Erdheim-Chester Disease Presenting With Diplopia: A Challenging Diagnosis With Effective Treatment

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Erdheim–Chester Disease Presenting With Diplopia: A Challenging Diagnosis With Effective Treatment Mehdi Tavakoli, MD, Shiva Roghaee, MD, Manasa Gunturu, MD, Antonio M. Omuro, MD, Byron L. Lam, MD, Carlos E. Mendoza-Santiesteban, MD E rdheim–Chester disease (ECD) is a rare form of nonLangerhans cell histiocytosis with multiorgan involvement, typically affecting middle-aged adults (1). ECD has a wide spectrum of presentations including bone, neurologic, renal, and pulmonary involvements (1). We report a patient with ECD with rarely reported presenting symptom of diplopia and challenging diagnostic dilemmas that led to confirmation of ECD through a third brain biopsy with positive genetic BRAF V600E mutation but negative BRAF V600E staining of the specimen. The patient responded rapidly to the novel therapy of dabrafenib and trametinib underscoring the importance of diagnosing ECD to initiate proper treatment. A 51-year-old man was referred to our ophthalmic emergency room with diplopia for 2 weeks, and intermittent blurry vision and unsteady gait for 3 months. The visual acuity was 20 of 20 in each eye with a moderate right esotropia and 50% limited abduction of the right eye consistent with a right sixth cranial nerve palsy. The rest of the ophthalmic examination was normal. Neurologic examinations revealed slightly decreased strength of the left hand and foot and some difficulties with tandem walking. The other cranial nerves, sensory, motor, deep tendon reflexes, and coordination were within the normal range. Brain MRI with contrast revealed multifocal fluid-attenuation inversion recovery (FLAIR) hyperintensities in the posterior fossa, involving the right brachium pontis, pons, midbrain, left cerebellum, vermis, and dorsal medulla (Fig. 1A). Cerebrospinal fluid (CSF) from lumbar puncture showed normal cell count University of Miami Miller School of Medicine (MT, SR, MG, BLL, CEM-S), Bascom Palmer Eye Institute, Miami, Florida; Department of Ophthalmology and Visual Sciences (MT), University of Alabama at Birmingham, Callahan Eye Hospital, Birmingham, Alabama; Department of Neurology (MG), University of Mississippi Medical Center, Jackson, Mississippi; and Department of Neurology (AMO), University of Miami Miller School of Medicine, Miami, Florida. Presented as a Walsh poster in North America NeuroOphthalmology Society (NANOS) meeting, March 16–21, 2019, Las Vegas, NV. de la Fuente MI, Rosenblum MK, Diamond EL, Tabar VS, Omuro A. Erdheim-Chester disease among neuroinflammatory syndromes: the case for precision medicine. Neurol Neuroimmunol Neuroinflamm. 2020;7:e686. The authors report no conflicts of interest. Address correspondence to Mehdi Tavakoli, MD, Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, 1720 University Boulevard, Birmingham, AL 35223; E-mail: [e-mail] e324 with negative cytology and flow cytometry. A positron emission tomography-computed tomography scan showed no systemic disease. Other inflammatory and infectious investigations including Lyme, tuberculosis, syphilis, HIV, and sarcoidosis were negative. A stereotactic brain biopsy missed the vermis lesion and showed gliosis and normal cerebellum. Intravenous methylprednisolone 1 g/day following by oral steroid showed no improvement clinically or radiographically. A second stereotactic biopsy was unsuccessful in sampling the leading vermian lesion because of hardware limitation, and the pathology was also nondiagnostic. Meanwhile, his balance was worsening, he became wheelchair-bound, and he was unable to work because of fatigue, diplopia, and gait instability. The MRI lesions were also more extensive than before (Fig. 1B). A third biopsy consisting of an open brain biopsy from the cerebellum revealed copious inflammatory changes with lymphocytic and histiocytic infiltration but no granuloma. Immunohistochemistry showed scattered histiocytes positive for langerin and CD1a, but these did not mark most of the cells, and BRAF V600E staining was negative. In situ hybridization and special stains for infectious organisms were also negative. However, genetic study of the specimen revealed BRAF V600E mutation which is indicative of ECD. This was later more confirmed by sclerosis of bilateral distal tibiae on PET body imaging studies and bilateral perinephric fat stranding. The patient underwent treatment with 2 specific protein-targeting agents of dabrafenib and trametinib, and after 3 months, his symptoms improved significantly, and he was able to return to work. The size of the brain MRI lesions in the brain MRI also improved substantially (Fig. 1C). In his last visit 1 year after starting treatment, he had normal neurologic function except for residual diplopia which was managed with prism glasses. The central nervous system involvement is the initial presentation in approximately 25% of patients with ECD, but almost 50% of patients will have some neurologic manifestations during the clinical course. Common neurologic findings include diabetes insipidus, panhypopituitarism, and cerebral ataxia. One common neuro-ophthalmic signs of ECD is unilateral or bilateral exophthalmos from orbital lesions which can present in up to 37% of patients (1). Our patient presented with diplopia which is rarely reported in ECD (2). There are no specific neuroradiologic findings for ECD. Our patient showed extensive T2 FLAIR white matter lesions in the brainstem and cerebellum similar to previous reports of Tavakoli et al: J Neuro-Ophthalmol 2021; 41: e324-e325 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A. Multifocal hyperintensities in the posterior fossa, most prominently involving the right brachium pontis, pons, and midbrain. Left: T1, post-gadolinium axial, right: T2 FLAIR scan. B. The T1 postgadolinium (left) and T2 FLAIR (right) axial scans 3 months after presentation and before starting dabrafenib and trametinib. C. The T1 postgadolinium (left) and T2 FLAIR (right) axial scans, 3 months after the treatment. The significant decrease in size of the lesions is evident. neurologic ECD. Such neuroradiological manifestations have broad differential diagnoses which warrant extensive blood and CSF studies including more common etiologies such as infections (tuberculosis, syphilis, and cryptococcosis), inflammations (multiple sclerosis, neuromyelitis optica, neurosarcoidosis, and neuroBehcet) and neoplasms (metastases, glioma, and lymphoma). Our patient underwent brain biopsy after all other studies were noncontributory, and his general condition worsened. The first 2 biopsies were taken from normal tissue, and the third biopsy was from the lesion, but histopathology only showed a nonspecific chronic cell infiltrate without any remarkable immunohistochemical findings. Tavakoli et al: J Neuro-Ophthalmol 2021; 41: e324-e325 The diagnosis of ECD was traditionally based on histologic findings including numerous macrophages with xanthomatous cytoplasm and small nuclei along with giant cells. The histiocytes are positive for CD68 and negative for CD1-A and protein S-100 (1). Recently, a strong association was found between ECD and BRAF V600E oncogenic mutation. The BRAF protein is part of the RAS-MEK signaling pathway regulating cell proliferation and survival. The BRAF gene belongs to the class of oncogenes and when mutated will dysregulate the cell proliferation cycle and cause cancer. The BRAF V600E mutation is linked to various malignancies including cutaneous melanoma, colorectal carcinoma, and breast cancers (1). ECD was traditionally treated with corticosteroids, interferon alpha, and other conventional chemotherapeutics (1). Recently, Bradshaw reported a patient with ECD with diplopia and ataxia who was successfully treated with vemurafenib, a potent BRAF kinase inhibitor (2). Subsequently, FDA approved the combination of BRAF kinase inhibitor dabrafenib with the MEK kinase inhibitor trametinib to treat patients with BRAF V600E or V600K mutations including metastatic melanoma. This combination treatment in 1 reported patient with ECD and brainstem presentations showed favorable outcomes (3). Similarly, our patient showed significant improvements of symptoms, function, and MRI abnormalities. This combination is associated with adverse effects of pyrexia and constitutional symptoms in 20% of patients. In addition, dabrafenib can induce cutaneous melanoma, and patients need interval skin examinations (4). Our patient developed no side effects with this combination within the first year of treatment. Currently, a phase 2 clinical trial to evaluate dabrafenib and trametinib in patients with ECD and BRAF V600E mutations has completed enrollment, but the results are not yet available (5). Neuro-ophthalmologists may be the first to encounter patients with ECD presenting with diplopia, nystagmus, or proptosis. The neuroradiologic features are nonspecific, and the diagnosis may be challenging requiring thorough systemic evaluation and histologic genetic studies to recognize BRAF V600E mutations and to start effective molecule-targeting medications. REFERENCES 1. Campochiaro C, Tomelleri A, Cavalli G, Berti A, Dagna L. Erdheim-Chester disease. Eur J Intern Med. 2015;26:223–229. 2. Bradshaw MJ, Pawate S, Bloch KC, Moots P, Reddy NM. Clinical Reasoning: a 52-year-old man with diplopia and ataxia. Neurology. 2016;87:e140–e143. 3. Al Bayati A, Plate T, Al Bayati M, Yan Y, Lavi ES, Rosenblatt JD. Dabrafenib and trametinib treatment for Erdheim-Chester disease with brain stem involvement. Mayo Clin Proc Innov Qual Outcomes. 2018;2:303–308. 4. Seebacher NA, Stacy AE, Porter GM, Merlot AM. Clinical development of targeted and immune based anti-cancer therapies. J Exp Clin Cancer Res. 2019;38:156. 5. Gahl Wl, National Human Genome Research Institute (NHGRI). Dabrafenib and trametinib in people with BRAF V600E mutation positive lesions in Erdheim Chester disease. Available at: https://clinicaltrials.gov/ct2/show/NCT02281760. Accessed April 25, 2020. e325 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.