Scottish Medical Journal

The features of γ-aminobutyric acid (GABA) as an inhibitory neurotransmitter are described, together with those of its receptor as defined by both iontophoretic and radiolabelled ligand binding techniques. Evidence is presented supporting the existence of a second GABA receptor at both peripheral nerve endings and within the CNS. At the classical receptor, GABA can produce a depolarisation of the ganglion cell body or mediate hyperpolarisation within the CNS by increasing membrane conductance to chloride ions. At this second receptor GABA acts in a bicuculline-insensitive manner to reduce neurotransmitter outflow.

Many GABA analogues active at the classical receptor are inactive at the second receptor but by contrast baclofen which is inactive at the classical receptor is a potent agonist at the novel site.

The particular and general features of spasticity are described, together with some reference to the physician's emphasis on changes in tone as opposed to the therapist's concentration on function. Spasticity is a complex phenomenon, impairing movement in various ways that depend partly upon the kinetics of the movement itself. Electromyographic recordings during voluntary movement may provide unexpected and useful information. The distinctive value of centrally and locally acting drugs in each of these circumstances is discussed.

It is proposed that analgesia might be achieved by pharmacological interruption of sensory input to the C.N.S. at the level of the spinal cord. On the basis of early reports that baclofen mimicked presynaptic inhibitory mechanisms in the spinal cord, baclofen was tested for potential analgesic activity in the mouse hot-plate test. Baclofen appeared to have some antinocisponsive activity in its own right and it potentiated the antinocisponsive effect of morphine. This observation has been confirmed and extended by several authors and the antinocisponsive activity appears to reside in the 1-isomer. Both spinal and supraspinal sites have been suggested for the locus of action in the C.N.S., whilst the underlying cellular mechanism may be inhibition of neurotransmitter release (via a bicuculline-refractory GABA receptor) or antagonism of the post-synaptic actions of substance P as a neurotransmitter.

Baclofen is compared with two other antinocisponsive agents (morphine and clonidine) in terms of its effects on release of neurotransmitters. Consideration is given to the possibility that a further characteristic is shared by these compounds, namely that following chronic administration, abrupt cessation of therapy might be accompanied by withdrawal or ‘rebound’ effects.

The results of an open trial of baclofen in children with spastic cerebral palsy are presented. In intelligent children with pure spastic diplegia there was improvement in mobility and in ability to wear orthoses. In more severely affected children the benefit lies in the possibility of preventing postural deformities, in allowing increased participation in physical therapy and in facilitating nursing care. The reduction in tone is most useful when it allows the child or his therapist to do something that had been prevented by spasticity. The drug seems to be of little value in mixed types of cerebral palsy and of no value at all in children with fixed deformities. A suitable starting dose is 5 mg twice or thrice daily increasing over two weeks to a total of 2− 2.5 mg/kg/day.

Sedation and hypotonia were occasionally seen but could be controlled by adjusting the dose. Control of epilepsy did not deteriorate.

A double blind crossover trial of baclofen against placebo was carried out in 20 children with spasticity in a day school for physically handicapped children. No significant benefit from baclofen in functional activities was observed and an unacceptable incidence of side-effects was recorded. However, interesting differences between the observations during formal testing and during everyday activities were noted and these may have implications for future trials. A longer study using a lower dose (e.g. 1 mg/kg) might achieve different results.

Gait was assessed by polarised light goniometry in 15 hemiplegic children aged 4−15 years. After initial clinical and goniometric assessment, baclofen 5−10 mg/day was started and increased over 4−6 weeks to a dose of 1−1.5 mg/kg/day. Assessment was repeated one week later. A statistically significant decrease in hip and knee flexion at the ‘toe-off’ phase of the gait cycle was found in both legs. Of the nine children who showed most change in goniometric assessment, five showed an obvious clinical improvement, two a slight improvement, one no change and one child's gait deteriorated. Of six children with minimal or no change goniometrically, four showed no change clinically, one minimal clinical improvement and one a deterioration clinically. Side effects included transient sedation (seven children), concentration difficulty (one child), behaviour disturbance (1 child) and nocturnal enuresis (three children). We concluded that although baclofen causes functional improvement in some hemiplegic children, its use should be carefully supervised in view of possible side effects and possible deterioration in gait.

Little work, using comparable protocols, has been done using baclofen in the management of patients following stroke. Extrapolation from trials in patients with spasticity and other spinal or cerebral pathology is not justified, partly because the symptoms and signs of stroke vary. However the reliable work which has been done indicates that baclofen is superior to diazepam in reducing spasticity and flexor spasms and in improving mobility and self help. Baclofen is as effective as diazepam in relieving clonus and pain associated with spasticity. The effect on bladder function is not reliably known. Unwanted effects are few and not serious: drowsiness is the most common, but occurs more frequently and noticeably with diazepam. Side effects were more likely to occur with doses in excess of 60 mg/day, if dose increments were made too rapidly and in patients with Parkinson's disease. More work is required with baclofen in managing patients after stroke.

The residual neurological deficits after stroke are discussed in this article. The main problems are weakness, spasticity and rigidity. Weakness may be amenable to help with a variety of physical aids and mobility maintained with a wheelchair. Spasticity is defined in terms of the neurological defect and its consequences examined in the clinical context of the stroke patient. The place of antispastic drugs and their method of use is described. The importance of sensory loss in the production of functional disability is also discussed.

A twenty-one month trial of the use of baclofen (Lioresal) in mental defective patients who exhibit self-injurious or other undesirable behaviour is reported. The first observed effect was in the mood of the patients who mostly became calmer and happier: subsequently many showed a diminution in their undesirable behaviour but hyperkinesis was not helped. A few patients maintained the improvement after stopping the drug, but in most it has had to be continued, sometimes with an increase in dosage. Side-effects are discussed.

The two main types of idopathic bladder instability are described using pressure recordings and the relationship to incontinence defined. In combination with urodynamic studies, using a micturating cysto-urethrogram recorded on videotape for future analysis, it is possible to correlate bladder pressures with physiological events.

Management of the unstable bladder is difficult and a variety of drug regimens have been attempted. Baclofen reduced detrusor-activity and produced a significant benefit in diurnal and nocturnal frequency and episodes of incontinence but not in enuresis. Seventy per cent of patients maintained this improvement three months after stopping treatment.

Advances in the investigation and treatment of pituitary tumours over the past decade have necessitated a major reappraisal of the management of these lesions. The recognition that prolactin-secreting pituitary adenomas (prolactinomas) not only represent a further sub-group of secretory tumours but may in fact be the commonest type of pituitary tumour has come at an appropriate time. Refinements in neuroradiological techniques and transphenoidal surgery and the introduction of the dopamine-agonist bromocriptine now offer prospects for early detection and effective treatment, either by selective adenomectomy or by non-invasive therapy with bromocriptine. In a study of 67 patients with large prolactin-secreting pituitary adenomas, 33 have undergone computerised tomography and metrizamide cisternography for assessment of tumour size. In ten of these patients repeat scans following bromocriptine therapy have shown reduction in prolactinoma size in eight. The two patients with no change in tumour size differed from the rest, having received a lower dose of bromocriptine and had prolactinomas as part of the multiple endocrine adenomatosis syndrome (Type I).

Bromocriptine has been compared with levodopa in a double blind trial of the management of Parkinson's disease. Both drugs were found to be equally effective when given in optimal dosage and side effects were similar, although the incidence of persistent confusional states was slightly greater with bromocriptine and after its withdrawal than with levodopa. It is in the long term management of severe cases of Parkinson's disease in whom late side effects have occurred with levodopa that there appears to be a definite advantage in combining bromocriptine with levodopa. In particular, the incidence of ‘on-off’ attacks is reduced.

Bromocriptine 2.5 mg. twice daily was given to 38 patients with cyclical breast pain and 15 with a non-cyclical pattern in a double blind trial lasting 6 cycles. Response to treatment was assessed by both clinician and patients independently and serum prolactin levels were monitored. Cyclical breast pain was significantly improved by bromocriptine but non-cyclical pain failed to respond. Although most patients were normoprolactinaemic before the trial, bromocriptine therapy produced a significant depression of the mean serum prolactin level.

The effects of bromocriptine were studied in 29 patients with acromegaly. The majority showed significant suppression of growth hormone secretion, often with symptomatic benefit.

The drug is a useful adjunct to primary methods of treatment, especially pituitary irradiation, but regular assessment of whether it is continuing to have a suppressive effect should be undertaken.

Daily plasma analysis of complete menstrual cycles from infertile women (n = 32) revealed transient hyperprolactinaemia in a significant number in comparison with normally cycling women. The prolactin elevations occurred for variable durations at different stages of the cycle. Transient hyperprolactinaemia occurring at mid-cycle was associated with reduced late luteal phase steroid levels and short luteal phases. When the prolactin elevations occurred at other times they were unrelated to ovarian steroid levels.

Treatment of patients with short luteal phases with bromocriptine (2.5 mg/day) normalised prolactin levels but also reduced gonadotrophins. The net result of these changes was a normalisation of the length of the luteal phase which was now deficient in steroid secretion. To alleviate these problems the treatments proposed for the short luteal phase are either bromocriptine (2.5 mg/day) for 7 days over the mid-cycle period only or bromocriptine for 7 days at mid-cycle in conjunction with a follicular stimulant in the early follicular phase.

Attention has been drawn to the particularly low fertility rate associated wth those infertile women who have no detectable abnormality as judged by classical gynaecological investigation. A proportion of these patients, defined as having ovulatory infertility, were shown to have deficient progesterone production during the early part of the luteal phase although the luteal phase was of normal length. This group of patients has also been shown to have a high incidence of transient hyperprolactinaemia, most of which occurs during the luteal phase. Although the use of bromocriptine has been associated with successful conception in some patients with ovulatory infertility the response is as yet unpredictable and a precise regime has still to be defined.

Studies with a dopamine agonist (Bromocriptine) and an antagonist (Haloperidol) suggest that elevated sex steroid synthesis such as may be found in the polycystic ovary syndrome (PCO) influence the pituitary lactotrope response to endogenous control mechanisms. A distinction between PCO with occasional elevation of plasma prolactin (PRL) and the galactorrhoea-amenorrhoea syndrome (GA) associated with hyperprolactinaemia can be established on the basis of differences in circulating levels of sex steroids and in the pattern of response to lactotrope cell stimulation. Thus, adrenal androgen synthesis can be strengthened in GA whereas in PCO both pathways, adrenal and ovarian, may be overstimulated. Also blunted PRL response to TRH or dopaminergic blockade is often seen in GA. The use of bromocriptine in patients with PCO and elevated PRL plasma levels has been shown to restore ovulation. The possible implications of dopaminergic mechanisms in the control of LH secretion independent of PRL release are discussed.

Bromocriptine has been compared with an oestrogen and a placebo in the management of the inhibition of puerperal lactation. In addition to the resolution of symptoms, the effect on plasma prolactin levels has been studied. Of the regimes employed, bromocriptine was shown to have some advantage and a scheme indicating its place on the general treatment of this condition is outlined.

In 1974 three members of the transplant team from the Western Infirmary in Glasgow moved to the new medical school in Leicester. The initial experience with 33 patients transplanted in Glasgow was published in 1972 and this paper compares the results of that series with the first 21 patients grafted in Leicester.

Despite improvements in tissue typing, better quality donor kidneys and fewer complications, there has been a failure to improve on the levels of graft survival. The overall one year graft survival rate in the Glasgow series was 79 per cent compared to 52 per cent in Leicester. In these two series the difference in results appears to be explained by blood transfusion. All the Glasgow patients had been poly-transfused but of the Leicester patients the 10 transfused pre-transplant had a one year graft survival of 90 per cent while in the 11 non-transfused patients the one year graft survival was only 18 per cent.

All 26 immunosuppressed renal transplant females attending the Renal Unit at the Western Infirmary, Glasgow were screened by cervical cytology and colposcopy for evidence of cervical neoplasia. Five patients (19.2%) were discovered to have cervical intraepithelial neoplasia, confirming the expected increase in this ‘at risk’ group. Regular cervical screening in these immunosuppressed women is recommended strongly.

Nine patients with pseudomembranous colitis (PMC) are described. Eight patients received prior therapy with antibiotics. Pyrexia and polymorph leukocytosis werecommonfeatures. Six relapses occurred in four of the six patients who were treated with vancomycin. Two patients who did not receive vancomycin died.

Since their introduction almost 30 years ago, topical corticosteroids have made a dramatic contribution to the management of a wide range of noninfective skin disorders. Their principal mode ofaction is anti-inflammatory and a variety of potencies and vehicles is available. Several important side effects have been described, of which skin atrophy is the most common, but with careful usage the risks are not great.

Topical corticosteroids are contraindicated in certain conditions.

During the two-year period (1st October 1974–30th September 1976), 2979 sera were tested for DNA antibodies by the Farr test. One thousand six hundred and ninety-five of these were tested because they had high ANA titres (1/256 or greater). In this group 285 sera were found to have raised DNA binding capacities (DNA-bc), 86 of which were found in patients having diagnoses other than SLE. When the diagnoses were reviewed following the finding of a raised DNA-bc, 55 of these patients were found to be suffering from SLE. Of the 1284 sera tested for DNA antibodies without the prior ANA screening procedures, 288 were positive, 36 of which came from patients not considered to have SLE; 30 of these patients were subsequently shown to have SLE. Thus the DNA-bc test is an important tool in the diagnos is of SLE, and the ANA test appears to be a valuable screening procedure. The level of DNA-bc was not of any diagnostic value.

Retrospective scrutiny of the documents authorising 240 consecutive emergency detentions to a Glasgow psychiatric hospital over a three-year period revealed that 15 per cent were incorrectly completed. Fourteen documents (5.8%) failed to meet a list ofminimum requirements supplied by the Central Legal Office and were therefore invalid. Invalid documentation was associated with a failure to use the recommended form. In practice, these documents were recognised at the hospital of detention and patients were either properly detained, informally admitted, or in three cases, discharged.

It is suggested that doctors who make Emergency Recommendations without using the printedform should always discuss the wording oftheir letter with the receiving psychiatrist who should in turn be familiar with the six minimum requirements of the Central Legal Office.

The incidence of acute self-poisoning with tricyclic and related antidepressant drugs has increased in recent years so that now approximately 20 per cent ofall acute overdoses in patients above the age of 12 are due to this cause. We report the results of a ten-year review of the psychiatric aspects associated with this poisoning in 316 consecutive patients admitted to a District General Hospital. Fifty-four per cent of these patients had sought medical advice in the period immediately prior to the overdosage. The final psychiatric diagnosis following the poisoning is related to the events previously and an attempt is made to judge how appropriate was the original treatment with antidepressant drugs. The important opportunities for prevention of this poisoning are discussed and suggestions made.

A clinical trial has shown that a technique of preoperative hand disinfection using a methanolic solution of chlorhexidine is faster, cheaper and more acceptable to users than the conventional aqueous detergent chlorhexidine preoperative scrub regime. The wound infection rate in general surgical patients was not influenced by the method used.

A 35-year-old man, who had spent 10 out of 18 months in hospital, has required repeated courses of intravenous nutrition (IVN) because of nutritional failure due to severe inflammatory bowel disease. He has been maintained on a nocturnal pump-fed liquid diet supplementing his day-time oral diet jar five months, four of which have been at home. The cost of such therapy is less than with an elemental diet and there are other advantages. This regime has been shown to be nutritionally adequate. The need to assess other cheaper liquid diets in patients with intestinal failure is recognised.

Andrew Moir was born in 1806, educated in King's College, Aberdeen and graduated M.A. in 1826. After becoming M.R.C.S., England, in 1828, he was a private anatomy teacher. He opened an anatomy theatre with a group of colleagues, but the hostile public feeling led to a riot in December 1831, and the building was destroyed. Three men were subsequently imprisoned, and there were complaints of official lack of concern.

Moir was popular with medical students, and mentioned in two short-lived journals of 1831 and 1835. He continued to teach and later became lecturer at the revived medical school oj King's College. Moir died in 1844: he was hardworking, appreciative of past anatomists and enthusiastic about practical dissection, vigorously defending his science against detractors.

There are now many reported successful pregnancies to renal transplant recipients, but this is believed to be the first reported successful case of triplets. The clinical course, complications and management of the pregnancy are described.

A patient who developed chronic renal failure secondary to the haemolytic uraemic syndrome subsequently developed life threatening microangiopathic haemolytic anaemia following renal transplantation. Transplant nephrectomy was necessary to prevent the progression ofthrombocytopenia and associated pulmonary haemorrhage.

A case of an acute asymmetrical polyarthritis occurring in a teenage boy is described. This was shown by serological tests to be secondary to a recent infection with Yersinia enterocolitica. Reactive arthritis following infection by this organism is well recognised in Scandinavia. Only recently have two cases been reported in the U.K. (1,2). This is the first reported case in Scotland and is unusual in that the initial infection was asymptomatic. Clinical improvement was associated with falling Y. enterocolitica titres and a reduction in the E.S.R. The patient was HLA B 27 positive. It is suggested that all patients presenting with an acute asymmetrical polyarthritis predominantly affecting the lower limbs should be screened by stool culture and serology for recent Y. enterocolitica infection.