Acute Transverse Myelitis and Dengue: A Systematic Review

Transverse Myelitis (TM), in turn, is a neurological syndrome that reaches from one to four people in 1 million inhabitants and its clinical diagnosis is defined by varying degrees of motor, sensory and autonomic dysfunction. The TM can be associated with different types of diseases, among which stand out systemic diseases, infections, vaccinations, radiation and vascular accidents. The idiopathic inflammatory demyelinating diseases (IIDD) of the central nervous system (CNS), may monophasically or recurrently evolve or be the initial manifestation of other conditions such as neuromyelitis optica (NMO) multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) [3].


Introduction
Dengue is a viral infection, whose etiologic agent is an arbovirus of the genus Flavivirus and Flaviridae family. This is the arbovirus that most affects the human being, affecting approximately 100 million people per year in the world. Epidemics occur frequently in tropical and subtropical countries, making it a serious public health problem [1,2].
Transverse Myelitis (TM), in turn, is a neurological syndrome that reaches from one to four people in 1 million inhabitants and its clinical diagnosis is defined by varying degrees of motor, sensory and autonomic dysfunction. The TM can be associated with different types of diseases, among which stand out systemic diseases, infections, vaccinations, radiation and vascular accidents. The idiopathic inflammatory demyelinating diseases (IIDD) of the central nervous system (CNS), may monophasically or recurrently evolve or be the initial manifestation of other conditions such as neuromyelitis optica (NMO) multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) [3].
The neurological manifestations related to dengue are exceptional occurrences and little described by literature. They may be justified by metabolic, hematological and hemodynamic changes that have occurred in the acute phase of the disease, by direct aggression of the virus to the CNS or by immunomediated processes [4][5][6]. Considering the epidemiological importance of dengue and its possible complications in tropical and subtropical countries, we seek to identify, by means of a systematic review, the associations between dengue and transverse myelitis described in literature, as well as to compare the clinical data, laboratory and epidemiological reported by these publications.
The articles identified by the search strategy were evaluated independently and blinded by two researchers (authors), strictly obeying the inclusion criteria: full text, search time (by October 2014), the target population (children, adolescent, adult and elderly), intervention (without delimitation), study type (without delimitation) and languages (Portuguese, English and Spanish). Studies were excluded if they did not comply with the inclusion criteria described above, if they were duplicated or if they were not directly related to the proposed goal of this study (association between transverse myelitis and dengue).
With the aim to preserve the relevance of the study in question, we applied the Kappa statistical test to evaluate the concordance between the researchers. In addition, we scheduled a consensus meeting for discussions about the possible discordances.

Results and Discussion
By the strategy of the initial search, conducted in the month of October 2014, 11 articles were identified. After applying the exclusion criteria, the remaining 9 articles were independently assessed by two authors. The Kappa statistical test showed total concordance between the authors, even so, a consensus meeting was held, not changing the result of the exclusion of two articles that had already been previously excluded. The characteristics of selected and excluded studies are arranged in Table 1. Thus, as detailed in Figure 1, were included only seven studies in the final selection, which contemplated the methodological criteria, stipulated for the proposed objective of this review. The comparison between the studies is summarized in Table 2.
From the selected studies five were case reports, one was characterized as a series of 10 cases, in which three were related with the proposed subject, and other was a survey of medical records with 26 cases, which amounts to the publication thirty-four cases regarding the association between transverse myelitis and dengue until October 2014. Regarding the origin of articles, 57% are from Brazil, 28% in Singapore and 14% in Thailand. With respect to the year of publication, they were found in the range of 2002 to 2014. The reports showed a slight predominance of the classification in females (1.43:1) and the age ranged from 11 to 71 years, with an average age of 36 to 24 years.
The quantity of studies found reveals the scarcity of scientific literature on the topic, which indicates the rare relationship between the dengue virus and the transverse myelitis, should not ignore the fact that the late post-infectious myelitis may lead to possible underreporting. The geographical origin of the articles confirmed the predominance of dengue in tropical regions. The small number of cases considerably impaired the association between age and genre for the classification in the study, with emphasis on the case of neuromyelitis optica reported by Miranda de Sousa et al. [7] to be the sole pediatric report.
Despite of the apparent controversy in the literature regarding the clinical form of dengue and neurological manifestations [8,9] the clinical classification of classical dengue was clearly defined by articles, not being described hemorrhagic complications. The myelitis was characterized by varying degrees of motor, sensory and sphincteric dysfunction, according to the clinical criteria proposed by "Transverse Myelitis Consortium Working Group" [3]. With respect to the installation of myelitis, they were in their majority (94.1% of cases) post infectious, arriving to manifest itself until 30 days after the onset of infection by dengue [10].
These manifestations reinforce the hypothesis of immune mediated mechanism where the virus could act as a trigger of the inflammatory process that has as its target forming cells of the myelin sheath. The cluster of post-dengue transverse myelitis with favorable clinical outcome corroborate this mechanism [7,11].
The titration of IgM antibodies against the dengue virus using the ELISA method is highly sensitive, confirming the laboratory diagnosis of dengue infection in all cases. The polymerase chain reaction (PCR) technique for detection of the viral genome was performed only by Leao et al. [12], however, this technique is not used routinely for epidemiological purposes [1,2].
The resonance examination of the spinal cord has confirmed the abnormalities of the neurological exam in 41,1% of the cases. The normal MRI was found in two thirds of the patients surveyed by Miranda de Sousa et al. [11], in one case described by Leao et al. [12], in one by Seet et al. [13] and in other by Puccioni Sohler et al. [10], a normal MRI does not invalidate the clinical diagnosis of transverse myelitis. The thoracic spinal cord was the most affected and T9 segment was slightly more associated with the disease compared to other spinal

SELECTED ARTICLES (N = 9)
Excluded articles (N=2) Reason: duplication    segments. Lesions in the cervical region were also described [10,14], with predominance in the lower cervical region.
Examination of the cerebrospinal fluid in the reviewed studies detected a breaking of the cerebrospinal fluid barrier characterized by increased proteins or by the presence of antibodies against the dengue virus. The study of oligoclonal bands when conducted was normal [7,14].
The outcome of myelitis was favorable with total recovery of vasomotor symptoms in 97% of cases, with the exception of one patient, 71 years old who developed spastic paraparesis [10], which was present even after one year of follow-up. There was a single case of permanent paresthesia of the lower limbs after six months [10] and one case of moderate weakness in the lower limbs after six months [11]. In two cases was reported the persistence of neurogenic bladder [10,14], however, in one of them, the follow-up time was very short (only five days), which weakens the verdict of this outcome; it should have been monitored for a longer period for further evaluation. The intravenous methylprednisolone in the form of pulse therapy was the drug of choice in the clinical intervention in eleven patients; however, human immunoglobulin was also used [14].

Final Considerations
Transverse myelitis related to infection by dengue virus are rare, the vast majority are post-infectious with a favorable clinical outcome either spontaneously or after methylprednisolone pulse therapy. Whereas dengue epidemics are frequent in tropical and subtropical countries, the dengue virus should always be part of the differential diagnosis for infectious and post-infectious myelitis.