Hemophagocytic lymphohistiocytosis (HLH) is a rare and complex syndrome characterized by aberrant immune system activation that results in hyperactivity of natural killer (NK) cells and/or cytotoxic T-lymphocytes. The resultant effect is dysregulation of inflammatory cytokine release, leading to tissue infiltration and destruction, particularly in the spleen, lymph nodes, bone marrow, liver, and CNS.^12,15

Because HLH can be a rapidly fatal disease, early diagnosis and treatment are vital. The initial presentation of HLH may mimic many other diseases, making it hard to establish an early diagnosis. The most common presenting symptoms include fever, hepatosplenomegaly, and cytopenia. Diagnosis, per guidelines from the Histiocyte Society, is made by satisfying 5 of the following 8 criteria, or molecular diagnosis⁹: fever; splenomegaly; cytopenia (2 of 3 lineages); hypertriglyceridemia or hyperfibrinogenemia; hemophagocytosis in bone marrow, spleen, or lymph nodes; low or absent NK cell activity; hyperferritinemia; and high IL-2. In atypical cases that do not fulfill the diagnostic criteria of HLH, alternate means of diagnosis, including extrareticuloendothelial tissue biopsy, have been reported.¹⁴

Although initially thought to be a rare presentation, recent studies have reported up to 63% of patients with CNS HLH at onset.⁴ Patients with CNS HLH most commonly present with seizures,^4,7,9,15 while other presentations may include impaired consciousness, meningismus, cranial nerve palsies, or ataxia. Focal neurological deficits are rare but have been reported to occur.¹⁵ Patients who present with focal neurological deficits often undergo cranial imaging and CSF analysis, which may or may not show abnormalities.^2,15 Herein, we report the case of a 17-year-old male patient who was diagnosed with CNS HLH following biopsy of a spinal nerve root lesion. To our knowledge, this represents the first case of CNS HLH diagnosed by nerve root biopsy.

Case Report

A 17-year-old boy, previously in good health, presented to our institution with complaints of progressive lower-extremity weakness, fatigue, and headache. At initial presentation, the patient was conscious, alert, and afebrile and had no evidence of hepatosplenomegaly. Complete blood count revealed hemoglobin of 12.4 g/dl, platelet count of 97 K/mm³, and leukocyte count of 3.2 K/mm³, with an absolute neutrophil count of 0.5 K/mm³. Serum electrolytes were within normal limits. Serum liver function tests showed levels that were slightly elevated, with an aspartate aminotransferase of 90 U/L, alanine aminotransferase of 63 U/L, and alkaline phosphatase of 115 U/L. His serum ferritin level was elevated at 1107.6 μg/L. Serum fasting triglyceride and plasma fibrinogen levels were within normal limits at 146 mg/dl and 195 mg/dl, respectively. His absolute NK cell value was within normal limits at 171 cell/μl, and his interleukin-2 receptor (CD25) level was elevated at 11,820 pg/ml. Polymerase chain reaction for Epstein-Barr virus (EBV) DNA revealed 6665 copies/ml. He was initially diagnosed with Guillain-Barré syndrome secondary to EBV, but oncological workup was pursued because of focal signal abnormalities discovered on neuroaxis MRI and because diffuse lymphadenopathy was present (Fig. 1). Neurosurgical consultation was requested at this point.

Brain and lumbosacral spine MR images obtained in March 2017. Left: T2-weighted FLAIR sequence of the brain showing hyperintensity within the internal auditory canal. Right: Postcontrast image of the lumbosacral spine revealing an enhancing intradural extramedullary mass lesion at the level of L1–2.

Neurological assessment revealed bilateral upper- and lower-extremity paresis with hyporeflexia and diminished lower-extremity proprioception. The patient was able to maintain continence of urine and stool. His CSF protein level was elevated at 119 mg/dl, with an opening pressure of 28 cm H₂O; however, all other CSF results were within normal limits. The result of a lymph node biopsy was considered benign, revealing sinus histiocytosis with mild paracortical hyperplasia. Bone marrow aspiration demonstrated no immunophenotypic abnormalities or evidence of malignancy. The patient received a course of intravenous immunoglobulin and rituximab under the guidance of the pediatric neurology and hematology-oncology services prior to discharge to a rehabilitation facility, with a presumptive diagnosis of Guillain-Barré syndrome and possible secondary immunological disorder.

Several weeks later, the patient returned with acutely worsening lower-extremity paraparesis and an inability to maintain bowel continence. Neuroaxis imaging revealed an intrathecal enhancing mass lesion at the level of T12–L1, with severe compression of the conus medullaris (Fig. 2). Multiple enhancing nerve roots were noted descending from the ventral thecal sac from the T12–L1 level. Additionally, there was a hyperintense T2 signal at the T6–9 levels, representing the development of a syringohydromyelia (Fig. 2). Given the degree of conus medullaris compression in combination with the patient’s acutely deteriorating clinical status, the decision was made to take the patient to the operating room for the purpose of obtaining tissue for biopsy and relieving his spinal cord compression. Once an L1–2 laminectomy was performed, a discolored dura was revealed underneath. Intraoperative ultrasound helped to confirm the location of the lesion. The dura was incised, revealing a large hemorrhagic lesion that was contained under pressure. The lesion was resected and sent for pathological analysis. Interestingly, however, frozen-section analysis of the lesion was reported as a blood clot, which prompted us to turn our attention toward further inspection of the neural structures. The conus medullaris appeared bulbous and infiltrated. Multiple nerve roots exhibited a blue discoloration, suspicious for infiltration and possible ischemic injury, as well (Fig. 3). Intraoperative nerve stimulation was performed using a hand-held stimulator; this confirmed that these nerve roots were inactive and allowed us to acquire a nerve root sample for biopsy. The patient tolerated the procedure well, and no new postoperative neurological deficits developed.

Brain and lumbosacral spine MR images obtained in August 2017. A: T2-weighted FLAIR sequence of the brain revealing regions of periventricular hyperintense signal abnormality. B and C: Axial and sagittal postcontrast sequences of the lumbosacral spine revealing an intradural extramedullary contrast-enhancing lesion at the level of L1–2 with significant compression of the conus medullaris.

Intraoperative imaging revealing discolored-appearing nerve roots of the conus medullaris (arrow).

Pathological analysis of the nerve root specimen revealed a dense atypical T-cell infiltrate. The infiltrate was positive for CD3, CD2, and granzyme B, with loss of CD5, and negative for perforin. The T-cells were predominantly CD8 positive (Fig. 4). These findings are consistent with CNS involvement of familial hemophagocytic lymphohistiocytosis. The patient was initiated on treatment with etoposide, cyclosporine A, intrathecal methotrexate, and dexamethasone. Genetic testing later revealed a compound heterozygous perforin gene mutation. The patient subsequently underwent an allogenic stem cell transplant, after which his lower-extremity strength improved dramatically, allowing him to ambulate with minimal assistance. He required a second allogenic stem cell transplant several months later, which was complicated by acute kidney injury and severe hemorrhagic cystitis. On post-transplant day 177, he suffered an acute change in mental status, followed by pulseless cardiac arrest. He achieved return of spontaneous circulation, but this resulted in severe hypoxic ischemic encephalopathy and acute respiratory distress syndrome. He ultimately died from complications of his cardiac arrest several weeks later.

Pathological slides from nerve root biopsy. Low- (A), medium- (B), and high- (C) magnification H & E–stained slides revealing dense lymphocytic infiltrate. Cells were avidly positive for S100 (D), CD3 (E), and CD163 (F).

Discussion

The pathophysiology of HLH is thought to be the result of a defect in the ability of NK cells and cytotoxic T-lymphocytes to eliminate active macrophages and lymphocytes. As a result, dysregulated cytokine production leads to tissue infiltration and destruction.^12,15 The particular cytokines frequently increased in HLH include interferon-gamma, tumor necrosis factor–alpha, interleukins, and CD25. Identification of aberrant expression of these cytokines, in addition to a constellation of clinical and laboratory findings, can be used to aid in the diagnosis of HLH, which is oftentimes challenging.

HLH can be subdivided into two broad categories: primary (genetic) HLH and secondary (acquired) HLH.^9,18 Common mutations causing primary HLH involve PRF1/perforin-1, UNC13D/Munc13-4, STX11/syntaxin-11, and STXBP3/Munc18-2. These genes encode proteins that are directly involved with the formation or exocytosis of cytolytic granules within the NK cells and cytotoxic T-cells, allowing them to eliminate their respective target cells. Familial HLH most often manifests in young children, but reports have shown this syndrome to develop in adults and even the elderly.^12,13 There are many ways in which HLH can be acquired; however, viral illness appears to be the most common, and association has been made specifically with EBV.¹⁸ In an autopsy case of EBV-associated HLH, the brain showed perivascular inflammation, with detection of EBV-encoded small RNAs in CD3-positive T cells and multiple foci of necrosis. There was especially severe involvement of the brainstem and spinal cord.¹⁶ CNS HLH is a known presentation of the disease, and many patients with neurological symptoms will undergo cranial imaging and/or CSF analysis as part of their hospital course. The most common MRI lesions include periventricular white matter signal abnormality with volume loss and ventriculomegaly.^4,5,7,12,17 Evidence of cranial nerve inflammation has also been reported on postcontrast imaging.³ CSF analysis is varied, and abnormalities are not always evident.^1,8,10 CSF analysis tends to reveal pleocytosis, a moderately elevated protein level, increased opening pressure, and hemophagocytosis.^9,17 CNS infiltration typically begins in the meninges and then induces perivascular changes. This leads to the diffuse infiltration of tissue and multifocal necrosis at a later stage in the course of the disease.⁷ It is therefore possible that neuroradiological findings may precede apparent clinical neurological manifestations. Microscopic findings are highly variable but often include accumulation of lymphocytes and macrophages, hemophagocytosis, few NK cells, and excess cytokines. Three stages of CNS HLH have been established based on these pathological findings¹¹: stage I: leptomeningeal inflammation; stage II: perivascular infiltration; and stage III: massive tissue infiltration.

The presence of CNS HLH is an important prognostic factor, making a definitive diagnosis more valuable to the patient and the physician. A study of 50 patients with HLH, including 23 with neurological symptoms, showed a statistically significant increase in mortality in patients with CNS HLH compared to those without CNS involvement.¹⁵ The cerebrum and cerebellum are predominantly affected, with lesser involvement of the brainstem and in rare cases the peripheral nerves. Relying on imaging and CSF analysis alone, however, may not be sufficient to make a strong diagnosis. In this case, biopsy of the spinal nerve roots was used to establish a definitive diagnosis, allowing for prompt initiation of the appropriate treatment.

HLH with CNS involvement may not be as rare as once thought, but spinal cord involvement is exceedingly uncommon, with only one prior case report detailing the treatment of an 11-year-old boy with lesions of the cervical and thoracic spinal cord.⁶ Postmortem analysis of a 41-year-old man with CNS HLH revealed multifocal lymphocytic inflammation, as well as necrosis, gliosis, and focal hemorrhage involving the spinal cord nerve roots.¹⁸

To our knowledge, this is the first reported case of CNS HLH presenting with diffuse neural axis involvement and diagnosis established by spinal nerve root biopsy. Early diagnosis and treatment of HLH are necessary to decrease morbidity and mortality. In our case, we used spinal nerve root biopsy to aid in the diagnosis. It is likely that there is spinal cord involvement in many patients with CNS HLH, but it is not routinely imaged. Our case highlights the variable CNS manifestations in pediatric patients with HLH and the challenges that accompany establishing diagnosis. We suggest including spinal cord imaging to accompany cranial imaging during the workup of any patient with suspected CNS HLH. From the experience of the present case, it is recommended that the diagnosis of HLH can be assisted with pathological confirmation of tissues other than bone marrow, spleen, liver, and lymph node if the patient’s clinical findings support HLH but do not meet established criteria.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Acquisition of data: Cooper, Harburg. Analysis and interpretation of data: Cooper, Harburg. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Cooper.