Hemophagocytic lymphohistiocytosis (HLH) is an immune dysregulatory disorder. Secondary HLH is most commonly associated with infections, malignancies, or rheumatologic disorders. Primary HLH is genetic in origin with most cases occurring in children and curative treatment involving hematopoietic stem cell transplant (HSCT). ^{Reference Henter, Horne and Aricó1} Documented adult cases are uncommon. ^{Reference Henter, Elinder, Söder and Öst2,Reference Song, Pei, Wang, Zhang and Wang3} Here we report three cases of primary HLH presenting with central nervous system (CNS) involvement in adults.

The first patient was a 17-year-old male reported previously with a focus on genetics. ^{Reference Woodward, Shah and Benseler4} He presented with 2 weeks of fever and respiratory symptoms before developing slurred speech and impaired balance. Brain magnetic resonance imaging (MRI) showed patchy T2 hyperintensities in the parietal lobes (Figure 1), pons, and midbrain. Lumbar puncture was nonspecific. CBC revealed neutropenia and thrombocytopenia and bone marrow biopsy showed a nonspecific increase in macrophages. The patient was discharged without a definite diagnosis.

Figure 1:

(A) Axial MR brain FLAIR sequence from patient one at time of initial presentation demonstrating bilateral hyperintensities in the centrum semiovale of the parietal lobes. (B) Post-gadolinium axial MR brain FLAIR sequence from patient one 14 months after initial presentation demonstrating progression of bilateral supratentorial white matter hyperintensities and left frontal lobe encephalomalacia at site of previous brain biopsy. (C) T2-weighted MR brain from patient two at time of initial presentation showing bilateral cerebellar hemisphere white matter hyperintensity with local mass effect and relative sparing of the cerebellar peduncles. (D) T2-weighted MR brain from patient two approximately 7 years after initial presentation showing progression of the bilateral cerebellar white matter hyperintensities, now with prominent involvement of the bilateral dentate nuclei.

Six months later, he presented with new diplopia and right-sided weakness. Repeat MRI showed new hyperintensity of the abducens nerve as well as discrete lesions in the thalami and internal capsules. CSF WBC was increased with prominence of T-cells on flow cytometry. He was pancytopenic with markedly elevated ferritin and hepatosplenomegaly. Whole exome sequencing was performed for suspicion of an immunodysregulatory disorder and demonstrated compound heterozygous mutations in the RAB27A gene. This was felt to be consistent with Griscelli syndrome type 2, ^{Reference Woodward, Shah and Benseler4} causing CNS HLH, despite the absence of albinism. He received dexamethasone that resulted in improvement of his CNS symptoms and cytopenias and subsequently started on cyclosporine to prevent a flare of presumed HLH. In spite of this, he developed profound thrombocytopenia causing refractory epistaxis and hematuria. He had 2 allogeneic stem cell transplants from unrelated donors. The first transplant failed to engraft and was complicated by infection. The second transplant was done 6 weeks later but he died shortly thereafter with autopsy showing persistent HLH.

The second patient was a 22-year-old female who presented with limb numbness and diplopia. MRI showed T2 hyperintensities in the cerebellar hemispheres and vermis as well as in the subcortical and periventricular white matter (Figure 1). Ferritin was mildly elevated; she was thrombocytopenic, and ultrasound showed splenomegaly. Diagnosis remained unclear after extensive investigations including CSF sampling.

The patient was stable for 2 years without treatment before developing subacute hemiparesis and incoordination. Repeat MRI revealed progression of cerebellar hyperintensities with new leptomeningeal involvement. A 2-month trial of oral prednisone yielded little symptomatic improvement, and she was monitored for disease progression without further active treatment.

One year later, she presented to hospital with high-grade fevers and fatigue. She was found to be pancytopenic with hemophagocytes noted on her bone marrow biopsy. Ferritin and serum soluble interleukin-2 receptor levels were markedly elevated and abdominal ultrasound revealed hepatosplenomegaly with ascites. Repeat MRI showed worsening leptomeningeal disease. Work-up for secondary causes of HLH was negative, and genetic testing revealed compound heterozygous mutations in the STXBP2 gene consistent with primary HLH. ^{Reference Zhang, Jordan and Marsh5} She received an abridged version of the HLH-1994 protocol and continued on maintenance cyclosporine monotherapy as she declined HSCT. She remained in remission for 2.5 years. She then developed worsening ataxia, headache, and tremor. MR showed interval progression in left frontal lobe and cerebellar lesions (Figure 1). She was treated again with the HLH-1994 protocol, including intrathecal methotrexate. Her symptoms improved markedly, and she was discharged home. Unfortunately, she was admitted to hospital shortly thereafter with bacterial sepsis and invasive fungal infection and passed away from infectious complications.

The third patient was a 30-year-old male who presented with sudden left-sided weakness and dysarthria. He had a history of mild hypertension treated with nifedipine. CT scan showed intraparenchymal hemorrhage involving the midbrain and thalamus. MR additionally visualized innumerable foci of intraparenchymal microhemorrhage throughout the infra and supratentorial compartments with a posterior fossa and midbrain predominance (Figure 2).

Figure 2:

(A) Dry axial CT head showing intraparenchymal hemorrhage involving the right thalamus and posterior limb of the internal capsule. (B) Susceptibility weighted imaging MR brain without contrast performed on initial presentation showing diffuse multifocal cerebellar and pontine microhemorrhages. (C) Subsequent susceptibility weighted imaging MR brain without contrast performed 5 years after initial presentation showing progression of posterior fossa microhemorrhages.

Cerebral angiogram was normal without features of vasculitis. Ferritin was not initially tested but was found to be elevated 3 months later without clear cause. At discharge, the stroke etiology was attributed to hypertension.

Three years later, the patient presented with cough and shortness of breath, progressing to fever, pancytopenia, and hyperferritinemia. Bone marrow biopsy showed increased histocytes with hemophagocytosis. Genetic workup revealed two mutations in PRF1. Abdominal imaging showed borderline splenomegaly. MRI brain showed significant increase in burden of microhemorrhages and multiple T2 hyperintensities in the supratentorial white matter. Primary HLH was diagnosed, and treatment was initiated using the HLH-2004 protocol. ^{Reference Henter, Horne and Aricó1} There was initial improvement, but his cytopenias persisted and treatment was re-escalated as he became febrile and his ferritin increased again. He was temporarily treated with rituximab and maintained on cyclosporine. However, his cyclosporine was discontinued several months later when he developed multiple infectious complications.

Over the subsequent years, his cognitive capacity declined along with his imaging profile, with the latter exhibiting an increasing burden of edema and microhemorrhages both infra and supratentorially. He passed away shortly thereafter.

HLH is a rare disorder with an estimated prevalence of 1.2 cases per 1,000,000 with an age of onset of less than 36 months in more than eighty percent of cases. ^{Reference Henter, Elinder, Söder and Öst2} The pathogenesis is a persistent overactivation of the immune system, specifically of macrophages and T lymphocytes, leading to infiltration of organs including the CNS. ^{Reference Zhang, Jordan and Marsh5} Imaging findings are nonspecific and include diffuse leptomeningeal and perivascular enhancement and T2 hyperintense lesions in the cerebral white matter. ^{Reference Okabe, Nozaki and Aida6}

All three patients we report had primary late-onset HLH. CNS involvement is less common in adults than in children in both forms of HLH and occurs in ˜10% of patients at any point. ^{Reference Cai, Wang, Liu, Han and Wang7} Literature review identified 5 other adult patients with isolated CNS presentation of primary HLH. All patients were between 18 and 28 years, seizures were common, and imaging findings typically involved the periventricular and subcortical white matter (Table 1).

Table 1:

Clinical, laboratory, imaging, and genetic characteristics of all eight patients, including three patients identified in this report, with adult-onset primary HLH identified in literature search. Normal range of ferritin 13–375 µg/l. Gene mutations known to be pathogenic unless otherwise specified

Our three patients had a variety of clinical and imaging findings. However, the patients’ PRF1, STXBP2, and RAB27A mutations are all implicated in the PRF1 cytotoxic pathway, which functions in lymphocytic regulation. ^{Reference Zhang, Jordan and Marsh5} Notably, the oldest patient in our study and more than half of those previously reported had PRF1 mutations. In this case series, we also report the first case of CNS microhemorrhages associated with HLH in an adult. This finding has previously been seen in pediatric patients, ^{Reference Okabe, Nozaki and Aida6} but the etiology remains unclear.

In conclusion, primary HLH is a rare cause of isolated CNS disease in adults. The diagnosis should be suspected in patients with progressive neurologic symptoms and atypical white matter lesions with otherwise negative work-up, especially with marked elevation in ferritin or hematologic abnormalities. Additionally, HLH is a rare cause of widespread microhemorrhages although more typical etiologies must be ruled out first. Genetic testing can assist in the diagnosis.