Homocysteine, folate, methylation, and monoamine metabolism in depression.

OBJECTIVES: Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression. METHODS: In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes. RESULTS: Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls. CONCLUSIONS: Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.

Vigabatrin and depression.

Ten patients who developed a major depressive episode in association with vigabatrin treatment for intractable epilepsy are reported. The depression usually occurred early in the course of treatment, but when delayed followed a recent increase in dose. Depressive symptoms occurred at doses varying between 1.5 g and 4 g a day, often but not always when patients were experiencing a decrease in their seizure frequency. Most patients had a history of affective disturbance, sometimes in association with other GABAergic drugs. The observations support a possible role for GABAergic mechanisms in the biology of mood disorders.

Multiple fractions daily for head and neck cancer: spinal cord effects and other late results.

Reports of late spinal cord damage after multiple fractions daily radiotherapy regimens for head and neck cancer are infrequent, but increasing. We have reviewed our experience of head and neck cancers treated thrice daily to examine this problem. Between 1982 and 1990, 65 patients with advanced head and neck cancer were treated by primary radiotherapy using three small fractions delivered on 5 days per week, with an inter-fraction interval of 3-4 hours during normal working hours. In 25 patients, the cervical spinal cord received > 39 Gy. In 13 patients, 39.6 Gy was given in 1.1 Gy fractions, and five received 41.8 Gy in 1.1 Gy fractions, two received 45.1 Gy in 1.1 Gy fractions and five received 45 Gy in 1.5 Gy fractions. Eleven of these patients have survived over 2 years, and can be assessed for late spinal cord damage. Ten of these received 1.1 Gy fractions with no cord damage. The only 2-year survivor whose cord received 45 Gy in 1.5 Gy fractions has developed mild, non-progressive long tract signs. Other late side effects were equivalent to those after conventionally fractionated radiotherapy. Tumour control was good, especially for the larynx. We feel that, for radiotherapy given with three small fractions daily and an inter-fraction interval of 3-4 hours, the spinal dose should not exceed 40 Gy.

Salvage laryngectomy after radical radiotherapy for laryngeal carcinoma.

Of 376 patients who were treated by radical radiotherapy for squamous carcinoma of the larynx, 56 subsequently underwent total laryngectomy. Residual or recurrent tumour was identified in 43 of the resection specimens, and necrosis alone in 13 cases, although a positive biopsy had been obtained in 3 of these prior to salvage laryngectomy. No disease related factors such as site or stage of the original tumour, or treatment related factors such as radiation type or dose, were found to be predictive of whether or not tumour was present. The clinical opinion of an experienced surgeon was found to have a positive predictive value of 0.86 for the presence of tumour. The fistula rate of salvage laryngectomy, 15 out of 56, was similar to that of other series. The actuarial cause specific 5-year survival for patients with tumour was 0.589, and for patients with necrosis only was 0.923. Intercurrent, smoking related disease was the cause of death in 16 of the 33 patients who have died.

Vitamin B12 metabolism in multiple sclerosis.

We have previously described 10 patients with multiple sclerosis (MS) and unusual vitamin B12 deficiency. We have therefore studied vitamin B12 metabolism in 29 consecutive cases of MS, 17 neurological controls, and 31 normal subjects. Patients with MS had significantly lower serum vitamin B12 levels and significantly higher unsaturated R-binder capacities than neurological and normal controls, and they were significantly macrocytic compared with normal controls. Nine patients with MS had serum vitamin B12 levels less than 147 pmol/L and, in the absence of anemia, this subgroup was significantly macrocytic and had significantly lower red blood cell folate levels than neurological and normal controls. Nine patients with MS had raised plasma unsaturated R-binder capacities, including three patients with very high values. There is a significant association between MS and disturbed vitamin B12 metabolism. Vitamin B12 deficiency should always be looked for in patients with MS. The cause of the vitamin B12 disorder and the nature of the overlap with MS deserve further investigation. Coexisting vitamin B12 deficiency might aggravate MS or impair recovery from MS.

Primary progressive non-fluent aphasia: a case study.

A case study of a 65 year old man is described with an eight-year history of progressive primary non-fluent aphasia accompanied by agrammatism, phonemic paraphasias and mild spelling dysgraphia. His naming ability, however, has remained at an exceptionally high level and there has been no evidence of impairment of word or sentence comprehension. Non-verbal skills and memory functions have also been preserved within the range of his very high premorbid level of abilities. Single photon emission computed tomography was consistent with bifrontal hypoperfusion. We argue that the selective language deficits in this patient are characteristic of dynamic aphasia and of other speech disturbances which are also known to be associated with left frontal lesions. The possible underlying pathology is discussed in the context of known degenerative disorders.

Mastoid surgery in childhood.

The presenting features and operative findings in 105 patients aged 16 years or less undergoing mastoid surgery are reviewed. In 94% surgery was for chronic otomastoiditis, usually acquired, and associated with cholesteatoma in 64%. Post-operative otorrhoea persisted beyond 6 months in 44% and contralateral disease required some form of surgical procedure in 20%. Post-operative hearing thresholds were improved or unchanged in the majority of patients, most of whom underwent cortical or modified radical mastoidectomy. An improvement in the therapeutic results of mastoid surgery in childhood is clearly necessary, but requires a greater understanding of the aetiology of chronic middle ear disease.

Multiple sclerosis and macrocytosis.

Twenty-seven patients with multiple sclerosis had mild but significant macrocytosis when compared with an individually matched neurological control group and the normal laboratory reference range. The cause of the macrocytosis is unknown, but our recent clinical observations implicate a possible disturbance in vitamin B12 metabolism, binding or transport.

Heparin and dihydroergotamine prophylaxis against thrombo-embolism after hip arthroplasty.

A prospective study involving 500 consecutive patients undergoing hip replacement was performed to find out whether a combination of heparin and dihydroergotamine was effective in preventing postoperative fatal and non-fatal emboli. Deep-vein thrombosis was demonstrated in 131 cases (26.2%), in 99 of whom thrombi were confined to the ipsilateral (operated) limb and in 13 to the contralateral limb; 19 patients developed bilateral thrombi. Nine patients (1.8%) died during the first four weeks after operation, before they were discharged from hospital; in one, major emboli were demonstrated in the right pulmonary artery. Three of the 500 patients developed non-fatal pulmonary emboli. Excessive bleeding occurred in 21 (4.2%) and in 19 of these prophylaxis was discontinued. Wound haematomas developed in 25 patients (5.0%); only six required evacuation but in none of these six did deep infection occur while in hospital; in three patients, however, the wound haematoma prolonged the stay in hospital. Thus the combination of heparin and dihydroergotamine proved an effective prophylaxis against pulmonary embolism in patients undergoing total hip replacement. The risk of bleeding complications is wholly acceptable when balanced against the advantages of the therapy.