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Cerebrospinal fluid transthyretin in the neonate and bloodЦcerebrospinal fluid barrier permeability.

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References
1. Marsden CD, Parkes JD. “On-off” effects in patients with Parkinson’s disease on chronic levodopa therapy. Lancet 1976;1:292295
2. Klawans HL, Weiner WJ. Textbook of clinical neuropharmacology. New York: Raven, 1981:l-37
3. de Jong GJ, Meerwaldt JD. Response variations in the treatment
of Parkinson’s disease. Neurology 1984;34:1507-1 509
4. Boomsma F, van der Hoorn FAJ, Schalekamp MADH. Determination of aromatic-L-amino acid decarboxylase in human plasma.
Clin Chim Acta 1986;159:173-183
5. Boomsma F, de Bruyn JHB, Derkx FHM, Schalekamp MADH.
Opposite effects of captopril on angiotensin I-converting enzyme “activity” and “concentration”; relation between enzyme
inhibition and long-term blood pressure response. Clin Sci
1981;60:49 1-498
6. Nutt JG, Woodward WR, Anderson JL. The effect of carbidopa
on the pharmacokinetics of intravenously administered levodopa:
the mechanism of action in the treatment of parkinsonism. Ann
Neurol 1985;18:537-543
Cerebrospinal Fluid
Transthyretin in the
Neonate and
Blood-Cerebrospinal Fluid
Barrier Permeability
Paul D. Larsen, MD,+t and Leonard DeLallo, BS”
We measured transthyretin levels in the cerebrospinal
fluid (CSF) of newborn infants, older children, patients
with viral and bacterial meningitis, and adults with increased CSF protein levels. Neonatal CSF transthyretin
levels are elevated disproportionately in comparison to
levels in the other groups. We conclude that increased
levels of transthyretin in the CSF of neonates are not
explained by increased permeability of the blood-CSF
barrier.
Larsen PD, DeLallo L. Cerebrospinal fluid
transthyretin in the neonate and bloodcerebrospinal fluid barrier permeability.
Ann Neurol 1989;25:628-630
Trsansthyretin (previously known as prealbumin) is one
of the major proteins in cerebrospinal fluid (CSF), and
From the Department of *Pediatrics and tMedicine (Neurology),
University of Texas Health Science Center at San Antonio, San
Antonio, TX.
Received Jun 7, 1988, and in revised form Oct 17 and Dec 9.
Accepted for publication Dec 11, 1988.
Address correspondence to Dr h s e n at his current address, Department of Neurology and Pediatrics, Scott and White Memorial
Hospital and Clinic, Scott, Sherwood and Brindley Foundation,
Texas A&M University College of Medicine, 2401 South 31st St,
Temple, T X 76508.
functions as an important transport protein for thyroxine and retinol-binding protein. In a previous study
we found that CSF transthyretin is increased in the
neonatal period when compared with levels in older
infants, children, and adults [l]. In the present study
we asked whether neonatal levels of transthyretin
(?TR) in CSF are elevated out of proportion to clinical
conditions in which the blood-CSF barrier exhibits
increased permeability.
Methods
‘ITR and albumin values in serum and CSF were determined
for the following five groups of patients:
Group 1 was the neonatal group (1 to 6 weeks old); n = 19.
These infants underwent lumbar puncture to rule out central
nervous system (CNS) infection and were found to have
normal CSF.
Group 2 was the comparison group (7 weeks to 14 years
old); n = 31. These patients also underwent lumbar puncture for clinical indications and were found to have normal
CSF.
Group 3 had aseptic meningitis (2 months to 14 years old); n
= 11. In this group the clinical illness was consistent with
viral meningitis; the white cell count in the CSF was greater
than 7/mm3, and CSF cultures for bacteria were negative.
Group 4 had bacterial meningitis (3 months to 2 years old); n
= 12. All patients had cultures of CSF that grew Hemophilzrs
tnjuenzae, Streptococcus pneumoniae, or Neisseria meningatidis.
Group 5 had other CNS diseases (all adults); n = 9. All
patients had increased CSF protein without pleocytosis.
CSF and serum values for ‘ITR were measured by an
electroimmunoassay using antihuman prealbumin in a 1%
agarose gel prepared with a barbital buffer at pH 8.6. Five
microliters of undiluted CSF and 5 pL of diluted serum
(1:20) from each patient were run in parallel and in duplicate
for 2.5 hours at 80 volts, using barbital acetate buffer (pH
8.6), and were stained with Coomassie blue (0.2%). Rocket
length was used to determine milligrams per deciliter of ‘ITR
by comparison with a curve generated for each run, using
standards of known concentration of TIR. CSF and serum
levels of albumin were also measured by electroimmunoassay PI.
As an index of blood-CSF barrier permeability, the ratio
of CSF level of albumin to serum level of albumin times
1,000 was determined for each patient [3], and the mean
CSF a1bumin:serum albumin ratio was calculated for each
patient group.
To determine the amount of ’ITR in CSF that was not
attributable to passive diffusion across the blood-CSF barrier, blood-CSF barrier-independent or native CSF ’ITR
was estimated with the following equation 141:
native CSF ‘ITR = total CSF ‘ITR -
i
CSF albumin
serum albumin
Serum
m)
The mean +- standard error (SE) of total and native CSF
‘ITR was calculated for each patient group. Analysis of vari-
628 Copyright 0 1989 by the American Neurological Association
Ratios of Cerebrospinal Fluid Albumin to Serum Albumin and Valuesfor Transthyretin in Cerebrospinal Fluid
Group
No.
1: Neonatal (1-6 wk)
2: Comparison (7 wk-14 yr)
3: Aseptic meningitis (2 mo-14 yr)
4: Bacterial meningitis (3 mo-2 yr)
5: Other CNS diseases (all adults)
19
31
11
12
"Values are expressed as mean
CSF
=
9
CSF A1bumin:Serum
Albumin Ratio"
Total CSF 'ITR
(mg/dl)a
Native CSF 'ITR
(mg/dl)a
10.2 -c 1.0
3.6 t 0.5
1.0 r 1.2
43.4 r 8.1
16.2 r 3.4
3.20 ?
2.04 &
2.23 ?
2.74 ?
2.44 t
3.10 t 0.16
1.94 ? 0.07
2.12 ? 0.15
2.32 2 0.26
2.06 t 0.09
0.16
0.08
0.15
0.23
0.13
* SE.
cerebrospinal fluid, TTR = transthyretin.
ance (ANOVA) and Bonferroni confidence intervals were
used for statistical analysis.
Results
The mean values & SE for CSF albumin: serum albumin ratio, total CSF 'ITR, and native CSF TTR for
each patient group are shown in the Table. The CSF
albumin: serum albumin ratio values were positively
skewed in all five groups; therefore, analysis was performed on the logarithm of the values. ANOVA
showed a significant difference among the five groups.
The Bonferroni test ( p < 0.01) showed that the CSF
albumin:serum albumin ratio was significantly increased in Groups 1, 3, 4 , and 5 when compared with
the comparison group (Group 2 ) and that the ratio for
Group 4 (bacterial meningitis) was significantly greater
than the ratios in groups 1, 3, and 5 , indicating a severe
disruption of the blood-CSF barrier with this disease.
ANOVA showed significant differences among the
five groups for total CSF 'ITR. Except for the group
with bacterial meningitis (Group 4), mean total CSF
TTR for the neonatal group (Group 1) was significantly different from that for all other groups ( p <
0.01). Even though there was no statistically significant
difference between the neonatal and bacterial meningitis groups, the mean total CSF TTR value for the
group with bacterial meningitis was still less than that
for the neonatal group, despite a CSF albumin:serum
albumin ratio that was four times greater than that for
the neonatal group. The mean total value for CSF TTR
for the bacterial meningitis group was significantly different from that in the comparison group (Group 2 ) ( p
< 0.01) but was not significantly different from that in
the group with other CNS diseases (5) and the aseptic
meningitis group (3). The group with other CNS diseases and the aseptic meningitis group were not
significantly different from the comparison group with
regard to mean total CSF TTR.
To determine the contribution of passive diffusion
to total CSF TTR,native, or barrier-independent, CSF
TTR was compared among the five groups. There was
a small contribution to total CSF TTR by passive diffusion. This seems to be in proportion to the degree
of blood-CSF barrier impairment. When native CSF
'ITR values were compared among the five groups
using ANOVA and the Bonferroni test, the neonatal
mean native CSF TTR was the only value significantly
higher than the rest ( p < 0.005).
These results indicate that altered blood-CSF barrier permeability can make a small contribution to the
total CSF TlX but that this mechanism is not the explanation for increased levels of TTR in neonatal CSF.
Even in patients with bacterial meningitis, in whom the
blood-CSF barrier is much more permeable than in
the neonate, CSF TTR values are less than in neonates.
Discussion
Protein levels in CSF result from passive diffusion
across the blood-CSF barrier, production of or transport by the choroid plexus, and CSF flow or turnover
rate 15). Our results indicate that passive diffusion
across the blood-CSF barrier does not account for the
increased levels of 'ITR in the neonatal CSF and that
some other mechanism is at work.
TIX is produced by both the liver and the choroid
plexus but the regulation of CSF TTR production by
the choroid plexus is independent of the liver [b).The
only known function of TIX is as a transport protein
for thyroxine and retinol-binding protein 17, 8). Although TTR is a minor serum transport protein for
thyroxine, 80% of CSF thyroxine is bound to TlX
19). Because thyroxine is necessary for critical periods
of neuronal proliferation and differentiation {lo], it is
important in brain development. The retinoid family
of proteins also has important effects on cellular function and might play a role in CNS development 111,
12). Increased levels of CSF 'ITR are found in both
the neonatal and the fetal periods [ l , 13). With these
considerations in mind, a possible explanation for elevated neonatal CSF TTR is increased choroid plexus
production. This, in turn, might be related to T " s
transport function for thyroxine and retinol-binding
protein during fetal and neonatal brain development.
The other possible explanation for increased CSF
TTR in the neonate is that CSF turnover rate may be
decreased in the newborn period [14, 151, which
would increase CSF protein content independent of
Brief Communication: Larsen et al: CSF Transthyretin in the Neonate
629
the permeability of the blood-CSF barrier. Native
(barrier-independent) CSF "TR has been shown to be
elevated in conditions of decreased CSF turnover 141.
Further study is needed in the newborn period to determine the effect of decreased CSF turnover on CSF
TTR and whether CSF TI'R is affected out of proportion to other CSF proteins.
In summary, we have demonstrated that increased
blood-CSF barrier permeability is not the explanation
for increased CSF "TR in the neonate. Other mechanisms must be considered.
An abstract of this material was presented at the Annual Meeting of
the Child Neurology Society, San Diego, CA, October 23, 1987.
Parhnsonism and
Amiodarone Therapy
Elke G. Werner, MD,
and C. Warren Olanow, MD, FRCP(C)
We report a case of reversible, dose-related parkinsonian
tremor in a patient taking amiodarone. In previous writings by others, basal ganglia dysfunction associated with
amiodarone was dose related and reversibility was inversely related to duration of therapy. Patients receiving
amiodarone are at risk for the development of basal ganglia dysfunction which may persist if the drug is not
discontinued or the dosage reduced.
Werner EG, Olanow CW. Parkinsonism
and amiodarone therapy.
Ann Neurol 1989;25:630-632
References
1. Larsen PD, DeLallo L. Increased cerebrospinal fluid transthyretin (prealbumin) in the neonatal period. Neurology 1987;37
(Suppl 1):345
2. Perry JJ, Hackett TN, Bray PF, et al. Laboratory diagnosis of
multiple sclerosis: evaluation of immunoglobulin G in cerebrospinal fluid. Rocky Mt Med J 1973;70:42-44
3. Tibbling G, Link H, Ohman S. Principle of albumin and IgG
analyses in neurological disorders. I. Establishment of reference
values. Scand J Clin Lab Invest 1977;37:385-390
4. Weisner B, Roethig HJ. The concentration of prealbumin in
cerebrospinal fluid (CSF), indicator of CSF circulation disorders.
Eur Neurol 1983;22:96-105
5. Felgenhauer K, Schliep G, Rapic N. Evaluation of the bloodCSF barrier by protein gradients and the humoral immune response within the central nervous system. J Neurol Sci 1976;
30:113-128
6. Dickson PW, Aldred AR, Marley PD, et al. Rat choroid plexus
specializes in the synthesis and the secretion of transthyretin
(prealbumin). J Biol Chem 1986;261:3475-3478
7. Oppenheimer JH. Role of plasma proteins in the binding, distribution and metabolism of the thyroid hormones. N Engl J Med
1968;278:1153-1162
8. Muto Y,Goodman DS. Vitamin A transport in rat plasma. J
Biol Chem 1972;247:2533-2541
9. Felding P. Prealbumin: metabolic and chemical studies (thesis).
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10. Adams RD, DeLong GR. The neuromuscular system and brain.
In: Ingbar SH, Braverman LE,eds. Werner's the thyroid. Philadelphia: JB Lippincott, 1986:1168-1180
11. Cope FO, Howard BD, Boutwell RK. The in vitro characterization of the inhibition of mouse brain protein kinase-C by
retinoids and their receptors. Experientia 1986;42;1023-1027
12. Bhat NR, Shanker G, Pieringer RA. Cell proliferation in growing cultures of dissociated embryonic mouse brain: macromolecule and ornithine decarboxylase synthesis and regulation
by hormones and drugs. J Neurosci Res 1983;10:221-230
13. Adinolfi M, Haddad SA. Levels of plasma proteins in human
and rat fetal CSF and the development of the blood-CSF barrier. Neuropadiatrie 1977;8: 345-3 5 3
14. Amtorp 0, Sorensen SC. The ontogenetic development of concentration differences for protein and ions between plasma and
cerebrospinal fluid in rabbits and rats. J Physiol 1974;243:387400
15. Bass NH, Lundborg P. Postnatal development of bulk flow in
the cerebrospinal fluid system of the albino rat: clearance of
carboxyl-('*C) insuhn after intrathecal infusion. Brain Res
1973;52:323-332
Case Report
A 73-year-old man was evaluated for new onset of Parkinson-type tremor of the left leg. He had a history of ischemic heart disease with paroxysmal atrial arrhythmias and
ventricular tachycardia refractory to verapamil and tocainide.
Amiodarone was initiated at a dose of 400 mg every 6 hours
for 2 days, then reduced to 400 mg every 8 hours. On the
fourth day of therapy he developed an intermittent, 6-Hz
coarse resting tremor of the left leg, indistinguishable from
that seen in Parkinson's disease. The tremor was present only
on recumbency with both legs at rest. It was abolished with
active or passive movement of either leg. Tremor was most
pronounced in the foot but at times involved the entire left
leg. Superimposed rapid jerks of the left foot were occasionally noted. There was no tremor of the head, jaw, voice,
arms, or right leg. There was no alteration of tone, bradykinesia, gait disturbance, or postural instability. Findings on
hemogram, routine blood chemistries, thyroid profile, electroencephalogram (EEG), and magnetic resonance imaging
(MRI) of the brain were normal. One day after the onset of
tremor amiodarone was discontinued, and the tremor
stopped 5 days later. The tremor recurred with reintroduction of amiodarone after a latency of 5 days and disappeared
when the dose was reduced.
Discussion
Amiodarone is a di-ionated benzofurane derivative
used primarily in the treatment of refractory ventricular and atrial tachyarrythmias 111. Multiple neurological side effects have been reported, including senso-
From the Department of Neurology, University of South Florida,
Tampa, FL.
Received Aug 10, 1988, and in revised form Oct 26 and Dec 9.
Accepted for publication Dec 11, 1988.
Address correspondence to Dr Olanow, Department of Neurology,
University of South Florida, Harbour Side Medical Tower, 4 Columbia Drive, #410, Tampa, FL 33606.
630 Copyright 0 1989 by the American Neurological Association
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