Journal of Neurology, Neurosurgery, and Psychiatry 199 1;54:741-743

SHORT REPORT

The muscle findings in the neuroleptic malignantsyndrome associated with lysergic aciddiethylamide

WM H Behan, AM 0 Bakheit, P 0 Behan, I A R More PhD

AbstractA detailed pathological description ofthe muscle findings in a case of theneuroleptic malignant syndrome (NMS)following ingestion of lysergic aciddiethylamide (LSD) is given, includingthe first ultrastructural analysis. Focalnecrosis, oedema, and hypercontractionof fibres with glycogen and lipid deple-tion, were identified, all of which hadresolved completely a year later. Thefindings are compared with those inmalignant hyperthermia. It is suggestedthat the results support the view that inNMS, the muscle rigidity is due to cen-tral mechanisms and, in both this disor-der and malignant hyperthermia, it isresponsible for the hyperpyrexia and itslife-threatening complications.

any other drugs. On admission he was uncon-scious, but could localise pain. His tem-perature was 37 5°C. There was severebilateral extrapyramidal rigidity with bilateralextensor plantar responses. The rest of theneurological and general physical examinationwas normal. The following day his consciouslevel improved spontaneously but hedeveloped transient visual hallucinations. Hewas not confused but his speech was slurredand he was profoundly hypokinetic. Over thenext five days his level of consciousness fluc-tuated rapidly and considerably, sometimeswith the deterioration lasting several hours.At the same time, he continued to have anintermittent low grade pyrexia. Dantrolenesodium therapy 25 mg three times dailyproduced an immediate, excellent responseand he recovered completely in ten days.

University of Glasgow,Glasgow, UKDepartment ofPathologyWM H BehanI A R MoreDepartment ofNeurologyA M 0 BakheitP 0 BehanCorrespondence to:Professor Behan, UniversityDepartment of Neurology,Institute of NeurologicalSciences, Southern GeneralHospital, Glasgow G51 4TF,UK

Received 3 October 1990.Accepted 11 December 1990

The neuroleptic malignant syndrome (NMS)is a rare, but almost certainly underdiagnosed,complication of neuroleptic therapy, occur-ring in from 0-5% to 1% of treated patientsand associated with a mortality rate of approx-imately 20%.' Numerous antipsychotic drugshave been shown to precipitate NMS, as mayabrupt discontinuation of anti-Parkinsonianagents.2 Cocaine has also been implicated3 andwe have recently seen a case associated withlysergic acid diethylamide (LSD). The disor-der is characterised by a high fever,extrapyramidal rigidity, altered consciousnessand increased creatine kinase concentrations.'Its clinical features are similar to those foundin malignant hyperthermia (MH)' butwhereas the muscle biopsy findings have beencarefully studied in the latter,5 they have notbeen commented on, apart from one briefreport,6 in NMS. We report the features inour case, including the results of a detailedexamination of the muscle, and compare thefindings in both conditions.

Case reportA 21 year old man was admitted unconsciousto hospital, having consumed a large amountof alcohol and one tablet of lysergic aciddiethylamide (LSD) a few hours previously.There was no significant family or pastmedical history. He was known to havesmoked cannabis in the past but had not used

Laboratory findingsHis haemoglobin was 15 g/dl, with a peri-pheral white blood cell count of 10 x 109/1.The ESR was 16 mm in the first hour. Serumurea, electrolytes and creatinine were normalas were the blood glucose and arterial bloodgases. Aspartate aminotransferase was126 IU/l and lactate dehydrogenase was727 IU/l (normal values for our laboratory are10-40 and 240-525 respectively). Serumcreatine phosphokinase was 807 IU/l onadmission, rising to 3090 IU/l after 10 days(normal 150 IU/1). Urine and repeated cul-tures were sterile. The CSF was normal withnormal pressure. Skull radiographs, an EEG,CT and MRI brain scans revealed no abnor-mality. The serum concentration of LSD was69 9 nanogrammes/ml 24 hours after admis-sion but tests for other drugs were negative.Urinary myoglobin was not detected.

Muscle biopsyfindingsThree needle cores of skeletal muscle weretaken from the right vastus lateralis on the dayof admission, orientated transversely using adissecting microscope and then fixed inthiopentane cooled with liquid nitrogen. Twotiny fresh fragments were fixed in 2% glutaral-dehyde and processed for electron micro-scopic examination. Frozen tissue sectionswere cut at 6 p in the cryostat and stainedwith haematoxylin and eosin, Gomori's tri-chrome, adenosine triphosphatase at pH 4.3and 9-4, succinate dehydrogenase, NADH-

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Behan, Bakheit, Behan, More

Figure 1 Early hyaline necrosis and peripheral phagocytosis offibre. R vastus lateralis.Gomori trichrome x 400.

tetrazolium reductase, alkaline phosphatase,periodic acid schiff (with and without diastase)and oil red 0 for lipid, as described.7On microscopy, there was mild generalised

oedema. Occasional fibres showed earlyevidence of necrosis, with a hyalineappearance and infiltration by macrophages(fig 1). In addition, an unusual feature was theappearance, most obvious on the H & E andGomori stains, of irregularly "scallopedfibres" showing a dense refractile rim (fig 2).Short, irregular contraction bands could alsobe seen easily in most fibres on transverse andlongitudinal section (fig 2). Histochemicalstains revealed moderate glycogen and lipiddepletion, especially in Type 1 fibres but noother abnormalities. Electron microscopyshowed complete fragmentation or dis-appearance of the Z lines in some fibres andstreaming and dispersal of band material inothers. No ruptured mitochondria, membra-nous bodies, increased sarcoplasmic fluid,

dilated sarcoplasmic reticulum or inclusionbodies were present.One year later the patient was rebiopsied,

samples being taken from the left vastuslateralis. Specimens processed in an identicalmanner were completely normal.

DiscussionThe case described here is typical of NMS,with extrapyramidal rigidity, pyrexia, a fluc-tuating level of consciousness and an increasedserum creatine phosphokinase concentration,lasting for several days. The patient also hadincreased liver enzymes, a common finding inNMS. The only drug he had taken was LSDand its presence was confirmed in a blood testtaken 24 hours after admission. Thus it appearsthat LSD precipitated the syndrome in thisyoung man. Its effectmay have been potentiatedby dehydration due to excessive alcohol intake.The muscle biopsy revealed evidence of

recent focal necrosis and generalised oedema.An intense irregular contraction of the fibreswas also visible, confirmed on ultrastructure.This change can be an artefact due to poorprocessing but the tissue for frozen studies andfor electron microscopy had been processed inthe usual manner, according to establishedmethods7 and other specimens processed at thesame time, did not show any contractions. Inaddition, when a rebiopsy was taken one yearlater, the fibres were completely normal. Insummary therefore there was obvious damageto the fibres in this patient with myodema, focalnecrosis, glycogen and lipid depletion. Severe,

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.iur.reual.salpdfbe wit shrt brokecontraction.bandsHSEx400.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~Figure 3 Irregular contraction within afibre: normal Zband in the myofibrils above, abnormal, streamed, Z bandbelow x 39,000.

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The muscle findings in the neuroleptic malignant syndrome associated with lysergic acid diethylamide

irregular contraction had also occurred. Noevidence ofany pre-existing muscle disease waspresent.There is only one report of the detailed

muscle pathology in NMS and that does notinclude ultramicroscopy. Martin and Swash6examined a biopsy taken one hour after death ina patient who died ofthe syndrome after a threeday history. They reported acute musclenecrosis with oedema and conspicuousglycogen depletion, findings similar to ours.They did not observe the same hypercontrac-tion but this may have been because the biopsywas taken after three days, and after death.Because they did not find lipid depletion theyconsidered that there was uncoupling ofmusclemetabolism and suggested that metabolic mus-cle damage had led to excessive muscle activityand rigidity, resulting in hyperthermia. Theythought the neuroleptic drug produced theassociated extrapyramidal signs, by a differentmechanism.We disagree with the concept that the drug

produces primarily a myopathic effect and thisleads to the hyperthermia. We think that areverse mechanism is occurring; in otherwords, the muscle damage is itself due tocentral nervous system mechanisms whichcause excessive and continuous muscle con-traction, and hyperpyrexia. A vicious circlethen ensues with the hyperpyrexia causingmore muscle damage, and the sustained muscleactivity increasing the body temperature. Ourview is supported by a recent careful, neuro-pathological study of a patient who died ofNMS.8 Localised necrosis of the anteriorhypothalamus was found, the area which hasbeen shown experimentally to play a major rolein temperature regulation. The authors sugges-ted that damage to neurons in this area couldlead to uninhibited release of neurotransmit-ters and an adverse effect on the adjacent centresof thermoregulation.8

It is important to compare the biopsy findingsin MNS with those in MH, since each condi-tion is associated with muscle rigidity andhyperpyrexia' 24 following drug (or anaes-thetic) administration. Harriman carried outan exhaustive survey of muscle in the lattercondition, personally examining a total of 1400biopsies and reviewing all the world literature.The majority of specimens had no evidence ofmuscle damage; when abnormalities werepresent, they were non-specific, consisting ofoccasional central nuclei, moth-eaten fibres andcores. Interestingly enough, however, somecases had hypercontraction of fibres andZ-band streaming, like the case we reporthere. Harriman considered, as we do in NMS,that the contraction went on to produce fibrenecrosis and not the other way round.5 Indeed,ultrastructural studies ofMH now support hisview, in suggesting that non-specific muscledamage follows the excessive contraction, andperhaps, the hyperpyrexia."

Malignant hyperthermia of course, has agenetic basis with an autosomal dominantinheritance and is considered to be due todefective membrane regulation of calcium inthe presence of certain anaesthetic agents.2Although there are no reports of NMS insiblings of affected cases, Caroff et al 9 havefound that in vitro exposure to halothane ofmuscle fibres from patients who have recoveredfrom NMS, shows the same response aspatients susceptible to MH. On the other hand,neuroleptic drugs have been reported to atten-uate, or even prevent, the development ofMHin its experimental model, in susceptible pigs.'0BothNMS andMH respond to dantrolene, a

specific muscle relaxant with no action on thecentral nervous system, smooth or cardiacmuscle.'2 It has been shown in NMS that thefall in temperature associated with dantrolenecoincides with muscle relaxation." Dantrolenesodium brought about a dramatic response inour patient: a few hours later, his high tem-perature and muscle rigidity had subsided andhis level of consciousness improved.

In NMS, there is evidence ofcentral nervousdamage, with structural lesions in the ther-moregulatory centre,8 accompanied byincreased urinary excretion of dopaminemetabolites'4 and a favourable response tobromocriptine. 5 We postulate that this damagefirst causes extrapyramidal rigidity and that thesustained tonic muscular contraction results inthermogenesis. Thus muscle rigidity is the finalcommon component in NMS and MH and,unless successfully treated, for example, bydantrolene, will compound the hyperpyrexiaand its life-threatening complications.

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3 Kosten TR, Kleber HD. Sudden death in cocaine abusers:relation to neuroleptic malignant syndrome. Lancet1987;i:1 198-9.

4 Gronert GA. Malignant hyperthermia. Anaesthesiology1980;53:395-423.

5 Harriman DGF. Malignant hyperthermia myopathy-acritical review. Br J Anaesth 1988;60:309-16.

6 Martin D, Swash M. Muscle pathology in the neurolepticmalignant syndrome. J Neurol 1987;235: 120-1.

7 Dubowitz V. Muscle biopsy. A practical approach, 2nd ed.London: Bailliere Tindall, 1985:19-40.

8 Horn E, Lach B, Lapierre Y, et al. Hypothalamic pathologyin the neuroleptic malignant syndrome. Am J Psychiatry1988;145:617-20.

9 Caroff SN, Rosenberg H, Fletcher JE, et al. Malignanthyperthermia susceptibility in neuroleptic malignant syn-drome. Anasethesiology 1987;67:20-5.

10 Somers CJ, McLoughlin JV. Malignant hyperthermia inpigs: calcium ion uptake by mitochondria from skeletalmuscle in susceptible animals given neuroleptic drugs andhalothane. J Comp Pathol 1982;92:191-8.

11 Schiller HH, Mair WGP. Ultrastructural changes ofmusclein malignant hyperthermia. J Neurol Sci 1974;21:93-100.

12 Ellis KO, Castellion AW, Honkomp LJ, et al. Dantrolene,a direct acting muscle relaxant. J Pharm Sci 1973;62:948-50.

13 Goulon M, de Rohan-Cabot P, Elkharrat D, et al. Beneficialeffects of dantrolene in the treatment of neurolepticmalignant syndrome: a report of two cases. Neurology(NY) 1983;33:516-18.

14 Tolleffson GD, Garvey MJ. The neuroleptic malignantsyndrome and central dopamine metabolites. J Clin Psy-chopharm 1984;4:150-3.

15 Mueller PS, Vester JW, Fermaglich J. Neuroleptic malig-nant syndrome: successful treatment with bromocriptine.JAMA 1983;249:386-8.

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