Abstract

BackgroundParoxysmal sympathetic hyperactivity (PSH) is a severe dysregulation of the sympathetic nervous system, often resulting from traumatic brain injury (TBI). With a prevalence of 10–30% in TBI patients, PSH poses diagnostic and therapeutic challenges. This study reviews advancements in diagnosis, management, and outcomes associated with PSH.

MethodsA comprehensive literature review of studies published in the past decade was conducted using PubMed, Scopus, Web of Science, and the Cochrane Library. Keywords included PSH, diagnostic criteria, treatment strategies, and clinical outcomes.

ResultsThe PSH Assessment Measure (PSH-AM), combining the clinical feature scale and diagnosis likelihood tool, enhances early detection and differentiates PSH from similar conditions. Acute management using opioids and benzodiazepines proved effective, while beta-blockers and alpha-2 agonists reduced episodic recurrence. Despite improved diagnostic accuracy, challenges persist, such as overlapping symptoms and difficulty quantifying autonomic dysfunction. PSH is associated with prolonged hospital stays and poorer neurological outcomes, emphasizing the importance of timely intervention.

ConclusionAccurate diagnosis using tools like PSH-AM is essential for mitigating PSH-related complications. Future research should explore biomarkers and personalized therapies to refine diagnosis and optimize long-term outcomes through multicenter trials.

Keywords: Diagnosis, Outcomes, Paroxysmal sympathetic hyperactivity, Traumatic brain injury, Treatment

INTRODUCTION

Paroxysmal sympathetic hyperactivity (PSH) is a condition characterized by dysregulated sympathetic activity caused by brain injury, either traumatic or non-traumatic. Traumatic brain injury (TBI), both moderate and severe, may cause PSH, while non TBI causes of PSH include autoimmune encephalitis associated with N-methyl-D-aspartate (NMDA) receptor antibodies, hemorrhagic/non-hemorrhagic stroke, and cerebral fat embolism.[ 19 , 20 ] In addition, tuberculous meningitis and tumors involving the thalamus or fourth ventricle have been reported as potential causes of PSH.[ 4 , 5 ]

The prevalence of PSH following TBI varies widely, ranging from 10% to 30% in both moderate and severe TBI.[ 9 , 13 , 18 ] However, there is insufficient evidence to establish a correlation between TBI severity and the risk of PSH.[ 17 ] Notably, the 30% prevalence of PSH following TBI, compared to only 6% after non-traumatic causes[ 22 ], indicates that TBI is the primary underlying cause of PSH. At present, the diagnosis of PSH is established using symptom-based assessment tools, commonly known as the PSH Assessment Measure (PSH-AM).[ 22 ] The PSH-AM consists of two components: the diagnosis likelihood tool (DLT), which evaluates the presence of features compatible with PSH, and the clinical feature scale (CFS), which assesses the severity of sympathetic nervous system hyperactivity and motor activity. However, several limitations hinder the accurate identification of PSH. First, the isolated features of PSH may be obscured by complications of the underlying etiology, such as seizures, sepsis, hypoxia, hypoglycemia, and traumatic pain.[ 22 ] Second, certain diagnostic criteria, such as quantifying the severity of sweating and dystonia or dynamically monitoring these features, are challenging to assess.[ 21 ]

Brain injury trauma patients diagnosed with PSH experience longer hospital stays, worse outcomes, and higher 6-month mortality rates compared to those without PSH.[ 12 ] Conversely, other studies have shown that patients for whom PSH is diagnosed early tend to have better clinical outcomes.[ 11 ] These findings highlight the importance of early detection of PSH in reducing its associated mortality and morbidity despite the challenges in establishing a definitive diagnosis. This article aims to elaborate on improved diagnostic approaches and provide updates on the management and outcomes of PSH patients.

MATERIALS AND METHODS

This study was a literature review elaborating publications from the past 10 years. Databases used were PubMed, Scopus, Web of Science, and the Cochrane Library, using modified keywords of “Paroxysmal Sympathetic Hyperactivity,” “Diagnostic Criteria,” “Treatments,” and “Outcomes” as part of the search strategy.

RESULTS AND DISCUSSION

Pathophysiology

The pathophysiology underlying PSH remains incompletely understood. However, several theories, including disconnection theory, excitatory/inhibitory ratio (EIR) theory, and neuroendocrine system, have been proposed to explain the occurrence of PSH.

Disconnection theory

The disconnection theory posits the existence of a functional connection between cortical inhibitory centers in the brain and sympathetic control centers. Under physiological conditions, sympathetic tone is regulated through the interaction of cortical inhibitory centers (e.g., the dorsolateral prefrontal cortex, amygdala, and basal ganglia) with sympathetic control centers (e.g., the brainstem, hypothalamus, and mesencephalon). However, this critical connection may be disrupted in PSH, leading to dysregulation of sympathetic tone.[ 21 ] The loss of cortical inhibitory function results in the overactivation of sympathetic control centers, causing exaggerated sympathetic responses to both internal and external stimuli [ Figure 1 ].[ 22 ] While this theory offers a plausible explanation for the hyperactivity of sympathetic responses in TBI, its main limitation is the inability to account for the episodic, or “paroxysmal,” nature of the observed sympathetic hyperactivity.[ 22 ]

Figure 1:

Schematic diagram of disconnection theory. The sympathetic autonomic system is regulated by the interaction between cortical inhibitory centers and sympathetic control centers (left). Disruption connection between cortical inhibitory centers and sympathetic control centers leads to dysregulation of sympathetic tone (right).

EIR theory

The EIR theory proposes an imbalance between excitatory and inhibitory processes in the nervous system.[ 22 ] This imbalance occurs in two stages. First, there is a loss of descending inhibition, where regulatory input from cortical centers is reduced. Second, an excitatory spinal circuit develops, leading to hyperactive responses.[ 17 ] Excessive spinal excitation causes various stimuli, including non-noxious ones, to be misinterpreted as harmful (noxious) by the brain.[ 21 ] This theory further suggests that compensatory mechanisms temporarily restore inhibitory control after the initial hyperactivity. These mechanisms involve partial recovery of descending pathways and increased levels of gamma-aminobutyric acid [ Figure 2 ]. However, this recovery is temporary and cyclical. Thus, EIR is able to explain the paroxysmal episodic sympathetic hyperactivity observed in PSH.[ 21 ]

Figure 2:

Schematic diagram of excitatory/inhibitory ratio theory. Brainstem centers modulate inhibitory signals directed toward spinal reflex regions; meanwhile, spinal centers relay sensory and perceptual input to higher centers and generate sympathetic and motor outputs, ensuring a balance between inhibitory and excitatory interneuronal functions (left). Dysfunctional descending inhibition leads to heightened activity in spinal circuits, whereas the partial recovery of descending pathways, which is temporary and cyclical, explains the paroxysmal episodes (right).

Neuroendocrine system

The neuroendocrine system plays a key role in the pathophysiology of PSH, particularly through dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which controls the body’s stress response. PSH is believed to activate the HPA axis excessively, resulting in uncontrolled adrenergic release and elevated catecholamine levels.[ 14 ] During the paroxysmal phase of PSH, blood levels of adrenocorticotropic hormone (ACTH), epinephrine, norepinephrine, and dopamine significantly increase.[ 22 ] In contrast, during the intermittent phase (when sympathetic hyperactivity subsides), norepinephrine and dopamine levels decrease.[ 22 ] This distinction arises because the sympathetic nervous system produces norepinephrine and dopamine, while epinephrine is mainly secreted by the adrenal medulla. During paroxysmal episodes, catecholamine levels rise two- to three-fold, and serum ACTH concentrations increase by approximately 40%. This hormonal surge further supports the neuroendocrine system’s involvement in PSH pathogenesis [ Figure 3 ].[ 21 ]

Figure 3:

Schematic diagram of neuroendocrine system theory. An increase in circulating catecholamines causes sympathetic excitation, leading to the paroxysmal phase.

Clinical manifestations

The hallmark of PSH is the sudden and simultaneous surges in sympathetic and motor activity. While six key symptoms that include six core sympathetic and motor features such as tachycardia, tachypnea, hypertension, hyperthermia, hyperhidrosis, and posturing define the condition, its clinical presentation varies widely among individuals. Most patients exhibit only a subset of these symptoms rather than the complete set.[ 22 ] Several symptoms have been found in PSH that arise from TBI which include pupil dilation, decreased consciousness, flushing, goosebumps (horripilation), and agitation. The broad range of clinical manifestations can be attributed to individual variability and the use of certain medications to treat TBI, which may conceal some symptoms.[ 7 ] PSH is a rare complication of spontaneous intracerebral hemorrhage (ICH). Patients with deep bleeding lesions in ICH are more likely to develop PSH. The most common symptoms are hyperthermia and hyperhidrosis, both reported in 80% of cases.[ 6 ] PSH has also been observed in cases of large benign tumors compressing the brainstem. Symptoms such as tachycardia, tachypnea, hyperthermia, hypertension, diaphoresis, and extensor posturing can occur with or without triggers. Activities like bathing or repositioning the body may provoke these symptoms.[ 5 ]

Studies have found a link between anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and PSH. Patients with PSH in anti-NMDAR encephalitis exhibited higher rates of having ovarian teratoma, involuntary movements, impaired consciousness, and central hypoventilation. Some studies found that the most common manifestations are tachycardia, tachypnea, posturing, hyperhidrosis, hyperthermia, and hypertension, respectively.[ 3 ] Others found that in severe cases of anti-NMDAR encephalitis, the most prominent symptoms of PSH were tachycardia and hyperthermia, with posturing being the least severe clinical feature.[ 20 ]

Recent evidence suggests that infections, such as tuberculous meningitis, can cause PSH. Clinical findings include episodic hypertonia, tachycardia, new-onset fever, hypertension, tachypnea, and diaphoresis.[ 4 ]

Diagnostic criteria

Over the past 10 years, the PSH-AM has been the most effective diagnostic tool to identify PSH in patients with TBI. The PSH-AM consists of two components: (1) the CFS, which rates the severity of sympathetic nervous system excitation and motor activity on a 0–3 scale [ Table 1 ], and (2) the DLT, which assigns a score of 1 when the diagnostic feature is present [ Table 2 ]. Each of the scores will be combined to determine the likelihood of PSH. The score is then categorized into unlikely for scores below 8, possible for scores between 8 and 16, and probable for scores of 17 or higher.[ 22 ]

Table 1:

Clinical feature scale, part of paroxysmal sympathetic hyperactivity-assessment measure.

Table 2:

Diagnosis likelihood tool, part of the paroxysmal sympathetic hyperactivity-assessment measure.

The PSH-AM scale has strengthened diagnostic accuracy by quantifying the severity of clinical signs and removing previous criteria such as horripilation and flushing. The use of this scale during intensive care unit (ICU) hospitalization also led to earlier diagnosis and demonstrated a change in PSH prevalence over time, with a decline from 32% to 18%, particularly in patients with traumatic injuries.[ 8 ] Enhances early detection of symptoms, quantifies their severity through the CFS, and helps exclude differential diagnoses using the DLT. PSH-AM can optimize resource allocation, minimize unnecessary interventions, and shorten hospital stays, thus improving patient outcomes.[ 16 ]

Although the scale improves diagnosis, it still has several limitations. Conditions such as septicemia, seizures, hydrocephalus, and hypoxia often present similar symptoms to PSH, leading to misdiagnosis or under-recognition. For instance, tachypnea and hyperthermia in PSH may mimic pulmonary embolism, while posturing can resemble epileptic seizures.[ 22 ] In addition, quantifying the severity of sweating and dystonia or continuously monitoring the symptoms remains challenging for clinicians.[ 21 ]

Laboratory findings and imaging

Numerous studies have now provided substantial empirical evidence supporting the early detection of PSH following TBI. While laboratory tests cannot definitively diagnose PSH, a diagnosis of exclusion is essential to rule out other potential causes, including infectious conditions (such as pneumonia or sepsis), drug-induced disorders (such as fever or neuroleptic malignant syndrome [NMS]), rhabdomyolysis, dehydration, seizures, pulmonary embolism, or deep vein thrombosis.[ 2 ]

In patients with TBI, negative microbial cultures from blood, cerebrospinal fluid, airway secretions, or urine offer valuable evidence for exclusionary diagnosis. In addition, normal electroencephalograms in patients with PSH aid in ruling out epilepsy and other neurological conditions. In essence, these diagnostic tests enhance the accuracy and timeliness of the diagnosis, even before the onset of definitive symptoms and confirmation.[ 22 ]

Procalcitonin (PCT) is employed to distinguish PSH from infections. When PCT levels are low (below 1 ng/mL) in the early stages of fever, it indicates a non-infectious systemic response, thereby preventing the unnecessary use of antibiotics. Conversely, an elevated PCT level points to an infectious cause, warranting the initiation of targeted antibiotic treatment.[ 1 ]

In addition, emerging evidence from imaging techniques has provided insights into predicting the onset of PSH in patients with TBI. A prior study indicated that the presence of focal lesions on computed tomography (CT) scans within the first 48 hours was linked to a higher likelihood of PSH episodes compared to patients with diffuse lesions or normal CT findings.[ 22 ]

Further studies using magnetic resonance imaging (MRI) have indicated that PSH is more commonly observed in patients with extensive structural and diffuse brain damage. MRI findings have categorized lesions into three distinct types: cortical and subcortical white matter, the corpus callosum or diencephalon, and the dorsolateral region of the midbrain and upper pons.[ 22 ]

Diffusion tensor imaging has shown that low fractional anisotropy values, which reflect white matter disconnectivity, particularly in the right posterior internal capsule and the splenium or corpus callosum, are strongly associated with the onset of PSH. However, due to the unclear pathology of PSH, these findings do not offer a definitive neuroanatomical characterization of the condition, nor can they serve as a conclusive diagnostic tool.[ 22 ]

Treatment

The management of PSH remains a challenging clinical area due to the absence of established guidelines. Current therapeutic strategies are broadly categorized into approaches aimed at symptom resolution, episode prevention, and treatment of refractory cases, with the overarching goal of minimizing both the acute and long-term complications associated with this condition.[ 15 ] Symptom resolution focuses on the rapid cessation of paroxysmal episodes through the use of medications characterized by a quick onset of action and a short half-life. First-line agents in this approach include morphine and short-acting benzodiazepines, which have demonstrated high efficacy in terminating acute episodes. These agents are employed to address hyperthermia-induced fever, control tachycardia, stabilize fluctuating blood pressure, provide timely sedation, and alleviate spasticity or muscular hypertonicity.[ 10 , 15 ] Morphine, administered intravenously in doses ranging from 1 to 10 mg, is considered the most effective agent for managing severe PSH episodes, particularly for symptoms such as hypertension, tachycardia, and allodynia. However, prolonged use of morphine may lead to withdrawal symptoms, and its major side effects include respiratory depression, sedation, and hypotension. Another commonly used agent is diazepam, administered intravenously at doses of 1–10 mg. Although less effective than opioids, diazepam possesses good liposolubility and is beneficial for its sedative properties. Nonetheless, its use is associated with potential adverse effects such as hypotension and respiratory depression.[ 22 ]

In contrast, symptom prevention focuses on reducing the frequency and severity of PSH episodes. This approach utilizes medications such as non-selective beta-blockers, alpha-2 agonists, and long-acting benzodiazepines. These agents offer prophylactic control of symptoms and are particularly effective in managing chronic or recurrent manifestations of the condition.[ 15 ] Propranolol, administered orally at doses of 20– 60 mg every 4–6 h, has been shown to reduce mortality rates in PSH patients. However, its primary effect is to ameliorate the consequences of the disorder rather than address the central mechanisms underlying autonomic dysfunction. Common side effects include bradycardia, hypotension, arrhythmias, and hypoglycemia. In addition, hypoglycemia is a particular concern in patients receiving insulin therapy. Dexmedetomidine, an alpha-2 agonist administered intravenously at 0.2–0.7 µg/kg/h, is widely used in intensive care settings to manage pain and anxiety while maintaining hemodynamic stability. Its advantages include minimal respiratory depression, eliminating the need for mechanical ventilation, and the ability to wake patients easily to assess consciousness. Dexmedetomidine is a promising preventive agent for PSH, particularly in patients with TBI. Long-acting benzodiazepines, such as clonazepam (0.5–8.0 mg/day, orally), can also be employed for prevention. Clonazepam’s high liposolubility enhances its efficacy; however, its use is associated with side effects such as sedation, hypotension, and respiratory depression.[ 22 ] Refractory treatment is reserved for symptoms that fail to respond to conventional therapies and pose a significant risk of secondary injury. Hyperpyrexia, posturing, and autonomic instability are among the most challenging symptoms to manage and are often associated with NMS, a condition linked to prolonged use of antipsychotic medications such as chlorpromazine or haloperidol. In these cases, continuous intravenous infusions of agents such as propofol, benzodiazepines, opioids, or dexmedetomidine are employed to achieve symptom control.[ 22 ]

Outcomes

PSH is more likely to occur after severe and diffuse brain injuries, which are linked to worse clinical outcomes both in the short and long term. Literatures consistently highlights that early diagnosis can significantly enhance patient outcomes by reducing ICU length of stay and mitigating long-term complications, including pulmonary infections resulting from prolonged mechanical ventilation, tracheostomy, and, in severe cases, mortality.[ 7 ] While earlier studies questioned PSH as an independent risk factor, more recent research indicates that PSH is linked to longer hospital stays and worse clinical outcomes. However, inconsistencies remain regarding its impact on hospitalization duration, mechanical ventilation, and long-term neurological outcomes, likely due to methodological limitations and insensitive outcome measures such as the Glasgow outcome scale or functional independence measure. Despite these uncertainties, clinical evidence suggests that PSH is an independent risk factor for poorer neurological outcomes.[ 10 ]

CONCLUSION

PSH remains a challenging condition, predominantly associated with traumatic brain injuries. Advances in understanding its pathophysiology and the development of diagnostic tools, such as the PSH-AM, have enhanced early detection and treatment precision. However, limitations in standardizing criteria and addressing refractory cases persist. Timely diagnosis and intervention are crucial in reducing complications and improving outcomes. Future research should prioritize integrating biomarkers, advanced imaging, and personalized therapies to refine diagnostic accuracy and optimize management strategies. Multicenter trials are essential to establish the long-term efficacy of emerging therapeutic approaches.

Ethical approval

The Institutional Review Board approval is not required as it is a retrospective study.

Declaration of patient consent

Patient’s consent was not required as there are no patients in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

Acknowledgment

The authors thank PubMed, Scopus, Web of Science, and Cochrane for the accessibility and wide publication of the journals that are collected and analyzed in this study.

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