Dengue-associated longitudinally extensive transverse myelitis

Abstract

We diagnosed a patient with dengue fever who developed acute onset of sensorimotor quadriparesis with bladder involvement, and facial nerve involvement. Despite initial negative results in routine investigations and cerebrospinal fluid analysis, spinal MRI confirmed longitudinally extensive transverse myelitis. The aetiological workup was negative, prompting an investigation into the presence of dengue in the cerebrospinal fluid, which returned positive. This case underscores the importance of considering rare neurological complications in dengue, the value of advanced diagnostic techniques and the potential effectiveness of tailored interventions in challenging cases.

Background

Dengue fever is a prevalent global health issue with a diverse array of neurological manifestations. Despite its historical classification as non-neurotropic, emerging evidence highlights its potential impact on the central nervous system (CNS). Healthcare professionals must remain vigilant about dengue as a potential cause of longitudinally extensive transverse myelitis (LETM), especially in endemic regions. The atypical nature of neurological complications necessitates a broad diagnostic perspective and advanced imaging for prompt identification.

Case presentation

An adolescent female sought medical attention reporting a fever over a 6-day period, concomitant with myalgia. On the ninth day of illness, she manifested an acute onset of progressive weakness affecting both lower extremities, leading to an inability to ambulate within 8 hours of onset. She experienced a sensation of limb heaviness and flaccidity. Subsequently, she observed weakness in both upper limbs, encountering difficulty in grasping objects and consuming food, although she was able to elevate her neck above the bed level. Her inability to urinate prompted catheterisation. There were no antecedents of seizures, cognitive impairment or involuntary movements. Notwithstanding, she noted slurred speech, challenges in masticating food and drooling of saliva. General physical examination yielded unremarkable findings, except for the neurological system. The patient remained conscious, oriented to time, place and person. Lower motor neuron-type bilateral facial nerve palsy, more pronounced on the right side, was evident. All other cranial nerves exhibited normal function. Motor examination revealed flaccid limbs with 0/5 power in both lower limbs, 3/5 power at the shoulder and elbow joints in the upper limbs, accompanied by a weak hand grip. Absence of deep tendon reflexes in the lower limb (knee and ankle) was noted, while upper limb and superficial reflexes were within normal limits. Bilateral Babinski’s sign was positive. The patient reported loss of touch and pain sensation throughout all limbs, with impaired proprioception in the great toe and ankle.

Investigations

The patient’s routine investigations, encompassing a complete blood count and assessments of kidney and liver function, yielded normal results except for mild thrombocytopenia. Serological testing for dengue IgM returned positive, while tests for typhoid (blood culture and serology) and malaria (antigen) were negative. Normal findings were observed in chest X-ray, X-ray of the cervical and lumbar spine and MRI of the brain. However, the MRI of the entire spine revealed a LETM, characterised by a long segment of small, peripheral, patchy T2 hyperintensity involving the cervical (C3–C7) and mid-thoracic (T3–T7) spinal cord, with no postcontrast enhancement or cord expansion on sagittal sections while subtle T2 hyperintensity was visualised on the axial section (figure 1).

Figure 1.

T2-weighted MRI spine. (A) Sagittal section. (B) Axial section showing long segment, small, peripheral, patchy, T2 hyperintensity (arrows) involving the cervical and mid-thoracic spinal cord from C3 to C7 and T3 to T7 with no postcontrast enhancement or cord expansion.

Lumbar puncture was performed, and cerebrospinal fluid (CSF) analysis showed five lymphocytes, glucose levels of 68 mg/dL and protein levels of 48 mg/dL. Adenosine deaminase was measured at 4 U/L, and CSF CBNAAT and cryptococcal antigen were negative. To further investigate LETM, CSF was subjected to tests for oligoclonal bands and viral PCRs, including herpes simplex virus, cytomegalovirus, Epstein-Barr virus and Japanese encephalitis. However, CSF serology for dengue was not sent in the initial evaluation as it is a rare differential. Oligoclonal bands were absent, and no albumin-cytological dissociation was noted. Aquaporin-4 antibodies and anti-MOG were not detected in the serum. Immunofluorescence analysis for antinuclear antibodies returned negative.

Despite an exhaustive diagnostic workup, the aetiology of the LETM remained elusive. Considering the positive result for dengue IgM, a CSF sample was sent specifically for dengue PCR, using multiplex assay kit revealing positivity for dengue serotype 2 (DENV-2 NGC) as shown in table 1.

Table 1.

Virology report of the patient from CSF

Specimen type: CSF
Dengue serotyping by RT-PCR
Dengue virus—1	Target not detected
Dengue virus—2	Target detected
Dengue virus—3	Target not detected
Dengue virus—4	Target not detected

CSF, cerebrospinal fluid.

Differential diagnosis

The initial assessment pointed to an acute onset of sensorimotor quadriparesis with bladder and bowel involvement, coupled with bilateral facial nerve palsy. The primary consideration for LETM included multiple sclerosis, characterised by white matter lesions in the brain, oligoclonal bands in CSF and a relapsing-remitting course. However, none of these features were evident in the present case. The second consideration was of neuromyelitis optica (NMO), confirmed by the presence of any one of the six core clinical characteristics and positive aquaporin antibodies, and any two core clinical characteristics with dissemination in space in absence of antibodies. The absence of aquaporin antibodies and any core clinical characteristics apart from LETM ruled out NMO.

Tuberculosis, prevalent in endemic regions like India, was considered as a crucial differential diagnosis. However, normal CSF analysis, and a normal MRI of the brain, and the brief clinical history rendered tuberculosis an improbable aetiology. Intramedullary tumours and radiation therapy have been associated with LETM-like presentations, but the MRI of the spine excluded the former, and there was no history of radiation exposure.

Postinfectious myelitis emerged as another potential cause for LETM, with commonly implicated viruses yielding negative results. Acute infectious myelitis is an alternative differential in such presentations and patient’s history of dengue fever prompted a focused investigation for its presence in the CSF, ultimately confirming the diagnosis of dengue-associated LETM.

Treatment

The patient underwent a regimen of intravenous methylprednisolone at a dosage of 1 g once daily for 5 days, followed by a maintenance dose of 40 mg/day. Due to the lack of improvement, intravenous immunoglobulin (IVIG) therapy was initiated. Unfortunately, the patient did not respond positively to this intervention. Subsequently, a decision was made to pursue four cycles of plasmapheresis, alongside the continuation of physiotherapy as part of the therapeutic approach.

Outcome and follow-up

The patient received ongoing and consistent physiotherapy and rehabilitation. Over the course of the following 6 weeks, she exhibited gradual improvement in lower limb strength, eventually achieving the ability to walk with support. By the end of the eighth week, she regained the capacity for independent urination. Progress was also noted in the upper limb strength, enabling her to self-feed. The patient remained under our follow-up care for a total of 12 weeks postdischarge, during which she was able to walk without the need for external support.

Discussion

Dengue, caused by the Flaviviridae family’s dengue virus (DENV), exhibits varied clinical presentations, ranging from asymptomatic cases to severe manifestations. WHO’s 2009 guidelines classify dengue into three groups: without warning signs, with warning signs and severe (involving plasma leakage, bleeding or organ failure). WHO acknowledges the CNS involvement in dengue and includes altered sensorium as one of the criteria for severe dengue.¹ Neurological involvement, once considered atypical, is now recognised, but the incidence remains ill-defined. The complications were previously categorised by pathogenesis but are now grouped as CNS, peripheral nervous system and postdengue immune-mediated syndromes as described in table 2.²

Table 2.

Classification of neurological complications of dengue

	CNS syndromes	PNS syndromes	Postdengue immune mediated
Infectious	Meningoencephalitis, cerebellitis, myelitis	Mononeuritis multiplex, brachial plexitis	Acute disseminated encephalomyelitis
Inflammatory	Vasculitis	GBS	Miller-Fisher variant GBS, transverse myelitis, neuromyelitis optica
Vascular	Subdural haematoma, ischaemic stroke, intracranial haemorrhage
Ophthalmological	Psoclonus, retinochoroiditis, retinal vasculopathy
Miscellaneous		Hypokalaemic quadriparesis, diaphragmatic paralysis	Cranial neuropathies

CNS, central nervous system; GBS, Guillain-Barré syndrome; PNS, peripheral nervous system.

The neuropathogenic mechanisms of DENV infection remain unclear. Both viral and host factors are presumed contributors to dengue-associated neurological syndromes. Despite DENV initially considered as non-neurotropic, neurological involvement, viral particles in CSF and blood-brain barrier (BBB) disruption suggest potential direct neurotropism. Research indicates neuroinflammation’s role in dengue pathogenesis. NS1Ag, a secreted glycoprotein aiding viral RNA replication, induces cytokine release. Early activation of natural killer cells stimulates T helper (Th) cells, leading to Th17 and Th9 cell differentiation. This cascade releases proinflammatory cytokines, exacerbating BBB impairment, facilitating immune-mediated brain infiltration and triggering neuroinflammation.^{1 3}

For the accurate diagnosis of any neurological disorder associated with DENV infection, adherence to the WHO’s defined criteria for confirming DENV infection is imperative. This entails meeting one of the following criteria: positivity in PCR testing, positive results in virus culture, seroconversion of IgM in paired serum samples or a fourfold increase in IgG titres in paired serum samples.^{2 4}

Spinal cord involvement is an uncommon complication in dengue fever, with transverse myelitis sparsely documented in the literature, primarily through isolated case reports. Notable instances of postinfectious transverse myelitis following dengue fever have been reported by Verma et al, Mo et al and Mota et al.^4–6 Fong et al presented a unique case involving a girl aged 12 years who developed flaccid quadriplegia 8 days after acute dengue fever onset. Subsequent spinal MRI revealed T2 hyperintensity and an epidural haematoma at the C3–C6 spinal cord level. Remarkably, this is one of the first report of longitudinal extensive transverse myelitis following dengue infection in the paediatric population.⁷ Despite an extensive literature search, no similar case reports have been identified in adults.

Crucially, diagnosing transverse myelitis or LETM heavily relies on positive spinal MRI findings of which T2 hyperintensity in the spinal cord serves as a supportive marker. Additionally, most patients demonstrate inflammatory reactions in CSF, aiding in diagnosis confirmation.^{8 9} The primary therapeutic approach for managing neurological complications of dengue involves high-dose steroids as the first-line intervention, with reported cases typically responding positively. In cases of resistance, alternative modalities like IVIG and plasmapheresis may be considered, as in our case. Supportive care, including physiotherapy and rehabilitation, is integral to the overall treatment strategy.^{1 3}

Learning points.

• Dengue can have diverse neurological manifestations either because of the disease severity or due to viral neurotropism.

• Longitudinal extensive transverse myelitis (LETM) stands out as a rare entity that necessitates consideration, particularly in patients presenting with quadriparesis or paraparesis after a febrile episode.

• The expeditious diagnosis of LETM and its aetiological workup is crucial for the timely initiation of therapeutic measures, as any delay in intervention may compromise the potential for complete recovery.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).