Abstract
Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.
Highlights
Patients and MethodsNeuroinflammatory disorders are a heterogenous group of severe diseases characterized by inflammation in the cerebrum or the spine
Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, inherited syndrome of immune dysregulation that is caused by impairment of the cytotoxic function of NK and T cells leading to uncontrolled immune cell activation, excessive secretion of inflammatory cytokines, and subsequent multiorgan cell-mediated immunopathology [2, 3]
The diagnosis of FHL was considered for the following reasons: (i) after eventual onset of systemic hemophagocytic lymphohistiocytosis (HLH) in 8 patients; (ii) following genetic investigations for unexplained neurological disease in 8 patients (iii) when disease pattern, imaging, and response to therapy were felt to be atypical in 5 patients; (iv) following brain biopsy in 6 patients; (v) due to the presence of hair or skin abnormalities in 3 patients; (vi) due to similar cases or cases in the literature in 2 patients; (vii) due to a family history of isolated CNS-HLH in 1 patient and (viii) not reported in 7 patients (Table 2)
Summary
Patients and MethodsNeuroinflammatory disorders are a heterogenous group of severe diseases characterized by inflammation in the cerebrum or the spine. The diagnosis of FHL was considered for the following reasons: (i) after eventual onset of systemic HLH in 8 patients; (ii) following genetic investigations for unexplained neurological disease in 8 patients (iii) when disease pattern, imaging, and response to therapy were felt to be atypical in 5 patients; (iv) following brain biopsy in 6 patients; (v) due to the presence of hair or skin abnormalities in 3 patients; (vi) due to similar cases or cases in the literature in 2 patients; (vii) due to a family history of isolated CNS-HLH in 1 patient and (viii) not reported in 7 patients (Table 2).
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