Mary Ann Werz

Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers

Background: The relative cognitive and behavioral effects of lamotrigine (LTG) and topiramate (TPM) are unclear. Methods: The authors directly compared the cognitive and behavioral effects of LTG and TPM in 47 healthy adults using a double-blind, randomized crossover design with two 12-week treatment periods. During each treatment condition, subjects were titrated to receive either LTG or TPM at a target dose of 300 mg/day for each. Neuropsychological evaluation included 17 measures yielding 41 variables of cognitive function and subjective behavioral effects. Subjects were tested at the end of each antiepileptic drug (AED) treatment period and during two drug-free conditions (pretreatment baseline and 1 month following final AED withdrawal). Results: Direct comparison of the two AEDs revealed significantly better performance on 33 (80%) variables for LTG, but none for TPM. Even after adjustment for blood levels, performance was better on 19 (46%) variables for LTG, but none for TPM. Differences spanned both objective cognitive and subjective behavioral measures. Comparison of TPM to the non-drug average revealed significantly better performance for non-drug average on 36 (88%) variables, but none for TPM. Comparison of LTG to non-drug average revealed better performance on 7 (17%) variables for non-drug average and 4 (10%) variables for LTG. Conclusions: Lamotrigine produces significantly fewer untoward cognitive and behavioral effects compared to topiramate (TPM) at the dosages, titrations, and timeframes employed in this study. The dosages employed may not have been equivalent in efficacy. Future studies are needed to delineate the cognitive and behavioral effects of TPM at lower dosages.

Orthostatic limb shaking from carotid hypoperfusion

Limb shaking and other involuntary episodic movements may be a concomitant of carotid artery occlusive disease.1-3 The possibility that limb shaking can be caused by cerebral ischemia has been supported by reports of patients in whom there was no response to antiepileptic medications and an absence of epileptiform activity on ictal and interictal encephalogram, but in whom there was abnormality of cerebral blood flow. In several instances, symptoms improved after treatment with antiplatelet agents or avoiding iatrogenic hypotension.2-4 We present a patient with this unusual syndrome that was initially treated as a seizure who eventually responded to an uncommon type of endarterectomy. A 66-year-old right-handed man with a history of hypercholesterolemia, coronary artery bypass graft surgery, and pacemaker insertion for sick sinus syndrome was referred for evaluation of recurrent left-sided involuntary movement. His spells began 14 months before presentation. He repeatedly dropped keys from his hand when getting out of his car. He noted clumsiness and tremorlike motion …

Phosphorylation enhances inactivation of N-type calcium channel current in bullfrog sympathetic neurons

We have investigated the effects of phosphatase and protein kinase inhibitors on calcium channel currents of bullfrog sympathetic neurons using the whole cell configuration of the patch clamp technique. Intracellular dialysis with the phosphatase inhibitors okadaic acid and calyculin A markedly enhanced the decline of inward current during a depolarizing voltage step. Tail current analysis demonstrated that this was genuine inactivation of calcium channel current, not activation of an outward current. The rapidly inactivating current is N-type calcium current (blocked by ω-conotoxin and resistant to nifedipine). Staurosporine, a nonselective protein kinase inhibitor, prevented the action of okadaic acid, suggesting that protein phosphorylation is involved. Under control conditions, the time course of inactivation could be described by the sum of two exponentials (τ= 150 ms and 1200 ms), plus a constant (apparently noninactivating) component, during depolarizations lasting 2 s. Okadaic acid induced a rapid inactivation process (τ=15 ms) that was absent or negligible under control conditions, without obvious effect on the two slower time constants. As in control cells, inactivation in okadaic-acid-treated cells was strongest near −20 mV, with less inactivation at more positive voltages. However, inactivation did not depend on calcium influx. Modulation of calcium channel activity by phosphorylation may underly the spontaneous shift between inactivating and noninactivating modes recently observed for N-type calcium channels. Differences in basal phosphorylation levels could also explain why N-type calcium channels, originally described as rapidly and completely inactivating, inactivate slowly and incompletely in many neurons.

Neurosarcoidosis presenting with simple partial seizures and solitary enhancing mass: case reports and review of the literature

A 37-year old woman, who had presented 5 years earlier with suspected simple partial seizures, returned with seizures increasing in frequency and intensity, confirmed by video/electroencephalography (VEEG) monitoring with left frontotemporal onset. A low-grade tumor was suspected, given a magnetic resonance imaging (MRI) study demonstrating enlargement of the left amygdala, anterior hippocampus, and adjacent mesial temporal neocortex, with modest gadolinium enhancement, and a positron emission tomography (PET) scan showing increased metabolism within that region. Surgical resection of the left mesial temporal lobe was performed and pathology revealed pathogen-free granulomas. She was given a diagnosis of sarcoidosis (following chest computed tomography that showed hilar adenopathy). She was treated with oral steroids for neurosarcoidosis with no further epileptic seizures in 19 months of follow-up. The second case was a young man, with known pulmonary sarcoidosis, who developed simple partial seizures and, later, complex partial seizures, with MRI revealing a left insular mass. Stereotactic biopsy again demonstrated pathogen-free granulomas. He has also done well in 4 years of follow-up. Review of the literature suggests that seizures associated with sarcoidosis do not invariably imply a poor prognosis. Certain features-multifocal parenchymal involvement, hydrocephalus, and chronic meningitis-were associated with poor outcome. In contrast, cases with isolated mass lesions often fared well.

Transverse myelitis associated with Acinetobacter baumanii intrathecal pump catheter-related infection.

Objective: To describe a late neurologic complication of intrathecal pump implantation and show the methods used for the diagnosis and successful treatment of transverse myelitis in this setting. Case report: A 32-year-old man with a chronic abdominal pain syndrome presented with right lower-extremity numbness 2 months after the placement of an intrathecal morphine pump. This progressed to bilateral lower extremity and ascending sensory loss to T12-L1 dermatome, significant lower-extremity weakness, constipation with overflow incontinence, and detrusor instability causing urinary incontinence in discrete episodes over the following 2 months consistent with a myelopathy. Magnetic resonance imaging (MRI) of the thoracic spine and cerebrospinal fluid (CSF) analysis were consistent with transverse myelitis. The intrathecal pump was removed and an Acinetobacter baumanii catheter-tip infection was diagnosed. Clinical course improved with the co-administration of intravenous corticosteroids and antibiotics, with significant clinical improvement within 30 days. Conclusions: Clinicians should recognize transverse myelitis as a possible late complication of intrathecal pump placement. Early medical intervention and removal of the intrathecal pump may be necessary to prevent irreversible spinal cord damage and may support good recovery.

Tolerability and efficacy of oral loading of levetiracetam.

Objective: Nonsedating antiepileptic drugs (AEDs) that can be initiated rapidly are desirable in a variety of clinical situations. Levetiracetam (LEV) is a newer AED, with a recently approved parenteral formulation, that can be initiated at doses effective in controlling seizures. We investigated whether oral loading of levetiracetam is well tolerated and facilitates stabilization and discharge of patients in epilepsy monitoring units (EMU). Methods: Adult patients in the EMU at two centers were identified who received 1,500 mg of LEV in a single dose. This was an observational study of these patients where LEV was thought to be an appropriate component of the therapeutic regimen. Patients were either LEV naïve or had been off all LEV for at least 3 days. LEV maintenance was begun 12 hours later at doses of 500 to 1,000 mg twice a day. Results: A total of 37 adult patients (20 female) were identified. There were no spontaneous complaints of side effects. Upon questioning, 33 patients (89%) denied side effects. The remaining 4 patients (11%) reported transient irritability, imbalance, tiredness, or lightheadedness. Eleven patients (mean weight = 85.0 Kg) had mean LEV serum concentration of 31.5 μg/mL after 1 hour, 23 (mean weight 85.7 Kg) had mean concentration of 30.77 μg/mL after 2 hours, five (mean weight 84.3 Kg) had mean concentration of 12.1 μg/mL after 12 hours, and two (mean weight 94 Kg) had mean concentration of 7.4 μg/mL after 14 hours. No seizures occurred within 24 hours of loading. All patients were able to be discharged 3 to 30 hours after loading. Conclusions: In the population surveyed, oral loading with levetiracetam was well-tolerated and rapidly yielded serum concentrations thought to decrease seizure frequency. This regimen facilitated discharge from the epilepsy monitoring units. GLOSSARY: AEDs = antiepileptic drugs; CBZ = carbamazepine; CZP = clonazepam; EMU = epilepsy monitoring units; GPN = gabapentin; LEV = levetiracetam; LTG = lamotrigine; OXC = oxcarbazepine; PB = phenobarbital; PHT = phenytoin; TPM = topiramate; VPA = valproic acid; ZNS = zonisamide.

Intracellular ATP and GTP are both required to preserve modulation of N-type calcium channel current by norepinephrine

Norepinephrine (NE) inhibits voltage-dependent calcium channels of sympathetic neurons. We investigated the role of intracellular nucleotides in this inhibition for clues to receptor-channel coupling mechanisms. Both ATP and GTP are required to preserve NE responsiveness during whole-cell dialysis. The response to NE was gradually lost in bullfrog sympathetic neurons dialyzed with GTP as the only nucleotide, ATP only, or no nucleotides. Replacing ATP with ATP[γ-S] resulted in spontaneous modulation of calcium channel current, possibly because of production of GTP[γ-S]. The nonhydrolyzable ATP analog p[NH]ppA could substitute for ATP to preserve NE responsiveness. The protein phosphatase inhibitors okadaic acid and calyculin-A did not affect NE inhibition of calcium channel current, or recovery from that inhibition. These results suggest protein phosphorylation is not involved in the inhibition of calcium channel current, but binding of ATP to some intracellular site is required for the coupling of adrenergic receptors to calcium channels.

Triple pathology in epilepsy: Coexistence of cavernous angiomas and cortical dysplasias with other lesions

Coexistence of cortical dysplasias (CD) with cavernomas has rarely been reported. We reviewed our surgical specimens from patients who underwent surgery for pharmacoresistant epilepsy between 2003 and 2008, and identified seven cases with cavernoma, of whom two had overlying CD. In addition, each of these patients had a third form of a potentially epileptogenic lesion: hippocampal sclerosis in one, and venous angioma in the other. We conclude that CD is heterogeneous, with milder forms appearing to co-exist with other pathologies, including vascular abnormalities and hippocampal sclerosis.

Subjective preference for lamotrigine or topiramate in healthy volunteers: Relationship to cognitive and behavioral functioning

OBJECTIVE Outcomes research emphasizes patient self-assessment and preferences in optimizing treatment. We previously showed that lamotrigine produces significantly less cognitive and behavioral impairment compared with topiramate. In the current study we extend these observations to subject self-report of preference for lamotrigine or topiramate independent of potentially confounding effects of seizures or seizure control. Additionally, drug preference was related to effects of lamotrigine and topiramate on objective neuropsychological tests as well as self-perception on behavioral instruments. METHODS Thirty-seven healthy volunteers completed a double-blind, randomized crossover design incorporating two 12-week treatment periods of lamotrigine and topiramate each titrated to a dose of 300 mg/day. Evaluation of 23 objective neuropsychological and 15 subjective behavioral measures occurred at four times: pretreatment baseline, first treatment, second treatment, and posttreatment baseline. Preference for lamotrigine or topiramate was assessed, while blinding was maintained, at the final study visit when each subject was asked which drug he or she would prefer to take. RESULTS A large majority (70%) preferred lamotrigine, 16% stated preference for topiramate, and 14% had no preference (drugs equivalent). Consistent with preference, those preferring lamotrigine performed better on 19 of 23 objective and 13 of 15 subjective behavioral measurements while on lamotrigine. Inconsistent with preference, subjects preferring topiramate performed better on 19 of 23 objective and 9 of 15 subjective behavioral measures while on lamotrigine. Topiramate preference also did not correlate with IQ, serum concentration, body mass index, age, or gender. Topiramate preference did relate to responses on the Profile of Mood States. CONCLUSION Lamotrigine was preferred by the majority of subjects, congruent with objective neuropsychological and subjective behavioral measures. In contrast, for those stating a preference for topiramate the results on objective neuropsychological measures were impaired while fewer complaints were noted on the Profile of Mood States. This suggests that preference for topiramate may be determined by an effect on mood.

Low Frequency Stimulation of Hippocampal Commissures Reduces Seizures in Chronic Rat Model of Temporal Lobe Epilepsy

Purpose:  To investigate the effects of low frequency stimulation (LFS) of a fiber tract for the suppression of spontaneous seizures in a rat model of human temporal lobe epilepsy.