Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy. METHODS: A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007. RESULTS: Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative. RECOMMENDATIONS: Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations.

Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy in WWE compared to other women, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. METHODS: A 20-member committee including general neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and February 2008. RESULTS: For WWE taking antiepileptic drugs, there is probably no substantially increased risk (greater than two times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (greater than 1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. Seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84%-92%) of remaining seizure-free during pregnancy. RECOMMENDATIONS: Women with epilepsy (WWE) should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high rate (84%-92%) of remaining seizure-free during pregnancy (Level B). However, WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery during pregnancy (Level C).

Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy. METHODS: Systematic review of relevant articles published between January 1985 and June 2007. RESULTS: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. RECOMMENDATIONS: If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of <7 (Level C).

An analysis of lifetime fractures in women with epilepsy.

OBJECTIVE: To clarify the relationship between fractures and antiepileptic drug (AED) use. METHODS: Menopausal women with epilepsy were interviewed at two clinics regarding site, year and circumstances of any fracture, duration of AED use and menopause. Fracture sites were analyzed according to AED use. RESULTS: Twenty-nine fractures occurred in 20 of the 50 interviewed subjects (mean age 54). Nine occurred prior to AEDs; seven attributed to accident and two to clumsiness. Twenty occurred on AEDs; 10 attributed to clumsiness (most in the leg and foot), eight to seizure (most in the arm or hand) and two to accident. Duration of AED exposure was similar in both groups and in osteoporotic vs non-osteoporotic sites. CONCLUSIONS: Epilepsy therapy may contribute more to the lifetime occurrence of fracture than seizures themselves. More screening for osteoporosis is required. While adjusting doses to prevent seizures, ongoing screening for neurotoxicity must be maintained in order to avoid fractures.

Seizure frequency is associated with age at menopause in women with epilepsy.

OBJECTIVE: To determine whether the age at menopause in women with epilepsy is associated with seizure frequency. METHODS: Women with epilepsy ages 45 and older from urban epilepsy centers were surveyed by interview and chart review for reproductive and general health characteristics, as well as seizure history, including frequency and treatment. Women who were not menopausal (> or = 1 year since last menses) were excluded. Subjects were divided into low, high, and intermediate seizure frequency groups. Statistical analyses included a one-way analysis of variance along with post hoc analysis (Bonferroni approach) to calculate pairwise comparisons. RESULTS: Sixty-eight subjects had a mean age at last menses (menopause) of 47.8 years (SD +/- 4.1, range 37 to 59 years). The age at menopause was 49.9 years in the low seizure frequency group (n = 15), 47.7 years in the intermediate seizure frequency group (n = 25), and 46.7 in the high seizure frequency group (n = 28). The difference in age at menopause in the three groups spanned approximately 3 years (p = 0.042). There was a negative correlation between the age at menopause and seizure group based on estimated lifetime seizures (p = 0.014, r = -0.310). No confounding influences such as history of cigarette smoking, number of pregnancies, or use of enzyme-inducing antiepileptic drugs were present. CONCLUSIONS: Seizure frequency or lifetime number of seizures is associated with the timing of cessation of reproductive cycling. Seizures may disrupt hypothalamic and pituitary function or alter neurally mediated trophic effects on the ovary.

Dysphagia due to cervical osteophytes.

A case of a 64-year-old man is presented with painless dysphagia and loud noise on swallowing due to large anterior cervical osteophytes demonstrated on plain radiographs and magnetic resonance imaging accompanied by a brief review of the literature.

Bilateral symmetrical basal ganglia infarction after intravenous use of cocaine and heroin.

A case is reported of a young man who developed bilateral symmetrical basal ganglia infarcts after intravenous use of cocaine and heroin. Ischemic infarcts of the brain are a known complication of to cocaine use, alone or in combination with heroin (speed balling). This symmetrical occurrence of infarction, however, is unusual and has not been reported after cocaine use.

Seizures in the critically ill: the role of imipenem.

PURPOSE: To determine the risk of seizures in critically ill patients receiving the antibiotic imipenem, a broad-spectrum antibiotic that has been associated with seizures. Reports generally have not considered other contributing factors such as dose, seizure history, and morbidity index of the underlying illness necessitating the antibiotic. METHODS: Charts of all patients in a 450-bed municipal hospital who received imipenem in a 6-month period, as determined by pharmacy records, were reviewed for dosage and duration of imipenem use, occurrence of seizures. and mortality outcome. Attention was paid to demographic features; pattern of seizure occurrence during, before, and after imipenem use; renal function; and correction for dosage based on size. RESULTS: Seventy-five charts were reviewed. Sixty-three patients had no seizures during the hospitalization, four had seizures while receiving imipenem, and eight had seizures during the hospitalization but before or after imipenem use. The incidence of seizures was 4/1,000 patient-days on, and 3.9/1,000 patient-days off imipenem (not significant). The risk of seizure in both groups was considerably higher in those patients with a history of seizures before hospitalization. The presence of other factors that could contribute to increased concentration of imipenem in the brain, such as renal failure or acute stroke, did not contribute to seizure incidence. Metabolic derangement, anoxia, and phenytoin discontinuation did contribute to seizure incidence. CONCLUSIONS: Seizure incidence is increased in all critically ill patients (16% of patients studied), but with no added risk during the period patients received imipenem. Determining the proper dose based on a patient's body mass, correction of dose in the presence of renal failure, and avoidance of excess of 2 g/day of imipenem removes any added risk for seizures from imipenem. Despite experimental data to suggest action of imipenem on the glutamate/N-methyl-d-aspartate receptor, or interference with binding to the gamma-aminobutyric acid receptor, and early clinical studies that warned against its use because of seizure risk, we found that careful use of this antibiotic is safe.

Molecular architecture of the rod domain of the Dictyostelium gelation factor (ABP120).

The Dictyostelium discoideum gelation factor is a two-chain actin-cross-linking protein that, in addition to an N-terminal actin-binding domain, has a rod domain constructed from six tandem repeats of a 100-residue motif that has an immunoglobulin fold. To define the architecture of the rod domain of gelation factor, we have expressed in E. coli a series of constructs corresponding to different numbers of gelation factor rod repeats and have characterised them by chemical crosslinking, ultracentrifugation, column chromatography, matrix-assisted laser desorption ionisation (MALDI) mass spectrometry and NMR spectroscopy. Fragments corresponding to repeats 1-6 and 5-6 dimerise, whereas repeats 1-5 and single repeats 3 and 4 are monomeric. Repeat 6 interacts weakly and was present as monomer and dimer when analysed by analytical ultracentrifugation. Proteolytic digestion of rod5-6 resulted in the generation of two polypeptides that roughly corresponded to rod5 and part of rod6. None of these polypeptides formed dimers after chemical crosslinking. Stable dimerisation therefore appears to require repeats 5 and 6. Based on these data a model of gelation factor architecture is presented. We suggest an arrangement of the chains where only the carboxy-terminal repeats interact as was observed for filamin/ABP280, the mammalian homologue of gelation factor.

The role of the cortical cytoskeleton: F-actin crosslinking proteins protect against osmotic stress, ensure cell size, cell shape and motility, and contribute to phagocytosis and development.

We generated Dictyostelium double mutants lacking the two F-actin crosslinking proteins alpha-actinin and gelation factor by inactivating the corresponding genes via homologous recombination. Here we investigated the consequences of these deficiencies both at the single cell level and at the multicellular stage. We found that loss of both proteins severely affected growth of the mutant cells in shaking suspension, and led to a reduction of cell size from 12 microns in wild-type cells to 9 microns in mutant cells. Moreover the cells did not exhibit the typical polarized morphology of aggregating Dictyostelium cells but had a more rounded cell shape, and also exhibited an increased sensitivity towards osmotic shock and a reduced rate of phagocytosis. Development was heavily impaired and never resulted in the formation of fruiting bodies. Expression of developmentally regulated genes and the final developmental stages that were reached varied, however, with the substrata on which the cells were deposited. On phosphate buffered agar plates the cells were able to form tight aggregates and mounds and to express prespore and prestalk cell specific genes. Under these conditions the cells could perform chemotactic signalling and cell behavior was normal at the onset of multicellular development as revealed by time-lapse video microscopy. Double mutant cells were motile but speed was reduced by approximately 30% as compared to wild type. These changes were reversed by expressing the gelation factor in the mutant cells. We conclude that the actin assemblies that are formed and/or stabilized by both F-actin crosslinking proteins have a protective function during osmotic stress and are essential for proper cell shape and motility.

Relation of cocaine use to seizures and epilepsy.

PURPOSE: Cocaine can provoke seizures, exacerbate a preexisting seizure disorder, or cause an ischemic or hemorrhagic stroke that leads to seizures. To determine the importance of cocaine use in patients with and without epilepsy, we studied these relations and other risk factors for seizures and the mode of cocaine use. METHODS: We reviewed all charts of emergency department visits and hospitalizations of patients with discharge diagnoses simultaneously listing seizures, epilepsy, and cocaine use during a 24-month period. Data collected included patient age, sex, route of cocaine use, seizure description and duration of epilepsy, provocative factors, results of electroencephalography and computed tomography, treatment, and outcome. RESULTS: Of 67,668 adult emergency department visits and 25,768 adult admissions, 1,900 were cocaine related, and 58 of these also had seizures or epilepsy. Seizure occurrences were approximately equally distributed among groups with idiopathic epilepsy, remote symptomatic localization-related epilepsy, cerebrovascular disease, and acute symptomatic seizures due to cocaine use alone. Less frequently, seizures were cryptogenic or symptomatic of metabolic abnormalities. CONCLUSIONS: Cocaine use can reduce seizure threshold in patients with underlying epilepsy as a direct toxic effect or indirectly by contributing to poor compliance with antiepileptic drug treatment, poor diet, or poor sleep habits. In 12 of the 58 patients, cocaine appeared to be the only provocative factor. This may be a less significant risk factor for epilepsy than either alcohol or head trauma.

Spontaneous spinal epidural hematoma. Another neurologic complication of cocaine?

OBJECTIVES: To describe a patient with a spontaneous spinal epidural hematoma associated with cocaine use and to present issues related to pathogenesis and management of this potential complication. DESIGN: Case report. SETTING: Municipal hospital. CASE: A spontaneous spinal epidural hematoma developed at the thoracic level in a 62-year-old man in association with cocaine use. Clinical, laboratory, and radiologic data are presented. MAIN OUTCOME AND RESULTS: The patient was treated medically with intravenous and oral dexamethasone sodium phosphate. His neurologic status gradually improved during a 12-day hospitalization. CONCLUSION: Cocaine use should be considered in the evaluation of spontaneous spinal epidural hemorrhage.

Subacute sclerosing panencephalitis and acquired immunodeficiency syndrome: role of electroencephalography and magnetic resonance imaging.

Subacute sclerosing panencephalitis (SSPE) had largely disappeared from the United States because of nearly universal measles vaccination, but it has reemerged in children infected with human immunodeficiency virus (HIV). Two children with SSPE are described. The first was HIV positive and presented with seizures and encephalopathy at the age of 21 months. The second developed myoclonus and dementia at age 4 years; she was not infected with HIV, but her mother had acquired immunodeficiency syndrome. Magnetic resonance imaging findings were nonspecific and could have been compatible with HIV encephalopathy. Electroencephalography was characteristic of SSPE, showing high-voltage, periodic slow-wave complexes and background slowing. The diagnosis of SSPE was confirmed by brain biopsy or high measles antibody titers in the cerebrospinal fluid.

Mechanical perturbation elicits a phenotypic difference between Dictyostelium wild-type cells and cytoskeletal mutants.

To determine the specific contribution of cytoskeletal proteins to cellular viscoelasticity we performed rheological experiments with Dictyostelium discoideum wild-type cells (AX2) and mutant cells altered by homologous recombination to lack alpha-actinin (AHR), the ABP120 gelation factor (GHR), or both of these F-actin cross-linking proteins (AGHR). Oscillatory and steady flow measurements of Dictyostelium wild-type cells in a torsion pendulum showed that there is a large elastic component to the viscoelasticity of the cell pellet. Quantitative rheological measurements were performed with an electronic plate-and-cone rheometer, which allowed determination of G', the storage shear modulus, and G", the viscous loss modulus, as a function of time, frequency, and strain, respectively. Whole cell viscoelasticity depends strongly on all three parameters, and comparison of wild-type and mutant strains under identical conditions generally produced significant differences. Especially stress relaxation experiments consistently revealed a clear difference between cells that lacked alpha-actinin as compared with wild-type cells or transformants without ABP120 gelation factor, indicating that alpha-actinin plays an important role in cell elasticity. Direct observation of cells undergoing shear deformation was done by incorporating a small number of AX2 cells expressing the green fluorescent protein of Aequorea victoria and visualizing the strained cell pellet by fluorescence and phase contrast microscopy. These observations confirmed that the shear strain imposed by the rheometer does not injure the cells and that the viscoelastic response of the cell pellet is due to deformation of individual cells.

Rhabdomyolysis and hyperthermia after cocaine abuse: a variant of the neuroleptic malignant syndrome?

Rhabomyolysis with myoglobinuria has been added relatively recently to the neurologic complications associated with the increased use of cocaine and the introduction of its alkaloid form (crack). This retrospective study reports our experience with 14 patients who presented with rhabdomyolysis after cocaine use in a municipal hospital over a 3-year period. Seven patients used "crack", 2 intravenous and 3 nasal insufflation. All patients but one had hyperthermia, 11 altered mental status, 8 tachycardia, and 4 muscle rigidity. Nine developed renal failure; 3 of these patients died. Two other patients died of cardiorespiratory arrest. Cocaine-related rhabdomyolysis has a high mortality. The observed association with hyperthermia and other central neurologic features resembles the neuroleptic malignant syndrome. Since chronic cocaine use may alter the availability of dopamine either through transmitter depletion or decrease in the number of dopamine receptors, a common pathogenetic mechanism is possible. However, other mechanisms, which are not mutually exclusive but rather frequently overlapping, may play an important role. These include agitation, hyperthermia, adrenergic overstimulation leading to vasoconstriction and ischemia or calcium release from the sarcoplasmic reticulum resulting in increased entry into the muscle cell leading to cell death; in addition, cocaine has direct toxic effect on the muscles.

Neurovascular complications of cocaine.

Use of cocaine in the USA, has reached epidemic proportions since 1983, when "crack" was introduced, its higher potency compared with cocaine HCl has been associated with a tremendous increase in the incidence of strokes. This study reports our experience with 55 cases of neurovascular events (25 ischemic and 30 hemorrhagic) related to cocaine use in 54 patients. Only 15 patients had other risk factors for stroke. Twenty six patients smoked "crack", 10 snorted cocaine and 12 injected it intravenously. Strokes occurred within 3 h of cocaine use in 15 patients with infarcts and 17 with hemorrhages. Ten infarcts occurred after an overnight binge. Of the hemorrhage group 9 were subarachnoid, 16 intracerebral (8 basal ganglia, 7 hemispheric and one brain stem) and 5 intraventricular. Computerized tomography (CT) showed an aneurysm of the anterior communicating artery, as well as one of the vein of Galen. Four aneurysms and 3 AVMs were identified on angiography. CT revealed 15 infarcts; it was normal in 7 patients with pure motor hemiparesis and in 3 with findings consistent with anterior spinal artery infarction. Several mechanisms may be responsible for the cerebrovascular complications. A sudden rise in systemic arterial pressure may cause hemorrhages, frequently in association with an underlying aneurysm or AVM. Vasospasm, arteritis, myocardial infarction with cardiac arrhythmias and increased platelet aggregation may provoke infarcts.