Secondary Hemophagocytic Lymphohistiocytosis Causing Hemorrhagic Encephalomyelitis and Spinal Subarachnoid Hemorrhage: A Case Report

Abstract

We are writing to present an interesting and novel case from our practice of a patient who presented with altered mental status and a rapidly progressive paraplegia as well as high fevers and pancytopenia. A bone marrow biopsy was diagnostic of hemophagocytic lymphohistiocytosis (HLH) and MRI showed hemorrhagic encephalitis and spinal subarachnoid hemorrhage. This case demonstrates the diverse neurological symptoms with which HLH presents, including spinal cord pathology. The astute neurologist should consider this diagnosis in the appropriate clinical context and diagnosis may require imaging to the complete neuraxis.

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder causing uncontrolled systemic immune activation and subsequent inflammatory response, more often seen in the pediatric population but also reported in adults. Fever, pancytopenia and hyperferritinemia are among the classic features of this disease. Neurological symptoms, when present, are variable and can be the lone presenting feature. In the adult population, involvement of the spinal cord has not been described. This is a case of a woman with HLH secondary to Erlichiosis who presented with altered mental status and a rapidly progressive paraplegia with a thoracic sensory level due to hemorrhagic encephalomyelitis and spinal subarachnoid hemorrhage. These findings have not previously been described in adult HLH and illustrate the broad spectrum of potential neurological involvement as well as the need to consider complete imaging of the neuraxis in appropriate cases. Informed consent was obtained from the patient.

Case

A 59-year-old woman with a history of chronic fatigue syndrome presented to the hospital with several days of worsening abdominal pain, fevers, confusion and bilateral lower extremity weakness 10 days after a tick bite. Her exam was significant for fluctuating mental status, severe abulia, and paraparesis which rapidly progressed to flaccid paraplegia with a thoracic sensory level.

Basic laboratory testing revealed pancytopenia and transaminitis and a mild coagulopathy, raising concern for an undiagnosed hematologic malignancy. Cerebrospinal fluid showed elevated RBC count with xanthochromia. Work-up for potential infectious etiologies was positive for Ehrlichia chaffeensis IgM and IgG and PCR. Further studies revealed markedly elevated LDH, ferritin, D-dimer, triglycerides and soluble IL-2. Fibrinogen was decreased and natural killer cell activity was normal. She was started on doxycycline for Ehrlichiosis without improvement in her neurological status.

Magnetic Resonance Imaging (MRI) of the brain showed (Figure 1) showed trace intraventricular hemorrhage, sulcal hyperintensity while MRI of the spine showed non-compressive subarachnoid hemorrhage (SAH) at the level of T6-T10 (Figure 2A-D). There was cord signal abnormality extending from T5-T8 with subtle enhancement of the cauda equina. Continuous electroencephalogram monitoring showed diffuse slowing consistent with encephalopathy. A differential diagnosis for hemorrhagic encephalomyelitis included hemorrhagic neoplasm, demyelinating lesions (neuromyelitis optica, anti-MOG associated syndrome), para-infectious/acute disseminated encephalomyelitis, infection (VZV, HSV, HTLV, TB), and vascular malformation. Testing for infectious etiologies was negative and cerebrospinal fluid analysis showed negative cytology and 5 oligoclonal bands and a normal IgG CSF: serum ratio.

Figure 1.

A, Susceptibility weighted imaging of the brain demonstrating a small amount of intraventricular hemorrhage within the bilateral occipital horns. B, T2 fluid attenuated inversion recovery (FLAIR) sequence of the brain demonstrating increased signal within the sulci in the parieto-occipital lobes as well as hyperintensities within the periventricular white matter.

Figure 2.

A, T1 compiled image of the full spine. B and C, T2 images of the cervical/upper thoracic and lower thoracic/lumbar spine respectively. There is a posterior intraspinal extramedullary loculated fluid collection extending from T6-7 to T10 levels causing mild abutment in the posterior aspect of the cord. Additional subarachnoid hemorrhage is seen posteriorly on the left from L3-L5 levels. An anterior epidural fluid collection is present at L4-L5. Arrows indicate areas of interest. D, Progression of thoracic lesion seen on T2-weighted sequence.

As the patient’s sensory level extended caudally, repeat MRI revealed persistent thoracic SAH and expansion of cord T2 hyperintensity from T2-3 to the conus medullaris with associated areas of restricted diffusion in the lower thoracic cord consistent with infarction (Figure 2D). A spinal magnetic resonance angiogram as well as a conventional digital subtraction angiography were performed and did not show evidence of a vascular malformation.

Bone marrow biopsy showed hemophagocytosis (Figure 3A-D). An H score was 178, consistent with hemophagocytic lymphohistiocytosis (HLH). She was started on dexamethasone and etoposide. Her mentation returned to baseline. However, she remained paraplegic. Follow-up MRI of the spine showed a decrease in spinal cord edema.

Figure 3.

A, H&E stained sections of the core biopsy showing normocellular bone marrow for the age of the patient with intact maturation of granulocytic and erythroid series. B, H&E stained sections of the core biopsy (×20) shows a prominence of histiocytes, some of which show hemophagocytosis. No granulomas or lymphoid aggregates are identified. C and D, H&E stained smear of bone marrow aspirate (×60) showing spiculated smear with myeloid: erythroid ratio within the normal range. Full spectrum maturation is seen in the granulocytic and erythroid series with no dyspoiesis or increase in blasts. Frequent histocytes containing erythrocytes, platelets, neutrophils and lymphocytes are identified (black arrows).

Discussion

Hemophagocytic lymphohistiocytosis is a rare and life-threatening syndrome of uncontrolled inflammatory response. In adults HLH is often secondary to malignancy, most of which are hematologic. Other etiologies include drugs, autoimmune disease, or infections. ¹ Rickettsial species such as Ehrlichia have previously been reported in association with secondary HLH. ¹ Dysfunction in cytotoxic CD8+ T-cells or NK cells leads to ineffective killing and inability to clear antigenic stimuli which causes an amplified immune response, leading to cytokine release and macrophage activation with resultant organ damage. ¹

HLH presents as a febrile illness with multi-system involvement. Diagnostic criteria include fever, splenomegaly, cytopenia affecting two or more cell lines, hypertriglyceridemia and/or hypofibrinoginemia, low or absent NK cell activity, elevated ferritin, elevated soluble IL-2. Decreased NK cell activity is common, reported in up to 67% of adult cases. Additionally hemophagocytosis in bone marrow, spleen or lymph nodes is required for diagnosis, thus necessitating tissue biopsy. ¹ Reported neurological presentations include meningitis, encephalitis, coma, seizures, ataxia, headache, psychiatric symptoms, cranial nerve palsies and hypotonia.^1,2 Neurological symptoms are less frequently reported in adults with an estimated incidence of 9%-25%. ¹ Histological studies have reported a spectrum of CNS involvement, ranging from subtle leptomeningeal lymphohistiocytic infiltrates to necrotizing infiltration of the meninges and brain. ³ CNS involvement of HLH may be due to direct infiltration of activated macrophages. ³ Treatment of HLH in adults typically consists of an 8-week course of etoposide and dexamethasone as well as disease-specific treatment if secondary HLH. ¹ Cyclosporine may be added to the regimen and intrathecal chemotherapy may be considered for severe CNS disease. Additional considerations include emapalumab, a monoclonal antibody against interferon-γ, for refractory or progressive disease as well as bone marrow transplant once stabilized. ¹

Spinal cord involvement seems rare. A recent case of a 17-year-old presenting with bilateral paraparesis was found to have both a compressive intrathecal lesion at the level of T12-L1 and T6-9 syringohydromyelia. Biopsy of this compressive lesion demonstrated blood clot within the intradural space. A spinal nerve root biopsy was diagnostic for HLH. ⁴ An adult case of nerve root involvement seen in autopsy has been reported; however, no cord involvement was noted. ⁵ Intracranial SAH has been previously reported in HLH, as a late effect following treatment, or a finding noted on autopsy.^6,7 While one such case was aneurysmal, a mechanism for SAH was not proposed in most reports. ⁶ Our patient may represent the first reported adult case of hemorrhagic encephalomyelitis with spinal SAH in HLH, although without CNS tissue biopsy we lack 100% diagnostic certainty.

Regarding possible mechanisms for spinal SAH, we considered spontaneous bleeding or bleeding of an occult vascular lesion, perhaps in the setting of thrombocytopenia and increased intracranial pressure due to vomiting. Both MR and digital subtraction angiography were negative, making an underlying lesion unlikely. Lumbar puncture can result in spinal SAH, however, xanthochromia was already present at the time of testing. Given that there was no evidence of cord compression, it is unlikely that the spinal SAH caused cord signal changes seen on MRI. A more likely possibility is a necrotic inflammatory thoracic lesion, causing bleeding into the subarachnoid space. This process would be consistent with other histological reports of brain and meningeal necrosis in HLH. We also considered that these findings may have been related to Ehrlichiosis but were unable to find reports of subarachnoid hemorrhage or myelitis attributed to Ehrlichia. It is possible that these findings were due to an infectious or para-infectious etiology, though a thorough investigation of potential causes was unrevealing.

This case demonstrates that hemorrhagic encephalomyelitis may be a rare but significant complication of HLH. Given the unexpected involvement of the spinal cord, this case also illustrates that complete neuraxis imaging may be needed.