Neurological manifestations of hepatitis E virus infection: An overview

Table 1 Hepatitis E virus: Epidemiological features

Genotype	Hosts/reservoir	Mode of transmission	Geographic distribution	Remarks	Reported neurological manifestations1
GT1	Only humans	Fecal-oral transmission	Mostly Asia and Africa	Large outbreaks; Self-limiting; High mortality in pregnancy	Yes (2 cases)
GT2	Only humans	Fecal-oral transmission	Africa and Mexico	Large outbreaks; Self-limiting; High mortality in pregnancy	None
GT3	Human, swine, wild boar, goat, cattle, deer, camel and yak	Zoonotic infections in humans; Blood transfusion	Worldwide including Europe and America	Can cause chronic infection in organ transplant patients	Yes (56 cases)
GT4	Human, swine, wild boar, goat, cattle, deer, camel and yak	Zoonotic infections in humans; Blood transfusion	China, Japan, South-east Asia	Can cause chronic infection in organ transplant patients	Yes (4 cases)

¹See Table 3 for reported neurological manifestations. GT: Genotype.

Table 2 Relationship of hepatitis E virus infection with extrahepatic manifestations

Extrahepatic manifestations	Likelihood of causal relationship, Hill criteria[9,97]	Evidence to support a casual role
Neurological disorders
Neuralgic amyotrophy	Very probable	Good
Guillain-Barré syndrome	Very probable	Good
Meningoencephaltis	Very probable	Good
Others1	Possible/under debate	Remains to be established
Kidney disorders
Membranoproliferative glomerulonephritis	Very probable	Good
Membranous glomerulonephritis	Very probable	Good
IgA nephropathy	Very probable	Good
Gastrointestinal disorder
Acute pancreatitis	Very probable	Remains to be established
Hematological diseases
Thrombocytopenia, monoclonal gammopathy of uncertain significance, Cryoglobulinemia, hemolytic anemia, aplastic anemia	Possible	Remains to be established
Miscellaneous
Autoimmune hepatitis, myocarditis, thyroiditis	Doubtful/under debate	Remains to be established

¹See Table 3 for other neurological disorders. IgA: Immunoglobulin A.

Table 3 Hepatitis E virus-related neurological manifestations

Diseases	n (%)	Geographic distribution	Mean age in yr	M:F ratio	Serological diagnosis	Serum HEV-RNA	Genotype	CSF HEV-RNA	Elevated bilirubin, n	Median (range) ALT in IU/L	Use of anti-viral	Recovery
Nerve root and plexus disorders
Neuralgic amyotrophy[13,15-17,28-56]	64 (39)	Europe: 62; SEAR: 1; United States: 1	45.7	6.5:1	51	44	GT3: 28	0	4	1007 (22-2579)	9	CR: 9; PR: 47; NM: 8
Guillain-Barré syndrome[13,15,16,20,36,58-85]	61 (37)	SEAR: 21; Europe: 30; China/Hong Kong: 5; Japan: 4; Iraq: 1	51.16	2.42:1	46	20	GT3: 10; GT4: 1; GT1: 2	3	11	1950 (57-4502)	1	CR: 23; PR: 14; Died: 1; NM: 23
Central nervous system disorder
Meningoencephalitis[17,20,35,86,87]	6 (4)	Europe: 2; China: 2; SEAR: 1; United States: 1	44	1:1	6	5	GT 3: 2	2	0	142 (20-479)	1	CR: 5; NM: 1
Cerebral ischemia[17,20]	5 (3)	Europe: 3; China: 2	66	4:1	5	4	GT3: 2	0	0	18 (8-28)	0	CR: 3; PR: 2
Seizures[17]	2 (1)	Europe	71	1:1	2	1	GT3: 1	0	0	19 (10-28)	0	CR: 2
Transverse myelitis[88]	1 (0.6)	Europe	62	0:1	1	1	GT3: 1	1	0	1152	0	PR: 1
Neuropathy
Mononeuritis multiplex[36]	6 (4)	Europe	53.16	1:1	6	4	GT3: 3	0	1	188 (118-3641)	1	CR: 5; PR: 1
Peripheral neuropathy[16,20,89]	5 (3)	Europe: 4; China: 1	57.4	3:2	5	5	GT3: 2	2	1	285 (30-1606)	1	CR: 2; PR: 3
Cranial neuropathy
Cranial neuropathy[16,17,90-92]	5 (3)	SEAR: 2; Europe: 2; Japan: 1	53	4:1	2	2	GT3: 1; GT4: 3; ND	0	0	1200 (60-3866)	0	CR: 5
Neuromuscular junction and muscle disorders
Myositis[93]	1 (0.6)	Europe	57	1:0	1	1	ND	0	1	1030	1	CR:1
Myasthenia gravis[18]	1 (0.6)	Europe	33	0:1	1	1	GT3: 1	0	0	190	1	NM: 1
Others neurological disorders
Meningoradiculitis[36,94,95]	6 (4)	Europe	53.33	1:1	6	6	GT3: 5	4	1	406 (40-822)	1	CR: 5; Died: 1
Total cases, n (%)
Total	163	Europe: 120 (74); WHO SEAR: 25 (15); China/Hong Kong: 10 (6), Japan: 4; United States: 2; Iraq: 1	53.9	2.84:1	132 (81)	94 (58)	GT3: 56 (90); GT4: 4; GT1: 2	12 (7)	19 (12)	345.5 (16-4502)	Ribavirin: 16 (10)	CR: 60 (46); PR: 68 (53) Died:2; NM 33 (20)

ALT: Alanine aminotransferase; CR: Complete recovery; CSF: Cerebrospinal fluid; GT: Genotype; HEV: Hepatitis E virus; M:F ratio: Male to female ratio; NM: Not mention; PR: Partial recovery; SEAR: South-East Asia Region; WHO: World Health Organization.

Table 4 Clinical description of nerve root and plexus disorders, n = 125

Nerve root and plexus disorders	Source of infection	Hepatitis-neurological involvement interval	Type of involvement, n (%)	Specific remarks, n (%)
Neuralgic amyotrophy (n = 64)	Described in 9. Sausage figatelli: 3; Vegetables: 2; Uncooked pork: 1; Manipulation of horse manure: 1; Travel history: 2	Described in 29. Mean delay: 8.4 d	Described in 54. Brachial plexus involvement: Bilateral 48 (89) [right > left: 15 (60); left > right: 10 (40); not described: 23]; Unilateral 6 (11) [right: 5 (83); left: 1]	94% had normal bilirubin levels. EMG findings mentioned: 34; Denervation and/or damage of brachial plexus: 31 (91)
Guillain-Barré syndrome (n = 61)	Described in 5. Sausage figatelli: 2; Uncooked pork: 1; Dear meat: 1; Contact with farm animals: 1	Described in 51. Mean delay:15 d; Concomitant: 6 patients	Described in 38. Acute inflammatory demyelinating polyneuropathy: 28 (74); Acute motor-sensory axonal neuropathy: 5 (13); Acute motor axonal neuropathy: 4 (11); Miller Fisher syndrome: 1 (3)	82% had normal bilirubin levels; Anti-ganglioside GM1 antibodies: 4; Anti-ganglioside GM 2 antibodies: 4; Anti-GQ1b ganglioside antibody: 1

EMG: Electromyography.