Dengue-Associated Postinfectious Meningoencephalomyelitis With Positive Anti-GFAP Antibody

PRACTICAL IMPLICATIONS

Consider GFAP antibody–mediated disease in postinfectious meningoencephalomyelitis.

Case

The patient is a 38-year-old Filipina woman who presented to the emergency department in September 2016 with complaints initially of vomiting and abdominal pain, resulting in the eventual diagnosis of emphysematous cystitis due to Escherichia coli, for which she received IV antibiotics. Medical history included hypertension, IgA nephropathy, depression, and anxiety. She had returned from the Philippines 3 weeks before presentation. She was hospitalized there for 1 week with fevers, whole-body aches, and mild confusion, with no clear diagnosis being reached. She made a full recovery. A week into hospitalization in Sydney for treatment of a urinary tract infection, it was noticed that she was drowsy, confused, and generally weak with muscle pain, despite improvement in inflammatory markers. Power was severely reduced, with grade 3/5 power generally in a pyramidal distribution. Reflexes were brisk. Sensation was intact, though altered, to the mid thoracic level. Bowel and bladder function were intact. There was no papilledema. Repeat investigation for infection was negative. Dengue serology showed positive immunoglobulin M (IgM) to all 4 serotypes, confirmed on repeat testing. Dengue NS1 antigen was negative. Other arbovirus serology was negative. The creatinine kinase level was not elevated. A lumbar puncture was performed, with a high opening pressure of 34 cm H₂O, elevated protein at 1.23 g/L, glucose of 2.7 mmol/L (serum 5.2 mmol/L), and 78 mononuclear cells. Oligoclonal bands were present. Dengue IgM was negative in CSF. Other extensive infective studies were negative. Antibodies for limbic encephalitis, including NMDA, acquaporin-4, and myelin oligodendrocyte protein antibodies, were negative in both serum and CSF via cell-based assay. Spine MRI showed edema and central T2 hyperintensity throughout the entire spinal cord, with extensive, patchy enhancement of the cord peripherally (Figure 1). Imaging of the brain showed extensive T2 signal hyperintensity involving the leptomeninges and cerebral cortex, extending along perforating vessels (Figure 2). An anti–glial fibrillary acid protein (GFAP) antibody was positive in serum and CSF via indirect immunofluorescence on primate brain (Inova San Diego) and confirmed to be anti-GFAP human embryonic kidney-transfected cells at the Mayo Clinic.² Repeat CSF 1 week later showed a repeat protein of 0.25 g/L, glucose 3.7 mmol/L, and 195 mononuclear cells. Repeat MRI 13 days after the initial MRI of the brain and spine showed considerable improvement. Dengue serology was performed 2 months after illness, now showing IgG positivity and negative IgM to all serotypes. Anti-GFAP antibody remained positive.

Figure 1. T2-Weighted Sagittal MRI.

MRI of the spine demonstrates longitudinally extensive myelitis.

Figure 2. Sagittal T1 Post-Contrast MRI.

MRI of the brain showing again linear, radial enhancement pattern.

The patient was diagnosed with an immune-mediated postinfectious meningoencephalomyelitis associated with anti-GFAP antibody secondary to recent dengue infection. She was treated with IV methylprednisolone 1 g/d for 5 days, in addition to 5 plasma exchanges. This was followed by an oral prednisone weaning dose over 2 months, now remaining on low dose oral prednisone in addition to mycophenolate, with good response.

Discussion

Anti-GFAP is a novel IgG antibody and is found in serum or CSF. It is specific for a cytosolic intermediate filament protein of astrocytes. There appears to be an association with other autoimmune disorders and malignancy in up to 2/3 of cases; however, a link with infectious disorders is not well described. There has been a single case associated with dengue fever.¹ There may also be coexistence with other antibodies, in NMDA (15%) and acquaporin-4 (3%). Clinical presentation includes headache, subacute encephalopathy, optic papillitis, inflammatory myelitis, postural tremor, and cerebellar ataxia. CSF typically shows high lymphocyte count (88%), and typical radiologic findings of striking radial, linear periventricular enhancement in the brain, with longitudinally T2-hyperintense lesions in the spinal cord.¹ Disease tends to follow a relapsing course and requires long-term treatment with immunosuppression,² in contrast to other postinfectious demyelinating syndromes, such as acute disseminated encephalomyelitis, which are typically monophasic.

Dengue virus is an RNA flavivirus and is transmitted by Aedes species mosquitoes, predominantly concentrated in the tropics, with increasing global spread. There has been increasing recognition of neurologic involvement in dengue recently, both as direct consequence of viral infection and of postinfectious immune-mediated conditions,³ such as acute disseminated encephalomyelitis and transverse myelitis.^4,5 Specific immune targets and antibodies, however, remain to be identified.

The co-occurrence of this antibody with dengue may be related to dengue's well-known effect on the vasculature, endothelial cells, and vascular endothelial growth factor receptors.⁶ It may be that this provides some insight into the typical perivascular and ventricular distribution of radiologically apparent inflammation and pathologic correlate of lymphocytic infiltration seen in anti–GFAP-associated disease.

The case we have presented broadens the spectrum of postinfectious immune-mediated conditions and, in particular, their association with novel autoantibodies. With increasing clinician recognition and testing, clinical picture, pathogenicity, and significance of GFAP antibodies in relation to other associated diseases may be further illuminated. In addition, their presence may indicate the need for longer-term immunosuppression.

Appendix. Authors

Study Funding

No targeted funding reported.

Disclosure

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