From the Service de Médecine Vasculaire and the Centre Claude
Bernard de Recherche sur les Maladies Vasculaires Périphériques
(E.H., A.R., J.E., J.-N.F.), the Service d'Anatomopathologie (P.F.), and
the Service de Psychiatrie (O.B.), Hôpital Broussais, Paris, France.
Abstract
Background—Neuropathological
data are very scarce in systemic sclerosis and fail to demonstrate
primary changes in the brains of such patients.
Case Descriptions—A 41-year-old woman with CREST syndrome
developed signs of dementia after an episode of severe dehydration and
died two months later of septic shock. A 63-year-old woman with CREST
syndrome and a history of two unexplained transient ischemic attacks
had had balance disorders since age 62. She died of severe pulmonary
hypertension. In both cases, the autopsy showed extensive wall
calcification of small arteries and arterioles in the brain, primarily
in the basal ganglia, and also in the frontal lobes and the cerebellar
area in the second case. No known cause of cerebrovascular
calcification was found in either patient.
Conclusion—The neuropathological findings in these two
patients suggest that systemic sclerosis may induce primary vascular
changes in the brain, of which calcification may be a marker.
No noteworthy
findings have been reported in the few available pathological studies
of the brain of patients with systemic sclerosis. Central nervous
system (CNS) manifestations seem relatively frequent in such
patients1 2 but have almost always been
considered secondary to the disease process.3 We
describe findings in two consecutive autopsies of women with systemic
sclerosis and CNS symptoms, showing advanced cerebrovascular
calcifications.
Case 1
A 41-year-old white woman developed Raynaud's phenomenon during
adolescence. She never smoked and did not have diabetes, hypertension,
or dyslipidemia. Systemic sclerosis (CREST variant) was
diagnosed in her early twenties. She had sclerodactyly, telangiectasias
on the face and hands, and tightness of the face skin. Anticentromere
antibodies were present at 1:1000 dilution. Antiphospholipid
antibodies and cryoglobulinemia were negative. She had a long history
of gastrointestinal tract disorders, with dysphagia and esophagitis,
constipation, intermittent bloating, abdominal cramping, and anal
incontinence. She had been severely depressed since age 24. She was
treated with calcium blockers, omeprazole, intestinal antispasmodic
agents, and various antidepressant drugs. She never received steroids
or immunosuppressive drugs. At age 35 a cutaneous ileostomy was
performed after she underwent surgery for a perforated intestinal
necrosis; this was complicated by chronic liquid diarrhea.
At age 41 the subject was hospitalized for severe dehydration due to
abundant intestinal losses that she failed to compensate for through
negligence. The blood pressure was 100/70 mm Hg, the heart rate
120 beats per minute, and the temperature 37°C. She was confused.
Physical examination was otherwise normal. She had a generalized
seizure on the day of admission. Laboratory assays showed functional
renal insufficiency with a serum creatinine of 530
µmol/L, proteinemia of 88 g/L, and moderate metabolic
acidosis with a plasma pH of 7.36 and a bicarbonate level of 13
mmol/L. Metabolic disorders normalized after 5 days of
intravenous rehydration. The baseline
creatinine was 75 µmol/L, and routine laboratory
assays were normal. Marked cerebral disorders persisted despite
adequate rehydration and included agitation, aggressiveness, loss of
appetite, insomnia, periods of groaning, compulsive rubbing of the back
of her neck on the bed, urinary incontinence, and total indifference to
her surroundings; it was impossible to communicate with her.
Neurological examination showed only a hyperactive palm-chin reflex.
Cerebral CT was normal except for mild basal ganglia calcification.
Lumbar puncture showed a cerebrospinal fluid protein content of 0.69
g/L but was otherwise normal. Thyroid hormones were normal. Two
consecutive electroencephalograms showed diffuse abnormalities with an
asynchronized, unorganized, slowed, and poorly reactive print.
High-dose intravenous antidepressant therapy with
clomipramine (Anafranil) had no effect. A diagnosis of dementia was
made by psychiatrists and neurologists.
Two months after the onset of neurological signs, the subject died of
septic shock of gastrointestinal origin. At autopsy the brain was
macroscopically normal except for mild swelling.
Histologically, the extraparenchymal arteries were
moderately thickened by intimal hyperplasia. Mineral deposits in the
walls of small arteries and arterioles (Fig 1
Case 2
A 63-year-old white woman developed Raynaud's phenomenon at age
30. She had no cardiovascular risk factors. A CREST
syndrome was diagnosed at age 35. She had sclerodactyly; tightness of
the face skin with thin and shortened lips; telangiectasias on the
hands, face, back, and palate; pyrosis; intermittent dysphagia; and
ocular and buccal dryness. She had been on a regimen of
trimethylcolchicinic acid and metoclopramide and occasionally
H2 blockers since that time. No steroids or
immunosuppressive drugs were given. At age 50 anticentromere antibodies
were detected at 1:1000 dilution. Antiphospholipid antibodies and
cryoglobulinemia were absent. After age 43 she gradually developed
exertional dyspnea and pulmonary hypertension.
At age 44 the subject was hospitalized for a transient ischemic
attack. On the day of admission she had two consecutive episodes of
expressive aphasia, each lasting approximately half an hour. The
neurological examination was normal. Cerebral CT, ultrasound
examination of the heart and carotid arteries, 24-hour ECG
recording, and cerebrospinal fluid examination were normal.
Low-dose aspirin was added to her treatment at hospital discharge. No
further transient ischemic attacks occurred. At age 62 she
complained of balance disorders, but no clear focal neurological
deficit was found. Cerebral CT showed moderate cerebral atrophy and
mild calcification in the basal ganglia (Fig 2
At age 63 the subject underwent surgery for unperforated intestinal
necrosis that required the ablation of 1.50 m of ileum. The
etiology of the intestinal necrosis remained unclear. Her respiratory
status worsened postoperatively, and she died 4 months later of
refractory right heart failure. At autopsy the brain was
macroscopically normal except for mild swelling.
Histologically, the extraparenchymal arteries were
moderately thickened by intimal hyperplasia. Vascular calcium deposits
were observed in the same areas as in case 1 (basal ganglia,
hippocampus, and dentate nucleus) and also in small-artery walls of
cortical areas, especially the frontal lobes, cerebellar cortex, and
mamillary bodies. Small foci of neuronal ischemic necrosis were
also observed, but there was no glial or inflammatory reaction. Severe
interstitial fibrosis and artery wall thickening were
observed in the lungs. The right heart cavities were moderately
dilated. The digestive tract showed moderate artery and arteriolar wall
thickening and no significant parietal fibrosis. Other organs were
unremarkable.
Discussion
Structural changes of the small arteries and arterioles (typically
concentric fibrous intimal thickening) have been described in nearly
every organ of patients with systemic sclerosis4
and play a key role in some of its main manifestations, such as
Raynaud's phenomenon, scleroderma renal crisis, pulmonary
hypertension, and myocardial ischemia.5
Blood vessels would also be expected to be involved in the CNS.
Cerebral hypoperfusion, suggestive of impaired microcirculation, was
recently observed in sclerodermic patients.6
However, pathological studies have failed to demonstrate primary
cerebrovascular changes in systemic sclerosis. Nonspecific cortical
necrotic foci were reported in 3 of 17 brains.1 A
cerebral infarct has been linked to arteritis localized in a single
internal carotid artery.7 Other studies showed
vascular changes that could be explained by concomitant hypertension or
atherosclerosis.3 8
Unfortunately, pathological data are lacking in 4 additional
sclerodermic patients with neurological disorders (severe headache,
generalized seizures, confusion, dysarthria, expressive aphasia,
hemiparesis, and hemianalgesia). In these 4 cases cerebral
arteriography showed bilateral narrowing of several medium-sized and
small cerebral arteries, with a suspicion of cerebral vasculitis in 3
cases9 10 11 and evidence of vasospastic phenomena
in the fourth case.12 Leptomeningeal biopsies,
performed in 2 cases, were normal.
The neuropathological findings in our patients were striking
considering their age. Histologically, mild
small-artery mineralization (consisting mainly of calcium but also
often of iron deposits), predominantly in the basal ganglia,
hippocampus, and dentate nucleus, is a common incidental finding in
elderly brains and is considered a nonspecific aging
phenomenon.13 More severe calcifications are
usually seen in patients with hypoparathyroidism, idiopathic
cerebrovascular ferrocalcinosis (Fahr disease), or hereditary diseases
such as mitochondrial cytopathies, Albright's hereditary
osteodystrophy, and Cockayne's syndrome,13 and
may be associated with clinical disturbances (chiefly
extrapyramidal movements). Other causes of basal ganglia
calcification include carbon monoxide and lead intoxication, birth
anoxia, CNS infection or hemorrhage, cranial therapeutic
irradiation, and methotrexate therapy.14
Hyperosmolality was suspected to be the cause of intracranial damage
followed by calcification in a 2-month-old boy with severe diabetic
ketoacidosis.15 Interestingly, basal ganglia
calcification was recently described in patients with cerebral
lupus16 and in patients with
AIDS,17 in whom it may correspond to scars of
vasculitis.
Hypoparathyroidism was unlikely in our patients, who both had normal
calcemia and phosphoremia. They had negative HIV tests. The
metabolic disorders during dehydration in patient 1 were
unlikely to cause CNS damage per se, since she had only moderate
acidosis and no hypernatremia. Neither patient had a family history or
clinical signs of hereditary disease or a personal history suggestive
of one of the other known causes of intracerebral
calcification. Vascular mineralization is usually
asymptomatic. However, cerebrovascular changes appeared to
play a role in the late neurological manifestations in patient 1, who
had severe dehydration before the onset of neurological signs. In view
of the autopsy findings, the most logical explanation is that she had
an encephalopathy of vascular origin, as a consequence of both low flow
and an impaired brain vasculature. In patient 2, the possible relation
between her postural instability and vascular changes in the cerebellar
area is more speculative, since she had no patent focal neurological
deficit. However, the latter patient had two unexplained transient
ischemic attacks, similar to three middle-aged women in a
previous report of 50 sclerodermic patients.18
In conclusion, the advanced calcifications of small vessels in the
brain of these two women with a long-lasting CREST syndrome suggest
that systemic sclerosis may induce primary cerebrovascular changes, of
which wall calcification may be a marker. Intracerebral
calcification can be detected by CT,14 15 16 17 which
should be useful in further prospective studies of CNS involvement in
systemic sclerosis.
Footnotes
Reprint requests to Jean-Noël Fiessinger, MD, Service de Médecine Vasculaire, Hôpital Broussais, 96 rue Didot, 75674 Paris Cedex 14, France.
Received November 3, 1997;
revision received December 11, 1997;
accepted January 6, 1998.
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© 1998 American Heart Association, Inc.
Case Reports
Brain Involvement in Scleroderma
Two Autopsy Cases
Key Words: basal ganglia • brain • calcification, vascular • scleroderma, systemic
) were abundant in the basal ganglia,
hippocampus, and dentate nucleus. They consisted of calcium deposits
evidenced by hematoxylin and eosin and von Kossa's stain but were free
of iron (negative Perls' staining). These areas contained small foci
of ischemic neuronal necrosis. There was no glial or
inflammatory reaction. Marked parietal fibrosis was found in the whole
gastrointestinal tract, as well as wall thickening of small arteries
and arterioles. Moderate intimal fibrosis also involved some
interlobular and arcuate renal arteries. Other organs were
normal.
View larger version (126K):
[in a new window]
Figure 1. Photomicrograph showing wall calcification in
small arteries in the basal ganglia of patient 1 (hematoxylin-eosin,
original magnification x250). ).
View larger version (131K):
[in a new window]
Figure 2. CT scan for patient 2 showing mild calcification
in the left globus pallidus.
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