Characteristics of Movement Disorders in Patients with Autoimmune GFAP Astrocytopathy

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) is a type of autoimmune corticosteroid-responsive meningoencephalitis that occurs with or without myelitis. Movement disorders have been reported in GFAP-A patients but have not been characterized. In this study, we examined the characteristics of movement disorders in GFAP-A patients. We retrospectively reviewed clinical data from 87 consecutive patients with GFAP-A attending Gifu University Hospital in Japan. We compared the demographics, clinical features, cerebrospinal fluid characteristics, and neuroimaging findings from patients with and without movement disorders. Seventy-four patients (85%) had movement disorders, including ataxia (49%), tremor (45%), myoclonus (37%), dyskinesia (2%), opsoclonus (2%), rigidity (2%), myokymia (1%), and choreoathetosis (1%). GFAP-A patients with movement disorders were significantly older than those without. Movement disorders are therefore common in GFAP-A patients, and the main types of movement disorders observed in this population were ataxia, tremor, and myoclonus. These abnormal movements can serve as clinical features that facilitate the early diagnosis of GFAP-A. Elderly GFAP-A patients are more likely to have movement disorder complications than younger patients.


Introduction
Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) is a type of autoimmune corticosteroid-responsive meningoencephalitis that occurs with or without myelitis [1,2]. The detection of immunoglobulin G (IgG) against GFAP (GFAP-IgG) in cerebrospinal fluid (CSF) is a biomarker of GFAP-A. GFAP-A was first described in 16 patients [1], and since then, it has been documented in several countries, including the USA, China, Italy, the UK, France, and Japan [3][4][5][6][7][8]. Patients generally present with headache and fever, followed by disturbed consciousness and signs of meningeal irritation [2,8]. Blurred vision related to optic disc edema has also been observed [2]. Some GFAP-A patients have a neoplasm such as ovarian teratoma [2,9]. Brain linear perivascular radial gadolinium enhancement (LPRGE) patterns, an imaging hallmark of GFAP-A, are noted in about half of all patients [2,7,8]. A neuropathological study reported inflammatory infiltrates, including T, B, and plasma cells surrounding blood vessels [4]. Although the pathophysiological mechanisms of GFAP-A have not yet been elucidated, GFAP-specific CD8 + T cells are likely effectors of this disorder [4,10,11]. GFAP-A is usually corticosteroidresponsive in the acute stage [2,7,8]. However, some patients are prone to relapse or even death [12]. Early diagnosis and initiation of corticosteroid therapies are important for patient prognoses [13].
The CSF examination showed mononuclear cell-predominant pleocytosis and elevated protein concentrations in almost all of the patients. The median cell count was 79 cells/µL (range: 4-472), and the median protein concentration was 146 mg/dL (range: 30-320). Forty-three out of 61patients (70%) had oligoclonal IgG bands.
Eighty-five out of the 87 patients (98%) were treated with corticosteroids. The median period from symptom onset to the initiation of corticosteroids was 24 days (range: 7-1084).
Eighty-five out of the 87 patients (98%) were treated with corticosteroids. The median period from symptom onset to the initiation of corticosteroids was 24 days (range: 7-1084).

Types and Frequencies of Movement Disorders in GFAP-A Patients
The types and frequencies of movement disorders in GFAP-A patients are shown in Table 2. The most frequently observed movement disorder was ataxia (truncal and/or limb ataxia), and it was found in 43/87 patients (49%). The second most frequent movement disorder was tremor, observed in 39/87 patients (45%). Tremor was postural and/or an action tremor. The part of the body most affected by tremor was the upper limbs. Tremor in 21/39 patients (54%) was confirmed within 28 days. The third most frequent movement disorder was myoclonus, observed in 32/87 patients (37%). The parts of the body most affected by myoclonus were the upper and lower limbs. Myoclonus in 17/32 patients (53%) was confirmed within 28 days.

Characteristics of GFAP-A Patients with Movement Disorders
To examine the characteristics of the GFAP-A patients with movement disorders, we compared the demographics, clinical features, CSF characteristics, and neuroimaging findings from patients with and without movement disorders (Table 3). GFAP-A patients with movement disorders (median age, 54 years; range: 5-83 years) were significantly older than those without (median age, 30 years; range: 17-76 years) (p = 0.005). There were no significant differences in the other demographics between the two patient groups. There were also no significant differences between the two patient groups in terms of clinical findings, CSF characteristics, and neuroimaging findings. We examined the association between age and movement disorders using multivariable logistic regression analysis to control for the potentially confounding effects of gender and concomitant tumor. Older age was associated with movement disorders in GFAP-A (OR 1.052, CI: 1.011-1.094, p = 0.013).

Discussion
In this study, we clarified the characteristics of movement disorders in individuals with autoimmune GFAP-A. The novel findings of this study are as follows. (1) Movement disorders are common neurological findings in GFAP-A patients. (2) The major types of movement disorders in this population were ataxia, tremor, and myoclonus. (3) GFAP-A patients with movement disorders were significantly older than those without.
The present study demonstrated that movement disorders are common in GFAP-A patients. In the previous literature, the most frequently described movement disorders were ataxia, followed by tremor and myoclonus. These three movement disorders were also common in our study population. Among patients with tremor and myoclonus, these symptoms were confirmed in about half of the patients within 28 days. These abnormal movements may thus be neurological findings characteristic of GFAP-A and can act as clinical features that would facilitate early diagnosis.
The pathophysiology of movement disorders in GFAP-A patients is unclear. GFAP is expressed exclusively in astrocytes, including Bergmann glia in the cerebellum. Extensive inflammatory lesions can occur in the central nervous system of GFAP-A patients [1,2,8]. The observed movement disorders might have been complicated by various central nervous system lesions. Although abnormal intensities in the cerebellum on brain MRI are rare, ataxia in the GFAP-A patients might have been caused by cerebellar dysfunction [2,8]. Ataxia was usually mild and was observed in the early phase. Most patients had both limb and truncal ataxia. Although it improved after immunotherapy, truncal ataxia persisted in some patients. Tremor was predominantly postural and/or an action tremor in the upper limbs. A surface electromyogram from one patient showed an 11-12 Hz tremor, indicating an essential tremor. Structural changes in cerebellar Purkinje cells and neighboring neuronal populations have been observed in post-mortem studies of essential tremor, and GABAergic dysfunction and dysregulation of the cerebellar-thalamic-cortical circuitry have been documented [42][43][44]. Tremor may also be associated with impairment of the cerebellar pathways. Myoclonus in this population was usually non-segmental multifocal myoclonus in the upper and lower limbs. A previous report described a GFAP-A patient with multifocal myoclonus in whom hypermetabolism of the spinal cord was associated with areas of cortical hyper-and hypometabolism in 18F-fluorodeoxyglucose positron emission tomography imaging [25].
Dyskinesia, observed in this study, has previously been reported [4][5][6]17,23,41]. One of two patients with dyskinesia had an N-methyl-D-aspartate receptor (NMDAR)-IgG and ovarian teratoma. GFAP-IgG was sometimes accompanied by anti-neuronal antibodies, including NMDAR-IgG [2,3,13]. Dyskinesia is a common manifestation of NMDAR encephalitis [45,46]. If a GFAP-A patient is a young woman presenting with dyskinesia, examinations for NMDAR-IgG and ovarian teratoma should be performed because their presence is important for determining the treatment strategy.
In this study, two patients with no medical history of Parkinson's disease or Parkinsonrelated disorders presented with rigidity in their upper limbs. The rigidity of one of these two patients was bilateral cogwheel rigidity dominant in the right upper limb. This patient also presented with bilateral hand postural tremor. The rigidity in these two patients improved after corticosteroid therapy. Brain MRI showed abnormal hyperintensity lesions, including in the cerebral white matter in both patients, and in the basal ganglia and the brainstem in one patient. Two reports have described parkinsonism in GFAP-A [6,14]. Tomczak et al. reported a case of GFAP-A with reversible parkinsonism, including rigidity, right hand action tremor, and bradykinesia [14]. This patient's brain MRI showed nonspecific white matter changes and attenuated nigrosomes on susceptibility-weighted images. Although the pathophysiology of parkinsonism is unknown, GFAP-A patients may present with reversible parkinsonism.
We compared the demographics, clinical features, CSF characteristics, and neuroimaging findings from patients with and without movement disorders. The age of the GFAP-A patients with movement disorders was significantly higher than that of the GFAP-A pa-tients without movement disorders. This result is important because movement disorders are common neurological features in elderly patients with neurodegenerative or cognitive disorders. GFAP-A should be differentiated in elderly patients with sudden-onset movement disorders.
The main limitations of this study are as follows: (i) the number of GFAP-A patients was small, (ii) the clinical information was based solely on the recall of the referring neurologist, (iii) the movement disorders were not evaluated by movement disorder experts, and (iv) the possibility of movement disorders becoming apparent during the clinical course cannot be ruled out in GFAP-A patients without movement disorders. To further examine the presence of movement disorders in GFAP-A patients, it will be necessary for movement disorder experts to prospectively observe clinical symptoms in a large group of GFAP-A patients.

Conclusions
Movement disorders are a common neurological feature of GFAP-A. Ataxia, tremor, and myoclonus are the major movement disorders found in GFAP-A patients, and these may be clinical features that can facilitate early diagnosis. GFAP-A should be differentiated in elderly patients who present with sudden-onset movement disorders.