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Systemic sclerosis (scleroderma) is a multisystem connective tissue disease of unknown aetiology, characterised by progressive fibrosis of the skin and internal organs including the lungs and gastrointestinal tract.1 Pathological calcification of soft tissues (known as calcinosis) is a common feature in the CREST syndrome of scleroderma (calcinosis, Raynaud’s phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia). By contrast, internal organ calcification is rare, and isolated cases of spinal calcinosis and calcific constrictive pericarditis have been reported.2 3 We report here the cases of two patients with systemic sclerosis whose CT examination disclosed extensive brain calcifications.
Case 1, a 48 year old man was referred to hospital because of polyarthralgia involving the wrists and ankles, Raynaud’s phenomenon, and tightness of hand skin. The patient’s wife had noticed that during the previous months, he had a slowed mentation and a depressive mood. Physical examination disclosed a sclerodactyly but no telangiectasias. Routine haematological tests were normal. Antinuclear antibodies were positive at a 1/2000 dilution with nucleolar fluorescence. Rheumatoid factors, antidouble stranded DNA and antiphospholipid antibodies were negative. There was no cryoglobulinaemia. Complement was normal. Lung function tests showed a restrictive syndrome (forced vital capacity=75% predicted). Chest radiography was normal, as were oesophageal manometry and cardiac ultrasonographic examination. A diagnosis of systemic sclerosis was made and the patient was given diltiazem (180 mg/day) and ketoprofene (150 mg/day).
Six months later the patient’s neurological status had worsened. He complained of memory loss, poor concentration, and insomnia. On neurological examination he was anxious and very slow in answering questions. Mini mental state examination score was 22/30. The patient was oriented to place, but not to time. Anterograde amnesia was noted. Agnosia, apraxia, and aphasia were absent. There was no muscle weakness and muscle tone was normal, as were tendon reflexes. Plantar responses were both flexor. There was no sensory loss or impairment of cranial nerves. Systemic sclerosis signs were unchanged. Routine hematological tests were normal. Results of blood chemical tests were also unremarkable (serum electrolytes, urea, creatinine, iron), including phosphorus and calcium metabolism (serum parathyroid hormone concentration, blood calcium and phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calciuria, and phosphaturia). Serum concentrations of free triodothyroxine, free thyroxine, and thyroid stimulating hormone were normal. Serological tests for syphilis, HIV-1,2, and Lyme disease were negative. Brain CT showed bilateral extensive calcification in the dentate nuclei (figure 1A), basal ganglia, and subcortical white matter (figure 1B). On MRI T1 weighted images and T2 weighted images, calcification was visible as a low intensity signal. The patient was given fluoxetine (20 mg/day) and bromazepam (6 mg/day). At follow up, 1 year later, the patient’s clinical status was unchanged, as was brain CT.
Case 2, a 64 year old right handed woman was admitted to hospital for evaluation of a Raynaud’s phenomenon which had lasted for more than 10 years. At physical examination, sclerodactyly and tightness of the facial skin were noted. Telangiectasias were present on the face, hands, and palate. The patient complained of pyrosis. Oesophageal manometry showed abnormalities of oesophageal motility. Hand radiography disclosed soft tissue calcifications. Anticentromere antibodies were positive at a 1/1000 dilution. A CREST syndrome was diagnosed and the patient was given buflomedil (600 mg/day) and prednisone (25 mg/day).
One year later she was admitted for the evaluation of recent transient ischaemic attacks (TIAs). During the previous week she had experienced three bouts of expressive aphasia and right hemiplegia, each lasting about 10 minutes. She never smoked and did not have diabetes, hypertension, or dyslipidaemia. The neurological examination was normal. Routine blood chemical tests were normal (serum electrolytes, urea, creatinine) including phosphorus and calcium metabolism (serum parathyroid hormone concentration, blood calcium and phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calciuria, and phosphaturia). Cranial CT showed bilateral calcifications of the basal ganglia, and faint calcifications of the dentate nuclei and rubrum nucleus. Moderate cerebral and cerebellar atrophy was noted. Duplex carotid ultrasound and 24 hour ECG recording were normal. Echocardiography showed a normal left ventricle with an ejection fraction of 60%. There was mild calcification and a thickening of the mitral valve leaflets. Aspirin (250 mg daily) was given at hospital discharge. No further TIA occurred during a 5 year follow up and the patient’s clinical status has remained unchanged.
Systemic sclerosis is a multisystem disease predominantly affecting the skin, lungs, vascular system, and gastrointestinal tract.1Neurological involvement occurs in a few patients (ranging from 0.8 to 18.5%) including cranial nerve abnormalities, peripheral neuropathy, CNS vasculitis, and autonomic peripheral neuropathy. To our knowledge, extensive cerebral calcifications have not yet been reported.
Calcification of the brain is discovered in 0.8 to 1.2% of subjects undergoing routine CT examination, mainly in the globus pallidus. In most cases the deposits are small and involve older patients who remain asymptomatic, leading to the concept of “physiological” senescent basal ganglia calcifications.4 On the other hand, basal ganglia calcifications, often associated with dentate nuclei calcifications, have been reported in more than 30 conditions, including abnormalities of calcium phosphorus metabolism such as pseudohypoparathyroidism.5
Systemic sclerosis leads to the formation of calcium deposits in the subcutaneous tissue. Rarely, the calcific process has been shown to involve the spine or pericardium.2 3 Recently, Heronet al described two cases of cerebral involvement in systemic sclerosis.6 In both cases necropsy showed extensive wall calcification of the small arteries and arterioles of the brain. Our two patients have scleroderma and extensive striopallidodentate calcifications and metabolic investigations failed to disclose any specific aetiology in either case. We think that scleroderma should be added to the list of conditions described as occurring with basal ganglia calcification.
The pathogenesis of the formation of calcium deposits in systemic diseases remains poorly understood. However, pathological calcification can be subdivided into metastatic (occurring in undamaged tissues when extracellular calcium and phosphate concentrations are increased) and dystrophic (ocurring in injured tissue when extracellular calcium and phosphate concentrations are normal) calcification.7 In our patients, as in the patients of Heron et al, the brain calcifying process may be related to primary cerebrovascular changes induced by systemic sclerosis.
Routine brain CT examination in systemic sclerosis could help to determine the true incidence of basal ganglia calcifications and their clinical relevance.