Vagus nerve stimulation for pharmacoresistant epilepsy: clinical symptoms with end of service.

PURPOSE: Limited capability exists to predict when vagus nerve stimulation (VNS) battery deterioration becomes significant. Initial models last 2-5 years. We evaluated the first 18 patients with pharmacoresistent epilepsy after reimplantation to examine the clinical course observed during VNS end of service (EOS). METHODS: Of 72 patients with VNS, 18 patients had generator replacement. EOS was estimated based on duration of use and stimulus parameters in accordance with manufacturer guidelines. Eight males and ten females had pharmacoresistent epilepsy for a mean of 17.9 years. Thirteen with localization-related epilepsy (LRE) and 5 nonverbal patients with symptomatic generalized epilepsy (SGE) failed a mean of 11.1 antiepileptic drugs (AEDs) over 21.5 years. Seven had intracranial evaluations and five failed epilepsy surgery. Reimplantation was performed after a mean of 34.4 months. Symptoms at end of service (EOS) were addressed by postoperative survey submitted at initial reprogramming within 2 weeks of reimplantation. Stimulus parameters were compared before and after surgery. RESULTS: Nine of thirteen (69.2%) verbal patients and 11 of 18 (61.1%) total patients had signs or symptoms prior to replacement, suggesting clinical EOS, and 4 of 18 (22.2%) failed interrogation denoting battery failure without symptoms; however, this did not reach significance (chi2=0.359,p=0.54). Increased seizures were the most frequent sign in 8 of 18 (44.4%), with intensification in 7 of 18 (38.9%). Irregular stimulation was detected in 5 of 18 (27.7%), with less intense stimulation in 4 of 18 (22.2%). Painful stimulation and behavioral worsening each occurred in 2 of 18 (11.1%). A subjective improvement in function after reimplantation was noted in 12 of 13 (92.3%) verbal patients, with greater intensity and consistency. Maximally tolerated reimplant current averaged -0.56 mA less. All but one (94.4%) felt surgery should be performed before clinical EOS occurred. CONCLUSIONS: We conclude that clinical signs and symptoms may arise during VNS EOS and following replacement. Seizure increase or a change in seizure pattern was most frequently observed. The tolerated reimplant current was less than the preoperative output current in most cases. Battery replacement before EOS appears desirable from a patient perspective.

Effects of a benz[e]indene on gamma-aminobutyric acid-gated chloride currents in cultured postnatal rat hippocampal neurons.

Benz[e]indenes (BIs) are tricyclic molecules that can be envisioned as steroids without an A-ring. Because certain steroids are known to alter gamma-aminobutyric acid (GABA) responses in central neurons, we examined the effects of a substituted BI resembling 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) on GABA-gated chloride currents in cultured postnatal rat hippocampal neurons. The compound, BI-1, reversibly potentiated GABA currents at concentrations of > 10 nM, with an EC50 value of 0.2 microM. BI-1 increased the apparent affinity of GABA for its receptor, decreasing the GABA EC50 from 9 microM to 3 microM. BI-1 had no effect on the shape of the GABA current-voltage relationship and did not alter the GABA reversal potential. The effects of BI-1 were not altered by benzodiazepine or picrotoxin site antagonists. At concentrations up to 10 microM, where maximal effects on GABA currents were seen, BI-1 did not directly activate a membrane current. This contrasts with the effects of 3 alpha-OH-DHP, which activated chloride currents at concentrations that were subsaturating for GABA potentiation. These results suggest that the BIs may be useful for determining the mechanisms by which steroids potentiate GABA responses and directly gate chloride channels.

Regulation of human prolactin secretion by gonadotropin-releasing hormone in vitro.

The regulation of human prolactin (PRL) secretion by gonadotropin-releasing hormone (GnRH) was evaluated with human pituitary monolayer cell cultures. Synthetic GnRH stimulated PRL secretion when exposed to cells in an estrogen-depleted environment. This response was inhibited by pretreatment of the cells with 17 beta-estradiol (E2). A 10(-5) M GnRH antagonist inhibited luteinizing hormone (LH) but not PRL secretion when cells were maintained in an estrogen-depleted environment. However, the GnRH antagonist inhibited basal PRL secretion when cells were maintained in medium containing 10(-8) M E2. The 10(-5) M GnRH antagonist, when coincubated with 10(-5) M GnRH inhibited the release of PRL in an estrogen-depleted environment. However, coincubation of the 10(-5) M GnRH antagonist with 10(-5) M thyrotropin-releasing hormone (TRH) failed to inhibit PRL secretion. Incubation of 10(-8) M TRH and 10(-8) M GnRH produced a synergistic release of PRL in an estrogen-depleted environment. These observations led us to conclude that GnRH stimulates PRL secretion by direct action on human pituitary cells and that GnRH acts either via the gonadotrope or through receptors on the galactotrope other than that acted upon by TRH to release PRL.

Long-term monolayer culture of human anterior pituitary cells: functional validation of a method.

This study demonstrates the response of human pituitary cell monolayers to a wide variety of hormonal stimuli. Appropriate release of luteinizing hormone (LH) and prolactin (PRL) was used as a verification of cell function. Cells that had been in culture for 20 days, with no hormonal additions, were exposed to LH-releasing hormone (LH-RH) continuously for 14 days. This resulted in an immediate fivefold increase in secretion of LH followed by a depression in LH production over the remaining 10-day period. After an 8-day period without hormonal additions, the same cultures again demonstrated a threefold increase in response to retreatment with LH-RH. In two similar studies, cells that had been in culture for 28 and 31 days were treated with bromocriptine, pergolide, dopamine, or thyrotropin-releasing factor (TRF). TRF elicited an increase of PRL in the medium by nearly double the control values. The addition of dopamine, pergolide, or bromocriptine resulted in a depression of PRL during the treatment period. This study has shown that human pituitary cells maintained in long-term monolayer culture respond predictably to a wide range of hormonal stimuli.