Under Pressure to Find a Diagnosis

A 27-year-old woman developed left foot numbness followed by headaches, vertigo, and imbalance. Her symptoms continued to worsen and within two months, she developed binocular diplopia, bilateral hearing loss, worsening numbness and required a walker for ambulation. On examination her vital signs were normal with mild nuchal rigidity. She had bilateral grade 3 disc edema with intact vision, bilateral internuclear ophthalmoplegia, skew deviation, mild bilateral hearing loss, left-sided tongue weakness, decreased sensation to pain and temperature of the lower extremities up to T10 level and ataxia. The remainder of her examination including strength and reflexes were normal.

“Under Pressure to Find a Diagnosis” Deena Tajfirouz 1, Ronald Go 2, Eoin Flanagan 2, Aditya Raghunathan 2, John Chen 2 1 Mayo Clinic - Rochester, MN, 2 Mayo Clinic History & Exam: A 27-year-old woman developed left foot numbness followed by headaches, vertigo, and imbalance. Her symptoms continued to worsen and within two months, she developed binocular diplopia, bilateral hearing loss, worsening numbness and required a walker for ambulation. On examination her vital signs were normal with mild nuchal rigidity. She had bilateral grade 3 disc edema with intact vision, bilateral internuclear ophthalmoplegia, skew deviation, mild bilateral hearing loss, left-sided tongue weakness, decreased sensation to pain and temperature of the lower extremities up to T10 level and ataxia. The remainder of her examination including strength and reflexes were normal. Brain MRI with contrast showed extensive enhancement of the leptomeninges and multiple cranial nerves including bilateral 3rd, 7th and 8th nerve complexes in addition to expansile mass-like lesion with enhancement and T2 signal of the brainstem and left orbital frontal gyrus. Spine imaging showed expansile intramedullary T2 hyperintensities within the cervicothoracic cord and conus medullaris without overt enhancement. Cerebral venogram did not show thrombosis. Extensive serologic evaluation including HIV, Syphilis, QuantiFERON-TB Gold, lyme, C-reactive protein, sedimentation rate, ACE, SSA/SSB and LDH were unrevealing. Cerebrospinal fluid (CSF) studies showed an elevated opening pressure of 30 cm H2O, lymphocytic pleocytosis with 104 white blood cell count with a normal protein, glucose, IgG index, and three oligoclonal bands. Further CSF studies were unremarkable including viral studies, bacterial/fungal cultures and testing for cryptococcus, Whipple’s PCR, Next Generation Sequencing, and cytology. There was no evidence of vasculitis on fluorescein angiogram and body PET CT was negative for malignancy or evidence of sarcoidosis. A diagnostic study was performed. Financial Disclosures: The authors had no disclosures. Grant Support: N/A 18 | North American Neuro-Ophthalmology Society “Under Pressure to Find a Diagnosis” Answer Final Diagnosis: Isolated central nervous system Erdheim-Chester-Disease. Summary of Case: Our patient was a 27-year-old-woman with progressive, meningo-encephalomyelitis involving the leptomeninges, multiple cranial nerves, multiple parenchymal regions, and the spinal cord. Lumbar puncture showed an elevated opening pressure and lymphocytic pleocytosis. The clinical presentation raised concern for malignancy, infection or an inflammatory condition such as neurosarcoidosis, however a comprehensive evaluation for such conditions were negative. Whole body PET/CT and bone scintigraphy showed no skeletal lesions. Empiric treatment with intravenous steroids yielded no improvement. After five months of symptoms, a cerebellar biopsy showed a foamy histiocytic proliferation involving the folia and leptomeninges. There was no infection, vasculitis, granuloma, demyelination or parenchymal necrosis. The atypical cellular infiltrates were CD163+, but subsets were positive for Cyclin D1 and OCT2, concerning for a histiocytic neoplasm. There was no expression of S100, CD1a, BRAF-V600E, or ALK. Next-generation sequencing revealed POT1/PTPN11 mutation, and CSF1R variant of unknown significance (VUS). The findings led to diagnosis of Erdheim Chester Disease (ECD), a rare, non-Langerhans cell histiocytosis (1). A clonal hematopoietic neoplasm promoted by mutations in the MAPkinase pathway, ECD is also known Polyostotic Sclerosing Histiocytosis due to the high frequency of skeletal involvement amongst a multitude of other potential affected organ systems (2,3). Central nervous system involvement is common, occurring in approximately half of cases, however isolated CNS involvement is extremely rare (3,4). The discovery of MAPK/ERK mutations led to recognition of a point mutation, BRAFV600E, in approximately half of ECD cases, and the development of vemurafenib, a targeted inhibitor, now FDA approved for neoplasms which harbor this mutation. Ineligible for vemurafenib because she lacked the BRAFV600E mutation, other selective MAPK inhibitors and antimetabolite chemotherapy were trialed, but the disease progressed. By compassionate use, an investigative selective inhibitor of CSF1R, pexidartinib was given, which led to rapid and sustained clinical improvement in clinical symptoms, and radiographic findings (5). Struggle/Dilemma of the Clinical Presentation Description: The patient’s symptomology could have been inflammatory, infectious, or neoplastic. A thorough investigation failed to yield an infectious source, associated finding of inflammatory disorder, nor evidence of malignancy, including absence of bone lesions on PET. Although frequently including neurologic manifestations, osteolytic lesions are the most common clinical manifestation of histiocytic disorders and a lacking clue in this case, whose presentation with leptomeningeal enhancement was also unique compared to reviews on CNS involvement of ECD. Keywords: Diplopia, Hearing loss, Tumor, Magnetic resonance imaging (MRI), Meningo-encephalitis References: 1. Parks NE, Goyal G, Go RS, Mandrekar J, Tobin WO. Neuroradiologic manifestations of ErdheimChester disease. Neurol Clin Pract. 8(1):15-20. 2018. 2. Garg N, Lavi ES. Clinical and Neuroimaging Manifestations of Erdheim-Chester Disease: A Review. J Neuroimaging. (1):35-44. 2021. 3. Wagner KM, Mandel JJ, Goodman JC, Gopinath S, Patel AJ. Intracranial Erdheim-Chester Disease Mimicking Parafalcine Meningioma: Report of Two Cases and Review of the Literature. World Neurosurg. 110:365-370. 2018. 4. Haque A, Pérez CA, Reddy TA, Gupta RK. Erdheim-Chester Disease with Isolated CNS Involvement: A Systematic Review of the Literature. Neurol Int. 14(3):716-726. 2022. 5. Abeykoon JP, Lasho TL, Dasari S, Rech KL, et al. Mayo Clinic-University of Alabama at Birmingham Histiocytosis Working Group. Sustained, complete response to pexidartinib in a patient with CSF1Rmutated Erdheim-Chester disease. Am J Hematol. 97(3):293-302. 2022. Contact Information: Deena Tajfirouz, MD, [e-mail] 2023 Annual Meeting Syllabus | 19