Seronegative Autoimmune Encephalomyelitis with Area Postrema Symptoms Open Access

Patients presenting with acute or subacute encephalopathy and longitudinally extensive myelitis pose a challenging diagnosis. Medical history, neurological symptoms, and diagnostic test results should be carefully considered. Area postrema (AP) symptoms, such as hiccoughs and intractable vomiting, may help narrow the differential diagnosis. Neuromyelitis optica (NMO) spectrum disorders with either aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) antibodies may present with encephalopathy and AP features. The less common clinical syndrome of glial fibrillary acidic protein (GFAP) autoimmune encephalitis (GFAPE) resembles AQP4 and MOG-associated NMO [1, 2] with meningoencephalitis in 54% of cases, myelitis in 10.5%, optic neuritis in 30–60%, and AP syndrome in 30%, with large regional variations [3, 4]. AP-related symptoms may be the presenting complaint [5] and tend to manifest with intractable hiccoughs rather than nausea and vomiting, which is more common in NMO [5]. However, some patients with the clinical phenotype of encephalomyelitis and AP syndrome are seronegative, suggesting the presence of additional associated antibodies which are yet to be characterized.

We present a patient in whom all the typically implicated autoantibodies were negative, and based on clinico-radiological observations, we hypothesize that the immune target in this case could be tanycytes. Tanycytes are highly specialized ependymal cells that form a blood-cerebrospinal fluid (CSF) barrier along the ventricular walls of the AP, among others.

This previously well gentleman in his 70s presented with a generalized headache. Over the next 48 h, he developed fever, night sweats, and confusion. He then had a witnessed, self-terminating generalized tonic-clonic seizure, with persistently depressed level of consciousness (Glasgow Coma Score 6/15). The patient was intubated, ventilated, and admitted to the intensive care unit. Persistent hiccoughing developed over the next 3 days.

The patient had a past medical history of hypercholesterolemia and lumbar spondylosis. He lived with his wife, rarely consumed alcohol, and did not smoke.

Non-contrast CT brain was normal. Lumbar puncture revealed a mildly elevated opening pressure of 29 cm CSF, 440 leukocytes (98% lymphocytes and 2% neutrophils), elevated protein at 2.02 g/L, and glucose 2.7 mmol/L (concurrent blood sugar level 6.5 mmol/L). There were no bacteria on Gram staining. Tests for meningococcus, herpes zoster virus, varicella zoster virus, Listeria monocytogenes, and Cryptococcus were all negative. Blood cultures, respiratory viral panels, human immunodeficiency virus, and hepatitis serology and urine cultures were all normal/negative. An electroencephalogram showed diffuse slowing of the background rhythm, classified as dysrhythmia grade 3, and no ongoing epileptiform activity.

The patient was first treated for possible infective encephalitis with benzylpenicillin, ceftriaxone, and acyclovir and loaded with sodium valproate and levetiracetam to prevent seizures. MRI of the brain, with T2-weighted fluid-attenuated inversion recovery images, showed foci of increased signal intensity in the periaqueductal gray matter, ventral medulla oblongata, pons, right midbrain, and both lentiform nuclei, with patchy leptomeningeal enhancement over both cerebral hemispheres (Fig. 1, 2). MRI of the spine revealed longitudinally extensive transverse myelitis with intramedullary T2-hyperintense signal abnormalities involving the central gray matter throughout the cord (Fig. 3).

In keeping with a working diagnosis of autoimmune/inflammatory encephalomyelitis, the patient was then treated with intravenous methylprednisolone and subsequently plasma exchange. Immunological tests on serum and CSF were obtained prior to plasma exchange and repeated later in the course of the illness. Pre-exchange serum AQP4, MOG, and GFAP antibodies returned negative. A post-plasma exchange serum sample subsequently showed weakly positive GFAP-IgG levels, suggesting evolving antibody dynamics, but this finding was interpreted with caution because pre-exchange CSF GFAP antibodies were negative.

Sedation was weaned, and neurological examination demonstrated severe quadriparesis, with Medical Research Council (MRC) Scale for muscle strength grade 0/5 power in both lower limbs and urinary catheter dependence. Fundal examination showed no evidence of papilloedema.

Following 5 sessions of plasma exchange, the patient became alert and responsive, the hiccoughs resolved, and there was gradual improvement in arm muscle strength power, but no improvement in leg power. He was later loaded with 2 g rituximab in divided doses. His recovery was complicated by hospital-acquired pneumonia and abdominal pseudo-obstruction, which was treated conservatively. He was transferred to rehabilitation services. At last clinic review, he was making further gains in arm power, and sensory perception in the legs had improved, but there was no improvement in leg weakness or sphincter function. Repeat MRI showed resolution of the previous radiological changes (not shown).

Patients presenting with encephalopathy pose a significant diagnostic and therapeutic challenge. The diagnosis relies on clinical assessment, blood biomarkers, CSF analysis, and neuroimaging. Our patient presented with encephalopathy and AP symptoms, severe longitudinally extensive myelopathy, inflammatory CSF, and cranial MRI features of brainstem involvement, with leptomeningeal and ventricular ependymal enhancement. Although infective causes were initially considered and excluded, the patient’s clinical course and partial response to intensive immunological treatment supported a diagnosis of inflammatory autoimmune encephalomyelitis.

The clinical course and radiological features in this case were most consistent with GFAPE, despite negative serological confirmation. CSF antibodies are found in 93% of patients with GFAPE [4]. Other differential diagnoses include acute disseminated encephalomyelitis. AP features are characteristic of AQP4 NMO spectrum disorders (10–15%) [2], MOG antibody disease [6], acute disseminated encephalomyelitis [7], and GFAP encephalitis, but have also been reported in rare cases of Bickerstaff encephalitis [8], Guillain-Barré syndrome, multiple sclerosis, cerebral ischemia [9], and tumors.

GFAP is an intermediate type III protein found in various glial cells including tanycytes. Its primary role is to provide mechanical support for glia with long cellular processes. Immunofluorescent GFAP-IgG staining occurs mainly in the pial, periventricular, and perivascular regions, and is more evident in proinflammatory states, such as astrogliosis. GFAP-positive neural stem cells are present in the dorsal aspect of the spinal cord’s central canal, indicating that these cells are affected in GFAP autoimmune myelitis [10]. The weakly positive serum GFAP antibody, found later in the course of the disease, is interpreted with caution since there were no CSF autoantibodies during the acute phase. The classical radiological findings in GFAP autoimmunity include leptomeningeal and linear gadolinium enhancement in the periventricular white matter, associated with a longitudinally extensive myelitis, as evidenced by areas of increased T2-signal in the grey matter of the spinal cord surrounding the central canal [11]. Additional signal abnormalities in the brain may include T2-hyperintense lesions in the hypothalamus (15%), pons (68%), midbrain, cerebellum (36%), medulla (36%), and area postrema (30%) [11]. There is one previous report of a patient with clinical features of a GFAP-encephalitis, including typical MRI radial perivascular changes, but negative antibodies [12]. While GFAP encephalomyelitis is primarily considered an astrocytopathy, evidence suggests involvement of other glial cell types, such as tanycytes, radial glia, subventricular neural stem cells, and Muller cells. Indications of this include the following: (1) The original antibody tests included GFAP delta and GFAP alpha; GFAP delta was detected in 80% of cases. GFAP delta is found only in neuro-progenitor cells, radial glia, and tanycytes. (2) MRI images show changes in the periventricular area consistent with tanycytes and radial glia locations. (3) The optic changes associated with papillitis in GFAP encephalitis likely involve Muller cells rather than astrocytes. (4) Tanycytes heavily populate circumventricular organs, including the area postrema. (5) Longitudinal spinal cord changes around the central canal suggest involvement of neuroprogenitor cells or tanycytes. We hypothesize that an under-recognized glial cell: tanycytes as well as mature astrocytes may also be an immune target in GFAPE for the reasons stated above. This could be an explanation in our case for the negative antibodies as only GFAP alpha is routinely tested. We propose that tanycytes, alongside mature astrocytes, may represent an additional immune target in GFAP-encephalitis, a hypothesis that could explain negative antibody results since routine testing typically includes only GFAP alpha. Tanycytes are ependymal-glial cells originating from the ventricular ependyma with long processes penetrating the white matter. They are embryologically related to subventricular zone neural stem cells and radial glial cells, retaining neural stem cell markers (eg, Nestin, Vimentin, SOX2) and capable of differentiating into neurons and glial cells. Functionally, tanycytes, considered part of the neuroendocrine system, transport molecules from the CSF to portal venous systems for neural detection and are densely located in circumventricular organs, including the area postrema, where they detect toxins, drugs, cytokines, and other molecules [13, 14].

In summary, autoimmune encephalomyelitis with AP involvement represents a rare, distinctive clinic-radiological syndrome. AQP4, MOG, and GFAP antibody testing should be performed, but some patients are seronegative, suggesting that additional antibodies are yet to be identified.The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000545402).

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

P.M.P. and D.A.P. conceived the study and contributed significantly to data analysis, interpretation, and revising the manuscript. R.A., L.K.K., and T.J. made significant contributions to the study’s data acquisition, analysis, and interpretation and were also involved in drafting or critically revising the manuscript for important intellectual content. All authors participated in discussions and contributed to the final version of the manuscript.

The data presented in this case report are not publicly available due to patient privacy and confidentiality concerns. All relevant clinical details have been included in the manuscript, ensuring that no identifying information is disclosed. Further information may be made available from the corresponding author upon request.