Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem condition associated with uncontrolled overproduction and infiltration of lymphocytes and histiocytes predominantly in liver, lymph nodes, spleen, and central nervous system. Neuroimaging findings on MRI are fairly nonspecific and classically include periventricular white matter signal abnormalities and diffuse atrophy. Focal parenchymal lesions may demonstrate post contrast ring or nodular enhancement and calcification. However, the MR imaging characteristics can be highly variable. Here, we present two cases of HLH in infants with multiple hemorrhagic lesions mostly depicted in both thalami and basal ganglia regions. Thalamic, basal ganglia, and brain stem involvement with hemorrhagic changes in HLH are rarely described in literature. Early diagnosis of HLH may be lifesaving. Awareness of the disease is necessary to investigate its characteristic findings and avoiding a delay in diagnosis

de Vries, Andrica C. H.

Dremmen, Marjolein H. G.

Hunfeld, Maayke A. W.

Kroon, Andre A.

Lequin, Maarten H.

Neuteboom, Rinze F.

Pak, Neda

Selehnia, Anseh

Utrecht University Repository

SHORT REPORTAtypical neuroimaging characteristics of hemophagocyticlymphohistiocytosis in infants: a case series of hemorrhagic brainlesions in the deep grey matterNeda Pak1,2 & Anseh Selehnia2 & Maayke A. W. Hunfeld3 & Maarten H. Lequin4 & Rinze F. Neuteboom3 &Andrica C. H. de Vries5 & Andre A. Kroon6 & Marjolein H. G. Dremmen1Received: 30 July 2020 /Accepted: 27 October 2020# The Author(s) 2020AbstractHemophagocytic lymphohistiocytosis (HLH) is a rare multisystem condition associated with uncontrolled overproduction andinfiltration of lymphocytes and histiocytes predominantly in liver, lymph nodes, spleen, and central nervous system.Neuroimaging findings on MRI are fairly nonspecific and classically include periventricular white matter signal abnormalitiesand diffuse atrophy. Focal parenchymal lesions may demonstrate post contrast ring or nodular enhancement and calcification.However, the MR imaging characteristics can be highly variable. Here, we present two cases of HLH in infants with multiplehemorrhagic lesions mostly depicted in both thalami and basal ganglia regions. Thalamic, basal ganglia, and brain stem involve-ment with hemorrhagic changes in HLH are rarely described in literature. Early diagnosis of HLHmay be lifesaving. Awarenessof the disease is necessary to investigate its characteristic findings and avoiding a delay in diagnosis.Keywords Hemophagocytic lymphohistiocytosis .MRI brain . InfantIntroductionHemophagocytic lymphohistiocytosis (HLH) is an uncom-mon life-threatening hematologic disease more prevalent inchildren than in adults. The factual incidence is unknowndue to difficulties in identifying the disease. An estimatedprevalence of pediatric HLH cases is 1.07/100,000 [1]. Thedisease is characterized by uncontrolled overproduction andinfiltration of lymphocytes and histiocytes. HLH typically in-volves multiple organ systems and predominantly affects theliver, spleen, lymph nodes, and the central nervous system(CNS) [1]. The primary form of HLH is familial (autosomalrecessive or X-linked) and occurs in infants with predisposinginherited immune deficiencies. In addition, “acquired” HLHcan be seen in older children secondary due to infection, au-toimmune disease, immunosuppression, and malignancies [1,2]. The diagnosis of HLH requires five out of eight definedclinical and laboratory criteria to be fulfilled as defined by theHistiocyte Society: fever, splenomegaly, cytopenia, hypertri-glyceridemia, hemophagocytosis, low or absent NK-cell ac-tivity, elevated ferritin, and elevated soluble CD25 [1]. CNSinvolvement is frequent and is one of the major causes ofmortality in HLH patients [1, 2]. Variable neurologic mani-festations such as seizures, cranial nerve palsies, ataxia, nys-tagmus, irritability, depressed consciousness level, and hypo-tonia have been reported [3].Neuroimaging findings typically are not very specific andinclude periventricular white matter signal abnormalities andring or nodular enhancement of focal parenchymal lesions onMR imaging [4]. Involvement of deep gray matter and hem-orrhagic lesions are rare findings in HLH disease [5].* Marjolein H. G. Dremmenm.dremmen@erasmusmc.nl1 Department of Radiology & Nuclear Medicine, Erasmus MedicalCenter—Sophia Children’s Hospital,P.O. Box 2060CB 3000 Rotterdam, The Netherlands2 Department of Radiology, Tehran University of MedicalSciences—Children’s Medical Center, Tehran, Iran3 Department of Neurology, Erasmus Medical Center—SophiaChildren’s Hospital, Rotterdam, The Netherlands4 Department of Radiology, University Medical CenterUtrecht—Wilhelmina Children’s Hospital, Utrecht, The Netherlands5 Department of Pediatrics, Erasmus Medical Center—SophiaChildren’s Hospital, Rotterdam, The Netherlands6 Department of Neonatology, Erasmus Medical Center—SophiaChildren’s Hospital, Rotterdam, The Netherlandshttps://doi.org/10.1007/s00234-020-02595-6/ Published online: 6 November 2020Neuroradiology (2021) 63:285–288This review presents two cases of HLHwith multiple hem-orrhagic lesions mostly depicted in both thalami and basalganglia region.Case 1A 3-month-old girl presented with poor feeding, vomiting,altered state of consciousness, and pallor. Her mother passedaway 2 weeks after (a non-complicated) delivery, because ofpulmonary edema followed by multi-organ failure (no autop-sy performed). Physical exam revealed small head circumfer-ence (38.5 cm (−1.6 SD)) and hepatosplenomegaly. The eyeswere deviated to the left with a nystagmus, repeated protrusionof the tongue was seen, and there was axial hypotonia.Laboratory findings showed anemia, thrombocytopenia, ele-vated levels of ferritin, triglyceride, and soluble interleukin-2.On abdominal ultrasound, hepatosplenomegaly andnephromegaly were present. Cranial ultrasound demonstratedincreased echogenicity of the basal ganglia.Brain MRI was performed and demonstrated extensiveasymmetric bilateral non-enhancing T2 hyperintense abnor-malities with microbleeds in the basal ganglia and thalamiand to a lesser extent in the cortical-subcortical region of bothhemispheres and in the mesencephalon (Fig. 1). Two nodularenhancing lesions were present in the right caudate head andright thalamus. These neuroimaging features lead to acutehemorrhagic leukoencepalopathy (AHEM), (autosomal dom-inant) acute necrotizing encephalitis of childhood (ANEC),and viral encephalitis as differential diagnoses. Because ofthe predominant involvement of the basal ganglia and espe-cially the thalami with multiple hemorrhagic lesions, HLHwith CNS involvement was not considered as most likelydiagnosis based on the imaging findings. However clinicalfindings could be consistent with HLH as she fulfilled 5criteria. Despite treatment (methylprednisolone andetoposide) the girl deteriorated and developed irregularbreathing pattern, a further decrease in consciousness and ep-ilepsy. Follow-up MRI showed extensive progression of thelesions especially in the subcortical regions and brain stem(Fig. 1). The patient did not survive. Postmortem brain tissuestudy revealed extensive cavitating changes of bothwhite and gray matter with influx of macrophages andhistiocytes and lack of demonstrable micro-organisms inkeeping with the suspected diagnosis of HLH with CNSinvolvement. Genetic tests including whole exome se-quencing did not reveal abnormalities as a possiblecause for primary HLH (Fig. 2).Case 2A 2-day-old boy was born at 36 weeks of gestation. Caesariansection was performed because of placenta insufficiency andfetal distress in the context of maternal smoking. On the secondday of life, the boy developed symptoms of sepsis caused byKlebsiella oxytoca grown from a central venous line. The boydeveloped respiratory problems, direct hyperbilirubinemia, per-sistent thrombocytopenia, leukopenia, anemia, acute liver fail-ure, ascites, and subcutaneous edema. During the diseasecourse, the patient was treated by, e.g., antibiotics, blood trans-fusion, and blood exchange. Increased ferritin leads to liverbiopsy which was negative for neonatal hemochromatosis.Secondary HLH in the context ofKlebsiella oxytoca septicemiawas suspected; treatment with dexamethasone and etoposidewas not effective. On the 20th day of life, the patient died dueto multi-organ failure. Postmortem brain MRI demonstratedmultiple hemorrhagic lesions in the deep gray matter structuresand in the periventricular and deep white matter. The signalintensities of the hemorrhages were in keeping with early sub-acute degradation of blood. In the cerebellum blood products ina later subacute stage were seen.Fig. 1 Axial T2-weighted (a) andSWI (b) MR images of the brainat the level of the basal gangliaand thalami. Extensive signal ab-normalities are shown in both thebasal ganglia and thalami (a) withhemorrhagic foci mainly locatedin the thalami (b)286 Neuroradiology (2021) 63:285–288DiscussionThree neuropathological stages of HLH have been describedand these stages are associated with the severity of disease andincreased lymphocytic and histiocytic infiltration. Stage 1 dis-ease shows leptomeningeal infiltration. Stage 2 demonstratesadditional involvement of the adjacent brain parenchyma withperivascular infiltrations (as route of spread). Stage 3 consistsof massive parenchymal infiltration which leads to demyelin-ation, parenchymal necrosis, and calcification [6]. Both of ourpresented cases had large parenchymal lesions with hemor-rhage and necrosis compatible with stage 3 HLH disease.These neuroinflammatory processes are considered to be relat-ed to systemic inflammation in HLH in which circulating cy-tokines cause endothelium injury in multiple organs ultimatelyleading to parenchyma injury and multi-organ failure [7].The typical neuroimaging findings reported in literature areT2 hyper- or hypointense parenchymal lesions and brain atro-phy in later stages. The T2 hypo-intensity of some of thelesions is assumed to be caused by calcifications. The lesionscan demonstrate ring or nodular enhancement. In addition,leptomeningeal and perivascular enhancement can be seen[4, 8, 9]. Nodular or ring enhancing lesions are likely to beassociated with compromised blood-brain barrier and activedemyelination [2]. This is also reflected by peripheral restrict-ed diffusion in the non-hemorrhagic parenchymal brain le-sions corresponding to the enhancing part of the HLH lesions[1, 2]. This pattern of restriction helps to differentiate the HLHbrain lesions from pyogenic or fungal abscess typically dem-onstrating central diffusion restriction. Both parenchymal at-rophy and disturbances in circulation of cerebrospinal fluid(CSF) secondary to leptomeningeal infiltration lead toventriculomegaly and sometimes subdural effusion [8] .In the presented cases, the diffuse hemorrhagic transforma-tion of the brain lesions, involving both basal ganglia andthalami as well as the brainstem, is in contrast to the typicalimaging findings reported in literature.In a study evaluating 46 cases of primary HLH with CNSinvolvement, thalamic or brain stem lesions have not beendetected in any of the patients [5]. On the contrary, the pres-ence of lesions located in the thalami or brain stem was con-sidered useful in differentiating acute disseminated encepha-lomyelitis (ADEM) from HLH [4, 5]. CNS involvement pre-dominantly presenting with thalamic and brainstem lesions israre in HLH disease [10]. There are a few case reports describ-ing involvement of basal ganglia and/or thalami in HLH withCNS involvement [7, 11, 12]. Basal ganglia and thalamiclesions in the setting of HLH are considered to express themore focal imaging pattern of HLH or be a part of the mixeddiffuse/focal variant [12]. Abnormalities of the thalami, basalganglia, and brainstem on neuroimaging are reported in thesetting of Griscelli’s disease [13, 14], a rare autosomal reces-sive disorder in which HLH can develop. In the acute stage,lymphohistiocytic infiltration is thought to cause areas ofinflammation/ischemia resulting in edema and swelling. Inlater stages calcifications are described probably as a sequelto necrosis and atrophy [13]. The more diffuse imaging pat-tern of HLH shows abnormalities consistent with demyelin-ation, edema, and gliosis [12].In addition to thalamus and basal ganglia involvement inHLH, the hemorrhagic features of the lesions are also contro-versial. In a limited amount of studies evaluating neuroimag-ing findings of patients with HLH disease and CNS involve-ment, hemorrhagic transformation of the parenchymal lesionsin the cerebral and cerebellar white matter have been depictedand a very few are identified in the basal ganglia, but none ofthese multifocal hemorrhagic changes were located in the thal-ami [2, 7]. The hemorrhagic transformation of the brain le-sions found in HLH might be due to ischemic injury andnecrosis following perivascular infiltration [2, 12–14] in theFig. 2 Axial T2-weighted MRimage (a) at the level of the deepwhite matter and axial SWI MRimage (b) at the level of the thal-ami. Focal hemorrhagic lesionsare shown in the deep white mat-ter (a) and more confluent hem-orrhagic foci are demonstrated inboth thalami (b)287Neuroradiology (2021) 63:285–288setting of systemic inflammation characterized by cytokinestorm and in the end multi-organ failure [7].The differential diagnosis of bilateral hemorrhagic lesionsof the central gray matter includes acute necrotizing encepha-lopathy (ANE), typically involving the bilateral thalami withnecrosis and hemorrhage being the predominant findings.ANE is associated with respiratory viruses as causative factor,but also genetic causes are identified [15]. Acute hemorrhagicencephalomyelitis (AHEM) is a rare and severe form ofADEM in which variable involvement of the central graymatter is seen in addition to tumefactive white matter lesions.In cases of thalamic involvement this entity mimics ANE [11,15]. Deep cerebral venous thrombosis of both internal cerebralveins can lead to hemorrhagic thalamic lesions due to venousischemia with variable involvement of the basal ganglia. Onneuroimaging thrombosis of the occluded veins is appreciated[15]. However HLH is generally not included in the differen-tial diagnosis of hemorrhagic lesions of the basal ganglia andthalami.In conclusion, despite the fact that neuroimaging manifes-tations of HLH disease are nonspecific and may overlap withmany diseases such as inflammatory, infectious or infiltrativecentral nervous system disorders, multifocal hemorrhagic le-sions involving the periventricular white matter, basal ganglia,thalami, and brainstem should suggest the possibility of HLHdisease.Funding No funding was received for this study.Compliance with ethical standardsConflict of interest The authors declare that they have no conflict ofinterest.Ethics approval All procedures performed in the studies involving hu-man participants were in accordance with the ethical standards of theinstitutional and/or national research committee and with the 1964Helsinki Declaration and its later amendments or comparable ethicalstandards.Informed consent Informed consent and consent to publish were ob-tained from the parent(s) of all individual participants included in thestudy.Abbreviation HLH, Hemophagocytic lymphohistiocytosisOpen Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing, adap-tation, distribution and reproduction in any medium or format, as long asyou give appropriate credit to the original author(s) and the source, pro-vide a link to the Creative Commons licence, and indicate if changes weremade. The images or other third party material in this article are includedin the article's Creative Commons licence, unless indicated otherwise in acredit line to the material. If material is not included in the article'sCreative Commons licence and your intended use is not permitted bystatutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/.References1. Janka GE (2007) Familial and acquired hemophagocyticlymphohistiocytosis. Eur J Pediatr 166(2):95–1092. Fitzgerald NE, MacClain KL (2003) Imaging characteristics ofhemophagocytic lymphohistiocytosis. Pediatr Radiol 33(6):392–4013. Henter J-I, Nennesmo I (1997) Neuropathologic findings and neu-rologic symptoms in twenty-three children with hemophagocyticlymphohistiocytosis. J Pediatr 130(3):358–3654. 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Atypical neuroimaging characteristics of hemophagocytic lymphohistiocytosis in infants: a case series of hemorrhagic brain lesions in the deep grey matter

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Atypical neuroimaging characteristics of hemophagocytic lymphohistiocytosis in infants: a case series of hemorrhagic brain lesions in the deep grey matter

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