History and Physical
A 5-year-old girl presented with headache and vomiting. She initially experienced mild sore throat and headache, which progressed to emesis and severe headaches over several days. Her speech slowed and she developed difficulties with articulation and word finding. She also appeared more clumsy than usual with slight gait ataxia. Consciousness was preserved.
Diagnostic Workup
Brain MRI showed extensive areas of abnormal T2/FLAIR hyperintensity in the cerebellar hemispheres, cerebellar peduncles, internal capsules, and periventricular white matter extending into the corona radiata ( Fig. 55.1 ). There was also involvement of the left cerebral peduncle, left subthalamic region, and right occipital lobe. Postcontrast T1 imaging revealed “salt and pepper” enhancement within the regions of T2/FLAIR hyperintensity, most extensive within the cerebellum. DWI showed variable degrees of restricted diffusion within the lesions. MRI of the spine was normal.
Hemophagocytic lymphohistiocytosis. Brain MRI, (A–C) axial FLAIR, shows multifocal hyperintense signal within the cerebellar white matter, periventricular white matter, and corona radiata. (D) There is corresponding punctate and curvilinear enhancement on postcontrast T1. FLAIR , Fluid-attenuated inversion recovery.
LP was performed and revealed normal protein and glucose and 10 WBCs (88% lymphocytes). She had no oligoclonal bands and her IgG index was normal. She had a normal CBC except for slightly elevated white count of 10.8. ESR and CRP were normal. Antiphospholipid antibodies, von Willebrand factor antigen, lupus anticoagulant, ACE, ANA, SS A , SS B , antineutrophil cytoplasmic antibody (ANCA), and titers for CMV, varicella zoster virus (VZV), EBV, Mycoplasma, and Lyme ELISA and Western blot were all normal.
The patient was initially diagnosed with clinically isolated syndrome and treated with IV methylprednisone, but experienced clinical relapses during each taper attempt, even after the addition of monthly IVIG. Serial MRI showed radiologic progression concerning for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), and brain biopsy was performed. This revealed mixed chronic inflammatory infiltrates with perivascular inflammation diffusely involving the white matter, gray matter, and leptomeninges. She underwent induction treatment with glucocorticoids and cyclophosphamide followed by mycophenolate mofetil, which slowed but did not halt her disease progression. She went on to develop progressive tremor, ataxia, dysarthria, dysconjugate gaze, and slowed speech and response time. Next-generation sequencing of CSF and brain tissue was unrevealing. She stabilized on natalizumab for 3 years but subsequently progressed both clinically and radiologically. CSF phenotyping and soluble biomarker analysis revealed activation of her innate immune system. PRF1 gene sequencing identified a pathogenic mutation compatible with hemophagocytic lymphohistiocytosis (HLH). She was treated with intrathecal methotrexate and hydrocortisone and systemic dexamethasone with clinical improvement and normalization of CSF neopterin levels. She received a curative stem cell transplant at 10 years of age. At age 18 years, she has stable and permanent neurological deficits.
Clinical Differential Diagnoses
The initial clinical presentation of headache, emesis, ataxia, and dysarthria has a broad differential including demyelinating, autoimmune, and infectious processes.
Symptoms were consistent with a clinically isolated event or first-time presentation of MS, MOG, or NMO, although these are less typically associated with severe headaches. She did not have altered mental status, excluding ADEM.
Infectious etiologies, such as viral or bacterial meningitis, could present with slowed processing speed and severe headache.
Autoimmune parainfectious cerebellitis could present with dysarthria and ataxia.
Imaging Differential Diagnoses
An important consideration is chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) ( Fig. 55.2 ). The diagnosis is defined by imaging characteristics, but can have various underlying etiologies such as HLH or malignancy. On MRI, the initial findings are infratentorial punctate and curvilinear enhancing lesions, predominating in the pons and cerebellum. Disease can spread to spinal cord and brain, involving both white and deep gray matter, but typically spares the cortex. Radiographic criteria include homogeneous contrast-enhancing nodules measuring <3 mm in diameter. There should not be significant ring enhancement, mass effect, or T2 signal beyond the areas of enhancement. Lesions should improve with steroid treatment.
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain and cervical spine MRI, postcontrast T1, shows patchy enhancing punctate and curvilinear lesions throughout the pons, middle cerebellar peduncles, cerebellum, and cervical cord.
CNS lymphoma may also show T1 hypointense, T2 iso- to hyperintense lesions with patchy enhancement. These are typically supratentorial and can have associated edema ( Fig. 55.3 ). MRS will show increased Cho, decreased NAA, and slightly decreased Cr. PET can also reveal high metabolism of 18F-FDG in primary lesions, with decreased metabolism after treatment due to necrosis.
