Isolated Sixth Nerve Palsies in a Child With Familial Hemophagocytic Lymphohistiocytosis Type 2

A previously healthy 2-year-old boy presented with a left sixth cranial nerve palsy. There was a family history of multiple sclerosis and optic neuritis. Neuroimaging showed multiple foci of T2/FLAIR hyperintense signal abnormality in both cerebral hemispheres and in the brainstem. The initial diagnosis was suspicious for demyelinating disease. However, there was no clinical improvement after a course of corticosteroids, and there was no change in his follow-up MRI. He later developed bilateral sixth nerve palsies, with esotropia addressed with bilateral medial rectus botulinum toxin injections. A brain biopsy was planned. However, his 3-month-old sister was separately admitted for fever and pancytopenia. She had markedly elevated ferritin, D-dimer, triglycerides, sIL-2R, CXCL9, and IL-18 and low fibrinogen. Her bone marrow biopsy showed hemophagocytosis. Genetic testing of both siblings revealed biallelic mutations in the PRF1 locus. The final diagnosis of familial hemophagocytic lymphohistiocytosis Type 2 was made. Both siblings underwent chemotherapy. The boy's sixth nerve palsies and MRI abnormalities resolved. Both siblings then went on to undergo bone marrow transplant.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD Isolated Sixth Nerve Palsies in a Child With Familial Hemophagocytic Lymphohistiocytosis Type 2 Homer H. Chiang, MD, Sebastian Fernandez-Pol, MD, PhD, Gordon H. Bae, MD, Kerri E. Rieger, MD, PhD, Hisham M. Dahmoush, MBBCh, Shannon J. Beres, MD Abstract: A previously healthy 2-year-old boy presented with a left sixth cranial nerve palsy. There was a family history of multiple sclerosis and optic neuritis. Neuroimaging showed multiple foci of T2/FLAIR hyperintense signal abnormality in both cerebral hemispheres and in the brainstem. The initial diagnosis was suspicious for demyelinating disease. However, there was no clinical improvement after a course of corticosteroids, and there was no change in his follow-up MRI. He later developed bilateral sixth nerve palsies, with esotropia addressed with bilateral medial rectus botulinum toxin injections. A brain biopsy was planned. However, his 3-month-old sister was separately admitted for fever and pancytopenia. She had markedly elevated ferritin, D-dimer, triglycerides, sIL2R, CXCL9, and IL-18 and low fibrinogen. Her bone marrow biopsy showed hemophagocytosis. Genetic testing of both siblings revealed biallelic mutations in the PRF1 locus. The final diagnosis of familial hemophagocytic lymphohistiocytosis Type 2 was made. Both siblings underwent chemotherapy. The boy’s sixth nerve palsies and MRI abnormalities resolved. Both siblings then went on to undergo bone marrow transplant. Journal of Neuro-Ophthalmology 2023;43:137–140 doi: 10.1097/WNO.0000000000001807 © 2022 by North American Neuro-Ophthalmology Society Dr. Chiang and Dr. Beres: A 2-year-old man without recent infections, vaccinations, or illnesses presented to the neuro-ophthalmology clinic for a head turn that started 1 and 1.5 months prior, Department of Ophthalmology (HHC), Stanford University School of Medicine, Palo Alto, California; and Departments of Pathology (SFP), Dermatology (GHB), Pathology and Dermatology (KER), Radiology (HMD), and Ophthalmology, Neurology and Neurosciences (SJB), Stanford University School of Medicine, Stanford, California. The authors report no conflicts of interest. Address correspondence to: Shannon J. Beres, MD, Stanford University Department of Neurology and Neurosciences, Department of Ophthalmology, 2452 Watson Court, Palo Alto, CA 94303; E-mail: [e-mail] Chiang et al: J Neuro-Ophthalmol 2023; 43: 137-140 with the left eye turning in over the preceding 2 weeks. With the birth of his baby sister 6 weeks prior, the family attributed the head turn to a new behavior from the stress of having a new sibling. He had no headache or weakness in the face or extremities and no drooling or dysphagia. He had a large head that was consistently tracking on his own growth curve and was followed closely by his pediatrician. The family history was notable for a maternal grandfather with multiple sclerosis and mother with a history of isolated optic neuritis 10 years prior. His maternal great grandmother had strabismus, and his paternal great uncle had undergone strabismus surgery. The examination showed a left eye abduction deficit with an esotropia of 55 prism diopters in primary gaze, 25 prism diopters in right gaze, and .55 in left gaze. The anterior segments of both eyes were normal. There was very subtle blurring of the optic disc margin in the right eye, and the left optic nerve could not be easily viewed due to the large esotropia. Dr. Dahmoush: An urgent brain MRI with and without contrast was ordered, and he was instructed to begin patching the right eye due to amblyopia risk. Brain MRI showed multiple patchy illdefined foci of T2/FLAIR hyperintense signal abnormality and enhancement in both cerebral hemispheres, corpus callosum, cerebellum, and brainstem (Fig. 1). The original interpretation for these abnormalities favored a demyelinating process including acute disseminated encephalomyelitis and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) or other inflammatory conditions with propensity for brainstem involvement and, in particular, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. Dr. Chiang and Dr. Beres: He was admitted for expedited workup including cerebrospinal fluid (CSF) studies, which were unrevealing. Soluble 137 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. Brain MRI at presentation. A. Sagittal T2 FLAIR cube. B, C. Axial T2 FLAIR. D. Coronal T1 postcontrast. These images show faint and patchy nodular enhancement in the dorsal pons/upper medulla and periventricular white matter including the right atrium/splenium of the corpus callosum and left cuneus, as well as scattered signal abnormality of the subcortical white matter. IL-2 receptor and CXCL9 were within normal limits, and CSF flow cytometry was normal. Due to his presentation and the strong family history of demyelinating disease, the working diagnosis was a demyelinating condition. However, a high-dose IV corticosteroid pulse did not improve his esotropia. Repeat MRI brain with and without contrast 2 weeks later was unchanged. One month later, he developed new right sixth palsy on top of the persistent left sixth nerve paresis. A third MRI showed increased abnormal signal in the brain but with no changes in the brainstem lesions. Given increased suspicion for malignancy, he underwent a second lumbar puncture, which was unrevealing. On discussion with neurosurgery, a brain biopsy was planned. One day before the biopsy, his now 3-month-old sister was admitted for fever and pancytopenia. She had markedly elevated serum ferritin, D-dimer, triglycerides, sIL-2R, CXCL9, and IL-18. She had low fibrinogen. evidence of a B-cell or T-cell lymphoma or an abnormal myeloblast population. Among the T cells, there was a prominent population of CD5 dim, CD38 moderately bright, and CD8-positive T cells consistent with activated T cells that can be seen in hemophagocytic lymphohistiocytosis (1). Dr. Fernandez-Pol, Dr. Bae, and Dr. Rieger: DISCUSSION The girl underwent bone marrow biopsy, which showed increased histiocytes engulfing nucleated cells (Fig. 2). This finding is nonspecific but fulfills the criterion of hemophagocytosis that can contribute to a diagnosis of hemophagocytic lymphohistiocytosis. Flow cytometry showed no HLH is a rare, life-threatening syndrome of excessive immune activation, characterized by a cytokine storm and aberrantly activated macrophages which cannot be deactivated normally. It is most frequently seen in children but can present at any age. 138 Dr. Chiang and Dr. Beres: A familial hemophagocytic lymphohistiocytosis (HLH) was suspected, and the decision was made to cancel the brother’s brain biopsy. Rapid whole genome sequencing in the sister and subsequent targeted HLH gene analysis in the brother revealed biallelic mutations in the PRF1 locus. Final Diagnosis Familial HLH Type 2 causing bilateral sixth palsies. Chiang et al: J Neuro-Ophthalmol 2023; 43: 137-140 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 2. A. Wright-Giemsa–stained bone marrow aspirate smears show histiocytes with engulfed intracytoplasmic nucleated cells ·40. B. Immunohistochemical staining with CD163 performed on the bone marrow core biopsy highlights histiocytes engulfing nucleated cells ·20. Neurological features are fairly common, occurring in about one third of patients. In one single-center study, 29 of 289 Chinese adults (10%) with HLH developed central nervous system (CNS) manifestations at diagnosis or during disease course. Of these, 6 exhibited cranial nerve palsies (2). Another study in Chinese children found that 12 of 92 patients (13%) had neurological symptoms at diagnosis, 2 of which consisted of cranial nerve palsies (3). Finally, a neuropathologic study in Swedish children found 2 of 23 patients each with sixth and seventh nerve palsies (4). When the CNS is involved, the most common radiographic finding is T2/FLAIR hyperintensity and enhancement. Brain parenchymal lesions can involve white matter and to a lesser degree deep gray matter structures, the cerebellum (including a pattern of diffuse cerebellar involvement), and the brainstem (with predilection for the dorsal pons) (5). Atrophy, restricted diffusion, T1 hyperintensity, hypodense areas, and necrosis have also been reported (3,6). HLH can be primary (familial) or secondary (acquired), although a trigger such as infection (frequently Epstein-Barr virus) or malignancy (often a T-cell lymphoma) may set off primary HLH. Primary and secondary HLH may not be completely distinct entities. Diagnosis is made either genetically or when meeting 5 of 9 criteria defined by the HLH-2004 study of 369 patients (2). These include fever, splenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis on biopsy, decreased natural killer cell activity, high ferritin, sIL-2R, and/or CXCL9. Although his sister met almost all of these diagnostic criteria, our patient’s diagnosis was made genetically. Had his sister not been diagnosed, the planned brain biopsy may have yielded pathological evidence to support the diagnosis. Indeed, in Henter and colleagues’ neuropathologic study, hemophagocytosis was present in 20/23 (87%) of samples (4). The siblings began chemotherapy concurrently with dexamethasone, etoposide, and emapalumab, according to the HLH-2004 protocol (7). Given the boy’s radiographic (Fig. 3) and clinical CNS involvement (i.e., cranial neuropathy), additional intrathecal hydrocortisone/methotrexate was included in his treatment. After 1 month of chemotherapy, his sixth nerve palsies resolved. Dr. Dahmoush: Furthermore, his brain MRI abnormalities also resolved, so etoposide and intrathecal methotrexate/hydrocortisone were FIG. 3. A. Axial T2 FLAIR at presentation. B. Axial T2 FLAIR lesions improved at 4 month follow-up while on chemotherapy. Chiang et al: J Neuro-Ophthalmol 2023; 43: 137-140 139 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study nucleated cells (Fig. 4), confirming his first extracranial site of hemophagocytosis. Dr. Chiang and Dr. Beres: Unfortunately, our patient experienced rejection of his first transplant and died due to complications of his second transplant at 3 years of age. REFERENCES FIG. 4. A. H&E ·10. B. H&E ·40. Skin biopsy also showed histiocytes engulfing nucleated cells. stopped. He underwent an unrelated donor bone marrow transplant 4 weeks after his sister completed her bone marrow transplant. Dr. Fernandez-Pol, Dr. Bae, and Dr. Rieger: At the time of his transplant, new skin lesions appeared and biopsy showed scattered histiocytes with intracytoplasmic 140 1. 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