A 12-year-old female patient with a history of sickle beta thalassaemia presented to the emergency department with a presumed pain crisis. During her hospitalisation, she rapidly deteriorated, developing respiratory distress requiring intubation, seizures, hyperthermia unresponsive to antipyretics, and acute encephalopathy.
On MRI of the brain, there were several punctate and confluent areas of diffusion restriction with associated T2/FLAIR hyperintensity in the supratentorial and infratentorial compartments, including the splenium of the corpus callosum, middle cerebellar peduncles, and centrum semi-ovale (Figs. 1 and 2). There were also innumerable punctate foci of magnetic susceptibility scattered throughout the white matter of both hemispheres (Fig. 3). No abnormal parenchymal or leptomeningeal enhancement was seen, but mild pachymeningeal enhancement was seen.
Background: Haemophagocytic lymphohistiocytosis (HLH) is a rapidly progressive lethal disease of unregulated immune system activation. Overproduction of proinflammatory cytokines along with mass recruitment of macrophages and T-cells create a hypercellular infammatory environment. Histiocytes with haemophagocytosis proliferate throughout multiple organ systems, causing widespread dysfunction . There are primary familial cases which present in an autosomal recessive fashion as well as secondary reactive cases, found in immunocompromised individuals, many with infectious and malignant aetiologies . The patient in this case carried a diagnosis of sickle cell disease and beta thalassaemia, and she had an extensive history of hospital admissions for pain crises.
Clinical Perspective: The patients present with nonspecific symptoms, making the diagnosis of HLH a challenge. Additionally, as this disease is found frequently in patients who already have severe conditions, the list of differentials for these patients is oftentimes long and the rareness of HLH places is low on the differential list. The current criteria require 5 out of the 8 diagnostic criteria be met. Criteria include fever, splenomegaly, peripheral blood cytopenia of at least two lines, hypertriglyceridaemia, haemophagocytosis, low or absent NK-cell activity, ferritin >500 ng/mL, or elevated soluble CD25 . There is frequent involvement of the central nervous system; an estimated 30% of patients will have neurologic symptoms. Seizures, altered levels of consciousness, ataxia, and coma have been reported . The patient in this case developed neurological storming and eventual encephalopathy.
Imaging Perspective: CT and MRIs are useful for supporting a diagnosis of HLH. On MRI, parenchymal volume loss and and focal necrosis with perivascular and leptomeningeal enhancement may be found. The hypercellularity and oedema present as diffusion restricting lesions . On CT atrophy and focal hypodensities are found. Signs of nonspecific inflammation are frequently observed . The diffusion restriction in our case, while nonspecific, was favoured to represent neuronal loss and cytotoxic oedema . Innumerable foci of haemosiderin/haemorrhagic degradation products are seen on susceptibility weight imaging. These imaging findings overlap significantly with those of cerebral fat embolism, which can also occur during sickle cell crisis and may be indistinguishable. However, HLH is considered more likely as the patient met clinical criteria and had haemophagocytosis on bone marrow-biopsy. In addition, none of the lesions demonstrated inherent T1-hyperintense signal to suggest macroscopic fat.
Outcome: While there is often a delay in diagnosis due to comorbidities and nonspecific symptoms, even with early intervention HLH remains a lethal syndrome and mortality is high . Current standard of care follows the HLH-94 protocol, which consists of dexamethasone, etoposide, methotrexate, and hydrocortisone along with supportive care . However, 30% of patients do not respond to this treatment protocol . Allogenic haematopoietic cell transplant has also shown success as a long-term cure . Imaging findings may support the diagnosis and offer a modality to assess disease progression and treatment success.
Written patient consent for this case was waived by the Editorial Board. Patient data may have been modified to ensure patient anonymity.
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