Discussion

GFAP is the main intermediate filament protein in mature astrocytes and a component of their cytoskeleton. It is the main target of autoimmune GFAP astrocytopathy,1 a disease with a physiopathology which remains poorly understood. This type of autoimmune disease was first defined through the discovery of GFAP-IgG antibodies, using different methods such as immunofluorescence assay, CBA or western blot.1 However, this disease is hypothesised to be caused by a cytotoxic response mediated by T cells; therefore, GFAP-IgGs would be neural autoantibody intermediaries in the autoimmune response, since GFAP is an intracellular antigen.2

Autoimmune GFAP astrocytopathy is associated with other autoimmune disorders like type 1 diabetes, Graves’s thyroiditis or even autoimmune encephalitis, such as anti-N-methyl-D-aspartic acid encephalitis.1 2 In addition to this, autoimmune GFAP astrocytopathy is a paraneoplastic phenomenon in a third of the patients, and ovarian teratoma is the most commonly found neoplasm.3

According to the most recent studies, consisting mostly of case reports and case series, the median age of onset of autoimmune GFAP astrocytopathy is 40–50 years4 5 (range 8–103)4 . No gender predilection has been reported.2 Clinically, autoimmune GFAP astrocytopathy usually presents as an acute disorder,6 although there are unusual cases of subacute or even chronic presentation.5 A history of symptoms of upper respiratory tract infection is found in 40% of the cases.2 The most common manifestations include headache, abnormal vision, ataxia, altered consciousness, myelitis and seizures.5 7 8 Movement disorders and neuropsychiatric alterations are less frequent;4 9 bulbar syndrome,7 sensorimotor neuropathy6 or bilateral sensorineural hearing loss10 are even more uncommon. Syndromes are often defined as encephalitis, meningoencephalitis, myelitis or their combinations. Some of the demographic data, symptoms and clinical syndromes reported in the most recent literature can be found in the online supplemental table 1.1 4–8 10 11

Inflammatory parameters are usually found in CSF (monocytic pleocytosis, elevated protein level and low glucose level). Brain and spinal cord MRI usually show non-specific findings such as T2-hyperintense lesions, gadolinium-enhanced lesions in T1 sequences, and even leptomeningeal enhancement.2 Nevertheless, neuroimaging studies show no alterations in half of the patients.7

For acute treatment, patients are usually given intravenous methylprednisolone boluses (0.5–1 g/day for 5 days), with great clinical improvement.2 However, intravenous immunoglobulins or plasma exchange is sometimes necessary to achieve disease remission.5 Chronic immunosuppressive therapy, with mycophenolate mofetil, azathioprine or rituximab, is required in 20%–50% of the cases to prevent relapses.2 Prognosis is usually favourable;6 however, it is worse in some case series8 due to unknown causes, but the time of disease progression might contribute as an important factor. More information on these topics can be found in the online supplemental table 1.1 4–8 10 11

Considering all the above-mentioned data, we report an atypical case of autoimmune GFAP astrocytopathy bearing in mind both its initial clinical progression and manifestations. Chronic progression of autoimmune GFAP astrocytopathy, as in our patient (6 months), is an unusual finding, and only a few patients having disease progression for months have been reported previously.8 Moreover, our patient only presented for these 6 months ataxia, bulbar symptomatology (with predominance of dysphagia) and myoclonus. More frequent manifestations such as headache, loss of visual acuity, seizures or myelitis were not present. Bulbar symptomatology, to our knowledge, has been reported only twice,1 7 and dysphagia has been described only in one case.1 Some case series have also described movement disorders7 and dyskinesias,5 but we have found only one case specifically reporting myoclonus as in our patient.11 Cognitive disturbances, which are typical symptoms according to the literature,4 5 7 9 appeared only weeks after first hospitalisation in our patient, approximately after 7–8 months of disease progression. Moreover, hypermetric ocular saccades were noted during the second hospitalisation. It is our belief that this is the first time this neurological finding is reported in autoimmune GFAP astrocytopathy. In addition to this, no upper tract respiratory symptoms were reported in our case, neuroimaging studies showed no lesions and we could not find any signs of neoplasms.

However, and consistently with other studies, our patient did have both inflammatory parameters in CSF (monocytic pleocytosis and elevated protein level) and showed great clinical improvement when given corticosteroid treatment. Nevertheless, we suspect that the patient was given this therapy too late, delay caused by the uncommon manifestations of autoimmune GFAP astrocytopathy found in our patient, provoking secondary functional deterioration. This may have contributed to the patient’s decease after he was finally discharged from hospital.

In summary, we report new, atypical manifestations of autoimmune GFAP astrocytopathy, to facilitate the early recognition of this disease and prevent neurological and functional deterioration due to its progression. Autoimmune GFAP astrocytopathy should be considered in the differential diagnosis of patients presenting with manifestations as the ones described in this paper. Further research is necessary to know the full spectrum of manifestations of this recently defined autoimmune neurological disease.