J Am Board Fam Pract: first published as 10.3122/jabfm.5.3.327 on 1 May 1992. Downloaded from Neuroleptic Malignant Syndrome

Mark A. Connelly, M.D., It and Eric K. Fowler, M.D.

Neuroleptic malignant syndrome is a potentially percent MM fraction. Results of a chest radio­ lethal condition of unclear cause seen in as many graph, complete blood count, electrocardiogram, as 1 percent of patients taking neuroleptic medi­ electrolyte measurement, and thyroid and liver cations.I The syndrome was first described in function tests were normal. Magnetic resonance 1959 by Preston2 and is characterized by imaging of the brain showed mild atrophic hyperthermia, muscular rigidity, mental status changes with no intracerebral bleeding or mass. changes, and autonomic instability. Widespread Trifluoperazine was discontinued. The patient use of neuroleptic and other psychotropic medi­ was given benztropine mesylate (Cogentin TIl), cations has made the diagnosis and management amantadine (Symmetrel TIl), and bromocriptine of neuroleptic malignant syndrome important for (parlodel TIl) sequentially without relief of rigidity. all primary care physicians. On the 4th hospital day, he began exhibiting bi­ zarre behavior for which loxapine hydrochloride Case Report (Loxitane TIl), a less-potent neuroleptic, was pre­ A 57-year-old man with an 18-year history of scribed. On the 7th hospital day, the patient be­ paranoid schizophrenia was successfully managed came markedly more rigid and his oral tempera­ with trifluoperazine (Stelazine TIl). The patient ture was 4O.1°C (104.2°F). A repeat CPK was came to the office with complaints of increasing 10.92 J.LkatIL (655 UIL). The diagnosis of neuro­ stiffness, confusion, and anorexia, which were leptic malignant syndrome was made, and the diagnosed as extrapyramidal side effects of his patient was transferred to the critical care unit. neuroleptic medication. He was treated sequen­ Findings from a chest radiograph, blood cultures, tially with oral benztropine (Cogentin TIl), tri­ urinalysis, urine culture, thyroid function tests, hexyphenidyl (Artane TIl), and diphenhydramine and a lumbar puncture were all normal. The pa­ (Benadryl TIl) without success. After 11 days of tient received intravenous dantrolene sodium therapy without improvement, he was admitted (Dantrium TIl) and benztropine, as well as oral to the hospital. bromocriptine. To avoid the possibility of acute

The patient was a thin, well-groomed man who renal failure from myoglobinuria, the patient was http://www.jabfm.org/ walked with a shuffling gait. A mental status ex­ provided with vigorous hydration. A cooling amination revealed mild confusion, but no delu­ blanket helped control hyperthermia. He had sev­ sions or hallucinations. His temperature, blood eral short-lived hypotensive episodes that re­ pressure, and pulse and respiration rates were sponded to Trendelenburg positioning and intra­ normal. His facies were masked with marked venous fluid. tongue fasciculations. Extremity examination By the 8th hospital day, the patient was afebrile, on 1 October 2021 by guest. Protected copyright. showed bilateral "lead pipe" rigidity and a coarse and his blood pressure was stable. Because of re­ hand . sidual stiffness and a rising CPK, oral doses of dan­ On admission a laboratory evaluation of trolene, bromocriptine, and benztropine were his creatine phosphokinase (CPK) level was maintained. His CPK peaked at 48.46 J.LkatIL 3.98 J.LkatIL (239 UIL) (normal laboratory value (2907 UIL) on day 9 but fell stejldily thereafter. is < 4.48 J.LkatIL [269 UILl). The CPK was 100 Renal function remained normal. As he continued to improve, he was gradually weaned from his medi­ cations. On hospital day 17, the patient was dis­ charged to home. At that time he was of any Submitted, revised, 22 October 1991. his free From the Department of Family Practice ofLanc:aster General delusions, hallucinations, or confusion and had only Hospital, Lancaster, PA. Address reprint requests to Eric K. minimal rigidity. The benzodiazepine clonazepam Fowler, M.D., 626 Patriot Drive, Lancaster, PA 17601. (Klonopin TIl) was prescribed for mild agitation, '"Deceased. This article is dedicated to the memory of Mark A. Connelly, however, and the dopamine agonist amantadine M.D., who was killed while serving in the Persian Gulf War. was continued for his residual rigidity.

Neuroleptic Malignant Syndrome 327 Clinical Presentation age, and in both medical and psychiatric patients. J Am Board Fam Pract: first published as 10.3122/jabfm.5.3.327 on 1 May 1992. Downloaded from As illustrated above, neuroleptic malignant syn­ There is a 2: 1 predominance of men to women. 10 drome is characterized by muscular rigidity, Although most often associated with neurolep­ hyperpyrexia, altered mental status, and auto­ drugs, this syndrome also has been re­ nomic instability. Muscular hypertonicity is the ported after treatment with tricyclic antidepres­ most common presenting symptom. It has been sants and monoamine oxidase inhibitors, as described as having a "lead pipe" quality and can well as after the withdrawal of dopaminergic be associated with dyskinetic or choreiform antiparkinsonian medicines, such as amantadine movements.3 The fever of neuroleptic malignant and levodopa.5,10 Of the neuroleptic drugs, the syndrome occurs in conjunction with or shortly depot formulations (e.g., fluphenazine decanoate after the onset of muscular rigidity; it can be quite and decanoate) and those with dramatic, and temperatures can reach 41°C or the highest antidopaminergic potency (e.g., higher.2 The patient's level of consciousness can droperidol, haloperidol, trifluoperazine, and range from mild confusion to obtundation or thiothixene) are most likely to induce an episode coma.4 Autonomic dysfunction can be manifested of neuroleptic malignant syndrome.6 Other pre­ by incontinence, diaphoresis, pallor, labile blood disposing factors include dehydration, electrolyte pressure, and tachycardia.5 Less frequent signs of imbalances, exhaustion, organic brain syndrome,S neuroleptic malignant syndrome include , and hypothyroidism. I I trismus, oculogyric crisis, sialorrhea, retrocollis, The exact pathophysiology of neuroleptic ma­ the Babinski sign, and opisthotonos.6 lignant syndrome is unknown. It has been theo­ Although no laboratory test is pathognomonic rized, however, that its clinical features are due of neuroleptic malignant syndrome, there are to either a disruption of certain central nervous suggestive findings. As a result of intense muscu­ system pathways or to a peripheral induction of lar rigidity, serum CPK is often elevated and can intense striated muscle contraction. be as high as 1250.25 ~tIL (75,000 U/L).7 The first theory proposes that central Leukocytosis, with a cell count in the range of dopaminergic blockade leads to the symp­ 15-30 X 109/L (15,000-30,OOO/mm3), with or toms seen in neuroleptic malignant syndrome. without a left shift, might also be present.4 Elec­ More specifically, the hyperthermia is thought trolytes can reflect dehydration. Other abnormal­ to be precipitated by hypothalamic path­ ities can include elevated liver function tests.5 An way blockade, while the muscular rigidity is electroencephalogram can show diffuse slowing believed to result from the blockage of nigrostria­ http://www.jabfm.org/ or be normal.4 analysis is nor­ tal pathways. This theory is supported by the mal, as is central structure when success of such central dopamine agonists as visualized by computed tomography or at post­ bromocriptine in treating neuroleptic malignant mortem autopsy.4 syndrome. 12 The patient with neuroleptic malignant syn­ The second theory relies upon the similarity of

drome must be carefully observed for signs of neuroleptic malignant syndrome to malignant on 1 October 2021 by guest. Protected copyright. complications. Decreased chest wall compliance hyperthermia, an inherited autosomal dominant caused by muscle rigidity can result in aspiration trait. Malignant hyperthermia is characterized by pneumonia or respiratory failure. 3 Intense muscle muscular rigidity and hyperpyrexia triggered by contraction can lead to myonecrosis, myo­ inhaled anesthetics, most commonly halothane.13 globinuria, and. acute renal failure.8 Other com­ In susceptible individuals, these agents cause an plications include disseminated intravascular co­ increase of calcium permeability of skeletal mus­ agulation,9 Escherichia coli fascitis, cardiac cle sarcoplasmic reticulum resulting in unregu­ dysrhythmias, and thromboembolism.s The esti­ lated actin and myosin cross-bridge cycling and mated mortality for neuroleptic malignant syn­ tetani. If unchecked, this process results in in­ drome ranges from 20 to 30 percent.4 creased heat production, generalized cellular de­ struction, and eventually death. The response of Cause and PathophJSiology both malignant hyperthermia and neuroleptic Neuroleptic malignant syndrome is an idiosyn­ malignant syndrome to dantrolene therapy, which cratic reaction that can occur in either sex, at any decreases sarcoplasmic reticulum calcium per-

328 JABFP May-June 1992 Vol. 5 No.3 meability, is suggestive of a common cause for neuroleptic malignant syndrome. Computed J Am Board Fam Pract: first published as 10.3122/jabfm.5.3.327 on 1 May 1992. Downloaded from both syndromes. I4 tomographic or magnetic resonance imaging will Unlike malignant hyperthermia, however, help identify these intracerebral possibilities. there appears to be no genetic transmission of Heatstroke is a possibility, if the patient taking neuroleptic malignant syndrome. Also, whereas a neuroleptic medication is exposed to high ambi­ curare or pancuronium will cause a flaccid paraly­ ent temperatures and humidity or is additionally sis in those with neuroleptic malignant syndrome, predisposed to heat injury in some way. The they have no effect on patients with malignant neuroleptic medications do increase risk for tem­ hyperthermia. IS Obviously, there is much that re­ perature regulation difficulties. One may well see mains to be elucidated concerning the pathogen­ elevated CPK in heatstroke victims, but muscle esis of neuroleptic malignant syndrome. rigidity is less common.s As noted above, malignant hyperthermia must Differential DIagnosis be considered when there has been any recent Neuroleptic malignant syndrome is largely a history of exposure to inhalation anesthetics. clinical diagnosis. The patient's psychiatric and Also, as previously mentioned, a therapeutic trial pharmacologic history, combined with a good of pancuronium or curare can be helpful in differ­ reView of systems and physical examination, entiating between neuroleptic malignant syn­ should lead the clinician quickly to consider drome and malignant hyperthermia. This is not neuroleptic malignant syndrome. The dramatic without risk, however, and requires immediately symptoms of neuroleptic malignant syndrome, available respiratory support.I6 however, usually prompt consideration of other Thyroid storm should also be included in the significant diagnostic possibilities (fable 1). differential diagnosis, especially in patients who One must consider central nervous system in­ have a history of thyroid disease. Serum triiodo­ fection, given the patient's hyperthermia and thyronine (f3)' thyroxine (f.J, T3 resin uptake, mental status changes. and encephali­ and free T 4 index should be measured early in the tis are possibilities, thus a white cell count and evaluation of these patients. lumbar puncture with cerebrospinal fluid exami­ Lethal catatonia was first described in 1934. Its nation are indicated. The cerebrospinal fluid is cause is unclear, but it seems related to a state of always normal in neuroleptic malignant syn­ prolonged extreme agitation, usually mania, lead­ drome.s Careful neurologic examination and per­ ing to fever, dehydration, electrolyte imbalances,

haps consultation will augment the his­ and disruption in calcium metabolism. Auto­ http://www.jabfm.org/ tory to help exclude movement disorders, such as nomic dysfunction is usually not described. This severe Parkinson disease or Huntington chorea. potentially fatal complication can be seen in psy­ Other central nervous system insults, such as chiatric patients who do or do not take neurolep­ trauma, tumor, hemorrhage, or infarction, can tic medications. IS lead to a symptom complex similar to that seen in 1iea1ment After a careful differential diagnosis is rapidly on 1 October 2021 by guest. Protected copyright. Central nervous system infeCtion entertained and evaluated, treatment for neuro­ Meningitis leptic malignant syndrome must begin im­ mediately (fable 2). Discontinuation of the causa­ with fever from another source tive agent should be followed quickly by transfer Parkinson disease Chorea to an intensive care setting for one-on-one nurs­ Cerebrovascular accident ing. Aggressive supportive measures are aimed at 'Ifauma lowering body temperature, as well as maintain­ Tumor ing blood pressure, tissue perfusion, and renal Hemorrhage In&rction function. Serum electrolytes, blood urea nitro­ Heatstroke gen, creatinine, and CPK levels should be meas­ Malignant hyperthennia ured frequently. Thyroid storm Simultaneously, specific pharmacologic treat­ Lethal catatonia ment should be initiated. Dantrolene is a direct-

Neuroleptic Malignant Syndrome 329 J Am Board Fam Pract: first published as 10.3122/jabfm.5.3.327 on 1 May 1992. Downloaded from 'DIllIe z. 'lftllbaeat of NnroIepdc MaIIpaat s,udrome. Prognosis Remove inciting agent If the patient survives, recovery occurs over days Aggressive supportive care - transfer to intensive to weeks. Low-dose pharmacologic therapy is care unit continued as needed. Recovery can proceed more Lower body temperature slowly in schizophrenic patients than in other Support blood pressure Insure renal perfusion medical patients with neuroleptic malignant syn­ 19 Specific phannacologic therapy drome. Unless absolutely necessary, neuroleptic Dantrolene sodium agents should not be restarted. Recurrence of Dopunine agonists (bromocriptine) neuroleptic malignant syndrome after reinstitu­ Anticholinergics (tribexyphenidyl, benztropine) tion of medications is well docu­ mented. Even the new antipsychotic clozapine acting muscle relaxant that, by blocking leak­ (Clozaril 1'1() has been implicated in causing neuro­ age of calcium from the sarcoplasmic reticulum, leptic malignant syndrome.20,21 Certainly, psychi­ decreases peripheral muscular rigidity. This atric consultation would be in order before rein­ action lowers fever and decreases rhabdomyoly­ stituting any antipsychotic medication. sis.s,8 Initially, the dosage is 2 to 10 mglkg/d intravenously in four divided doses. After stabili­ Summary zation, the oral maintenance dosage ranges from Neuroleptic malignant syndrome is a relatively 50 to 200 mg/d in four divided doses. Upon insti­ uncommon life-threatening disorder. The wide­ tution of the dantrolene therapy, one should see a spread use of the neuroleptic and psychotropic decrease in muscular rigidity and a falling CPK medications, however, makes it important for the level. primary care physician to understand the clinical Another important pharmacologic agent is presentation, differential diagnosis, and manage­ the central dopamine agonist bromocriptine. ment of neuroleptic malignant syndrome. Early Bromocriptine is a direct postsynaptic dopamine recognition should be possible. Rapid diagnosis receptor agonist that works to reverse central followed by aggressive supportive care and spe­ dopaminergic blocbde.4,s It is given as 2.5 to 10 cific pharmacologic therapy can be life saving. mg orally three times a day. A good starting dose during a crisis is 5 mg three times daily. While the mainstay of dopamine agonist therapy re­ References 1. Delay J, Denikar P. Drug induced extrapyramidal http://www.jabfm.org/ mains bromocriptine,17 such presynaptic agents syndromes. In: Vinken PJ, Bruyn Gw, editors. as amantadine have been tried with limited Handbook of clinical neurology. Vol. 6. Diseases of success. The initial dose for amantadine is the . New York: Wiley, 1968:246-66. 100 mg orally twice daily. Dialysis is not effective 2. PrestonJ. Central nervous system reactions to small because most neuroleptics are significandy doses of tranquilizers: report on one death. Am Prac Dig Treatment 1959; 10:627-30. protein bound and therefore not dialyzable. 3. Smego RA, Durack DT. The neuroleptic malignant

Prior to the demonstrated efficacy of dantrolene syndrome. Arch Intern Med 1982; 142:1183-5. on 1 October 2021 by guest. Protected copyright. and bromocriptine, the pharmacologic treatment 4. Guze BH, Baxter LRJr. Current concepts. Neuro­ of choice was the anticholinergic agents. leptic malignant syndrome. N Engl J Med 1985; Trihexyphenidyl (Artane 1'I()10,18 and benztropine 313:163-6. (Cogentin 1'1()6 have been used most commonly 5. Parikh AM, Camara EG. Neuroleptic malignant syndrome. Am Fam Physician 1988; 37:296-8. in an attempt to reverse the severe anticholiner­ 6. Talbot JA, Hales RE, Yudofslcy SC, editors. The gic and extrapyramidal effects of the offending American Psychiatric Press textbook of psychiatry. agent. Washington, DC: American Psychiatric Press, As with all critical care patients, it is important 1988:784-5. to keep in close communication with family mem­ 7. Henderson vw, WootenJF. Neuroleptic malignant syndrome: a pathogenetic role for dopamine recep­ is bers. Neuroleptic malignant syndrome usually tor blockade? Neurology 1981; 31:132-7. dramatic in its evolution and treatment, and a 8. Eiser AR, NeffMS, Sliflcin RR Acute myoglobinuric well-informed family will serve as a valuable ally renal failure. A consequence of neuroleptic malig­ in the care of the patient. nant syndrome. Arch Intern Med 1982; 142:601-3.

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Neuroleptic Malignant Syndrome 331