Hepatitis E virus infection presenting with paraesthesia

Introduction

Hepatitis E virus infection is an emerging disease in developed countries.^1–3 This is mainly thought to be caused via zoonosis from infected pigs, and in Europe infection is generally caused by genotype 3. ² Acute and chronic infection has been reported, with chronic infection being increasingly reported in immunocompromised patients.^1,2 Neurological disorders are an emerging manifestation of both acute and chronic hepatitis E virus (HEV) infection.^1–10 Here, we describe a patient with HEV presenting with paraesthesia. To our knowledge this is the first case in Scotland of HEV presenting only with neurological symptoms.

Case

A 77-year-old female presented with paraesthesia and was found to have abnormal liver function tests (LFTs) and therefore was admitted to hospital by GP referral in March 2014. The patient had a three-day history of pain and tightness in her arms which had spread to behind the legs, but did not affect mobility. The patient was otherwise well with no constitutional upset. The only regular medication taken by the patient was four to six paracetamol tablets per day (2–3 g). A paracetamol level taken at admission was <15 mg/L, ruling out drug-induced hepatitis. There was no recent travel history or antibiotic use. The patient was a smoker, had moderate alcohol intake.

Neurological examination revealed normal tone, power, reflexes and sensation. Blood tests revealed a transaminitis with LFTs of total bilirubin 25 µmol/L (reference <20 µMol/L), alanine transaminase (ALT) 1606 U/L (reference <50 U/L), aspartate transaminase (AST) 832 U/L (reference <40 U/L) and alkaline phosphatase (AP) 263 U/L (reference 30–130 U/L); C-reactive protein (CRP) was 23 mg/L (reference <10 mg/L).

A full hepatitis screen was carried out. Her autoimmune hepatitis screen and ferritin levels were normal. Serology for hepatitis A, B and C was negative, but serum was found to be positive for HEV IgM, IgG and RNA. Lumbar puncture was not performed, LFTs normalised after three weeks and her neurological symptoms completely resolved. No further HEV testing was carried out.

Discussion

Hepatitis E is classified within the genus Hepevirus, family Hepeviridae. Four genotypes have been identified. Genotypes 1 and 2 infect humans only and transmission is faecal–oral. Genotype 1 is found in Asia, whereas genotype 2 is found in Africa and Mexico. Genotypes 3 and 4 infect a range of mammalian species, including pigs and humans and have been identified as a major cause of sporadic cases of autochthonous hepatitis E in developed countries, and is thought to be transmitted via the consumption of infected, undercooked pork products. Contaminated water may also be a route of transmission. Genotype 3 is found worldwide and is responsible for autochthonous cases in the UK. Genotype 4, previously predominant in South East Asia, has recently has been found in European domestic pigs. ¹

The majority of HEV infections are asymptomatic; clinical symptoms of HEV infection are non-specific and can include jaundice, fever, malaise, abdominal pain and vomiting. ³ HEV is usually self-limiting requiring no treatment; however, patients with severe acute hepatitis have been successfully treated with ribavirin. Chronic HEV infection has increasingly been documented in immunocompromised patients including HIV, solid organ transplant and hematopoietic stem cell transplant patients.^2,3,11 The clinical features of chronic infection are often unremarkable in immunosuppressed patients, with LFTs often only mildly abnormal. Liver biopsies of chronic HEV organ transplant patients have shown rapid progression to liver fibrosis with 10% of patients progressing to cirrhosis. ¹ As with acute infection, treatment of chronic infection with three months of ribavirin resulted in a sustained virological response in 78% of patients. ¹¹

There have been several case reports of HEV infection causing extrahepatic symptoms including pancreatitis, acute thrombocytopenia, aplastic anaemia and renal disease. ¹¹ Over 20 cases of HEV-associated neurologic illness have now been reported in the literature. The spectrum of symptoms is wide and includes: Guillain-Barre syndrome (most commonly reported association), brachial neuritis (Parsonage Turner syndrome), polyradiculopathy, peripheral neuropathy, transverse myelitis, encephalitis and ataxia. In some cases where tested, HEV RNA has been detected in the CSF. Patients often have transaminitis with no overt clinical symptoms of hepatitis which can make diagnosis difficult. Neurologic outcomes resolved fully in most cases reported, and a temporal association has been seen between the clearance of HEV viremia and resolution of neurologic signs and symptoms.^1,11

Other cases of paraesthesia as a symptom of HEV infection has been reported previously.^{1,5,7,12–14} Loly et al. ⁴ reported a 66-year-old male patient presenting only with elevation of LFTs that were carried out during a routine check-up; a few days later the patient developed neurological symptoms involving paraesthesia of the lower limbs, ataxia and neutropathic pain appeared a few days later. Serological testing showed IgM antibodies to HEV. Despierres et al. ⁵ reported two case reports of patients presenting with paraesthesia. A 54-year-old woman was hospitalised for sub-acute diffuse paraesthesia; the patient also had headaches, cervicalgia, photophonophobia, transient fever and nausea, and LFTs were found to be abnormal. HEV infection was diagnosed by detection of HEV IgM and HEV RNA in serum. In the second case, a 49-year-old man was hospitalised for proximal muscle weakness associated with paraesthesia and pain of upper and lower limbs, LFTs were found to be elevated. HEV infection was again diagnosed by serology and PCR. In addition, paraesthesia is a symptom of several other conditions that have been associated with HEV infection including GBS, polyradiculopathy, peripheral neuropathy, transverse myelitis and encephalitis.

The mechanisms for neurological involvement in HEV infection are unknown, although several theories have been proposed. For Guillain-Barre syndrome, it has been suggested that the anti-ganglioside antibodies may be triggered by HEV infection and play a pathogenic role. ¹⁵ Brachial neuritis is also proposed to be autoimmune-mediated in genetically susceptible patients. ² Interestingly, Kamar et al. ¹⁵ identified different viral sequences of HEV within the CSF and serum of a chronically infected patient suggesting that quasispecies could be emerging that can affect the nervous system, suggesting the possibility that the virus in the CSF could be neurotropic; however, it is thought that this is less probable in acute infections which clear in a few days.

Conclusion

This is the first case of HEV-associated CNS disease reported in Scotland.

This case demonstrates that HEV infection should be considered in patients with neurologic disorders, especially in those found to also have deranged LFTs.