Paroxysmal Sympathetic Hyperactivity in Childhood Tuberculous Meningitis: A New Association

Dysautonomia in a critical care setting was a complex entity with multiple terminologies, definitions, and diagnostic criteria until a unifying term, paroxysmal sympathetic hyperactivity (PSH), was proposed in 2010. A conceptual definition and diagnostic criteria were established in 2014. ¹ Paroxysmal sympathetic hyperactivity is defined as a syndrome characterized by episodic increases in sympathetic and motor activity observed within weeks or months after a severe acquired brain injury. ¹ Historically, paroxysmal sympathetic hyperactivity is described to have 3 phases: the first phase is vague, lasting approximately a week, and corresponds with the immediate posttraumatic brain injury period when patients are mostly under sedation. The transition into the second phase coincides with the cessation of sedation and the appearance of clinical features of dysautonomia. Finally, the third phase, or the “burnt out” phase, is characterized by residual spasticity and dystonia as the most common clinical features. ²

A review of literature published before 2010 suggested that 80% of paroxysmal sympathetic hyperactivity cases are associated with traumatic brain injury. ³ However, there has been a gradual accumulation of data in the form of case reports and small series linking paroxysmal sympathetic hyperactivity with nontraumatic etiologies.^4-6 In anecdotal reports on children, paroxysmal sympathetic hyperactivity has been associated with traumatic brain injury, cardiac arrest, severe hypoxic injury, and encephalitis. Data on the occurrence of paroxysmal sympathetic hyperactivity in central nervous system infections such as tuberculous meningitis are scarce.^7,8 Tuberculous meningitis is considered an evolving disease associated with a multitude of complications, prolonged hospital stays, and significant morbidity.^9,10 The current study was undertaken to analyze the prevalence, presentation, management, and outcome of paroxysmal sympathetic hyperactivity in children with newly diagnosed tuberculous meningitis.

Methods

An ambispective analysis of all newly diagnosed tuberculous meningitis cases admitted to a tertiary care hospital in Northern India from September 2019 through January 2022 was conducted following approval from the institute's ethics committee. The first case of paroxysmal sympathetic hyperactivity in tuberculous meningitis within our department was diagnosed in September 2019. Since then, as a protocol, the Paroxysmal Sympathetic Hyperactivity Assessment Measure has been routinely applied to all admitted children with tuberculous meningitis when new signs or symptoms, such as paroxysms of unexplained fever, diaphoresis, tachycardia, tachypnea, dystonia, posturing, or fluctuations in blood pressure, are observed. However, the diagnosis of paroxysmal sympathetic hyperactivity is only established when new-onset sepsis, shock, electrolyte imbalance, drug resistance, or any other apparent cause for neurologic worsening is ruled out.

Hospital records of all children aged 6 months to 14 years with newly diagnosed tuberculous meningitis admitted during the study period were retrieved from the Medical Record Department of the institute. Each file contained detailed clinical history and examination findings in a problem-oriented medical record (POMR) format, daily progression notes in a subjective objective assessment plan (SOAP) structure, investigation sheets, monitoring sheets, temperature chart, and nursing charts with details of treatment. Serial neuroimaging (head computed tomography [CT], brain magnetic resonance imaging [MRI] and spine MRI) were accessed using the unique hospital identity of the patients from the online database of the Department of Radiology. Similarly, hematology, biochemistry, cultures, and other blood and cerebrospinal fluid investigations were accessed using the unique hospital identity of patients from the institute's patient database available on the intranet.

Tuberculous meningitis was diagnosed using international consensus criteria for tuberculous meningitis. ¹¹ To maintain a homogeneous study population, only newly diagnosed cases were enrolled. Cases where hospital records suggested that antitubercular drugs and steroids (dexamethasone, prednisolone, or methylprednisolone) were initiated before admission, or there was the presence of other chronic illnesses such as autoimmune disorders, a concomitant human immunodeficiency virus (HIV)–positive status, or recent head injury within the last 12 weeks before admission were excluded from the screening population. Case records of patients who showed features of sympathetic hyperactivity, as mentioned in the daily progression notes or daily monitoring sheets with a mention of the diagnosis of paroxysmal sympathetic hyperactivity along with Paroxysmal Sympathetic Hyperactivity Assessment Measure scoring, were selected for detailed analysis. The selected patients were prospectively contacted to inquire about their current functional status and the reappearance of any symptoms that could suggest paroxysmal sympathetic hyperactivity. A hospital visit was scheduled, and written informed consent was obtained from the parents of these children. If the child could not visit the hospital, a request for recent pictures, videos, and outpatient pediatric neurology clinic prescription cards was made to the parents. Clinical, demographic, and neuroimaging data of all children with documented Paroxysmal Sympathetic Hyperactivity Assessment Measure scores were entered into an Excel sheet. The duration of hospital stay in children with paroxysmal sympathetic hyperactivity was compared with those who did not develop paroxysmal sympathetic hyperactivity.

The consensus scoring system, the Paroxysmal Sympathetic Hyperactivity Assessment Measure, was used to establish the diagnosis of paroxysmal sympathetic hyperactivity. The Paroxysmal Sympathetic Hyperactivity Assessment Measure consists of 11 clinical items divided into 2 subsections: the Clinical Feature Scale score and the Diagnosis Likelihood Tool. The Clinical Feature Scale grades the severity of signs of autonomic hyperactivity (6 features). Each item is scored from zero to 3 using age-dependent reference values, with a maximum score of 18. The Clinical Feature Scale subtotal grades the severity into 4 grades: 0 = nil; 1-6 = mild; 7-12 = moderate; and ≥13 = severe. ¹ Pediatric reference values were used for Clinical Feature Scale scoring. ¹² The Diagnosis Likelihood Tool scores the likelihood of the presence of paroxysmal sympathetic hyperactivity. It has 11 features, with 1 point for each feature and a maximum score of 11. One item in Diagnosis Likelihood Tool, “Features persist >2 weeks post-brain injury,” was revised to “Features persist >2 weeks post–central nervous system insult” to incorporate nontraumatic brain injury. The Paroxysmal Sympathetic Hyperactivity Assessment Measure total score is calculated by adding the Clinical Feature Scale and Diagnosis Likelihood Tool subtotal scores. Paroxysmal sympathetic hyperactivity is considered unlikely if the total score is <8, possible if the score is between 8 and 16, and probable at a score ≥17.

Results

A total of 47 children were admitted with a diagnosis of tuberculous meningitis during the study period. Six were excluded as they were already diagnosed cases and were admitted with neurologic or nonneurologic complications. Hospital records of 41 children with tuberculous meningitis were finally analyzed. The median age of the admitted children with tuberculous meningitis was 10 years (interquartile range: 4-12 years; females 23 of 41, 56%). Paroxysmal sympathetic hyperactivity was diagnosed in 6 of 41 cases (14.6%; probable paroxysmal sympathetic hyperactivity 5 of 6, mean Paroxysmal Sympathetic Hyperactivity Assessment Measure score 21.6 [17-25]; possible paroxysmal sympathetic hyperactivity 1 of 6, Paroxysmal Sympathetic Hyperactivity Assessment Measure score 11). Children with paroxysmal sympathetic hyperactivity were younger, with a median age of 5 years (range 1-5 years) (Table 1). Laboratory workup for secondary infection, such as blood and cerebrospinal fluid culture, was sterile, and serum procalcitonin and C-reactive protein were within normal limits at the onset of paroxysmal sympathetic hyperactivity.

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Table 1.

Baseline Characteristics of Children With Tuberculous Meningitis (TBM) With Paroxysmal Sympathetic Hyperactivity (PSH).

Characteristics	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Age, y	5	5	5	4	5	1
Gender	Male	Female	Female	Male	Female	Male
PSH-AM score	22	17	21	25	11	23
Form of CNS tuberculosis	TBM	TBM + tuberculoma	TBM + tuberculoma	TBM	TBM + tuberculoma	TBM + tuberculoma
CSF GenXpert	Rif sensitive MTb detected	Rif sensitive MTb detected	Rif sensitive MTb detected	MTb not detected	MTb not detected	MTb not detected
HIV status	Negative	Negative	Negative	Negative	Negative	Negative
Duration of illness (TBM) at the time of PSH diagnosis, wk	18	14	4	4	25	12
GCS	7/15	6/15	7/15	6/15	8/15	9/15
Mechanical ventilation	Yes	Yes	Yes	Yes	No	No
Inotropic support	No	Yes	No	No	No	No
Surgical procedures	Decompressive hemicraniectomy	EVD	EVD, VP Shunt	EVD, VP shunt	VP shunt	VP Shunt

Abbreviations: CNS, central nervous system; EVD, external ventricular drain; GCS, Glassgow Coma Scale; MTb, Mycobacterium tuberculosis; PSH-AM, Paroxysmal Sympathetic Hyperactivity Assessment Measure; Rif, rifampicin; VP, ventriculoperitoneal.

All 6 children diagnosed with paroxysmal sympathetic hyperactivity were neurotypical with no preexisting comorbidities. Hydrocephalus was observed in 41.5% (17/41) of tuberculous meningitis cases. A significantly higher proportion of children who developed paroxysmal sympathetic hyperactivity had hydrocephalus at the time of diagnosis of tuberculous meningitis (5/6 [83.3%] in comparison to tuberculous meningitis without paroxysmal sympathetic hyperactivity (12 of 35 [34.3%], P = .035). Surgical drainage to mitigate raised intracranial pressure was required in all cases of tuberculous meningitis with paroxysmal sympathetic hyperactivity (decompressive craniectomy 1 of 6, extraventricular drainage (EVD) alone 1 of 6, extraventricular drainage followed by ventriculoperitoneal (VP) shunt 2 of 6, and VP shunt alone 2 of 6). Four children required mechanical ventilation at presentation (Table 1). Symptoms of paroxysmal sympathetic hyperactivity appeared after a mean duration of 17 weeks (12-25 weeks) from the diagnosis of tuberculous meningitis in 4 of 6 children and at 4 weeks in 2 of 6 children. Clinical findings included hypertonia with episodic worsening (6 of 6), tachycardia (6 of 6), new-onset fever (4 of 6), hypertension (4 of 6), tachypnea (4 of 6), and diaphoresis (3 of 6). Symptoms and signs of paroxysmal sympathetic hyperactivity presented acutely in 2 of 6 children, whereas the presentation was gradual (evolving over days) in 4 of 6 children. All the clinical features of Clinical Feature Scale were present in 5 of the 6 patients at the peak of illness. Leptomeningeal enhancement, basal exudates, communicating hydrocephalus (varying severity), and periventricular white matter involvement were noted in all 6 children. Multiple tuberculomas were present in 4 of 6 patients. Other areas involved were thalamus (3 of 6), hypothalamus (3 of 6), and brainstem (2 of 6).

A combination of medications was used for the management of paroxysmal sympathetic hyperactivity. Three children received a combination of morphine, clonidine, and propranolol. In 1 child each, dexmedetomidine, midazolam, or fentanyl was used instead of morphine along with clonidine (Table 2). Symptoms of paroxysmal sympathetic hyperactivity reduced within a week of treatment initiation (mean Paroxysmal Sympathetic Hyperactivity Assessment Measure score at 1 week of therapy was 13 [range 10-17]) (Table 2). The Modified Rankin Scale score at the time of discharge from the hospital was in the range of 4 to 5 in all patients. The mean duration of hospital stay in children with probable paroxysmal sympathetic hyperactivity was significantly prolonged than in those without paroxysmal sympathetic hyperactivity (71.2 ± 26.8 vs 20.8 ± 11.6 days; P < .0001).

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Table 2.

Management and Outcome of Children With Tuberculous Meningitis Who Developed Paroxysmal Sympathetic Hyperactivity (PSH).

Characteristics	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Drugs used to manage PSH	Morphine, propranolol	Fentanyl infusion, clonidine	Morphine, propranolol	Midazolam infusion, clonidine	Dexmedetomidine, clonidine	Morphine, clonidine
PSH-AM score (1 wk later)	13	10	16	12	10	17
Symptomatic improvement	Y	Y	Y	Y	Y	Y
Hospital stay, d	80	53	120	87	21	66
Modified Rankin scale score at discharge	4	4	5	5	5	5
Symptoms persisting at the time of discharge	Spasticity, hypertension	Spasticity, dystonia, hypertension	Dystonia	Dystonia	Spasticity, dystonia	Spasticity
PCPC scale score at 3-mo follow-up	4	4	4	4	4	4
Recurrence or worsening of symptoms of PSH	No	No	No	No	No	No

Abbreviation: PCPC, Pediatric Cerebral Performance Category.

At 3 months of follow-up, all the children with paroxysmal sympathetic hyperactivity were alive but bedridden. All of them had a score of 4 on the Pediatric Cerebral Performance Category scale (Table 2). None of the children had a recurrence of symptoms. However, residual spasticity persisted in all.

Discussion

Individually, both paroxysmal sympathetic hyperactivity and tuberculous meningitis are enigmatic conditions, posing unique challenges for intensivists and neurologists. Intercurrent fever and neurologic worsening in tuberculous meningitis are common and are often attributed to primary disease progression, resistant mycobacterium, hospital-acquired superadded infection, paradoxical reaction, cerebral salt wasting, and mechanical obstruction.^7-9,13 Paroxysmal sympathetic hyperactivity as a cause of neurologic worsening in a subset of children with tuberculous meningitis is a novel finding, with only anecdotal case reports describing this association.^8,13,14

The most robust data on the prevalence of paroxysmal sympathetic hyperactivity in critically ill children come from studies on severe traumatic brain injury, where it ranges between 6% and 20%.^3,15,16 The prevalence of paroxysmal sympathetic hyperactivity among admitted children with central nervous system infections is largely speculative. In our study, we diagnosed paroxysmal sympathetic hyperactivity in 6 of 41 patients (14.6%) with central nervous system tuberculosis. In a previous retrospective cohort of 59 critically ill children with encephalitis and meningoencephalitis, paroxysmal sympathetic hyperactivity was identified in 41% of cases. ¹⁷ A recent prospective study from China on adult patients with severe nontraumatic brain injury found the prevalence of paroxysmal sympathetic hyperactivity to be low (3.6%). ³ The variability in the prevalence of paroxysmal sympathetic hyperactivity in nontraumatic brain insult across various studies may be secondary to the study design (retrospective/ambispective/prospective), the etiology of nontraumatic central nervous system insult, whether a single or multiple etiologies were studied, or could have resulted from the lack of usage of a uniform diagnostic criteria for paroxysmal sympathetic hyperactivity. In our study, the data on paroxysmal sympathetic hyperactivity emerged from the repeated application of the currently accepted (Paroxysmal Sympathetic Hyperactivity Assessment Measure) tool in all admitted children with a single etiology (tuberculous meningitis). Thus, the observed prevalence of paroxysmal sympathetic hyperactivity in tuberculous meningitis in the index study is proposed as closest to the true prevalence of this entity in tuberculous meningitis.

We observed in our study cohort that children with central nervous system tuberculosis who developed paroxysmal sympathetic hyperactivity were younger (5 years or less) compared to those who didn’t develop this complication. The central autonomic network in a young brain might be more vulnerable to injury resulting in paroxysmal sympathetic hyperactivity. However, other pediatric studies do not confer the same.^3,15,18 Another interesting observation in the study cohort was that hydrocephalus was significantly associated with development of paroxysmal sympathetic hyperactivity. It may be argued that it was hydrocephalus or raised intracranial pressure that resulted in paroxysmal sympathetic hyperactivity rather than tuberculous meningitis. However, not all children with hydrocephalus developed paroxysmal sympathetic hyperactivity, making this association less likely.

Previous studies have not explored the evolution of symptoms, though it has been mentioned that the peak of paroxysmal sympathetic hyperactivity symptoms is reached by 1-2 weeks post traumatic brain injury.^1,15,19,20 In this study, symptoms of paroxysmal sympathetic hyperactivity developed earliest by 4 weeks. In the majority, it appeared around 17 weeks from the onset of clinical symptoms of tuberculous meningitis. The child with possible paroxysmal sympathetic hyperactivity (case 5) had an unusually delayed appearance of paroxysmal sympathetic hyperactivity symptomatology at 25 weeks. However, unlike traumatic brain injury, where the time of injury to the brain is reliably known, tuberculous meningitis is an evolving insult, so it is difficult to accurately pinpoint the onset of severe brain injury. This might explain the wide time period during which paroxysmal sympathetic hyperactivity appears post tuberculous meningitis.

Over time, a variety of hypotheses have been proposed to explain the pathophysiology of paroxysmal sympathetic hyperactivity. The disconnection syndrome and, more recently, the excitatory-inhibitory ratio model are the 2 most acceptable hypotheses that tried to elucidate the complex mechanism underlying paroxysmal sympathetic hyperactivity. ¹ Literature suggests that patients with lesions in the midbrain (especially periaqueductal gray matter), pons, periventricular white matter, corpus callosum, hypothalamus, and other deep gray nuclei are at an increased risk of developing dysautonomia. ¹ Structural damage is a prerequisite for the development of paroxysmal sympathetic hyperactivity, but it is not enough to explain the entire symptomatology of paroxysmal sympathetic hyperactivity. Thus, the most plausible explanation for paroxysmal sympathetic hyperactivity is a combination of “structural damage” and a “functional” trigger. ²⁰ This nonnociceptive functional trigger leads to an exaggerated sympathetic discharge, resulting in paroxysms of symptoms in paroxysmal sympathetic hyperactivity. ²¹ The pathophysiology of nontraumatic brain injury–associated paroxysmal sympathetic hyperactivity might be theoretically similar to what happens in traumatic brain injury; however, the same has not been appropriately studied.

Paroxysmal sympathetic hyperactivity increases morbidity in traumatic brain injury. ²² Literature linking nontraumatic brain injury–associated paroxysmal sympathetic hyperactivity independently with a poor outcome does not exist. We observed that the hospital stay in cases exhibiting signs of paroxysmal sympathetic hyperactivity (probable paroxysmal sympathetic hyperactivity n = 5) was significantly longer than those who did not. Whether the increased severity of tuberculosis-related brain injury was solely responsible for the prolonged hospital stay or paroxysmal sympathetic hyperactivity also contributed is difficult to determine. It may be possible that a more severe disease prolonged the hospital stay and predisposed these children to develop paroxysmal sympathetic hyperactivity. However, we did observe in the first case that the discharge from the hospital was delayed because of paroxysmal sympathetic hyperactivity symptoms. Once the anti–paroxysmal sympathetic hyperactivity measures were initiated and the sympathetic surge was controlled, the child could be discharged within a week. Three patients required prolonged ventilation and could be extubated only after paroxysms of paroxysmal sympathetic hyperactivity were controlled. Case 5 with possible paroxysmal sympathetic hyperactivity had a shorter hospital stay, similar to cases not exhibiting paroxysmal sympathetic hyperactivity.

The ambispective nature of data collection and a small number of cases with diagnosed paroxysmal sympathetic hyperactivity were the major limitations of the study. A prospective study of childhood tuberculous meningitis and other central nervous system infections with repeated screening for the presence of paroxysmal sympathetic hyperactivity is required to understand the contribution paroxysmal sympathetic hyperactivity makes to the morbidity of these illnesses.

Conclusion

Approximately 1 in 7 children with tuberculous meningitis may develop paroxysmal sympathetic hyperactivity, typically as a late complication. Paroxysmal sympathetic hyperactivity should be suspected if there is neurologic worsening or a new-onset fever in a child with central nervous system tuberculosis. The presence of hydrocephalus increases the chance of developing paroxysmal sympathetic hyperactivity. Intensivists and neurologists must maintain a high index of suspicion for its diagnosis and should repeatedly screen children with Paroxysmal Sympathetic Hyperactivity Assessment Measure during intensive care unit stay. Early identification of paroxysmal sympathetic hyperactivity symptomatology and pharmacologic intervention may improve the immediate clinical course of tuberculosis and possibly reduce hospital stay. Longitudinal prospective studies are required to define the contribution of paroxysmal sympathetic hyperactivity to intermediate and long-term outcomes in childhood central nervous system tuberculosis.