Introduction

Paroxysmal sympathetic hyperactivity (PSH) is a dysautonomic syndrome characterized by paroxysmal and episodic increases in sympathetic and motor activity ( ). PSH occurs after severe acquired brain injury of diverse etiology, and core clinical features of PSH include tachycardia, hypertension, tachypnea, hyperthermia, diaphoresis, and increased motor activity ( ). Additional clinical features may include agitation, mydriasis, decreased level of consciousness, horripilation, and flushing. Most reported cases of PSH follow traumatic brain injury (TBI), stroke, and anoxic brain injuries ( ); however, case reports of patients with PSH have also included etiologies such as hydrocephalus ( ) and encephalitis ( ). Although the clinical presentation is similar across etiologies ( ), we will focus on PSH after TBI.

Nomenclature

The syndrome that we refer to as PSH has been known by at least 31 other names in the published literature ( ); common terms include dysautonomia, sympathetic storm, diencephalic or autonomic seizures, autonomic dysfunction or storm, and paroxysmal autonomic instability with dystonia. The Consensus Working Group proposed that the term PSH accurately and specifically describes the syndrome without making an assumption about the underlying pathology driving the symptoms and thus should be the term used to unify literature on the syndrome ( ).

Incidence

In the first seven days post-TBI, autonomic arousal is very common; the incidence in an ICU population of individuals with severe TBI reached 92% ( ). However, not all of the individuals with autonomic arousal experience it to a pathological level. PSH incidence estimates range from 8% to 33% in the moderate-severe TBI population ( ), though the higher estimates are likely inflated due to inconsistencies in diagnostic criteria (eg, diagnosis at time of admission to hospital; ) and inclusion criteria (eg, febrile patients in the ICU; ). Incidence of PSH in patients with moderate-severe TBI who survive to rehabilitation is estimated to be 5.3% ( ). Reports of PSH in the pediatric literature are rarer, but estimates of incidence in children with acquired brain injury range from 9.7% ( ) to 14% ( ).

Mechanism: Theories

case study of a 41-year-old female with a tumor near the third ventricle who presented with episodes of autonomic hyperactivity was commonly believed to be the first published case of PSH. Penfield termed the patient’s syndrome diencephalic autonomic epilepsy. However, the patient’s paroxysmal symptoms (including hypertension, tachycardia, hypothermia, and lacrimation) were characteristic of mixed (ie, both sympathetic and parasympathetic) autonomic hyperactivity ( ) and were likely due to intermittent obstructive hydrocephalus and increased intracranial pressure ( ). Thus, this case does not meet the current diagnostic criteria for PSH; instead, a case study presented by which meets the diagnostic criteria described earlier, likely represents the first published case of PSH ( ).

Although once thought to contribute, seizure activity has been ruled out as a cause of PSH, as electroencephalography has revealed no epileptiform activity during the sympathetic episodes. Further, antiepileptics are not successful in management of the syndrome ( ). Instead, there are now two predominant theories of the pathophysiology driving PSH: the disconnection theory and the excitatory:inhibitory model. The disconnection theory postulates that sympathetic hyperactivity is driven by a disconnection between the sympathoexcitatory centers in the hypothalamus or brainstem and higher control centers ( ). The excitatory:inhibitory ratio (EIR) model is an extension of the disconnection theory ( ). The EIR model is not specific to PSH; rather, it attempts to account for all of the acute autonomic overactivity syndromes (eg, autonomic dysreflexia, malignant hyperthermia). This model proposes that allodynia (the reinterpretation of a normal stimulus as nociceptive) occurs at the level of the spinal cord. Disconnection between the spinal cord and the tonic inhibitory system (located in the diencephalon) leads to an increased sympathetic response to the allodynia, which accounts for the observed symptoms in PSH. The model presumes that the damage is located below the diencephalon and that a triggering event is responsible for the onset of the sympathetic hyperactivity.

Neurological and Functional Outcomes

It is well established that patients who sustain trauma experience an increase in catecholamines postinjury ( ). Regardless of the mechanism behind the excessive sympathetic outflow in PSH, the observed catecholamine surge (a marker of sympathetic hyperactivity) can have deleterious effects. In patients with TBI, the level of catecholamines (especially norepinephrine) present in the first week postinjury is correlated with injury severity ( ) and predictive of short-term outcomes: higher levels of catecholamines are correlated with poorer neurological recovery ( ). However, not all studies support these findings ( ).

The occurrence of PSH is also associated with poorer outcomes. Some studies have found that PSH is related to longer stays in the ICU ( ), hospital ( ), and/or rehabilitation ( ). Additionally, findings suggest that individuals with PSH may require tracheostomy and mechanical ventilation at higher rates and for longer duration ( ), though data are inconsistent. Individuals with PSH remain in a coma longer ( ), have more systemic infections ( ), higher rates of spasticity ( ), and longer posttraumatic amnesia ( ). Findings related to global neurologic and functional outcomes are mixed; some studies have found greater disability outcomes among individuals with PSH ( ), while other studies have not ( ). As with estimates of incidence, it is difficult to synthesize the literature related to outcomes after PSH due to differences in diagnostic criteria and study methodologies. However, when differences are found between individuals with PSH and individuals without, those with PSH have poorer outcomes across studies, follow-up times, and domains.

Systemic Consequences

Up to 89% of patients with severe TBI experience nonneurologic organ dysfunction during their ICU stay, which is an independent predictor of in-hospital mortality and neurologic outcome ( ). Nonneurologic organ dysfunction accounts for 40% of in-hospital deaths after severe TBI ( ); the cardiovascular and respiratory systems are the most commonly affected ( ). Cardiovascular and/or respiratory dysfunction occurs most commonly between 2 and 4 days postinjury ( ), but may occur days to weeks later. The cardiopulmonary consequences of TBI are due in part to the excess of sympathetic outflow. For example, cardiac arrhythmias are often observed after TBI, though the majority resolve within 2 weeks of injury ( ). However, permanent changes on ECG, including QT interval prolongation and U waves, have been observed ( ); prolonged QT interval is a risk factor for fatal ventricular arrhythmias ( ). Additionally, myocardial injury and necrosis may occur, with left ventricular dysfunction as a common outcome ( ). A long-term decrease in heart rate variability is also associated with dysautonomia ( ). This “cardiac uncoupling” has been shown to be an independent predictor of mortality in a trauma ICU population ( ). PSH can also cause pulmonary hypertension and pulmonary edema ( ). Other systemic consequences of the sympathetic hyperactivity observed in PSH include immune suppression ( ) and hypermetabolism ( ).

Psychiatric Consequences

Episodic agitation, though not a core clinical feature in the Consensus Working Group’s definition, is often observed in individuals with PSH ( ). Agitation after TBI can be defined as a state of excess behavior that occurs after TBI while a patient is experiencing posttraumatic amnesia (or in some cases even after the resolution of posttraumatic amnesia; ) that can include aggression, akathisia, disinhibition, or emotional lability ( ). Estimates of agitation after brain injury range from 11% ( ) to 96% ( ). The commonly used Rancho Los Amigos Levels of Cognitive Function Scale includes agitation as one of the defining characteristics of emergence from coma after TBI ( ). Individuals who are agitated post-TBI have a longer duration of posttraumatic amnesia, longer length of stay in rehabilitation, and reduced cognitive function at discharge from rehabilitation. Differences in functional outcome between TBI patients with agitation and TBI patients without are not present by 6 months. Persistent agitation is correlated with persistent functional deficits ( ). Depression and younger age at time of injury are predictive of long-term aggression ( ). Simple agitation associated with emergence from coma can be differentiated from agitation due to PSH by the lack of autonomic instability in the former ( ). The incidence of agitation associated specifically with PSH is unknown.

Management of PSH

Management of PSH consists of efforts to eliminate the cause of the sympathetic hyperactivity, to decrease the frequency of episodes, or to minimize the intensity of the episodes ( ). With the exception of a case series using hyperbaric oxygen therapy with success ( ), published attempts to manage PSH have been primarily pharmacological in nature. Three approaches to pharmacological management of PSH exist ( ). The first approach targets allodynia (the trigger for PSH as described in the EIR model). Baclofen (a GABA-b receptor agonist) and gabapentin (a structural analogue of GABA) can be used in this manner. The second approach is inhibition of the increased sympathetic outflow itself by using centrally acting medications. This approach is consistent with both mechanistic theories. Commonly used medications in this category of intervention include morphine (an opiate agonist) and bromocriptine (a dopamine agonist). The third approach, also consistent with both mechanistic theories, is to block the impact of the catecholamines at the end organ. Medications in this category will be discussed in the following. Strong evidence to support the use of a specific medication regimen within any of these approaches is lacking; the literature is limited primarily to evidence from case reports and cohort studies. Discrepancies in the efficacy of medications within case report and cohort findings are likely due to medication factors (eg, timing, dosage, medication interactions), personal factors (eg, age, comorbidities), and other unknown modifiers.