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Cerebrospinal fluid levels of quinolinic acid in Huntington's disease and schizophrenia.

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be related to a lysosomal storage disorder. However,
they were unable to identify a specific lysosomal enzyme abnormality.
In summary, we have described the pathological features of muscle biopsy specimens from 3 infantile cases
of Marinesco-Sjogren syndrome. W e have identified
an unusual ultrastructural feature that we believe is
specific for the syndrome. This emphasizes the role of
muscle biopsy in the differential diagnosis of MSS and
highlights the involvement of skeletal muscle in the
disorder.
W e are grateful to the Muscular Dystrophy Group of Great Britain
and Northern Ireland for financial support and to Mrs C. A. Lovegrove and Mrs C. Hutson for technical expertise. We also thank Mrs
C. Trand for typing the manuscript. Dr Voit is the recipient of a
postdoctoral grant from the Deutsche Forschungsgemeinschaft,
Bonn, FRG.
References
1. Alexianu M, Christodorescu D, Vasilescu C, ei: al: Sensorimotor
neuropathy in a patient with Marinesco-Sjogren syndrome. Eur
Neurol 22:222-226, 1983
2. Alter M, Kennedy W: The Marinesco-Sjijgren syndrome: hereditary cerebello-lental degeneration with mental retardation.
Minn Med 51:901-906, 1968
3. Anderson B: Marinesco-Sjogren syndrome: spinocerebellar
ataxia, congenital cataract, somatic and mental retardation. Dev
Med Child Neurol 7:249-257, 1965
4. Dubowitz V: Muscle Biopsy: A Practical Approach (2nd ed.).
London, Bailliere Tindall, 1985
5. Heckmatt JZ, Moosa A, Hutson C, et al: Diagnostic needle
muscle biopsy-a
practical and reliable alternative to open
biopsy. Arch Dis Child 59:528-532, 1984
6. Herva R, von Wendt L, von Wen& G, e t al: A syndrome with
juvenile catwact, cerebellar atrophy, mental retardation and myopathy. Neuropediatrics 18:164-169, 1987
7. Komiyama A, Kawamura M, Hirayama K: Muscle involvement
in patients with Marinesco-Sjogren syndrome: with reference to
clinical manifestations of adult patients. Ririsho Shinkeigaku
25:1131-1140, 1985
8. Mahloudjhi M, Amirhakimi G H , Haghighi P, Khodadoust AA:
Marinesco-Sjogren syndrome: report of an autopsy. Brain
95675-680, 1972
9. Marinesco G , Draganesco S,Vasiliu D: Nouvelle maladie famliale caracteriske par une cataracte congenitale e t un arret du
developpement somato-neuro-psychique. Encephale 2697109, 1931
10. Nyberg-Hansen R, Gronvik 0, Refsum S: Hereditary cerebellar ataxia associated with congenital cataracts: four cases of the
Marinesco-Sjiigren syndrome with some unusual features. Acta
Neurol Scand 48:257-260, 1972
11. Ron MA, Pearce J: Marinesco-Sjiigren-Garland syndrome with
unusual features. J Neurol Sci 13:175-179, 1971
12. Schroeder JM: Pathologie der Muskularur. Springer-Verlag.
Berlin, 1982, pp 272-276
13. Sewry CA: Ultrastructural changes in diseased muscle. In
Dubowitz V: Muscle Biopsy: A Practical Approach (2nd ed.).
London. Bailliere Tindall, 1985, pp 129-183
14. Sjijgren T: Hereditary congenital spinocerebellar ataxia combined with congenital cataract and oligophrenia. Acta Psychiatr
Scand 46 (Suppl):286-289, 1947
15. Skre H , Bassoe H H , Berg K, Frovig AG: Cerebellar ataxia and
hypergonadotropic hypogonadism i n two kindreds: c hanc-e con.
currence, pleiotropism or linkage! Clin Genet 0:23/&-.244,
1976
16. Superneau DW, Wertelecki W, Zkllweger H, Bastian F: M y
opathy in Marinesco-Sj6p;ren syndrome. Eur Neurol 268- 10,
1987
17. Walker PD, Blitzer MG, Shapira E: Marinesco-Slijgren syndrome: evidence for a lysosomal storage disorder. Necrology
3 5 1 4 1 5 4 1 9 , 1985
Cerebrospinal Fluid Levels
of Quinolinic Acid in
Huntington's Disease
and Schizophrenia
Robert Schwarcz, PhD,* Carol A. Tamminga, MI),"
Roger Kurlan, MD,t and Ira Shoulson, MDI~~
The concentration of the endogenous excitotoxin cluinolinic acid was determined in the cerebrospinal fluid of
drug-free patients suffering from Huntington's disease
or schizophrenia (control group). In both diseases,
quinolinic acid concentrations were highly variable
(< 4-48 nM) but the mean levels for each disease
group were not significantly different from each other
or from the quinolinic acid concentration of normal
cerebrospinal fluid. Analysis of steady-state cerehrospinal fluid quinolinic acid concentration is unlikely to be
of value as a diagnostic tool in Huntington's disease.
Schwarcz R, Tamminga CA, Kurlan R. Shoulson 1.
Cerebrospinal fluid levels of quiriolinic acid
in Huntington's &ease and schizophrenia.
Ann Neurol 1988;24:580-582
_--
The brain metabolite quinolinic acid (QUIN) has recently been linked hypothetically to the pathogenesis
of Huntington's disease (HD) [I). In particular, it has
been proposed that the accumulation of hyperphysiological amounts of QUIN in the brain causes the
specific pattern of neuronal loss observed in the
striatum of HD victims. This idea is in line wiLh our
recent demonstration of a greatly increased activity of
QUIN's biosynthetic enzyme 3-hydroxyanthranik
From the 'Maryland Psychiatric Research Center, Baltimore, MI),
and the +Department of Neurology, University of Rochcster School
of Medicine, Rochester, NY.
Received Dec 29, 1987, anri in reviscd form Mar 31. 1988. Accepted for publication Apr 3, 1988.
Address correspondence to Dr Schwarcz, Maryland Psychiatric Research Center, Maple and Locust Streets, Baltimore, M D 2 1228.
580 Copyright 0 1988 by the American Neurological Association
Data on Huntington's Dijease and Schizophrenic (Control) Patients
Patient No.
Huntington's disease
1
2
3
4
5
6'
7
8'
9
10'
Mean t SE
Schizophrenia
1
2
3
4
5
6
7
Mean t SE
Age (yr)
Sex
46
43
27
34
33
29
M
M
F
F
18
54
25
35.8
22
25
34
31
26
32
26
28.0
5
Quinolinic Acid
Concentration (nM)
4
I1
I
I
I1
I
I1
36
30
12
6
<4
I1
I1
IV
7
6
5.1
3.9
I1
?
0.7
6
6
13
7
8
M
F
F
F
F
F
* 1.8
Severity
of Illnessb
4
3
5
4
8
4
4
F
F
M
F
M
F
40
Duration of
Illness" (yr)
Moderate
Moderate
Severe
Moderate
Moderate
Moderate
Mild
5
9
M
7.7
5
1.1
12
18
32
18
32
20 t 4
18
14
22
48
40
46
<4
27
?
7
"Onset of Huntington's disease is defined by the occurrence of motor features
bHuntington's disease stages follow the scale of Shoulson and Fahn [6].
'Juvenile rigidhypokinetic features.
acid oxygenase (3HAO) in postmortem HD brain
specimens [2]. However, it is unclear at present how
the activity of the bran kynurenine pathway, and especially of 3HA0, is related to the extracellular concentration of QUIN. This question is of the utmost relevance, since only Q U I N that had left its cellular
confinement could be expected to interact with membrane receptors on vulnerable neurons, thereby killing
the cells through the initiation of excitotoxic mechanisms [l, 31.
In normal subjects, the average concentration of cerebrospinal fluid (CSF) Q U I N has been shown to be
between 20 and 30 nM 14, 53. We now report the
concentration of CSF Q U I N in drug-free (at least 4
weeks) HD patients and, as a control group, unmedicated (at least 3 weeks neuroleptic-free) schizophrenics. Additional (data on the groups of 10 and 7
patients, respectively, are given in the Table. Three
HD patients had jutenile rigidhypokinetic features;
all had a confirmatory family history of HD.
Methods
Lumbar CSF was obtained using conventional techniques.
The fluid was rapidly collected between 10 AM and 4 PM, put
on ice immediately, and then stored at - 70°C until QUIN
analysis. In all cases, QUIN content was measured in aliquots
from the first 15 ml sampled. Q U I N was determined
radioenzymatically [7] (assay sensitivity: 0.2 pmol) in duplicate samples of 50 pl undiluted CSF. In preliminary experi-
ments, prepurification of the samples was proven to be unnecessary. Parallel tubes containing a known amount of
authentic Q U I N (10 pmol) as an internal standard were included in each assay.
Results
As illustrated in the Table, CSF Q U I N concentrations
in the two patient populations did not differ significantly from each other (t = 1.06 and p = 0.304,
Student's t test). Moreover, no correlations were detected between Q U I N concentration and age or duration of illness (v = 0.003, age; Y = -0.04, duration;
Pearson's correlation). Finally, the data were virtually
identical to those reported by Moroni and associates
[4] and our own laboratory [ S ] for CSF from normal
controls.
Discussion
While the lack of difference beween CSF Q U I N concentration in HD and schizophrenia probably renders
this parameter of little use for diagnostic purposes in
these diseases, the present data do not invalidate the
Q U I N hypothesis of HD. Chronic exposure of rat
organotypic cultures to only slightly hyperphysiological Q U I N concentrations (100 nM) has been demonstrated to result in excitotoxic lesions in vitro [S]. It is
therefore possible that small but prolonged increases
in CSF Q U I N concentration may underlie nerve cell
Brief Communication: Schwarcz et al: CSF Quinolinic Acid
581
loss in a slowly progressing disorder such as HI). Such
minor changes are unlikely to be revealed in a single
analysis of steady-state CSF Q U I N concentrations as
reported here.
Since extracellular Q U I N is rapidly cleared from the
brain in vivo [91, and homeostasis of QUIN in the CSF
is probably maintained by replenishment from cerebral
pools, a future study should be devoted to the measurement of CSF QUIN in situations where QUIN
synthesis or release is acutely enhanced by bioprecursor administration or pharmacological means. Under
those conditions, the established increase in 3HA0
activity in the HD brain may well be reflected IJY transient elevations in CSF QUIN and make its measurement a valuable diagnostic tool in HD.
This work was supported by USPHS grants N S 16102, N S 20509,
and N S 17978, and rhe N I H Clinical Research Center at the University of Rochester (RF-00044).
We greatly appreciate the technical assistance of Mr Dan Ehugher.
Absence Status Epilepticus
with Computed
Tomographic Brain
Chanies Following
MetrGamide Myelography
Tahir Obeid, MRCP(UK), Basim Yaqub, MRCP(UK),
Chrysostomos Panayiotopoulos, MD, PhD,
Saleh Al-Jasser, MBBS, Azzam Shabaan, DMRD,
and Nour El-Din Hawass, MD, FRCR
Absence status epilepticus following metrizamide myelography was associated with computed tomographic
scan evidence of a high concentration of the dye i n brain
gray matter. W e suggest that absence status epilepticus
is due to the direct effect of metrizamide on t h e cortex
and that this clinically treatable condition may have escaped diagnosis i n previous reports.
Obeid T , Yaqub B, Panayiotopoulos CP,
Al-Jasser S, Shabaan A, Hawass N E-D. Absence
status epilepticus with computed tomographic brain
changes following metrizamide myelography.
Ann Neurol I988;24:582-584
References
1. Schwarcz R, Shoulson I. Excitotoxins and Huntington’s disease.
In: Coyle JT, ed. Animal models of dementia. New York: A R
Liss, 1987:39-68
2. Schwarcz R, Bird ED, Whetsell WO Jr. The quinolinic acidsynthesizing enzyme is increased in the brains of Huntington’s
disease victims. SOL Neurosci Abstr 1987; 13:66.5
3 . Schwarcz R, Foster AC, French ED, er al. Excitoroxic models for
neurodegenerative disorders. Life Sci 1984;35: 19-32
4.Moroni F, Lombardi G, Carla V, et al. Increase in the content of
quinolinic acid in cerebrospinal fluid and frontal correx of patients with hepatic failure. J Neurochem 1986;47:166;’-1671
5. Schwarcz R, Okuno E, Speciale C, et al. Neuronal degeneration
in animals and man: the quinolinic acid connection. In: Jenner P,
ed. Neurotoxins and their pharniacological implications. New
York: Raven, 1987:19-32
6. Shoulson I, Fahn S. Huntington’s disease: clinical care and evaluation. Neurology 1979;29:1-3
7. Foster AC, Okuno E, Brougher DS, Schwarcz R. A radioenzymatic assay for quinolinic acid. Anal Biochem 1986;158:98-103
8. Whetsell W O Jr, Schwarcz R. Studies of effects of chronic lowlevel quinolinic acid exposure in organorypic cultures of the rat
corticosrriaral system. Soc Neurosci Abstr 1987;13:287.9
9. Foster AC, Miller LP, Oldendorf W H , Schwarcz R. Studies on
the disposition of quinolinic acid after intracerebral o r systemic
adminisrrarion in the rat. Exp Neurol 1984;84:428-440
Absence status epilepticus (ASE) following metrizamide myelography has been described previously in 3
patients I: 1-31, but associated brain computed tomographic (CT) scan changes axe not known. To our
knowledge, this is the first reported case of ASE with
CT scan evidence of brain gray matter penetration of
metrizamide; this finding favors a primarily cortical origin of ASE.
Case Report
A 38-year-old man was admitted because of prolapse of a
lower lumbar disc. There was no personal or family history
of seizures. He was not taking medication and had no history
of allergy or systemic disease. Lumbar myelography was performed with 10.5 ml of metrizamide (240 mg iodineiml); dye
was not carried above the lumbar region. There was no immediate adverse effect from the procedure. The patient was
instructed to lie with his head elevated 45 degrees for at least
6 hours. Four hours later he developed severe headache and
vomiting. O n examination, there were no signs of meningeal
irritation or other neurological abnormalities. The next
morning he was confused, with global disorientation and
slow responses to commands. Neurological examination was
From the Departments of Neurology and Neurophysiology and
Radiology, G n g Khalid University Hospital, Riyadh, Saudi Arabia.
Received Mar 11, 1988. Accepted for publicdtion Apr 16, 1988.
Address correspondence to Dr Obeid, King Khalid University Hospital, P O Box 7805 (38), Riyadh 11472, SauJi Arabia.
582
Copyright 0 1988 by the American Neurological Association
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