Central Nervous System Involvement in Adult-Onset Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease marked by high cytokine levels, uncontrolled lymphocyte, and macrophage proliferation. It is generally a systemic disorder with varying degrees of central nervous system (CNS) involvement, with the vast majority of cases affecting children. We report a case of CNS-HLH in a 51-year-old male who initially presented with fevers, night sweats, fatigue, bilateral arthralgia, and altered mental status. Computed tomography (CT) of the chest, abdomen, and pelvis showed hepatosplenomegaly. Magnetic resonance imaging (MRI) of the brain showed enhancing lesions mainly in the right frontal lobe with a small hemorrhagic focus. An extensive workup for infectious, autoimmune, and neoplastic and genetic etiologies was only significant for cytopenia with markedly elevated C-reactive protein (CRP), ferritin, and lactate dehydrogenase (LDH), in addition to mild triglyceridemia. Bone marrow and liver biopsy revealed hemophagocytosis. Brain biopsy revealed no evidence of malignancy or infection. The patient was treated with high-dose dexamethasone and etoposide and fully recovered with resolution of all of HLH parameters and decrease/resolution of brain lesion. Clinicians should have a high index of suspicion for CNS-HLH in adults who present with sepsis-like illness with fevers, altered mental status, and cytopenia but negative cultures and unusual radiographic cerebral abnormalities so that early diagnosis and treatment can be initiated to prevent end-organ failure and death.


Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome caused by a highly active but ineffective immune response. It includes impaired or absent function of natural killer (NK) cells and cytotoxic T cells, and the release of proinflammatory cytokines [1]. The primary form (familial HLH) is typically seen during infancy and early childhood, whereas adult-onset HLH is often secondary to an underlying disease such as infection, malignancy, or autoimmune disease [2]. Though HLH is typically a systemic disease with varying degrees of central nervous system (CNS) involvement, cases with primarily CNS involvement are more common in the pediatric population and manifest as meningitis, seizures, and optic neuritis [3]. We present a rare case of CNS-HLH in a middle-aged male with no genetic mutations suggestive of familial HLH and with no infectious, malignancy, or autoimmune disease.

Case Presentation
A 51-year-old male with a medical history of bipolar disorder type II presented to the clinic in June of 2019 with a three-month history of unintentional weight loss (25 pounds), bilateral knee pain, fatigue, exertional shortness of breath, and night sweats but no fevers. One month prior to this presentation, he was treated at a local walk-in clinic with doxycycline in a setting of a suspected tick bite while camping. In the clinic, he denied fevers or chills. Initial laboratory findings are summarized in Table 1. Since he had elevated inflammatory markers, he underwent autoimmune test and infectious disease workup including tickborne illness, flow cytometry on peripheral smear, and fungal serology, which were all negative. Fecal occult blood test was negative with subsequent normal colonoscopy examination. Computed tomography (CT) of the chest, abdomen, and pelvis showed mild splenomegaly but otherwise no acute pathology.  In December of 2019, the patient was seen in the clinic as a routine follow-up during which he reported gradual symptoms resolution and stabilization of his weight over months without any specific treatment. He denied fevers, chills, or night sweats. He still had mild knee pain but was otherwise functional without any deficit. His labs at this time are shown in Table 1.
In June of 2020, he returned to the clinic with similar complaints of weight loss, fatigue, and bilateral knee pain with occasional fevers and night sweats. At this time, he had lost up to 15 pounds since the last visit. Repeat labs are shown in Table 1. There was a suspicion for HLH even though the lactate dehydrogenase (LDH) was not elevated enough to support this. The patient was referred to the hematology service.
A week later, he woke up with severe shortness of breath, lightheadedness, and confusion, and was brought to the emergency department (ED). His vital signs included a heart rate of 100 bpm, blood pressure of 98/60 mmHg, temperature of 37.5°C (99.5°F), and pulse oximetry of 98% in room air. Physical examination was notable for an ill-appearing middle-aged male who was alert, oriented but occasionally confused. Respiratory examination revealed clear breath sounds bilaterally. Neurological examination showed no deficit. Venous blood gas was normal, D-dimer was 1.21 ug/mL FEU (normal < 0.49 ug/mL FEU), and haptoglobin was normal; the remainder of laboratory findings in the ED are summarized in Table 2. Electrocardiography (EKG) showed sinus tachycardia with a heart rate of 104 bpm. Chest X-ray was normal. Computed tomography angiography (CTA) of the chest did not show evidence of pulmonary embolism. CT of the abdomen and pelvis showed mild hepatosplenomegaly ( Figures 1A, 1B). The patient was admitted to the hospital for further evaluation and management.   Angioimmunoblastic T-cell lymphoma related NHL or gamma/delta hepatosplenic T-cell lymphoma were also considered though less likely given long clinical course of the patient's symptoms. Low-grade HLH was also on the differential given the patient met 4/8 diagnostic criteria (hemophagocytosis, splenomegaly, high ferritin, and mildly increased triglyceride (156 mg/dL; normal 50-150 mg/dL).
The patient underwent bone marrow biopsy with aspiration, which revealed hypercellular marrow and evidence of hemophagocytosis, though no evidence of B-cell, T-cell lymphoma or Hodgkin lymphoma (Figures 2A, 2B) was found. The interleukin-2 receptor (IL-2)/soluble CD25 (sCD25) level was significantly elevated at 9,700 pg/mL (normal: 175-858.2 pg/mL). Magnetic resonance imaging (MRI) of the brain was obtained, which showed multiple abnormally enhancing lesions mainly in the right frontal lobe with a small hemorrhagic focus ( Figure 3A). Cerebrospinal fluid (CSF) analysis was not suggestive of an infectious cause. A stereotactic needle brain biopsy revealed no evidence of malignancy or infection. Liver biopsy confirmed evidence of hemophagocytosis with no evidence of malignancy or lymphoma. A diagnosis of CNS-HLH was made, and the patient was started on high-dose dexamethasone 20 mg and etoposide 150 mg/m 2 per the HLH-94 protocol for eight weeks alongside prophylactic BactrimÔ DS 800-160mg and acyclovir 400 mg. He had an excellent response with resolution of all his symptoms and normalizations of all HLH parameters ( Table 3). Follow-up brain MRI showed decrease/resolution of previous parenchymal frontal abnormalities ( Figure 3B). HLH genetic screening test showed no abnormalities.

Discussion
HLH is a hyper-inflammatory condition induced by the overactivation of lymphocytes and macrophages, as well as elevated cytokine levels [3,4]. There are two forms of HLH: a primary form that manifests in children with established genetic abnormalities affecting the cytotoxic activity of NK cells and T cells, and a secondary form that manifests in adults with an underlying disorder, such as infection or malignancy, but no known genetic abnormality [3,5,6]. Fever, malaise, hepatosplenomegaly, jaundice, lymphadenopathy, cytopenia, and a number of neurological symptoms are some of the clinical manifestations [4,7]. Changes in mental state, seizures, meningitis, ataxia, and cranial nerve palsies are all signs of CNS involvement [3,8,9]. The majority of such cases occur in the pediatric population up to 75% and represent primary CNS-HLH [3,4].
The frequency of CNS-HLH involvement in adults has been studied only in a few cases. CNS-HLH was reported in 73% of patients with HLH at the time of diagnosis in one case series of 34 patients, and CNS complications eventually developed in 100% of HLH patients who did not receive bone marrow transplantation [10]. In a separate study, 56% of 30 patients had CNS involvement, with 46% of those presenting with neurological symptoms [11]. In another study, 30% of CNS-HLH patients had an underlying autoimmune disorder [12]. In the HLH-94 study, 37% of the 193 patients had neurological symptoms at the time of diagnosis and 52% had abnormal CSF [13]. Another major retrospective study discovered that 10% of [9].
In our case, the patient met 6/8 criteria (hemophagocytosis, splenomegaly, high ferritin, slightly increased triglyceride, elevated IL-2/soluble CD25, and hemophagocytosis on liver biopsy) and had an enhancing lesion on brain MRI, indicating CNS-HLH. Dexamethasone, etoposide, and cyclosporine A, as well as intrathecal methotrexate, are used in the HLH-94 protocol [4]. In genetic or refractory case, a stem cell transplant may be considered [14]. Since he tested negative for genetic changes, he most likely had a case of acquired HLH with unknown causes such as infection, malignancy, autoimmune disease, or medications. Prior to his initial presentation in the summer of 2019, he was briefly treated for suspected tick bite with doxycycline, but testing for tick-borne diseases was negative. It is possible that he was exposed to an environmental trigger such as a virus for a short period of time, which might have precipitated CNS-HLH. He was successfully treated with high-dose dexamethasone and etoposide and fully recovered with resolution of all HLH parameters and improvement in previous parenchymal frontal abnormalities on MRI.

Conclusions
In conclusion, astute clinicians should have a high index of suspicion for HLH in adults who present with unexplained fevers, altered mental status, and cytopenia so that adequate testing can be performed rapidly and early treatment can be initiated to control hypercytokinemia, which can result in end-organ failure and death if left untreated. Imaging results should also be associated with clinical symptoms in addition to laboratory and pathological findings.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.