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Research ArticlePediatric Neuroimaging

MRI Patterns in Pediatric CNS Hemophagocytic Lymphohistiocytosis

P. Malik, L. Antonini, P. Mannam, F.N. Aboobacker, A. Merve, K. Gilmour, K. Rao, S. Kumar, S.E. Mani, D. Eleftheriou, A. Rao, C. Hemingway, S.V. Sudhakar, J. Bartram and K. Mankad
American Journal of Neuroradiology October 2021, DOI: https://doi.org/10.3174/ajnr.A7292
P. Malik
aFrom the Departments of Diagnostic Imaging (P. Malik, P. Mannam, S.E.M.)
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L. Antonini
dDepartment of Paediatric Hemato-Oncology (L.A.), G. Salesi Hospital, Ancona, Italy
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P. Mannam
aFrom the Departments of Diagnostic Imaging (P. Malik, P. Mannam, S.E.M.)
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F.N. Aboobacker
bHematology (F.N.A.)
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A. Merve
gDepartment of Histopathology (A.M.)
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K. Gilmour
jImmunology (K.G.)
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K. Rao
hBone Marrow Transplant Unit (K.R.)
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S. Kumar
cChild Health (S.K.), Christian Medical College, Vellore, India
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S.E. Mani
aFrom the Departments of Diagnostic Imaging (P. Malik, P. Mannam, S.E.M.)
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D. Eleftheriou
kPaediatric Rheumatology (D.E.), Great Ormond Street Hospital for Children, London, UK
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A. Rao
iDepartments of Pediatric Hematology (A.R., J.B.)
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C. Hemingway
eDepartment of Pediatric Neurology (C.H.)
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S.V. Sudhakar
fPediatric Neuroradiology Unit (S.V.S., K.M.)
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J. Bartram
iDepartments of Pediatric Hematology (A.R., J.B.)
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K. Mankad
fPediatric Neuroradiology Unit (S.V.S., K.M.)
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  • FIG 1.
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    FIG 1.

    Findings of 4 patients with subpattern 1.2 (brainstem–predominant pattern). Axial T2WI (A1–D1) and axial postcontrast T1WI (A2–D2) at the level of the pons show multiple punctate (dashed white arrow, B2, D2) to nodular (solid white arrow, A2 and C2), enhancing foci and extension of the T2 signal abnormality (black arrow, A1–D1) beyond the enhancement in all cases.

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    FIG 2.

    Findings of subpattern 1.3 (cerebellitis). Axial T2WI at the level of the fourth ventricle (A1–C1), lateral ventricles (A3–C3), and midline sagittal T1WI (A2–C2). Onset MR imaging (December 2016) shows severe cerebellar edema and expansion (white arrow, A1) with mass effect on the brainstem, effacement of the prepontine cistern (dashed white arrow, A2), and foramen magnum crowding (white arrow, A2). Lateral ventricular dilation (asterisk, A3) and transependymal CSF seepage (dashed black arrow, A3) are also noted. Mild reduction in cerebellar edema and mass effect (dashed arrow, B2) with new cerebellar (white arrow, B1), parieto-occipital (dashed arrow, B3), and deep gray nuclei (black arrow, B3) hyperintensities were found in June 2017. Last MR imaging in November 2017 shows cerebral (white arrow, C3) and cerebellar (white arrows, C1–2) atrophy, diffuse white matter hyperintensities, and ventriculomegaly (asterisk, C3).

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    Table 1:

    Clinical, treatment, and outcome profilesa

    Profiles
    Age
     Age at onset (median) (IQR) (mo)36 (5.5–80.8)
     Age at CNS presentation (median) (IQR) (mo)49.2 (11–96)
    Male/female (ratio)34:23 (1.4:1)
    General symptoms
     Fever45/56 (80)
     Hepato-/splenomegaly46/56 (82)
     Abdominal distension14/56 (25)
    CNS symptoms45/57, 79%
     Seizures28 (62)
     Decreased sensorium22 (49)
     Meningismus13 (29)
     Gait ataxia12 (27)
     Hypotonia11 (24)
    Minimal symptoms (mild irritability) or clinically silent patients (no symptoms with CSF abnormalities)12 (21)
    CSF findings
     CSF analyzed at presentation50/57 (87)
     Abnormal CSF42/50 (84)
     CSF pleocytosis (>10 leucocytes/μL)25/50 (50)
     CSF proteinosis (>45 mg/dL)32/50 (64)
    Treatment
     HLH 1994/200435/57 (61)
     IT methotrexate17 (30)
     HSCT25 (45)
    Outcome profiles
     Death19 (32)
      Death before 8 weeks7
      Death after 8 weeks12
    Alive at last follow-up36 (63)
    Lost to follow-up2
    • Note:—IQR indicates interquartile range; IT, intrathecal.

    • ↵a Total (n = 57). Data collected are both continuous and categorical, and the analysis method used has been referred to under statistical analysis heading.

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    Table 2:

    Pattern characteristics and analysisa

    SubpatternsP ValuePattern 1 OverallPattern 2P Value
    1.11.21.3
    Median age at onset (mo)45.46680.5.555.516.004
    Symptoms
     Seizures11/21 (52%)4/5 (80%)4/6 (67%).519/32 (59%)9/25 (36%).08
     Encephalopathy11/21 (52%)1/5 (20%)4/6 (67%).316/32 (50%)6/25 (24%).04
     Gait ataxia5/21 (24%)3/5 (60%)3/6 (50%).0812/32 (34%)0.001
     Limb weakness6/21 (29%)1/5 (20%)1/6 (17%).88/32 (25%)1/25 (4%).03
     Dysarthria02/5 (40%)1/6 (17%).013/32 (9%)1/25 (4%).4
     Diplopia01/21 (5%)2/5 (40%)2/6 (33%).065/32 (16%)0.03
    Abnormal CSF18/20 (90%)4/5 (80%)5/5 (100%).627/30 (90%)15/20(75%).2
    Proteinosis13 (65%)4 (80%)4 (80%).521 (70%)11 (55%).3
    Pleocytosis10 (50%)4 (80%)5 (100%).0819 (63%)6 (30%).04
    Pooled mutation group4/6 (67%)2/3 (67%)3/3 (100%).329/12 (75%)13/13 (100%).09
     Mortality9/20 (45%)3/5 (60%)2/6 (33%).314/31 (45%)5/24 (21%).06
    Deficit-free at follow-up8/20 (40%)1/5 (20%)1/6 (17%).110/31 (32%)13/25(52%).06
    • ↵a Data collected are both continuous and categorical, and the analysis method used has been referred to under statistical analysis heading.

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    Table 3:

    Relevant literature review of CNS HLH cases with brainstem or cerebellitis patterns with available MR imaging and genetic data

    Literature ReviewImaging PatternGenetic VariantsAge of Onset, Relation to Systemic HLHImaging Findings
    Benson et al23 casesBrainstem–predominant pattern (CLIPPERS- like)1 disruptive, 2 with missense mutations and absent protein expression
    Pt 1: PRF1 c.452A>T (p.H151L) and c.666C>A (H222Q), Perforin expression 0%
    Pt 2: PRF1 c.443C>G (p.A148G) and c.666C>A (H222Q), Perforin expression 0%
    Pt 3: UNC13D c.2346_2349delGGAG(p.R782fs), c.2588G>A (p.G863D)
    5–7 yr, all 3 CNS-restricted HLHCLIPPERS MR imaging criteria NA
    Taieb et al284 patientsBrainstem–predominant pattern (CLIPPERS- like)4 cases, all with missense mutations and retained-but-decreased protein expression
    Pt 1: PRF1 c.272C>T(p.A91V) homozygous, perforin expression 38%
    Pt 2: UNC13D c.919C>T (p.Q307*) and c.2038C>T (p.R680W), not applicable
    Pt 3: PRF1 c.116C>A (p.P39H) and c.272C>T (p.A91V), perforin expression 25%
    Pt 4: PRF1 c.82C>T (p.R28C) and c.272C>T (p.A91V), perforin expression 38%
    Adults (42–73 yr), all had CNS-restricted HLHThree-fourths had atypical MR imaging CLIPPERS features (confluent contrast-enhancing lesions)
    Bhoopalan et al26 1 patientCerebellitis1 patient with compound heterozygous PRF1 gene mutations with at least 1 disruptive mutation PRF1: c.50delT (p.L17fs) and c.527G>A(p.C176Y))8 yr, CNS-restricted HLHCerebellitis, tonsillar herniation, no multifocal lesions
    Khan et al271 patientCerebellitis1 patient with homozygous missense mutation c. 173T > C (p.L58P) in STX11 (syntaxin 11) gene2 yr 7 months, systemic HLH already presentCerebellitis, tonsillar herniation, diffuse-to-multifocal lesions already present
    Astigarraga et al3 1 patientCerebellitis1 patient with compound heterozygous missense PRF mutations PRF1: c.643C>A (p.L215I) and c.785C>A (p.Ala262Asp) (perforin expression data NA)3 yr, preceded systemic HLHRecurrent cerebellitis, tonsillar herniation, subsequently multifocal lesions
    Taieb et al281 patientCerebellitisPatient 3’s (in CLIPPERS series) brother’s; granddaughter, monoallelic PRF1 mutation (genetic variant NA)Not specified, self-limited CNS-restricted presentationNA
    Chiapparini et al29 1 patientCerebellitis1 patient with homozygous missense PRF1 mutation c.673C>T (p.Arg225Trp) (perforin expression data NA)13 yr, preceded systemic HLHCerebellitis, tonsillar herniation followed by multifocal lesions
    • Note:—NA indicates not available; Pt, patient.

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Cite this article
P. Malik, L. Antonini, P. Mannam, F.N. Aboobacker, A. Merve, K. Gilmour, K. Rao, S. Kumar, S.E. Mani, D. Eleftheriou, A. Rao, C. Hemingway, S.V. Sudhakar, J. Bartram, K. Mankad
MRI Patterns in Pediatric CNS Hemophagocytic Lymphohistiocytosis
American Journal of Neuroradiology Oct 2021, DOI: 10.3174/ajnr.A7292

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MRI Patterns in Pediatric CNS Hemophagocytic Lymphohistiocytosis
P. Malik, L. Antonini, P. Mannam, F.N. Aboobacker, A. Merve, K. Gilmour, K. Rao, S. Kumar, S.E. Mani, D. Eleftheriou, A. Rao, C. Hemingway, S.V. Sudhakar, J. Bartram, K. Mankad
American Journal of Neuroradiology Oct 2021, DOI: 10.3174/ajnr.A7292
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