Gerhard H. Fromm

Role of inhibitory mechanisms in trigeminal neuralgia

Segmental inhibition was elicited in the spinal trigeminal nucleus of cats by delivering a conditioning stimulus to the maxillary nerve 100 msec before the test stimulus. Carbamazepine, baclofen, and phenytoin markedly facilitated this segmental inhibition, as well as depressing the response to an unconditioned maxillary nerve stimulus. Phenobarbital, on the other hand, usually depressed the segmental inhibition. These results suggest that drugs that relieve trigeminal neuralgia both facilitate inhibitory mechanisms and depress excitatory mechanisms in the spinal trigeminal nucleus. The facilitation of inhibitory mechanisms appears to be at least as important as the depression of excitatory mechanisms and suggests that a failure of inhibitory mechanisms may play a significant role in the pathogenesis of trigeminal neuralgia.

Comparison of L‐baclofen and racernic 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 obsemations indicating that D-baclofen antagonizes the action of L-baclofen.

Imipramine in absence and myoclonic‐astatic seizures

A double-blind crossover study with imipramine was conducted in 10 patients with absence and myoclonic-astatic seizures who had not responded to conventional medications. Imipramine produced a significant initial decrease in seizure frequency in 5 of the 10 patients, and in 2 patients the beneficial effect was maintained for more than 1 year. An open trial of imipramine in another 16 patients showed an initial reduction in seizure frequency in 10 patients (63 percent), and this decrease persisted for more than 1 year in 4 patients (25 percent). The effect of imipramine on the EEG did not always correlate with the clinical response. Serum content of imipramine in the patients who showed a long-term response was 40 to 120 ng per milliliter, on a total daily dose of 0.7 to 3.5 mg per kilogram. These results suggest that imipramine is a valuable addition to the treatment of seizures.

Effect of some anticonvulsant drugs on the spinal trigeminal nucleus.

IN PREVIOUS EXPERIMENTS~ we found that 10 to 15 mg. per kilogram of diphenylhydantoin ( Dilantina) administered intravenously increased the latency of response of single neurons in the spinal trigeminal nucleus of cats to electrical stimulation of the maxillary nerve, while the latency and amplitude of the presynaptic spike was only minimally affected. These results were interpreted to mean that Dilantin@ primarily inhibits synaptic transmission. However, since the effect of DilantinB on antidromic stimulation of spinal trigeminal neurons was not studied, the possibility of the drug’s action being on the cell rather than on the synapse could not be completely ruled out. Moreover, it now appears that 10 mg. per kilogram of DilantinB is a toxic dose for cats when continued for several days,z just as it is for human beings. Thus, it seemed desirable to repeat our experiments with nontoxic doses and with antidromic, as well as orthodromic, stimulation. We also have investigated the effects of carbamazepine ( Tegretola) , a new anticonvulsant not related to the hydantoins. Our own clinical observations have amply confirmed Blom’s reports374 that it is a much better drug for the treatment of trigeminal neuralgia than Dilantinm. TegretolB has been reported to decrease the amplitude of the trigeminal evoked potential as recorded with macroelectrodes.5 In addition, we did some experiments with phenobarbital and imipramine hydrochloride (Tofranila) to note the action of related drugs that do not relieve tic douloureux. METHOD

The role of inhibitory pathways in petit ma1 epilepsy

* O n e a p p r o a c h to the investigation of epilepsy is t o examine the mechanism of action of anticonvulsant drugs. Elucidation of the neuropharmacology of these drugs may further our understanding of the pathophysiology of the seizures they serve t o control and also provides us with laboratory tests for predicting the potential usefulness of new drugs. The marked ability t o trimethadione (TridioneB) t o protect experimental animals against pentylenetetrazol (Metrazolq-induced seizures’ has made this a standard test for screening new compounds for possible use in the treatment of petit ma1 epilepsy. However, Metrazol really induces major rather than minor seizures’ and, therefore, does not tell us t o o much about why Tridione prevents petit ma1 spells. We have found the spinal trigeminal nucleus of cats anesthetized with alpha-chloralose t o be a more useful experimental model. This nucleus offers several significant advantages for studying the mechanism of action of anticonvulsant drugs. It is an easily accessible site in the central nervous sytem, and quite a bit of anatomical and physiologic information is Furthermore, and most importantly, the trigeminal nucleus is subject t o a considerable degree of corticofugal inhibition and facilitathus permitting an evaluation of the effect of the anticonvulsants on some cortical pathways. Previously we had examined the effect of various anticonvulsant drugs on single neuron activity in the spinal trigeminal nucleus because of the ability of some of these drugs t o stop the paroxysms of pain in trigeminal neuralgia.’ ’ ,’ The latency of response of spinal trigeminal neurons to transsynaptic excitation was increased by diphenylhydantoin (DilantinB) and carbamazepine (Tegretol@), while their re-

Antiabsence drugs and inhibitory pathways

Conditioning stimuli to the coronal gyrus or periventricular gray matter inhibit the activity of spinal trigeminal neurons. Valproate decreased the corticofugal inhibition of the spinal trigeminal nucleus, as did ethosuximide, trimethadione, and imipramine. Valproate and ethosuximide also decreased the periventricular inhibition of the spinal trigeminal nucleus, indicating that antiabsence drugs depress subcortical inhibitory pathways as well as pathways of cortical origin. These results support the hypothesis that ability to depress inhibitory pathways is an important characteristic of antiabsence drugs. The effect of valproate and ethosuximide on periventricular inhibition also suggests that these anticonvulsants may act by preventing the spread of seizure activity through subcortical pathways.

Spontaneous remission of paraneoplastic ocular flutter and saccadic intrusions

We report two women with ocular flutter and saccadic intrusions, documented by electro-oculography, who had complete spontaneous remission of their ocular motor findings prior to the appearance of a primary neoplastic process remote from the nervous system. Transient elevation of blood HVA and VMA levels was detected in one patient who subsequently had breast cancer. These cases indicate that spontaneous remission of saccadic oscillations does not necessarily imply a benign outcome. Patients with this ocular motor abnormality should be followed closely for signs of a remote neoplasm even if initial investigation is negative.

A Double-blind Comparison of Nitrazepam versus Diazepam in Myoclonic Seizure Disorders

In 9 patients with drug‐resistant myoclonic seizure disorders studied for 1 year in a double‐blind fashion, nitrazepam and diazepam in combination with phenobarbital were found to be equal in effectiveness at maximum tolerable doses. Five patients had a 50 per cent or better clinical response on both drugs, but in the other four patients there was no essential change at the end of the study compared with pre‐treatment level.