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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.51.8.1109 on 1 August 1988. Downloaded from

Letters 1109 8 Milligan NM, Newcombe R. Compston DAS. 4 April, she was alert, and had a tem- the of which has been A double blind description NMS,' controlled trial of high dose perature of 37 4°C. Neurological exam- noted in association with the use of neu- methylprednisolone in patients with multiple ination revealed I sclerosis: 1. clinical effects. J Neurol Neuro- marked hypertonus in neck roleptic medication. The use of surg Psvc/hiairt' 1987;50:511-6. and limbs, akinesia, dysphagia, and dys- antidepressant2 3 or discontinuance of 9 Compston DAS, Milligan NM. Hughes PJ. arthria, which confined her to bed and kept medication such as levodopa Gibbs J, McBroom V, Morgan BP. Camp- her mute. Pertinent laboratory data and ' 4 have also been known to bell AK. A double blind controlled trial of included white blood cell count, 8,200/mm3; produce identical symptoms. The marked high dose methylprednisolone in patients erythrocyte sedimentation rate (ESR), 12 decrease in functioning of dopaminergic with multiple sclerosis: 2. laboratory results. mm/h; blood urea nitrogen, 19 mg/dl; serum neurons has been postulated as the cause of J Neurol Neurosurg Psvc/hiairV 1987;50: 65 35 the 517-22. GOT, IU; GPT, IU; C-reactive development of NMS.' Our case is note- 10 Kurtzke JF. Further notes on disability evalu- protein (CRP), 0-7 mg/dl (normal, 0 < 0 5); worthy because the NMS was produced fol- ation in multiple sclerosis with scale creatinekinase (CK), elevated markedly up lowing a single use of as either DA modification. Neurologj 1965;15:654-61. to 2,152 IU (27-118). Urine study, cere- agonist or antagonist. Sulpiride, a substi- brospinal fluid cytochemical examination, tuted compound, differs from the Accepted 15 April 1988 chest radiographs, ECG, and brain CT was typical neuroleptics by exhibiting an inabil- normal. ity to inhibit DA-stimulated adenylate Sulpiride was stopped immediately, but cyclase activity and has been proposed as a the extrapyramidal signs did not improve selective blocker at D-2 receptors. As far as and the temperature reached 37 7°C. The we know, 10 cases of NMS associated with patient lapsed into lethargy after several sulpiride have been reported so far.5- In days. The EEG showed diffuse slowing of every case, however, sulpiride was used in 6-7 Hz on 9 April. Then, all the medication combination with the drugs which have been Neuroleptic malignant syndrome due to sul- was stopped and dantrolene sodium 50 mg reported in association with NMS or its pmde three times/day was started by nasogastric identical symptoms. In 1984, Hermesh et tube, the dose of which was increased to 100 al'2 reported a case of NMS due to tiapride, Sir: Neuroleptic malignant syndrome mg/day by 15 April. Within 5 days after the another specific D-2 receptor blocker of the (NMS) is recognised as a lethal compli- start, temperature fell to around 37 0°C benzamide group, and suggested theProtected by copyright. cation of neuroleptic drugs, in which hyper- and consciousness began to improve. On 14 involvement of D-2 receptors in the patho- tonia and hyperthennia occur. We have seen April, the serum CK level was in the normal genesis of NMS. Because sulpiride was used a case of a woman who developed NMS fol- range (91 IU), although the hypertonia solely as either DA agonist or antagonist, lowing a single use of sulpiride, a selective remained severe. On 19 April, the tem- our case offers additional evidence that the D-2 (DA) receptor blocker, as perature again rose and reached 38 7°C. selective blockade at D-2 receptors could either DA agonist or antagonist. This time, the white blood cell count was produce NMS. The patient was a 70 year old woman 7,900/mm3; ESR, 35 mm/hr; CRP, 5-7 Our case is also of interest because sul- who had no family history of note and had mg/dl; and serum CK, 121 IU. The blood piride, as a cause of extrapyramidal signs, is been well until 14 March 1986, when she culture grew coagulase negative staphy- rare compared with typical neuroleptics. But was found to have hypertension. lococci. Following treatment with anti- in vitro, sulpiride blocks D-2 receptors with Trichlormethiazide, trapidil, and benzo- biotics, the temperature fell in several days. approximately the same as chlor- diazepine derivatives (tofisopam, 100mg/ Following this recovery, the extrapyramidal .'4 l This discrepancy between day, until December, 1986, followed by signs were noted to reduce gradually. By the D-2 receptor blocking effect in vivo and chlordiazepoxide, 10mg/day) were adminis- May, the extrapyramidal signs had disap- in vitro may in part be attributed to its poor tered for almost a year. In February, 1987, peared completely and routine blood and ability to cross the blood-brain barrier. 16 In she complained of anorexia, insomnia, urine study became normal, although the our case, the extrapyramidal signs were headache, and decreased interest in her mild dysorientation and night induced soon after starting the medication usual with of 300 a dose which activities. Physical examination remained. In June, dantrolene was stopped sulpiride mg/day, http://jnnp.bmj.com/ revealed normal findings. Because she was and medication with amantadine (150 usually does not have complications. This depressed a physician started sulpiride, 300 mg/day), meclofenoxate (600 mg/day), and fact suggests that the effects of sulpiride to mg three times/day, on 20 February. Soon mianserin (20 mg/day) was started. In block central dopaminergic transmission after this addition, extrapyramidal signs August, she was alert and oriented, free might have been potentiated. Some organic including gait disturbance, dysarthria, dys- from any mental problem, took care of changes in blood-brain barrier function phagia, and hypersalivation developed. On herself, and could walk with a walker. In and/or age related decline in functioning of 26 February she was admitted to hospital October, she was discharged without any dopaminergic neurons'7 might play a role because of the anorexia and extrapyramidal sign of NMS nor its sequela. on this potentiation. signs. The laboratory examination of blood In this patient, the rapid deterioration of on September 27, 2021 by guest. and urine were normal. After the day of motor function characterised by general admission, the dose of sulpiride was hypertonia and akinesia, several autonomic decreased to 150 mg/day. But the extra- dysfunctions, low grade fever reaching KENICHI KASHIHARA* pyramidal signs did not diminish. On 26 37 7°C, clouded consciousness, elevated KOICHI ISHIDAt March there was rapid deterioration of the serum CK level, and no trace of infection Department ofNeurology* extrapyramidal signs. On March 29, the were noted after 5 weeks' use of sulpiride. and ofInternal Medicine,t body temperature began to rise and hyper- Although the fever was not so remarkable, National Sanyoso Hospital, salivation and sweating became marked. On the symptoms of the patient correspond to 685 Higashikiwa, Ube 755-02, J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.51.8.1109 on 1 August 1988. Downloaded from

1110 Letters References 7 Arita T, Itoh N, Onda A, Takeuchi H, Fuwano 12 Hermesh H, Huberman M, Radvan H, Kott E. S, Sano T. Two cases of syndrome maline Recurrent neuroleptic malignant syndrome treated with dantrolene and . due to tiapride and : the possible I Addonizio G, Susman VL, Roth SD. Neu- Clin Psychiatry 1985;27:966-9. (in Japanese) role of D-2 dopamine receptors. J Nerv Ment roleptic malignant syndrome: review and 8 Nishizima K, Ishiguro T, Kato B. Neuroleptic Dis 1984;172:692-5. analysis of 115 cases. Biol Psychiatry malignant syndrome induced by a with- 13 Schachter M, Bedard P, Debono AG, et al. The 1987;22:1004-20. drawal of an anti-parkinsonian drug, a role of D- I and D-2 receptors. Nature 2 Bowen LW. Fatal hyperpyrexia with anti- antidepressant and neuroleptics. 1980;286: 157-9. depressant drugs. Br Med J 1964;5:1465-6. Jpn J Clin Psychiatry 1985;14:1845-54. (in 14 Seeman P. Brain dopamine receptors. Pharma- 3 Johnson HM, Boucher JV. A fatality associ- Japanese) col Rev 1981;32:229-313. ated with antidepressant therapy. Am J 9 Ogyu H, Hosaka T, Turumaru Y, Oeda Y, 15 Imafuku J. The characterization of [3H1 sul- Psychiatry 1964;120: 125-6. Shirakura K. A case with recurrent hyper- piride binding sites in rat striatal mem- 4 Henderson VW, Wooten GF. Neuroleptic thermia and increased serum level of CPK branes. Brain Res 1987;402:331-8. malignant syndrome: a pathogenetic role for during neuroleptic therapy. Clin Psychiatrs 16 Benakis A, Pongis MA, Sugnaux F, Glasson B, blockade? Neurology 1986;28:91-6. (in Japanese) Jirounek H, Redard M, Vitas J. 1981;31:132-7. 10 Makitsubo T, Sahashi K, Gotoh S, Mitsuma T. Localization, distribution, elimination and 5 Bleichner G, Squara P, Parent A. Hypertonia A case of neuroleptic malignant syndrome metabolism of "C-sulpiride in rat. Eur J and malignant hyperthermia due to mor- during a long term treatment with sulpiride, Drug Metab Pharmacokinet 1976;1:51-62. phine and neuroleptic. Lancet 1981 ;i:386-7. amantadine and trihexyphenidyl. Neurol 17 McGeer PL, McGeer EG, Suzuki JS. Aging 6 Kleinknecht D, Parent A, Blot P, Bochereau Med 1986;24:412-4. (in Japanese) and extrapyramidal function. Arch Neurol G, Lallement PY, Pourriat JL. Rhab- II Neuroleptic malignant syndrome due to sul- 1 977;34:33-5. domyolyses avec insuffisance renale aigue et piride. Drug Information (Japanese Ministri syndrome malin des neuroleptiques. Ann of Health and Welfare) 1987;85:1-2. (in Accepted 2 April 1988 Med Interne (Paris) 1982;133:549-52. Japanese)

as TI 1. I have observed it in patients with Correction Protected by copyright. Matters arising lesions at the foramen magnum, but not Enlargement of the third ventricle and with lesions above this level. It is probably hyponatraemia in aneurysmal subarachnoid McArdle's sign in multiple sclerosis most useful in demonstrating weakness that haemorrhage, by Wijdicks, van Dongen, van would not otherwise be clearly evident. Gijn, Hijdra and Vermeulen (J Neurol Sir: Your readers may be interested in the MJ MCARDLE Neurosurg Psychiatry 1988;51:516-20). background to the observation of increased 3 Kingsdowin, Part of the last sentence of the second pyramidal weakness with neck flexion in pa- 1/5o Ridlgeas'a.1, paragraph ofthe introduction was deleted. It tients with spinal cord disease.' This phe- Wi41jbledont, should read "Therefore, the relationship nomenon was first brought to my attention Londlot, SWI9 4RL. UK. between hyponatraemia and the size of the in the mid-1960s by a patient with multiple third ventricle was separately investigated". sclerosis who was referred to me at the Na- tional Hospital, Queen Square. He had a Reference marked spastic foot drop and had found that he could dorsiflex his foot if he fully I O'Neill JH. Mills KR. Murray NMF. extended his head. McArdle's sign in multiple sclerosis. J Neu- rol Ncurosurg 9X7:50: 1691-3. I was able to confirm this observation and PsYlhhaurY I also found that weakness of hip flexion, as

tested by straight leg raising against re- http://jnnp.bmj.com/ sistance, which is usually the earliest sign of pyramidal weakness in the leg, was weaker on full neck flexion. I thought that this was the motor equivalent of L'hermitte's sign and due to stretch of the spinal cord in full neck flexion. The effect of neck movement is often slight and thertfore, hip flexion should be

tested with the neck in full flexion and in full on September 27, 2021 by guest. extension to show the difference. I subsequently tried this test on a large number of patients and found that it could occur in any condition affecting the spinal cord, although most easily demonstrated in multiple sclerosis. It may even be found in patients with lesions of the lower thoracic cord such as a thoracic meningioma as low