The cerebrospinal fluid lactate is decreased in early stages of multiple sclerosis

Abstract

The purpose of this study was to investigate if the concentration of lactate can provide additional information for pathologies that need examination of the cerebrospinal fluid (CSF) in their diagnostic controls or protocols.
A prospective study carried out in the year 2001 at the University Hospital of Bellvitge (Barcelona), on 92 samples of CSF from patients who needed this examination. The concentration of lactate, glucose, and the cell count was determined. One year later, the diagnosis revealed from the previous analyzed samples were sorted into groups according to the diagnosis.
In the group with multiple sclerosis (MS) (n = 30), there was a significant decrease in lactate concentration (1.52 +/- 0.19 mmol/L) compared to the control group (1.89 +/- 0.11 mmol/L) (p < 0.001). The glucose concentration remained within the normal range and the cell count was < 4 cell/microL even in the relapses.
In the early stages of MS, the lactate concentration in CSF is decreased and this could be related to alterations in sensitivity observed in those patients. Further studies are needed to evaluate if this lactate concentration is a prognostic indicator of the disease.

Full text

171
PRHSJ Vol. 27 No. 2
June, 2008 Multiple Sclerosis and Lactate
Fonalledas, M. A., et al.
The cerebrospinal fluid lactate is decreased in early stages of multiple
sclerosis
MARÍA ASSUMPTA FONALLEDAS PERELLÓ, MD*; JOSÉ VALERO POLITI, MD†;
MARÍA ANTÓNIA LIZARRAGA DALLO, MD*; RAMÓN SEGURA CARDONA, MD*
*Departament de Ciències Fisiològiques II. Facultat de Medicina. Universitat de
Barcelona. L’Hospitalet de Llobregat. Barcelona, †Laboratori Clínic. Hospital
Universitari de Bellvitge. L’Hospitalet de Llobregat. Barcelona.
Address correspondence to: M. Assumpta Fonalledas, MD, Departament
Ciències Fisiològiques II. Facultat de Medicina.Campus de Bellvitge.
Universitat de Barcelona. 08907 L’Hospitalet de Llobregat. Barcelona.Spain, Tel:
034934024517, FAX: 034934024268, E-mail: afonalledas@hotmail.com
Background: The purpose of this study was to
investigate if the concentration of lactate can provide
additional information for pathologies that need
examination of the cerebrospinal fluid (CSF) in their
diagnostic controls or protocols.
Methods: A prospective study carried out in the year
2001 at the University Hospital of Bellvitge (Barcelona),
on 92 samples of CSF from patients who needed this
examination. The concentration of lactate, glucose, and
the cell count was determined. One year later, the
diagnosis revealed from the previous analyzed samples
were sorted into groups according to the diagnosis.
Results: In the group with multiple sclerosis (MS)
(n=30), there was a significant decrease in lactate
concentration (1.52 ± 0.19 mmol/L) compared to the
control group (1.89 ± 0.11 mmol/L) (p<0.001). The
glucose concentration remained within the normal
range and the cell count was < 4 cell/μL even in the
relapses.
Conclusions: In the early stages of MS, the lactate
concentration in CSF is decreased and this could be
related to alterations in sensitivity observed in those
patients. Further studies are needed to evaluate if this
lactate concentration is a prognostic indicator of the
disease.
Key words: Cerebrospinal fluid; Lactate; Multiple
Sclerosis.
In recent years, knowledge of lactic acid
physiopathology has increased its usefulness as a
biological indicator outside the limits of anaerobic
metabolism. The ionization potential (pK) of lactic acid at
37ºC (3.87) (1), assures the dissociation to the anion lactate
in the cerebrospinal fluid (CSF) within its physiological
pH levels (7.35-7.40). Lactate is a more reliable indicator in
CSF than in blood, owing to less variation in cerebral pH.
In some infectious processes, such as meningitis, the
determination of CSF lactate has been used to establish the
differential diagnosis between a viral or a bacterial aetiology
(2) but, as far as we know, there is not much information
about these questions, and therefore, the use of lactate as a
biological indicator, is still practically unknown.
The objective of this study is to determine if the
concentration of lactate can provide additional information
in those pathologies that need examination of CSF in their
diagnostic protocols or controls.
Materials and Methods
The prospective study was carried out for 4 months in
2001. The samples of CSF were from 92 patients from the
clinical laboratory at the University Hospital of Bellvitge
(Barcelona).
One hour after collecting the samples obtained by
lumbar puncture, the glucose values were determined
using the glucose-oxidase method (Roche Diagnostics /
Hitachi 911, Mannheim, Germany) and the cell count was
obtained in a Fuchs-Rosenthal chamber. The samples were
then centrifuged and stored at -80ºC to prevent
degradation of the lactate (3).
The lactate concentration was determined in an YSI 1500
analyser (YSI Inc., EUA) by an enzymatic method that
uses lactate-oxidase to transform the lactate into hydrogen
peroxide, which in turn is oxidised on a platinum anode
that produces electrons until it reaches equilibrium.
Two of the samples were discarded due to haematic
contamination.
A year later, the clinical histories were consulted and
the 90 diagnoses were checked. The cases were grouped
according to generic diagnosis that included a minimum
of 5 samples (Table 1).
The control group (C) consisted of 8 samples of CSF
corresponding to 8 patients that showed normality in the

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June, 2008
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Multiple Sclerosis and Lactate
Fonalledas, M. A., et al.
analysis and a slight clinical diagnosis. The clinical
diagnoses were: Slight cognitive deterioration; slight
traffic accident control; cortical dysfunction; subacute
dementia; radiculopathy L5-S1; discopathy L4-L5;
psychotic disorder and migraine. Prior to the group
distribution, 5 samples with an associated diagnosis that
could mask results were excluded
Statistical analysis: The differences between groups
were analysed using the Mann-Whitney U test and in all
the contrasts, statistical significance was established as
p<0.05. The data obtained was analysed using the
statistical program “SPSS for Windows”, version 14.0
Results
The data from the 85 CSF samples finally included in the
study are shown in Tables 1 and 2.
A) All groups (Table 1)
In the multiple sclerosis (MS) group, statistically
significant differences were observed with respect to group
C for lactate concentration values of 19.6 % lower (p<0.001),
and for glucose concentration values of 15.6 % lower
(p=0.003). For cell counts, higher values were observed
(p<0.01).
In the demyelinating diseases group other than MS
(DM), statistically significant differences were observed
with respect to group C for lactate concentration values
of 20.6% lower (p<0.01).
In the subacute inflammatory diseases (SI) group, no
statistically significant differences were observed with
respect to group C.
In the acute infections (AI) group, statistically
significant differences were observed with respect to group
C for lactate concentration values of 33.3% higher (p<0.05),
and for glucose concentration values of 48.1% lower
(p<0.01).
In the neoformations (NEO)group, statistically
significant differences were observed with respect to group
C for lactate concentration values of 121% higher (p<0.01).
B) MS groups (Table 2)
In the relapsing remitting multiple sclerosis (RRMS)
subgroup, statistically significant differences were
observed with respect to the primary progressive multiple
sclerosis (PPMS) subgroup for lactate concentration
values of 11.1% lower (p<0.05).
In the clinically isolated syndrome (CIS) subgroup,
statistically significant differences were observed with
respect to the PPMS subgroup, for lactate concentration
values of 11.6 % lower (p<0.05).
Discussion
In the present study, we observed that a substantial
percentage of the samples had a diagnosis of demyelinating
diseases, especially MS, as their diagnostic protocol
included the presence of oligoclonal bands of Ig G and/or
the index of Ig G in CSF (4).
In the MS group, 93% of the CSF samples collected in
clinical early stages to analyse and establish the definite
diagnosis show a significantly reduced lactate
concentration (1.52 ± 0.19 mmol/L) as compared to group
C (1.89 ± 0.11 mmol/L). The values in group C are
comparable with the normal values obtained in other similar
studies (2). Within the MS group, the decrease in lactate
Table 1. Clinical and CSF data in patients with various diseases.
Groups Diagnoses No. of Sex Age Lactate Glucose Cells
cases (M/F) years mmol/L mmol/L no/μμ
μμ
μL
Range (M±SD) (M±SD) Range
C Controls 8 5/3 23-75 1.89 ± 0.11 3.78 ± 0.50 0-3
MS Multiple sclerosis 30 10/20 21-72 1.52 ± 0.19 3.19 ± 0.38 0-4
DM Demyelinating diseases 5 4/1 31-70 1.50 ± 0.10 3.18 ± 0.59 0-4
SI Subacute inflammations 6 4/2 31-68 1.87 ± 0.27 3.43 ± 0.54 0-20
AI Acute infections 5 3/2 20-66 2.52 ± 0.48 1.96 ± 1.03 35-850
NEO Neoformations 8 7/1 22-68 4.18 ± 2.06 3.17 ± 2.02 0-250
OD Other diseases 23 11/12 21-79 1.59 ± 0.76 3.59 ± 2.01 0-7
M ± SD: Mean ± Standard Deviation
Mann-Whitney test:
Comparison C vs MS: p<0.001 and p=0.003 for lactate and glucose concentration.
Comparison C vs DM: p<0.01 for lactate concentration.
Comparison C vs AI: p<0.05, p<0.01 and p<0.01 for lactate and glucose concentration, and cell count.
Comparison C vs NEO: p<0.01 for lactate concentration.
The other comparisons are not significants.

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June, 2008 Multiple Sclerosis and Lactate
Fonalledas, M. A., et al.
concentration is more marked in RRMS and CIS, which
show values lower than those obtained in PPMS (Table
2), in agreement with other publications (5), suggesting
that PPMS constitutes a separate disease entity different
from RRMS.
The decrease in lactate concentration in the CSF of
patients with MS, may explain the alterations in sensitivity
in some of these patients. In the present study, the lowest
values in the lactate concentration (mean 1.25 mmol/L)
range corresponded to 3 patients from the group of other
diseases (OD), with isolated symptoms of deficient
sensitivity (lower limb paraesthesias; hemibody
hypoesthesia; neurosensorial hypoacusia), similar
symptoms to those seen in some patients with early stages
of MS, suggesting alterations in the ionic acid-sensitive
channels, because of the increased resistance of these
channels to opening and depolarisation when the effect
of lactate is reduced. This facilitates the opening of the
channels (pores) due to their capacity of removing Ca²+
cations that block them (6).
The decrease in lactate concentration in the CSF of
patients with MS may be due to an increase in the
consumption of lactate satisfying a double need:
maintaining myelination as well as a minimum level of
glucose. In fact, it has been noted that, on one hand, the
oligodendrocytes prefer lactate for synthesizing myelin
(7) and, on the other hand, that, experimentally, in cases of
glucose depletion, the lactate is used as the energy source
of first choice (8). In these conditions, thermodynamically,
the step from lactate to pyruvate (when entering into the
tricarboxilic acid cycle) is preferred over the conversion of
glucose to pyruvate, which does not require the previous
investment of adenosine triphosphate (ATP).
These observations concur with other results in the
present study showing glucose concentration values in
the CSF of patients with MS (3.19 ± 0.38 mmol/L) 15.6%
lower with respect to group C (3.78 ± 0.50 mmol/L).
Although these values remain within the normality of the
method used here (interval reference: 2.8-4.2 mmol/L), they
are at the lower range limit. According to our knowledge,
low levels of CSF glucose in patients with MS have not
been described, although reduced levels of the cerebral
metabolism of glucose have been observed in the frontal
cortex and the basal ganglia, using functional techniques
such as positron emission tomography (PET) in patients
with MS and fatigue (9).
The results of the present study are in agreement with a
published article (10) whose authors have observed a
decrease in lactate concentration and other gluconeogenic
metabolites, such as glutamine in the CSF of patients with
MS, by means of a proton magnetic resonance
spectroscopy (1H-RMS).
Other authors (11) are in apparent disagreement with
our results. In 1H-RMS, they have observed increases in
lactate concentration and, correlatively, in the cell count
of CSF of patients with RRMS during relapses. But, this
study was done in patients who had been previously
diagnosed with MS. It is known, that the diagnosis of MS
always involves a certain waiting time, generally over a
year. However, in our present study, the CSF samples and
their subsequent analysis were done in the early clinical
stages with the objective of establishing a definite
diagnosis: In 65 % of the patients who were subsequently
diagnosed with MS, a lumbar puncture was performed
within a week of the relapse and, in not later than a month.
Therefore, chronologically, the results of preceding authors
are not comparable with those shown here. But, it needs
to be pointed out that the low cell count levels in the CSF
of patients with MS studied here, that are within the normal
range (0-4 cells/ML) (12), are not in disagreement with the
positive correlation between lactate and the cell count
observed by these authors.
Finally, in the present study, it is important to note that,
although the number of CSF samples used as controls is
Table 2. Values of parameters in the CSF of patients with multiple sclerosis.
Subgroups MS Clinical forms No. of Lactate Glucose Cells
cases mmol/L mmol/L n.o/μμ
μμ
μL
(M + SD) (M + SD) Range
CIS Clinically isolated syndrome 7 1.44 ± 0.23 3.09 ± 0.29 0-4
RRMS Relapsing-remitting 20 1.53 ± 0.17 3.17 ± 0.38 0-4
PPMS Primary progressive 3 1.71 ± 0.06 3.57 ± 0.46 0-1
M + SD: Mean + Standard Deviation.
Mann-Whitney test:
Comparison CIS vs PPMS: p<0.05 for lactate concentration.
Comparison RRMS vs PPMS: p<0.05 for lactate concentration.
The other comparisons are not significants.

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small, this limitation has been corrected accepting as
completely valid those results in the MS group, taking
into consideration the values already known and confirmed
by the parameters studied in the remaining groups that
were analysed (Table 1) that contributed to verification of
the results. Thus, for example, the confirmation of the high
values in the lactate concentration already described from
samples with a diagnosis of IA (13), or the high values in
the lactate concentration from samples with a diagnosis
of NEO correspond with the poly-medicated patients.
To summarise, the results of the present study show a
decrease in CSF lactate concentration in the early stages
of MS that may explain some alterations in the sensitivity
of these patients, and also suggest a greater consumption
of lactate as an alternative energy source, in order to
preserve a minimum level of glucose. However, further
studies are necessary to confirm these results and evaluate
if the lactate concentration is a prognostic indicator of the
disease.
Resumen
La propuesta de este estudio era investigar si la
concentración de lactato puede aportar información
adicional en aquellas patologías que precisan el examen
del liquido cefalorraquídeo (LCR) en sus protocolos de
diagnóstico o control. Estudio prospectivo realizado en el
año 2001 en el Hospital Universitario de Bellvitge
(Barcelona), sobre 92 muestras de LCR de pacientes que
precisaban este examen, determinándose la concentración
de lactato, de glucosa y el recuento de células. Un año
después se develaron los diagnósticos de las muestras
previamente analizadas, y se clasificaron en grupos según
los diagnósticos. En el grupo con esclerosis múltiple (EM)
(n=30), se halló una concentración de lactato (1.52 ± 0.19
mmol/L) significativamente disminuida en comparación con
el grupo control (1.89 ± 0.11 mmol/L) (p<0.001). La
concentración de glucosa permaneció dentro de los límites
de la normalidad y el recuento de células fue < 4 cel/µL,
incluso en los brotes. En las fases tempranas de la EM, la
concentración de lactato en el LCR se haya disminuida,
pudiendo estar relacionada con alteraciones de la
sensibilidad observadas en estos pacientes. Serán
necesarios más estudios para valorar si esta concentración
de lactato es un indicador pronóstico de la enfermedad.
Acknowledgements
To Prof. Dr.Txomin Arbizu, Unidad de Esclerosis
Múltiple, Hospital Universitari de Bellvitge, Barcelona,
Spain, for reviewing the manuscript and the Fonalledas
Foundation of Puerto Rico for the financial support.
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