGs were reviewed. They were divided into groups depending on the etiology of the GPEDs, whether the patients were in SE or not, and whether they were alive or not at discharge. A comparison of histories and GPED characteristics among groups was undertaken using parametric and nonparametric t tests. Twenty-five patients were enrolled: 7 (28%) had toxic-metabolic encephalopathy, 10 (40%) had anoxia and toxic-metabolic encephalopathy, and 8 (32%) had a primary neurologic process. Eight patients (32%) were in SE. In the SE group, GPED amplitude was higher (110 versus 80 microV, P < 0.05), GPED duration was longer (0.5 versus 0.3 seconds, P < 0.05), and inter-GPED amplitude was higher (34 versus 17 microV, P < 0.05). Nine patients (36%) were alive at discharge; they were more likely to be younger (51 versus 68 years, P < 0.05), have a better mental status at the time of their EEG, and have a higher inter-GPED amplitude (33 versus 18 microV, P < 0.05). A variety of conditions, including SE, can cause GPEDs. Intergroup differences in historic and GPED features exist between those patients in SE and those not in SE and those with good and poor prognoses.

Depression in sleep disorders clinics.

PURPOSE: The purpose of this paper was to determine the incidence of depression in our sleep disorders clinics (and it's relation to patient characteristics) and to determine whether the incidence of depression varies in patients with and without sleep apnea. METHODS: The Beck Depression Inventory (BDI) was administered to evaluate patients for depression. We reviewed records of all new patients between November, 1995 and May, 1996 and determined their BDI scores and polysomnogram (PSC) results. Patients were divided based on their respiratory disturbance index (RDI); a cut off value of 15 was chosen. Patients were re-divided based on the BDI score (13 or greater suggestive of depression). The age, sex, body mass index (BMI), BDI or RDI (as appropriate) and arousal indices were compared. RESULTS: Sixty-three patients were enrolled; 29% were depressed. BDI scores and PSG data were available in 42 patients. Those with a high RDI had significantly lower BDI scores and higher arousal indices. Those with a high and low BDI scores were not significantly different in any of the parameters evaluated. CONCLUSIONS: Symptoms of depression are commonly seen in a sleep clinic. In patients with symptoms suggestive of SA but with low RDI scores, a diagnosis of depression should be entertained. The presence of depression, however, should not negatively influence a decision to perform PSG.

Transesophageal echocardiography in diagnosing cardioembolic stroke.

Stroke is a disease with high morbidity and mortality that afflicts older people. The most common type of stroke is ischemic, and 15-20% of these strokes are cardioembolic. Because clinical features are not very specific for the type of stroke, diagnostic aides are needed to identify the mechanism of stroke so that appropriate therapy can be initiated. Numerous studies have shown that transesophageal echocardiography (TEE) is a more sensitive tool for diagnosing cardioembolic stroke than transthoracic echocardiography (TTE). However TTE and TEE are still considered complementary as they both provide unique information. The many abnormalities that can be identified by TEE and their therapy are discussed in this review, along with indications and complications of TEE. TEE has demonstrated that cardioembolic causes of stroke are much more common than previously thought. With a more precise diagnosis, appropriate therapy can be provided to help prevent cardiogenic stroke.