Primary hemophagocytic lympho-histiocytosis (HLH) is a hyperinflammatory syndrome with devastating consequences. Multisystem involvement is a hallmark of HLH; however, HLH may rarely present with signs and symptoms isolated to the central nervous system (CNS). Within the brain, HLH can mimic demyelination, chronic infection, or vasculitis, leading to a diagnostic delay of months to years. We describe here a 7-year-old boy who presented with a history of prolonged fever and multiple focal neurologic deficits, which were being treated as CNS tuberculosis at the referring hospital. In view of the relapsing course with multiple areas of hemorrhagic tumefactive lesions on neuroimaging, the diagnosis was revised to acquired demyelination, and he received multiple cycles of immunotherapy. A brain biopsy was inconclusive. Subsequently, 13 months after disease onset, the child presented with features of systemic HLH in the form of fever, pancytopenia, splenomegaly, elevated ferritin, and triglycerides. Primary HLH was suspected, and genetic testing revealed a likely pathologic compound heterozygous variation in the PRF1 gene confirming the diagnosis. We planned a hematopoietic stem cell transplant as definitive therapy, but the child succumbed to an episode of sepsis and aspiration pneumonia. We infer from this case that primary HLH is a great mimicker. A high index of suspicion is required to establish a timely diagnosis. Primary HLH may stay isolated to CNS for months and should be considered in the differential diagnosis of all refractory cases of demyelination.

As a consequence of growing awareness about neuroimmunologic disorders, clinicians are more commonly encountering children with atypical chronic or recurrent brain inflammatory syndromes. Establishing an accurate diagnosis in these cases may be difficult, especially when common local infections, parainfectious inflammation, or acquired demyelinating conditions fail to explain the presentation or the disease course. In such cases, genetically susceptible hyperinflammatory syndromes may be considered. Hemophagocytic lympho-histiocytosis (HLH) is one such potentially fatal hyperinflammatory condition. It is a multisystem inflammatory disorder that results from an unregulated cytokine storm and the activation of cytotoxic T cells and antigen-presenting cells. Although HLH typically affects multiple organ systems, HLH may involve only the central nervous system (CNS).1  On the basis of the underlying etiology, HLH is broadly divided into primary HLH (with an underlying genetic mutation) and secondary HLH, which occurs in association with severe infection, malignancies, or rheumatologic disorders.2  The presence of organomegaly, lymphadenopathy, cytopenias, and elevated serum inflammatory markers, such as ferritin, with elevated triglycerides in a setting of prolonged fever should prompt the consideration of a diagnosis of HLH. CNS involvement in systemic HLH is common and may be seen in 45% to 75% of all cases.2,3  Children usually present with systemic manifestations of HLH, and the neurologic manifestations appear later in the course of the disease, especially in severe and untreated cases. Primary HLH rarely presents with neurologic signs and symptoms, so differentiating this disease from other common neurologic conditions may be difficult. We describe a patient who was initially diagnosed with CNS tuberculosis and then with a demyelinating disorder before a late presumptive diagnosis of primary HLH was made. The enigma continued until a genetically confirmed final diagnosis of primary HLH was established. Written informed consent for the publication of clinical details and images was obtained from the parents.

A 7-year-old boy presented to our hospital with complaints of multiple neurologic deficits, including right facial paresis, new-onset squint in the right eye, and weakness of the left lower limb. He had an uneventful birth with age-appropriate development. There was no history of similar illnesses in the family. This child had been symptomatic for 7 months. He initially presented with a febrile illness and encephalopathy, right sixth nerve palsy, and signs of increased intracranial pressure. He was diagnosed with tuberculous meningitis at an outside medical facility and was empirically started on 4-drug antitubercular therapy (ATT) with oral dexamethasone at 0.6 mg/kg/day in 4 divided doses for 2 months followed by the tapering of dexamethasone over the next 4 weeks. A contrast-enhanced MRI of the brain revealed multifocal bilateral lesions with areas of subacute hemorrhage and thick, incomplete ring-like contrast enhancement (Fig 1.1). However, staining for acid-fast bacilli and a nucleic acid amplification test (GenXpert) of the cerebrospinal fluid for tuberculosis was negative. Three months after an initial period of defervescence, the child developed new focal deficits and recrudescence of fever coincident with the tapering and cessation of oral steroids. This was managed outside as a paradoxical reaction on ATT. Oral dexamethasone was restarted and continued for another 45 days. The child’s clinical condition stabilized; however, he manifested additional focal deficits 7 months after disease onset despite the continuation of oral dexamethasone and ATT. At this time point, the child was referred to our tertiary care center.

FIGURE 1

Evolution of brain lesions on MRI in the index case. 1.1 (first row) T1W (A1, B1), T2W (C1, D1), and postcontrast T1W (E1, F1) MRI brain images from July 2017 (disease onset) reveal multifocal bilateral lesions in the brain parenchyma (the 2 largest lesions are seen in the right occipital and left parietal lobes). T1 bright areas represent subacute hemorrhage. Irregular thick contrast enhancement is present in most lesions. 1.2 (second row) T1W (A2, B2), T2W (C2, D2) and postcontrast T1W (E2, F2) MRI brain images from February 2018 (first presentation to our center) reveals a reduction in the size of older lesions with resolution of hemorrhage and decrease in contrast enhancement. New lesions have appeared in the left frontal lobe (dissemination in time and space). 1.3 (third row) MRI brain images from August 2018 (at the time when the patient had developed clinical features of systemic HLH) reveal further resolution of the right occipital, left parietal, and left frontal lesions and a new large hemorrhagic lesion in the right temporal area with irregular contrast enhancement.

FIGURE 1

Evolution of brain lesions on MRI in the index case. 1.1 (first row) T1W (A1, B1), T2W (C1, D1), and postcontrast T1W (E1, F1) MRI brain images from July 2017 (disease onset) reveal multifocal bilateral lesions in the brain parenchyma (the 2 largest lesions are seen in the right occipital and left parietal lobes). T1 bright areas represent subacute hemorrhage. Irregular thick contrast enhancement is present in most lesions. 1.2 (second row) T1W (A2, B2), T2W (C2, D2) and postcontrast T1W (E2, F2) MRI brain images from February 2018 (first presentation to our center) reveals a reduction in the size of older lesions with resolution of hemorrhage and decrease in contrast enhancement. New lesions have appeared in the left frontal lobe (dissemination in time and space). 1.3 (third row) MRI brain images from August 2018 (at the time when the patient had developed clinical features of systemic HLH) reveal further resolution of the right occipital, left parietal, and left frontal lesions and a new large hemorrhagic lesion in the right temporal area with irregular contrast enhancement.

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On presentation to our hospital, the child appeared cushingoid. The clinical history, examination, and neuroimaging were reanalyzed. A neurologic examination revealed right upper motor neuron facial palsy, right sixth nerve palsy, and left lower limb monoparesis. There was no organomegaly. The hemoglobin, total leukocyte count, and platelets were 10.6 g/dL, 8100/µL, and 310 000/µL, respectively. His liver function tests were within normal limits. We did not initially obtain a ferritin level. A repeat contrast-enhanced brain MRI revealed a reduction in the size of older lesions, reduced contrast enhancement, the resolution of hemorrhage, and a new lesion in the left frontal lobe (Fig 1.2). We considered diagnoses of recurrent tumefactive demyelination and CNS vasculitis, which prompted a stereotactic brain biopsy of the left parietal lesion. The microscopy revealed fragments of brain parenchyma with dense chronic inflammatory infiltrate composed of lymphocytes and histiocytes. There were no granulomas or vascular-based lesions, and the acid fast bacilli stain result was negative. We considered the possibility of chronic hemorrhagic demyelinating disorder and, in view of dissemination in time and space, a provisional diagnosis of pediatric-onset multiple sclerosis was made. ATT was stopped. The child was initiated on intravenous methylprednisolone pulse therapy for 5 days followed by maintenance steroids for 12 weeks. Oral azathioprine was added while tapering steroids for maintenance immunosuppression. After 4 months of intravenous methylprednisolone pulse therapy, the child again relapsed with clinical features of unsteadiness of gait, irrelevant talking, fever, hepatosplenomegaly, and cervical lymphadenopathy, along with laboratory features of systemic HLH (pancytopenia, increased ferritin [1990 ng/mL]), increased triglycerides (360 mg/dL), and hemophagocytosis on bone marrow aspiration. The workup for chronic infections, such as bacteriological cultures, Epstein-B virus serology, Chlamydia, Mycoplasma, a rapid antigen test for malaria, etc, were nondiagnostic. A fine needle aspiration cytology of an enlarged lymph node revealed reactive lymphadenitis. A contrast-enhanced computed tomography scan of the chest and abdomen revealed no pathology. A diagnosis of HLH was established, and the child was treated with empirical antibiotics along with dexamethasone for 8 weeks as per the HLH 2004 protocol,4  which led to the resolution of the fever, lymphadenopathy, pancytopenia, and the regression of splenic enlargement. A repeat brain MRI scan revealed a new large hemorrhagic lesion in the right temporal area and the continued resolution of older lesions (Fig 1.3). In view of recurrent episodes of CNS demyelination along with systemic features of HLH, primary HLH was suspected, and exome sequencing was performed. This revealed a heterozygous nonsense variation in exon 3 of the PRF1 gene that results in a stop codon and the premature truncation of the protein (c.1519G>T; p.Glu507Ter) and a heterozygous missense variation in exon 3 of the PRF1 gene (c.1349C>T; p.Thr450Met), which has been previously reported in patients affected with familial HLH.5  On the basis of the American College of Medical Genetics criteria, the first variant was classified as pathogenic, the second variant was classified as likely pathogenic, and the overall interpretation was likely pathogenic compound heterozygous variants associated with familial hemophagocytic lymphohistiocytosis-2. Subsequently, the child had another CNS relapse. A brief timeline of key events is illustrated in Fig 2. Definitive therapy in the form of a hematopoietic stem cell transplant (HSCT) was planned but could not be performed because the child succumbed to an episode of sepsis and aspiration pneumonia in the following months.

FIGURE 2

Timeline depicting the key events of the index child with familial HLH type 2.

FIGURE 2

Timeline depicting the key events of the index child with familial HLH type 2.

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The case represented both a diagnostic challenge and a lost opportunity. The time lag between symptom onset and the final diagnosis was 1.5 years. Familial HLH most frequently presents with systemic features with or without central nervous system (CNS) involvement. Our case was unusual because the clinical presentation was restricted to the CNS for many months before other systemic features of HLH surfaced. The clinical and laboratory work up at the disease onset suggests that the initial findings in the index child were restricted to CNS alone. However, the possibility of oral steroids masking the early signs and symptoms of systemic spread cannot be completely ruled out. The description of primary HLH presenting with neurologic features is limited to a few anecdotal cases only (Table 1). Algahtani et al described a 20-year-old man who presented with vision loss and headache and was initially diagnosed with acute disseminated encephalomyelitis. PRF1 mutation-positive primary HLH was accidentally identified through exome sequencing, primarily sent for hereditary white matter disease.2  The results of a workup for systemic features of HLH were negative in this patient. Another retrospective chart review of 4 children with CNS-isolated HLH was reported by Benson et al.1  These patients were also initially managed as demyelinating syndromes and CNS vasculitis and were eventually diagnosed as familial HLH 2 to 6 years after initial presentation. These children were enrolled in the Undiagnosed Diseases Program at the National Institutes of Health during the course of their illnesses, and the clinical and radiologic course of the first patient assisted in more prompt diagnoses of the other cases. This underscores the importance of awareness about this rare yet potentially treatable entity. The neurologic manifestations in all published cases mimicked demyelination, CNS vasculitis, leukodystrophy, malignancy, or chronic infection.

TABLE 1

Comparative Review of Previously Published Familial HLH Cases Presenting With Isolated or Predominant Neurologic Features11,14 

Reference NoAge of Symptom Onset, YTime to DiagnosisNeurologic SyndromeRadiologic FindingSystemic Signs/SymptomsGenetic Mutation InformationBrain BiopsyOutcome
12  3.5 9 mo (approximately) Headache, ataxia and visual disturbances Multiple supra- and infratentorial lesions with peripheral contrast enhancement and central necrosis None except reduced NK cell activity 3 heterozygous variations in PRF1 gene. 1 nonsense mutation, Glu46stop, and 2 missense alterations, Ala91Val and Arg119Trp. Almost absent perforin expression on CD8+ cells, reduced CD56+ cells and reduced NK cell function. T-cell mediated necrotizing lymphocytic vasculitis Underwent HSCT, Doing well at 5 mo post HSCT 
13  16 2 y Focal deficits, tingling, sensory deficits, severe episodic headache Patchy areas of focal demyelination Yes (Fever, splenomegaly, cytopenias) 2 different missense mutations in the coding sequence of PRF1 gene, 1066C>T and 1349C>T, both associated with late onset disease. No. and % of NK cells normal, NK cytotoxicity not done. Not done Could not be done 
14 Not mentioned Seizures, focal deficits Multiple ring enhancing lesions at the gray-white matter junction None Compound heterozygous mutation (allele 1: c50delT(p.L17 fs); allele 2: c.1229G>C (p.R410P) consistent with FHLH2. NK cell function was decreased and complete absence of perforin protein expression in cytotoxic cells. Lymphohistiocytic infiltrate Underwent HSCT, surviving >2 y after HSCT  
2  20 8 mo (approximately) Vision loss, headache  None Homozygous variant c. 1081 A>T, p.(Arg361Trp) in PRF1 gene Not done Process for HSCT initiated at the time of writing 
1  5, 6, 7, N/A 5, 2, 6, N/A Case 1: Headache, ataxia initially then progressive tremors, dysarthria, dysconjugate gaze, slowed speech Case 1: Multifocal contrast-enhancing cerebral and cerebellar T2-hyperintense lesions Case 1: None except for decreased NK cell activity Case 1: Bi-allelic pathogenic mutation in PRF1 gene (c.452A>T (p.H151L) and c.666C>A (H222Q) Case 1: cerebellar lesion: Chronic inflammatory infiltrate, no histiocytosis HSCT performed successfully for all cases 
  Case 2: Vomiting, headache, psychiatric symptoms, cognitive decline, focal SE Case 2: Contrast-enhancing cerebral and cerebellar T2 hyperintense white matter lesions Case 2: None except for decreased NK cell activity Case 2: PRF1 gene (c.443C>G (p.A148G) and c.666C>A (H222Q) Case 2: Perivascular lymphocytic foci  
  Case 3: Diplopia, right hemiparesis, ataxia Case 3: Multifocal bran lesions, including a large brainstem lesion Case 3 and Case 4: None except absent NK cell activity Case 3: UNC13D gene (c.2346_2349delGGAG (p.R782fs), c.2588G>A (p.G863D) Case 3: Vascular, perivascular, and parenchymal mixed inflammatory infiltrates with occasional small vessel vasculitis  
  Case 4: Asymptomatic sister of Case 3 Case 4: Multifocal white matter lesions, 1 of which was contrast-enhancing  Case 4: UNC13D (c.2346)2349delGGAG (p.R782fs), c.2588G>A (p.G863D) Case 2 (relapse): Dense, destructive perivascular and parenchymal lympho-histiocytic infiltrate  
Reference NoAge of Symptom Onset, YTime to DiagnosisNeurologic SyndromeRadiologic FindingSystemic Signs/SymptomsGenetic Mutation InformationBrain BiopsyOutcome
12  3.5 9 mo (approximately) Headache, ataxia and visual disturbances Multiple supra- and infratentorial lesions with peripheral contrast enhancement and central necrosis None except reduced NK cell activity 3 heterozygous variations in PRF1 gene. 1 nonsense mutation, Glu46stop, and 2 missense alterations, Ala91Val and Arg119Trp. Almost absent perforin expression on CD8+ cells, reduced CD56+ cells and reduced NK cell function. T-cell mediated necrotizing lymphocytic vasculitis Underwent HSCT, Doing well at 5 mo post HSCT 
13  16 2 y Focal deficits, tingling, sensory deficits, severe episodic headache Patchy areas of focal demyelination Yes (Fever, splenomegaly, cytopenias) 2 different missense mutations in the coding sequence of PRF1 gene, 1066C>T and 1349C>T, both associated with late onset disease. No. and % of NK cells normal, NK cytotoxicity not done. Not done Could not be done 
14 Not mentioned Seizures, focal deficits Multiple ring enhancing lesions at the gray-white matter junction None Compound heterozygous mutation (allele 1: c50delT(p.L17 fs); allele 2: c.1229G>C (p.R410P) consistent with FHLH2. NK cell function was decreased and complete absence of perforin protein expression in cytotoxic cells. Lymphohistiocytic infiltrate Underwent HSCT, surviving >2 y after HSCT  
2  20 8 mo (approximately) Vision loss, headache  None Homozygous variant c. 1081 A>T, p.(Arg361Trp) in PRF1 gene Not done Process for HSCT initiated at the time of writing 
1  5, 6, 7, N/A 5, 2, 6, N/A Case 1: Headache, ataxia initially then progressive tremors, dysarthria, dysconjugate gaze, slowed speech Case 1: Multifocal contrast-enhancing cerebral and cerebellar T2-hyperintense lesions Case 1: None except for decreased NK cell activity Case 1: Bi-allelic pathogenic mutation in PRF1 gene (c.452A>T (p.H151L) and c.666C>A (H222Q) Case 1: cerebellar lesion: Chronic inflammatory infiltrate, no histiocytosis HSCT performed successfully for all cases 
  Case 2: Vomiting, headache, psychiatric symptoms, cognitive decline, focal SE Case 2: Contrast-enhancing cerebral and cerebellar T2 hyperintense white matter lesions Case 2: None except for decreased NK cell activity Case 2: PRF1 gene (c.443C>G (p.A148G) and c.666C>A (H222Q) Case 2: Perivascular lymphocytic foci  
  Case 3: Diplopia, right hemiparesis, ataxia Case 3: Multifocal bran lesions, including a large brainstem lesion Case 3 and Case 4: None except absent NK cell activity Case 3: UNC13D gene (c.2346_2349delGGAG (p.R782fs), c.2588G>A (p.G863D) Case 3: Vascular, perivascular, and parenchymal mixed inflammatory infiltrates with occasional small vessel vasculitis  
  Case 4: Asymptomatic sister of Case 3 Case 4: Multifocal white matter lesions, 1 of which was contrast-enhancing  Case 4: UNC13D (c.2346)2349delGGAG (p.R782fs), c.2588G>A (p.G863D) Case 2 (relapse): Dense, destructive perivascular and parenchymal lympho-histiocytic infiltrate  

HSCT, hematopoietic stem sell transplantation; N/A, not available; NK sell, natural killer cell; SE, status epilepticus.

In addition to a relapsing course and partial response to immunomodulation, the initial hemorrhagic nature of CNS lesions was a peculiar finding in our case. Hemorrhagic lesions in the thalami, basal ganglia, and brain stem have been described recently in 2 cases of HLH in infants.6  The hemorrhagic transformation of the lesions is thought to be due to ischemic injury after perivascular infiltration in the setting of systemic inflammation. The hemorrhagic component of demyelinating lesions should trigger suspicion for other conditions, such as CNS vasculitis and HLH. However, the distinction between the 2 is difficult. Findings of stenosis, tortuosity, beading, and the occlusion of proximal vessels in conventional and/or magnetic resonance angiography may suggest a diagnosis of CNS vasculitis affecting large- and medium-sized vessels.7  In small-vessel CNS vasculitis, magnetic resonance angiography may not be useful. A histopathological examination of brain tissue may remain inconclusive, as revealed by our case and previously reported CNS-restricted HLH cases (Table 1).1  No hemophagocytosis could be identified in the brain.

The index case had 2 mutations associated with familial HLH type 2 in the PRF1 gene, 1 was nonsense and the other was missense. A 14-year-old boy with an identical mutation was described in a large series of 101 familial HLH patients from India.8  The later age of onset is explained by the presence of 1 missense mutation, owing to residual cytotoxic function.9  In a previous cohort, CNS involvement was reported in 60% of cases of familial HLH type 3, as compared with 36% of patients with familial HLH type 2.10,1114  Strikingly, the index case of familial HLH type 2 had a CNS-predominant presentation.

The availability of promising therapy, such as HSCT, in primary HLH, especially early in the disease course, makes a prompt, accurate diagnosis imperative. Exome sequencing should be considered in patients with chronic or recurrent brain inflammation who have an atypical presentation, have an unexpected response to therapy, or manifest systemic features consistent with HLH. Benson and colleagues have demonstrated the effectiveness of HSCT in 4 children with primary HLH. All children tolerated the procedure well without any major treatment-related complications and achieved long-term disease remission. These cases highlight the potential for HSCT to be curative for primary HLH.

Primary HLH may present with isolated neurologic manifestations, which can precede the systemic features by months. It is a great mimicker of more common etiologies, such as demyelination syndromes, chronic infections, malignancy, and CNS vasculitis. A high index of suspicion is required for diagnosing HLH restricted to CNS. A relapsing course, partial or no response to immunomodulatory drugs, and hemorrhagic CNS lesions are important pointers to the diagnosis of this entity. With the advent of HSCT as a potentially curative therapy, the timely recognition of primary HLH may be lifesaving.

We thank the neurosurgery team for performing the brain biopsy of the case and the pathology team for examining the histopathology of the brain biopsy.

Drs Prashant and Juhi conceptualized and designed the study, collected data, and drafted the initial manuscript; Drs Atin, Biswaroop, and Aditya provided the neuroradiology and neurooncology inputs for the diagnosis and management of the case and collected data; Drs Sheffali and Rachna provided the pediatric neurology and pediatric oncology inputs for the diagnosis and management of the case, conceptualized and designed the study, and collected and interpreted the data; and all authors reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.

ATT

antitubercular therapy

CNS

central nervous system

HLH

hemophagocytic lympho-histiocytosis

HSCT

hematopoietic stem cell transplant

IvMP

intravenous methylprednisolone pulse

1.
Benson
LA
,
Li
H
,
Henderson
LA
, et al
.
Pediatric CNS-isolated hemophagocytic lymphohistiocytosis
.
Neurol Neuroimmunol Neuroinflamm
.
2019
;
6
(
3
):
e560
2.
Algahtani
H
,
Absi
A
,
Bassuni
W
,
Shirah
B
.
Adult-onset hemophagocytic lymphohistiocytosis type 2 presenting as a demyelinating disease
.
Mult Scler Relat Disord
.
2018
;
25
:
77
82
3.
Kim
MM
,
Yum
MS
,
Choi
HW
, et al
.
Central nervous system (CNS) involvement is a critical prognostic factor for hemophagocytic lymphohistiocytosis
.
Korean J Hematol
.
2012
;
47
(
4
):
273
280
4.
Henter
JI
,
Horne
A
,
Aricó
M
, et al
.
HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis
.
Pediatr Blood Cancer
.
2007
;
48
(
2
):
124
131
5.
Ishii
E
,
Ueda
I
,
Shirakawa
R
, et al
.
Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions
.
Blood
.
2005
;
105
(
9
):
3442
3448
6.
Pak
N
,
Selehnia
A
,
Hunfeld
MAW
, et al
.
Atypical neuroimaging characteristics of hemophagocytic lymphohistiocytosis in infants: a case series of hemorrhagic brain lesions in the deep grey matter
.
Neuroradiology
.
2021
;
63
(
2
):
285
288
7.
Cellucci
T
,
Benseler
SM
.
Central nervous system vasculitis in children
.
Curr Opin Rheumatol
.
2010
;
22
(
5
):
590
597
8.
Shabrish
S
,
Kelkar
M
,
Yadav
RM
, et al
.
The spectrum of clinical, immunological, and molecular findings in familial hemophagocytic lymphohistiocytosis: experience from India
.
Front Immunol
.
2021
;
12
:
612583
9.
Trizzino
A
,
zur Stadt
U
,
Ueda
I
, et al;
Histiocyte Society HLH Study group
.
Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations
.
J Med Genet
.
2008
;
45
(
1
):
15
21
10.
Sieni
E
,
Cetica
V
,
Santoro
A
, et al
.
Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis type 3
.
J Med Genet
.
2011
;
48
(
5
):
343
352
11.
Li
H
,
Benson
LA
,
Henderson
LA
, et al
.
Central nervous system-restricted familial hemophagocytic lymphohistiocytosis responds to hematopoietic cell transplantation
.
Blood Adv
.
2019
;
3
(
4
):
503
507
12.
Moshous
D
,
Feyen
O
,
Lankisch
P
, et al
.
Primary necrotizing lymphocytic central nervous system vasculitis due to perforin deficiency in a four-year-old girl
.
Arthritis Rheum
.
2007
;
56
(
3
):
995
999
13.
Beaty
AD
,
Weller
C
,
Levy
B
, et al
.
A teenage boy with late onset hemophagocytic lymphohistiocytosis with predominant neurologic disease and perforin deficiency
.
Pediatr Blood Cancer
.
2008
;
50
(
5
):
1070
1072
14.
Khazal
S
,
Polishchuk
V
,
Soffer
G
, et al
.
Allogeneic hematopoietic stem cell transplantation is associated with cure and durable remission of late-onset primary isolated central nervous system hemophagocytic lymphohistiocytosis
.
Pediatr Transplant
.
2018
;
22
(
1
):
e13101