ORIGINAL Studies
Clinical Analysis of 134 Children with Nervous System Damage Caused by Enterovirus 71 Infection Yue Hu, MD, PhD,*†‡§ Li Jiang, MD, PhD,*†‡§ and Hai-lun Peng, MBBS*†‡§ Objective: The purpose of this study was to evaluate the clinical characteristics of nervous system damage caused by enterovirus 71 (EV71) infection in pediatric patients. Study Design: Clinical data and outcomes were retrospectively analyzed for 134 cases of laboratory confirmed pediatric EV71 infection admitted to the Children’s Hospital of Chongqing Medical University from January to December 2013. Results: EV71 infection was significantly more common in patients 1–4 years of age, in males and during the months of April–July. Fifty-six cases complicated by hand, foot and mouth disease were diagnosed. Fever was the most common symptom (128 of 134 patients) and lasted on average 5.3 ± 2.1 days. The most common neurologic complication was aseptic meningitis (n = 74), followed by brain stem encephalitis (n = 24), acute flaccid paralysis (AFP; n = 20), acute parencephalitis (n = 12) and encephalomyelitis (n = 4). Each was characterized by a unique profile of clinical symptoms. Damage to the pons and medulla oblongata was apparent in 28 brain magnetic resonance images. Lesions associated with AFP were concentrated in the cervical spinal cord and thoracic 8. The anterior root of the spinal anterior horn was a specific lesion. Fourteen of the AFP patients had unilateral or bilateral femoral nerve involvement. None of the patients died, and in 132 of 134 patients, follow-up visits showed that their physical and neuropsychologic abilities had returned to normal. Conclusions: Most children infected with EV71 have a good prognosis if they are diagnosed early and receive proper supportive treatment. Key Words: Enterovirus 71, nervous system damage, brain stem encephalitis, acute flaccid paralysis, aseptic meningitis (Pediatr Infect Dis J 2015;34:718–723)
E
nterovirus 71 (EV71) and poliovirus belong to the RNA enterovirus family. EV71 is one of the important pathogens that cause hand, foot and mouth disease (HFMD).1,2 The majority of HFMD cases are benign, and patient prognosis is good. However, EV71 is neurotropic and can spread through the nervous system from the blood, or the virus can enter a peripheral nerve and be carried to the central nervous system (CNS) by axonal transport.3,4 This causes a severe immune response in the nervous system resulting in neurologic diseases, such as aseptic meningoencephalitis, brainstem encephalitis, parencephalitis, encephalomyelitis and acute flaccid paralysis (AFP). In the few brainstem encephalitis patients, the disAccepted for publication December 30, 2014. From the*Department of Neurology, Children’s Hospital Affiliated to Chongqing University of Medical Sciences, Chongqing, China; †Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; ‡Key Laboratory of Pediatrics in Chongqing, CSTC2009CA5002, Chongqing, China; and §Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Li Jiang, MD, PhD, Department of Neurology, Children’s Hospital of Chongqing Medical University, No.136 Zhongshan 2nd Road, Yu Zhong District, Chongqing 400014, China. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3407-0718 DOI: 10.1097/INF.0000000000000711
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ease progresses rapidly, and other severe complications occur, such as pulmonary edema, pulmonary bleeding and circulatory failure. Thus, the consequences of an EV71 infection are generally more serious than seen with other enteroviruses.5,6 The neurotoxicity of EV71 was recognized when 44 patients with EV71 infections died of a polio-like illness in Bulgaria in 1975. Soon after, EV71-associated neurotoxicity events were reported in New York, Malaysia and Taiwan.7–10 The clinical differences between different types of neurologic damage were not thoroughly addressed in previous studies. In this study, the clinical data and outcomes were analyzed retrospectively for 134 pediatric patients with neurologic damage caused by EV71 infection to provide the basis for diagnosing and treating nervous system infection caused by EV71.
MATERIALS AND METHODS Patient Enrollment and Diagnosis A retrospective analysis of the clinical features, auxiliary examination, treatment and prognosis was performed in 134 pediatric patients with nervous system damage caused by EV71 infection. Patients were admitted to the Children’s Hospital affiliated with Chongqing University of Medical Sciences from January to December 2013. This study was approved by the Ethics Committee for the Children’s Hospital affiliated with Chongqing University of Medical Sciences. Informed consent was obtained from the subjects or their legal guardians via signed consent forms. EV71 diagnosis was confirmed by EV71 antibodies in the cerebrospinal fluid (CSF) and blood and EV71 nucleic acids in stool testing. HFMD was diagnosed using the Guidelines for Diagnosis and Treatment of HFMD (version 2011).11 Aseptic meningitis, brainstem encephalitis, parencephalitis and AFP were diagnosed based on clinical manifestations and laboratory examinations.12,13 The clinical diagnostic criteria for aseptic meningitis include symptoms such as fever, headache, vomiting, possible convulsions, disturbance of consciousness, possible positive meningeal stimulation, possible pathological reflex and changes to the CSF, such as increased CSF pressure, CSF white blood cell (WBC) counts exceeding 15 × 106/L in patients more than 1-month old and germiculture negative. Brain stem encephalitis is a localized diagnosis, which is confirmed in the brain stem with magnetic resonance imaging (MRI). Cerebellitis symptoms may include difficulty balancing while sitting or walking, astasia, inaccurate performance in finger-to-nose test or fetch, lalopathy, nystagmus and tremor. The clinical diagnostic criteria of AFP are acute onset of degenerated muscle strength, hypomyotonia and weak or absent tendon reflex in one or more limb. All the patients received a lumbar puncture, head and/or spinal cord MRI or nerve conduction.
Treatment Treatment was provided according to the Guidelines for Diagnosis and Treatment of HFMD (version 2011).9 Twentyfour patients (17.9%) were given an intravenous human gamma globulin (IVIG) infusion at a dose of 2 g/kg for 2 or 5 days. Fifty patients (37.3%) were given glucocorticoid therapy. Of those patients, 10 received low-dose dexamethasone (0.3–0.5 mg/kg/d)
The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
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The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
TABLE 1. Age Distribution of Pediatric Patients with Nervous System EV71 Infections Age (years)
n
Constituent Ratio (%)
5
10 64 26 24 6 4
7.5 47.7 19.4 17.9 4.5 3.0
Statistical Analysis Statistical analysis was performed with SPSS version 16.0 software. The data are presented as the mean ± SEM and the median values and range. The data distribution was analyzed using the χ2 test or binomial test. Differences were considered statistically significant when P 40
6 10 42 68 4
Constituent Ratio (%) 4.5 7.5 31.3 50.7 6.0
intravenously for 3–5 days and were then switched to oral prednisone for 2 weeks. The other 40 patients on glucocorticoids received a methylprednisolone infusion. Of these, 26 patients received methylprednisolone (1–2 mg/kg/d) for 3–5 days intravenously and then switched to take prednisone orally for 2 weeks. The remaining 14 patients had brain stem involvement or serious limb paralysis complicated with cerebrospinal meningitis. They received high-dose dexamethasone (15–20 mg/kg/d) intravenously for 3–5 days and then switched to oral prednisone for 1–3 months and received IVIG. Other treatments included protecting vital organs, reducing intracranial pressure, maintaining homeostasis, supplementing with B vitamins, nourishing nerves and other symptomatic or supportive treatment. Five patients required transfer to the intensive care unit for treatment within 3 days of progressive development of the disease. Four of the five patients required ventilator-assisted breathing. There were 2 patients who experienced frequent convulsions and were given oral sodium valproate for short-term prevention for 2–3 months. Once signs of life were steady and the disease was controlled, the patients were transferred into the rehabilitation department for early rehabilitation training. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Fever was observed in 128 of 134 (95.5%) of pediatric EV71 patients. The fever lasted an average of 5.3 ± 2.1 days (range: 2–15 days), and the median body temperature was 39.3°C. The severity of the fever varied significantly between patients (χ2 = 121.538, P 100 × 109/L, which were mainly mononuclear cells. Eight patients had slightly elevated CSF protein levels and normal levels of glucose and chlorides. There were 30 patients with an abnormal brain MRI. Brain damage was present in 28 of 30 patients and was most evident in the pons and medulla oblongata. Of the 28 patients where brain damage was evident, 20 had lesions in the posterior portion of the medulla oblongata and pons, 4 had cerebellar damage, 4 had cerebellum and spinal cord injury and 2 had abnormal signals in the double frontal and parietal cortex. In the patients with AFP, 19 of 20 patients had abnormal spinal cord MRI results from either a spinal sagittal MRI showing a diverse range of strip using a long T1 and long T2 signals or an identical T1 and long T2 signals intramedullary from cervical to cone. Most of the lesions were in the cervical cord and thoracic 8-cone grade. The horizontal axis displayed bilateral or unilateral lesions to the anterior horn of the spinal cord using either the long T1 and long T2 signals or an identical T1 and long T2 signals. Five cases involved the cervical spinal cord, 8 cases involved the thoracic-lumbar spinal cord and 6 cases involved the lumbosacral region, cone and horsetail. The enhanced spinal MRI scan showed that the ventricornu or nerve root enhanced abnormally in 8 cases. An initial electrophysiological examination to assess nerve conduction was performed an average of 4.6 days (range: 3–7 days) after the onset of paralysis. The initial electromyography (EMG) detection was performed in 2–8 weeks after the onset. The unilateral or bilateral femoral nerve(s) was(were) involved in 14 of the patients (93.3%) with single paralysis or paraplegia. The primary symptoms of an abnormal femoral nerve included significantly reduced or absent compound muscle action potential amplitude and in some cases, a prolonged latency period. Only 2 patients had
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Headache and Vomiting
0 2 (50.0)
confirmed tibial/peroneal nerve damage in both legs tested, and 1 patient had confirmed nerve damage (median/ulnar nerve) in both upper limbs. In the EMG test, 61 muscle parts were tested, of these 32 (52.5%) were found to be abnormal. The observed abnormalities were increased insertion potential (n = 19, 59.4%), spontaneous potentials at the resting state (n = 10, 31.3%), increased duration of motor unit potentials under light contraction (n = 27, 84.4%), increased amplitude under light contraction (n = 24, 75%), reduced recruitment under heavy contraction (n = 11, 34.4%) and a lack of motor unit under heavy contraction (n = 10, 31.3%).
Outcomes The median hospitalization time was 10 days (range: 4–22 days). There were no deaths. Two patients who had experienced frequent convulsions were successfully treated and followed for 3–6 months, and no further convulsion seizures occurred. Two patients with eyeball movement disorder were completely recovered 2 months after the end of therapy. All 28 ataxia patients recovered within 1–3 months. Twelve patients were able to recover while they were hospitalized (8–14 days), and the remaining 16 patients recovered after discharge. Finally, 2–6 months after discharge from hospital, all the patients, except 1 with brainstem encephalitis and 1 with encephalomyelitis, showed comparable neuropsychological development to children of the same age (Wechsler intelligence test or Gesell Developmental Diagnostic Scale). There were a total of 24 children with AFP (including brainstem and spinal cord involvement). The muscle strength of the affected limb began to recover a median of 10 days (range: 3–14 days) after the onset of paralysis. The muscle strength recovered at 28 days and 6 months after paralysis is summarized in Table 4. Although all the patients showed improved muscle strength, only 4 patients with grades III and IV monoplegia had fully recovered to grade V at 28 days. Within 2–3 months, 17 of 24 patients had fully recovered their muscle strength in the affected limb to grade V. By 6 months, all the patients were able to walk. Two patients, 1 with single lower limb paralysis and 1 with quadriplegia had some residual weakness and were lame. In addition, the proximal muscle strength for 1 patient with single upper limb paralysis remained grade IV (Table 4). However, the uninvolved limbs for the patient with single upper limb paralysis could move freely. The affected joints recovered starting distally (finger and toe joints) and gradually moved proximally up the limb (eg, ankle and wrist to knees and elbows). Finally, proximal muscle strength and muscle tone recovered. Tendon reflexes, and muscle tone recovered along with muscle strength.
DISCUSSION The characteristics of EV71 infections in our study were largely consistent with work from previous scholars.14–16 The highest frequency of CNS infections because of EV71 was observed in © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
Positive Neck Obstruction
Ataxia
Positive Pyramidal Tract
Tachycardia >140 beats/min
Excessive Sweating, Pale Face, Cold Extremities
22 (29.7)
0
13 (17.6)
8 (10.8)
6 (8.1)
4 (16.7)
15 (62.5)
2 (8.3)
11 (45.8)
8 (33.3)
3 (15.0)
0
0
1 (5.0)
0
1 (8.3) 3 (75.0)
0 2 (50.0)
0 1 (25.0)
12 (100.0) 1 (25.0)
0 1 (25.0)
children 1–4 years of age; there was a higher incidence in males and a strong seasonal distribution peaking in July. Interestingly, only 11.9% of the patients with EV71-associated neurologic disease presented with the typical HFMD rash. This suggests that EV71 should be routinely considered when there is reason to suspect a nervous system infection. Given the complex clinical presentation of neurologic complications associated with EV71 infection, our aim was to establish a clinical profile to aid in diagnosing and treating affected patients.
Aseptic Meningitis Aseptic meningitis was the primary nervous system lesion caused by EV71 infection in our study and in previous outbreaks worldwide.7,8,17–19 The primary clinical manifestations of aseptic meningitis were fever, startle, headache, vomiting and convulsive seizures soon after infection. A few patients appeared to have mild brain parenchyma involvement, manifested as irritability, drowsiness or lethargy, but there were generally no serious symptoms of brain parenchymal damage, such as paralysis, coma or status epilepticus. Laboratory tests suggested that aseptic meningitis was similar to viral meningitis, both presenting slight increases in the number of cells and proteins in CSF. Patients in our study frequently recovered within 1–2 weeks with no significant neurologic sequelae, which is in contrast to the previous report from Chang et al.20 Previous studies have shown that EV71 infection with CNS involvement was associated with long-term neurologic sequelae, delayed neurodevelopment and reduced cognitive function. The reason for this discrepancy was unclear; however, one possibility is that different subgroup(s) of EV71 caused the epidemic in Chongqing.
Brainstem Encephalitis Brainstem encephalitis is the most serious neurologic complication of EV71 infection. It usually manifests as extensions of spinal cord lesions and most often involves the medullary oblongatum, reticular formation, pons and midbrain structures.21–23 Consistent with these observations, the primary brain regions affected in our study were the pons and medulla oblongata. Clinical symptoms including vomiting, tachycardia, hypertension and dysphagia are important symptoms of brainstem
Pediatric EV71 Neurologic Complications
Increase or Decrease in Blood Pressure 0 6 (25.0) 0 0 2 (50.0)
Difficulty in Breathing
VentilatorAssisted Breathing
0
0
8 (33.3) 0
2 (8.3) 0
0 2 (50.0)
0 2 (50.0)
dysfunction.23,24 In our study, the primary symptoms were fever, myoclonic seizures, ataxia and apparent vegetative nerve dysfunction. Rare cases showed abducent nerve involvement. The occurrence of myoclonic jerking during deep sleep and wakefulness periods, rather than normal sleep myoclonus, suggested that brainstem encephalitis could be characterized by brief involvement of pontine tegmentum. Severe brainstem encephalitis is characterized by rapid progression and high mortality attributable to acute pulmonary edema or pulmonary hemorrhage. Descriptions of neurogenic EV71associated pulmonary edema have primarily come from the Asia Pacific region.24–27 Our study was not designed to address EV71associated death because of neurogenic pulmonary edema. The inclusion criteria required pediatric patients with detectable EV71 antibodies in CSF and blood or detectable EV71 nucleic acids in the stool. Patients who died from neurogenic pulmonary edema were excluded because they did not undergo CSF testing given the rapid progression of disease.
Acute Flaccid Paralysis EV71 is the most common non-polio enterovirus leading to AFP and shares many pathogenic features with polio. It has been suggested that EV71 causes paralysis by infecting or injuring motor neurons in the anterior horn of the spinal cord and possibly through immune dysfunction and other mechanisms.28,29 AFP has been reported in several outbreaks worldwide.9,30,31 In our study, most AFP cases involved only a single limb. Interestingly, all the AFP patients who developed quadriplegia had multiple brain regions involved, including the brainstem and cerebellum, and the major clinical process was encephalomyelitis. Compared with a polio virus infection, the clinical symptoms for EV71-associated AFP were relatively mild. Consistent with previous work,32 most patients were able to fully recover, and only 15% of patients had permanent neurologic sequelae such as limb paralysis. Our study indicated that the MRI results were highly correlated to the clinical manifestations. Lesions in the anterior horn or ventral root at different segments of the spinal cord often lead to impairment in the corresponding motor function of pediatric
TABLE 4. Muscle Strength in Pediatric Patients with EV71-Associated Acute Flaccid Paralysis After Infection Paralyzed Parts
Muscle Strength
28 Days
4 cases of monoplegia 7 cases of monoplegia 5 cases of monoplegia 2 cases of paraplegia 2 cases of paraplegia 2 cases of quadriplegia 2 cases of quadriplegia
Grades III and IV Grades II and III Grades 0 and I Grades II and III Grades I and II Grades II and III Grades I and II
Grade V Grade IV Grades II and III Grade IV Grades II and III Grade IV Grades II and III
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6 Months Grade V Grade V 3 cases of grade IV Grade V Grade V Grade V 1 case of the right leg claudication
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Hu et al
patients. Abnormal femoral nerve conduction was documented in 93.3% of the patients with EV71 infection-associated AFP, with lesser injuries to the tibial and fibular nerves. These results confirmed that EV71 selectively causes damage to the lumbar and cervical enlargements, especially lumbar, resulting in an early and heavy paralysis in the proximal major muscle group but with little effect on the sacrum. Spontaneous muscle potentials (fibrillation potentials and positive potentials) detected by EMG often occur 10 days after the peripheral nerve injury, and the recruitment potential can have varying degrees of decrease. It is possible we did not detect denervation potentials in some patients because of the shorter timeframe.33 Whether these findings can aid the early and differential diagnosis of AFP associated with EV71 infection requires further verification.
Cerebellar Ataxia EV71 infection can cause acute cerebellar ataxia whose typical symptom includes trunk ataxia with or without nystagmus,28 which generally recovers. Our study confirmed that acute cerebellar ataxia occurs in both brainstem encephalitis and simple acute parencephalitis. The main symptoms for the children with parencephalitis included fever, ataxia, headache and/or vomiting and obvious vegetative nerve dysfunction. However, there was no neck obstruction or pyramidal signs. All patients had a good prognosis.
Treatment We actively gave severe cases mannitol to lower the intracranial pressure and used glucocorticoids (37.3%), IVIG (17.9%) and other treatment methods as recommended. IVIG not only neutralizes the virus and prevents further spread but may also regulate the inflammatory reaction at the cytokine level and help prevent immunopathogenesis.34,35 Glucocorticoids can reduce alveolar surface tension, promote absorption of pulmonary edema and alleviate cerebral edema.36 It remains controversial whether pulse therapy using high-dose glucocorticoids improves the prognosis of HFMD complicated with nervous system damage,36,37 and it therefore, should be used with caution. In summary, given the lack of effective antiviral drugs, only by fully understanding the characteristics of this disease, close observation, early identification of nervous system involvement and the implementation of effective management, the mortality and disability rate can be reduced.
CONCLUSIONS The most common neurologic complication of EV71 infection was aseptic meningitis, followed by brain stem encephalitis, AFP, acute parencephalitis and encephalomyelitis. Each complication manifested a unique profile of clinical symptoms. The majority of children infected with EV71 have a good prognosis if they are diagnosed early and receive proper treatment. REFERENCES 1. Chan LG, Parashar UD, Lye MS, et al. Deaths of children during an outbreak of hand, foot, and mouth disease in Sarawak, Malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group. Clin Infect Dis. 2000;31:678–683. 2. Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929–935. 3. Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti Infect Ther. 2009;7:735–742. 4. Chen YC, Yu CK, Wang YF, et al. A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol. 2004;85: 69–77.
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5. Wang SM, Liu CC. Update of enterovirus 71 infection: epidemiology, pathogenesis and vaccine. Expert Rev Anti Infect Ther. 2014;12:447–456. 6. Lin JY, Shih SR. Cell and tissue tropism of enterovirus 71 and other enteroviruses infections. Eur J Paediatr Neurol.2013;17:486–491. 7. Shindarov LM, Chumakov MP, Voroshilova MK, et al. Epidemiological, clinical, and pathomorphological characteristics of epidemic poliomyelitislike disease caused by enterovirus 71. J Hyg Epidemiol Microbiol Immunol. 1979;23:284–295. 8. Ishimaru Y, Nakano S, Yamaoka K, et al. Outbreaks of hand, foot, and mouth disease by enterovirus 71. High incidence of complication disorders of central nervous system. Arch Dis Child. 1980;55:583–588. 9. Liu CC, Tseng HW, Wang SM, et al. An outbreak of enterovirus 71 infection in Taiwan, 1998: epidemiologic and clinical manifestations. J Clin Virol. 2000;17:23–30. 10. Qiu J. Enterovirus 71 infection: a new threat to global public health? Lancet Neurol. 2008;7:868–869. 11. Clinical HFMD Expert Group of Ministry of Health. Experts consensus for clinical treatment of enterovirus 71 (EV71) infection in severe cases (2011 edition). Chin J Pediatr. 2011; 49:675–678. 12. Tunkel AR, Glaser CA, Bloch KC, et al; Infectious Diseases Society of America. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47: 303–327. 13. Wu X, Lin Q. Pediatric Nervous System Diseases Basic and Clinical Aspects. 2nd ed. Beijing: People’s Medical Publishing House;2009: 494–495. 14. Chen SC, Chang HL, Yan TR, et al. An eight-year study of epidemiologic features of enterovirus 71 infection in Taiwan. Am J Trop Med Hyg. 2007;77:188–191. 15. Zhang Z, Li M, Liu ZF, et al. Clinical epidemiological characteristics of 194 cases with severe hand-foot-mouth disease in Nanjing China. Jiangsu Med J. 2012;28:450–452. 16. Cai J, Lin JF, Lü HK, et al. [Retrospective analysis of clinical and epidemiological characteristics of hand-foot-and-mouth disease deceased cases in Zhejiang Province]. Zhonghua Er Ke Za Zhi. 2013;51:265–269. 17. Hagiwara A, Tagaya I, Yoneyama T. Epidemic of hand, foot and mouth disease associated with enterovirus 71 infection. Intervirology. 1978;9:60–63. 18. Nagy G, Takátsy S, Kukán E, et al. Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Arch Virol. 1982;71:217–227. 19. Koroleva GA, Lukashev AN, Khudiakova LV, et al. Encephalomyelitis caused by enterovirus type 71 in children. J Microbiol Immunol Infect. 2000;33:1–8. 20. Chang LY, Huang LM, Gau SS, et al. Neurodevelopment and cognition in children after enterovirus 71 infection. N Engl J Med. 2007;356:1226–1234. 21. Chen F, Li J, Liu T, et al. MRI characteristics of brainstem encephalitis in hand-foot-mouth disease induced by enterovirus type 71—will different MRI manifestations be helpful for prognosis? Eur J Paediatr Neurol. 2013;17:486–491. 22. Zeng H, Wen F, Gan Y, et al. MRI and associated clinical characteristics of EV71-induced brainstem encephalitis in children with hand-foot-mouth disease. Expert Rev Anti Infect Ther. 2009;7:735–42. 23. Jiang M, Wei D, Ou WL, et al. Autopsy findings in children with hand, foot, and mouth disease. N Engl J Med. 2012;367:91–92. 24. Chang LY, Lin TY, Hsu KH, et al. Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease. Lancet. 1999;354:1682–1686. 25. Hao B, Gao D, Tang DW, et al. [Distribution of human enterovirus 71 in brainstem of infants with brain stem encephalitis and infection mechanism]. Fa Yi Xue Za Zhi. 2012;28:85–88, 91. 26. Liu JT, Peng D, Guan XH, et al. Clinical characteristics and treatment assessments of severe enterovirus 71 infected children. Vopr Virusol. 2010;55:4–10. 27. Zhang Y, Zhu Z, Yang W, et al. An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of hand foot and mouth disease in Fuyang city of China. Virol J. 2010;7:94. 28. McMinn PC. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev. 2002;26:91–107. 29. Chen F, Li JJ, Liu T, et al. Clinical and neuroimaging features of enterovirus71 related acute flaccid paralysis in patients with hand-foot-mouth disease. Asian Pac J Trop Med. 2013;6:68–72.
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30. Hayward JC, Gillespie SM, Kaplan KM, et al. Outbreak of poliomyelitis-like paralysis associated with enterovirus 71. Pediatr Infect Dis J. 1989;8:611–616. 31. Performance of acute flaccid paralysis (AFP) surveillance and incidence of poliomyelitis 2012. Wkly Epidemiol Rec. 2013;88:167–172. 32. Ding H, Huang LM, Ge Q. Analysis of non-polio enterovirus infection among acute flaccid paralysis cases in Hangzhou city, 2001–2008. Chin Prevent Med. 2010;11:172–174. 33. Oh SJ. Clinical Electmmyography: Nerve Conduction Studies. Baltimore: University Park Press; 1984. 34. Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti Infect Ther. 2009;7:735–742.
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Pediatric EV71 Neurologic Complications
35. Zhang Q, MacDonald NE, Smith JC, et al. Severe enterovirus type 71 nervous system infections in children in the Shanghai region of China: clinical manifestations and implications for prevention and care. Pediatr Infect Dis J. 2014;33:482–487. 36. Wu J, Cheng YB, Li ZF, et al. [Evaluation of adrenocortical function in children with severe and critical enterovirus 71 infection]. Zhonghua Er Ke Za Zhi. 2012;50:249–254. 37. Ma H, He F, Wan J, et al. Glucocorticoid and pyrazolone treatment of acute fever is a risk factor for critical and life-threatening human enterovirus 71 infection during an outbreak in China, 2008. Pediatr Infect Dis J. 2010;29:524–529.
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Clinical Analysis of 134 Children with Nervous System Damage Caused by Enterovirus 71 Infection Yue Hu, MD, PhD,*†‡§ Li Jiang, MD, PhD,*†‡§ and Hai-lun Peng, MBBS*†‡§ Objective: The purpose of this study was to evaluate the clinical characteristics of nervous system damage caused by enterovirus 71 (EV71) infection in pediatric patients. Study Design: Clinical data and outcomes were retrospectively analyzed for 134 cases of laboratory confirmed pediatric EV71 infection admitted to the Children’s Hospital of Chongqing Medical University from January to December 2013. Results: EV71 infection was significantly more common in patients 1–4 years of age, in males and during the months of April–July. Fifty-six cases complicated by hand, foot and mouth disease were diagnosed. Fever was the most common symptom (128 of 134 patients) and lasted on average 5.3 ± 2.1 days. The most common neurologic complication was aseptic meningitis (n = 74), followed by brain stem encephalitis (n = 24), acute flaccid paralysis (AFP; n = 20), acute parencephalitis (n = 12) and encephalomyelitis (n = 4). Each was characterized by a unique profile of clinical symptoms. Damage to the pons and medulla oblongata was apparent in 28 brain magnetic resonance images. Lesions associated with AFP were concentrated in the cervical spinal cord and thoracic 8. The anterior root of the spinal anterior horn was a specific lesion. Fourteen of the AFP patients had unilateral or bilateral femoral nerve involvement. None of the patients died, and in 132 of 134 patients, follow-up visits showed that their physical and neuropsychologic abilities had returned to normal. Conclusions: Most children infected with EV71 have a good prognosis if they are diagnosed early and receive proper supportive treatment. Key Words: Enterovirus 71, nervous system damage, brain stem encephalitis, acute flaccid paralysis, aseptic meningitis (Pediatr Infect Dis J 2015;34:718–723)
E
nterovirus 71 (EV71) and poliovirus belong to the RNA enterovirus family. EV71 is one of the important pathogens that cause hand, foot and mouth disease (HFMD).1,2 The majority of HFMD cases are benign, and patient prognosis is good. However, EV71 is neurotropic and can spread through the nervous system from the blood, or the virus can enter a peripheral nerve and be carried to the central nervous system (CNS) by axonal transport.3,4 This causes a severe immune response in the nervous system resulting in neurologic diseases, such as aseptic meningoencephalitis, brainstem encephalitis, parencephalitis, encephalomyelitis and acute flaccid paralysis (AFP). In the few brainstem encephalitis patients, the disAccepted for publication December 30, 2014. From the*Department of Neurology, Children’s Hospital Affiliated to Chongqing University of Medical Sciences, Chongqing, China; †Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; ‡Key Laboratory of Pediatrics in Chongqing, CSTC2009CA5002, Chongqing, China; and §Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Li Jiang, MD, PhD, Department of Neurology, Children’s Hospital of Chongqing Medical University, No.136 Zhongshan 2nd Road, Yu Zhong District, Chongqing 400014, China. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3407-0718 DOI: 10.1097/INF.0000000000000711
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ease progresses rapidly, and other severe complications occur, such as pulmonary edema, pulmonary bleeding and circulatory failure. Thus, the consequences of an EV71 infection are generally more serious than seen with other enteroviruses.5,6 The neurotoxicity of EV71 was recognized when 44 patients with EV71 infections died of a polio-like illness in Bulgaria in 1975. Soon after, EV71-associated neurotoxicity events were reported in New York, Malaysia and Taiwan.7–10 The clinical differences between different types of neurologic damage were not thoroughly addressed in previous studies. In this study, the clinical data and outcomes were analyzed retrospectively for 134 pediatric patients with neurologic damage caused by EV71 infection to provide the basis for diagnosing and treating nervous system infection caused by EV71.
MATERIALS AND METHODS Patient Enrollment and Diagnosis A retrospective analysis of the clinical features, auxiliary examination, treatment and prognosis was performed in 134 pediatric patients with nervous system damage caused by EV71 infection. Patients were admitted to the Children’s Hospital affiliated with Chongqing University of Medical Sciences from January to December 2013. This study was approved by the Ethics Committee for the Children’s Hospital affiliated with Chongqing University of Medical Sciences. Informed consent was obtained from the subjects or their legal guardians via signed consent forms. EV71 diagnosis was confirmed by EV71 antibodies in the cerebrospinal fluid (CSF) and blood and EV71 nucleic acids in stool testing. HFMD was diagnosed using the Guidelines for Diagnosis and Treatment of HFMD (version 2011).11 Aseptic meningitis, brainstem encephalitis, parencephalitis and AFP were diagnosed based on clinical manifestations and laboratory examinations.12,13 The clinical diagnostic criteria for aseptic meningitis include symptoms such as fever, headache, vomiting, possible convulsions, disturbance of consciousness, possible positive meningeal stimulation, possible pathological reflex and changes to the CSF, such as increased CSF pressure, CSF white blood cell (WBC) counts exceeding 15 × 106/L in patients more than 1-month old and germiculture negative. Brain stem encephalitis is a localized diagnosis, which is confirmed in the brain stem with magnetic resonance imaging (MRI). Cerebellitis symptoms may include difficulty balancing while sitting or walking, astasia, inaccurate performance in finger-to-nose test or fetch, lalopathy, nystagmus and tremor. The clinical diagnostic criteria of AFP are acute onset of degenerated muscle strength, hypomyotonia and weak or absent tendon reflex in one or more limb. All the patients received a lumbar puncture, head and/or spinal cord MRI or nerve conduction.
Treatment Treatment was provided according to the Guidelines for Diagnosis and Treatment of HFMD (version 2011).9 Twentyfour patients (17.9%) were given an intravenous human gamma globulin (IVIG) infusion at a dose of 2 g/kg for 2 or 5 days. Fifty patients (37.3%) were given glucocorticoid therapy. Of those patients, 10 received low-dose dexamethasone (0.3–0.5 mg/kg/d)
The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
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The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
TABLE 1. Age Distribution of Pediatric Patients with Nervous System EV71 Infections Age (years)
n
Constituent Ratio (%)
5
10 64 26 24 6 4
7.5 47.7 19.4 17.9 4.5 3.0
Statistical Analysis Statistical analysis was performed with SPSS version 16.0 software. The data are presented as the mean ± SEM and the median values and range. The data distribution was analyzed using the χ2 test or binomial test. Differences were considered statistically significant when P 40
6 10 42 68 4
Constituent Ratio (%) 4.5 7.5 31.3 50.7 6.0
intravenously for 3–5 days and were then switched to oral prednisone for 2 weeks. The other 40 patients on glucocorticoids received a methylprednisolone infusion. Of these, 26 patients received methylprednisolone (1–2 mg/kg/d) for 3–5 days intravenously and then switched to take prednisone orally for 2 weeks. The remaining 14 patients had brain stem involvement or serious limb paralysis complicated with cerebrospinal meningitis. They received high-dose dexamethasone (15–20 mg/kg/d) intravenously for 3–5 days and then switched to oral prednisone for 1–3 months and received IVIG. Other treatments included protecting vital organs, reducing intracranial pressure, maintaining homeostasis, supplementing with B vitamins, nourishing nerves and other symptomatic or supportive treatment. Five patients required transfer to the intensive care unit for treatment within 3 days of progressive development of the disease. Four of the five patients required ventilator-assisted breathing. There were 2 patients who experienced frequent convulsions and were given oral sodium valproate for short-term prevention for 2–3 months. Once signs of life were steady and the disease was controlled, the patients were transferred into the rehabilitation department for early rehabilitation training. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Fever was observed in 128 of 134 (95.5%) of pediatric EV71 patients. The fever lasted an average of 5.3 ± 2.1 days (range: 2–15 days), and the median body temperature was 39.3°C. The severity of the fever varied significantly between patients (χ2 = 121.538, P 100 × 109/L, which were mainly mononuclear cells. Eight patients had slightly elevated CSF protein levels and normal levels of glucose and chlorides. There were 30 patients with an abnormal brain MRI. Brain damage was present in 28 of 30 patients and was most evident in the pons and medulla oblongata. Of the 28 patients where brain damage was evident, 20 had lesions in the posterior portion of the medulla oblongata and pons, 4 had cerebellar damage, 4 had cerebellum and spinal cord injury and 2 had abnormal signals in the double frontal and parietal cortex. In the patients with AFP, 19 of 20 patients had abnormal spinal cord MRI results from either a spinal sagittal MRI showing a diverse range of strip using a long T1 and long T2 signals or an identical T1 and long T2 signals intramedullary from cervical to cone. Most of the lesions were in the cervical cord and thoracic 8-cone grade. The horizontal axis displayed bilateral or unilateral lesions to the anterior horn of the spinal cord using either the long T1 and long T2 signals or an identical T1 and long T2 signals. Five cases involved the cervical spinal cord, 8 cases involved the thoracic-lumbar spinal cord and 6 cases involved the lumbosacral region, cone and horsetail. The enhanced spinal MRI scan showed that the ventricornu or nerve root enhanced abnormally in 8 cases. An initial electrophysiological examination to assess nerve conduction was performed an average of 4.6 days (range: 3–7 days) after the onset of paralysis. The initial electromyography (EMG) detection was performed in 2–8 weeks after the onset. The unilateral or bilateral femoral nerve(s) was(were) involved in 14 of the patients (93.3%) with single paralysis or paraplegia. The primary symptoms of an abnormal femoral nerve included significantly reduced or absent compound muscle action potential amplitude and in some cases, a prolonged latency period. Only 2 patients had
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Headache and Vomiting
0 2 (50.0)
confirmed tibial/peroneal nerve damage in both legs tested, and 1 patient had confirmed nerve damage (median/ulnar nerve) in both upper limbs. In the EMG test, 61 muscle parts were tested, of these 32 (52.5%) were found to be abnormal. The observed abnormalities were increased insertion potential (n = 19, 59.4%), spontaneous potentials at the resting state (n = 10, 31.3%), increased duration of motor unit potentials under light contraction (n = 27, 84.4%), increased amplitude under light contraction (n = 24, 75%), reduced recruitment under heavy contraction (n = 11, 34.4%) and a lack of motor unit under heavy contraction (n = 10, 31.3%).
Outcomes The median hospitalization time was 10 days (range: 4–22 days). There were no deaths. Two patients who had experienced frequent convulsions were successfully treated and followed for 3–6 months, and no further convulsion seizures occurred. Two patients with eyeball movement disorder were completely recovered 2 months after the end of therapy. All 28 ataxia patients recovered within 1–3 months. Twelve patients were able to recover while they were hospitalized (8–14 days), and the remaining 16 patients recovered after discharge. Finally, 2–6 months after discharge from hospital, all the patients, except 1 with brainstem encephalitis and 1 with encephalomyelitis, showed comparable neuropsychological development to children of the same age (Wechsler intelligence test or Gesell Developmental Diagnostic Scale). There were a total of 24 children with AFP (including brainstem and spinal cord involvement). The muscle strength of the affected limb began to recover a median of 10 days (range: 3–14 days) after the onset of paralysis. The muscle strength recovered at 28 days and 6 months after paralysis is summarized in Table 4. Although all the patients showed improved muscle strength, only 4 patients with grades III and IV monoplegia had fully recovered to grade V at 28 days. Within 2–3 months, 17 of 24 patients had fully recovered their muscle strength in the affected limb to grade V. By 6 months, all the patients were able to walk. Two patients, 1 with single lower limb paralysis and 1 with quadriplegia had some residual weakness and were lame. In addition, the proximal muscle strength for 1 patient with single upper limb paralysis remained grade IV (Table 4). However, the uninvolved limbs for the patient with single upper limb paralysis could move freely. The affected joints recovered starting distally (finger and toe joints) and gradually moved proximally up the limb (eg, ankle and wrist to knees and elbows). Finally, proximal muscle strength and muscle tone recovered. Tendon reflexes, and muscle tone recovered along with muscle strength.
DISCUSSION The characteristics of EV71 infections in our study were largely consistent with work from previous scholars.14–16 The highest frequency of CNS infections because of EV71 was observed in © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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The Pediatric Infectious Disease Journal • Volume 34, Number 7, July 2015
Positive Neck Obstruction
Ataxia
Positive Pyramidal Tract
Tachycardia >140 beats/min
Excessive Sweating, Pale Face, Cold Extremities
22 (29.7)
0
13 (17.6)
8 (10.8)
6 (8.1)
4 (16.7)
15 (62.5)
2 (8.3)
11 (45.8)
8 (33.3)
3 (15.0)
0
0
1 (5.0)
0
1 (8.3) 3 (75.0)
0 2 (50.0)
0 1 (25.0)
12 (100.0) 1 (25.0)
0 1 (25.0)
children 1–4 years of age; there was a higher incidence in males and a strong seasonal distribution peaking in July. Interestingly, only 11.9% of the patients with EV71-associated neurologic disease presented with the typical HFMD rash. This suggests that EV71 should be routinely considered when there is reason to suspect a nervous system infection. Given the complex clinical presentation of neurologic complications associated with EV71 infection, our aim was to establish a clinical profile to aid in diagnosing and treating affected patients.
Aseptic Meningitis Aseptic meningitis was the primary nervous system lesion caused by EV71 infection in our study and in previous outbreaks worldwide.7,8,17–19 The primary clinical manifestations of aseptic meningitis were fever, startle, headache, vomiting and convulsive seizures soon after infection. A few patients appeared to have mild brain parenchyma involvement, manifested as irritability, drowsiness or lethargy, but there were generally no serious symptoms of brain parenchymal damage, such as paralysis, coma or status epilepticus. Laboratory tests suggested that aseptic meningitis was similar to viral meningitis, both presenting slight increases in the number of cells and proteins in CSF. Patients in our study frequently recovered within 1–2 weeks with no significant neurologic sequelae, which is in contrast to the previous report from Chang et al.20 Previous studies have shown that EV71 infection with CNS involvement was associated with long-term neurologic sequelae, delayed neurodevelopment and reduced cognitive function. The reason for this discrepancy was unclear; however, one possibility is that different subgroup(s) of EV71 caused the epidemic in Chongqing.
Brainstem Encephalitis Brainstem encephalitis is the most serious neurologic complication of EV71 infection. It usually manifests as extensions of spinal cord lesions and most often involves the medullary oblongatum, reticular formation, pons and midbrain structures.21–23 Consistent with these observations, the primary brain regions affected in our study were the pons and medulla oblongata. Clinical symptoms including vomiting, tachycardia, hypertension and dysphagia are important symptoms of brainstem
Pediatric EV71 Neurologic Complications
Increase or Decrease in Blood Pressure 0 6 (25.0) 0 0 2 (50.0)
Difficulty in Breathing
VentilatorAssisted Breathing
0
0
8 (33.3) 0
2 (8.3) 0
0 2 (50.0)
0 2 (50.0)
dysfunction.23,24 In our study, the primary symptoms were fever, myoclonic seizures, ataxia and apparent vegetative nerve dysfunction. Rare cases showed abducent nerve involvement. The occurrence of myoclonic jerking during deep sleep and wakefulness periods, rather than normal sleep myoclonus, suggested that brainstem encephalitis could be characterized by brief involvement of pontine tegmentum. Severe brainstem encephalitis is characterized by rapid progression and high mortality attributable to acute pulmonary edema or pulmonary hemorrhage. Descriptions of neurogenic EV71associated pulmonary edema have primarily come from the Asia Pacific region.24–27 Our study was not designed to address EV71associated death because of neurogenic pulmonary edema. The inclusion criteria required pediatric patients with detectable EV71 antibodies in CSF and blood or detectable EV71 nucleic acids in the stool. Patients who died from neurogenic pulmonary edema were excluded because they did not undergo CSF testing given the rapid progression of disease.
Acute Flaccid Paralysis EV71 is the most common non-polio enterovirus leading to AFP and shares many pathogenic features with polio. It has been suggested that EV71 causes paralysis by infecting or injuring motor neurons in the anterior horn of the spinal cord and possibly through immune dysfunction and other mechanisms.28,29 AFP has been reported in several outbreaks worldwide.9,30,31 In our study, most AFP cases involved only a single limb. Interestingly, all the AFP patients who developed quadriplegia had multiple brain regions involved, including the brainstem and cerebellum, and the major clinical process was encephalomyelitis. Compared with a polio virus infection, the clinical symptoms for EV71-associated AFP were relatively mild. Consistent with previous work,32 most patients were able to fully recover, and only 15% of patients had permanent neurologic sequelae such as limb paralysis. Our study indicated that the MRI results were highly correlated to the clinical manifestations. Lesions in the anterior horn or ventral root at different segments of the spinal cord often lead to impairment in the corresponding motor function of pediatric
TABLE 4. Muscle Strength in Pediatric Patients with EV71-Associated Acute Flaccid Paralysis After Infection Paralyzed Parts
Muscle Strength
28 Days
4 cases of monoplegia 7 cases of monoplegia 5 cases of monoplegia 2 cases of paraplegia 2 cases of paraplegia 2 cases of quadriplegia 2 cases of quadriplegia
Grades III and IV Grades II and III Grades 0 and I Grades II and III Grades I and II Grades II and III Grades I and II
Grade V Grade IV Grades II and III Grade IV Grades II and III Grade IV Grades II and III
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6 Months Grade V Grade V 3 cases of grade IV Grade V Grade V Grade V 1 case of the right leg claudication
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Hu et al
patients. Abnormal femoral nerve conduction was documented in 93.3% of the patients with EV71 infection-associated AFP, with lesser injuries to the tibial and fibular nerves. These results confirmed that EV71 selectively causes damage to the lumbar and cervical enlargements, especially lumbar, resulting in an early and heavy paralysis in the proximal major muscle group but with little effect on the sacrum. Spontaneous muscle potentials (fibrillation potentials and positive potentials) detected by EMG often occur 10 days after the peripheral nerve injury, and the recruitment potential can have varying degrees of decrease. It is possible we did not detect denervation potentials in some patients because of the shorter timeframe.33 Whether these findings can aid the early and differential diagnosis of AFP associated with EV71 infection requires further verification.
Cerebellar Ataxia EV71 infection can cause acute cerebellar ataxia whose typical symptom includes trunk ataxia with or without nystagmus,28 which generally recovers. Our study confirmed that acute cerebellar ataxia occurs in both brainstem encephalitis and simple acute parencephalitis. The main symptoms for the children with parencephalitis included fever, ataxia, headache and/or vomiting and obvious vegetative nerve dysfunction. However, there was no neck obstruction or pyramidal signs. All patients had a good prognosis.
Treatment We actively gave severe cases mannitol to lower the intracranial pressure and used glucocorticoids (37.3%), IVIG (17.9%) and other treatment methods as recommended. IVIG not only neutralizes the virus and prevents further spread but may also regulate the inflammatory reaction at the cytokine level and help prevent immunopathogenesis.34,35 Glucocorticoids can reduce alveolar surface tension, promote absorption of pulmonary edema and alleviate cerebral edema.36 It remains controversial whether pulse therapy using high-dose glucocorticoids improves the prognosis of HFMD complicated with nervous system damage,36,37 and it therefore, should be used with caution. In summary, given the lack of effective antiviral drugs, only by fully understanding the characteristics of this disease, close observation, early identification of nervous system involvement and the implementation of effective management, the mortality and disability rate can be reduced.
CONCLUSIONS The most common neurologic complication of EV71 infection was aseptic meningitis, followed by brain stem encephalitis, AFP, acute parencephalitis and encephalomyelitis. Each complication manifested a unique profile of clinical symptoms. The majority of children infected with EV71 have a good prognosis if they are diagnosed early and receive proper treatment. REFERENCES 1. Chan LG, Parashar UD, Lye MS, et al. Deaths of children during an outbreak of hand, foot, and mouth disease in Sarawak, Malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group. Clin Infect Dis. 2000;31:678–683. 2. Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929–935. 3. Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti Infect Ther. 2009;7:735–742. 4. Chen YC, Yu CK, Wang YF, et al. A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol. 2004;85: 69–77.
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Pediatric EV71 Neurologic Complications
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