Diclofenac-induced pseudomembranous colitis

126

CATECHOLAMINERGIC NEURON COUNTS

NI, Becker BE, McGovern WA. A study in experimental tremor. Confin Neurol 1962; 22: 397-429. 7. Graybiel AM. Neurotransmitters and neuromodulators in the basal ganglia. TINS 1990; 13: 244-54. 8. Graybiel AM, Baughman RW, Eckenstein F. Cholinergic neuropil of the striatum observes striosomal boundaries. Nature 1986; 323: 625-27. 9. Narabayashi H. Surgical approach to tremor. In: Marsden CD, Fahn S, eds. Neurology 2: movement disorders. London: Butterworth, 1981: 292-99. 10. Moon-Edley S, Graybiel AM. The afferent and efferent connections of the feline nucleus tegmenti pedunculopontinus, pars compacta. J Comp Neurol 1983; 217: 187-215. 6. Aronson

Argyria from excessive use of topical silver sulphadiazine mean estimated percent loss (SEM) of catecholaminergic neurons compared with mean values for controls *p==0 017 between patients with (mean age 68 2 [4]) and without tremor (72-66

Values represent

[5]).

been receiving levodopa, with similar dose in those with and without tremor. As expected, the number of catecholaminergic neurons was decreased in each region studied except in the central grey substance. The loss of dopaminergic neurons in cell group A8 was significantly greater in patients with tremor than in those without tremor (table). A significant difference between the tremor and non-tremor groups was not observed for the other catecholaminergic cell groups analysed, although the number of dopaminergic neurons was reduced (non-significantly) in the substantia nigra pars compacta (p 0-08) and the ventral tegmental area (p=047) of patients with tremor, compared with those without. The more severe generalised loss of dopamine neurons in most parts of the nigral complex of patients with tremor may not in itself account for the tremor, as massive degeneration of the mesostriatal dopaminergic neurons generally results in a severe akinetic-rigid syndrome without tremor.4 Our findings thus raise the possibility that the loss of dopaminergic neurons in cell group A8 may contribute to the development of tremor in Parkinson’s disease. This hypothesis is compatible with experimental data showing that lesion of the midbrain region, including dopaminergic cell group A8, results in tremor in monkeys.s,6 Dopaminergic neurons from cell group A8 project preferentially to specific subregions within the striatum called the matrix.7 It would be worthwhile investigating whether the dopaminergic innervation of the striatal matrix is more severely affected in patients with tremor than in those without tremor. This could, in turn, affect specific output connections from the striatum, in particular the outputs towards the ventrolateral part of the thalamus,’°g a site of action of surgical treatment against tremor.9 The loss of extranigral dopaminergic neurons from the perirubral and retrorubral region A8 could thus contribute differentially to the pathophysiology of parkinsonian rest tremor. 10 =

INSERM U289, Hôpital de la Salpêtrière, 75013 Paris, France

ETIENNE C. HIRSCH ANNICK MOUATT BAPTISTE FAUCHEUX ANNE-MARIE BONNET FRANCE JAVOY-AGID

Department of Brain and Cognitive Sciences, College, MIT. Cambridge, Massachusetts, USA

ANN M. GRAYBIEL

INSERM U289, Hôpital de la Salpêtrière

YVES AGID

Whitaker

Irwin I, Fomo LS, Delanney LE. Parkinson’s disease, aging and MPTP. clinical and experimental observations. In Fahn S, Marsden CD, Calne D, Goldstein M, eds. Recent developments in Parkinson’s disease. Florham Park, NJ: MacMillan Healthcare Informations, 1987: 59-74. 2. Benabid AL, Pollak P, Hommel M, et al. Traitement du tremblement parkinsonien par stimulation chronique du noyau ventral intermediaire du thalamus. Rev Neurol 1989; 145: 320-23. 3. Hirsch EC, Graybiel AM, Agid Y. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 1988; 334: 345-48. 4. Marsden CD. The pathophysiology of movement disorders. Neurol Clin 1984; 2: 435-59. 5 Ward AA, McCulloch WS, Magoun HW. Production of an alternating tremor at rest in monkeys. J Neurophysiol 1948; 11: 317-30. 1

Langston JW,

SIR,-Silver poisoning has been associated with renal and hepatic complications, peripheral neuropathies, and encephalitis. It is uncommon, usually being reported with chronic application of silver nitrate to open wounds.1-3 We report a unique case of argyria due to excessive use of silver sulphadiazine. A 59-year-old man had had recurrent, bilateral, extensive venous leg ulcers since 1955. The venous hypertension was secondary to inferior vena caval obstruction, a complication of tuberculous spondylitis. Compression bandaging met with resistance from the patient because of pain. Alternative treatments were sought and from January until May, 1991, on the patient’s initiative, he and his district nurse treated the leg ulcers with silver sulphadiazine 1% cream (Flamazine). The extent of ulcers was such that a 50 g tube was used every 2 days, for 5 months. However, there was no improvement, although the surface of the ulcers became tarnished like unpolished silver, and his thighs became light blue. Sensation loss was noted over the forearms and legs and the question of argyric neuropathy was raised. Electrophysiological investigation was only possible in the arms because of the painful leg ulcers, and revealed a generalised sensorimotor polyneuropathy with evidence of both axonal loss and demyelination. Plasma silver concentration was 10 pg/1 (reference range less than 1). 3 weeks after discontinuing Flamazine, plasma silver had decreased to 5-11 µg/1 and at 12 weeks it was 1 J.1g/1. Our patient had argyria caused by continued Flamazine application to venous leg ulcers. Silver intoxication caused by flamazine is a recognised complication when the drug is used on extensive burns, but has not been reported in the treatment of venous leg ulcers. Argyric neuropathy has been described with silver-based cement in hip prostheses.’ It is rare and reversible, and may result in substantial neurological deficit. The long excretion time of silver from the body means that clinical improvement may be slow.

William

Harvey Hospital,

Ashford, Kent TN24 0LZ, UK

CHRISTOPHER M. E. ROWLAND PAYNE CHRISTOPHER BLADIN ALAN C. F. COLCHESTER JEREMY BLAND RUTH LAPWORTH D. LANE

Wang XW, Wang NZ, Zhang OZ. Tissue deposition of silver following topical use of silver sulphadiazine in extensive burns. Burns 1985; 11: 197-201. 2. Owens CJ, Yarborough DR, Brackett NC. Nephrotoxic syndrome following topically applied sulphadiazine silver therapy. Arch Intern Med 1974; 134: 332-35. 3. Fullear FW, Engler PE. Leukopenia in non-septic burn patients receiving topical 1% silver sulphadiazine cream therapy: a survey. J Burn Care Rehab 1988; 9: 606-09 4. Vik H, Anderson KJ, Julshamn K, Lodnem K. Neuropathy caused by silver absorption from arthroplasty cement. Lancet 1985; i: 872. 1.

Diclofenac-induced pseudomembranous colitis SIR,-Serious lower gastrointestinal tract side-effects of nonanti-inflammatory drugs (NSAIDs) are rare. We report

steroidal

pseudomembranous colitis associated with diclofenac. An 80-year-old healthy women complained in May, 1992, of acute lumbago. Intramuscular diclofenac 75 mg twice daily was prescribed. On the fifth day of treatment she had diarrhoea (7-8 stools per day). There was no history of gastrointestinal symptoms. Diclofenac was discontinued but the diarrhoea did not stop, and the patient was admitted 8 days after the onset of symptoms. She was severely dehydrated, with weight loss of 3 kg. She had depletion

127

hyponatraemia (Na 126 mmol/1) and functional renal failure (urea 19 mmolll, creatinine 160 (imol/1). A stool smear was positive for leucocytes, and stool samples were negative for routine culture and for parasites. Flexible proctosigmoidoscopy showed a pseudomembranous mucosa. Histopathological examination confirmed the diagnosis of pseudomembranous colitis. The patient was treated with 500 mg vancomycin daily and she rapidly improved. Some serious lower gastrointestinal tract side-effects of NSAIDs have been described: non-specific colitis,l activation of quiescent idiopathic inflammatory bowel disease,2 collagenous colitis3 ulceration of the colon,4 and acute eosinophilic colitis.5 However, pseudomembranous colitis has never been reported in association with NSAIDs. A link with antibiotics is well known.6 Pseudomembranous colitis has also been reported during gold therapyNSAIDs are widely used, especially in the elderly, and we suggest that rectosigmoidoscopy should be done when diarrhoea develops after the start of NSAID therapy. Harvier Medical Clinic, Central University Hospital, 29609 Brest Cédex, France

A. GENTRIC Y. L. PENNEC

1 Ravi S, Keat AC, Keat ECB. Colitis caused by non-steroidal anti-inflammatory drugs.

Postgrad Med J 1986; 62: 773-76. 2. Kaufmann HJ, Taubin HL. Non-steroidal anti-inflammatory drug activates quiescent inflammatory bowel disease. Ann Intern Med 1987; 107: 513-16. 3 Giardiello FM, Hansen FC, Lazenby AJ, et al. Collagenous colitis in setting of non-steroidal anti-inflammatory drugs and antibiotics. Dig Dis Sci 1990; 35: 257-60. 4. Uribe A, Hohansson C, Slezak P, et al. Ulcerations of the colon associated with naproxen and acetylsalicylic acid treatment. Gastrointest Endosc 1986; 32: 242-43. 5 Bridges AJ, Marshall JB, Diaz-Arias AA. Acute eosinophilic colitis and hypersensitivity reaction associated with naproxen therapy. Am J Med 1990; 89: 526-27. 6. Price AB, Davies DR. Pseudomembranous colitis. J Clin Pathol 1977; 30: 1-12. 7. Reinhart WH, Kappeler M, Halter F. Severe pseudomembranous and ulcerative colitis during gold therapy. Endoscopy 1983; 15: 70-72.

Peripheral neuropathy associated with fluoroquinolones have been associated with adverse system (0-9-4-4% of patients), including headache, agitation, dizziness, sleep disturbance, and seizures in those with predisposing factors.1 We report a case of peripheral neuropathy associated with fluoroquinolones therapy. A 37-year-old man with chronic vertebral osteomyelitis, caused by a methicillin-susceptible Staphylococcus aureus, received oral pefloxacin 400 mg twice daily with excellent clinical and microbiological response. Many other oral regimens had failed previously, including flucloxacillin and clindamycin. After 5 months of pefloxacin, the patient had paraesthesia in his lower legs with a stocking-glove distribution, followed by progressive right foot weakness and difficulty in walking. Common peroneal nerve conduction velocity was 43 m/s. Electromyography (EMG) revealed fibrillations and polyphasic motor unit potentials in the tibialis anterior and peroneus longus muscles. Laboratory profile was normal and he denied alcohol misuse. Biopsy of rectal mucosa was negative for amyloidosis. No epidural abscess, transverse myelitis, or other causes could be found. The patient had been cured 15 years before from Hodgkin’s disease with radiochemotherapy, including vincristine for a total dose of 18 mg. Discontinuation of pefloxacin resulted in a dramatic improvement of peripheral neuropathy within 10 days. Osteomyelitis recurred 6 months later, and treatment with ofloxacin 200 mg twice a day resulted in relapse of peripheral neuropathy within 15 days, which remitted within 7 days of stopping ofloxacin. He was treated with flucloxacillin and fusidic acid for 2 months, which was stopped for a relapse of infection, which most probably resulted from poor compliance due to gastrointestinal tolerance. Because it was the only antibiotic that had demonstrated efficacy in this patient, pefloxacin, at the same dose, was resumed cautiously. Unfomtunately, peripheral neuropathy recurred within 15 days. Ciprofloxacin 250 mg twice daily orally was given instead and could be maintained for 2 months with minimum limb paraesthesia. Thereafter, these symptoms became unbearable, necessitating withdrawal of ciprofloxacin. The common peroneal nerve

SIR,-Fluoroquinolones

effects in the central

nervous

was then 37 m/s with reduced amplitide of the digitorum brevis muscle (< 1 mV). EMG was typical of a subacute neuropathy with fibrillations and prolonged polyphasic motor unit potentials ( > 17 ms). Such alterations are indicative of a probably toxic axonal neuropathy. Patients receiving prolonged therapy with fluoroquinolones, and who had previously received neurotoxic drugs such as vinca alkaloids, should be evaluated carefully for peripheral neuropathy. Other neurotoxic agents or conditions may have the same capacity to potentiate fluoroquinolone-induced peripheral neuropathy.

conduction velocity extensor

Infectious Diseases Clinic and Microbiology Laboratory, Institut Jules Bordet, 1000 Bruxelles, Belgium

Institut Jules Bordet

M. AOUN C. JACQUY L. DEBUSSCHER D. BRON

Neurology Service, Hôpital de Tivoli

M. LEHERT

Neurology Service, Hôpital Saint-Pierre

P. NOEL

Institut Jules Bordet

P.

Haematology Service,

VAN DER

AUWERA

1. Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev 1989; 2: 378-424. 2. Donofrio PD, Albers JW. Polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve 1990; 13: 889-903.

Cholesterol inhibition, cancer, and coronary heart disease SIR,-Professor Buchwald’s hypothesis (May 9, p 1154) that cholesterol inhibition can inhibit tumour growth exposes a fascinating paradox. Reductase inhibitors have been marketed for cholesterol lowering in the hope of decreasing coronary heart disease. Yet, there is evidence that they may actually increase coronary endpoints when used in the secondary prevention of coronary disease. Reductase inhibitors inhibit 3-hydroxy-3-methylglutarylcoenzyme A reductase, the rate limiting enzyme of the cholesterogenesis pathway, resulting in a decreased formation of mevalonate from its precursor 3-hydroxy-3-methylglutarylcoenzyme A. It is the inhibition of mevalonate and not cholesterol that is linked to inhibition of tumour cell replication.2 Other metabolites of mevalonate besides cholesterol that are decreased by reductase inhibitors include ubiquinone and isoprenoids. Isoprenoids are involved in the prenylation of proteins, and prenylated proteins are linked to DNA synthesis and ensuing cell division.3 Therein lies the connection with reductase inhibitors and tumour growth inhibition. Reductase inhibitors result in lower tissue levels of ubiquinone, a compound indispensable for the bioenergetics of cardiac muscle function. There is evidence that the reduction of ubiquinone results in a measurable decrease in cardiac function.4 This may be especially bothersome in those with

impaired coronary reserve. In the Expanded Clinical Evaluation of Lovastatin Study5,6 33 (0-5%) of 6582 patients in the drug treated group died compared with 3 (0-18%) of 1663 patients in the placebo group during 48 weeks. 31 of the 36 deaths were attributed to coronary disease and were predominantly individuals with known coronary disease at baseline.7 These findings suggest that reductase inhibitors could be deleterious in the secondary prevention of coronary disease, perhaps via the reduction of ubiquinone. Therefore, it is plausible that reductase inhibitors can lead to an increase in coronary endpoints in those with known coronary disease, mediated by decreases in ubiquinone, and equally plausible that they can lead to an inhibiton of the growth of tumours via decreases in isoprenoids. These possibilities raise several questions. Will reductase inhibitors prove beneficial in the primary prevention of coronary disease? Will they be efficacious in the secondary prevention of such disease in subsets of individuals with normal coronary reserve? Will reductase inhibitors help to prevent certain malignant diseases. Will lipophilic reductase inhibitors be more advantageous than hydrophilic reductase inhibitors in tumour inhibition? Will reductase inhibitors increase deaths due to one disease while decreasing deaths from