Paroxysmal Autonomic Instability with Dystonia After Brain Injury

NEUROLOGICAL REVIEW

SECTION EDITOR: DAVID E. PLEASURE, MD Paroxysmal Autonomic Instability With Dystonia After Brain Injury

James A. Blackman, MD, MPH; Peter D. Patrick, PhD; Marcia L. Buck, PharmD; Robert S. Rust, Jr, MD

complication of severe brain injury is a syndrome of intermittent agitation, diaphoresis, hyperthermia, hypertension, tachycardia, tachypnea, and extensor posturing. To capture the main features of this syndrome, derived through literature review and our own case series, we propose the term paroxysmal autonomic instability with dystonia.AWe reviewed reports of autonomic dysregulation after brain injury and extracted essential features. From the clinical features, consistent themes emerge regarding signs and symptoms, differential diagnosis, and pharmacological therapies. We used these findings to make recommenda- tions regarding diagnosis and treatment. Paroxysmal autonomic instability with dystonia appears to be a distinctive syndrome after brain injury that can mimic other life-threatening conditions. Early recognition may lead to fewer diagnostic tests and a rational approach to management. Pro- spective trials of specific drugs are needed to determine optimal efficacy. Arch Neurol. 2004;61:321-328

A complication of severe brain injury, re- lack of a standardized nomenclature is a gardless of etiology, is a syndrome of major problem with research into this con- marked agitation, diaphoresis, hyper- dition.1 Based on a review of limited ex- thermia, hypertension, tachycardia, and isting literature, generally consisting of re- tachypnea accompanied by hypertonia and ports of a single or only a few cases, and extensor posturing. Usually episodic, it first of our own case series, we propose the fol- appears in the intensive care setting but lowing name for this syndrome: paroxys- may persist into the rehabilitation phase mal autonomic instability with dystonia for weeks to months after injury in indi- (PAID). We will define its characteristics viduals who remain in a low-response as precisely as possible, provide guide- state. The syndrome engenders alarm be- lines for distinguishing it from other con- cause it may be difficult to distinguish from ditions with similar characteristics, and life-threatening conditions such as sep- suggest a rational treatment approach. sis, impending herniation, or epileptic sei- The pathophysiology of PAID can be zure. These manifestations could lead to best explained by dysfunction of auto- secondary hypertensive or hyperthermic nomic centers in the diencephalon (thala- encephalopathy and even death. mus or hypothalamus) or their connec- Various labels have been applied to tions to cortical, subcortical, and brainstem this phenomenon, such as paroxysmal sym- loci that mediate autonomic function. pathetic storms, diencephalic seizures, or Bullard2 suggested a release phenom- midbrain dysregulatory syndrome. How- enon in which loss of cortical and sub- ever, the syndrome remains poorly un- cortical control of vegetative functions derstood and underrecognized, despite its occurs, including regulation of blood distinctive and characteristic features. The pressure and temperature. Boeve et al3 expanded this concept by speculating From the Kluge Children’s Rehabilitation Center, Department of Pediatrics that the mechanism likely involves acti- (Drs Blackman, Patrick, and Buck), and the Division of Pediatric Neurology, vation (or disinhibition) of central sym- Department of Neurology (Dr Rust), University of Virginia, Charlottesville. pathoexcitatory regions such as the para-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 ventricular hypothalamic nucleus, lateral periaqueductal cause the various constituent parts of the syndrome may gray substance, lateral parabrachial nucleus, or rostral ven- be caused by a wide variety of processes that may occur tricular medulla. Cortically provoked release of adreno- in these very ill patients, including seizures, infection, the medullary catecholamines during PAID episodes may con- effects of drugs, withdrawal from drug therapy, pain, or tribute to the rise in blood pressure as well as tachycardia agitation. PAID signs occur at a time when the patient’s and tachypnea.4,5 mental status is abnormal, and tests such as electroen- Thermoregulatory dysfunction may also be pro- cephalography may be difficult to obtain or coordinate with duced by hypothalamic dysfunction, as has been dem- the intermittent phenomena. These signs invariably in- onstrated experimentally6 and clinically. The tempera- clude temperature elevation (as high as 41°C), increases ture elevations associated with PAID may also be in heart and breathing rates, hypertension, diaphoresis, agi- explained, at least in part, by the hypermetabolic state tation, and extensor posturing. Creatine kinase levels are that accompanies sustained muscular contractions. rarely reported; in one case these values were within the Rigidity and decerebrate posturing are seen experi- reference range, and in another, elevated. mentally and clinically with lesions in the midbrain, block- The most commonly used drugs for treatment of ing normal inhibitory signals to pontine and vestibular PAID are morphine sulfate, bromocriptine mesylate, pro- nuclei.7 This allows these nuclei to become tonically ac- pranolol hydrochloride, clonidine hydrochloride, lora- tive, transmitting facilitatory signals to the spinal cord zepam, and dantrolene sodium. Each one of these drugs control circuits. Spinal reflexes become hyperexcitable, is rational and addresses a component of the PAID syn- evoked by sensory input signals that are usually below drome (Table 2). the threshold for excitation of a motor response. Opioid receptors are found in brain cardiovascular nuclei, the heart, and blood vessels.20 Opiates such as LITERATURE REVIEW morphine, when peripherally injected into healthy ani- mals, produce hypotension.21 Morphine induces anal- Episodic agitation, diaphoresis, hyperthermia, tachycar- gesia, respiratory depression, and bradycardia. Its anal- dia, tachypnea, and rigid decerebrate posturing after se- gesic properties may interfere with pain as an inciting vere brain injury were first noted in a report by Strich in factor, and its sedative effects may counter the tachycar- 1956.8 He called these events brainstem attacks. Subse- dia and tachypnea. Constipation is a problematic ad- quently, this constellation of clinical signs has received verse effect of morphine and narcotic dependency. a variety of labels, including autonomic dysfunction syn- Withdrawal from opiate therapy may provoke signs drome, fever of central origin, neurostorming, acute mid- that falsely suggest PAID. brain syndrome, hypothalamic-midbrain dysregulation syn- The use of dopamine antagonists or the with- drome, hyperpyrexia associated with sustained muscle drawal of dopamine agonist therapy may also result in contractions, dysautonomia, sympathetic storms, paroxys- neuroleptic malignant syndrome (NMS), the clinical fea- mal sympathetic storms, acute hypothalamic instability, and tures of which suggest PAID. Thus, it is not surprising diencephalic seizures. that the use of bromocriptine, a dopamine agonist, has Table 1 provides a summary of the clinical fea- been found to be helpful in PAID. tures of relevant case reports. We have included a series Because excitation of the sympathetic nervous of our own patients. Permission was obtained from the system appears to be a major feature of PAID, the uses Human Investigation Committee, University of Vir- of ␤-adrenergic blockade, such as propranolol (nonse- ginia, Charlottesville, to review patient records for this lective ␤-adrenergic blockade) or labetalol hydrochlo- ␤ ␣ report. Because some of these patients received inten- ride (nonselective - plus 1-adrenergic blockade), are sive care at other hospitals and their daily nursing and logical choices and have proven clinically useful in the physician notes were not available, it was not possible amelioration of some of the most important clinical to determine the time of initial onset of PAID signs or signs (eg, hypertension), but not cholinergic signs (eg, their total duration. diaphoresis) of PAID. In the experience of Do et al,9 ␤ Although some heterogeneity in manifestations has 1-adrenergic selective antagonists (eg, metoprolol or been noted, there is a sufficient degree of uniformity to atenolol) are not effective, as in mitigating autonomic justify viewing these cases as a syndrome. The cases have dysregulation. ␣ in common autonomic dysregulation and rigidity due to Clonidine, an 2-adrenergic agonist, reduces blood dystonia (involuntary sustained muscle contraction and pressure, has a behavior-stabilizing effect, and causes se- extensor posturing). The PAID syndrome has been re- dation. These features treat the sympathetic signs and may ported in children and adults. Traumatic and hypoxic interrupt feedback into the system that otherwise would brain injury account for most cases, but some were due perpetuate the cycle of autonomic dysregulation. to tumors, intracranial hemorrhage, or hydrocephalus. The benzodiazepines, such as lorazepam, have anx- It is most likely to be encountered after processes that iolytic and sedating effects and muscle relaxant proper- produce diffuse axonal or brainstem injury. ties that may account for benefits observed in treatment The onset of PAID signs often occurs in the first week of PAID. after severe brain injury, when differential diagnosis is In addition to its direct muscle relaxant properties, most difficult, and continues for weeks to months, in some dantrolene may diminish fever due to prolonged muscle cases for longer than 1 year. We have found that the epi- contraction and may also reduce the somatosympa- sodes tend to persist the longest in patients with brain thetic spinal reflexes that contribute to sympathetic injury due to anoxia. Early diagnosis is challenging be- excitation.

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No. of Duration No. of Cycles of Each Total Treatment Term Used Source Subjects Age, y Origin Onset, d per Day Episode Duration Signs or Drugs to Describe University of 7 9-29 MVC, near NA NA NA NA T, 38°C-41.8°C; HR, Atenolol, NA Virginia drowning, 161-216 beats/min; lorazepam, hanging, BP, 123-171/78-101 diazepam, assault mm Hg; rigid or methadone decerebrate hydrochloride, posturing; propranolol diaphoresis; agitation hydrochloride, clonidine hydrochloride Thorley 1 20 MVC 1 NA Minutes to 2 wk T, 40.0°C; HR, 156 Midazolam, Acute et al,12 hours beats/min; extremity lorazepam, hypothalamic 2001 posturing; morphine instability diaphoresis; sulfate, agitation; CPK, 61 oxycodone, U/L bromocriptine mesylate, dantrolene sodium Cuny et al,11 4 17-37 MVC 24-60 2-16 NA 1-8 wk Hyperthermia; Intrathecal Dysautonomia 2001 hypertonia; baclofen tachycardia Do et al,9 1 21 MVC 450 3 1-2 h NA T, 39.1° C; HR, 140-160 Labetalol Paroxysmal 2000 beats/min; BP, hydrochloride sympathetic 170-180/100 storm mm Hg; diaphoresis; flexor posturing Baguley,1 14 NA Hypoxia, TBI NA NA NA NA Classic features NA Paroxysmal 1999 described by Boeve sympathetic et al3 (1998) storms Goh et al,10 1 7 Midbrain glioma 3 NA NA NA T, 38.4°C-39.5°C; HR, Phenytoin sodium, Diencephalic 1999 150-180 beats/min; diazepam, seizures SBP, 180 mm Hg; lorazepam, DBP, 120 mm Hg; clonidine sweating, muscle spasms; decorticate posturing; nystagmus; teeth grinding Boeve et al,3 1 17 MVC 5 1-3 2-4, 12 mo T, 39°C-42°C; HR, Morphine, Paroxysmal 1998 8-10 h 140-190 beats/min; bromocriptine, sympathetic RR, 26-40 dantrolene storms breaths/min; SBP, sodium (diencephalic 150-170 mm Hg; seizures) increased decerebrate/ opisthotonic posturing Scott et al,13 1 11 Hydrocephalus, NA 2-4 2-6 h NA T, 39°C-42°C; HR, Chlorpromazine Hypothalamic 1997 tumor 140-160 beats/min; hydrochloride, storming RR, 30-60 bromocriptine, breaths/min; SBP, propranolol, 160 mm Hg; DBP, levodopa/ 110-120 mm Hg; carbidopa diaphoresis; increased muscle tone; tremors Sneed,14 1 2 Near drowning 14 NA Days to a 85 wk T, 39.5°C; diaphoresis; Clonazepam Hyperpyrexia 1995 week opisthotonic associated posturing; increased with sustained CPK level muscle contractions Meythaler 3 15, 20, 21 TBI NA NA NA NA Tachycardia; T, Propranolol Fever of central and 38.9°C-40.6°C; origin Stinson,15 sweating; decorticate 1994 posturing

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No. of Duration No. of Cycles of Each Total Treatment Term Used Source Subjects Age, y Origin Onset, d per Day Episode Duration Signs or Drugs to Describe Pranzatelli 3 7-19 Hypothalamic 6 1-6 NA NA T, 39°C-40°C; HR, Fentanyl citrate, Hypothalamic- et al,16 astrocytoma, 140-160 beats/min; pancuronium midbrain 1991 MVC, CHI RR, 40-45 bromide, dysregulation breaths/min; SBP, lorazepam, syndrome 150-160 mm Hg; clonazepam, DBP, 105-115 dantrolene, mm Hg; diaphoresis; bromocriptine, decerebrate acetaminophen, posturing/ methadone, opisthotnous diazepam, propranolol Rossitch and 9 NA 6 CHI, 2 1 NA Minutes NA Increased T, HR, RR, Morphine, Autonomic Bullard,17 hydrocephalus, to and BP; dilated dantrolene, dysfunction 1988 1 ICH hours pupils; increased bromocriptine syndrome extensor posturing; diaphoresis Talman 2 26, 57 Acute NA NA NA NA T, 39°C-41°C, HR, 160 Shunt revision Hyperthermic et al,18 hydrocephalus beats/min; RR, 32-36 syndrome 1988 breaths/min; SBP, 150-158 mm Hg; DBP, 90-100 mm Hg; rigidity; decerebrate posturing; diaphoresis Bullard,2 2 24 MVC 1-6 2-3 2-5 h 3 wk T, 38°C-40°C; HR, Morphine, Diencephalic 1986 100-150 beats/min; bromocriptine, seizures RR, 60-148 dantrolene breaths/min; SBP, 170-190 mm Hg; DBP, 80-120 mm Hg; extensor/decerebrate posturing; increased ICP; dilated pupils Klug et al,19 25 11-68 NA NA NA NA NA Changes in T, HR, RR, NA Decerebrate 1984 BP rigidity and vegetative signs Strich,8 1956 3 27, 28, 32 TBI 3 NA NA NA Hyperpnea; extensor NA Brainstem posturing; attacks decerebration; salivation; sweating

Abbreviations: BP, blood pressure; CHI, closed head injury; CPK, creatine phosphokinase; DBP, diastolic BP; HR, heart rate; ICH, intracranial hemorrhage; ICP, intracranial pressure; MVC, motor vehicle crash; NA, not available; RR, respiratory rate; SBP, systolic BP; T, temperature; TBI, traumatic body injury.

DIFFERENTIAL DIAGNOSIS tice has diminished the occurrence of NMS in such patients. Because a considerable number of safer agents are The following clinical entities have features in common now available, the use of neuroleptics in this setting is gen- with PAID and may share underlying pathophysiologi- erally considered to be contraindicated. cal mechanisms (Table 3). Several cases have been reported with withdrawal of dopamine agonists (levodopa/carbidopa22 and amanta- Neuroleptic Malignant Syndrome dine hydrochloride.23 Numerous reports also associate the syndrome with the use of the dopamine receptor antago- Neuroleptic malignant syndrome is a severe disturbance nist metoclopramide hydrochloride (Reglan),24-27 a drug of motor tone seen in patients taking dopamine receptor– commonly used to stimulate gastric emptying and re- blocking agents, ie, phenothiazines such as thioridazine duce aspiration risk in patients with brain injury. Two case hydrochloride (Mellaril) and prochlorperazine (Com- reports implicating metoclopramide involved chil- pazine) and butyrophenones such as haloperidol (Haldol). dren,28,29 and in 1 case symptoms were likely triggered by This syndrome consists of fever, muscle rigidity, auto- metoclopramide but did not reach their full manifesta- nomic instability, alteration of consciousness, and elevation until after the therapy was discontinued.30 tion of serum creatine phosphokinase levels. Formerly, neu- Neuroleptic malignant syndrome apparently re- roleptics such as haloperidol were frequently used to treat sults from deficient compensatory mechanisms after agitation in brain-injured patients. The decline in this prac- blockade of dopaminergic regulation of muscle tone and

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Drug Actions T1⁄2 Peak Action Typical Uses Major Adverse Effects Typical Dose Range

Bromocriptine Dopamine D2 agonist 7 h 1.6 h Puerperal lactation Hyperprolactinemia, Adults and adolescents, mesylate suppression, mental status changes 1.25 mg PO twice Parkinson (eg, confusion, daily initially, titrated disease hallucinations), to 10 to 40 mg/d dyskinesia

Clonidine ␣2-Adrenergic agonist; 12-16 h 3-5 h Hypertension, Sedation, hypotension, Children, 5-10 µg/kg per hydrochloride decreased sympathetic ADHD rebound hypertension day PO given in (Catapres) outflow from CNS; with abrupt withdrawal divided doses; adults, decreased BP 0.2-1.2 mg/d PO in divided doses Dantrolene sodium Dissociates excitation 5-9 h 30 min Muscle relaxation, Hepatotoxicity, Children, 0.5 mg/kg per (Dantrium) contraction by malignant drowsiness, dose PO given 2 to 4 interfering with Ca++ hyperthermia generalized weakness times daily; adults, 25 release from mg/d PO given 2-4 sarcoplasmic times daily up to a reticulum maximum of 400 mg Lorazepam Interacts with GABA 12 h 2 h Sedative, Lightheadedness, Children, 0.05 mg/kg IV (Ativan) receptor site anxiolytic lassitude, motor or PO, up to 2 mg modulating its activity anticonvulsant, incoordinaton, every 4-8 h; adults, muscle relaxant confusion 2-4 mg IV or PO every 4-8 h Morphine sulfate Opioid µ-receptor agonist 2 h IV/IM, Analgesia Drowsiness, Children, 0.2-0.5 mg/kg 30 min nausea/vomiting, PO every 4-6 h or euphoria, histamine 0.1-0.2 mg/kg per release, hypotension, dose IV; adults, 10-30 pruritis, ileus mg PO or 2.5-10 mg IV given up to every 4-6 h

Propranolol ␤1,2-Adrenergic blockade 3-5 h 90 min Hypertension, Bradycardia, Children, 0.5-1 mg/kg hydrochloride thyrotoxicosis, light-headedness, per day PO given in (Inderal) anxiolytic lassitude, weakness, divided doses; adults, bronchospasm 10-20 mg PO given 2-4 times daily

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; BP, blood pressure; CA++, calcium ion; CNS, central nervous system; GABA, ␥-aminobutyric acid;

IM, intramuscular; IV, intravenous; NA, not applicable; PO, by mouth; T1⁄2, half-life.

Table 3. Comparison of Clinical Signs in Conditions That Mimic PAID After Traumatic Brain Injury

Rigidity/ Mental Heart Breathing Blood Pupil Extensor Status Temperature Rate Rate Pressure Size Diaphoresis Agitation Posturing CPK Myoglobinuria PAID ↓↑↑↑↑↑++↑ ?NA Malignant hyperthermia ↓↑↑↑±↓ NA NA NA +Ͼ− ↑ + Neuroleptic malignant ↓↑↑↑↑or ↓ NA + NA + ↑ + syndrome Increased ICP ↓↓↓↑NA NA NA ± NA NA Central fever ↑↑↑NA NA NA NA NA NA NA Infection/sepsis ±↓↑↑↑± ± NA NA NA NA Nonconvulsive epilepsy NA NA NA NA NA ±↑ NA ± NA NA NA Agitation (RLA level IV)* ±↓ NA ↑↑ NA ↑ + + NA NA NA Narcotic withdrawal ±↓ NA ↑↑ NA ↑ + + NA NA NA Autonomic dysreflexia NA ↑↑↑↑NA + NA NA NA NA

Abbreviations: CPK, creatine phosphokinase; ICP, intracranial pressure; PAID, paroxysmal autonomic instability with dystonia; RLA, Rancho Los Amigos Scale; downward arrow, decreased; plus sign, increased; plus-minus sign, may or may not be present; upward arrow, increased; question mark, unknown. *Explained in Hagen et al.49

autonomic function.31 Neuroleptic malignant syn- nition and appropriate treatment, mortality due to NMS drome occurs in only 1% of individuals taking neuro- is low. Treatment includes stopping the neuroleptic leptics. The incidence of NMS is likely lower than this therapy and providing supportive care. with the newer antipsychotic drugs. Cases have been reported in children as young as 1 year after a single acci- Malignant Hyperthermia dental dose.32 Symptoms usually occur 3 to 9 days after starting therapy. Extrapyramidal signs may be associ- Malignant hyperthermia (MH) is a disease of skeletal ated with other NMS clinical features. With early recog- muscle characterized by hypermetabolism that occurs with

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 exposure to a triggering agent such as inhalational an- term seizure is a misnomer, because there has never been esthetic agents or depolarizing muscle relaxant drugs (eg, a demonstration of an epileptogenic focus during a PAID succinylcholine chloride), usually during induction or episode, and most patients with PAID do not benefit from sometimes within 2 to 3 hours and rarely more than 24 antiepileptic medications. Thus, diencephalic seizures con- hours later. After surgery, MH has been reported to oc- stitute a syndrome distinct from PAID. cur in the absence of administration of a known triggering agent and may continue for several days.33 Autonomic Dysreflexia Malignant hyperthermia may also follow head injury without any exposure to anesthesia or surgery.34 A Autonomic dysreflexia (AD) occurs in individuals with 21-year-old man became agitated and diaphoretic 36 hours spinal cord injury at the level of T6 through T8 or above. after head injury. His temperature rose to 42.3°C; he was Any noxious stimulus below this level, such as a dis- tachycardic, hypotensive, tachypneic, and displayed de- tended bladder, may initiate reflexive sympathetic activ- cerebrate posturing. Rhabdomyolysis and renal and liver ity resulting in life-threatening hypertension uncon- failure developed. Results of a muscle biopsy confirmed trolled by feedback parasympathetic activity.47 Other the diagnosis of MH, including a characteristically ab- manifestations of AD include headache, flushing and normal response of muscle to halothane in vitro. sweating of the face and upper torso, and apprehension. Malignant hyperthermia tends to occur most com- Removing the inciting stimulus relieves AD. Patients with monly in younger persons; 52% were younger than 15 spinal cord injury may have brain injuries as well, pre- years in 1 case series.35 Inheritance of MH is primarily disposing them to sympathetic dysregulation at the spi- autosomal dominant, although it may also be autoso- nal cord and brain levels. mal recessive, polygenic (genes on chromosomes 3, 17, and 19 have been implicated), or sporadic.36-39 Central Fever Abnormal calcium regulation appears to be the ba- sic underlying defect resulting in tonic muscle contrac- Fever is common after central nervous system trauma.48 tion with production of excessive heat, resulting in a rise Causes include wound infection, meningitis, blood in the in body temperature to as high as 44°C. Skeletal muscle cerebrospinal fluid, drug fever, and pneumonia/ rigidity can be local or diffuse, and is often first ob- atelectasis. Central fever is a diagnosis of exclusion, at- served in the masseter muscles, extremities, and chest. tributed to trauma if it affects the base of the brain or the Damaged muscles release large amounts of tissue throm- hypothalamus. The fever, often very high and persisting boplastin, leading to coagulopathy, and myoglobin, lead- for weeks after injury, is relatively resistant to antipy- ing to myoglobinuria and acute tubular necrosis. retic therapy and occurs in the absence of perspiration. Apart from discontinuing the triggering agent, if known, the use of dantrolene is the only effective treat- Agitation ment for MH. Dantrolene blocks calcium release from the sarcoplasmic reticulum causing muscle relaxation, and The clinical sign that is probably most often confused with has reduced mortality due to MH dramatically. PAID is simple agitation. After emergence from true coma (return of sleep/awake cycles) with returning—albeit Diencephalic Seizures sometimes very slowly—arousal and awareness, the patient typically becomes agitated with extensor postur- The PAID syndrome frequently has been termed and con- ing and thrashing about the bed. The following tabula- fused with true diencephalic seizures. In 1929, Pen- tion shows the levels of cognitive functioning of the field40 described a 41-year-old women with a tumor of Rancho Los Amigos Scale49: the third ventricle who displayed paroxysmal dis- Level Description charges of the vegetative nervous system that he de- I No response scribed as autonomic epilepsy. Subsequent case reports II Generalized response of episodes characterized by irregular respirations, al- III Localized response tered heart rate, labile blood pressure, hypothermia, and IV Confused, agitated diaphoresis were associated with neoplasms of the dien- V Confused, inappropriate cephalon,41 agenesis of the corpus callosum,42-44 trapped VI Confused, appropriate 45 VII Automatic, appropriate third ventricle, and a suprasellar arachnoid cyst. The VIII Purposeful, appropriate key features of hypothermia and profuse sweating generally responded to anticonvulsants, although electro- If the patient is at level II, there may be no purposeful encephalographic studies did not typically show epilep- movements. The lack of autonomic instability (ie, ex- tiform discharges. One case of periodic hypothermia, cessive rise in temperature and blood pressure) distin- described as diencephalic epilepsy, responded only to total guishes agitation from PAID. Pain or discomfort from any sympathectomy.46 source (eg, musculoskeletal, visceral, or headache) can Several cases of what appears to us to be the PAID produce agitation. When purposeful movements are ob- syndrome have been described in the literature as dien- served with agitation, such as pulling out tubes or hit- cephalic seizures.2,3 Gohetal10 described a 7-year-old child ting, as seen at Rancho Los Amigos levels III and IV, PAID with repeated episodes of sympathetic hyperactivity due is clearly not the cause of agitation. Another possible cause to a midbrain glioma as having a variant of diencephalic of agitation is narcotic withdrawal, as almost all pa- seizures. They acknowledged in the discussion that the tients with severe brain trauma accompanied by other in-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 juries such as fractures receive narcotics in the inten- ered, especially treatable intracranial abnormalities such sive care setting, and they are weaned from the drugs as as hydrocephalus, increased intracranial pressure, or extra- they progress toward rehabilitation. axial blood or fluid accumulation. Other treatable irri- In acute brain injury, the pathophysiology of PAID tants, such as dehydration, constipation, fracture site pain, may be similar in some ways to that of NMS or MH. Drug or uncomfortable casts must be alleviated. Drugs or an- exposure or withdrawal or even stress may initiate as- esthetics that might precipitate or exacerbate PAID should pects of these conditions, confusing the diagnosis. Any be avoided, and caution should be used in the sudden of the single features of PAID, such as hypertension, agi- withdrawal of dopamine agonist therapy. tation, or hypertonia, could stimulate the full-blown syn- As described earlier, a finite number of drugs have drome. This might explain why a single drug that ad- been used singly or in combination to alleviate PAID. No dresses 1 feature (eg, dantrolene for hypertonia) could clear evidence suggests that one medication regimen is interrupt and perhaps abort the process, especially if superior to another, and drugs seem to work well for some therapy is initiated early. Four cases of posttraumatic dys- patients but not others. The goal is to maximize effec- autonomia successfully treated with intrathecal bac- tiveness while minimizing adverse effects. For example, lofen, a muscle relaxant, illustrate this point.11 Most of- sedation medications that are administered as needed, like ten, more than 1 drug is required for control. narcotics or benzodiazepines, may quiet an episode but It is clear that PAID is not associated with seizure depress arousal and awareness between episodes. Cloni- activity and, thus, the term diencephalic or hypothalamic dine will reduce blood pressure effectively, but also is se- seizure is not appropriate to describe this condition. Un- dating. Dantrolene as a muscle relaxant may be prefer- less there are comorbid seizures, antiepileptic drugs for able to baclofen because it does not sedate; however, its PAID are not a rational choice except for use as mood use may be limited by toxic effects to the liver. ␤-Block- stabilizers, possibly treating the agitation feature. ers will lessen sympathetic features, but should be used with caution in patients with asthma or diabetes. CRITERIA FOR PAID A logical approach is to choose target signs, con- sider safety of particular drugs for the individual, and set It seems useful clinically and for future research to estab- a time frame for determination of efficacy before a drug lish a single name that encompasses and clearly denotes is changed or a second drug is added. In our center, we the main features of the clinical phenomena described in try to devise a regimen that will prevent or ameliorate this report. Paroxysmal autonomic instability with dysto- rather than rely on as-required drugs that may overtreat nia appears to accomplish this. Based on the literature re- the condition. view and our own experience, we propose specific crite- Greater awareness of PAID and appropriate early in- ria for the PAID syndrome. Within the clinical setting of tervention may minimize repetitive and expensive tests traumatic brain injury, signs of PAID syndrome include (eg, sepsis workups), ease nursing management, avoid (1) severe brain injury (Rancho Los Amigos level, ՅIV), pharmacological excess, prevent secondary injury, and (2) temperature of at least 38.5°C, (3) pulse of at least 130 allay the anxiety of parents and health care workers ob- beats/min, (4) respiratory rate of at least 140 breaths/ serving repeated episodes. min, (5) agitation, (6) diaphoresis, and (7) dystonia (ie, Further research is needed to evaluate individual rigidity or decerebrate posturing). The duration is at least or combination pharmacotherapy for PAID. A clearer defi- 1 cycle per day for at least 3 days. Finally, other condi- nition of this syndrome may facilitate cross-institutional tions must be ruled out. In addition to recognizing con- studies. sistent features of PAID, it is as important to recognize signs of other diseases or conditions that require prompt atten- Accepted for publication October 29, 2003. tion and a different diagnostic or treatment approach. Author contributions: Study concept and design (Drs Blackman and Patrick); acquisition of data (Dr Black- ASSESSMENT AND TREATMENT man); analysis and interpretation of data (Drs Blackman, Buck, and Rust); drafting of the manuscript (Drs Black- Differential diagnosis is challenging, especially in the phase man and Rust); critical revision of the manuscript for im- of acute brain injury. Because patients may be heavily se- portant intellectual content (Drs Blackman, Patrick, Buck, dated for ventilation or pain management, temperature and Rust); administrative, technical, and material support elevation is usually the first concern, prompting body fluid (Drs Blackman, Buck, and Rust); study supervision (Dr cultures, leukocyte counts, and various imaging studies Blackman). to rule out sepsis. If these test results are negative, fever Corresponding author and reprints: James A. Black- may be attributable to noninfectious causes. man, MD, MPH, Kluge Children’s Rehabilitation Center, Uni- As sedation and analgesia are withdrawn, more typi- versity of Virginia, 2270 Ivy Rd, Charlottesville, VA 22903 cal cycles of PAID may become evident. Typically, the (e-mail: [email protected]). next sign of concern is elevated blood pressure, leading to the initiation of antihypertensive therapy. 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