1256
BRITISH MEDICAL JOURNAL
22 MAY 1976
SHORT REPORTS Polyneuropathy after perhexiline maleate therapy Though generally considered not to cause serious side effects perhexiline maleate may occasionally cause hypoglycaemia,5 severe hepatic dysfunction,2 or peripheral neuropathy.' 4This paper is the first to report the histclogical findings in a case of neuropathy due to this drug. Case report A 46-year-old man was referred to us with a one-year history of peripheral neuropathy. Except for gout, he had had no notable illness before December 1973, when he suffered myocardial infarction. He was given perhexiline maleate 100 mg twice a day, and this dosage was continued from January 1974 to October 1975. In October 1974 he complained of cramps and of tingling in his hands and feet. After 10 weeks he developed muscular weakness, first in the lower then in the upper limbs. In March 1975 conduction speeds were 33 m/s in the ulnar and 19 m/s in the peroneal nerves; cerebrospinal fluid (CSF) proteins were 1 10 g/l (1-6 cells/ul). In June 1975 his weakness was such that walking was impossible and handling of objects a problem. He also became impotent. In October 1975 there was considerable weakness of all four limbs with moderate muscle wasting. Deep tendon reflexes were absent. Sensation to touch, pain, and temperature was altered over a "socks and gloves" distribution. Postural sensibility and vibration appreciation were impaired in the lower limbs. The patient's general condition was good. Blood pressure was 150-90 mm Hg; CSF contained 1 58 g/l proteins (6 gamma-globulins) and 1-6 cell/rtl; conduction speed was 19 m/s (right ulnar nerve); chest radiographs were normal; ECG showed signs of an old anterior myocardial infarction. Blood cell count; erythrocyte sedimentation rate; serum electrolytes; blood urea; and serum protein electrophoresis and serum lipid, cholesterol, and triglyceride concentrations were within normal limits. A screening test for phytanic acid was negative. Perhexiline maleate was discontinued. After two weeks muscular weakness and paresthesiae became stationary, and after one month they started to recover. By 28 January 1976 the patient could walk by himself and handle objects normally. Sensory signs had diminished, tendon reflexes had reappeared in the arms, conduction speed was 33 m/s (right ulnar nerve). Biopsy findings-Macroscopically the superficial peroneal nerve was enlarged. By light microscopy peroneus brevis muscle tissue showed severe neurogenic atrophy. Many small inclusions were seen scattered in the muscle fibres in the cryostat sections stained with Sudan black and in the unstained thick Araldite-embedded sections. The superficial peroneal nerve showed severe loss of myelinated fibres and many osmiophilic bodies in the cytoplasm of the Schwann and endothelial cells. Teased preparations showed evidence of segmental demyelination. By electron microscopy these inclusions were polymorphous (fig): some resembled multilamellated bodies; others had a regular, crystalline-like lattice pattern on which small dense particles were often superimposed; a few others had a dense homogenous appearance.
Discussion That perhexiline maleate caused the peripheral neuropathy in this case is strongly supported by the fact that withdrawal of the drug was followed by recovery. Furthermore, as in other reported cases of neuropathy due to the drug,' 4the symptoms began several months after therapy was started, weakness affected proximal as well as distal muscles, muscle wasting was discrete, nerve conduction speeds were appreciably reduced, and the CSF protein level was raised. These last two findings are consistent with the morphological changes in the Schwann cells. The ultrastructural aspects of the nerve and muscle inclusions resemble those of hypocholesterolaemic drug toxicity.5 This might suggest a disturbance in phospholipidic metabolism. Since neuropathy seems to be a rare side effect, such a disturbance could exist only in persons with some latent inborn metabolic disorder. We thank Dr H Duclos for calling our attention to toxic side effects of perhexiline maleate.
ADDENDUM-Since this report was written one of us (MF) has observed similar histological findings in two other cases of polyneuropathy due to perhexiline maleate. I 2
Roger, P, et al, Nouvelle Presse Medicale, 1975, 4, 2663. Abaza, et al, Nouvelle Presse Mddicale, 1973, 2, 2820. 3 Bourrat, G, Viala, J J, and Guastaal, J R, Nouvelle Presse Medicale, 1975, 4, 2528. Bousser, M G, et al, Coeur et Medecine interne. In press. Rawlins, F A, and Uzman, B G, Laboratory Investigation, 1970, 23, 184.
H8pital de la Salpe^triere, Paris F LHERMITTE, MD, professor of neurology and neuropsychology M FARDEAU, MD, maitre de recherche CNRS F CHEDRU, MD, chef de cinique assistant J MALLECOURT, MD, chef de clinique assistant
Prevention of postoperative deep vein thrombosis by leg bandaging and oxyphenbutazone Anticoagulants are contraindicated for preventing postoperative deep vein thrombosis owing to the risk of wound haematoma. Bleeding may have disastrous effects on the result of an orthopaedic operation, especially total hip arthroplasty. Low-dose heparin is less apt to cause postoperative bleeding but its prophylactic effect in hip surgery is insufficient.' Bandaging of the leg increases the venous blood velocity,2 although it has not been convincingly shown significantly to reduce thrombosis after major surgery.3 Phenylbutazone preparations decrease platelet aggregation. Oxyphenbutazone inhibits platelet aggregation due to collagen and adenosine diphosphate (ADP) in rats in vitro and also experimentally induced thrombosis in vivo.2 This paper reports a clinical trial of leg bandaging and concomitant oxyphenbutazone treatment.
Electron micrograph showing cytoplasm of Schwann cell filled with polymorphous, lamellated inclusions. (Uranyl acetate and lead citrate x 17-066.)
Patients, methods, and results Fifty consecutive patients aged over 50 years undergoing hip surgery were randomly distributed between a control (23 patients) and a treated group (27 patients). All were moblised the day after operation but were not allowed to sit in a chair for six days. They did walking and breathing exercises twice a day and were given physiotherapy of the hip and instructions for exercises
BRITISH MEDICAL JOURNAL
22
MAY
1257
1976
on their own. The treated group were given oxyphenbutazone 250 mg twice daily in a suppository and had their legs bandaged with Lohmann's Dauerbinde (strong, or krdftig) for 14 days after the operation. Both legs were bandaged from toe to knee immediately after operation. The bandages were 10- or 12-cm wide, depending on the size of the patient's feet and legs. They were changed twice daily, or more often if necessary, and were worn at night. The bandaging significantly increased the velocity of the venous blood.2 Blood coagulation, blood in faeces, white cell count, packed cell volume, and electrolytes were recorded for 18 days postoperatively to detect any adverse reaction to treatment, especially to oxyphenbutazone. Ascending phlebography4 was performed 14 days or more postoperatively, or earlier when indicated clinically. The average was 19 days. Altogether 18 patients developed deep vein thrombosis. Of these, 5 were in the treated group (5127) and 13 were controls (13/23). The difference was significant (P
BRITISH MEDICAL JOURNAL
22 MAY 1976
SHORT REPORTS Polyneuropathy after perhexiline maleate therapy Though generally considered not to cause serious side effects perhexiline maleate may occasionally cause hypoglycaemia,5 severe hepatic dysfunction,2 or peripheral neuropathy.' 4This paper is the first to report the histclogical findings in a case of neuropathy due to this drug. Case report A 46-year-old man was referred to us with a one-year history of peripheral neuropathy. Except for gout, he had had no notable illness before December 1973, when he suffered myocardial infarction. He was given perhexiline maleate 100 mg twice a day, and this dosage was continued from January 1974 to October 1975. In October 1974 he complained of cramps and of tingling in his hands and feet. After 10 weeks he developed muscular weakness, first in the lower then in the upper limbs. In March 1975 conduction speeds were 33 m/s in the ulnar and 19 m/s in the peroneal nerves; cerebrospinal fluid (CSF) proteins were 1 10 g/l (1-6 cells/ul). In June 1975 his weakness was such that walking was impossible and handling of objects a problem. He also became impotent. In October 1975 there was considerable weakness of all four limbs with moderate muscle wasting. Deep tendon reflexes were absent. Sensation to touch, pain, and temperature was altered over a "socks and gloves" distribution. Postural sensibility and vibration appreciation were impaired in the lower limbs. The patient's general condition was good. Blood pressure was 150-90 mm Hg; CSF contained 1 58 g/l proteins (6 gamma-globulins) and 1-6 cell/rtl; conduction speed was 19 m/s (right ulnar nerve); chest radiographs were normal; ECG showed signs of an old anterior myocardial infarction. Blood cell count; erythrocyte sedimentation rate; serum electrolytes; blood urea; and serum protein electrophoresis and serum lipid, cholesterol, and triglyceride concentrations were within normal limits. A screening test for phytanic acid was negative. Perhexiline maleate was discontinued. After two weeks muscular weakness and paresthesiae became stationary, and after one month they started to recover. By 28 January 1976 the patient could walk by himself and handle objects normally. Sensory signs had diminished, tendon reflexes had reappeared in the arms, conduction speed was 33 m/s (right ulnar nerve). Biopsy findings-Macroscopically the superficial peroneal nerve was enlarged. By light microscopy peroneus brevis muscle tissue showed severe neurogenic atrophy. Many small inclusions were seen scattered in the muscle fibres in the cryostat sections stained with Sudan black and in the unstained thick Araldite-embedded sections. The superficial peroneal nerve showed severe loss of myelinated fibres and many osmiophilic bodies in the cytoplasm of the Schwann and endothelial cells. Teased preparations showed evidence of segmental demyelination. By electron microscopy these inclusions were polymorphous (fig): some resembled multilamellated bodies; others had a regular, crystalline-like lattice pattern on which small dense particles were often superimposed; a few others had a dense homogenous appearance.
Discussion That perhexiline maleate caused the peripheral neuropathy in this case is strongly supported by the fact that withdrawal of the drug was followed by recovery. Furthermore, as in other reported cases of neuropathy due to the drug,' 4the symptoms began several months after therapy was started, weakness affected proximal as well as distal muscles, muscle wasting was discrete, nerve conduction speeds were appreciably reduced, and the CSF protein level was raised. These last two findings are consistent with the morphological changes in the Schwann cells. The ultrastructural aspects of the nerve and muscle inclusions resemble those of hypocholesterolaemic drug toxicity.5 This might suggest a disturbance in phospholipidic metabolism. Since neuropathy seems to be a rare side effect, such a disturbance could exist only in persons with some latent inborn metabolic disorder. We thank Dr H Duclos for calling our attention to toxic side effects of perhexiline maleate.
ADDENDUM-Since this report was written one of us (MF) has observed similar histological findings in two other cases of polyneuropathy due to perhexiline maleate. I 2
Roger, P, et al, Nouvelle Presse Medicale, 1975, 4, 2663. Abaza, et al, Nouvelle Presse Mddicale, 1973, 2, 2820. 3 Bourrat, G, Viala, J J, and Guastaal, J R, Nouvelle Presse Medicale, 1975, 4, 2528. Bousser, M G, et al, Coeur et Medecine interne. In press. Rawlins, F A, and Uzman, B G, Laboratory Investigation, 1970, 23, 184.
H8pital de la Salpe^triere, Paris F LHERMITTE, MD, professor of neurology and neuropsychology M FARDEAU, MD, maitre de recherche CNRS F CHEDRU, MD, chef de cinique assistant J MALLECOURT, MD, chef de clinique assistant
Prevention of postoperative deep vein thrombosis by leg bandaging and oxyphenbutazone Anticoagulants are contraindicated for preventing postoperative deep vein thrombosis owing to the risk of wound haematoma. Bleeding may have disastrous effects on the result of an orthopaedic operation, especially total hip arthroplasty. Low-dose heparin is less apt to cause postoperative bleeding but its prophylactic effect in hip surgery is insufficient.' Bandaging of the leg increases the venous blood velocity,2 although it has not been convincingly shown significantly to reduce thrombosis after major surgery.3 Phenylbutazone preparations decrease platelet aggregation. Oxyphenbutazone inhibits platelet aggregation due to collagen and adenosine diphosphate (ADP) in rats in vitro and also experimentally induced thrombosis in vivo.2 This paper reports a clinical trial of leg bandaging and concomitant oxyphenbutazone treatment.
Electron micrograph showing cytoplasm of Schwann cell filled with polymorphous, lamellated inclusions. (Uranyl acetate and lead citrate x 17-066.)
Patients, methods, and results Fifty consecutive patients aged over 50 years undergoing hip surgery were randomly distributed between a control (23 patients) and a treated group (27 patients). All were moblised the day after operation but were not allowed to sit in a chair for six days. They did walking and breathing exercises twice a day and were given physiotherapy of the hip and instructions for exercises
BRITISH MEDICAL JOURNAL
22
MAY
1257
1976
on their own. The treated group were given oxyphenbutazone 250 mg twice daily in a suppository and had their legs bandaged with Lohmann's Dauerbinde (strong, or krdftig) for 14 days after the operation. Both legs were bandaged from toe to knee immediately after operation. The bandages were 10- or 12-cm wide, depending on the size of the patient's feet and legs. They were changed twice daily, or more often if necessary, and were worn at night. The bandaging significantly increased the velocity of the venous blood.2 Blood coagulation, blood in faeces, white cell count, packed cell volume, and electrolytes were recorded for 18 days postoperatively to detect any adverse reaction to treatment, especially to oxyphenbutazone. Ascending phlebography4 was performed 14 days or more postoperatively, or earlier when indicated clinically. The average was 19 days. Altogether 18 patients developed deep vein thrombosis. Of these, 5 were in the treated group (5127) and 13 were controls (13/23). The difference was significant (P
