Paroxysmal Autonomic Instability with Dystonia After Brain Injury
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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, 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- Atonia. 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- 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- (REPRINTED) ARCH NEUROL / VOL 61, MAR 2004 WWW.ARCHNEUROL.COM 321 ©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