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Frequency and Severity of Central Nervous System Lesions in
Hemophagocytic Lymphohistiocytosis
By Elie Haddad, Maria-Luisa Sulis, Nada Jabado, Stephane Blanche, Alain Fischer, and Marc Tardieu
We have retrospectively assessed the neurological manifestations in 34 patients with hemophagocytic lymphohistiocytosis (HLH) in a single center. Clinical, radiological, and
cerebrospinal fluid (CSF) cytology data were analyzed according to treatment modalities. Twenty-five patients (73%)
had evidence of central nervous system (CNS) disease at
time of diagnosis, stressing the frequency of CNS involvement early in the time course of HLH. Four additional patients who did not have initial CNS disease, who did not die
early from HLH complications, and who were not transplanted, also developed a specific CNS disease. Therefore,
all surviving and nontransplanted patients had CNS involvement. Initially, CNS manifestations consisted of isolated
lymphocytic meningitis in 20 patients and meningitis with
clinical and radiological neurological symptoms in nine patients. For these nine patients, neurological symptoms consisted of seizures, coma, brain stem symptoms, or ataxia.
The outcome of patients treated by systemic and intrathecal
chemotherapy and/or immunosuppression exclusively (n !
16) was poor, as all died following occurrence of multiple
relapses or CNS disease progression in most cases. Bone
marrow transplantation (BMT) from either an HLA identical
sibling (n ! 6) or haplo identical parent (n ! 3) was performed in nine patients, once first remission of CNS and
systemic disease was achieved. Seven are long-term survivors including three who received an HLA partially identical
marrow. All seven are off treatment with normal neurological function and cognitive development. In four other patients, BMT performed following CNS relapses was unsuccessful. Given the frequency and the poor outcome of CNS
disease in HLH, BMT appears, therefore, to be the only available treatment procedure that is capable of preventing HLH
CNS disease progression and that can result in cure when
performed early enough after remission induction.
q 1997 by The American Society of Hematology.
H
Enfants Malades (Paris, France). In this single center retrospective
study, the diagnosis of HLH was based in 25 patients on the occurrence of a hemophagocytic syndrome with a family history of consanguinity or of siblings affected by the same syndrome. In nine
cases, the patient was the first affected child of the family and there
was no consanguinity. In these cases, the diagnosis was based on
the occurrence of: (1) a hemophagocytic syndrome without detection
of concomitant infection known to induce this condition, and (2) the
recurrence of hemophagocytic syndrome once a complete remission
was observed either spontaneously or following appropriate treatment. Treatment modalities for 26 of these patients have been previously reported.12-14
Involvement of the CNS was documented by clinical evaluation,
examination of cerebrospinal fluid (CSF), and neuroradiological
studies. The clinical neurological evaluation excluded the observation of isolated ‘‘hypotonia’’ or ‘‘hypertonia’’ during high fever or
painful episodes of systemic hemophagocytic syndrome. Patients
with CNS involvement were classified as suffering from either
‘‘meningitis’’ (no neurological symptoms except meningismus and
abnormal CSF) or from ‘‘neurological symptoms’’ (any neurological
deficit or seizures associated with CSF abnormalities). In this last
group of patients, brain stem involvement was defined by the presence of a coma with opisthotonos and irregularities in cardiac or
respiratory rates.
Nineteen patients were treated by chemotherapy alone and 15
patients (mostly in more recent years), after initial chemotherapy,
also underwent a bone marrow transplantation (BMT). In all cases,
an intensive supportive care protocol was used during hemophagocytic syndromes. During the maintenance phases, the children received intravenous gammaglobulin every 3 weeks and trimethoprimsulfamethoxazole orally.
Patients were treated according to previously published regimens.12-15 Between 1981 and 1990, chemotherapy consisted of steroids, VP16-213 (etoposide) and intrathecal methotrexate injections
(MTX IT) (6 to 12 mg according to age) (n Å 19).12,13 Since 1991,
VP16-213 was replaced by Cyclosporine A (CSA) and rabbit antithymocyte globulin (ATG) (Institut Merieux, Lyon, France) (n Å 15).14
During the maintenance therapy of both regimens, MTX IT was
given usually every month. The number of MTX IT injections depended on the intensity of CNS disease and the analysis of CSF
performed before each IT injection.
The conditioning regimen of BMT consisted of VP16-213, busulfan, and cyclophosphamide.13 Graft-versus-host disease (GVHD)
EMOPHAGOCYTIC lymphohistiocytosis (HLH) is a
lethal disease characterized by the occurrence of a
hemophagocytic syndrome including high fever, hepatosplenomegaly, pancytopenia, low fibrinogen level, hemodilution, elevation of liver enzymes, and hypertriglyceridemia.1,2 Most reported cases indicate an autosomal recessive
inheritance, but the cause of the disease remains unknown.
The main histopathologic feature is a nonmalignant diffuse
infiltration by lymphocytes and macrophages, most typically
with hemophagocytosis, into visceral organs, lymph nodes,
bone marrow, and central nervous system (CNS). This appears to reflect a massive activation of T lymphocytes3,4 and
cells of the macrophage-histiocyte lineage.5
Neurological manifestations of HLH have been recognized,6-11 but their frequencies, characteristics, and influence
on the outcome remain relatively ill-defined. In the present
study, we reviewed the characteristics of the neurological
manifestations that occurred in 34 consecutive patients with
HLH followed in a single center. The outcome according to
treatment regimen and CNS disease status has been assessed.
PATIENTS AND METHODS
Patients. Thirty-four patients (19 girls, 15 boys) with HLH were
consecutively hospitalized from 1981 to 1993 at Hôpital Necker-
From Unité d’Immuno-Hématologie et Unité INSERM 429, Hôpital Necker-Enfants Malades, Paris; and Service de Neurologie Pédiatrique et Laboratoire Virus, Neurone et Immunité, Hôpital Bicêtre,
Le Kremlin Bicêtre, France.
Submitted July 2, 1996; accepted September 23, 1996.
Address reprint requests to Elie Haddad, MD, Unité d’Immunologie et d’ Hématologie Pédiatriques, Département de Pédiatrie, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75749 Paris Cedex
15, France.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
q 1997 by The American Society of Hematology.
0006-4971/97/8903-0028$3.00/0
Blood, Vol 89, No 3 (February 1), 1997: pp 794-800
794
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CNS LESIONS IN LYMPHOHISTIOCYTOSIS
795
Fig 1. Neurological manifestations and outcome in 34 patients with HLH.
prophylaxis consisted of the associaton of methotrexate (10 mg/m2
on days 1, 3, 6, and 10) and CSA.16 Patients who received a haplo
identical BMT were also treated by monoclonal anti-leukocyte function adhesion 1 (anti-LFA1) and anti-CD2 antibodies (n Å 4)17 or
by anti-LFA1 antibody alone (n Å 3) to prevent graft rejection.18
Prevention of GVHD was based on T-cell depletion by E-rosetting
(four patients) or by Campath 1-M plus human complement (three
patients).19
Until 1990, the decision to perform BMT was based on the occurrence of relapse and on the availability of an HLA-identical sibling.
From 1990 to 1993, BMT was performed in case of relapse even
when no HLA-identical sibling was available. After 1993, BMT was
performed as soon as a complete remission was achieved.
Methods. CSF studies consisted of determination of the protein
level and microscopic analysis of cells detected on the cytospin
preparation. After staining by Giemsa, immunohistochemistry was
performed using anti-HLA DR (major histocompatibility complex
[MHC] class II) antibody. Neuroradiological studies were performed
in 19 patients and consisted of neuroradiologic magnetic resonance
(MR) imaging with administration of gadopentate dimeglumine and/
or computed tomographic (CT) scans.
RESULTS
Thirty-four consecutive patients were diagnosed with
HLH. Twenty-five patients had CNS involvement at the time
of the diagnosis (Fig 1). Among the nine patients without
CNS involvement at diagnosis, three died within weeks of
the diagnosis at 3, 4, and 8 months, respectively, of age and
two received a BMT before the occurrence of any neurological symptoms (one, transplanted at the age of 4 months, is
alive and well 5 years post-BMT and the second, transplanted at the age of 12 months, died of graft failure). The
remaining four patients developed CNS disease (Fig 1). Together, 29 patients had CNS involvement as defined above
and were studied further.
Description of the initial CNS manifestations. The initial
CNS manifestations consisted of meningitis in 20 patients
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and neurological symptoms in nine (Fig 1). Mean age at
time of meningitis was 6.9 months (median, 3; range, 1 to
31), while mean age at the time of neurological symptoms
was 16 months (median, 4; range, 1 to 58) (P Å .05). The
CNS involvement was associated with a systemic hemophagocytic syndrome in all cases.
Meningitis characteristics were detection of 20 to 80 lymphocytes/mL of CSF with an elevated spinal fluid protein
varying between 0.5 and 1 g/L. Cytospin preparation of the
CSF showed hemophagocytosis in 11 cases, the presence of
HLA DR-positive activated lymphocytes in eight cases (both
in five cases), while neither hemophagocytosis nor HLA
DR(/) lymphocytes were detected in six cases. Cultures of
CSF for bacterial, viral, and fungal infectious agents were
negative in all cases. In 9 of the 20 patients with meningitis,
a neuroradiological study was performed; brain imaging was
abnormal in 4 patients, demonstrating pericerebral diffuse
subdural dilatation and white matter abnormalities in 2 cases
each.
Among the nine children with initial neurological symptoms, seizures were the most frequent initial symptom in the
youngest patients, whereas ataxia was found in the two oldest
patients (46 and 58 months old, respectively) (Table 1). All
nine patients had the same CSF abnormalities as patients
with meningitis only. Eight of these nine patients had a
neuroradiological study performed at the time of their first
neurological symptoms (Table 1). The two most frequent
lesions were focal necrosis with parenchymal volume loss
and atrophy (Fig 2A and C) and white matter abnormalities
(Fig 2B). Several small focal lesions with hypersignal at MR
imaging that enhanced after administration of gadopentate
dimeglumine (or contrast on CT scan) were also observed
in two cases.
Subsequent neurological manifestations according to
treatment regimen. Intravenous (IV) and IT chemotherapy
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HADDAD ET AL
Table 1. Characteristics of CNS Disease in 16 Patients at Time of Their First Overt Clinical Neurological Manifestations
Age (mo)
Primary (I) or
Secondary Onset (II)
1
I
1.5
2
I
I
3
I
4
I
17
I
19
I
46
I
58
6
I
II
7
8
13
II
II
II
13
II
14
57
II
II
Clinical Symptoms
Radiological Symptoms
Coma
Seizures
Brain stem symptoms
Brain stem symptoms
Coma
MRI: White matter abnormalities
CT Scan: Calcifications
Abnormal contrast enhancement
ND
CT Scan: Abnormal contrast enhancement
Subdural space dilatation
CT Scan: Severe necrotic areas
White matter abnormalities
Subdural space dilatation
CT Scan: Severe atrophy
Coma
Seizures
Brain stem symptoms
Seizures
Brain stem symptoms
Coma
Seizures
Coma
Seizures
Hemiplegia
Ataxia
Somnolence
Meningism
Ataxia
Coma
Tetraparesis
Brain stem symptoms
Developmental delay
Developmental delay
Seizures
Developmental delay
CT Scan: Severe atrophy
CT Scan: Necrotic areas
CT Scan: White matter abnormalities
CT Scan: White matter abnormalities
ND
CT Scan: Calcifications
CT Scan: Severe atrophy
MRI: White matter abnormalities
CT Scan: Calcifications
Abnormal contrast enhancement
MRI: White matter abnormalities
CT Scan: Normal
Developmental delay
Coma
Seizures
Tetraparesis
Coma
Ataxia
MRI: White matter abnormalities
MRI: Necrotic areas
White matter abnormalities
Abbreviations: MRI, magnetic resonance imaging; CT Scan, computed tomographic scans; ND, not determined.
led to complete systemic and neurological remission in the
20 patients with initial meningitis (Fig 1). Among the nine
patients who presented neurological symptoms as the initial
CNS manifestation, IV and IT chemotherapy led to a complete remission in only three patients who, nonetheless, developed neurological sequelae.
Once complete remission was achieved (n Å 23), one
patient died of sepsis 2 months following initial chemotherapy (Fig 1). In 12 patients, maintenance treatment only was
given, and CNS relapses occurred within a median delay of
6 months (range, 1 to 26) associated with systemic disease
in eight patients. Nine of the 12 had new clinical neurological
manifestations. At time of relapse, 2 patients were still under
IV and IT treatment, 4 were under IV treatment with the
last MTX IT injection performed respectively, 2, 5, 10, and
30 months earlier, and 3 were off therapy for 1, 2, and 3
months, respectively.
Together, 19 patients had primary severe CNS disease
progression or CNS relapse (Fig 1). Three of 19 had a CNS
relapse characterized by meningitis only. Neurological
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symptoms occurred in 16 of these 19 patients (9 from the
onset and 7 after the initial meningitis) (Fig 1). No clinical
or neuroradiological difference was detected between the
patients who developed neurological symptoms as the initial
CNS manifestation or after initial meningitis (Table 1). The
occurrence of these neurological manifestations marked a
turning point in the evolution of the disease, as chemotherapy
led to an improvement of the neurological symptoms in only
three patients despite the use of intensive treatment by MTX
IT. In these three patients, neurological sequelae persisted
after the first symptoms and a relapse occurred within 3 to
10 months. Brain imaging was repeated during chemotherapy for four patients with progression of the CNS disease:
in three patients, a severe brain atrophy developed (Fig 3A
and B) and in the last patient who initially had contrast
enhancement in cerebellar white matter, a cerebellum parenchymal loss was observed (Fig 2C). All of these 19 patients
treated by chemotherapy only (n Å 15) died during a last
episode of coma and brain stem symptoms associated with
a systemic hemophagocytic syndrome, 6 { 6 months after
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CNS LESIONS IN LYMPHOHISTIOCYTOSIS
797
Fig 2. Three different aspects of brain imaging in HLH
patients. (A) CT scan of a 3-month-old baby showing a
large subdural effusion, several necrotic areas and hypodensities of the white matter. (B) Brain magnetic resonance of a 14-month-old boy showing large confluent
areas of hypersignal in T2-weighted images. (C) Large
symmetrical necrotic areas of cerebellar white matter in
a 41/2-year-old girl (MRI).
the first neurological symptom (irrespective of the age at
this first event). Four of these 19 patients were transplanted
(one patient received an HLA-identical BMT, three an HLApartially identical BMT). Median delay between diagnosis
and BMT was 14 months (range, 2 to 20 months). All of
these four patients died of BMT-related toxicity and/or disease progression.
Nine patients were transplanted soon after the remission
of initial CNS and systemic manifestations. All of these
patients had meningitis only as the CNS manifestation. The
median delay between diagnosis and BMT was 4 months
(range, 2 to 14 months). Two patients died of BMT-related
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toxicity (both recipients of an HLA-identical BMT). Seven
patients are alive and well with normal neurological examination, normal CSF tap, and normal cognitive development
after a follow-up of 18 to 132 months (median, 55 months)
(four recipients of an identical BMT and three of a partiallyidentical BMT). After BMT, chimerism studies demonstrated full or partial engraftment in all of these seven
patients. MRI was performed before and after the transplantation in three cases. Two patients had a normal MRI
or an isolated subarachnoidal and subdural space dilatation
before transplantation and a normal MRI, respectively 4
years and 18 months after transplantation. One patient had
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798
HADDAD ET AL
Fig 3. Evolution of brain lesions during HLH. (A) MRI of a 41/2-year-old girl showing focal white matter hypersignal on T2-weighted images.
(B) MRI of the same child 1 year later with an important atrophy of both the white matter and the cortices.
white matter abnormalities before transplantation, which remained identical 2 years after transplantation (Fig 4).
DISCUSSION
We have retrospectively reviewed the frequency, characteristics, and outcome of neurological manifestations of
Fig 4. MRI of a symptom-free 31/2-year-old child who received BMT
at 18 months showing the persistent white matter abnormalities.
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HLH. Twenty-five of 34 HLH patients (73%) had CNS disease at time of diagnosis. In addition, 4 of 9 patients without
CNS involvement at diagnosis later developed a CNS relapse, while the 5 others either died early or received a
BMT. Therefore, 100% of evaluable patients developed CNS
lesions in the absence of transplantation. The observed frequency of CNS disease at diagnosis appears slightly higher
than that reported in other studies. Janka1 reported CSF abnormalities in 17 of a series of 33 patients and neurological
symptoms in less than 10% of the patients. In a multicenter
retrospective study, Arico et al20 reported CSF abnormalities
at diagnosis in 55 of 94 patients (58%). Hirst et al21 found
clinical neurological manifestations at diagnosis in seven of
23 patients and CSF abnormalities in 13 of 17 evaluable
patients, and Henter et al22 reported CSF abnormalities in
four of seven patients with neurological symptoms in three
cases. No data are available in the literature that describe
the frequency of CNS disease occurrence during the course
of HLH disease.
Despite the chemotherapy-induced normalization of CSF
after initial meningitis, neurological symptoms developed
within months in all evaluable patients treated by chemotherapy alone, regardless of the chemotherapy regimen and frequency and number of IT methotrexate injections. Onset of
an overt neurological disease represented a major milestone
in the outcome since, subsequently, repeated relapses and
CNS disease progression led to more severe neurological
lesions and ultimately death within months.
Abnormalities on brain imaging appeared to roughly parallel the severity of clinical manifestations. All patients with
neurological symptoms, but also half of the patients with
initial meningitis, had abnormal brain imaging usually consisting of a combination of diffuse white matter abnormali-
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CNS LESIONS IN LYMPHOHISTIOCYTOSIS
799
ties and necrotic areas with parenchymal volume loss, as
previously described.8,23 In patients with isolated meningitis,
however, only white matter abnormalities were detected,
whereas necrotic lesions and cerebral atrophy were found in
patients with neurological symptoms. These lesions progressed despite chemotherapy. Previous neuropathological
studies have demonstrated infiltration by monocytes and activated lymphocytes of leptomeninges and brain parenchyma
along penetrating vessels.24,25 Infiltration is associated with
focal and confluent areas of myelin pallor, as well as neuronal loss, tissue necrosis, and cavitation,24,25 findings that
were also demonstrated in the neuropathologic study of five
patients in our series. Leukocytes infiltrating the CNS probably secrete cytokines and other neurotoxic factors, such as
tumor necrosis factor-a (TNF-a), which may be responsible
for the myelinic alteration observed in neurologically asymptomatic patients. Infiltrating leukocytes could also activate
in parallel the numerous resident brain macrophages (the
microglial cells) and astrocytes, which in turn, can secrete
neurotoxic glutamate and free radicals.26
The efficiency of allogenic BMT in preventing relapses
of peripheral HLH manifestations has already been reported,
including by our group.13,27,28 In this study, we describe the
remarkable effect of BMT on the prevention of subsequent
neurological manifestations and the good cognitive and neurological evolution of the seven transplanted children who
are long-term survivors. In addition, brain imaging performed several months or years after BMT showed a normal
aspect or a stabilization of white matter abnormalities. These
seven patients had initial meningitis, but never developed
neurological symptoms before BMT. Therefore, this study
does not allow conclusions on the potential beneficial effects
of BMT in patients with neurological symptoms. Nevertheless, it is likely that when atrophy and/or necrotic lesions are
present, BMT could probably, at best, lead to stabilization of
lesions carrying a risk of neurological and cognitive sequelae. We, therefore, believe that the optimal strategy for
the treatment of HLH patients is to perform a BMT as early
as possible once complete (systemic and neurological) remission has been achieved. Today, BMT from alternative donors, ie, matched unrelated29 and haplo-identical related donors (Jabado et al submitted), can also be considered.
However, this approach raises the question of the accuracy
of HLH diagnosis in patients without a family history or
consanguinity. In this setting, it may be more appropriate to
wait until relapse to confirm the HLH diagnosis, although
the risk of severe CNS lesion occurring in the meantime is
significant.
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1997 89: 794-800
Frequency and Severity of Central Nervous System Lesions in
Hemophagocytic Lymphohistiocytosis
Elie Haddad, Maria-Luisa Sulis, Nada Jabado, Stephane Blanche, Alain Fischer and Marc Tardieu
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