D. Franciotta

E. Nobile-Orazio

E. Zardini

M. Gastaldi

AIR Universita degli studi di Milano

DOI: 10.1111/jns.12253 Journal of the Peripheral Nervous System 23:70–72 (2018)
LETTER TO THE EDITOR
Cerebrospinal ﬂuid total protein determination in acute
and chronic inﬂammatory demyelinating
polyneuropathies: a critical reappraisal
Dear Editor,
Albumino-cytologic dissociation is a typical fea-
ture of Guillain-Barré syndrome (GBS) and its variants
(Fokke et al., 2014), and of chronic inﬂammatory
demyelinating polyradiculoneuropathy (CIDP), rep-
resenting one of the supportive criteria for the
diagnosis (Joint Task Force of the EFNS and the
PNS, 2010). Notwithstanding the explicit reference
to the term “albumin”, the criteria entail that the dis-
sociation is evaluated by measuring cerebrospinal
ﬂuid (CSF) total proteins and counting CSF cells.
Semantic violation apart, the topic deserves a reap-
praisal, since using CSF total proteins as a marker of
inﬂammation-dependent increased permeability of the
blood-CSF barrier (B-CSF-B) might lead to inaccurate
evaluations. The calculation of the most accurate
albumin quotient (QAlb =CSF albumin/serum albumin)
has long substituted for CSF total proteins in the area
of multiple sclerosis and other acquired demyelinating
syndromes (Andersson et al., 1994; Gastaldi et al.,
2017).
Preliminarily, it is worth noting that inﬂammation
in GBS/CIDP affects the blood-spinal nerve root barrier
(B-SNR-B), but not the B-CSF-B, formed by choroid
plexuses, nor the blood–brain barrier, whose increased
permeability, in turn, cannot be evaluated with the CSF
analysis (Thompson, 1988), as not infrequently done
(e.g., Stich et al., 2016).
Another important physiological aspect is that
∼80% of the CSF proteins are plasma-derived
and only ∼20% intrathecally produced (Thomp-
son, 1988). Therefore, assessing the degree of
B-SNR-B/B-CSF-B permeability as an index of spinal
nerve roots/intrathecal inﬂammation by means of CSF
total protein concentrations implies two shortcom-
ings: (1) serum total protein concentrations, on which
CSF total protein concentrations strictly depend,
Address correspondence to:Diego Franciotta, IRCCSMondino Foun-
dation, via Mondino 2, I-27100 Pavia, Italy. Tel: +(39)0382-380365;
Fax: +(39)0382-380286; E-mail: diego.franciotta@mondino.it
are not considered and (2) intrathecally produced
proteins – mainly immunoglobulin G (IgG) during
immuno-inﬂammatory CNS disorders – can be consid-
ered as part of the bulk of CSF total proteins although
their CSF concentrations are obviously independent
from any increase of B-SNR-B/B-CSF-B permeability.
As a result, patients with chronic or transient
low concentrations of plasma proteins (e.g., from
kidney or liver diseases) might show “normal” CSF
total protein concentrations even in the presence
of a leaky B-SNR-B/B-CSF-B (false negative results);
vice versa, patients with abnormally high concen-
trations of plasma proteins (e.g., paraproteinemic
patients; patients with previous therapy with intra-
venous immunoglobulins), or with intrathecal IgG
production (e.g., from chronic immuno-inﬂammatory
CNS disorders or combined central and periph-
eral demyelination) might have “abnormal” CSF
total protein concentrations notwithstanding a pre-
served B-SNR-B/B-CSF-B permeability (false positive
results).
Albumin is produced by liver only, is not catab-
olized in the CNS, and thus, originating exclusively
from blood, represents an ideal molecule to assess
B-SNR-B/B-CSF-B permeability, as long as its serum
concentrations are compared with the CSF concen-
trations (Thompson, 1988; Andersson et al., 1994).
It can be immuno-nephelometrically/-turbidimetrically
measured in serum and CSF with automated ana-
lyzers and the ensuing QAlb, being a pure number,
has also the analytical advantage of compensating
for inaccuracies in measurements and for biological
variability (Thompson, 1988; Infusino and Panteghini,
2013). Moreover, colorimetry, commonly used for CSF
total protein determinations, is less accurate than
immuno-nephelometry/-turbidimetry (Infusino and
Panteghini, 2013).
As a proof of principle, to address the topic we
measured total protein concentrations in 50 prop-
erly stored (Teunissen et al., 2009) CSF samples
(turbidimetry, Cobas Core, Roche Diagnostics) from
© 2018 Peripheral Nerve Society 70
Letter to the Editor Journal of the Peripheral Nervous System 23:70–72 (2018)
Table 1. Examples of false negative values of cerebrospinal ﬂuid total protein concentrations as compared with the
albumin quotient values.
Patient Diagnosis
Topic-related
laboratory characteristic
Albumin quotient*
(< 0.70)
CSF total protein
(< 45.0 mg/dl)
1 Optic neuritis None 0.80 44.0
2 Mild cognitive impairment Hypoalbuminemia, 2,515mg/dl 1.00 42.1
3 Primary cerebral vasculitis Hypoalbuminemia, 2,291mg/dl 0.79 29.2
Reference values are indicated in parentheses.
CSF, cerebrospinal ﬂuid.
*Calculated as CSF albumin/serum albumin %.
neurological patients who underwent lumbar punc-
ture for diagnostic purposes. CSF total protein con-
centrations correlated with the respective QAlb values
that had been determined as part of our CSF routine
diagnostics (R2 =0.93; p= 0.002). However, in three
cases (two of them characterized by hypoalbuminemia)
QAlb values were abnormally increased, whereas CSF
total protein concentration were within the reference
range (Table 1), while in another three patients with
high values of intrathecal IgG production, CSF total
protein concentrations were near the upper reference
range, whereas QAlb values well within the reference
range (not shown). These ﬁndings show that especially
false negative results can occur in establishing the
inﬂammation-related increases in B-SNR-B/B-CSF-B
permeability, if evaluations of CSF total protein con-
centrations are used. Considering a routine analysis on
unselected CSF samples, our ﬁndings suggest that the
misclassiﬁcation rate might be low, but not negligible
(∼5%), affecting cases with values near the reference
ranges. Noteworthily, neuroimmunology laboratories
currently measure serum and CSF albumin for assess-
ing intrathecal IgG production (IgG index and Reiber’s
IgGLoc), and therefore QAlb could be calculated without
extra costs.
Both CSF total protein concentrations and QAlb
values are in inverse correlation with the CSF ﬂow
rate, which physiologically decreases with age. Their
respective age-related upper reference limits have
been recently assessed on a large number of patients
and useful formulae were produced for the age-related
corrections (Hegen et al., 2016). Again, the limits of
total proteins in the CSF were reported without con-
sidering their dependence on serum concentrations.
In summary, although CSF total protein determina-
tions could fulﬁll the diagnostic needs in the majority
of GBS/CIDP cases, the easy-to-obtain and more accu-
rate QAlb should be considered at least in patients with
diseases affecting total serum protein concentrations
and in those with diseases associated with intrathe-
cal IgG production. QAlb could also improve accuracy
in the evaluation of B-SNR-B/B-CSF-B permeability in
multicenter research settings.
Disclosure
No potential conﬂict of interest is reported by the
authors.
Acknowledgement
This work was supported by the Italian Ministry
of Health ‘Ricerca Corrente’ 2017-2019 Grant to IRCCS
Mondino Foundation.
Sincerely,
Diego Franciotta1, Matteo Gastaldi1,2,
Elisabetta Zardini1,2, and Eduardo Nobile-Orazio3
1Laboratory of Neuroimmunology, IRCCS Mondino
Foundation, Pavia, Italy; 2Department of Brain and
Behavioral Sciences, University of Pavia, Pavia, Italy;
and 3Neuromuscular and Neuroimmunology Service,
Department of Medical Biotechnology and
Translational Medicine, Humanitas Clinical and
Research Institute, Milan University, Milan, Italy
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Cerebrospinal fluid total protein determination in acute and chronic inflammatory demyelinating polyneuropathies : A critical reappraisal

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Cerebrospinal fluid total protein determination in acute and chronic inflammatory demyelinating polyneuropathies : A critical reappraisal

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