Brain damage resembling acute necrotizing encephalopathy as a specific manifestation of haemophagocytic lymphohistiocytosis - induced by hypersensitivity
© The Author(s). 2016
Received: 8 April 2016
Accepted: 3 August 2016
Published: 31 August 2016
Both haemophagocytic lymphohistiocytosis and acute necrotizing encephalopathy are life-threatening condition. It presents major diagnostic difficulties, since it may have a diversity in clinical picture and with many conditions leading to the same clinical presentation. So it is key important to understand the disorders.
We report a pediatric case of haemophagocytic lymphohistiocytosis with specific presentation which predominantly featured as acute necrotizing encephalopathy of childhood. We discuss the diagnosis and differential diagnosis, and speculate the etiology of haemophagocytic lymphohistiocytosis is due to hypersensitivity.
Haemophagocytic lymphohistiocytosis and brain damage in this case may be induced by hypersensitivity, which have good clinical outcome if diagnosed and treated early.
Hemophagocytic lymphohistiocytosis (HLH) was first reported by Risdall et al. . It is a life-threatening condition that can rapidly deteriorate and lead to multiple organ failure and death . Cardinal symptoms of HLH are prolonged fever, hepatosplenomegaly and cytopenias, and characteristic laboratory findings in HLH include hyperferritinemia, hypertriglyceridemia, cytopenia, hypoalbuminemia, decreased fibrinogen, hypercholesterolemia, and abnormal liver function .
Acute necrotizing encephalopathy of childhood (ANEC) represents an entity of acute encephalopathy which manifests with symptoms of coma, convulsions, and hyperpyrexia . This disease is associated with severe neurological sequelae and profoundly high mortality . ANEC is characterized by multiple and symmetrical lesions with edema and necrosis in the thalamus, the cerebral and cerebellar medulla, and the brainstem tegmentum .
Haemophagocytic lymphohistiocytosis and acute necrotizing encephalopathy of childhood are life-threatening conditions with severe consequences and high mortality. It is key important to understand the disorders. The present paper describes the case of a 3-month-old boy presenting with characteristic manifestation resembling acute necrotizing encephalopathy of childhood associated with hemophagocytic lymphohistiocytosis, which was thought due to allergic reaction.
The 3-month-old boy, the only child of non-consanguineous parents, was hospitalized in Shenzhen Children's Hospital because of persistent fever and skin rash for more than two weeks, resistant to conventional therapy. He had no cough, vomiting, lethargy or irritability. His past history included allergic rashes, and his mother suffered allergic reaction. There was no HLH patient in his family.
The main laboratory parameters detected in this patient
Anti-cyclic-citrullinated peptide antibody
Antineutrophil cytoplasmic antiboby
Anti jo-1 antibody
Anti-double-stranded dna antibody
Anti-SS A antibody
Anti-SS B antibody
CD3+ T cell
68 % ± 10.7 %
CD4+ T cell
31.5 % ± 8.8 %
CD8+ T cell
25.7 % ± 6.5 %
CD19 B cell
15.6 % ± 5.8 %
5.6 % - 31 %
1.5 ± 0.5
3.22 – 14.0 g/L
0.57 – 1.41 g/L
0.24 – 1.79 g/L
0.8 – 1.6 g/L
0.1 – 0.4 g/L
0 – 20 KIU/L
9 – 30 umol/L
0.7 – 2.1 mmol/L
Activated partial thromboplastin time
26.1 – 40.73 s
29.7a, over the upper limit of detectionb
9.3 –12.9 s
12.8a, over the upper limit of detectionb
International normalized ratio
0.72 – 1.15
1.09a, over the upper limit of detectionb
13.2 – 20.1 s
20a, over the upper limit of detectionb
1.57 – 3.93 g/L
Blood lipid levels
3.1 – 5.8 mmol/L
0.23 – 1.7 mmol/L
High density lipoprotein
0.9 – 1.8 g/L
Low density lipoprotein
2.07 – 4.1 g/L
22 – 322 ng/ml
Values of eosinophils
0.02 – 0.5 × 109/L
0.26a, 4.01c, 0.01d
Variations of the HLH related genes and the references 
c.900C > T p.His300His
c.117 + 59C > T
c.279C > T p.Pro93Pro
c.388 + 122C > T
c.888G > C p.Pro296Pro
c.1596 + 36A > G
c.1728-48 T > C
c.1977C > T p.Thr659Thr
c.2299-46C > T
c.2709 + 48C > T
c.3198A > G.Glu1066Glu
c.38-7C > T
c.816 C > T p.Ser272Ser
c.1247-43 T > C
c.1356 + 18A > G
c.1443 T > C .Asp481Asp
c.1696 + 28G > C
c.1696 + 77G > A
c.1697-26 T > G
c.1099 + 264G > C
c.*12A > G
The diagnosis of hemophagocytic lymphohistiocytosis and acute necrotizing encephalopathy was made based on the above findings. The HLH-2004 treatment protocol was used once diagnosis made. The clinical symptoms were rapidly improved. Followed up to 3½ years old, he was well. The neurological image (MRI) showed slightly abnormal shape of bi-lateral ventricular, not any other obvious abnormal noticed.
HLH may occur either as a primary condition with a genetic mutation or as a secondary condition associated with an infection, immunologic disorder, malignancy, or metabolic disease [6–8]. This patient presented with persistent fever, skin rash, ensuing hypersensitive to all blood products, hepatosplenomegaly, pancytopenia, and central nervous symptoms. He fulfilled 5 of the 8 criteria for acquired HLH . Hemophagocytosis is one of the criteria and reported to be negative at diagnosis in about 20-25 % of cases as reported before and more recently in a case series [10, 11]. As some researcher reported that the repetitive bone marrow aspirations may reveal hemophagocytosis in the further course . No hemophagocytosis was detected in the first four bone marrows in this case, but the fifth bone marrow biopsy displayed large amount of hemophagocytic histiocytes. It is important to note that the diagnosis of HLH does not depend on this morphological finding. The genes relevant to familial HLH (FHLH) including PRF1, UNC13D, STX11, STXBP2 , were analyzed to confirm the mutations, as well the genes related to immune deficiency syndromes associated with HLH: XIAP and SH2D1A [3, 13]. Sequencing results showed that all these variations were synonymous or in intron region and untranslated region. Analysis of the genetic data revealed that no variation was likely to produce modified amino acid sequence, thus to cause a severe impairment of protein function in this patient, with addition of the fact that there was no HLH patient or consanguinity in his family. This information is therefore relevant in that it is not likely to be genetic HLH.
This patient presented with neck stiffness, convulsion and light coma; and the severe lesions of brain MRI showed changes mainly in thalamus, basal ganglia, brainstem and white matter as described in patients with ANEC [14, 15], which is characterized by multiple and symmetrical lesions with edema and necrosis in the thalamus, the cerebral and cerebellar medulla, and the brainstem tegmentum [4, 16], which evoked the diagnosis of acute necrotizing encephalopathy of childhood. The clinical feature of typical ANEC is fulminant, with severe neurologic sequelae and profoundly high mortality . However, the discrepancy between the severe MRI findings, the relatively mild neurological manifestations, and the unexpected clinical outcome was not consistent with ANEC. We speculated that the brain damage was not true ANEC, but it was caused by transient ischemia induced by allergic vasculitis due to hypersensitivity. The extensive allergic vasculitis involves central nerve system, and extravasation of plasma takes place secondary to local vascular lesions. This is followed by destruction and necrosis of glial cells and neurons . The neurological signs were improved promptly with the subsiding of hypersensitivity, which gave a good interpretation to our speculation.
The central nervous system (CNS) involvement was reported in about a third of the children with HLH, which could easily be misdiagnosed in many children because its radiologic manifestations are nonspecific and overlap with various infectious and inflammatory disorders. Therefore, differential diagnosis of resembling diseases is very important for this patient. A wide range of disorders should be considered in the differential diagnosis, including Leigh disease, hypoxic-ischemic encephalopathy, viral encephalitis, hemorrhagic encephalitis, acute disseminated encephalomyelitis, and Reye syndrome. First of all, the brain damages focused on thalami and brainstem was not consistent with CNS involvement in HLH . Absence of inflammatory cells in cerebrospinal fluid and the symmetric brain lesions in this case differentiates from the entities of acute disseminated encephalomyelitis and acute hemorrhagic encephalitis. Reye syndrome can be excluded by hyperammonemia, hypoglycemia, and lactic acidosis absent in this case , as well as Leigh disease. The differentiation from hypoxic-ischemic encephalopathy presented much more difficulty in this patient. In spite of shocks, the oxygen saturation, heart rate and blood pressure were corrected quickly, which did not influence cerebral perfusion severely. Moreover, the imaging findings could not explain hypoxic-ischemic brain damage which focuses on obscuration of grey-white matter junctions and widespread laminar necrosis of the cortex . Furthermore, certain viral encephalitis may be difficult to exclude clinically e.g. Japanese encephalitis may also involve the deep gray matter symmetrically. However, the involvement of the brain stem is uncommon in Japanese encephalitis, and thalamic involvement is not necessarily symmetrical .
The etiologies of acquired HLH and ANEC were suggested to be associated with infectious, metabolic, immune related causes [6, 7, 15], and hypersensitivity was more recently reported to be complicated by hemophagocytic lymphohistiocytosis in a case series [22–24]. This boy did not meet the diagnostic criteria of systemic lupus erythematosus , and there was no arthritis during the disease course so he was not consistent with the diagnosis of juvenile idiopathic arthritis ; moreover, there was not any evidence of scleroderma and mixed connective tissue disease, though he was detected anti-nuclear and anti-neutrophil auto-antibodies and severe pancytopenia. He suffered allergy in his past and had positive allergy family history; eosinophils and IgE significantly elevated after IVIG and blood transfusion then gradually declined followed steroids; furthermore, he was hypersensitive to all kinds of blood and blood products, and subsequently, developed cytopenias. All above, it led us to speculate that allergic reaction was involved in the pathogenesis of HLH and brain lesions in this patient. This was never reported previously.
Increase of eosinophils and reaction to blood products suggests type I, II and III hypersensitivity was involved in the pathogenesis in this case. Hypersensitivity and HLH appear somewhat similar, being characterized by activated lymphocytes and hypercytokinemia . Hypersensitivity results in hypercytokinemia, leading to uncontrolled activation of benign scavenger macrophages and development of hemophagocytosis . The pathogenesis of HLH involves the dysfunction of natural killer (NK) cells and cytotoxic T cells leading to prolonged and intense activation of antigen-processing cells (macrophages and histiocytes)  and CD8+ T cells, and excessive proliferation and ectopic migration of T cells, which triggers overproduction of proinflammatory cytokines, and unrestrained hemophagocytosis . It is suggested that cell destruction by cytotoxic antibodies and a reversible depression of stem cell activity with myeloid maturation blockade contribute to the pathophysiology of the cytopenias. The deposited immune complexes can trigger neutrophils to release free radicals and enzymes causing tissue destruction, which can lead to endothelial cell necrosis . Hypercytokinemia and the hyperpermeability of both the blood-brain barrier and the capillary walls of the central nervous system might be essential in the pathogenesis of acute necrotizing encephalopathy .
Hemophagocytic lymphohistiocytosis has a poor prognosis . Patients with secondary HLH have had only a 55 % survival at 3 years . This boy was followed up regularly after continuation therapy. Followed up to 3½ years old, he is doing well; there is not any symptom that could be due to central nervous system dysfunction; the routine blood count, blood lipid level, liver function and ferritin were normal, and the bone marrow cytology demonstrated sustained remissions. The neurological image (MRI) showed no obvious abnormal.
This is a rare case of hemophagocytic lymphohistiocytosis, with specific presentation resembling ANEC. Hypersensitivity may involve in the etiologies of HLH and brain damage, which have good clinical and neurologic outcome if treated early. From this study, we should have the awareness of such a rare disease as delay of diagnosis and treatment is common with subsequent poor outcome. Early diagnosis is crucial to reduce mortality rates. It is of importance to know that hypersensitivity may result in HLH and brain damage resembling ANEC from the findings in this study.
ANEC, acute necrotizing encephalopathy of childhood; CNS, central nervous system; DNA, deoxyribose nucleic acid; HLH, hemophagocytic lymphohistiocytosis; Ig, immunoglobulin; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging; NK, natural killer; PICU, pediatric intensive care unit
The authors wish to thank the patient and their families for allowing us to use the medical documentation and information leading to the present article, and we wish to thank Dr Philippa Mills (PhD, Lecturer in Metabolic pediatrics, Biochemistry Research Group, Clinical & Molecular Genetics Unit, Institute of Child Health & Great Ormond Street Hospital for Sick Children, University College London) for assistance to gene analysis, Gang Xu (M.D, Clinical Laboratory Department of Shenzhen Children's Hospital) for marrow cytology inspection, technical and material support, and Dr Weiguo Cao (M.D, Radiologist, Radiology Department of Shenzhen Children's Hospital) for imaging technical assistance. There is not any conflict of interest for both Dr Philippa Mills, Gang Xu and Weiguo Cao.
This study was funded by Shenzhen Innovation and Technology Committee (Grant number CXZZ20130320172336579).
Availability of data and materials
The dataset(s) supporting the conclusions of this article is (are) included within the article.
DD: writing of manuscript, critical revision of the manuscript. DD and SL: caring for the patients, performing the treatment protocol, and data collection. FW: study concept and design. SZ: analysis and interpretation of data. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Signed consent was obtained from the parents for analysis of DNA samples from their child, for publication of the case report and any accompanying images.
Ethics approval and consent to participate
This study was approved by Research Ethics Committee of Shenzhen Children’s Hospital (Reference Number: SCH ethical (article) 2016 (002)).
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