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Balo's concentric sclerosis New observations on lesion development.

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Balo’s Concentric Sclerosis:
New Observations on Lesion Development
G. R. Wayne Moore, MD,”? Paul E. Neumann, MD,”? Kinuko Suzuki, MD,”?$ Hugo N. hjtmaer, MD,§
Ute Traugott, MD,”?” and Cedric S. Raine, PhD, DSc”lJ
A 54-year-old woman with a four-month history of progressive neurological illness was found at postmortem examination to have lesions of Balo’s concentric sclerosis. Balo lesions were found in several areas scattered widely throughout
the central nervous system, including the spinal cord, a previously unreported location, and were studied by histological and ultrastructural methods. Bdo lesions consisted of bands of intact myelin alternating with zones of demyelination. These lesions were centered on a perivascular cuff of inflammatory cells. The center of the lesion was the oldest
area with the concentric rings of demyelination decreasing in age with increasing distance from the center. The bands
of intact myelin comprised mainly remyelinated fibers, were similar to those seen at the edges of chronic active
multiple sclerosis plaques, and may have represented the repaired margins of preceding episodes. The occurrence of
small foci of acute demyelination centered on perivascular cuffs and other changes typical of both acute and chronic
active multiple sclerosis may indicate that the lesion of Balo’s concentric sclerosis represents an intermediate stage in
the development of an established multiple sclerosis lesion.
Moore GRW, Neumann PE, Suzuki K, Lijtmaer HN, Traugott U, Raine CS: Balo’s concentric sclerosis:
new observations on lesion development. Ann Neurol 17604-61 1, 1985
Concentric sclerosis (Balo’s “encephalitis periaxialis
concentrica”) is one of several unusual variants of multiple sclerosis (MS) { 191. The characteristic concentric
bands of intact myelin alternating with zones of demyelination in this condition have been described previously in various sites in the hemispheric white matter
and brainstem. The pathogenesis of the concentric
bands in these lesions has been an enigma since their
original description El, 2, 121. It is difficult to explain
how such an alternating pattern of demyelination and
intact myelin might be produced, although several theories have been put forward [b}.The present study has
addressed this problem by examining the neuraxis in a
patient with Balo’s concentric sclerosis diagnosed at
postmortem examination using histopathological and
ultrastructural methods. In addition to the description
of Balo’s lesions in unusual sites, the present report
provides new morphological data that may help to explain the unusual histopathological characteristics of
this condition.
Case Report
Clinical History
A 54-year-old woman first developed diplopia on April 1,
1983. This was followed four or five days later by “profound
From the Departments of *Pathology (Neuropathology), fNeuroscience, and “Neurology, and the ?Rose F. Kennedy Center for Research in Mental
Einstein College of Medicine, 1300 Morris Park Ave, The Bronx,
N Y 10461; and §Neurology Group of Bergen County, 106 Prospect St, Ridgewood, NJ 07450.
weakness” and dizziness upon standing, nausea, vomiting,
and diarrhea. Examination revealed horizontal nystagmus in
both directions of lateral gaze, especially prominent upon
standing. A questionable right hemiparesis and facial weakness were noted and she was reported to be “a little confused.’’ Subsequent investigation revealed normal cerebrospinal fluid (CSF) and normal computed tomographic (CT)
scan. Electroencephalography (EEG) showed intermittent
left hemispheric delta waves. After approximately one week,
her condition improved and she was discharged.
On May 14, she noted weakness and “numbness and tingling” involving the right arm. Examination revealed nystagmus, drift of the right arm, and a tendency to lean to the
right when walking. By early June, the numbness involved
the right leg. She had a recurrence of nausea and vomiting
and was found to be sluggish and mildly confused. Lumbar
puncture at that time revealed CSF oligoclonal banding. MS
was diagnosed tentatively and a course of steroids was commenced. Her confusion worsened and recurrent episodes of
unresponsivenesswith staring and urinary incontinence were
noted. Steroids were discontinued; haloperidol and amantadine treatment was started and she became calmer after a
few days.
On June 20, a CT scan revealed two lesions of decreased
attenuation without mass effect in the right parietal and posterior frontal areas (Fig 1). There was also a suggestion of a
third lesion in the left temporal area.
Received Aug 13, 1984, and in revised form Nov 29. Accepted for
publication Nov 29, 1984
Address reprint requests to Dr Moore, Department of Pathology
(Neuropathology), Albert Einstein College of Medicine, 1300 Marris Park Ave, The Bronx, NY 10461,
Fig 1 . Computed tomographic scan, with contrast enhancement,
81 days afier the onset offirst symptom. There are radiolucent
white matter lesions without mass eflect in the right posterior
frontal and parietal areas (long arrows) and a possible similar
lesion in the ldt posterior temporal region (short arrow).
Fig 2. Coronal section ofthe unjixed brain showing Balo’s
concentricsclerosis involving the right parietal white matter
On June 29, neurological examination revealed disorientation as to date, poor attention, and complete inability to
recall names of objects after five minutes, although immediate recall was intact. Nystagmus was noted in all directions. Bilateral hyperreflexia and bilateral dysmetria were
present. Her subsequent course was characterized by deterioration of level of consciousness and respiratory problems.
A deep ri&t frontal brain biopsy revealed only mild hypertensive changes. The patient died of respiratory failure on
July 23, 114 days after the onset of her illness.
Postmortem Findzngs
Postmortem examination was performed approximately 18 hours after death. General findings were
essentially negative aside from small focal areas of
bronchopneumonia bilaterally.
The brain weighed 1200 gm and was bisected sagittally in its fresh state. The left hemisphere, brainstem,
cerebellum, and most of the spinal cord were fixed in
10% formalin. Tissue blocks were embedded in
paraffin and sections were stained with hematoxylin
and eosin, Heidenhain, and Bodian stains. The right
half of the brain and several segments from different
levels of the spinal cord were cut fresh and processed
for ultrastructural and later immunocytochemical
study. Thin (0.5 cm) slices of fresh brain for ultrasuucturd study were placed in 5% glutarddehyde for 24
hours, further sectioned into l-mm-thick slices, osmicated for 2 hours, dehydrated, and embedded in
Epon. One-micron-thick epoxy sections were stained
with toluidine blue and thin sections of selected regions were stained with uranyl acetate and lead citrate
Fig 3 . Small lesion of Balo’s concentric sclerosis involving
parawentricdur white matter. (Heidenhain stain; x 8.)
and examined with a Siemens 101 electron microscope.
In the fresh state, and upon sectioning the formalinfixed material, the white matter demonstrated large
round multilamellar lesions up to 3 cm in diameter (Fig
2 ) in the locations noted on the CT scan. A similar
lesion not visualized by CT was found in the right
temporal lobe. The temporal lesions extended medially to involve the hippocampal fimbriae bilaterally.
In the fresh state, the lesions consisted of bands of
intact white matter that alternated with regions of
brownish yellow discoloration (see Fig 2 ) .
Moore et al: &do’s Concentric Sclerosis 605
Fig 4. Nonconcentric lamelkzr lesion in optic chiasm (arrowhead). (Heidenhain stain; x 5.)
Fig 5 . Medulla oblongata with several iwegular nonconcentric lesions. A multiple sclerosis plaque is also present (arrow).
(Heidenhain stain; x 4.)
Fag 7 . A small perzvascular cuff of
mononuclear cells infiltrating adjacent cerebral whzte matter. (HG-E;
x 200.)
606 Annals of Neurology Vol 17 No 6 June 1985
Fig 6. Lumbar spinal cord. A large lamellar, nonconcentric lesion occupies the lateralfuniculus. Upon casual inspection, the
plaque in the posterior columns is not lamellar, but close examination reveals a subtle band of myelin in both posterior columns.
(Heidenhain stain; x 5 . )
Myelin stains confirmed that Balo lesions comprised
bands of intact myelin alternating with bands of demyelination and also demonstrated concentric ring patterns in some smaller lesions (Fig 3). However, most
lesions showed an irregular nonconcentric lamellar pattern, such as ones seen in the optic chiasm and shown
in Figure 4. Particularly impressive were multiple nonconcentric lamellar lesions intermixed with a MS
plaque within the medulla oblongata (Fig 5). Multiple
sections of the lumbar spinal cord also showed Balo
lesions (Fig 6). The cervical and thoracic spinal cord
did not show lesions.
Throughout the cerebral white matter, numerous
venules showed cuffs of inflammatory cells, some of
which were seen to infiltrate the adjacent parenchyma
(Fig 7). Perivascular cuffs were occasionally sur-
Fig 8. One-micron-thick epoxy section of a punctate area of acute
demyelination centered on venule with a prominent perivascular
cuff of mononuclear cells (seen at the lefti. To the right, acute demyelination and an axonal spheroid (arrow) are seen. (ToIuidine blue; x 480.)
rounded by small punctate, well-demarcated areas of
acute demyelination in which axonal spheroids were a
frequent feature (Fig 8).
One-micron-thick epoxy sections of Balo lesions revealed that the bands of myelin (Fig 9) were largely
populations of thinly myelinated fibers (Fig 10). Ultrastructurally such fibers showed thin myelin sheaths,
occasionally attenuated by the premature termination
of myelin lamellae in cytoplasmic loops, on both the
external and internal aspect of the sheath (Fig 11).
Prominent cellular constituents of the preserved band
of myelin included frequent oligodendrocytes, lymphocytes, and hypertrophied astrocytes (Fig 12). Occasional oligodendrocytes showed aberrant myelination
Fig 9. One-micron-thick epoxy section of a portion of a Balo lesion. A band of myelin (center) separates two zones ofdemyelination. (Toluidine blue; X 30.)
as evidenced by a few layers of myelin around the cell
soma (Fig 13). A few normally myelinated and some
demyelinated axons were seen within the band of myelin (see Fig 12). These features are highly reminiscent
of the appearance of the edge of a chronic active MS
plaque Ll5, 17, 201, except that the remyelinative response was more pronounced in the Balo lesion.
On the other hand, the bands of demyelination
showed myelin breakdown, gliosis, and, in those of
more advanced age, prolific remyelination. The central
core of demyelination within the Balo lesion consisted
of a venule with a cuff of mononuclear inflammatory
cells, reminiscent of the perivascular location of the
small isolated punctate lesions of demyelination described earlier. The central core appeared to be the
oldest part of the concentric lesion, being intensely
gliotic. Moreover, as also noted by previous authors
{2, 61, the farther away a given band of demyelination
was located from the central core, the less advanced
was the stage of demyelination (i.e., the younger its
age), based on the degree of gliosis and stage of myelin
Ultrastructurally, the mechanism of myelin stripping
resembled that described previously in MS, experimental autoimmune encephalomyelitis, and other demyelinating conditions [lo, 14, 17, 18, 24, 28). This
involved myelin vesiculation or myelinolysis and myelin stripping by macrophages. Occasionally demyelination was associated with peculiar fingerlike projections within the macrophage cytoplasm, reminiscent of
the “endocytosis vermiformis” described in MS by
Prineas and Connell {14) and thought to be a variant
of receptor-mediated phagocytosis of myelin {S, 161.
Myelin degradation within macrophages was seen as
membrane-bound profiles with lamellar or granular
Moore et al: Balo’s Concentric Sclerosis 607
Fig 10. Higher magnification of a band of myelin in a Balo lesion shows a population of remyelinatedfibers with disproportionately thin myelin sheaths. (Toluidine blue; x 300.)
Fig 11. An electron micrograph of a longitudinally sectioned
fiber shows an attenuated thin myelin sheath. Some myelin
kzmellae terminate prematurely as loops of oligodendroglialcytoplasm (arrows). ( X 16,000.)
Annals of Neurology
Vol 17 No 6 June 1985
patterns, also previously well documented [lo]. Many
macrophages contained droplets of neutral lipid.
Fig 12. A I-micron-thick epoxy section shows some of the cellular constituents at the edge of a thin band of myelin. Oligodendrocytes (long arrows), lymphocytes (short arrows), and reactive
astrocytes (center right) are present. In the middle of the feld, an
axon is being divested of its myelin sheath. Normal myelin
sheaths are also present. (Tohidine blue; x 480.)
Fig 13. (A) An electron micrograph of an oligodendrocyte
within a band of remyelination shows the cell encompassed by
abewant myelination (arrow). ( x 14,000 before 7% reduction.)
(B)The thin sheath of abewant myelin is shown at x 60,000
(before 5 % reduction).
The histopathological and ultrastructural features of a
case of Balo’s concentric sclerosis diagnosed at postmortem examination are presented. Concentric and
lamellar lesions were found throughout the central
nervous system, including the medulla and spinal cord.
There has been only one previous report of medullary
lesions in concentric sclerosis 12 1) and the occurrence
of spinal cord lesions has never been documented.
The distinctive pattern of the lesion of Balo’s concentric sclerosis has intrigued investigators since its initial description. The history of the various hypotheses
of its pathogenesis was reviewed thoroughly by Courville [6]. The lesion was first described in 1906 by
Marburg [12) and subsequently by Barre and associates 133 in 1926. The lesions were named after
Bal6 who described the concentric lesions in a case
report written in Hungarian and published in 1927 [I]
and followed the next year by a report in English [2].
Since then, approximately forty case reports have appeared [4, 6, 7, 9). In addition, lesions reminiscent of
concentric sclerosis have been discovered in unusual
cases of demyelinating disease of uncertain classification 125). Bal6 felt that “encephalitis periaxialis
concentrica” could be regarded as a disease entity distinct from MS, partially by the absence of spinal cord
lesions [27. However, although Balo lesions have until
now not been reported in the spinal cord, it is generally agreed that the lesion of concentric sclerosis is a
variant of the MS plaque. Indeed, many cases of MS,
including the present one, have examples of this unusual lesion superimposed on the pathological features
of MS {GI.
Explanations for the alternating rings of myelin and
demyelination have usually involved consideration of
physicochemical or vascular factors, as reviewed by
Courville [G), and are based on the supposition that
the myelin bands comprised normal myelin. Study of
plastic embedded material in the present case allowed
for a more detailed histological study at the light microscopy level as well as ultrastructural examination,
and the findings support the idea that the predominant
feature of the bands of myelin in the Balo lesion is
remyelination. This is based on a number of appearances. The first observation is the presence of epoxy
within the myelinated band of fibers with disproportionally thin sheaths relative to the axon diameter. This
has been repeatedly recognized as the hallmark of remyelination [ll, 15, 18, 20, 28). Second, oligodendroglial perikarya were occasionally covered by a few
layers of myelin, a finding noted previously in remyelinated borders of chronic MS plaques {IS} and in
other regenerative states C23, 271. Third, the presence
Moore et al: Balo’s Concentric Sclerosis
of numerous oligodendrocytes within the band demonstrated that the cell responsible for myelin regeneration was present in abundance. Fourth, the occurrence
of attenuated myelin sheaths with oligodendroglial cytoplasmic loops within the band of myelin might be
regarded as evidence of remyelination, previously
demonstrated in the peripheral nervous system [ 5 ] .
This feature has been reported in various demyelinating conditions C13, 22, 231 and within the hypercellular edge of chronic active MS plaques [13, 22J. Overall, the changes within the myelin band of the Balo
lesion (remyelination, oligodendroglial preservation,
gliosis, a few naked axons, axons undergoing demyelination, and normally myelinated axons) were highly
reminiscent of those seen at the edge of a chronic
active MS plaque [13, 15, 17, 20, 221, except that the
remyelinative response was more pronounced in the
Balo lesion.
From our ultrastructural analysis it would appear
that the concentric myelin bands represent the remyelinated plaque borders of successive episodes of demyelination and that the lesion originated as a small
focus of acute demyelination around a perivascular inflammatory cuff. Since the centers of lesions possessed
the most long-standing changes, there appeared to
have occurred centrifugal progression of episodes of
demyelination and remyelination. The immunopathological ramifications of such lesions are unknown
but might involve local immunoregulatory mechanisms such as those that operate at the margin of an MS
plaque [26].
The clinical course in the present and most other
cases of concentric sclerosis [61 was relatively short
(usually a matter of weeks to months). It is of considerable interest that in the present case there were separate lesions typical of acute MS, and changes within the
Balo lesion consistent with chronic active MS. It is
possible, therefore, that the Balo lesion may be an
intermediate stage in the progression of an MS plaque.
In fact, some cases show Balo-like changes at the advancing edges of MS lesions “91. Further studies of
cases of Balo’s concentric sclerosis will be necessary to
clarify these issues.
Supported in part by United States Public Health Service Grants
NS 08952, NS 11920, NS 07098, NS 03356, and NS 10803,
and National Multiple Sclerosis grants RG 1001-E-5 and 1664-A-I.
Dr Moore is a research fellow of the Multiple Sclerosis Society
of Canada.
We would like to thank Dr J. W. Prineas and Dr F. Gray for helpful
discussion; Dr G. Dunn for pathological advice; Howard Finch,
Pablo Garcia, Marie Hess, Patricia Kennedy, Miriam Pakingan, and
Earl Swanson for technical assistance; and Agnes Geoghan and
Nanci E. Legg for typing the manuscript.
610 Annals of Neurology Vol 17 No 6 June 1985
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Simply Stated
“Some seventy years ago a promising young neurologist made a discovery that necessitated the addition
of a new word to the English vocabulary. He insisted
that this should be knee-jerk, and knee-jerk it has remained, in spite of the efforts of patellar reflex to
dislodge it. He was my father; so perhaps I have inherited a prejudice in favour of home-made words.”
Sir Ernest Gowers, The Complete Plain Words, 1954
Moore et al: Balo’s Concentric Sclerosis 611
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