To the best of our knowledge, this is the first study to analyze the clinical features and risk factors of autonomic dysfunction and PSH in patients with anti-NMDAR encephalitis. The overall prevalence of autonomic dysfunction and PSH in our cohort was 27.3% and 9.1% respectively, and was associated with a higher incidence of ICU admission, mechanical ventilation, ovarian teratomas, along with elevated NMDAR antibody titers and glucose levels in the CSF. Most PSH episodes can be suppressed by the acute administration of suitable drugs. Although longer hospital stays did not compromise the neurological recovery of patients with autonomic dysfunction/PSH, cardiac autonomic dysfunction was associated with poor outcome at 6 months.
Autonomic dysfunction is common in patients with neurological disorders and predominantly affects the cardiovascular, thermoregulatory, gastrointestinal, urinogenital organs. TBI, cerebrovascular diseases, infectious diseases, immune-mediated diseases and degenerative neurological disorders are some of the common causes of autonomic dysfunction. While PSH is the main clinical manifestation of severe TBI, hypoxic brain injury and stroke, orthostatic hypotension, thermoregulatory disorders and detrusor hyperactivity commonly develop during degenerative neurological disorders. Sinus tachycardia, hypertension and hyperhidrosis were the most common symptoms in anti-NMDAR encephalitis patients, and were observed in two-thirds of those with autonomic dysfunction.
PSH is a relatively common but often unrecognized complication of various acute brain diseases, with estimated prevalence ranging from 7.7 to 32.6% among various cohorts of patients with severe TBI[17, 18]. Raquel et al. reported PSH in 40.7% of the patients with meningoencephalitis and/or encephalitis in the pediatric ICU. In the present study, the overall prevalence of PSH was 9.1%, which increased to 25.6% in the ICU patients. Given the high sensitivity and low specificity of the diagnostic criteria for PSH-AM, PSH episodes tend to be confused with or superimposed on central hypoventilation, epileptic seizure or involuntary movements in anti-NMDAR encephalitis. Since only probable PSH was diagnosed in this study, the true incidence of PSH may have been underestimated. It is unclear whether the onset of PSH after anti-NMDAR encephalitis presents with unique features compared to acquired brain injury with other etiologies. The most common symptoms of PSH in our cohort were tachycardia (100%), tachypnea (100%) and hypertonia (100%), which contradicts previous reports indicating that PSH after TBI and ICH mainly manifest as hypertonia (94%) and hyperhidrosis (77%), or hyperthermia (80%) and hyperhidrosis (80%).
Regardless of the type of brain injury, the underlying mechanism of autonomic dysfunction and PSH remains unclear. Impairment of the central autonomic regulatory centers, such as the insular cortex, anterior cingulate and ventral prefrontal regions, as well as lower centers located in the amygdala, hypothalamus, brainstem and spinal cord, have been frequently implicated[12, 23]. Attempts have been made to identify the location of structural lesions that increase the likelihood of autonomic instability or PSH. However, we found no association between structural abnormalities of the brain and autonomic instability or PSH and only patients with autonomic dysfunction have a higher propensity for insular lobe abnormalities, suggesting that those autonomic centers involvement may have occurred at the molecular level without structural MR detection. Besides, the new theory of PSH is help to explain this negative finding, as PSH may not be caused by a single lesion, but rather by disruption of sympathetic circuits, thus explaining the contingency of this condition and its different causes[23, 25].
Several risk factors of autonomic dysfunction/PSH have been identified in recent years, such as younger or older age , tracheostomy, lower admission GCS scores, higher diffuse axonal injury grade[18, 28] and deep parenchymal lesions. In this study, ICU admission, mechanical ventilation, ovarian teratoma and elevated CSF NMDAR antibody titers, all of which are strongly associated with disease severity, were more prevalent in patients with autonomic dysfunction and PSH. Interestingly, the levels of CSF glucose were significantly higher in patients with autonomic instability or PSH, although the exact association remains unclear. The central nervous system regulates glucose homeostasis through ANS-mediated control of metabolic organs such as the liver, pancreas, skeletal muscle, intestine, and brown and white adipose tissues. Autonomic dysregulation leads to excessive sympathetic impulses and reduced parasympathetic function, which impairs metabolic homeostasis and leads to hyperglycemia.
ANS abnormalities are usually transient, mildly symptomatic, and recover on their own or with only oral medications. Most PSH episodes are related to various types of stimuli such as turning, back patting, suctioning and emotional excitement. However, the treatment of PSH is not standardized due to poor understanding of its pathophysiology. Identifying triggers can help reduce the occurrence of symptoms, and different classes of drugs such as intravenous anesthetics, β-adrenergic blockers, α2-agonists and benzodiazepines have been used to treat patients with PSH. However, the efficacy of these drugs have not been compared extensively. A retrospective cohort study quantified the effect of several drugs in 26 PSH patients, and found that the most commonly used analgesic drugs were not very effective whereas benzodiazepine drugs had satisfactory effects. In this study, we compared the efficacy of different intravenous medications, and found that diazepam was frequently administered and highly effective in PSH patients without prior exposure to sedative drugs. However, the efficacy of monotherapy was lower in patients with a history of sedative drug use to control dysphoria, epilepsy or other conditions, and half of them needed a combination of drugs. This can be attributed to the development of drug tolerance in those patients. Phenobarbitone combined with one anesthetic (dexmedetomidine, midazolam or propofol) is the most commonly used combination drug therapy with relatively high efficacy, and can reduce the use of more than two anesthetics.
The correlation between autonomic instability and prognosis of anti-NMDAR encephalitis is ambiguous. Lim et al found that autonomic instability was associated with worse mRS scores in 32 patients with anti-NMDAR encephalitis. Schubert et al. also confirmed that autonomic dysfunction led to worse neurologic outcomes at discharge in 120 patients with autoimmune encephalitis. In contrast, Dubey et al. found that autonomic dysfunction predicted favorable prognosis in patients with autoimmune epilepsy receiving immunotherapy. It is possible that this cohort included some cases without an autoimmune etiology, and since autonomic dysfunction is associated with true autoimmune epilepsy, these cases likely responded to immunotherapy. Most studies show that PSH is associated with a worse functional outcome compared to patients without PSH symptoms in other diseases[19, 35–37]. In this study, we found that patents with autonomic dysfunction or PSH had a longer ICU stay, although this did not appear to compromise their neurological recovery. Similar results have been reported for disease severity and prognosis of anti-NMDAR encephalitis. Most anti-NMDAR encephalitis patients have good prognosis after active treatment, and the PSH patients in our cohort received active combined immunotherapy. However, cardiac autonomic dysfunction was associated with short-term poor prognosis, which may be related to a greater susceptibility to hemodynamic instability in this group of patients. Consistent with our findings, Byun et al. showed that cardiac autonomic function, specifically sympathetic activity, was reduced and cardiac autonomic dysfunction was associated with poor function at 3 months in 11 patients with anti-NMDAR encephalitis.
Our study has some limitations that should be acknowledged. First, asymptomatic autonomic symptoms such as tachycardia, hypertension etc. are easily overlooked, especially in the mildly symptomatic patients, without electrocardiograph monitoring. Furthermore, some parasympathetic excitatory symptoms like hypohidrosis, xerostomia and xerophthalmia can be easily missed. Second, the objective quantification of autonomic dysfunction, such as using heart rate variability and pupillary dynamics, are associated with global patient outcome and other neurophysiological measures, while all autonomic symptoms in this study were assessed based on clinical presentation. Third, individual drugs and drug combinations are typically chosen on the basis of the physician’s experience rather than objective evidence. The small sample size of patients with PSH episodes and relatively high number of drug subgroups prevented the comparison of the efficacy of different drugs. Further randomized clinical trials are needed to address the above points.