Movement Disorder Emergencies 1 4 Robert L. Rodnitzky

Abstract Movement disorders can be the source of signifi cant occupational, social, and functional disability. In most circumstances the progression of these disabilities is gradual, but there are circumstances when onset is acute or progression of a known movement disorders is unexpectedly rapid. These sudden appearances or worsening of abnormal involuntary movements can be so severe as to be frightening to the patient and his family, and disabling, or even fatal, if left untreated. This chapter reviews movement disorder syndromes that rise to this level of concern and that require an accurate diagnosis that will allow appropriate therapy that is suffi cient to allay anxiety and prevent unnecessary morbidity.

Keywords Movement disorders • Emergencies • Acute Parkinsonism • Dystonia • Stiff person syndrome • Stridor • Delirium

severe as to be frightening to the patient and his Introduction family, and disabling, or even fatal, if left untreated. This chapter reviews movement disor- Movement disorders can be the source of signifi - der syndromes that rise to this level of concern cant occupational, social, and functional disabil- and that require an accurate diagnosis that will ity. In most circumstances the progression of allow appropriate therapy that is suffi cient to these disabilities is gradual, but there are circum- allay anxiety and prevent unnecessary morbidity. stances when onset is acute or progression of a known movement disorders is unexpectedly rapid. These sudden appearances or worsening Acute Parkinsonism of abnormal involuntary movements can be so The sudden or subacute onset of signifi cant par- R. L. Rodnitzky , MD (*) kinsonism, especially akinesia, is potentially very Neurology Department , Roy J. and Lucille A. Carver frightening to the affected patient and his/her College of Medicine, University of Iowa , Iowa City , IA , USA family members. Of more concern is the potential e-mail: [email protected] for severe untreated akinesia to lead to serious

K.L. Roos (ed.), Emergency Neurology, DOI 10.1007/978-0-387-88585-8_14, 259 © Springer Science+Business Media, LLC 2012 260 R.L. Rodnitzky complications, such as pulmonary embolism, persistent hydrocephalus, or to shunt revision, aspiration, and pneumonia. Seven general etio- levodopa therapy is usually effective both in the logic categories of acute parkinsonism can be short term and chronically [2, 4– 6 ] . identifi ed and the likelihood of arriving at the Acute cerebral infarction involving the stria- correct clinical diagnosis can be greatly enhanced tum or the substantia nigra is another structural by systematically considering which one or com- insult that can result in acute parkinsonism. The bination of these etiologies may be at play in a common term “vascular parkinsonism,” as used given acutely parkinsonian patient. The seven today, refers to the gradual appearance of parkin- etiologic categories of acute parkinsonism are as sonian features, usually a parkinsonian gait, due follows (1) structural, (2) toxic, (3) impaired to diffuse, bihemisphere small vessel ischemic levodopa absorption, (4) iatrogenic, (5) infec- disease. Large artery infarctions, on the other tious, (6) surgery, and (7) de novo (spontaneous hand, produce unilateral or bilateral parkinsonism acute parkinsonism). over a matter of days to months. When a striatal infarction is associated with signifi cant hemipa- resis, unilateral parkinsonism typically evolves Structural once the hemiparesis begins to improve [ 7 ] . Striatal infarctions are relatively common, but The two most common structural causes of acute only a small percentage result in parkinsonism parkinsonism are stroke and hydrocephalus, [ 8] . Parkinsonism can also develop after infarc- although neither is extremely common in an tion of the substantia nigra [9 ] . Infarction of the absolute sense. Parkinsonism due to acute hydro- pedunculopontine nuclei in the brainstem can cephalus is to be distinguished from the gradu- cause acute onset of gait freezing, similar to that ally evolving form of parkinsonism that can seen in Parkinson’s disease [ 10 ] . Therapy of occur in patients with chronic hydrocephalus, infarction-related parkinsonism with levodopa is especially normal pressure hydrocephalus. Acute most effective in those cases where the pathology parkinsonism can occur simultaneously with the is in, or close to, the substantia nigra [11 ] . development of acute hydrocephalus [1 ] but can Somewhat paradoxically, stroke involving the also occur after shunt placement [2, 3] or shunt tuberothalamic artery can improve parkinsonian revision [4 ] in patients with long-standing tremor, presumably through damage to the vent- hydrocephalus. The rapid onset of parkinsonism rolateral thalamic nucleus, similar to the lesion of in acute hydrocephalus is probably due to a therapeutic thalamotomy [ 12 ] , or deep brain direct compression or shearing force on the stimulation of this structure. substantia nigra secondary to changing pressure dynamics of the rapidly enlarging ventricles [5 ] . Parkinsonism due to shunt revision or placement Toxic is due to rapidly shrinking ventricles with subse- quent midbrain distortion [2 ] . The simultaneous A variety of nonindustrial toxins can also cause occurrence of other signs of rostral midbrain acute parkinsonism. The more common toxic dysfunction, along with parkinsonism, after exposures that might present to a community shunting supports the notion that the postshunt- Emergency Department are discussed here. ing fi ndings are all due to mechanical distortion Organophosphate insecticides, either through of the midbrain [6 ] . In patients whose akinesia inadvertent ingestion on food or exposure in an appears to be related to acute hydrocephalus with agricultural setting, can cause acute, reversible acutely enlarging ventricles, shunting is indi- parkinsonism. In these cases, treatment with cated and could be lifesaving. Parkinsonism levodopa [13 ] has been less effective than amanta- might be improved by this intervention, or dine [ 14 ] and dopamine agonists [15 ] . Carbon as mentioned above, could be exacerbated. monoxide (CO) poisoning results in subacute par- In parkinsonism related to acute hydrocephalus, kinsonism. In a large series of 242 CO poisoning 14 Movement Disorder Emergencies 261 cases, 10% of the individuals affected developed resultant impaired levodopa absorption should be parkinsonism with a latency of 2–26 weeks strongly suspected. Gastroparesis in PD patients (median 4 weeks) after the acute exposure [ 16 ] . has also been reported in the presence of acute Imaging of the brain in these patients reveals evi- duodenal ulcer and intestinal volvulus [ 21 ] . In dence of bilateral pallidal necrosis with symmetric addition to treating the primary medical cause of hypodensity on CT scan and high signal intensity delayed gastric emptying, prokinetic agents can on FLAIR and T2-weighted MRI sequences [ 17 ] . be useful to reduce gastric stasis. Domperidone, a There is, however, not a complete correlation peripheral dopamine receptor antagonist, is use- between the appearance of pallidal necrosis on CT ful for this purpose but is not yet approved in the or MRI and parkinsonism in CO poisoning. Of 17 USA. Administering levodopa with a carbonated patients with CO-related parkinsonism in one and/or caffeinated beverage may enhance pas- series, only 47% had abnormal CT scans [ 16 ] . In sage of levodopa through the stomach and this series, levodopa and anticholinergic drugs enhance absorption. Replacing an oral dopamine were not effective, but 81% of affected individuals agonist with a transdermal agent, such as rotigo- recovered gradually over a 6-month period of tine [22 ] (if available), would be useful. For very time. Initial hyperbaric oxygen therapy of CO poi- severe absorptive dysfunction with signifi cant soning in the acute phase may reduce subsequent akinesia such as after gastrointestinal surgery, neurologic sequelae, but controlled studies of this subcutaneous apomorphine may prove useful therapeutic approach are still lacking [18 ] . [23 ] , although in this circumstance, some patients Purposeful or accidental ingestion of ethylene gly- become relatively refractory to all dopaminergic col or methanol can result in acute parkinsonian agents, including apomorphine [ 21 ] . akinesia, often associated with hemorrhagic necro- sis of the basal ganglia [ 19 ] . Levodopa therapy can improve the rigidity and bradykinesia associ- Iatrogenic ated with these two toxic exposures [ 19 ] . The inadvertent or ill-advised use of drugs that are dopamine receptor blocking agents (DRBA) Impaired Levodopa Absorption can rapidly result in a severely exacerbated par- kinsonian state in PD patients. Occasionally, non- Gastric emptying is commonly slightly delayed PD patients or PD patients not yet known to have in PD patients, but superimposed gastrointestinal clinically apparent PD can be rendered acutely or disorders can further delay passage of levodopa subacutely akinetic by the administration of through the pylorus resulting in a signifi cant DRBAs, particularly if used at a high dosage. decrease in levodopa absorption in its main Among DRBAs, the typical antipsychotic agents, absorptive site in the jejunum. The consequence such as haloperidol, have the greatest potential to of such an acute or subacute decrease in levodopa cause signifi cant akinesia, but other classes of absorption is an acute increase in parkinsonian dopamine antagonists, including most of the symptoms, including akinesia. In these cases, atypical antipsychotic agents and the DRBA anti- identifi cation and treatment of the comorbid gas- emetic drugs, such as prochlorperazine and meto- trointestinal disorder is the fi rst therapeutic mea- clopramide, have this potential as well [ 24 ] . The sure that should be taken. In a review of 146 most serious iatrogenic forms of acute akinesia non-parkinsonian patients with acute gastropare- are neuroleptic malignant syndrome (NMS) and sis, the three most common associated clinical the closely related condition known as parkin- features were abdominal pain, depression on anti- sonism-hyperpyrexia syndrome (PHS), as these depressant therapy, and gastroesophageal refl ux conditions, left untreated, can result in major [20 ] . Should recent onset or worsening of any of disability and are potentially fatal. Serotonin syn- these comorbid conditions be present in the drome shares some clinical features with NMS, acutely akinetic PD patient, gastroparesis with including some parkinsonian phenomena. 262 R.L. Rodnitzky

NMS is an acute reaction that can occur either of the offending drug, or who have had previous as a result of treatment with a dopamine blocking electroconvulsive therapy [41, 42 ] . Elevation of agent [25 ] , or after rapid withdrawal or reduction serum creatine kinase during a previous psychotic of one or more dopaminergic drugs in a episode unassociated with NMS may be a risk Parkinson’s disease patient, in which case it is factor for NMS developing during future admin- referred to as parkinsonism-hyperpyrexia syn- istration of DRBAs [43 ] . drome (PHS) [26 ] . PHS can also occur in other In addition to dehydration, risk factors for forms of parkinsonism, such as progressive PHS include several characteristics of the under- supranuclear palsy or multiple system atrophy lying parkinsonism. Thus, more severe parkinso- (MSA) [27 ] . The onset of NMS is usually within nian symptoms, longer disease duration, a history a month after beginning DRBA therapy or an of “wearing off,” and a history of an early age of increase in dosage, but as many as 16% of cases parkinsonism onset are risk factures for PHS of NMS begin within the fi rst 24 h of therapy and [ 44] . Serious PHS has occurred after periopera- 30% by 2 days [ 25 ] . PHS developing in tive withdrawal of antiparkinsonian medications Parkinson’s disease patients usually presents [ 45 ] . PHS has also been reported in Parkinson’s shortly after the discontinuance or reduction of a patients who abruptly discontinued fava bean dopaminergic medication [26 ] . In one series, ingestion, which was being taken for its levodopa PHS occurred at a mean of 93 h after medication content [46 ] . The syndrome has also occurred in withdrawal [28 ] . All neuroleptic drugs can cause Parkinson’s patients during extreme periods of NMS, as can all atypical antipsychotic agents ambient heat even in the absence of medication [29– 32] . The overall incidence of NMS appears withdrawal [47 ] . Acute akinesia related to to be lower in patients receiving atypical antipsy- levodopa resistance after a surgical procedure chotic agents, and at least in the case of clozapine resembles PHS [21 ] . [ 33 ] , olanzapine [34 ] , and risperidone [31 ] , a The cardinal clinical manifestations of NMS milder syndrome with less prominent fever or and PHS are virtually identical and include fever, rigidity [35 ] and less elevation of creatinine muscular rigidity, autonomic instability, and con- kinase may develop. However, in one recent fusion or alteration in consciousness [ 37 ] . Among review of the literature [36 ] , 68 reported cases of autonomic symptoms, tachypnea, tachycardia, NMS were related to atypical antipsychotics, and labile blood pressure, diaphoresis, and urinary in this survey, clozapine was associated with retention are most common [48 ] . The most fre- NMS as often as other atypical agents, suggest- quent movement disorder in NMS is rigidity, ing that low extrapyramidal syndrome-inducing which is often preponderantly axial. Other move- potential does not necessarily reduce the occur- ment disorders are possible, including dystonia rence of NMS. Antiemetic DRBAs, such as meto- and chorea. Fever is typically at least 38°C and clopramide and prochlorperazine, can also result often higher. Creatine kinase levels are usually in NMS [ 37 ] . Antidepressants, including tricy- above 2,000 IU/L and often in the range of clics [38 ] , selective serotonin reuptake inhibitors 15,000–20,000 IU/L [ 49, 50] . The white blood [39 ] , and lithium [40 ] , either alone or in combi- cell count is often elevated, but usually without a nation, have all been reported to cause a syn- left shift. Milder or atypical forms of the syndrome drome resembling NMS, but such cases are without one of the classic features, such as muscle uncommon and often the clinical presentation is rigidity [ 51 ] or fever [ 31, 52] , may exist. Cases atypical or indistinguishable from serotonin syn- without rigidity may simply present as a fever of drome. Although discontinuance of any unknown origin [ 53 ] . PHS is especially likely to Parkinson’s drug can result in PHS, stopping present with fever as the fi rst symptom [ 27 ] . levodopa is the most common cause. NMS is The treatment of NMS and PHS should be more likely to occur in young patients, in males, considered emergent, especially in cases in which and in patients who are agitated, dehydrated, all of the clinical criteria are fulfi lled or in patients have received large rapidly administered dosages with extremely high fever and rhabdomyolysis. 14 Movement Disorder Emergencies 263

In these cases, there can be serious morbidity and case reports and small series culled from the occasionally a fatal outcome. The most common literature. However, a large retrospective review complications affecting the prognosis are cardiac of 734 cases of NMS concluded that treatment failure, cerebellar degeneration, respiratory dis- with bromocriptine, dantrolene, or amantadine turbances, and renal failure, the latter of which reduced mortality more than supportive care can be associated with disseminated intravascu- alone [62 ] . For NMS cases that are refractory to lar coagulation and rhabdomyolysis [ 54, 55 ] . The medical therapy, electroconvulsive therapy has fi rst therapeutic measure that must be taken is been found to be useful in both adults and chil- discontinuing the offending neuroleptic or other dren [63 ] , as well as in the PHS [64 ] . causative dopamine blocking drug, or in Recovery from NMS typically occurs over a Parkinson’s patients with PHS, replacing a 1- to 2-week period, but resolution after recovery recently withdrawn or altered dopaminergic drug. from the acute phase may be delayed in those Supportive measures, such as hydration and low- having received long-acting depot neuroleptics. ering of fever, must be started early. Some sequelae, especially neuropsychiatric Anticholinergic drugs should be discontinued in symptoms, can persist for weeks or months [ 65 ] . Parkinson’s disease patients, since they inhibit Pulse methylprednisolone therapy has been heat dissipation. Tapering anticholinergics is reported to signifi cantly shorten the recovery advised rather than abrupt cessation to avoid phase in patients with Parkinson’s disease [66 ] . rebound rigidity. Respiratory support may be Rechallenge with neuroleptics after recovery needed because of severe rigidity of respiratory results in reoccurrence of NMS in less the 15% of muscles. Cardiac arrhythmias and blood pressure cases. To minimize the likelihood of reoccur- abnormalities must be treated [ 56 ] . In patients rence, rechallenge should be delayed for at least with dangerously high body temperature, anti- 2 weeks after recovery and a lower potency neu- pyretics such as aspirin are usually ineffective, roleptic agent or atypical antipsychotic drug but a noninvasive body surface cooling device should be used. (Arctic Sun® , MediVance Inc.) can be very useful Serotonin syndrome (SS ) has become increas- to reverse hyperthermia [57 ] . ingly more common, refl ecting the increased The specifi c fi rst-line medical therapies for number and increased use of serotonergic medi- NMS include bromocriptine, orally or by naso- cations. This pattern of increased use also includes gastric tube, dantrolene, and amantadine [37 ] . the pediatric population. In a survey of North Bromocriptine is administered in an initial dos- Carolina Medicaid prescriptions, the prevalence age of 2.5 mg every 4 h, being careful to observe of prescriptions for SSRIs in the 6–14-year-old for induction or worsening of hypotension. The age group increased sevenfold from 0.2% to 1.5% dose can be increased daily, if required, to as between 1992 and 1998 [67 ] . This syndrome, like much as 50 mg per day. An alternative dopamine NMS, includes involuntary abnormal move- agonist is subcutaneous apomorphine, which can ments, especially myoclonus and tremor, and as produce a rapid clinical response [58, 59 ] . such is considered a movement disorder emer- Dantrolene can be administered intravenously, if gency. As the name implies, serotonin syndrome needed, in a dosage of 1–10 mg/kg/day in three occurs in patients receiving one or more seroton- divided dosages. Most patients will require dos- ergic drugs. There are two commonly utilized ages in the lower part of this range [60 ] . diagnostic criteria for serotonin syndrome, the Dantrolene is a good choice for initial therapy Sternbach Criteria [ 68 ] and the Hunter Serotonin alone or in combination with bromocriptine when Toxicity Criteria [ 69 ] . Using the Sternbach there is severe rigidity and rhabdomyolysis. Criteria, there are three requirements: Carbamazepine is a possible second-line therapy (a) After the addition of or increase in dosage of [61 ] . None of these medical therapies have been a serotonergic agent, at least three of the fol- proven to be effective by prospective studies, but lowing clinical features must be present: agi- rather derive their reputation for effi cacy from tation, mental status changes, myoclonus, 264 R.L. Rodnitzky

hyperrefl exia, diaphoresis, shivering, tremor, Table 14.1 Serotonin syndrome. Comparison with neu- diarrhea, incoordination, and fever. roleptic malignant syndrome (b) Other etiologic causes (infectious, meta- SS NMS bolic, substance abuse or withdrawal) have Mental status change + ++ been ruled out. Fever ++ +++ (c) An antipsychotic has not been started or Tachypnea/tachycardia ++ +++ increased in dosage before the onset of the Diarrhea +++ 0 symptoms. Diaphoresis ++ +++ Rigidity/bradykinesia 0 +++a To fulfi ll the Hunter Serotonin Toxicity Stupor + +++a Criteria, the patient must have taken a serotoner- Tremor +++b + gic agent and meet one of the following Shivering +++b 0 requirements: Myoclonus +++b + (a) Exhibit spontaneous clonus Hyperrefl exia/clonus +++b 0 (b) Have inducible clonus plus agitation or Elevated CK + +++a diaphoresis Pupillary dilation ++ 0 (c) Exhibit ocular clonus plus agitation or Acute onset +++b + diaphoresis a Important differentiating feature of neuroleptic malignant (d) Have hypertonia syndrome (NMS). b (e) Have a temperature greater than 38°C plus Important differentiating feature of serotonin syndrome (SS). ocular clonus or inducible clonus Both sets of criteria are useful, but a compari- son of their utility in patients with an established rather than NMS. A comparison of common fea- serotonin syndrome diagnosis suggested that the tures of serotonin syndrome, NMS, and features Hunter Criteria was more sensitive than the that most accurately discriminate the two syn- Sternbach Criteria (84% vs. 75%), and minimally dromes from one another is shown in Table 14.1 . more specifi c (97% vs. 96%) [69 ] . Misdiagnosis, especially early in the course of The clinical signs of serotonin syndrome serotonin syndrome, is common. For example, resemble those of NMS and in many cases the the presence of hyperrefl exia and clonus can lead two syndromes appear to overlap in the same to the false impression of a pyramidal syndrome patient [70 ] . For determining proper therapy, dis- and the presence of diarrhea plus fever can lead tinguishing the two syndromes from one another to the incorrect diagnosis of an infectious gastro- is very important, since their respective medical enteritis [71 ] . therapies are distinct. Both syndromes include The offending therapies that have the potential mental status changes, fever, autonomic dysfunc- to contribute to serotonin syndrome fall into one tion, and a variety of movement disorders, but the of the following seven pharmacologic categories relative severity of these signs in the two syn- (Table 14.2). Although serotonin syndrome is dromes can be a differentiating factor. Compared thought to result from stimulation of 5-HT1A and to NMS, in serotonin syndrome, fever, elevation 5-HT2A receptors [73 ] , some drugs that stimulate of creative kinase, and alteration in sensorium are other classes of receptors, such as most triptan generally less prominent, while myoclonus, gas- agents, probably can contribute to the develop- trointestinal symptoms, a shivering-type tremor, ment of serotonin syndrome. hyperrefl exia, clonus, and pupillary dilatation are Although any of these drugs and treatments more prominent. Among these differences, hyper- taken alone can cause serotonin syndrome, the refl exia with clonus, the presence of otherwise risk is greatest when two or more serotonergic unexplained myoclonus, and a rapid onset (within therapies are administered simultaneously [74, hours of the offending pharmacologic event) 75 ] . The greatest risk is in those receiving a non- are among the most useful clues that the selective MAO inhibitor along with a potent sero- patient is suffering from serotonin syndrome, tonin reuptake inhibitor [ 76 ] . Higher dosages of 14 Movement Disorder Emergencies 265

Table 14.2 Agents that can cause serotonin syndrome 1. Inhibitors of serotonin reuptake: all of the SSRIs, SNRIs several tricyclic antidepressants, dextromethorphan, amphetamine, cocaine, MDMA (ecstasy), St. John’s wort 2. Inhibitors of serotonin metabolism: selective MAO-B inhibitors (selegiline or rasagiline), non-selective MAO inhibitor antidepressants, non-selective MAO inhibitor antibiotic (linezolid) 3. Agents that increase serotonin synthesis: l -tryptophan 4. Enhancers of serotonin release: amphetamines, cocaine, fenfl uramine, MDMA (ecstasy) 5. Serotonin agonists: buspirone, triptans, ergotamines 6. Non-specifi c enhancers of serotonin activity: lithium, electroconvulsive therapy 7. Serotonergic effect, mechanism is uncertain (methylene blue) Adapted from Lane R, Baldwin D [72 ]. these medications also increase the risk and the Parkinson’s disease. Serotonin syndrome was severity of the syndrome. For example, several reported in only 11 patients receiving a triptan cases of serotonin syndrome in children have alone in the FDA adverse event reporting system resulted from accidental ingestion of a large and [ 83 ] . However, triptans taken along with other pharmacologically excessive amount of a parent’s serotonergic agents, especially the commonly medication [77, 78 ] . Methylenedioxymetham- used SSRIs, have been reported to cause the sero- phetamine (MDMA), also known as “ecstasy,” is tonin syndrome [84 ] . In 2006, the FDA issued an an amphetamine-derived street drug that is com- alert concerning the potential of serotonin syn- monly used by high school and college students, drome in patients taking triptans and SSRIs or especially while attending drug-inspired dance SNRIs, based on 29 reported cases. Subsequent gatherings known as “raves” [79 ] during which analysis of these cases has suggested that the risk there is a high ambient temperature and vigorous is very small, and in fact not all of the FDA cases physical activity leading to dehydration. This may have met the diagnostic criteria for serotonin drug has serotonergic properties and either alone syndrome [85, 86] . In regard to selegiline, there or in combination with other serotonergic drugs is concern that this agent could cause the sero- can produce a syndrome with features of sero- tonin syndrome in patients also receiving other tonin syndrome [ 70 ] . Fatalities have occurred due serotonergic drugs. Despite this concern, there to MDMA-related serotonin syndrome, often are very few well-documented cases of this inter- associated with delayed diagnosis in part due to action, and a similar level of risk seems likely for unawareness of the history of illicit drug inges- the newer selective, irreversible MAO-B inhibi- tion. Purposefully combining MDMA with an tor, rasagiline. Recently, it has become apparent MAO inhibitor to enhance its effect has proven that the widely used antibiotic linezolid is an especially lethal [80 ] . In the United Kingdom, MAO inhibitor that can cause serotonin syn- 605 ecstasy-related deaths were reported in a drome when used along with other serotonergic 7-year period [81 ] . Generally, what contributes to drugs [ 87 ] . a potential fatal outcome in serotonin syndrome is Prevention is very important in the serotonin the development of rhabdomyolysis, myoglobin- syndrome. To avoid an interaction leading to emia, and renal failure. Acute myocardial infarc- serotonin syndrome, there should be a period of tion has also occurred in the setting of serotonin at least 2 weeks between stopping an SSRI and syndrome [82 ] . starting an MAO inhibitor, and approximately Of interest to neurologists are the risks associ- 5 weeks after discontinuance of fl uoxetine, which ated with some serotonin-enhancing drugs that has a much longer half-life. Treatment of the are commonly used in neurologic practice, acute serotonin syndrome begins with the discon- including antimigraine agents, such as triptans tinuation of all serotonergic medications. This and dihydroergotamine, and the selective MAO-B strategy alone will often result in resolution of inhibitors, selegiline and rasagiline, used in the syndrome within 24 h. When symptoms are 266 R.L. Rodnitzky particularly resistant or severe, begin direct med- uncovered latent Parkinson’s disease [ 91 ] . The ical therapy with the serotonin antagonist, cypro- initial treatment of drug-induced parkinsonism is heptadine in a dosage of 8 mg [ 72, 88 ] . It has to discontinue the offending drug, if medically been suggested that reversal of mydriasis within feasible. Discontinuance may not always be pos- an hour of cyproheptadine is a useful indication sible in the case of effective antipsychotic agents that the drug is working [ 89 ] . Rehydration and used to treat a serious psychiatric condition. Even control of fever are important in the presence of with discontinuance, improvement in parkin- severe hyperthermia. A noninvasive cooling sonism cannot be expected for days to weeks and device (Arctic Sun® ) can be used to lower body occasionally several months. Once the offending temperature similar to its use in NMS [ 57 ] . drug has been discontinued, immediate medical Antipyretic agents, such as aspirin and acetamin- therapy begins with anticholinergic agents or ophen, are not effective for lowering fever of this amantadine. If these are not effective, then a origin. In the presence of severe muscle rigidity, course of levodopa can be considered with appro- dantrolene can be used. Chlorpromazine has been priate caution regarding the exacerbation of psy- suggested as a therapy for serotonin syndrome, chosis that this treatment can cause. The but its use depends on absolute certainty that the parkinsonism caused by chemotherapy agents patient does not have NMS instead, which might can be dramatically responsive to levodopa [92 ] . be worsened by this therapeutic approach.

Drug-induced parkinsonism : Administration of Infection dopamine blocking drugs, including typical antipsychotic agents, atypical antipsychotic Any intermittent infection, whether viral or bac- agents, and dopamine blocking antiemetics can terial, can exacerbate ongoing parkinsonian all cause rapid-onset parkinsonism, especially symptoms, especially in moderately or severely when administered in high dosages [ 24 ] . A large advanced PD patients. A recent survey of PD number of other drugs that are not primary dop- patients admitted to the hospital confi rmed that amine blocking agents, such as selective sero- infection was the most common reason for admis- tonin uptake inhibitors, valproic acid, amiodarone, sion, and among infections, pneumonia was most and certain chemotherapeutic agents, rarely cause common followed by urinary tract infection [93 ] . severe de novo parkinsonism and can also occa- Occult infection, especially pneumonia or uri- sionally signifi cantly exacerbate parkinsonian nary tract infection, should always be considered symptoms in a known PD patient [ 90 ] . The cal- in PD patients presenting with unexplained wors- cium channel blockers, cinnarizine and fl unariz- ening of symptoms. ine, neither marketed in the USA, can cause Acute or subacute parkinsonism has been parkinsonism due to their signifi cant dopamine reported as a complication of several different blocking capacity. Drug-induced parkinsonism forms of viral encephalitis including encephalitis can resemble ordinary Parkinson’s disease, due to Herpes Simplex Virus-1, West Nile virus, although there is a tendency for less tremor and Coxsackieviruses, St. Louis encephalitis virus, more symmetry in the drug-induced syndrome. and HIV [ 94– 96] . A major clue to this etiology of Some patients with drug-induced parkinsonism acute parkinsonism is the recent history or con- actually have Parkinson’s disease that has been current presence of seizures, fever, or extreme uncovered by the administration of the offending somnolence. Standard antiparkinsonian drugs, drug. These patients may be even more suscepti- such as trihexyphenidyl and carbidopa/levodopa, ble to drugs that are less obvious dopamine may improve parkinsonian symptoms during the blockers such as selective serotonin uptake inhib- acute phase of a viral illness [ 95 ] . Encephalitis itors [91 ] . SPECT imaging of the dopamine lethargica, which occurred as a pandemic in the transporter can be used to help determine whether early twentieth century, is a well-accepted cause a drug has caused transient parkinsonism or has of parkinsonism, and although rare, still does 14 Movement Disorder Emergencies 267 occur [97 ] . The presence of antineuronal antibod- Another potential cause of acute akinesia in ies and the absence of positive viral PCR in par- the postoperative period is enteral nutrition [101 ] . kinsonian patients with encephalitis lethargica This phenomenon is largely the result of persis- suggest that the parkinsonism is due to an auto- tent interference with levodopa absorption by the immune condition rather than an acute viral ill- high-protein content of continuous tube feedings. ness, and may require immunomodulatory It can be combated by changing from continuous therapy [98 ] . Another form of infection that can to intermittent bolus enteral feedings and staging lead to autoimmune akinesia is parkinsonism levodopa dosages in between and temporally dis- after streptococcal infection with associated anti- tant from boluses of tube feedings. basal ganglia antibodies [99 ] . For PD patients undergoing planned or elec- The treatment of infection-related forms of tive operations, the surgical team should be fore- parkinsonism is to fi rst treat the underlying viral warned to avoid administering dopamine blocking or bacterial infection with appropriate antiviral antiemetics or antipsychotic drugs in the postop- agents or antibiotics. For the parkinsonian fea- erative period, if at all possible, since these agents tures themselves, standard antiparkinsonian ther- can further exacerbate postoperative parkin- apy such as levodopa is often effective [95, 100 ] . sonism. In place of the dopamine blocking antin- Those infections associated with antibasal gan- ausea drugs (such as droperidol, prochlorperazine, glia antibodies may respond to immunomodula- or metoclopramide), domperidone (not available tory therapy, such as corticosteroids [99 ] . in the USA) or trimethobenzamide should be used instead.

Surgery De Novo Parkinsonism Parkinson’s disease patients undergoing major surgery commonly note worsening of their symp- There is one form of degenerative parkinsonism toms in the postoperative period. Most often, the that typically has an acute or subacute onset. degree of worsening is mild or moderate, but Rapid-onset dystonia-parkinsonism (RDP) is an occasionally it can be severe and associated with autosomal dominant condition in which both profound akinesia [ 21 ] . While any type of sur- dystonia and parkinsonism develop as rapidly as gery can have this effect, joint surgery is one of over a few minutes to as long 30 days [102 ] . In the more common precipitants of postoperative this condition, parkinsonian symptoms, such as PD worsening. This syndrome appears to be bradykinesia and hypophonia, pursue a rostral– independent of abnormalities of levodopa absorp- caudal pattern of progression. RDP can be dif- tion and in its most severe form, is associated ferentiated from idiopathic PD by its sudden with refractoriness to all dopaminergic agents onset, its initial rapid progression, the rostral– [21 ] . Despite concern for refractoriness to dop- caudal progression, and the absence of tremor. aminergic agents, therapy with oral levodopa or Family history, if present, is useful, but the auto- nonoral dopaminergic agents, such as subcutane- somal dominant gene in this condition displays ous apomorphine or transdermal rotigotine, variable penetrance. Another somewhat helpful should be attempted if either is available. Should differentiating feature from PD is that the great there be no benefi t from these agents, supportive majority of patients with RDP are under the age care for the immobilized patient is paramount of 30, and in fact, almost half are under the age of until responsiveness to medication resumes, often 20 [102 ] . A variety of triggers leading to the ini- in 2–7 days. It is wise to foreworn PD patients tial clinical presentation have been reported in undergoing elective surgery that some worsening this condition including fever, trauma, and psy- is likely to occur in the postoperative period in chiatric events, the latter sometimes falsely rais- order to minimize personal and family anxiety ing the possibility of psychogenic parkinsonism. over this occurrence. Typically, these patients’ parkinsonian symptoms 268 R.L. Rodnitzky are refractory to dopaminergic therapy [ 103 ] . swallowing is intact and the patient has already While pharmacologic therapy of this form of ingested a controlled release levodopa prepara- acute parkinsonism is not very effective, patients tion, administration of a high-protein snack can be can be reassured that in the majority of cases attempted in the hope of limiting further gastroin- most of the symptoms are minimally progressive testinal absorption of levodopa and inhibiting its after the initial presentation, with only a small passage across the blood–brain barrier through number of patients experiencing a second later competition for the active transport system for episode of abrupt worsening. large neutral amino acids [105 ] . If it is necessary to restart dopaminergic medications at the same dosage to control parkinsonian symptoms, strate- Severe or Acute Levodopa-Induced gies to reduce the potential for recurrent severe Dyskinesias dyskinesias should be employed including adding amantadine for its antidyskinesia effect and Parkinson’s disease patients are susceptible to replacing levodopa partially or completely with a severe medication-induced dyskinesias that can dopamine agonist, since this class of agents has a be choreic, dystonic, or both. These involuntary lower potential to cause dyskinesias. movements are usually a complication of dop- aminergic medications and can be further exacer- bated by levodopa enhancing preparations Acute Behavioral Change such as COMT inhibitors or MAO inhibitors. in Parkinsonism: Psychosis, Dyskinesias related to levodopa and/or dopamine Delirium Panic Attack agonist medications typically remit spontane- ously given suffi cient time, but if the involuntary A variety of behavioral abnormalities can occur movements are of extremely high amplitude or in PD. The most common, dementia, is gradual in involve many body parts simultaneously, they evolution and is not typically viewed as an emer- can prove to be frightening and/or exhausting to gency, but many other behaviors can appear sud- the patient and to family members, resulting in an denly, especially in the chronically demented PD Emergency Department visit. For example, these patient. These conditions can result in emergency movements can be suffi ciently prolonged and room visits, emergency inpatient consultations, severe to result in a signifi cant elevation of or involvement by security or law enforcement plasma creatine kinase [104 ] . offi cials. Under these circumstances, the causative medication(s) should be temporarily suspended with a plan to reintroduce them at a slightly lower Psychosis dosage once the dyskinesias have remitted. It is probably unwise to entirely discontinue chroni- Psychosis in PD commonly results in visual hal- cally administered dopaminergic medicines for lucinations, delusional thoughts, and illusory any sustained period of time for fear of inducing phenomena. Auditory and tactile hallucinations the PHS and to avoid producing severe prolonged can occur, but are much less common. Psychosis akinesia. If there is not an immediate reduction in typically appears in PD patients with cognitive the severity of the dyskinetic movements, then impairment, but can also occasionally be seen in medical therapy will be required in the emergency nondemented patients. Psychotic symptoms can room setting. Benzodiazepine preparations such be rapid in appearance or escalation, suddenly as diazepam, lorazepam, or clonazepam can be reaching a critical point in severity and resulting very helpful, both in relieving the severity of the in an emergency presentation. The most common dyskinesias and diminishing the associated anxi- emergency presentations are hallucinations that ety that accompany them. Often a parenteral route are frightening to the patient or delusions that are of administration provides more rapid relief. If threatening. Both have the potential to result in a 14 Movement Disorder Emergencies 269 state of agitation. In these circumstances, reas- not uncommon in Parkinson’s disease, may result surance may be somewhat helpful, but in the in an emergency room visit. A recent study of most severe cases is inadequate. Delusions of anxiety disorders in PD found a lifetime preva- harm from family or friends or hallucinations of lence of 49% of all forms of anxiety, whereas the intruders in the home may result in calls from the specifi c prevalence of panic disorders in PD patient to police or other emergency responders. patients was 10% [ 112 ] . Panic disorder is more Recognizing that medications are often a contrib- likely to appear in patients with an earlier age of uting cause of acute psychosis, recent additions PD onset and in those with a family history of or dosage increases in antiparkinsonian drugs, or parkinsonism [112 ] . other medications, particularly those with anti- Typical panic attack symptoms include an cholinergic properties, should be evaluated and at intense discomfort or fear with sudden onset of least temporarily discontinued if needed. associated symptoms such as a sense of impend- Pharmacologic therapy will often be required for ing death, choking, breathlessness, palpitations, or more immediate relief of psychotic symptoms, chest pain. A panic attack sometimes is associated especially in the emergency room setting. The with the “off” state in PD. In that circumstance, atypical antipsychotic agents are useful in revers- pharmacologic measures to reverse the parkinso- ing psychotic symptoms in PD. Clozapine is the nian “off” state will also improve the sense of most useful, but has potentially serious adverse panic. When readjustment of antiparkinsonian effects, including agranulocytosis, and should medications to correct the off state does not reverse not be administered emergently without a thor- a panic attack, anxiolytic therapy will be required. ough review of possible previous administration A short-acting, rapid-onset benzodiazepine, such and adverse effects, a process that cannot be eas- as alprazolam, is useful for reducing the ily accomplished quickly in the emergency room intensity of panic-associated symptoms. Selective setting [106 ] . The next most useful and com- serotonin reuptake inhibitors are also useful for monly used atypical antipsychotic agent is que- panic disorders, but the absence of a rapid-onset tiapine [ 107 ] . Although some studies have formulation makes them less useful for acute questioned its effi cacy [ 108 ] , common experi- panic attacks in the emergency setting than for the ence supports its benefi t. The only atypical antip- treatment of an ongoing panic disorder. sychotic agents readily available in parenteral form for acute administration are olanzapine and ziprasidone. Olanzapine in effective dosages Delirium worsens parkinsonism and is not a good choice, whereas ziprasidone has less potential to exacer- The most common causes of acute delirium in bate parkinsonian symptoms and early experi- PD are intercurrent illness (especially infection), ence suggests that when administered or the postoperative state. When an identifi able intramuscularly, it can improve acute psychotic infection is present, appropriate antibiotic ther- symptoms within 1–2 h [109, 110 ] . The use of apy will aid reversal of delirium. Any form of atypical antipsychotic agents should be tempered surgery, especially orthopedic procedures, may by the “black box” warning of a slight increased result in postoperative delirium. The greatest risk risk of death when used to treat elderly patients for postoperative delirium is preexistent demen- with dementia [111 ] . tia. In anticipation of the possibility that delirium may develop postoperatively in such patients, certain preventative measures are useful. Thus, in Panic PD patients with known dementia, the use of regional rather than general anesthesia and Anxiety is common in PD. Most forms such as employing less deep levels of sedation are useful generalized anxiety or social phobia seldom pres- strategies that can lessen the risk of delirium after ent as an emergency, but panic attacks, which are surgery [113, 114 ] . 270 R.L. Rodnitzky

In addition to treating concurrent illnesses, MSA patients, it can occasionally be among the such as infection, environmental methods to rees- presenting signs of this condition [ 122 ] . An early tablish normal day, night, place, and time orienta- clue to the presence of stridor may be peculiar tion should be employed. Encouraging a family high pitched, nonposition dependent snoring dur- member to sit with the patient and provide a focus ing sleep. In many patients, this may be the exclu- of orientation can be useful in this regard. In the sive time of day that stridor occurs. Laryngoscopy severely agitated patient, pharmaceutical man- is the defi nitive diagnostic technique for identify- agement will more likely be required. Whereas ing laryngeal abductor dysfunction, and in patients haloperidol is standard therapy for delirium, it with stridor that occurs exclusively at night, the cannot be used in PD patients without severely procedure may have to be performed during sleep worsening their parkinsonism. An atypical antip- to identify the problem. Some patients experience sychotic agent, preferably quetiapine, should be stridor during the daytime as well as the night, used instead [115, 116 ] . In some non-PD popula- which is even more ominous in terms of the poten- tions, the alpha-2-agonist dexmedetomidine has tial for serious respiratory embarrassment. One been shown to be more effective in treating delir- study suggested that MSA patients who develop ium than either lorazepam [ 117 ] or haloperidol daytime stridor have a mean survival of less than [118 ] . There are no apparent contraindications to 1 year [123 ] . Since stridor has been associated the use in PD of this agent [119 ] . with sudden death in MSA patients, it is truly an emergency that requires immediate therapeutic attention. Rarely, stridor can be seen in other Suicide movement disorders, including Parkinson’s dis- ease, Creutzfeldt–Jacob disease, and Machado– One fi nal behavioral emergency in PD is suicidal Joseph disease [124 ] . ideation, which has been estimated to occur in as The simplest therapy for stridor associated many as one third of PD patients [120 ] . The sui- with MSA is CPAP [ 125 ] . Nocturnal video- cide rate is especially high in PD patients having laryngoscopy has documented that CPAP is capa- undergone deep brain stimulation of the subtha- ble of producing separation of the adducted vocal lamic nucleus (STN). A recent meta-analysis cords and improvement of stridor [ 126 ] . In more found that suicide attempts were observed in 1% advanced patients, where there may also be cen- of STN DBS patients and successful suicides tral hypoventilation, BIPAP has been suggested were documented in 0.5% [121 ] . These data point as the preferred therapy instead [127 ] . Should out that suicidal thoughts, gestures, and attempts none of these approaches be practical or success- in PD patients, especially in DBS patients, are ful, or if there is daytime stridor, tracheostomy, true emergencies and appropriate psychiatric the most defi nitive therapy, is required [125 ] . consultation is required in these patients, with Precipitation or exacerbation of central sleep consideration of admission to the hospital and apnea has been reported to occur after institution need to be taken very seriously. of tracheostomy in some MSA patients, occasion- ally with a fatal outcome [ 128 ] . Some deaths dur- ing sleep have also been reported in MSA patients Inspiratory Stridor in Multiple System despite adequate CPAP therapy, and in these cases Atrophy concurrent autonomic dysfunction is suspected to have resulted in a cardiac demise [ 129 ] . MSA can be associated with inspiratory stridor. Whether stridor in this clinical condition is due to laryngeal abductor weakness or adductor dystonia Acute Dystonic Reaction is uncertain, but the potential of a fatal outcome due to narrowing of the inspiratory pathway, if Acute dystonic reactions (ADR) typically occur left untreated, is without question. While stridor is after exposure to DRBA. Neuroleptic agents such more common in moderately or severely advanced as haloperidol, or antiemetic agents such as 14 Movement Disorder Emergencies 271 prochlorperazine are the most common offending risperidone reported that none of 49 children agents. Over 50% of ADRs occur within 24 h developed ADR [141 ] . Cocaine used together after DRBA exposure and approximately 90% with a DRBA predisposes to the development of occur within 5 days [ 130 ] . In the typical clinical ADR, and cocaine can cause ADR even when presentation, the muscles of the mouth, face, used alone [143 ] . Prophylactic pretreatment with eyes, and neck are involved resulting in one or anticholinergic drugs can reduce the incidence of more dystonic manifestations such as retrocollis, ADR in susceptible individuals [132 ] . back arching, lateral fl exion of the trunk, trismus, Children are not only at risk for ADR as a tongue protrusion, or deviation of the eyes [131 ] . result of administration of prescribed DRBA, but Trismus can be severe enough to dislocate the also from secretive (parent’s medication) or jaw. A potentially fatal form of ADR is dystonic unwise (excessive dose) ingestion of these agents laryngospasm with compromise of the airway [ 144 ] . In one example, several teenagers and one [130, 132] . This must be correctly identifi ed and younger child developed ADR after ingesting a distinguished from an anaphylactic reaction as medication they believed was “street Xanax,” but the therapy of the two conditions is entirely dif- actually contained haloperidol instead [145 ] . ferent. The presence of stridor is an important The treatment of ADR consists of administer- marker of laryngeal dystonia. ing intravenous diphenhydramine (25–50 mg) or Risk factors for ADR include young age, male benztropine (1–2 mg). Intravenous diazepam, a gender, a primary psychotic disorder, and prior second-line therapy, is also usually effective. drug-induced dystonic reactions. Patients with These therapies are extremely effective and the homozygous mutations in the CYPZD6 gene that prompt benefi t they produce helps confi rm the results in slow DRBA drug metabolism are also diagnosis of ADR, and in the case of laryngos- at greater risk for ADRs [133 ] . Drug dosage does pasm, may be lifesaving. After initial therapy of not seem to be a risk factor. Children have a an ADR, it is wise to continue oral anticholin- greater risk for this adverse effect compared to ergic agents for 2 weeks, especially if a long- adults. The incidence of ADR seems to be higher acting DRBA was used or in those cases where after administration of very potent DRBAs, such DRBA therapy must be continued. Premature as haloperidol [132 ] , but milder DRBA such as discontinuance can result in recrudescence of metoclopramide [134 ] and drugs with little effect symptoms [146 ] . Discontinuing anticholinergics on dopaminergic transmission, such as selective should be done with a slow taper to avoid rebound serotonin reuptake inhibitors [135 ] , are also worsening. Rarely, ADR can continue to recur capable of inducing the same syndrome. Rare over months despite discontinuance of the offend- cases of ADR have been reported after adminis- ing drug, requiring longer term anticholinergic tration of drugs that have no apparent dopamine therapy [147 ] . blocking function, and patients with this syn- drome exhibit the typical brisk response to anti- cholinergic therapy [ 136 ] discussed below. As an Dystonic Storm example of this phenomenon, both the antiviral drug foscarnet [ 137 ] and the commonly used Dystonic storm, also known as status dystonicus, antihistamine agent cetrizine [137 ] have been is characterized by an acute onset of severe dys- associated with ADR. ADR have also been tonic spasms or acute exacerbation of preexisting reported with “ecstasy” (MDMA) use [138 ] . dystonia such that the patient is in extreme pain Although atypical antipsychotic agents have been and/or at extreme risk for life-threatening com- associated with ADR [ 139 ] , the incidence is plications. Dystonic storm can develop in patients lower than that associated with older neuroleptic with primary dystonia (e.g., DYT1 dystonia) or agents [140, 141] . For example, a 25% incidence secondary dystonia (e.g., Batten’s disease or of ADR was reported in autistic children being cerebral palsy). Acute onset of dystonia can occur treated with haloperidol [ 142 ] , while a more in the setting of initiation of a new drug (espe- recent trial of autistic children being treated with cially a dopamine blocking agent), withdrawal of 272 R.L. Rodnitzky drugs in a dystonic patient (especially anticholin- [ 150] . A variety of additional agents have been ergic agents or intrathecal baclofen), or may sim- reported in individual cases to have provided ply be a severe spontaneous progression of a benefi t in cases of severe and acute dystonia, neurological condition for which dystonia is one including dantrolene, baclofen, levodopa, car- possible clinical component (e.g., Wilson’s dis- bamazepine, and various benzodiazepines. ease). More commonly, dystonic storm is an Intrathecal baclofen has been reported to be of event-related exacerbation of preexisting, gener- benefi t in a few patients refractory to medical alized dystonia such as that associated with the therapy, but is not uniformly benefi cial [151 ] . On DYT1 mutation. In patients with long-standing the other hand, there are cases in which intrathe- dystonia, an acute exacerbation may have an cal baclofen was ultimately of benefi t despite obvious precipitant, such as an intercurrent infec- lack of effi cacy of a test bolus prior to proceeding tion, recent trauma, or a change in medications. to an implantable pump [ 152 ] . Despite the most Alternatively, there may be no apparent cause for aggressive medical therapy, severe dystonic the sudden exacerbation of dystonia. The poten- spasms may continue, raising the possibility that tial systemic complications of severe sustained therapeutic paralysis, deep sedation, and ventila- dystonia are the main reason to consider this a tion may be required in an intensive care setting medical emergency. Much like the systemic com- [ 153] . Deep sedation can be successfully achieved plications of NMS, patients experiencing dys- with propofol [154 ] or midazolam [ 155 ] , both tonic storm can suffer respiratory embarrassment, short-acting agents with the additional benefi t of rhabdomyolysis and myoglobinuria, potentially having gabaergic properties that might contribute leading to renal failure [ 148 ] . Because of these to the antidystonic effect. potentially life-threatening developments, these While in the intensive care unit, supportive patients are typically managed in an intensive measures will be required, including rehydration, care unit. control of fever, and careful monitoring of cardiac The circumstances that have precipitated dys- function and blood pressure. In patients, who are tonic storm in each individual patient are impor- still uncontrolled after a period of paralysis, ste- tant to understand since they may dictate the reotactic surgery including pallidotomy or bilat- therapeutic approach. Thus, dystonic storm eral pallidal deep brain stimulation may ultimately related to intercurrent infection requires urgent be required [156, 157 ] . initiation of appropriate antibacterial or antiviral therapy. Similarly, withdrawal of an offending medication or reinstitution of a precipitously Stiff Person Syndrome withdrawn medication will prove to be the most important therapeutic step in other patients. The stiff person syndrome (SPS) is associated Once the precipitating circumstance has been with autoantibodies directed against glutamic identifi ed and neutralized, therapy must be initi- acid decarboxylase (GAD). Although there is ated to improve the dystonia itself and the sys- controversy about the role of these antibodies, temic complications that have resulted from it. they presumably act by reducing GABA-mediated Medical therapy of dystonia may require any or a inhibition of spinal interneurons with resultant combination of dopamine-depleting agents (tet- axial and limb rigidity [ 158 ] . GAD antibodies are rabenazine), anticholinergic drugs (trihexypheni- also found in patients with type 1 diabetes, but dyl), and/or dopamine blocking agent typically at much lower titers. The clinical syn- (haloperidol), each titrated to an effective or drome consists of profound rigidity of predomi- maximally tolerated safe dosage [ 148, 149 ] . nantly axial and proximal limb muscles with Anticholinergic agents may be tolerated at higher superimposed, often stimulus sensitive, muscle dosages in those already receiving this class of spasms that can be severe enough to produce long medication and are also similarly well tolerated bone fractures. These spasms, and the ongoing in high dosages by adolescents or young adults rigidity, can occasionally be life threatening, in 14 Movement Disorder Emergencies 273 that they can result in respiratory embarrassment, system, such as pump failure or catheter leakage, autonomic dysfunction, or both [159 ] . The clini- can cause a baclofen withdrawal syndrome with cian should be aware that any combination of an even more severe exacerbation of rigidity one, two or three, or all four limbs can be involved [ 170 ] , making it imperative that both the clinician separately, giving rise to a variant of the condi- and the patient be aware of this possibility. tion termed “stiff limb” syndrome [160 ] . Recently, the GABA receptor potentiator, propo- There is also a paraneoplastic form of SPS, fol, in modest intravenous dosages, has been used related to antiamphiphysin antibodies. Unlike with signifi cant benefi t to provide immediate ordinary SPS which has a male predominance, relief of SPS spasms without attendant sedation the paraneoplastic form, most common in breast [ 171 ] . In this circumstance it can be used as a ther- cancer, has a female predominance. In SPS the apeutic bridge pending the placement of a baclofen legs and axial muscles, especially the lower pump or until potent immunotherapy takes effect. paraspinal muscles, are most commonly affected, whereas in amphiphysin antibody SPS, the arms and neck muscles are often most prominently Hemiballism and Hemichorea affected [161 ] . A still more serious, although rarer form, is progressive encephalomyelitis with Large amplitude, proximally predominant fl ing- rigidity and myoclonus (PERM). The autoim- ing movements are characteristic of ballism. mune form of SPS is associated with a high inci- These movements are thought to exist on a clini- dence of other autoimmune conditions, such as cal continuum with the smaller amplitude, more thyroiditis and systemic lupus, and in fact may be distally predominant movements of chorea. The the initial manifestation of a systemic autoim- fact that these two different types of abnormal mune condition such as lupus [ 162 ] . Similarly, involuntary movements are pathophysiologically paraneoplastic SPS can be the presenting symp- related is supported by the observation that both toms of an occult carcinoma [ 163 ] . The clinician may exist in the same individual at the same time, who is unfamiliar with this syndrome can easily and ballism, as it improves, may evolve into cho- conclude that a patient with SPS is hysterical, as rea. In those cases in which chorea and ballism sensory, long tract, cognitive, and coordination coexist or the abnormal movement is in an inde- fi ndings are typically absent [ 164 ] , and on occa- terminate zone between the two, the term sion, only one, two, or three limbs are affected. hemichorea/hemiballism is often used. Ballistic Symptomatic therapy of the rigidity in this movements are anatomically classifi ed as monob- condition consists of administration of gabaergic allism (involving one limb), hemiballism (involv- agents, such as clonazepam, diazepam, and ing one side of the body), biballism (involvement baclofen. A variety of antiepileptic drugs, includ- of both side of the body), or paraballism (involve- ing vigabatrin, tiagabine, gabapentin, and leveti- ment of both lower extremities). In those cases in racetam, are considered to be somewhat benefi cial which hemiballism is due to involvement of the [ 165 ] . Treatment of the underlying autoimmune STN, the somatotopic organization of this struc- condition can be carried out with IVIg [166 ] , ture may account for the selective involvement of corticosteroids [ 167 ] , and, as recently demon- only one limb on one side of the body [ 172 ] , and strated, rituximab [ 168 ] . IVIG is the best studied the same could be said of patients with a cortical immunosuppressive therapy and is generally lesion. Although the STN is a common location considered the preferred agent in this of structural pathology associated with hemibal- category [ 164 ] . Although immunosuppressive lism, modern neuroimaging has proven that it therapy may be effective, it cannot be expected to may not be the structure involved in the majority have an immediate effect in an emergency room of cases. Other structures in the STN afferent or setting. Intrathecal baclofen can result in more efferent pathways such as the striatum, thalamus, rapid clinical improvement [ 169] , but paradoxi- globus pallidus, and cerebral cortex may also be cally any dysfunction in the baclofen pump the locus of pathology [ 173] . In one of the largest 274 R.L. Rodnitzky series in the literature with poststroke hemicho- associated with nonketotic hyperglycemia has rea/hemiballism, only four of 27 patients had been reported increasingly more frequently in lesions confi ned to the STN, while six each were recent years [ 182 ] and now represents the second in the stratum or cortex, with other isolated most common cause of hemiballism, stroke being lesions being found in the putamen, caudate, or the most common. This syndrome appears to be globus pallidus [173 ] . much more common in patients of Asian descent Ischemic and hemorrhagic strokes are the [ 182] . In these cases, CT scan of the brain typi- most common causes of hemiballism. In some cally reveals hyperintensity in the contralateral cases of apparent vascular hemiballism, neuroim- striatum corresponding to MRI scans that show aging is totally normal, and in others, the CT scan increased signal intensity on T1-weighted images result is normal but MRI reveals a lacunar infarc- and a decreased signal on T2-weighted scans. tion in the STN or elsewhere [ 174 ] . Hemichorea/ A high signal is occasionally seen on diffusion- hemiballism develops on the day of stroke onset weighted imaging [183 ] . After metabolic in the vast majority of cases, but in up to 10% it correction of the hyperglycemic state, the abnor- may develop a day later, and in rare cases as long mal involuntary movement usually disappears as 5 days later [ 173 ] . Vascular hemichorea can along with the CT and MRI abnormalities. In also appear in the form of a TIA, so-called limb- some cases, however, hemiballism persists shaking TIAs [ 175 ] . Although the prognosis for despite disappearance of the MRI abnormality survival in those with vascular hemiballism was [ 184, 185 ] . Interestingly, the same CT and MRI once thought to be worse than other stroke fi ndings have been seen in some hyperglycemic patients, especially in the preneuroleptic era, patients with no involuntary movements [ 186 ] . recent studies suggest that vascular hemiballism The exact nature of the striatal pathology remains patients, many of whom have had lacunar strokes, unclear. The fi nding of normal gradient-echo MR have a risk of stroke recurrence and death that is images in hyperglycemic hemiballism along with similar to stroke patients in general [176 ] . As in striatal high signal intensity on a diffusion- the case with other stroke syndromes, surgical or weighted scan has suggested to some authors that neurointerventional procedures that improve hyperviscosity with associated cytotoxic edema cerebral circulation may have a salutary effect on may play a role in this syndrome [ 183 ] . However, vascular hemiballism [177 ] , as discussed below. autopsy and biopsy evaluation of the striatal tis- A variety of other pathologies including sue demonstrating MRI hyperintensity has encephalitis, systemic lupus erythematosus, mul- revealed evidence of multiple foci of recent tiple sclerosis, basal ganglia calcifi cation, and infarcts and/or gliosis [187, 188 ] . PET scans per- nonketotic hyperglycemia can also result in formed in the acute and subacute phases have hemiballism [178 ] . Structural pathologies such suggested glucose hypometabolism in the affected as bacterial or tuberculosis abscess, neoplasm, regions of the brain [189 ] . moyamoya disease, HIV-related toxoplasmosis, The fi rst therapeutic measure in treating or arteriovenous malformation have also been hemiballism is to correct the underlying meta- associated with hemiballism. Stereotactic abla- bolic, infectious, or vascular abnormality to the tion of the STN for the treatment of Parkinson’s extent possible. In the circumstance of nonketotic disease can result in hemiballistic movements hyperglycemia and ischemic stroke, the two most that are transient and improve in a matter of common causes of hemiballism, this means cor- weeks [179 ] , but can also rarely result in perma- recting the hyperglycemia in the former condi- nent hemiballism [180 ] . Similarly, therapeutic tion, and reversing the ischemia in the second stimulation of the STN for Parkinson’s disease condition through methods such as supporting can produce hemiballism that resolves when the blood pressure, thrombolytic therapy, and endo- stimulation is adjusted below a given threshold vascular procedures. Acutely reversing ischemia voltage [181 ] . will have little effect on hemiballism due to a The syndrome of hemiballism–hemichorea completed stroke, but can be effective when the and magnetic resonance striatal hyperintensity abnormal movements are related to transient 14 Movement Disorder Emergencies 275 ischemia [175, 177 ] . Hemiballism related to placement for obstructive hydrocephalus. J Clin hyperglycemia may reverse within hours of cor- Neurosci. 2006;13(3):373–8. 3. Prashantha DK, Netravathi M, Ravishankar S, Panda recting the metabolic abnormality, but up to 20% S, Pal PK. Reversible parkinsonism following ven- of patients continue to have ballism for months. triculoperitoneal shunt in a patient with obstructive Vascular hemiballism due to a completed stroke hydrocephalus secondary to intraventricular neuro- improves spontaneously in the majority of cysticercosis. Clin Neurol Neurosurg. 2008;110(7): 718–21. patients. In a series of 25 such patients followed 4. Kim MJ, Chung SJ, Sung YH, Lee MC, Im JH. for up to 3 years, hemiballism completely disap- Levodopa-responsive parkinsonism associated with peared in 56% of cases after a mean duration of hydrocephalus. Mov Disord. 2006;21(8):1279–81. 15 days [173 ] . In another series of the same size, 5. Racette BA, Esper GJ, Antenor J, Black KJ, Burkey A, Moerlein SM, et al. Pathophysiology of parkin- full recovery was noted after 3–15 days in 56% sonism due to hydrocephalus. J Neurol Neurosurg of patients [176 ] . Psychiatry. 2004;75(11):1617–9. In the absence of spontaneous or therapeutic 6. Kinugawa K, Itti E, Lepeintre JF, Mari I, Czernecki reversal of hemiballism, it must then be treated V, Heran F, et al. Subacute dopa-responsive Parkinsonism after successful surgical treatment symptomatically. For control of the abnormal of aqueductal stenosis. Mov Disord. 2009;24(16): involuntary movement itself, DA blocking or 2438–40. depleting drugs are the most effective symptom- 7. Vaamonde J, Flores JM, Gallardo MJ, Ibanez R. atic therapy. Traditionally, typical neuroleptics Subacute hemicorporal parkinsonism in 5 patients with infarcts of the basal ganglia. J Neural Transm. such as haloperidol have been used for this pur- 2007;114(11):1463–7. pose, but more recently low-dose clozapine, 8. Peralta C, Werner P, Holl B, Kiechl S, Willeit J, olanzapine, and other atypical antipsychotic Seppi K, et al. Parkinsonism following striatal agents have also been found to be effective [190, infarcts: incidence in a prospective stroke unit cohort. 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