Patients with epilepsy who die suddenly have cardiac disease.

BACKGROUND: Approximately 1 in 1000 patients with epilepsy dies suddenly and unexpectedly with no obvious medical cause. The purpose of this study was to determine if the hearts of such individuals harbor occult cardiac pathology. DESIGN: Following a comprehensive protocol, we performed careful pathologic evaluations of the hearts of 7 patients with epilepsy who died suddenly and 13 previously healthy people who died by hanging or a drug overdose. Hearts were studied only when there was no history or gross anatomical evidence of heart disease or the use of adrenergic drugs. METHODS: Multiple sections of each heart were evaluated independently by 2 cardiac pathologists who were blinded to patient group. RESULTS: Pathologic conditions were found in 5 hearts in the group with epilepsy and in none of the hearts in the comparison group. Four of the 7 hearts in the group with epilepsy had evidence of irreversible pathology in the form of perivascular and interstitial fibrosis. These 4 hearts plus a fifth had evidence of reversible pathology in the form of myocyte vacuolization. Lesions occurred predominantly in the subendocardium. CONCLUSION: Our results support the hypothesis that patients with epilepsy who die suddenly and unexpectedly have cardiac pathologic conditions that may be responsible for their deaths.

Pre-trigeminal neuralgia.

Eighteen patients who subsequently developed typical trigeminal neuralgia experienced a prodromal pain termed "pre-trigeminal neuralgia." These patients described their prodromal pain as a toothache or sinusitis-like pain lasting up to several hours, sometimes triggered by jaw movements or by drinking hot or cold liquids. Typical trigeminal neuralgia developed a few days to 12 years later, and in all cases affected the same division of the trigeminal nerve. Six additional patients experiencing what appeared to be pre-trigeminal neuralgia became pain-free when taking carbamazepine or baclofen. Recognition of pretrigeminal neuralgia makes it possible to relieve the pain with appropriate medications and avoid unnecessary irreversible dental procedures.

Effects of D-baclofen and L-baclofen on the trigeminal nucleus.

D-Baclofen reduced the response to L-baclofen in the feline trigeminal nucleus, the spinal cord of the rat and in patients with trigeminal neuralgia, but not in slices of hippocampus or neocortex. The iontophoretic application of 10-20 nA L-baclofen depressed excitatory transmission in the trigeminal nucleus oralis, similar to the effect of 0.1-0.4 mg/kg L-baclofen, given intravenously. The concomitant iontophoresis of 10-20 nA D-baclofen reduced the effect of iontophoretically applied L-baclofen. However, larger doses of D-baclofen (30-60 nA) did not, while still larger doses (200-400 nA) by themselves depressed response of the neuron, similar to the action of small doses of L-baclofen. The iontophoresis of 30-40 nA L-baclofen had a stronger effect than that previously obtained with systemic administration and D-baclofen was not able to block it. These observations suggest that D-baclofen is a partial agonist at the GABAB receptor. Failure to observe a blocking effect of D-baclofen in slices of hippocampus or neocortex could be due to the larger doses used or to a difference in receptor types. The observations emphasise the need to test drugs at therapeutic concentrations in an appropriate model, in order to predict reliably their therapeutic actions.

Limbic system symptomatology associated with colloid cyst of the third ventricle.

The clinical manifestations of olfactory and gustatory hallucinations are commonly attributed to temporal lobe involvement. The case is presented of a 46-year-old man with prolonged episodes of olfactory and gustatory hallucinations, who was found to have a colloid cyst of the third ventricle. Exhaustive electroencephalographic and radiological studies were negative except for the cyst. Stereotaxic aspiration of the cyst resulted in immediate cessation of all symptomatology with a follow-up of 14 months.

Effect of zonisamide (CI-912) on a synaptic system model.

The effect of the experimental antiepileptic drug zonisamide (1,2-benzisoxazole-3-methanesulfonamide, ZNS) on the trigeminal complex of cats was compared with the effect of established antiepileptic drugs. Intravenous administration of 10-40 mg/kg ZNS significantly depresses descending excitatory mechanisms, as well as segmental and descending inhibitory mechanisms, but has only a minor effect on segmental excitatory mechanisms. This spectrum of activity is similar to that of valproate, and suggests that ZNS should also be a broad-spectrum antiepileptic drug. In agreement with our experimental observations, it has been found that ZNS is effective against complex partial, generalized tonic clonic, and myoclonic seizures. The antiepileptic profile of ZNS in conventional screening tests resembles that of carbamazepine (CBZ) and phenytoin. However, CBZ exacerbates rather than prevents myoclonic seizures. Our experimental model thus provides a more accurate prediction of ZNS's clinical spectrum of activity. The relationship of these findings to the mechanism of action of antiepileptic drugs is discussed.

Comparison of L-baclofen and racemic baclofen in trigeminal neuralgia.

L-Baclofen was compared with racemic baclofen (Lioresal) in a double-blind crossover trial in 15 patients with typical trigeminal neuralgia. L-Baclofen was more effective than five times as much racemic baclofen in nine patients. Six of these nine patients have continued pain-free on L-baclofen for 4 to 17 months (mean, 10 months). L-Baclofen was much better tolerated than racemic baclofen. Our results suggest that L-baclofen represents a significant improvement over racemic baclofen in the treatment of trigeminal neuralgia, and support our laboratory observations indicating that D-baclofen antagonizes the action of L-baclofen.

Differential effect of ethosuximide and of electrical stimulation on inhibitory and excitatory mechanisms.

Much longer trains of conditioning stimuli are required to elicit inhibition descending from the reticular formation than to elicit segmental inhibition in the trigeminal nucleus. In contrast, a single conditioning stimulus is the most effective in eliciting descending facilitation, while the test stimulus alone is most effective in eliciting segmental excitation. Ethosuximide (ESM) selectively depresses descending inhibition and to a lesser extent segmental inhibition. Thus, ESM only depresses pathways requiring repetitive stimulation, such as inhibitory pathways in the reticular formation. This action would account for ESM's specificity for absence seizures, which are probably due to paroxysmal activity in inhibitory pathways.

The neurologic manifestations of fat embolism.

We reviewed the clinical features of 12 patients with fat embolism seen in 10 years. Based on neurologic manifestations, patients were grouped into those with focal cerebral syndromes and those with diffuse encephalopathy. Patients with focal signs tended to present earlier with neurologic findings alone, did not have fever, and had less risk of pulmonary disorder than patients with encephalopathy.

Sinus arrest in epilepsy.

In contrast to the usual occurrence of tachycardia during epileptic seizures, a 23-year-old man had episodic prolonged sinus arrest that lasted up to 9 seconds at the time of clinically observed seizures. There was no demonstrable cardiac disease.

Comparison of progabide with other antiepileptic and GABAergic drugs.

The effect of the experimental antiepileptic gamma-aminobutyric acid (GABA) agonist drug progabide, [alpha-(chloro-4-phenyl)fluor-5-hydroxy-2-benzilideneamino]-4-buty ramide, on the trigeminal complex of cats was compared with the effect of established antiepileptic drugs and with the effect of various GABA agonists and antagonists. Intravenous administration of 10-40 mg/kg progabide depressed excitatory transmission and descending periventricular inhibition, similar to carbamazepine and phenytoin. However, progabide depressed, rather than facilitated, segmental inhibition. The serum levels of progabide were comparable with those in patients receiving long-term treatment with progabide. The GABA antagonist bicuculline had the opposite effect of progabide on our experimental model, but the other GABA agonists THIP (4,5,6,7-tetrahydroisoxazolo-5,4-C-pyridine-3-ol) and muscimol did not have the same effects as progabide. THIP had no effect on excitatory transmission, periventricular inhibition, or segmental inhibition, whereas muscimol facilitated periventricular inhibition and sometimes segmental inhibition and had no effect on excitatory transmission. Our experiments thus indicate that progabide, but not THIP or muscimol, should have antiepileptic properties, in agreement with the clinical experiences that have been reported. The reason for the differential effect of these three GABA agonists remains to be elucidated.

Baclofen as an analgesic in chronic peripheral nerve disease.

Baclofen has shown analgesic properties in a number of animal studies but has failed as a conventional analgesic in the human postoperative dental pain model. In order to test baclofen's analgesic properties in more chronic pain conditions, we selected postherpetic neuralgia and diabetic neuropathy pain as possible trial diseases for baclofen analgesia. 15 patients with postherpetic neuralgia and 10 with diabetic neuropathy pain were treated with baclofen. In the spinal postherpetic neuralgia group and diabetic neuropathy group, there was little evidence of analgesic effect. 6 of 7 patients with facial postherpetic neuralgia had a good response to baclofen during the 3-week trial. Baclofen does not appear to be a conventional analgesic.

Differential effect of antiepileptic and non-antiepileptic drugs on the reticular formation.

The effect of the antiepileptic drugs carbamazepine and phenytoin, and of the non-antiepileptic drug baclofen, was compared on various inhibitory and excitatory mechanisms in the feline trigeminal nucleus. Baclofen resembled carbamazepine and phenytoin in depressing segmental excitatory and facilitating segmental inhibitory mechanisms. However, baclofen facilitated the periventricular and periaqueductal inhibition of the trigeminal nucleus, while carbamazepine and phenytoin depressed these descending inhibitory mechanisms. Baclofen also resembles carbamazepine and phenytoin in its effectiveness in trigeminal neuralgia, but baclofen is not a clinically effective antiepileptic agent. Our experiments indicate that the ability to depress the reticular formation of the diencephalon and midbrain is an important characteristic of antiepileptic drugs. This suggests that the reticular core is involved in the spread and generalization of seizures.

Trigeminal neuralgia. Current concepts regarding etiology and pathogenesis.

There has long been a controversy over the cause of trigeminal neuralgia. Most clinical data favor a peripheral cause. However, most of the experimental data tend to favor a central mechanism. Drugs that are effective in the treatment of trigeminal neuralgia facilitate segmental inhibition in the trigeminal nucleus, as well as depressing excitatory transmission. The most plausible hypothesis to reconcile all of these observations is that trigeminal neuralgia has a peripheral cause and a central pathogenesis. Chronic irritation of the trigeminal nerve apparently leads to both a failure of segmental inhibition in the trigeminal nucleus, and ectopic action potentials in the trigeminal nerve. This combination of increased firing and impaired efficiency of inhibitory mechanisms leads to paroxysmal discharges in the trigeminal nucleus, which are perceived as attacks of trigeminal neuralgia when they involve nociceptive trigeminothalamic-relay neurons.

Baclofen in the treatment of trigeminal neuralgia: double-blind study and long-term follow-up.

A double-blind crossover study of the effects of baclofen was conducted on 10 patients with typical trigeminal neuralgia. Baclofen significantly decreased the number of painful paroxysms in 7 of the 10 patients. An open trial in another 50 patients with trigeminal neuralgia refractory to or unable to tolerate carbamazepine showed that 37 (74%) were relieved of their attacks by baclofen, either alone (12 patients) or in combination with previously ineffective doses of carbamazepine or phenytoin (25). On long-term follow-up of one to five years (mean, 3.0 years), 18 of the 60 patients (30%) continued pain free while receiving baclofen; 10 (17%) went into remission after 3 to 6 months; 13 (22%) became refractory to baclofen after 1 to 18 months; and 2 (3%) elected operation despite a good response to baclofen. The results indicate that baclofen is a useful drug in the treatment of trigeminal neuralgia.

Effect of cinromide on inhibitory and excitatory mechanisms.

The effect of the experimental anticonvulsant cinromide (3-bromo-N-ethylcinnamamide) on various inhibitory and excitatory mechanisms was investigated in the trigeminal nucleus of cats. Intravenous administration of 20-80 mg/kg cinromide depressed excitatory transmission and facilitated segmental inhibition to the same extent as phenytoin, but less than carbamazepine. These doses of cinromide also depressed periventricular inhibition, similar to valproate and ethosuximide. In addition, cinromide had a marked depressant effect on the EEG, suggesting a pronounced sedative effect. The serum levels of cinromide and of its active metabolites (3-bromocinnamamide and 3-bromocinnamic acid) were comparable to those in patients receiving long-term treatment with cinromide. Our results agree with those in other experimental models, which also suggest that cinromide is a broad-spectrum anticonvulsant, and with cinromide's effect in the clinical trials reported so far.

Triglycerides as a risk factor in extracranial atherosclerotic cerebrovascular disease.

A retrospective study was carried out on a group of 138 patients undergoing carotid endarterectomy for extracranial vascular disease. Risk factors of cerebrovascular disease and routine laboratory evaluations were assessed. Of the laboratory evaluations of blood lipids, only mean triglycerides were found to be significantly different from laboratory normals. Stroke as a clinical event has been suggested not to be correlated with blood lipids in a number of large studies, but the present investigation supports the notion that extracranial vascular disease may be associated with blood lipid concentrations. Previous studies of stroke and lipids have not separated out the anatomical site responsible for the cerebral infarction, and thus probably have underestimated the effect of lipids as a risk factor in cervical extracranial atherosclerosis and brain infarction.

Effect of baclofen enantiomorphs on the spinal trigeminal nucleus and steric similarities of carbamazepine.

The seemingly structurally different drugs, baclofen and carbamazepine, have a similar neurophysiologic effect on the cat spinal trigeminal nucleus and a similar clinical effect in the amelioration of trigeminal neuralgia pain. In this investigation, we report on the enhancement of segmental inhibition by carbamazepine and l-baclofen; d-baclofen produced no effect on segmental inhibition. Doses of l-baclofen one fifth its equivalent racemic dosage produced a much greater enhancement of segmental inhibition. d-Baclofen, when given prior to l-baclofen, blocked the effect of l-baclofen on segmental inhibition and the unconditioned response at previously effective doses. Pretreatment with d-baclofen also blocked the effect of subsequent carbamazepine on segmental inhibition, but had no effect on the unconditioned response. Crystallographic evaluation of carbamazepine and the enantiomorphs of baclofen revealed a surprisingly good fit of baclofen isomers to moieties of the carbamazepine molecule. The results suggest that the baclofen enantiomorphs and carbamazepine have a common mechanism of action in the cat spinal trigeminal nucleus, and that d-baclofen, though inactive, is capable of interfering with the effect of l-baclofen and to a lesser extent with carbamazepine.

Is baclofen an analgesic?

Baclofen has been reported to be an analgesic in a wide variety of animal pain models. To study the analgesic potential of baclofen in humans, we used a postoperative dental pain model. Thirty-three patients were enrolled in a double-blind study using either baclofen, acetaminophen, or placebo. There was a statistically significant difference in pain reduction at 1 and 2 h after acetaminophen ingestion, compared to that of placebo. Baclofen was not statistically superior to placebo at any one of the four hourly measurements. In contrast to the promising animal work with baclofen as an analgesic, our study in humans does not support the notion that baclofen is an analgesic.

Baclofen. Its effect on seizure frequency.

Baclofen has been reported to be epileptogenic in man, but many animal studies have demonstrated an anticonvulsant effect. In 12 patients with a history of epilepsy, baclofen was given in the conventional dosage range. In the six patients with anticonvulsant-controlled seizures, none had a seizure during baclofen therapy. In the six patients with uncontrolled epilepsy, two patients had one more seizure per month while receiving baclofen, and a third went from four seizures per month to one per month. Baclofen does not appear to have a deleterious effect in patients with epilepsy.