Feb. 22, 2017
Researchers at Mayo Clinic in Rochester, Minnesota, have identified an astrocytic autoantibody as a biomarker of a relapsing autoimmune meningoencephalomyelitis. The antibody — which targets glial fibrillary acidic protein (GFAP) — has been found in more than 100 patients screened at Mayo Clinic.
"This is a new antibody, verifiable by all the stringent tests that we use," says Vanda A. Lennon, M.D., Ph.D., a consultant in neuroimmunology at Mayo Clinic's campus in Minnesota. "Although GFAP has been associated in the literature with other conditions, to date we find this GFAP antibody only in the spectrum of autoimmune meningoencephalomyelitis."
"GFAP meningoencephalomyelitis is a rapidly progressive disorder and can be potentially devastating neurologically. However, it is exquisitely steroid responsive," adds Andrew McKeon, M.B., B.Ch., M.D., an autoimmune neurologist at Mayo Clinic's campus in Minnesota.
Prominent clinical manifestations of the condition include headache, subacute encephalopathy, optic papillitis, inflammatory myelitis, postural tremor and cerebellar ataxia. "Patients might have weakness, behavioral problems or forgetfulness," Dr. Lennon says. The condition can be mistaken for meningeal tumor, multiple sclerosis, central nervous system vasculitis, central nervous system lymphoma or sarcoidosis.
A clinical test for the GFAP autoantibody is expected to be available from Mayo Clinic in autumn 2017. In the meantime, the Mayo Clinic Neuroimmunology Research Laboratory can accept patient samples of blood and cerebrospinal fluid (CSF) for testing, and report the results to referring physicians.
Since Dr. Lennon established the Neuroimmunology Laboratory 35 years ago, she and colleagues have conducted groundbreaking research on neural autoantibodies. The laboratory's algorithm for neural-specific immunoglobulin G detection incorporates a mouse tissue-based immunofluorescence assay that reveals clinically pertinent autoantibodies.
"This assay has been an amazing discovery tool since the 1960s, when it was first described," Dr. Lennon says. "Rather than developing a theory and then searching for an antibody that fits it, we put patient serum on sections of mouse tissues, see what binds, and then further investigate. Through this we've been discovering a series of very informative antibodies, which are then subjected to molecular confirmation."
The novel GFAP autoantibody drew the researchers' attention due to its unique staining pattern resembling astrocytes. The autoantibody was subsequently found in CSF and serum samples of 103 patients who underwent testing for potential autoimmune neurological disorders at Mayo Clinic. Retrospective review of medical records confirmed Dr. McKeon's early observation that many of these seropositive patients were women with ovarian teratoma or women with encephalitis who subsequently developed ovarian teratoma.
In a study published in JAMA Neurology, the Mayo Clinic researchers focused on the initial 16 GFAP autoantibody positive cases. Their median age at neurological symptom onset was 42 years. CSF was inflammatory in 13 of 14 patients with data available. Neoplasia was diagnosed within three years of neurological onset in six of the 16 patients (38 percent).
Long signal abnormalities in the spinal cord
Sagittal T2-weighted MRI of the thoracic spine demonstrates a longitudinally extensive T2-hyperintense spinal cord lesion (arrows).
Fingerlike projections from the lateral ventricles outward
On the left, axial T2-weighted MRI of the head demonstrates diffuse T2-hyperintense signal within the white matter. On the right, T1-weighted post-gadolinium image shows the characteristic radial enhancement pattern.
Brain MRIs of seropositive patients showed characteristic fingerlike projections from the lateral ventricles outward, and post-gadolinium enhancement of those areas. Long signal abnormalities were apparent in the spinal cord.
Neurological improvement followed treatment with high-dose corticosteroids, with patients tending to relapse without long-term immunosuppression. "This condition is eminently treatable," Dr. McKeon says.
Although the GFAP antibody is present in serum and CSF, the specificity for autoimmune central nervous system disease appears more robust in spinal fluid. Dr. McKeon recommends that referring physicians who suspect the disorder submit to Mayo Clinic both patient CSF and serum samples for an autoimmune encephalopathy evaluation.
"As well as doing the routine autoimmune tests, we can also look for this very specific antibody on a research basis," he says. A Mayo Clinic neurologist will contact the physician about the test results and advise on treatment if the results are positive.
Dr. Lennon notes that at least one-third of the patients screened at Mayo Clinic who have the GFAP antibody are subsequently found to have neoplasms, at varied locations. "The tumors we're finding might be in the ovary, the prostate gland or the gastrointestinal tract. Some are benign and some malignant," she says.
Further research is underway to determine whether different forms of the GFAP antigen might be more predictive of cancer, and more generally to gain insight into the pathophysiology of this newly recognized autoimmune meningoencephalomyelitis. "There are likely to be unusual neurological presentations we haven't encountered yet," Dr. Lennon says.
For more information
Fang B, et al. Autoimmune glial fibrillary acidic protein astrocytopathy: A novel meningoencephalomyelitis. JAMA Neurology. 2016;73:1297.