Journal of Clinical Virology 60 (2014) 60–62
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case Report
Association between hepatitis E and neurological disorders: Two case studies and literature review A. Deroux a,∗ , J.P. Brion b , L. Hyerle b , A. Belbezier a , M. Vaillant c , E. Mosnier b , S. Larrat d , P. Morand d , P. Pavese c a
Service de médecine interne, CHU A. Michallon, 38700 La Tronche, France Service de maladies infectieuses, CHU A. Michallon, 38700 La Tronche, France c Service de neurologie, CHU A. Michallon, 38700 La Tronche, France d Service de virologie, CHU A. Michallon, 38700 La Tronche, France b
a r t i c l e
i n f o
Article history: Received 20 December 2013 Received in revised form 22 January 2014 Accepted 27 January 2014 Keywords: Hepatitis E Neurological disorders Parsonage-Turner Encephalitis Viral hepatitis
a b s t r a c t Hepatitis E (HEV) is an emerging disease in our developed countries, but is not routinely tested for in case of liver cytolysis. However, a growing number of extra-hepatic manifestations of HEV infection associated with acute hepatitis are reported. In this article, we discuss two cases of HEV with neurological symptoms, one with encephalitis, and the other with Parsonage Turner syndrome. All these disorders appeared concomitantly with liver cytolysis and disappeared quickly, following the viral kinetics. Only twenty cases of neurological manifestation of HEV have been described before. The use of HEV serology in patients with concurrent liver cytolysis and neurological symptoms has to be improved. © 2014 Elsevier B.V. All rights reserved.
1. Why this case is important Hepatitis E virus (HEV) is an under-diagnosed infection in developed countries, with significant morbidity and mortality potential. Like other viral hepatitides, extra-hepatic manifestations can occur; in particular, neurological disorders have been described. Here we report two cases of new neurological involvement in the shape of Parsonage Turner syndrome and encephalitis associated with cerebellitis, and conduct a literature review.
2. Cases description 2.1. First case A 41-year-old man was admitted in August 2011 for walking difficulties, neuropathic pain of all four limbs, cerebellar ataxia, upper limb hypermetria, dysarthria, headache, and transient fever lasting 72 h. Reflexes were all present, without any pyramidal signs. No abnormalities were found on the medullar and cerebral magnetic resonance imaging. Electroencephalogram (EEG) and nerve
∗ Corresponding author. Tel.: +33 04 76 76 75 75. E-mail address: [email protected] (A. Deroux). 1386-6532/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcv.2014.01.026
conduction study was normal. The patient had no notable medical history. At admission, alanine aminotransferase level was 479 IU/L (reference values 8–34 IU/L), aspartate aminotransferase level was 100 IU/L (reference values 9–42), ␥-glutamyl transferase level was 236 IU/L (reference 9–38 IU/L), alkaline phosphatase level was 112 IU/L (reference 42–98 IU/L), and bilirubin was 13 mol/L (reference 2–17 mol/L). Serum amylase level was 30 IU/L (reference 25–115 IU/L) and lipase was 133 IU/L (reference 73–393 IU/L). Cerebrospinal fluid (CSF) was clear; protein and glucose levels were 0.56 g/L (reference 0.15–0.45) and 3.6 mmol/L (reference 3.0–4.5 mmol/L) respectively; leukocyte count was 12 cells/mm3 , including 80% of mononuclear cells. No antibiotics were given. CSF culture remained sterile at day 5. Several infectious diseases responsible for neurologic symptoms (HIV, syphilis, cytomegalovirus, Epstein–Barr virus, mycoplasma, HSV, VZV, measles, parvovirus B19, Lyme disease, HHV6, HHV8, toxoplasmosis, leishmaniasis, arboviruses) and acute hepatitides (hepatitis A, B, C, delta) were excluded by nucleic acid and serologic assays performed on serum and CSF. In contrast, an HEV infection was diagnosed through the detection of anti-HEV immunoglobulin (Ig) M (index 12.00; threshold value 1 [ELISA test DIAPRO]) and HEV RNA in serum and CSF [1], though the test failed to find HEV RNA in stools. Genotype 3f was identified through phylogenetic analysis, which is common in
A. Deroux et al. / Journal of Clinical Virology 60 (2014) 60–62
61
3. Other similar and contrasting cases in the literature
Fig. 1. Winged scapula, amyotrophy in the supraspinatus and infraspinatus fossae and abduction as well as external rotation impairment in the second case. Typical symptomatology for brachial neuritis or Parsonage-Turner syndrome.
autochthonous cases in France. The contamination mode was the consumption of Corsican meat (figatelli). Liver parameters returned to normal within 1 week, and the patient recovered fully 12 weeks after the neurological disorders’ onset. HEV RNA was cleared in serum 2 weeks after the first blood sample.
2.2. Second case A 38 year-old man was hospitalized in December 2012 for Parsonage Turner syndrome with cytolytic hepatitis. He presented with a sudden onset of violent pains in the left shoulder girdle, associated with a painful paresis without esthesic impairment. Physical examination noted a winged scapula, amyotrophy in the supraspinatus and infraspinatus fossae (Fig. 1) and an abduction as well as external rotation impairment. The patient had no notable medical history or treatment. At admission, alanine aminotransferase level was 1612 IU/L (normal levels 8–34 IU/L), aspartate aminotransferase level was 772 IU/L (reference 9–38 IU/L). Alkaline phosphatase, ␥-glutamyl transferase, lipase level and bilirubin were in the normal range. Electromyogram found right long thoracic and suprascapular nerve damage with acute denervation criteria. Infectious diseases responsible for neurologic symptoms were excluded by serologic assays performed on serum (borrelia, toxoplasmosis, HIV, B and C hepatitis, arboviruses, EBV, CMV) and on CSF (HSV, VZV, borrelia). Auto immunity was ruled out (negative AAN, ANCA, and antigangliosides antibodies). CSF was clear; protein and glucose levels were at 0.68 g/L and 3.30 mmol/L respectively. It was a transudate, with moderate blood brain barrier damage (albumin quotient: 10.58 × 10−3 ); IgG index was normal (0.49, normal levels inferior to 0.7) and isoelectrofocusing showed normal repartition of immunoglobulin. Leukocyte count was under 5 cells/mm3 . However, HEV infection was diagnosed by detection of anti-HEV immunoglobulin M (index 3.00, ELISA test Wantai Bio-Pharm® ); unfortunately no nucleic acid assay could be performed during hospitalization, HEV RT-PCR performed one month later was negative in serum and CSF. Neurologic symptoms disappeared in four months, but a painful amyotrophy persisted. Liver parameters returned within normal range in 4 weeks, and HEV IgM were negative six months later with an increasing IgG count (index: 60.273).
These 2 cases establish some strong arguments in favor of an association between acute hepatitis E and neurological disorders. Temporal association, atypical neurological features, exclusion of other potential etiologies led to consider HEV as a possible cause of encephalitis or other neurological disorders. Several cases have been described since the first patient was reported in 2000 [2]. A recent multicentric case series from Southwest England and Toulouse [3] found a high prevalence (5.5% – 7 out of 126 patients) of neurological complications associated with HEV infections. Only 19 cases were documented enough to report this association. Most (8 patients) of the cases concerned acute HEV infection associated with Guillain–Barre syndrome [2–9], 3 others were associated with brachial neuritis [3,10,11], 3 with polyradiculopathy [3,12], 3 with peripheral neuropathy [3,12,13], one with transverse myelitis [14], while acute encephalitis [3] or ataxia [3] was also reported. HEV RNA in CSF was only detected in five of these patients [3,12] like our first case; acute encephalitis and cerebellitis associated with hepatitis E was only described once before. These two patients showed complete recovery in a few months, without any sequel.
4. Discussion and references Several mechanisms for neurological symptoms associated with HEV have been suggested. For neuropathies such as Guillain–Barre syndrome, anti-ganglioside antibodies (GM1, GM2) may be triggered by HEV infection and play a pathogenic role [5–7,15]. In one case, Kamar et al. [3] showed different viral sequences within CSF and serum in the same patient; these could be caused by the emergence of neurotropic quasispecies which could directly affect the nervous system. However, this mechanism seems less probable in cases of acute infection resolving within days. Pathogenesis for peripheral neuropathy and other neurological disorders caused by HEV may involve multiple mechanisms, such as predisposing 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. Moreover, both acute HE or chronic HE acquired in immunocompromised patient could lead to neurological disorders, which are often discontinued with HEV treatment by ribavirin [16]. Peg-IFN alpha 2a seems to be inefficient in chronic forms as reported in a liver transplant recipient [13]. Impact of HEV genotype seems to be important. All of the reported cases were genotype 3, which is found in developed countries. Autochthonous HE (genotype 3) has a distinctive clinical feature that separates it from epidemic forms due to genotypes 1 and 2 [16]. Genotype 3 HEV infections are usually subclinical and mild, have highest rates among older adults and seem to be associated with neurological manifestations. No physiopathological explanation for this association could be found. Previous and current observations suggest that HEV diagnostic testing should be performed in patients who have concurrent liver cytolysis and neurologic symptoms, after ruling out the most common etiologies.
Funding None.
Competing interests None declared.
62
A. Deroux et al. / Journal of Clinical Virology 60 (2014) 60–62
Ethical approval Not required. References [1] Jothikumar N, Cromeans TL, Robertson BH, Meng XJ, Hill VR. A broadly reactive one-step real-time RT-PCR assay for rapid and sensitive detection of hepatitis E virus. J Virol Methods 2006;131(January (1)):65–71. [2] Sood A, Midha V, Sood N. Guillain–Barre syndrome with acute hepatitis E. Am J Gastroenterol 2000;95:3667–8. [3] Kamar N, Bendall RP, Peron JM, Cintas P, Prudhomme L, Masuy JM, et al. Hepatitis E virus and neurologic disorders. Emerg Infect Dis 2011;17: 173–9. [4] Kamani P, Baijal R, Amarapurkar D, Gupte P, Patel N, Kumar P, et al. Guillain–Barre syndrome associated with acute hepatitis E. Indian J Gastroenterol 2005;24:216. [5] Maurissen I, Jeurissen A, Strauven T, Sprengers D, De Schepper B. First case of antiganglioside GM1-positive Guillain–Barre syndrome due to hepatitis E virus infection. Infection 2012;40(3):323–6. [6] Loly JP, Rikir E, Seivert M, Legros E, Defrance P, Belaiche J, et al. Guillain–Barre syndrome following hepatitis E. World J Gastroenterol 2009;15: 1645–7.
[7] Cronin S, McNicholas R, Kavanagh E, Reid V, O’Rourke K. Anti-glycolipid GM2positive Guillain–Barre syndrome due to hepatitis E infection. Ir J Med Sci 2011;180:255–7. [8] Khanam RA, Faruq MO, Basunia RA, Ahsan ASM. Guillain–Barre syndrome associated with acute HEV hepatitis. Ibrahim Med Coll J 2008;2:32–4. [9] Kumar R, Bhoi S, Kumar M, Sharma B, Singh BM, Gupta BB. Guillain–Barre syndrome and acute hepatitis E: a rare association. JIACM 2002;3:389–91. [10] Cheung MC, Maguire J, Carey I, Wendon J, Agarwal K. Hepatitis E – an unexpected problem at home. Scand J Gastroenterol 2012;47:253. [11] Fong F, Illahi M. Neuralgic amyotrophy associated with hepatitis E virus. Clin Neurol Neurosurg 2009;111:193–5. [12] Despierres LA, Kaphan E, Attarian S, Cohen-Bascrie S, Pelletier J, Pouget J, et al. Neurologic disorders and hepatitis E, France, 2010. Emerg Infect Dis 2011;17:1510–2. [13] Maddukuri VC, Russo MW, Ahrens WA, Emerson SU, Engle RE, Purcell RH, et al. Chronic hepatitis E with neurologic manifestations and rapid progression of liver fibrosis in a liver transplant recipient. Dig Dis Sci 2013;58:2413–6. [14] Mandal K, Chopra N. Acute transverse myelitis following hepatitis E virus infection. Indian Pediatr 2006;43:365–6. [15] Kusunoki S, Kaida K. Antibodies against gangliosides complexes in Guillain–Barre syndrome and related disorders. J Neurochem 2011;116:828–32. [16] Hoofnagle JH, Kenrad E, Nelson KE, Purcell RH. Current concepts: hepatitis E. N Engl J Med 2012;367:1237–44.
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case Report
Association between hepatitis E and neurological disorders: Two case studies and literature review A. Deroux a,∗ , J.P. Brion b , L. Hyerle b , A. Belbezier a , M. Vaillant c , E. Mosnier b , S. Larrat d , P. Morand d , P. Pavese c a
Service de médecine interne, CHU A. Michallon, 38700 La Tronche, France Service de maladies infectieuses, CHU A. Michallon, 38700 La Tronche, France c Service de neurologie, CHU A. Michallon, 38700 La Tronche, France d Service de virologie, CHU A. Michallon, 38700 La Tronche, France b
a r t i c l e
i n f o
Article history: Received 20 December 2013 Received in revised form 22 January 2014 Accepted 27 January 2014 Keywords: Hepatitis E Neurological disorders Parsonage-Turner Encephalitis Viral hepatitis
a b s t r a c t Hepatitis E (HEV) is an emerging disease in our developed countries, but is not routinely tested for in case of liver cytolysis. However, a growing number of extra-hepatic manifestations of HEV infection associated with acute hepatitis are reported. In this article, we discuss two cases of HEV with neurological symptoms, one with encephalitis, and the other with Parsonage Turner syndrome. All these disorders appeared concomitantly with liver cytolysis and disappeared quickly, following the viral kinetics. Only twenty cases of neurological manifestation of HEV have been described before. The use of HEV serology in patients with concurrent liver cytolysis and neurological symptoms has to be improved. © 2014 Elsevier B.V. All rights reserved.
1. Why this case is important Hepatitis E virus (HEV) is an under-diagnosed infection in developed countries, with significant morbidity and mortality potential. Like other viral hepatitides, extra-hepatic manifestations can occur; in particular, neurological disorders have been described. Here we report two cases of new neurological involvement in the shape of Parsonage Turner syndrome and encephalitis associated with cerebellitis, and conduct a literature review.
2. Cases description 2.1. First case A 41-year-old man was admitted in August 2011 for walking difficulties, neuropathic pain of all four limbs, cerebellar ataxia, upper limb hypermetria, dysarthria, headache, and transient fever lasting 72 h. Reflexes were all present, without any pyramidal signs. No abnormalities were found on the medullar and cerebral magnetic resonance imaging. Electroencephalogram (EEG) and nerve
∗ Corresponding author. Tel.: +33 04 76 76 75 75. E-mail address: [email protected] (A. Deroux). 1386-6532/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcv.2014.01.026
conduction study was normal. The patient had no notable medical history. At admission, alanine aminotransferase level was 479 IU/L (reference values 8–34 IU/L), aspartate aminotransferase level was 100 IU/L (reference values 9–42), ␥-glutamyl transferase level was 236 IU/L (reference 9–38 IU/L), alkaline phosphatase level was 112 IU/L (reference 42–98 IU/L), and bilirubin was 13 mol/L (reference 2–17 mol/L). Serum amylase level was 30 IU/L (reference 25–115 IU/L) and lipase was 133 IU/L (reference 73–393 IU/L). Cerebrospinal fluid (CSF) was clear; protein and glucose levels were 0.56 g/L (reference 0.15–0.45) and 3.6 mmol/L (reference 3.0–4.5 mmol/L) respectively; leukocyte count was 12 cells/mm3 , including 80% of mononuclear cells. No antibiotics were given. CSF culture remained sterile at day 5. Several infectious diseases responsible for neurologic symptoms (HIV, syphilis, cytomegalovirus, Epstein–Barr virus, mycoplasma, HSV, VZV, measles, parvovirus B19, Lyme disease, HHV6, HHV8, toxoplasmosis, leishmaniasis, arboviruses) and acute hepatitides (hepatitis A, B, C, delta) were excluded by nucleic acid and serologic assays performed on serum and CSF. In contrast, an HEV infection was diagnosed through the detection of anti-HEV immunoglobulin (Ig) M (index 12.00; threshold value 1 [ELISA test DIAPRO]) and HEV RNA in serum and CSF [1], though the test failed to find HEV RNA in stools. Genotype 3f was identified through phylogenetic analysis, which is common in
A. Deroux et al. / Journal of Clinical Virology 60 (2014) 60–62
61
3. Other similar and contrasting cases in the literature
Fig. 1. Winged scapula, amyotrophy in the supraspinatus and infraspinatus fossae and abduction as well as external rotation impairment in the second case. Typical symptomatology for brachial neuritis or Parsonage-Turner syndrome.
autochthonous cases in France. The contamination mode was the consumption of Corsican meat (figatelli). Liver parameters returned to normal within 1 week, and the patient recovered fully 12 weeks after the neurological disorders’ onset. HEV RNA was cleared in serum 2 weeks after the first blood sample.
2.2. Second case A 38 year-old man was hospitalized in December 2012 for Parsonage Turner syndrome with cytolytic hepatitis. He presented with a sudden onset of violent pains in the left shoulder girdle, associated with a painful paresis without esthesic impairment. Physical examination noted a winged scapula, amyotrophy in the supraspinatus and infraspinatus fossae (Fig. 1) and an abduction as well as external rotation impairment. The patient had no notable medical history or treatment. At admission, alanine aminotransferase level was 1612 IU/L (normal levels 8–34 IU/L), aspartate aminotransferase level was 772 IU/L (reference 9–38 IU/L). Alkaline phosphatase, ␥-glutamyl transferase, lipase level and bilirubin were in the normal range. Electromyogram found right long thoracic and suprascapular nerve damage with acute denervation criteria. Infectious diseases responsible for neurologic symptoms were excluded by serologic assays performed on serum (borrelia, toxoplasmosis, HIV, B and C hepatitis, arboviruses, EBV, CMV) and on CSF (HSV, VZV, borrelia). Auto immunity was ruled out (negative AAN, ANCA, and antigangliosides antibodies). CSF was clear; protein and glucose levels were at 0.68 g/L and 3.30 mmol/L respectively. It was a transudate, with moderate blood brain barrier damage (albumin quotient: 10.58 × 10−3 ); IgG index was normal (0.49, normal levels inferior to 0.7) and isoelectrofocusing showed normal repartition of immunoglobulin. Leukocyte count was under 5 cells/mm3 . However, HEV infection was diagnosed by detection of anti-HEV immunoglobulin M (index 3.00, ELISA test Wantai Bio-Pharm® ); unfortunately no nucleic acid assay could be performed during hospitalization, HEV RT-PCR performed one month later was negative in serum and CSF. Neurologic symptoms disappeared in four months, but a painful amyotrophy persisted. Liver parameters returned within normal range in 4 weeks, and HEV IgM were negative six months later with an increasing IgG count (index: 60.273).
These 2 cases establish some strong arguments in favor of an association between acute hepatitis E and neurological disorders. Temporal association, atypical neurological features, exclusion of other potential etiologies led to consider HEV as a possible cause of encephalitis or other neurological disorders. Several cases have been described since the first patient was reported in 2000 [2]. A recent multicentric case series from Southwest England and Toulouse [3] found a high prevalence (5.5% – 7 out of 126 patients) of neurological complications associated with HEV infections. Only 19 cases were documented enough to report this association. Most (8 patients) of the cases concerned acute HEV infection associated with Guillain–Barre syndrome [2–9], 3 others were associated with brachial neuritis [3,10,11], 3 with polyradiculopathy [3,12], 3 with peripheral neuropathy [3,12,13], one with transverse myelitis [14], while acute encephalitis [3] or ataxia [3] was also reported. HEV RNA in CSF was only detected in five of these patients [3,12] like our first case; acute encephalitis and cerebellitis associated with hepatitis E was only described once before. These two patients showed complete recovery in a few months, without any sequel.
4. Discussion and references Several mechanisms for neurological symptoms associated with HEV have been suggested. For neuropathies such as Guillain–Barre syndrome, anti-ganglioside antibodies (GM1, GM2) may be triggered by HEV infection and play a pathogenic role [5–7,15]. In one case, Kamar et al. [3] showed different viral sequences within CSF and serum in the same patient; these could be caused by the emergence of neurotropic quasispecies which could directly affect the nervous system. However, this mechanism seems less probable in cases of acute infection resolving within days. Pathogenesis for peripheral neuropathy and other neurological disorders caused by HEV may involve multiple mechanisms, such as predisposing 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. Moreover, both acute HE or chronic HE acquired in immunocompromised patient could lead to neurological disorders, which are often discontinued with HEV treatment by ribavirin [16]. Peg-IFN alpha 2a seems to be inefficient in chronic forms as reported in a liver transplant recipient [13]. Impact of HEV genotype seems to be important. All of the reported cases were genotype 3, which is found in developed countries. Autochthonous HE (genotype 3) has a distinctive clinical feature that separates it from epidemic forms due to genotypes 1 and 2 [16]. Genotype 3 HEV infections are usually subclinical and mild, have highest rates among older adults and seem to be associated with neurological manifestations. No physiopathological explanation for this association could be found. Previous and current observations suggest that HEV diagnostic testing should be performed in patients who have concurrent liver cytolysis and neurologic symptoms, after ruling out the most common etiologies.
Funding None.
Competing interests None declared.
62
A. Deroux et al. / Journal of Clinical Virology 60 (2014) 60–62
Ethical approval Not required. References [1] Jothikumar N, Cromeans TL, Robertson BH, Meng XJ, Hill VR. A broadly reactive one-step real-time RT-PCR assay for rapid and sensitive detection of hepatitis E virus. J Virol Methods 2006;131(January (1)):65–71. [2] Sood A, Midha V, Sood N. Guillain–Barre syndrome with acute hepatitis E. Am J Gastroenterol 2000;95:3667–8. [3] Kamar N, Bendall RP, Peron JM, Cintas P, Prudhomme L, Masuy JM, et al. Hepatitis E virus and neurologic disorders. Emerg Infect Dis 2011;17: 173–9. [4] Kamani P, Baijal R, Amarapurkar D, Gupte P, Patel N, Kumar P, et al. Guillain–Barre syndrome associated with acute hepatitis E. Indian J Gastroenterol 2005;24:216. [5] Maurissen I, Jeurissen A, Strauven T, Sprengers D, De Schepper B. First case of antiganglioside GM1-positive Guillain–Barre syndrome due to hepatitis E virus infection. Infection 2012;40(3):323–6. [6] Loly JP, Rikir E, Seivert M, Legros E, Defrance P, Belaiche J, et al. Guillain–Barre syndrome following hepatitis E. World J Gastroenterol 2009;15: 1645–7.
[7] Cronin S, McNicholas R, Kavanagh E, Reid V, O’Rourke K. Anti-glycolipid GM2positive Guillain–Barre syndrome due to hepatitis E infection. Ir J Med Sci 2011;180:255–7. [8] Khanam RA, Faruq MO, Basunia RA, Ahsan ASM. Guillain–Barre syndrome associated with acute HEV hepatitis. Ibrahim Med Coll J 2008;2:32–4. [9] Kumar R, Bhoi S, Kumar M, Sharma B, Singh BM, Gupta BB. Guillain–Barre syndrome and acute hepatitis E: a rare association. JIACM 2002;3:389–91. [10] Cheung MC, Maguire J, Carey I, Wendon J, Agarwal K. Hepatitis E – an unexpected problem at home. Scand J Gastroenterol 2012;47:253. [11] Fong F, Illahi M. Neuralgic amyotrophy associated with hepatitis E virus. Clin Neurol Neurosurg 2009;111:193–5. [12] Despierres LA, Kaphan E, Attarian S, Cohen-Bascrie S, Pelletier J, Pouget J, et al. Neurologic disorders and hepatitis E, France, 2010. Emerg Infect Dis 2011;17:1510–2. [13] Maddukuri VC, Russo MW, Ahrens WA, Emerson SU, Engle RE, Purcell RH, et al. Chronic hepatitis E with neurologic manifestations and rapid progression of liver fibrosis in a liver transplant recipient. Dig Dis Sci 2013;58:2413–6. [14] Mandal K, Chopra N. Acute transverse myelitis following hepatitis E virus infection. Indian Pediatr 2006;43:365–6. [15] Kusunoki S, Kaida K. Antibodies against gangliosides complexes in Guillain–Barre syndrome and related disorders. J Neurochem 2011;116:828–32. [16] Hoofnagle JH, Kenrad E, Nelson KE, Purcell RH. Current concepts: hepatitis E. N Engl J Med 2012;367:1237–44.
