Clinical blindness in conjunction with childhood bacterial meningitis

Although rarely reported, bilateral loss of vision is a severe complication of childhood bacterial meningitis. We assessed its frequency in five prospective treatment trials performed in Europe, Latin America, and Angola in 1984–2017. Course of illness, follow-up findings, and child’s sight were recorded. Sight was examined at discharge, and conditions permitting, also at 1–3 months post-hospitalization and in Angola on hospital day 7. Experienced pediatricians diagnosed clinical blindness if the child did not make eye contact, did not blink or move the eyes, or remained unresponsive to bright light or movement of large objects before their eyes. Of 1515 patients, 351, 654, and 510 were from Finland, Latin America, and Angola, respectively. At discharge, blindness was observed in 0 (0%), 8 (1.2%), and 51 (10%) children, respectively. In Angola, 64 children appeared to be blind on day 7; 16 of these children died. Blindness found at discharge in Angola was not invariably irreversible; approximately 40% had restored the sight at follow-up visit. Clinical blindness rarely occurred in isolation and was usually associated with young age and poor general condition at hospital arrival. Various other serious sequelae were common among the survivors with clinical blindness.

condition was graded with the age-adjusted Glasgow Coma Scale (GCS, range 3-15) 17 .This grading was important, as scoring below 13 on GCS in BM indicates increased risk for poor outcomes regardless of etiology 18 .The course of illness was monitored with several clinical and laboratory indices, some of which are shown in Table 1.
Another thorough clinical investigation was performed at discharge.Special attention was given to neurological and audiological outcomes."Severe neurological sequelae" were defined as blindness, severe psychomotor retardation, quadriplegia, or hydrocephalus requiring a shunt."Any neurological sequelae" included those with moderate psychomotor retardation, hemiparesis, monoparesis, or ataxia.Hearing was measured by the Brainstem
Impaired consciousness at hospital arrival was another factor for blindness (Fig. 2).Children with blindness more often had GCS < 13 (42/51; 82.4%) than children without blindness (180/454; 39.6%) (P < 0.0001).When compared to children without blindness, children with blindness more often exhibited symptoms and signs indicative of poor outcome, such as seizures before or at presentation, severe anemia, focal neurological signs, or combinations thereof.In contrast, there was no association between blindness and severe underweight, HIV, malaria thick film positivity, or quinine treatment for malaria.Sickle-cell anemia did not increase the risk for blindness.
Table 2 shows multivariate analysis of at-admission detected factors that associated with clinical blindness in Angolan children at discharge.Independent predictors of blindness were GCS < 13, delay > 5 days, age < 1 year, and seizures.
Vision was examined in 512 children on day 7, of whom 64 (12.5%) were clinically blind.Of these, 16 (25%) died in hospital (Fig. 3).Only 6/448 (1.3%) of children without visual loss on day 7 died.The children diagnosed with blindness on day 7 were not invariably the same individuals who had blindness at discharge, and vice versa (Fig. 3).Of the 48 surviving children who had blindness on day 7, 16 (33%) were not diagnosed with blindness at discharge.
A follow-up visit (mostly at 1-3 months posthospitalization) was attended by 278 (55%) children, of whom 36 (13%) were diagnosed with blindness at discharge (Fig. 3).The differences of the characteristics of clinically blind vs not blind children at follow-up visit were alike the differences at discharge (Supplementary table 1).In multivariate analysis, only GCS < 13 at admission associated significantly with clinical blindness at follow-up visit (Supplementary table 2).Compared to the situation at discharge, 16 (44%) individuals were no longer clinically blind.When compared with children who were still blind at this follow-up visit, at least four characteristics were associated with this observation: duration of altered consciousness (1 day vs. 16 days; p < 0.0001), seizures at ward (49% vs. 88%; p < 0.0001), days with focal neurological signs (3 days vs. 13 days; p = 0.004), and ataxia (81% vs.  www.nature.com/scientificreports/100%; p = 0.039).Duration of prehospital symptoms, GCS < 13, and severe psychomotor retardation were not significantly associated.A 12-month-old child who had pneumococcal meningitis and was not diagnosed blind at discharge was clinically blind at the follow-up visit.

Discussion
Despite the considerable impact of vision loss, little is known of blindness in conjunction with BM [1][2][3][7][8][9][10] . This ay be explained by the paucity of this complication in industrialized countries; there were no cases identified among the 351 Finnish patients examined.In LatAm, 8/654 children had blindness, whereas in Angola, 51/510 (10%) children had blindness at discharge.The frequency of blindness at discharge in Luanda is similar to the reported 8% in children with BM in South Africa 20 .Dissimilar etiology and the special risk in S. pneumoniae meningitis partly explained the preponderance of blindness in Luanda.Here, blindness at discharge due to pneumococcal, Haemophilus, and meningococcal meningitis was observed in 7%, 3%, and 0.4%, respectively.In a previous African review, the corresponding figures were 2%, 1 to 3% percent, and 3% 10 .
Distinguishing BM from cerebral malaria is a concern in tropical Africa.Adjunct quinine was sometimes administered in Luanda.Quinine binds to α1-acid glycoprotein and other plasma proteins; this binding is increased in P. falciparum malaria 19 .Therefore, cinchonism, a constellation comprising various symptoms, including visual (and hearing) disturbances up to full blindness, may explain why many children with blindness at discharge regained vision a few months later.
The pathogenesis of vision loss in BM is not precisely known.Anoxia or inflammation of the cerebral cortex, thrombosis, and cerebral infarcts may lead to cortical blindness 1,7,8 .In our study, quadriplegia and focal neurological signs (such as monoparesis and hemiparesis) were more common in children with blindness, suggesting anoxic or circulatory (or both) brain damage.Hydrocephalus was also associated with blindness; this was also observed in tuberculous meningitis, where increased intracranial pressure can cause papilledema and optic neuropathy 5 .Both tuberculous and other bacterial meningitis can cause optic nerve, chiasm, or tractus involvement and damage 5,9 .
In African children with BM, visual loss has been reported at discharge in 1 to 8% and in 0 to 11% at followup visit 10 .In a follow-up study from industrialized countries, of 14 children with cortical blindness and mostly Haemophilus meningitis, 7 children regained vision, 4 children recovered some vision, and 3 children remained blind 7 .In Bangladesh, of 51 children with pneumococcal meningitis, vision loss was diagnosed in 4 children at 1 month after discharge and in 2 children at 6-24 months after discharge 21 .Spontaneous improvement has also been observed in impaired hearing in conjunction with BM 22 .
This study has some limitations.Ophthalmologic services were not available in Angola and the attending pediatricians did not record pupillary reflexes or eye movements and did not perform ophthalmoscopy.However, it is highly unlikely that a child who is completely unresponsive to light and stimuli (such as moving fingers or toys before their face) would have any meaningful visual capacity.Importantly, examining the vision of children with impaired consciousness or neurological sequelae is also challenging in industrialized countries.Therefore, we believe our information is relevant and sufficiently important to warrant full ophthalmological exploration in future meningitis studies.
Our three series (Finland, LatAm, Africa) were dissimilar in terms of socioeconomic conditions and in many other aspects.However, the disease (BM) was the same, the causative agents were similar, data were collected prospectively in a similar manner, and the entire series is the largest to date.Although the risk of BM in childhood is reduced due to vaccinations, the importance of vision loss associated with this disease merits further attention.We recommend that at least children with BM and risk factors for blindness undergo ophthalmological examinations 1-3 months after hospitalization.

Figure 1 .
Figure 1.Etiology of bacterial meningitis among the clinically blind and not-blind children, in Finland, Latin America and Angola.

Figure 2 .Table 2 .Figure 3 .
Figure 2. Glasgow Coma Score at admission among the clinically blind and not-blind children in Angola.

Table 1 .
Characteristics of Angolan children admitted with bacterial meningitis and with or without blindness at discharge.Data are presented as no.(%) or median (interquartile range).a Strabismus, ptosis, nervus facialis paresis, monoparesis, hemiparesis.b Cerebrospinal fluid.c Severe psychomotor retardation, quadriplegia, or hydrocephalus needing a shunt.d Severe neurological sequelae and moderate psychomotor retardation, hemiparesis, monoparesis, or ataxia.All data were computed and analyzed using JMP® Pro 14.1.0(SAS Institute Inc, Cary, NC, USA) for Windows.Descriptive data are expressed as counts and percentages or medians with interquartile range (IQR), whichever appropriate.Potential differences in the basic characteristics between groups were examined by Wilcoxon/Kruskal-Wallis tests or χ 2tests in accordance with data type.We used nominal logistic analysis and calculated odds ratios (OR) with 95% confidence intervals (95% CI) for blindness.For multivariate analysis, we used at-admission-detectable clinical characteristics that in univariate analysis showed p value < 0.01.Ethics approval and consent to participate.The Luanda Children's Hospital's Ethics Committeeapproved the studies in Angola, and the relevant Ethics Committees or Hospital Boards approved the studies in Latin America and in Finland.Once the registration of clinical trials commenced, the Angolan studies were registered (ISRCTN62824827, 4/10/2005 and NCT01540838, 29/2/2012).The patients were enrolled after written or oral informed consent was obtained from the guardian.All methods were carried out in accordance with the Declaration of Helsinki.