Article Figures & Data
Figures
- 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.
- 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).
Tables
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 Fever 45/56 (80) Hepato-/splenomegaly 46/56 (82) Abdominal distension 14/56 (25) CNS symptoms 45/57, 79% Seizures 28 (62) Decreased sensorium 22 (49) Meningismus 13 (29) Gait ataxia 12 (27) Hypotonia 11 (24) Minimal symptoms (mild irritability) or clinically silent patients (no symptoms with CSF abnormalities) 12 (21) CSF findings CSF analyzed at presentation 50/57 (87) Abnormal CSF 42/50 (84) CSF pleocytosis (>10 leucocytes/μL) 25/50 (50) CSF proteinosis (>45 mg/dL) 32/50 (64) Treatment HLH 1994/2004 35/57 (61) IT methotrexate 17 (30) HSCT 25 (45) Outcome profiles Death 19 (32) Death before 8 weeks 7 Death after 8 weeks 12 Alive at last follow-up 36 (63) Lost to follow-up 2 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.
Subpatterns P Value Pattern 1 Overall Pattern 2 P Value 1.1 1.2 1.3 Median age at onset (mo) 45.4 66 80.5 .5 55.5 16 .004 Symptoms Seizures 11/21 (52%) 4/5 (80%) 4/6 (67%) .5 19/32 (59%) 9/25 (36%) .08 Encephalopathy 11/21 (52%) 1/5 (20%) 4/6 (67%) .3 16/32 (50%) 6/25 (24%) .04 Gait ataxia 5/21 (24%) 3/5 (60%) 3/6 (50%) .08 12/32 (34%) 0 .001 Limb weakness 6/21 (29%) 1/5 (20%) 1/6 (17%) .8 8/32 (25%) 1/25 (4%) .03 Dysarthria 0 2/5 (40%) 1/6 (17%) .01 3/32 (9%) 1/25 (4%) .4 Diplopia 01/21 (5%) 2/5 (40%) 2/6 (33%) .06 5/32 (16%) 0 .03 Abnormal CSF 18/20 (90%) 4/5 (80%) 5/5 (100%) .6 27/30 (90%) 15/20(75%) .2 Proteinosis 13 (65%) 4 (80%) 4 (80%) .5 21 (70%) 11 (55%) .3 Pleocytosis 10 (50%) 4 (80%) 5 (100%) .08 19 (63%) 6 (30%) .04 Pooled mutation group 4/6 (67%) 2/3 (67%) 3/3 (100%) .32 9/12 (75%) 13/13 (100%) .09 Mortality 9/20 (45%) 3/5 (60%) 2/6 (33%) .3 14/31 (45%) 5/24 (21%) .06 Deficit-free at follow-up 8/20 (40%) 1/5 (20%) 1/6 (17%) .1 10/31 (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.
- Table 3:
Relevant literature review of CNS HLH cases with brainstem or cerebellitis patterns with available MR imaging and genetic data
Literature Review Imaging Pattern Genetic Variants Age of Onset, Relation to Systemic HLH Imaging Findings Benson et al23 cases Brainstem–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 HLH CLIPPERS MR imaging criteria NA Taieb et al284 patients Brainstem–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 HLH Three-fourths had atypical MR imaging CLIPPERS features (confluent contrast-enhancing lesions) Bhoopalan et al26 1 patient Cerebellitis 1 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 HLH Cerebellitis, tonsillar herniation, no multifocal lesions Khan et al271 patient Cerebellitis 1 patient with homozygous missense mutation c. 173T > C (p.L58P) in STX11 (syntaxin 11) gene 2 yr 7 months, systemic HLH already present Cerebellitis, tonsillar herniation, diffuse-to-multifocal lesions already present Astigarraga et al3 1 patient Cerebellitis 1 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 HLH Recurrent cerebellitis, tonsillar herniation, subsequently multifocal lesions Taieb et al281 patient Cerebellitis Patient 3’s (in CLIPPERS series) brother’s; granddaughter, monoallelic PRF1 mutation (genetic variant NA) Not specified, self-limited CNS-restricted presentation NA Chiapparini et al29 1 patient Cerebellitis 1 patient with homozygous missense PRF1 mutation c.673C>T (p.Arg225Trp) (perforin expression data NA) 13 yr, preceded systemic HLH Cerebellitis, tonsillar herniation followed by multifocal lesions Note:—NA indicates not available; Pt, patient.
