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Neuroleptic Malignant Syndrome. Diagnostic challenges.


Neuroleptic Malignant Syndrome represents a severe complication of antipsychotic treatment, displayed as a neurological emergency that usually emerges after 10-14 days of treatment with typical but also atypical neuroleptics. It is correlated with the existence of a particular susceptibility or of an organic substrate. Currently, it is well known that second-generation antipsychotic, too (Clozapine, Risperidone, Olanzapine) may induce NMS, mainly among patients predisposed to it or with a history of NMS determined by conventional antipsychotics (1, 2, 3).

Hyperthermia, diaphoresis, sialorrhea, akinetic-hypertonic syndrome, stupor, dyspnoea, blood pressure oscillations and oniric confusion syndrome are only some of the symptoms requiring careful supervision in a specialized medical unit, symptomatic treatment and cessation of neuroleptic medication (2, 3, 4). Through their antagonist mechanism of D2 receptors in the hypothalamus, nigro-striatal pathway and spine, antipsychotics may cause an array of symptoms, escalating in Neuroleptic Malignant Syndrome (3, 4).

Among the favouring factors of NMS onset, the most significant are as follows:

--high-dose antipsychotic treatment, mostly long-acting formulas,

--certain structural or functional brain anomalies (tumours, dementia or delirium),



--decrease in antiparkinson medication doses,

--dehydration or high environmental temperature,

--catatonic syndrome,

--psychomotor agitation,

--a previous episode of Neuroleptic Malignant Syndrome in the patient's history,

--simultaneous administration of other drugs with action upon D2 receptors, such as: Metoclopramide, anticholinergic medication, lithium, Amoxapine, Promethazine, Prochlorperazine (3, 4, 5, 6).

It is often a real challenge to diagnose Neuroleptic Malignant Syndrome. Hence, an entire array of other medical conditions may determine major confusions concerning diagnosis (7).

Catatonia is often mistaken for NMS. Behavioural changes such as apathy, verbal and food refusal, episodes of psychomotor agitation precede akinesia, rigidity and high temperature. This contrasts with NMS onset, where the first symptom is muscle stiffness. The patient's medical history shows that he had catatonic episodes even when he was not taking neuroleptic medication. A differential diagnosis is urgent; in case of a harmful catatonia, neuroleptic treatment must be instated as fast as possible (1, 6, 7, 8).

Malignant hyperthermia must be eliminated in case of a suspicion of NMS; patients display a pathological response to the administration of muscle relaxants or general anaesthesia with severe hyperthermia and muscle stiffness. Certain scientists and clinicians believe that the two syndromes are related through the genetic factor. However, whereas for malignant hyperthermia the genetic cause is clear, there are ongoing studies meant to prove the same background for NMS (5, 7, 8, 9).

At the same time, serotonin syndrome can mimic NMS, too. The differentiation can be made simply by analyzing the recent medical history of the patient, by marking the class of medications used and by noting that serotonin syndrome does not entail severe muscle stiffness (8, 9, 10).

Other syndromes to be ruled out for a patient with suspicion of NMS are as follows: anaphylaxis, epileptic status, alcoholic or benzodiazepine withdrawal syndrome, encephalopathies, SNC infections, (especially the viral ones) (9).


A 40-year-old patient is brought in by ambulance, accompanied by his family, from a local hospital, for an array of polymorphic symptoms: verbal negativism and food refusal, stupor, hypertonia. From a somatic perspective, the patient displays cogwheel phenomenon and the Noica sign, urinary incontinence, oscillatory blood pressure, tachycardia, sialorrhea, muscle stiffness, deglutition disturbances, subfebrility (37,6C).

The personal psychiatric history of the patient shows--in the absence on concrete medical documents, however--that the diagnosis of Paranoid Schizophrenia was established at the age of 19. Its onset was insidious, overlapping a schizoid background, with interpretativeness and paranoid delirious ideation and with elements of negativism, affective flatness and marked social withdrawal (mother's statement). The evolution of the patient was characterized by frequent relapses with polymorphic schizophrenic symptoms, which pleads for Undifferentiated Schizophrenia, without an exact dominance of positive or negative symptoms, or disorganization or catatonic symptoms.

From the onset, the patient showed extremely low therapeutic adherence; he kept on changing his general physician and the antipsychotic medication scheme, implicitly. In the absence of medical records attesting past consults and prescriptions, the only available information is the one provided by the patient's mother.

The patient does not display other diagnosed somatic conditions. From the perspective of socio-familial report, he lives with his mother, he is not married and he was hired legally for less than a year, as a seller, 15 years ago, but he gave up on the job in the context of psychotic symptomatology and persistence of negative symptoms. From an anamnestic standpoint, he denies neuroleptic impregnation in the past, in the context of the treatment with first-generation antipsychotics and second-generation antipsychotics.

In this context of therapeutic nonadherence, with precarious socio-familial functionality, without professional insertion, the patient followed a treatment with 350mg of Clozapine, provided by his local physician; this was eliminated gradually and replaced with Risperidone tablets, 4 mg/day, for reasons that neither the patient nor his family were able to explain. Apparently, the physician's intention was to increase the patient's therapeutic compliance, by subsequently prescribing a long-acting atypical antipsychotic compound.

Hence, the patient started the treatment with long-acting injectable Risperidone and maintained it for the three first weeks, as well as orally administered Risperidone.

Positive symptomatology was replaced with verbal negativism, mutism and food refusal. The patient's state degraded progressively 7 days from the administration of the first dose of long-lasting Risperidone two weeks from the initiation of psychotropic treatment with orally administered Risperidone.

The patient is sent to the neurology clinic, where the paraclinical observations were the following:

--markedly modified hepatic tests (TGO=424 U/l, TGP=241 U/l);



--leukocytes with values at the upper limit 9.780/microL.

Craniocerebral CT showed no acute neurological phenomenon; lumbar puncture ruled out one more time the infectious or purely organic causality for the emergence of aforementioned symptomatology.

According to the clinical-anamnestic and paraclinical data, the diagnosis of Neuroleptic Malignant Syndrome was set and the intervention was conducted according to protocols, thus stopping the administration of antipsychotic treatment.

After rebalancing the patient in the ICU ward of the Neurology hospital, he returned for admission to the "Socola" Institute of Psychiatry after two weeks. The patient was in a good general state; cogwheel phenomenon and Noica sign absent; he responded to stimuli and to questions; he ate on his own. Furthermore, from a psychiatric perspective, the following observations can be made: bizarre behaviour; non-systematized delirious ideation; auditory hallucinations ("there is a voice telling me it's going to kill me"); impulsive manifestations; psychomotor agitation in the presence of the family; motor stereotypies.

A treatment was initiated: Gabapentin 600 mg/day, in two doses, Aripiprazole 5 mg/ day and Clonazepam 1 mg in the evening. To these, 6 mg Trihexyphenidyl/day, in three doses, as well as neurotrophics, vitaminotherapy and hepatoprotective medication were added.

When we tried to increase the dose of Aripiprazole to 10 mg/ day, the patient developed akathisia and tasikinesia phenomena. Hence, this antipsychotic was decreased until cessation and another treatment was initiated: Quetiapine 50 mg per day, XR form, administered at 7 PM, for two weeks, 400 mg per day.

The psychoproductive episodes have mitigated; his impulsivity has decreased; the bizarre behaviour has become rarer; stereotypies still mark the clinical picture of the patient. He accepts the medication; he eats by himself; he communicates with the family and the medical personnel; his evolution is favourable.


The case presented in this paper constituted a real diagnostic challenge, mostly in the nebulous context of the patient's personal psychiatric history. The symptoms described above and the current ones suggested Undifferentiated Schizophrenia, considering the mixture of auditory hallucinations, paranoid delirious ideation, bizarre behaviour, social withdrawal, behavioural disorganization, flashes of psychomotor agitation, hypertonic episodes, waxy flexibility and posturing (especially "the mental pillow"). The absence of NMS history and of dystonia or dyskinesia phenomena in the context of neuroleptic impregnation --despite the fact that this patient followed numerous therapeutic schemes, including both atypical antipsychotics and first-generation antipsychotics --made the differential diagnosis even more difficult. Of course, the difficulty was also entailed by the polymorphic symptomatology. Hence, it was highly necessary to rule out the organic causality and especially infectious causes.

Similarly, after ruling out a catatonic decompensation of the underlying condition, a very thorough judgment became mandatory. Furthermore, beyond diagnosing and finding a solution for the acute and possibly life threatening condition, this case has been a real challenge in terms of treatment a la longue for the underlying psychiatric condition, considering the current reactivity of the patient to the administration of antipsychotic medication.


The authors declare that they have no potential conflicts of interest to disclose.


(1.) Berman, B.D., Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011 Jan 1(1):41-7. doi: 10.1177/1941875210386491.

(2.) Friedman, J.H., Feinberg, S.S., Feldman, R.G., A neuroleptic malignant like syndrome due to levodopa therapy withdrawal. JAMA. 1985;254:2792-2795.0098-7484(1985)254<2792:ANMSDT>2.0.CG;2.

(3.) Yang, Y., Yahui, G., Zhang, A., Neuroleptic malignant syndrome in a patient treated with lithium carbonate and haloperidol, Shanghai Arch Psychiatry. 2014; 26(6): 368-370.

(4.) Kawanishi, C., Genetic predisposition to neuroleptic malignant syndrome: implications for antipsychotic therapy. Am J Pharmacogenetics. 2003;3:89-95.

(5.) Fink, M., Catatonia: syndrome or schizophrenia subtype? Recognition and treatment. J Neural Transm. 2001;108:637-44.

(6.) Hadad, E., Weinbroum, A.A., Ben-Abraham, R., Drug-induced hyperthermia and muscle rigidity: a practical approach. Eur J Emerg Med. 2003;10:149-54.

(7.) Ananth, J., Parameswaran, S., Gunatilake, S. et al., Neuroleptic malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry. 2004 65:464-470.

(8.) Keck, P. Jr., Arnold, L., The serotonin syndrome. Psychiatr Ann. 2000;30:333-343. 00485713(2000)030<0333:TSS>2.0.C0;2.

(9.) Lurdes, T., Alsadair, M., Vila-Rodriquez, F., Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective. Curr Neuropharmacol. 2015; 13(3): 395-406.

(10.) Stahl, S.M., Prescriber's Guide Stahl's Essential Psychopharmacology. 5th Edition. 2014.

Ioana NECHIFOR--M. D., Resident in Psychiatry, "Socola" Institute of Psychiatry, Iasi, Romania

Nicoleta NITA--M. D., "Socola" Institute of Psychiatry, Iasi, Romania

Ilinca UNTU--M. D., Ph. D. Student, "Socola" Institute of Psychiatry, Iasi, Romania

Roxana CHIRITA--Prof., M. D., Ph. D., "Socola" Institute of Psychiatry, Iasi, Romania


Ilinca UNTU

"Socola" Institute of Psychiatry No. 36 Bucium, Iasi, Romania e-mail:

Submission: January, 12th, 2016

Acceptance: February, 02nd, 2016
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Article Details
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Title Annotation:Case Reports
Author:Nechifor, Ioana; Nita, Nicoleta; Untu, Ilinca; Chirita, Roxana
Publication:Bulletin of Integrative Psychiatry
Article Type:Clinical report
Date:Mar 1, 2017
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