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CSF changes during acute meningoencephalitis in mice caused by encephalomyocarditis virus.

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Caucasians, with n o other major difference in motor
performance [ 111. A genetic predisposition to ITD
may relate to precursors (e.g., tyrosine) of neurotransmitters and neuromelanin within the central
nervous system and the precursors of melanin external to it [4, 121. Since different enzymes operate on
tyrosine within (tyrosine hydroxylase) and external to
(tyrosinase) the central nervous system, one may envisage a linkage in function of this precursor to a
common coenzyme acting peripherally and centrally.
No such coenzyme is known, although both primary
enzymes are dependent on copper and operate in the
presence of large quantities of ascorbic acid. This
hypothesis could explain the general predisposition
of Caucasians toward disorders of voluntary movement and account for the greater incidence of lightcolored irises in patients with ITD.
Supported in part by the Charles E. Merrill Trust, the Heckscher
Foundation, Grant 8-0168-708 from the New York University
Medical Center Neurology Research Fund, the ICD Research and
Rehabilitation Center, Mrs Ann Weisenthal, Mrs Renate Elias, and
Mr Martin Sloate.
Presented at the 105th Annual Meeting of the American Neurological Association, Boston, MA, Sept 8- 10, 1080.
I wish to acknowledge Drs J. Brudny, E. Balis, and H. Demopoulos and Ms L. Levidow for their aid and cooperation in this
study.
11. Landers DM, Obermeier GE, Patterson AH: Iris pigmentation and reactive motor performance. J Motor Behav 8:171179, 1976
12. Moses HL, Ganote CE, Beaver DL, Schuffman SS: Light and
electron microscopic studies of pigment in human and rhesus
monkey substantia nigra and locus coeruleus. Anat Rec
155: 167-184, 1966
13. Paddison RM, Griffith RP: Occurrence of Parkinson’s disease
in black patients at Charity Hospital in New Orleans. Neurology (Minneap) 24:688-690, 1974
14. Waardenburg PJ, Franceschetti A, Klein D: Genetics and
Ophthalmology. Springfield, IL, Assen, The Netherlands, and
Oxford, England, Thomas, Royal Van Gorcum, and
Blackwell, 1961, pp 693-741
15. Yahr MD: Abnormal involuntary movements induced by
DOPA: clinical aspects. In Barbeau A, McDowell FH (eds):
L-Dopa and Parkinsonism. Philadelphia, Davis, 1970, chap 4,
pp 101-109
CSF Changes During Acute
Meningoencep halitis in
Mice Caused by
Encephalomyocarditis
Virus
Diane
E. Griffin, MD, PhD
References
1. Bart RS, Schnall S: Eye color in darkly pigmented basal-cell
carcinomas and malignant melanomas: an aid in their clinical
differentiation. Arch Dermatol 107:206-207, 1973
2. Eldridge R: The torsion dystonias: literature review and genetic and clinical studies. Neurology 20: part 2:l-78, 1970
3. Eldridge R, Fahn S (eds): Dystonia. Adv Neurol vol 14, 1976
4. Foley JM, Baxter D: O n the nature of pigment granules in the
cells of the locus coeruleus and substantia nigra. J Neuropathol Exp Neurol 17:586-598, 1958
5. Gellin GA, Kopf AW, Garfinkel L: Malignant melanoma: a
controlled study of possibly associated factors. Arch Dermatol
99:43-48, 1969
6. Golden GS: Dystonia in the Black and Puerto Rican population. In Eldridge R, Fahn S (eds): Dystonia. Adv Neurol
14:121-124, 1976
7. Korein J, Brudny J: Integrated EMG feedback in the management of spasmodic torticollis and focal dystonia: a prospective study of 80 patients. In Yahr M D (ed): The Basal
Ganglia. New York, Raven, 1976, pp 385-424
8. Korein J, Brudny J, Grynbaum B, Sachs-Frankel G, Weisinger
M, Levidow L Sensory feedback therapy of spasmodic torticollis and dystonia: results in treatment of 55 patients. In
Eldridge R, Fahn S (eds): Dystonia. Adv Neuroi 14:375-402,
1976
9. Kurland LT, Kurtzke JF, Goldberg ID, et al: Parkinsonism. In
Kurland LT, Kurtzke JF, Goldberg I D (eds): Epidemiology of
Neurologic and Sense Organ Disorders. Cambridge, MA,
Harvard University Press, 1973, chap 3, pp 41-63
10. Kurtzke JF: Huntington’s disease: mortality and morbidity
data from outside the United States. In Chase T N , Wexler
NS, Barbeau A (eds): Huntington’s Disease. Adv Neurol
23:13-25, 1979
E n c e p h a l o m y e l i t i s was induced in mice b y i n t r a v e n o u s
inoculation with e n c e p h a l o m y o c a r d i t i s virus. Exami n a t i o n of the cerebrospinal fluid revealed marked
p l e o c y t o s i s and i n c r e a s e d a m o u n t s of protein, i n c l u d ing immunoglobulins. These p r o t e i n s entered the cerebrospinal fluid b y t r a n s f e r from serum d u r i n g the
period of central nervous s y s t e m infection.
Griffin DE: CSF changes during acute
meningoencephalitis in mice caused
by encephalomyocardiris virus.
A n n N e u r o l 10:55-57, 1981
Infection of the central nervous system (CNS) precipitates a number of diagnostically useful changes in
the cerebrospinal fluid (CSF) content of cells and
protein. These CSF changes reflect the meningeal
From the Howard Hughes Medical Institute Laboratory in the
Departments of Medicine and Neurology, The Johns Hopkins
University School of Medicine, Baltimore, MD.
Received Nov 10, 1980, and in revised form Jan 14, 1981. Accepted for publication Jan 16, 1981.
Address reprint requests to Dr Griffin, Traylor 721, The Johns
Hopkins University School of Medicine, Baltimore, M D 2 1205.
0364-5134/81/070055-03$01.25 @ 1981 by t h e American Neurological Association
55
inflammatory response; alteration of the bloodbrain barrier, due either to the infectious process itself or to inflammation; and the local immune response within the CNS. Most natural infections of
the CNS enter from the bloodstream. In order to
examine CSF changes in meningoencephalitis after
viral invasion of the CNS from the blood, encephalomyocarditis virus (EMCV) infection of mice
was studied.
EMCV is a picornavirus with a wide range of hosts,
including humans, which may cause myocarditis,
pancreatitis, or encephalitis [ 3 , 41. Encephalitic
strains are cleared slowly from the bloodstream [2]
and consistently invade the CNS after peripheral inoculation to produce a rapidly fatal encephalitis.
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Methods and Materials
Six- to 8-week old BALB/c mice (Charles River Breeding
Laboratories, Wilmington, MA) were used. EMCV (American Type Culture Collection No. 129, Rockville, MD) was
passaged once in suckling mouse brain. Stock EMCV was
prepared in L-929 cells and contained 4.5 x 10: plaqueforming units (pfu) per milliliter. Homogenates of brain o r
blood from a single mouse were prepared in Hank's balanced salt solution (HBSS), and the virus content was assayed.
Mice were infected by intravenous inoculation of 0.2 ml
of the stock virus diluted in HBSS. CSF was obtained from
methoxyflurane-anesthetized mice by cisternal puncture
[7]. Cell counts were done o n individual samples, while
protein was determined in samples pooled from 3 to 6 animals. Virus neutralizing antibody was measured by 50%)
plaque reduction.
Total protein was measured using the Bradford reagent
(Biorad Laboratories, Rockville Centre, NY) with bovine
gamma globulin as the standard. IgG and IgA in the CSF
were measured using a solid-phase radioimmunoassay [7]
o r enzyme-linked immunosorbent assay.
IgG was prepared from pooled normal mouse serum by
adsorption to a staphylococcal protein A Sepharose (Pharmacia Fine Chemicals, Piscataway, NJ) affinity column and
elution with 1 M acetic acid. This IgG was dialyzed against
phosphate-buffered saline and iodinated using lactoperoxidase. Specific activity of the iodine 125-labeled
IgG was 5 x 10; cpm per microgram of protein. Each
mouse was inoculated intravenously with 5 x lo7cpm, and
CSF and serum were sampled 24 hours later.
Results
The basic characteristics of the viral encephalitis and
optimal viral inoculum were determined. This strain
of EMCV was very neurotropic and neurovirulent,
since 10 pfu inoculated intravenously was sufficient
to kill at least 50% of the mice with encephalitis. All
deaths occurred by day 7, but were earlier when
larger amounts of virus were inoculated. The onset
and magnitude of the pleocytosis were determined in
mice receiving 10, 30, and 100 pfu. Cell counts were
56 Annals of Neurology Vol 10 No 1 July 1981
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DAYS AFTER INFECTION
Protein changes in the CSF during infection ujith encephalomyocarditis (EMC) virus, showing transfer of 1gG
from serum t o CSF (@-------.)
as well as total protein
(0*), 1 6 (
0
o),and 1gA (AA ) leveis
i n the CSF after intravenous infection with I0 pfu of EMC
Vil74S.
greatly increased by day 2 in mice receiving 100 pfu
and by day 3 in those receiving 10 pfu. This difference probably reflected some delay in the growth of
virus to substantial amounts in the CNS with the
smaller inoculum. Peak cell counts occurred at day 3
or 4 and ranged between 4,000 and 10,000 cells per
cubic millimeter.
Virus growth in brain, viremia, and the appearance
of neutralizing antibody in the serum were determined for mice receiving 10 pfu. A viremia was detectable on days 2 and 3 and cleared on day 4 simultaneous with the appearance of antibody in the
serum. Virus was first detected in the brain on day 2,
peaked on day 4 at 5 x lo7 pfu per gram, and was
cleared by day 6 from those animals which survived.
Examination of CSF proteins in the mice with encephalitis revealed that total protein, including IgG
and IgA, increased during the period of encephalitis
(Figure). The transfer of 1251-labeled IgG from
blood to CSF was studied as a measure of blood-brain
barrier integrity (Figure). Heightened transfer of IgG
from blood to CSF was observed during the period
when CSF proteins were elevated and returned to
normal by day 6.
Discussion
These studies demonstrate that during EMCV
meningoencephalitis caused by the most common
route of viral entry, invasion of the CNS from the
bloodstream, acute changes occur in the protein and
cell content of the CSF. The changes coincide with
the time of maximum virus replication and maximum
blood-brain barrier dysfunction. This barrier is represented anatomically by tight junctions connecting
capillary endothelial cells, arachnoidal cells, and
epithelial cells of the choroid plexus [ 1,8]. Normally,
proteins enter CSF from blood in quantities determined by the size of the proteins [6], and possibly
also by their structural characteristics.
During CNS infection, this normal balance is disrupted and plasma proteins enter the CSF in much
larger amounts. This disruption of the normal barrier
to protein entry correlates best with CSF pleocytosis
[6], which presumably reflects meningeal inflammation. CNS infection with EMCV is usually, and
perhaps always, fatal, secondary to damage caused by
viral replication. Nevertheless, the blood-brain barrier alterations and inflammatory changes are quantitatively and qualitatively similar to those which
occur during the fatal immunopathological CNS disease caused by lymphocytic choriomeningitis virus
[ 51 and the nonfatal meningoencephalitis induced by
intracerebral inoculation of Sindbis virus [ 71. Thus,
when the disease is fatal, blood-brain barrier dysfunction resulting in transudation of plasma proteins
cannot be implicated alone as the cause of death.
Supported in part by Research Grant 1235 from the National
Multiple Sclerosis Society.
References
1. Brightman MW, Reese TS: Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol
40:648-677, 1969
2. Campbell JB, Colter JS: Studies of three variants of Mengo encephalomyelitis virus. IV. Affinities for mouse tissues in vitro
and in viva. Virology 32:69-73, 1967
3. Craighead JE: Pathogenicity of the M and E variants of the encephalornyocarditis (EMC) virus. I. Myocardiotropic and
neurotropic properties. Am J Pathol 48:333-345, 1966
4. Craighead JE, Steinke J: Diabetes mellitus-like syndrome in
mice infected with encephalomyocarditis virus. Am J Pathol
63:119-134, 1971
5 . Doherty PC, Zinkernagel RM: T-cell-mediated immunopathology in viral infections. Transplant Rev 1989-120,
1974
6. Felgenhauer K: Protein size and cerebrospinal fluid composition. Klin Wochenschr 52:1158-1164, 1974
7. Griffin DE: Immunoglobulins in the cerebrospinal fluid:
changes during acute viral encephalitis in mice. J Immunol
126:27-31, 1981
8. Reese TS, Karnovsky MJ: Fine structural localization of a
blood-brain barrier to exogenous peroxidase. J Cell Biol
34:207-217, 1967
Computed Tomography
in the Diagnosis
of Canavan's Disease
Alan R . Rushton, MD, PhD,'
B e n n e t t A. Shaywitz, MD,"t Charles C. D u n c a n , MD,:
R o b e r t B . G e e h r , M D , § and Elias E. Manuelidis, MD"
Computed tomography (CT scan) demonstrated a
symmetrical decrease in white matter attenuation of
the cerebral hemispheres of two young children with
macrocephaly and normal neurological examination.
Subsequent developmental delay led to brain biopsy,
which documented Canavan's disease (spongy degeneration of the brain, Van Bogaert-Bertrand type). The
CT scans obtained from these patients with proved
Canavan's disease appeared to be quite characteristic
in differentiating this disorder from Alexander's disease and adrenoleukodystrophy (Schilder's disease).
The CT scan may decrease the necessity for diagnostic
brain biopsy in these white matter disorders.
Rushton A R , Shaywitz B A , D u n c a n CC, G e e h r RB,
Manuelidis EE: C o m p u t e d tomography in t h e diagnosis
of Canavan's disease. A n n N e u r o l 10:57-60, 1981
The leukodystrophies are a group of hereditary disorders of myelin metabolism that result in clinical
spasticity and developmental delay. Several of these
diseases have recently been shown to result from
specific enzyme deficiencies that alter the composition of myelin in the central nervous system [6]. Alexander's disease [8] and Canavan's disease (spongy
degeneration of the brain, Van Bogaert-Bertrand
disease) [9] are also accompanied by megalencephaly.
No biochemical abnormalities have been found in
tissues from these patients; accurate diagnosis depends upon brain biopsy [61.
We report two children with megalencephaly who
had normal neurological examinations and C T scans
that demonstrated a characteristic abnormality of the
cerebral white matter. Brain biopsy confirmed the
clinical diagnosis of Canavan's disease.
Patient 1
A n Italian-American girl was referred at 1 I m o n t h s of age
for evaluation of increasing head circumference. Birth and
From the Departments of "Pediatrics, ?Neurology, $Surgery
(Section of Neurosurgery), $Diagnostic Radiology (Section of
Neuroradiology), and the I'Section of Neuropathology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 065 10.
Received Apr 17, 1980, and in revised form Dec 12. Accepted for
publication Dec 20, 1980.
Address reprint requests to Dr Shaywitz.
0364-5 134/81/070057-04$01.25 @ 1981 by t h e American Neurological Association
57
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