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We describe the basic pharmacological principles underlying the activity of the alpha2-adrenergic receptor agonist clonidine, including its interactions with the cholinergic, histaminergic, serotoninergic, endorphinergic and possibly dopaminergic systems. The use of clonidine for the therapy of various neuropsychiatric indications in which it appears to be beneficial is described. These conditions include migraine, Korsakoff's psychosis, Tourette's syndrome, withdrawal states, tardive dyskinesia, essential tremor, neuroleptic-induced akathisia, neurogenic bladder, idiopathic orthostatic hypotension, paroxysmal localised hyperhydrosis, diabetic neuropathy and stiff-man syndrome. The need for long term evaluation of this agent in some of these diseases is stressed.

Cysticercosis is a parasitic infestation that commonly affects the central nervous system. This is a report of an elderly man who presented with progressive dementia, labelled as Alzheimer's disease, in whom diffuse cerebral cysticercosis was subsequently demonstrated. The dementia responded favorably to treatment with steroids and mebendazole. This report demonstrates the importance of excluding cerebral cysticercosis as a treatable cause of progressive dementia.

We report a patient in whom Tourette's syndrome (TS) and Type I schizophrenia coincided, and suggest, based on clinical features and pharmacological responses, that both conditions in this patient could have a common pathophysiological basis.

In the following communication we discuss evidence that impaired peripheral and central glucose and insulin metabolism may be significant in the pathophysiology of neuroleptic-induced tardive dyskinesia. Such an association between alterations in glucose metabolism and pathophysiology of tardive dyskinesia may open new avenues in the prevention and pharmacological management of this often therapy-resistant chronic neurological disorder.

In this communication we discuss the clinical features and pathophysiology of primary sensory symptoms in Parkinson's disease.

The term dystonia was introduced by Oppenheim and Vogt in 1911 to describe the relatively slow, sustained, frequently forceful contorting movements involving striatal muscles. Dystonia is characteristically seen in childhood ("primary dystonia"), but also occurs in a variety of other disorders of the CNS ("secondary dystonia"). In the case of childhood dystonia (dystonia musculorum deformans) symptoms usually occur in young patients in which case the illness is usually inherited as either autosomal dominant or recessive. In cases of adult onset dystonia, genetic factors are less likely (Eldridge, 1970). Although dystonic movement disorders have been presumed to originate from dysfunction of the basal ganglia, examination of the brains of patients who have died with idiopathic or hereditary dystonia musculorum deformans have revealed no consistent neuropathological or neurochemical abnormalities (Zeman, 1970). Furthermore, therapy of value in the treatment of other basal ganglia disorders, in these conditions, has not been helpful (Fahn, 1982). The following paper will discuss evidence implicating deranged hypothalamic neuropeptidergic functions in dystonia. We have developed a hypothesis, which reviews and incorporates published data, in which we discuss the role of deranged hypothalamic neuropeptidergic function in the pathnophysiology of idiopathic dystonia.

A case of L-tryptophan associated eosinophilia, myalgia, eosinophilic fasciitis, peripheral sensorimotor neuropathy, and multiple white matter lesions on MRI scan is reported. The various effects of eosinophilia on the nervous system are reviewed. The persistence of the neurological complications despite resolution of eosinophilia and steroid therapy is emphasized.

Adminstration of the serotonin precursor L-tryptophan in a patient with neuroleptic-induced tardive dyskinesia, produced a dramatic reduction in the severity of the abnormal movements within 24 hours. This report supports our hypothesis that alterations in the function of serotoninergic neurotransmission are implicated in the pathophysiology of neuroleptic-induced tardive dyskinesia.

Plasma baseline levels of gonadotropins and sex steroids were measured in 17 patients with Tourette's Syndrome (TS). In addition, a Gonadotropin Stimulation test, using a synthetic Gonadotropin releasing factor analogue (GnRH, 100 micrograms, i.v.), was performed in 7 patients. Plasma levels of Luteinizing Hormone (LH) were uniformly low in all patients, while those of Follicle Stimulating hormone (FSH) and sex steroids were less depressed in some patients and in the normal range in others. In all patients, stimulation with GnRH analogue produced a marked rise in LH levels, but the FSH responses were much less dramatic and did not significantly exceed that of normal controls. Our findings indicate reduced gonadotropin release in patients with TS, and support the hypothesis of hypothalamic involvement in the disease.

Narcolepsy has been defined as a disorder of excessive sleep often associated with cataplexy, sleep paralysis and hypnagogic hallucinations. Although the pathophysiology of the narcoleptic syndrome is not well understood, derangement in the functions of CNS catecholamines and serotonin (5-HT) have been implicated. In the present paper we summarize evidence to suggest a role for the endogenous opioids in the regulation of normal sleep and in the pathophysiology of the narcoleptic syndrome.

The following paper discusses clinical and neurochemical evidence for a role of sexual hormones in the pathophysiology of Tourette's syndrome.

We discuss a case of a patient with restless legs syndrome that was responsive to administration of amitriptyline. The possible mode of action of amitriptyline in ameliorating this patient's symptoms is discussed.

The discovery of opiate receptors and then their endogenous ligands in 1974 (Snyder et al., 1974) has elucidated a vast pharmacology of opiates providing a basis for their diverse clinical applications. With the awareness of quality of life as a primary goal in terminal cancer patients, widespread attention has been drawn to the direct delivery of long-term intraspinal analgesics to cancer patients for who all medical pain control regimens have failed (Coombs & Saunders, 1974). Intraspinal administration of opiates and nonopiate analgesics is not only appealing on theoretical grounds but provides a minimally invasive method to insure otherwise unobtainable pain relief while eliminating obtundation and systemic side-effects associated with conventional therapy (Cobb et al., 1984; Harbaugh et al., 1982; Leavens et al., 1982; Malone et al., 1985; Onofrie et al., 1981; Poletti et al., 1981). Although intraspinal opiates have been used in the treatment of postoperative and benign-pain syndromes (Asari et al., 1981; Cousins & Mather, 1984), in our discussion we review the basic science, current techniques and possible future improvements in spinal analgesia in the control of chronic cancer pain.

Although a recent report by Devinsky (1983) has suggested that dysfunction at a midbrain level is most likely to underlie the major symptoms of Tourette's syndrome, several features of the disease including alterations in the severity of the disease during puberty and premenstrually, disorders of appetite, amelioration of tics with rise in body temperature, and sleep point to hypothalamic involvement in the pathophysiology of the disease.

Two patients with similar clinical features are presented: both patients had chronic renal failure, on hemodialysis for many years but recently begun on a high-flux dialyzer; both had been receiving a carbidopa/levodopa preparation; and both had the onset of hallucinosis and recurrent seizures, which were refractory to anticonvulsants. The first patient died without a diagnosis; the second patient had a dramatic recovery following the administration of vitamin B6. Neither patient was considered to have a renal state sufficiently severe enough to explain their presentation.

Sleep disorders have been reported in approximately 80% of Tourette's syndrome (TS) patients. Sleep studies in TS patients have demonstrated a 30% reduction in delta-sleep (slow-wave sleep) in nontreated subjects, decreased percentage of REM-sleep and the presence of tics during sleep. A subgroup of young TS patients was reported to have an increased percentage of delta sleep. Although these findings were initially thought to result from deranged dopaminergic and serotoninergic functions in TS, we suggest that abnormalities of hypothalamic-mediated control mechanisms involving the intrinsic opioids may also account for the observed derangements in sleep-wave patterns in TS patients. Evidence for impaired hypothalamic regulation in TS patients includes our preliminary observations of abnormal growthhormone release to administration of the opiate antagonist naloxone in TS. These data further suggest an interrelationship of neurochemical mechanisms involving opioid-mediated hyperactivity, slow-wave sleep and growth hormone at the level of the hypothalamus.

Two patients with postpolio syndrome are presented. The first case developed mild Parkinson's syndrome, for which she was treated with a levodopa/carbidopa combination followed by the institution of deprenyl. An unexpected improvement in the symptoms of postpolio syndrome was noted. The second patient who was unaffected by Parkinson's syndrome was started on deprenyl alone and reported a similar improvement in symptomatology

Gilles de la Tourette's syndrome (GTS) is a chronic neuropsychiatric disorder characterized by multiple involuntary motor and phonic tics associated with behavioural disturbances including obsessive-compulsive and aggressive behavior, depression and, rarely, psychosis.The relationship of GTS, presumed to be predominantly a dopammergic disorder, and depression, presumed to be a noradrenergic-serotoninergic deficiency state, is currently poorly understood. The reports published to date on the effects of tricylic antidepressants in GTS have been contradictory; while Messiha et al. (1976) used imipramine successfully in one GTS patient, Abuzzahab and Anderson (1973) and Fras (1978) on the other hand, found imipramine to exacerbate GTS symptoms and cautioned its usage in this syndrome. A more recent report suggested that imipramine is useful in GTS patients who exhibit symptoms of attention deficit disorder (Dillon et al., 1985). We report a patient with GTS whose depression and behaviour improved considerably when low-dose imipramine (Tofranil) was added to the regimen of anti-GTS medication. This report suggest that tricyclic antidepressants may be useful adjuncts in the management of GTS, and hints at norepinephrinergic and serotoninergic deficiencies as being components of the pathogenesis of the syndrome.

The release of corticotrophin-releasing factor (CRF) in the human has been shown to be under a direct inhibitory control derived from the locus coeruleus (LC). Opioids have been shown to inhibit CRF release. Based on our hypothesis of deranged opioid-noradrenergic activity in Tourette's syndrome (TS), we studied the effect of a naloxone challenge on plasma cortisol levels in 6 TS patients. In all patients naloxone produced a significant rise in cortisol secretion. These results support our hypothesis and suggest that in TS, noradrenergic LC receptors involved in CRF release are supersensitive as a result of chronic excessive endorphinergic activity.

Restless legs syndrome (RLS) is a poorly understood, often distressing condition that is particularly prevalent among patients with chronic renal failure. A wide variety of medications have been used to treat RLS with variable results. In order to evaluate the efficacy of carbidopa/levodopa therapy, eight consecutive uremic patients with RLS on maintenance hemodialysis were treated with doses ranging from 25/100 to 25/250 twice daily. Six of eight patients obtained satisfactory relief which has continued for 3 months follow-up. Carbidopa/levodopa appears to be an effective option in management of RLS in patients with chronic renal failure.

A 21-year-old man with posttraumatic epilepsy was poorly controlled on conventional anticonvulsant agents (phenytoin, carbamazepine). However, co-administration of the GABA mimetic agent baclofen improved significantly his seizure control, suggesting that the latter agent could be useful in the management of refractory epilepsy.

Opiates and opioid peptides have been shown to stimulate the release of Growth hormone (GH) in the rat and naloxone was reported to block this response (Kato et al., 1978; Bruni et al., 1977). Studies in man, however, failed to demonstrate any changes of GH release to administration of opiates (Morley et al., 1980). Moreover, GH levels stimulated by arginine, sleep, exercise, L-dopa and hypoglycaemia are modestly or not at all inhibited by naloxone (Morley 1981; Grossman & Rees, 1983), suggesting that opioids are not important modulators of GH secretion in man. We have recently demonstrated a significant rise of GH following naloxone administration in young Tourette's syndrome (TS) subjects aged 6-12 years (Sandyk & Barnford, in press, a). We have extended our study to evaluate the effects of acute naloxone challenge on GH release in an older group of TS-patients and in a small group of non-TS disease controls (6 narcoleptics). Following an overnight fast, naloxone (1.2 mg I.M.) was administered at 12:00 p.m. to six unmedicated TS patients aged 16-68 years (5 males, 1 female). Blood levels of GH were drawn 30 minutes after naloxone administration. Basal levels were drawn just prior to the naloxone challenge. Results are given in Table 1. While in the young TS patients, acute naloxone challenge produced a significant rise in plasma GH levels (Sandyk & Bamford, in press, a), in the adult group, naloxone produced suppression of GH plasma levels in 4 patients within 30 minutes of administration. The control group did not show any response to naloxone which is consistent with the reported norm (Grossman & Rees, 1983). These findings (1) suggest alterations in opioid control of GH release in TS that are maturation-related, and (2) complement many other clinical physiological and biochemical phenomena in TS that are also maturation-related. A variety of studies have demonstrated the absence of any direct effect of the opioids on pituitary GH release (Wehrenberg et

Huntington's disease (HD) is an invariably fatal condition having an autosomal dominant mode of inheritance. Although the pathological gene has a high penetrance, its presence in at risk individuals cannot usually be detected until obvious neurological or behavioral signs are manifest. Consequently, several electrophysiological parameters have been studied in an attempt to predict the presence of the gene for HD before the onset of the clinical syndrome. Despite the lack of an effective treatment for the disorder such information is vital to the genetic counseling of at risk individuals. Thus, the R2 response of the blink reflex has been reported abnormal in 41% of descendants of HD patients (Esteban et al., 1981), while 73% of children born to HD affected parents show EEG abnormalities similar to those found in overt cases of HD (Patterson et al., 1948). It has recently been demonstrated that the electromyographic silent period (ESP) is shortened in patients with HD (Sandyk, 1982; Hufschmidt & Linke, 1977). Here we have examined the ESP in 24 individuals considered to be at risk for HD.

Currently the most prevailing hypothesis attempting to explain the pathophysiology of Tourette's syndrome (TS) suggests that the disease results from dopaminergic (DA) hyperactivity (Golden, 1986). Evidence for this hypothesis is indirect and includes the favorable response of these patients to haloperidol, exacerbation of symptoms with dopaminergic drugs (e.g., methylphenidate) and the findings of reduced DA metabolites in the CSF of some TS patients (Singer et al., 1982). We have recently suggested that deranged opioid functions may also be important in the pathophysiology of TS (Sandyk, 1985). Our hypothesis was based on the favorable response of a subgroup of patients to administration of opiate antagonists (e.g., naloxone, naltrexone) (Sandyk et al., 1986), and is also supported by a recent finding demonstrating depletion of striatal dynorphins in a subject with TS (Haber et al., 1986). Furthermore, based on several clinical features of the disease, we have recently suggested that the hypothalamus could be a site of dysfunction in the disease (Sandyk et al., 1986). To investigate the possible role of deranged opioid-mediated hypothalamic functions in TS further, we tested the effects of acute naloxone (Nx) challenge on plasma FSH and LH levels in 5 male TS patients (aged 11-16 years) and in 4 non-TS-diseased controls (narcoleptics). The plasma FSH and LH levels were drawn prior to and 30 min following the intramuscular administration of 1.2 mg of naloxone.