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Measurement of Cerebrospinal Fluid Protein Is Unnecessary inChildren with Leukemia
Ashley Barber, BA,1 James Lovato, MS,2 Garick Hill, MD,1 and Thomas W. McLean, MD1*
INTRODUCTION
During the typical course of treatment for acute lymphoblastic
leukemia (ALL), patients receive 15–18 lumbar punctures (LPs)
while those with acute myelogenous leukemia (AML) receive
2–4 LPs. LPs are used for therapeutic and diagnostic purposes.
Therapeutically, chemotherapy is delivered directly to the central
nervous system (CNS), greatly reducing the probability of CNS
relapse and improving long-term event-free survival [1]. Diagnosti-
cally, cerebrospinal fluid (CSF) is obtained for studies to test for the
presence of leukemia. These studies may include a cell count and
differential, total protein level, and microscopic examination of the
cells after CSF centrifugation (‘‘cytospin’’).
Elevated CSF protein is a nonspecific indicator of CNS
pathology such as infection, degenerative processes, and neoplastic
disease. CSF protein can be elevated because of ‘‘increased
permeability of the blood–brain barrier, decreased resorption at
the arachnoid villi,mechanical obstruction ofCSFflowdue to spinal
block above the site of puncture, or an increase in intrathecal
immunoglobulin synthesis’’ [2]. Patients can have falsely elevated
protein levels if the LP is traumatic. CSF protein can be low
normally in infants 6 months to 2 years old, with repeated LP, a
chronic leak, acute water intoxication, or idiopathic intracranial
hypertension [3]. Causes for abnormal CSF protein are summarized
in Table I.
There are few data that total CSF protein is helpful in the
diagnosis or management of acute leukemia. At least one study has
suggested that an elevatedCSFprotein at diagnosis is an adverse risk
factor in children with ALL [4]. When a CSF protein level is
abnormal (high or low), the results rarely, if ever, appear to impact
patient management. The objectives of this study were to determine
the incidence of abnormal CSF protein in children with acute
leukemia, determine if abnormal CSF protein was associated with
clinical outcome, and determine the frequency of abnormal CSF
protein impacting patient management.
METHODS
With approval from our Institutional Review Board, a retro-
spective chart reviewwas performedon all pediatric (age�18 years)
patients diagnosed with ALL or AML at Brenner Children’s
Hospital (Winston-Salem, NC, USA) between 1998 and June 2006.
Data obtained included age, gender, race/ethnicity, leukemia
type, date of diagnosis, CSF laboratory results (CSF cell count
and differential, cytospin, and protein), and outcome (remission,
relapse, and death). Abnormal CSF protein values were defined as
below15mg/dLor above 45mg/dL [2].Anyproteinvalue defined as
abnormal was investigated further to determine whether the patient
was having CNS symptoms at the time and whether any action was
taken based on the result of the protein level.
A generalized estimating equations model with a binomial
probability distribution and logit link was fit. The model was
adjusted for the following factors: the patient’s age at time of the LP,
race, gender, CSF white blood cells (WBC) count, CSF red blood
cell (RBC) count, presence of CNS symptoms, leukemia type, and
To determine the incidence and importance of abnormalcerebrospinal fluid (CSF) protein in children with acute leukemia,we performed a retrospective chart review. On 160 pediatric patientsa total of 2,172 LPs were performed (median per patient¼15; range1–38). Overall, 314 (14%) of CSF protein measurements wereabnormal: 141 (7%) were abnormally low (<15mg/dL) and 158 (7%)
were abnormally high (>45 mg/dL). In no case did an abnormalCSF protein impact patient management. We conclude thatroutine measurement of CSF protein is not indicated in childrenwith acute leukemia. Pediatr Blood Cancer 2008;51:428–430.� 2008 Wiley-Liss, Inc.
Key words: Central nervous system; Cerebrospinal fluid; Leukemia; Pediatric; Protein
——————1Department of Pediatrics, Wake Forest University School of
Medicine, Winston-Salem, North Carolina; 2Department of
Biostatistical Sciences, Wake Forest University School of Medicine,
Winston-Salem, North Carolina
*Correspondence to: Thomas W. McLean, Department of Pediatrics,
Wake Forest University School of Medicine, Medical Center
Boulevard, Winston-Salem, NC 27157. E-mail: [email protected]
Received 28 September 2007; Accepted 11 March 2008
� 2008 Wiley-Liss, Inc.DOI 10.1002/pbc.21586
428 Brief Reports
CNS disease status. P-values were computed from type 3 score
statistics.
RESULTS
Between 1998 and June 2006, 166 pediatric patients with acute
leukemia were diagnosed. Of the 166 patients, 5 were excluded
because they did not undergo an LP or have aCSF proteinmeasured.
Another patient with recurrent AMLwas also excluded because she
had severe encephalitis of unknown etiology with a markedly and
persistently elevated CSF protein. Of the remaining 160 patients, a
total of 2,172 LPs were performed (median number of LPs for all
patients¼ 15 (range 1–38); median for patients with ALL¼ 17
(range 1–38); median for patients with AML¼ 3 (range 1–7).
Table II summarizes patient characteristics and results.
The mean CSF protein level for all samples was 30 mg/dL;
median 25 mg/dL; range 1–101 mg/dL. Overall, 299 (14%) of CSF
protein measurements were abnormal: 141 (7%) were abnormally
low (<15 mg/dL) and 158 (7%) were abnormally high
(>45 mg/dL). Three hundred forty six (16%) LPs were traumatic
(defined as CSF with 10–499 RBC/mL and 67 (3%) were bloody
(defined as CSF with �500 RBC/mL) [5].Abnormal CSF protein did not correlate with age, race/ethnicity,
gender, CSF WBC count, cytospin result, or leukemia type. The
presence of CNS symptoms (e.g. headache) was associated with an
abnormal CSF protein (P¼ 0.002). The presence of elevated RBCs
was the most common association with an elevated CSF protein.
When traumatic LPswere excluded from the analysis, therewere no
significant changes in any of these results. Likewise, when AML
patients were excluded and only ALL patients were analyzed, the
same results hold true. On review of each occurrence of an abnormal
CSF protein, it was determined that no change in management was
made in any case. Specifically, no intrathecal therapieswere held, no
further tests were ordered, and noCNS relapses were detected based
on CSF protein.
DISCUSSION
In this series of pediatric patients with acute leukemia, CSF
protein levels were abnormal in 14% of samples. Approximately
half of the abnormal values were high and half were low. For the
majority of abnormal values, the etiologies were not known,
although themost common associationwith an elevatedCSFprotein
was a traumatic or bloody LP, and an abnormal (high or low) CSF
proteinwas associatedwith the presence ofCNS symptoms.Despite
these associations, in no case did an abnormal CSF protein impact
patient management.
Some earlier ALL protocols within the Pediatric OncologyGroup
(now part of the Children’s Oncology Group (COG)) required
measurement of CSF protein and glucose. Glucose measurement
Pediatr Blood Cancer DOI 10.1002/pbc
TABLE I. Conditions Associated with Abnormal CSF Protein Levels [2,3,6]
Conditions associated with a low CSF protein Conditions associated with an elevated CSF protein
Infants 6 months to 2 years old Newborns
Repeated LPs Infection
Chronic leak Inflammation
Acute water intoxication Intracranial hemorrhage
Idiopathic intracranial hypertension CNS malignancies
Obstruction of the CSF
Multiple sclerosis
Guillain Barre syndrome
Some endocrinopathies
Certain medicines
During the first 100 days after BMT
Traumatic LP (falsely elevated)
CSF: cerebrospinal fluid; LP: lumbar puncture; BMT: bone marrow transplant.
TABLE II. Patient Characteristics of 160 Pediatric Patients withAcute Leukemia
Characteristic Number %
Race
White (non-Hispanic) 121 76
Black (non-Hispanic) 23 14
Hispanic 13 8
Other 3 2
Gender
Male 100 62
Female 60 38
Leukemia type
AML 25 16
Precursor B-cell ALL 115 71
Precursor T-cell ALL 20 13
Age at diagnosis (years)
Mean (s.d.) 6.7 (4.9)
Median (range) 4.5 (0.4–18)
Initial blood WBC/mm3
Mean (s.d.) 43.5 (78.4)
Median (range) 12 (0.5–575)
# LPs/pt
Mean (s.d.) 13.6 (7.6)
Median (range) 15 (1–38)
# Abnormal LP/pt
Mean (s.d.) 2 (3.5)
Median (range) 1 (0–26)
% Abnormal LP/pt
Mean (s.d.) 15.3
Median (range) 5 (0–100)
CSF protein (n¼ 2,172)
Low (<15 mg/dL) 141 7
Normal (15–45 mg/dL) 1,873 86
High (>45 mg/dL) 158 7
ALL: acute lymphoblastic leukemia, AML: acute myelogenous
leukemia, WBC: white blood cell, LP: lumbar puncture, s.d.: standard
deviation, pt: patient.
Brief Reports 429
was dropped in the early 1990s, and the current COG protocols for
ALL and AML do not request CSF protein measurement. Our data
confirm that CSF protein measurement is usually unnecessary.
In our institution, the current charge of a CSF protein measure-
ment is $28.50. Using that price over the 8 years of the study for the
2,172 tests, the total cost equals $61,902. Although this is a
relatively small amount compared to the total costs of leukemia
therapy for 160 patients, eliminating routine CSF protein measure-
ments will obviously save money.
This study is limited by its retrospective nature and exclusion of
adults. It is possible that other, more specific CSF proteins may
prove useful in detecting minimal or occult CNS leukemia, or
potentially even provide early signs of leukoencephalopathy or
neurocognitive decline. To date, however, reliable tests for these
conditions do not exist.More sensitive tests for the detection of these
conditions are required.
In summary, in pediatric patients with acute leukemia the fre-
quency of abnormal CSF protein levels is 14%.Half of the abnormal
values were high and half were low. In no instances did an abnormal
CSF protein impact patient management. Routine measurement of
CSF protein is not indicated in children with acute leukemia.
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1. Pui CH, Mahmoud HH, Rivera GK, et al. Early intensification of
intrathecal chemotherapy virtually eliminates central nervous
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Blood 1998;92:411–415.
2. Strandell C, DeBoer BG, Schmidt MPH, et al. Cerebrospinal fluid
studies. In: Fischbach FT, editor. Manual of laboratory & diagnostic
tests. Philadelphia: Lippincott Williams & Wilkins; 2004. 309–
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3. SeehusenDA,ReevesMM, FominDA. Cerebrospinal fluid analysis.
Am Fam Physician 2003;68:1103–1108.
4. Rautonen J. Elevated cerebrospinal fluid leukocyte count and
protein concentration at diagnosis: independent risk factors in
children with acute lymphoblastic leukemia. Blut 1988;56:265–
268.
5. Howard SC, Gajjar AJ, Cheng C, et al. Risk factors for traumatic and
bloody lumbar puncture in children with acute lymphoblastic
leukemia. JAMA 2002;288:2001–2007.
6. van den Berg H, Gerritsen EJ, Haraldsson A, et al. Changes in cell
and protein content of cerebrospinal fluid in children with acute
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Recurrent Melanotic Neuroectodermal Tumor in the Orbit Successfully TreatedWith Resection Followed by Pediculated Periosteal Flaps
Kyoichi Nakanishi, MD1,* Hiroki Hori, MD, PhD,1 Toshio Matsubara, MD, PhD,2 Kazuyuki Matsuda, MD,1
Takao Deguchi, MD, PhD,1 and Yoshihiro Komada, MD, PhD1
INTRODUCTION
Melanotic neuroectodermal tumor of infancy (MNTI) is a
pigmented neoplasm of neural crest origin that develops during the
first year of life. This rare tumor commonly arises from orofacial
bones, grows rapidly and often recurs after incomplete resection.
The maxilla is involved in approximately 70% of cases [1]. MNTI
arising from the orbit, that is, frontotemporosphenoid area, is rare
[2]. A complete excision is the primary modality of treatment for
this tumor while recurrence following surgical excision is reported
to reach 10–15% of cases [1]. Surgery usually causes boney defects
that lead cosmetic and functional problems. Chemotherapy has been
tried against recurrent or residual tumors although indication for
infants with non-metastatic MNTI is arguable [3]. Reconstruction
of bone defects after tumor resection in infantile patients is of
particular importance because their orofacial skeleton is growing.
Autogenous and allogenous grafts have been used for the
reconstruction in these cases [4,5].
In this article, we report a newborn case of MNTI in the lateral
wall of the right orbit with recurrence 3 months after the initial
surgery. She was successfully treated with the second surgery and
Melanotic neuroectodermal tumor of infancy (MNTI) is a raretumor arising mainly in the orofacial bones. Among more than200 cases described in articles, only seven cases involved orbitalregions. We present a case of newborn with recurrent MNTI in thelateral wall of right orbit. The patient underwent complete surgicalresections at onset and relapse. The bone defects following
the second surgery were successfully reconstituted with pediculatedperiosteal flaps from parietofrontal bones. In this article, we describeclinical course of recurrent MNTI in the orbit and discuss manage-ment of the tumor involving the orbit. Pediatr Blood Cancer2008;51:430–432. � 2008 Wiley-Liss, Inc.
Key words: melanotic neuroectodermal tumor of infancy; orbit; periosteal flaps; surgery
——————1Department of Pediatric and Developmental Science, Mie University
Graduate School of Medicine, Tsu, Japan; 2Department of
Neurosurgery, Mie University Graduate School of Medicine, Tsu,
Japan
*Correspondence to: Kyoichi Nakanishi, Department of Pediatric and
Developmental Science, Mie University Graduate School of Medicine,
2-174 Edobashi, Tsu-shi, Mie-ken 514-8507, Japan.
E-mail: [email protected]
Received 20 December 2007; Accepted 28 March 2008
� 2008 Wiley-Liss, Inc.DOI 10.1002/pbc.21607
430 Brief Reports
