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Central nervous system nitric oxide formation in cerebral systemic lupus erythematosus.

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8. Graham BH, Waymire KG, Cottrell B, et al. A mouse model
for mitochondrial myopathy and cardiomyopathy resulting
from a deficiency in the heardmuscle isoform of the adenine
nucleotide translocator. Nat Genet 1997;16:226-234
9. Beal MF. Mitochondria, free radicals, and neurodegeneration.
Curr Opin Neurobiol 1996;6:661-666
10. Smirnow NW,Dunin-Barkowski WI. Mathematische Statistik
in der Wissenschaft. Berlin: DVW, 1973:39-40
11. Jenuth JP, Peterson AC, Fu K, et al. Random genetic drift in
the female germ line explains the rapid segregation of mammalian mitochondrial DNA. Nat Genet 1996;14:146-151
12. Antozzi C, Franceschetti S, Filippini G, et al. Epilepsia partialis
continua associated with NADH-coenzyme Q reductase deficiency. J Neurol Sci 1995;129:152-161
13. Elia M, Musumeci SA, Ferri R. Leigh syndrome and partial
deficit of cytochrome c oxidase associated with epilepsia partialis continua. Brain Dev 1996;18:207-21 l
14. Reid FM, Vernham GA, Jacobs HT. A novel mitochondrial
point mutation in a maternal pedigree with sensorineural deafness. Hum Mutat 1994;3:243-247
15. Ooiwa Y, Uematsu Y, Terada T, et al. Cerebral blood flow in
mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes. Stroke 1993;24:304-309
16. Enriquez JA, Chomyn A, Attardi G. mtDNA mutation in
MERFF syndrome causes defective aminoacylation of tRNALYs
and premature translation termination. Nat Genet 1995;lO:
17. Degoul F, Franqois D, Diry M, et al. A near homoplasmic
T8993G mtDNA mutation in a patient with atypic Leigh syndrome not present in the mother’s tissues. J Inherit Metab Dis
1997;20:49 -53
18. Shoubridge FA. Mitochondria1 DNA diseases: histological and
cellular studies. J Bioenerg Biomembr 1994;26:301-310
19. Yoneda M, Chomyn A, Martinuzzi A, et al. Marked replicative
advantage of human mtDNA carrying a point mutation that
causes the MELAS encephalomyopathy. Proc Natl Acad Sci
USA 1992;89:11164-11168
20. Weber K, Wilson JN, Taylor L, et al. A new mtDNA mutation
showing accumulation with time and restriction to skeletal
muscle. Am J Hum Genet 1997;60:373-380
21. Lissens W, Sermon K. pre-implantation diagnosis: current status and new developments. Hum Reprod 1997;12:1756-1761
Central Nervous System
Nitric Oxide Formation in
Cerebral Systemic Lupus
L. Brundin, MD,* E. Svenungsson, MD,?
E. Morcos, MD,* M. Anderson, MD,*$
T. Olsson, MD,$ I. Lundberg, MD,?
and N. P. Wiklund, MD*
Systemic lupus erythematosus (SLE)is an inflammatory
disease in which up to two thirds of the patients present
neurological symptoms. The diagnosis of the disease is
based on clinical findings and the presence of autoantibodies, and the pathogenesis is unclear. The purpose of
this study was to determine if the pathogenesis was partly
mediated via nitric oxide (NO) formation. Cerebrospinal
fluid (CSF) samples from 15 patients with cerebral SLE
were analyzed for the NO metabolites nitrite and nitrate
using capillary electrophoresis. The severity of neurological symptoms was scored by dividing the patients into
two groups with either mild or moderatehevere CNS involvement. All patients with cerebral SLE showed increased levels of NO metabolites. In CSF, there was a
relationship between signs of NO production and clinical
results showing that increased levels of nitrite and nitrate
were associated with more severe neurological symptoms.
These findings may shed new light on the pathogenesis of
cerebral SLE, and analysis of nitrate and nitrate may
prove to be of value in monitoring the activity of the
Brundin L, Svenungsson E, Morcos E,
Anderson M, Olsson T, Lundberg I,
Wiklund NP. Central nervous system nitric
oxide formation in cerebral systemic lupus
erythernatosus. Ann Neurol 1998;44:704-706
Systemic lupus erythematosus (SLE) is an inflammatory disease mainly affecting women of fertile age. The
diagnosis is based on clinical findings of typical multiorgan involvement in combination with laboratory
tests showing increased production of defined autoantibodies. Up to two thirds of these patients experience
From the *Department of Clinical Neuroscience, Divisions of
TRheumatology and $Urology, and SNeuroimmunology Unit of the
Department of Medicine, Karolinska Institute, Karolinska Hospital,
Stockholm, Sweden.
Received Dec 2, 1997, and in revised form May 13, 1998. Accepted
for publication May 13, 1998.
Address correspondence to Dr Brundin, Department of Clinical
Neuroscience, Division of Neurology, Karolinska Institute, Karolinska Hospital, S 171 77 Stockholm, Sweden.
Copyright 0 1998 by the American Neurological Association
neuropsychiatric symptoms,’ which may be focal
(stroke, epileptic seizures, transverse myelitis) or general (psychosis, depression, cognitive impairment, dementia) in origin. These symptoms may respond to
immunosuppressive therapy but are often misdiagnosed
as they may be clinically indistinguishable from other
neurological/psychiatric conditions. To a large extent,
the pathogenesis is still unclear.
Nitric oxide (NO) is synthesized from L-arginine by
the enzyme N O synthase; NO is an important mediator of vascular tone and pulmonary perfusion and acts
as a neurotransmitter in both the central (CNS) and
peripheral nervous systems.’ In the CNS, astrocytes
and microglia contain iNOS, which can be induced
and cause neuronal cell death.3 Increased expression of
iNOS in the CNS system has been clearly demonstrated in patients with bacterial meningitis,* in experimental autoimmune en~ephalomyelitis,~~‘
and in some
studies of patients with multiple ~ c l e r o s i s .N~O
~ ~is
rapidly broken down to the more stable oxidation
products nitrite and nitrate in biological tissues.’ Thus,
assays of nitrite and nitrate are widely used as indicators of N O formation.’
The purpose of this study was to determine if patients with cerebral SLE showed increased N O production in the CNS and if the severity of the neuropsychiatric symptoms was reflected in measurements of
N O metabolite levels in cerebrospinal fluid (CSF).
Patients and Methods
All patients entering the study fulfilled the American College
of Rheumatology criteria for SLE.” Patients with diagnosed
SLE presenting with neurological symptoms were examined
by a neurologist and a rheumatologist. The symptoms were
scored as follows: mild SLE when there was cognitive impairment and moodlanxiety syndromes but no focal signs,
and moderatelsevere SLE when there was paresis, epileptic
seizures, psychosis, severe neuralgia, or dementia. Patients
presenting with two or more of these symptoms were rated
as severely affected. Plasma samples and samples of CSF were
obtained (the latter by routine lumbar puncture) with patient
consent. The protocol was authorized by the Ethics Committee of the Karolinska Hospital. The clinicians rating the
symptoms had no access to the nitrite/nitrate determinations.
We applied no food or drink restrictions to the patients or
controls entering the study.
Sample Analysis
Sample analysis for NO metabolites was performed using a
capillary electrophoresis technique.’ Vials and equipment
were rinsed in deionized distilled water (Elgastat prima 1-3,
Elga, Buckinghamshire, UK). The samples were diluted
l : l O , ultrafiltered at 5000 g through Ultrafree-MC filters
(Millipore; Bedford, MA), and analyzed on a Hewlett Packard 3D capillary electrophoresis system (Hewlett Packard,
Waldbronn, Germany). The electrolyte consisted of 25 mM
of sodium sulphate containing 5% NICE-Pak OFM
Anion-BT (osmotic flow modifier) in deionized distilled water. Samples were injected by electromigration for 20 seconds
at -6 kV and analyzed at a negative potential of 300
Vcm-’ . Data were acquired at a response time of 0. I second
at 214 nm onto a Hewlett Packard 3D CE Chem Station
data system. The samples were coded to the laboratory staff.
The correlation between symptom and nitratelnitrite levels
was evaluated by ANOVA.
When compared with age- and gender-matched controls, CSF levels of nitrite and nitrate in patients with
low/moderate symptoms (SLE+) were significantly increased. The total concentrations of nitrite plus nitrate
were 6.6 t 0.7 mM for controls and 10.4 L 1.2 mM
for the mildly affected patients. In severely affected patients (SLE+ +), the increase in nitrite and nitrate levels was even more pronounced, giving a mean concentration of 19.7 -+ 2 mM. Interestingly, the plasma
nitrite and nitrate levels correlated neither to CSF levels nor to severity of the neurological symptoms (Fig).
The maximum concentration 22 pM was obtained
from a patient previously diagnosed with cerebral SLE,
who became acutely psychotic. After cortisone treatment, she recovered from the attack and nitrate/nitrite
Fig. Cerebrospinalj u i d (CSfJ concentration of nitric oxide
(NO) oxidation products in the CSF of normal controls, patients with mild neurological symptoms (SLE+), and patients
with moderateheveve neurological impairment (SLES +) (p <
Samples of CSF from age- and gender-matched headache patients were used as controls. The CSF of control patients was
screened for protein, glucose, and cell content and underwent spectrophotometry. Guidelines for control patients
were that they should be healthy in other respects, not
present with neurological signs, and be relieved of their headache within 5 days.
SLE ++
Brief Communication: Brundin et al: CNS N O Formation in Cerebral SLE
concentrations were down at 7.8 FM in the chronic
state of the disease.
In a recent report, SLE patients with pulmonary symptoms had increased levels of N O in exhaled air." NO
formation may constitute a common inflammatory
pathway, because increased levels of N O metabolites
appear in CSF, indicating increased NO formation in
the CNS. Patients with CNS SLE may respond to cortisone treatment, which is in agreement with the finding that glucocorticoids inhibit the expression of
iNOS.12 Furthermore, these results suggest that CNS
involvement in SLE is proportional to the levels of NO
metabolites measured in CSF.
The means of objectively monitoring the CNS involvement in this disease are scarce, because there are
no tests previously described that reveal acute activity
or remission. Monitoring CSF levels of NO oxidation
products may distinguish between a psychological reaction and a relapse of cerebral SLE. In addition, it
should be of interest to study whether NO, per se, is
instrumental for the neuropsychiatric disturbances seen
during SLE or whether it serves as a marker for other
inflammatory events systemically or intrathecally involved in CNS damage. NO formation in the CNS may
shed new light on the pathogenesis of cerebral SLE.
This work was supported by the Swedish Medical Council and the
Konung Gustav V Memorial Foundation.
1. West SG. Neuropsychiatric lupus. Rheum Dis Clin North Am
1994:129-1 58
706 Annals of Neurology Vol 44
No 4
October 1998
2. Moncada S, Higgs A. The L-arginine-nitric oxide pathway.
N Engl J Med 1993;329:2002-2012
3. Dawson VL, Brahmbatt HP, Mong JA, et al. Expression of inducible nitric oxide synthase causes delayed neurotoxicity in
primary mixed neuronal glial cell cultures. Neuropharmacology
4. Kornelisse RF, Hoekman K, Visser JJ, et al. The role of nitric
oxide in bacterial meningitis in children. J Infect Dis 1996;174:
5. Koprowski H, Zheng YM, Heber-Katz E, et al. In vivo expression of inducible nitric oxide synthase in experimentally induced neurological diseases. Proc Natl Acad Sci USA 1993;90:
6. Cross AH, Misko TP, Hickey WF, et al. Aminoguanidine, an
inhibitor of nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. J Clin Invest 1994;
7. BO L, Dawson TM, Wesselingh S, et al. Induction of nitric
oxide synthase in demyelinated regions of multiple sclerosis
brains. Ann Neurol 1994;36:778-786
8. Brosnan CF, Cannella B, Battistini L, et al. Cytokine localization in multiple sclerosis lesions: correlation with adhesion molecule expression and nitrogen species. Neurology 1995;
45 (Suppl):16-2 1
9. Leone AM, Francis PL, Rhodes P, et al. A rapid and simple
method for the measurement of nitrite and nitrate in plasma by
high performance capillary electrophoresis. Biochem Biophys
Res Comm 1994;200:951-957
10. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria
for the classification of lupus erythematosus. Arthritis Rheum
1982;25: 1271-1277
11. Rolla G, Brussino L, Bertero MT, et al. Increased nitric oxide
in exhaled air of patients with systemic lupus erythematosus.
J Rheumatol 1997;24:1066-1071
12. Radomski MW, Palmer RMJ, Moncada S. Glucocorticoids inhibit the expression of the inducible but not the constitutive
nitric oxide synthase in vascular endothelial cells. Proc Natl
Acad Sci USA 1990;87:11043-11047
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central, lupus, oxide, nervous, formation, systemic, nitric, erythematosus, system, cerebral
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