Guillain-Barre syndrome caused by hepatitis E infection: case report and literature review

Hepatitis E virus (HEV) infection, one of the most common causes of acute viral hepatitis, is an important public-health concern and leads to substantial morbidity [1]. HEV causes acute and chronic hepatitis, but most of these infections are asymptomatic [2]. In symptomatic patients, HEV can cause fulminant acute hepatitis, fibrosis, or cirrhosis [3, 4] Numerous extra-hepatic manifestations, including many neurological illnesses, are associated with acute or chronic hepatitis E [5]. In this article, we report a rare case of a patient clinically diagnosed with Guillain-Barre syndrome (GBS) due to acute HEV infection. We also reviewed English language scientific literature for the clinical characteristics of HEV associated with GBS.

A 58 year-old non-immunocompromised man presented general fatigue, anorexia, cough, mild jaundice, and excretion of tea-colored urine for 7 days. He was referred to a local hospital, wherein his liver function tests showed elevated levels of aspartate aminotransferase (AST) at 273 U/L, alanine aminotransferase (ALT) at 664 U/L, total bilirubin at 51.8 μmol/L, and conjugated bilirubin at 20.5 μmol/L. Serological study was positive for IgM antibodies for HEV. A working diagnosis of acute hepatitis E was performed, and liver protection treatment was applied to the patient. However, on the 4th day of admission, the patient complained about progressive muscle weakness on his lower limbs, numbness, and abnormal pinprick sensation in his plantar that render him unable to walk. The patient was subsequently transferred to our hospital for further treatment because of the rapidly progressive symmetrical weakness of his lower and upper limbs.

The patient had a history of recovered schistosomiasis. He had never been exposed to a polluted environment or affected animals. He also had no history of blood transfusions, risky sexual behavior, or drug addiction.

Upon admission, general examination on the patient revealed unremarkable findings. His temperature was 36.4 °C, and his blood pressure was 130/99 mmHg. Physical examination showed asthenia, jaundice, blepharoptosis, and paresthesia. His cranial nerve examination showed unilateral facial nerve palsy, Romberg’s sign and the straight leg raising test was positive. Motor weakness was present in all limbs, with power of 4/5 in the upper limbs and 2/5 in the lower limbs. His triceps, biceps, and brachioradialis reflexes were normal, whereas his patellar and Achilles tendon reflexes were absent bilaterally. Two days after admission, he developed dysphagia, choking, areflexia and labored breathing. Neurological examination showed and unilateral cranial palsy with left blepharoptosis, flat nasolabial fold and incomplete eyelid closure of right side. Muscle weakness in his four limbs progressed rapidly. The power of the upper extremity was 2/5 for the proximal muscles and 4/5 for the distal muscles. The power grade of both proximal and distal legs was 1/5. GBS was suspected, and lumbar puncture was conducted on the 2nd day. Cerebrospinal fluid (CSF) examination showed 0/μL monocyte, 4.6 mmol/L glucose level, and 275.3 mg/dL protein level, which suggested albuminocytologic dissociation. Nerve conduction studies showed evidence of demyelinating neuropathy with dysfunction of motor and sensory nerve fibers.

Laboratory investigations showed 20 μmol/L total bilirubin, 10 μmol/L conjugated bilirubin, 126 U/L alanine aminotransferase, and 160 U/L gamma-glutamyl transpepidase. Serologic studies for IgM and IgG anti-HEV were both positive. No serological evidence was found for hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and syphilis or human immunodeficiency virus. Epstein–Barr virus and cytomegalovirus serology indicated positive IgG. Serum antibodies to anti-ganglioside antibodies GM1 and GM2 were negative, while the level of serum immunoglobulin G was increased.

Cerebral computed tomography and magnetic resonance imaging scans indicated normal results. (The clinical course is summarized in Fig. 1).

The clinical history, physical examination, and biochemical findings of the patient were consistent with the diagnosis of acute HEV-associated GBS. He was treated with intravenous immunoglobulin at a dose of 0.4 mg/kg per day for 5 days. Meanwhile, methylprednisolone were also used to suppress inflammatory response. Glycyrrhizin, glutathione, and ademetionine were simultaneously administered for liver therapy. During the next 2 weeks, his clinical condition and muscle power improved gradually, and the patient had no complaints of respiratory distress or malaise. Repeat CSF examination 2 weeks after admission revealed 10/μL monocyte and 85.7 mg/dL protein level. At discharge, the patient had 5/5 power bilaterally in his arms and 4/5 power bilaterally in his legs. A month later, his liver function substantially improved, and his serum levels of AST and ALT were nearly normal. Six months after discharge, serological study (Wantai HEV-IgM ELISA) showed that IgM anti-HEV antibodies became negative, which suggested full recovery from the acute phase of hepatitis E. The patient responded well to treatment with his muscle power returning to normal, but still felt weakness in his right arm.

HEV, previously known as waterborne or enterically transmitted viral hepatitis, is hyper-endemic in many developing countries and endemic in developed countries [6]. Aside from hepatitis symptoms, HEV-associated neurological injuries also cause significant morbidity. Neurologic complications develop in 7 (5.5%) out of 126 patients with acute and chronic HEV infections in the United Kingdom and France [7]. The clinical spectrum of neurological injury is broad. GBS and neuralgic amyotrophy are the most frequently reported conditions [8]. Other neurological disorders include transverse myelitis, encephalitis, cranial nerve palsy, and meningoradiculitis [9, 10].

GBS is an acute immune-mediated polyradiculoneuropathy that results in rapidly progressing symmetric motor paralysis, limb palsy, hypoflexia, areflexia, and other neurological disorders. GBS is also a heterogeneous disorder with several forms, including acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor–sensory axonal neuropathy (AMSAN), and Miller Fisher syndrome (MFS). GBS is usually preceded by an infection, which evokes an immune response that cross-reacts with peripheral nerve components via molecular mimicry [11]. Anti-ganglioside GM1or GM2 positive has been measured in three out of six cases of HEV-associated GBS. This condition may lead to autoimmune inflammatory polyneuropathy [12‐17].

A literature review was performed using the PubMed database to identify other published cases and clarify the clinical characteristics of HEV-associated GBS. We used combinations of keywords, including hepatitis E and Guillain–Barre syndrome, and hepatitis E and MFS. Fifty-two cases described HEV-associated GBS. With the addition of our patient, 53 cases were counted, and the clinical characteristics of these cases are summarized in Table 1. The mean age of the reported patients was 47 years (20–73 years), and most of them are middle-aged men (30 men out of 53 cases: 57.7%). These patients developed HEV-associated GBS within an acute onset and have experienced hepatitis symptoms, including jaundice, malaise, nausea, and vomiting. GBS symptoms include motor weakness, cranial nerve palsy, and sensory disorder, which usually manifest after the occurrence of hepatitis symptoms. The mean delay between acute hepatitis E and GBS symptoms was 12 days (with a range of 3–73). Genotyping was performed among 11patients. Most of these patients revealed type 3, which suggested that HEV3 had high tropism of GBS. Most of our reviewed cases were found in Western Europe and Southern and Eastern Asia, where genotype 3 is prevalent. HEV RNA was found in the serum of 17 patients. Furthermore, HEV RNA was positive in the serum and the CSF of one patient.

Among the 47 cases with available details of nerve conduction studies, 23(48.9%) had experienced AIDP. Other variants of GBS, including AMAN, AMSAN, and sensory neuropathy, were also detected. Anti-ganglioside GM1, anti-ganglioside GM2, and GQ1b were detected in eight patients. Thus, the pathogenesis of GBS-associated HEV may be related to GM1, GM2, and GQ1b antibodies. Among the 31 cases with available details of treatments, 25 used intravenous immunoglobulin (IVIg), 4 used plasmapheresis (PP), and 1 used ribavirin. Some patients recovered spontaneously without IVIg or PP administration. Mechanical ventilation was performed in seven patients due to the involvement of respiratory muscles. Almost all the reviewed patients achieved complete neurological recovery within several weeks to several months, which suggested good prognosis for HEV-associated GBS. However, one patient died after cardiac arrest 1 month after the onset of neurological symptoms.

In conclusion, GBS is an emerging extrahepatic manifestation of HEV infection. HEV infection should be strongly considered in patients with neurological symptoms, especially those with elevated levels of liver enzymes. In our case, HEV infection was confirmed by IgM anti-HEV in the serum. This infection could also be supported by HEV RNA. CSF examination showed an increased level of proteins alongside with pleocytosis, which is supported with the suspicion of GBS. Nevertheless, the elevation of CSF proteins is frequent in encephalitis or encephalopathy as well. Thus, the diagnosis of GBS should be cautious. In removes under other resembling disease’s premise. Testing for HEV genotype and anti-ganglioside antibodies will likely help in further studying the pathogenesis of HEV-associated GBS.

HEV infection is a self-limiting disorder, and most patients require no treatment. IVIg and PP are both effective treatments for GBS. However, IVIg has replaced PP as the first line of treatment in most hospitals due to the convenience and availability of the former [18]. There is no significant difference between intravenous methylprednisolone with IVIg or IVIg alone.