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Neuroleptic malignant syndrome (NMS) is an uncommon but potentially fatal adverse effect of neuroleptic drugs. It is commonly characterized by muscular rigidity, fever, altered mental status, and autonomic dysfunction. Emerging of NMS is possible with all neuroleptics, classic and atypical. NMS occurs most often during the first week of treatment or after increasing the dosage of the neuroleptic medication. The frequency of NMS ranges from 0.07 to 2.2%. Its pathophysiology is not clearly understood but the blockade of dopamine receptors appears to be the central mechanism. Issues of NMS are those of diagnosis, treatment and reintroduction of antipsychotic treatment or not.We here present an interesting case because of its atypical clinical presentation and its slow resolution, illustrating the various problems linked to the NMS.A 55-year-old woman with a history of mental retardation and infantile psychosis is hospitalized for worsening of her psychiatric symptoms. She is treated by risperidone long-acting injection every 2weeks, escitalopram 20 mg/d and oxazepam 10 mg/d. Early December 2012, she had fever spikes treated with many antibiotics and neuroleptics were stopped, without improvement. Early January 2013, a pulmonary embolism was diagnosed, and a treatment with loxapine is introduced and her injection of risperidone is done because of the state of agitation of the patient. Two weeks later, a NMS is suspected to hyperthermia, tremor of the limbs, a slight stiffness, and neuroleptics are stopped. Dantrolene is then introduced, but after 7days of treatment the fever is still important. Other assumptions are then discussed: infection, serotonin syndrome, encephalopathy, catatonia, malignant hyperthermia. But diagnosis of NMS is finally retained because of the recurrence of symptoms after introduction of clozapine early February.In this patient, diagnosis was made more difficult by the use of long-acting neuroleptic. NMS was indeed partly rejected because of the lack of improvement despite 7 days of dantrolene treatment, but the release of risperidone lasts 7weeks after the injection. This NMS is also of atypical presentation with a minor muscular rigidity. And this case is particularly interesting because of the recurrence of NMS with clozapine, allowing to finally diagnose it. This atypical neuroleptic is not known to be a major provider of NMS but the very short period before reintroduction and possible persistence of risperidone in the body could explain the recurrence.NMS can be hard to diagnose. It is a diagnosis of exclusion, but we should keep in mind that there is great variability of its clinical presentation in order to not exclude too quickly this syndrome in a patient treated by neuroleptic.

The medicinal treatment of spasticity includes use of oral treatments (baclofène and tizanidine), botulinum toxin, intrathecal baclofène and local application of alcohol or phenol. However, spasticity may not be uncomfortable and may even be useful. Therefore, all spastic diseases do not systematically require treatment. First-line treatments (oral treatments and botulinum toxin) can be considered depending on the local or diffuse nature of the spasticity and depending on the etiology.

Dystonia is not uncommon in childhood, but is clinically very heterogeneous. Therefore, introduction and follow-up of the treatment of dystonia in children are often a challenge for the physicians. Progresses in functional neurosurgery have open new fields in the treatment of dystonia in children, but it should be managed by a multidisciplinary team. This paper reviews the various therapeutic options available for childhood-onset dystonia, with a specific attention to dosage and side effects of the drugs regarding pediatric population according to the data of the literature. The rational strategy for therapeutic management of the various types of childhood dystonia is discussed.

The present study, conducted for the consensus conference "Orthotic management of stroke patients", organized by the International Society of Prosthetics and Orthotics, on September 2003, reviews the pharmacological, general, or local treatments available for post-stroke upper-limb spasticity.A search of the international literature in the Medline and the Reedoc data banks for papers related to post-stroke upper-limb spasticity. Each paper was given a rating of A, B, or C (in term of quality) according to the instructions of the organization committee.General pharmacological treatments such as use of baclofen, tizanidine and dantrolene, regional treatments such as intrathecal baclofen, and local treatments with use of chemical neurolysis and alcohol or phenol are recommended for conditions described in papers with a grade of B. Neuromuscular blockade with botulinum toxin is recommended for conditions described in papers with a grade of A.Despite a satisfactory grade of recommendation, general pharmacological treatments are limited by adverse events and lack of evidence of functional benefit. Intrathecal baclofen should be discussed for upper-limb spasticity, but further studies are needed before its use can be recommended. The place of chemical neurolysis with use of alcohol or phenol should be evaluated with surgical neurotomy and botulinum toxin therapy. The use of botulinum toxin is the only treatment supported by scientific results, but many questions remain about the site of injection, how to improve efficacy and influence on neurological recovery.

Malignant hyperthermia is a potentially fatal pharmacogenetic disease triggered by volatile anesthetics and/or succinylcholine. Dysregulation of intracellular calcium homeostasis is the trigger of the acute crisis. Malignant hyperthermia crisis correspond to an hypermetabolic state, which occurred acutely and interesting skeletal muscular cell. Early manifestations grouped tachycardia, tachypnea, masseter spasm, mixed acidosis and raise of the end expiratory CO2 pressure. Hyperthermia is a late sign, rhabdomyolysis is a sign of the severity of the malignant hyperthermia. The successful treatment is based on an early diagnosis, immediately interruption of triggering agents, intravenous administration of Dantrolene in sufficient dosage and starting of adequate symptomatic treatment. Prevention of this complication is based on asking the patient about genetic predisposition to malignant hyperthermia. Confirmation of the susceptibility to malignant hyperthermia can be provided by in vitro contracture test with halothane or caffeine after muscle biopsy.

Malignant hyperthermia is a serious anesthetic complication, presenting with various manifestations, with high mortality and morbidity. There are several incomplete and abortive forms, and the clinicians must be aware of the possibility of malignant hyperthermia, and recognize the first signs of the hyperthermic crisis hyperthermia, hypermetabolism and muscular rigidity. Screening is performed by in vitro contracture testing on a muscular biopsy. Treatment is based on discontinuation of triggering agents and dantrolene administration, as well as supportive care. Cellular investigations demonstrate that the malignant hyperthermia crisis presents as an intracellular flooding with calcium, leading to an abnormal muscular contracture. Several mutations in particular involving the ryanodine receptor gene have been linked to malignant hyperthermia.

Malignant hyperthermia (MHS) is a rare potentially fatal complication of general anesthesia. Anesthetic agents most frequently incriminated are succinylcholine and halogenated agents. Respiratory acidosis is the most specific and sensitive sign. Hyperthermia per se may occur secondarily or may stay totally absent. Tachycardia and/or arrhythmias often develop due to hyperkalemia and metabolic acidosis. Muscle rigidity whenever present is pathognomonic The "gold standard" test for the diagnosis of MHS is the halothane-caffeine contracture test. Dantrolene is the treatment of choice and prognosis depends on the early administration of this agent.

Drug induced pleurisy is often a diagnosis of elimination because the clinical presentation, paraclinical features and anatomicopathological aspect are relatively non-specific. The pleural effusions are typically chronic and somewhat torpid, most often bilateral but may be unilateral. Two types of lesion are found: effusion or thickening and these may be associated. The peculiarity of these pleural diseases are the frequent coexistence of accompanying signs: for example pulmonary, cutaneous, ocular, hepatic, peritoneal, pericardial as well as evidence of inflammation and depending on the medicaments hypereosinophilia, cytolysis, cholestasis or antinuclear antibodies. Anatomicopathogically there is dense fibrosis which is diffuse, pauci-cellular and with little inflammation. The progress is variable according to the drug either going on to complete regression on the cessation of the medication or the persistence of a degree of pleural thickening. The causative drugs are essentially the derivatives of Ergotamine and amongst others bromocryptine and dantrolene.

Mémoire de DES (Diplôme d'Etudes Spécialisées) tenant lieu de thèse d'exercice.; L'hyperthermie maligne (HM) anesthésique est une myopathie infraclinique rare, génétiquement transmissible, déclenchée au cours d'une anesthésie générale par des agents pharmacologiques : gaz halogénés (comme l'halothane) ou curares dépolarisants. La crise d'HM est d'évolution potentiellement fatale. De nombreuses hypothèses sur l'étiopathogénie de l'HM ont été évoquées. Le facteur déclenchant de la crise d'HM est lié à une anomalie fonctionnelle du récepteur à la ryanodine, responsable d'une brusque élévation de la concentration intracytosolique de Ca2+. Mais d'autres structures cellulaires pourraient aussi avoir un rôle dans l'étiopathogénie de l'HM, ce qui appuierait l'hypothèse génétique que l'HM n'est pas liée à une seule anomalie. Le dépistage de la sensibilité à l'HM repose actuellement sur le test de contracture in vitro à partir d'une biopsie chirurgicale. La Spectroscopie par Résonance Magnétique Nucléaire du phosphore 31 (SRM 31 P) in vivo pourrait jouer le rôle de test de dépistage non invasif du caractère HM. Les principaux résultats ont montré une élévation plus importante du rapport phosphate inorganique/phosphocréatine (Pi/PCr) ainsi qu'une anomalie parmi les phosphodiesters (PDE) chez les patients HM-sensibles (HMS). Le but de ce travail a été d'essayer de répondre à plusieurs questions suite à ces résultats : - quelle est l'espèce biochimique visualisée dans la région des PDE dans les spectres in vivo? ; - l'augmentation de ce PDE était-elle vérifiée in vitro dans des extraits perchloriques de biopsies musculaires de sujets HMS? ; - quelle pouvait être l'origine de cette différence de concentration en PDE (composition en fibres musculaires, modification du métabolisme des phospholipides... ) ? L'étude par SRM 31 P in vitro de 19 extraits musculaires en milieu acide a permis d'identifier la glycérophosphorylcholine (GPC) comme étant l'espèce majoritaire de la région des PDE. La concentration relative de GPC [GPC/(Pi+PCr)] a été plus élevée pour les sujets HMS (p

The aim of this study was to verify whether a relationship exists between neuroleptic malignant syndrome (NMS) and anaesthetic-induced malignant hyperthermia (MH) or not. The in vitro halothane-caffeine tests were performed on muscle tissue obtained from 32 patients with documented NMS episodes. The diagnosis of NMS relied on Levenson's criteria. The results, expressed in accordance with the criteria of the European MH Group, defined 29 subjects as MH non-susceptible. Three patients were classified as MH equivocal. These findings demonstrate the lack of any link between NMS and MH. Therefore, patients with a history of NMS are not likely to be at risk of developing MH and special measures against MH are not required for anaesthesia in these patients.

The natural course of untreated neuroleptic malignant syndrome (NMS) does not usually exceed 3 weeks. Its duration is reduced by dantrolene and/or bromocriptine. We report a patient in whom NMS developed after an injection of haloperidol decanoate and fluctuated during 3 months. This was due perhaps because the initial treatment with oral neuroleptic was pursued, or because the doses of dantrolene were insufficient.

Sixty-two suspected crises of anaesthetic malignant hyperthermia (MH) were collected between 1969 and 1988 by a retrospective inquiry which lasted four years. 33 patients (53%) died whilst 29 survived. 20 cases were confirmed to be MH, either directly or indirectly by way of muscle biopsy and halothane and caffeine contracture tests carried out according to the European MH group protocol by two laboratories. This group included 11 of the deaths, one family member of whom, at least, is sensitive (MHS), 7 MHS survivors and 2 survivors too young to undergo muscle biopsy but belonging to MHS families. 21 cases were highly suspect of MH: 15 of the deaths which occurred in a typical way, and 6 patients of three different families who have suffered from anaesthetic deaths which, clinically, suggested MH. Another 15 were possible MH cases, all survivors, including one case of Steinert's disease and a brother of a case of central core disease. 2 cases were still being debated, because they had equivocal results for the caffeine test (MHEc); the last 4 had negative muscle biopsies and were excluded. 33 close relatives of the MH patients were diagnosed as MHS. 44 others were found to be free from the genetic predisposition. It was strongly recommended to yet 11 others that they carry the MHS card because they were MHEc. The clinical, surgical and anesthetic pictures were always as described in the literature. The anaesthetic protocols included inhalational agents in 90% of cases; these were combined with suxamethonium in 55% of cases. Dantrolene was only used in 32% of cases, and then at inadequate doses and very often too late; this probably explains the large number of treatment failures. The number of severe forms of MH was also very high in this series (70%). The need to increase the means of prevention and screening for MH in France is stressed.

Death from malignant hyperthermia (MH) still occurs in France. However, anaesthesia of the MH susceptible (MhS) patient is quite possible without any more risk than for patients who are not MhS. Guidelines have been worked out: "trigger" drugs such as volatile anaesthetics (halothane, enflurane, isoflurane) and depolarizing muscle relaxants must be imperatively avoided; "non-trigger" drugs should be used, such as nitrous oxide, barbiturates, benzodiazepines, propofol, opiates, non-depolarizing muscle relaxants, amide or ester local anaesthetics at the usual doses without adrenaline. Moreover, dantrolene should be available in all hospitals, 12 bottles being a minimum at hand, or, better, 30 (about 10 mg.kg-1). In some cases, such as emergencies, an unprepared operating theatre, or an unprepared ventilator, the patient should be premedicated with 2.5 mg.kg-1 dantrolene intravenously. The ventilator, the circuit and the operating theatre should not contain any trace of halogenated vapour. The usual parameters, as well as temperature and expired CO2 concentration, should be closely monitored. MhS patients must also be given counselling. This includes explanations about MH, its genetic features, the main laboratory tests used to detect susceptibility, as well as advice about lifestyle, the use of drugs other than general and local anaesthetics, and a discussion concerning the association of MH with other diseases. This counselling is not always easy to provide, because many answers are not, as yet, definitive.

A 33 year old woman, with myotonia atrophica and a known susceptibility to malignant hyperthermia, presented during her second pregnancy with multiple episodes of hyperthermia. They were associated with a rapid rise in the serum creatine phosphokinase (CPK) level, and not with infection or a myotonic crisis. Because of the obstetric conditions, caesarean section was planned. Preoperative oral dantrolene was used as prophylaxis. Six days after the start of this treatment, CPK and serum myoglobin levels were back within the normal range. There were no side-effects for the mother nor for the foetus. There were no further increases in either CPK or serum myoglobin levels during surgery or afterwards, but the rectal temperature remained markedly raised for 48 h after the delivery. Oral dantrolene was given during the first nine postoperative days. The occurrence of episodes of high fever during pregnancy linked to MHS and myotonia atrophica is discussed, as well as the anaesthetic management of such a patient. Side-effects of dantrolene for the mother or the foetus are also considered, especially as foetal levels of this drug would seem not to reach therapeutic levels. It would appear interesting to measure maternal dantrolene blood levels, especially if high doses are administered, to avoid reaching therapeutic levels in the foetus.

Calcium blockers (CB) are routinely used. This could lead to possible interference with anaesthetic drugs. CB prevent calcium from entering the cell by inhibiting the slow voltage-dependent calcium channels. They act mostly on heart and smooth muscle. Of all the possible indications, the three that are confirmed are coronary heart disease, arterial hypertension and supraventricular rhythm disturbances. Most of the work published and the cases reported concerns interactions between CB and halogenated anaesthetic agents; the latter's actions on the heart depend on cellular calcium exchange. Also, the cardiovascular effects of these anaesthetics are similar to that of CB. Experimentally, halothane and enflurane have direct cardiac inhibitory effects similar to verapamil and diltiazem, whereas isoflurane's properties seem closer to the dihydropyridines (nifedipine and nicardipine). Giving verapamil or diltiazem increases the number of sino-atrial and atrio-ventricular blocks when using a halogenated agent. Clinically, interpreting the effects of CB during anaesthetic induction is difficult because of the pathology (coronary heart disease, cardiac failure), the other drugs (beta-blockers and nitrates) and the type of anaesthesia (emergency or elective). Interactions can give rise to anything from a severe cardiovascular collapse, requiring catecholamines, to a mild fall in blood pressure which responds well to plasma expansion, or even no effect on blood pressure. Rebound is seen on stopping CB in patients with coronary heart disease or arterial hypertension; stopping them before surgery does not therefore seem justified. However, extreme care must be taken when using halogenated agents for patients under treatment with CB and/or beta-blockers. A wary anaesthetist will be able to adapt the technique to the patient. It has been suggested that CB could be used to treat preoperatively myocardial ischaemia (diltiazem), hypertensive crises (nifedipine, nicardipine) and ventricular rhythm disturbances (verapamil); this must be done with caution, the patient being closely monitored (haemodynamic and electrocardiographic monitoring). Postoperatively, intranasal nifedipine, continuous intravenous nicardipine or diltiazem have been used to treat increases in arterial blood pressure during recovery and to adapt the cardiovascular system to the increased metabolic needs. Here again, close patient monitoring is essential. In any case, treatment with CB which has been stopped should be started up again as soon as possible.

The authors have studied the antispastic action of Dantrium in 50 patients with multiple sclerosis; in all cases, hypertonia, spasms or clonus constituted a severe obstacle to remedial therapy or nursing. After one year, the authors have found that Dantrium is effective in reducing hypertonia in 40% of the patients, in improving spasms in 65% and in reducing clonus in 50% of the cases. Secondary effects are fairly frequent (60%), characterized in most cases by diminished muscular strength and greater fatigability.

A case is reported of cardiac failure with repeated pulmonary oedema in a female patient suffering from renal failure and having been given incremental doses of dantrolene sodium. On withdrawal of the drug, all symptoms disappeared. This muscle relaxant was considered not to have any depressive myocardial side-effects. However, recent studies on isolated myocardial fibres showed the existence of a constant dose-dependent negative inotropic effect of dantrolene sodium, only noticeable with high concentrations of the drug.

Dantrolene sodium, a hydantoin derivative with skeletal muscle relaxant properties, quickly reduces the cytosolic calcium concentration of the Barnacle (Balanus nubilus) giant muscle fibre, by direct action on the sercoplasmic reticulum. This inhibitory effect subsequently reduces the 45Ca efflux out of the cell although the 45Ca influx remains unchanged.

Malignant hyperthermia (MH), triggered by anaesthesia, is a rare and potentially fatal condition. It requires immediate and specific treatment. This review focuses on anticipation and organisation of treatment. Anticipation means that dantrolene should be available, that an anaesthetic machine should be kept free from all vapours of halogenated anaesthetics, and methods of cooling should be planned. A prompt availability in all operating theatres of dantrolene and the required machines is emphasized. Treatment of a MH episode includes stopping the administration of triggering agents, administering dantrolene, correcting metabolic and respiratory acidosis, and cooling. Different aspects of the cardiovascular pharmacology of dantrolene are discussed. Other drugs are seldom required if proper treatment is started soon enough after the crisis. Complications may arise during a fulminant episode. They are difficult to treat, and may lead to sequelae. A rational approach to the treatment of hyperkalaemia, circulatory and renal failure is discussed. After the crisis, dantrolene should be continued for a short time. Finally, the nonspecific signs which can give the earliest diagnosis possible of MH are discussed: an early diagnosis and early treatment with dantrolene are essential in reducing the mortality of malignant hyperthermia.