CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis

Abstract

Objectives: To differentiate onset of CNS involvement in primary hemophagocytic lymphohistiocytosis (HLH) from that of other CNS inflammatory diseases and to identify early symptoms linked to abnormal cognitive outcome.Methods: Forty-six children with primary HLH who had neurologic evaluation within 2 weeks and brain MRI within 6 months of diagnosis were included. Initial symptoms, CSF study, brain MRI, and neurologic outcome were assessed. Brain MRIs were compared with those of 44 children with acute disseminated encephalomyelitis (ADEM).Results: At disease onset, 29 children (63%) had neurologic symptoms and 7 (15%) had microcephaly. Twenty-three (50%) children had abnormal CSF study, but only 15 (33%) had abnormal brain MRI. The latter showed that patients with HLH, unlike patients with ADEM, had symmetric periventricular lesions, without thalamic and brainstem involvement and with infrequent hyposignal intensity on T1. At the end of follow-up (3.6 Ϯ 3.6 years), 17 of the 28 (61%) surviving patients had normal neurologic status, 5 (18%) had a severe neurologic outcome, and 6 (21%) had mild cognitive difficulties. Abnormal neurologic outcome was not influenced by age or type of genetic defect, but by the presence of neurologic symptoms, MRI lesions, or abnormal CSF study at onset. Early clinical and MRI symptoms may regress after treatment.Conclusion: Neurologic symptoms are frequent at the onset of primary HLH and are mostly associated with abnormal CSF findings, but with normal brain MRI. In cases of abnormal brain MRI, the observed lesions differ from those of ADEM. Neurology ® 2012;78:1150-1156 GLOSSARY ADEM ϭ acute disseminated encephalomyelitis; CHS ϭ Chediak-Higashi syndrome; CRF ϭ case report form; FHLH ϭ familial hemophagocytic lymphohistiocytosis; FLAIR ϭ fluid-attenuated inversion recovery; GS ϭ Griscelli syndrome; HLH ϭ hemophagocytic lymphohistiocytosis; HPS ϭ Hermansky-Pudlak syndrome; HSCT ϭ hematopoietic stem cell transplantation; MTX ϭ methotrexate; PID ϭ primary immunodeficiencies; SE ϭ spin-echo; WI ϭ weighted image; XLP ϭ X-linked lymphoproliferative syndrome.

Synchronous brain and intravascular B‐cell lymphoma after remission of an adult hemophagocytic syndrome

“…In children, white matter abnormalities are characteristic of CNS involvement in HLH 5, 7. On brain MRI, the lesions are usually multiple, asymmetrical and fuzzy, hyperintense on T2 with contrast enhancement, and a periventricular or juxtacortical distribution 5, 7. These abnormalities are not usually considered a feature of adult HLH, although this case, like others 8, suggests that this may be a wrong assumption.…”

“…The central nervous system (CNS) is commonly affected in children with HLH where white matter abnormalities are characteristic 5. In adults, neurological manifestations have been reported in up to 25% of cases 1, 2, although HLH is not usually considered in the differential diagnosis of white matter abnormalities in this age group.…”

Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation

“…23 Neurodegeneration has been reported as a possible feature of FHL2 and sporadic HLH, [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] with a frequency of 37-69%. 23,29,39,40 A third of patients have neurological symptoms at diagnosis, 40 and 36% of those with PRF1 mutations have some CNS involvement. 23 Although there is an association of variations in PRF1 with susceptibility to multiple sclerosis, 41 very few patients with HLH have had neurological symptoms as the sole presenting feature, and consistent with the expected ascertainment and reporting bias, 29,30,32,39 all developed the diagnostic features of FHL2-HLH, with the exception of one individual who was diagnosed by brain histopathology but without identification of a mutation.…”

“…23,29,39,40 A third of patients have neurological symptoms at diagnosis, 40 and 36% of those with PRF1 mutations have some CNS involvement. 23 Although there is an association of variations in PRF1 with susceptibility to multiple sclerosis, 41 very few patients with HLH have had neurological symptoms as the sole presenting feature, and consistent with the expected ascertainment and reporting bias, 29,30,32,39 all developed the diagnostic features of FHL2-HLH, with the exception of one individual who was diagnosed by brain histopathology but without identification of a mutation. 25,26,29,[31][32][33]36,42 The sisters reported herein are therefore the first individuals reported with neurodegeneration, biallelic pathogenic PRF1 mutations and no diagnostic features suggestive of FHL-HLH (Table 2).…”

Treatment of CNS Vasculitis in Children

“…The clinical picture of HLH includes fever, hepatosplenomegaly, pancytopenia, hyperferritinemia, raised liver enzymes, and hypertriglyceridemia [57,58]. CNS vasculitis is well described in children with HLH [56,59] (Fig. 3).…”