'Hardening of the Arteries' in the Central Nervous System in Scleroderma

By John J. Caronna, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Caronna reports no financial relationships relevant to this field of study.

Synopsis: Young patients with scleroderma, free of neurological symptoms, still show abnormalities in cognitive function and cerebrovascular reactivity.

Source: Giuliodori G, Fraticelli P, Bartolini M, et al. Cognitive and cerebral hemodynamic impairment in scleroderma patients. Eur J Neurol Doc: 10. 1111/j. 1468-1331. 2009.02714

Scleroderma is the characteristic feature of a heterogeneous group of autoimmune conditions labeled systemic sclerosis (SSc). Cutaneous involvement may be diffuse or limited (LcSSc). LcSSc is associated with CREST syndrome (Calcinosis, Raynaud phenomenon Esophageal dysmotility, Sclerodactyly, and Telangiectasia) Central nervous system (CNS) involvement is uncommon but may be the first and only manifestation of SSc. Typically there is multiple sclerosis-like demyelination with positive oligoclonal bands in CSF.1 Ischemic lesions also occur in the brain as a late complication of hypertension or antiphospholipid antibodies.2 Some authors, however, have hypothesized that a microangiopathy is present at all stages of SSc and is responsible for the pathogenesis.3

This study investigated the possible presence of subclinical involvement of the CNS in young patients with SSc by evaluating cognition and cerebral hemodynamics. Cognitive function was assessed by means of a standard neuropsychological battery, and cerebrovascular reactivity (CVR) by means of transcranial Doppler ultrasonography. Subjects were recruited from consecutive scleroderma patients attending a medical clinic in Ancona, Italy during 2006 and 2007. Patients were excluded who had one or more vascular risk factors, an abnormal brain MRI, cerebrovascular disease detected by ultrasonography, or were older than 45 years of age. Sixteen patients, 11 women and 5 men, age range from 20 to 43 years, were studied and compared to 16 healthy control subjects without vascular risk factors and matched for age, sex, and education level.

CVR to hypercapnia was evaluated by means of the Breath-Holding Index (BHI) calculated by dividing the percentage increase of mean flow velocity (MFV) in the middle cerebral arteries after breath holding by seconds of apnea (S):

[(MFV after breath-holding – MFV at rest) / MFV at rest x 100] ÷ S

Patients with scleroderma had a parallel compromise of cognitive performance and cerebral hemodynamics. Neuropsychological testing of SSc patients indicated a significant reduction in visual-spatial and problem solving abilities. Scleroderma patients had a higher number of errors than control subjects on the Modified Card Sorting Test (11± 5.5 vs. 7 ± 3.25, p<0.001) and needed more time in seconds to complete the Trail Making Time Test Parts A (48.5 ± 6.5 vs. 34.5 ± 6.75, p <0.001) and B (101 ± 14 vs. 18 ± 25, p < 0.05). CVR to hypercapnia also was reduced in patients with SSc; BHI values were lower in patients than in controls (0.82 ± 0.44 vs. 1.34 ± 0.18, p<0.0001).


The authors detected evidence of cerebrovascular dysfunction and cognitive deficits in asymptomatic young patients with scleroderma. The early detection of impaired CVR suggests that therapeutic interventions such as the use of antiplatelet agents, could be beneficial. In particular, statins, which can improve CVR4, could be employed and their effect on CVR and cognitive performance assessed. Positron emission tomography could be used in these patients to determine whether there were changes in perfusion of brain areas involved in visual spatial information processing.

Whether alterations in CVR indicate that endothelial damage is a specific aspect of the pathogenesis of CNS damage in SSc remains to be established. If so, "hardening of the arteries" may become the appropriate term for the cause of cognitive decline in patients with scleroderma.


1. Kister I, Inglese M, Laxer RM, et al. Neurologic manifestations of localized scleroderma: A case report and literature review. Neurology 2008;71:1538-1545.

2. Cikes N, Bosnic D, Sentic M. Non-MS autoimmune demyelination. Clin Neurol Neurosurg 2008;110:905-912.

3. Cerinic MM, Valentini G, Sorano GG, et al. Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum 2003;32:285-295.

4. Pretnar-Oblak J, Sabovic M, Sebestjen M, et al. Influence of atorvastatin treatment on L-arginine cerebrovascular reactivity and flow-mediated dilatation in patients with lacunar infarctions. Stroke 2006;37:2540-2545.