Hemophagocytic lymphohistiocytosis (HLH), which may be familial or acquired, is a severe inflammatory disorder caused by disruption of T-cell function that triggers a state of hypercytokinemia, resulting in a highly stimulated but ineffective immune response. Downbeat nystagmus (DBN) is an uncommon disorder of ocular motility that typically localizes to the posterior fossa, particularly the cervicomedullary junction. We are unaware of previous reports of DBN occurring in the setting of HLH.
A previously healthy ex-full-term 10-month-old dizygotic twin girl was brought by her parents to the emergency department for second opinion after suffering 2 months of intermittent fevers to 40.5°C, diarrhea, and progressive abdominal distension. Previously, she had been hospitalized for intensive supportive care including empiric intravenous ceftazidime and gentamicin. Her course had been further complicated by hepatosplenomegaly, lymphadenopathy, and disseminated intravascular coagulation. Because of new-onset strabismus, the ophthalmology service was consulted.
On examination, the patient was hypotonic with open and flat anterior fontanelles. She could fix and follow with each eye but had a marked abduction deficit with saccadic slowing of the left eye. Pupils were equal and reactive without a relative afferent defect. The anterior and posterior segments were normal. The examination was most notable for prominent primary position downbeat nystagmus (DBN).
Laboratory testing demonstrated a white blood cell count of 5,400/cm3 (normal: 6,000–17,500/cm3), hemoglobin of 8.5 g/dL (normal: 9.5–13.5 g/dL), platelet count of 134,000/cm3 (normal: 165,000–415,000/cm3), mild hyponatremia, and normal hepatic function tests. Erythrocyte sedimentation rate was 120 mm/hr, triglycerides 1,065 mg/dL (normal: 30–200 mg/dL), and fibrinogen 151 mg/dL (normal: 99–466 mg/dL). Opening pressure on lumbar puncture was normal, and cerebrospinal fluid (CSF) analysis showed a polyclonal, predominantly T-cell population highlighted with CD45 gating. Cultures for bacteria and fungus and parasitology studies were negative; polymerase chain reaction for cytomegalovirus, Epstein–Barr virus and Parvovirus B19 was negative. Further testing revealed increased ferritin of 2,284 ng/mL (normal: 10–150 ng/mL), increased mean channel fluorescence of perforin in natural killer (NK) cells, absent NK cell function, cell function, decreased NKT cells, increased CD8 T lymphocytes (26%; normal: 0%–4%), and increased slL-2 receptor (CD25) (>3000; normal: 0–1033).
Magnetic resonance imaging (MRI) of the brain showed diffuse cerebral atrophy with mild increase in cerebellar volume (Fig. 1A) and leptomeningeal enhancement of the cerebellum (Fig. 1B). The cerebellar tonsils were low-lying and crowded with decreased CSF space at the cervicomedullary junction, but no Arnold-Chiari malformation was noted.
Bone marrow aspirate demonstrated hemophagocytosis (Fig. 2A) with increased bone marrow macrophages (Fig. 2B). Results of flow cytometry from the bone marrow were similar to those obtained from the CSF.
Genetic testing revealed a mutation in the STXBP2 gene with normal UNC13D. There was no known history of consanguinity in the parents.
The patient was treated with etoposide and dexamethasone, and, after 48 hours, there was improvement in mental status with resolution of DBN and the left sixth nerve palsy. Follow-up MRI revealed decreased cerebellar swelling (Fig. 3). The patient received an allogenic hematopoietic stem cell transplant (HSCT) 6 months after the initial presentation and had 90% engraftment with normal antibody titers 18 months later.
Hemophagocytic lymphohistiocytosis (HLH) is part of a heterogeneous group of disorders initially described in 1952 by Farquhar and Claireaux (1). The frequency of this disorder is difficult to assess but estimated as 1 in 50,000–100,000 live births (2,3). On the molecular level, familial forms of the disorder often are caused by defects in perforin or other proteins involved in granule-dependent cytotoxicity (4–7). NK and cytotoxic T lymphocytes normally store perforin and granzyme proteins in specialized secretory lysosomes that are released upon encountering a target cell, leading to target cell apoptosis (8). When this mechanism is dysfunctional, there is an abnormal and excessive production of T-cell–derived cytokines (“cytokine storm”) leading to uncontrolled accumulation of activated T lymphocytes and activated histiocytes (macrophages) in various tissues, resulting in hemophagocytosis and organ damage (8–10).
Genetic defects in familial hemophagocytic lymphohistiocytosis (fHLH) are autosomal recessive and continue to expand. Currently, 5 genetic loci (FHL 1–5) have been identified (9). FHL1 encodes an as-yet unidentified protein. FHL2 accounts for up to one-third of fHLH cases because of defects in PRF1 (perforin), a cytolytic protein used by NK and cytotoxic T lymphocytes. Perforin polarizes to the plasma membrane of target cells, delivering cytotoxic enzymes (granzymes) to the target cell, inducing apoptosis. Other genetic loci in fHLH encode proteins facilitating delivery of perforin to target cells, including a priming factor munc13-4 (UNC13D), and membrane fusion proteins syntaxin 11 (STX11) and munc18-2 (STXBP2).
The clinical syndrome of HLH also can be trigged by infection, autoimmune disease, and malignancy, and are designated acquired HLH (7,11). Macrophage activation syndrome typically is used to designate HLH due to autoimmune diseases, particularly juvenile arthritis and systemic lupus erythematosus (11,12). The pathophysiologic mechanism of acquired HLH is not well understood; as genetic testing has improved, it has become evident that some cases may in fact represent fHLH (13). Interestingly, the same conditions associated with acquired HLH can trigger it in familial forms. Given the increasingly blurred distinction between familial and acquired forms of HLH, some believe that the syndrome should not be classified into distinct subtypes. Rather, there may be a continuum of risk to developing HLH, including both genetic and environmental factors (14).
Regardless of etiology, HLH remains a syndrome diagnosed by a unique pattern of clinical findings. HLH diagnostic guidelines have been published (15) (Table 1) and our patient exhibited 7 of the 8 diagnostic criteria: fever, splenomegaly, hypertriglyceridemia, hemophagocytosis, absent NK cell activity, elevated ferritin, and elevated soluble interleukin-2 receptor.
Although not listed as part of the diagnostic criteria, neurological symptoms can predominate the initial clinical presentation of HLH. Deiva et al (16) reported that approximately 63% of children have neurologic symptoms at the onset of fHLH, including irritability, seizures, impaired consciousness, meningismus, and cranial nerve palsies. Parenchymal edema of the brain, which may occur in HLH, can affect the cerebellum (17,18). In the most extreme cases, this can lead to fatal tonsillar herniation.
Neuropathologic staging of HLH has been established and correlated with clinical manifestations: Stage 1—leptomeningeal infiltrates of lymphocytes and histiocytes; Stage 2—adjacent parenchymal involvement with perivascular infiltration; Stage 3—massive parenchymal infiltration via lymphocytes and histiocytes, with tissue necrosis (19). These cellular changes lead to neuroimaging findings, including edema, focal areas of necrosis with parenchymal volume loss, diffuse white matter abnormalities, and leptomeningeal or perivascular enhancement (20).
There is a single report of vertical nystagmus in a patient with HLH (21). This occurred in a 13-month-old boy accompanied by a bulging fontanelles, papilledema, and CSF pleocytosis. Computed tomography of the brain showed “no specific abnormality,” and the patient's condition improved with steroid therapy.
Treatment of HLH to stabilize signs and symptoms involves the use of immunosuppressive agents, including dexamethasone, etoposide, cyclosporine A, and intrathecal methotrexate (15). Curative therapy is HSCT (22). Even with HSCT, the estimated overall 3-year probability of survival has been reported at approximately 64% (15). Reduced-intensity conditioning HSCT has significantly improved survival, with the current reports of approximately 92% survival at 3 years (23). Despite these recent advances, untreated HLH is still a rapidly fatal disease that warrants urgent diagnosis and intervention.
Our case is unique in both documenting the occurrence of DBN in HLH and the resolution of DBN with treatment of cerebellar edema.
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