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A case of relapsing–remitting facial palsy and ipsilateral brachial plexopathy caused by HSV-1
Journal of Clinical Virology 78 (2016) 62–65
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
A case of relapsing–remitting facial palsy and ipsilateral brachial plexopathy caused by HSV-1 Karl B. Alstadhaug a,b,∗ , Hanne W. Kvarenes b,c , Jan Prytz b,d , Christian Vedeler e,f a
Department of Neurology, Nordland Hospital Trust, Bodø, Norway Institue Clinical Medicine, UiT The Arctic University of Tromsø, Tromsø, Norway Department of Infectious Diseases, Nordland Hospital Trust, Bodø, Norway d Department of Radiology, Nordland Hospital Trust, Bodø, Norway e Department of Neurology, Haukeland University Hospital, Bergen, Norway f Department of Clinical medicine, University of Bergen, Norway b c
a r t i c l e
i n f o
Article history: Received 31 December 2015 Received in revised form 3 March 2016 Accepted 5 March 2016 Keywords: Bell’s palsy Herpes simplex Brachial neuritis Acyclovir Mannose-binding lectin deficiency
a b s t r a c t The etiologies of Bell’s palsy and brachial neuritis remain uncertain, and the conditions rarely co-occur or reoccur. Here we present a woman in her twenties who had several relapsing-remitting episodes with left-sided facial palsy and brachial neuropathy. The episodes always started with painful left-sided oral blisters. Repeat PCRs HSV-1 DNA from oral vesicular lesions were positive. Extensive screening did not reveal any other underlying cause. Findings on MRI T2-weighted brachial plexus STIR images, using a 3.0-Tesla scanner during an episode, were compatible with brachial plexus neuritis. Except a mannosebinding lectin deficiency, a congenital complement deficiency that is frequently found in the general Caucasian population, no other immunodeficiency was demonstrated in our patient. In vitro resistance to acyclovir was tested negative, but despite prophylactic treatment with the drug in high doses, relapses recurred. To our knowledge, this is the first ever reported documentation of relapsing-remitting facial and brachial plexus neuritis caused by HSV-1. © 2016 Elsevier B.V. All rights reserved.
1. Why this case is important?
2. Case description
Over the years, several explanations for Bell’s palsy (BP) have been given, but the etiology remains uncertain. The reason may be that there is no common etiological factor [1], but a common etiological pathogenesis. Both viral and autoimmune mechanisms have been suggested [2]. Herpes simplex virus type 1 (HSV-1) was postulated as the causative agent over 40 years ago [3], but direct evidence for HSV-1 infection in patients with BP is still lacking. Likewise, brachial plexus neuritis (BPN) is predominantly considered an autoimmune condition, but as with BP it rarely recurs [4]. Herein we present a woman with mannose-binding lectin deficiency (MBLD) who had several relapsing-remitting episodes with left-sided facial palsy and brachial neuropathy associated with ipsilateral herpetic gingivostomatitis. Our case supports existing evidence that HSV1 may be a direct cause of BP [5]. It also documents HSV-1 as a potential cause of BPN.
A 24-year-old Caucasian woman with polycystic ovary syndrome (PCOS) experienced in mid-August 2012 painful blisters on her tongue (middle lateral part) and inside her mouth (in the posterior part, outside the lower row of teeth in the mandibular gingivae) on the left side. A week later she woke up with an ipsilateral facial palsy accompanied with ear pain, facial numbness, and altered taste on the left side of the tongue. On August 27 she was hospitalized due to slight pain in her anterior left shoulder that had gradually been replaced by weakness and numbness on the lateral side of the upper arm, radial forearm, and the hand. On examination she had a complete peripheral facial palsy with Bell’s phenomenon. Sensory loss was found in the distribution of the trigeminal nerve, as well as in several cervical dermatomes (C5-C8). A minor generalized motor deficit in the left upper limb was confirmed, however, most pronounced in the shoulder girdle where muscle power for abduction was graded 4/5. Deep tendon reflexes were depressed, but symmetric. Magnetic resonance imaging (MRI) of the brain, the cervical spine and the brachial plexus was normal. Complete blood count, anti-GM, anti-MAG, anti-GQ1b antibodies and antibodies against Borrelia burgdorferi did not reveal underlying pathology. IgG, but
∗ Corresponding author at: Department of Neurology, Nordland Hospital Trust, Bodø 8092, Norway. E-mail address: [email protected] (K.B. Alstadhaug). http://dx.doi.org/10.1016/j.jcv.2016.03.003 1386-6532/© 2016 Elsevier B.V. All rights reserved.
K.B. Alstadhaug et al. / Journal of Clinical Virology 78 (2016) 62–65
not IgM, for both VZV and HSV was present. The cerebrospinal fluid (CSF) was also normal, including cells, glucose, protein, IgG index and oligoclonal IgG bands, as well as viral polymerase chain reaction (PCR) assays for varicella-zoster virus (VZV), HSV types 1 and 2. The patient was diagnosed with facial palsy and brachial neuritis, presumably caused by reactivation of VZV, and treated with acyclovir and prednisolone in conventional doses. At a follow-up-visit 3 months later the patient had almost completely recovered, and a nerve conduction study was normal, but in the following 3 years she experienced 10 stereotype relapses consistently preceded by painful blisters inside the posterior left cheek, often also associated with pain in the angle of the jaw. She was left with minor asymmetry in the left side of her face, a slight reduced sensation in the C8 dermatome and a depressed triceps tendon reflex. Nerve conduction and electromyography showed polyphasic potentials in the left orbicularis muscle due to axonal injury. Neurophysiological examination of the extremities was normal with no signs of nerve conduction block. Except a mannosebinding lectin deficiency (serum level <500 ng/ml and MBL activity <200 U/ml), the patient was totally immune-competent. Work-up, including measurements of serum angiotensin-converting enzyme, genetic testing (PMP22 duplication), total immunoglobulin as well as subclass levels, immunophenotyping, anti-neuronal antibodies, viral serology, rheumatology tests, bone marrow examination, and repeated CSF-analyses, was normal. The patient was previously exposed to Bacillus Calmette-Guérin (BCG) vaccination, and a Mantoux-test, performed to assess cellular immunity in vivo, was positive. In vitro resistance to both acyclovir (IC50 ≤ 2 g/ml) and foscarnet (IC50 ≤ 60 g/ml) was tested negative. The patient had no concurrent orofacial edema and fissured tongue which has been reported with recurrent facial palsy due to Melkersson-Rosenthal syndrome. Six months after the first event, mouth blisters, ipsilateral facial palsy and upper limb sensorimotor dysfunction recurred. HSV-1 DNA PCR from oral vesicular lesions was positive. Standard treatment with acyclovir tablets and corticosteroids was given as before, but this time valacyclovir (500 mg daily) was continued as a prophylactic medication. Again signs and symptoms regressed. In the beginning of May 2013 she had her second relapse, and acyclovir was given intravenously. The valacyclovir-prophylaxis was increased to 500 mg twice daily, but later stopped due to whished pregnancy that came true after using metformin. At gestational week 37, previous neurological symptoms reappeared, and she was again treated with acyclovir. Prophylaxis with valacyclovir (500 mg daily) was reinstated. Symptoms slowly regressed, and the patient gave birth to her first child around estimated due date in April.
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One month postpartum a new relapse occurred, and again HSV-1 was detected in oral vesicular lesions. Despite increasing the prophylactic valacyclovir dose to 1000 mg three times a day, new episodes were encountered after another 3 and 4 months. A repeat cerebral and cervical MRI in September 2014 did not show any pathology, but findings on T2-weighted brachial plexus STIR images, using a 3.0-Tesla scanner, was compatible with plexus neuritis (Fig. 1). The prophylaxis was removed, but reinstated after one month when the patient’s 8th relapse occurred. Three months later, prednisolone was tried immediately when she again got blisters on the left lower gums, but it did not prevent yet another episode of neurological symptoms. In June 2015, the patient experienced her 10th relapse, and presented on the same day as new HSV-1 positive blisters appeared. 3. Other similar and contrasting cases in the literature There is quite sound evidence that VZV may cause both unilateral peripheral facial nerve palsy [2] and BPN [6], but we found only three cases of BP associated with documented herpes simplex gingivostomatitis in the litterature [7–9]. In a case series presented by Vahlne et al., one of the patients had overt herpes labialis during the BP [10]. Ghonmin reported two cases with bilateral BP following a recent presumed herpetic gingivostomatitis, but viral conformation was not documented [11]. Only one case of BPN due to HSV-1 is reported [12]. 4. Discussion To our knowledge, this is the first reported association between HSV-1 reactivation and facial palsy combined with brachial plexopathy. Documented recurrent intraoral HSV is uncommon. The underlying predisposition to frequent reactivations is unknown, but low cell-mediated immunity probably plays an important role [13], and reduced MBL-mediated complement activation increases susceptibility to viral infections [14], including herpes [15,16]. The patient’s PCOS may also be of importance. Experimental works support that ovarian factors, alone or in combination with estrogen, strongly influence susceptibility to HSV-1 infection [17]. In general, estrogen may have protective effects, possibly through macrophage antiviral resistance, but late pregnancy is, despite high levels of estrogen during third trimester, a well-known risk factor for both herpes reactivation and BP. Gestational immunosuppression induced by rise in cortisol levels has been postulated to cause reactivation of a latent herpes simplex virus. The puerperium is also a well-known risk factor for BP [18].
Fig. 1. Coronal T2-weighted fat-suppressed images (TR 3700 msek, TI 230 msek, TE 44 msek, Simens Medical System GMBH, Erlangen, Germany): A, Normal right brachial plexus (arrow). B, Increased signal in fascicules of left brachial plexus (arrow) consistent with inflammatory edema. Fat-suppressed T1-weighted images post intravenous contrast revealed no enhancement (not shown).
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K.B. Alstadhaug et al. / Journal of Clinical Virology 78 (2016) 62–65
Reactivation may occur simultaneously in neurons of diverse sensory ganglia (e.g. trigeminal, geniculate, and cervical) [19]. How the facial motor nerves are affected is still unclear, but viral spread from the geniculate ganglion via the greater superficial petrosal nerve has been postulated [20,21]. Whether other anastomoses between sensory and motor nerves may provide a route for spread of virus remains to be shown, but anatomically it is absolutely possible (Refs. 22 and 23 provide detailed information about neuronal communications among the cranial nerves and their branches), e.g. the auriculotemporal branch of the trigeminal nerve strongly and consistently anastomoses with the facial nerve [22]. The facial nerve also connects to multiple cutaneous branches of the cervical plexus [23]. In the present case, the associated pain in the angle of the jaw (supplied by C2 and C3) may indicate that the cervical plexus was involved in the viral reactivation. The cervical plexus is superiorly connected with the hypoglossal nerve and inferiorly with the brachial plexus [24]. Concurrent BPN and BP, termed ‘extended neuralgic amyotrophy syndrome’, has previously been described [4]. Reactivated viruses, lysing the ganglion cells and entering the endoneurial fluid [5], may result in inflammation and edema. Compression due to swelling [25], immune-mediated mechanisms [2], and infection of Schwann cells [26] may all lead to demyelination and eventually axonal damage. The relapsing-remitting course in our patient, the relatively rapid and good recovery, and the MRI-scan of the brachial plexus support a demyelinating inflammatory process. Anti-viral therapy has been proven effective in both treating and reducing the occurrences of HSV-1 at oral sites [27], but the effects in BP are more controversial [28]. The lack of prophylactic effect of high doses of valacyclovir in our case indicates that the drug had little or no effect on the reactivation of the virus in the peripheral nerves. Notably, however, the symptoms of BPN became less prominent in her latest attacks, and even absent in some, indicating a weaker viral reactivation. An alternative pathophysiological explanation is that the first infectious episode may have caused exposure of auto-antigens that made anatomical structures vulnerable to later immune attacks. Lewis-Sumner syndrome is considered a rare atypical variant of chronic demyelinating polyneuropathy characterized by asymmetric weakness, typically in the distribution of individual nerves, and with either a relapsing or progressive course [29]. Presumed immune-mediated brachial neuropathy (neuralgic amyotrophy) may also recur and involve nerves outside the brachial plexus [4]. However, these conditions are not preceded by mucocutaneous HSV-1 infections. Furthermore, concurrent facial palsy is extremely rare, and relapses as many as in the present case are unlikely. Cranial neuropathies often occurs weeks after acute zoster has developed [20], but in our case the latency was very short. In conclusion, the present case shows that HSV-1 may cause relapsing-remitting facial and brachial plexus neuritis. Despite questionable effects of antiviral treatment [28], the stereotype neurological symptoms confined to the same anatomical areas during each episode, with short latency of the HSV-1 reactivation, favor a local infectious neuropathy, but such a direct cause-effect remains to be proven.
Ethics The patient read the text and gave informed consent to publishing it.
Ethical approval Ethical approval was given by the patient safety deputy, reference number 12/2015.
Conflicts of interest The authors have nothing to disclose.
Acknowledgment This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References [1] E. Peitersen, Bell’s palsy: the spontaneous course of 2500 peripheral facial nerve palsies of different etiologies, Acta Otolaryngol. Suppl. (2002) 4–30. [2] A. Greco, A. Gallo, M. Fusconi, C. Marinelli, G.F. Macri, M. de Vincentiis, Bell’s palsy and autoimmunity, Autoimmun. Rev. 12 (2012) 323–328. [3] D.P. McCormick, Herpes-simplex virus as a cause of Bell’s palsy, Lancet 1 (1972) 937–939. [4] N. van Alfen, Clinical and pathophysiological concepts of neuralgic amyotrophy, Nat. Rev. Neurol. 7 (2011) 315–322. [5] S. Murakami, M. Mizobuchi, Y. Nakashiro, T. Doi, N. Hato, N. Yanagihara, Bell palsy and herpes simplex virus: identification of viral DNA in endoneurial fluid and muscle, Ann. Intern. Med. 124 (1996) 27–30. [6] V.A. Fabian, B. Wood, P. Crowley, B.A. Kakulas, Herpes zoster brachial plexus neuritis, Clin. Neuropathol. 16 (1997) 61–64. [7] S.M. Sapiro, Bell’s palsy associated with acute herpetic gingivostomatitis, Oral Surg. Oral Med. Oral Pathol. 39 (1975) 403–408. [8] M.D. Smith, G.M. Scott, S. Rom, G. Patou, Herpes simplex virus and facial palsy, J. Infect. 15 (1987) 259–261. [9] E. Nasatzky, J. Katz, Bell’s palsy associated with herpes simplex gingivostomatitis: a case report, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 86 (1998) 293–296. [10] A. Vahlne, S. Edstrom, P. Arstila, M. Beran, H. Ejnell, O. Nylen, et al., Bell’s palsy and herpes simplex virus, Arch. Otolaryngol. (Chicago, Ill: 1960) 107 (1981) 79–81. [11] M.R. Ghonim, C. Gavilan, M.J. Sarria, Bilateral simultaneous Bell’s palsy. Two cases following herpes simplex gingivostomatitis, ORL J. Otorhinolaryngol. Relat. Spec. 50 (1988) 269–272. [12] P. Seror, P. Valenti, Amyotrophic neuralgia, a multiple atypical form possible role of herpes simplex virus, Presse Med. (Paris, France: 1983) 24 (1995) 735. [13] S. Haginimori, T. Ichihara, A. Mori, A. Kawata, H. Tang, Y. Mori, Varciella-zoster virus-specific cell-mediated immunity in Ramsay Hunt syndrome, Laryngoscope 126 (2016) E35–E39. [14] M.P. Keizer, D. Wouters, L.J. Schlapbach, T.W. Kuijpers, Restoration of MBL-deficiency: redefining the safety, efficacy and viability of MBL-substitution therapy, Mol. Immunol. 61 (2014) 174–184. [15] J.M. Lubinski, M. Jiang, L. Hook, Y. Chang, C. Sarver, D. Mastellos, et al., Herpes simplex virus type 1 evades the effects of antibody and complement in vivo, J. Virol. 76 (2002) 9232–9241. [16] M. Gadjeva, S.R. Paludan, S. Thiel, V. Slavov, M. Ruseva, K. Eriksson, et al., Mannan-binding lectin modulates the response to HSV-2 infection, Clin. Exp. Immunol. 138 (2004) 304–311. [17] A.S. Brown, J.M. Davis, E.A. Murphy, M.D. Carmichael, J.A. Carson, A. Ghaffar, et al., Susceptibility to HSV-1 infection and exercise stress in female mice: role of estrogen, J. Appl. Physiol. (Bethesda, Md: 1985) 103 (2007) 1592–1597. [18] A.D. Walling, Bell’s palsy in pregnancy and the puerperium, J. Fam. Pract. 36 (1993) 559–563. [19] P. Schulz, V. Arbusow, M. Strupp, M. Dieterich, E. Rauch, T. Brandt, Highly variable distribution of HSV-1-specific DNA in human geniculate, vestibular and spiral ganglia, Neurosci. Lett. 252 (1998) 139–142. [20] D.H. Gilden, B.K. Kleinschmidt-DeMasters, J.J. LaGuardia, R. Mahalingam, R.J. Cohrs, Neurologic complications of the reactivation of varicella-zoster virus, N. Engl. J. Med. 342 (2000) 635–645. [21] L.J. Vanopdenbosch, K. Verhoeven, J.W. Casselman, Bell’s palsy with ipsilateral numbness, J. Neurol. Neurosurg. Psychiatry 76 (2005) 1017–1018. [22] M.M. Shoja, N.M. Oyesiku, C.J. Griessenauer, V. Radcliff, M. Loukas, J.J. Chern, et al., Anastomoses between lower cranial and upper cervical nerves: a comprehensive review with potential significance during skull base and neck operations, part I: trigeminal, facial, and vestibulocochlear nerves, Clin. Anat. (New York, NY) 27 (2014) 118–130. [23] M. Diamond, C.T. Wartmann, R.S. Tubbs, M.M. Shoja, A.A. Cohen-Gadol, M. Loukas, Peripheral facial nerve communications and their clinical implications, Clin. Anat. (New York, NY) 24 (2011) 10–18. [24] M.M. Shoja, N.M. Oyesiku, G. Shokouhi, C.J. Griessenauer, J.J. Chern, E.B. Rizk, et al., A comprehensive review with potential significance during skull base and neck operations, Part II: glossopharyngeal, vagus, accessory, and hypoglossal nerves and cervical spinal nerves 1–4, Clin. Anat. (New York, NY) 27 (2014) 131–144. [25] Ai K, Sun M, Liu Y, Guo B, Tu M, Zhao J, et al. Total facial nerve decompression in severe idiopathic recurrent facial palsy. European archives of oto-rhino-laryngology: official journal of the European Federation ofOto-Rhino-Laryngological Societies (EUFOS): affiliated with the German
K.B. Alstadhaug et al. / Journal of Clinical Virology 78 (2016) 62–65 Society for Oto-Rhino-Laryngology − Head and Neck Surgery, 2014. [26] J.J. Townsend, P.K. Collins, Peripheral nervous system demyelination with herpes simplex virus, J. Neuropathol. Exp. Neurol. 45 (1986) 419–425. [27] J.F. Rooney, S.E. Straus, M.L. Mannix, C.R. Wohlenberg, D.W. Alling, J.A. Dumois, et al., Oral acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebo-controlled trial, Ann. Intern. Med. 118 (1993) 268–272.
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[28] J.R. de Almeida, Antivirals in combination With corticosteroids compared to corticosteroids alone improve facial recovery in severe Bell’s palsy.. and possibly more? Evid. Based Med. 20 (2015) 178. [29] R. Lefaucheur, J.P. Bouwyn, D. Wallon, A.L. Bedat-Millet, P. Ahtoy, G. Perot, et al., Recurrent diplopia over a 30-year period: natural history of a Lewis and Sumner syndrome, Acta Neurol. Belg. 112 (2012) 199–201.
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
A case of relapsing–remitting facial palsy and ipsilateral brachial plexopathy caused by HSV-1 Karl B. Alstadhaug a,b,∗ , Hanne W. Kvarenes b,c , Jan Prytz b,d , Christian Vedeler e,f a
Department of Neurology, Nordland Hospital Trust, Bodø, Norway Institue Clinical Medicine, UiT The Arctic University of Tromsø, Tromsø, Norway Department of Infectious Diseases, Nordland Hospital Trust, Bodø, Norway d Department of Radiology, Nordland Hospital Trust, Bodø, Norway e Department of Neurology, Haukeland University Hospital, Bergen, Norway f Department of Clinical medicine, University of Bergen, Norway b c
a r t i c l e
i n f o
Article history: Received 31 December 2015 Received in revised form 3 March 2016 Accepted 5 March 2016 Keywords: Bell’s palsy Herpes simplex Brachial neuritis Acyclovir Mannose-binding lectin deficiency
a b s t r a c t The etiologies of Bell’s palsy and brachial neuritis remain uncertain, and the conditions rarely co-occur or reoccur. Here we present a woman in her twenties who had several relapsing-remitting episodes with left-sided facial palsy and brachial neuropathy. The episodes always started with painful left-sided oral blisters. Repeat PCRs HSV-1 DNA from oral vesicular lesions were positive. Extensive screening did not reveal any other underlying cause. Findings on MRI T2-weighted brachial plexus STIR images, using a 3.0-Tesla scanner during an episode, were compatible with brachial plexus neuritis. Except a mannosebinding lectin deficiency, a congenital complement deficiency that is frequently found in the general Caucasian population, no other immunodeficiency was demonstrated in our patient. In vitro resistance to acyclovir was tested negative, but despite prophylactic treatment with the drug in high doses, relapses recurred. To our knowledge, this is the first ever reported documentation of relapsing-remitting facial and brachial plexus neuritis caused by HSV-1. © 2016 Elsevier B.V. All rights reserved.
1. Why this case is important?
2. Case description
Over the years, several explanations for Bell’s palsy (BP) have been given, but the etiology remains uncertain. The reason may be that there is no common etiological factor [1], but a common etiological pathogenesis. Both viral and autoimmune mechanisms have been suggested [2]. Herpes simplex virus type 1 (HSV-1) was postulated as the causative agent over 40 years ago [3], but direct evidence for HSV-1 infection in patients with BP is still lacking. Likewise, brachial plexus neuritis (BPN) is predominantly considered an autoimmune condition, but as with BP it rarely recurs [4]. Herein we present a woman with mannose-binding lectin deficiency (MBLD) who had several relapsing-remitting episodes with left-sided facial palsy and brachial neuropathy associated with ipsilateral herpetic gingivostomatitis. Our case supports existing evidence that HSV1 may be a direct cause of BP [5]. It also documents HSV-1 as a potential cause of BPN.
A 24-year-old Caucasian woman with polycystic ovary syndrome (PCOS) experienced in mid-August 2012 painful blisters on her tongue (middle lateral part) and inside her mouth (in the posterior part, outside the lower row of teeth in the mandibular gingivae) on the left side. A week later she woke up with an ipsilateral facial palsy accompanied with ear pain, facial numbness, and altered taste on the left side of the tongue. On August 27 she was hospitalized due to slight pain in her anterior left shoulder that had gradually been replaced by weakness and numbness on the lateral side of the upper arm, radial forearm, and the hand. On examination she had a complete peripheral facial palsy with Bell’s phenomenon. Sensory loss was found in the distribution of the trigeminal nerve, as well as in several cervical dermatomes (C5-C8). A minor generalized motor deficit in the left upper limb was confirmed, however, most pronounced in the shoulder girdle where muscle power for abduction was graded 4/5. Deep tendon reflexes were depressed, but symmetric. Magnetic resonance imaging (MRI) of the brain, the cervical spine and the brachial plexus was normal. Complete blood count, anti-GM, anti-MAG, anti-GQ1b antibodies and antibodies against Borrelia burgdorferi did not reveal underlying pathology. IgG, but
∗ Corresponding author at: Department of Neurology, Nordland Hospital Trust, Bodø 8092, Norway. E-mail address: [email protected] (K.B. Alstadhaug). http://dx.doi.org/10.1016/j.jcv.2016.03.003 1386-6532/© 2016 Elsevier B.V. All rights reserved.
K.B. Alstadhaug et al. / Journal of Clinical Virology 78 (2016) 62–65
not IgM, for both VZV and HSV was present. The cerebrospinal fluid (CSF) was also normal, including cells, glucose, protein, IgG index and oligoclonal IgG bands, as well as viral polymerase chain reaction (PCR) assays for varicella-zoster virus (VZV), HSV types 1 and 2. The patient was diagnosed with facial palsy and brachial neuritis, presumably caused by reactivation of VZV, and treated with acyclovir and prednisolone in conventional doses. At a follow-up-visit 3 months later the patient had almost completely recovered, and a nerve conduction study was normal, but in the following 3 years she experienced 10 stereotype relapses consistently preceded by painful blisters inside the posterior left cheek, often also associated with pain in the angle of the jaw. She was left with minor asymmetry in the left side of her face, a slight reduced sensation in the C8 dermatome and a depressed triceps tendon reflex. Nerve conduction and electromyography showed polyphasic potentials in the left orbicularis muscle due to axonal injury. Neurophysiological examination of the extremities was normal with no signs of nerve conduction block. Except a mannosebinding lectin deficiency (serum level <500 ng/ml and MBL activity <200 U/ml), the patient was totally immune-competent. Work-up, including measurements of serum angiotensin-converting enzyme, genetic testing (PMP22 duplication), total immunoglobulin as well as subclass levels, immunophenotyping, anti-neuronal antibodies, viral serology, rheumatology tests, bone marrow examination, and repeated CSF-analyses, was normal. The patient was previously exposed to Bacillus Calmette-Guérin (BCG) vaccination, and a Mantoux-test, performed to assess cellular immunity in vivo, was positive. In vitro resistance to both acyclovir (IC50 ≤ 2 g/ml) and foscarnet (IC50 ≤ 60 g/ml) was tested negative. The patient had no concurrent orofacial edema and fissured tongue which has been reported with recurrent facial palsy due to Melkersson-Rosenthal syndrome. Six months after the first event, mouth blisters, ipsilateral facial palsy and upper limb sensorimotor dysfunction recurred. HSV-1 DNA PCR from oral vesicular lesions was positive. Standard treatment with acyclovir tablets and corticosteroids was given as before, but this time valacyclovir (500 mg daily) was continued as a prophylactic medication. Again signs and symptoms regressed. In the beginning of May 2013 she had her second relapse, and acyclovir was given intravenously. The valacyclovir-prophylaxis was increased to 500 mg twice daily, but later stopped due to whished pregnancy that came true after using metformin. At gestational week 37, previous neurological symptoms reappeared, and she was again treated with acyclovir. Prophylaxis with valacyclovir (500 mg daily) was reinstated. Symptoms slowly regressed, and the patient gave birth to her first child around estimated due date in April.
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One month postpartum a new relapse occurred, and again HSV-1 was detected in oral vesicular lesions. Despite increasing the prophylactic valacyclovir dose to 1000 mg three times a day, new episodes were encountered after another 3 and 4 months. A repeat cerebral and cervical MRI in September 2014 did not show any pathology, but findings on T2-weighted brachial plexus STIR images, using a 3.0-Tesla scanner, was compatible with plexus neuritis (Fig. 1). The prophylaxis was removed, but reinstated after one month when the patient’s 8th relapse occurred. Three months later, prednisolone was tried immediately when she again got blisters on the left lower gums, but it did not prevent yet another episode of neurological symptoms. In June 2015, the patient experienced her 10th relapse, and presented on the same day as new HSV-1 positive blisters appeared. 3. Other similar and contrasting cases in the literature There is quite sound evidence that VZV may cause both unilateral peripheral facial nerve palsy [2] and BPN [6], but we found only three cases of BP associated with documented herpes simplex gingivostomatitis in the litterature [7–9]. In a case series presented by Vahlne et al., one of the patients had overt herpes labialis during the BP [10]. Ghonmin reported two cases with bilateral BP following a recent presumed herpetic gingivostomatitis, but viral conformation was not documented [11]. Only one case of BPN due to HSV-1 is reported [12]. 4. Discussion To our knowledge, this is the first reported association between HSV-1 reactivation and facial palsy combined with brachial plexopathy. Documented recurrent intraoral HSV is uncommon. The underlying predisposition to frequent reactivations is unknown, but low cell-mediated immunity probably plays an important role [13], and reduced MBL-mediated complement activation increases susceptibility to viral infections [14], including herpes [15,16]. The patient’s PCOS may also be of importance. Experimental works support that ovarian factors, alone or in combination with estrogen, strongly influence susceptibility to HSV-1 infection [17]. In general, estrogen may have protective effects, possibly through macrophage antiviral resistance, but late pregnancy is, despite high levels of estrogen during third trimester, a well-known risk factor for both herpes reactivation and BP. Gestational immunosuppression induced by rise in cortisol levels has been postulated to cause reactivation of a latent herpes simplex virus. The puerperium is also a well-known risk factor for BP [18].
Fig. 1. Coronal T2-weighted fat-suppressed images (TR 3700 msek, TI 230 msek, TE 44 msek, Simens Medical System GMBH, Erlangen, Germany): A, Normal right brachial plexus (arrow). B, Increased signal in fascicules of left brachial plexus (arrow) consistent with inflammatory edema. Fat-suppressed T1-weighted images post intravenous contrast revealed no enhancement (not shown).
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Reactivation may occur simultaneously in neurons of diverse sensory ganglia (e.g. trigeminal, geniculate, and cervical) [19]. How the facial motor nerves are affected is still unclear, but viral spread from the geniculate ganglion via the greater superficial petrosal nerve has been postulated [20,21]. Whether other anastomoses between sensory and motor nerves may provide a route for spread of virus remains to be shown, but anatomically it is absolutely possible (Refs. 22 and 23 provide detailed information about neuronal communications among the cranial nerves and their branches), e.g. the auriculotemporal branch of the trigeminal nerve strongly and consistently anastomoses with the facial nerve [22]. The facial nerve also connects to multiple cutaneous branches of the cervical plexus [23]. In the present case, the associated pain in the angle of the jaw (supplied by C2 and C3) may indicate that the cervical plexus was involved in the viral reactivation. The cervical plexus is superiorly connected with the hypoglossal nerve and inferiorly with the brachial plexus [24]. Concurrent BPN and BP, termed ‘extended neuralgic amyotrophy syndrome’, has previously been described [4]. Reactivated viruses, lysing the ganglion cells and entering the endoneurial fluid [5], may result in inflammation and edema. Compression due to swelling [25], immune-mediated mechanisms [2], and infection of Schwann cells [26] may all lead to demyelination and eventually axonal damage. The relapsing-remitting course in our patient, the relatively rapid and good recovery, and the MRI-scan of the brachial plexus support a demyelinating inflammatory process. Anti-viral therapy has been proven effective in both treating and reducing the occurrences of HSV-1 at oral sites [27], but the effects in BP are more controversial [28]. The lack of prophylactic effect of high doses of valacyclovir in our case indicates that the drug had little or no effect on the reactivation of the virus in the peripheral nerves. Notably, however, the symptoms of BPN became less prominent in her latest attacks, and even absent in some, indicating a weaker viral reactivation. An alternative pathophysiological explanation is that the first infectious episode may have caused exposure of auto-antigens that made anatomical structures vulnerable to later immune attacks. Lewis-Sumner syndrome is considered a rare atypical variant of chronic demyelinating polyneuropathy characterized by asymmetric weakness, typically in the distribution of individual nerves, and with either a relapsing or progressive course [29]. Presumed immune-mediated brachial neuropathy (neuralgic amyotrophy) may also recur and involve nerves outside the brachial plexus [4]. However, these conditions are not preceded by mucocutaneous HSV-1 infections. Furthermore, concurrent facial palsy is extremely rare, and relapses as many as in the present case are unlikely. Cranial neuropathies often occurs weeks after acute zoster has developed [20], but in our case the latency was very short. In conclusion, the present case shows that HSV-1 may cause relapsing-remitting facial and brachial plexus neuritis. Despite questionable effects of antiviral treatment [28], the stereotype neurological symptoms confined to the same anatomical areas during each episode, with short latency of the HSV-1 reactivation, favor a local infectious neuropathy, but such a direct cause-effect remains to be proven.
Ethics The patient read the text and gave informed consent to publishing it.
Ethical approval Ethical approval was given by the patient safety deputy, reference number 12/2015.
Conflicts of interest The authors have nothing to disclose.
Acknowledgment This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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