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Special Article   |    
Sympathoadrenal Hyperactivity and the Etiology of Neuroleptic Malignant Syndrome
Ronald J. Gurrera, M.D.
Am J Psychiatry 1999;156:169-180.

OBJECTIVE: The author’s goal was to develop a pathophysiological model for neuroleptic malignant syndrome with greater explanatory power than the alternative hypotheses of hypothalamic dopamine antagonism (elevated set point) and direct myotoxicity (malignant hyperthermia variant). METHOD: Published clinical findings on neuroleptic malignant syndrome were integrated with data from human and animal studies of muscle physiology, thermoregulation, and autonomic nervous system function. RESULTS: The data show that the sympathetic nervous system’s latent capacity for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centers are disrupted. These tonic inhibitory inputs are relayed to preganglionic sympathetic neurons by way of dopaminergic hypothalamospinal tracts. The sympathetic nervous system mediates hypothalamic coordination of thermoregulatory activity and is a primary regulator of muscle tone and thermogenesis, augmenting both of these when stimulated. In addition, the sympathetic nervous system modulates all of the other end-organs that function abnormally in neuroleptic malignant syndrome. CONCLUSIONS: There is substantial evidence to support the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most, if not all, features of neuroleptic malignant syndrome. A predisposition to more extreme sympathetic nervous system activation and/or dysfunction in response to emotional or psychological stress may constitute a trait vulnerability for neuroleptic malignant syndrome, which, when coupled with state variables such as acute psychic distress or dopamine receptor antagonism, produces the clinical syndrome of neuroleptic malignant syndrome. This hypothesis provides a more comprehensive explanation for existing clinical data than do the current alternatives.

Abstract Teaser
Figures in this Article

It is widely believed that dopamine D2 (D2) receptor antagonism causes hyperthermia in neuroleptic malignant syndrome by blocking heat-loss pathways in the anterior hypothalamus, by increasing heat production secondary to extrapyramidal rigidity R15602CEBCDBAI, or both, but this model has been criticized as inadequate R15602CEBDJCIF, R15602CEBDFHDB and lacking sufficient evidence R15602CEBCAEJD. An alternative hypothesis is that neuroleptics are directly toxic to muscle tissue, as volatile anesthetics are in malignant hyperthermia R15602CEBCEJCI, but neuroleptic malignant syndrome and malignant hyperthermia likely have distinct mechanisms R15602CEBBGBDJ, R15602CEBCEEIA. Neither model enables clinicians to identify specific patients at greater risk for neuroleptic malignant syndrome or to make reliable treatment choices R15602CHDCIBGDR15602CHDBGGBI.

Autonomic dysfunction is a core component of neuroleptic malignant syndrome R15602CHDECGAH, R15602CHDBCJAJ, DSM-IV), and peripheral catecholamines are typically elevated R15602CHDBHIDCR15602CHDCEEEG, but a pathophysiological role for excess catecholamines in neuroleptic malignant syndrome has been relatively overlooked. This paper provides an overview of the sympathetic nervous system and its regulatory role in body temperature, muscle function, and other organ systems that are affected in neuroleptic malignant syndrome. These data are then integrated with published clinical observations in support of the hypothesis that dysregulated sympathetic nervous system hyperactivity is the pathophysiological basis of neuroleptic malignant syndrome. The central premises of this hypothesis are the intrinsic capacity of the sympathetic nervous system for autonomous, fragmented function and its ubiquitous involvement in all of the physiological processes relevant to neuroleptic malignant syndrome. F1 summarizes this thesis schematically, and the reader will find it helpful to consult it frequently.

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Anatomy of the Autonomic Nervous System

Most organs are innervated by sympathetic and parasympathetic divisions of the autonomic nervous system, but the adrenal medulla, sweat glands, and somatic blood vessels are regulated exclusively by the sympathetic nervous system R15602CHDEAFFC. Preganglionic sympathetic nervous system fibers synapse within the adrenal medulla R15602CHDEAFFC and promote catecholamine secretion R15602CHDCAFIH. Sympathetic nervous system and adrenomedullary responses are often dissociated R15602CHDCJFJD and can be complementary R15602CHDBDBFI, R15602CHDDHJAG. The relative independence of the sympathetic nervous system from central nervous system (CNS) regulation R15602CHDEAFFC, its more permeable blood-nerve barrier R15602CHDCADBF, and the ability of its end-organs to continue functioning when autonomic nerves are interrupted R15602CHDEAFFC all contribute to its capacity for autonomous function.

The sympathetic nervous system is regulated by the frontal cortex and hypothalamus. The sulcal prefrontal cortex tonically influences the hypothalamus to lower body temperature R15602CHDBBEFI. Sympathetic nervous system hyperactivity ensues when the hypothalamus is released from cortical control R15602CHDEAGBC, and systems lower in the neuraxis operate independently following hypothalamic lesion R15602CHDDJCCB. Sweating is tonically inhibited by the frontal cortex R15602CHDBGEFD, and a similar hierarchical inhibitory relationship exists between spinal cervicothoracic and thoracolumbar sudomotor (sweat gland) regulatory centers R15602CHDCJAFC.

The sympathetic nervous system is regulated by the lateral and posterior hypothalamus, whereas the parasympathetic division is controlled by the anterior and medial hypothalamus R15602CHDEAFFC, R15602CHDEAGBC. Stimulation of the lateral hypothalamus increases adrenal nerve activity R15602CHDCAFIH, and the lateral hypothalamic area provides organ- or site-specific regulation of sympathetic nervous system activity R15602CHDCDDEA. Most dorsal hypothalamic spinal projection neurons are dopaminergic and appear to be involved in autonomic function R15602CHDDBAFJ. Dopamine terminal axon density is highest in the intermediolateral cell columns of the spinal cord, where preganglionic sympathetic nervous system neurons originate, and microelectrophoretic dopamine application there inhibits sympathetic preganglionic neurons R15602CHDBBCGG. Retrograde labeling has identified caudal lateral hypothalamic area neurons as likely sympathetic nervous system "central command neurons" R15602CHDDJCCC.

Autopsy findings have implicated only the posterior hypothalamus in neuroleptic malignant syndrome R15602CHDCBJCF. Other autopsy results are inconclusive R15602CHDBIAJB or negative R15602CHDCDEAC, R15602CHDBGJBB, R15602CHDCCJDI with respect to hypothalamic pathology.

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Functional Neuropharmacology of the Sympathetic Nervous System

Preganglionic sympathetic nervous system neurons release acetylcholine, but postganglionic sympathetic nervous system neurons release norepinephrine. Exceptions are sudomotor neurons and vasodilator neurons in the muscle, whose postganglionic neurons release acetylcholine, and the adrenal medulla, whose preganglionic neurons release norepinephrine R15602CHDEAFFC, R15602CHDBIDGA. Norepinephrine acts only within the neuroeffector junction into which it is released R15602CHDBFIFF. Plasma norepinephrine levels reflect overflow from sympathetic nervous system neuroeffector junctions, and there is good correlation between muscle sympathetic nerve activity and plasma norepinephrine levels R15602CHDEADJA. Norepinephrine promotes its own release by means of prejunctional β-adrenoceptors; at higher concentrations it inhibits its own release by means of prejunctional α-adrenoceptors R15602CHDDBCAF. Trains of high frequency action potentials may cause norepinephrine to accumulate, potentiating its functional effects R15602CHDDCHJG. Symptoms of norepinephrine toxicity include anxiety, pallor, and intense diaphoresis R15602CHDBIGCE.

Epinephrine is the major catecholamine produced by the adrenal medulla; in contrast to norepinephrine, it is released into the circulation and acts at distant receptor sites R15602CHDBFIFF. Symptoms of epinephrine toxicity include fear, anxiety, tenseness, restlessness, tremor, weakness, dizziness, pallor, respiratory difficulty, and palpitations R15602CHDBIGCE. Norepinephrine constitutes no more than 20% of the catecholamine content of the adrenal medulla R15602CHDBIGCE, and epinephrine has no significant activity at sympathetic nerve endings R15602CHDBFIFF.

Norepinephrine activates predominantly α- and β1-adrenoceptors R15602CHDDEDBI and is more potent at α1 than α2 receptors R15602CHDBBCIA. Epinephrine is active primarily at β-adrenoceptors R15602CHDDEDBI and is much more potent than norepinephrine at β2 receptors, where norepinephrine has minimal activity R15602CHDCCAGC. Second messengers for adrenoceptors are adenylate cyclase (activated by β, inhibited by α2) and intracellular Ca2+ (increased by α1) R15602CHDDBJGG. Adrenoceptors in smooth muscle and glands are predominantly α1R15602CHDCJFJD, whereas vasodilator β2-adrenoceptors in skeletal muscle normally predominate over vasoconstrictor α-adrenoceptors R15602CHDCCAGC. Skeletal muscle contractility is increased by β2-adrenoceptors R15602CHDCCAGC, and cardiac rate and contraction strength are both increased by β-adrenoceptors R15602CHDBIDGA. A newly identified β-adrenoceptor subtype, β3, promotes lipolysis and plays a functional role in sympathetically induced thermogenesis R15602CHDBBCIA, R15602CHDECCJH.

High levels of D2 receptor mRNA are expressed in the normal adrenal gland R15602CHDBACFA and increased in human pheochromocytoma tissue R15602CHDDHEID. In animals, D2 agonists inhibit catecholamine release from adrenal glands, and D2 presynaptic receptors located on norepinephrine nerve terminals inhibit norepinephrine release if activated during nerve stimulation R15602CHDBDFCD. In humans, D2 agonists cause inhibition of sympathetic output that is abolished by D2 antagonists, but only at higher degrees of sympathetic stimulation R15602CHDBDFCD. These data are consistent with previously discussed anatomical evidence for dopaminergic inhibition of sympathetic nervous system function and indicate that state-dependent factors mediate D2 antagonist effects.

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Hierarchical and Regional Organization of the Sympathetic Nervous System

The functional components of the sympathetic nervous system exhibit considerable autonomy. For example, sympathetic vasoconstrictor pathways are distinct from pilomotor and visceromotor pathways and can be activated differentially R15602CHDCFFID. In cats, vasoconstrictor pathways for skin and muscle are independent of one another R15602CHDDIJFC and exercise-induced sympathetic discharge is regulated differently in the kidney and muscle R15602CHDCEEAF. Individual peripheral sympathetic nerves exhibit a high degree of coherence at rest but respond uniquely to experimentally induced cerebral ischemia, indicating that sympathetic nervous system circuits can convert a generalized excitatory stimulus into specific and desynchronized discharge patterns R15602CHDCIGFJ.

Sympathoadrenomedullary responses also vary according to stressor: some stressors increase sympathetic nervous system activity but not adrenomedullary secretion, and others have the opposite effect R15602CHDCEGII. Moreover, sympathetic nervous system outflows to different organs vary depending on the nature and intensity of the stressor R15602CHDCEGII. Autonomous and uncoordinated activity of sympathetic nervous system functional components following disruption of regulatory (hierarchical) inputs, coupled with varying affinities of norepinephrine and epinephrine for diverse and widely distributed adrenoceptor subtypes, could account for many of the clinical features of neuroleptic malignant syndrome, including its fluctuating course.

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The Biochemistry of Mammalian Thermogenesis

The two principal sources of thermogenesis in mammals are uncoupled oxidative phosphorylation in mitochondria and the contractile apparatus of skeletal muscle.

Brown adipose tissue is specialized to generate large amounts of heat rapidly, a process referred to as "nonshivering thermogenesis." Brown adipose tissue is rich in mitochondria containing uncoupling protein, which permits respiratory chain oxidation to liberate energy in the form of heat R15602CHDBFBEI. Norepinephrine is a major regulator of uncoupling protein synthesis R15602CHDDICFC, R15602CHDBEIID but may also have a direct thermogenic effect on brown adipose tissue R15602CHDBEIID. Hypertrophy of brown adipose tissue and increased uncoupling protein synthesis have been induced in the skeletal muscle of mice following 2 weeks of treatment with a β3 agonist R15602CHDDBDHE.

The contraction-relaxation cycle of skeletal muscle tissue is another important thermal energy source in mammals; the term for heat generated by the contractile apparatus is "shivering thermogenesis." Contraction is initiated when Ca2+ is released from its intracellular storage site in the sarcoplasmic reticulum and binds to contractile proteins (mainly troponin) in the sarcoplasm. Relaxation begins when intracellular [Ca2+] reaches a critical level, terminating further Ca2+ release and activating Ca2+ reuptake pumps in the sarcoplasmic reticulum membrane to move Ca2+ from sarcoplasm to sarcoplasmic reticulum against a steep gradient.

Ca2+ release from the sarcoplasmic reticulum, Ca2+ binding to troponin, Ca2+ reuptake by the sarcoplasmic reticulum, and the oxidative chemical reactions of the postcontraction recovery phase all produce heat R15602CHDBAEGE, and intracellular Ca2+ transport plays a role in normal thermogenesis R15602CHDDBDIC. Intracellular free [Ca2+] regulates contraction-relaxation R15602CHDCHEDB, and agents that lead to sustained elevation of sarcoplasmic [Ca2+] can induce persistent contraction in the absence of an action potential R15602CHDBAEGE. Creatine phosphokinase participates in regenerating high-energy cellular stores during the relaxation phase R15602CHDCHEDB and is an integral component of intracellular energy metabolism.

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The Hierarchical Organization of Normal Mammalian Thermoregulation

Homeothermy evolved as existing physiological reflexes were recruited for thermoregulatory functions, gradually creating a hierarchically organized collection of parallel subsystems, each of which regulates its phylogenetic predecessor. The neutral zone, defined as the body temperature range within which no thermoeffectors (heating or cooling reflexes) are activated, narrows progressively at each level of this hierarchy, so there is an illusion of a single fixed set point (in humans, about 98.6˚F) R15602CHDBBIFJ. However, homeothermy represents the interaction of two separate groups of neurons—warm-sensitive and cold-sensitive R15602CHDBJFCI. Warm sensitivity is mediated primarily by temperature-sensitive membrane ion conductances R15602CHDDCBCG, whereas cold sensitivity requires intact local synaptic networks R15602CHDDCBCG, R15602CHDDFAEJ. Warm-sensitive neurons activate cold effectors (e.g., sweat glands) to lower body temperature, and cold-sensitive neurons activate warm effectors (e.g., brown adipose tissue) to raise body temperature. Warm and cold effectors are never activated simultaneously by an intact thermoregulatory system R15602CHDBJFCI.

Thermoregulation can be dissociated in a variety of ways. The neurotoxin capsaicin disables heat-defense responses but leaves cold-defense responses intact R15602CHDBBEFI. Shivering and nonshivering thermogenesis are modulated separately following CNS lesion, and stimulation of the hypothalamus and spinal cord by opposing temperatures produces mutually independent and antagonistic thermoeffector (heating and cooling) responses R15602CHDBBIFJ. Almost all thermoeffectors also serve nonthermoregulatory functions, so competition between thermal and nonthermal drives is likely R15602CHDBBEFI, R15602CHDDEFID. Thermosensitive neurons in the hypothalamus are very sensitive to emotional and behavioral inputs, and their response is determined by perturbation magnitude rather than hedonic attributes R15602CHDBBEFI. Sympathetic nervous system activity in human skin is increased by mental stress as well as thermal inputs R15602CHDDEFJD, and many dorsal horn spinal neurons are excited by both mechanical and thermal stimuli R15602CHDCAHGF. Emotional fever is provoked by restraint or novel stimuli in some species, and anticipation can elevate body temperature in humans. These are true fevers in that they result from coordinated thermoeffector function (heat effectors turned on, cold effectors turned off) R15602CHDBABEE, R15602CHDBDABE.

Stimulation of the preoptic hypothalamus can induce fever, but this structure is not essential because fever is under the control of multiple CNS structures R15602CHDBABEE. The mammalian spinal cord has thermosensory and thermoregulatory properties R15602CHDDIJFC, but only extreme changes in body temperature elicit thermoregulatory responses in the absence of the hypothalamus R15602CHDBBIFJ. Humans with spinal cord transections have wider core temperature fluctuations R15602CHDBDABE, and subjects with complete cervical cord transections have increased core temperatures despite preserved regional heat-induced sweating R15602CHDCJAFC. Some capacity for thermoregulation is preserved when hypothalamic regulatory inputs are interrupted, so hypothalamic dysfunction alone cannot explain the extreme hyperthermia sometimes encountered in neuroleptic malignant syndrome.

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CNS Dopamine and Mammalian Thermoregulation

It is widely believed that central dopamine receptor antagonism within the hypothalamus is necessary for neuroleptic malignant syndrome to occur, but the thermoregulatory role of dopamine is more complex. d-Amphetamine (an indirect dopamine agonist) produces hypothermia or hyperthermia in rats, depending on the ambient temperature, apparently by way of independent pathways R15602CHDCDDFD, R15602CHDDIBCJ. Acutely and chronically reserpinized rats demonstrate a reciprocal and state-dependent D1-D2 receptor interaction in their thermoregulatory responses R15602CHDCECHA. Neuroleptic malignant syndrome has followed neuroleptic dose reduction R15602CHDCEJDI, discontinuation R15602CHDCAEJI, and long-term stable dosing R15602CHDCBABC. Also, there is a report of severe extrapyramidal symptoms and hypothermia with fluphenazine, followed by rebound hyperthermia when this drug was discontinued R15602CHDBGBFA. Body temperature is highly correlated with plasma prolactin in thermally stressed men R15602CHDCDCHH, suggesting that normal heat defense is associated with decreased central dopamine, and intraventricular haloperidol produces a coordinated heat-defense response R15602CHDDGBDH. These reports refute a unique or essential role for central dopamine antagonism in neuroleptic malignant syndrome hyperthermia and provide additional evidence that state-dependent factors are important mediators of dopamine antagonist effects.

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The Role of the Sympathetic Nervous System in Normal Muscle Function

The sympathetic nervous system plays an integral role in normal muscle function. Force is potentiated by β-adrenoceptor agonists in mammalian skeletal muscle, and adrenoceptors on skeletal myocyte membranes are predominantly β2R15602CHDDFBHA, indicating that epinephrine normally is directly involved in regulating skeletal muscle contraction. In skeletal and heart muscle fibers, β-adrenoceptor agonists promote phosphorylation of Ca2+ channels, increasing the probability of their being open R15602CHDCABFH. Epinephrine increases contraction strength by way of this altered Ca2+ influx R15602CHDCABFH, apparently by increasing the amount of Ca2+ released from the sarcoplasmic reticulum into sarcoplasm during activation R15602CHDBAAAG. Epinephrine-induced Ca2+ influx by way of myocyte membrane channels also increases intracellular [Ca2+], and the same effect is seen with the α1-adrenoceptor agonist phenylephrine R15602CHDBAAAG. Liver Ca2+ homeostasis and muscle Ca2+ homeostasis are similar, and norepinephrine induces a sustained rise in hepatocellular [Ca2+] R15602CHDDBDIC. In rabbits, α1-adrenoceptor agonists cause dose-dependent increases in peak skeletal muscle tension R15602CHDBHIDA. Thus, norepinephrine and epinephrine are both potent activators of skeletal muscle and exert this effect by altering intracellular [Ca2+].

Norepinephrine has similar effects on smooth muscle. In rabbits, norepinephrine triggers Ca2+-induced Ca2+ release R15602CHDBGCHE, a process whereby a large amount of Ca2+ is released from the sarcoplasmic reticulum in response to a much smaller amount of Ca2+ outside the sarcoplasmic reticulum R15602CHDCFDHH. Norepinephrine-induced Ca2+ release can activate smooth muscle contraction fully R15602CHDDDGEE, and in guinea pig myocytes, norepinephrine produces spontaneous Ca2+-induced transmembrane electrical transients that can cause depolarization R15602CHDCAGEG. Ca2+-induced Ca2+ release is responsible for caffeine-induced contractures in skeletal muscle R15602CHDBFBCD.

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The Role of the Sympathetic Nervous System in Normal Mammalian Thermoregulation

All thermoeffector activity is regulated by the sympathetic nervous system. Both the sympathetic nervous system and the adrenal medulla are capable of preventing fatal hypothermia when the other is incapacitated R15602CHDEBDII. Norepinephrine is the primary regulator of brown adipose tissue metabolic activity and growth R15602CHDDJCCB, and norepinephrine also stimulates hormone-sensitive lipase, the principal lipolytic enzyme in white adipose tissue R15602CHDEBDII. Persistent β-adrenergic stimulation induces brown adipose tissue hypertrophy and accelerated uncoupling protein gene transcription in rats R15602CHDDBDHE, and although brown adipose tissue is probably not a major thermogenic tissue in man R15602CHDEBDII, it does persist throughout adulthood R15602CHDBHEAE and can be reactivated following intense sympathetic stimulation (e.g., in cold acclimation or by a pheochromocytoma) R15602CHDDJCCB. Repeated norepinephrine infusions potentiate thermogenesis in humans R15602CHDEBHBA.

Uncoupling protein synthesis can be induced in rat skeletal muscle following persistent adrenergic stimulation R15602CHDDBDHE, and skeletal muscle is the primary site of sympathomimetic-induced thermogenesis in humans R15602CHDBHEAE. Catecholamine-induced increases in intracellular [Ca2+] generate heat because chemical-mechanical transduction efficiency is low R15602CHDCGGDJ. Salbutamol, a selective β2-adrenergic agonist, is thermogenic in humans R15602CHDECFIH. Ephedrine, a mixed α- and β-adrenoceptor agonist, has a potent thermogenic effect in humans R15602CHDBHEAE that is mediated by norepinephrine and probably involves β3-adrenoceptors R15602CHDECCJH. Isoproterenol, a nonselective β-adrenoceptor agonist, substantially increases the metabolic rate in humans, apparently through β1- and β3-adrenoceptors R15602CHDCDIGB. In one mammal, norepinephrine substantially increases skeletal muscle thermogenesis through α1-adrenoceptors, independent of uncoupling protein R15602CHDCIJDI.

Nonsteroidal anti-inflammatory agents are ineffective against the hyperthermia of neuroleptic malignant syndrome, and dantrolene provides only inconsistent benefit, so it is worth noting that both indomethacin and dantrolene fail to inhibit phenylephrine-stimulated thermogenesis in small mammals R15602CHDCIJDI. These treatments would not be expected to reverse hyperthermia caused by a hyperadrenergic state in which unregulated thermogenesis, due to uncoupled phosphorylation and/or disrupted intracellular Ca2+ homeostasis, predominates.

The following general principles should now be evident:

  • Hierarchically organized thermoregulatory centers are located at all levels of the CNS.

  • The sympathetic nervous system is intimately involved in all aspects of thermoregulation.

  • The sympathetic nervous system consists of potentially autonomous components whose functions are normally coordinated and integrated by the hypothalamus, but which function independently when these regulatory inputs are disrupted.

  • Dopamine antagonists interrupt tonic inhibitory modulation of sympathetic nervous system function at the spinal cord level, an effect that is most evident when the sympathetic nervous system is hyperactive.

  • Sympathetic nervous system hyperactivity is associated with intense emotional stress and frontal cortical dysfunction.

  • The sympathetic nervous system can augment or initiate skeletal muscle contractile activity by means of adrenoceptor-mediated increases in intracellular Ca2+ levels.

The following sections explore the role of sympathetic nervous system hyperactivity in the clinical presentation of neuroleptic malignant syndrome. Again, the reader will find F1 helpful in following the discussion.

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Neuroleptic Malignant Syndrome Risk Factors

Organic brain disease is a risk factor for neuroleptic malignant syndrome R15602CHDCIBGD, R15602CHDCGFFCR15602CHDBIJBC and for increased morbidity and mortality from this disorder R15602CHDCFCIG, R15602CHDBJJEG. Mental retardation is relatively frequent among cases of neuroleptic malignant syndrome R15602CHDCIBGD, R15602CHDBIAJB, R15602CHDCCEBG, and in one small series the most severe syndrome was associated with bilateral frontal lesions R15602CHDBCDGA. Catatonia, considered a harbinger of neuroleptic malignant syndrome by some R15602CHDBBGGD, is likely a frontal lobe syndrome R15602CHDBDHFI, R15602CHDCIJEE.

Affective illness is another risk factor for neuroleptic malignant syndrome R15602CHDBIJBC, R15602CHDBJJEG, R15602CHDEAIAE, R15602CHDBDHIH. Sympathetic nervous system activity is increased in major depression R15602CHDBIAFB; the relative contributions of the sympathetic nervous system and adrenomedullary components vary by depression subtype R15602CHDDJIHJ. In manic patients, adrenomedullary activity is associated with affective and behavioral symptoms but sympathetic nervous system activity is correlated more strongly with agitation R15602CHDBDBFI. Rhabdomyolysis has been observed in mania R15602CHDEBIJE. Plasma catecholamines and their metabolites are elevated in periodic catatonia R15602CHDCJCGG, R15602CHDCACIB, which may be a variant of bipolar disorder R15602CHDBDHFI and bears a strong clinical resemblance to neuroleptic malignant syndrome.

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Illness Onset and Course

The temporal pattern in which specific features of neuroleptic malignant syndrome emerge is inconsistent across cases R15602CHDBJJEG, R15602CHDBCDGA, R15602CHDCCEHE, but autonomic hyperactivity is often the earliest clinical finding. Although fulminant neuroleptic malignant syndrome may present suddenly, more often the course is indolent, with unexplained episodic tachycardia and blood pressure fluctuations observed early on R15602CHDCCEHE. In particular, elevated diastolic blood pressure may be antecedent R15602CHDDBHDD. In the prodrome that frequently precedes a full-blown syndrome R15602CHDBHJHD, dysautonomic features typically predominate R15602CHDBJJEG, R15602CHDCHADH, R15602CHDBHJBF. Dysautonomia can appear without hyperthermia R15602CHDDJADC or precede hyperthermia R15602CHDCAEJI, R15602CHDDBHDD, R15602CHDBHJBF, R15602CHDCDIDF, which sometimes emerges relatively late R15602CHDBCDGA, R15602CHDCCEHE. Individual differences in the rates of catecholamine release and clearance, which are the primary determinants of their physiological effect R15602CHDEBACI, may contribute to the variability of the clinical course. Opposing effects of α- and β-adrenoceptor stimulation, as well as differing affinities of epinephrine and norepinephrine for these receptors, provide additional sources of variability in clinical presentation over time.

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Major Clinical Features

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Altered mental status

Altered consciousness is considered by some R15602CHDBEFFI to be a sine qua non for the diagnosis of neuroleptic malignant syndrome. In one relatively large series R15602CHDBIJBC, "a striking, frightened facial expression was observed in all cases," accompanied by "a sense of doom" and "overwhelming anxiety" (p. 719). Tollefson R15602CEBBGBDJ described a mute and akinetic patient with neuroleptic malignant syndrome as having "an exaggerated startle response." Catatonic patients retrospectively report intense, uncontrollable anxieties R15602CHDCIJEE. Healthy volunteers viewing a frightening film have increased plasma norepinephrine, but their other catecholamine and endocrine levels are normal R15602CHDBHFIB. Psychological stress is positively correlated with plasma vanillylmandelic acid but not 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, or 5-hydroxyindoleacetic acid, suggesting that the sympathetic nervous system is activated more by transient emotional stress than by persistent emotional conditions R15602CHDBFGED.

Acute, but not subacute or chronic, psychosis and Brief Psychiatric Rating Scale scores indicating global psychopathology and anxiety are positively correlated with serum creatine phosphokinase levels R15602CHDCICCE. Catatonic excitement has been promoted as a highly reliable risk factor for neuroleptic malignant syndrome R15602CHDBBGGD, and labile mood and insomnia consistently precede lethal catatonia R15602CHDBCGHB. "Emotional disturbance" can trigger hyperthermia and many of the clinical features usually associated with neuroleptic malignant syndrome R15602CHDBGGGG, as can acute phencyclidine-induced psychosis R15602CHDCCHFF. Intense emotional or psychological disturbance, with altered frontal cortical function, could be a pathophysiological link between these syndromes and neuroleptic malignant syndrome.

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Dysautonomia

Diaphoresis is common in neuroleptic malignant syndrome R15602CHDBCGHB, with rates from 50% to 100% R15602CHDBIJBC, R15602CHDBJJEG, R15602CHDEAIAE, and is due to direct sympathetic nervous system stimulation rather than circulating catecholamines R15602CHDEAFFC, R15602CHDBIDGA. In contrast to its role in true fever, diaphoresis in neuroleptic malignant syndrome is not part of a coordinated effort to lower body temperature R15602CHDBFFAE. Eccrine sweat glands are the only mammalian organs with a purely thermoregulatory function R15602CHDBBEFI and have the capacity to dissipate heat faster than it can be generated R15602CHDDGGJB, so hyperthermia in neuroleptic malignant syndrome implicates a defective heat-loss mechanism in addition to any increase in thermogenesis. Excessive sweat gland activity is probably responsible for neuroleptic-malignant-syndrome-associated dehydration in some cases R15602CHDBHCGF, and dehydration may contribute to hyperthermia.

Tachypnea and tachycardia in neuroleptic malignant syndrome reflect a hyperadrenergic state, but increased metabolism makes additional demands on the cardio­pulmonary system. In one drug-induced syndrome similar to neuroleptic malignant syndrome, body temperature increased in tandem with blood pressure and heart rate R15602CHDCBCII, and body temperature accounts for as much as 16% of the respiratory rate variance in neuroleptic malignant syndrome R15602CHDBFFAE.

Urinary incontinence is another clinical manifestation of autonomic dysfunction in neuroleptic malignant syndrome. The bladder base and internal sphincter consist of smooth muscle innervated exclusively by predominantly α-adrenergic sympathetic nervous system fibers. Voluntary restraint of micturition requires the frontal lobes, and lesions in either hemisphere can cause bladder incontinence R15602CHDEAFFC, R15602CHDDEFJD. In spinal cord patients, diaphoresis and bladder incontinence are associated with flexor spasms of the lower extremities, suggesting an intrinsic relationship among these motor responses R15602CHDCJAFC.

Catecholamine excess alone can produce a syndrome similar to neuroleptic malignant syndrome, as illustrated by the case of a 34-year-old woman who experienced the sudden onset of palpitations, inability to move or speak, and labile postural tachycardia and hypertension R15602CHDCACIB. Mutism, increased muscle tone, hyperactive tendon reflexes, and catalepsy were reproduced reliably by physical activity and anxiety-pro­voking situations and were always associated with hypertension and tachycardia. Plasma epinephrine and norepinephrine were markedly elevated and correlated with amount of time upright, but urine 24-hour catecholamine and monoamine metabolite levels were normal. She was found to have a hyperactive sympathetic response and peripheral α1-adrenoceptor subsensitivity R15602CHDCACIB.

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Hyperthermia

Hyperthermia can occur when the heat-loss apparatus is defective or when intact thermoeffectors are poorly coordinated. The ineffectiveness of diaphoresis, normally a potent cold effector, in neuroleptic malignant syndrome has already been discussed. The simultaneous activation of both warm and cold effectors in neuroleptic malignant syndrome indicates that although thermoeffectors remain operational, their activities are not coordinated R15602CHDCBABC, R15602CHDBFFAE, R15602CHDCJHCD. This condition alone would be sufficient for hyperthermia to supervene, but in addition there are two likely sources of excess thermogenesis in neuroleptic malignant syndrome: accelerated brown-adipose-tissue-like metabolism (uncoupled phosphorylation) and excessive catecholamine-induced Ca2+ release from the sarcoplasmic reticulum.

Persistent stimulation of sarcoplasmic reticulum Ca2+ release would lead to continuous activation of Ca2+ reuptake mechanisms, releasing heat as a by-product. This could account for the observation that serum creatine phosphokinase levels are positively correlated with 24-hour urinary catecholamine metabolite excretion in neuroleptic malignant syndrome R15602CHDCEEEG. The appearance of elevated muscle enzyme levels in neuroleptic malignant syndrome before clinical signs of autonomic instability are evident indicates that hyper­metabolism may precede the full syndrome R15602CHDDFDCE. Hypermetabolism related to hyperthyroidism, in the absence of central dopamine blockade, can produce a syndrome similar to neuroleptic malignant syndrome R15602CHDDDFCG.

Peripheral catecholamines also directly stimulate uncoupled phosphorylation in mitochondria, as occurs in some cases of pheochromocytoma, cold exposure, and treatment with sympathomimetic agents. As in these other examples, prolonged elevation of peripheral catecholamine levels in neuroleptic malignant syndrome may even lead to induction of uncoupling protein mRNA and increased thermogenic tissue mass, suggesting a possible physiological basis for persistent hyperthermia during recovery from neuroleptic malignant syndrome. This thermogenic mechanism is distinct from that related to intracellular Ca2+ homeostasis. Hyperthermia in neuroleptic malignant syndrome can be dissociated from muscle rigidity R15602CHDBIAJB, R15602CHDCAGGD and creatine phosphokinase levels R15602CHDBGEAF, precede extrapyramidal signs R15602CHDCHADH, and persist despite curar­ization-induced flaccidity R15602CHDBIAJB. The lack of glycogen and lipid stores in muscle biopsies strongly suggests that uncoupled phosphorylation contributes to hyperthermia in neuroleptic malignant syndrome R15602CHDCEJEB.

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Rigidity, elevated creatine phosphokinase, and rhab­­do­­myolysis

Asymptomatic creatine phosphokinase elevations occur in patients with psychotic disorders, whether clinically stable or acutely ill, following oral treatment with typical or atypical neuroleptics R15602CHDCFCEHR15602CHDCAABC. Clozapine is associated with more frequent and higher creatine phosphokinase elevations than are typical neuroleptics R15602CHDCAABC; this is noteworthy because cloza­pine has significantly greater α2-adrenoceptor activity R15602CHDBCDBE, which is probably the cause of de novo diabetes mellitus in clozapine-treated patients R15602CHDECCEF. Substantial creatine phosphokinase elevations accompanied only by tachycardia and elevated blood pressure may follow neuroleptic treatment R15602CHDDGHEJ, suggesting a hypermetabolic effect mediated by the sympathetic nervous system.

Cardiac lesions caused by elevated catecholamines are indistinguishable from atherosclerotic lesions R15602CHDDJHFA. Short-term hypoxia permits creatine phosphokinase-MB to escape without necrosis R15602CHDBFCCC, and intravenous isoproterenol causes elevated creatine phospho­kinase-MB in childhood asthmatics R15602CHDEBHCF. Elevated creatine phosphokinase and focal skeletal myositis occur in pheochromocytoma R15602CHDBAFBD, which releases mainly norepinephrine R15602CHDEBACI. Ischemia mediated by catecholamine-induced vasoconstriction in skeletal muscle is probably the cause of muscle injury in pheochromocytoma R15602CHDDDIBI. Creatine phosphokinase elevations and myoglobinuria in neuroleptic malignant syndrome may exist without rigidity or tremor R15602CHDCHECJ, and haloperidol-induced rhabdomyolysis is associated with autonomic dysfunction but not rigidity R15602CHDBJBHH.

Urinary catecholamines and catecholamine metabolites are positively correlated with blood creatine phosphokinase levels in acute neuroleptic malignant syndrome, but other clinical features are not R15602CHDCEEEG. In patients with neuroleptic malignant syndrome, serum creatine phosphokinase covaries nonlinearly with other muscle enzymes and exceeds by as much as 15-fold the normal extracellular-intracellular gradient, indicating that muscle necrosis alone cannot account for elevated creatine phosphokinase levels R15602CHDEAJIA. Experimental tissue injury models suggest that increased enzyme synthesis represents a reparative response to a noxious agent R15602CHDDAEIC. The noxious event in neuroleptic malignant syndrome could be a relative hypoxia created by a metabolism-perfusion mismatch caused by a hyperactive and unregulated sympathetic nervous system.

Catecholamine-induced Ca2+ release from the sarcoplasmic reticulum may also cause cell death R15602CHDCFCGE. Focal myocardial necrosis occurs in patients with pheochromocytoma R15602CHDEAADE, in rats infused with epinephrine and norepinephrine R15602CHDDJHFA, and in dogs infused with inotropic amines R15602CHDBEBAI. Muscle necrosis in these settings is apparently due to a direct effect of catecholamines on Ca2+ influx R15602CHDCABFH, R15602CHDEAADE. Oxidation of excess catecholamines to catecholamine-O-quinones, with subsequent formation of superoxide radicals that attack cellular membrane and protein constituents essential to energy metabolism, is another mechanism by which excess catecholamines can damage myocytes R15602CHDBADAI.

Muscle biopsy findings in patients with neuroleptic malignant syndrome have yielded minimal or inconsistent results (compare references R15602CEBBGBDJ and R15602CHDBEBGF with references R15602CHDBGJBB, R15602CHDBEFFI, R15602CHDCEJEB, and R15602CHDBDGCD. Muscle abnormalities that have been detected in neuroleptic malignant syndrome resemble those found in malignant hyperthermia R15602CHDBDGCD or consist of endomysial edema with a striking absence of both glycogen and lipid substrate stores R15602CHDCEJEB. Profound depletion of intracellular energy stores strongly implicates uncoupled phosphorylation as the source of hyperpyrexia R15602CHDCEJEB, and the resemblance to malignant hyperthermia in these cases implicates Ca2+ overload as a common etiological factor. A majority of patients with severe neuroleptic malignant syndrome have documented serum hypocalcemia R15602CHDBIJBC, which could reflect a sudden net influx of Ca2+ into myocytes that coincides with a "malignant" phase of the syndrome.

Extrapyramidal signs associated with neuroleptic malignant syndrome include rigidity, tremor, cogwheeling, dystonia, chorea, dyskinesia, opisthotonos, opsoclonus, and posturing R15602CEBDFHDB, R15602CEBCEJCI, DSM-IV). As the data presented here indicate, rigidity in neuroleptic malignant syndrome could be caused by catecholamine-induced changes in intracellular [Ca2+], and tremors could also reflect elevated peripheral catecholamines. Increased muscle tone caused by sympathetic nervous system hyperactivity is independent of, but may coexist with, effects of neuroleptics on the extrapyramidal system, and the presence of more complex motor signs implicates concomitant basal ganglia involvement in some cases of neuroleptic malignant syndrome.

+

Associated Clinical Findings

Granulocytosis is a feature of neuroleptic malignant syndrome R15602CEBDFHDB, R15602CHDCFCIG, and sympathetic nervous system fibers innervate lymphoid tissue R15602CHDCBACC. Catecholamines stimulate lymphocytes at low concentrations, but at high concentrations they are inhibitory R15602CHDCBACC. Lymphocyte circulation is mediated mainly by plasma membrane β2-adrenoceptors, whereas granulocyte circulation increases are mediated by α-adrenoceptor stimulation R15602CHDDEDBI. An injection of norepinephrine can raise neutrophil levels to two to three times normal R15602CHDCBICE, and increased peripheral norepinephrine turnover is associated with reduced lymphocyte proliferation R15602CHDCCEHH. The net effect of sympathetic nervous system stimulation is leukocytosis with a "shift to the left."

Blood sugar homeostasis is regulated by the sympathetic nervous system and can be impaired in neuroleptic malignant syndrome. A 44-year-old man with no previous history of diabetes mellitus developed neuroleptic malignant syndrome and fatal diabetic ketoacidosis precipitously following a test dose of zuclopen­thixol decanoate R15602CHDDGCDG. Under normal physio­logical circumstances, the sympathetic nervous system tonically suppresses insulin release through α-adrenoceptors R15602CHDCBGBE; stimulation of the pancreatic sympathetic nerve decreases insulin secretion and increases glucagon secretion R15602CHDCBDGH.

Bilateral E coli anterior tibial fasciitis in one case of neuroleptic malignant syndrome R15602CHDBFGBA may have resulted from ischemic muscle necrosis. Noncardiogenic pulmonary edema in neuroleptic malignant syndrome R15602CHDCAIEA could be caused by excess sympathetic nervous system activity because pheochromocytomas can cause pulmonary edema R15602CHDDDIBI. Necrotizing colitis without fever, possibly a result of sympathetic-nervous-system-mediated vasoconstriction, has been attributed to neuroleptic treatment R15602CHDCJAGH, and ischemic bowel followed respiratory failure in another case of neuroleptic malignant syndrome R15602CHDBHJHD. Paralytic ileus in neuroleptic malignant syndrome R15602CHDCGJAJ may be the result of intense sympathetic nervous system activation R15602CHDCCAGC.

The intrinsic capacity of the sympathetic nervous system for fragmented, autonomous activity normally is suppressed by inhibitory regulatory inputs originating in the frontal cortex and mediated by hypothalamic nuclei. The hypothalamus integrates afferent thermosensory information and coordinates thermoeffector responses by means of dopaminergic modulation of preganglionic sympathetic nervous system neurons. Disruption of these inhibitory inputs leads to dysregulated sympathetic nervous system hyperactivity with uncoordinated, excessive stimulation of end-organs by autonomous functional components of the sympathetic nervous system—vasomotor, sudomotor, inotropic, thermogenic, and others. In particular, extreme psychic distress (altered frontal lobe function) or acute dopamine antagonism (of hypothalamospinal tracts) may alter sympathetic nervous system function and lead to profound disturbances of homeostasis. Manifestations of dysregulated sympathetic nervous system hyperactivity include increased muscle metabolism and tone (due to increased intracellular [Ca2+]), of which elevated creatine phosphokinase is one indicator; increased mitochondrial thermogenesis (caused by uncoupled oxidative phosphorylation); ineffective heat dissipation related to unregulated vasomotor and sudomotor activity; fluctuations in vasomotor tone leading to labile blood pressure, flushing, and pallor; granulocytosis; and urinary incontinence.

The inherent autonomy of these circuits permits these effects to be produced independently of one another, but they may interact to destabilize homeothermic and hemodynamic systems, producing the clinical syndrome of neuroleptic malignant syndrome. F1 illustrates how such a pathophysiological cascade might occur. The relative mutual independence of neural and adrenal segments of the sympathetic nervous system, and the differential effects of norepinephrine and epinephrine at adrenoceptors, contribute to the unpredictable course and fluctuating clinical signs and symptoms that characterize this disorder. Direct effects of neuroleptics on extrapyramidal systems may interact with sympathetic nervous system dysfunction to produce the final clinical picture.

Presented in part at the 53rd Annual Scientific Convention of the Society of Biological Psychiatry, Toronto, May 27–31, 1998. Received March 2, 1998; revision received July 30, 1998; accepted Aug. 25, 1998. From the Department of Psychiatry, Harvard Medical School, Brockton-West Roxbury DVA Medical Center. Address reprint requests to Dr. Gurrera, Brockton DVAMC (116A), 940 Belmont St., Brockton, MA 02301; rgurrera@worldnet.att.net (e-mail). Supported by DVA Medical Research Funds.

 
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Figure 1.

Pathophysiology Cascade in Neuroleptic Malignant Syndrome

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Figure 1.

Pathophysiology Cascade in Neuroleptic Malignant Syndrome

+

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