Neuropathology 2019

doi:10.1111/neup.12545

Case Report

Localized atrophy of the pontine base as a sequela of
prolonged ischemia: Report of an autopsy case
Masayuki Shintaku1

and Daita Kaneda2

1

Department of Pathology, Shiga General Hospital, Moriyama and 2Department of Neurology, Osaka City Kosaiin
Hospital, Osaka, Japan

An 80-year-old man with a history of diabetes mellitus
and hypertension died of a progressive neurological disorder characterized by truncal ataxia, extraocular movement
disturbance, and muscular rigidity. Neuroradiological
examination showed progressive atrophy restricted to the
pontine base. Autopsy revealed localized atrophy of the
pontine base, in which both neurons and nerve fibers were
lost, especially in the central region. Medium-sized and
small arteries in the parenchyma of the pontine base
showed marked fibro-hyalinous thickening of the walls
with luminal stenosis, but no distinct tissue defect as seen
in lacunar infarct was observed. Perivascular lymphocytic
infiltration was mostly absent, and reactive astrocytic proliferation was weak. The pontine tegmentum, midbrain,
and medulla oblongata were well preserved. Localized
atrophy of the pontine base is a rare pathological condition, and its pathogenesis in the present case can be best
explained by a prolonged ischemic state (hypoperfusion)
due to marked sclerotic changes of perforating arteries. It
is unique that the lesions were restricted to the pontine
base and the formation of lacunas was not observed.
Localized metabolic derangement resembling that seen in
central pontine myelinolysis might have also contributed
to the pathogenesis of this peculiar localized atrophy.
Key words: arteriosclerosis, chronic ischemia, lacunar
infarct, localized atrophy, pontine base.

INTRODUCTION
Brainstem infarct occurs as a result of stenosis or occlusion
due to an atherosclerotic or microembolic process involving the vertebro-basilar artery system in most cases, and
the pontine base is the most commonly affected site.1,2
Infarct of the pontine base usually takes one of two

Correspondence: Masayuki Shintaku, MD, Department of Pathology,
Shiga General Hospital, Moriyama, Shiga 524-8524, Japan.
Email: masa-s@sings.jp
Received 29 October 2018; revised and accepted 05 February 2019.

© 2019 Japanese Society of Neuropathology

pathological forms. The first is infarct involving large areas
of the pontine base (territorial infarct).1 It is caused by
arterial thrombosis or an atheromatous embolism and usually produces a single large lesion, in which extensive
destruction of parenchymal tissue takes place and, in the
chronic stage, gross atrophy with deformity of the contour
of the pontine base often develops. The second form of
pontine infarct is lacunar infarct.3,4 It is caused by arteriosclerosis (lipohyalinosis) of small perforating arteries, and
multiple, small tissue defects (“lacunas”) are formed,
mostly in the central area.3,4 The contour of the pontine
base is preserved, and global atrophy of the pontine base
is rare. Another rare form of pontine infarct is “branch
atheromatous disease”, in which the orifices of perforating
branches of the basilar artery are occluded by atheromatous changes, and characteristic, wedge-shaped lesions are
formed.5,6
The case we report here differed from the above forms
of pontine infarct. Although marked sclerotic changes
were noted in small perforating arteries of the pontine
base, there were neither small tissue defects (lacunas) nor
large tissue defects with deformities of the contour. There
were multiple, confluent small foci of tissue destruction or
rarefaction, and they resulted in progressive, global atrophy of the pontine base. We consider that a prolonged
ischemic state (hypoperfusion) due to severe sclerotic
changes of arteries irrigating the pontine base was the
most likely cause of the peculiar localized atrophy in
this case.

CLINICAL SUMMARY
The patient was an elderly man with a history of type
2 diabetes mellitus, hypertension, and sensory hearing disturbance with tinnitus from his fifties. He presented to the
hospital with dizziness at the age of 72 years. Magnetic
resonance imaging (MRI) demonstrated a slightly highintensity area in the pontine base on a T2-weighted image
(Fig. 1), but he did not show any significant neurological
symptoms or signs other than dizziness at that time.

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M Shintaku and D Kaneda

Fig. 1 MRI findings of the brain showing the progression of localized atrophy of the pontine base (images in the lower row were taken
6 years after those in the upper row). No atrophy is noted in the midbrain or cerebellum. Focal dilatation of the cerebral sulci seen in
the left frontoparietal lobes is most likely a congenital anomaly.

Localized thinning of the gyri in a portion of the left
fronto-parietal lobe was also observed. Two years later, he
developed gait disturbance, and neurological examination
demonstrated truncal ataxia, supranuclear disturbance of
extraocular movements, muscular rigidity, and exaggerated deep tendon reflexes. On MRI examination, atrophy
of the pontine base had progressed and was associated
with localized T2-high intensity. Gait disturbance gradually deteriorated, and swallowing difficulty also developed.
At the age of 78, he became unable to walk, and gastric
tube feeding was started. On MRI, the pontine base
showed a hemorrhagic change in addition to marked atrophy, but the “cross sign” was not observed. He became
unable to maintain a standing posture at the age of
79, and spontaneous speech decreased. He lost visual acuity of the left eye because of glaucoma and hearing difficulty became marked, but cognitive impairment was not
apparent. He died of aspiration pneumonia at the age of
80, about 8 years after the onset of neurological symptoms. The clinical diagnosis was not definite: overall, the
clinical features suggested progressive supranuclear palsy,
but corticobasal degeneration and multiple system atrophy

were considered as other possibilities. Neuro-Behçet disease was also considered, but cutaneous or ocular symptoms suggestive of Behçet disease were not observed and
HLA typing did not demonstrate the characteristic haplotype of that disease (HLA-B51). General autopsy demonstrated organizing bronchopneumonia with pulmonary
fibrosis and multiple microabscesses in the kidney.

NEUROPATHOLOGICAL FINDINGS
The brain weighed 1170 g, and the most pronounced
change was marked atrophy restricted to the pontine base
(Fig. 2A), which showed brownish discoloration on the cut
surfaces (Fig. 2B). In contrast, the pontine tegmentum,
midbrain, medulla oblongata, and cerebellum retained
their normal appearances. Medium-sized and small arteries on the brain base showed moderate to marked sclerotic
changes, but no luminal occlusion was observed. The cerebrum appeared grossly normal on external examination,
except that a portion of the left fronto-parietal lobe
exhibited focal thinning of the gyri. On coronal sections,
the cerebral cortex, white matter, basal ganglia, and
© 2019 Japanese Society of Neuropathology

Localized atrophy of the pontine base

3

Fig. 2 Macroscopic findings of the brain. (A) At autopsy, the brain shows marked atrophy localized to the pontine base. The cerebral
and cerebellar hemispheres retain their normal appearances. Atherosclerosis of the basilar artery is evident. (B) Step sections of the
midbrain and pons demonstrate atrophy with brownish discoloration of the pontine base. The pontine tegmentum appears normal.

thalamus did not show any prominent pathological alterations. The basal ganglia showed mild “état lacunaire”.
Histopathological changes on sections stained with
hematoxylin-eosin (HE) and Luxol fast blue-periodic acid
Schiff (LFB-PAS) were mostly restricted to the pontine
base. The pontine base showed a markedly reduced volume and appeared diffusely pale on HE (Fig. 3A) and
myelin (Fig. 3B) stains. There were patchy or confluent
multiple foci of loss of neurons and nerve fibers, but the
formation of small lacuna-like cavities was not observed
(Fig. 4). The patchy deposition of calcium salts was seen
in the neuropil of the pontine nuclei. Neurons of the pontine nuclei tended to be preserved in comparison with the

longitudinal or transverse fibers, and occasionally showed
a chromatolytic change. Ten binucleated neurons were
counted in the pontine nuclei on four sections taken from
different levels of the pons. Small numbers of “foamy
spheroids” (Fig. 5A) and Rosenthal fibers (Fig. 5B) were
also noted, and aggregates of hemosiderin-laden macrophages were mainly observed around blood vessels
(Fig. 5C). Although a few microglial nodules and microabscesses, probably reflecting a septic process in the terminal stage, were found, perivascular lymphocytic infiltration
was mostly absent. Activated microglia diffusely proliferated throughout the pontine base (Fig. 6A), but reactive
astrocytic proliferation and fibrous gliosis were weak

Fig. 3 Semimacroscopic findings of the pontine sections (the same as those of Figure 2B) stained with HE (A) and LFC-PAS (B).
Whereas the pontine base shows atrophy and pale staining as a whole, no distinct tissue defects (lacunes) are found (A). The pontine
base shows a patchy or confluent loss of the stainability of myelin sheaths.

© 2019 Japanese Society of Neuropathology

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M Shintaku and D Kaneda
were found. No ischemic or anoxic changes were observed
in the hippocampus. Mild dilatation of the perivascular
space was seen in the basal ganglia and thalamus, but arteriosclerotic changes were consistent with the patient’s age
and not markedly abnormal. In the spinal cord, secondary
degeneration of the bilateral pyramidal tracts was evident.
On immunohistochemical examination, no deposition of
abnormally phosphorylated tau or phosphorylated
α-synuclein was demonstrated in the pontine base.

DISCUSSION

Fig. 4 A microphotograph of a pontine base section stained with
LFB-PAS. In the patchy lesions, nerve fibers of the white matter
are markedly lost, but neurons of the pontine nuclei are spared in
comparison with nerve fibers.

(Fig. 6B). The lesions were accentuated in the central area
of the pontine base, and the peripheral area, tegmentum,
and brachium pontis were spared.
Medium-sized and small arteries in the pontine base
showed markedly sclerotic changes (Fig. 7). These arteries
exhibited meandering, and their walls had lost smooth
muscle cells and elastic fibers that were replaced by thick,
hyalinized connective tissue. Although mild lymphocytic
infiltration was noted in the adventitia of a few arteries,
fibrinoid necrosis was not observed. The vascular lumina
were markedly stenotic, but neither fresh nor organized
thrombi were observed. No amyloid deposition was demonstrated on the vascular walls. The basilar artery on the
pontine surface showed eccentric intimal thickening but
no luminal occlusion.
The cerebrum and cerebellum retained a mostly normal
appearance. Although a small number of microglial nodules and microabscesses were scattered, no apparent neuronal loss, degenerative changes, or ballooned neurons

The characteristic neuropathological findings of the present case can be summarized as follows: (i) whereas the
pontine base showed marked atrophy, the tegmentum was
well preserved, and the midbrain and medulla oblongata
also retained their normal volumes, (ii) in spite of the
multifocal loss of neurons and nerve fibers, the formation
of cavities (“lacunas”) was not seen in the pontine base,
(iii) neurons of the pontine nuclei tended to be preserved
in comparison with nerve fibers, (iv) reactive hyperplasia
of astrocytes and fibrous gliosis were weak, and
(v) whereas sclerotic changes of medium-sized and small
arteries were marked in the pontine base, those in the
basal ganglia and thalamus were not marked and were
consistent with the patient’s age.
Vascular lesions seen in the pontine base of the present
case were marked arteriosclerotic changes and similar to
those found in cases of lacunar infarct.2,3 The long history
of diabetes mellitus and hypertension had most likely
aggravated the arteriosclerotic changes.2,3 Lacunar infarct
is one of the common forms of brain infarct and preferentially involves the basal ganglia, thalamus, and pontine
base. Poirier and Derouesne classified it into three types:
type 1, small ischemic infarct forming a tissue defect surrounded by gliotic tissue, type 2, small cavities resulting
from microhemorrhage, and type 3, dilatation of the perivascular space.7 Lammie et al. further subdivided type

Fig. 5 Microphotographs of pontine
base sections stained with HE. A few
foamy spheroids (A) and a small
amount of Rosenthal fibers (B) are
found. Aggregates of hemosiderinladern macrophages are mainly seen
around blood vessels (C).

© 2019 Japanese Society of Neuropathology

Localized atrophy of the pontine base

Fig. 6 Microphotographs of pontine base sections immunostained for CD68 (A) and GFAP (B). Whereas activated microglial cells diffusely proliferate throughout the pontine base (A),
reactive astrocytosis is weak, and hypertrphic astrocytes are
sparsely distributed (B).

Fig. 7 Microphotographs of pontine base sections stained with
LFB-PAS (A) and Masson-trichrome (B). Medium-sized and
small arteries show marked fibro-hyalinous thickening of the
walls. Mild lymphocytic infiltration is observed within the fibrotic
adventitia in a few arteries. The vascular lumens are stenotic.

1 into types 1a and 1b.8 Type 1b is an incomplete form of
ischemic infarct caused by a transient embolic occlusion or
prolonged reduction of local blood flow.8,9 In most cases
the lesion is restricted to small areas,9 but when it affects
an extensive area, local tissue atrophy without forming distinct cavitation develops as a long-term effect.2,8,9 The
lesion of incomplete infarct comprises edema, rarefaction
of the neuropil, loss of neurons or oligodendrocytes, and
proliferation of astrocytes.8,9
The present case shares some neuropathological findings with the type 1b lacunar infarct and may represent a
peculiar form of chronic ischemic encephalopathy
© 2019 Japanese Society of Neuropathology

5
localized to the pontine base. We suggest that marked
sclerotic lesions of perforating arteries led to prolonged
reduction of the local blood flow involving the pontine
base and, because of the survival of some neurons and
astrocytes and preservation of the tissue structure, local
atrophy without cavitation developed.9 In a postmortem
microangiographic study on the pathogenesis of lacunar
infarct of the pontine base, Takeshima emphasized the
importance of vascular tortuosity of the paramedian branches of the basilar artery and local vulnerability of the
vascular wall.4 In the present case, too, the specific architecture and local vulnerability of small arteries irrigating
the pontine base might have contributed to the progression of arteriosclerotic lesions and pathogenesis of the
selective atrophy of the pontine base.
It is unknown why marked arteriosclerotic changes
almost solely affected perforating arteries of the pontine
base in this case. Among the specific circulatory disturbances of the pontine base, “branch atheromatous disease”, caused by narrowing or occlusion of the orifices of
the branching arteries by an atheromatous process, is well
known.5,6 However, the distribution pattern of lesions in
this disorder differs from that of the present case.
In the present case, some of the sclerotic vessels might
be small veins. In incomplete infarct of the cerebral white
matter, fibro-hyalinous thickening of the vascular wall with
luminal stenosis affects not only small arteries and arterioles but also small veins and venules.10 Fibro-hyalinous
thickening of the venous wall (phlebosclerosis) is a relatively rare phenomenon that occurs under specific pathological conditions, such as chronic thrombosis of the
superior sagittal sinus,11 or venous congestive myelopathy.12 Perivascular hemosiderin deposition and the formation of Rosenthal fibers, which were reported in these
disorders, were also found in our case. It is conceivable
that a local disturbance of venous drainage due to phlebosclerosis contributed to the pathogenesis of the pontine
lesions in the present case, although venous infarct or stagnant brain damage solely involving the pontine base has,
to our knowledge, not been documented.
The localized atrophy of the brain stem also occurs in
neuro-Behçet disease13–16 or chronic brainstem encephalitis.17 In this respect, a problematic finding in our case was
that 10 binucleated neurons were counted in the pontine
nuclei in four sections, because we previously reported
that the appearance of many binucleated neurons is, albeit
not specific, a characteristic finding of neuro-Behçet disease.16 The possibility that the pontine base atrophy in the
present case represents a long-term sequela of neuroBehçet disease is thus difficult to exclude completely.
However, cutaneous or ocular symptoms suggestive of
Behçet disease were absent in our case, and HLA typing
did not demonstrate the characteristic haplotype.

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M Shintaku and D Kaneda

Perivascular inflammatory cell infiltration or findings of
vasculitis (phlebitis) were mostly lacking in the present
case, and severe sclerotic changes of the vascular walls are
usually not seen in neuro-Behçet disease. Finally, the
absence of lesions in the pontine tegmentum, midbrain, or
medulla oblongata also does not support the diagnosis of
neuro-Behçet disease.
As mentioned above, we consider that a chronic ischemic state due to severe arteriosclerotic changes was the
most important cause of a loss of neurons and nerve fibers
and localized atrophy of the pontine base in the present
case. However, considering the distribution pattern of the
lesions and also the relative preservation of neurons in
comparison with nerve fibers, the possibility remains that
some other unknown metabolic disturbances resembling,
for example, central pontine myelinolysis (CPM)4,18 or
multiple spongy necrosis of the pontine base19 might have
also contributed to the pathogenesis of the pontine lesions.
The weak astrocytic reaction may suggest the presence of
some metabolic abnormalities of astrocytes. CPM is occasionally seen in association with lacunar infarct of the pontine base, and some investigators consider that its
pathogenesis is closely related to the specific vascular
architecture and local vulnerability of the pontine base.4

DISCLOSURE
We declare that we have no conflict of interest.

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© 2019 Japanese Society of Neuropathology