Introduction

Dengue is the most frequent arbovirosis worldwide [1]. Although most symptomatic cases are self-limiting, a small proportion of cases will develop severe life-threatening forms of Dengue. The frequency, the clinical characteristics, and the prognosis of these severe forms of dengue is highly variable[2]. It may depend on the social environment of the territory where it occurs and the performance and accessibility of its health system. The local epidemiology, the circulating viruses also may influence the clinical spectrum of disease [3,4]. The definition of severe forms has been modified by WHO because, in practice, the former definition was difficult to use in all settings and did not adequately reflect the clinical polymorphism [2,5–9]. Such a broad definition aims at being more sensitive to avoid missing severe atypical cases. The Pathophysiology of severe dengue is still incompletely understood involving a mixture of host and viral factors [4]. Having a broad definition may thus be important for the clinicians but it may not be optimal to improve our understanding of the various forms of severity. The recent modifications of the WHO definition now include neurological manifestations which may directly result from the dengue virus or from indirect mechanisms such as liver dysfunction, bleeding, metabolic disorders. Dengue fever is associated with a range of neurological manifestations such as encephalopathy, encephalitis, immune-mediated syndromes, dengue muscle dysfunction, and neuro-ophtalmic disorders [10–15]. A recent review of neurological manifestations of dengue found that in South East Asia between 0.5% and 5.4% percent of patients had neurological manifestations, and that in Brazil this figure went up to 21% [15]. The involvement of the central nervous system has been described in all 3 classical types of dengue, dengue fever, dengue hemorrhagic fever, and dengue shock syndrome.

In French Guiana, a French overseas territory in South America, all four serotypes circulate with an increasing frequency and magnitude of epidemics. In the present study the objective was to determine the incidence of neurological signs and their predictive factors using longitudinal data from cases of dengue seen in Cayenne Hospital during the Dengue 2 epidemic in 2013.

Methods

Results

General results and incidence rate

A total of 1574 patients were included 221 of whom developed central nervous system signs (17 patients had central nervous system signs at their first consultation and thus were not included in the survival analysis). There were no details regarding whether these incident signs were linked to encephalopathy or encephalitis. There were 9298person-days of follow-up and the overall incidence rate for central nervous system signs was 2.37 per 100 person-days.Overall, after reviewing the files, 718 were probable dengue fever cases and 887 were biologically confirmed dengue either by NS1 (N = 742) and/or dengue-specific IgM seroconversion (N = 310).

Among patients, 50.5% were males and 49.5% were females; there were 60 children aged<1 year, 649 aged between 1 and 15 years, 843 aged between 16 and 65, and 29 aged over 65 years.

Fig 1 shows that over 20% of patients had CNS signs and that the highest incidence occurred between day 5 and day 6 of the fever. Fig 2 shows the incidence of CNS signs stratified by age, age groups <1 year and over 65 years had few patients (60 and 30, respectively).

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Fig 1. “Kaplan Meier curve for neurological disorder during dengue fever”.

https://doi.org/10.1371/journal.pone.0150828.g001

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Fig 2. “Kaplan Meier curve for neurological disorder during dengue fever by age group”.

https://doi.org/10.1371/journal.pone.0150828.g002

Clinical predictive factors

Table 1 shows the result of the model including clinical variables only. Table 1 shows that headaches, fatigue, malaise and lipothymia, aches, bleeding, and abdominal pain were significantly associated with CNS signs. The numbers reported represent the numbers of patients who, at some time had the sign. Therefore since a patient can initially have no given sign may then develop the sign, the totals for each variable exceed the total number of patients. The magnitude of the increased associated risk for these variables was moderate ranging between 1.5 and 2.2. Age and having a skin rash were not linked to CNS signs. For temperature, it seemed that having a moderate temperature elevation (between 37.5 and 38.4) was associated with a lower risk of CNS signs than temperatures below or above these values.

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Table 1. Stratum specific incidence rates and adjusted hazard ratios for central nervous system signs for different clinical covariates.

https://doi.org/10.1371/journal.pone.0150828.t001

Biological predictive factors

Table 2 shows the model with the biological variables only. Table 2 shows that higher serum protein concentrations, and lower lymphocyte counts were significantly associated with CNS signs. Creatinine and sodium concentration, neutrophils and platelet counts were not significantly associated with central nervous system dysfunction and were not retained in the parsimonious model.

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Table 2. Stratum specific incidence rates and adjusted hazard ratios for central nervous system signs for different significant biological covariates.

https://doi.org/10.1371/journal.pone.0150828.t002

Clinical and biological predictive factors

Table 3 shows that in the final model including both significant clinical and biological variables, the clinical variables in Table 1 were still significantly associated with the outcome but that for the biological variables identified in Table 2 most of the significant associations disappeared, and that the significance of the association between proteinemia in the second quartile and CNS signs was not clear. Thus clinical variables were more reliable at predicting CNS anomalies than biological variables. The adjustment using the probable/confirmed dengue was not significantly associated with the outcome (P = 0.25) and did not change the findings. It was thus discarded from the final model. Models without purpura (which was presumed to be correlated to hemorrhage) and headaches (a common non-specific sign of dengue) were attempted but the AIC (Akaike’s Information criterion) showed that they were less informative than models with these variables which were thus retained. Overall, headaches, fatigue, malaise and lipothymia, aches, bleeding, and abdominal pain were significantly associated with an increased risk of CNS signs.

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Table 3. Stratum specific incidence rates and adjusted hazard ratios for central nervous system signs for different significant clinical and biological covariates.

https://doi.org/10.1371/journal.pone.0150828.t003

Discussion

Here in a small city with easy access to emergency care, quality care and a policy of hospitalizing patients with any clinical, biological or social warning sign, over 20% of the patients seen for dengue fever had central nervous system dysfunction mostly around the 5th or 6th day of fever. This proportion is much higher than in the studies in South East Asia [16–19] but similar to a study in Brazil [20]. The study in Brazil recruited patients admitted to a tertiary care whereas our study included all patients seen at the hospital, both outpatients consulting an infectiologist and hospitalized patients. Given the non specific nature of the data collection form, it was difficult to know whether CNS signs were linked to encephalopathy or encephalitis, or if these signs reflected general exhaustion. Most patients did not have CSF examination because thrombocytopenia was assumed to make the spinal tap risky. All these clinical anomalies of unknown pathophysiology were spontaneously resolutive.

The incidence of CNS dysfunction was statistically linked to Headaches, fatigue, malaise and fainting, aches, bleeding, and abdominal pain. Headaches may have been preceding more patent cerebral dysfunction. Bleeding manifestations and signs that may have reflected hypovolemia could alter the central nervous system's function. Variables that have been reported to be associated with encephalopathy such as liver enzymes, sodium concentration were not significantly linked to CNS dysfunction. Patients on admission receive prompt intraveinous rehydration, thus avoiding in many cases the severe complications of dengue. Here, the incidence rate of CNS dysfunction of 2.37 per 100 person-days assumed that hospitalized patients were initially neurologically not symptomatic. Thus 17 patients that arrived with such signs on admission were not counted in the incidence rate calculation.

A review [15] of neurological disorders during dengue fever reports the frequent overlap between encephalopathy and encephalitis and immune mediated syndromes, and the absence of a standardized definition of encephalitis or encephalopathy. It is also reported that in most studies cerebrospinal fluid testing for dengue virus or dengue-specific IgM or NS1 antigen testing are not consistently performed, as was the case in French Guiana. Apart from the neurological manifestations themselves, the studies on neurological manifestations of dengue also report various degrees of underlying severity with some reporting severe dengue in most cases [19], whereas some showed a prominent neurological aspect[11]. The reported case fatality rates are often high, notably when encephalopathy reflects the severity of dengue [15] but the study from Brazil [20] found that the presence of CNS involvement did not influence the prognosis of dengue.

Neurological manifestations of dengue generally require supportive care, airway maintenance, and correction of fluid and electrolyte balance when possible [15]. In contrast with many studies, in the present study, no fatality was reported among those with CNS involvement. Given the prompt rehydration and the specific dengue follow up set up during the epidemic much of the severity may have been averted. Also the definition of neurological dysfunction may have varied between studies.

The present epidemic was caused by a Dengue 2 virus. This was based on aggregated data from the reference center for the epidemiologic surveillance of arboviruses, and the data was not connected to individual patients. Since 95% of the viruses were DEN-2 it seems plausible that most patients with CNS dysfunction had DEN-2 viruses. However, it is not possible to rule out that certain serotypes were overrepresented in patients with CNS dysfunction [21]. It is not known whether other viruses have similar consequences on neurological signs, either through varying degrees of neurotropism or differences in virulence. Thus, the incidence and the predictive factors of CNS anomalies should be assessed in epidemics caused by different viruses. Furthermore, prior infection by different dengue viruses may also have influenced the incidence of CNS anomalies in those concerned because of facilitating antibodies. However, this hypothesis should be tested formally. In a study in Brazil, including patients with encephalopathy or encephalitis, it was suggested that the pathogenesis of neurological involvement was distinct from the pathogenesis of dengue hemorrhagic fever [20]. The number of patients involved and the mix of encephalitis and encephalopathy may however have been insufficient to conclude regarding pathogenesis, notably for encephalopathy in cases of dengue hemorrhagic fever [19,22]. Thus while encephalitis may be linked to neurotropism, encephalopathy seems more related to overall severity

This is the first large longitudinal study to provide incidence rates for CNS signs during dengue fever among patients seen at a reference hospital. Overall, the present study suggests that neurological signs of dengue are not exceptional even in patients without the most severe features of dengue. These manifestations were spontaneously resolutive and were associated with patients various algic or hemorrhagic manifestations. Given the coarse clinical definition of the studied outcome and the lack of cerebral spinal fluid data further studies should better define the neurologic syndromes and document the nature of the CNS anomalies to understand the pathogenesis of different manifestations and their respective frequency [15].