Hepatitis E virus (HEV) infection was previously thought to be a disease primarily of developing countries. However, there is now growing body of evidence showing HEV infection is also endemic in developed countries. Although the illness is usually self-limiting, it may lead to severe extra-hepatic manifestations such as hematological disorders, glomerulonephritis, pancreatitis and thyroiditis. Among these extra-hepatic manifestations, neurological manifestations have been found to be as high as 7.5% of the cases.1 Reported neurological complications include Guillain-Barré syndrome (GBS), neuralgic amyotrophy, transverse myelitis, meningoencephalitis, inflammatory polyradiculopathy, bilateral brachial neuritis, ataxia/proximal myopathy, and encephalitis.2
To the best of our knowledge, HEV-associated acute pandysautonomia (also known as autonomic GBS) has not been reported so far. Herein, we report a case of a 54-year-old patient who was diagnosed with acute pandysautonomia during the course of his illness, with cecal cancer and acute pancreatitis. This uncommon variant of GBS was successfully treated with immunoglobulin therapy, with no residual symptoms at the one-month follow-up.
Case Report
A 54-year-old male patient was admitted to our hospital with the chief complaints of bloody diarrhoea (frequency: 10 times/day). He also complained of abdominal pain, anorexia, and leg pain for the past week. His past surgical history indicated percutaneous coronary intervention done two years ago for ischemic heart disease. The patient had been on dual antiplatelet therapy since then.
The patient had a recent history of acute viral hepatitis (positive IgM antibodies for HEV) and acute pancreatitis (evident by elevated amylase [204] and lipase level [1602]) 15-days ago. There was no evidence of hepatitis B virus infection or glucose-6-phosphate dehydrogenase (G6PD) deficiency. Moreover, ultrasound sonography and magnetic resonance cholangiopancreatography revealed the presence of cholelithiasis. Past laboratory investigations in previous hospitalizations demonstrated elevated prothrombin time (PT). The patient was referred to our hospital for further management.
At the time of admission, the patient was afebrile and systolic blood pressure was 70 mm/Hg in supine position. We suspected hypovolemic shock and was resuscitated with intravenous fluid. As the patient had bloody diarrhoea, oesophago-gastroduodenoscopy (OGD) and colonoscopy were performed, which demonstrated erosive gastritis and caecal ulcer, respectively. He was successfully treated with adrenaline injection and gold probe coagulation for caecal ulcer. There were no post-procedural complications. The patient’s blood-pressure needed to be managed with intravenous infusion of noradrenaline and dopamine. There was no incidence of diarrhea after the procedure, and his hemoglobin remained stable. However, we were unable to taper dose of ionotropes after two days of endoscopic treatment. Moreover, despite of all the corrective measures, patient experienced frequent episodes of giddiness and orthostatic hypotension on day 4. Blood pressure recording were 90/60 mm/Hg while supine and dropped to 60/0 mm/Hg while sitting. Blood-pressure measurements (from post-procedural day 1 to the discharge) are shown in Figure 1. He also experienced intermittent episodes of bradycardia, which reverted to normal spontaneously or sometimes it was treated with intravenous atropine. Systematic cardiovascular examinations, including biomarker and two-dimensional echocardiography, were found to be normal. Liver function tests and biomarkers of pancreatitis were abnormal (Table 1). However, the rest of the laboratory investigations were within normal limits (Table 1).
On post-operative day-5, despite adequate fluid, we were not able to reduce the dose of ionotropes. The patient was unresponsive to fludrocortisone with persistent syncopal attacks, and the frequency had increased. Deep tendon reflexes and superficial sensations in both the extremities were normal. None of the finding was suggestive of autonomic neuropathy caused by paraneoplastic syndrome (electrophoresis and Bence-Jones protein), and systemic imaging (ultrasound sonography) did not detect apparent malignancies. Guillain-Barré syndrome (GBS) was suspected causing autonomic dysfunction. Therefore, lumbar puncture was done to examine cerebrospinal fluid (CSF). The examination showed a higher concentration of protein (100 mg/dL) and glucose (61 mg/dL) with fewer white blood cells (5 cells/mm3; 100% lymphocytes). Hence, albumino-cytologic dissociation confirmed the diagnosis of GBS-related dysautonomia (autonomic GBS).
The patient was treated with intravenous immunoglobulin (IVIG) at a dose of 0.4g/kg/day for 5 consecutive days. After the treatment with IVIG, the patient’s blood pressure was 100/70 mmHg (heart rate- 86 beats/min) in the supine position and 90/60 mmHg (heart rate 90 beats/min) in the upright position. We could finally wean off ionotropes after starting IVIG therapy. Syncope or disabling dizziness no longer occurred. The patient was discharged from the hospital twenty days after the onset of symptoms. At the one-month follow-up, the patient was found to be stable and was able to perform his routine work.
Discussion
GBS is divided into five major subtypes: acute inflammatory demyelination polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN); acute sensory neuropathy, and acute pandysautonomia.3 Identified infectious agents associated with subsequent GBS (AIDP) include Campylobacter jejuni, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Mycoplasma pneumonia, as well as hepatitis A virus, hepatitis B virus, hepatitis C virus, and HEV.4 However, none of the previous case-reports have shown HEV-associated acute pandysautonomia. Ours is the first case-report to demonstrate this association.
In our case, the patient experienced autonomic dysfunction without sensory and motor impairment. At this point, autoimmune autonomic ganglionopathy and GBS (acute pandysautonomia) were considered as possible causes of autonomic dysfunction. Although autoantibodies are the established gold-standard for diagnosis, it was not feasible in our case due to cost-constrain (the patient declined). We assumed a possible link between recent Hepatitis-E viral infection and autonomic GBS. Moreover, mildly abnormal liver function tests (a characteristic laboratory findings identified in HEV-associated GBS in published literature) supported the occurrence of GBS as a consequence of HEV infection.5 Hence, we performed a CSF examination, postulating that albumino-cytologic dissociation would confirm the diagnosis of GBS. In our case, albumino-cytologic dissociation confirmed the diagnosis of acute pandysautonomia, an uncommon variant of GBS and the patient recovered after IVIG therapy.
Conclusion
HEV infection-induced acute pandysautonomia is rare. We recommend that patients diagnosed HEV-infection should be systematically evaluated, as the infection is likely to precipitate neurological disorders. Although acute pandysautonomia is rare following HEV-infection, it should be considered as one of the neurological manifestation of the infection.
References
- Woolson KL, Forbes A, Vine L, Beynon L, McElhinney L, Panayi V, et al. Extra-hepatic manifestations of autochthonous hepatitis E infection. AlimentPharmacolTher. 2014;40:1282-91.
- Kamar N, Abravanel F, Lhomme S, Rostaing L, Izopet J. Hepatitis E virus: chronic infection, extra-hepatic manifestations, and treatment. ClinResHepatol Gastroenterol. 2015;39(1):20-7.
- Hughes RA, Cornblath DR. Guillain-Barre Syndrome. Lancet (London, England). 2005;366(9497):1653-66.
- van den Berg B, van der Eijk AA, Pas SD, Hunter JG, Madden RG, Tio-Gillen AP, et al. Guillain-Barre syndrome associated with preceding hepatitis E virus infection. Neurology. 2014;82(6):491-7.
- Mericle RA, Triggs WJ. Treatment of acute pandysautonomia with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry. 1997;62(5):529-31.