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Vol. 11. Issue 5.
Pages 618-622 (September - October 2012)
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Vol. 11. Issue 5.
Pages 618-622 (September - October 2012)
Open Access
Review of the neurological manifestations of hepatitis E infection
Michelle C.M. Cheung*,*, James Maguire*, Ivana Carey*, Julia Wendon*, Kosh Agarwal*
* Institute of Liver Studies, King’s College Hospital, Denmark Hill, London, United Kingdom, SE5 9RS
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Tables (2)
Table 1. Summary of acute hepatitis E with neurological manifestation.
Table 2.. Summary of chronic hepatitis E with neurological manifestation.
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Hepatitis E (HEV) is a common infection worldwide and is an emerging disease in developed countries. The presence of extra-hepatic manifestation of HEV infection is important to bear in mind so that the diagnosis is not missed, since HEV is not routinely tested for in acute hepatitis due to perceived rarity of this infection outside of endemic countries. This article reviews the neurological presentations of acute and chronic HEV, and discusses the viral kinetics against symptomatology, and outcomes of specific treatment. Possible mechanisms of pathogenesis are considered.

Key words:
Hepatitis E
Viral hepatitis
Neurological disease
Autochthonous infection
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Hepatitis E (HEV) is an under-diagnosed infection in developed countries, with the potential to cause significant morbidity as well as mortality.1,2 The actual incidence of local HEV in developed countries is uncertain, especially as subclinical infection is common.1

Clinical manifestations of HEV typically include jaundice, fever, malaise, abdominal pain and vomiting, lasting 2 to 18 weeks with a median of 4 weeks.1 As with other viral hepatitises, extra-hepatic manifestations can occur,3 and the spectrum of clinical disorders is still emerging.4-6 In particular, neurological disorders with a predominance of peripheral nerve disorders have been described.6 A literature review found 25 cases reporting neurological manifestations of HEV in both acute and chronic infections 4,6-24 (Tables 1 and 2). Guillain-Barre syndrome and brachial neuritis are most frequently reported. Other reported disorders include transverse myelitis, cranial nerve palsies, seizure and intracranial hypertension. 17,21-24

Table 1.

Summary of acute hepatitis E with neurological manifestation.

Country  Age/gender  Significant co-morbidity  Neurological manifestation  Preceding jaundice or other symptoms  Diagnosis  Viral clearance from serum  Normalisation of liver function tests after presentation  Specific treatment  Neurological outcome  Ref. 
France  60/female  Type 1 diabetes  Guillain-Barre syndrome  7 days  Serum RNA (genotype 3f) CSF negative for HEV  4 weeks  4 weeks  IVIG 0.4 g/kg/day for 5 days  Residual motor deficit at 18 months 
India  50/male  None  Guillain-Barre syndrome  5 days  HEV IgM  NA  1 month  None  Resolution by 1 month 
India  58/female  None  Guillain-Barre syndrome Cranial nerve palsy 5 days later  7 days  HEV IgM  NA  3 weeks  IV IG for 5 days Plasmapheresis with albumin 40 mL/kg/day 3 days  Improvement in cranial nerve palsy after 5 days IVIG and resolution of all neurological symptoms in 7 days 
Belgium  51/female  None  Guillain-Barre syndrome (anti-GM1 positive)  3 days  NA  NA  NA  IVIG  Resolution 
Belgium  66/male  None  Guillain-Barre syndrome (anti-GM2 positive)  < 1 week  HEV IgM  NA  1 week  IV IG 0.4g/kg/day for 5 days  Resolution in 4 months  10 
Ireland  40/male  NA  Guillain-Barre syndrome (anti-GM2 positive)  2 weeks  HEV IgM  NA  1 month  IVIG 0.4 g/kg/day for 5 days Plasmapheresis  Resolution after 1 month  11 
Bangladesh  20/male  NA  Guillain-Barre syndrome  7 days  HEV IgM  NA  NA  None  Resolution in 2 weeks  12 
India  35/male  None  Guillain-Barre syndrome  20 days  HEV IgM  NA  2 weeks  IVIG 0.4 g/kg/day for 5 days  Resolution with residual weakness in 2 weeks  13 
United Kingdom  56/male  None  Bilateral brachial neuritis  1 day  Serum RNA (genotype 3) 1,000,000 copies/mL  6 week  10 days  None  Residual pain and weakness at 10 months  14 
United Kingdom  53/male  None  Bilateral brachial neuritis  Nil  HEV IgM  NA  2 weeks  None  Resolution in 2 years  15 
United Kingdom  38/male  Type 1 diabetes  Bilateral brachial neuritis  5 days  Serum RNA (genotype 3e)  6 weeks  6 months  None  Residual motor deficit at 18 months 
United Kingdom  42/male  None  Polyradiculoneuropathy  NA  Serum RNA (genotype 3e) CSF negative for HEV  NA  6months  None  Resolution in 3 months 
France  49/male  None  Polyradiculoneuropathy  Nil  Serum RNA (genotype 3) CSF negative for HEV  2 months  NA  None  2 weeks  16 
France  54/female  None  Peripheral neuralgia  Nil  Serum RNA CSF RNA (genotype 3)  3 weeks  2 weeks  None  2 weeks  16 
India  12/female  None  Transverse myelitis  20 days  HEV IgM  NA  Normal at time of Neurological presentation  None  Resolution within 10 days  17 
Hong Kong  NA  NA  Guillain-Barre syndrome  NA  NA  NA  NA  NA  NA  18 
France  NA  NA  Neuralgic amyotrophy (brachial neuritis)  NA  NA  NA  NA  NA  NA  19 
Thailand  NA  NA  Neuralgic amyotrophy  NA  Serum RNA (genotype 3)  NA  NA  NA  NA  20 
India  NA  NA  Occulomotor nerve palsy  NA  NA  NA  NA  NA  NA  21 
India  NA  NA  Seizure  NA  NA  NA  NA  NA  NA  22 
India  Paediatric (intracranial hypertension)  NA  Pseudotumor cerebri  NA  NA  NA  NA  NA  NA  23 
India  NA  NA  Bell’s palsy  NA  NA  NA  NA  NA  NA  24 

IVIG: intravenous immunoglobulin. CSF: cerebrospinal fluid.

Table 2..

Summary of chronic hepatitis E with neurological manifestation.

Country  Age/Gender  Duration of HEV infection before neurological symptoms  Neurological manifestation  Significant comorbidity  Diagnosis  Specific treatment  Viral kinetic and liver parameters  Neurological outcome  Ref. 
NW Europe  60/male  30 months  Ataxia, confusion, frontal dysfunction, proximal lower limb weakness  Kidney-pancreas transplant (infection acquired 27 months post-transplant)  Serum RNA (genotype 3f) 1572 copies/mL CSF RNA  Immunosuppression change  Serum viral clearance in 4 months  Resolution of higher function, residual motor deficit at 10 months 
NW Europe  35/male  3 years  Acute encephalitis  Kidney transplant (infection acquired 48 months post-transplant)  Serum RNA (genotype 3f) 2,154,000 copies/mL CSF RNA  Immunosuppression stopped, IV IG 2 g/kg, Foscarnet 6 g/d  Serum and CSF viral clearance at 1 year  Complete resolution in 2 months 
France  44/male  33 months  Polyradiculoneuropathy, ataxia, sphincter dysfunction  Kidney transplant  Serum RNA (genotype 3f) 260,000 copies/mL CSF RNA (viral sequence different to serum)  Immuosuppression change, IV IG 0.4 g/kg/day for 5 days    Death from decompensated liver disease  4, 6 
United Kingdom  48/male  Preceeded HEV diagnosis by 2 years  Painful sensory peripheral neuropathy  HIV-1 (CD4 30 × 109/L)  Serum RNA (genotype 3a) CSF RNA  Peg-interferon α 2α/ribavirin  Serum viral clearance on symptom resolution; CSF RNA level approximately halved  Complete resolution on completion of antiviral therapy (duration unclear) 

IVIG: intravenous immunoglobulin. CSF = cerebrospinal fluid.

Neurological disease occurred in sporadic and endemic infection within this cohort. Most case reports come from developing countries, reflecting the geographical distribution of HEV. All genotyped cases showed genotype 3 infection, which is found in developed countries. Cases from the Indian subcontinent are likely to be genotype 1.

A recent case series from Southwest England and Toulouse found a 5.5% prevalence (7 out of 126 over five years) of neurological complications in locally-acquired HEV infections.6 Most of the reported cases of acute HEV were evidenced only by positive serology (anti-HEV IgM), which persists after viral clearance and therefore does not indicate duration of infection.1 However the temporal relationship between development of transaminitis and neurological symptoms with evidence of HEV infection, and exclusion of other hepatotrophic causes, suggest this association is causal. Moreover, the presence of similar cases which were confirmed by RNA isolation substantiates a true association between HEV infection and neurological disorders.

Acute HEV infection is self-limiting. In cases of Guillain-Barre, where intravenous immunoglobulin and plasma exchange both have established effectiveness,25 its use was associated with complete resolution of symptoms, but benefit over supportive treatment cannot be concluded. Cases of brachial neuritis were comparatively slower to resolve and none received specific therapies.

Severity of HEV infection is related to viral load 1 but the number of cases with established level of viraemia is too small to ascertain if HEV has a dose effect on neurological symptoms and outcomes. There is no clear correlation between viral clearance, liver enzyme tests and duration of neurological symptoms.

Four reports exist of neurological symptoms in chronic HEV in immunosuppressed patients following organ transplant or HIV infection.4,6 The temporal relationship between viral kinetics and symptom onset and resolution is variable in chronic HEV. The duration of infection before onset of neurological symptoms ranged from 18 months to 3 years. Chronic infection was evidenced by liver biopsy showing chronic hepatitis or cirrhosis and detection of RNA; serology in these patients may be unreliable. Demonstration of HEV RNA in cerebrospinal fluid (CSF) may account for involvement of the central nervous system, however, two patients with virus in CSF did not display disturbance of higher functions. Development of liver cirrhosis and decompensation are potential confounding factors. Despierres, et al. suggested the presence of HEV in the CSF may be related serum viral load,16 but in Kamar's case there was low serum viral low but detectable virus in CSF and marked central nervous system disturbance (60). Therefore this is insufficient explanation for the selective occurrence of central nervous system symptoms.

There is no established treatment for chronic HEV; lowering of immunosuppression therapy is recommended26 and pegylated interferon alpha has been used successfully in liver transplants.26,27 In one case the use of pegylated interferon alpha with ribavarin resulted in viral clearance and neurological symptom resolution.6

Several mechanisms of HEV causing neurological disease have been proposed. In neuropathies following infections such as Guillain-Barre syndrome after Campylobacter, influenza and cytome-galovirus, anti-ganglioside antibodies are thought to play a pathogenic role.28 Anti-ganglioside antibodies were positive in 3 out of 6 cases of HEV-GBS where they were measured, with one case of GM1 antibody and remainder of GM2.9-11 Their production may be triggered by HEV infection which in turn leads to autoimmune inflammatory polyneuropathy via molecular mimicry. Treatment with immunoglobulin targets the autoimmune nature of GBS but due to the small number of HEV-associated cases, it is difficult to comment on treatment response.

Brachial neuritis is also thought to be autoimmune in origin in genetically susceptible individuals. 29 More than half of patients develop an immune event preceding neurological symptoms, such as viral infections (HIV, coxsackie, EBV), vaccination and pregnancy.29 HEV may cause brachial neuritis by precipitating such an autoimmune response.

The isolation of different viral sequences within CSF and serum of the same patient suggest the possible emergence of neurotropic quasispecies which can directly affect the nervous system.4,6 However in acute infection which can resolve within days, this mechanism is less probable.

The pathogenesis of HEV causing peripheral neuropathy and other neurological disorders may involve multiple mechanisms, predisposing and host immune factors, to account for the variety in manifestations, but the small number of cases and distribution in developing countries makes further investigations difficult.


Hepatitis E infection has well-documented neurological manifestations which can lead to significant morbidity. The spectrum of disease is wide and natural history variable. Specific therapies targeting the potential autoimmune aetiology did not produce consistent responses in the few cases used. Clinicians are challenged with uncertainties in prognosis and management. Hepatitis E is increasingly seen in developed countries as locally-acquired infections, and should be tested for in acute hepatitis, especially in seronegative or suspected drug-related cases. In addition, HEV infection should be considered in neurological disturbance associated with abnormal liver function tests.

Conflict Of Interest

Statement of conflicts of interests: none declared.

Statement of funding sources: none declared.

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