Progressive neurologic disorder: Initial manifestation of hemophagocytic lymphohistiocytosis

Case report. A 14-year-old Caucasian female presented with a 3-month history of headaches, progressive rightsided convergent squint, dysarthria, gait abnormality with progressive difficulty in climbing up the stairs and being able to stand, and hyperesthesia involving her left arm and leg. She had a longstanding history of pervasive refusal disorder for which she was receiving psychiatric support. Ophthalmology examination revealed a VI cranial nerve palsy and papilledema. She had normal tone, with decreased power in upper and lower limbs and absent reflexes, and no ankle clonus; there was no hepatosplenomegaly and no peripheral lymphadenopathy detected. Brain and spine MRI revealed leptomeningeal enhancement and generalized white matter lesions, in addition to mid–cervical cord contrast-enhancing lesions (figure, A–D). EMG demonstrated motor and sensory neuropathy; sural nerve biopsy showed axonal degeneration with mild inflammatory changes but no vasculitis. Hemoglobin was 14.7 g/dL (reference range [RR] 12–16 g/dL), platelet count 261 3 10/L (RR 150–450 3 10/L), white cell count 5.63 3 10/L (RR 4.0–11.0 3 10/L), alanine transaminase 17 U/L (RR 10–45 U/L), and fibrinogen 2.8 g/L (RR 1.7–4.0 g/L); ferritin was not tested. Oligoclonal bands were positive on CSF examination, suggesting a CNS inflammatory process; other extensive investigations excluded infective, rheumatologic, metabolic, and malignant causes. She was considered to have an unclassified neuroinflammatory disease and was treated empirically with IV immunoglobulin (1 g/kg) and corticosteroids (IV methylprednisolone at 30 mg/kg over 3 days and oral prednisolone 2 mg/kg/d tapered over 8 weeks), with resolution of white matter lesions and improvement of the dysarthria, squint, papilledema, headaches, and hyperesthesia, although her mobility remained impaired despite intense physiotherapy. Thirteen months later, she developed a generalized seizure requiring admission to intensive care, with fever and pancytopenia (hemoglobin at 7.6 g/dL, platelet count 55 3 10/L, and white cell count 3.5 3 10/L). Blood PCR for Epstein-Barr virus was positive at 850,000 copies/mL. She was thought to have viral-induced secondary HLH on the background of a neuroinflammatory syndrome. She was treated with IV methylprednisolone at 30 mg/kg/d for 3 days, oral prednisolone 2 mg/kg/d tapered over 4 months, rituximab (375 mg/m weekly for 4 weeks), and mycophenolate mofetil (1,200 mg/m/d). Whole exome sequencing revealed known pathogenic compound heterozygous mutations in UNC13D: exon 10 (c.C817T; p.R273X) and exon 14 (c.G1241T; p.R414L), confirmed using Sanger sequencing (figure, E; e-Methods and table e-1 on the Neurology® Web site at Neurology.org), Munc 13-4 protein was absent (figure, F), and defective CD8 T cell degranulation was demonstrated (figure, G; e-Methods). Based on these results, the patient was fast-tracked to allogeneic hematopoietic stem cell transplantation. At the time of writing, she remains well with no further hematologic and/or neurologic manifestations of HLH at 4 months after allogeneic hematopoietic stem cell transplantation.