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Clinical Case of the Month – Opsoclonus-Myoclonus-Ataxia Syndrome Following Allogeneic HSCT in a Patient with Pre-B ALL

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Clinical Case

Title: Opsoclonus-Myoclonus-Ataxia Syndrome (OMAS) Following Allogeneic HSCT in a Patient with Pre-B ALL

Submitted by Ksenia Boriskina, MD, Department of Cell Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, and Department of Laboratory Medicine, Karolinska Institutet, Karolinska Comprehensive Cancer Center, Karolinska ATMP Center, Sweden.

Physician expert perspectives: 

Ksenia Boriskina, MD, Stephan Mielke, MD. Department of Cell Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, and Department of Laboratory Medicine, Karolinska Institutet, Karolinska Comprehensive Cancer Center, Karolinska ATMP Center, Sweden.

Jakob Theorell, MD, Rayomand Press, MD, Katharina Fink MD. The Neurology Medical Unit, Karolinska University Hospital, Sweden.

Bertil Stojanovic, MD, Medical Unit for Infectious Diseases, Karolinska University Hospital, Sweden.

A male patient (born 1995) was diagnosed with Pre-B ALL in 2007 and relapsed in 2018 (isolated testicular) and 2021 (bone marrow). A matched unrelated donor allogeneic hematopoietic stem cell transplant (HSCT) was performed in January 2022 following conditioning with etoposide, 12 Gy total body irradiation, and anti-thymocyte globulin. 

Two months post-transplant, the patient developed involuntary eye movements, vertigo, generalized myoclonus, and ataxia. Neuroimaging (MRI, CT) performed several times was unremarkable. Cerebro-spinal fluid (CSF) analysis revealed elevated neurofilament light protein (NFL; repeated measurements over 5000 ng/L), high CXCL13 (over 500 ng/L), and intrathecal immunoglobulin synthesis, but no evidence of infectious agents or neuronal/paraneoplastic antibodies. The patient was commenced on immunotherapy with corticosteroids, rituximab, and intravenous immunoglobulin (IVIg) leading to minimal clinical improvement. Subsequent neurological deterioration was managed by plasmapheresis and high-dose corticosteroids, leading to temporary stabilization. A further neurological episode in January 2023 was treated with plasmapheresis, IVIg, and rituximab. Maintenance rituximab was continued at 6-month intervals thereafter. Throughout this period, the patient remained in complete hematologic remission, and no typical graft-versus-host disease (GvHD) of significance was observed. Later, while being neurologically stable, patient developed chronic GvHD and the most recent follow-up in May 2025 showed severe chronic GvHD involving the skin, oral mucosa, and joints. No further neurological deterioration has been reported since the last intervention.

With this information, what would be your diagnostic options?

A: Opsoclonus-Myoclonus-Ataxia Syndrome (OMAS)
B: CNS Infection
C: CNS GvHD / Neuroinflammation

Physician expert perspectives:

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neurological disorder that is infrequently observed following HSCT. OMAS is significantly more common in pediatric patients, often associated with neuroblastoma. OMAS in adults is an uncommon and diverse condition presenting with involuntary eye movements, myoclonus, coordination issues, and neuropsychiatric symptoms such as behavioral and sleep disruptions. It is thought to have an immune-mediated etiology, typically associated with paraneoplastic or post-infectious causes in non-transplant patients. OMAS can occur as an immune-mediated complication following allogeneic HSCT, even in the absence of active GvHD or detectable autoantibodies. CSF biomarkers such as cytokines, chemokines, and neurofilament levels correlate with OMAS activity and outcome but lack specificity and sensitivity, limiting their practical use. This case highlights a rare instance of OMAS in the post-HSCT setting, characterized by elevated CSF CXCL13 and NfL, consistent with intrathecal inflammation and axonal damage. OMAS is described after treatment with checkpoint-inhibitors but the patient had no history of such therapy. The absence of structural findings on imaging, alongside initially therapy-resistant clinical evolution, suggests a likely immune-mediated pathology. Rituximab and plasmapheresis appeared to provide partial control, though relapses occurred. Altered immune reconstitution or subclinical GvHD has been discussed as triggering factors.

No microbiological agents were revealed by CSF cultures, PCR or serology tests. However, metagenomic analysis of CSF showed the presence of HERV-K113 retrovirus. HERV-K113 is a human endogenous retrovirus (HERV), which belongs to the HERV-K family. HERVs are remnants of ancient viral infections that became integrated into the human germline DNA millions of years ago. The distribution of HERV-K113 in human tissues is a direct consequence of its integration as a provirus in the germline; it is not acquired somatically or through infection. K113 is believed to be relatively intact, there is no evidence of infectious virus being produced in humans under normal circumstances. Although HERVs were identified over 25 years ago, their exact roles in normal biological processes and disease are still not well understood. Several research findings have provided evidence that the insertional polymorphism of HERV-K113 is ethnically dependent. To our knowledge, there are no well-documented cases reporting the presence or behavior of HERV‑K113 specifically in HSCT recipients even though the virus itself has been shown to be expressed in hematopoietic stem cells from bone marrow and cord blood, as well as in some leukemia samples. Clinical significance of HERV-K113 finding in this particular patient is unclear but this virus has been linked potentially triggering or exacerbating inflammatory diseases like multiple sclerosis.

CNS-GvHD is uncommon and its diagnosis is often challenging and controversial. It is still a matter of debate whether CNS symptoms are truly GvHD-related or due to other potential causes. Diagnosing CNS-GvHD is difficult due to the lack of well-established criteria and standardized diagnostic methods. Available criteria, established in 2010, only allow the ‘possible’ diagnosis of chronic CNS-GvHD in the presence of typical clinical signs of non-neurological chronic GvH. In animal models, acute CNS-GvHD is marked by neurobehavioral deficits, T cell infiltration, neuronal apoptosis, and inflammatory responses, mimicking aspects of the human disease and supporting its existence as a distinct GvHD manifestation. As there is no distinct or pathognomonic symptom pattern that defines CNS-GvHD, reported clinical presentations are highly variable and nonspecific, ranging from encephalopathy, seizures, cognitive dysfunction, and motor deficits to mood and behavioral changes. These manifestations overlap significantly with other post-transplant complications, including infections, drug-related neurotoxicity, metabolic disturbances, and disease relapse. CNS-GvHD might be underrecognized, as some studies report a high rate of noninfectious neurological complications following allo-HCT showing that both acute GvHD and extensive chronic GvHD may independently  be linked to an increased risk of neurological disorders.

In conclusion, the patient was diagnosed with OMAS without identified triggering factor. The existence of HERV-K113 remains of unclear clinical significance. Such a virus could theoretically mount allogenic immunity, so that the borders of neuroinflammation, CNS-GvHD and OMAS remain vague.

Correct answer - A 

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