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Adult-onset central nervous system hemophagocytic lymphohistiocytosis: a case report
© Pastula et al. 2015
Received: 27 March 2015
Accepted: 8 October 2015
Published: 14 October 2015
Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome with both genetic and acquired causes characterized by elevated cytokine levels, hyperinflammation, and overactivation of lymphocytes and macrophages. It is typically a systemic disease with variable degrees of CNS involvement. Cases with predominantly central nervous system (CNS) involvement are very rare, with the vast majority of these occurring in infants and young children. This report documents a case of adult-onset CNS-HLH involving a middle-aged man.
A 55 year-old man developed progressive left hemiparesis and aphasia over the course of several months. Brain MRI showed multifocal, mass-like enhancing lesions with increased susceptibility consistent with blood products. An extensive workup for infectious, autoimmune, and neoplastic etiologies was significant only for a markedly elevated serum ferritin at 1456 ng/mL. Two brain biopsies showed a non-specific inflammatory process. The patient was treated empirically with steroids and plasmapheresis, but he continued to suffer a progressive neurological decline and died one year after onset of neurological symptoms. Autopsy revealed profound histiocytic infiltration, perivascular lymphocytosis, and emperipolesis, compatible with CNS-HLH.
This case report describes an exceedingly rare presentation of an adult patient with CNS predominant HLH. This diagnosis should be considered in the differential diagnosis of adults presenting with progressive brain lesions, even in the absence of typical systemic signs of HLH.
Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome characterized by elevated cytokine levels, hyperinflammation, and overactivation of lymphocytes and macrophages [1–5]. In infants and young children, the disease is primarily caused by a genetic mutation in one of the genes responsible for cytotoxic function of natural killer cells and cytotoxic T lymphocytes. In older children, adolescents, and adults, acquired causes predominate and include infectious, neoplastic, autoinflammatory, autoimmune, and immunodeficiency etiologies. While HLH is more frequently a systemic disease with variable degrees of central nervous system (CNS) involvement, cases with predominantly CNS involvement can occur with resulting meningitis, seizures, and optic neuritis [6–12]. In such cases, the vast majority of patients are infants and young children. This report documents a case of adult-onset CNS-HLH involving a middle-aged man, which is an exceedingly rare presentation of which physicians should be aware.
A 55 year-old healthy male business owner presented to a local community hospital after two months of painless left calf swelling that developed in January 2012. An ultrasound ruled out deep vein thrombosis, but an MRI suggested diffuse myositis of his left soleus muscle. Initially he was treated for cellulitis, but after failing to improve with antibiotics, the diagnosis of autoimmune myositis was entertained. A muscle biopsy showed nonspecific endomysial inflammation, and prednisone was started. His left calf swelling improved partially over the next several weeks.
In May 2012 the patient developed disequilibrium and gait unsteadiness over a period of a few days. This was followed a week later by a left foot drop, and then two weeks later by right hand parasthesias. He denied any fevers, weight loss, night sweats, or unusual rashes. He was referred to a local rheumatologist who, being concerned about the progressive symptoms, admitted him to our hospital for an expedited workup.
He had a daughter with AML and both a maternal grandmother and maternal cousin with strokes in their 40s. He was married with two children. Other than the prednisone that he had started for possible myositis, he was taking no other medications. He was not allergic to any medications.
On examination at the time of admission in June 2012, he was afebrile without rash, lymphadenopathy, or hepatosplenomegaly. He did have left lower extremity swelling. He was alert, fully oriented, with fluent speech and normal language. He had normal attention (digits forward of 6), but had poor short-term recall (0/3 at 5 min even with cues). On cranial nerve testing he was found to have a right facial droop. He had diffuse left lower extremity weakness that was worse distally in a pyramidal distribution. His deep tendon reflexes were brisk on the left compared to the right, and he had a Babinski response on the left. He had decreased sensation to pinprick over the right fifth finger. Finger-to-nose was on-target bilaterally. He had a positive Romberg test, and had a steppage gait on his left.
Initial admission laboratory tests from early June 2012
Blood urea nitrogen (BUN)
White blood cell count
3.7 X 10^9/L
204 X 10^9/L
Mean corpuscular volume
Activated partial thromboplastin time
International normalized ratio
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Rapid plasma reagin (RPR)
Hepatitis B Core Antibody
Hepatitis B Surface Antigen
Hepatitis C Antibody
Erythrocyte sedimentation rate (ESR)
Anti-double stranded DNA antibody
Angiotensin converting enzyme
Red blood cells
43 X 10^6/L
White blood cells
1 X 10^6/L
M. Tuberculosis Complex PCR
Multiple bands in CSF and serum
Subsequent laboratory tests June-December 2013
Russel viper venom test
Anti beta-2 glycoprotein antibodies
Anti cardiolipin antibodies
Serum protein electrophoresis
No paraprotein spike
Thyroid stimulating hormone
Anti thyroperoxidase antibody
Anti thyroglobluin antibody
Anti SSA antibody
Anti SSB antibody
Natural killer cell function
Soluble interleukin 2 receptor
16 s rDNA primer set
28 s rDNA primer set
MELAS A3243G mutation: blood
Urine protein electrophoresis
Kappa/Lambda light chain ratio
Venereal disease research laboratory test
Varicella zoster virus polymerase chain reaction
Whipple polymerase chain reaction
Shortly after admission, the patient suffered a focal seizure with secondary generalization and was started on levetiracetam. He declined neurologically throughout June 2012 with worsening confusion, aphasia, and left-sided weakness. He developed occasional fevers as high as 39.9 during this month without ever having a confirmed infection.
Two brain biopsies were performed in late June 2012. The first, from a right parietal lobe lesion, showed a macrophage-rich process associated with areas of necrosis and a mild-moderate chronic inflammatory infiltrate. The second, from a right temporal lobe lesion, showed a similar macrophage-rich process involving both the cerebral cortex and white matter. No evidence of vasculitis was present in either specimen. A bone marrow biopsy was also unrevealing.
Despite this extensive workup, no clear diagnosis could be made. Suspecting an autoimmune process, IV solumedrol was administered, followed by plasmapheresis and a 5-month steroid taper. He was discharged to a skilled nursing facility in August 2012.
Despite immunosuppression, the patient continued to decline. By September 2012, he was wheelchair-bound with spastic quadriparesis, mute, and unable to maintain proper nutrition by mouth. A percutaneous endoscopic gastrostomy tube was placed in the fall of 2012. He died of aspiration pneumonia in the spring of 2013. An autopsy was performed.
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by overactivation of lymphocytes and macrophages in association with high levels of cytokines [1–5]. In children, the disease is relatively uncommon, with an estimated prevalence of approximately 1/100,000  and incidence of 1.2/1,000,000 per year . Clinically, it can be associated with fevers, hepatomegaly, splenomegaly, pancytopenia, hypertriglyceridemia, hyperferritinemia, and various neurologic manifestations. The hallmark of disease is the finding of hemophagocytosis on pathologic examination of tissues. Treatment options include immunosuppression and stem cell transplantation [1, 3–5]. The disease has primary and acquired causes. Primary HLH usually manifests as a result of defects in genes that encode proteins involved in the exocytosis of cytotoxic granules in natural killer (NK) cells, which leads to hyperactivation of the immune system. Genes encoding for perforin, syntaxin 11, Munc 13-4, and Munc 18-2 proteins have been implicated . Primary HLH typically manifests in childhood. Acquired HLH is associated with various conditions, including infectious and neoplastic etiologies, which are thought to trigger the syndrome. Acquired HLH manifests predominantly in adulthood [1, 3–5]. Most cases of HLH present first with systemic involvement, [1, 3–5] though cases of central nervous system HLH (CNS-HLH) have been reported where the disease presents first with destructive lesions of the brain and spinal cord with associated meningitis, seizures, or optic neuritis [6–12]. The majority of such cases occur in the pediatric population and represent primary CNS-HLH.
In this case, the pathologic findings at autopsy are diagnostic of CNS-HLH. In retrospect, the patient’s presentation of progressive right hand clumsiness with associated brain lesions ten years earlier likely represents the earliest manifestation of this disease rather than sub-acute infarcts as it was deemed at the time. The time course and radiological similarity with subsequent lesions are also compatible with acute-on-chronic manifestations of CNS-HLH.
HLH is diagnosed clinically by either 1) having a proven genetic mutation known to be associated with HLH or 2) fulfilling 5 out of 8 clinical criteria (fever, splenomegaly, cytopenias of at least 2 cell lines, hypertriglyceridemia and/or hypofibrinogenemia, hyperferritinemia, abnormally low NK cell activity, high levels of soluble IL-2 receptor, and pathologic evidence of hemophagocytosis in tissues) [1, 3, 5, 14]. Our patient had 3 of the 8 clinical criteria: fever, hyperferritinemia, and hemophagocystosis at the time of brain biopsy. He had a transient decrease in absolute neutrophil count to 1.25 ×109/L and platelets to 119 ×109/L during his initial hospitalization but these values do not meet the diagnostic criteria for cytopenia in HLH. According to the HLH-94 protocol, therapy includes corticosteroids, etoposide, and cyclosporine A, with intrathecal methotrexate for those with progressive neurologic symptoms. In genetic or refractory cases, a stem cell transplant may be considered [1, 3, 5, 14, 16]. Our patient was treated empirically with corticosteroids and plasmapheresis for a presumed autoimmune condition since he did not meet clinical criteria for HLH.
The frequency of CNS involvement in HLH is unclear, especially in adults. In one small series CNS involvement was identified in up to 73 % of patients at the time of diagnosis . In another, CNS involvement was present in 30 % of patients who had both HLH and an underlying autoimmune disorder . In the pediatric population, neurologic symptoms are variably seen at presentation (between 13–63 % of patients), and patients may also show neuroimaging as well as CSF abnormalities [7, 9, 19–21]. Compared to patients who only have systemic symptoms, neurologic symptoms tend to occur in older patients and are associated with higher sodium levels, lower ferritin, lower levels of liver enzymes, and a worse prognosis [9, 22]. MRI findings include global volume loss, calcifications, enhancing lesions of the gray and white matter, delayed myelination, and MR spectroscopy changes (lower N-acetyl aspartate to creatinine ratios) . CSF involvement may manifest as lymphocytic pleocytosis and elevated protein [19, 23, 24] and may indicate a worse prognosis with increased mortality . Of importance to neurologists, isolated neurologic symptoms as the presenting sign of HLH have been observed in several pediatric reports [24–28] but are not particularly common [7, 9].
It is unknown whether our patient had primary or acquired HLH. While genetic causes are thought to occur mainly in children and infants, hypomorphic mutations can result in manifestation of the disease in adulthood . Furthermore, defects in the gene encoding for the syntaxin-11 protein have been shown to cause both HLH and acute myeloid leukemia (AML) . Intriguingly, the patient’s daughter has a history of AML, which raises consideration for a syntaxin-11 mutation and predisposition to the development of HLH. Alternatively, our patient could have been exposed to an environmental trigger (such as a virus) that could have precipitated CNS-HLH. How the therapy with solumedrol altered the inflammatory milieu prior to the autopsy is unclear; the lack of significant inflammation in the liver and other systemic organs could be due to the corticosteroid therapy. However, since the patient’s laboratories were obtained prior to initiation on solumedrol, the therapy is not a confounder in the lack of clinical/laboratory evidence necessary for a diagnosis of systemic HLH. Furthermore, the autopsy clearly demonstrates that corticosteroid therapy was not sufficient to prevent the severe destruction of brain parenchyma. Therefore, the evidence in this case is most consistent with a case of CNS-HLH presenting in adulthood.
In conclusion, HLH should be considered in the differential diagnosis of adults presenting with progressive brain lesions alone or in association with recurrent fevers, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and/or hyperferritinemia. Further work is needed to identify diagnostic markers of CNS-HLH and to determine the role of environmental factors in the development of HLH.
The patient’s widow, who was his medical decision-maker in life, read this manuscript and provided consent for its publication and any accompanying images.
There are no additional acknowledgements. This manuscript was prepared without funding. Publication of the manuscript for open access, if accepted, will be funded through a combination of institutional support through an open access agreement between the University of California, San Francisco and BioMed Central and Dr. Douglas’s Sara & Evan Williams Foundation Endowed Neurohospitalist Chair. The funding sources had no role in the preparation of this manuscript.
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