Case Reports

Brain Involvement in Scleroderma

Two Autopsy Cases
Emmanuel Héron, MD; Paul Fornes, MD, PhD; Arnaud Rance, MD;
Joseph Emmerich, MD, PhD; Olivier Bayle, MD; Jean-Noël Fiessinger, MD

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. (Stroke. 1998;29:719-721.)
Key Words: basal ganglia n brain n calcification, vascular n scleroderma, systemic

N o noteworthy findings have been reported in the few

available pathological studies of the brain of patients with
systemic sclerosis. Central nervous system (CNS) manifesta-
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
tions seem relatively frequent in such patients1,2 but have was otherwise normal. She had a generalized seizure on the day
almost always been considered secondary to the disease pro- of admission. Laboratory assays showed functional renal insuf-
cess.3 We describe findings in two consecutive autopsies of ficiency with a serum creatinine of 530 mmol/L, proteinemia
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women with systemic sclerosis and CNS symptoms, showing of 88 g/L, and moderate metabolic acidosis with a plasma pH
advanced cerebrovascular calcifications. of 7.36 and a bicarbonate level of 13 mmol/L. Metabolic
disorders normalized after 5 days of intravenous rehydration.
Case 1 The baseline creatinine was 75 mmol/L, and routine laboratory
A 41-year-old white woman developed Raynaud’s phenom- assays were normal. Marked cerebral disorders persisted despite
enon during adolescence. She never smoked and did not have adequate rehydration and included agitation, aggressiveness,
diabetes, hypertension, or dyslipidemia. Systemic sclerosis loss of appetite, insomnia, periods of groaning, compulsive
(CREST variant) was diagnosed in her early twenties. She had rubbing of the back of her neck on the bed, urinary inconti-
sclerodactyly, telangiectasias on the face and hands, and tight- nence, and total indifference to her surroundings; it was
ness of the face skin. Anticentromere antibodies were present impossible to communicate with her. Neurological examina-
at 1:1000 dilution. Antiphospholipid antibodies and cryoglob- tion showed only a hyperactive palm-chin reflex. Cerebral CT
ulinemia were negative. She had a long history of gastrointes- was normal except for mild basal ganglia calcification. Lumbar
tinal tract disorders, with dysphagia and esophagitis, constipa- puncture showed a cerebrospinal fluid protein content of 0.69
tion, intermittent bloating, abdominal cramping, and anal g/L but was otherwise normal. Thyroid hormones were
incontinence. She had been severely depressed since age 24. normal. Two consecutive electroencephalograms showed dif-
She was treated with calcium blockers, omeprazole, intestinal fuse abnormalities with an asynchronized, unorganized,
antispasmodic agents, and various antidepressant drugs. She slowed, and poorly reactive print. High-dose intravenous
never received steroids or immunosuppressive drugs. At age antidepressant therapy with clomipramine (Anafranil) had no
35 a cutaneous ileostomy was performed after she underwent effect. A diagnosis of dementia was made by psychiatrists and
surgery for a perforated intestinal necrosis; this was compli- neurologists.
cated by chronic liquid diarrhea. Two months after the onset of neurological signs, the
At age 41 the subject was hospitalized for severe dehydration subject died of septic shock of gastrointestinal origin. At
due to abundant intestinal losses that she failed to compensate autopsy the brain was macroscopically normal except for mild

Received November 3, 1997; final revision received December 11, 1997; accepted January 6, 1998.
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.
Reprint requests to Jean-Noël Fiessinger, MD, Service de Médecine Vasculaire, Hôpital Broussais, 96 rue Didot, 75674 Paris Cedex 14, France.
© 1998 American Heart Association, Inc.

719
 720 Cerebrovascular Calcification in Scleroderma

Figure 1. Photomicrograph showing wall calcification in small

arteries in the basal ganglia of patient 1 (hematoxylin-eosin,
original magnification 3250).

swelling. Histologically, the extraparenchymal arteries were

moderately thickened by intimal hyperplasia. Mineral deposits
in the walls of small arteries and arterioles (Fig 1) 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 inflam-
matory 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 Figure 2. CT scan for patient 2 showing mild calcification in the
left globus pallidus.
some interlobular and arcuate renal arteries. Other organs were
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normal.
The etiology of the intestinal necrosis remained unclear. Her
Case 2 respiratory status worsened postoperatively, and she died 4
A 63-year-old white woman developed Raynaud’s phenom- months later of refractory right heart failure. At autopsy the
enon at age 30. She had no cardiovascular risk factors. A brain was macroscopically normal except for mild swelling.
CREST syndrome was diagnosed at age 35. She had sclero- Histologically, the extraparenchymal arteries were moderately
dactyly; tightness of the face skin with thin and shortened lips; thickened by intimal hyperplasia. Vascular calcium deposits
telangiectasias on the hands, face, back, and palate; pyrosis; were observed in the same areas as in case 1 (basal ganglia,
intermittent dysphagia; and ocular and buccal dryness. She had hippocampus, and dentate nucleus) and also in small-artery
been on a regimen of trimethylcolchicinic acid and metoclo- walls of cortical areas, especially the frontal lobes, cerebellar
pramide and occasionally H2 blockers since that time. No cortex, and mamillary bodies. Small foci of neuronal ischemic
steroids or immunosuppressive drugs were given. At age 50 necrosis were also observed, but there was no glial or inflam-
anticentromere antibodies were detected at 1:1000 dilution. matory reaction. Severe interstitial fibrosis and artery wall
Antiphospholipid antibodies and cryoglobulinemia were ab- thickening were observed in the lungs. The right heart cavities
sent. After age 43 she gradually developed exertional dyspnea were moderately dilated. The digestive tract showed moderate
and pulmonary hypertension. artery and arteriolar wall thickening and no significant parietal
At age 44 the subject was hospitalized for a transient fibrosis. Other organs were unremarkable.
ischemic attack. On the day of admission she had two
consecutive episodes of expressive aphasia, each lasting approx- Discussion
imately half an hour. The neurological examination was Structural changes of the small arteries and arterioles (typically
normal. Cerebral CT, ultrasound examination of the heart and concentric fibrous intimal thickening) have been described in
carotid arteries, 24-hour ECG recording, and cerebrospinal nearly every organ of patients with systemic sclerosis4 and play
fluid examination were normal. Low-dose aspirin was added to a key role in some of its main manifestations, such as
her treatment at hospital discharge. No further transient Raynaud’s phenomenon, scleroderma renal crisis, pulmonary
ischemic attacks occurred. At age 62 she complained of balance hypertension, and myocardial ischemia.5 Blood vessels would
disorders, but no clear focal neurological deficit was found. also be expected to be involved in the CNS. Cerebral
Cerebral CT showed moderate cerebral atrophy and mild hypoperfusion, suggestive of impaired microcirculation, was
calcification in the basal ganglia (Fig 2). recently observed in sclerodermic patients.6 However, patho-
At age 63 the subject underwent surgery for unperforated logical studies have failed to demonstrate primary cerebrovas-
intestinal necrosis that required the ablation of 1.50 m of ileum. cular changes in systemic sclerosis. Nonspecific cortical ne-
 Héron et al 721

crotic foci were reported in 3 of 17 brains.1 A cerebral infarct impaired brain vasculature. In patient 2, the possible relation
has been linked to arteritis localized in a single internal carotid between her postural instability and vascular changes in the
artery.7 Other studies showed vascular changes that could be cerebellar area is more speculative, since she had no patent
explained by concomitant hypertension or atherosclerosis.3,8 focal neurological deficit. However, the latter patient had two
Unfortunately, pathological data are lacking in 4 additional unexplained transient ischemic attacks, similar to three middle-
sclerodermic patients with neurological disorders (severe head- aged women in a previous report of 50 sclerodermic patients.18
ache, generalized seizures, confusion, dysarthria, expressive In conclusion, the advanced calcifications of small vessels in
aphasia, hemiparesis, and hemianalgesia). In these 4 cases the brain of these two women with a long-lasting CREST
cerebral arteriography showed bilateral narrowing of several syndrome suggest that systemic sclerosis may induce primary
medium-sized and small cerebral arteries, with a suspicion of cerebrovascular changes, of which wall calcification may be a
cerebral vasculitis in 3 cases9 –11 and evidence of vasospastic marker. Intracerebral calcification can be detected by CT,14 –17
phenomena in the fourth case.12 Leptomeningeal biopsies, which should be useful in further prospective studies of CNS
performed in 2 cases, were normal. involvement in systemic sclerosis.
The neuropathological findings in our patients were striking
considering their age. Histologically, mild small-artery miner- References
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