Paroxysmal sympathetic hyperactivity - incidence, pathophysiology, diagnosis, treatment, prognosis and implications for treatment Paroxysmal sympathetic hyperactivity is frequently seen in survivors of acute severe brain injury (ASBI). It is most commonly associated with severe traumatic brain injury (sTBI) with a reported incidence of 10-20% among survivors of sTBI. Survivors of anoxic brain injury have a higher incidence of PSH (approximately 30%). The pathophysiology of PSH is incompletely understood. Current consensus is that it the result of disconnection between with neuroinhibitory higher centers in the diencephalon and the excitatory pathways in the brainstem and spinal cord (10). PSH is characterized by a constellation of symptoms such as tachycardia, tachypnea, hypertension, hyperthermia, rigidity, tremors, sweating, and pupillary dilation as a result of sympathetic hyperactivity due to the brain injury. Research on PSH has been hampered by lack of a uniform definition and use of various terms such as neurostorming, dysautonomia. Consensus diagnostic criteria and a scoring algorithm (CFS) were developed in 2014 (Table 1a,1b). This tool has 2 components - Clinical Feature Scale to score the severity of symptoms and Diagnosis Likelihood Tool (DLT) that lists the diagnostic features to help with initial diagnosis of PSH (Table 1b). The combined CFS and DLT scores are used to assess the likelihood of PSH (Table 1b). We will use a CFS+DLT cut-off of ≥ 10 to diagnose PSH. PSH increases the risk for secondary brain injury and is associated with worse functional outcomes, longer hospitalization and higher healthcare costs. Appropriate treatment of PSH is important for patient comfort and to prevent secondary brain damage.

Currently, PSH is treated using a combination of multiple neurotropic medications (narcotics, benzodiazepines, sympatholytics, gabapentin, muscle relaxants etc.) that can result in complications due to their side effects such as excessive sedation, respiratory depression, drug dependence, and constipation. Some of these medications necessitate ICU stay due to their CNS depressant effects thus potentially increasing healthcare costs. There has been very little research into novel ways of treating PSH other than the use of various neurotropic medications.

Measurement of autonomic function - HRV and Pupillometry Autonomic function can be evaluated clinically and is most commonly measured using heart rate variability (HRV). Established standards for measurement of HRV are available. HRV has been studied in various disease states in the intensive care environment such as post-acute MI, sepsis, multi-organ dysfunction, brain injury, and brain death. HRV is decreased or lost in severe disease and has been shown to be associated with increased mortality in the ICU. Higher sympathetic activity in severe disease states is associated with decreased HRV. HRV was shown to be significantly different between children and adults with ASBI and controls. Similarly, pupillary reactivity is also under autonomic control. Recently, pupillometry has also been used to measure autonomic activity. A pupillometer quantitatively measures pupil size (size, minimum size with light stimulus, % change in pupil size) and reactivity (constriction velocity, max constriction velocity, latency, dilation velocity) that can be compared to established norms and trended over time. These parameters have been shown to reflect sympathetic (dilation velocity) and parasympathetic system (% change in pupil size, latency, constriction velocity) activity and sympatho-parasympathetic balance (baseline pupil size). PSH, as the name implies, is associated with uncontrolled paroxysms of sympathetic activity that results in pupillary dilation among other symptoms. It is conceivable that an increase in parasympathetic activity would alter these parameters that could be compared using the patient as his/her own control.

PENFS device - description, mechanism of action, and applications The PENFS (auricular neurostimulator) device is a novel, non-pharmacological therapy that has been effectively used for various conditions such as functional abdominal pain, chronic pain, and narcotic withdrawal. Recent data from CW also demonstrates efficacy in a pilot study for children with cyclic vomiting syndrome, with improvement in episode severity and frequency lasting an average 5 months (unpublished data). Cyclic vomiting syndrome (CVS) is a disorder of autonomic imbalance manifested by severe sympathetic hyperactivity. Symptoms of nausea/vomiting, pallor, diaphoresis, and tachycardia are similar to PSH. Many of the symptoms of narcotic withdrawal are also very similar to those of PSH including tachycardia, tachypnea, hypertension, fever, tremors, and sweating. Clonidine, an alpha-2 agonist with sympatholytic properties is commonly used as an adjunct in the treatment of narcotic withdrawal syndrome. Clonidine is also one of the first-line medications used for treatment of PSH. Thus, it is plausible that PENFS could be effective in treatment of PSH.

The PENFS device is applied over the external ear and is continuously worn for 120 hours at a time. The electrical current stimulates the auricular branch of the vagus nerve (ABVN) and auricular branches of cranial nerves V, VII and IX. The nerves project to the various parts of the brain, including the brainstem nucleus tractus solitarius. fMRI scans in healthy human volunteers have shown significant activation of the central vagal projections by stimulating ABVN. Sympathoinhibition has been shown to be one of the primary mechanisms of action of the device in the various conditions for which it is used. Electrical stimulation of the tragus has been shown to cause central sympathoinhibition in rats by up to 36% within 5 minutes of stimulation. This central sympathoinhibition by the PENFS device could improve the symptoms of PSH.

One of the advantages of PENFS in the treatment of PSH is that it is continuously active while it is worn thus providing symptomatic treatment throughout that period. This could help prevent or ameliorate the paroxysmal symptoms classically seen in PSH and thus reduce the need for rescue medications. The device also has been shown to have a relatively rapid onset of action. A recent study showed that the onset of action was rapid with 63% reduction in narcotic withdrawal score within 20 minutes of activation of the device and 85% reduction within 60 minutes. Thus, PENFS could offer a non-pharmacological tool for managing PSH, helping to decrease the need for maintenance and rescue medications and thus limiting the side effects of some of these medications. Decreased need for neurosedative medications could further decrease the length of ICU stay for these patients thus decreasing healthcare costs. The device is also well-tolerated without any serious adverse effects.