Neurological Manifestations of Dengue- Editorial commentary.

Dengue is one of the most common arboviral infections worldwide. Dengue virus belongs to the family Flaviviridae and has four closely related serotypes: DEN V1 to DEN V4. The classical presentation of dengue includes fever with a frontal predominant headache, retro-orbital pain, rash, hemorrhagic manifestations, severe myalgias, and arthralgias. Neurological manifestations of dengue have been reported increasingly, however, the exact incidence in different geographical regions is unclear. Neurological involvement was first reported in 1976, and the incidence rates vary from 0.5 to 20%.[2]

Although the dengue virus was considered initially as a non-neurotropic virus, demonstration of viral antigen in brain autopsy and positive reverse transcriptase-polymerase chain reaction (RT PCR) particles in the cerebrospinal fluid (CSF) demonstrated the ability to invade neural tissues.[3] Neurological manifestations have also been hypothesized to be secondary to autoimmune reactions and metabolic alterations.

The neurological manifestations can be broadly divided into three categories based on the proposed pathogenesis. First, the manifestations related to direct neuroinvasion comprise encephalitis, meningitis, myelitis, and myositis. Second, manifestations due to systemic complications of dengue infection can be encephalopathy, stroke, and hypokalemic paralysis. Lastly, manifestations related to post-infectious immunological complications, e.g. encephalomyelitis, acute disseminated encephalomyelitis, neuromyelitis optica, optic neuritis, myelitis, Guillain–Barre syndrome (GBS), Miller-Fisher syndrome, long thoracic neuropathy, and oculomotor palsy.[4]

Among the central nervous system involvement, encephalopathy and encephalitis are the most common.[5] Dengue encephalopathy is usually secondary to systemic manifestations of dengue-like shock, or metabolic abnormalities secondary to renal and hepatic dysfunction. The incidence ranges from 15 to 31%.[67] The usual manifestation is decreased alertness, cognitive impairments, seizures, and behavioral abnormalities. CSF studies can be normal. The paper published in this issue concurs with various other studies showing a varied frequency of dengue encephalitis ranging from 15 to 33%.[678] Clinical presentation usually consists of altered sensorium, seizures, and headache and is believed to be due to direct neurotropism. A characteristic T2/FLAIR (fluid-attenuated inversion recovery) hyperintensity in bilateral thalami with intense diffusion restriction at center and hemorrhages named as “double doughnut sign” has been described in dengue encephalitis.[9] Meningitis is a rarer manifestation of the dengue infection. Both encephalopathy and encephalitis reflect severe disease and are associated with poorer recovery.[6]

Cerebrovascular accidents, both ischemic and hemorrhagic, have been associated with dengue. Hemorrhagic stroke has been seen with thrombocytopenia, platelet dysfunction, or vasculopathy. Management of coagulopathy must be done in addition to the traditional measures for stroke management in these cases.[10]

Acute disseminated encephalomyelitis (ADEM), an acute inflammatory demyelinating disease of the central nervous system (CNS) with the monophasic course and multifocal white matter involvement is rare—postulated to occur due to transient autoimmune reaction to myelin or other self-antigens.[411] Myelitis can also present with sudden onset sensorimotor and sphincter disturbances, transverse myelitis, or in the case of coagulopathy, with spinal hematoma.[12] Neuroimaging and CSF studies may be needed to establish the diagnosis. Although no established treatment is available for ADEM or transverse myelitis, steroids have been effective in the acute phase.

Ophthalmological complications of dengue fever are infrequent. The most frequent sign is maculopathy. Additionally, optic neuropathy, retinal vasculopathy, cranial nerve palsy, uveitis, and vitreous hemorrhages have also been reported. The mechanism of these presentations is unclear but is believed to involve immunological processes or coagulation abnormalities.[2] Most of these complications resolve spontaneously, however, a few patients might require systemic steroids and intravenous immunoglobulins (IVIg).

Peripheral nervous system involvement has been reported in 5% of the neurological manifestations of dengue.[2] Several case reports of GBS following a dengue infection have been published and the majority among them are in the pediatric population. The average onset of GBS symptoms has been reported to be between 1 and 20 days of the onset of dengue infection. Although the pathophysiology remains unclear, the role of pro-inflammatory substances against peripheral nerve constituents has been proposed. Plasma exchange and IVIg have been found effective in the treatment of GBS associated with dengue infection.

Dengue-associated hypokalemic periodic palsy resembling GBS has been reported by several authors. However, hypokalemia has been reported in up to 28% of the individuals with dengue infection without any associated weakness. The pathogenesis of hypokalemia in dengue remains obscure. It has been suggested as a systemic complication of dengue fever.[4] Potassium supplementations achieve a satisfactory recovery.

Myositis is another rarely reported peripheral nervous system manifestation of dengue infection postulated to occur due to direct muscular invasion by virus and the effect of myotoxic cytokines, particularly tumor necrosis factor (TNF). The clinical presentation may range from severe myalgia, asymmetric weakness of lower extremities, acute onset quadriplegia, and truncal weakness progressing to respiratory failure and rhabdomyolysis. The clinical manifestation of the dengue virus infection, raised dengue antibodies, high levels of creatinine phosphokinase levels, and myopathic features on electromyographic studies usually confirm the diagnosis. Histopathological features include dense endomysial inflammation with infiltration of lymphocytes and plasma cells.[12] Plasma exchange, intravenous (IV) steroids, and IVIg have been used for the management of dengue associate myositis.

Neuritis can be a rare manifestation of dengue infection. Multiple case reports of brachial neuritis, long thoracic nerve palsy, phrenic nerve palsy, and peripheral facial nerve palsy with dengue infection have been published. The pathogenesis of neuritis is likely to be immune-mediated. They usually respond to supportive treatment or steroids.

The varied manifestations of dengue in the neuraxis need to be studied and followed up to find out the long-term implications for management and prognosis. The present study describes different neurological manifestations of dengue in a large retrospective cohort.[7]