Original Studies
Ataxia and Its Association with Hearing Impairment in Childhood Bacterial Meningitis Irmeli Roine, MD,* Tuula Pelkonen, MD,†‡ Luis Bernardino, MD,‡ Manuel Leite Cruzeiro, MD,‡ Heikki Peltola, MD,† and Anne Pitkäranta, MD§ Introduction: Ataxia, deemed usually a minor sequela, follows childhood bacterial meningitis (BM) in up to 18% of cases. Although mostly transient and benign, it can predict permanent hearing loss and vestibular dysfunction. We explored the clinical meaning of ataxia by following its course in a large number of BM patients and examining its relation with hearing loss. Methods: The presence, degree (no, mild, moderate and severe) and course (transient, prolonged and late) of ataxia in BM were registered prospectively by predefined criteria. These data were compared with several patient, disease, and outcome variables including hearing loss (none, moderate, severe and profound) on day 7 of treatment and at a follow-up visit 1 month after discharge. Results: Ataxia was present in 243 of 361 (67%) patients on day 7, being slight in 21%, moderate in 38% and severe in 41%. Its course was transient in 41%, prolonged in 24% and late in 5%, whereas 30% of the patients did not present ataxia at any time. Ataxia associated most significantly not only with several measures of BM severity and suboptimal outcome (P < 0.0001), but also specifically, albeit not consistently, with hearing loss (P = 0.001). The degree of ataxia correlated with the extent of hearing loss (rho, 0.37; P < 0.0001). Conclusions: Ataxia is more frequent and lasts longer after BM than learned from previous studies. The presence and intensity of ataxia associate with hearing loss and its magnitude. Key Words: ataxia, hearing loss, bacterial meningitis, prevalence (Pediatr Infect Dis J 2015;34:809–813)
C
hildhood bacterial meningitis (BM) is still prevalent in areas with a low vaccine coverage,1 where also the mortality and morbidity figures remain high.2 An especially poor prognosis is associated with late arrival for treatment,3 a moribund stage of illness4 and underlying malnutrition.5 Worldwide, 12–35% of survivors are left with sequelae. This figure can double in Africa.2,6 Among all sequelae, ataxia (poor coordination and unsteadiness7) is considered a minor disability, if any,2 and has received relatively little attention. The studies that report its frequency separately, Accepted for publication January 25, 2015. From the *Faculty of Medicine, University Diego Portales, Santiago, Chile; †Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; ‡Pediatric Hospital David Bernardino, Luanda, Angola; and §Department of Otorhinolaryngology, Helsinki University Hospital, University of Helsinki, Finland. This work was supported by grants from the Sigrid Jusélius Foundation, the Helsinki University Central Hospital Research Foundation and the Foundation for Paediatric Research, Finland. The authors have no conflicts of interest to disclose. Address for correspondence: Irmeli Roine, MD, Faculty of Medicine, University Diego Portales, Los Misioneros 2237, 7520179 Santiago, Chile. E-mail: [email protected]; Anne Pitkäranta, Department of Otorhinolaryngology, Helsinki University Hospital, University of Helsinki, Haartmaninkatu 4 E, 000290 Helsinki, Finland. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3408-0809 DOI: 10.1097/INF.0000000000000738
without grouping it with other minor sequelae, have found it in 1–5% of patients with mostly meningococcal8,9 or Haemophilus influenzae meningitis10–12 and in 18% of patients with pneumococcal meningitis.13 The prognosis of ataxia after BM is deemed good14 and its course as transient,8,9 but there is an old report of 7 children in whom ataxia lasted for months.15 What makes ataxia interesting to clinicians is its association with hearing impairment8,9,15 and vestibular dysfunction,16,17 and that the degree of ataxia correlates with both disorders.17 This finding agrees with the belief that ataxia after BM may have a vestibular origin,15 instead of being cerebellar, like most cases of acquired postinfectious ataxia of childhood.18 Our large BM trial,19 which prospectively registered and graded ataxia by predefined, age-adjusted criteria, allowed a detailed description of its prevalence and evolution. Because hearing thresholds were examined at the same time, we could also test how often ataxia was associated with hearing loss, and if they correlated in severity.
METHODS This study was part of a previously reported clinical trial on 723 children with BM at the Pediatric Hospital of Luanda, Angola.19 The Hospital’s Ethics Committee approved the study protocol, and all patients were at age 2 months to 13 years with presumed BM (Fig. 1), and their guardian’s informed consent were enrolled during July 2005 to June 2008. The children were often severely ill on admission and 272 (38%) died. All received cefotaxime as antimicrobial treatment without dexamethasone (declined by the Ethics Committee). This study included the patients with confirmed BM19 and a register of the presence and severity of ataxia on day 7 of treatment (Fig. 1). Ataxia was defined as truncal or gait instability, depending on the child’s age and categorized as mild when the patient could sit but had wobbly head control or a slightly unsteady gait, moderate when he/she needed support to stay sitting or some support to walk and severe when he/she could not sit or walk without support. Its presence was recorded by the physician examining the patient by pulling a prone child from the arms up to a sitting position, or placing the child on her/his feet on day 7 of treatment, at discharge and at a follow-up visit 1 month after discharge. The course of ataxia was described in the patients evaluated both on day 7 of treatment and at the follow-up visit and categorized as (1) transient, when present on day 7, but not at the follow-up visit; (2) prolonged, when present at both evaluations; or (3) late, when present only at the follow-up visit and (4) absent, when absent at both times. Hearing was tested on day 7 of treatment and at the followup visit by trained nurses using Madsen Octavus (Otometrics, Taastrup, Denmark) auditory brain stem response audiometry with auditory click stimuli of 40, 60 and 80 dB separately for each ear after excluding ears with a perforated or immobile tympanic membrane, as described earlier.20 Hearing was deemed normal if the hearing threshold was 40 dB, moderate if 60 dB, severe if 80 dB and profound when >80 dB. Nystagmus was not registered. Other patient, laboratory and outcome data were collected prospectively according to the study protocol (ISRCTN62824827).
The Pediatric Infectious Disease Journal • Volume 34, Number 8, August 2015
www.pidj.com | 809
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
The Pediatric Infectious Disease Journal • Volume 34, Number 8, August 2015
Roine et al
RESULTS
a
Enrolled : 723 b
Confirmed bacterial meningitis : 553 Died, 187; No ataxia evaluation: 5 Ataxia evaluation on day 7: 361 Died: 19 Ataxia evaluation at discharge: 342
Ataxia evaluation at the 1 month follow-up visit: 195
FIGURE 1. Flowchart depicting the formation of the study group and the number of patients who attended the follow-up visit 1 month after discharge. Superscript a, symptoms and signs compatible with BM and cloudy CSF, or a CSF sample positive for Gram-staining, or CSF with >50 white cells (predominantly polymorphs)/mm3. Superscript b, symptoms and signs compatible with BM and positive CSF culture, or positive blood culture, or positive CSF antigen detection by polymerase chain reaction, or at least with 2 of the following criteria: CSF leukocytes exceeding 100/mm3 (predominantly polymorphs), positive Gram-stain, positive latex agglutination test or serum C-reactive protein (CRP) exceeding 40 mg/L.
Statistics The prevalence of ataxia was described in numbers and percentages. Its presence was compared with the hearing threshold and other clinical and laboratory findings, and outcome using χ2, Student’s t test or Mann−Whitney U test, whichever appropriate. The degree of ataxia, rated as none (0), mild (1), moderate (2) or severe (3) was compared with the degree of hearing impairment in the better ear, rated as normal (0), moderate (1), severe (2) or profound (3) by Spearman correlation. A logistic regression model was used to calculate how strongly age, etiology and other independent variables associated with the course of ataxia. The results are expressed as odds ratio (OR) with 95% confidence intervals (95% CI). A P value below 0.05 was taken as significant.
Three hundred and sixty-one patients fulfilled the inclusion criteria (Fig. 1). They were median 12 months old (interquartile range, IQR, 28), 184 (51%) male, diagnosed as BM after median 4 days (IQR, 4) of acute illness and presented on admission with a median Glasgow coma score of 13 (IQR, 6). The etiology was H. influenzae in 129 patients, Streptococcus pneumoniae in 104, Neisseria meningitidis in 43, other in 13 and unknown in 72 patients. The median length of stay was 10 days (IQR, 7). All, except the 19 patients who died after day 7, were evaluated for ataxia at discharge (N = 342), and 195 (57%) of them attended the follow-up visit. The patients who did and did not attend the follow-up visit did not differ (P > 0.05) in age, severity of disease on admission, its course or Glasgow outcome score on day 7, but they had more frequently S. pneumoniae etiology (P = 0.01) and a lower cerebrospinal fluid (CSF) glucose concentration on admission (P = 0.04; see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C135). Ataxia was present on day 7 of treatment in 243 of 361 (67%) patients, at discharge in 182 of 347 (54%) and at the followup visit in 56 of 195 (29%) patients (see Table, Supplemental Digital Content 2, http://links.lww.com/INF/C136). Its course (Table 1) was transient in 80 of 195 (41%) patients, prolonged in 47 of 195 (24%) and late in 9 of 195 (5%), whereas 59 of 195 (30%) patients did not present ataxia at any time. The degree of ataxia on day 7 was mild in 21% (51 of 243 patients), moderate in 38% (92 of 243 patients) and severe in 41% (100 of 243 patients). During the follow-up (Fig. 2), its degree diminished until disappearance in 63% (80 of 127), to a lesser degree in 13% (16 of 127), remained at the same level in 23% (29 of 127) and increased in severity in 1% (2 of 127) of the patients. In addition, 9 of 68 (13%) patients without ataxia on day 7 presented it at the follow-up visit: 4 slight, 2 moderate and 3 severe. Ataxia was one of the manifestations of severe BM in patients recovering with other sequelae as well with a lower Glasgow outcome score on day 7 and at the follow-up visit (P < 0.0001 and P < 0.0001, respectively; see Table, Supplemental Digital Content 2, http://links.lww.com/INF/C136). Specifically, ataxia was associated with severe or moderate psychomotor retardation (P < 0.0001 for each, respectively), blindness (P < 0.0001), quadriplegia (P = 0.02) and monoparesis (P = 0.03) but not with
TABLE 1. Strength of the Association between the Course of Ataxia and Patient, or Disease Characteristics and Outcome
Variable Age < 12 months Malnutrition† Sick >3 days before admission Streptococcus pneumoniae etiology Glasgow coma score 40 dB¶ Glasgow coma score 5 days Glasgow outcome score on day 7,
Ataxia and Its Association with Hearing Impairment in Childhood Bacterial Meningitis Irmeli Roine, MD,* Tuula Pelkonen, MD,†‡ Luis Bernardino, MD,‡ Manuel Leite Cruzeiro, MD,‡ Heikki Peltola, MD,† and Anne Pitkäranta, MD§ Introduction: Ataxia, deemed usually a minor sequela, follows childhood bacterial meningitis (BM) in up to 18% of cases. Although mostly transient and benign, it can predict permanent hearing loss and vestibular dysfunction. We explored the clinical meaning of ataxia by following its course in a large number of BM patients and examining its relation with hearing loss. Methods: The presence, degree (no, mild, moderate and severe) and course (transient, prolonged and late) of ataxia in BM were registered prospectively by predefined criteria. These data were compared with several patient, disease, and outcome variables including hearing loss (none, moderate, severe and profound) on day 7 of treatment and at a follow-up visit 1 month after discharge. Results: Ataxia was present in 243 of 361 (67%) patients on day 7, being slight in 21%, moderate in 38% and severe in 41%. Its course was transient in 41%, prolonged in 24% and late in 5%, whereas 30% of the patients did not present ataxia at any time. Ataxia associated most significantly not only with several measures of BM severity and suboptimal outcome (P < 0.0001), but also specifically, albeit not consistently, with hearing loss (P = 0.001). The degree of ataxia correlated with the extent of hearing loss (rho, 0.37; P < 0.0001). Conclusions: Ataxia is more frequent and lasts longer after BM than learned from previous studies. The presence and intensity of ataxia associate with hearing loss and its magnitude. Key Words: ataxia, hearing loss, bacterial meningitis, prevalence (Pediatr Infect Dis J 2015;34:809–813)
C
hildhood bacterial meningitis (BM) is still prevalent in areas with a low vaccine coverage,1 where also the mortality and morbidity figures remain high.2 An especially poor prognosis is associated with late arrival for treatment,3 a moribund stage of illness4 and underlying malnutrition.5 Worldwide, 12–35% of survivors are left with sequelae. This figure can double in Africa.2,6 Among all sequelae, ataxia (poor coordination and unsteadiness7) is considered a minor disability, if any,2 and has received relatively little attention. The studies that report its frequency separately, Accepted for publication January 25, 2015. From the *Faculty of Medicine, University Diego Portales, Santiago, Chile; †Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; ‡Pediatric Hospital David Bernardino, Luanda, Angola; and §Department of Otorhinolaryngology, Helsinki University Hospital, University of Helsinki, Finland. This work was supported by grants from the Sigrid Jusélius Foundation, the Helsinki University Central Hospital Research Foundation and the Foundation for Paediatric Research, Finland. The authors have no conflicts of interest to disclose. Address for correspondence: Irmeli Roine, MD, Faculty of Medicine, University Diego Portales, Los Misioneros 2237, 7520179 Santiago, Chile. E-mail: [email protected]; Anne Pitkäranta, Department of Otorhinolaryngology, Helsinki University Hospital, University of Helsinki, Haartmaninkatu 4 E, 000290 Helsinki, Finland. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3408-0809 DOI: 10.1097/INF.0000000000000738
without grouping it with other minor sequelae, have found it in 1–5% of patients with mostly meningococcal8,9 or Haemophilus influenzae meningitis10–12 and in 18% of patients with pneumococcal meningitis.13 The prognosis of ataxia after BM is deemed good14 and its course as transient,8,9 but there is an old report of 7 children in whom ataxia lasted for months.15 What makes ataxia interesting to clinicians is its association with hearing impairment8,9,15 and vestibular dysfunction,16,17 and that the degree of ataxia correlates with both disorders.17 This finding agrees with the belief that ataxia after BM may have a vestibular origin,15 instead of being cerebellar, like most cases of acquired postinfectious ataxia of childhood.18 Our large BM trial,19 which prospectively registered and graded ataxia by predefined, age-adjusted criteria, allowed a detailed description of its prevalence and evolution. Because hearing thresholds were examined at the same time, we could also test how often ataxia was associated with hearing loss, and if they correlated in severity.
METHODS This study was part of a previously reported clinical trial on 723 children with BM at the Pediatric Hospital of Luanda, Angola.19 The Hospital’s Ethics Committee approved the study protocol, and all patients were at age 2 months to 13 years with presumed BM (Fig. 1), and their guardian’s informed consent were enrolled during July 2005 to June 2008. The children were often severely ill on admission and 272 (38%) died. All received cefotaxime as antimicrobial treatment without dexamethasone (declined by the Ethics Committee). This study included the patients with confirmed BM19 and a register of the presence and severity of ataxia on day 7 of treatment (Fig. 1). Ataxia was defined as truncal or gait instability, depending on the child’s age and categorized as mild when the patient could sit but had wobbly head control or a slightly unsteady gait, moderate when he/she needed support to stay sitting or some support to walk and severe when he/she could not sit or walk without support. Its presence was recorded by the physician examining the patient by pulling a prone child from the arms up to a sitting position, or placing the child on her/his feet on day 7 of treatment, at discharge and at a follow-up visit 1 month after discharge. The course of ataxia was described in the patients evaluated both on day 7 of treatment and at the follow-up visit and categorized as (1) transient, when present on day 7, but not at the follow-up visit; (2) prolonged, when present at both evaluations; or (3) late, when present only at the follow-up visit and (4) absent, when absent at both times. Hearing was tested on day 7 of treatment and at the followup visit by trained nurses using Madsen Octavus (Otometrics, Taastrup, Denmark) auditory brain stem response audiometry with auditory click stimuli of 40, 60 and 80 dB separately for each ear after excluding ears with a perforated or immobile tympanic membrane, as described earlier.20 Hearing was deemed normal if the hearing threshold was 40 dB, moderate if 60 dB, severe if 80 dB and profound when >80 dB. Nystagmus was not registered. Other patient, laboratory and outcome data were collected prospectively according to the study protocol (ISRCTN62824827).
The Pediatric Infectious Disease Journal • Volume 34, Number 8, August 2015
www.pidj.com | 809
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
The Pediatric Infectious Disease Journal • Volume 34, Number 8, August 2015
Roine et al
RESULTS
a
Enrolled : 723 b
Confirmed bacterial meningitis : 553 Died, 187; No ataxia evaluation: 5 Ataxia evaluation on day 7: 361 Died: 19 Ataxia evaluation at discharge: 342
Ataxia evaluation at the 1 month follow-up visit: 195
FIGURE 1. Flowchart depicting the formation of the study group and the number of patients who attended the follow-up visit 1 month after discharge. Superscript a, symptoms and signs compatible with BM and cloudy CSF, or a CSF sample positive for Gram-staining, or CSF with >50 white cells (predominantly polymorphs)/mm3. Superscript b, symptoms and signs compatible with BM and positive CSF culture, or positive blood culture, or positive CSF antigen detection by polymerase chain reaction, or at least with 2 of the following criteria: CSF leukocytes exceeding 100/mm3 (predominantly polymorphs), positive Gram-stain, positive latex agglutination test or serum C-reactive protein (CRP) exceeding 40 mg/L.
Statistics The prevalence of ataxia was described in numbers and percentages. Its presence was compared with the hearing threshold and other clinical and laboratory findings, and outcome using χ2, Student’s t test or Mann−Whitney U test, whichever appropriate. The degree of ataxia, rated as none (0), mild (1), moderate (2) or severe (3) was compared with the degree of hearing impairment in the better ear, rated as normal (0), moderate (1), severe (2) or profound (3) by Spearman correlation. A logistic regression model was used to calculate how strongly age, etiology and other independent variables associated with the course of ataxia. The results are expressed as odds ratio (OR) with 95% confidence intervals (95% CI). A P value below 0.05 was taken as significant.
Three hundred and sixty-one patients fulfilled the inclusion criteria (Fig. 1). They were median 12 months old (interquartile range, IQR, 28), 184 (51%) male, diagnosed as BM after median 4 days (IQR, 4) of acute illness and presented on admission with a median Glasgow coma score of 13 (IQR, 6). The etiology was H. influenzae in 129 patients, Streptococcus pneumoniae in 104, Neisseria meningitidis in 43, other in 13 and unknown in 72 patients. The median length of stay was 10 days (IQR, 7). All, except the 19 patients who died after day 7, were evaluated for ataxia at discharge (N = 342), and 195 (57%) of them attended the follow-up visit. The patients who did and did not attend the follow-up visit did not differ (P > 0.05) in age, severity of disease on admission, its course or Glasgow outcome score on day 7, but they had more frequently S. pneumoniae etiology (P = 0.01) and a lower cerebrospinal fluid (CSF) glucose concentration on admission (P = 0.04; see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C135). Ataxia was present on day 7 of treatment in 243 of 361 (67%) patients, at discharge in 182 of 347 (54%) and at the followup visit in 56 of 195 (29%) patients (see Table, Supplemental Digital Content 2, http://links.lww.com/INF/C136). Its course (Table 1) was transient in 80 of 195 (41%) patients, prolonged in 47 of 195 (24%) and late in 9 of 195 (5%), whereas 59 of 195 (30%) patients did not present ataxia at any time. The degree of ataxia on day 7 was mild in 21% (51 of 243 patients), moderate in 38% (92 of 243 patients) and severe in 41% (100 of 243 patients). During the follow-up (Fig. 2), its degree diminished until disappearance in 63% (80 of 127), to a lesser degree in 13% (16 of 127), remained at the same level in 23% (29 of 127) and increased in severity in 1% (2 of 127) of the patients. In addition, 9 of 68 (13%) patients without ataxia on day 7 presented it at the follow-up visit: 4 slight, 2 moderate and 3 severe. Ataxia was one of the manifestations of severe BM in patients recovering with other sequelae as well with a lower Glasgow outcome score on day 7 and at the follow-up visit (P < 0.0001 and P < 0.0001, respectively; see Table, Supplemental Digital Content 2, http://links.lww.com/INF/C136). Specifically, ataxia was associated with severe or moderate psychomotor retardation (P < 0.0001 for each, respectively), blindness (P < 0.0001), quadriplegia (P = 0.02) and monoparesis (P = 0.03) but not with
TABLE 1. Strength of the Association between the Course of Ataxia and Patient, or Disease Characteristics and Outcome
Variable Age < 12 months Malnutrition† Sick >3 days before admission Streptococcus pneumoniae etiology Glasgow coma score 40 dB¶ Glasgow coma score 5 days Glasgow outcome score on day 7,
