Article, Internal Medicine

Coexistence of neuroleptic malignant syndrome and a hyperosmolar hyperglycemic state

39.3 mm Hg, pO2 57.5 mm Hg, HCO– 21.2 mmol/L, and O

3

2

hyperosmolar hyperglycemic state Abstract

neuroleptic malignant syndrome (NMS) is a rare idiosyncratic disorder characterized by muscle rigidity, hyperthermia, Autonomic dysfunction, and altered con- sciousness. Although the incidence of NMS is low, it may be fatal if early recognition is delayed. There are a variety of precipitating factors for NMS including systemic illness and dehydration. The combination of NMS with systemic illness can be difficult to diagnose because the systemic illness may mask the coexistence of NMS. We report a patient with hyperosmolar hyperglycemic state with coexistent NMS to remind physicians that hyperosmolar hyperglycemic state may precipitate the development of NMS in patients receiving neuroleptics.

A 34-year-old woman presented to the emergency department (ED) with a 1-day history of obtunded consciousness. She had a history of bipolar affective disorder treated with lithium for more than 10 years. There was no history of other systemic disease such as diabetic mellitus, hypertension, or thyroid disease or the use of illicit drugs. There was no family history of diabetes mellitus or diabetes insipidus. Two weeks before admission, she experienced polyuria and nocturia, followed by the binge drinking of 4 to 5 L of sugar-containing beverages per day.

Initial examination in the ED revealed a comatose woman with a blood pressure of 110/66 mm Hg; pulse rate, 112/min; respiratory rate, 20/min; and oral temperature, 35.6?C. Apart from dry tongue and mucous membranes, there were no physical findings of note. Neurologic examination revealed no focal motor or sensory deficits. The most striking biochemical finding was a Serum glucose level of 1576 mg/dL with elevated blood osmolality 401 mOsm/L. Other blood tests showed hemoglobin level of 13.0 g/dL; white blood cell count, 10 960/uL (89% neutrophils); blood urea nitrogen, 18 mg/dL; creatinine, 2.1 mg/dL; sodium, 115 mmol/L; potassium, 5.46 mmol/L; and chloride, 81.2 mmol/L. Arterial blood gas analysis showed pH 7.336, pCO2

saturation 87.8% in room air. There were no ketone bodies or pyuria on urinalysis. Based on the above data, a diagnosis of hyperosmolar hyperglycemic coma was made. Because there was no history of diabetes mellitus, it was assumed that her condition was because of dietary indiscretion. The patient was admitted to the intensive care unit, and soluble human insulin was given intravenously. This was accompanied by intravenous fluid supplementation.

After 1 day of this management, her blood glucose dropped to 532 mg/dL; however, her consciousness did not improve with remission of the hyperglycemic state. In addition, high fever up to 39?C developed along with muscle rigidity, especially in the neck. Computed tomog- raphy of the brain was performed and showed no particular findings. Meningitis was suspected initially, but cerebro- spinal fluid analysis revealed no abnormalities. Empirically, broad-spectrum antibiotics were administrated after the blood and urine cultures were collected. Repeated urinalysis was positive for occult blood on the chemical strip but negative for red blood cells on microscopic examination. Rhabdomyolysis was suspected, and follow-up blood biochemistry revealed highly elevated creatine phosphoki- nase (70 612 IU/L) as well as deteriorating renal function. Her C-reactive protein, Serum electrolytes, and Liver enzymes were all within normal limits; electrocardiogram and chest x-ray showed no abnormalities. Detailed review of her medication history disclosed that haloperidol (20 mg/d), chlorpromazine (100 mg/d), and trihexyphenidyl (4 mg/d) had been prescribed 3 days before admission for her binge drinking behavior. Based on the presence of fever, muscle rigidity, disturbance of consciousness, and recent exposure to neuroleptics, a diagnosis of neuroleptic malignant syndrome (NMS) was suggested by a psychiatrist. Bromocriptine was started immediately, and emergency hemodialysis was performed because of the oliguric state. Despite this management, her condition deteriorated rapidly; and she died 3 days later because of profound hypotension. After the patient died, pending laboratory results showed that the septic workup was negative; and her hemoglobin A1c level (5.5%) and thyroid function were within normal limits.

0735-6757/$ – see front matter (C) 2012

833.e2 Case Report

Hyperosmolar hyperglycemic state (HHS) typically occurs in elderly patients with a history of diabetes mellitus and has precipitating causes such as infection, dehydration, or drugs. Although it is known that chlorpromazine and lithium may impair glucose tolerance, they rarely lead to full- blown diabetes mellitus. In the absence of a history of diabetes mellitus and a normal hemoglobin A1c level, the binge drinking of sugar-containing beverages may be the most plausible explanation for hyperglycemia in this patient. Another possible predisposing factor for HHS is lithium- related diabetes insipidus. Lithium can cause nephrogenic diabetes insipidus that usually presents with mild symptoms such as polyuria and secondary polydipsia. Although diabetes insipidus typically presents with hypernatremia and low urine osmolality, serum sodium and osmolality can be maintained within the reference range if fluid intake is not restricted. The fluid depleting effect of diabetes insipidus may precipitate the development of HHS, as has been reported in the literature [1,2].

Neuroleptic malignant syndrome is a rare idiosyncratic disorder characterized by hyperthermia, muscle rigidity, autonomic dysfunction, and Altered consciousness on expo- sure to neuroleptic medications. Its incidence ranges from 0.07% to 0.15% [3,4]; and it may be fatal if there is a delay in early recognition, withdrawal of neuroleptic medications, and intensive care with attention to hydration and fever reduction. A variety of precipitating factors for NMS have been proposed. These include agitation, dehydration, organic brain disease, high doses or rapid dose titration of neuroleptics, abrupt discontinuation of antiparkinsonism agents, and concurrent lithium therapy [5-10]. The patho- physiology of NMS is not fully understood; and it may involve the central dopaminergic system, muscle cell membranes, and the sympathetic nervous system [6,7]. There were several possible Predisposing factors for the development of NMS in our patient. These included concurrent lithium therapy, dehydration, and, possibly, the hyperglycemic state.

To the best of our knowledge, HHS and NMS have rarely been reported as occurring together [11,12]. Contrary causal relationships have been proposed for the coexistence of these 2 syndromes. In 1, the hypermetabolic state of NMS may activate the sympathetic system, which, in turn, suppresses insulin secretion and increases the secretion of glucagons [6]. The imbalance between insulin and gluca- gons may produce hyperglycemia even in patients without a history of diabetes. In the other, hyperglycemia and the concomitant dehydration of HHS have been reported to precipitate the development of NMS [12,13].

Because of physician alertness and prompt therapy, mortality from NMS alone is now unusual; however, when coexisting with HHS, rhabdomyolysis, and acute renal failure, the prognosis for NMS is grave [11,14,15]. Early recognition of NMS with discontinuation of neuroleptics,

adequate hydration, and fever reduction will reduce the risk of acute renal failure. This case should remind physicians that HHS may precipitate the development of NMS; consequently, importance of the Drug history and an awareness of NMS cannot be overemphasized.

Chung-Wei Yang MD

Ching Lu MD Chih-Cheng Wu MD Szu-Chi Wen MD

Department of Internal Medicine Hsin Chu General Hospital

School of Medicine, National Yang-Ming University

Hsinchu City 300, Taiwan E-mail address: wucc01@ms66.hinet.net

doi:10.1016/j.ajem.2011.02.031

References

  1. Azam H, Newton RW, Morris AD, et al. Hyperosmolar nonketotic coma precipitated by lithium-induced nephrogenic diabetes insipidus. Postgrad Med J 1998;74:39-41.
  2. MacGregor DA, Baker AM, Appel RG, et al. Hyperosmolar coma due to lithium-induced diabetes insipidus: report of a meeting of Critical Care Physicians, Bowman Gray School of Medicine. Lancet 1995;346: 413-7.
  3. Gelenberg AJ, Bellinghausen B, Wojcik JD, et al. A prospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital. Am J Psychiatry 1988;145:517-28.
  4. Keck PE, Pope HG, McElroy SL. Declining frequency of neuroleptic malignant syndrome in a hospital population. Am J Psychiatry 1991;148:880-2.
  5. Rosebush P, Stewart T. A Prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 1989;146:717-25.
  6. Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry 1999;156:169-80.
  7. Ebadi M, Pfeiffer RF, Murrin LC. Pathogenesis and treatment of neuroleptic malignant syndrome. Gen Pharmacol 1990;21:367-86.
  8. Hermesh H, Aizenberg D, Weizman A, et al. Risk for definite neuroleptic malignant syndrome. A prospective study in 223 consecutive in-patients. Br J Psychiatry 1992;161:254-67.
  9. Sechi GP, Tanda F, Mutani R. Fatal hyperpyrexia after withdrawal of levodopa. Neurology 1984;34:249-51.
  10. Onofrj M, Thomas A. Acute akinesia in Parkinson disease. Neurology 2005;64:1162-9.
  11. Rock W, Elias M, Lev A, et al. Haloperidol-induced neuroleptic malignant syndrome complicated by hyperosmolar hyperglycemic state. Am J Emerg Med 2009;27(8):1018.e1-3.
  12. Balzan M, Cacciottolo JM. Neuroleptic malignant syndrome present- ing as hyperosmolar non-ketotic diabetic coma. Br J Psychiatry 1992;161:257-8.
  13. de Boer C, Gaete HP. Neuroleptic malignant syndrome and diabetic keto-acidosis. Br J Psychiatry 1992;161:856-8.
  14. Korzets Z, Zeltzer E, Bernheim J. Acute renal failure in the setting of the neuroleptic malignant syndrome. Nephrol Dial Transplant 1996;11:885-6.
  15. Becker BN, Ismail N. The neuroleptic malignant syndrome and acute renal failure. J Am Soc Nephrol 1994;4:1406-12.