Michelle D. Sherwood, MD, Soren Gantt, MD, PhD, MPH, Mary Connolly, MD, FRCPC, Simon Dobson, MD, MBBS

Acute flaccid paralysis in a child infected with D68: A case report

A broad range of tests for viral, bacterial, and autoimmune causes was undertaken when a 9-year-old presented with -like symptoms.

ABSTRACT: Enterovirus D68 is in- nterovirus D68 (EV-D68) is horn cells of the spinal cord.7 AFP creasingly being reported as a cause increasingly being reported is nearly always asymmetric, affects of severe respiratory illness across as a cause of severe respira- proximal more than distal muscle E 1 North America, with several children tory illness across North America. groups, progresses over 2 to 3 days, in Canada testing positive for this Members of the Picornaviridae fam- and is associated with neck or back and experiencing concurrent ily, (EVs) are non- pain.7 There is reduced muscle tone polio-like symptoms. In one recent enveloped, single-stranded RNA vi- and weakness, but typically sensation case in British Columbia, a 9-year- ruses that have traditionally been is unaffected. EV-D68, which pri- old patient presented with acute classified as , coxsacki- marily causes respiratory infections, flaccid paralysis of his left arm fol- eviruses A, B, and is another serotype that may cause lowing a respiratory illness and fever. echoviruses E.2 Recently, human en- AFP.5,6,8 EV-D68 was first identified Enterovirus D68 was eventually iso- teroviruses have been subdivided into in in 1962 and appears to lated in a nasopharyngeal specimen four species—enterovirus A, B, C, be relatively uncommon.9 However, and the patient was treated with in- and D—of which there are more than travenous immunoglobulin. To date 100 serotypes.3 Dr Sherwood is a third-year Child and Fam- the patient has experienced only Transmission of EVs is by the ily Research Institute (CFRI) resident in pe- slight improvement in his left arm fecal-oral route, respiratory secre- diatrics at BC Children’s Hospital. Dr Gantt function. This case illustrates the tions, or close contact with infected is a senior associate clinician scientist with importance of appropriate screen- people.4 Peak EV transmission oc- the CFRI, and an associate professor in the ing for polio and nonpolio enterovi- curs in the summer and fall in temper- Division of Infectious and Immunological ruses. Clinicians faced with a case of ate climates.4 Nonpolio EV infections Diseases, Department of Pediatrics, Uni- acute flaccid paralysis should con- are largely asymptomatic, but can re- versity of British Columbia. Dr Connolly is tact their regional health authority sult in a range of diseases, including a clinical investigator with the CFRI, and a or the BC Centre for Disease Control respiratory illnesses and central ner- clinical professor and division head in the for early guidance on how to collect vous system infections.5 Specifically, Division of Neurology, Department of Pedi- specimens for testing. While there nonpolio EVs have increasingly been atrics, University of British Columbia. She is no established treatment protocol reported in association with acute flac- is also director of the Epilepsy Surgery Pro- for enterovirus D68 infection, we do cid paralysis (AFP) in immunocompe- gram at BC Children’s Hospital. Dr Dobson know that and avoid- tent North American children.5,6 is a clinical investigator with the CFRI, and ing close contact with ill people can Like , enterovirus A71 a clinical associate professor in the Division prevent transmission. (EV-A71) and others are known to of Infectious and Immunological Diseases, cause AFP, which results from inflam- Department of Pediatrics, University of mation and destruction of the anterior British Columbia.

bc medical journal vol. 56 no. 10, december 2014 bcmj.org 495 Acute flaccid paralysis in a child infected with enterovirus D68: A case report

because EV-D68 is not reportable in There was no history of contact with (117 × 106/L) and mild pleocytosis North America, the incidence of in- sick individuals, insect bites, recent (88 × 106/L; neutrophils 41% and fection may be underestimated.5 Dur- vaccination, toxin exposures, animal lymphocytes 44%), normal glucose, ing an outbreak of EV-D68-related exposures, trauma, rash, visual distur- and elevated protein (0.5 g/L). respiratory illness between 2008 and bance, dysphagia, or bowel or blad- Intravenous vancomycin, cefota­ 2010 in Asia, , and the United der dysfunction. Earlier in childhood xime, and acyclovir were started. An States,9 a previously healthy 5-year- he had received four doses of inacti- MRI of the spine revealed asymmet- old presented with a fatal case of fe- vated poliovirus vaccine according ric, fusiform swelling of the cervi- ver, , and AFP.10 In that to the schedule recommended in BC cal cord between the second cervical case, examination of the cerebrospi- and had not traveled outside of North vertebra (C2) and the upper border of nal fluid (CSF) revealed aseptic men- America, making poliovirus infection the first thoracic vertebra (T1), with ingitis, and EV-D68 was detected by unlikely. His family history was neg- left-sided predominance Figure 1 . PCR.10 A second case of EV-D68 as- ative for childhood cancer, immuno­ There was T2/FLAIR hyperintensity sociated with AFP was then identified deficiency, or vascular disease. in the C2 to T1 region Figure 2 . There through nationwide surveillance.11 Physical examination of the was no distal intraspinal abnormality Between 2012 and 2014, 23 cases patient revealed a temperature of noted, and the brain appeared normal, of AFP were identified in California 38.3°C with a heart rate of 131, a other than for a single subtle hyperin- with no definitive cause identified, al- respiratory rate of 12, oxygen satu- tense focus in the left posterior pons though respiratory specimens for two ration of 98%, and blood pressure of uncertain significance. of the children tested positive for EV- of 128 mm Hg over 82 mm Hg. He Nucleic acid testing of a nasopha- D68.5 In September 2014, EV-D68 appeared anxious but alert. While he ryngeal swab was positive for entero- was detected in the respiratory speci- had a full range of motion in his neck virus, which was subsequently typed as mens of several children with con- and back, and no evidence of menin- EV-D68 by sequencing . The specimen current AFP in Canada and the US.5,6 gmus, he did have tenderness along was negative for , influenza, While the full spectrum of EV-D68 the cervical vertebrae. The results of parainfluenza, respiratory syncytial vi- infections and any causal relationship a cranial nerve examination, includ- rus, human metapneumovirus, adeno- with AFP have not been fully estab- ing fundoscopy, were normal. He had virus, coronavirus, and mycoplasma. lished, the medical community needs normal right arm and bilateral leg CSF cultures were also negative and to be aware that acute flaccid paraly- strength. Other than slight left thumb all antimicrobials were discontinued sis can be associated with this entero- abduction, he had no strength (0/5) in after 48 hours. Serology results were virus infection, as illustrated by a case his left arm (deltoid, biceps, triceps, negative for herpes simplex virus of AFP in a child with EV-D68 infec- wrist, and intrinsic muscles). The (HSV) 1 and 2, syphilis, cytomegalo- tion in British Columbia. left arm was hypotonic and areflexic. virus (CMV), and Epstein-Barr virus Sensation was difficult to assess, but (EBV). Results were negative for My- Case data was judged to be grossly normal to all coplasma pneumoniae IgG antibodies, A previously healthy, fully immu- modalities. The patient was slightly but positive for M. pneumoniae IgM nized 9-year-old boy presented to unsteady during the tandem gait test. antibodies. PCR testing of CSF was BC Children’s Hospital with sudden- The results from the remainder of his negative for enterovirus, HSV, CMV, onset left arm weakness and inability physical examination were normal, EBV, and human herpes virus 6. There to move his left arm in the morning. with no significant respiratory, car- were no oligoclonal bands in the CSF He had an upper respiratory illness diovascular, or skin findings. and antibodies for neuromyelitis op- that had begun 5 days earlier with Results from a complete blood tica were negative. fever, cough, rhinorrhea, and post­ count were normal, with the excep- One day after admission, the child tussive emesis. He had had headaches tion of a slightly elevated neutrophil developed mild weakness in his right for 2 days accompanied by neck and count. Serum electrolytes, coagula- shoulder and neck flexors (–4/5). left shoulder pain. His history was sig- tion factors, liver enzymes, C-reac- Nerve conduction tests in the right nificant for travel to the south Atlan- tive protein, chest X-ray, and CT of arm and neck found no abnormalities, tic region of the US 1 month earlier. the head without contrast revealed in contrast to studies of the left arm, Family members had similar cold- no abnormalities. CSF examination which showed motor nerve conduc- like symptoms around the same time. showed red blood cells in the CSF tion was absent despite normal sen-

496 bc medical journal vol. 56 no. 10, december 2014 bcmj.org Acute fl accid paralysis in a child infected with enterovirus D68: A case report

sory nerve function. The child defer- symptom onset and before administra- vesced by day 2 of admission and his tion of IVIG.5 Specimens include two headaches decreased in intensity. He stool samples collected more than 24 received two courses of intravenous hours apart, CSF, acute-phase serum, immunoglobulin (IVIG) at 1 g/kg/d and nasopharyngeal and throat swabs. starting on day 3 of admission, which Unfortunately, EVs can be diffi cult to did not result in any improvement in isolate even when appropriate speci- motor function of the left arm. mens are obtained during acute illness. Unfortunately, to date the patient The differential diagnosis for has not recovered left arm motor acute fl accid paralysis in a child can function. This fi nding is similar to include both upper and lower motor other cases of polio-like illness that neuron pathologies, as both may pres- have shown poor to no recovery of ent acutely with fl accid paralysis.13 motor function despite aggress ive Upper motor neuron causes of AFP initial treatments with pulse steroids, include stroke, postictal paresis, and IVIG, plasma exchange, or all three.8 spinal cord pathologies related to trau- At the patient’s most recent follow-up ma, abscess, tumor/paraneoplastic appointment, 7 weeks after discharge, syndromes, or inflammatory pro- 13 there was slight improvement of the cesses such as transverse myelitis. Figure 1. MRI T2-weighted coronal view left arm function with grade 3 exten- Lower motor neuron causes include of patient’s spine showing asymmetric sion, but the left arm continued to be diseases that affect the anterior horn T2/FLAIR hyperintensity in cervical cord between C2 and T1, with left-sided hypotonic and arefl exic. Subtle right cells, peripheral nerve, neuromuscu- predominance. arm and neck weakness had resolved. lar junction, and muscle. Lower mo- tor neuron disorders that cause AFP Discussion include infections (bacterial or viral), Since the eradication of wild-type postinfectious autoimmune condi- poliovirus from most areas through tions (for example, Guillain Barré successful vaccination programs, syndrome), brachial plexus injury/ acute fl accid paralysis has become trauma, toxins (for example, botuli- rare.8 The last case of paralytic polio- num), and neoplasms.13 The potential myelitis in North America was in viral causes of motor neuron disease 1979.5 Currently, wild-type polio- include poliovirus, nonpolio EVs, virus is only endemic in Afghanistan, fl aviviruses (for example, West Nile Nigeria, and Pakistan, but there have virus, tick-borne encephalitis), HSV, been cases of transmission to other and rabies.3 Bacterial causes include countries that previously were polio- Borrelia burgdorferi, Corynebacte- free.12 Vaccine-associated AFP can rium diphtheriae, Clostridium botuli- Figure 2. MRI T2-weighted sagittal view 3 occur with the oral (live) poliovirus num, and Mycoplasma pneumoniae. of cervicothoracic region revealing T2/ vaccine, which has not been used in From the broad range of tests for FLAIR hyperintensity in the cervical cord North America since 2000.5 Around , bacteria, and autoimmune between C2 and T1. the world, AFP now occurs at a rate conditions done for our patient, the of approximately 1 case per 100000 only abnormalities found were CSF primarily affect white matter.14 To our children under age 15.8 pleocytosis, EV-D68 in the naso- knowledge, however, AFP is not a The US Centers for Disease Con- pharynx, and M. pneumoniae IgM recognized complication of M. pneu- trol and Prevention (CDC) recom- antibodies in the patient’s blood. M. moniae infection. Furthermore, M. mends testing for poliovirus in all pneumoniae infection is associated pneumoniae serology is not specifi c cases of AFP of unknown cause or with a number of uncommon central for acute infection,15 and the PCR suspected viral origin.5 For highest nervous system manifestations, such assay of the nasopharyngeal specimen yield, CDC guidelines recommend as transverse myelitis and acute dis- was negative for mycoplasma. We collecting specimens within 14 days of seminated encephalomyelitis, that therefore conclude that it is unlikely

bc medical journal vol. 56 no. 10, december 2014 bcmj.org 497 Acute flaccid paralysis in a child infected with enterovirus D68: A case report

our patient’s syndrome was attribut- Summary myelitis—California, June 2012-June able to M. pneumoniae infection. A recent case in British Columbia 2014. MMWR Morb Mortal Wkly Rep It is not possible to prove that illustrates the importance of appro- 2014;63:903-906. EV-D68 was the cause of acute flaccid priate screening for polio and non- 6. Pastula DM, Aliabadi N, Haynes AK, et al. paralysis in this case. Although detec- polio enteroviruses. When a patient Acute neurologic illness of unknown etiol- tion of an enterovirus in the cerebro- presented recently with acute flaccid ogy in children—Colorado, August- spinal fluid of a patient with AFP is paralysis of his left arm following a September 2014. MMWR Morb Mortal definitive, PCR results are typically respiratory illness and fever, clini- Wkly Rep 2014;63:901-902. negative even in acute poliomyelitis.8 cians conducted a physical examina- 7. Solomon T, Lewthwaite P, Perera D, et al. Our patient’s gender, age, and pre- tion and collected samples for various Virology, epidemiology, pathogenesis, sentation resembled those of 23 AFP laboratory investigations. Enterovi- and control of . Lancet In- cases in California (June 2102 to June rus D68 was eventually identified in fect Dis 2010;10:778-790. 2014), where males with a median a nasopharyngeal specimen and the 8. Rukovets O. News from the AAN annual age of 10 years were more frequent- patient was treated with intravenous meeting. Unexplained polio-like illness in ly affected, and the patients had an immunoglobulin. Clinicians should California: What neurologists should upper respiratory illness less than 10 be aware of the association between know. Neurology Today 2014;14:58-59. days prior to onset of AFP and there enterovirus infection and acute flac- 9. Centers for Disease Control and Preven- was CSF pleocytosis and an absence cid paralysis, and should contact their tion. Clusters of acute respiratory illness of sensory findings.5 Similarly, there regional health authority or the BC associated with human enterovirus 68— have been nine recent cases of AFP in Centre for Disease Control for early Asia, Europe, and United States, 2008- Colorado presenting 3 to 16 days fol- guidance on collecting specimens for 2010. MMWR Morb Mortal Wkly Rep lowing the onset of a febrile respira- testing. 2011;60:1301-1304. tory illness.6 Four of the patients were 10. Kreuter JD, Barnes A, Mccarthy JE, et al. found to have EV-D68 in their naso- Competing interests A fatal central nervous system enterovirus pharyngeal specimens. None declared. 68 infection Arch Pathol Lab Med The lesson from this case for cli- 2011;135:793-796. nicians is that patients with AFP of References 11. CDC Khetsuriani N, Lamonte-Fowlkes A, uncertain cause must be screened 1. Owens B. Rare enterovirus continues to Oberst S, et al.; Centers for Disease Con- appropriately for polio and nonpolio circulate in North America. Lancet trol and Prevention. Enterovirus sur- enteroviruses. In particular, EV test- 2014;384(9950):1250. Accessed 2 No- veilance—United States, 1970-2005. ing should be considered when there vember 2014. http://dx.doi.org/10.1016/ MMWR Surveill Summ 2006;55:1-20. is inflammation of the spinal cord that S0140-6736(14)61753-0. 12. Moturi EK, Porter KA, Wassilak SGF, et mostly involves gray matter, and there 2. Pallansch M, Roos R. Enteroviruses: Po- al. Progress toward polio eradication— are polio-like symptoms (weakness lioviruses, coxsackieviruses, echoviruses, worldwide, 2013-2014. MMWR Morb with lack of sensory involvement). and newer enteroviruses. In: Fields virol- Mortal Wkly Rep 2014;63:468-472. Most importantly, clinicians should ogy. 5th ed. Knipe D, Griffin D, Lamb R, et 13. Tsarouhas N, Decker JM. Weakness. In: remember that association does not al. (eds). Philadelphia: Lippincott Williams Textbook of pediatric emergency medi- prove causation, and thus more data & Wilkins; 2008. cine. 6th ed. Fleisher GR, Ludwig S (eds). are needed to confirm the relationship 3. Laxmivandana R, Yergolkar P, Gopalkrish- Philadelphia: Lippincott Williams & between EV-D68 and the neurologi- na V, et al. Characterization of the non- Wilkins; 2010. cal symptoms seen in some cases. The polio enterovirus infections associated 14. Narita M. Pathogenesis of neurologic regional health authority and the BC with acute flaccid paralysis in South- manifestations of Mycoplasma pneu- Centre for Disease Control should Western India. PLoS One 2013;8:e61650. moniae infection. Pediatr Neurol 2009; be contacted early for guidance on 4. Non-Polio Enterovirus Infection: Enterovi- 41:159-166. collecting specimens when patients rus D68-Centers for Disease Control and 15. Spuesens EB, Fraaij PL, Visser EG, et al. present with possible enterovirus Prevention. Enterovirus D68. Accessed Carriage of Mycoplasma pneumoniae in infection. As yet there is no estab- 3 November 2014. www.cdc.gov/non the upper respiratory tract of symptom- lished treatment protocol. Preventive -polio-enterovirus/about/ev-d68.html. atic and asymptomatic children: An ob- measures include hand washing and 5. Ayscue P, Haren K Van, Sheriff H, et al. servational study. PLoS Med 2013; avoiding contact with ill people. Acute flaccid paralysis with anterior 10:e1001444.

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