Chronopharmacology of Anti-Convulsive Therapy

Approximately one-third of patients with epilepsy continue to have seizures despite antiepileptic therapy. Many seizures occur in diurnal, sleep/wake, circadian, or even monthly patterns. The relationship between biomarkers and state changes is still being investigated, but early results suggest that some of these patterns may be related to endogenous circadian patterns whereas others may be related to wakefulness and sleep or both. Chronotherapy, the application of treatment at times of greatest seizure susceptibility, is a technique that may optimize seizure control in selected patients. It may be used in the form of differential dosing, as preparations designed to deliver sustained or pulsatile drug delivery or in the form of ‘zeitgebers’ that shift endogenous rhythms. Early trials in epilepsy suggest that chronopharmacology may provide improved seizure control compared with conventional treatment in some patients. The present article reviews chronopharmacology in the treatment of epilepsy as well as future treatment avenues

Subunit Composition of Neurotransmitter Receptors in the Immature and in the Epileptic Brain

Neuronal activity is critical for synaptogenesis and the development of neuronal networks. In the immature brain excitation predominates over inhibition facilitating the development of normal brain circuits, but also rendering it more susceptible to seizures. In this paper, we review the evolution of the subunit composition of neurotransmitter receptors during development, how it promotes excitation in the immature brain, and how this subunit composition of neurotransmission receptors may be also present in the epileptic brain. During normal brain development, excitatory glutamate receptors peak in function and gamma-aminobutiric acid (GABA) receptors are mainly excitatory rather than inhibitory. A growing body of evidence from animal models of epilepsy and status epilepticus has demonstrated that the brain exposed to repeated seizures presents a subunit composition of neurotransmitter receptors that mirrors that of the immature brain and promotes further seizures and epileptogenesis. Studies performed in samples from the epileptic human brain have also found a subunit composition pattern of neurotransmitter receptors similar to the one found in the immature brain. These findings provide a solid rationale for tailoring antiepileptic treatments to the specific subunit composition of neurotransmitter receptors and they provide potential targets for the development of antiepileptogenic treatments

Demographic characteristics of patients with extrapulmonary tuberculosis in Germany

The aim of the present study was to determine the demographics of patients with extrapulmonary tuberculosis in Germany. Data on 26,302 tuberculosis cases from a national survey carried out during the period 1996-2000 were analysed. The crude proportion of tuberculosis patients with extrapulmonary manifestations was 21.6%. Extrapulmonary tuberculosis was most likely among females, children aged <15 yrs and persons originating from Africa and Asia. Females tended to be more likely to have any form of extrapulmonary tuberculosis than males, except pleural tuberculosis. The strength of this association was strongest in the age range 25-64 yrs and less pronounced amongst the oldest patients. Children were particularly prone to the development of lymphatic and meningeal tuberculosis, whereas the likelihood of genitourinary tuberculosis increased with increasing age. Asian and African patients were generally more likely than persons from other areas to have lymphatic, osteoarticular, meningeal and miliary tuberculosis. The analysis shows important differences, by age, sex and origin, in the likelihood of a tuberculosis patient presenting with extrapulmonary tuberculosis. Since the relative contribution of the foreign-born to tuberculosis in low-prevalence countries is rising, extrapulmonary tuberculosis must be taken into account more often in the differential diagnostic work-up of these patients, particularly among those originating from Asia and Africa

Repeated Intracarotid Amobarbital Tests

Rationale:Our goal was to determine the frequency of repeated intracarotid amobarbital test (IAT) at our center and to estimate the retest reliability of the IAT for both language and memory lateralization. Methods: A total of 1,249 consecutive IATs on 1,190 patients were retrospectively reviewed for repeat tests. Results: In 4% of patients the IAT was repeated in order to deliver satisfactory information on either language or memory lateralization. Reasons for repetition included obtundation and inability to test for memory lateralization, inability to test for language lateralization, no hemiparesis during first test, no aphasia during first test, atypical vessel filling, and bleeding complications from the catheter insertion site. Language lateralization was reproduced in all but one patient. Repeated memory test results were less consistent across tests, and memory lateralization was unreliable in 63% of the patients. Discussion: In spite of test limitations by a varying dose of amobarbital, crossover of amobarbital from one side to the other, testing of both hemispheres on the same day, practice effects, unblinded observers, fluctuating cooperation of the patients, and a biased sample of patients language lateralization was reproduced in all but one patient. In contrast, repeated memory test results were frequently contradictory. Memory results on IAT therefore seem much less robust than the results of language testing. Gain of reliable information versus the risks of complications and failed tests has to be considered when a patient is subjected to an IAT

Screening of COPD patients for abdominal aortic aneurysm

Purpose: Screening for abdominal aortic aneurysm (AAA) in “men aged over 65 years who have ever smoked” is a recommended policy. To reduce the number of screenings, it may be of value to define subgroups with a higher prevalence of AAA. Since chronic obstructive pulmonary disease (COPD) and AAA are associated with several common risk factors, this study investigates the prevalence of AAA in COPD patients. Patients and methods: Patients with COPD were identified via the hospital information system. Inclusion criteria were: COPD stage I–IV, ability to give full consent, and age >18 years; exclusion criteria were: patient too obese for an ultrasound check, previously diagnosed AAA, prior surgery for AAA, or ethical grounds such as concomitant advanced malignant or end-stage disease. The primary endpoint of the study was an aortic diameter measured by ultrasound of ≥30 mm. Defined secondary endpoints were evaluated on the basis of medical records and interviews. Results: Of the 1,180 identified COPD patients, 589 were included in this prospective study. In 22 patients (3.70%), the aortic diameter was ≥30 mm, representing an AAA prevalence of 6.72% among males aged >65 years. The risk of AAA increased with the following comorbidities/risk factors: male sex (odds ratio [OR] 2.98), coronary heart disease (OR 2.81), peripheral arterial occlusive disease (OR 2.47), hyperlipoproteinemia (OR 2.77), AAA in the family history (OR 3.95), and COPD stage I/II versus IV (OR 1.81). Conclusion: The overall AAA prevalence of 3.7% in our group of COPD patients is similar to that of the general population aged >65 years. However, the frequency of AAA in male COPD patients aged >65 years is considerably higher (6.72%) and increased further still in those individuals with additional comorbidities/risk factors. Defining subgroups with a higher risk of AAA may increase the efficiency of screening

Atypical Language Lateralization in Epilepsy Patients

Purpose:  To investigate whether atypical language dominance in epilepsy patients is related to localization and type of lesions. Methods:  Four hundred and forty-five epilepsy patients received bilateral Wada testing. Language was classified as left (L), right (R), bilateral-dependent (BD, speech arrest after left and right injections), or bilateral-independent (BI, no speech arrest after either injection). Groups were compared regarding handedness and magnetic resonance imaging (MRI) lesions. Lesions were classified as “early” (congenital), “late” neocortical (acquired after birth), and hippocampal sclerosis (HS). Results:  Of all patients, 78% were L, 6% R, 7% BD, and 9% BI. Right-handers with left lesions did not differ from those without lesions. Left-handers with normal MRI did not differ from right-handers. Left-handers with early left lesions were most likely R (46%). Left-handers with late neocortical left lesions were most likely BD (37%); those with left HS were most likely BD (33%) or L (33%). In both latter groups, R language was rare (13% and 11%, respectively). Discussion:  The data support the notion that R dominance may indicate development of functional language areas in the right hemisphere following an early insult. BD language may signal defective maintenance of right hemispheric language caused by a late left hemispheric insult at a time when left dominance has already started to develop. In contrast, BI language may represent a variant with functional language representation in both hemispheres

Risk Factors Associated with Death in In-Hospital Pediatric Convulsive Status Epilepticus

Objective: To evaluate in-patient mortality and predictors of death associated with convulsive status epilepticus (SE) in a large, multi-center, pediatric cohort. Patients and Methods: We identified our cohort from the KID Inpatient Database for the years 1997, 2000, 2003 and 2006. We queried the database for convulsive SE, associated diagnoses, and for inpatient death. Univariate logistic testing was used to screen for potential risk factors. These risk factors were then entered into a stepwise backwards conditional multivariable logistic regression procedure. P-values less than 0.05 were taken as significant. Results: We identified 12,365 (5,541 female) patients with convulsive SE aged 0–20 years (mean age 6.2 years, standard deviation 5.5 years, median 5 years) among 14,965,571 pediatric inpatients (0.08%). Of these, 117 died while in the hospital (0.9%). The most frequent additional admission ICD-9 code diagnoses in addition to SE were cerebral palsy, pneumonia, and respiratory failure. Independent risk factors for death in patients with SE, assessed by multivariate calculation, included near drowning (Odds ratio [OR] 43.2; Confidence Interval [CI] 4.4–426.8), hemorrhagic shock (OR 17.83; CI 6.5–49.1), sepsis (OR 10.14; CI 4.0–25.6), massive aspiration (OR 9.1; CI 1.8–47), mechanical ventilation >96 hours (OR9; 5.6–14.6), transfusion (OR 8.25; CI 4.3–15.8), structural brain lesion (OR7.0; CI 3.1–16), hypoglycemia (OR5.8; CI 1.75–19.2), sepsis with liver failure (OR 14.4; CI 5–41.9), and admission in December (OR3.4; CI 1.6–4.1). African American ethnicity (OR 0.4; CI 0.2–0.8) was associated with a decreased risk of death in SE. Conclusion: Pediatric convulsive SE occurs in up to 0.08% of pediatric inpatient admissions with a mortality of up to 1%. There appear to be several risk factors that can predict mortality. These may warrant additional monitoring and aggressive management

Continuous Spikes and Waves during Sleep: Electroclinical Presentation and Suggestions for Management

Continuous spikes and waves during sleep (CSWS) is an epileptic encephalopathy characterized in most patients by (1) difficult to control seizures, (2) interictal epileptiform activity that becomes prominent during sleep leading to an electroencephalogram (EEG) pattern of electrical status epilepticus in sleep (ESES), and (3) neurocognitive regression. In this paper, we will summarize current epidemiological, clinical, and EEG knowledge on CSWS and will provide suggestions for treatment. CSWS typically presents with seizures around 2–4 years of age. Neurocognitive regression occurs around 5-6 years of age, and it is accompanied by subacute worsening of EEG abnormalities and seizures. At approximately 6–9 years of age, there is a gradual resolution of seizures and EEG abnormalities, but the neurocognitive deficits persist in most patients. The cause of CSWS is unknown, but early developmental lesions play a major role in approximately half of the patients, and genetic associations have recently been described. High-dose benzodiazepines and corticosteroids have been successfully used to treat clinical and electroencephalographic features. Corticosteroids are often reserved for refractory disease because of adverse events. Valproate, ethosuximide, levetiracetam, sulthiame, and lamotrigine have been also used with some success. Epilepsy surgery may be considered in a few selected patients

2014 Epilepsy Benchmarks Area III: Improve Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects

The Epilepsy Benchmark goals in Area III focus on making progress in understanding and controlling seizures and related conditions as well as on developing biomarkers and new therapies that will reduce seizures and improve outcomes for individuals with epilepsy. Area III emphasizes a need to better understand the ways in which seizures start, propagate, and terminate and whether those network processes are common or unique in different forms of epilepsy. The application of that knowledge to improved seizure prediction and detection will also play a role in improving patient outcomes. Animal models of treatment-resistant epilepsy that are aligned with etiologies and clinical features of human epilepsies are especially encouraged as necessary tools to understand mechanisms and test potential therapies. Antiseizure therapies that target (either alone or in combination) novel or multiple seizure mechanisms are prioritized in this section of the Benchmarks. Area III goals also highlight validation of biomarkers of treatment response and safety risk, effective self-management, and patient-centered outcome measures as important areas of emphasis for the next five to ten years