Andrew S. Blum

Cognitive behavioral therapy for psychogenic nonepileptic seizures.

Treatment trials for psychogenic nonepileptic seizures (PNES) are few, despite the high prevalence and disabling nature of the disorder. We evaluated the effect of cognitive behavioral therapy (CBT) on reduction of PNES. Secondary measures included psychiatric symptom scales and psychosocial variables. We conducted a prospective clinical trial assessing the frequency of PNES in outpatients treated using a CBT for PNES manual. Subjects diagnosed with video/EEG-confirmed PNES were treated with CBT for PNES conducted in 12 weekly sessions. Seizure calendars were charted prospectively. Twenty-one subjects enrolled, and 17 (81%) completed the CBT intervention. Eleven of the 17 completers reported no seizures by their final CBT session. Mean scores on scales of depression, anxiety, somatic symptoms, quality of life, and psychosocial functioning showed improvement from baseline to final session. CBT for PNES reduced the number of PNES and improved psychiatric symptoms, psychosocial functioning, and quality of life.

Multicenter Pilot Treatment Trial for Psychogenic Nonepileptic Seizures A Randomized Clinical Trial

IMPORTANCE There is a paucity of controlled treatment trials for the treatment of conversion disorder, seizures type, also known as psychogenic nonepileptic seizures (PNES). Psychogenic nonepileptic seizures, the most common conversion disorder, are as disabling as epilepsy and are not adequately addressed or treated by mental health clinicians. OBJECTIVE To evaluate different PNES treatments compared with standard medical care (treatment as usual). DESIGN, SETTING, AND PARTICIPANTS Pilot randomized clinical trial at 3 academic medical centers with mental health clinicians trained to administer psychotherapy or psychopharmacology to outpatients with PNES. Thirty-eight participants were randomized in a blocked schedule among 3 sites to 1 of 4 treatment arms and were followed up for 16 weeks between September 2008 and February 2012; 34 were included in the analysis. INTERVENTIONS Medication (flexible-dose sertraline hydrochloride) only, cognitive behavioral therapy informed psychotherapy (CBT-ip) only, CBT-ip with medication (sertraline), or treatment as usual. MAIN OUTCOMES AND MEASURES Seizure frequency was the primary outcome; psychosocial and functioning measures, including psychiatric symptoms, social interactions, quality of life, and global functioning, were secondary outcomes. Data were collected prospectively, weekly, and with baseline, week 2, midpoint (week 8), and exit (week 16) batteries. Within-group analyses for each arm were performed on primary (seizure frequency) and secondary outcomes from treatment-blinded raters using an intention-to-treat analysis. RESULTS The psychotherapy (CBT-ip) arm showed a 51.4% seizure reduction (P = .01) and significant improvement from baseline in secondary measures including depression, anxiety, quality of life, and global functioning (P < .001). The combined arm (CBT-ip with sertraline) showed 59.3% seizure reduction (P = .008) and significant improvements in some secondary measures, including global functioning (P = .007). The sertraline-only arm did not show a reduction in seizures (P = .08). The treatment as usual group showed no significant seizure reduction or improvement in secondary outcome measures (P = .19). CONCLUSIONS AND RELEVANCE This pilot randomized clinical trial for PNES revealed significant seizure reduction and improved comorbid symptoms and global functioning with CBT-ip for PNES without and with sertraline. There were no improvements in the sertraline-only or treatment-as-usual arms. This study supports the use of manualized psychotherapy for PNES and successful training of mental health clinicians in the treatment. Future studies could assess larger-scale intervention dissemination. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00835627.

Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures

Objective: There have been few treatment trials for psychogenic nonepileptic seizures (PNES). Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We evaluated a pharmacologic intervention to test the hypothesis that sertraline would reduce PNES. Methods: We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with video-EEG–confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks. Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables. Results: Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure rates from baseline to final visit (p = 0.03) vs an 8% increase in placebo (p = 0.78). Secondary outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline. Conclusions: PNES were reduced in patients treated with a serotonin selective reuptake inhibitor, whereas those treated with placebo slightly increased. This study provides feasibility data for a larger-scale study. Level of evidence: This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a placebo control arm (risk ratio 0.51, 95% confidence interval 0.25–1.05, p = 0.29), adjusting for differences at baseline.

Duration of refractory status epilepticus and outcome: Loss of prognostic utility after several hours

Purpose:  Outcome for patients with status epilepticus (SE) depends strongly on etiology. Duration of SE is also predictive, at least in the first 2 h, but beyond this it is unclear that duration of SE influences outcome significantly. We sought to determine the influence of duration of SE on outcome in patients with prolonged SE, and to compare this influence with that of other factors.

Low-dose zalcitabine-related toxic neuropathy Frequency, natural history, and risk factors.

We studied the features and frequency of sensory neuropathy among 79 HIV-1-infected individuals participating in a multicenter clinical trial of zalcitabine (2 prime 3 prime-dideoxycytidine, or ddC) antiretroviral therapy. The trial compared zalcitabine monotherapy (2.25 mg/day) versus combination therapy (2.25 mg/day ddC) with zidovudine (ZDV, formerly AZT) versus monotherapy with ZDV alone. Neuropathy developed in 34% of ddC recipients but in only 4% of comparable patients treated with ZDV alone--a 7.9-fold increase in the attack rate of neuropathy. Using risk factor analysis, we found that diabetes mellitus was significantly associated with the development of toxic neuropathy (p equals 0.02), and weight loss may contribute to its appearance. Like HIV-associated sensory neuropathy, ddC-related toxic neuropathy is a predominantly sensory, length-dependent, symmetric, painful neuropathy. Dose reduction lessened the severity of symptoms, although objective signs of neuropathy persisted. Patients with subclinical neuropathies or significant neuropathy risks such as diabetes may be poor candidates for ddC therapy. NEUROLOGY 1996;46: 999-1003.

Oxygen desaturations triggered by partial seizures: implications for cardiopulmonary instability in epilepsy

Summary: Purpose: The occurrence of hypoxemia in adults with partial seizures has not been systematically explored. Our aim was to study in detail the temporal dynamics of this specific type of ictal‐associated hypoxemia.

Detection and treatment of refractory status epilepticus in the intensive care unit.

Status epilepticus (SE) is not rare in critically ill intensive care unit (ICU) patients, but its diagnosis is often delayed or missed, in part because it is mistaken for other causes of altered mental status. Even once diagnosed, SE in the ICU can be refractory to treatment. We sought to determine the causes, clinical features, and difficulties in diagnosis of SE in the ICU, and the effects of antiepileptic drugs (AEDs) on its course. We reviewed the course of ICU patients with both clinical and EEG evidence of SE, attempting to determine which patients are at risk for unsuspected SE, what was the typical delay in diagnosis, and whether AED treatment made a difference in their clinical courses. By clinical and EEG evidence, 91 ICU patients with SE were identified, all with abnormal mental status: 74 were comatose. Vascular disease (in 24) and anoxia (22) were the most common causes; most had multiple medical problems. Although 76 patients had clinically evident seizures earlier (and 56, clinical SE) only 20 were thought to be in SE at the time of the diagnostic EEG. There was a median delay of 48 hours from clinical deterioration until diagnosis in patients with earlier clinical seizures and 72 hours without seizures. Among the 68 nonanoxic patients treated with AEDs, 38 (56%) seemed to improve in alertness, including 25 who were comatose. Although patients who were stuporous or confused (vs. comatose) improved more often on AEDs, they were less often realized to be in SE before the EEG. Patients with earlier seizures were also more likely to improve, but no more likely to be diagnosed before the EEG. Patients who responded to AEDs were more likely to survive. ICU patients with altered mental status and EEG evidence of SE often have severe medical and surgical illnesses, refractory SE, and a high mortality. The delay to diagnosis is substantial, but a significant subset of patients improves on AEDs once SE is discovered. This diagnosis should be sought more often in ICU patients with abnormal mental status, especially after clinical seizures or SE without full recovery.

Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use

Objective: To determine whether 1) combined oral contraceptive (COC) use affects serum levels of valproate (VPA) as well as lamotrigine (LTG) and 2) the naturally occurring high (mid-luteal) and low (early-mid follicular) reproductive steroid level phases of the menstrual cycle might affect antiepileptic drug levels as well. Methods: This investigation compared serum antiepileptic drug levels at two timepoints during a single menstrual cycle in four groups of women with epilepsy: 12 on VPA, 12 on VPA plus COC (VPA-COC), 12 on LTG, and 12 on LTG plus COC (LTG-COC). Results: Both VPA and LTG levels were lower (p < 0.01) on active COC than on inactive pill with median declines of 23.4% for the VPA-COC group and 32.6% for the LTG-COC group. Serum LTG levels showed a notable but not significant 31.3% median decline during the mid-luteal phase compared to the early-mid follicular phase in the non-COC group. The non-COC valproate group showed the least change of any group between the two measured timepoints with a decline of 8.3% (p = NS). Conclusions: The findings suggest that valproate (VPA), like lamotrigine (LTG), has substantially and significantly lower serum levels while women take active combined oral contraceptives as compared to inactive pills. Larger sample sizes will be required to determine whether LTG levels may drop significantly also during the luteal (high steroid) phase of natural menstrual cycles and whether VPA levels may show greater stability in levels across the phases of the menstrual cycle. AED = antiepileptic drug; BMI = basal metabolic index; COC = combined oral contraceptive; EIAED = enzyme-inducing antiepileptic drug; IGE = idiopathic generalized epilepsy; LRE = localization-related epilepsy; LTG = lamotrigine; VPA = valproate.

EEG-Linked functional magnetic resonance imaging in epilepsy and cognitive neurophysiology.

The ability to trigger functional magnetic resonance imaging (fMRI) acquisitions related to the occurrence of EEG-based physiologic transients has changed the field of fMRI into a more dynamically based technique. By knowing the temporal relationship between focal increases in neuronal firing rates and the provoked focal increase in blood flow, investigators are able to maximize the fMR-linked images that show where the activity originates. Our mastery of recording EEG inside the bore of a MR scanner has also allowed us to develop cognitive paradigms that record not only the fMR BOLD images, but also the evoked potentials (EPs). The EPs can subsequently be subjected to localization paradigms that can be compared to the localization seen on the BOLD images. These two techniques will most probably be complimentary. BOLD responses are dependent on a focal increase in metabolic demand while the EPs may or may not be related to energy demand increases. Additionally, recording EPs require that the source or sources of that potential come from an area that is able to generate far-field potentials. These potentials are related to the laminar organization of the neuronal population generating that potential. As best we know the BOLD response does not depend on any inherent laminar neuronal organization. Therefore, by merging these two recording methods, it is likely that we will gain a more detailed understanding of not only the areas involved in certain physiologic events, e.g. focal epilepsy or cognitive processing, but also on the sequencing of the activation of the various participating regions.

Respiratory physiology of seizures.

Comonitoring of seizures and respiratory function with pulse oximetry has shown that ictal respiratory changes (IRCs) accompany tonic–clonic convulsions and even partial seizures, especially those of temporal lobe origin. IRCs occur in children and adults, and diminished central drive is frequent, although peripheral obstruction is observed occasionally. Case reports of sudden unexplained death in epilepsy (SUDEP) have suggested IRC as a mechanism. In a series of 15 witnessed SUDEP cases, overt convulsions with marked respiratory difficulty were observed in 12. For two cases, obstructive mechanisms may have predominated. One near-SUDEP case implicated central apnea, but another case implicated postictal laryngospasm. Inhibition of brainstem respiratory control circuits likely subserves IRCs. The pre-Bötzinger complex in the rostral ventrolateral medulla is a key locus for respiratory rhythm generation, with expiratory control neurons near the nucleus ambiguous. Inputs to these neurons descend from the insula, hypothalamus, and reticular formation. Direct stimulation of limbic targets in humans causes apnea. Animal models of focal seizures with IRCs and SUDEP have produced inconsistent results: some support central mechanisms, whereas others implicate peripheral obstruction. Serotonin seems relevant in a mouse model of SUDEP. These models may elucidate how seizures embarrass respiration and possibly predispose patients to SUDEP.