Journal http://jcn.sagepub.com/ of Child Neurology Enterovirus 71 Infection−Associated Acute Flaccid Paralysis: A Case Series of Long-Term Neurologic Follow-Up Hsiu-Fen Lee and Ching-Shiang Chi J Child Neurol published online 21 January 2014 DOI: 10.1177/0883073813516193 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/01/20/0883073813516193
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Original Article
Enterovirus 71 Infection–Associated Acute Flaccid Paralysis: A Case Series of Long-Term Neurologic Follow-Up
Journal of Child Neurology 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813516193 jcn.sagepub.com
Hsiu-Fen Lee, MD1,2 , and Ching-Shiang Chi, MD2,3
Abstract The authors undertook long-term neurologic outcomes of 27 patients aged 0 to 15 years with enterovirus 71–related acute flaccid paralysis from June 1998 to July 2012. Motor function outcome was graded from class I (complete recovery) to class V (permanent paralytic limbs). Twelve of 20 patients (60%) who received intravenous immunoglobulin for treatment of acute flaccid paralysis had motor function outcomes in classes III to V. The median duration of follow-up was 6 months, during which time 7 of 13 patients (54%) with central nervous system infection, 3 of 6 patients (50%) with autonomic nervous system dysregulation, and 3 of 8 patients (37%) with heart failure showed motor function outcomes in classes III to V. These findings suggested that the usage of intravenous immunoglobulin and the severity of disease staging at disease onset might not be able to predict long-term motor function outcomes. Keywords enterovirus 71, acute flaccid paralysis, motor function outcome Received September 29, 2013. Received revised October 27, 2013. Accepted for publication November 14, 2013.
Acute poliovirus infection was the most common etiology of acute flaccid paralysis in infants and children several decades ago. In 1988, the World Health Assembly adopted a resolution calling for global eradication of poliomyelitis by the year 2000.1 With the eradication of circulating wild poliovirus, other nonpolio enteroviruses, including coxsackieviruses, echoviruses, and enteroviruses, are being more commonly identified as the cause of poliomyelitis-like paralysis in acute flaccid paralysis surveillance.2-9 Among these, enterovirus 71 has replaced poliovirus as the most common likely viral cause of acute flaccid paralysis.9 Enterovirus 71 belongs to the family Picornaviridae and was first recognized in 1974 after isolation studies were performed using samples taken from a series of patients in California between 1969 and 1973 who had severe neurologic diseases.10 Since its discovery in 1974, numerous outbreaks, either sporadically or in epidemics, have occurred worldwide.11-18 Like the poliovirus, neurovirulence of enterovirus 71 infection had been identified in autopsy cases from a large epidemic outbreak in Bulgaria in 197519 as well as in animal studies.20 This virus exhibits great variability of clinical manifestations, ranging from mild prodromal illness of hand, foot, and mouth disease with or without subsequent development of variable neurologic complications, including aseptic meningitis, encephalitis, brainstem encephalitis, so-called rhombencephalitis, Guillain-Barre´ syndrome, and/or poliomyelitis-like paralytic disease.21,22 Clinical
outcomes of enterovirus 71 infection–related polio-like paralytic illness display diverse features, such as complete recovery, residual weakness, persistent flaccid paralysis, and death.4-8,19,23,24 In Taiwan, enterovirus 71 infection has become an annual endemic problem since the first reported epidemic outbreak in 1988.17 During that large outbreak, some fatality cases and critical patients exhibited acute flaccid paralysis as one of their first recognizable neurologic presentations, and symptoms and signs of autonomic nerve system dysfunction with or without acute left heart failure would occur in the following hours or days.17,21,25 Therefore, acute flaccid paralysis is considered a clinical warning sign of central nervous system involvement suggestive of probable progress onto a fulminant disease course. National stage-based management guidelines
1
Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan 2 Institute of Biochemistry and Biotechnology, College of Medicine, Chung Shan Medical University, Taichung, Taiwan 3 Department of Pediatrics, Tungs’ Taichung Metroharbor Hospital, Taichung, Taiwan Corresponding Author: Ching-Shiang Chi, MD, Department of Pediatrics, Tungs’ Taichung Metroharbor Hospital, 699, Taiwan Boulevard Sec. 8, Wuchi, Taichung, 435, Taiwan. Email: [email protected]
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for critical enterovirus 71 infection have been established by Taiwan’s Center for Disease Control. Intravenous immunoglobulin has been suggested to be used in infants and children with enterovirus 71–associated acute flaccid paralysis; however, the efficacy of intravenous immunoglobulin administration for those cases is controversial, and long-term neurologic outcomes of enterovirus 71–related acute flaccid paralysis remain unclear. The aim of this study was to review cases of enterovirus 71 infection in infants and children up to 15 years of age in whom acute flaccid paralysis was a clinical symptom during the disease course from June 1998 to July 2012. We analyzed longterm motor function outcomes of flaccid paralytic illness based on intravenous immunoglobulin treatment, neuroimaging results, and disease staging of enterovirus 71 infection.
Methods Patients’ Classification Based on Disease Staging and Clinical Definitions Based on the staging of enterovirus 71 infection revised by Taiwan’s Center for Disease Control on May 2012, 4 stages of disease process were categorized: (1) herpangina or hand, foot, mouth disease, (2) central nervous system infection, (3) autonomic nerve system dysregulation, and (4) heart failure. Clinical symptoms and signs and management guidelines of 4 stages are briefly summarized in Table 1. Patients at the stage 1 disease showed herpangina, hand, foot, mouth disease, or febrile illness with contact history of enterovirus 71 infection during the period of epidemic transmission. Herpangina was defined as febrile illness with vesicles or ulcers on the posterior parts of soft palate and/or anterior pillar. Symptoms of hand, foot, mouth disease included febrile illness with oral ulcers plus skin vesicles and rash on the palms, soles, or buttocks. Patients at the stage 2 disease exhibited herpangina or hand, foot, mouth disease–related encephalitis/encephalomyelitis, or rhombencephalitis/rhombencephalomyelitis. Clinical presentations of encephalitis included febrile illness and altered levels of consciousness with or without headache or vomiting. Encephalomyelitis was defined as patients with clinical symptoms of encephalitis and acute flaccid paralysis. Acute flaccid paralysis was defined as acute onset of weakness of 1 or more limbs and decrease or lack of deep tendon reflexes. Rhombencephalitis/rhombencephalomyelitis, that is, brainstem encephalitis/encephalomyelitis, was characterized by symptoms of encephalitis/encephalomyelitis plus brainstem involvement related neurologic symptoms, such as ataxia, tremor, opsoclonus, myoclonic jerks, gaze paresis, and/or bulbar palsies. Patients at the stage 3 disease manifested clinical manifestations of central nervous system involvement plus tachypnea, cold sweating, mottled skin, obvious tachycardia, and/or hypertension. In this stage, severe cases may present with acute cardiac dysfunction with or without pulmonary edema. Acute cardiac dysfunction was defined as reduced cardiac contractility on echocardiography as evidenced by left ventricular ejection fraction of less than 60% (normal 64%– 83%). Ejection fraction was calculated as [(left ventricular dimension at end diastole)3 – (left ventricular dimension at end systole)3] / (left ventricular dimension at end diastole)3. Pulmonary edema was diagnosed when a patient’s chest radiograph showed bilateral pulmonary infiltration without cardiomegaly and the patient presented
with respiratory distress or pink frothy secretion exuding from the endotracheal tube. Patients were considered to be in the stage 4 disease if clinical symptoms of central nervous system involvement and autonomic nerve system dysregulation with critical tachycardia and evident hypertension, or hypotension and/or shock plus acute left heart failure were present. Acute left heart failure was defined as progressive reduction of left ventricular ejection fraction to below 40%.
Patients’ Data Collection and Clinical Outcomes From June 1998 to July 2012, patients who were diagnosed with enterovirus 71 infection–related acute flaccid paralysis in the disease stages 2 to 4, and survived from acute disease course, were included. Enterovirus 71 infection was confirmed by positive culture or reverse transcription polymerase chain reaction using throat swabs,26 but subtypes of enterovirus 71 were not performed in our case series. Patients’ clinical information, including age, gender, provisional diagnosis, and progression from illness onset to paralytic disease, was collected. All patients underwent detailed physical and neurologic examinations, and basic laboratory tests, including complete blood count, blood sugar, creatine phosphokinase, electrolytes, liver function test, renal function test, and arterial blood gas analysis. Chest radiograph and continuous monitoring of ejection fraction of left ventricle were performed. The first brain magnetic resonance imaging (MRI) and/or spinal MRI were carried out in patients with clinically stable status. Motor function outcomes of enterovirus 71 infection-related acute flaccid paralysis were graded from classes I to V (Table 2). Longterm motor function outcomes of flaccid paralytic illness based on intravenous immunoglobulin therapy, neuroimaging findings, and their corresponding disease staging were analyzed.
Results Twenty-seven patients, 18 boys and 9 girls, aged from 6 months to 9 years 1 month, with a median age of 1 year 9 months, were included. The antecedent illness, progression of illness onset to flaccid paralysis, paralytic limbs, enterovirus 71 disease staging, treatment methods, and neuroimaging findings are summarized in Table 3. All but 1 of the patients exhibited acute flaccid paralysis between day 3 and day 6 of disease process. Twenty-two patients manifested acute flaccid paralysis under the age of 3 years. Sixteen patients exhibited 1 limb involvement and 11 had involvement of 2 limbs. Of the 27 patients with enterovirus 71 infection-related acute flaccid paralysis, 13 were categorized in stage 2, 6 were in stage 3, and 8 were in stage 4. Twenty patients were given intravenous immunoglobulin for treatment of enterovirus 71 infection–related acute flaccid paralysis (Table 4). Twelve of 20 patients (60%) had motor function outcomes in classes III to V, in whom 7 of 10 patients (70%) were in stage 2, 2 of 4 (50%) were in stage 3, and 3 of 6 (50%) were in stage 4. Seven patients were not given intravenous immunoglobulin during the disease course. All of them had motor function outcomes in class I or class II, except that 1 patient, case 18, who was in stage 3, exhibited motor function outcome in class III.
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Table 1. Concise Summary of Staging and Management Guidelines of Enterovirus 71 Infection Revised by Taiwan’s Center for Disease Control in 2012. EV 71 staging Symptoms and signs (S/S)
Stage 1
Stage 2
Stage 3
Stage 4
Herpangina/HFMD
CNS infection
ANS dysregulation
Heart failure
Herpangina HFMD
Treatment Supportive treatment
Encephalitis Fever Altered level of consciousness Headache, and/or Vomiting Encephalomyelitis S/S of encephalitis, plus Acute flaccid paralysis Rhombencephalitis/ Rhombencephalomyelitis S/S of encephalitis/ encephalomyelitis, plus Ataxia Tremor Opsoclonus Myoclonic jerks Gaze paresis, and/or Bulbar palsies Fluid restriction IVIg (?) Consult pediatric neurologists Neuroimaging study if indicated CSF analysis if indicated Observation of the S/S of stage 3 or 4
S/S
Admission to PICU Consider early intubation Fluid restriction IVIg (?) Medications with inotropes Milrinone Dobutamine Observation of the S/S of stage 4
of CNS infection, plus Tachypnea Sweating Mottled skin Obvious tachycardia Hypertension, and/or Acute cardiac dysfunction with or without pulmonary edema
S/S of CNS infection and ANS dysregulation, plus Critical tachycardia Evident hypertension Acute left heart failure Hypotension, and/or Shock
Admission to PICU Early intubation Fluid restriction Medications with inotropes Milrinone Dobutamine Dopamine Epinephrine May consider ECLS
Abbreviations: ANS, autonomic nervous system; CNS, central nervous system; CSF, cerebrospinal fluid; ECLS, extracorporeal life support; EV, enterovirus; HFMD, hand-foot-mouth disease; IVIg, intravenous immunoglobulin; PICU, pediatric intensive care unit; (?), The usage of intravenous immunoglobulin is controversial.
Table 2. Classification of Motor Function Outcomes of Enterovirus 71 Infection–Associated Acute Flaccid Paralysis. Motor function outcome Class I Class II Class III Class IV Class V
Upper limb(s)
Lower limb(s)
Complete recovery Elevate the hand above the level of shoulder Elevate the hand at the level of shoulder Elevate the hand below the level of shoulder Unable to elevate the hand
Complete recovery Run with a drop foot Walk with a drop foot Walk with a drop foot and back knee Unable to walk
The results of the first brain MRI and/or spinal MRI are shown in Tables 3 and 4. A total of 26 brain MRIs and 22 spinal MRIs were performed. Normal brain MRI features were found in 7 patients, 5 in stage 2 and 2 in stage 3. Normal spinal MRI findings were noted in 7 patients, 3 in stage 2, 2 in stage 3, and 2 in stage 4. The involvement of the dorsal aspect of medulla
oblongata was suggestive of clinical disease severity. That is to say, 6 of 13 patients (46%) were in stage 2, 3 of 5 patients (60%) were in stage 3, and all 8 patients (100%) were in stage 4. Isolated spinal cord involvement was found in 4 cases, and all of them exhibited disease processes in stage 2. Two distinct spinal cord lesions on MRI could be identified either by diffuse lesion from the cervical cord to the lumbar cord (Figure 1A and B) or segmental lesion in the involved cord (Figure 1C and D). MRI findings and corresponding motor function outcomes are shown in Table 4. Three patients with normal results on both brain and spinal MRIs manifested favorable motor function outcomes in class I or class II. Three of 4 patients (75%) with isolated lesion sites in the spinal cord, 2 of 8 (25%) with signal changes in the pons and/or medulla oblongata, and 7 of 11 patients (64%) with lesion sites in both brainstem and spinal cord exhibited unfavorable motor function outcomes in class III to class V. Three patients had diffuse lesions in the spinal cords and brainstem involvement exhibiting unfavorable motor outcomes in class III to class V (Table 4).
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F M M M F M F M F M M M F M F F M M M F F M M M M M M
26 mo 13 mo 109 mo 55 mo 27 mo 38 mo 41 mo 22 mo 21 mo 15 mo 30 mo 30 mo 9 mo 6 mo 13 mo 15 mo 13 mo 13 mo 24 mo 36 mo 27 mo 45 mo 13 mo 10 mo 20 mo 9 mo 6 mo
Age of disease onset
HFMD HFMD Herpangina Herpangina HFMD Herpangina HFMD HFMD HFMD HFMD Herpangina HFMD Fever Herpangina Herpangina HFMD HFMD HFMD HFMD HFMD HFMD HFMD HFMD Herpangina HFMD HFMD Herpangina
D3 D3 D12 D6 D3 D3 D3 D5 D5 D3 D4 D4 D5 D4 D3 D6 D4 D4 D5 D4 D3 D2 D3 D3 D3 D4 D4
Antecedent illness Day (D) 2 limbs (RL and LL) 2 limbs (LU and LL) 2 limbs (RL and LL) 2 limbs (RL and LL) 1 limb (LL) 2 limbs (LU>LL) 1 limb (RU) 1 limb (LU) 1 limb (LL) 1 limb (LL) 1 limb (RU) 2 limbs (RL and LL) 2 limbs (RL and LL) 1 limb (RU) 1 limb (RU) 2 limbs (LU > LL) 1 limb (LU) 1 limb (RL) 2 limbs (RL and LL) 1 limb (RU) 1 limb (LU) 2 limbs (RL and LL) 1 limb (LU) 1 limb (LL) 1 limb (RL) 1 limb (RU) 2 limbs (RU and RL)
Paralytic limb(s) 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 4 4 4 4 4 4 4 4
Others
Yes HV No HV No No No No Yes No Yes No Yes No Yes No Yes No Yes No Yes HV Yes No Yes No Yes HV Yes No No No Yes HV No HV Yes Milrinone Yes ECLS No Milrinone þ ECLS No ECLS Yes ECLS Yes ECLS Yes Milrinone þ ECLS Yes Milrinone þ ECLS Yes No
EV 71 staging IVIg
Treatment
Yes No No Yes No Yes Yes No No No No No No No No No Yes ND Yes Yes Yes Yes Yes No Yes Yes Yes
No Yes No Yes No No Yes Yes No No Yes Yes No No Yes No Yes ND Yes Yes Yes Yes Yes Yes Yes Yes Yes
Pons Medulla Not done C2-C6 S1-S5 No No No C2-C7 C1-T5 L1-L5 L1-L5 Not done Whole cord T11-T12 No C1-C7 No C2-C6 Not done Whole cord C3-T1 C1-C7 No Not done No Whole cord C1-C7 Not done
Cord
Signal changes on the first MRI
2 11 1 2 1 1 48 3 2 4 4 12 35 5 24 1 6 6 3 6 85 53 51 54 130 119 88
mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo
Duration of follow-up
Othersa I Nil I Nil I Nil I Nil I Nil II (LU)/I (LL) Nil III Nil III Nil III Nil III Nil IV Nil IV(LL)/ I(RL) Nil V Nil I Nil I Nil II Nil III Nil III Nil V (LL>RL) B and R I Nil II Nil II Nil II B II Nil III Nil V B and R V B and R
Motor function
Neurologic outcomes
Abbreviations: C, cervical cord; ECLS, extracorporeal life support; EV, enterovirus; F, female; HFMD, hand-foot-mouth disease; HV, hyperventilation therapy; IVIg, intravenous immunoglobulin; L, lumbar cord; LL, left lower limb; LU, left upper limb; M, male; mo, months; MRI, magnetic resonance imaging; Pt, patient; RL, right lower limb; RU, right upper limb; T, thoracic cord. a Others, other significantly neurologic morbidities included bulbar dysfunction (B) and respiratory failure (R). b Case 3 was diagnosed as Guillain-Barre´ syndrome based on his nerve conduction velocity showing axonal degeneration.
1 2 3b 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Patient Gender
Illness onset to paralysis
Table 3. Clinical Features, Magnetic Resonance Imaging (MRI) Findings, and Neurologic Outcomes of Enterovirus 71 Infection–Associated Acute Flaccid Paralysis.
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Table 4. Magnetic Resonance Imaging (MRI) Findings, Intravenous Immunoglobulin Administration, Disease Staging, and Motor Function Outcomes of Enterovirus 71 Infection–Associated Acute Flaccid Paralysis. Motor function outcomes MRI findings Normal results Stage 2 Stage 3 Stage 4 Lesions in the spinal cords Stage 2 Stage 3 Stage 4 Lesions in the brainstem lesion Stage 2 Stage 3 Stage 4 Lesions in both brainstem and spinal cord Stage 2 Stage 3 Stage 4 Intravenous immunoglobulin Yes Stage 2 Stage 3 Stage 4 No Stage 2 Stage 3 Stage 4
Total no. 3
4
8
11
20
7
Class I
Class II
Class III
2 1 1 0 1 1 (S) 0 0 2 2 0 0 3 1 (S) 1 (S) 1 (S)
1 0 1 0 0 0 0 0 4 1 0 3 1 0 0 1 (S)
0 0 0 0 2 2 0 0 0 0 0 0 4 2 1 1
5 2 2 1 3 3 0 0
3 1 0 2 3 0 1 2
6 4 1 1 1 0 1 0
(S)
(S) (S) (D)
Class IV
Class V
0 0 0 0 0 0 0 0 1 1 0 0 1 1 (D) 0 0
0 0 0 0 1 1 (S) 0 0 1 0 0 1 2 0 1 (D) 1 (S)
2 2 0 0 0 0 0 0
4 1 1 2 0 0 0 0
Abbreviations: D, diffuse lesion in the spinal cord; MRI, magnetic resonance imaging; S, segmental lesion in the spinal cord.
The duration of neurologic follow-up of acute flaccid paralysis ranged from 1 month to 5 years 10 months, with a median of 6 months. As shown in Table 3, 13 of the 27 patients (48%) exhibited unfavorable motor function outcomes in class III to class V, in whom 7 of 13 patients (54%) were in stage 2, 3 of 6 (50%) were in stage 3, and 3 of 8 (37%) were in stage 4. Other significant morbidities, including bulbar dysfunction and/or respiratory failure, were found in case 19, who was in stage 3, and cases 23, 26, and 27, who were in stage 4.
Discussion Our case series showed that 52% of patients exhibiting enterovirus 71 infection–associated acute flaccid paralysis were at disease stages 3 and 4. Among them, 93% of patients developed devastating clinical process under the age of 3 years. Younger age and limb weakness have been suggested to be one of the risk factors of critical enterovirus 71 cases in an epidemic and annual endemics in Taiwan.27,28 Fatal enterovirus 71 infection–associated paralytic diseases were also described in a severe epidemic of the central nervous system disease that occurred in Bulgaria in 1975, and the case fatality rate was 29.5% in the paralytic cases.11 Our findings were consistent with the literature that paralytic disease in infants and children
with enterovirus 71 infection could be a warning sign suggestive of possible progression to a fulminant disease course. Based on the national stage–based treatment guidelines for enterovirus 71 infection in Taiwan, intravenous immunoglobulin has been suggested to be used in infants and children with enterovirus 71–related acute flaccid paralysis. This treatment concept was employed on the presumptive basis that it would neutralize the virus and have anti-inflammatory properties.29,30 However, the merits and risks of intravenous immunoglobulin usage were unclear because such cases might exhibit rapid disease progression to autonomic nerve system dysregulation and may even develop left ventricular failure within hours. Under this circumstance, adequate fluid restriction for avoidance of left ventricular failure is crucial, and intravenous immunoglobulin administration might aggravate fluid overload.25,26 Our case series showed that 60% of patients who received intravenous immunoglobulin for enterovirus 71 infection–associated paralytic disease had unfavorable outcomes of motor function, that is, class III to class V. In contrast, 6 of 7 (86%) patients with various disease severities who did not receive intravenous immunoglobulin had favorable outcomes of motor function, that is, classes I and II. Our clinical observation showed that the usage of intravenous immunoglobulin in patients with enterovirus 71 infection–associated acute flaccid paralysis at disease
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Figure 1. Spinal magnetic resonance imaging (MRI) findings of enterovirus 71 infection–associated acute flaccid paralysis. (A and B) Spinal MRIs of case 19. (A) Sagittal view (TE/TR 87 ms/ 9000 ms) reveals high signal intensity in the dorsal aspects of pons and medulla, and the whole spinal cord. (B) Axial view (TE/TR 97 ms/ 3750 ms) reveals blurred high signal intensity in the cervical spinal cord. (C and D) Spinal MRIs of case 20. (C) Sagittal view (TE/TR 86ms/ 2800 ms) reveals high signal intensity in the dorsal aspect of pontomedullary junction, medulla, and cervical spinal cord. (D) Axial view (TE/TR 106 ms/ 5591 ms) reveals high signal intensity in the bilateral anterior horns of the cervical cord.
onset might not be able to predict long-term motor function outcomes. Nevertheless, there were limitations in this retrospective study because the number of cases was too small to compare between the patients with and without intravenous immunoglobulin therapy among different disease stages. The efficacy of intravenous immunoglobulin for treatment of infants and children with enterovirus 71 infection still needs to be confirmed.31,32 Regarding the first MRI findings in our case series, we observed that 100% of patients whose initial cranial and spinal MRI scans were normal had favorable outcomes. Further, 75%
of patients with isolated spinal cord signal changes manifested unfavorable motor function outcomes, with class III to class V classification, compared with 64% of patients with lesions in both the brainstem and spinal cord and 25% of patients with lesion sites in the brainstem. Hundred percent of the patients with diffuse lesions in whole spinal cords and brainstem involvement showed unfavorable motor function outcomes in class III to class V. Our study revealed that lesion sites in the spinal cords with or without brainstem involvement had a higher probability of unfavorable motor function outcomes during the period of neurologic follow-up. We also found that 54% of patients with stage 2 exhibited class III to class V motor function outcomes versus 23% of patients in stage 3, and 23% in stage 4 of enterovirus 71 infection–associated acute flaccid paralysis. Case 19, who was in stage 3, had antecedent illness (hand, foot, mouth disease) and exhibited acute flaccid paralysis on day 5 of disease course. He showed transient Cushing phenomenon followed by cold sweating and rapid progression to critical tachycardia and hypertension; however, there was no further progression of disease beyond the phase of autonomic nerve system dysfunction. His brain MRI and spinal cord MRI revealed prominent signal changes in the dorsal aspects of pons and medulla as well as diffuse lesion in the whole spinal cord (Figure 1A). He was rescued by intensive medical treatment, but suffered significant neurologic sequelae, including flaccid paralytic limbs at motor function in class V, bulbar dysfunction dependent on gastrostomy tube feeding, and respiratory failure with ventilator support. Case 20 developed a more devastating clinical course compared with that of case 19. Acute left ventricular failure with ejection fraction of left ventricle less than 30% accompanied by pulmonary edema and hemorrhage occurred during the acute disease course despite intensive medical treatment. Extracorporeal life support was conducted to rescue her heart function. Her brain MRI revealed characteristic features of enterovirus 71 infection with signal changes in the dorsal aspects of medulla and pontomedullary junction and linear high signal intensity in the cervical cord (Figure 1C). She recovered completely and no neurologic sequelae were noted during the follow-up period. This observation suggested that long-term follow-up motor function outcomes of enterovirus 71–related acute flaccid paralysis did not always correspond to the severity of disease staging at disease onset. In conclusion, the motor function outcomes during the period of long-term follow-up in patients with enterovirus 71–related acute flaccid paralysis were not always favorable. Lesion sites in the spinal cord with or without brainstem involvement on the MRI revealed a higher probability of unfavorable motor function outcomes. Nevertheless, the administration of intravenous immunoglobulin and the severity of disease staging at disease onset might not be able to predict long-term motor function outcomes. Author Contributions H-FL cared for the patients, performed data analysis, and wrote the first draft of the manuscript. C-SC cared for the patients, participated
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in the design of the study, supervised the data collection, and substantially revised the manuscript. 12.
Authors’ Note The study was performed at the Departments of Pediatrics of Taichung Veterans General Hospital and Tungs’ Taichung Metroharbor Hospital.
13.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval
14.
15.
16.
The study was approved by the Institutional Review Board of the Taichung Veterans General Hospital (IRB TCVGH No: CF12303). 17.
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the central nervous system in northern Taiwan, 1994-2003. J Microbiol Immunol Infect. 2005;38:417-424. 29. Wang SM, Liu CC, Tseng HW, et al. Clinical spectrum of enterovirus 71 infection in children in southern Taiwan, with an emphasis on neurological complications. Clin Infect Dis. 1999;29:184-190. 30. Lin TY, Chang LY, Hsia SH, et al. The 1988 enterovirus 71 outbreak in Taiwan: pathogenesis and management. Clin Infect Dis. 2002;34:S52-S57.
31. Ooi MH, Wong SC, Lewthwaite P, et al. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol. 2010; 9:1097-1105. 32. World Health Organization: Regional Office for the Western Pacific. Clinical features and case management. In: A Guide to Clinical Management and Public Health Response for Hand, Foot and Mouth Disease (HFMD). Manila, Philippines: WHO Publications; 2011.
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Original Article
Enterovirus 71 Infection–Associated Acute Flaccid Paralysis: A Case Series of Long-Term Neurologic Follow-Up
Journal of Child Neurology 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813516193 jcn.sagepub.com
Hsiu-Fen Lee, MD1,2 , and Ching-Shiang Chi, MD2,3
Abstract The authors undertook long-term neurologic outcomes of 27 patients aged 0 to 15 years with enterovirus 71–related acute flaccid paralysis from June 1998 to July 2012. Motor function outcome was graded from class I (complete recovery) to class V (permanent paralytic limbs). Twelve of 20 patients (60%) who received intravenous immunoglobulin for treatment of acute flaccid paralysis had motor function outcomes in classes III to V. The median duration of follow-up was 6 months, during which time 7 of 13 patients (54%) with central nervous system infection, 3 of 6 patients (50%) with autonomic nervous system dysregulation, and 3 of 8 patients (37%) with heart failure showed motor function outcomes in classes III to V. These findings suggested that the usage of intravenous immunoglobulin and the severity of disease staging at disease onset might not be able to predict long-term motor function outcomes. Keywords enterovirus 71, acute flaccid paralysis, motor function outcome Received September 29, 2013. Received revised October 27, 2013. Accepted for publication November 14, 2013.
Acute poliovirus infection was the most common etiology of acute flaccid paralysis in infants and children several decades ago. In 1988, the World Health Assembly adopted a resolution calling for global eradication of poliomyelitis by the year 2000.1 With the eradication of circulating wild poliovirus, other nonpolio enteroviruses, including coxsackieviruses, echoviruses, and enteroviruses, are being more commonly identified as the cause of poliomyelitis-like paralysis in acute flaccid paralysis surveillance.2-9 Among these, enterovirus 71 has replaced poliovirus as the most common likely viral cause of acute flaccid paralysis.9 Enterovirus 71 belongs to the family Picornaviridae and was first recognized in 1974 after isolation studies were performed using samples taken from a series of patients in California between 1969 and 1973 who had severe neurologic diseases.10 Since its discovery in 1974, numerous outbreaks, either sporadically or in epidemics, have occurred worldwide.11-18 Like the poliovirus, neurovirulence of enterovirus 71 infection had been identified in autopsy cases from a large epidemic outbreak in Bulgaria in 197519 as well as in animal studies.20 This virus exhibits great variability of clinical manifestations, ranging from mild prodromal illness of hand, foot, and mouth disease with or without subsequent development of variable neurologic complications, including aseptic meningitis, encephalitis, brainstem encephalitis, so-called rhombencephalitis, Guillain-Barre´ syndrome, and/or poliomyelitis-like paralytic disease.21,22 Clinical
outcomes of enterovirus 71 infection–related polio-like paralytic illness display diverse features, such as complete recovery, residual weakness, persistent flaccid paralysis, and death.4-8,19,23,24 In Taiwan, enterovirus 71 infection has become an annual endemic problem since the first reported epidemic outbreak in 1988.17 During that large outbreak, some fatality cases and critical patients exhibited acute flaccid paralysis as one of their first recognizable neurologic presentations, and symptoms and signs of autonomic nerve system dysfunction with or without acute left heart failure would occur in the following hours or days.17,21,25 Therefore, acute flaccid paralysis is considered a clinical warning sign of central nervous system involvement suggestive of probable progress onto a fulminant disease course. National stage-based management guidelines
1
Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan 2 Institute of Biochemistry and Biotechnology, College of Medicine, Chung Shan Medical University, Taichung, Taiwan 3 Department of Pediatrics, Tungs’ Taichung Metroharbor Hospital, Taichung, Taiwan Corresponding Author: Ching-Shiang Chi, MD, Department of Pediatrics, Tungs’ Taichung Metroharbor Hospital, 699, Taiwan Boulevard Sec. 8, Wuchi, Taichung, 435, Taiwan. Email: [email protected]
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for critical enterovirus 71 infection have been established by Taiwan’s Center for Disease Control. Intravenous immunoglobulin has been suggested to be used in infants and children with enterovirus 71–associated acute flaccid paralysis; however, the efficacy of intravenous immunoglobulin administration for those cases is controversial, and long-term neurologic outcomes of enterovirus 71–related acute flaccid paralysis remain unclear. The aim of this study was to review cases of enterovirus 71 infection in infants and children up to 15 years of age in whom acute flaccid paralysis was a clinical symptom during the disease course from June 1998 to July 2012. We analyzed longterm motor function outcomes of flaccid paralytic illness based on intravenous immunoglobulin treatment, neuroimaging results, and disease staging of enterovirus 71 infection.
Methods Patients’ Classification Based on Disease Staging and Clinical Definitions Based on the staging of enterovirus 71 infection revised by Taiwan’s Center for Disease Control on May 2012, 4 stages of disease process were categorized: (1) herpangina or hand, foot, mouth disease, (2) central nervous system infection, (3) autonomic nerve system dysregulation, and (4) heart failure. Clinical symptoms and signs and management guidelines of 4 stages are briefly summarized in Table 1. Patients at the stage 1 disease showed herpangina, hand, foot, mouth disease, or febrile illness with contact history of enterovirus 71 infection during the period of epidemic transmission. Herpangina was defined as febrile illness with vesicles or ulcers on the posterior parts of soft palate and/or anterior pillar. Symptoms of hand, foot, mouth disease included febrile illness with oral ulcers plus skin vesicles and rash on the palms, soles, or buttocks. Patients at the stage 2 disease exhibited herpangina or hand, foot, mouth disease–related encephalitis/encephalomyelitis, or rhombencephalitis/rhombencephalomyelitis. Clinical presentations of encephalitis included febrile illness and altered levels of consciousness with or without headache or vomiting. Encephalomyelitis was defined as patients with clinical symptoms of encephalitis and acute flaccid paralysis. Acute flaccid paralysis was defined as acute onset of weakness of 1 or more limbs and decrease or lack of deep tendon reflexes. Rhombencephalitis/rhombencephalomyelitis, that is, brainstem encephalitis/encephalomyelitis, was characterized by symptoms of encephalitis/encephalomyelitis plus brainstem involvement related neurologic symptoms, such as ataxia, tremor, opsoclonus, myoclonic jerks, gaze paresis, and/or bulbar palsies. Patients at the stage 3 disease manifested clinical manifestations of central nervous system involvement plus tachypnea, cold sweating, mottled skin, obvious tachycardia, and/or hypertension. In this stage, severe cases may present with acute cardiac dysfunction with or without pulmonary edema. Acute cardiac dysfunction was defined as reduced cardiac contractility on echocardiography as evidenced by left ventricular ejection fraction of less than 60% (normal 64%– 83%). Ejection fraction was calculated as [(left ventricular dimension at end diastole)3 – (left ventricular dimension at end systole)3] / (left ventricular dimension at end diastole)3. Pulmonary edema was diagnosed when a patient’s chest radiograph showed bilateral pulmonary infiltration without cardiomegaly and the patient presented
with respiratory distress or pink frothy secretion exuding from the endotracheal tube. Patients were considered to be in the stage 4 disease if clinical symptoms of central nervous system involvement and autonomic nerve system dysregulation with critical tachycardia and evident hypertension, or hypotension and/or shock plus acute left heart failure were present. Acute left heart failure was defined as progressive reduction of left ventricular ejection fraction to below 40%.
Patients’ Data Collection and Clinical Outcomes From June 1998 to July 2012, patients who were diagnosed with enterovirus 71 infection–related acute flaccid paralysis in the disease stages 2 to 4, and survived from acute disease course, were included. Enterovirus 71 infection was confirmed by positive culture or reverse transcription polymerase chain reaction using throat swabs,26 but subtypes of enterovirus 71 were not performed in our case series. Patients’ clinical information, including age, gender, provisional diagnosis, and progression from illness onset to paralytic disease, was collected. All patients underwent detailed physical and neurologic examinations, and basic laboratory tests, including complete blood count, blood sugar, creatine phosphokinase, electrolytes, liver function test, renal function test, and arterial blood gas analysis. Chest radiograph and continuous monitoring of ejection fraction of left ventricle were performed. The first brain magnetic resonance imaging (MRI) and/or spinal MRI were carried out in patients with clinically stable status. Motor function outcomes of enterovirus 71 infection-related acute flaccid paralysis were graded from classes I to V (Table 2). Longterm motor function outcomes of flaccid paralytic illness based on intravenous immunoglobulin therapy, neuroimaging findings, and their corresponding disease staging were analyzed.
Results Twenty-seven patients, 18 boys and 9 girls, aged from 6 months to 9 years 1 month, with a median age of 1 year 9 months, were included. The antecedent illness, progression of illness onset to flaccid paralysis, paralytic limbs, enterovirus 71 disease staging, treatment methods, and neuroimaging findings are summarized in Table 3. All but 1 of the patients exhibited acute flaccid paralysis between day 3 and day 6 of disease process. Twenty-two patients manifested acute flaccid paralysis under the age of 3 years. Sixteen patients exhibited 1 limb involvement and 11 had involvement of 2 limbs. Of the 27 patients with enterovirus 71 infection-related acute flaccid paralysis, 13 were categorized in stage 2, 6 were in stage 3, and 8 were in stage 4. Twenty patients were given intravenous immunoglobulin for treatment of enterovirus 71 infection–related acute flaccid paralysis (Table 4). Twelve of 20 patients (60%) had motor function outcomes in classes III to V, in whom 7 of 10 patients (70%) were in stage 2, 2 of 4 (50%) were in stage 3, and 3 of 6 (50%) were in stage 4. Seven patients were not given intravenous immunoglobulin during the disease course. All of them had motor function outcomes in class I or class II, except that 1 patient, case 18, who was in stage 3, exhibited motor function outcome in class III.
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Table 1. Concise Summary of Staging and Management Guidelines of Enterovirus 71 Infection Revised by Taiwan’s Center for Disease Control in 2012. EV 71 staging Symptoms and signs (S/S)
Stage 1
Stage 2
Stage 3
Stage 4
Herpangina/HFMD
CNS infection
ANS dysregulation
Heart failure
Herpangina HFMD
Treatment Supportive treatment
Encephalitis Fever Altered level of consciousness Headache, and/or Vomiting Encephalomyelitis S/S of encephalitis, plus Acute flaccid paralysis Rhombencephalitis/ Rhombencephalomyelitis S/S of encephalitis/ encephalomyelitis, plus Ataxia Tremor Opsoclonus Myoclonic jerks Gaze paresis, and/or Bulbar palsies Fluid restriction IVIg (?) Consult pediatric neurologists Neuroimaging study if indicated CSF analysis if indicated Observation of the S/S of stage 3 or 4
S/S
Admission to PICU Consider early intubation Fluid restriction IVIg (?) Medications with inotropes Milrinone Dobutamine Observation of the S/S of stage 4
of CNS infection, plus Tachypnea Sweating Mottled skin Obvious tachycardia Hypertension, and/or Acute cardiac dysfunction with or without pulmonary edema
S/S of CNS infection and ANS dysregulation, plus Critical tachycardia Evident hypertension Acute left heart failure Hypotension, and/or Shock
Admission to PICU Early intubation Fluid restriction Medications with inotropes Milrinone Dobutamine Dopamine Epinephrine May consider ECLS
Abbreviations: ANS, autonomic nervous system; CNS, central nervous system; CSF, cerebrospinal fluid; ECLS, extracorporeal life support; EV, enterovirus; HFMD, hand-foot-mouth disease; IVIg, intravenous immunoglobulin; PICU, pediatric intensive care unit; (?), The usage of intravenous immunoglobulin is controversial.
Table 2. Classification of Motor Function Outcomes of Enterovirus 71 Infection–Associated Acute Flaccid Paralysis. Motor function outcome Class I Class II Class III Class IV Class V
Upper limb(s)
Lower limb(s)
Complete recovery Elevate the hand above the level of shoulder Elevate the hand at the level of shoulder Elevate the hand below the level of shoulder Unable to elevate the hand
Complete recovery Run with a drop foot Walk with a drop foot Walk with a drop foot and back knee Unable to walk
The results of the first brain MRI and/or spinal MRI are shown in Tables 3 and 4. A total of 26 brain MRIs and 22 spinal MRIs were performed. Normal brain MRI features were found in 7 patients, 5 in stage 2 and 2 in stage 3. Normal spinal MRI findings were noted in 7 patients, 3 in stage 2, 2 in stage 3, and 2 in stage 4. The involvement of the dorsal aspect of medulla
oblongata was suggestive of clinical disease severity. That is to say, 6 of 13 patients (46%) were in stage 2, 3 of 5 patients (60%) were in stage 3, and all 8 patients (100%) were in stage 4. Isolated spinal cord involvement was found in 4 cases, and all of them exhibited disease processes in stage 2. Two distinct spinal cord lesions on MRI could be identified either by diffuse lesion from the cervical cord to the lumbar cord (Figure 1A and B) or segmental lesion in the involved cord (Figure 1C and D). MRI findings and corresponding motor function outcomes are shown in Table 4. Three patients with normal results on both brain and spinal MRIs manifested favorable motor function outcomes in class I or class II. Three of 4 patients (75%) with isolated lesion sites in the spinal cord, 2 of 8 (25%) with signal changes in the pons and/or medulla oblongata, and 7 of 11 patients (64%) with lesion sites in both brainstem and spinal cord exhibited unfavorable motor function outcomes in class III to class V. Three patients had diffuse lesions in the spinal cords and brainstem involvement exhibiting unfavorable motor outcomes in class III to class V (Table 4).
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F M M M F M F M F M M M F M F F M M M F F M M M M M M
26 mo 13 mo 109 mo 55 mo 27 mo 38 mo 41 mo 22 mo 21 mo 15 mo 30 mo 30 mo 9 mo 6 mo 13 mo 15 mo 13 mo 13 mo 24 mo 36 mo 27 mo 45 mo 13 mo 10 mo 20 mo 9 mo 6 mo
Age of disease onset
HFMD HFMD Herpangina Herpangina HFMD Herpangina HFMD HFMD HFMD HFMD Herpangina HFMD Fever Herpangina Herpangina HFMD HFMD HFMD HFMD HFMD HFMD HFMD HFMD Herpangina HFMD HFMD Herpangina
D3 D3 D12 D6 D3 D3 D3 D5 D5 D3 D4 D4 D5 D4 D3 D6 D4 D4 D5 D4 D3 D2 D3 D3 D3 D4 D4
Antecedent illness Day (D) 2 limbs (RL and LL) 2 limbs (LU and LL) 2 limbs (RL and LL) 2 limbs (RL and LL) 1 limb (LL) 2 limbs (LU>LL) 1 limb (RU) 1 limb (LU) 1 limb (LL) 1 limb (LL) 1 limb (RU) 2 limbs (RL and LL) 2 limbs (RL and LL) 1 limb (RU) 1 limb (RU) 2 limbs (LU > LL) 1 limb (LU) 1 limb (RL) 2 limbs (RL and LL) 1 limb (RU) 1 limb (LU) 2 limbs (RL and LL) 1 limb (LU) 1 limb (LL) 1 limb (RL) 1 limb (RU) 2 limbs (RU and RL)
Paralytic limb(s) 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 4 4 4 4 4 4 4 4
Others
Yes HV No HV No No No No Yes No Yes No Yes No Yes No Yes No Yes No Yes HV Yes No Yes No Yes HV Yes No No No Yes HV No HV Yes Milrinone Yes ECLS No Milrinone þ ECLS No ECLS Yes ECLS Yes ECLS Yes Milrinone þ ECLS Yes Milrinone þ ECLS Yes No
EV 71 staging IVIg
Treatment
Yes No No Yes No Yes Yes No No No No No No No No No Yes ND Yes Yes Yes Yes Yes No Yes Yes Yes
No Yes No Yes No No Yes Yes No No Yes Yes No No Yes No Yes ND Yes Yes Yes Yes Yes Yes Yes Yes Yes
Pons Medulla Not done C2-C6 S1-S5 No No No C2-C7 C1-T5 L1-L5 L1-L5 Not done Whole cord T11-T12 No C1-C7 No C2-C6 Not done Whole cord C3-T1 C1-C7 No Not done No Whole cord C1-C7 Not done
Cord
Signal changes on the first MRI
2 11 1 2 1 1 48 3 2 4 4 12 35 5 24 1 6 6 3 6 85 53 51 54 130 119 88
mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo mo
Duration of follow-up
Othersa I Nil I Nil I Nil I Nil I Nil II (LU)/I (LL) Nil III Nil III Nil III Nil III Nil IV Nil IV(LL)/ I(RL) Nil V Nil I Nil I Nil II Nil III Nil III Nil V (LL>RL) B and R I Nil II Nil II Nil II B II Nil III Nil V B and R V B and R
Motor function
Neurologic outcomes
Abbreviations: C, cervical cord; ECLS, extracorporeal life support; EV, enterovirus; F, female; HFMD, hand-foot-mouth disease; HV, hyperventilation therapy; IVIg, intravenous immunoglobulin; L, lumbar cord; LL, left lower limb; LU, left upper limb; M, male; mo, months; MRI, magnetic resonance imaging; Pt, patient; RL, right lower limb; RU, right upper limb; T, thoracic cord. a Others, other significantly neurologic morbidities included bulbar dysfunction (B) and respiratory failure (R). b Case 3 was diagnosed as Guillain-Barre´ syndrome based on his nerve conduction velocity showing axonal degeneration.
1 2 3b 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Patient Gender
Illness onset to paralysis
Table 3. Clinical Features, Magnetic Resonance Imaging (MRI) Findings, and Neurologic Outcomes of Enterovirus 71 Infection–Associated Acute Flaccid Paralysis.
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Table 4. Magnetic Resonance Imaging (MRI) Findings, Intravenous Immunoglobulin Administration, Disease Staging, and Motor Function Outcomes of Enterovirus 71 Infection–Associated Acute Flaccid Paralysis. Motor function outcomes MRI findings Normal results Stage 2 Stage 3 Stage 4 Lesions in the spinal cords Stage 2 Stage 3 Stage 4 Lesions in the brainstem lesion Stage 2 Stage 3 Stage 4 Lesions in both brainstem and spinal cord Stage 2 Stage 3 Stage 4 Intravenous immunoglobulin Yes Stage 2 Stage 3 Stage 4 No Stage 2 Stage 3 Stage 4
Total no. 3
4
8
11
20
7
Class I
Class II
Class III
2 1 1 0 1 1 (S) 0 0 2 2 0 0 3 1 (S) 1 (S) 1 (S)
1 0 1 0 0 0 0 0 4 1 0 3 1 0 0 1 (S)
0 0 0 0 2 2 0 0 0 0 0 0 4 2 1 1
5 2 2 1 3 3 0 0
3 1 0 2 3 0 1 2
6 4 1 1 1 0 1 0
(S)
(S) (S) (D)
Class IV
Class V
0 0 0 0 0 0 0 0 1 1 0 0 1 1 (D) 0 0
0 0 0 0 1 1 (S) 0 0 1 0 0 1 2 0 1 (D) 1 (S)
2 2 0 0 0 0 0 0
4 1 1 2 0 0 0 0
Abbreviations: D, diffuse lesion in the spinal cord; MRI, magnetic resonance imaging; S, segmental lesion in the spinal cord.
The duration of neurologic follow-up of acute flaccid paralysis ranged from 1 month to 5 years 10 months, with a median of 6 months. As shown in Table 3, 13 of the 27 patients (48%) exhibited unfavorable motor function outcomes in class III to class V, in whom 7 of 13 patients (54%) were in stage 2, 3 of 6 (50%) were in stage 3, and 3 of 8 (37%) were in stage 4. Other significant morbidities, including bulbar dysfunction and/or respiratory failure, were found in case 19, who was in stage 3, and cases 23, 26, and 27, who were in stage 4.
Discussion Our case series showed that 52% of patients exhibiting enterovirus 71 infection–associated acute flaccid paralysis were at disease stages 3 and 4. Among them, 93% of patients developed devastating clinical process under the age of 3 years. Younger age and limb weakness have been suggested to be one of the risk factors of critical enterovirus 71 cases in an epidemic and annual endemics in Taiwan.27,28 Fatal enterovirus 71 infection–associated paralytic diseases were also described in a severe epidemic of the central nervous system disease that occurred in Bulgaria in 1975, and the case fatality rate was 29.5% in the paralytic cases.11 Our findings were consistent with the literature that paralytic disease in infants and children
with enterovirus 71 infection could be a warning sign suggestive of possible progression to a fulminant disease course. Based on the national stage–based treatment guidelines for enterovirus 71 infection in Taiwan, intravenous immunoglobulin has been suggested to be used in infants and children with enterovirus 71–related acute flaccid paralysis. This treatment concept was employed on the presumptive basis that it would neutralize the virus and have anti-inflammatory properties.29,30 However, the merits and risks of intravenous immunoglobulin usage were unclear because such cases might exhibit rapid disease progression to autonomic nerve system dysregulation and may even develop left ventricular failure within hours. Under this circumstance, adequate fluid restriction for avoidance of left ventricular failure is crucial, and intravenous immunoglobulin administration might aggravate fluid overload.25,26 Our case series showed that 60% of patients who received intravenous immunoglobulin for enterovirus 71 infection–associated paralytic disease had unfavorable outcomes of motor function, that is, class III to class V. In contrast, 6 of 7 (86%) patients with various disease severities who did not receive intravenous immunoglobulin had favorable outcomes of motor function, that is, classes I and II. Our clinical observation showed that the usage of intravenous immunoglobulin in patients with enterovirus 71 infection–associated acute flaccid paralysis at disease
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Figure 1. Spinal magnetic resonance imaging (MRI) findings of enterovirus 71 infection–associated acute flaccid paralysis. (A and B) Spinal MRIs of case 19. (A) Sagittal view (TE/TR 87 ms/ 9000 ms) reveals high signal intensity in the dorsal aspects of pons and medulla, and the whole spinal cord. (B) Axial view (TE/TR 97 ms/ 3750 ms) reveals blurred high signal intensity in the cervical spinal cord. (C and D) Spinal MRIs of case 20. (C) Sagittal view (TE/TR 86ms/ 2800 ms) reveals high signal intensity in the dorsal aspect of pontomedullary junction, medulla, and cervical spinal cord. (D) Axial view (TE/TR 106 ms/ 5591 ms) reveals high signal intensity in the bilateral anterior horns of the cervical cord.
onset might not be able to predict long-term motor function outcomes. Nevertheless, there were limitations in this retrospective study because the number of cases was too small to compare between the patients with and without intravenous immunoglobulin therapy among different disease stages. The efficacy of intravenous immunoglobulin for treatment of infants and children with enterovirus 71 infection still needs to be confirmed.31,32 Regarding the first MRI findings in our case series, we observed that 100% of patients whose initial cranial and spinal MRI scans were normal had favorable outcomes. Further, 75%
of patients with isolated spinal cord signal changes manifested unfavorable motor function outcomes, with class III to class V classification, compared with 64% of patients with lesions in both the brainstem and spinal cord and 25% of patients with lesion sites in the brainstem. Hundred percent of the patients with diffuse lesions in whole spinal cords and brainstem involvement showed unfavorable motor function outcomes in class III to class V. Our study revealed that lesion sites in the spinal cords with or without brainstem involvement had a higher probability of unfavorable motor function outcomes during the period of neurologic follow-up. We also found that 54% of patients with stage 2 exhibited class III to class V motor function outcomes versus 23% of patients in stage 3, and 23% in stage 4 of enterovirus 71 infection–associated acute flaccid paralysis. Case 19, who was in stage 3, had antecedent illness (hand, foot, mouth disease) and exhibited acute flaccid paralysis on day 5 of disease course. He showed transient Cushing phenomenon followed by cold sweating and rapid progression to critical tachycardia and hypertension; however, there was no further progression of disease beyond the phase of autonomic nerve system dysfunction. His brain MRI and spinal cord MRI revealed prominent signal changes in the dorsal aspects of pons and medulla as well as diffuse lesion in the whole spinal cord (Figure 1A). He was rescued by intensive medical treatment, but suffered significant neurologic sequelae, including flaccid paralytic limbs at motor function in class V, bulbar dysfunction dependent on gastrostomy tube feeding, and respiratory failure with ventilator support. Case 20 developed a more devastating clinical course compared with that of case 19. Acute left ventricular failure with ejection fraction of left ventricle less than 30% accompanied by pulmonary edema and hemorrhage occurred during the acute disease course despite intensive medical treatment. Extracorporeal life support was conducted to rescue her heart function. Her brain MRI revealed characteristic features of enterovirus 71 infection with signal changes in the dorsal aspects of medulla and pontomedullary junction and linear high signal intensity in the cervical cord (Figure 1C). She recovered completely and no neurologic sequelae were noted during the follow-up period. This observation suggested that long-term follow-up motor function outcomes of enterovirus 71–related acute flaccid paralysis did not always correspond to the severity of disease staging at disease onset. In conclusion, the motor function outcomes during the period of long-term follow-up in patients with enterovirus 71–related acute flaccid paralysis were not always favorable. Lesion sites in the spinal cord with or without brainstem involvement on the MRI revealed a higher probability of unfavorable motor function outcomes. Nevertheless, the administration of intravenous immunoglobulin and the severity of disease staging at disease onset might not be able to predict long-term motor function outcomes. Author Contributions H-FL cared for the patients, performed data analysis, and wrote the first draft of the manuscript. C-SC cared for the patients, participated
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in the design of the study, supervised the data collection, and substantially revised the manuscript. 12.
Authors’ Note The study was performed at the Departments of Pediatrics of Taichung Veterans General Hospital and Tungs’ Taichung Metroharbor Hospital.
13.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval
14.
15.
16.
The study was approved by the Institutional Review Board of the Taichung Veterans General Hospital (IRB TCVGH No: CF12303). 17.
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