1 SUBMITTED 22 NOV 22 1 REVISIONS REQ. 26 JAN & 5 MAR 23; REVISIONS RECD. 16 FEB & 19 MAR 23 2 ACCEPTED 21 MAR 23 3 ONLINE-FIRST: MARCH 2023 4 DOI: https://doi.org/10.18295/squmj.3.2023.020 5 6 Ramsay Hunt Syndrome Associated with Varicella-Zoster Virus Encephalitis 7 in a Child 8 Eman Y. Ahmed,1,2 Hatem Al Rawahi,2 Fatema Al Amrani,2 9 Laila Al Masaoudi,3 *Laila Al Yazidi2 10 11 1School Clinic, Ahlia School, Al Qurayya, Bahrain; Departments of 2Child Health and 3Surgery, 12 Sultan Qaboos University Hospital, Muscat, Oman 13 *Corresponding Author’s e-mail: lailay@squ.edu.om 14 15 Abstract 16 Ramsay Hunt Syndrome (RHS) is a triad of peri-auricular pain, ipsilateral facial nerve palsy and 17 vesicular rash around the ear pinna. It is caused by reactivation of varicella-zoster virus (VZV) 18 that lies dormant in the geniculate ganglia. It can be complicated by VZV encephalitis rarely. We 19 report the case of an 8-year-old previously healthy boy who presented to a tertiary care hospital 20 in Muscat, Oman in 2021 with fever, progressive left ear pain, vesicular rash around his ear 21 pinna and left-sided facial nerve palsy. His course was complicated by VZV encephalitis where 22 he was managed with IV acyclovir and IV corticosteroids. He improved significantly and was 23 asymptomatic with a normal neurology examination at the 6-months follow-up. 24 Keywords: Varicella Zoster Virus; Ramsay Hunt Syndrome; Encephalitis; Children. 25 26 Introduction 27 Ramsay Hunt syndrome (RHS), which is also known as geniculate neuralgia, is caused by 28 reactivation of varicella zoster virus (VZV) that lies dormant in the geniculate ganglion after the 29 primary infection with chickenpox.1-3 It was described for the first time by James Ramsay Hunt, 30 mailto:lailay@squ.edu.om 2 an American neurologist in 1907.3 It tends to be less frequent and less severe in children 31 compared to adults but there is limited data on how to manage pediatric RHS.4 It is responsible 32 for about 16.7% of cases of facial paralysis in children and it can be complicated rarely with 33 encephalitis.1,3,5 RHS has a low incidence in children with a rate of 2.7/100.000 in younger than 34 10 years of age, and is more common in children 6 to 15 years of age.3 35 36 Case Report 37 An 8-year-old previously healthy boy presented to the emergency department of a tertiary care 38 hospital in Muscat, Oman, in 2020 with a 3-day history of fever, progressive left ear pain and 39 swelling and vesicular rash around the left ear pinna. In addition, he had poor oral intake but no 40 seizure or behavioral changes. There was no history of a previous chicken pox, recent travel or 41 any sick contacts. No history of recurrent ear infections, ear trauma or swimming in a pool was 42 given. His immunization was up-to-date and he got the varicella vaccine at 12 months of age as 43 per Oman’s immunization schedule. 44 45 Upon initial examination, his left ear was swollen with redness extended to the pre-auricular and 46 postauricular area. He had vesicular lesions with red base on the outer ear canal, extending to the 47 left side maxillary dermatome, with yellowish discharge as well as tender enlarged left cervical 48 node (2 x 3 cm) Figure (1). His throat was clear and the examination of his right ear was 49 unremarkable. 50 51 Laboratory investigations showed normal full blood count, C-reactive protein, serum electrolytes 52 and random blood sugar. Based on the clinical findings, Ramsay Hunt syndrome diagnosis was 53 made and Acyclovir (450 mg orally every 6 hours) was started. Varicella zoster virus (VZV) 54 polymerase chain reaction (PCR) from the ear swab was reported positive while both bacterial 55 culture and Herpes simplex PCR were negative. The patient developed lower motor neuron facial 56 nerve palsy on day 2 of admission and later developed dizziness and he was noticed to be more 57 sleepy. On day 3 of admission, he developed vomiting, dysarthria and unsteady gait. No changes 58 in personality, seizures, meningeal signs or motor or sensory deficits were reported. At this stage, 59 Acyclovir was switched to intravenous formulation (15 mg/kg/dose 8 hourly) and prednisolone 1 60 mg/kg daily was added. He also underwent an urgent brain magnetic resonance imaging (MRI) 61 3 and magnetic resonance venography (MRV) and both were reported to be normal. Cerebrospinal 62 fluid was obtained and it showed 10 leukocytes (8 mononuclear cells and 2 polymorphonuclear 63 cells), and 2 red cells with normal protein and glucose. Bacterial culture was negative and VZV 64 PCR reported positive from the cerebrospinal fluid. In the following few days, his ear pain, 65 swelling, vomiting and the unsteady gait improved significantly and was asymptomatic on 66 discharge. He received 10 days of intravenous Acyclovir and 7 days of predinsolone of 67 1mg/kg/day. Eye care and physiotherapy was provided. He remained completely asymptomatic 68 and had a normal MRI with no evidence of cerebral arteritis vasculopathies on the 6 months 69 follow-up. Paternal consent was obtained for publication purposes. 70 71 72 Discussion 73 Ramsy hunt syndrome is uncommon in children. Our patient had a classic presentation on 74 admission. RHS is characterized by a triad of periauricular pain, ipsilateral peripheral facial 75 nerve palsy and erythematous vesicular rash around the ear pinna and outer ear canal or in the 76 oral mucosa.5 The clinical symptoms begin with otalgia which can last for 1 to 3 days.1,4,5 Facial 77 nerve palsy usually develops within 1–2 weeks after the rash appearance.3 RHS can affect both, 78 the facial and vestibulocochlear nerves.5 If the vestibulocochlear nerve gets affected, the patient 79 can develop nausea, vomiting, vertigo, tinnitus, and nystagmus.1,5 Hearing loss is reported in 80 24% of children with RHS.3 Our patient has normal hearing during his presentation and on 81 follow-up. 82 83 RHS is usually diagnosed clinically.3-5 Our patient presented with classic symptoms of RHS so 84 acyclovir was started from the beginning. Laboratory and imaging investigations are not 85 necessary to make the diagnosis most of the time and they do not affect the patient’s outcomes.5 86 Confirming diagnosis can be done using molecular testing from skin lesions and this can be 87 considered when the diagnosis of RSH is doubtful. The use of serum anti-VZV IgG and IgM 88 antibody titers is recommended for the routine laboratory diagnosis of pediatric patients with 89 acute peripheral facial paralysis.3,5 90 91 4 Childhood immunization with varicella vaccine can reduce the risk of getting RHS.4 Although 92 our patient had varicella vaccine at 12 months of age but he still developed RHS. He has no clear 93 history of chickenpox in the past, so RHS either resulted from a reactivation of subclinical 94 infection in the past or because of a vaccine-related strain. 95 96 RHS carry worse prognosis compared to Bell’s palsy in children.5 Advanced facial paralysis at 97 presentation, audiovestibular findings and delayed treatment are unfavorable prognostic factors.1 98 Early treatment with Acyclovir and high-dose corticosteroid therapy should be considered in all 99 patients with RHS.3 The combination of Acyclovir ( for 7 -10 days) and corticosteroid therapy 100 has been found to be more effective than treatment with Acyclovir alone.1,3,5 Acyclovir inhibits 101 viral replication and help with rapid healing of lesions and corticosteroids help with reducing 102 edema and pain by reducing the inflammation in peripheral neurons.3 Hato et al. and his 103 colleagues examined the recovery of facial nerve function after initiating treatment in the first 104 three days, at 3–7 days, or later than seven-days and found that the recovery was better when 105 Acyclovir was started within 3-days of presentation. The recovery rates were 75, 48, and 30%, 106 respectively.6 Full recovery from RHS-related facial paralysis has been reported to vary between 107 27 and 70% even with early treatment.5 Our patient improved significantly and he was 108 asymptomatic with normal neurology examination at the 6-months follow-up after using the 109 combination of Acyclovir and corticosteroids. 110 111 Our patient’s course was complicated by VZV encephalitis. He was sleepy, lethargic, and 112 complaining of headache and vomiting. His physical examination showed signs of cerebellar 113 involvement manifested as a wide-base gait with unsteadiness and dysarthria. Although some of 114 these symptoms can be explained by vestibular involvement, however, the headache, lethargy, 115 sleepiness, and wide base gait cannot be explained by vestibular involvement alone. The 116 constellation of these symptoms along with the isolation of VZV from cerebrospinal fluid 117 support the diagnosis of encephalitis. Although most of the reported patients with Ramsy Hunt 118 Syndrome associated with encephalitis, have abnormal MRI-brain, Ricigliano et al reported that 119 around 31% of patients with RHS-associated encephalitis have negative MRI-brain. Therefore, 120 normal MRI-brain in the context of RHS- associated varicella encephalitis does not exclude this 121 diagnosis.7 122 5 123 VZV can affect CNS disease through 3 mechanisms including acute VZV encephalitis, post-124 VZV cerebellitis and VZV vasculopathy.2,5 Development of VZV encephalitis following RHS is 125 extremely rare in an immunocompetent patient, which is the case in our patient.2,3,5,8 The 126 available literature report only 6 adults with RHS complicated by VZV encephalitis and 2 of 127 them are immunocompetent.8-10 We could not find any pediatric cases of RHS complicated by 128 VZV encephalitis. Hematogenous spread of VZV to the central nervous system or dissemination 129 through the cerebrospinal fluid pathway has been hypothesized which could be the case in our 130 patient.8 131 132 Acyclovir-induced encephalopathy should be considered in the differential diagnosis of our 133 patient encephalopathy. Furthermore, this adverse effect is more common in patients with renal 134 insufficiency, which is not the case in our patient.11 The main treatment of this entity is dialysis 135 along with cessation of acyclovir.11 Our patient showed improvement of his clinical symptoms 136 without any dosing adjustment, and he improved before the end of the acyclovir course. 137 Therefore, it is unlikely for his presentation to be secondary to acyclovir-induced 138 encephalopathy. 139 140 There is limited data on how to manage VZV encephalitis. The Association of British 141 Neurologists and British Paediatric Allergy, Immunology and Infection Group recommend 142 giving intravenous Acyclovir (500 mg/m2 if 3 months -12 years of age or 10 -15 mg/kg in > 12 143 years of age) for management of VZV encephalitis in children for total of 10 - 14 days.2 In 144 immunocompromised patients with VZV encephalitis, prolonged course of antivirals may be 145 required.2 If vasculopathy present, then it is recommended to use corticosteroids with or without 146 Acyclovir.2 The limitation of this report is that we could not prove that our patient has RHS-147 associated encephalitis because he has a normal MRI. The CSF pleocytosis can accompany 148 nerve inflammation. The mild clinical syndrome and the normal MRI may be secondary to early 149 initiation of antiviral therapy and corticosteroids in our patient. 150 151 Conclusion 152 Careful examination and early trial of treatment with antiviral therapy and corticosteroids should 153 6 be considered in children with RHS. VZV encephalitis, although uncommon, can complicate 154 RHS in children. 155 156 Authors’ Contribution 157 Dr Eman Ahmed wrote the first draft which was directly supervised by Dr Laila Al Yazidi. All 158 other co-authors helped with the literature review and the manuscript writing and revision. 159 160 References 161 1. Derin S, Derin H, Sahan M, Caksen H. A pediatric case of ramsay hunt syndrome. Case 162 Rep Otolaryngol. 2014;2014:469565. https://doi.org/10.1155/2014/469565 163 2. Kneen R, Michael BD, Menson E, Mehta B, Easton A, Hemingway C, et al. 164 Management of suspected viral encephalitis in children - Association of British 165 Neurologists and British Paediatric Allergy, Immunology and Infection Group national 166 guidelines. J Infect. 2012 May;64(5):449–77. https://doi.org/10.1016/j.jinf.2011.11.013 167 3. Aydoğdu İ, Ataç E, Saltürk Z, Atar Y, Özdemir E, Uyar Y, et al. Pediatric Ramsay Hunt 168 Syndrome: Analysis of Three Cases. Case Rep Otolaryngol. 2015;2015:1–4. 169 https://doi.org/10.1155/2015/971249 170 4. Masukume G, Chibwowa S, Ndlovu M. Full recovery of a 13-year-old boy with pediatric 171 Ramsay Hunt syndrome using a shorter course of aciclovir and steroid at lower doses: a 172 case report. J Med Case Reports. 2011;5:376. https://doi.org/10.1186/1752-1947-5-376 173 5. Çiçek M, Kılıç Z, Mercen Y, Karaoğlan E, Öztarhan K. A Rare Cause of Facial Paralysis 174 in Children: A Case of Ramsay Hunt Syndrome. J Pediatr Neurol. 2021;19(1):43–175 5.http://doi.org/10.1055/s-0040-1719052. 176 6. Hato N, Matsumoto S, Kisaki H, Takahashi H, Wakisaka H, Honda N, et al. Efficacy of 177 Early Treatment of Bell’s Palsy With Oral Acyclovir and Prednisolone: Otol Neurotol. 178 2003;24(6):948–51. 179 7. Ricigliano VAG, Saraceno L, Cavalli M, Rodegher M, Meola G. Slowly progressing 180 varicella zoster brainstem encephalitis complicating Ramsay Hunt syndrome in an 181 immunocompetent patient: case report and review of literature. J. Neurovirol. 182 2017;23(6):922-928. Doi: 10.1007/s13365-017-0575-3. 183 https://doi.org/10.1016/j.jinf.2011.11.013 https://doi.org/10.1155/2015/971249 http://www.thieme-connect.de/DOI/DOI?10.1055/s-0040-1719052 http://www.thieme-connect.de/DOI/DOI?10.1055/s-0040-1719052 http://www.thieme-connect.de/DOI/DOI?10.1055/s-0040-1719052 7 8. Chan TLH, Cartagena AM, Bombassaro AM, Hosseini-Moghaddam SM. Ramsay Hunt 184 Syndrome Associated with Central Nervous System Involvement in an Adult. Can J 185 Infect Dis Med Microbiol ;2016:1–4. https://doi.org/10.1155/2016/9859816 186 9. Elshereye A, Erdinc B, Sahni S. Disseminated Varicella-Zoster Virus Infection 187 Complicated by Encephalitis and Ramsay Hunt Syndrome in an HIV Patient. Cureus. 188 2020;12(7):e9235. https://doi.org/10.7759/cureus.9235 189 10. Shen YY, Dai TM, Liu HL, Wu W, Tu JL. Ramsay Hunt Syndrome Complicated by 190 Brainstem Encephalitis in Varicella-zoster Virus Infection. Chin Med J (Engl). 191 2015.;128(23):3258–9. https://doi.org/10.4103/0366-6999.170275 192 11. Sakamoto H, Hirano M, Nose K, Ueno S, Oki T, Sugimoto K, et al. A case of severe 193 ganciclovir-induced encephalopathy. Case Rep Neurol. 2013;5(3):183-6. doi: 194 10.1159/000355638. 195 196 197 Figure 1: Shows redness, swelling and crusting of the left ear associated with vesicular rash in 198 the maxillary dermatome. 199 https://doi.org/10.1155/2016/9859816 https://doi.org/10.1155/2016/9859816 https://doi.org/10.4103/0366-6999.170275