Pediatric CNS-isolated hemophagocytic lymphohistiocytosis

Abstract

Objective: To highlight a novel, treatable syndrome, we report 4 patients with CNS-isolated inflammation associated with familial hemophagocytic lymphohistiocytosis (FHL) gene mutations (CNS-FHL).

Methods: Retrospective chart review.

Results: Patients with CNS-FHL are characterized by chronic inflammation restricted to the CNS that is not attributable to any previously described neuroinflammatory etiology and have germline mutations in known FHL-associated genes with no signs of systemic inflammation. Hematopoietic stem cell transplantation (HCT) can be well tolerated and effective in achieving or maintaining disease remission in patients with CNS-FHL.

Conclusions: Early and accurate diagnosis followed by treatment with HCT can reduce morbidity and mortality in CNS-FHL, a novel, treatable syndrome.

Classification of evidence: This study provides Class IV evidence that HCT is well tolerated and effective in treating CNS-FHL.

Figure 1. Imaging and histopathologic characteristics of patients with CNS-FHL

FLAIR (row A) and post-contrast T1 (row B) MRI findings for patients before initial diagnosis or at relapse. Note the varied lesion appearance with small multifocal, confluent, and tumefactive lesions. Punctate and curvilinear enhancement resembling CLIPPERS is common to 3 of the 4 patients early in disease. Patient 4 had multifocal small lesions with a single area of enhancement. Avid enhancement was a common feature of new or active lesions. Over time, lesions became confluent, and diffuse atrophy evolved in patients 1 and 2. Representative histopathology (row C) images from prediagnosis or relapse biopsies demonstrating a diffuse mixed chronic inflammatory infiltrate in patient 1, foci of perivascular lymphocytes (arrow) extending into the parenchyma for patient 2 prediagnosis, perivascular (arrow) and parenchymal mixed chronic inflammatory infiltrate with small vessel vasculitis in patient 3, and destructive perivascular (arrow) and parenchymal lymphohistiocytic infiltrate in patient 2 at relapse (magnification: ×40 objective). Post-HCT FLAIR (row D) and post-contrast T1 (row E) MRI images demonstrate resolved enhancement and no development of new lesions for patients 1, 3, and 4 after HCT #1 and for patient 2 after HCT #2. CLIPPERS = chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; FLAIR = fluid-attenuated inversion recovery; HCT = hematopoietic cell transplantation.

Figure 2. Patient 1 MRI evolution over time

(A) Confluent cerebellar FLAIR lesions with punctate, folia, and curvilinear enhancement without SWI change evolved to cerebellar atrophy with confluent nodules of enhancement and associated accumulation of microhemorrhages. Pattern persists posttransplant but without enhancement. (B) Supratentorial multifocal asymmetric small well-circumscribed lesions all with avid enhancement without initial SWI change evolving to confluent FLAIR lesions with punctate and confluent areas of enhancement and SWI change over time leading up to transplant. Imaging remains stable posttransplant. FLAIR = fluid-attenuated inversion recovery; SWI = susceptibility-weighted imaging.

Figure 3. Patient 2 MRI evolution over time before relapse

(A) Cerebellar FLAIR lesions with punctate and curvilinear enhancement without SWI change evolved to cerebellar atrophy with confluent nodules of enhancement and associated accumulation of microhemorrhages. Pattern persists posttransplant, but enhancement responded to treatment. (B) Supratentorial multifocal asymmetric lesions with white matter, cortical, deep gray, and insular predilection with initial punctate enhancement evolving to curvilinear cortical enhancement. No initial SWI change evolving to punctate and confluent areas of SWI change consistent with hemorrhage over time leading up to transplant. Posttransplant FLAIR lesions become smaller with further global brain atrophy. FLAIR = fluid-attenuated inversion recovery; SWI = susceptibility-weighted imaging.

Figure 4. Patient 3 MRI evolution over time

(A) Initial attack and follow-up FLAIR and T1 post-contrast images showing tumefactive brainstem lesions with heterogeneous enhancement pattern. Significant improvement with steroids at 4-month follow-up. (B) Attack 7 months from onset with multifocal FLAIR lesions throughout the brain and spinal cord with punctate, speckled enhancement throughout. (C) Pre- and post-HCT images of the cerebellar involvement with minimal atrophy over time in this patient despite 7 years of disease. FLAIR = fluid-attenuated inversion recovery; HCT = hematopoietic cell transplantation.