Autonomic Dysfunction

Cherina Cyborski

BACKGROUND

The autonomic nervous system (ANS) maintains homeostasis, without conscious direction, via a balance between two main subsystems: the parasympathetic and sympathetic nervous systems.

• Sympathetic nervous system (SNS): increases heart rate and cardiac ejection fraction, raises blood pressure, shunts blood to musculoskeletal system, dilates pupils.

• Parasympathetic nervous system (PNS): slows heart rate, shunts blood to the gastrointestinal tract, contracts pupils.

Peripherally, the ANS spans from the end organ integrating into the spinal cord, brainstem, hypothalamus, amygdala, hippocampus, insular cortex, cingulate cortex, dorsolateral prefrontal cortex, and middle temporal cortices. The “central autonomic network” integrates visceral perception and efferent autonomic responses with emotion and behavior [1]. The more damage to the cerebral ANS pathways, the less refined the homeostatic response [2].

Autonomic dysfunction after a traumatic brain injury (TBI) can be classified into three categories [2]. Of these, the first two will be reviewed only briefly and the third will be addressed in more detail in the sections which follow.

AUTONOMIC INCOORDINATION SYNDROME

This is the mildest form of autonomic dysfunction; it’s existence as a distinct entity is controversial and lacking literature. Theoretically, when multiple homeostatic challenges compete, nonspecific symptoms can arise that may be similar to those experienced with psychological distress, including subjective temperature intolerance and excessive sweating [3]. Objective work up in autonomic laboratories can be equivocal. Depending on the person’s personality, this may be a life altering change with increased associated anxiety because of lack of objective validation and feeling dismissed. There are no treatment paradigms [2].

SELECTIVE AUTONOMIC FAILURE (POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME (POTS))

• Likely etiology is from discrete brainstem damage, which occurs only in association with the most severe TBIs [2].

• Defined as orthostatic intolerance of greater than 6 months duration with a heart rate increase of at least 30 beats/min (or greater than 120 beats/min) within the first 10 minutes of upright posture.

• Symptoms include fatigue, orthostatic palpitations, exercise intolerance, lightheadedness, decreased concentration, headache, presyncope/syncope.

• Diagnosed by history, clinical features, and findings from head upright tilt table testing.

• Posttraumatic POTS has been described in a case series of eight TBI patients (with unknown severities)

Insidious onset of POTS ranging from 3 months to 3 years post injury.

No medication is approved to treat POTS; however, the following can be tried: fludrocortisone, midodrine, methylphenidate, erythropoietin, octreotide, serotonin and norepinephrine reuptake inhibitor (SNRI), clonidine, and combined alpha and beta blockers [4].

WIDESPREAD AUTONOMIC DYSREGULATION: PAROXYSMAL SYMPATHETIC HYPERACTIVITY

Historically, this condition has been known by several other names including: dysautonomia, paroxysmal autonomic instability with dystonia (PAID), sympathetic/autonomic storming, and autonomic dysfunction syndrome [2].

Definition

• A 26 member working group published the consensus term paroxysmal sympathetic hyperactivity (PSH) and definition in 2014: “A syndrome, recognized in a subgroup of survivors of severe acquired brain injury, of simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity [5].” Because the consensus term and the diagnostic criteria have only been published since 2014, most (earlier) literature has a wide range of findings resulting from a previous lack of a unified definition or process to evaluate PSH or its cause/effects.

Epidemiology

• Eight to thirty-three percent of patients with severe TBI develop prolonged PSH (greater than 7 days post injury), most literature supports the lower end of the range [2,6–8].

• PSH is associated with worse outcome, prolonged swallowing abnormalities, longer time to follow commands, longer posttraumatic amnesia, longer length of hospital stay, and greater health care cost [2,6–8].

Risk Factors

• Younger age at time of injury [1,6,8,9]

• Lower GCS [6]

• Longer coma duration [1,10]

• Concomitant fractures [10]

Etiology

• PSH can occur from many etiologies, most commonly TBI, but has been noted to happen after hypoxic/anoxic injury, subarachnoid hemorrhage, encephalitis (autoimmune, infectious), stroke, thalamic tumor, vasculitis, fulminant multiple sclerosis, postpartum vasoconstriction, cerebral fat embolism, leukemia, and acute disseminated encephalomyelitis [11].

Pathophysiology

• Current theory is that PSH results from a lack of central inhibitory pathway control on regulation of afferent information, which causes increased activation of the SNS, leading to excessive autonomic reactions either to traditional sympathetic trigger or without an obvious trigger [2,12]. The lack of control may be from local toxic effects (temporary) or structural (permanent) injury.

• There is an association with elevated levels of catecholamines at the time of PSH episodes [2].

Clinical Presentation

• PSH occurs across a spectrum of severity and not every patient has every feature. Tachycardia is almost universal, however [11].

• Typical onset is within 7 to 10 days post injury [9,11] but the first episode can happen up to 22 to 65 days after injury [10].

• Episodes tend to be triggered by and are more severe with noxious stimuli, including pain, suctioning, passive movements, bowel or bladder issues, or loud noise [2].

• Episodes can last 27.9 to 30.8 minutes (ranging from 15 to 50 minutes) for an average of 5.01 to 5.6 times per day [9,13].

• Episodes become less severe, shorter, and less frequent over time [2]

In one study, 80% of PSH episodes resolved at 12 month follow up [9].

• Improvement often coincides with neurologic recovery [2].

• Earlier diagnosis, hence earlier treatment, may decrease pursuing costly negative evaluations [11].

Diagnosis

• The diagnosis is made when the features described earlier in the Definition section occur after an acquired brain injury and in the following context (as noted earlier, not every patient has every feature) [5]:

Simultaneity of clinical features

Clinical features are paroxysmal

Sympathetic over-reactivity to normally nonpainful stimuli

Absence of intraparoxysmal parasympathetic features during episodes

Features persist greater than or equal to 3 consecutive days

Features persist greater than or equal to 2 weeks post injury

Features persist despite treatment of alternative differential diagnoses (e.g., infection)

Medication administered to decrease sympathetic features

Lack of alternative explanations

• There are proposed adjustments to the consensus guidelines for age-specific heart rate, respiratory rate, and blood pressure ranges for the pediatric population [14].

• PSH is a diagnosis of exclusion. Need to consider/rule out the following as appropriate: infection (most common cause of hyperthermia in TBI patients); seizures; acute hydrocephalus; increased intracranial pressure; neuroleptic malignant syndrome; serotonin syndrome; malignant hyperthermia; thyroid storm; venous thromboembolism; medication reaction; withdrawal from medications, illicit drug or alcohol ingestion; concomitant spinal cord injury/autonomic dysreflexia; acute coronary syndrome; pain (undiagnosed fractures, spasticity, constipation, pressure area, heterotopic ossification (HO)); and subarachnoid hemorrhage.

• A proposed research tool, PSH-Assessment Measure (PSH-AM), is undergoing validation. This tool has two components which are combined to give a PSH diagnostic likelihood:

Clinical feature scale: grades the presence and severity of increased heart rate, respiratory rate, systolic blood pressure, temperature, sweating, and posturing during episodes.

Diagnosis likelihood tool: assesses the clinical context. [5]

Radiologic Findings

• There may be an association between PSH and damage to the right insular cortex as seen on diffusion tensor imaging (DTI) [1]

• A CT study showed more focal parenchymal lesions in those with PSH [13] and an MRI study showed an association with deep lesions, including periventricular white matter, corpus callosum, basal ganglia, and brainstem [6,15]. However, another study showed no correlation between CT findings and PSH [9]. Yet another MRI study showed that PSH was associated with DAI [10]. These conflicting studies may be because of a lack of consensus diagnostic criteria, timing of imaging, different imaging techniques, and/or different interpreters.

Treatment

• Given the lack of understanding of the pathophysiology, it is difficult to target underlying etiology and there is little literature to guide management of symptoms [2].

• Initiate treatment as early as possible because

Core temperatures above 38°C to 39°C have produced neuronal death in animal models.

An increased catabolic state may lead to loss of body weight.

PSH is associated with an increased risk of developing critical illness polyneuropathy.

Spasticity/dystonia can lead to contractures, pressure areas, and/or pain [16]

• Environmental management

Assess for triggers

Decrease noxious stimuli: remove cervical collars as soon as possible, remove indwelling bladder catheters, prevent pressure areas, prevent constipation, use rubber tubes for suctioning, premedicate prior to known triggers.

Minimize noise and activity around the patient.

Be proactive and expeditious in adjusting hydration and caloric needs [17].

• Pharmacologic treatment: medication recommendations are anecdotal, not evidence based [2]. That said, many patients need more than one medication for symptom control, especially acutely (range from 0 to 5 medications, most often 2) [11,18].

• Medications should be used with caution as they can be sedating, potentially impair cognition, and/or affect recovery/neuroplasticity.

• Medications that affect afferent spinal cord sensitization:

Gabapentin (voltage-dependent calcium channels)

Modifies reactivity of neurologic circuits in spinal cord [16]

Controls the autonomic symptoms and the dystonic posturing and may also be beneficial in treating neuropathic pain

Intrathecal baclofen (ITB) (GABA B antagonists)—most effective but most invasive

Years long follow-up of TBI patients who received ITB for PSH symptoms shows that, on average, it was placed 6.6 months after injury, with an average baclofen dose of 232.6 μg/day, with higher doses and earlier placement in those with longer coma duration and lower preoperative Glasgow Coma Scale (GCS).

Complication rate over 10-year follow-up was 90.7% and included overdose, withdrawal, battery failure, pain, infection, sedation, catheter migrations, and pump failures [19]

• Medications that affect centrally mediated sympathetic outflow:

Propofol, diazepam, lorazepam, midazolam (GABA A antagonists)

Anecdotal reports favor midazolam and diazepam [20]

Bromocriptine (dopamine D2 agonist):

May be useful for centrally mediated fever and dystonia

Contraindicated in uncontrolled hypertension

Carbi/levodopa (dopamine agonist) [20,21]

Morphine (mu opioid receptor agonist): when it is effective, it is from modulation of central pathways, suppression of sympathetic outflow, and decreased pain [21,22]

Methadone [21]

• Medications that have a central and peripheral effect:

Propanolol (nonselective beta antagonist) and labetalol (nonselective beta and alpha1 agonist)

Lipophilic, so crosses the blood brain barrier

Decreases circulating catecholamines, reduce cardiac work and catabolic drive

Propanolol may decrease in hospital mortality [23]

Decreases hypertension and hemodynamic abnormalities

Do not alter diaphoresis (mediated by sympathetic cholinergic neurons)

Clonidine (alpha agonist)

Modulates blood pressure and heart rate (through decreased plasma catecholamines)

• Medications that act peripherally:

Dantrolene

Inhibits calcium release in sarcoplasmic reticulum

Poorly supported in the literature, treats extensor posturing/spasticity with minimal effect on other symptoms

Chemodenervation/lysis with alcohol or botulinum toxin: decreases noxious trigger (spasticity/pain) for PSH [24]

• Other treatment:

Hyperbaric oxygen therapy (HBOT): One case report of 6 TBI patients (30–70 days post injury, pre-HBOT GCS 8-11) who were given HBOT with 100% oxygen up to 1.5 atm for 120 minutes once daily for 10 days, 5 days of rest, then another course of daily treatment for 10 days found that all PSH symptoms resolved after 3 to 10 treatments [25]

• In the pediatric population, medications discussed in the literature include: acetaminophen ± codeine, benzodiazepines, and antihistaminergic antipsychotics; with clonazepam, delorazepam, and hydroxyzine found to be most efficacious in suppressing PSH episodes [14]

Prognosis

• Subclinical sympathetic over-responsiveness may persist indefinitely, especially in response to a noxious stimuli; this can be measured by heart rate variability [2,26]

• Studies differ on how PSH affects prognosis: most studies show those with PSH have worse functional independence measures (FIM) scores, worse Glasgow Outcome Scale (GOS) scores, increased length of stay in the intensive care unit (ICU), greater length of hospitalization, more infections, more tracheostomy placement, greater healthcare cost overall, worse disability rating scale (DRS), and lower modified Rankin scores at 6 and 12 months [1,9,10,20,27]

In contrast, however, one study showed that PSH did not affect GOS at 12 months [9]