NEUROLOGICAL REVIEW

SECTION EDITOR: DAVID E. PLEASURE, MD Movement Disorders Emergencies Part 1 Hypokinetic Disorders

Bradley J. Robottom, MD; William J. Weiner, MD; Stewart A. Factor, DO

ovement disorders usually do not require emergent intervention; nevertheless, there are acute/subacute clinical settings in which the neurologist is consulted. It is in these circumstances that the neurologist must be prepared to accurately diagnose and properly treat the patient. We have reviewed the literature regarding move- mentM disorder emergencies and divided them into hypokinetic (part 1) and hyperkinetic (part 2) presentations. In part 1, drug-induced including neuroleptic malignant , par- kinsonism hyperpyrexia syndrome, and syndrome will be discussed. Emergency com- plications related to the management of Parkinson , including falling, motor fluctuations, and psychiatric issues, will also be reviewed. Arch Neurol. 2011;68(5):567-572

Movement disorders often have an insidi- DRUG-INDUCED MOVEMENT ous onset and slow progression and are not DISORDER EMERGENCIES often associated with emergency situa- tions. However, neurologists may be called Neuroleptic Malignant Syndrome on to diagnose and treat evolving move- ment disorders or acute complications of Neuroleptic malignant syndrome, first de- existing in the emergency depart- scribed in 1960,2 is an iatrogenic disorder re- ment or intensive care unit. Such situa- sulting from exposure to drugs that block tions meet the working definition of an receptors. While most cases are “emergency,” a rapidly evolving disorder caused by neuroleptics (both typical and (hours to days) in which the failure to di- atypical,evenclozapine),3-6 othermedications agnose and treat may lead to significant such as , morbidity or mortality.1 This review is di- hydrochloride, droperidol, and prometha- vided into 2 parts based on phenomenol- zine hydrochloride are also implicated.7 ogy, hypokinetic and hyperkinetic disor- Diagnostic criteria integrating clinical and ders, and it discusses rapidly evolving laboratory features (Table 1) have been de- situations that require emergency inter- veloped.8 Because the incidence of NMS is vention. A number of the disorders dis- low, 0.2%,9 a high index of suspicion is nec- cussed are rare. Data regarding preva- essary to make the appropriate diagnosis. lence and incidence have not been Neuroleptic malignant syndrome is impor- evaluated. In part 1, we review hypoki- tant to consider in any patient with acute- netic disorders including the drug- onset and because it is induced emergen- life threatening (mortality rate of 5%-20%). cies neuroleptic malignant syndrome Young and middle-aged men appear to be at (NMS), parkinsonism-hyperpyrexia syn- higher risk.10 drome (PHS), and Neurolepticmalignantsyndromeisaclini- (SS) as well as emergent complications of calsyndromecomprisingfever,rigidity,men- Parkinson disease (PD). talstatuschange,autonomicdysfunction,and other movement disorders (, dysto- Author Affiliations: Department of , University of Maryland School of nia, and ) (Figure 1). Key labo- Medicine, Baltimore (Drs Robottom and Weiner); and Movement Disorders ratoryabnormalitiesincludeleukocytosisand Program, Emory University School of Medicine, Atlanta, Georgia (Dr Factor). elevated creatine kinase level. Additionally,

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 acute-phase reactants, including albumin and serum iron drome occurs in patients with PD who abruptly withdraw levels, are decreased.11 Symptoms often begin after initia- or reduce . It was first reported tion or an increase in neuroleptic dose.5 Neuroleptic malig- in the context of abrupt discontinuation of antiparkinso- nant syndrome increases in severity over 48 to 72 hours and nian medications during “levodopa holidays” in the lasts 7 to 14 days. Medical complications can be chronic and 1980s.16,17 While levodopa holidays are no longer recom- irreversible including renal failure from , mended, patient noncompliance or abrupt changes in medi- respiratory failure from decreased chest wall compliance, cation replicate that scenario. Aggressive ad- aspiration pneumonia, and other complications of immo- justments are not uncommon, particularly after deep brain bility such as deep venous thrombosis and pressure ulcers. stimulation surgery in PD. Clinicians must realize that PHS Pulmonaryembolism,pneumonia,orrenalfailuremayresult is a potential complication and that deep brain stimula- in death. tion surgery does not protect the patient from PHS.18 De- No prospective randomized trials exist in NMS. Key steps hydration and metabolic disturbances may also precipi- in treatment include withdrawal of the causative agent and tate it.19 Treatment involves supportive measures and treatmentwithdopaminergicagents.Bromocriptinemesylate reinstituting dopaminergic therapy. and dan- has been used most often and is considered the drug of trolene may be added as additional therapy. High-dose in- choice12; however, other dopaminergic agents are equally travenous methylprednisolone has been proposed as ad- effective. Dantrolene sodium, a nonspecific muscle relax- junctive therapy, and it appears to be effective based on 1 ant, reduces muscular rigidity and minimizes rhabdomyoly- small randomized trial.20 Despite treatment, permanent sisifthedopaminergicagentdoesnotreversethesymptoms.13 worsening of PD and fatalities have been reported.21 Combinationtherapyhasbeenfoundtobesafeandeffective,12 and treatment should continue for 7 to 10 days depending Serotonin Syndrome on the half-life of the causative agent. One-third of patients may relapse if neuroleptic treatment is restarted too early, Any drug that enhances transmission can so waiting at least 2 weeks after NMS has cleared is good prac- precipitate SS, which has the core clinical features of fe- tice.14 In patients who require immediate treatment of psy- ver, myoclonus, and altered mental status.22 Serotonin chosis, electroconvulsive therapy has been successful.15 syndrome was first described in 1960 in patients receiv- ing inhibitor monotherapy23 but is Parkinsonism-Hyperpyrexia Syndrome now encountered in patients taking 2 or more drugs with serotonergic actions (tricyclic or selec- Parkinsonism-hyperpyrexia syndrome may be indistin- tive serotonin reuptake inhibitors in combination with guishable from NMS except that it occurs in patients with nonselective monoamine oxidase inhibitors)24 (Table 2). preexisting parkinsonism. Parkinsonism-hyperpyrexia syn- Many of the clinical features overlap with NMS (Table 3); however, SS may have additional clinical features such as myoclonus, , , and mood alter- Table 1. Diagnostic Criteria for Neuroleptic ation (restlessness, elevated mood).26 This overlap may a Malignant Syndrome relate to the impact elevated serotonin levels have on low- ering dopamine levels. Treatment consists of discontinu- Criteria Feature ation of the causative agent, supportive therapy, and Major Fever, rigidity, and elevated creatine kinase level hydrochloride for severe cases. Cypro- Minor , abnormal , tachypnea, heptadine, an antihistamine and serotonin antagonist, is altered consciousness, diaphoresis, and leukocytosis given in divided doses up to a maximum dose of 32 mg/ d.27 Serotonin syndrome may resolve quickly25 or is po- a The presence of all 3 major, or 2 major and 4 minor, criteria indicates a high likelihood of neuroleptic malignant syndrome in the appropriate clinical tentially fatal. Like NMS and PHS, the rarity and seri- context. ousness of SS precludes large randomized trials.

A B

Figure 1. Jaw-opening (trismus) (A) and hand dystonia (B) secondary to neuroleptic malignant syndrome.

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 2. Drugs Reported to Cause Serotonin Syndrome Table 3. Comparison of Neuroleptic Malignant Syndrome and Serotonin Syndromea Drug Neuroleptic Serotonin Monoamine oxidase inhibitors Malignant Syndrome Syndrome Selective serotonin reuptake inhibitors Serotonin- reuptake inhibitors Onset Acute Subacute (days) Tricyclic antidepressants (minutes to hours) L- Resolution Gradual (average 9 d) Improves in Ͻ24 h hydrochloride Physical Altered sensorium Altered sensorium Opiates (except morphine) examination (Ͼ90%) (50%) Muscle rigidity Muscle rigidity Ͼ ( 90%) (50%) 3,4-Methylenedioxymethamphetamine (ecstasy) Autonomic Autonomic Ͼ Lysergic acid diethylamide dysfunction ( 90%) dysfunction (50%-90%) (Ͼ90%) Hyperthermia (50%) Hyperreflexia (50%) Myoclonus (50%) Laboratory Elevated creatine Elevated creatine PARKINSONISM abnormalities kinase level (Ͼ90%) kinase level (Ͻ20%) Elevated hepatic Elevated hepatic Emergency Department Admissions in PD transaminase levels transaminase levels (Ͼ75%) (Ͻ10%) Leukocytosis Leukocytosis Parkinson disease is a neurodegenerative disorder charac- (Ͼ90%) (Ͻ15%) terized by tremor, rigidity, bradykinesia, and postural in- 28-30 stability. Three recent studies examined why patients a Adapted from Mills.25 with PD present to emergency departments, and each found similar results. The most common reasons were not dis- ease specific (infectious disease, 21%-32%; cardiovascular/ Table 4. Etiologies of Acute Parkinsonism cerebrovascular, 12%-26%; gastrointestinal, 8%-11%; and metabolic, 2%-6%). Of disease-specific problems, the most Etiology common were trauma/falls (13%-27%), motor fluctuations/ Structural (8%), and psychiatric disturbances (8%). Subdural hematoma Falls in PD Drug induced Neuroleptics As PD progresses, falls become increasingly common, with Antiepileptics up to 70% of patients with advanced PD reporting at least Antidepressants 1 fall per year.31 Postural instability or freezing of gait re- Chemotherapeutic agents sult in up to 80% of falls.32 There is a 3-month fall rate Amiodarone of 46%, with the best predictor of falling being a history Toxic 33 1-Methyl-1-4-phenyl-4-proprionoxypiperidine of 2 or more falls in the previous year. Injuries occur from approximately 25% of falls, with hip fractures a com- Carbon disulfide mon result. Postural instability is not levodopa respon- sive, making treatment a challenge. Physical therapy and Cyanide assistive devices may be preventive. Infectious Motor Fluctuations and Dyskinesia Viral Human immunodeficiency Whipple disease Motor fluctuations are common in advanced PD, seen in Postinfectious 40% of patients by 4 to 6 years, with an increasing fre- Metabolic quency of 10% per year.34 Generally not dangerous, mo- Central pontine myelinolysis tor fluctuations are one of the more common disease- Hereditary specific reasons that patients seek emergency treatment. Wilson disease Rapid-onset dystonia-parkinsonism During “off” periods, prominent rigidity, bradykinesia, and Psychiatric postural instability may develop, making it impossible for Catatonia patients to care for themselves or to walk. Psychiatric fea- Psychogenic tures may become pronounced, including depressed mood, anxiety, and panic. Dysautonomia, including tachycardia, diaphoresis, and variations in blood pressure, may oc- dictable or prolonged off periods) are more likely to seek cur.35 While off periods do not usually result in a visit to urgent evaluation.35 In these situations, investigation should the emergency department, some situations lead to emer- search for a potential cause of the abrupt change. A care- gency evaluation. Patients with suddenly worsening off pe- ful medication history may be necessary to ensure that no riods associated with new symptoms (eg, freezing, unpre- changes have been made to the antiparkinsonian regi-

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Figure 2. T2-weighted axial magnetic resonance image demonstrating hyperintensity in the pons (A) and (B) (central and extra pontine myelinolysis) of a patient with acute parkinsonism.

men. Patients should also be questioned about the addi- nations and usually consist of complex, formed visual im- tion of medications to their regimen, particularly dopa- ages, often of unknown but nonthreatening people.42 Para- mine receptor blockers ( and antiemetics). noid delusions may accompany and Concurrent infection (urinary tract infection, pneumo- constitute a greater threat. Hallucinations and mild de- nia) or metabolic derangement should be considered. In a lusions may be treated at home; paranoia may become patient with falls and abruptly worsening PD, subdural he- extreme and require hospitalization. Parkinson disease matoma should be considered.36 psychosis may be precipitated by metabolic derange- Dyskinesia is usually not dangerous and is most of- ments, infections (urinary tract infection, pneumonia), ten managed in the outpatient setting. However, severe and changes in drug therapy including addition of any dyskinesia may lead to rhabdomyolysis and dehydra- or . tion.35 Generalized may be complicated by Emergency treatment of psychosis requires a multi- involvement of respiratory muscles, with patients report- faceted approach. The patient’s living conditions need to ing symptoms of dyspnea, tachypnea, chest wall discom- be assessed to determine if hospitalization is required. A fort, and involuntary grunting.37 Failure to recognize res- thorough workup for metabolic or infectious disorders piratory dyskinesia may lead to unnecessary testing. is indicated. Nonessential psychoactive medications Greater emphasis on medical and medication history may should be discontinued. Dopaminergic drugs that are least improve the diagnosis of respiratory dyskinesia in the potent with respect to motor function should be re- emergency setting. Treatment of dyskinesia should in- duced (anticholinergics, , dopamine ago- clude lowering (or holding) levodopa dosage. Benzodi- nists, inhibitors, catechol-O- azepines may be useful to treat concomitant anxiety. Neu- methyl transferase inhibitors).43 The daily levodopa dose roleptics should not be used. Long-term management for may also need to be lowered. medication chronic dyskinesia may involve the addition of amanta- treatment can be started and is often necessary to re- dine hydrochloride or deep brain stimulation surgery.38 solve psychosis. Useful antipsychotics include cloza- pine and quetiapine. Clozapine has the most robust evi- Psychosis in PD dence base.44 Despite the lack of compelling evidence for quetiapine fumarate,44 it is often prescribed because of Psychosis in PD is a common reason for inpatient ad- clozapine’s risk of agranulocytosis and the need for moni- mission and a strong predictor of nursing home place- toring complete blood cell count on a frequent basis. Other ment.39 It is more commonly encountered in PD with de- antipsychotics, typical and atypical, may cause unaccept- mentia, occurring in 45% to 64% of patients.40,41 Visual able worsening of motor function and should not be used hallucinations are more common than auditory halluci- for treatment of psychosis in PD.43,44

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 cal trials sponsored by the National Institute of Neuro- logical Disorders and Stroke, Westat, Elan Pharmaceu- ticals, and Medivation. Dr Weiner reports receiving research support from Santhera, Boehringer Ingelheim, and the National Institutes of Health and has served in advisory or consulting roles for Santhera, Novartis, GlaxoSmithKline, and Boehringer Ingelheim. Dr Factor reports receiving grant support from Teva, Ipsen, and Schering-Plough and has served as a consultant to UCB, Allergan, Lundbeck, and Boehringer Ingelheim.

REFERENCES

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