CONVULSIONS AFTER ABRUPT WITHDRAWAL OF BACLOFEN

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corticosteroids but I do believe that when new data are presentedand commented on, the not extensive previously published workshould be reviewed. Experience still strongly supports the use ofsteroids in acute asthma. An important subgroup of patients recoverslowlyb and it may be that if these could be selected at presentationthey would be the patients who would benefit most from steroids. Inaddition, on the basis of data we have collected in general practice, 7the domiciliary use of combined injected steroids andbronchodilators had a strongly protective effect against the

subsequent need to admit to hospital by comparison with similarlyill patients treated with either drug singly.Osler Chest Unit,Churchill Hospital,Oxford OX3 7LJ D.J.LANE

STILL PINCH GRAFTING?

SIR,-It would be intriguing to know how widespread the practiceof pinch grafting remains, following the recommendation of thispractice for acceleration of healing of venous ulcers by Dr Dodd(Aug. 21, p. 437), who inadvertently underlines the misconceptionthat a pinch graft is full thickness in nature whereas, if correctlyharvested, it is only full thickness at the very centre, shelvingthrough all degrees of split thickness to its edge.Although John Staige Davis is rightly regarded as the father of

plastic surgery in the U.S.A., were he alive today he would surelyacknowledge the advances in understanding of graft vascularisationand in the technology of skin harvesting that have occurred in thehalf century since his description of the small deep graftl andendorse the practice of applying split skin of even, known thicknessto such surfaces. If the area to be grafted is sufficiently small forpinch grafting to be entertained, then split skin may equally easilybe harvested under local anaesthesia, with Silva’s graft knife (which,designed to take an ordinary safety razor blade, should bestandard equipment in all accident and emergency and dermatologydepartments). If the underlying surface is less than ideal, split skinmay be either expanded by cutting multiple symmetrical slits in itwith a scalpel blade (hand meshing) or cut into smaller pieces beforeapplication; in more favourable conditions it may be laid on withoutsuch measures.The donor site heals spontaneously, is readily concealed (e.g.

upper inner arm) despite slight cosmetic blemish, and may be re-used. This compares with the "cigarette burn" appearance of pinchgraft donor sites allowed to heal spontaneously, not infrequentlywith attendant suppuration in the groin, or the need to sutureeither each donor site, in which case each closure will produce asmall unsightly "dog-ear" at each end, or a larger wound created byelliptical excision of the entire area of pinch graft harvest.Whichever technique is used at the pinch graft donor site, some fullthickness tissue is lost and this cannot regenerate for subsequent re-use.

Finally, the application of amniotic membrane superficial tomeshed or patches of autograft skin may enhance the rate ofautograft epithelial spread;2 Staige Davis was the first to report theapplication of amnion to a raw surface (at the behest of one of hisstudents) in the hope of accelerating healing,3 illustrating anextension of another of this great surgeon’s pioneering practices.Perhaps Dr Openshaw (Aug. 21, p. 437) will consider this originalallusion an adequate salve for his indignation over the alleged sins oferror and omission committed by kindred spirits from St Thomas’.

Department of Plastic Surgery,West Middlesex University Hospital,Isleworth, Middlesex TW7 6AF R. N. MATTHEWS

6. Smith AP. Patterns of recovery from acute severe asthma. Br J Dis Chest 1981; 75:132-40.

7. Arnold AG, Zapata E, Lane DJ. Br J Dis Chest (in press).1. Davis J. The small deep graft. Description of its use. Ann Surg 1929; 89: 902-16.2. Matthews RN, Faulk WP, Bennett JP. A review of the role of amniotic membranes in

surgical practice In Wynn RD, ed. Obstetrics and gynecology annual 1982.Norwalk, Connecticut Appleton-Century-Crofts, 1982, 11: 31-58.

3. Davis JS. Skin transplantation with a review of 550 cases at the Johns HopkinsHospital. Johns Hopkins Hosp Rep 1910; 15: 307-95.

CAERULOPLASMIN AND THE SUPEROXIDE RADICAL

SIR,-Dr Lewis and Dr Paton (July 24, p. 188) proposed aninteresting hypothesis and we hope that it is soon tested byexperiment. However, their statement that caeruloplasmin is anextracellular scavenger of superoxide radical (02 - -) requires someclarification. Caeruloplasmin, one of the acute-phase proteinssynthesised in increased amounts during tissue injury, does notcatalyse removal of O2. -: at best it reacts stoichiometrically withit. Indeed, the concentrations of caeruloplasmin present in humansynovial fluid are insufficient to remove anv significalit’amount of02 - .2 The antioxidantactivity of this proteinis most likely due toits ability to inhibit the metal-ion-catalysed peroxidation ofmembrane lipids even under conditions in which 02. - is notinvolved in this process.3-5Department of Biochemistry,King’s College,London WC2

National Institute of Biological Standardsand Control,

London NW3

B. HALLIWELL

J. M. C. GUTTERIDGE

CONVULSIONS AFTER ABRUPT WITHDRAWAL OFBACLOFEN

SiR,-Baclofen is widely used in the management, of musclespasticity after spinal cord transection. 6 months after a

compression fracture of the seventh cervical vertebra with anincomplete cord transection and consequent paraplegia a 48-year-old woman acquired a painful extensor spasm in her legs which wascontrolled by diazepam 12 mg four times daily and baclofen 10 mgthree times daily.

3 years later, in view of drowsiness and inadequate control ofspasm, treatment was modified. The diazepam dosage was reducedand dantrolene was substituted for baclofen, which was withdrawngradually over 5 weeks with no ill-effects. Continued inadequatecontrol necessitated reintroduction of baclofen 2 years later. The

patient remained well controlled for a year on baclofen 10 mg fourtimes daily, dantrolene 50 mg four times daily, and diazepam 5 mg atnight.

In December, 1981, slurred speech and mild confusiondeveloped. These symptoms were attributed to baclofen, which wasabruptly discontinued. 24 h after the final dose of baclofen thepatient had a grand mal convulsion and was admitted to hospital. 3 hlater a second convulsion was controlled by intravenous diazepam.On the following day a third convulsion resulted in aspiration ofgastric contents and cardiac arrest. She was resuscitated butremained deeply unconscious for a week.

Artificial ventilation was started at the cardiac arrest andanticonvulsant therapy (phenytoin and phenobarbitone) was

prescribed. A severe aspiration pneumonitis necessitated continuedventilation for 3 weeks, after which the patient was able to resumespontaneous respiration. She appeared to have no new neurologicallesions and was discharged from intensive care.Computerised tomography a few hours post arrest detected "no

focal lesion" and electroencephalograms 1 day and 17 days postarrest were reported as showing "diffuse slow wave activity but nofocal or paroxysmal changes".We feel that this patient’s convulsions were caused by the abrupt

withdrawal of baclofen. She had no history of seizures and the only

1. Bannister JV, Bannister WH, Hill HAO, Mahood JF, Willson RL, Wolfenden BS.Does caeruloplasmin dismute superoxide? No. FEBS Lett 1980; 118: 127-29.

2. Blake DR, Hall ND, Treby DA, Halliwell B, Gutteridge JMC. Protection againstsuperoxide and hydrogen peroxide in synovial fluid from rheumatoid patients. ClinSci 1981; 61: 483-86.

3. Al-Timimi DJ, Dormandy TL. The inhibition of lipid autoxidation by humancaeruloplasmin. Biochem J 1977; 168: 283-88.

4. Gutteridge JMC, Richmond R, Halliwell B. Oxygen free-radials and lipidperoxidation. Inhibition by the protein caeruloplasmin. FEBS Lett 1980; 112:269-72.

5. Stocks J, Gutteridge JMC, Sharp RJ, Dormandy TL. The inhibition of lipidautoxidation by human serum and its relation to serum proteins and &agr;-tocopherol.Clin Sci 1974; 47: 223-32.

557

change in drug treatment preceding the onset of convulsions was thediscontinuation of baclofen. She had been weaned off baclofen

previously without incident, but on that occasion the dose had beengradually reduced over 5 weeks.There have been re orts of hallucinations after abrupt

withdrawal of baclofen, but only one previous report hasdescribed convulsions.3 Of the two patients described by Terrenceand Fromm,3 one had baclofen and dantrolene therapy stoppedsimultaneously while the other had a history of convulsion afterintracranial surgery.

Department of Anaesthesia,Ninewells Hospital,Dundee DD2 1UD

IAN BARKERIAN S. GRANT

LABORATORY CONTROL OF ANTICOAGULANTS

SiR,—Dr Loeliger and Dr Lewis (Aug. 7, p. 318) have clearlydefined the concepts and definitions to be employed instandardisation of laboratory control. A new statistical approachfor the calibration of thromboplastin reagents for the prothrombintime has been successfully applied in a European CommunityBureau of Reference collaborative exercise. This is based on a

complex orthogonal regression analysis incorporating a largenumber of comparisons of normal and coumarin plasmas with thetest thromboplastin and the reference thromboplastin. Aninternational system of reporting-i.e., the InternationalNormalised Ratio (INR)-is thus made available relating to theW.H.O. international reference preparation. The system is

designed so that manufacturers can calibrate their material beforeissue. Fortunately it will not be necessary for hospital laboratories toundertake this procedure.The introduction of the new system is facilitated by the fact that

there is negligible difference between the British Ratio, which hasbeen long established in clinical practice in the U.K. and overseas,and the proposed INR. It is thus possible to make a direct

comparison of the INR therapeutic ranges recommended byLoeliger and Lewis with the British Ratios. The therapeutic rangeswith British Comparative Thromboblastin (BCT) have been

gradually evolved by clinical trials at home and overseas and by thecumulative experience of the U.K. hospitals since the introductionof the British system for anticoagulant control in 1969. TheHaemostasis and Thrombosis Task Force of the British Committeefor Standardisation in Haematology has recommended that theprothrombin time ratio with BCT and Manchester ComparativeReagent be adjusted to prothrombin time ratios between 2 - 0 and4 - 0 for different clinical conditions.4 A recent survey conducted bythe U.K. External Quality Assessment Scheme (E.Q.A.S.) in BloodCoagulation Testing indicates that the clinical ranges which arecurrently used in U.K. hospitals are closely in accord with thoseproposed by Loeliger and Lewis. The intensity of anticoagulation ismodified according to different clinical states. Overall, a greaterdegree of anticoagulation is given to patients in the U.K. withestablished venous and arterial thrombosis than for prophylaxis.Over two-thirds of the hospitals in the E.Q.A.S. survey indicatedthat the upper limit of their therapeutic range for the preoperativeprophylaxis of venous thrombosis was a British Ratio of 3-0. Forestablished venous thrombosis, myocardial infarction, and heartvalve prostheses, over 70% of U.K. centres quoted an upper limit ofmore than 3 - 0. The most intense therapy quoted for this group wasan upper limit of 5-0. There is therefore excellent agreementbetween the established clinical practice in the U.K. and theproposals on therapeutic ranges put forward by Loeliger and Lewis.

It is hoped that the initiative of the E.E.C. countries in adoptingthe new statistical approach using INR will be followed elsewhere

1. Young RR, Delwaide PJ Spasticity. N Engl J Med 1981; 304: 96-99.2. Lees AJ, Clarke CR, Harrison MJ. Hallucinations after withdrawal ofbaclofen Lancet

1977; i: 858.3. Terrence CF, Fromm GH. Complications of baclofen withdrawal. Arch Neurol 1981;

38: 588-89.4. Shinton NK. Therapeutic control of anticoagulant treatment Br Med J 1982, 284:

1871.

and when linked to the wide international use of BCT, with itsestablished therapeutic ranges, will result in safer and moreeffective anticoagulation on a world scale. The present anomaloussituation whereby vastly different intensities of anticoagulation areadministered in different geographical locations, 5 resulting partlyfrom differences in laboratory control of anticoagulants, shouldthen be improved.

National (U K.) Reference Laboratory forAnticoagulant Reagents and Control,

Withington Hospital,Manchester M20 8LR

L. POLLERJEAN M. THOMPSON

EPIDEMIOLOGY OF T-CELL LEUKAEMIA/LYMPHOMA

SIR,-Much interest has developed of late in the epidemiology ofadult T-cell leukaemia/lymphoma. The cause has been the

discovery of a type C retrovirus associated with mycosis fungoides(MF) and sensory syndrome in the United States and with aJapanese variety of adult T-cell leukaemia/lymphoma (ATCL)which clusters in Kyushu, Japan. 1,2 The pursuit of this virus wouldbe aided by knowledge of other clusters of mycosis fungoides or ofATCL.

INTERNATIONAL MORTALITY RATES FOR MYCOSIS FUNGOIDES,AGE ADJUSTED TO 1960 U.S. CENSUS, PER MILLION

There is little published information on international rates ofmycosis fungoides. I prepared the accompanying table from WorldHealth Organisation data.3 Surprisingly, Japan has the lowestmortality rate of the countries listed. Switzerland has a mortalityrate more than ten times that of Japan, and five times those of theU.K. and the U.S.A. There is an interesting north-central

European cluster of countries with higher rates including Norway,the Netherlands, and Denmark. Since all the countries listed aredeveloped, variation in diagnostic facilities is unlikely to be

responsible.These large variations require further study. If indeed the same

retrovirus is responsible for both MF and ATLV, it clearly hasconsequences profoundly different for the Swiss than for the

Japanese. The connections between Epstein-Barr virus andBurkitt’s lymphoma in Africa as well as with nasopharyngeal cancerin China suggest that such a dual role for a virus may not be far-fetched, and may be related to either genetic or environmentalfactors. Alternatively, mycosis fungoides may have a variety ofaetiological factors, including a retrovirus.

2 Poller L, Taberner DA. Dosage and control of oral anticoagulants: An internationalsurvey Br J Haematol 1982; 51: 479-85.

1. Editorial. Tumour viruses. Lancet 1982; i: 317-18.2. The T- and B-cell Malignancy Study Group. Statistical analysis of immunologic,

clinical and histopathologic data on lymphoid malignancies in Japan. Jap J ClinOncol 1981; 11: 15-38.

3. World Health Organisation. Mortality from malignant neoplasms, 1955-1965, parts Iand II. Geneva W H.O., 1970.