Autoimmune glial fibrillary acid protein (GFAP) astrocytopathy

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Autoimmune glial fibrillary acid protein (GFAP) astrocytopathy, or simply GFAP astrocytopathy, is a rare inflammatory central nervous system (CNS) disorder.

Epidemiology

Given the rarity of the condition, epidemiological data pertaining to autoimmune GFAP astrocytopathy are not well established. Based on existing case series-level data, it tends to manifest in middle-aged adults and there may be a slight female preponderance .

Associations

There may be an association with an underlying tumor or malignancy (e.g. ovarian teratoma, a variety of adenocarcinomas, small cell lung cancer), although this is detected in a minority of cases .

Clinical presentation

Autoimmune GFAP astrocytopathy has a broad clinical neuropsychiatric and temporal spectrum . The most common phenotypical syndromes are those of meningoencephalitis or meningoencephalomyelitis , which can manifest over an acute, subacute, or chronic time-frame . Within those syndromes, the most common clinical features include :

  • headache
  • delirium
  • neck stiffness
  • fever
  • psychiatric symptoms (e.g. psychosis)
  • blurred vision (due to optic papillitis)
  • motor and sensory changes (due to myelopathy)
  • cerebellar ataxia
  • movement disorders (e.g. tremor, chorea, myoclonus)
  • drug-refractory seizures
  • autonomic dysfunction
  • bulbar symptoms

Additionally, a coryzal or flu-like prodrome is also a common clinical feature, being present in 30-67% of patients .

Pathology

Etiology

The pathophysiology of autoimmune GFAP astrocytopathy has not been fully elucidated and is not well understood. It is known that GFAP is an intracellular protein that forms an integral component of astrocyte cytoskeletons and also plays a pivotal role in multiple astrocytic functions . In autoimmune GFAP astrocytopathy, there are IgG autoantibodies that target GFAP in astrocytes, which leads to an eventual loss of astrocytes, and presumably the resultant clinical phenotype . These autoantibodies may have a paraneoplastic or parainfectious etiological basis .

Markers

The key marker is the GFAP antibody, which has a higher positive predictive value when present in the CSF than in the serum . Additionally, CSF will often have an inflammatory phenotype, with high protein and a pleocytosis . Co-existing autoantibodies (e.g. NMDA receptor antibody, aquaporin-4 antibody) may also be present .

Microscopic appearance

Typical neuropathological features include :

  • extensive perimicro-vascular inflammation, sparing the vessel itself
  • microglial activation

Radiographic features

MRI

Radiographic abnormalities of the neuraxis are very common in autoimmune GFAP astrocytopathy .

Brain

Typical findings include:

  • T2/FLAIR: hyperintense, diffuse, confluent, periventricular white matter lesions , often extending into the centrum semiovale, deeper brain structures, and/or brainstem 
  • DWI: normal
  • T1 C+ (Gd): characteristic linear, perivascular pattern of contrast-enhancement extending radially from the periventricular surface and through the cerebral white matter
    • other less characteristic and less common patterns of enhancement include leptomeningeal and periependymal
  • MR angiogram: normal

Notably, in patients with a predominantly cerebellar ataxia phenotype, diffuse cerebellar atrophy may be the only radiographic feature . Furthermore, despite visual changes being a relatively common feature of autoimmune GFAP astrocytopathy, optic nerves often appear normal on imaging.

Spinal cord

Typical findings, most commonly in the cervicothoracic spinal cord, include:

Nuclear medicine
PET-CT

FDG PET-CT of the neuraxis may reveal increased FDG uptake indicative of hypermetabolism, often corresponding with regions of signal abnormality on MRI brain and/or spinal cord .

Treatment and prognosis

Autoimmune GFAP astrocytopathy is typically steroid-responsive . In cases that are steroid-refractory, often in the setting of concurrent underlying malignancy or co-existing autoantibody, there may be response to other immunotherapy (e.g. rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, intravenous immunoglobulin) .

The disease is most often monophasic, however may have a relapsing course in approximately 20% of patients . Overall, the prognosis is generally good .

History and etymology

Autoimmune GFAP astrocytopathy was first described by Boyan Fang, Vanda Lennon, and colleagues from the Mayo Clinic in their 2016 seminal paper . It is thought that some cases previously labeled as 'nonvasculitic autoimmune inflammatory meningoencephalitis' may actually have been autoimmune GFAP astrocytopathy .