Neurologic Malignant Syndrome (NMS)
1959-1980

a chronological annotated bibliography

prepared by John M. Friedberg, MD

February 5, 1997

This catastrophic reaction to dopamine blocking agents,especially HALDOL, more recently RESPIRADOL, (but all the so-called major tranquilizers have been implicated) can lead to death in up to 50% of cases, especially if not immediately recognized.

The causative agents must be stopped immediately and never started again.

Three Principal Indicators:

• Extreme muscle rigidity - one patient had to have a tenosynovotomy of her Achilles tendons (heel cords cut).

• Extreme autonomic instability especially rapid heart rate (over 100), temperatures up to 108 (at which point the brain’s proteins denature like the white of an egg and there’s no return), sweating, high blood pressure (sometimes over 200 systolic), incontinence. Pulmonary emboli may occur.

• Extreme mental status changes including restlessness, delirium, stupor and coma although patient may be conscious and “locked in.” Often mistaken for catatonic schizophrenia (another imaginary “disease of the mind”) and treated with even more of the hair of the dog, the anti-psychotic medications and even with electroconvulsive therapy (ECT)!

Laboratory testing can be helpful: the white blood count is elevated and a muscle enzyme, the CPK is usually elevated as well.

Electromyography may show widespread fasciculations (ref: Anderson SA, Weinschenk K: Peripheranl neuropathy as a component of the neuroleptic malignant syndrome: Am J Med 1987 Jan: 82 (1): 169-70) and muscle biopsy is shows diffuse increase in fibres with internal nuclei - see arrows below.

Adams J, Graham D:
An Introduction to Neuropathology.
Churchill Linvingstone,
NY. 1988. page 273.

Case reports of NMS and literature reviews were readily available in both psychiatric and neurologic journals from 1956, a few years after the introduction of the first phenothiazine, Chlorpromazine (Thorazine).

As this chronology shows, there was a flurry of reports throughout the decade of the 1970’s.

As stated in a The Neuroleptic Malignant Syndrome and Related Conditions*: “Interest and increased awareness in febrile catatonic states associated with neuroleptic administration was quite evident by the mid 1970’s. At this time, NMS had been fairly well reported in France, Japan and England. Several American authors cognizant of the French reports, also began to use the term neuroleptic malignant syndrome to describe similar cases in the United States.” (p 5)

The French were the first to observe the artificial hibernation produced by the anti-histamine related group of drugs called phenothiazines and the first to apply this observation for human behavioral control. It is not surprising that the very term Neurologic Malignant Syndrome is a translation of the French term “syndrome malin des neuroleptiques.”

Despite the recent obfuscation (e.g. in the book cited above) of NMS and “Lethal Catatonia of Stauder,” the epidemic of NMS which followed the epidemic of neuroleptics in the 1860’s was clearly a new and alarming phenomenon.

NMS shares one key sign, hyperthermia, with Malignant Hyperthermia, a reaction to anesthetics first noted in the 1920’s.

1956

1. Ayd, F: Fatal Hyperpyrexia during Chlorpromazine Therapy. Journal of Clinical and Experimental Psychopathology, volume xvii, number 2, June 1956, p 189-192.

A 41 year old man was given increasing doses of Chlorpromazine (Thorazine, the first “major tranquilizer”) to 2.5 gms/day. On the 21st day his temperature went to 108, he had several seizures and died.

“Chlorpromazine may cause sudden elevations of temperature accompanied by perspiration and some feelings of prostration.”

The syndrome had no name in this first case report.

1959

1. Delay J, Pichot P, Lemperiere T, Glissalde B, Peigne F: Le neuroleptique majeur non phenothiazinique et non reserpinique, l’haloperidol, dans le traitement es psychoses. Societe Medico Psychologique: Ann. Med.-psych., 118th anne, Janvier, Seance du 21 Decembre 1959.

This is a study of the new (“non-phenothiazine”) neuroleptic haloperidol (Haldol). It summarizes its administration to 63 women ages 19 to 73. These authors find that haldol has a “remarkable efficacy and rapidity.”

In the section on “effets neurologiques“ they comment:

“The syndrome of hypertonic immobility was observed in almost every case albeit to varying degrees. It appeared progressively during the first week, sometimes within two or three days. The intensity is a function of the dose and the susceptibility of the individual subject.”

The immobility may be observed first in the face as a lack of expression. In the majority of cases, a moderate parkinsonian syndrome is produced with trembling, “impatience motrice” (a nice turn of phrase for akathisia) of the legs. It is noted that the first reports on any medical enterprise are often the most honest. Here in 1959, at the very introduction of Haldol, the principal culprit in NMS, the authors clearly describe the effects on the human motor system.

“In cases where rigidity is intense, the effect is total, literally petrifying the patient.”

“Thus, in three of the patients, difficulties in chewing and swallowing together with excessive salivation, total insomnia and rapid wasting, obliged us to interrupt treatment. Complete disappearance of these extrapyramidal signs was obtained one to two weeks after stopping the Haldol.” (page 151)

The authors then comment on five instances of “crises excitomtrices” (agitated motoric crises) were observed five times. These occurred in the first two days of treatment in patients receiving less than ten miligrams per day. The crises had to do with spasms of the face, tongue and throat muscles with trismus, protrusion of the tongue, sucking or pouting movements, facial spasms, either unilateral or bilateral.

“Crises of spasmodic torticollis, rolling movements of the body, forced upgaze, were sometimes evident in addition. In the course of these crises, we have observed ’perturbations neurovegetatives intenses:’ racing heart rate, hypersalivation, tearing, hypersweating, sometimes even difficulty breathing with respiratory compromise.”

The authors are enthusiastic about Haldol which had been first tried a year prior and in their view was a landmark advance in the “chemotherapy of psychoses.” Every single “side effect“ since recorded ad nauseum was observed in these sixty-two women. The initial doses varied from 2 miligrams per day up to 25 miligrams and the only cautionary conclusion recommended by these pioneers was that the dose used should be “moderate” 3-7 mg per day. Doses today remain in that range.

2. May, RH: Catatonic Like States Following Phenothiazine Therapy. American Journal of Psychiatry 115: 1119-1120, 1959. Prompt report followed in the American literature.

3. Preston, Jane: Central Nervous System Reactions to Small Doses of Tranquilizers - Report of One Death. American Practitoner and Digest of Treatment. April, 1959, pages 627-630. Six cases of fever, muscular rigidity, salivatin, dysphagia are reported and the author warns “The cases described here should serve as a warning that tranquilizers (Stelazine, Thorazine, Trilafon and one case of Compazine) even in small doses may give rise to serious reactions, which occasionally end in death.”

1964

4. Delay J. and Deniker P.: In: Handbook of Clinical Neurology Published by Elsevier 1964 pages 248 to 266. The “handbook“ is a misnomer: this multi-volume comprehensive text has long been regarded as the “Old Testament” of neurology and hence, this article by Delay and Deniker has come to be regarded as the landmark paper identifying NMS.

1970

5. Zelman, S. and Guillan R.: Heat Stroke in Phenothiazine Treated Patients. A Report of Three Fatalities. American Journal of Psychiatry. 127, 1787-1790, 1970.

1971

6. Crane, E. (1971), Motor Disorders Induced by Neuroleptics. Archives of General Psychiatry. Volume 24: 179, 1971.

1972

7. Behrman, Simon: Mutism Induced by Phenothiazines. Psychiat.(1972), 121:599-604.

Eleven case histories e.g. case 4: 59 year old woman treated with Thorazine becomes progressively mute and dies after 3 years on treatment.

In Dr. Berhrman’s summary on page 604, he comments “The central feature was impairment of vocalization...and diminution of psychomotor activities eventually leading to akinetic mutism (coma vigil).”

8. Kammerer et. al. : Syndrome Neuroleptique Malin ou Surdosage Neuroleptique. Societe Medico Psychologique Seance du Lundi. 23 Octobre, 1972.

This is a case report of a 39 year old man who developed a full-blown syndrome including elements of Korsakoff’s “psychosis.”

1973

9. Meltzer HY: Rigidity, Hyperpyrexia and Coma Following Fluphenazine Enanthate. Psychopharamacologia 29:337-346, 1973.

One of the sources credited as establishing the diagnostic entity of NMS. Both Metlzer and Weinberger (see below) called attention to the importance of not confusing it with with Stauder’s (1934) “lethal catatonia.”

10. Oppenheim, G: Mutism and Hyperthermia in a Patient Treated with Neuroleptics. Med. J. Aust., 1973, 2:228-229.

This reports a 38 year old man on Haldol, Thorazine and cogentin brought in “almost unconscious” during a heatwave. In this case, the symptoms began 18 months after initiation of neuroleptics.

1974

11. Cohen, W. and Cohen, N.: Lithium Carbonate and Halopyrodol and Irreversible Brain Damage. JAMA 230: 1283-1287, 1974. This is a report on four patients on both haldol and lithium, a combination which remains quite fashionable and most likely is especially dangerous: “Symptoms consisted of lethargy, fever, tremulousness, confusion, and extrapyramidal and cerebellar....”

Two patients suffered widespread, devastating, irreversiblebrain damage. Two others were left with persistent diskinesias.

The significance of this paper is two fold:

a) The emphasis on the encephalopathy or central nervous system effect and b) The exceptional malignancy of the combination of lithium and Haldol.

1975

12. Simpson, G: CNS Effects of Neuroleptic Agents, Psychiatric Annals 5:11, November 1975.

“Neuroleptics and phenothiazines in particular can occasionally affect (sic) the temperature center - producing hyperthermia which is TREATED BY DISCONTINUING THE DRUG AND TAKING STEPS TO LOWER THE TEMPERATURE.” p 60.

The point of my emphasis is that the basic response to the diagnosis of NMS was established and remains: immediate discontinuation of the offending agent.

1976

13. Greenblatt, et. al: Fatal Hyperthermia Following Haldol Therapy of Sedative Hypnotic Withdrawal. J Clin Psychiatry 39: 673-675, 1976.

A 30 year old Quaalude user was treated for “Delirium Tremens” with Haldol, developed a fever of 103F on the 5th day and died on the 12th hospital day. The authors first statement is: “phenothiazine derivatives are known to produce impairment of thermoregulation. Numerous cases of coma and hyperpyrexia have been attributed to these drugs, some of which have been fatal.”

In their discussion they comment that “many afflicted individuals develop intense muscular rigidity.” This effect on temperature regulation caused several deaths in prisoners forcibly treated at Vacaville during a heat wave and may account for the many deaths among the elderly (commonly treated with haldol for “sundowner syndrome“ agitation at night) during last summer’s heatwave in Chicago.

14. Shields,W. and Bray, F.: A Danger of Halopiredol Therapy in Children. Journal of Pediatrics 88, 301-303 1976.

The case of a 5 year old girl who developped opisthotonous (figure 1) related to Haldol is presented and the authors conclude with regard to Haldol in children: “...we believe that in most cases the risk of incurring a serious neurologic side effect is too great to warrant its use.”

1977

15. Rigestein et. al.: Sudden Catatonic Stupor with Disastrous Outcome JAMA 238; pages 618-620 1977.

16. Toru M, et. al.: Neuroleptic Malignant Syndrome-like State Following a Withdrawal of Antiparkinsonian Drugs. Journal of Nervous and Mental Diseases Volume 169, pages 324-327, 1977.

After reporting the case of a 63 year old woman in which anti-Parkinsonian (dopaminergic) drugs were abruptly withdrawn producing an NMS like syndrome, the authors “suggest that dopaminergic hypoactivity in the brain” may exist in NMS, a condition produced by chronicv dopamine blockade.

EEG slowing is documented.

17. Weinberger D and Kelly M: Catatonia and Malignant Syndrome: A Possible Complication of Neurolteptic Administration: Report of a Case Involving Haloperidol. Journal of nervous and Mental Disease Vol 165 No 4, 1977.

A 20 year old foreign exchange student was admitted to Harvard’s Peter Bent Brigham Hospital with a diagnosis of “catatonic schizphrenia.” After a total of 25mg over 24 hours of IM HALDOL “...he stood motionless on one leg with his other leg extended and his eyes staring fixedly...he was immobile with generalized muscular hypertonicity and typical flexibilitas cerea (a “pathognomonic” sign of catatonic schizophrenia). His doctors interpreted this change as either a worsening of his psychiatric condition or a severe extrapyramidal reaction....” He survived.

18. Gellenberg and Mandel: Catatonic Reactions to High Potency Neuroleptic Drugs. Archives of General Psychiatry, 34, 947-950, 1977.

“Eight patients developed a syndrome marked by features of catatonia...while receiving high-potency neuroleptic drugs.”

The authors suspect the dopamine blockading effects of phenothiazines but state “While it’s mechanisms are obscure, it is clear that a syndrome characterized by stiffness, rigidity, withdrawal, regression, and other catatonic and parkinsonian features can occur in patients treated with high potency anti-psychotic drugs.... The drug induced nature of this syndrome should be recognized so that the patients are not subjected to increasing dosage of psychotropic medication...we recommend that when a clinician observes catatonic signs developing in a patient receving neuroleptic medication, he first consider the posibility of a drug induced catatonic syndrome before assuming a schizophrenic process.”

The Archives of General Psychiatry comes free to all psychiatrists who are members of the AMA. It is among the most widely read journal in psychiatry. This warning regarding NMS was essentially broadcast loud and clear to the psychiatric community with this 1977 article.

1978

19. Scialli, J. and Thonton, W: Toxic Reactions from a Halopiredol Overdose in Two Children - Thermal and Cardiac Manifestations. JAMA January 2, 1978 Volume 239 No. 1 pages 48-49.

1979

20. Geller,B. and Greydanuus, D: Halopyridol Induced Comatose State with Hyperthermia and Rigidity in Adolescents: Two case reports with a literature review. J Clin Psychiatry 40:102-103, 1979.

“Two adolescents developed severe extrapyrimadal reactions due to haloperidol...this is a rarely reported result of utilizing this medication in children and youth and caution is urged in its use. Prolonged reactions have occurred.”

21 Bernstein, R: Malignant Neuroleptic Syndrome, An Atypical Case. Psychosomatics December 1979 Volume 20, No. 12 pages 840-846. A 36 year old woman on Thorazine and Trilafon developed parkinsonian symptoms on her 8th day of psychiatric hospitalization.

“During this period (day 11 to 13) the patient went from a state of passive hopelessness with fear of impending death to a highly agitated manic state.”

The significance of this paper is that on 3 separate challenges intentional resumption of medication) the patient developed recurrences.

The persistent vulnerability of victims of NMS was established in 1979 and yet as of 1997, some psychiatric authorities condone resumption of the causitive drug even while acknowledging 30% recurrence rates.

22. Gunhaus N. et. al.: NMS Due to Depot Fluphenazine. Journal of Clinical Psychiatry 40:99-100, 1979. These authors give credit to Delay and Deniker (1964) for term “Nuroleptic Malignant Syndrome.”

This paper reports on a fifteen year old female and a twelve year old male both of whom developed fevers to 104F and all the other symptoms of NMS. Both had been getting Haldol.

In a discussion of the literature prior to 1979, the authors state:

“‘Syndrome malin’ is a term used to describe hyprthermia, hyprtension, disphoesis, regidity and various levels of coma occurring during the course of halopyridol therapy.... It has also been referred to as the hypothalamic syndrome and the neuroleptic malignant syndrome.... Treatment consists of early recognition, immediate cessation of the drug, supportive care as needed, and a trial of medications.”

This widely read journal establishes the standard of knowledge of NMS as of 1979. Its’ references range from 1963 to 1976. They credit three french authors with identifying a “fatal malignant syndrome” in 1971.

* Lazarus A, Mann S and Caroff S: Neuroleptic Malignant Syndrome and Related
   Conditions. American Psychiatric Press, 1989.

• • • OISM Newsletter • • •
Subscrine to OISM Newsletter and you’ll always be kept up to date via eMail on the news in the field of mental health and the struggle against psychiatry... CLICK HERE TO SUBSCRIBE!