Sodium valproate and clonazepam in the treatment of intractable epilepsy.

Of 88 patients with intractable epilepsy, 60 have been treated with clonazepam for up to three years and 60 have been treated with sodium valproate for up to 18 months. Each agent was used sequentially in an overlapping group of 32 patients. Both agents have proven effective in the control of petit mal absences and myoclonic jerks, although some patients responded to one and not to the other. Clonazepam has given better results than valproate in temporal lobe and other partial (focal) epilepsies, while valproate has given better results in grand mal seizures and atonic attacks. Both preparations were more effective in patients with spike and wave paroxysms in their EEG recordings, the correlation being more conspicuous with valproate. Both medications appear to be safe and useful additions to anticonvulsant therapy.

Symptoms of pheochromocytoma, with particular reference to headache, correlated with catecholamine production.

In a series of 27 patients with proved pheochromocytoma, differential analysis of catecholamines in blood, urine, and tumor specimens of 19 patients enabled grouping of subjects into those whose tumors produced predominantly norepinephrine (NE) (11 patients), predominantly epinephrine (E [Two patients]) and approximately equal amounts of both (six patients). Sustained hypertension was more common in the first group and pallor and tremor in the latter two groups, but no distinctive syndrome could be recognized as signifying the secretion of NE or E. Headache was a symptom in 20 of 27 patients and was related to sudden, transient elevation of the blood pressure, rather than sustained hypertension. The variable duration and intensity of the headache in different patients can be explained by the pressor and cranial vasoconstrictor effects of the secreted amines, which respectively enhance and diminish vascular headache.

Current concepts of migraine pathogenesis.

Migraine is a neurovascular reaction to sudden changes in the internal or external environment. Each individual has a hereditary "migrainous threshold," with the degree of susceptibility depending on the balance between excitation and inhibition at various levels of the nervous system. The mechanism of migraine has been presented as an unstable trigeminovascular reflex with a segmental defect in the pain control pathway. This defect permits excessive discharge of part of the spinal nucleus of the trigeminal nerve and its thalamic connections in response to excessive afferent input or corticobulbar drive. The end result is the interaction of brain stem and cranial blood vessels, with the afferent impulses from the latter creating the throbbing (pulsating) character of the headache. Diffuse projections from the locus ceruleus to the cerebral cortex could initiate cortical oligemia and possibly spreading depression. Activity in this system could account for the migrainous aura that may occur quite independently of the headache. The headache phase may be interrupted by therapy aimed at either the central or peripheral end of the trigeminovascular afferent pathway. Strong evidence suggests that serotonin (5-hydroxytryptamine, 5-HT) plays an important part in the genesis of migraine. Whether 5-HT is effective in central pain control pathways, the serotonergic projection to the cerebral cortex, its direct action on the cranial blood vessels, or its action at all three sites remains uncertain. It seems probable that the 5-HT agonists act to terminate migraine through the cerebral and extracranial circulations, whereas medications used for prophylaxis may act centrally.

The red ear syndrome.

The complaint of a painful, burning, red ear may be associated with irritation of the third cervical root, temporomandibular joint dysfunction, or thalamic syndrome. It may also occur without obvious structural cause in response to touch or heat. The condition may be an example of the ABC (Angry Back-firing C-nociceptor) syndrome with the increase in ear temperature being caused by the antidromic release of vasodilator peptides.

Intermittent claudication of one cerebral hemisphere.

A 13-year-old girl consistently developed unilateral sensory and motor symptoms on hyperventilation, suggesting the diagnosis of hysteria. Investigation disclosed hypoplasia of one internal carotid artery and part of the circle of Willis, responsible for compromising blood flow to one hemisphere sufficiently to produce ischemic deficit during hypocapnia.

Thermographic changes in cluster headache.

Eleven patients were examined thermographically during spontaneous cluster headaches and 22 during attacks induced by nitroglycerin or alcohol. In cluster headache, heat loss increased from the affected orbital region, and in some patients, this spread above and below the eye, down the nose, and to the affected temple. Inhalation of 100% oxygen reduced or abolished cluster pain in 22 of 25 instances, and asymmetry of heat loss then disappeared. Since the unilateral increase in blood flow usually followed the onset of pain in affected areas, the vascular changes of cluster headache are probably secondary phenomena, initiated by a vasodilator pathway, with the trigeminal nerve as the afferent and the greater superficial petrosal nerve as the efferent limb.

Internal and external carotid vascular responses to vasoactive agents in the monkey.

Internal and external carotid blood flows in anesthetized monkeys were measured simultaneously using electromagnetic flowmeters. Complete dose-response relationships were established for the effects of intracarotid infusion of several humoral agents implicated in migraine. Both the internal and external carotid vasculatures were constricted by serotonin and prostaglandin F2alpha and dilated by bradykinin, histamine, and acetylcholine. Noradrenalin and adrenaline constricted the external carotid vasculature but had little direct effect in the internal carotid territory. Prostaglandin E1 dilated the external carotid vasculature. Low doses of prostaglandin E1 produced dilation in the internal carotid circulation, but with higher doses there was a paradoxical abolition of this effect.

Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation.

Electrical stimulation at 1-200/s of the locus coeruleus in 12 Macaca nemestrina monkeys caused a frequency-dependent drop in vascular resistance in the extracerebral circulation which was twice as great on the side stimulated. Accompanying this dilatation of the extracerebral vasculature was a frequency-dependent rise in internal carotid vascular resistance, usually seen only on the side ipsilateral to stimulation. This constrictor response was maximal at low frequencies of stimulation and minimal at higher frequencies. Neither the dilator nor constrictor responses were affected by sectioning of the vagus nerve or sympathetic trunk in the neck. The simultaneous occurrence of intracranial vasoconstriction and extracranial vasodilatation has not been demonstrated previously, and bears a remarkable resemblance to the vascular changes of migraine.

Stimulation of the trigeminal ganglion increases flow in the extracerebral but not the cerebral circulation of the monkey.

The trigeminal ganglion of 9 anesthetized paralysed artificially ventilated Macaca nemestrina monkeys was electrically stimulated with frequencies varying from 0.2 to 200 Hz. This stimulation led to a frequency-dependent decrease in external carotid resistance but no significant change in internal carotid resistance was recorded. The response is probably mediated as previously described in the cat, i.e. predominantly through the greater superficial petrosal branch of the facial nerve and a small proportion through antidromic activation of the trigeminal system. Elucidation of the physiological and pharmacological mechanisms underlying such a response may aid in a better understanding of the pathophysiology of vascular headache.

The mechanism of cerebrovascular vasoconstriction in response to locus coeruleus stimulation.

Stimulation of the locus coeruleus in 11 Macaca nemestrina monkeys resulted in a frequency-dependent increase in internal carotid resistance (vasoconstriction) and a frequency-dependent decrease in external carotid resistance (vasodilation). The internal carotid constrictor response is maximal at low frequency stimulation (5 s-1), and decreases as frequency of stimulation is increased or decreased. It is blocked by the non-specific alpha-adrenoceptor blocker phentolamine and the alpha-2 adrenoceptor blocker yohimbine, but is unaffected by the alpha-1 adrenoceptor blocker prazosin. It is concluded that the cerebral vasoconstrictor response to locus coeruleus stimulation is mediated by alpha-2 adrenoceptors.

Effects of locus coeruleus stimulation on carotid vascular resistance in the cat.

The locus coeruleus was stimulated in 62 cats in order to investigate the effect on cephalic blood flow and cephalic vascular resistance. Flow was measured by electromagnetic flow probes applied to the common carotid artery. Stimulation over a range of frequencies (0.2-200 s-1) produced a frequency-dependent fall in carotid vascular resistance, greater on the ipsilateral side. This response was not affected by either cervical sympathectomy or spinal cord section. The response was blocked by bilateral section of the facial nerve but was not abolished by classical cholinergic, histaminergic or adrenergic blocking agents. Stimulation of the locus coeruleus also resulted in a pressor response through spinal mechanisms in which coeruleo-hypothalamic projections were not involved. A post-stimulation constriction in the carotid vasculature followed the dilator response and was attributed to release of catecholamines from the adrenal medulla.

Low pharmacological responsiveness of the vertebro-basilar circulation in Macaca nemestrina monkeys.

We have examined the responsiveness of the vertebro-basilar circulation of the anesthetized Macaca nemestrina monkey to vasoactive agents infused directly into the artery. Infusion of noradrenaline caused a slight increase in vertebral arterial resistance. This constriction was less than that seen in previous experiments with either the internal or vertebral arterial resistance. This constriction was less than that seen in previous experiments with either the internal or external carotid arteries. In the presence of vasodilatation caused by inhalation of a CO2-rich gas mixture, this constriction became a dilatation. Serotonin was without significant effect on the vertebral arterial bed. Bradykinin, histamine and prostaglandin E1 all produced slight dilatation, with bradykinin being the most potent. In all cases the concentration required to produce an effect on the vasculature was much greater in the vertebral circulation than it is in the internal carotid and extracerebral circulations. We conclude that the intact vertebro-basilar circulation is much less sensitive to vasoactive agents than experiments with isolated segments of these arteries would indicate and that therefore these agents are unlikely to play a significant part in the pathogenesis of vertebro-basilar migraine.

Effects of low doses of clonidine in the monkey cranial circulation.

Migraine therapy using low doses of clonidine has been based on the proposal that clonidine directly inhibits vascular smooth muscle reactivity. In anaesthetized monkeys in which internal and external carotid vascular resistances were measured, the only significant effects of clonidine administered acutely (0.5 and 2 microgram x kg-1 i.v.) or chronically (2 microgram x kg-1 i.m. daily for 7 days) on cranial vascular responses to the constrictors noradrenaline and 5-hydroxytryptamine, and the dilators histamine, prostaglandin E1 and bradykinin, were small potentiations of some of the responses. Acute clonidine initially increased blood pressure and constricted the cranial vasculature, then induced hypotension without involvement of the cranial circulation. It also decreased the external carotid vasoconstrictor response to low frequency cervical sympathetic nerve stimulation. The low chronic dose of clonidine had no hypotensive effect. The pressor response to common carotid occlusion was inhibited by both acute and chronic clonidine. These experiments thus provide no evidence that clonidine inhibits cranial vascular reactivity at doses equivalent to those used in migraine.

Effects of methysergide, pizotifen and ergotamine in the monkey cranial circulation.

Internal and external carotid vascular resistances were measured, in anaesthetized monkeys, to asses the direct cranial vascular effects of i.v. methysergide, pizotifen and ergotamine, and their effects on the cranial vascular responses to the constrictors 5-hydroxytryptamine and noradrenaline and the dilators histamine, prostaglandin E1 and bradykinin. Methysergide reduced responses to 5-HT, and tended to potentiate the external carotid responses to noradrenaline. Pizotifen blocked responses to histamine; it tended to reduce internal carotid responses to 5-HT, but it potentiated external carotid 5-HT responses. Ergotamine reduced responses to 5-HT and noradrenaline, but this was probably related to its cranial vasoconstrictor effects, especially in the external carotid circulation. Methysergide induced weak transient cranial vasoconstriction and pizotifen had no direct effects. These findings may be relevant to the therapeutic actions of these drugs in migraine, since the doses used approximated to those used clinically.

Decreased carotid arterial resistance in cats in response to trigeminal stimulation.

Stimulation of the trigeminal nerve or ganglion in the cat caused a frequency-dependent reduction in carotid vascular resistance. Systemic arterial blood pressure (SABP) decreased at low frequencies (0.2 to 5 sec-1) and increased at higher frequencies, thus increasing carotid blood flow at the higher frequencies. The effect on resistance was predominantly ipsilateral and was unaltered by cervical sympathectomy, but was abolished or substantially reduced by section of the trigeminal root proximal to the ganglion. Diminution of carotid vascular resistance was replicated by stimulation of the greater superficial petrosal (GSP) nerve without any change in SABP. Section of the seventh cranial nerve reduced or abolished the response to stimulation of the trigeminal nerve but not that from the GSP nerve. The trigeminal response was prevented by ganglion-blocking drugs in seven out of eight cats. The resistance response was unaffected by noradrenergic, cholinergic, serotonergic, and histamine-2 blocking agents. No neural connection could be demonstrated between the GSP and the trigeminal ganglion, and the vascular response to GSP stimulation persisted after trigeminal section. It is concluded that activation of the trigeminal system increases carotid blood flow by a pathway involving the seventh cranial nerve, the GSP and Vidian nerves, and a parasympathetic synapse employing an unconventional transmitter. A varying proportion of the response (greatest in the third division) may be mediated by antidromic activation of trigeminal nerves. These findings may have clinical implications for the vascular changes of migraine and other facial pain.

Action myoclonus, Ramsay Hunt syndrome, and other cerebellar myoclonic syndromes.

Action myoclonus, reviewed in this chapter, is the term applied to arrhythmic muscular jerking induced by voluntary movement. It is made worse by attempts at precise or coordinated movement (intention myoclonus) and may also be provoked by certain sensory stimuli. The effective stimuli for action myoclonus is probably feedback from muscle afferents, although it may be initiated by corollary discharge from motor cortex to reticular formation before or at the onset of voluntary movement. The condition is usually associated with diffuse neuronal disease such as post-hypoxic encephalopathy, uremia, and the various forms of PME, although action myoclonus may be limited to one limb in some cases of focal cerebral damage. It is caused by hyperexcitability of the sensorimotor cortex (cortical reflex myoclonus) or reticular formation (reticular reflex myoclonus), or both. No consistent pathological change has been reported in autopsied cases of action myoclonus. The underlying disorder appears to be a loss of inhibitory mechanisms involving serotonin and possibly GABA as transmitter agents. The term PME is used for the association of myoclonus with degenerative changes in the nervous system which are commonly diffuse but may predominate in certain systems. There may or may not be associated tonic-clonic seizures, other manifestations of epilepsy, or dementia. Those cases of PME associated with Lafora inclusion bodies and cerebral storage diseases can be distinguished from the system degenerations. Systems which may be involved in the latter group include cerebellodentatorubral, pyramidal, extrapyramidal, optic, auditory, posterior columns and gracile and cuneate nuclei, spinocerebellar pathways, motor neurons of cranial nerves and anterior horns, and muscle fibers. Confronted with this diversity of pathological change, it seems unnecessary to make any clinical distinction between Ramsay Hunt syndrome and Unverricht-Lundborg syndrome (Baltic myoclonus) because cerebellar signs are found in patients described under both headings. Additional systems may be involved in individuals or families who are otherwise typical. All three names could well be joined in an eponymous title (Unverricht-Lundborg-Hunt disease) or the condition simply known as the systems degeneration type of PME, as Halliday (43) suggested. The cause of the condition (or spectrum of conditions) is at present unknown. Action myoclonus usually responds to sodium valproate or clonazepam, and some individuals, particularly those with posthypoxic myoclonus, improve with the administration of serotonin precursors.

What is a migraine?

The migrainous patient appears to differ in reaction to stress or environmental changes from nonmigrainous subjects quantitatively rather than qualitatively. An inherited pattern of monoamine metabolism may render the patient more susceptible to such changes, which represent a threat, real or imagined, to the integrity of the brain. The migraine attack may thus be interpreted as a neurohumoral reaction aimed at protecting the brain from some noxious influence by shunting blood away from the cortex. The headache itself may be a by-product of such a reaction, serving, like any pain, to alert the organism to potential danger. The predominantly unilateral site of migraine remains unexplained. A more comprehensive clinical classification of migraine is proposed in the hope that certain entities may prove to correlate with variations in pathophysiology and thus permit more selective therapy.

Bulbo-cortical pathways and their possible relevance to migraine and epilepsy.

Facilitation of the visual evoked response from the reticular formation in the cat has been shown to depend on nicotinic cholinergic receptors distinct from the muscarinic cholinergic receptors responsible for the arousal reaction. An increase in the amplitude of visual evoked responses in migraineurs does not therefore imply any change in reticulocortical activity of relevance to epilepsy. Stimulation of locus ceruleus and nucleus raphe dorsalis exerted comparatively minor effects on the visual evoked response and did not alter the discharge rate of cortical neurons in the resting state. It is concluded that the changes in cerebral blood flow previously reported to result from stimulation of these monoaminergic brainstem nuclei, which resemble those observed in migraine, must be exerted directly on the cortical microcirculation and not simply follow the metabolic demand of cortical neurons. There is thus a place in the management of migraine for pharmaceutical agents acting on cerebral vessels even if the neural hypothesis for the mechanism of migraine proves to be correct.

The pathophysiology of migraine.

New knowledge of intrinsic serotonergic and noradrenergic pathways, projecting from brainstem rostrally to cerebral cortex and caudally to spinal cord, makes a neurogenic hypothesis for migraine more plausible than the previously held humoral theory. Low frequency stimulation of locus ceruleus in the monkey increases cerebral vascular resistance, thus diminishing blood flow, while high frequency stimulation increases external carotid arterial flow by connections with the greater superficial petrosal component of the facial nerve. The latter connection also serves the 'trigeminovascular reflex' whereby stimulation of the trigeminal nerve causes vasodilatation in the external carotid circulation in cat and man. Vascular changes evoked from the locus ceruleus are predominantly unilateral and stimulate those recorded in classical migraine, suggesting that excessive discharge of ascending monoaminergic pathways may initiate these phenomena in man. Since descending monoaminergic pathways play an important part in the endogenous pain control system, a phase of monoamine depletion could open the pain gate and give rise to headache. The referral of ice-cream headache and ice-pick pains to the habitual site of migraine headache in some patients, even in the period between attacks, suggest a dormant neural excitability which becomes active periodically to induce a migrainous episode. The symptomatology and phenomena of clinical migraine can now be explained in terms of instability of central monoaminergic pathways, a hypothesis that can be tested experimentally and which should lead to more precise pharmacological management of migraine in the future.

Neurological disorders in AIDS: a study of 18 cases.

Neurological disorders were studied in 18 patients diagnosed to have AIDS and their findings are analysed. Amongst the problems seen were toxoplasmosis (9), cryptococcal meningitis (5), tuberculous meningitis (1), AIDS dementia complex (3), peripheral neuropathy (2), vertebrobasilar stroke, and a possible AIDS myelopathy in one case each. Their findings are discussed, and literature on the neurological disorders in AIDS reviewed.