Paroxysmal Autonomic Instability With Dystonia After Brain Injury

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SECTION EDITOR: DAVID E. PLEASURE, MD

Paroxysmal Autonomic Instability With DystoniaAfter Brain Injury

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

Acomplication of severe brain injury is a syndrome of intermittent agitation, diapho-

resis, 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 dys-

tonia. We reviewed reports of autonomic dysregulation after brain injury and extracted essential

features. From the clinical features, consistent themes emerge regarding signs and symptoms, dif-ferential 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-gardless of etiology, is a syndrome ofmarked agitation, diaphoresis, hyper-

thermia, hypertension, tachycardia, andtachypnea accompanied by hypertonia andextensor posturing.Usually episodic,it firstappears in the intensive care setting butmay persist into the rehabilitation phasefor weeks to months after injury in indi-viduals who remain in a low-responsestate. The syndrome engenders alarm be-cause it may be difficult to distinguishfromlife-threatening conditions such as sep-sis, impending herniation, or epileptic sei-zure. These manifestations could lead tosecondary hypertensive or hyperthermicencephalopathy and even death.

Various labels have been applied tothisphenomenon, suchasparoxysmal sym-pathetic storms, diencephalic seizures, ormidbrain dysregulatory syndrome. How-ever, the syndrome remains poorly un-derstood and underrecognized, despiteitsdistinctiveand characteristic features. The

lack of a standardized nomenclature is amajor problem with research into this con-dition.1 Based on a review of limited ex-

isting literature, generally consisting of re-ports of a single or only a few cases, andof our own case series, we propose the fol-lowing name for this syndrome: paroxys-mal autonomic instability with dystonia(PAID). We will define its characteristicsas precisely as possible, provide guide-lines for distinguishing it from other con-ditions with similar characteristics, andsuggest a rational treatment approach.

The pathophysiology of PAID can bebest explained by dysfunction of auto-nomic centers in the diencephalon (thala-mus or hypothalamus) or their connec-

tions to cortical, subcortical, andbrainstemloci that mediate autonomic function.Bullard2 suggested a release phenom-enon in which loss of cortical and sub-cortical control of vegetative functionsoccurs, including regulation of bloodpressure and temperature. Boeve et al3

expanded this concept by speculatingthat the mechanism likely involves acti-vation (or disinhibition) of central sym-pathoexcitatory regions such as the para-

From the Kluge Childrens Rehabilitation Center, Department of Pediatrics(Drs Blackman, Patrick, and Buck), and the Division of Pediatric Neurology,Department of Neurology (Dr Rust), University of Virginia, Charlottesville.

NEUROLOGICAL REVIEW

(REPRINTED) ARCH NEUROL/ VOL 61, MAR 2004 WWW.ARCHNEUROL.COM321

2004 American Medical Association. All rights reserved.

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ventricular hypothalamic nucleus, lateral periaqueductalgraysubstance,lateral parabrachial nucleus,or rostral ven-tricular medulla. Cortically provoked release of adreno-medullary catecholamines during PAID episodes may con-tribute to the rise in blood pressure as well as tachycardiaand tachypnea.4,5

Thermoregulatory dysfunction may also be pro-duced by hypothalamic dysfunction, as has been dem-onstrated experimentally6 and clinically. The tempera-

ture elevations associated with PAID may also beexplained, at least in part, by the hypermetabolic statethat accompanies sustained muscular contractions.

Rigidity and decerebrate posturing are seen experi-mentally andclinicallywithlesions in the midbrain, block-ing normal inhibitory signals to pontine and vestibularnuclei.7 This allows these nuclei to become tonically ac-tive, transmitting facilitatory signals to the spinal cordcontrol circuits. Spinal reflexes become hyperexcitable,evoked by sensory input signals that are usually belowthe threshold for excitation of a motor response.

LITERATURE REVIEW

Episodic agitation, diaphoresis, hyperthermia, tachycar-dia, tachypnea, and rigid decerebrate posturing after se-vere brain injury were first noted in a report by Strich in1956.8 He called these events brainstem attacks. Subse-quently, this constellation of clinical signs has receiveda variety of labels, including autonomic dysfunction syn-drome, fever of central origin, neurostorming, acute mid-brain syndrome, hypothalamic-midbrain dysregulation syn-drome, hyperpyrexia associated with sustained musclecontractions, dysautonomia, sympathetic storms, paroxys-mal sympathetic storms, acutehypothalamic instability, anddiencephalic seizures.

Table 1 provides a summary of the clinical fea-tures of relevant case reports. We have included a series

of our own patients. Permission was obtained from theHuman Investigation Committee, University of Vir-ginia, Charlottesville, to review patient records for thisreport. Because some of these patients received inten-sive care at other hospitals and their daily nursing andphysician notes were not available, it was not possibleto determine the time of initial onset of PAID signs ortheir total duration.

Although some heterogeneity in manifestations hasbeen noted, there is a sufficient degree of uniformity tojustify viewing these cases as a syndrome. The cases havein common autonomic dysregulation and rigidity due todystonia (involuntary sustained muscle contraction andextensor posturing). The PAID syndrome has been re-

ported in children and adults. Traumatic and hypoxicbrain injury account for most cases, but some were dueto tumors, intracranial hemorrhage, or hydrocephalus.It is most likely to be encountered after processes thatproduce diffuse axonal or brainstem injury.

Theonsetof PAID signsoftenoccurs in thefirst weekafter severe brain injury, when differential diagnosis ismost difficult, andcontinues for weeksto months, in somecases for longer than 1 year. We have found that the epi-sodes tend to persist the longest in patients with braininjury due to anoxia. Early diagnosis is challenging be-

cause the various constituent parts of the syndrome maybe caused by a wide variety of processes that may occurin these very ill patients, including seizures, infection, theeffects of drugs, withdrawal from drug therapy, pain, oragitation. PAID signs occur at a time when the patientsmental status is abnormal, and tests such as electroen-cephalography maybe difficultto obtain or coordinate withthe intermittent phenomena. These signs invariably in-clude temperature elevation (as high as 41C), increases

in heart andbreathingrates, hypertension,diaphoresis,agi-tation, and extensor posturing. Creatine kinase levels arerarely reported; in one case these values were within thereference range, and in another, elevated.

The most commonly used drugs for treatment ofPAID are morphine sulfate, bromocriptinemesylate, pro-pranolol hydrochloride, clonidine hydrochloride, lora-zepam, and dantrolene sodium. Each one of these drugsis rational and addresses a component of the PAID syn-drome (Table 2).

Opioid receptors are found in brain cardiovascularnuclei, the heart, and blood vessels.20 Opiates such asmorphine, when peripherally injected into healthy ani-mals, produce hypotension.21 Morphine induces anal-

gesia, respiratory depression, and bradycardia. Its anal-gesic properties may interfere with pain as an incitingfactor, and its sedative effects may counter the tachycar-dia and tachypnea. Constipation is a problematic ad-verse effect of morphine and narcotic dependency.Withdrawal from opiate ther apy may provoke signsthat falsely suggest PAID.

The use of dopamine antagonists or the with-drawal of dopamine agonist therapy may also result inneuroleptic malignant syndrome (NMS), the clinical fea-tures of which suggest PAID. Thus, it is not surprisingthat the use of bromocriptine, a dopamine agonist, hasbeen found to be helpful in PAID.

Because excitation of the sympathetic nervous

system appears to be a major feature of PAID, the usesof-adrenergic blockade, such as propranolol (nonse-lective -adrenergic blockade) or labetalol hydrochlo-ride (nonselective - plus 1-adrenergic blockade), arelogical choices and have proven clinically useful in theamelioration of some of the most important clinicalsigns (eg, hypertension), but not cholinergic signs (eg,diaphoresis) of PAID. In the experience of Do et al,9

1-adrenergic selective antagonists (eg, metoprolol oratenolol) are not effective, as in mitigating autonomicdysregulation.

Clonidine, an2-adrenergic agonist, reduces bloodpressure, has a behavior-stabilizing effect, and causes se-dation. These features treat thesympathetic signs andmay

interrupt feedback into the system that otherwise wouldperpetuate the cycle of autonomic dysregulation.

The benzodiazepines, such as lorazepam, have anx-iolytic and sedating effects and muscle relaxant proper-ties that may account for benefits observed in treatmentof PAID.

In addition to its direct muscle relaxant properties,dantrolene may diminish fever due to prolonged musclecontraction and may also reduce the somatosympa-thetic spinal reflexes that contribute to sympatheticexcitation.





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Table 1. Reports of Patients With Paroxysmal Autonomic Instability With Dystonia

SourceNo. of

Subjects Age, y Origin Onset, d

No. ofCycles

per Day

Durationof EachEpisode

TotalDuration Signs

Treatmentor Drugs

Term Usedto Describe

University ofVirginia

7 9-29 MVC, neardrowning,hanging,assault

NA NA NA NA T, 38C-41.8C; HR,161-216 beats/min;BP, 123-171/78-101mm Hg; rigid ordecerebrateposturing;diaphoresis; agitation

Atenolol,lorazepam,diazepam,methadonehydrochloride,propranololhydrochloride,clonidinehydrochloride

NA

Thorleyet al,12

2001

1 20 MVC 1 NA Minutes tohours

2 wk T, 40.0C; HR, 156beats/min; extremityposturing;diaphoresis;agitation; CPK, 61U/L

Midazolam,lorazepam,morphinesulfate,oxycodone,bromocriptinemesylate,dantrolenesodium

Acutehypothalamicinstability

Cuny et al,11

20014 17-37 MVC 24-60 2-16 NA 1-8 wk Hyperthermia;

hypertonia;tachycardia

Intrathecalbaclofen

Dysautonomia

Do et al,92000

1 21 MVC 450 3 1-2 h NA T, 39.1 C; HR, 140-160beats/min; BP,170-180/100mm Hg; diaphoresis;flexor posturing

Labetalolhydrochloride

Paroxysmalsympatheticstorm

Baguley,1

199914 NA Hypoxia, TBI NA NA NA NA Classic features

described by Boeveet al3 (1998)

NA Paroxysmalsympatheticstorms

Goh et al,10

19991 7 Midbrain glioma 3 NA NA NA T, 38.4C-39.5C; HR,

150-180 beats/min;SBP, 180 mm Hg;DBP, 120 mm Hg;sweating, musclespasms; decorticateposturing;nystagmus; teethgrinding

Phenytoin sodium,diazepam,lorazepam,clonidine

Diencephalicseizures

Boeve et al,3

19981 17 MVC 5 1-3 2-4,

8-10 h12 mo T, 39C-42C; HR,

140-190 beats/min;RR, 26-40breaths/min; SBP,150-170 mm Hg;increaseddecerebrate/opisthotonicposturing

Morphine,bromocriptine,dantrolenesodium

Paroxysmalsympatheticstorms(diencephalicseizures)

Scott et al,13

19971 11 Hydrocephalus,

tumorNA 2-4 2-6 h NA T, 39C-42C; HR,

140-160 beats/min;RR, 30-60breaths/min; SBP,160 mm Hg; DBP,110-120 mm Hg;diaphoresis;

increased muscletone; tremors

Chlorpromazinehydrochloride,bromocriptine,propranolol,levodopa/carbidopa

Hypothalamicstorming

Sneed,14

19951 2 Near drowning 14 NA Days to a

week85 wk T, 39.5C; diaphoresis;

opisthotonicposturing; increasedCPK level

Clonazepam Hyperpyrexiaassociatedwith sustainedmusclecontractions

MeythalerandStinson,15

1994

3 15, 20, 21 TBI NA NA NA NA Tachycardia; T,38.9C-40.6C;sweating; decorticateposturing

Propranolol Fever of centralorigin

(continued)





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DIFFERENTIAL DIAGNOSIS

The following clinical entities have features in commonwith PAID and may share underlying pathophysiologi-cal mechanisms (Table 3).

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome is a severe disturbanceof motor tone seen in patients taking dopamine receptorblocking agents, ie, phenothiazines such as thioridazinehydrochloride (Mellaril) and prochlorperazine (Com-pazine)andbutyrophenonessuchas haloperidol (Haldol).This syndrome consists of fever, muscle rigidity, auto-nomic instability, alteration of consciousness, and eleva-tionof serum creatinephosphokinase levels.Formerly, neu-rolepticssuch as haloperidol were frequently used to treatagitation in brain-injured patients. Thedecline in this prac-

tice has diminished the occurrence of NMS in such pa-tients. Because a considerable number of safer agents arenow available,the useof neuroleptics in this setting is gen-erally considered to be contraindicated.

Several cases have been reported with withdrawal ofdopamine agonists (levodopa/carbidopa22 and amanta-dine hydrochloride.23 Numerous reports also associate the

syndrome with the use of the dopamine receptor antago-nist metoclopramide hydrochloride (Reglan),24-27 a drugcommonly used to stimulate gastric emptying and re-duce aspiration risk in patientswith brain injury. Two casereports implicating metoclopramide involved chil-dren,28,29 and in 1 case symptoms were likely triggered bymetoclopramide but did not reach their full manifesta-tion until after the therapy was discontinued.30

Neuroleptic malignant syndrome apparently re-sults from deficient compensatory mechanisms afterblockade of dopaminergic regulation of muscle tone and

Table 1. Reports of Patients With Paroxysmal Autonomic Instability With Dystonia (cont)

SourceNo. of

Subjects Age, y Origin Onset, d

No. ofCycles

per Day

Durationof EachEpisode

TotalDuration Signs

Treatmentor Drugs

Term Usedto Describe

Pranzatelliet al,16

1991

3 7-19 Hypothalamicastrocytoma,MVC, CHI

6 1-6 NA NA T, 39C-40C; HR,140-160 beats/min;RR, 40-45breaths/min; SBP,150-160 mm Hg;DBP, 105-115mm Hg; diaphoresis;decerebrateposturing/opisthotnous

Fentanyl citrate,pancuroniumbromide,lorazepam,clonazepam,dantrolene,bromocriptine,acetaminophen,methadone,diazepam,propranolol

Hypothalamic-midbraindysregulationsyndrome

Rossitch andBullard,17

1988

9 NA 6 CHI, 2hydrocephalus,1 ICH

1 NA Minutestohours

NA Increased T, HR, RR,and BP; dilatedpupils; increasedextensor posturing;diaphoresis

Morphine,dantrolene,bromocriptine

Autonomicdysfunctionsyndrome

Talmanet al,18

1988

2 26, 57 Acutehydrocephalus

NA NA NA NA T, 39C-41C, HR, 160beats/min; RR, 32-36breaths/min; SBP,150-158 mm Hg;DBP, 90-100mm Hg; rigidity;decerebrateposturing;diaphoresis

Shunt revision Hyperthermicsyndrome

Bullard,2

19862 24 MVC 1-6 2-3 2-5 h 3 wk T, 38C-40C; HR,

100-150 beats/min;RR, 60-148breaths/min; SBP,170-190 mm Hg;DBP, 80-120 mm Hg;extensor/decerebrateposturing; increasedICP; dilated pupils

Morphine,bromocriptine,dantrolene

Diencephalicseizures

Klug et al,19

198425 11-68 NA NA NA NA NA Changes in T, HR, RR,

BPNA Decerebrate

rigidity andvegetativesigns

Strich,8

1956 3 27, 28, 32 TBI 3 NA NA NA Hyperpnea; extensorposturing;decerebration;salivation; sweating

NA Brainstemattacks

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.





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autonomic function.31 Neuroleptic malignant syn-drome occurs in only 1% of individuals taking neuro-leptics. The incidence of NMS is likely lower than thiswith the newer antipsychotic drugs. Cases have been re-ported in children as young as 1 year after a single acci-dental dose.32 Symptoms usually occur 3 to 9 days afterstarting therapy. Extrapyramidal signs may be associ-ated with other NMS clinical features. With early recog-

nition and appropriate treatment, mortality due to NMSis low. Treatment includes stopping the neuroleptictherapy and providing supportive care.

Malignant Hyperthermia

Malignant hyperthermia (MH) is a disease of skeletalmusclecharacterizedby hypermetabolism thatoccurs with

Table 2. Drugs Commonly Used for Paroxysmal Autonomic Instability With Dystonia

Drug Actions T12 Peak Action Typical Uses Major Adverse Effects Typical Dose Range

Bromocriptinemesylate

Dopamine D2 agonist 7 h 1.6 h Puerperal lactationsuppression,Parkinsondisease

Hyperprolactinemia,mental status changes(eg, confusion,hallucinations),dyskinesia

Adults and adolescents,1.25 mg PO twicedaily initially, titratedto 10 to 40 mg/d

Clonidinehydrochloride(Catapres)

2-Adrenergic agonist;decreased sympatheticoutflow from CNS;decreased BP

12-16 h 3-5 h Hypertension,ADHD

Sedation, hypotension,rebound hypertensionwith abrupt withdrawal

Children, 5-10 g/kg perday PO given individed doses; adults,0.2-1.2 mg/d PO individed doses

Dantrolene sodium(Dantrium)

Dissociates excitationcontraction byinterfering with Ca++

release fromsarcoplasmicreticulum

5-9 h 30 min Muscle relaxation,malignanthyperthermia

Hepatotoxicity,drowsiness,generalized weakness

Children, 0.5 mg/kg perdose PO given 2 to 4times daily; adults, 25mg/d PO given 2-4times daily up to amaximum of 400 mg

Lorazepam(Ativan)

Interacts with GABAreceptor sitemodulating its activity

12 h 2 h Sedative,anxiolyticanticonvulsant,muscle relaxant

Lightheadedness,lassitude, motorincoordinaton,confusion

Children, 0.05 mg/kg IVor PO, up to 2 mgevery 4-8 h; adults,2-4 mg IV or PO every4-8 h

Morphine sulfate Opioid -receptor agonist 2 h IV/IM,30 min

Analgesia Drowsiness,nausea/vomiting,

euphoria, histaminerelease, hypotension,pruritis, ileus

Children, 0.2-0.5 mg/kgPO every 4-6 h or

0.1-0.2 mg/kg perdose IV; adults, 10-30mg PO or 2.5-10 mgIV given up to every4-6 h

Propranololhydrochloride(Inderal)

1,2-Adrenergic blockade 3-5 h 90 min Hypertension,thyrotoxicosis,anxiolytic

Bradycardia,light-headedness,lassitude, weakness,bronchospasm

Children, 0.5-1 mg/kgper day PO given individed doses; adults,10-20 mg PO given2-4 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; T12, half-life.

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

MentalStatus Temperature

HeartRate

BreathingRate

BloodPressure

PupilSize Diaphoresis Agitation

Rigidity/Extensor

Posturing CPK Myoglobinuria

PAID + + ? NA

Malignant hyperthermia NA NA NA + +

Neuroleptic malignantsyndrome

or NA + NA + +

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

Narcot ic 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





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exposure to a triggering agent such as inhalational an-esthetic agents or depolarizing muscle relaxant drugs (eg,succinylcholine chloride), usually during induction orsometimes within 2 to 3 hours and rarely more than 24hours later. After surgery, MH has been reported to oc-cur in the absence of administration of a known trigger-ing agent and may continue for several days.33

Malignant hyperthermia may also follow head in-jury without any exposure to anesthesia or surgery.34 A

21-year-old manbecameagitated anddiaphoretic 36 hoursafter head injury. His temperature rose to 42.3C; he wastachycardic, hypotensive, tachypneic, and displayed de-cerebrate posturing. Rhabdomyolysis and renal and liverfailure developed. Results of a muscle biopsy confirmedthe diagnosis of MH, including a characteristically ab-normal response of muscle to halothane in vitro.

Malignant hyperthermia tends to occur most com-monly in younger persons; 52% were younger than 15years in 1 case series.35 Inheritance of MH is primarilyautosomal dominant, although it may also be autoso-mal recessive, polygenic (genes on chromosomes 3, 17,and 19 have been implicated), or sporadic.36-39

Abnormal calcium regulation appears to be the ba-

sic underlying defect resulting in tonic muscle contrac-tion with production of excessive heat, resulting in a risein body temperature to as high as 44C. Skeletal musclerigidity can be local or diffuse, and is often first ob-served in the masseter muscles, extremities, and chest.Damaged muscles release large amounts of tissue throm-boplastin, leading to coagulopathy, and myoglobin, lead-ing to myoglobinuria and acute tubular necrosis.

Apart from discontinuing the triggering agent, ifknown, the use of dantrolene is the only effective treat-ment for MH. Dantrolene blocks calcium release from thesarcoplasmic reticulum causing muscle relaxation, andhas reduced mortality due to MH dramatically.

Diencephalic Seizures

The PAID syndrome frequently has been termedand con-fused with true diencephalic seizures. In 1929, Pen-field40 described a 41-year-old women with a tumor ofthe third ventricle who displayed paroxysmal dis-charges of the vegetative nervous system that he de-scribed as autonomic epilepsy. Subsequent case reportsof episodes characterized by irregular respirations, al-tered heart rate, labile blood pressure, hypothermia, anddiaphoresis were associated with neoplasms of the dien-cephalon,41 agenesis of the corpus callosum,42-44 trappedthird ventricle,45 and a suprasellar arachnoid cyst. Thekey features of hypothermia and profuse sweating gen-

erally responded to anticonvulsants, although electro-encephalographic studies did not typically show epilep-tiform discharges. One case of periodic hypothermia,described as diencephalic epilepsy, responded only to totalsympathectomy.46

Several cases of what appears to us to be the PAIDsyndrome have been described in the literature as dien-cephalic seizures.2,3 Gohet al10 described a 7-year-oldchildwith repeated episodes of sympathetic hyperactivity dueto a midbrain glioma as having a variant of diencephalicseizures. They acknowledged in the discussion that the

term seizure is a misnomer, because there has never beena demonstration of an epileptogenic focus during a PAIDepisode, and most patients with PAID do not benefit fromantiepileptic medications. Thus,diencephalicseizures con-stitute a syndrome distinct from PAID.

Autonomic Dysreflexia

Autonomic dysreflexia (AD) occurs in individuals with

spinal cord injury at the level of T6 through T8 or above.Any noxious stimulus below this level, such as a dis-tended bladder, may initiate reflexive sympathetic activ-ity resulting in life-threatening hypertension uncon-trolled by feedback parasympathetic activity.47 Othermanifestations of AD include headache, flushing andsweating of the face and upper torso, and apprehension.Removing the inciting stimulus relieves AD. Patients withspinal cord injury may have brain injuries as well, pre-disposing them to sympathetic dysregulation at the spi-nal cord and brain levels.

Central Fever

Fever is common after central nervous system trauma.48

Causes include wound infection, meningitis, blood in thecerebrospinal fluid, drug fever, and pneumonia/atelectasis. Central fever is a diagnosis of exclusion, at-tributed to trauma if it affects the base of the brain or thehypothalamus. The fever, often very high and persistingfor weeks after injury, is relatively resistant to antipy-retic therapy and occurs in the absence of perspiration.

Agitation

Theclinicalsign that is probably most oftenconfused withPAID is simpleagitation. After emergence from true coma(return of sleep/awake cycles) with returningalbeit

sometimes very slowlyarousal and awareness, the pa-tient typically becomes agitated with extensor postur-ing and thrashing about the bed. The following tabula-tion shows the levels of cognitive functioning of theRancho Los Amigos Scale49:

Level Description

I No response

II Generalized response

III Localized response

IV Confused, agitated

V Confused, inappropriate

VI Confused, appropriate

VII Automatic, appropriate

VIII Purposeful, appropriate

If the patient is at level II, there may be no purposefulmovements. The lack of autonomic instability (ie, ex-cessive rise in temperature and blood pressure) distin-guishes agitation from PAID. Pain or discomfort from anysource (eg, musculoskeletal, visceral, or headache) canproduce agitation. When purposeful movements are ob-served with agitation, such as pulling out tubes or hit-ting, as seen at Rancho Los Amigos levels III and IV, PAIDis clearly notthecauseof agitation. Another possible causeof agitation is narcotic withdrawal, as almost all pa-tients with severe brain trauma accompanied by other in-





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juries such as fractures receive narcotics in the inten-sive care setting, and they are weaned from the drugs asthey progress toward rehabilitation.

In acute brain injury, the pathophysiology of PAIDmay be similar in some ways to that of NMS or MH. Drugexposure or withdrawal or even stress may initiate as-pects of these conditions, confusing the diagnosis. Anyof the single features of PAID, such as hypertension, agi-tation, or hypertonia, could stimulate the full-blown syn-

drome. This might explain why a single drug that ad-dresses 1 feature (eg, dantrolene for hypertonia) couldinterrupt and perhaps abort the process, especially iftherapy is initiated early.Four cases of posttraumatic dys-autonomia successfully treated with intrathecal bac-lofen, a muscle relaxant, illustrate this point.11 Most of-ten, more than 1 drug is required for control.

It is clear that PAID is not associated with seizureactivity and, thus, the term diencephalic or hypothalamicseizure is not appropriate to describe this condition. Un-less there are comorbid seizures, antiepileptic drugs forPAID are not a rational choice except for use as moodstabilizers, possibly treating the agitation feature.

CRITERIA FOR PAID

It seems useful clinically and for future research to estab-lish a single name that encompasses and clearly denotesthe main features of the clinical phenomena described inthis report. Paroxysmal autonomic instability with dysto-nia appears to accomplish this. Based on the literature re-view and our own experience, we propose specific crite-ria for the PAID syndrome. Within the clinical setting oftraumatic brain injury, signs of PAID syndrome include(1) severe brain injury (Rancho Los Amigos level,IV),(2) temperatureof at least 38.5C, (3) pulse of at least 130beats/min, (4) respiratory rate of at least 140 breaths/min, (5) agitation, (6) diaphoresis, and (7) dystonia (ie,

rigidity or decerebrate posturing). The duration is at least1 cycle per day for at least 3 days. Finally, other condi-tions must be ruled out. In addition to recognizing con-sistent features of PAID, it is as importantto recognize signsof other diseases or conditions that require prompt atten-tion and a different diagnostic or treatment approach.

ASSESSMENT AND TREATMENT

Differential diagnosisis challenging,especially in thephaseof acute brain injury. Because patients may be heavily se-dated for ventilation or pain management, temperatureelevation is usually the first concern, prompting body fluidcultures, leukocyte counts, and various imaging studies

to rule out sepsis. If these test results are negative, fevermay be attributable to noninfectious causes.

As sedation and analgesia are withdrawn, more typi-cal cycles of PAID may become evident. Typically, thenext sign of concern is elevated blood pressure, leadingto the initiation of antihypertensive therapy. Gradually,thecyclicalnature of thePAID signs becomes evidentwithepisodes daily or several times daily and with the returnof vital signs to normal between episodes.

Before accepting PAID as a diagnosis, alternativecauses of autonomic dysregulation should be consid-

ered, especially treatable intracranial abnormalities suchas hydrocephalus, increasedintracranial pressure, or extra-axial blood or fluid accumulation. Other treatable irri-tants, suchas dehydration, constipation, fracture sitepain,or uncomfortable casts must be alleviated. Drugs or an-esthetics that might precipitate or exacerbate PAIDshouldbe avoided, and caution should be used in the suddenwithdrawal of dopamine agonist therapy.

As described earlier, a finite number of drugs have

been used singly or in combination to alleviate PAID. Noclear evidence suggests that one medication regimen issuperior to another, anddrugs seem to work well for somepatients but not others. The goal is to maximize effec-tiveness while minimizing adverse effects. For example,sedationmedications that are administeredas needed, likenarcotics or benzodiazepines, may quiet an episode butdepress arousal and awareness between episodes. Cloni-dine will reduce blood pressure effectively, but also is se-dating. Dantrolene as a muscle relaxant may be prefer-able to baclofen because it does not sedate; however, itsuse may be limited by toxic effects to the liver. -Block-ers will lessen sympathetic features, but should be usedwith caution in patients with asthma or diabetes.

A logical approach is to choose target signs, con-sider safety of particular drugs for the individual, and seta time frame for determination of efficacy before a drugis changed or a second drug is added. In our center, wetry to devise a regimen that will prevent or amelioraterather than rely on as-required drugs that may overtreatthe condition.

Greater awareness of PAID and appropriate early in-tervention may minimize repetitive and expensive tests(eg, sepsis workups), ease nursing management, avoidpharmacological excess, prevent secondary injury, andallay the anxiety of parents and health care workers ob-serving repeated episodes.

Further research is needed to evaluate individual

or combinationpharmacotherapyfor PAID.A clearer defi-nition of this syndrome may facilitate cross-institutionalstudies.

Accepted for publication October 29, 2003.Author contributions: Study concept and design(Drs

Blackman and Patrick); acquisition of data (Dr Black-man); analysis and interpretation of data (Drs Blackman,Buck, and Rust); drafting of the manuscript (Drs Black-man and Rust); critical revision of the manuscript for im-portant intellectual content (Drs Blackman, Patrick, Buck,and Rust); administrative, technical, and material support(Drs Blackman, Buck, and Rust); study supervision (DrBlackman).

Corresponding author and reprints: James A. Black-man, MD, MPH, Kluge ChildrensRehabilitationCenter, Uni-versity of Virginia, 2270 Ivy Rd, Charlottesville, VA 22903(e-mail: [email protected]).

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Paroxysmal Autonomic Instability With Dystonia After Brain Injury