- Email: [email protected]
Central Nervous System Complications of Varicella-Zoster Virus
Central Nervous System Complications of Varicella-Zoster Virus Michelle Science, MD, MSc1, Daune MacGregor, MD2,3, Susan E. Richardson, MD4,5, Sanjay Mahant, MD, MSc2, Dat Tran, MD, MSc1,2, and Ari Bitnun, MD, MSc1,2 Objective To describe the spectrum of central nervous system complications of varicella-zoster virus (VZV) in children admitted to The Hospital for Sick Children between January 1999 and December 2012.
Study design Children aged 1 month to 18 years (n = 84) admitted with neurologic manifestations associated with a characteristic VZV rash or a confirmatory laboratory test (positive lesion scraping or cerebrospinal fluid polymerase chain reaction) were included in the study. Acute neurologic complications were included if they occurred within 4 weeks of VZV infection. Stroke was considered related to VZV if it occurred within 6 months of VZV infection, the neuroimaging was characteristic, and other causes were excluded. Results Clinical syndromes included acute cerebellar ataxia (n = 26), encephalitis (n = 17), isolated seizures (n = 16), syndrome (n = 2), acute disseminated encephalomyelitis (n = 2), and stroke (n = 10), meningitis (n = 10), Guillain-Barre Ramsay Hunt syndrome (n = 1). In those with acute complications (nonstroke), neurologic symptoms occurred a median of 5 days after rash onset (range 6 to +16). The time between rash onset and stroke ranged from 2 weeks to 26 weeks (median 16.0 weeks). Three children with encephalitis died. Residual neurologic sequelae at one year occurred in 9 of 39 (23%) of children with follow-up data. Only 4 children were reported to have received the varicella vaccine. Conclusion Neurologic complications of VZV infection continue to occur despite the availability of an effective vaccine. Neurologic symptom onset can predate the appearance of the VZV exanthem and in rare cases may occur in the absence of an exanthem. (J Pediatr 2014;165:779-85).
C
entral nervous system (CNS) complications of varicella-zoster virus (VZV) are uncommon. Population-based epidemiologic studies undertaken in the pre-VZV vaccine era suggest an incidence of 1 to 3 per 10 000 varicella cases.1,2 Such complications, although rare, are a leading cause of VZV-associated hospital admission3-5 and can be associated with significant long-term morbidity and mortality.6 Although a significant reduction in the incidence of chickenpox and its complications have been documented after the introduction of the VZV vaccine,7,8 there remains a paucity of data specifically pertaining to the impact of vaccine availability on neurologic complications. The live, attenuated VZV vaccine was approved for use in Canada in December 1998 to prevent VZV infection and its complications. Recommendations for its use in healthy, susceptible individuals older than 1 year of age were published by the National Advisory Committee on Immunization in May 1999.9 Public funding of universal varicella vaccination in Ontario began in September 2004. The objective of this study was to describe the spectrum of neurologic complications associated with VZV, their clinical presentation, and outcome before and after the public funding of the VZV vaccine in Ontario.
Methods All children ages 1 month to 18 years admitted to The Hospital for Sick Children (SickKids) between January 1999 and December 2012 with neurologic manifestations associated with a characteristic VZV rash or a confirmatory laboratory test (positive lesion scraping or cerebrospinal fluid [CSF] polymerase chain reaction [PCR]) were included in the study. Cases were identified using 4 independent sources: the SickKids Encephalitis Registry, the Infectious Disease inpatient consult service database, International Classification of Diseases, 9th Revision (ICD-9) or International Classification of Diseases, 10th Revision (ICD-10) discharge codes from the Health Records database and the Department of Pediatric Laboratory Medicine database. The SickKids Encephalitis Registry is a prospective registry in place since 1994. Enrollment criteria, data collection, and investigations have been described previously.10 The data for the Encephalitis Registry are collected by a dedicated study nurse who identifies patients by daily ADEM CNS CSF ICD-9 ICD-10 PCR SickKids VZV
Acute disseminated encephalomyelitis Central nervous system Cerebrospinal fluid International Classification of Diseases, 9th Revision International Classification of Diseases, 10th Revision Polymerase chain reaction The Hospital for Sick Children Varicella-zoster virus
From the 1Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children; 2Department of Pediatrics, University of Toronto; 3Division of Neurology, Department of Pediatrics, 4Division of Microbiology, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children; and 5 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.06.014
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review of admissions and quarterly review of ICD-9 or ICD-10 codes. All patients with the ICD-9 discharge codes “post-varicella encephalitis,” “varicella with other specified complications,” “varicella with unspecified complication,” and the ICD-10 codes “varicella encephalitis,” “varicella meningitis,” or “varicella with other complication,” were screened for possible inclusion. The Infectious Disease consult service database contains information on all patients with which the Infectious Disease team is involved when admitted to hospital. Finally, the Department of Pediatric Laboratory Medicine database was used to identify patients with positive CSF VZV PCR test results. Ethical approval for the study was obtained from the Research Ethics Board of at SickKids. Neurologic complications were grouped as acute nonstroke complications and stroke (acute or nonacute). A VZVassociated acute nonstroke neurologic complication was defined as the onset of neurologic symptom(s) 4 weeks before to 4 weeks after the VZV rash or detection of VZV within the CSF and the absence of an alternative explanation for the symptom(s). Encephalitis was defined as the presence of encephalopathy (altered level of consciousness including lethargy, irritability, or personality or behavioral change persisting $24 hours) and 2 or more of the following: fever ($38 C), seizure, focal CNS findings, CSF pleocytosis (>5 white blood cells/mm3), electroencephalogram abnormalities, or diagnostic imaging abnormalities consistent with encephalitis.10 The presence of ataxia without evidence of encephalitis was diagnostic of acute cerebellar ataxia. VZV-associated stroke was defined as the development of focal neurologic deficits accompanied by neuroimaging abnormalities indicating cerebral ischemia, infarction, or hemorrhage with angiographic evidence of the characteristic vasculopathy (narrowing or beading in cerebral
Vol. 165, No. 4 arteries)11 within 6 months of VZV infection and exclusion of other causes. Six months was chosen on the basis of a recent study in which the authors found that children with chickenpox were at increased risk of stroke in the subsequent 6 months.12 Neurologic impairment was considered “minor” if near full recovery was expected, there was minimal or no impact on function, and strength was $4 of 5 on the motor strength scale. Neurologic outcomes were considered to be “major” if they had significant impact on function or there was focal weakness with strength <4 of 5 on the motor strength scale. Statistical Analyses Statistical analysis was performed using SPSS version 20 (SPSS Inc, Chicago, Illinois). Medians and proportions were used to describe continuous and categorical variables, respectively. Admission rates to SickKids were compared before and after September 1, 2004. The total number of admissions related to VZV-neurologic complications for each time period was divided by the total number of hospitalizations to the inpatient units over the same time period.
Results A total of 84 children with neurologic complications associated with VZV infection were admitted to SickKids between January 1999 and December 2012 (Figure 1). The rate of admission with VZV-related CNS complications to SickKids was 55 per 100 000 before full vaccine coverage in Ontario (September 1, 2004) and 20 per 100 000 after full coverage. The median age was 7.3 years (range, 4 months to 16.5 years); 49% were male. Most had no underlying medical conditions (n = 68; 81%). The remainder had neurologic or
Figure 1. Number of admissions for VZV-associated CNS complications per year. NACI, National Advisory Committee on Immunization. 780
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October 2014 developmental disorders (n = 6), malignancy (n = 5), skin disorder (n = 1), genitourinary disorder (n = 1), AIDS (n = 1), Crohn’s disease on immunomodulator therapy (n = 1), or suspected primary immunodeficiency (n = 1). Only 4 of 84 subjects were reported to have received the varicella vaccine. Of the 55 subjects who had a clear history of not receiving the vaccine, 45 (82%) were eligible for vaccination according to the National Advisory Committee on Immunization guidelines. Fourteen (31%) of these subjects were hospitalized after September 1, 2004, when free universal VZV vaccination was implemented in Ontario. Of the 24 subjects eligible for vaccination in whom the caregiver was uncertain of previous VZV vaccination, only 5 (19%) were admitted after September 1, 2004 (Figure 2). Because none of the caregivers of the remaining 19 children recalled purchasing the vaccine, it is almost certain the vaccine was not administered to these subjects. Acute nonstroke neurologic complications accounted for 88% (n = 74) of VZV-associated neurologic complications. Acute cerebellar ataxia was most common (n = 26), followed by encephalitis (n = 17), isolated seizures (n = 16), meningitis (n = 10), demyelinating conditions (n = 4), and Ramsey Hunt Syndrome (n = 1). The clinical characteristics and laboratory features according to CNS complication are shown in Table I. The median interval between onset of rash and onset of neurologic manifestations was 5 days (range 6 days before to 16 days after the appearance of rash). Five patients presented with neurologic symptoms before the development of the rash; two with a febrile seizure 1 day before the rash, one with ataxia 6 days before rash, and one each with encephalitis and meningitis 3 days before rash. Two subjects with meningitis never developed the typical exanthem. Both were teenagers presenting with fever, headache, and photophobia; both had CSF pleocytosis; and in both VZV
was detected by PCR in the CSF. One subject had Crohn’s disease and was on an antitumor necrosis factor agent (infliximab). The other had a history of chicken pox at 18 months of age but no underlying medical conditions. Ten patients (12%) had VZV-associated stroke. Their clinical characteristics and laboratory features are summarized in Table II. The median age was 4.25 years (range, 2-11.5 years); 50% were male. Only 1 patient had underlying immunodeficiency. The interval between VZV exanthem and onset of neurologic symptoms ranged from 2 to 26 weeks (median, 16.0 weeks). Lumbar puncture, obtained in 7 patients, revealed a median white blood cell count of 2 cells 106/L (range, 0-84) and median protein of 19 mg/dL (range, <10-133 mg/dL). Overall, CSF was evaluated for the presence of VZV DNA by PCR in 46 subjects. VZV was detected in 6 of 7 (86%) patients with meningitis, 3 of 12 (25%) patients with encephalitis, 1 of 9 (11%) patients with acute cerebellar ataxia, 1 of 10 (10%) patients with isolated seizures, and 1 of 5 (20%) patients with stroke. The patient with stroke also initially had clinical signs of meningitis. CSF PCR was negative in all those tested with demyelinating conditions (n = 3). All positive PCR tests were performed within 5 days of neurologic symptom onset. Five of the 12 patients with positive PCR testing were immunocompromised (P = .003). Management and Outcome Among patients presenting with acute nonstroke complications, the median duration of hospitalization was 5 days (range, 1-58 days). Patients with demyelinating conditions and encephalitis had the longest admissions, ranging from 6 to 31 days (median, 14 days) and from 3 to 58 days (median, 11.5 days), respectively. Eight patients required admission to the intensive care unit, 5 with encephalitis and one
Figure 2. Vaccination status of participants with CNS complications. Central Nervous System Complications of Varicella-Zoster Virus
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Table I. Clinical characteristics of acute nonstroke neurologic complications of VZV infection CSFx Syndrome
Age,* median, y
Onset,† Sex, % M median (range), d
VZV diagnosisz
WBC,* cells/mm3
Protein,* mg/dL
Acute cerebellar ataxia (n = 26)
7.0 (4.0, 8.0)
54
7 (6 to +14)
Clinical (n = 25) PCR: CSF (n = 1)
12.0 (6.0, 51.0)
23 (16, 31)
Encephalitis (n = 17)
8.0 (7.0, 10.5)
29
5 (3 to +16)
18.5 (2.0, 105.0)
23 (18, 43)
3 (0.5, 7.5)
50
2 (1 to +6)
Clinical (n = 12) PCR: CSF (n = 2), skin (n = 2) both skin and CSF (n = 1) Clinical (n = 10) PCR: CSF (n = 1), skin (n = 5)
2 (0.5, 2.0)
15 (14, 18)
13.0 (8.0, 14.5)
60
4 (3 to +6)
ADEM (n = 2)
8, 15
50
3, 12
GBS (n = 2)
4, 12
50
10, 15
Isolated seizures (n = 16; febrile n = 12, afebrile n = 4) Meningitis (n = 10)
Neuroimaging{ CT (n = 12): normal MRI (n = 5): 2 abnormal – increased T2 signal in posterior occipital and cerebellar regions and increased FLAIR in cerebellum CT (n = 11): abnormal in 2 subjects MRI (n = 12): abnormal in 7 subjects
CT (n = 9): normal MRI (n = 2): 1 abnormal: nonspecific peritrigonal WM signal changes unknown significance Clinical (n = 4) 337.5 (171.0, 439.0) 61 CT (n = 4): normal PCR: CSF (n = 5), (42, 102) MRI (n = 1): normal both skin and CSF (n = 1) Clinical (n = 2) 44, 69 39, 65 MRI (n = 2): abnormal in both. Extensive signal abnormalities and WM changes in brain and spinal cord Clinical (n = 2) 9, ND 130, ND CT (n = 1): normal MRI (n = 1): thickened nerve roots
CT, computed tomography; FLAIR, fluid-attenuated inversion recovery; GBS, Guillain-Barre syndrome; M, male; MRI, magnetic resonance imaging; ND, not done; WBC, white blood cell; WM, white matter. *Depicted as median (IQR); for ADEM and GBS, specific values are provided because there were only 2 cases in each category. †Interval between onset of rash and onset of neurologic manifestation in days ( indicates onset before rash, + indicates onset after rash). zA clinical diagnosis of VZV was based on the presence of the characteristic vesicular rash at the time of hospitalization. xCSF sample analyzed: cerebellar ataxia (n = 15, 61%); isolated seizures (n = 13, 81%); encephalitis (n = 12, 71%); meningitis (n = 10, 100%); for ADEM and GBS cases, specific values are provided because there were only 2 cases in each category. {Neuroimaging performed: cerebellar ataxia (n = 16); isolated seizures (n = 9); encephalitis (n = 16); meningitis (n = 4), ADEM (n = 2), GBS (n = 1).
each with acute disseminated encephalomyelitis (ADEM), seizures, and Guillain-Barre syndrome. Fifty-two patients (70%) received intravenous acyclovir, including all those with encephalitis and ADEM. Seven or more days of acyclovir was administered to 4%, 30%, 50%, and 76% of those with cerebellar ataxia, meningitis, ADEM, and encephalitis, respectively. Among those with acute nonstroke CNS VZV complications, outcomes were most severe for patients with encephalitis and ADEM. At discharge from hospital, 1 of the 2 patients with ADEM had major neurologic impairment. Three patients with encephalitis died. Residual neurologic impairment was present at 1 year in 2 patients with encephalitis and 1 patient with ADEM. Three children who initially presented with isolated seizures went on to develop seizure disorders and had abnormal neurologic evaluations at 1 year. All of the patients with 1-year follow-up data who had acute cerebellar ataxia (n = 7), meningitis (n = 4), and Guillain-Barre syndrome (n = 2) had normal examinations. Patients with stroke were admitted for a median of 10.5 days (range, 2-79 days); 1 required intensive care. Treatment with acyclovir was given to 3 patients (30%) for a median of 782
28 days; 1 was immunocompromised with herpes zoster, and 2 were previously healthy, 1 with chickenpox and 1 without skin lesions or signs of disseminated disease. At discharge from hospital, severe neurologic impairment was present in 40% of patients (Table II). Two patients had complete resolution of their symptoms. After 1 year, neurologic deficits persisted in 3 children (33%).
Discussion The lack of widespread uptake of the VZV vaccine in our community, both before and after universal vaccination in a universal health care system, likely resulted in a persistence of the occurrence of neurologic complications of VZV infection, many with severe clinical outcomes. All of the children in our cohort were admitted to the hospital after the VZV vaccine was approved for use in Canada in 1999, and only 4 reported receiving the vaccine. Nineteen were admitted after September 2004 when full vaccine coverage was provided by the Ministry of Health and Long Term Care, Ontario. Thus, a failure of primary prevention through vaccination, rather than vaccine failure per se, was an issue. This finding Science et al
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Central Nervous System Complications of Varicella-Zoster Virus
Table II. Clinical characteristics of children with VZV-associated stroke CSF
Outcome
Age, y
Sex
Onset,* wk
WBC, cells/mm3
Protein, mg/dL
PCR
Clinical presentation
1
2
M
25.5
ND
ND
ND
2
3.5
F
14
13
<10
3
5
F
18.5
17
4
3
M
17
5
8
F
6
3
M
7 8
3.5 10
M F
9
11.5
F
10
9.0
M
Patient
VZV diagnosis†
Neuroimaging
Right hemiparesis
Clinical
ND
Left hemiparesis
Clinical
19
ND
Slurred speech Left hemiparesis
Clinical
0
<10
NEG
Right hemiparesis
Clinical
Focal infarct posterior limb of internal capsule on left and narrowing of ICA Right MCA infarct, narrowing distal right internal carotid Right MCA ischemic changes and right ICA abnormalities in M1/A1 segments of MCA and ACA Left MCA infarct
24.5
0
18
NEG
Right hemiparesis
Clinical
8.5
ND
ND
ND
Right sided weakness Right facial droop
Clinical
15 2
2 ND
20 ND
NEG ND
Left facial weakness Right hemiparesis
Clinical
26
2
14
NEG
Right hemiparesis
Clinical
84
133
POS
Blurred vision and hallucinations
Clinical (zoster) and lesion scrape PCR-POS
6.5
1 year Normal
Left arm and leg hemiplegia
Increased tone left side, power 4/5
Mild left sided weakness
Normal exam
Right sided weakness, walking with support Right sided weakness, word finding difficulties Mild weakness
Mild right hemiparesis Weakness right arm, short term memory problems Normal exam
CN VII palsy Hemiparesis, speech difficulties
None available Normal
Right facial droop, mild weakness
Normal
Normal
Normal
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ACA, anterior cerebral artery; CN, cranial nerve; F, female; ICA, internal carotid artery; MCA, middle cerebral artery; NEG, negative; POS, positive. *Interval between onset of rash and onset of neurologic manifestation in days ( indicates onset before rash, + indicates onset after rash). †A clinical diagnosis of VZV was based on a record in the patient’s chart of chickenpox during the 6 months preceding the stroke.
MCA infarct and left ICA narrowing Restricted diffusion left caudate head and body and left putamen Right thalamic infarct Several focal areas of hypoattenuation c/w multiple infarcts Small acute infarcts involving left globus pallidus/left internal capsule and enhancement along the vessel with narrowing at left origin of MCA Small focus of infarction with micro hemorrhagic transformation in the left midbrain tegmentum in the region of the left P1 posteromedial perforator
Discharge Normal
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is consistent with recent literature from Public Health Ontario showing vaccine coverage is lowest in Ontario for varicella (47.2% among 7-year-old subjects).13 A second point of failure was with respect to secondary prevention. When administered to contacts within 3 days of exposure to VZV, and possibly within 5 days, vaccine has been shown to be over 90% effective in preventing disease.14,15 In our cohort, 55% of the children had a documented exposure to chickenpox, mainly a sibling (41%), yet none received postexposure vaccination. Had current guidelines pertaining to postexposure vaccination been followed, a significant number of these neurologic complications could have potentially been averted.16 None of the 6 immunocompromised patients in our cohort had a documented chickenpox exposure, and therefore, their disease would not have been remediable by postexposure immunoglobulin. The spectrum of neurologic complications in our cohort was similar to that of previous studies with acute cerebellar ataxia being most common, accounting for one-third of cases.2,17 The number of patients with stroke was greater than in other cohorts,6 possibly reflecting the presence of a stroke program at our institution and referral bias. As expected, complete neurologic recovery was observed for subjects with acute cerebellar ataxia, isolated seizures and meningitis. In contrast, one-third of children with encephalitis or ADEM died or suffered long-term neurologic sequelae. A previous review of children hospitalized at our institution between 1956 and 1967 noted a mortality rate of 35% in those with VZV encephalitis.18 Similar to previous reports,19,20 the prognosis for VZV-associated stroke was poor with only 2 of 10 demonstrating complete resolution of symptoms at hospital discharge. The phenomena of neurologic disease due to VZV manifesting prior to, or in the absence of exanthem in children is an uncommon but important observation. This scenario has been well documented in immunocompromised individuals, but is less well recognized in the context of the immunocompetent host.21 In our cohort, 5 immunocompetent patients developed neurologic manifestations prior to the exanthem, none of whom had been previously vaccinated. These cases serve to reinforce the need to consider VZV as a potential cause of neurologic disease even if the typical exanthem is not present at the time of neurologic symptom onset. Two subjects never developed an exanthem and had VZV meningitis confirmed by PCR analysis of the CSF. These latter cases illustrate the possibility of end organ disease due to VZV in the absence of an exanthem. Furthermore, one of these cases had a history of chickenpox at 18 months of age. In this circumstance, meningitis may reflect reactivation of the virus, which has been described previously.22 Analysis of CSF by PCR can be important for the diagnosis of VZV-associated CNS disease particularly in the absence of rash. In our cohort, we found CSF VZV PCR was most sensitive for the diagnosis of meningitis where 83% of the specimens tested were positive, 2 in the absence of rash. Outside of meningitis, 6 (15%) of the 39 specimens tested were positive. Therefore, the absence of detectable VZV DNA in the 784
Vol. 165, No. 4 CSF does not preclude the possibility of VZV neurologic complications. This is likely related to the fact that VZV is a highly cell-associated virus and the utility of PCR in nonmeningeal disease may be low.23 Concerns regarding the sensitivity of CSF PCR for the diagnosis of encephalitis have been raised in other studies,24,25 which questions the sole use of PCR for diagnosis. It has been suggested that serum and cerebrospinal IgM may be valuable additions to PCR especially when the diagnosis is in question because of the absence of rash.24 Key limitations of this study were its restriction to a single center and predominant retrospective design. As our institution is a tertiary care center, disease spectrum was likely skewed towards the more severe end. The availability of a stroke program, encephalitis registry, and demyelination program also may have contributed to the relatively high proportion of subjects with stroke, encephalitis, and ADEM. Long-term follow-up was inconsistent particularly for children with milder disease, likely reflecting the fact that such children were followed in the community. Furthermore, although much of the data were collected prospectively, this was not the case for outcome assessment. Thus, the outcome data should be viewed as incomplete. In our setting of universal health care and vaccination program, incomplete uptake of standard primary and postexposure vaccination recommendations was implicated as a key factor in the ongoing occurrence of these complications with 69 of 80 unvaccinated children being vaccine eligible (age 12 months or older and immunocompetent). Clinicians should be aware that neurologic symptom onset can predate the appearance of the VZV exanthem and in rare cases, involving immunocompromised individuals, may occur in the absence of an exanthem. n Submitted for publication Dec 20, 2013; last revision received Apr 14, 2014; accepted Jun 5, 2014. Reprint requests: Ari Bitnun, MD, MSc, FRCPC, Division of Infectious Diseases, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8. E-mail: [email protected]
References 1. Choo PW, Donahue JG, Manson JE, Platt R. The epidemiology of varicella and its complications. J Infect Dis 1995;172:706-12. 2. Guess HA, Broughton DD, Melton LJ III, Kurland LT. Population-based studies of varicella complications. Pediatrics 1986;78:723-7. 3. Koturoglu G, Kurug€ ol Z, Cetin N, Hizarcioglu M, Vardar F, Helvaci M, et al. Complications of varicella in healthy children in Izmir, Turkey. Pediatr Int 2005;47:296-9. 4. Liese J, Grote V, Rosenfeld E, Fischer R, Belohradsky B, v Kries R. The burden of varicella complications before the introduction of routine varicella vaccination in Germany. Pediatr Infect Dis J 2008;27:119-24. 5. Ziebold C, von Kries R, Lang R, Weigl J, Schmitt H. Severe complications of varicella in previously healthy children in Germany: a 1-year survey. Pediatrics 2001;108:E79. 6. Rack A, Grote V, Streng A, Belohradsky B, Heinen F, von Kries R, et al. Neurologic varicella complications before routine immunization in Germany. Pediatr Neurol 2010;42:40-8. 7. Seward JF, Watson BM, Peterson CL, Mascola L, Pelosi JW, Zhang JX, et al. Varicella disease after introduction of varicella vaccine in the United States, 1995-2000. JAMA 2002;287:606-11.
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October 2014 8. Spackova M, Muehlen M, Siedler A. Complications of varicella after implementation of routine childhood varicella vaccination in Germany. Pediatr Infect Dis J 2010;29:884-6. 9. NACI. An advistory committee statement. Statement on recommended use of varicella virus vaccine. Can Commun Dis Rep 1999; 25(ACS-1):1-16. 10. Kolski H, Ford-Jones E, Richardson S, Petric M, Nelson S, Jamieson F, et al. Etiology of acute childhood encephalitis at The Hospital for Sick Children, Toronto, 1994-1995. Clin Infect Dis 1998;26:398-409. 11. Nagel M, Cohrs R, Mahalingam R, Wellish M, Forghani B, Schiller A, et al. The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features. Neurology 2008;70:853-60. 12. Thomas SL, Minassian C, Ganesan V, Langan SM, Smeeth L. Chickenpox and risk of stroke: a self-controlled case series analysis. Clin Infect Dis 2014;58:61-8. 13. Public Health Ontario (PHO). Summary of immunization coverage for Ontario school pupils, 2011/12 school year. Monthly Infect Dis Surveillance Rep 2013;2:7-10, http://www.publichealthontario.ca/en/DataAnd Analytics/Documents/PHO_Monthly_Infectious_Diseases_Surveillance_ Report_-_December_2013.pdf. Accessed June 12, 2014. 14. Watson B, Seward J, Yang A, Witte P, Lutz J, Chan C, et al. Postexposure effectiveness of varicella vaccine. Pediatrics 2000;105:84-8. 15. Salzman MB, Garcia C. Postexposure varicella vaccination in siblings of children with active varicella. Pediatr Infect Dis J 1998;17:256-7. 16. American Academy of Pediatrics Committee on Infectious Diseases. Prevention of varicella: recommendations for use of varicella vaccines in
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children, including a recommendation for a routine 2-dose varicella immunization schedule. Pediatrics 2007;120:221-31. Connolly A, Dodson W, Prensky A, Rust R. Course and outcome of acute cerebellar ataxia. Ann Neurol 1994;35:673-9. Johnson R, Milbourn P. Central nervous system manifestations of chickenpox. Can Med Assoc J 1970;102:831-4. Ganesan V, Hogan A, Shack N, Gordon A, Isaacs E, Kirkham FJ. Outcome after ischaemic stroke in childhood. Dev Med Child Neurol 2000;42:455-61. Askalan R, Laughlin S, Mayank S, Chan A, MacGregor D, Andrew M, et al. Chickenpox and stroke in childhood: a study of frequency and causation. Stroke 2001;32:1257-62. Leahy T, Webb D, Hoey H, Butler K. Varicella zoster virus associated acute aseptic meningitis without exanthem in an immunocompetent 14-year-old boy. Pediatr Infect Dis J 2008;27:362-3. Esposito S, Bosis S, Pinzani R, Morlacchi L, Senatore L, Principi N. A case of meningitis due to varicella zoster virus reactivation in an immunocompetent child. Italian J Pediatr 2013;39:72. Nagel M, Forghani B, Mahalingam R, Wellish M, Cohrs R, Russman A, et al. The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology 2007;68:1069-73. Koskiniemi M, Piiparinen H, Rantalaiho T, Er€ank€ o P, F€arkkil€a M, R€aih€a K, et al. Acute central nervous system complications in varicella zoster virus infections. J Clin Virol 2002;25:293-301. Gilden D, Kleinschmidt-DeMasters B, LaGuardia J, Mahalingam R, Cohrs R. Neurologic complications of the reactivation of varicellazoster virus. N Engl J Med 2000;342:635-45.
785
Study design Children aged 1 month to 18 years (n = 84) admitted with neurologic manifestations associated with a characteristic VZV rash or a confirmatory laboratory test (positive lesion scraping or cerebrospinal fluid polymerase chain reaction) were included in the study. Acute neurologic complications were included if they occurred within 4 weeks of VZV infection. Stroke was considered related to VZV if it occurred within 6 months of VZV infection, the neuroimaging was characteristic, and other causes were excluded. Results Clinical syndromes included acute cerebellar ataxia (n = 26), encephalitis (n = 17), isolated seizures (n = 16), syndrome (n = 2), acute disseminated encephalomyelitis (n = 2), and stroke (n = 10), meningitis (n = 10), Guillain-Barre Ramsay Hunt syndrome (n = 1). In those with acute complications (nonstroke), neurologic symptoms occurred a median of 5 days after rash onset (range 6 to +16). The time between rash onset and stroke ranged from 2 weeks to 26 weeks (median 16.0 weeks). Three children with encephalitis died. Residual neurologic sequelae at one year occurred in 9 of 39 (23%) of children with follow-up data. Only 4 children were reported to have received the varicella vaccine. Conclusion Neurologic complications of VZV infection continue to occur despite the availability of an effective vaccine. Neurologic symptom onset can predate the appearance of the VZV exanthem and in rare cases may occur in the absence of an exanthem. (J Pediatr 2014;165:779-85).
C
entral nervous system (CNS) complications of varicella-zoster virus (VZV) are uncommon. Population-based epidemiologic studies undertaken in the pre-VZV vaccine era suggest an incidence of 1 to 3 per 10 000 varicella cases.1,2 Such complications, although rare, are a leading cause of VZV-associated hospital admission3-5 and can be associated with significant long-term morbidity and mortality.6 Although a significant reduction in the incidence of chickenpox and its complications have been documented after the introduction of the VZV vaccine,7,8 there remains a paucity of data specifically pertaining to the impact of vaccine availability on neurologic complications. The live, attenuated VZV vaccine was approved for use in Canada in December 1998 to prevent VZV infection and its complications. Recommendations for its use in healthy, susceptible individuals older than 1 year of age were published by the National Advisory Committee on Immunization in May 1999.9 Public funding of universal varicella vaccination in Ontario began in September 2004. The objective of this study was to describe the spectrum of neurologic complications associated with VZV, their clinical presentation, and outcome before and after the public funding of the VZV vaccine in Ontario.
Methods All children ages 1 month to 18 years admitted to The Hospital for Sick Children (SickKids) between January 1999 and December 2012 with neurologic manifestations associated with a characteristic VZV rash or a confirmatory laboratory test (positive lesion scraping or cerebrospinal fluid [CSF] polymerase chain reaction [PCR]) were included in the study. Cases were identified using 4 independent sources: the SickKids Encephalitis Registry, the Infectious Disease inpatient consult service database, International Classification of Diseases, 9th Revision (ICD-9) or International Classification of Diseases, 10th Revision (ICD-10) discharge codes from the Health Records database and the Department of Pediatric Laboratory Medicine database. The SickKids Encephalitis Registry is a prospective registry in place since 1994. Enrollment criteria, data collection, and investigations have been described previously.10 The data for the Encephalitis Registry are collected by a dedicated study nurse who identifies patients by daily ADEM CNS CSF ICD-9 ICD-10 PCR SickKids VZV
Acute disseminated encephalomyelitis Central nervous system Cerebrospinal fluid International Classification of Diseases, 9th Revision International Classification of Diseases, 10th Revision Polymerase chain reaction The Hospital for Sick Children Varicella-zoster virus
From the 1Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children; 2Department of Pediatrics, University of Toronto; 3Division of Neurology, Department of Pediatrics, 4Division of Microbiology, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children; and 5 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.06.014
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review of admissions and quarterly review of ICD-9 or ICD-10 codes. All patients with the ICD-9 discharge codes “post-varicella encephalitis,” “varicella with other specified complications,” “varicella with unspecified complication,” and the ICD-10 codes “varicella encephalitis,” “varicella meningitis,” or “varicella with other complication,” were screened for possible inclusion. The Infectious Disease consult service database contains information on all patients with which the Infectious Disease team is involved when admitted to hospital. Finally, the Department of Pediatric Laboratory Medicine database was used to identify patients with positive CSF VZV PCR test results. Ethical approval for the study was obtained from the Research Ethics Board of at SickKids. Neurologic complications were grouped as acute nonstroke complications and stroke (acute or nonacute). A VZVassociated acute nonstroke neurologic complication was defined as the onset of neurologic symptom(s) 4 weeks before to 4 weeks after the VZV rash or detection of VZV within the CSF and the absence of an alternative explanation for the symptom(s). Encephalitis was defined as the presence of encephalopathy (altered level of consciousness including lethargy, irritability, or personality or behavioral change persisting $24 hours) and 2 or more of the following: fever ($38 C), seizure, focal CNS findings, CSF pleocytosis (>5 white blood cells/mm3), electroencephalogram abnormalities, or diagnostic imaging abnormalities consistent with encephalitis.10 The presence of ataxia without evidence of encephalitis was diagnostic of acute cerebellar ataxia. VZV-associated stroke was defined as the development of focal neurologic deficits accompanied by neuroimaging abnormalities indicating cerebral ischemia, infarction, or hemorrhage with angiographic evidence of the characteristic vasculopathy (narrowing or beading in cerebral
Vol. 165, No. 4 arteries)11 within 6 months of VZV infection and exclusion of other causes. Six months was chosen on the basis of a recent study in which the authors found that children with chickenpox were at increased risk of stroke in the subsequent 6 months.12 Neurologic impairment was considered “minor” if near full recovery was expected, there was minimal or no impact on function, and strength was $4 of 5 on the motor strength scale. Neurologic outcomes were considered to be “major” if they had significant impact on function or there was focal weakness with strength <4 of 5 on the motor strength scale. Statistical Analyses Statistical analysis was performed using SPSS version 20 (SPSS Inc, Chicago, Illinois). Medians and proportions were used to describe continuous and categorical variables, respectively. Admission rates to SickKids were compared before and after September 1, 2004. The total number of admissions related to VZV-neurologic complications for each time period was divided by the total number of hospitalizations to the inpatient units over the same time period.
Results A total of 84 children with neurologic complications associated with VZV infection were admitted to SickKids between January 1999 and December 2012 (Figure 1). The rate of admission with VZV-related CNS complications to SickKids was 55 per 100 000 before full vaccine coverage in Ontario (September 1, 2004) and 20 per 100 000 after full coverage. The median age was 7.3 years (range, 4 months to 16.5 years); 49% were male. Most had no underlying medical conditions (n = 68; 81%). The remainder had neurologic or
Figure 1. Number of admissions for VZV-associated CNS complications per year. NACI, National Advisory Committee on Immunization. 780
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October 2014 developmental disorders (n = 6), malignancy (n = 5), skin disorder (n = 1), genitourinary disorder (n = 1), AIDS (n = 1), Crohn’s disease on immunomodulator therapy (n = 1), or suspected primary immunodeficiency (n = 1). Only 4 of 84 subjects were reported to have received the varicella vaccine. Of the 55 subjects who had a clear history of not receiving the vaccine, 45 (82%) were eligible for vaccination according to the National Advisory Committee on Immunization guidelines. Fourteen (31%) of these subjects were hospitalized after September 1, 2004, when free universal VZV vaccination was implemented in Ontario. Of the 24 subjects eligible for vaccination in whom the caregiver was uncertain of previous VZV vaccination, only 5 (19%) were admitted after September 1, 2004 (Figure 2). Because none of the caregivers of the remaining 19 children recalled purchasing the vaccine, it is almost certain the vaccine was not administered to these subjects. Acute nonstroke neurologic complications accounted for 88% (n = 74) of VZV-associated neurologic complications. Acute cerebellar ataxia was most common (n = 26), followed by encephalitis (n = 17), isolated seizures (n = 16), meningitis (n = 10), demyelinating conditions (n = 4), and Ramsey Hunt Syndrome (n = 1). The clinical characteristics and laboratory features according to CNS complication are shown in Table I. The median interval between onset of rash and onset of neurologic manifestations was 5 days (range 6 days before to 16 days after the appearance of rash). Five patients presented with neurologic symptoms before the development of the rash; two with a febrile seizure 1 day before the rash, one with ataxia 6 days before rash, and one each with encephalitis and meningitis 3 days before rash. Two subjects with meningitis never developed the typical exanthem. Both were teenagers presenting with fever, headache, and photophobia; both had CSF pleocytosis; and in both VZV
was detected by PCR in the CSF. One subject had Crohn’s disease and was on an antitumor necrosis factor agent (infliximab). The other had a history of chicken pox at 18 months of age but no underlying medical conditions. Ten patients (12%) had VZV-associated stroke. Their clinical characteristics and laboratory features are summarized in Table II. The median age was 4.25 years (range, 2-11.5 years); 50% were male. Only 1 patient had underlying immunodeficiency. The interval between VZV exanthem and onset of neurologic symptoms ranged from 2 to 26 weeks (median, 16.0 weeks). Lumbar puncture, obtained in 7 patients, revealed a median white blood cell count of 2 cells 106/L (range, 0-84) and median protein of 19 mg/dL (range, <10-133 mg/dL). Overall, CSF was evaluated for the presence of VZV DNA by PCR in 46 subjects. VZV was detected in 6 of 7 (86%) patients with meningitis, 3 of 12 (25%) patients with encephalitis, 1 of 9 (11%) patients with acute cerebellar ataxia, 1 of 10 (10%) patients with isolated seizures, and 1 of 5 (20%) patients with stroke. The patient with stroke also initially had clinical signs of meningitis. CSF PCR was negative in all those tested with demyelinating conditions (n = 3). All positive PCR tests were performed within 5 days of neurologic symptom onset. Five of the 12 patients with positive PCR testing were immunocompromised (P = .003). Management and Outcome Among patients presenting with acute nonstroke complications, the median duration of hospitalization was 5 days (range, 1-58 days). Patients with demyelinating conditions and encephalitis had the longest admissions, ranging from 6 to 31 days (median, 14 days) and from 3 to 58 days (median, 11.5 days), respectively. Eight patients required admission to the intensive care unit, 5 with encephalitis and one
Figure 2. Vaccination status of participants with CNS complications. Central Nervous System Complications of Varicella-Zoster Virus
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Table I. Clinical characteristics of acute nonstroke neurologic complications of VZV infection CSFx Syndrome
Age,* median, y
Onset,† Sex, % M median (range), d
VZV diagnosisz
WBC,* cells/mm3
Protein,* mg/dL
Acute cerebellar ataxia (n = 26)
7.0 (4.0, 8.0)
54
7 (6 to +14)
Clinical (n = 25) PCR: CSF (n = 1)
12.0 (6.0, 51.0)
23 (16, 31)
Encephalitis (n = 17)
8.0 (7.0, 10.5)
29
5 (3 to +16)
18.5 (2.0, 105.0)
23 (18, 43)
3 (0.5, 7.5)
50
2 (1 to +6)
Clinical (n = 12) PCR: CSF (n = 2), skin (n = 2) both skin and CSF (n = 1) Clinical (n = 10) PCR: CSF (n = 1), skin (n = 5)
2 (0.5, 2.0)
15 (14, 18)
13.0 (8.0, 14.5)
60
4 (3 to +6)
ADEM (n = 2)
8, 15
50
3, 12
GBS (n = 2)
4, 12
50
10, 15
Isolated seizures (n = 16; febrile n = 12, afebrile n = 4) Meningitis (n = 10)
Neuroimaging{ CT (n = 12): normal MRI (n = 5): 2 abnormal – increased T2 signal in posterior occipital and cerebellar regions and increased FLAIR in cerebellum CT (n = 11): abnormal in 2 subjects MRI (n = 12): abnormal in 7 subjects
CT (n = 9): normal MRI (n = 2): 1 abnormal: nonspecific peritrigonal WM signal changes unknown significance Clinical (n = 4) 337.5 (171.0, 439.0) 61 CT (n = 4): normal PCR: CSF (n = 5), (42, 102) MRI (n = 1): normal both skin and CSF (n = 1) Clinical (n = 2) 44, 69 39, 65 MRI (n = 2): abnormal in both. Extensive signal abnormalities and WM changes in brain and spinal cord Clinical (n = 2) 9, ND 130, ND CT (n = 1): normal MRI (n = 1): thickened nerve roots
CT, computed tomography; FLAIR, fluid-attenuated inversion recovery; GBS, Guillain-Barre syndrome; M, male; MRI, magnetic resonance imaging; ND, not done; WBC, white blood cell; WM, white matter. *Depicted as median (IQR); for ADEM and GBS, specific values are provided because there were only 2 cases in each category. †Interval between onset of rash and onset of neurologic manifestation in days ( indicates onset before rash, + indicates onset after rash). zA clinical diagnosis of VZV was based on the presence of the characteristic vesicular rash at the time of hospitalization. xCSF sample analyzed: cerebellar ataxia (n = 15, 61%); isolated seizures (n = 13, 81%); encephalitis (n = 12, 71%); meningitis (n = 10, 100%); for ADEM and GBS cases, specific values are provided because there were only 2 cases in each category. {Neuroimaging performed: cerebellar ataxia (n = 16); isolated seizures (n = 9); encephalitis (n = 16); meningitis (n = 4), ADEM (n = 2), GBS (n = 1).
each with acute disseminated encephalomyelitis (ADEM), seizures, and Guillain-Barre syndrome. Fifty-two patients (70%) received intravenous acyclovir, including all those with encephalitis and ADEM. Seven or more days of acyclovir was administered to 4%, 30%, 50%, and 76% of those with cerebellar ataxia, meningitis, ADEM, and encephalitis, respectively. Among those with acute nonstroke CNS VZV complications, outcomes were most severe for patients with encephalitis and ADEM. At discharge from hospital, 1 of the 2 patients with ADEM had major neurologic impairment. Three patients with encephalitis died. Residual neurologic impairment was present at 1 year in 2 patients with encephalitis and 1 patient with ADEM. Three children who initially presented with isolated seizures went on to develop seizure disorders and had abnormal neurologic evaluations at 1 year. All of the patients with 1-year follow-up data who had acute cerebellar ataxia (n = 7), meningitis (n = 4), and Guillain-Barre syndrome (n = 2) had normal examinations. Patients with stroke were admitted for a median of 10.5 days (range, 2-79 days); 1 required intensive care. Treatment with acyclovir was given to 3 patients (30%) for a median of 782
28 days; 1 was immunocompromised with herpes zoster, and 2 were previously healthy, 1 with chickenpox and 1 without skin lesions or signs of disseminated disease. At discharge from hospital, severe neurologic impairment was present in 40% of patients (Table II). Two patients had complete resolution of their symptoms. After 1 year, neurologic deficits persisted in 3 children (33%).
Discussion The lack of widespread uptake of the VZV vaccine in our community, both before and after universal vaccination in a universal health care system, likely resulted in a persistence of the occurrence of neurologic complications of VZV infection, many with severe clinical outcomes. All of the children in our cohort were admitted to the hospital after the VZV vaccine was approved for use in Canada in 1999, and only 4 reported receiving the vaccine. Nineteen were admitted after September 2004 when full vaccine coverage was provided by the Ministry of Health and Long Term Care, Ontario. Thus, a failure of primary prevention through vaccination, rather than vaccine failure per se, was an issue. This finding Science et al
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Table II. Clinical characteristics of children with VZV-associated stroke CSF
Outcome
Age, y
Sex
Onset,* wk
WBC, cells/mm3
Protein, mg/dL
PCR
Clinical presentation
1
2
M
25.5
ND
ND
ND
2
3.5
F
14
13
<10
3
5
F
18.5
17
4
3
M
17
5
8
F
6
3
M
7 8
3.5 10
M F
9
11.5
F
10
9.0
M
Patient
VZV diagnosis†
Neuroimaging
Right hemiparesis
Clinical
ND
Left hemiparesis
Clinical
19
ND
Slurred speech Left hemiparesis
Clinical
0
<10
NEG
Right hemiparesis
Clinical
Focal infarct posterior limb of internal capsule on left and narrowing of ICA Right MCA infarct, narrowing distal right internal carotid Right MCA ischemic changes and right ICA abnormalities in M1/A1 segments of MCA and ACA Left MCA infarct
24.5
0
18
NEG
Right hemiparesis
Clinical
8.5
ND
ND
ND
Right sided weakness Right facial droop
Clinical
15 2
2 ND
20 ND
NEG ND
Left facial weakness Right hemiparesis
Clinical
26
2
14
NEG
Right hemiparesis
Clinical
84
133
POS
Blurred vision and hallucinations
Clinical (zoster) and lesion scrape PCR-POS
6.5
1 year Normal
Left arm and leg hemiplegia
Increased tone left side, power 4/5
Mild left sided weakness
Normal exam
Right sided weakness, walking with support Right sided weakness, word finding difficulties Mild weakness
Mild right hemiparesis Weakness right arm, short term memory problems Normal exam
CN VII palsy Hemiparesis, speech difficulties
None available Normal
Right facial droop, mild weakness
Normal
Normal
Normal
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ACA, anterior cerebral artery; CN, cranial nerve; F, female; ICA, internal carotid artery; MCA, middle cerebral artery; NEG, negative; POS, positive. *Interval between onset of rash and onset of neurologic manifestation in days ( indicates onset before rash, + indicates onset after rash). †A clinical diagnosis of VZV was based on a record in the patient’s chart of chickenpox during the 6 months preceding the stroke.
MCA infarct and left ICA narrowing Restricted diffusion left caudate head and body and left putamen Right thalamic infarct Several focal areas of hypoattenuation c/w multiple infarcts Small acute infarcts involving left globus pallidus/left internal capsule and enhancement along the vessel with narrowing at left origin of MCA Small focus of infarction with micro hemorrhagic transformation in the left midbrain tegmentum in the region of the left P1 posteromedial perforator
Discharge Normal
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is consistent with recent literature from Public Health Ontario showing vaccine coverage is lowest in Ontario for varicella (47.2% among 7-year-old subjects).13 A second point of failure was with respect to secondary prevention. When administered to contacts within 3 days of exposure to VZV, and possibly within 5 days, vaccine has been shown to be over 90% effective in preventing disease.14,15 In our cohort, 55% of the children had a documented exposure to chickenpox, mainly a sibling (41%), yet none received postexposure vaccination. Had current guidelines pertaining to postexposure vaccination been followed, a significant number of these neurologic complications could have potentially been averted.16 None of the 6 immunocompromised patients in our cohort had a documented chickenpox exposure, and therefore, their disease would not have been remediable by postexposure immunoglobulin. The spectrum of neurologic complications in our cohort was similar to that of previous studies with acute cerebellar ataxia being most common, accounting for one-third of cases.2,17 The number of patients with stroke was greater than in other cohorts,6 possibly reflecting the presence of a stroke program at our institution and referral bias. As expected, complete neurologic recovery was observed for subjects with acute cerebellar ataxia, isolated seizures and meningitis. In contrast, one-third of children with encephalitis or ADEM died or suffered long-term neurologic sequelae. A previous review of children hospitalized at our institution between 1956 and 1967 noted a mortality rate of 35% in those with VZV encephalitis.18 Similar to previous reports,19,20 the prognosis for VZV-associated stroke was poor with only 2 of 10 demonstrating complete resolution of symptoms at hospital discharge. The phenomena of neurologic disease due to VZV manifesting prior to, or in the absence of exanthem in children is an uncommon but important observation. This scenario has been well documented in immunocompromised individuals, but is less well recognized in the context of the immunocompetent host.21 In our cohort, 5 immunocompetent patients developed neurologic manifestations prior to the exanthem, none of whom had been previously vaccinated. These cases serve to reinforce the need to consider VZV as a potential cause of neurologic disease even if the typical exanthem is not present at the time of neurologic symptom onset. Two subjects never developed an exanthem and had VZV meningitis confirmed by PCR analysis of the CSF. These latter cases illustrate the possibility of end organ disease due to VZV in the absence of an exanthem. Furthermore, one of these cases had a history of chickenpox at 18 months of age. In this circumstance, meningitis may reflect reactivation of the virus, which has been described previously.22 Analysis of CSF by PCR can be important for the diagnosis of VZV-associated CNS disease particularly in the absence of rash. In our cohort, we found CSF VZV PCR was most sensitive for the diagnosis of meningitis where 83% of the specimens tested were positive, 2 in the absence of rash. Outside of meningitis, 6 (15%) of the 39 specimens tested were positive. Therefore, the absence of detectable VZV DNA in the 784
Vol. 165, No. 4 CSF does not preclude the possibility of VZV neurologic complications. This is likely related to the fact that VZV is a highly cell-associated virus and the utility of PCR in nonmeningeal disease may be low.23 Concerns regarding the sensitivity of CSF PCR for the diagnosis of encephalitis have been raised in other studies,24,25 which questions the sole use of PCR for diagnosis. It has been suggested that serum and cerebrospinal IgM may be valuable additions to PCR especially when the diagnosis is in question because of the absence of rash.24 Key limitations of this study were its restriction to a single center and predominant retrospective design. As our institution is a tertiary care center, disease spectrum was likely skewed towards the more severe end. The availability of a stroke program, encephalitis registry, and demyelination program also may have contributed to the relatively high proportion of subjects with stroke, encephalitis, and ADEM. Long-term follow-up was inconsistent particularly for children with milder disease, likely reflecting the fact that such children were followed in the community. Furthermore, although much of the data were collected prospectively, this was not the case for outcome assessment. Thus, the outcome data should be viewed as incomplete. In our setting of universal health care and vaccination program, incomplete uptake of standard primary and postexposure vaccination recommendations was implicated as a key factor in the ongoing occurrence of these complications with 69 of 80 unvaccinated children being vaccine eligible (age 12 months or older and immunocompetent). Clinicians should be aware that neurologic symptom onset can predate the appearance of the VZV exanthem and in rare cases, involving immunocompromised individuals, may occur in the absence of an exanthem. n Submitted for publication Dec 20, 2013; last revision received Apr 14, 2014; accepted Jun 5, 2014. Reprint requests: Ari Bitnun, MD, MSc, FRCPC, Division of Infectious Diseases, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8. E-mail: [email protected]
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