Jaw-opening dystonia (trismus) (A) and hand dystonia (B) secondary to neuroleptic malignant syndrome.
T2-weighted axial magnetic resonance image demonstrating hyperintensity in the pons (A) and basal ganglia (B) (central and extra pontine myelinolysis) of a patient with acute parkinsonism.
Kayser-Fleischer rings, golden brown and surrounding the iris, are found in the majority of patients with neurologic manifestations of Wilson disease.
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Robottom BJ, Weiner WJ, Factor SA. Movement Disorders Emergencies Part 1: Hypokinetic Disorders. Arch Neurol. 2011;68(5):567–572. doi:10.1001/archneurol.2011.84
Movement 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 movement disorder emergencies and divided them into hypokinetic (part 1) and hyperkinetic (part 2) presentations. In part 1, drug-induced syndromes including neuroleptic malignant syndrome, parkinsonism hyperpyrexia syndrome, and serotonin syndrome will be discussed. Emergency complications related to the management of Parkinson disease, including falling, motor fluctuations, and psychiatric issues, will also be reviewed.
Movement disorders often have an insidious onset and slow progression and are not often associated with emergency situations. However, neurologists may be called on to diagnose and treat evolving movement disorders or acute complications of existing diseases in the emergency department or intensive care unit. Such situations meet the working definition of an “emergency,” a rapidly evolving disorder (hours to days) in which the failure to diagnose and treat may lead to significant morbidity or mortality.1 This review is divided into 2 parts based on phenomenology, hypokinetic and hyperkinetic disorders, and it discusses rapidly evolving situations that require emergency intervention. A number of the disorders discussed are rare. Data regarding prevalence and incidence have not been evaluated. In part 1, we review hypokinetic disorders including the drug-induced movement disorder emergencies neuroleptic malignant syndrome (NMS), parkinsonism-hyperpyrexia syndrome (PHS), and serotonin syndrome (SS) as well as emergent complications of Parkinson disease (PD).
Neuroleptic malignant syndrome, first described in 1960,2 is an iatrogenic disorder resulting from exposure to drugs that block dopamine receptors. While most cases are caused by neuroleptics (both typical and atypical, even clozapine),3-6 other medications such as prochlorperazine, metoclopramide hydrochloride, droperidol, and promethazine hydrochloride are also implicated.7 Diagnostic criteria integrating clinical and laboratory features (Table 1) have been developed.8 Because the incidence of NMS is low, 0.2%,9 a high index of suspicion is necessary to make the appropriate diagnosis. Neuroleptic malignant syndrome is important to consider in any patient with acute-onset parkinsonism and fever because it is life threatening (mortality rate of 5%-20%). Young and middle-aged men appear to be at higher risk.10
Neuroleptic malignant syndrome is a clinical syndrome comprising fever, rigidity, mental status change, autonomic dysfunction, and other movement disorders (tremor, dystonia, and myoclonus) (Figure 1). Key laboratory abnormalities include leukocytosis and elevated creatine kinase level. Additionally, acute-phase reactants, including albumin and serum iron levels, are decreased.11 Symptoms often begin after initiation or an increase in neuroleptic dose.5 Neuroleptic malignant syndrome increases in severity over 48 to 72 hours and lasts 7 to 14 days. Medical complications can be chronic and irreversible including renal failure from rhabdomyolysis, respiratory failure from decreased chest wall compliance, aspiration pneumonia, and other complications of immobility such as deep venous thrombosis and pressure ulcers. Pulmonary embolism, pneumonia, or renal failure may result in death.
No prospective randomized trials exist in NMS. Key steps in treatment include withdrawal of the causative agent and treatment with dopaminergic agents. Bromocriptine mesylate has been used most often and is considered the drug of choice12; however, other dopaminergic agents are equally effective. Dantrolene sodium, a nonspecific muscle relaxant, reduces muscular rigidity and minimizes rhabdomyolysis if the dopaminergic agent does not reverse the symptoms.13 Combination therapy has been found to be safe and effective,12 and treatment should continue for 7 to 10 days depending on the half-life of the causative agent. One-third of patients may relapse if neuroleptic treatment is restarted too early, so waiting at least 2 weeks after NMS has cleared is good practice.14 In patients who require immediate treatment of psychosis, electroconvulsive therapy has been successful.15
Parkinsonism-hyperpyrexia syndrome may be indistinguishable from NMS except that it occurs in patients with preexisting parkinsonism. Parkinsonism-hyperpyrexia syndrome occurs in patients with PD who abruptly withdraw or reduce dopaminergic medications. It was first reported in the context of abrupt discontinuation of antiparkinsonian medications during “levodopa holidays” in the 1980s.16,17 While levodopa holidays are no longer recommended, patient noncompliance or abrupt changes in medication replicate that scenario. Aggressive medication adjustments are not uncommon, particularly after deep brain stimulation surgery in PD. Clinicians must realize that PHS is a potential complication and that deep brain stimulation surgery does not protect the patient from PHS.18 Dehydration and metabolic disturbances may also precipitate it.19 Treatment involves supportive measures and reinstituting dopaminergic therapy. Bromocriptine and dantrolene may be added as additional therapy. High-dose intravenous methylprednisolone has been proposed as adjunctive therapy, and it appears to be effective based on 1 small randomized trial.20 Despite treatment, permanent worsening of PD and fatalities have been reported.21
Any drug that enhances serotonergic transmission can precipitate SS, which has the core clinical features of fever, myoclonus, and altered mental status.22 Serotonin syndrome was first described in 1960 in patients receiving monoamine oxidase inhibitor monotherapy23 but is now encountered in patients taking 2 or more drugs with serotonergic actions (tricyclic antidepressants or selective serotonin reuptake inhibitors in combination with nonselective monoamine oxidase inhibitors)24 (Table 2). Many of the clinical features overlap with NMS (Table 3); however, SS may have additional clinical features such as myoclonus, hyperreflexia, seizures, and mood alteration (restlessness, elevated mood).26 This overlap may relate to the impact elevated serotonin levels have on lowering dopamine levels. Treatment consists of discontinuation of the causative agent, supportive therapy, and cyproheptadine hydrochloride for severe cases. Cyproheptadine, an antihistamine and serotonin antagonist, is given in divided doses up to a maximum dose of 32 mg/d.27 Serotonin syndrome may resolve quickly25 or is potentially fatal. Like NMS and PHS, the rarity and seriousness of SS precludes large randomized trials.
Parkinson disease is a neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and postural instability. Three recent studies28-30 examined why patients with PD present to emergency departments, and each found similar results. The most common reasons were not disease specific (infectious disease, 21%-32%; cardiovascular/cerebrovascular, 12%-26%; gastrointestinal, 8%-11%; and metabolic, 2%-6%). Of disease-specific problems, the most common were trauma/falls (13%-27%), motor fluctuations/dyskinesia (8%), and psychiatric disturbances (8%).
As PD progresses, falls become increasingly common, with up to 70% of patients with advanced PD reporting at least 1 fall per year.31 Postural instability or freezing of gait result in up to 80% of falls.32 There is a 3-month fall rate of 46%, with the best predictor of falling being a history of 2 or more falls in the previous year.33 Injuries occur from approximately 25% of falls, with hip fractures a common result. Postural instability is not levodopa responsive, making treatment a challenge. Physical therapy and assistive devices may be preventive.
Motor fluctuations are common in advanced PD, seen in 40% of patients by 4 to 6 years, with an increasing frequency of 10% per year.34 Generally not dangerous, motor fluctuations are one of the more common disease-specific reasons that patients seek emergency treatment. During “off” periods, prominent rigidity, bradykinesia, and postural instability may develop, making it impossible for patients to care for themselves or to walk. Psychiatric features may become pronounced, including depressed mood, anxiety, and panic. Dysautonomia, including tachycardia, diaphoresis, and variations in blood pressure, may occur.35 While off periods do not usually result in a visit to the emergency department, some situations lead to emergency evaluation. Patients with suddenly worsening off periods associated with new symptoms (eg, freezing, unpredictable or prolonged off periods) are more likely to seek urgent evaluation.35 In these situations, investigation should search for a potential cause of the abrupt change. A careful medication history may be necessary to ensure that no changes have been made to the antiparkinsonian regimen. Patients should also be questioned about the addition of medications to their regimen, particularly dopamine receptor blockers (antipsychotics and antiemetics). Concurrent infection (urinary tract infection, pneumonia) or metabolic derangement should be considered. In a patient with falls and abruptly worsening PD, subdural hematoma should be considered.36
Dyskinesia is usually not dangerous and is most often managed in the outpatient setting. However, severe dyskinesia may lead to rhabdomyolysis and dehydration.35 Generalized dyskinesias may be complicated by involvement of respiratory muscles, with patients reporting symptoms of dyspnea, tachypnea, chest wall discomfort, and involuntary grunting.37 Failure to recognize respiratory dyskinesia may lead to unnecessary testing. Greater emphasis on medical and medication history may improve the diagnosis of respiratory dyskinesia in the emergency setting. Treatment of dyskinesia should include lowering (or holding) levodopa dosage. Benzodiazepines may be useful to treat concomitant anxiety. Neuroleptics should not be used. Long-term management for chronic dyskinesia may involve the addition of amantadine hydrochloride or deep brain stimulation surgery.38
Psychosis in PD is a common reason for inpatient admission and a strong predictor of nursing home placement.39 It is more commonly encountered in PD with dementia, occurring in 45% to 64% of patients.40,41 Visual hallucinations are more common than auditory hallucinations and usually consist of complex, formed visual images, often of unknown but nonthreatening people.42 Paranoid delusions may accompany hallucinations and constitute a greater threat. Hallucinations and mild delusions may be treated at home; paranoia may become extreme and require hospitalization. Parkinson disease psychosis may be precipitated by metabolic derangements, infections (urinary tract infection, pneumonia), and changes in drug therapy including addition of any dopaminergics or anticholinergics.
Emergency treatment of psychosis requires a multifaceted approach. The patient's living conditions need to be assessed to determine if hospitalization is required. A thorough workup for metabolic or infectious disorders is indicated. Nonessential psychoactive medications should be discontinued. Dopaminergic drugs that are least potent with respect to motor function should be reduced (anticholinergics, amantadine, dopamine agonists, monoamine oxidase B inhibitors, catechol- O-methyl transferase inhibitors).43 The daily levodopa dose may also need to be lowered. Antipsychotic medication treatment can be started and is often necessary to resolve psychosis. Useful antipsychotics include clozapine and quetiapine. Clozapine has the most robust evidence base.44 Despite the lack of compelling evidence for quetiapine fumarate,44 it is often prescribed because of clozapine's risk of agranulocytosis and the need for monitoring complete blood cell count on a frequent basis. Other antipsychotics, typical and atypical, may cause unacceptable worsening of motor function and should not be used for treatment of psychosis in PD.43,44
Acute or subacute onset of parkinsonism has a broad differential diagnosis (Table 4). Parkinsonism as part of a primary neurodegenerative disease is insidious in onset and slowly progressive. However, when parkinsonism develops over a period of days to weeks, a secondary cause should be considered. In this situation, a review of the medication list, investigation for a structural lesion, and examination for pathognomonic findings are most important (Figure 2 and Figure 3).
The diagnosis and management of parkinsonism encountered in the emergency setting can be difficult because neurologists do not often associate this syndrome with consultations in the emergency department or intensive care unit. In acute or worsening parkinsonism, drug or toxic exposures (Table 2 and Table 4), infection, or changes in treatment regimen (especially in PD) should be considered. Subacute dramatic changes in the motor or cognitive status of patients with PD are often precipitated by non–disease-specific etiologies (infectious disease, 21%-32%; cardiovascular/cerebrovascular, 12%-26%; gastrointestinal, 8%-11%; and metabolic, 2%-6%). In NMS, PHS, and SS, an accurate medication history is essential. Part 2, hyperkinetic movement disorder emergencies, will examine chorea, myoclonus, tics, and dystonia.
Correspondence: Bradley J. Robottom, MD, Department of Neurology, University of Maryland School of Medicine, 110 S Paca St, Room 3-S-128, Baltimore, MD 21201 (firstname.lastname@example.org).
Accepted for Publication: April 27, 2010.
Author Contributions:Study concept and design: Robottom, Weiner, and Factor. Analysis and interpretation of data: Weiner. Drafting of the manuscript: Robottom, Weiner, and Factor. Administrative, technical, and material support: Robottom, Weiner, and Factor. Study supervision: Weiner.
Financial Disclosure: Dr Robottom has received clinical research support from Chelsea Therapeutics and Solvay Pharmaceuticals and served as an investigator for clinical trials sponsored by the National Institute of Neurological Disorders and Stroke, Westat, Elan Pharmaceuticals, 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.