Hepatitis E and diaphragmatic dysfunction: Case series and review of the literature

Abstract

Introduction The causes of diaphragmatic paresis are manifold. An association between neuralgic amyotrophy (NA) and hepatitis E virus (HEV) infection has been reported. We wondered about the prevalence of diaphragmatic disfunction and hepatitis E infection in our clinic.

Methods From July 1st, 2020 to August 31st, 2023, patients presenting with diaphragmatic dysfunction and simultaneous clinical symptoms of an acute NA, or a history of NA, as well as patients with previously unexplained diaphragmatic dysfunction were examined for HEV infection.

Results By August 31st, 2023, 13 patients with diaphragmatic dysfunction and HEV infection were diagnosed (4 women, 9 men). Mean age was 59 ± 10 years. Liver values were normal in all patients. The median latency to diagnosis was five months (range: 1–48 months); nine patients, 4 of them with typical symptoms of NA, presented with acute onset three patients showed bilateral diaphragmatic dysfunction. All patients had a positive IgG immunoblot. Seven patients, three with NA, had an elevated hepatitis E IgM titer and six of them also a positive IgM immunoblot. In all cases, O2C hepatitis genotype 3 was identified. In eight cases, all those with a high IgG titer >125, the O2 genotype 1 was also detected.

Conclusion NA that shows involvement of the phrenic nerve resulting in diaphragmatic dysfunction and dyspnoea, may be associated with HEV infection. The observation of 13 patients with diaphragmatic dysfunctions and HEV infection within a period of three years indicates a high number of undetected HEV-associated diaphragmatic dysfunction in the population, especially in the absence of NA symptoms. Therefore, even in diaphragmatic dysfunction without NA symptoms and causative damaging event, HEV infection should be considered, as it may represent a subform of NA with only phrenic nerve involvement. Therapy of HEV-associated diaphragmatic dysfunction in the acute phase is an open question. In view of the poor prognosis for recovery, antiviral therapy should be discussed. However, no relevant data are currently available.

Zusammenfassung

Einleitung Die Ursachen einer Zwerchfellparese sind vielfältig. Mittlerweile wird über einen Zusammenhang zwischen Neuralgischen Amyotrophie (NA) und einer Infektion durch Hepatitis-E-Virus(HEV) berichtet, sodass sich die Frage nach der Prävalenz von Zwerchfellstörungen und HEV-Infektionen in unserer Klinik ergab.

Methoden Vom 1. Juli 2020 bis zum 31. August 2023 wurden Patienten mit einer Zwerchfellfunktionsstörung und gleichzeitigen klinischen Symptomen einer akuten NA oder einer NA in der Vorgeschichte sowie einer bislang ungeklärten Zwerchfellfunktionsstörung auf eine HEV-Infektion hin untersucht.

Ergebnisse Bis zum 31. August 2023 wurden bei 13 Patienten eine Zwerchfellfunktionsstörung und eine Hepatitis-E-Infektion diagnostiziert (4 Frauen, 9 Männer). Das Durchschnittsalter betrug 59 ± 10 Jahre. Die Leberwerte waren bei allen Patienten normal. Die mittlere Latenzzeit bis zur Diagnose betrug 5 Monate (Bereich: 1–48 Monate). 9 Patienten – 4 davon mit typischen NA-Symptomen – stellten sich mit einem akuten Krankheitsverlauf vor. 3 Patienten zeigten eine beidseitige Zwerchfelldysfunktion. Alle Patienten hatten einen positiven IgG-Immunoblot. 7 Patienten, davon 3 mit NA, hatten einen erhöhten Hepatitis-E-IgM-Titer und 6 von ihnen auch einen positiven IgM-Immunoblot. In allen Fällen fand sich der O2C-Genotyp 3. Bei 8 Patienten – allesamt mit einem hohen IgG-Titer >125 – wurde auch der O2-Genotyp 1 nachgewiesen.

Schlussfolgerung Eine NA, die eine Beteiligung des Nervus phrenicus mit Zwerchfelldysfunktion und Dyspnoe zeigt, kann mit einer HEV-Infektion verbunden sein. Die Beobachtung von 13 Patienten mit Zwerchfellfunktionsstörungen und HEV-Infektion innerhalb eines Zeitraums von 3 Jahren lässt eine hohe Anzahl unentdeckter HEV-assoziierter Zwerchfellfunktionsstörungen in der Bevölkerung vermuten, insbesondere wenn keine NA-Symptome vorliegen. So sollte auch bei Zwerchfellfunktionsstörungen ohne NA-Symptome und ursächliches Schädigungsereignis eine HEV-Infektion in Betracht gezogen werden, da es sich möglicherweise um eine Unterform der neuralgischen Amyotrophie handelt, bei der nur der Nervus phrenicus betroffen ist. Die Therapie der HEV-assoziierten Zwerchfelldysfunktion in der Akutphase ist eine offene Frage. Angesichts der schlechten Prognose der Genesung sollte eine antivirale Therapie diskutiert werden. Allerdings liegen hierzu bisher keine Daten vor.

Keywords

Hepatitis E - neuralgic amyotrphy - diaphragmatic paresis - diaphragmatic dysfunction - phrenic nerve

Schlüsselwörter

Hepatitis E - neuralgische Amyotrophie - Zwerchfellparese - Zwerchfelldysfunktion - N. phrenicus

Publication History

Received: 05 December 2023

Accepted after revision: 18 March 2024

Article published online:
24 April 2024

• References

• 1 McCool FD, Tzelepis GE. Dysfunction of the diaphragm. N Engl J Med 2012; 366: 932-942 DOI: 10.1056/NEJMra1007236. Erratum in: N Engl J Med 2012; 366: 2138 (PMID: 22397655)
• 2 Zimmermann M, Wollsching-Strobel M, Majorski DS. et al. Die neuralgische Amyotrophie: eine häufige Ursache uni- oder bilateraler Zwerchfellparesen [Neuralgic amyotrophy: a common cause of unilateral and bilateral diaphragmatic pareses]. Pneumologie 2023; 77: 814-824 DOI: 10.1055/a-2113-0385.
• 3 van Egmond ME, Luijckx GJ, Kramer H. et al. Diaphragmatic weakness caused by neurobor-reliosis. Clin Neurol Neurosurg 2011; 113: 153-155 DOI: 10.1016/j.clineuro.2010.09.011.
• 4 Faul JL, Ruoss S, Doyle RL. et al. Diaphragmatic paralysis due to Lyme disease. Eur Respir J 1999; 13: 700-702 DOI: 10.1183/09031936.99.13370099. (PMID: 10232450)
• 5 Winterholler M, Erbguth FJ. Tick bite induced respiratory failure. Diaphragm palsy in Lyme disease. Intensive Care Med 2001; 27: 1095 DOI: 10.1007/s001340100968. (PMID: 11497145)
• 6 Reddy KP, McCannon JB, Venna N. Diaphragm paralysis in lyme disease: late occurrence in the course of treatment and long-term recovery. Ann Am Thorac Soc 2015; 12: 618-620 DOI: 10.1513/AnnalsATS.201501-070LE. (PMID: 25897747)
• 7 Schmitt M, Daubail B, Bohm A. Parsonage-Turner syndrome secondary to Lyme disease. Joint Bone Spine 2018; 85: 387-388 DOI: 10.1016/j.jbspin.2017.05.018. (PMID: 28549944)
• 8 Wendling D, Sevrin P, Bouchaud-Chabot A. et al. Parsonage-Turner syndrome revealing Lyme borreliosis. Joint Bone Spine 2009; 76: 202-204 DOI: 10.1016/j.jbspin.2008.07.013. (PMID: 19147387)
• 9 Jiguet M, Troussier B, Phélip X. Syndrome de Parsonage et Turner. A propos dʼune observation, avec mise en évidence dʼune infection à Borrelia burgdorferi [Parsonage and Turner syndrome. Apropos of a case, with demonstration of Borrelia burgdorferi infection]. Rev Rhum Mal Osteoartic 1991; 58: 409-411
• 10 Zhang S, Zhang LQ, Wright M. et al. Challenging Diagnosis and Inpatient Rehabilitation of Acute Bilateral Neuralgic Amyotrophy Possibly Attributed to Lyme Disease: A Case Report. PM R 2018; 10: 770-774 DOI: 10.1016/j.pmrj.2017.11.018.
• 11 Farr E, DʼAndrea D, Franz CK. Phrenic Nerve Involvement in Neuralgic Amyotrophy (Parsonage-Turner Syndrome). Sleep Med Clin 2020; 15: 539-543 DOI: 10.1016/j.jsmc.2020.08.002. (PMID: 33131663)
• 12 Dai Y, Patel A, Bierner SM. Phrenic nerve palsy in patients with neuralgic amyotrophy: case series study. Eur J Phys Rehabil Med 2019; 55: 519-521 DOI: 10.23736/S1973-9087.19.05294-8. (PMID: 31058474)
• 13 van Alfen N, Doorduin J, Rosmalen MHJ van. et al. Phrenic neuropathy and diaphragm dysfunction in neuralgic amyotrophy. Neurology 2018; 91: e843-e849 DOI: 10.1212/WNL.0000000000006076. (PMID: 30054437)
• 14 Nardone R, Bernhart H, Pozzera A. et al. Respiratory weakness in neuralgic amyotrophy: report of two cases with phrenic nerve involvement. Neurol Sci 2000; 21: 177-181 DOI: 10.1007/s100720070094.
• 15 Lahrmann H, Grisold W, Authier FJ. et al. Neuralgic amyotrophy with phrenic nerve involvement. Muscle Nerve 1999; 22: 437-442 DOI: 10.1002/(sici)1097-4598(199904)22:43.0.co;2-f.
• 16 Cranovsky C. Die neuralgische Schulteramyotrophie [Neuralgic shoulder amyotrophy]. Schweiz Med Wochenschr 1996; 126: 111-119 (PMID: 8578292)
• 17 Billings R, Grahame R. Neuralgic amyotrophy with hemidiaphragmatic paralysis. Rheumatol Rehabil 1975; 14: 260-261 DOI: 10.1093/rheumatology/14.4.260. (PMID: 1198020)
• 18 Parsonage MJ, Turner JW. Neuralgic amyotrophy; the shoulder-girdle syndrome. Lancet 1948; 1: 973-978 DOI: 10.1016/s0140-6736(48)90611-4. (PMID: 32487526)
• 19 Feinberg J. Fall von Erb-Klumpke schwere Lähmung nach Influenza. Centralbl 1897; 16: 588-637
• 20 Miller NJ, Hooper DR, Sharma A. Bilateral neuralgic amyotrophy in a patient with livestock-associated hepatitis E virus infection. CMAJ 2022; 194: E495-E499 DOI: 10.1503/cmaj.211679. Erratum in: CMAJ 2022; 194: E616
• 21 Ameer MZ, Haiy AU, Bajwa MH. et al. Association of Parsonage-Turner syndrome with COVID-19 infection and vaccination: a systematic review. J Int Med Res 2023; 51: 3000605231187939 DOI: 10.1177/03000605231187939.
• 22 Mahajan S, Zhang F, Mahajan A. et al. Parsonage Turner syndrome after COVID-19 vaccination. Muscle Nerve 2021; 64: E3-E4 DOI: 10.1002/mus.27255. (PMID: 33890680)
• 23 Gstoettner C, Mayer JA, Rassam S. et al. Neuralgic amyotrophy: a paradigm shift in diagnosis and treatment. J Neurol Neurosurg Psychiatry 2020; 91: 879-888 DOI: 10.1136/jnnp-2020-323164. (PMID: 32487526)
• 24 Mulvey DA, Aquilina RJ, Elliott MW. et al. Diaphragmatic dysfunction in neuralgic amyotrophy: an electrophysiologic evaluation of 16 patients presenting with dyspnea. Am Rev Respir Dis 1993; 147: 66-71 DOI: 10.1164/ajrccm/147.1.66.
• 25 Alfen N van, Engelen BG van. The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain 2006; 129: 438-450 DOI: 10.1093/brain/awh722. (PMID: 16371410)
• 26 Eijk JJJ van, Dalton HR, Ripellino P. et al. Clinical phenotype and outcome of hepatitis E virus-associated neuralgic amyotrophy. Neurology 2017; 89: 909-917 DOI: 10.1212/WNL.0000000000004297. (PMID: 28768846)
• 27 Alfen N van. Clinical and pathophysiological concepts of neuralgic amyotrophy. Nat Rev Neurol 2011; 7: 315-322 DOI: 10.1038/nrneurol.2011.62. (PMID: 21556032)
• 28 Holtbernd F, Zehnhoff-Dinnesen AA, Duning T. et al. An unusual case of neuralgic amyotrophy presenting with bilateral phrenic nerve and vocal cord paresis. Case Rep Neurol 2011; 3: 69-74 DOI: 10.1159/000325061.
• 29 Chen YM, Hu GC, Cheng SJ. Bilateral neuralgic amyotrophy presenting with left vocal cord and phrenic nerve paralysis. J Formos Med Assoc 2007; 106: 680-684 DOI: 10.1016/S0929-6646(08)60028-5. (PMID: 17711804)
• 30 Fong F, Illahi M. Neuralgic amyotrophy associated with hepatitis E virus. Clin Neurol Neurosurg 2009; 111: 193-195 DOI: 10.1016/j.clineuro.2008.09.005. (PMID: 18986757)
• 31 Dalton HR, Eijk JJJ van, Cintas P. et al. Hepatitis E virus infection and acute non-traumatic neurological injury: A prospective multicentre study. J Hepatol 2017; 67: 925-932 DOI: 10.1016/j.jhep.2017.07.010. (PMID: 28734938)
• 32 Dartevel A, Colombe B, Bosseray A. et al. Hepatitis E and neuralgic amyotrophy: Five cases and review of literature. J Clin Virol 2015; 69: 156-164 DOI: 10.1016/j.jcv.2015.06.091. (PMID: 26209399)
• 33 Garofoli R, Zauderer J, Seror P. et al. Neuralgic amyotrophy and hepatitis E infection: 6 pro-spective case reports. RMD Open 2020; 6: e001401 DOI: 10.1136/rmdopen-2020-001401.
• 34 Wang Y, Wang S, Wu J. et al. Hepatitis E virus infection in acute non-traumatic neuropathy: A large prospective case-control study in China. EBioMedicine 2018; 36: 122-130 DOI: 10.1016/j.ebiom.2018.08.053. (PMID: 30190208)
• 35 Pischke S, Ryll U, De Weerth A. et al. Neuralgische Schulteramyotrophie: Eine extrahepatische Manifestation der Hepatitis E [Neuralgic amyotrophy: an extrahepatic manifestation of hepatitis E]. Dtsch Med Wochenschr 2016; 141: 1239-1242 DOI: 10.1055/s-0042-102289.
• 36 Lhomme S, Abravanel F, Cintas P. et al. Hepatitis E Virus Infection: Neurological Manifestations and Pathophysiology. Pathogens 2021; 10: 1582 DOI: 10.3390/pathogens10121582. (PMID: 34959537)
• 37 Scanvion Q, Perez T, Cassim F. et al. Neuralgic amyotrophy triggered by hepatitis E virus: a particular phenotype. J Neurol 2017; 264: 770-780 DOI: 10.1007/s00415-017-8433-z. (PMID: 28247042)
• 38 Eijk JJ van, Madden RG, Eijk AA van der. et al. Neuralgic amyotrophy and hepatitis E virus infection. Neurology 2014; 82: 498-503 DOI: 10.1212/WNL.0000000000000112. (PMID: 24401685)
• 39 Ripellino P, Lascano AM, Scheidegger O. et al. Neuropathies related to hepatitis E virus infection: A prospective, matched case-control study. Eur J Neurol 2024; 31: e16030 DOI: 10.1111/ene.16030. (PMID: 37548584)
• 40 Dudareva S, Faber M, Zimmermann R. et al. Epidemiologie der Virushepatitiden A bis E in Deutschland [Epidemiology of viral hepatitis A to E in Germany]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2022; 65: 149-158 DOI: 10.1007/s00103-021-03478-8.
• 41 Fritz-Weltin M, Niedermeier L, Frommherz E. et al. Hepatitis E virus and Bellʼs palsy. Eur J Neurol 2022; 29: 820-825 DOI: 10.1111/ene.15175. (PMID: 34748257)
• 42 Silva M, Wicki B, Tsouni P. et al. Hepatitis E virus infection as a direct cause of neuralgic amyotrophy. Muscle Nerve 2016; 54: 325-327 DOI: 10.1002/mus.25096. (PMID: 26939568)
• 43 Tian D, Li W, Heffron CL. et al. Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood-brain barrier, and invades the central nervous system. Proc Natl Acad Sci U S A 2022; 119: e2201862119 DOI: 10.1073/pnas.2201862119. (PMID: 35671427)
• 44 https://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_HepatitisE.html#doc6819228bodyText2
• 45 Schemmerer M, Wenzel JJ, Stark K. et al. Molecular epidemiology and genotype-specific disease severity of hepatitis E virus infections in Germany, 2010–2019. Emerg Microbes Infect 2022; 11: 1754-1763 DOI: 10.1080/22221751.2022.2091479. (PMID: 35713010)
• 46 Fraga M, Doerig C, Moulin H. et al. Hepatitis E virus as a cause of acute hepatitis acquired in Switzerland. Liver Int 2018; 38: 619-626 DOI: 10.1111/liv.13557. (PMID: 28834649)
• 47 Belbézier A, Deroux A, Sarrot-Reynauld F. et al. Screening of hepatitis E in patients presenting for acute neurological disorders. J Infect Public Health 2020; 13: 1047-1050 DOI: 10.1016/j.jiph.2019.12.012. (PMID: 32224109)
• 48 Rawla P, Raj JP, Kannemkuzhiyil AJ. et al. A Systematic Review of the Extra-Hepatic Manifestations of Hepatitis E Virus Infection. Med Sci (Basel) 2020; 8: 9 DOI: 10.3390/medsci8010009. (PMID: 32033102)
• 49 Shinder N, Polson A, Pringle E. et al. Neuralgic amyotrophy: A rare cause of bilateral diaphragmatic paralysis. Can Respir J 1998; 5: 139-142 DOI: 10.1155/1998/926375. (PMID: 9707457)
• 50 Rice BL, Ashton RW, Wang XF. et al. Modeling of Lung Function Recovery in Neuralgic Amyotrophy With Diaphragm Impairment. Respir Care 2017; 62: 1269-1276 DOI: 10.4187/respcare.05568.
• 51 Hughes PD, Polkey MI, Moxham J. et al. Long-term recovery of diaphragm strength in neuralgic amyotrophy. Eur Respir J 1999; 13: 379-84 DOI: 10.1183/09031936.99.13237999. (PMID: 10065685)
• 52 Mackrill S, Chakrabarti P, Butterworth R. et al. Hepatitis E virus-associated brachial neuritis presenting with orthopnoea as a result of bilateral diaphragmatic weakness. Br J Hosp Med (Lond) 2023; 84: 1-3 DOI: 10.12968/hmed.2022.0280.
• 53 Noushad MA, Limnatitou D, Bhattacharjee S. et al. Diaphragmatic paralysis resulting in respiratory failure as a feature of hepatitis E virus-associated neuralgic amyotrophy. BMJ Case Rep 2021; 14: e242113 DOI: 10.1136/bcr-2021-242113. (PMID: 33849882)
• 54 Avila JD, Lacomis D, Lam EM. Neuralgic Amyotrophy Associated With Hepatitis E Virus Infection: First Case in the United States. J Clin Neuromuscul Dis 2016; 18: 96-100 DOI: 10.1097/CND.0000000000000137. (PMID: 27861224)
• 55 IJspeert J, Janssen RMJ, Alfen N van. Neuralgic amyotrophy. Curr Opin Neurol 2021; 34: 605-612 DOI: 10.1097/WCO.0000000000000968. (PMID: 34054111)