S E M I N A R S I N NEUKO1,OC;Y-VOLUME
1 1, N O . 3
SEPTEMBER 1991
Neuroleptic Malignant Syndrome or Parkinsonism Hyperpyrexia Syndrome
Neuroleptic malignant syndrome (NMS) is a rare and sometimes h t a l illness that was initially described in the American literature by Delay and Deniker in 1968.' Awareness of the syndrome was heightened by Caroff's incisive review in 1980,' and the clinical bounds of the disorder were expanded by case reports of NMS due to the withdrawal of dopamine agonists in patients with idiopathic parkinsonism (IP).3-7 The hypothesis followed that NMS was an idiosyncratic reaction that could occur in one of two pharmacologic settings: (1) Administration of drugs that blocked dopamine receptors in the central nervous system (CNS),and (2) withdrawal of dopamine agonists in patients with IP. Diagnostic criteria were proposed by Levenson in 1985,' which included "major" (fever, rigidity, elevated creatine kinase [CK]) and "minor" (tachycardia, abnormal blood pressure, tachypnea, altered consciousness, diaphoresis, leukocytosis) manifestations. T h e proliferation of case reports of purported NMS since then may represent heightened awareness of the syndrome." A careful review of the case descriptions, however, reveals that many cases of so-called NMS occur-red in settings of drug usage other than those just described and lacked one or more of the major diagnostic criteria. Instead of fostering an understanding of the biochemical basis of NMS, these cases often served to confuse the picture. Further clarification of NMS is the goal of this review. In the absence of pathognomonic signs or definitive laboratory studies, the diagnosis of a syndrome such as NMS depends on application of clearly defined clinical characteristics. Delay and Deniker's original description was based on the presence of autonomic changes ("pallor and py-
rexia"), parkinsonism (akinesia, hypertonicity, dyskinesias), and "signs in the lungs."' After analysis of a large number of reported cases as well as those personally observed, we argue that NMS is a syndrome of parkinsonism and hyperpyrexia. Obligate clinical features would then be rigidity (with or without tremor) and fever; in a large review, each of these was present in virtually all cases (98% and 100%, respectively)."' Parkinsonism and hyperpyrexia therefore form the cornerstone of the diagnosis of NMS. Minor or secondary clinical features include changes in mental status, autonomic instability, and a variety of other nonspecific neurologic signs such as nystagmus, opisthotonos, and seizures." Elevated CK has been considered a major criterion by some authors,' but in other series it occurred in less than half the cases.','0 This suggests that CK elevations are not directly linked to the pathogenesis of' NMS and that their presence, while supportive of NMS, should not be considered a diagnostic criterion of the syndrome.
PATHOGENESIS T h e precise pathogenesis of NMS has yet to be proven, but a wealth of circumstantial evidence exists in support of the theory that the essential process is one of reduced dopaminergic activity in the CNS. First, NMS clearly occurs in at least two pharmacologic settings: the administration of dopamine-receptor antagonists and the sudden cessation or reduction of dopamine agonists in patients with IP. Second, NMS responds to treatment with I d o p a or dopamine agonists such as bromocriptine and amantadine." Third, dopamine neuro-
Department of Neurology, University of Virginia IIealth Sciences Ccnter, Charlottesville. Virginia Reprint requests: Dr. Wooten, Department of Neurology-Box Sciences Center, Charlottesville, VA 22908
394, University of' Virginia, Health
Copyright O 1991 by Thierne Medical Publishen, Inc., 381 Park Avenue South, New York, NY 100 16. All rights reserved.
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
Mark A. Granner, M.D., and G. Frederick Wooten, M.D.
pecially susceptible to heat stroke during heat waves.'"I7
DOPAMZNE AND FEVER
DOPAMZNE AND PARKZNSONZSM
Maintenance of body temperature within a narrow range regardless of ambient temperature is a feature universal to mammals. To maintain a constant body temperature, mammals must sustain an equilibrium between the production and dissipation of' heat. T h e central control of body temperature is integrated primarily in the hypothalamus, the posterior portion of which contains a "set point," and the anterior portion of which compares blood temperature to this "set point" and is responsible for the generation (through shivering), preservation (through peripheral vasoconstriction), and dispersion (through peripheral vasodilation and sweating) of heat." T h e generation, preservation, and dispersion of heat is carried out through the activity of' the autonomic nervous system. Dopaminergic neurons play a role in these pathways. In the rat, intraventricular in.jection of either dopamine o r apomorphine (a potent dopamine-receptor agonist) produced a decrease in core temperature and a rise in tail skin temperature.'"This effect was completely blocked by the preadministration of pimozide, a dopamine-receptor blocker. Administration of chlorpromazine, another dopamine receptor antagonist, to rats in either hot o r cold ambient temperatures resulted in a failure to maintain homeostasis.'" T h e animals became hypothermic in cold environments and hyperthermic in hot environments. T h e failure to dissipate heat in chlorpr-ornazine-treated rats exposed to an exogenous heat load was d u e to a lack of compensatory peripheral vasodilation and salivation, both of which are normally employed to disperse heat. An identical failure to maintain homeostasis in cold o r hot anlbient temperatures was seen in patients tak''' patients were esing neuroleptic d r i ~ g s . ' ~ .These
IP occurs as a result of reduced striatal dopaminergic activity caused by degeneration of nigrostriatal neurons. A variety of extrapyramidal signs, including rigidity and rest tremor, may be present. Neuroleptic medications, by blocking striatal dopamine receptors, may cause drug-induced parkinsonism, which is clinically indistinguishable from IP.IXT h e parkinsonism of NMS is likewise clinically similar to that of ID, and in the absence of an alternate hypothesis is likely to be due to reduced striatal dopaminergic transmission. FEVER AND PARKZNSONZSM
Patients with IP have been found to have abnormal thermoregulatory mechanisms, including abnormal sweating. A primary hypothalamic pathologic condition was thought to play a role in this abnormality."' Untreated patients with IP exposed to heat had increased sweating on the fice and neck when compared with controls, but decreased sweating elsewhere on the body."' T h e degree of sweating impairment related directly to the severity of disease. Appenzeller" speculated that the facial hyperhidrosis is a compensatory mechanism in the setting of impaired sweating elsewhere. Also, untreated patients with I P had impaired ahility to generate surface temperature elevations when exposed to exogenous heat compared with age-matched controls." This difference disappeared following the administration of dopaminergic drugs. Therefore patients with I P are unable to dissipate heat appropriately when challenged with a thermal load. By extension, NMS patients, with a deficiency of both striatal and hypothalamic dopaminergic activity, are simultaneously challenged
Figure 1. Proposed mechanism of hyperthermia in neuroleptic malignant syndrome.
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
transmission is known to be involved in the control of body temperature arid the pathophysiology of parkinsonisrn.
SEMINARS I N NEUKOLO
1 1, N O . 3
SEPTEMBER 1991
Neuroleptic Malignant Syndrome or Parkinsonism Hyperpyrexia Syndrome
Neuroleptic malignant syndrome (NMS) is a rare and sometimes h t a l illness that was initially described in the American literature by Delay and Deniker in 1968.' Awareness of the syndrome was heightened by Caroff's incisive review in 1980,' and the clinical bounds of the disorder were expanded by case reports of NMS due to the withdrawal of dopamine agonists in patients with idiopathic parkinsonism (IP).3-7 The hypothesis followed that NMS was an idiosyncratic reaction that could occur in one of two pharmacologic settings: (1) Administration of drugs that blocked dopamine receptors in the central nervous system (CNS),and (2) withdrawal of dopamine agonists in patients with IP. Diagnostic criteria were proposed by Levenson in 1985,' which included "major" (fever, rigidity, elevated creatine kinase [CK]) and "minor" (tachycardia, abnormal blood pressure, tachypnea, altered consciousness, diaphoresis, leukocytosis) manifestations. T h e proliferation of case reports of purported NMS since then may represent heightened awareness of the syndrome." A careful review of the case descriptions, however, reveals that many cases of so-called NMS occur-red in settings of drug usage other than those just described and lacked one or more of the major diagnostic criteria. Instead of fostering an understanding of the biochemical basis of NMS, these cases often served to confuse the picture. Further clarification of NMS is the goal of this review. In the absence of pathognomonic signs or definitive laboratory studies, the diagnosis of a syndrome such as NMS depends on application of clearly defined clinical characteristics. Delay and Deniker's original description was based on the presence of autonomic changes ("pallor and py-
rexia"), parkinsonism (akinesia, hypertonicity, dyskinesias), and "signs in the lungs."' After analysis of a large number of reported cases as well as those personally observed, we argue that NMS is a syndrome of parkinsonism and hyperpyrexia. Obligate clinical features would then be rigidity (with or without tremor) and fever; in a large review, each of these was present in virtually all cases (98% and 100%, respectively)."' Parkinsonism and hyperpyrexia therefore form the cornerstone of the diagnosis of NMS. Minor or secondary clinical features include changes in mental status, autonomic instability, and a variety of other nonspecific neurologic signs such as nystagmus, opisthotonos, and seizures." Elevated CK has been considered a major criterion by some authors,' but in other series it occurred in less than half the cases.','0 This suggests that CK elevations are not directly linked to the pathogenesis of' NMS and that their presence, while supportive of NMS, should not be considered a diagnostic criterion of the syndrome.
PATHOGENESIS T h e precise pathogenesis of NMS has yet to be proven, but a wealth of circumstantial evidence exists in support of the theory that the essential process is one of reduced dopaminergic activity in the CNS. First, NMS clearly occurs in at least two pharmacologic settings: the administration of dopamine-receptor antagonists and the sudden cessation or reduction of dopamine agonists in patients with IP. Second, NMS responds to treatment with I d o p a or dopamine agonists such as bromocriptine and amantadine." Third, dopamine neuro-
Department of Neurology, University of Virginia IIealth Sciences Ccnter, Charlottesville. Virginia Reprint requests: Dr. Wooten, Department of Neurology-Box Sciences Center, Charlottesville, VA 22908
394, University of' Virginia, Health
Copyright O 1991 by Thierne Medical Publishen, Inc., 381 Park Avenue South, New York, NY 100 16. All rights reserved.
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
Mark A. Granner, M.D., and G. Frederick Wooten, M.D.
pecially susceptible to heat stroke during heat waves.'"I7
DOPAMZNE AND FEVER
DOPAMZNE AND PARKZNSONZSM
Maintenance of body temperature within a narrow range regardless of ambient temperature is a feature universal to mammals. To maintain a constant body temperature, mammals must sustain an equilibrium between the production and dissipation of' heat. T h e central control of body temperature is integrated primarily in the hypothalamus, the posterior portion of which contains a "set point," and the anterior portion of which compares blood temperature to this "set point" and is responsible for the generation (through shivering), preservation (through peripheral vasoconstriction), and dispersion (through peripheral vasodilation and sweating) of heat." T h e generation, preservation, and dispersion of heat is carried out through the activity of' the autonomic nervous system. Dopaminergic neurons play a role in these pathways. In the rat, intraventricular in.jection of either dopamine o r apomorphine (a potent dopamine-receptor agonist) produced a decrease in core temperature and a rise in tail skin temperature.'"This effect was completely blocked by the preadministration of pimozide, a dopamine-receptor blocker. Administration of chlorpromazine, another dopamine receptor antagonist, to rats in either hot o r cold ambient temperatures resulted in a failure to maintain homeostasis.'" T h e animals became hypothermic in cold environments and hyperthermic in hot environments. T h e failure to dissipate heat in chlorpr-ornazine-treated rats exposed to an exogenous heat load was d u e to a lack of compensatory peripheral vasodilation and salivation, both of which are normally employed to disperse heat. An identical failure to maintain homeostasis in cold o r hot anlbient temperatures was seen in patients tak''' patients were esing neuroleptic d r i ~ g s . ' ~ .These
IP occurs as a result of reduced striatal dopaminergic activity caused by degeneration of nigrostriatal neurons. A variety of extrapyramidal signs, including rigidity and rest tremor, may be present. Neuroleptic medications, by blocking striatal dopamine receptors, may cause drug-induced parkinsonism, which is clinically indistinguishable from IP.IXT h e parkinsonism of NMS is likewise clinically similar to that of ID, and in the absence of an alternate hypothesis is likely to be due to reduced striatal dopaminergic transmission. FEVER AND PARKZNSONZSM
Patients with IP have been found to have abnormal thermoregulatory mechanisms, including abnormal sweating. A primary hypothalamic pathologic condition was thought to play a role in this abnormality."' Untreated patients with IP exposed to heat had increased sweating on the fice and neck when compared with controls, but decreased sweating elsewhere on the body."' T h e degree of sweating impairment related directly to the severity of disease. Appenzeller" speculated that the facial hyperhidrosis is a compensatory mechanism in the setting of impaired sweating elsewhere. Also, untreated patients with I P had impaired ahility to generate surface temperature elevations when exposed to exogenous heat compared with age-matched controls." This difference disappeared following the administration of dopaminergic drugs. Therefore patients with I P are unable to dissipate heat appropriately when challenged with a thermal load. By extension, NMS patients, with a deficiency of both striatal and hypothalamic dopaminergic activity, are simultaneously challenged
Figure 1. Proposed mechanism of hyperthermia in neuroleptic malignant syndrome.
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
transmission is known to be involved in the control of body temperature arid the pathophysiology of parkinsonisrn.
SEMINARS I N NEUKOLO
