Polyneuropathy with vagus and phrenic nerve involvement in breast cancer. Report of a case with spontaneous remission.

Dysphagia, respiratory insufficiency, and bilateral vocal cord paralysis developed in a 70-year-old woman seven years after resection of a breast carcinoma. There was spontaneous partial remission of symptoms before death, in the absence of treatment. Necropsy showed both inflammatory and metastatic infiltrates of vagus nerves, with demyelination out of proportion to axonal loss. Spontaneous resolution of metastases-evoked inflammation within vagus and phrenic nerves may have been the basis of clinical remission.

Dezinamide for partial seizures: results of an n-of-1 design trial.

BACKGROUND: Dezinamide (DZM, ADD 94057) is a potential antiepileptic drug that binds to the voltage-sensitive sodium channel and showed preliminary evidence of efficacy and safety in an open-label study. METHODS: Our double-blind, placebo-controlled trial at two sites used an n-of-1 (single-patient) design. All 15 patients had medically intractable partial-onset seizures and were comedicated with phenytoin (PHT) only. Treatment was for six 5-week periods (three active paired with three placebo in random sequence). Assuming nonlinear kinetics, we used an initial pharmacokinetic profile to estimate dosages for reaching target plasma concentrations of DZM. RESULTS: Statistically significant seizure reduction was found by both a randomization test (p = 0.0025) and a signed rank test (p = 0.048). Median seizure frequency decreased 37.9%, and 40% of patients had > 50% seizure reduction, both compared with placebo. Pharmacokinetic predictions were not accurate; mean plasma concentrations fell well below target values. Plasma PHT concentrations increased (mean = 17.1%) during DZM treatment. The most common adverse experiences were fatigue, light-headedness, and abnormal gait; five patients required DZM dosage reductions. CONCLUSIONS: DZM showed minimal clinical toxicity and significant efficacy despite lower plasma concentrations than predicted by pharmacokinetics. This trial establishes the suitability of the n-of-1 design to investigational antiepileptic drug trials.

Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.

OBJECTIVE: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. BACKGROUND: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. METHODS: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. RESULTS: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. CONCLUSIONS: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

Functional mapping of the early stages of status epilepticus: a 14C-2-deoxyglucose study in the lithium-pilocarpine model in rat.

Continuous convulsive activity in status epilepticus generally does not occur suddenly in response to the inciting epileptogenic agent, but is rather the culmination of a stereotyped sequence of stages. Initially seizures are discrete, then undergo waxing-and-waning of convulsive/electroencephalographic severity. Following a transitional EEG-recorded fast-and-slow spiking phase, continuous fast spiking with invariant convulsive behavior ensues. We sought to map the seizure anatomic substrates corresponding to these stages, utilizing the 14C-2-deoxyglucose technique, in order to make inferences about underlying mechanisms. The lithium-pilocarpine status epilepticus model in rat was employed. Cerebral autoradiographs associated with discrete seizures revealed non-uniform cerebral metabolic activation, with rostral cortical and olfactory areas especially involved. Portions of basal ganglia were also activated, consistent with projections from seizure-activated areas. Successive stages of status entry displayed additional limbic and cortical activation, along with subcortical projection sites, so that by fast-and-slow spiking most forebrain areas were recruited. Based on these results, a model is proposed whereby cyclical seizure-attenuating mechanisms cause, in the initial stages of status entry, fluxing of seizure anatomic extents between small and large cerebral domains, with corresponding cycling of convulsive severity. In the later stages of status entry, these mechanisms become ineffective, resulting in steady-state maximal forebrain recruitment, associated with continuous and invariant convulsive behavior and electrographic fast spiking.

Functional mapping of the late stages of status epilepticus in the lithium-pilocarpine model in rat: a 14C-2-deoxyglucose study.

Pilocarpine administration to lithium chloride-pretreated rats results initially in discrete convulsive seizures, each behaviorally and electroencephalographically terminated, which then progress to convulsive activity with waxing-and-waning behavioral and electrographic severity; finally, a continuous convulsive state ensues, associated electrographically with continuous fast spiking. This stage does not last indefinitely but is followed by a dramatic electrographic change to periodic epileptiform discharges. The purpose of the present study was to determine with the 14C-2-deoxyglucose functional mapping technique what changes occur in the seizure anatomic substrate during and after this transition, in order to enable inferences about underlying mechanisms. Behavior associated with early and late continuous fast spiking consisted of head twitching; corresponding deoxyglucose autoradiographs displayed seizure-induced intense glucose utilization in most forebrain areas; extranigral brainstem was normal. At 2-3 h of status, fast spiking became interrupted by flat periods; periodic complexes soon dominated the electroencephalogram. Behaviorally, convulsive severity increased. Despite this dramatic electrographic evolution, little change in generalized forebrain metabolic hyperactivation occurred, except that the zona incerta/pretectal/superior colliculus complex displayed markedly increased activity. Deoxyglucose studies in late stages of periodic epileptiform discharges established a sequence of further changes. In late periodic discharges with clonic jerks, at 4 h after status entry, generalized forebrain hyperactivation still prevailed, but to a lesser degree than in early periodic discharges with clonic jerks. At a still later stage, late periodic discharges, subtle convulsive, autoradiographs revealed constriction of the seizure-activated anatomic substrate: hyperactivation was lost in most of neocortex and thalamus, and in caudal olfactory structures, cortical amygdala, and entorhinal areas, but retained in deep occipital cortex and many limbic areas. In the last stage, late periodic discharges, electrical, not associated with convulsive behavior, autoradiographs revealed residual activation in only Ammon's horn; in contrast, much of the forebrain displayed below-normal glucose utilization. These results demonstrate that in the later stages of status epilepticus, the transition from fast spiking to periodic complexes is not associated with a reduction in the seizure anatomic substrate. The electrographic entity of periodic epileptiform discharges is not anatomically or behaviorally homogeneous, but proceeds through successive stages characterized initially by a reduction of glucose utilization within generalized seizure-activated forebrain, then a contraction of the seizure anatomic substrate. Possible mechanisms underlying the transition to periodic complexes are discussed.

Functional [14C]2-deoxyglucose mapping of progressive states of status epilepticus induced by amygdala stimulation in rat.

Electrical stimulation of rat amygdala induced self-sustained steady-state seizures (status epilepticus (SE] within 60 min. These SE states varied in behavioral severity from mere alteration of motility to frank clonic convulsions. Four distinct behavioral states were observed: immobility, exploration, mastication and clonus. These SE states were associated with [14C]2-deoxyglucose (2-DG) autoradiography anatomic patterns that were correspondingly more extensive and complex. Four distinct 2-DG activation patterns were observed: a restricted pattern involving several discrete limbic nuclei, including amygdala; more extensive patterns involving numerous limbic areas, first unilaterally, then bilaterally; finally the most extensive pattern involving widespread areas of forebrain. These data imply a systematic progression of seizure activity: originating in the amygdala, then spreading to some direct amygdala projection areas, and from there to a restricted network of interconnected ipsilateral limbic nuclei. This restricted network then recruits most of the remaining limbic structures, first ipsilaterally, then contralaterally. Finally, most of the basal ganglia, thalamus and neocortex are recruited.

Inhibition by dopamine agonists of dopamine accumulation following gamma-hydroxybutyrate treatment.

The increase in the dopamine (DA) concentration of rat (whole) brain induced by gamma-hydroxybutyrate was inhibited by the reputed dopamine agonists apomorphine, apocodeine, 2-bromo-alpha-ergocryptine, piribedil, ergocornine and 5,6-dihydroxy-2-dimethylaminotetralin. The last three drugs raised DA levels in saline controls. Haloperidol, which decreased DA in controls slightly, prevented any agonist-induced rise in controls. However, haloperidol antagonized only apomorphine and piribedil in regard to the inhibition of the gamma-hydroxybutyrate induced rise in DA; this neuroleptic did not affect the inhibition by the other agonists. It is concluded that these data provide evidence for local receptor control of DA synthesis and that the DA agonists do not act through a common mechanism.

A new, non-pharmacologic model of convulsive status epilepticus induced by electrical stimulation: behavioral/electroencephalographic observations and response to phenytoin and phenobarbital.

Much remains to be learned about mechanisms underlying entry into, and temporal progression of, status epilepticus (SE). This report describes a non-pharmacologic model of generalized convulsive SE in rat. Pulsed trains of suprathreshold electric current, were administered bilaterally to either of four rostral forebrain sites: orbital cortex, medial precentral cortex, deep prepiriform cortex, or rostral caudate-putamen (n = 8 per site). This induction method resulted in 30/32 animals attaining limb-clonic convulsive SE within a mean of 30-35 min for each forebrain site, with no differences between sites. Subsequent SE proceeded without further interventions, permitting observation of the natural course of progression. A stereotyped behavioral/electrographic sequence occurred, characterized by devolution. Behaviorally, animals progressed from predominantly limb clonus to head clonus, then to subtle twitching, and finally to electrical SE before cessation of spikes. The corresponding electrographic progression was from fast and slow spiking to periodic epileptiform discharges (PEDs). In 20 animals surviving to 48 h, pathologic damage affected mainly limbic sites; damage was related to total convulsive time rather than to clonic activity. High-dose phenobarbital but not phenytoin suppressed SE when given during orbital cortex-induced limb-clonic SE. These findings are compatible with human observations and indicate that this model will enable investigations of generalized SE mechanisms and evaluation of new therapeutic agents for refractory SE.

Effect of an adenosine antagonist and an adenosine agonist on status entry and severity in a model of limbic status epilepticus.

Adenosine is an endogenous neuromodulator that suppresses excitatory neurotransmission. We postulated that adenosine-mediated mechanisms resist status epilepticus (SE) entry and limit SE severity. In the first experiment rats were given an adenosine agonist (2-chloroadenosine), an adenosine antagonist (aminophylline), or saline vehicle, prior to SE induction with pulsed-train current delivered to amygdala in successive 5-min current-on sessions. Saline-treated animals entered limbic SE, with predominantly exploratory behavior, after 6.0 +/- 0.9 current-on sessions. Aminophylline increased major convulsive activity during stimulation and resulted in entry into convulsive SE after only 2.1 +/- 0.1 sessions. 2-Chloroadenosine, in contrast, suppressed major convulsive activity during stimulation, and blocked (in 3/7) or delayed (4/7) SE entry, with successes requiring 12.8 +/- 0.9 stimulation sessions. In a second experiment, animals already in exploratory SE were administered a single injection of saline vehicle, aminophylline, or 2-chloroadenosine. Aminophylline converted exploratory SE into lethally severe convulsive SE. 2-Chloroadenosine suppressed SE behaviorally and electrographically, and protected recipients from the seizure-associated cerebral damage seen in saline-administered SE controls. These results support the hypothesis that endogenous adenosine mechanisms resist SE entry, modulate the severity of ongoing SE, and limit the anatomic spread of seizure activity.

Electrogenic status epilepticus induced from numerous limbic sites.

We have previously shown that pulsed-train electrical stimulation of the amygdala results, within 60-90 min, in status epilepticus in which one of four behavioral states is predominant: immobile, exploratory, minor convulsive and clonic convulsive. These four states form a hierarchy which appears, on electrographic and behavioral grounds, to belong to the same order of severity as limbic-kindled seizures, but not representing steady-state versions. We tested the hypothesis that it should be possible to induce prolonged seizure states from numerous limbic sites, as is the case with kindled seizures. It was found that electrogenic status epilepticus could be generated at any of 11 extra-amygdala sites, including parts of hippocampal formation, olfactory/limbic cortical areas, and caudate putamen. These four status categories could each be engendered from numerous sites without any site-specific behavioral features. Midline cortical and caudate stimulation was more prone to elicit clonic convulsive status. Such findings provide further evidence that kindled seizures and electrogenic status states belong to the same progression, and share the same underlying anatomic substrates.

Seizure suppression by systemic epinephrine is mediated by the vagus nerve.

The present study investigated the seizure-suppressing effects of systemic epinephrine. Rats were injected with epinephrine, and seizures induced with pentylenetetrazol. Seizure severities were significantly reduced 15 min after 1 mg/kg of epinephrine. Severing the subdiaphragmatic vagus nerves abolished this effect, demonstrating that epinephrine-induced seizure suppression is mediated by subdiaphragmatic vagal afferents. The development of novel anti-epileptic drugs that exploit this peripheral pathway may yield new seizure treatments.

Paraneoplastic subacute necrotic myelopathy.

A 79 year old male acutely developed a Brown-Sequard syndrome two weeks following resection of renal cell carcinoma. The subsequent clinical course was marked by subacute progression of spinal cord signs. Pathologic studies showed extensive multifocal spinal cord necrosis that could not be attributed to vascular occlusion or to vasculitis. This case appears to be a rare example of paraneoplastic subacute necrotic myelopathy.

Implications of stimulus factors governing kindled seizure threshold.

Seizure threshold was measured in kindled rats by delivering trains of specified duration, consisting of bipolar pulses of specified width, at increasing current intensities, at specified intertrain intervals. The effect of decreasing pulse width was to elevate seizure threshold, but considerably less total energy was required to elicit a seizure. Seizure threshold was also found to be an inverse function of train duration, within asymptotic limits. Seizure "threshold" is not a single number but a function of stimulus-duration factors. In the case of train length, a putative threshold-altering agent may alter one or the other asymptotic value so that the curve is shifted upward or to the right.

Suppression of harmaline-induced tremor in rats by vagus nerve stimulation.

We studied whether vagus nerve stimulation could suppress tremor in the harmaline tremor model in the rat. Animals were chronically implanted with helical leads around the left vagus nerve and a disk-shaped electrode positioned subcutaneously in the dorsal neck. Harmaline-induced tremor was recorded on a physiograph while each animal received a sequence of five 20-minute trials. Each trial consisted of five minutes of pre-stimulation baseline, five minutes of vagus nerve stimulation, and ten minutes of post-stimulation. Vagus nerve stimulation significantly suppressed harmaline-induced tremor. The suppressive effect was present within the first minute of stimulation and was reproducible across the five trials of the study. The results of this study suggest that the central generator or expression of tremor in the harmaline animal model can be suppressed by vagus nerve stimulation.

Hierarchy of seizure states in the electrogenic limbic status epilepticus model: behavioral and electrographic observations of initial states and temporal progression.

Repeated electrical stimulation was delivered to the amygdala in a paradigm of electrogenic limbic status epilepticus induction in rats. We observed four distinct initial behavioral states associated with prolonged spiking, comprising an ordered hierarchy of severity: immobile, exploratory, minor convulsive, and clonic convulsive. The EEG and behavioral topography of the initial prolonged seizure state behaviorally and electrographically resembled the acute seizures that occurred earlier during induction. Onset of status epilepticus on limbic induction appears to represent not a new type of seizure activity, but instead the extended version of repeated brief limbic-onset seizures as seizure-terminating mechanisms gradually become ineffective. These prolonged seizure states can therefore be used to study the anatomy and mechanisms of brief limbic seizures. We also examined the temporal progression of amygdala-induced prolonged-seizure states. At one end of the severity spectrum, immobile-associated spiking was prone to terminate early, within 90 min, accompanied by normalization of behavior. At the other end of the spectrum, clonic convulsive status epilepticus slowly decreased in behavioral severity together with a change in EEG from fast to slow spiking. Exploratory status epilepticus was characterized by incessant explorationlike behavior that could last hours and was associated with slow periodic spike-complexes on EEG. The long-term course consisted either of slow devolution, with eventual cessation of spiking, or of spontaneous late ascension to convulsive status. Prolonged-seizure states may thus be considered to fall not only within an anatomic/behavioral hierarchy of severity, but also within a temporal physiologic progression.

Efficacy and tolerance of long-term, high-dose gabapentin: additional observations.

Gabapentin (GBP) has shown antiepileptic efficacy and good tolerance in clinical trials. Much remains to be learned about its clinical use. As a participating center in the US Gabapentin Study Group, we report observations that have practical implications for patient management. Twenty-three patients with intractable partial-onset seizures initiated open-label treatment after a blinded placebo-controlled add-on dose efficacy study. In the titration phase, GBP and concurrent antiepileptic drugs (AEDs) were adjusted to achieve optimal efficacy on maximally tolerated GBP doses. Nine patients had no significant improvement in seizure control and discontinued GBP. The remaining 14 patients were observed while treated long-term with stable-dose GBP and concurrent AEDs. Improvement was maintained as long as patients were followed: < or = 4 years. The protocol-allowed upper dose limit, 2,400 mg/day, was well tolerated by 16 of 23 patients, indicating that higher doses may be tolerated. GBP discontinuation did not cause rebound increases in seizure frequency. The most common adverse events (AEs) (in 14 of 23) were similar to those induced by concurrent AEDs and responded to reduction of concurrent AEDs. Many patients reported positive psychostimulatory effects. These observations extend previous findings indicating that GBP is an effective and well-tolerated drug for treatment of partial-onset seizures.

Mapping of limbic seizure progressions utilizing the electrogenic status epilepticus model and the 14C-2-deoxyglucose method.

We have previously described a model of limbic status epilepticus in which chronic prolonged seizure states of immobile, exploratory, minor convulsive or clonic convulsive behavior are induced by intracerebral electrical stimulation; these states appear to belong to the same behavioral progression as kindled seizures. We postulated that the underlying seizure substrates, as mapped by the 14C-2-deoxyglucose method, should reflect a corresponding anatomic progression of discharge spread. Status epilepticus was induced in rat by pulsed-train current delivered for up to 90 min to one of several subcortical areas. Autoradiographs revealed that most of the observed patterns of seizure-induced metabolic activation comprised a hierarchical sequence, such that progressively more extensive patterns subsumed anatomic territories activated in less extensive patterns, thus allowing inferences as to the progression of discharge spread. In this sequence, the basolateral amygdala ipsilateral to the induction electrode was among the first structures to be activated. In successively larger activation patterns a small unilateral network related to basolateral amygdala was involved; this evolved through a transitional state to a unilateral extensive limbic pattern; which in turn was succeeded by bilateral extensive limbic activation. This hierarchical sequence culminated in a neocortical activation pattern, in which most of the forebrain was involved in intense seizure-induced activation. Seizure behaviors increased in severity in correspondence with the underlying seizure-activated anatomic substrate. In contrast, patterns of seizure activation were observed which did not fit within the early stages of the above sequence, although analysis indicates that the later stages of spread may be shared. The study of these patterns and those reported in the literature indicates that although limbic seizure networks may be anatomically distinct at their origination, further expansion is characterized by overlap; upon assumption of extensive patterns of activation the number of nuclei participating is so vast that the identity of the limbic originator is lost and common convulsive manifestations occur.

Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats.

PURPOSE: Early animal studies of the therapeutic mechanisms of vagus nerve stimulation (VNS) suggested that seizure suppression requires maximal activation of small, unmyelinated vagal C fibers. However, effective therapeutic stimulation parameters appear to be subthreshold for these fibers in humans, and there are no clinical reports of the autonomic side effects that would be expected if these fibers were maximally activated. We report here that selective destruction of C fibers with capsaicin does not affect VNS-induced seizure suppression in rats. METHODS: Rats were pretreated with capsaicin or vehicle in three injections over a 2-day period. A cuff electrode was later implanted on the left cervical vagus nerve. Two days after surgery, VNS was given to half of the capsaicin- and vehicle-treated rats. The remaining rats were connected to the stimulator but did not receive VNS. Thirty seconds after VNS onset, seizures were induced by pentylenetetrazol (PTZ), and seizure severity was measured. Two days later, the reciprocal VNS treatment was given, and PTZ-induced seizure severity was again measured. RESULTS: VNS effectively reduced seizure severity in both capsaicin- and vehicle-treated rats as compared with their non-VNS baselines. CONCLUSIONS: These results indicate that activation of vagal C fibers is not necessary for VNS-induced seizure suppression.

Rising dose study of safety and tolerance of flunarizine.

In a recent NIH-sponsored parallel-group placebo-controlled blinded study of flunarizine for the treatment of partial-onset seizures, the flunarizine serum concentration was controlled to a constant level among patients in order to reduce response variability. Flunarizine was found to exhibit modest anti-epileptic efficacy. A potential criticism of this study is that the chosen controlled concentration was too low to determine optimal efficacy. As a participating center in this study we investigated the effect of higher doses of open-label flunarizine on seizure frequency in 16 patients with refractory partial seizures. Following the completion of the blinded placebo/flunarizine phase, all patients were initiated at the flunarizine dose calculated to result in a serum concentration of 60 ng.ml-1. The dose was subsequently increased each 8-12 weeks to a maximum of 2.7 times the initial dose. On the initial maintenance flunarizine dose, seizure control was improved, with an average seizure reduction of 47% compared to pre-blinded-phase baseline. When higher doses were administered, adverse reactions were more common yet improved seizure control did not occur in most patients. These findings complement those of the concentration-controlled NIH study and suggest that appropriate flunarizine doses were utilized in that study.