Paroxysmal sympathetic hyperactivity
Paroxysmal sympathetic hyperactivity (PSH), also known as sympathetic storming, autonomic storms, or dysautonomia, is a clinical syndrome characterized by recurrent episodes of excessive sympathetic nervous system activation following severe acquired brain injury.[1] It manifests as paroxysmal increases in heart rate, blood pressure, respiratory rate, body temperature, sweating, and abnormal motor posturing, often triggered by non-noxious stimuli such as touch or noise.[2] PSH typically emerges within the first week after injury and can persist for weeks to months, complicating recovery in affected patients.[3] The condition most commonly arises after traumatic brain injury (TBI), accounting for approximately 80% of cases, but it has also been documented following hypoxic-ischemic injury (10%), stroke (5%), encephalitis, tumors, or other forms of severe brain damage.[1] Epidemiological data indicate an incidence of 8-33% among adults with severe TBI, with higher rates in younger males and those with diffuse axonal injury; in pediatric cases, older age is associated with increased risk (as of studies through 2025).[1] The underlying pathophysiology involves a loss of descending inhibitory control from higher brain centers (e.g., hypothalamus and cortex) on brainstem sympathetic nuclei, leading to an imbalance between excitatory and inhibitory pathways and elevated catecholamine levels—up to 200-300% above baseline during episodes.[3] This "disconnection" theory explains the hyperadrenergic state, though ongoing research explores additional mechanisms like inflammation and excitotoxicity.[1] Diagnosis of PSH relies on clinical observation and exclusion of mimics such as sepsis, seizures, pulmonary embolism, or drug withdrawal, using tools like the Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM) developed in a 2014 international consensus.[1] The PSH-AM scores the likelihood (Diagnosis Likelihood Tool) and severity (Clinical Feature Scale) of symptoms, with a total score ≥8 indicating likely PSH; it assesses episodic sympathetic overactivity (e.g., heart rate ≥100 bpm, systolic blood pressure ≥140 mmHg, temperature ≥38.5°C, tachypnea, diaphoresis) with agitation or posturing, alongside negative investigations for alternatives (e.g., normal EEG, cultures).[3] Management focuses on minimizing triggers through environmental control (e.g., reducing noise and suctioning) and pharmacological interventions, including opioids like morphine for initial suppression, beta-blockers such as propranolol (20-60 mg doses), alpha-2 agonists like clonidine, and anticonvulsants like gabapentin.[2] Multimodal therapy combining these agents is often more effective than monotherapy, though evidence is primarily from case series and retrospective studies, with no large randomized trials available.[1] Recent approaches include botulinum toxin for refractory dystonia, and PSH episodes are associated with poorer functional outcomes, prolonged ICU stays, and increased mortality risk if untreated.[1]Clinical Presentation
Signs and Symptoms
Paroxysmal sympathetic hyperactivity (PSH) manifests as recurrent paroxysmal episodes of sympathetic nervous system overactivity, often following severe acquired brain injury such as traumatic brain injury or stroke. These episodes typically last from a few minutes to several hours, with an average duration of around 30 minutes, and occur multiple times per day, averaging about 5.8 episodes in affected patients.[2] The core clinical features during episodes include simultaneous elevations in vital signs and autonomic responses, such as tachycardia with heart rate exceeding 100 beats per minute (or higher thresholds like >120 beats per minute in some cases), hypertension with systolic blood pressure above 140 mmHg (or >160 mmHg without antihypertensive medication), hyperthermia with body temperature greater than 38°C (or >38.3°C), and tachypnea with respiratory rate over 20 breaths per minute (or >25 breaths per minute). Profuse diaphoresis and pupillary dilation (mydriasis) are also hallmark signs, reflecting widespread sympathetic discharge.[4][5][6] In addition to these autonomic signs, severe episodes may involve agitation, dystonia, or posturing, which can contribute to patient distress and complicate care. Episodes are frequently triggered by non-noxious stimuli, such as touch, noise, suctioning, or passive movement, occurring in approximately 72% of cases.[2][3] The progression of an individual episode typically begins with a sudden onset of rising vital signs and autonomic symptoms, reaches a peak of intensity where multiple features coincide, and then gradually resolves over time, often without intervention in milder cases. This cyclic pattern underscores the episodic nature of PSH, distinguishing it from persistent autonomic dysregulation.[6][2]Epidemiology
Paroxysmal sympathetic hyperactivity (PSH) occurs in 8% to 33% of adults with severe traumatic brain injury (TBI).[1][2] In non-traumatic acquired brain injuries, the incidence is lower, ranging from 6% to 13%.[7][2] A meta-analysis of adult brain injury patients reported a combined incidence of 27.4% (95% confidence interval, 19.0%–35.8%).[8] These rates are primarily derived from intensive care unit settings, where PSH is more readily identified through standardized assessment tools.[1] Demographically, PSH predominantly affects younger adults, with affected patients exhibiting a mean age of approximately 36 years (standard deviation ±13 years).[7] There is a male predominance, consistent with the higher incidence of severe TBI in males.[1][2] In pediatric populations, incidence rates are reported around 10-30% following severe brain injury, showing similar patterns tied to injury severity.[1][9][10] Key risk factors include severe brain injury, as indicated by a Glasgow Coma Scale score below 8 on admission.[8][2] Diffuse axonal injury significantly elevates the risk (odds ratio, 4.75; 95% confidence interval, 1.22–18.46).[8] Prolonged coma and conditions such as hydrocephalus further contribute to susceptibility.[8] Younger age itself is an independent risk factor (standardized mean difference, -0.59; 95% confidence interval, -1.03 to -0.16).[8] Reported rates vary globally, with higher incidences in North American studies (37.3%) compared to those in China (16.4%) and Europe (23.1%), potentially reflecting differences in diagnostic vigilance and ICU protocols.[8] PSH is more frequently documented in TBI cohorts within intensive care environments, while underdiagnosis persists in non-TBI etiologies due to overlapping symptoms with other autonomic disturbances.[7][1]Etiology and Pathophysiology
Causes
Paroxysmal sympathetic hyperactivity (PSH) is primarily precipitated by severe acquired brain injury, with traumatic brain injury (TBI) being the most common underlying condition, accounting for approximately 80% of cases in early reviews and 19-30% prevalence among moderate to severe TBI patients.[11] TBI often involves diffuse axonal injury and damage to frontal and temporal lobes, periventricular white matter, corpus callosum, mesencephalon, or upper brainstem, increasing the risk in patients with lower Glasgow Coma Scale scores.[11][12] Non-traumatic causes include hypoxic-ischemic encephalopathy (HIE), which represents about 21% of recent cases, as well as intracerebral hemorrhage, ischemic or hemorrhagic stroke (around 21% in updated reviews), brain tumors (particularly those compressing the brainstem, such as in the thalamus or fourth ventricle), encephalitis (including autoimmune forms like anti-NMDA receptor encephalitis), and anoxic brain injury.[11][13] Less common precipitants encompass hydrocephalus, infections (e.g., tuberculous meningitis), and rare conditions such as Guillain-Barré syndrome or fat embolism syndrome.[12][13] Once PSH is established, episodes are often triggered by non-noxious stimuli, including endotracheal suctioning or sputum aspiration, pain from repositioning or bathing, fever, or environmental factors such as emotional arousal or body contact, due to heightened sympathetic responses in the context of brain injury.[11][13]Pathophysiology
Paroxysmal sympathetic hyperactivity (PSH) arises primarily from a disconnection syndrome, wherein brain injury disrupts descending inhibitory pathways from higher centers such as the cortex and hypothalamus to brainstem nuclei, leading to disinhibition of sympathetic outflow and episodic surges in autonomic activity.[14] This loss of regulatory control results in unchecked excitation of spinal sympathetic preganglionic neurons, manifesting as recurrent paroxysms of sympathetic overdrive.[15] The central autonomic network (CAN), which integrates autonomic regulation, becomes imbalanced due to this disconnection, allowing peripheral stimuli to trigger exaggerated responses without modulation from supraspinal inhibitory inputs.[1] Damage to specific structures, particularly the diencephalon and brainstem, plays a critical role in this pathophysiology by severing connections essential for autonomic homeostasis. Lesions in the diencephalon, including the hypothalamic paraventricular nucleus, impair the integration of sympathetic output and hypothalamic-pituitary-adrenal axis function, while brainstem involvement disrupts medullary centers that normally gate sympathetic reflexes.[15][1] Structural abnormalities in these regions, often visualized via magnetic resonance imaging as periventricular white matter damage or corpus callosum disruption, correlate with the severity and persistence of PSH episodes.[16] An underlying excitatory-inhibitory imbalance further exacerbates PSH, characterized by reduced GABAergic modulation and heightened glutamatergic excitation within the CAN. Decreased GABA transmission diminishes tonic inhibition on sympathetic pathways, while excessive glutamate release activates NMDA receptors, promoting neuronal hyperexcitability and spinal reflex amplification.[1][15] Secondary inflammatory processes contribute to the intensification of autonomic storms through cytokine-mediated excitotoxicity. Post-injury release of pro-inflammatory cytokines, such as interleukin-1β from neutrophil extracellular traps in the hypothalamus, amplifies glutamate secretion and triggers calcium influx, leading to oxidative stress and further neuronal damage that sustains sympathetic hyperactivity.[15][17]Diagnosis
Diagnostic Criteria
The diagnosis of paroxysmal sympathetic hyperactivity (PSH) relies on clinical identification of recurrent, paroxysmal episodes of sympathetic overactivity following acquired brain injury, in the absence of alternative explanations such as infection or metabolic disturbances. Essential criteria include the simultaneous occurrence of at least four sympathetic and motor features during episodes, such as tachycardia (heart rate ≥100 bpm), hyperthermia (temperature ≥38°C), hypertension (systolic blood pressure ≥140 mmHg), tachypnea (respiratory rate ≥18 breaths/min), diaphoresis, and dystonic posturing or spasticity, with episodes triggered by stimuli and returning to baseline between occurrences. These features must persist for at least three consecutive days and ideally beyond two weeks post-injury, without parasympathetic dominance during episodes. The Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM) provides a standardized, validated scoring system to confirm PSH and quantify severity, developed through international consensus for use in adults post-brain injury. It comprises two components: the Clinical Feature Scale (CFS), which scores the severity of six core features (heart rate, respiratory rate, systolic blood pressure, temperature, sweating, and posturing) on a 0-3 scale each during the maximum episode in the prior 24 hours (e.g., heart rate: 0 for <100 bpm, 1 for 100-119 bpm, 2 for 120-139 bpm, 3 for ≥140 bpm; temperature: 0 for <37°C, 1 for 37-37.9°C, 2 for 38-38.9°C, 3 for ≥39°C), yielding a subtotal of 0-18; and the Diagnosis Likelihood Tool (DLT), which awards 1 point for each of 11 supportive features (e.g., paroxysmal nature, persistence despite treating differentials, ≥2 episodes daily, antecedent brain injury), yielding 0-11. The total PSH-AM score (CFS + DLT) categorizes diagnostic likelihood as unlikely (<8), possible (8-16), or probable (≥17). Supportive investigations aid in confirming PSH by excluding mimics, including electroencephalography (EEG) to rule out subclinical seizures and laboratory tests such as complete blood count (CBC) and C-reactive protein (CRP) to exclude infection or inflammation. Serial PSH-AM assessments over days allow tracking of diagnostic certainty as the clinical course evolves.| Feature | Score 0 | Score 1 | Score 2 | Score 3 |
|---|---|---|---|---|
| Heart Rate (bpm) | <100 | 100-119 | 120-139 | ≥140 |
| Respiratory Rate (breaths/min) | <18 | 18-23 | 24-29 | ≥30 |
| Systolic BP (mmHg) | <140 | 140-159 | 160-179 | ≥180 |
| Temperature (°C) | <37 | 37-37.9 | 38-38.9 | ≥39 |
| Sweating | None | Mild | Moderate | Severe |
| Posturing | None | Mild | Moderate | Severe |
Differential Diagnosis
Paroxysmal sympathetic hyperactivity (PSH) presents with episodic autonomic dysregulation, including tachycardia, hypertension, hyperthermia, and dystonia, which can overlap with various conditions requiring careful differentiation to avoid misdiagnosis.[18] Distinguishing PSH from mimics involves excluding alternative causes through clinical history, laboratory tests, neuroimaging, and response to targeted therapies, often guided by diagnostic tools like the PSH Assessment Measure (PSH-AM).[19]Infectious Causes
Infections such as sepsis, meningitis, or pneumonia can mimic PSH through fever, tachycardia, and tachypnea due to systemic inflammation.[18] These conditions typically feature identifiable infection foci, elevated procalcitonin (PCT) or CD64 levels, and leukocytosis, unlike PSH where inflammatory markers remain normal.[18] Differentiation relies on response to antibiotics and antimicrobials, which resolve symptoms in infectious cases but not in PSH; cerebrospinal fluid analysis or cultures confirm meningitis or sepsis.[20] For instance, in suspected sepsis, blood cultures and imaging identify pathogens, while PSH episodes persist despite infection treatment.Metabolic and Endocrine Disorders
Metabolic and endocrine conditions like thyroid storm or pheochromocytoma present with episodic sympathetic overactivity, including tachycardia, hypertension, and hyperthermia, overlapping with PSH's paroxysms.[20] Thyroid storm is preceded by thyrotoxicosis signs such as goiter or exophthalmos and confirmed by abnormal thyroid function tests (e.g., low TSH, elevated free T4), which are normal in PSH.[20] Pheochromocytoma involves catecholamine-secreting tumors, diagnosed via plasma metanephrines or 24-hour urinary catecholamines, and surgical resection alleviates symptoms, contrasting PSH's persistence post-brain injury.[18] Withdrawal syndromes from alcohol, opioids, or sedatives cause autonomic instability with agitation and diaphoresis, but are differentiated by recent substance exposure history and resolution with reinstatement or substitution therapy.Neurological Conditions
Neurological mimics include seizures, neuroleptic malignant syndrome (NMS), and serotonin syndrome, all featuring autonomic instability alongside altered mental status.[18] Autonomic seizures arise from focal brain lesions and show non-stereotyped episodes with epileptiform activity on electroencephalography (EEG), responding to antiepileptic drugs, whereas PSH episodes are stereotyped and EEG-negative.[18] NMS, induced by antipsychotics, includes muscle rigidity, elevated creatine kinase, and fever, ruled out by absence of neuroleptic exposure and lack of rigidity in PSH.[20] Serotonin syndrome, from serotonergic medications, presents with hyperreflexia, clonus, and myoclonus, differentiated by drug history and resolution upon discontinuation, unlike PSH's link to diffuse brain injury.Iatrogenic and Other Causes
Iatrogenic factors, such as drug reactions or inadequately managed pain in intensive care unit (ICU) patients, can provoke sympathetic surges mimicking PSH. Malignant hyperthermia, a rare anesthetic reaction, features rapid-onset hyperthermia and rigidity post-surgery, excluded by timing (delayed in PSH) and genetic testing or dantrolene response.[20] Pain-induced responses in ICU settings cause transient tachycardia and hypertension, but abate with analgesia, unlike PSH's recurrent, unprovoked episodes.[18] Differentiation often involves medication review and trial of supportive measures; neuroimaging may reveal PSH-associated lesions in the diencephalon or brainstem absent in pure iatrogenic cases.[21]| Condition Category | Overlapping Features with PSH | Key Differentiating Features | Diagnostic Tools |
|---|---|---|---|
| Infectious (e.g., sepsis) | Fever, tachycardia, tachypnea | Elevated PCT/CD64, infection foci, antibiotic response | Cultures, labs, imaging[18] |
| Metabolic/Endocrine (e.g., thyroid storm) | Tachycardia, hypertension, hyperthermia | Abnormal TFTs or catecholamines, substance withdrawal history | Thyroid labs, urinary metanephrines, history[20] |
| Neurological (e.g., seizures) | Autonomic instability, dystonia | Epileptiform EEG, non-stereotyped episodes, AED response | EEG, drug history[18] |
| Iatrogenic (e.g., pain response) | Sympathetic surges, agitation | Recent drug exposure, analgesia response, no brain lesion | Medication review, trial therapies |