Pediatric migraine prophylaxis with divalproex.

We followed 23 patients with pediatric migraine, ranging in age from 7 to 17 years, who were treated with preventive divalproex sodium for migraine prophylaxis. Patients were evaluated for the presence or absence of comorbid psychiatric disorders or epilepsy to assess the possible differential effects of divalproex therapy. Doses ranged from 3.1 to 32.9 mg/kg/day. Seven patients had comorbid psychiatric disorders, whereas six patients had epilepsy (three rolandic, two generalized, and one indeterminate). Fifteen patients had a greater than 50% reduction in migraine; six patients became headache free. Divalproex doses used were not statistically different among the three groups. A favorable response and headache freedom were more likely in patients with migraine alone or with comorbid epilepsy, and less likely in patients with psychiatric comorbidity. Divalproex was well tolerated, and no significant side effects were reported. No notable changes were noted in behavioral problems, and patients with epilepsy were well controlled. In our cohort of patients, divalproex was most effective in patients with migraine alone or comorbid epilepsy.

Can current EMS dispatch protocols identify layperson-reported sentinel conditions?

INTRODUCTION: Managed care organizations are seeking opportunities to capitate for emergency medical services (EMS). These and others pressures are motivating EMS planners to find innovative ways to redeploy existing EMS resources. A successful redeployment of resources implies a mechanism for more carefully matching EMS resources to need than currently exists. OBJECTIVE: To determine whether the methods dispatchers currently use to assign nature codes (NCs) and severity codes (SCs) also can distinguish between patients with important sentinel conditions and those without. METHODS: This was a six-month prospective study (June to November 1997). Portland Fire Bureau (PFB) paramedic units documented dispatcher-assigned NCs and SCs and the presence or absence of study-established sentinel findings. The PFB paramedics also verified or corrected dispatcher-assigned NCs and SCs using dispatch algorithms identical to those in use at this urban dispatch center. Cross-tabulation tables (SPSS version 6.1) with chi-square statistics were established to illustrate the relationship between SC strata within specific NCs and the presence or absence of sentinel findings. RESULTS: One thousand two hundred eighty-five usable cases fell into 25 unique NCs. The designation SC 1 (emergent) was assigned by the dispatcher 307 (24%) times, SC 3 (urgent) was assigned 907 (71%) times, and SC 9 (neither emergent nor urgent) was assigned 26 (2%) times. The SC was missing 45 (3%) times. The PFB records were matched to 1,040 (82%) dispatch records. Sentinel conditions were identified in 411 (40%) of these cases. Eight (32%) of 25 NCs were stratified into two or more levels of dispatcher-determined SCs. One cross-tabulation table for each of these eight NCs was developed to display the relationship between SC strata and the presence or absence of a sentinel condition. Five tables produced statistically significant chi-square tables (p < 0.05). None achieved the study-specified level of 95% sensitivity. CONCLUSION: Current dispatcher-assigned NCs and SCs do not appear adequate to detect callers with study-developed sentinel criteria.

Do emergency medical services dispatch nature and severity codes agree with paramedic field findings?

UNLABELLED: Emergency medical services (EMS) systems increasingly seek to triage patients to alternative EMS resources. Emergency medical services dispatchers may be asked to perform this triage. New protocols may be necessary. Alternatively, existing protocols may be sufficient for this task. For an existing dispatch protocol to be sufficient, it at least must accurately categorize patient condition and severity based on an external standard. OBJECTIVE: To examine the extent to which nature codes (NCs), or patient condition codes, and severity codes (SCs) currently assigned in one urban 911 center agree with paramedic field findings. The null hypothesis was that there is no routine agreement (75%) between dispatcher-assigned NC or SC and paramedic-assigned NC or SC for the same patient using the same protocol. METHODS: Emergency medical services dispatch nature and severity code data and matching out-of-hospital data were prospectively gathered over six months. Dispatch data included the NC: caller-identified problem, and the SC: dispatcher-assessed severity. Each NC is modified by one of three SCs (1, 3, or 9): 1 is emergent, 3 is urgent, and 9 is neither. Paramedics verified and/or corrected dispatcher-assigned NCs and SCs using the same dispatch protocol. RESULTS: One thousand forty usable cases fell into 33 unique NC/SC combinations. The designation of SC 1 was assigned 275 times, SC 3 was assigned 736 times, and SC 9 was assigned 24 times. The SC was missing five times. The overall NC agreement was 0.70 (95% CI = 0.697 to 0.703). The overall SC agreement was 0.65 (95% CI = 0.645 to 0.655). The NC agreement exceeded 75% for ten (59%) NC/SC combinations. The SC agreement exceeded 75% for five (29%) NC/SC combinations. There was both NC and SC agreement for four (24%) combinations: urgent breathing problems, urgent diabetic problems, urgent falls, and urgent overdoses. The greatest NC/SC disagreement occurred within emergent and urgent traffic crashes. Paramedics adjusted SC toward lower severity 29% of the time and toward higher severity 5.4% of the time. There was no upward SC adjustment for eight (47%) combinations. CONCLUSIONS: Certain dispatcher-assigned NC and SC codes and NC/SC combinations achieved the study threshold. Overall agreement failed to achieve the threshold. The lowest SC level was rarely assigned, preventing a meaningful analysis of all severity levels.

Electrophysiologic assessment of autonomic function in epilepsy.

Sudden unexpected death associated with epilepsy (SUDEP) is an important clinical problem. Peri-ictal autonomic dysfunction is thought to play a role in SUDEP and few means exist for clinical identification of patients at risk. Sympathetic function was assessed by measuring sympathetic skin responses (SSR) elicited in the hand by auditory or tactile stimulation or by inspiration. Parasympathetic function was assessed by recording the R-R interval (RRI) and determining its variability in subsequent heartbeats. Fifty epilepsy patients had significantly greater SSR amplitudes and latencies than controls. The RRI was shorter in patients than in controls and the mean successive difference (MSD) was less, but significance was not reached. Twenty patients at possible risk for SUDEP (male, generalized seizures, intermittent medication noncompliance, drug and alcohol abuse, traumatic or structural aetiology) differed significantly from controls in SSR and RRI. Epilepsy patients may differ in autonomic function from the general population, and these differences may be relevant to SUDEP. The SSR and the RRI may be a simple means of assessing autonomic function in epilepsy outpatients.

Interictal quantitative EEG in epilepsy.

The interictal EEG is often normal in epilepsy patients, particularly with partial seizures of extratemporal origin. Quantitative techniques of EEG analysis may increase the yield of diagnostic abnormality in such patients. Thirty patients with partial seizures of frontal or temporal origin had EEG recorded from left frontal (F7-C3), right frontal (F8-C4), left posterior (T5-O1), and right posterior (T6-O2) derivations. Four-second epochs were used to compute power in the delta (0.25-4.0 Hz), theta (4.25-8.0 Hz), alpha (8.25-13 Hz), and beta (13.25-30 Hz) bands. The ratio of high (8.25-30 Hz) to low (0.25-8 Hz) power on the left and the right was measured, as was the ratio between the left and the right hemisphere total power. The mean frequency deviation in the alpha band between the left and the right hemispheres was also measured, and spectral mobility was determined in the right and the left frontal regions. These values were also calculated in normal subjects and tension headache patients with normal EEGs. Seizure patients with abnormal interictal EEGs had decreased ratios of high to low power, greater asymmetry of total power and alpha frequency, and reduced spectral mobility on the side of their EEG foci. Epileptics with normal interictal EEGs had lower ratios of high to low power, greater alpha frequency asymmetry, and lower spectral mobility than did headache patients or normal controls. Power and frequency measurements, and determination of spectral measures such as mobility, can be done with commercially available digital EEG equipment. They may demonstrate otherwise obscure asymmetries in the interictal EEG and thereby aid in epilepsy diagnosis and classification.

Multiple options and unique pathways: a new direction for EMS?

The same forces transforming the health care delivery system also are reshaping EMS. The changing economic and organizational structures of the health services delivery system may predict how EMS systems will redesign themselves. We discuss one template for future EMS systems.

Contingent negative variation in epilepsy.

The contingent negative variation (CNV) is a long-latency event-related potential elicited by paired or associated stimuli. We recorded contingent negative variation in 50 patients with complex partial and secondarily generalized seizures and in 20 neurologically and psychiatrically normal unmedicated controls. CNV was recorded from Fz, Cz, and Pz. A 2000 Hz tone was followed after 1.5 s by 1000 microseconds light flash, at which a button press was to be executed. Filter band pass was 0.1-20 Hz, analysis time was 10 s and 10 responses were replicated. Patients with complex partial seizures with and without secondary generalization had lower measurements of area under the CNV curve (AUC) than did controls, and CNV amplitude was significantly reduced. Patients with interictal behavioural symptoms had significantly smaller AUC and lower amplitude. No significant difference was found between depressed and non-depressed seizure patients with respect to AUC, but amplitude was significantly lower in depressed patients. Seizure patients with psychosis had significantly lower AUC but did not differ from non-psychotic patients in CNV amplitude. No differences were found between seizure patients with and without personality disorder with respect to CNV AUC or amplitude. Post-imperative negative variation was significantly more common in seizure patients than in controls and among patients with epilepsy, was significantly increased in those with inter-ictal behaviour disturbance generally and psychosis particularly. No specific effect of anticonvulsant monotherapy on AUC or amplitude was identified. These findings suggest that CNV may differ between partial epilepsy patients and controls, and that inter-ictal behaviour disturbance may particularly affect CNV measures. They also agree with previous evidence for a frontal lobe generator for the CNV, and a possible role for central dopaminergic pathways in the production of PINV.

Tiagabine therapy for complex partial seizures. A dose-frequency study. The Tiagabine Study Group.

OBJECTIVE: To evaluate the efficacy and safety of 2 regimens of tiagabine as add-on therapy for patients with complex partial seizures (CPSs) that are refractory to other treatment. DESIGN: Randomized, double-blind, placebo-controlled, add-on, parallel-group trial with an 8-week baseline period, 12-week experimental period (4 weeks of dose titration and 8 weeks of fixed-dose therapy), and 4-week termination period. SETTING: Twenty-six centers throughout the United States. PATIENTS: Three hundred fifty-one patients were enrolled, 318 were entered in the double-blind period, and 271 completed the study. INTERVENTIONS: Tiagabine, 16 mg 2 times per day (106 patients); tiagabine, 8 mg 4 times daily (105 patients); and placebo (107 patients). The doses of tiagabine were titrated in 3 steps to the fixed dose. MAIN OUTCOME MEASURE: The median change in the 4-week rate of CPSs from baseline to experimental period. RESULTS: The median change from baseline was -1.6 CPSs per 4 weeks in the group of patients who were given tiagabine 2 times per day, and it was -1.2 CPSs in the group of patients who were given tiagabine 4 time per day (P = .06 and P = .02, respectively, compared with placebo). The 4-week seizure frequency was reduced by 50% or more in 31% of the patients who were given tiagabine 2 times per day and in 27% of the patients who were given tiagabine 4 times per day vs 10% of the placebo-treated patients (P < or = .001 for each tiagabine-treated group compared with the placebo group). The most frequent adverse events involved the central nervous system and occurred in comparable proportions in the 3 treatment groups. Similar proportions of patients discontinued the study prematurely for adverse events. CONCLUSIONS: Tiagabine administered 2 and 4 times daily as add-on pharmacotherapy was effective in reducing CPSs in patients with epilepsy whose conditions were refractory to treatment with other antiepileptic agents, and it was well tolerated.

Auditory evoked potentials in postconcussive syndrome.

The neuropsychiatric sequelae of minor head trauma have been the source of controversy. Most clinical and imaging studies have shown no alteration after concussion, but neuropsychological and neuropathological abnormalities have been reported. Some changes in neurophysiologic diagnostic tests have been described in postconcussive syndrome. We recorded middle latency auditory evoked potentials (MLR) and slow vertex responses (SVR) in 20 individuals with prolonged cognitive difficulties, behavior changes, dizziness, and headache after concussion. MLR is utilized alternating polarity clicks presented monaurally at 70 dB SL at 4 per second, with 40 dB contralateral masking. Five hundred responses were recorded and replicated from Cz-A1 and Cz-A2, with 50 ms. analysis time and 20-1000 Hz filter band pass. SVRs were recorded with the same montage, but used rarefaction clicks, 0.5 Hz stimulus rate, 500 ms. analysis time, and 1-50 Hz filter band pass. Na and Pa MLR components were reduced in amplitude in postconcussion patients. Pa latency was significantly longer in patients than in controls. SVR amplitudes were longer in concussed individuals, but differences in latency and amplitude were not significant. These changes may reflect posttraumatic disturbance in presumed subcortical MLR generators, or in frontal or temporal cortical structures that modulate them. Middle and long-latency auditory evoked potentials may be helpful in the evaluation of postconcussive neuropsychiatric symptoms.

Middle latency auditory evoked potentials in epilepsy.

Middle latency auditory evoked potentials (MLAEPs) have been recorded after cortical lesions and seizure surgery. We recorded interictal MLAEPs in 14 patients with well documented complex partial and secondary generalized seizures. Na and Pa potentials did not differ in latency between patients and controls, although both were longer among seizure patients. Pa and Na were significantly reduced in amplitude in complex partial seizure patients compared to controls. These findings accord with previous suggestions that MLAEPs may be generated subcortically but modulated by temporal lobe structures. MLAEPs may be of value in differentiating temporal and extratemporal epilepsy. They may also help clarify interictal cognitive or behavioral symptoms related to epilepsy or the effects of antiepileptic medication.

Event-related potentials in Parkinson's disease.

The increasingly recognized occurrence of dementia in Parkinson's disease (PD) has prompted study of cognitive evoked potentials in this disorder. The P300 wave is related to cognitive performance, while the contingent negative variation (CNV) may reflect dopaminergic function. We measured P300 and CNV in 21 nondemented PD patients and compared them to elderly controls. The P300 was recorded from Cz with linked ear reference. 3,000 and 1,000 Hz tones were presented in an 80:20 ratio at 76 dBSL interstimulus interval was 1.1 seconds, and filter bandpass was 1-100 Hz. CNV recording utilized a 2000 Hz tone followed after 1.5 seconds by a light flash and button press, and was recorded from Fz with linked ear reference, 10-second analysis time, and 0.1-20 Hz filter bond pass. N200 and P300 amplitudes were significantly longer and latency significantly lower in PD patients than in controls, and P300 latency was correlated with composite score on cognitive tests. CNV amplitude was significantly reduced in PD patients, but was correlated with measures of motor disability rather than cognition. These findings suggest that bradyphrenia may occur in nondemented PD patients, and that P300 may measure cognitive changes in PD. CNV may be a dopaminergic slow potential and may correlate with motor function in nondemented PD patients.

EEG frequency analysis in obsessive-compulsive disorder.

The cerebral basis of obsessions and compulsions has attracted increasing attention in neuropsychology and neuropsychiatry. Clinical and imaging studies have suggested frontal lobe dysfunction in some cases of obsessive-compulsive disorder and Tourette syndrome with obsessional symptoms. We compared EEG spectral measures in 20 such patients not taking medications and 12 neurologically intact unmedicated controls. EEG was recorded from O1-A1+A2, O2-A1+A2, Fz-A1+A2, F7-C3, F8-C4, T5-O1 and T6-O2. One-minute epochs of artifact-free EEG were used for compressed spectral array and calculation of time domain descriptors. We measured modal alpha frequency (MAF), maximal alpha frequency (MxAF), spectral edge frequency and spectral mobility in left and right frontal regions (MOLF and MORF). MAF and MxAF were reduced in the frontal regions in patients as compared to controls, and MOLF and MORF were both lower. No significant differences between patients and controls were found in the temporal or occipital areas. These observations support the suggestions of a physiologic basis for obsessions and compulsions, and of frontal lobe disturbance in their pathophysiology.

Effect of frontal and temporal seizure foci on P50 auditory evoked potentials.

Event-related potentials have been occasionally investigated in epilepsy. We recorded P50 auditory evoked potentials in 25 patients with complex partial seizures of frontal and temporal lobe origin. P50 was significantly reduced in amplitude and prolonged in latency in temporal lobe seizure patients as compared to controls. Patients with complex partial seizures originating in the frontal lobes did not differ from controls in P50 amplitude. P50 attenuation differences may be related to interictal behavioral or cognitive changes, but could also reflect medication effects. Event-related potentials may be helpful in differentiating frontal and temporal seizure foci.

Aberrant pre-mRNA maturation is caused by LINE insertions into introns of the white gene of Drosophila melanogaster.

Insertional mutagenesis screens have provided thousands of mutant alleles for analysing genes of varied functions in Drosophila melanogaster. We here document mechanisms of insertional mutagenesis by a LINE element, the I factor, by determining the molecular structure of RNAs produced from two alleles of the white gene of D.melanogaster, wIR1 and wIR6. These alleles result from insertion of the I factor into introns of the gene. We show that sequences present within the element direct aberrant splicing and termination events. When the I factor is inserted within the white first intron it may lead to the use of a cryptic 3' splice site which does not contain the dinucleotide AG. This splicing gives rise to a chimeric messenger RNA whose synthesis is controlled differently in tissues where the mutated gene is expressed. When the I factor is inserted within the white last intron it induces synthesis of truncated mRNAs. These results provide, for the first time, mechanisms for I factor insertional mutagenesis. They are discussed in the more general context of RNA processing in Drosophila and the evolution of eukaryotic gene introns.

Flunarizine for treatment of partial seizures: results of a concentration-controlled trial.

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNR's long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).

Sleep apnea and periodic leg movements in epilepsy.

Sleepiness is a common complaint in the epilepsy clinic, and sleep disturbances are frequently reported by seizure patients. Polysomnography was performed in 6 patients with complex partial seizures, with and without secondary generalization, who had not yet started anticonvulsant treatment or whose medication had been discontinued. Five patients sleep through the night, but 1 slept only 3 hours. Two patients had reduced sleep efficiency and slow wave sleep was reduced or absent in 4 patients. No REM sleep disturbances occurred. Two patients had almost no periodic leg movements of sleep (PLMS), 2 had few or no arousals and PLMS indices of 5 or less, and 2 had markedly elevated PLMS and arousal indices. No apneas or significant hypopneas were recorded, but snoring indices were elevated in 2 patients. These findings suggest that sleep apnea is infrequent in unmedicated seizure patients. Some patients may have exaggerated PLMS with arousals, possibly related to epileptiform discharge and perhaps exacerbated by medications, but apparently not due to nocturnal seizures.

Multiple sleep latency tests in epilepsy.

Seizure patients often complain of sleepiness or disturbed sleep. Although susceptible of medication effect, the multiple sleep latency test (MSLT) may quantify daytime sleepiness and help to establish whether qualitative sleep disturbance accompanies epilepsy. In order to measure daytime sleepiness in epilepsy patients, 30 patients with newly diagnosed or presently untreated complex partial seizures had MSLT after an overnight sleep EEG that showed no sleep deprivation or nocturnal seizures. Four 20-minute naps were undertaken at 09:00, 11:00, 13:00, and 15:00, and sleep latency was recorded along with 8 channels of EEG. Twenty of 30 seizure patients reported subjective sleepiness. Eight patients had average sleep latencies less than 8 minutes, and 3 had latencies less than 5 minutes. No sleep onset REM or respiratory disturbance was noted. Twenty-five patients had EEG abnormalities but none had ictal seizures. Right temporal epileptiform activity correlated with sleepiness. MSLT may quantify sleepiness in epilepsy patients, which is common but may be subjective or psychophysiological. Some patients with partial seizures have persistent daytime sleepiness independent of medication, possibly related to residual medication effects or non-specific effect of their epileptogenic foci.