Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare inflammatory brain disease that more commonly presents with meningoencephalitis and myelitis. Rarely, affected patients may present with abnormal movements such as ataxia, tremors and myoclonus. Here, we describe a case of autoimmune GFAP astrocytopathy manifesting as a progressive encephalomyelitis with rigidity and myoclonus (PERM)‐like syndrome.
Case Report
An 82‐year‐old Chinese man presented with rapid functional and cognitive decline over 2 weeks. He had past history of ischemic heart disease, hypertension, hyperlipidemia and mild mixed Alzheimer's and vascular dementia, but was independent with his activities of daily living and ambulation. There were no preceding prodromal flu‐like symptoms, headaches, neck stiffness, vomiting, visual loss, limb weakness or numbness. Neurological examination revealed encephalopathy with no verbal output or response to commands, facial dyskinesias, asynchronous multifocal myoclonus of his upper limbs and generalized trunk and limb rigidity. There was no evidence of autonomic dysfunction.
Investigations revealed serum sodium of 111 mmol/L (normal: 135–145 mmol/L) secondary to syndrome of inappropriate anti‐diuretic hormone (SIADH). Other hematological, biochemical and infectious work‐up were normal. There was no neurological improvement despite gradual correction of serum sodium levels to normal limits over the course of a week. MRI brain with contrast was unremarkable; there were no features of osmotic demyelination. MRI whole spine with contrast showed no evidence of myelitis. CSF analysis revealed lymphocytic pleocytosis (white cell count 113 cells/μL; 90% lymphocytes) and raised protein (1.82 g/L). Microbiological evaluation for tuberculous, bacterial, fungal and viral etiologies were all negative. CSF cytology and flow cytometry were negative for malignancy. Chest‐abdomen‐pelvis PET‐CT scan showed no lymphadenopathy or solid organ malignancy. EEG showed severe diffuse encephalopathy with no evidence of seizures. EMG did not show neuromyotonia or continuous motor unit activity. Serum and CSF autoimmune antibody testing were negative for a wide array of autoantibodies (Table 1) including those associated with stiff‐person syndrome. Subsequently, GFAP antibodies returned positive in the CSF (1:64, normal titer <1:2) and serum (1:480, normal titer <1:240) (Mayo Clinic Laboratories). He was initially treated with 2 g/kg of intravenous immunoglobulin (IVIg) over 5 days with minimal response. Subsequently, treatment with intravenous methylprednisolone followed by plasmapheresis led to only partial improvement. He became more alert and was able to speak short sentences. Although myoclonus and dyskinesias improved, there was only minimal improvement in limb rigidity. He remains confined to a wheelchair, requiring maximum assistance with his activities of daily living. Our video (video 1) illustrates some of the abnormal neurological findings in our patient that largely persisted post‐treatment. His serum sodium levels were within normal limits at the point of video‐recording.
TABLE 1.
Serum and CSF tests for autoimmune diseases
| Requested analysis (sample type) | Results |
|---|---|
| Anti‐NMDAR (serum, CSF) | Negative |
| Anti‐CASPR2 (serum, CSF) | Negative |
| Anti‐LGI1 (serum, CSF) | Negative |
| Anti‐AMPAR1/2 (serum, CSF) | Negative |
| Anti‐DPPX (serum, CSF) | Negative |
| Anti‐GABABR (serum, CSF) | Negative |
| Anti‐Amphiphysin Ab (serum, CSF) | Negative |
| Anti‐SOX1/AGNA‐1 (serum, CSF) | Negative |
| Anti‐Hu/ANNA‐1 (serum, CSF) | Negative |
| Anti‐Ri/ANNA‐2 (serum, CSF) | Negative |
| ANNA‐3 (serum, CSF) | Negative |
| Anti‐CV2/Anti‐CRMP‐5 (serum, CSF) | Negative |
| Anti‐GAD65 (serum, CSF) | Negative |
| Anti‐IgLON5 (serum, CSF) | Negative |
| Anti‐mGluR1 (serum, CSF) | Negative |
| Anti‐NIF (serum, CSF) | Negative |
| Anti‐Tr (DNER)/Anti‐PCA‐Tr (serum, CSF) | Negative |
| Anti‐Yo/Anti‐PCA‐1 (serum, CSF) | Negative |
| Anti‐PCA‐2 (serum, CSF) | Negative |
| Anti‐GLRA1 (serum, CSF) | Negative |
| Anti‐Ma2/Ta/Anti‐PNMA2 (serum) | Negative |
| Anti‐recoverin (serum) | Negative |
| Anti‐titin (serum) | Negative |
| Anti‐Zic4 (serum) | Negative |
| Anti‐GFAP (serum, CSF) | Positive (1:480, 1:64) |
Abbreviations: NMDAR, N‐methyl‐d‐aspartate receptor; CASPR2, contactin‐associated protein‐like 2; LGI1, leucine‐rich glioma‐inactivated 1; AMPAR, alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor; DPPX, dipeptidyl‐peptidase‐like protein; GABABR, gamma aminobutyric acid B receptor; SOX1, SRY‐Box Transcription Factor 1; AGNA, anti‐glial nuclear antibody; ANNA, antineuronal nuclear antibody; CRMP5, collapsin response mediator protein 5; GAD65, glutamic acid decarboxylase 65‐kilodalton isoform; IgLON5, immunoglobulin‐like cell adhesion molecule 5; mGluR1, metabotropic glutamate receptor subtype 1; NIF, neuronal intermediate filament; DNER, Delta/notch‐like epidermal growth factor–related receptor; PCA, purkinje cell cytoplasmic autoantibody; GLRA1, glycine receptor alpha 1; PNMA, paraneoplastic Ma antigen; GFAP, glial fibrillary acidic protein.
Video 1.
This video shows our patient at presentation and 4‐months post treatment.
Discussion
Autoimmune GFAP astrocytopathy patients were initially described to have features such as meningoencephalitis, myelitis, optic disc edema, fever, headache, autonomic dysfunction, seizures, tremors and ataxia. 1 , 2 More recent case reports and series have described movement disorders such as chorea, myoclonus, parkinsonism and rigidity 3 , 4 ; Equiza and colleagues reported a patient with hyperekplexia, myoclonus and stiffness that resembled a PERM‐like clinical phenotype. 5 PERM is an autoimmune CNS disorder of the stiff‐person syndrome spectrum. It is characterized by the presence of muscle rigidity, spasms, myoclonus and encephalopathy and is most commonly associated with glycine antibodies. 6 Our patient's clinical phenotype closely resembles a “PERM‐like syndrome”. He had widespread myoclonus, rigidity and encephalopathy but lacked other features of classic PERM such as hyperekplexia, autonomic dysfunction and painful spasms. In our patient, the diagnosis of autoimmune GFAP astrocytopathy was confirmed by the presence of lymphocytic meningoencephalitis and GFAP antibodies in both his serum and CSF. The autoantibodies typically associated with stiff person syndrome disorders such as antibodies against glycine, amphiphysin, dipeptidyl‐peptidase‐like protein six (DPPX) and glutamic acid decarboxylase (GAD) were not detected.
GFAP is an intracellular protein integral to regulating the morphology and function of astrocytes. In autoimmune GFAP astrocytopathy, GFAP‐specific cytotoxic T cells rather than GFAP antibodies are directly involved in disease pathogenesis. 1 In stiff‐person spectrum disorders, autoantibodies disrupt antigens involved in GABAergic neurotransmission, resulting in decreased brainstem GABAergic inhibition which in turn causes overwhelming stiffness and spasms. 7 How autoimmune GFAP astrocytopathy could give rise to a PERM‐like clinical phenotype is unclear. We postulate that GFAP‐directed cytotoxic T cells induce astrocytic damage at the level of the brainstem; this disrupts neuronal GABAergic synaptic transmission resulting in the PERM‐like clinical manifestations seen in our case. This is further supported by the presence of GFAP antibodies in our patient's CSF, the exclusion of other etiologies such as CNS malignancy and infection and his partial clinical improvement to immunotherapy. Our report of this atypical manifestation of autoimmune GFAP astrocytopathy expands its clinical phenotype and alerts clinicians to consider it in the differential diagnosis of patients with PERM. Moreover, this case highlights the importance of considering an autoimmune etiology in patients presenting with rapid cognitive decline and abnormal movements.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.
G.Z.L.: 1A, 1B, 3A, 3B
L.G.Y.: 1A, 1B, 3A, 3B
D.F.C.: 1A, 1B, 3B
T.Y.: 1A, 1B, 3A, 3B
K.T.: 1A, 1B, 3A, 3B
Disclosures
Ethical Compliance Statement: Written patient consent was obtained for this manuscript. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work.
Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: The authors declare that there are no financial disclosures of the previous 12 months.
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