In 1929, Dr. Wilder Penfield described clinical features of diencephalic autonomic epilepsy whereby clinical features of paroxysmal sympathetic hyperactivity were noted in a patient with encapsulated tumor in the third ventricle with mass effect and compression of the anterior nucleus of the thalamus. Dysfunction of the autonomic nervous system was observed with attacks which took place in the following course: (1) prodromal restlessness, (2) sudden vasodilatation of skin in the area supplied by cervical sympathetic system with sudden rise in blood pressure, (3) lacrimation, diaphoresis, salivation, pupillary dilatation and contraction, increase in heart rate and pulse pressure, slowing of respiratory rate, presence of pilomotor reflex, alteration in consciousness, (4) followed by disappearance of superficial blush and drop in blood pressure, slowing and weakening of pulse, (5) hiccupping, (6) transient shivering, and (7) Cheyne-Stokes respirations. Paroxysmal sympathetic hyperactivity (PSH) or neurostorming can be observed following intracranial injuries such as brain hemorrhage and edema from conditions including trauma, cerebrovascular conditions, brain tumors and infections.
To date, there are no concrete explanations of the pathophysiologic mechanisms of paroxysmal sympathetic hyperactivity. Various theories have made attempts on such elucidation based on evolving evidence. The disconnection theory proposed that dorsolateral prefrontal cortex, amygdala and hippocampus act as inhibitory centers to modulate sympathetic outflow from the brainstem and spinal cord. Upon brain injury, damage or disconnection of these cortical inhibitory centers would induce imbalanced sympathetic responses. Yet, sympathetic hyperactivity may be observed as paroxysmal in nature. Neuroendocrine disturbances are also present due to impaired regulation with possible surges in circulating catecholamines such as norepinephrine, epinephrine and dopamine. Excessive activation of hypothalamic-pituitary-adrenal axis also results in increased adrenocorticotropic hormone release. In the Excitatory-Inhibitory Ratio model, presence of inhibitory centers within the brainstem and diencephalon provide downward suppression of excitatory spinal circuits. Following intracranial injury, downward pathways are impaired and hence responses to external stimuli are amplified. Regeneration of inhibitory factors occur after a delay which would explain paroxysmal spasms of sympathetic hyperactivity.
Pharmacological therapies include various combinations of medications which work synergistically to mitigate secondary injury cascades brought about by neurostorming. These agents include bromocriptine, gabapentin, dexmedetomidine, propranolol, clonidine and benzodiazepines. Others include morphine and derivatives, dilantin, baclofen and dantrolene.
Bromocriptine is a synthetic dopamine D2 agonist which is used to treat paroxysmal sympathetic hyperactivity-induced central hyperthermia. This medication has significant thermoregulatory effects on the preoptic area of the hypothalamus. Other involved pathways include pars compacta of the substantia nigra and nucleus accumbens. More common adverse effects include headaches, nasal congestion, nausea and vomiting; while rare side effects from longer term use include retroperitoneal fibrosis and psychomotor agitation. It is contraindicated in those with severe cardiovascular conditions including uncontrolled hypertension.
Gabapentin exerts its action by binding to the α2δ-1 subunit of voltage gated calcium channels which impairs release of excitatory neurotransmitters substance P, noradrenaline and glutamate. Gabapentin also acts centrally on the locus ceruleus, particularly its descending noradrenergic projections to the spinal cord. Its common side effects include sedation and dizziness. Other side effects include peripheral edema, ataxia, nystagmus, fatigue, nausea and vomiting. Rare serious side effect includes Stevens-Johnson syndrome.
Dexmedetomidine is a selective α2 adrenergic receptor agonist primarily used to treat hypertension, agitation and tachycardia in paroxysmal sympathetic hyperactivity. Although its mechanism of action is similar to clonidine, it exhibits much greater selectivity for α2 adrenergic receptors. More specifically, it is thought to inhibit norepinephrine release through activation of G-proteins by α2A-adrenoreceptors in the brainstem. Dexmedetomidine is also postulated to exert anti-inflammatory effects by binding to α2 adrenergic receptor expressed on microglial cells which inhibit ERK1/2 phosphorylation. Adverse effects of dexmedetomidine include tachyphylaxis, withdrawal syndrome, transient hypertension, bradycardia and sinus arrest and hyperthermia. This medication is contraindicated in advanced heart block, uncontrolled hypotension and acute cerebrovascular events.
Propranolol is a non-selective β-adrenergic receptor antagonist primarily used to treat hypertension and tachycardia in paroxysmal sympathetic hyperactivity. It blocks β1 adrenergic receptors found in the sinoatrial node and atrioventricular node to decrease cyclic AMP levels and hence decreased calcium channel opening. β1 adrenergic receptor blockade in the kidneys leads to decreased renin secretion by juxtaglomerular cells which results in decreased angiotensin II secretion. Propranolol also acts peripherally on presynaptic β-adrenergic receptors thus reducing catecholamine release. Due to its lipophilicity, propranolol is able to cross the blood-brain-barrier, hypothesized to be effective in suppressing neuroinflammatory cascades following intracranial injury from disruption of autonomic regulatory centers which trigger onset of paroxysmal sympathetic hyperactivity. Aside from reducing leukocyte mobilization, propranolol may be effective in blunting proinflammatory cytokine production by blocking β-adrenergic stimulation in microglial cells reducing vascular permeability. Labetolol, another commonly administered drug, exhibits non-selective β-antagonism in addition to α1-antagonism. Due to its low lipophilicity, labetolol does not readily cross the blood-brain-barrier. Beta blockers may worsen bradycardia and are used with caution in those with severe heart blocks.
Clonidine is a α2 adrenergic receptor agonist that acts on the brainstem to inhibit norepinephrine release. It is primarily used to suppress hypertension and tachycardia in paroxysmal sympathetic hyperactivity, which are both associated with excessive sympathetic outflow. Adverse effects include hypotension and bradycardia. Caution is noted for those with cardiovascular diseases especially heart blocks. Abrupt withdrawal of clonidine may lead to rebound hypertension.
Benzodiazepines such as midazolam and clonazepam enhance neurotransmission of gamma-aminobutyric acid (GABA) without influencing its synthesis or release. They are used for their sedative, amnestic, anticonvulsant, anxiolytic and muscle relaxant properties in the management of paroxysmal sympathetic hyperactivity. Side effects include CNS depression, respiratory depression, cardiac negative inotropy and hepatic impairment.
Further investigations are warranted into the prognostic implications of neurostorming after adjusting for clinical confounding factors including sepsis, thromboembolic diseases, seizures, drug-related adverse effects and deleterious effects associated with secondary cascades post intracranial injury.
References
1. Penfield W. Diencephalic Autonomic Epilepsy. Arch of Neur and Psychiat Aug 1929.
