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

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 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 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), 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.