Article Text

Download PDFPDF

Glial fibrillary acidic protein antibody-positive meningoencephalomyelitis
  1. Angeliki Zarkali1,
  2. Oliver Cousins1,
  3. Dilan Athauda1,2,
  4. Samuel Moses3,
  5. Nicholas Moran1,4,
  6. Sreedharan Harikrishnan1,4
  1. 1East Kent Neurology Unit, East Kent University Hospitals NHS Foundation Trust, Canterbury, UK
  2. 2University College London, London, UK
  3. 3East Kent Microbiology and Virology, East Kent University Hospitals NHS Foundation Trust, Canterbury, UK
  4. 4King’s College London, London, UK
  1. Correspondence to Dr Angeliki Zarkali, East Kent Neurology Unit, East Kent University Hospitals NHS Foundation Trust, Margate CT9 4AN, UK; angeliki.zarkali{at}nhs.net

Abstract

Glial fibrillary acidic protein antibody-positive meningoencephalomyelitis is a newly described, possibly under-recognised, severe inflammatory condition of the nervous system. The clinical presentation is variable but most commonly is a combination of meningitis, encephalitis and myelitis; other manifestations may include seizures, psychiatric symptoms and tremor. There is a significant association with malignancies, often occult, and with other autoimmune conditions. Although the disease responds well to corticosteroids acutely, it typically relapses when these are tapered, and so patients need long-term immunosuppression. We report a young man presenting with subacute meningoencephalitis and subsequent myelitis, and discuss the typical presentation and management of this severe but treatable condition.

  • immunology
  • meningoencephalitis
  • myelopathy

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Case

A 26-year-old right-handed man presented with a 2-week history of headache and confusion. Initially, he had experienced feverishness and sore throat; a week later, he developed gradual onset headache that was dull, bifrontal and associated with nausea and phonophobia. The next day, he flew from the UK to Austria for work. His symptoms progressed with impaired balance and light-headedness, and so he returned to the UK. Although his fever resolved, the headache persisted; over the next 2 days, he became confused, irritable and aggressive. At this point, he was admitted to hospital. On examination, he had neck stiffness and bilateral optic disc swelling (figure 1); he was disorientated to time and could not tandem walk; the remaining neurological examination was normal.

Figure 1

Fundi photography showing bilateral optic disc swelling.

He was a non-smoker with no history of alcohol or substance misuse. He had been previously well and took no regular medication. He worked as a senior manager in a media marketing company. There was no relevant family history. He lived with his girlfriend; he had a cat and a snake, to which he fed live rats bought from a pet store. Over the last 12 months, he had travelled to Lake Garda, Italy; Melbourne, Australia; the Canary Islands and Somerset, UK. He had no insect bites or rashes.

On admission, an unenhanced CT scan of head, full blood count, serum electrolytes, liver function tests, serum C-reactive protein and erythrocyte sedimentation rate were normal. The cerebrospinal fluid (CSF) opening pressure was 28 cmH2O, white cell count was 105/µL (≤5) (85% lymphocytes), protein was 2.55 g/L (0.15–0.45) and glucose was not sent. After starting acyclovir and ceftriaxone, his headache and confusion significantly improved; however, he had difficulty passing urine and was catheterised. The next day he was transferred to our regional neurology unit.

An MR scan of brain showed diffuse symmetrical leptomeningeal enhancement. A repeat lumbar puncture showed opening pressure 27 cmH2O, white cell count 93/µL (≤5) (85% lymphocytes), protein 1.4 g/L (0.15–0.45), glucose 2.2 mmol/L (plasma glucose 4.8 mmol/L), lactate 3.3 mmol/L and negative oligoclonal bands. Viral, fungal, bacterial PCR, cultures and cytology were negative (table 1).

Table 1

Results of relevant investigations

Five days after admission, he developed progressive bilateral leg weakness over 24 hours, with sensory loss to his mid-abdomen and severe constipation. On examination, he had a flaccid paraplegia, hyporeflexia and a T9 sensory level. An urgent MR scan of spine showed diffuse cord oedema (figure 2A); we started antituberculous and antifungal treatment (fluconazole), amoxicillin and pulsed methylprednisolone 1 g intravenously for 3 days. Unfortunately, his symptoms did not respond and so we subsequently gave a 5-day course of plasma exchange, while continuing a slowly weaning course of oral prednisolone. After 3 weeks, we stopped all the antibiotic, antiviral and antifungal treatments, as serology and cultures were negative. Visual evoked potentials showed only non-specific mild bilateral delay. A vasculitic screen, aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies, N-methyl-D-aspartate (NMDA) receptor antibodies, glutamic acid decarboxylase autoantibodies and neuronal antibodies were negative; glial fibrillary acidic protein (GFAP) antibody was positive in the CSF. We made a diagnosis of GFAP antibody-positive meningoencephalomyelitis.

Figure 2

MR scan of spine, T2-weighted axial images (A). Day 5 of admission, showing extensive diffuse cord oedema (B). Day 35 of admission post-plasma exchange and intravenous methylprednisolone, showing improvement in inflammatory changes.

Table 1 summarises his investigations.

After completing the plasma exchange 3 weeks after admission, his strength and sensation began to improve significantly and was transferred to the neurorehabilitation unit. A repeat MR scan of spine showed significant improvement (figure 2B). A CT scan of chest, abdomen and pelvis, and subsequently a positron-emission tomography/CT scan showed no evidence of malignancy. Two months after symptom onset, he could walk with a crutch and was continent of bowels and bladder. We discharged him home with a plan to start on azathioprine. Figure 3 summarises his presentation and recovery.

Figure 3

Timeline of the patient’s presentation. IVMP, intravenous methylprednisolone; LL, lower limbs; PLEX, plasma exchange.

Differential diagnosis

Given the initial presentation with subacute meningoencephalitis and the CSF lymphocytosis, we initially considered an infective cause as most likely (box 1). We therefore started him on broad-spectrum antimicrobial treatment with intravenous ceftriaxone, amoxicillin (to cover for Listeria), acyclovir, fluconazole and anti-tuberculous therapy. We discussed with him via conference call the imported fever service, particularly given his pet and travel history. Following this, we sent further tests for lymphocytic choriomeningitis, leptospirosis and West Nile virus. We took his travel history and animal/pet exposure into account when planning the exhaustive list of pathogen screening in serum and CSF (table 1).

Box 1

Differential diagnosis of subacute lymphocytic meningoencephalitis and longitudinally- -extensive transverse myelitis

Inflammatory/autoimmune

  • GFAP autoimmunity

  • Acute disseminated encephalomyelitis

  • Neurosarcoidosis

  • Neuro-Behçet’s disease

  • Systemic lupus erythematosus

  • Sjögren’s syndrome

Infectious

  • Viral (including herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein–Barr virus, HIV)

  • Bacterial (including syphilis, mycobacteria and Lyme disease)

Miscellaneous

  • Lymphoma

The delayed myelitis further complicated the clinical picture; it was unclear whether this was a biphasic disorder, infective or autoimmune, or an infective meningoencephalitis with a consequent parainfective immune-mediated myelitis. The strong possibility of inflammatory myelitis prompted our treatment with intravenous methylprednisolone followed by plasma exchange. We also considered other inflammatory conditions presenting with longitudinal-extensive myelitis, including neuromyelitis optica spectrum disorders (NMOSDs) (box 1).

Discussion

GFAP is highly expressed in the central nervous system, almost exclusively in astrocytes; it is the main filament protein of mature astrocytes and so seems to play a role in modulating astrocyte motility and shape.1 As an intracellular antigen, antibodies against GFAP are probably non-pathogenic, but serve as a marker of cytotoxic T-cell-mediated autoimmunity.2 3 Fang et al1 first reported antibodies to the intracellular GFAP antigen in 2016, in 16 patients with inflammatory meningitis, encephalitis and myelitis. In four published case series to date, GFAP antibody positivity is associated with a clinically defined, although heterogeneous, syndrome.2 4–6 In the largest case series of 102 patients, the typical presentation was with subacute meningitis, encephalitis or myelitis, or any combination of these.4 Other features include seizures, psychiatric symptoms, autonomic disturbances and tremor.2 4 6 The only pathological information comes from a single case where a brain biopsy showed a necrotising inflammatory process with infiltration of CD8+ lymphocytes and macrophages.2

Approximately one-third of patients with GFAP autoimmunity have an associated malignancy, with ovarian teratoma being the most commonly reported.4 About a quarter of patients have additional autoimmune conditions, particularly rheumatological and endocrinological.2 4 5 In a case series of 22 patients, Iorio et al noted that 27% of patients reported a prodromal illness initially diagnosed as infectious.3

Although disease associated with this antibody is newly described, the Mayo Clinic (USA) laboratory reports one patient per week testing positive for GFAP, compared with three per week with NMDA encephalitis, and seven per week with aquaporin-positive NMOSD.4 In addition, screening patients with suspected autoimmune neurological conditions found that 5% have GFAP-IgG positivity, indicating that the antibody is not rare.2

Diagnosis of GFAP autoantibody-positive meningoencephalomyelitis

The largest case series to date of 102 GFAP-positive patients showed that the MR scan of brain can be normal, although usually it shows non-specific abnormalities.4 The most common are T2 hyperintense lesions (56%; often enhancing) and less frequent is leptomeningeal, serpentine or ependymal enhancement.2 4 Flanagan et al reported that the radiological hallmark of GFAP autoimmunity (56% of patients) is a striking linear periventricular enhancement.5 Patients with spinal cord involvement mostly have longitudinally extensive lesions on MRI. The imaging abnormalities often resolve following corticosteroid treatment.1 3 5 6 Our patient had striking spinal imaging with diffuse cord oedema from the craniocervical junction to the conus, a pattern not previously reported.

CSF examination can be informative; 88% of patients have markedly elevated white cell count with a median of 78 cells/µL (≤5), 83% have raised protein (median 0.8 g/L) and 50% of patients have positive unmatched oligoclonal bands.4

In the same series by Flanagan et al, 45 of 49 patients had GFAP testing of both serum and CSF; 92% had GFAP-positive IgG in the CSF, as did this patient, while only 22 (45%) had antibody positivity in the serum. Antibody titres were not associated with disease severity or with the presence of an underlying malignancy.5

About 40% of patients have coexisting neural autoantibodies. The most commonly reported are NMDA receptor and aquaporin-4 antibodies; teratoma was more likely in patients who had both these autoantibodies.4

Clinical course and treatment

Corticosteroids lead to improvement in 87.5% of patients.4 Plasma exchange and pooled intravenous immunoglobulin have been used less frequently in the acute phase but may also lead to clinical improvement in a significant proportion of patients.4 Among the 16 patients followed up for over 2 years, relapse was common while tapering the corticosteroids; these relapses were often associated with recurrent gadolinium enhancement on MRI and elevated CSF white cell counts.4 Given the possibility of relapses, patients should be considered for long-term immunosuppressive agents, including mycophenolate mofetil and azathioprine.

GFAP antibody-positive meningoencephalomyelitis is a severe, newly described and potentially underidentified inflammatory condition of the central nervous system, which affects primarily the brain, leptomeninges and spinal cord in various degrees. Although it is not yet clear whether GFAP antibodies are pathogenic or an epiphenomenon, they are a biomarker for a clinically distinct cause of autoimmune meningoencephalomyelitis that responds to immunomodulation. The clinical spectrum and imaging can be heterogeneous and CSF antibodies are most sensitive in diagnosis. Patients need to be investigated for the possibility of other autoimmune conditions and malignancies, which can coexist. The response to corticosteroids is excellent in the acute setting; however, relapses can occur following corticosteroid tapering, and long-term immunosuppression is recommended.

Key points

  • Glial fibrillar acidic protein (GFAP) antibody-positive meningoencephalomyelitis is a newly recognised and treatable cause of autoimmune meningoencephalomyelitis.

  • Patients commonly have a marked cerebrospinal fluid (CSF) lymphocytosis.

  • One-third of patients with GFAP autoimmunity have a malignancy.

  • GFAP antibodies in the CSF are particularly sensitive, but those in the serum are significantly less so.

  • High-dose corticosteroids are highly effective, but because relapse is common, particularly on withdrawing corticosteroids, clinicians should consider long-term immunosuppression.

Acknowledgments

We thank Dr Andrew McKeon and the Mayo Clinic Neuroimmunology Laboratory for supporting us with laboratory testing.

References

Footnotes

  • Contributors All authors provided clinical care to the patient. AZ drafted the first version of the manuscript, and all authors contributed to and have approved the final version of the manuscript.

  • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Jackie Palace, Oxford, UK.

Other content recommended for you