Sneddon's syndrome: clinical and immunohistochemical findings

Clinical Seurolog~ and .hwrosurger~

ELSEVIER

Clinical Neurology and Neurosurgery

96 (1994) 310-313

Sneddon’s syndrome: clinical and immunohistochemical

findings

Vincenza Fetonia, Emilio 13ertib, Emanuela Ceccab, Francesco Carella”, Renato Albert0 Sinico’, Floriano Girotti”q* “Istituto Nazionale Neurologico C. Bestu, viu Cdoria Il. 10133 Milan, Ita!r bIstituto di Scienze Derrnatologiche. Universitci di Milano. Milan, Ital! ‘Divisione di Nqfrologiu. Osprdule S. Curlo. Milun. Itu(~~

Received 14 March 1994; revised 8 July 1994; accepted 8 July 1994 -.

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Abstract Results of immunological studies on skin biopsies of 5 patients with Sneddon’s syndrome are reported. Also studied were coagulation factors and autoantibodies believed to play a role in this syndrome. Hemostasis was normal except for a mild increase of fibrinogen in one subject; lupus anticoagulant (LAC) and anticardiolipin antibodies were negative in all. The skin biopsies ruled

out systemic vasculitis and vasculitis in association with connective tissue diseases. Sneddon’s syndrome is a peculiar clinicopathological condition, probably with several etiologies, but is distinct from primary antiphospholipid syndrome. Keywords: Sneddon’s syndrome; Livedo racemosa; Antiphospholipid antibodies -

1. Introduction Sneddon’s syndrome is a rare disease characterized by multiple cerebral ischemic lesions and livedo reticularis [l]. The etiology is unknown; pathologically, a non-inflammatory occlusive arteriopathy affecting small and medium size arteries of the skin and brain is demonstrated [24]. Cutaneous manifestations in Sneddon’s syndrome are referred to as livedo racemosa denoting a violaceous, irregular netlike patterning of the skin, best seen on the trunk and extremities, and which persists after warming the skin. This is distinguished from the regular netlike appearance of livedo reticularis which is caused by functional disturbances, i.e. vasoconstriction. Livedo racemosa results from persistent focal impairment of peripheral blood flow caused by occlusions of small arteries in cases of vasculitides or Sneddon’s syndrome [5]. Sneddon’s syndrome occurs more frequently in women, with a male/female ratio of 1:2 [2,4]. The onset of neurological signs has been reported to range between

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18 and 83 years, being more frequent below the age of 40. The livedo racemosa is a progressive manifestation involving all four limbs and trunk; it usually worsens during the acute phase of the neurological deficits [4]. Repeated cerebrovascular accidents bring about additive focal deficits with stepwise deterioration: less frequently the disease causes a progressive motor and cognitive decline attributable to the effect of multiple ischemic lesions [2,3,6,7]. Recent studies suggest that the presence of antiphospholipid antibodies plays a pathogenetic role in Sneddon’s syndrome [8- 1l] but this is controversial since some patients with Sneddon’s syndrome do not have antiphospholipid antibodies [ 12 151. Because of the conflicting results of previous studies, we performed immunological studies on skin biopsies of five patients with Sneddon’s syndrome, and also studied coagulation factors and autoantibodies believed to play a role in the condition. The coagulation factors investigated were: von Willebrand factor, antithrombin III, protein S, and protein C. Von Willebrand factor has been suggested to reflect vascular damage in systemic vasculitides [16]. Both protein S [17] and antithrombin 111 [ 181 have been found deficient in cases with clinical findings reminiscent of Sneddon’s syndrome. Finally. a

V. Fetoni

et al. IClinical

case of livedo reticularis associated with protein temic deficiency has also been reported [ 191.

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She had suffered from migraine since adolescence; had been treated for thrombophlebitis of the right lower limb, and had had three miscarriages. She became hypertensive about a year prior to first admission. She was admitted because of left hemiparesis and dysarthria preceded by transient blackout. On admission livedo racemosa was noted on the lower limbs; she had dysarthria and left ataxic hemiparesis with left Babinski sign. Extinction of double stimulus was present on the left side. She was not demented. ERS was 50 mm; LAC was positive on one occasion (Table 1) but not confirmed in two subsequent tests. Echocardiography showed slight mitral valve prolapse. Brain CT and MR revealed multiple ischemic lesions in the white matter and basal ganglia. Skin biopsy showed mild capillary dilatation with slight perivascular roundcell lymphocyte infiltration.

2. Methods Five female patients with a clinical diagnosis of Sneddon’s syndrome were studied. The following laboratory data were obtained in all cases: full blood count, fasting blood sugar, blood urea nitrogen, creatine clearance, lipid profile, CPK, LDH, SGOT, SGPT, erythrocyte sedimentation rate (ERS), serum protein electrophoresis, rheumatoid factor, serum pyruvate and lactate. The coagulation profile included prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, antithrombin III, LAC, anticardiolipin antibodies, protein C, protein S and von Willebrand factor. The Von Willebrand factor was assessed as described by Federici 20. We also tested for the presence of the following autoantibodies in all patients: antinuclear antibodies, anti-DNA antibodies and antineutrophil cytoplasmic antibodies (ANCA). ANCAs were detected by indirect immunofluorescence in leucocytes fixed with ethanol [21] and by ELISA using cytoplasmic extract, granule extract and myeloperoxidase as antigens [22]. Antiphospholipid antibodies were determined by ELISA. Table 1 shows the results of these determinations. Chest x-rays, ECG and echocardiogram, EEG, cerebral CT scan and MRI of the brain were performed in all patients. Cerebral angiography was performed in two patients. Skin biopsy was performed in 4 patients and in two cases we performed a direct immunofluorescence study on frozen samples. Most laboratory and radiological investigations were repeated in each patient during the course of several admissions. Only pathological findings are reported in the following case histories.

C&Ye2 This h&year-old married woman was a moderate smoker but had no family history for cerebrovascular disease. At 36 gestosis was followed by mild intellectual deterioration. At the age of 55 progressive mental and motor deterioration were observed. At 58 she had reduced verbal fluency and anomia, ideomotor and constructive apraxia, dysarthria, spastic tetraparesis. more marked on left side and reduced touch sensation on the left. At the age of 66 she was demented (Mini Mental State Examination = 10/30) and had lost motor sclf-sufficiency. She eventually developed akinetic mutism and died of bronchopneumonia at the age of 68. Livedo racemosa nad been noted for 10 years before her death. ERS was increased (30); fibrinogen was also increased (482 mg/dl; normal 150400 mg/dl). Cerebral CT and MR scans showed marked cortical atrophy and multiple small ischemic lesions in the white matter of the hemispheres, cerebellum and brainstem. Skin biopsy showed capillary vasodilation and mild perivascular lymphocyte infiltration.

3. Case histories Cuse 1 A 43-year-old married woman history for arterial hypertension Table

42/F 61/F 42/F 44/F 41/F

This 43-year-old woman was a moderate smoker but had negative familiarity for cerebrovascular disorders. She had occasionally been hypertensive and had taken

family stroke.

I

Case No., age (yrs)/sex

I 2 3 4 5

with positive and ischemic

LAC”

ACA

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a-granules

MPO

IIF

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5 5 5 5 5

50 27 28 47 23

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anti-DNA + antinuclear antibodies

ANCA

’ LAC, lupus anticoagulant; ACA, anticardiolipin antibodies; mycloperoxidase normal value < 90; IIF, immunofluorescence.

ANCA,

antineutrophil

cytoplasmic

antibodies

a-granules

~~ _ _ _ _ _ normal

value < 15: MPO,

oral contraceptives. At the age of 25, when 5 months pregnant, she developed transient right hemiparesis and focal motor fits of the right upper arm, later delivering uneventfully. At 26 livedo racemosa appeared on trunk and limbs. Slight right hemiparesis and mild mental deterioration (Mini Mental State Examination = 26) remained unchanged in the succeeding years. Laboratory investigations were normal, Slight mitral valve insufficiency was shown by echocardiography. CT of the brain showed an old left sylvian infarct; MR confirmed this and also revealed lacunar infarcts in the white matter of the right cerebral hemisphere. Skin biopsy showed a marked lymphohistiocytic infiltrate at the dermal junction where C3 granular deposits were demonstrated by direct immunofluorescence. Cuse 4 This 44-year-old woman had four sisters, one of whom died of stroke at the age of 34. The patient had had three spontaneous miscarriages and a child who died soon after birth. At 40 she was admitted because of progressive balance disturbances and dysarthria. On examination she was hypertensive, had livedo racemosa on the trunk and lower limbs and also acrocyanosis. Neurological examination showed horizontal nystagmus, dysarthria, ataxia of upper limbs, bilateral Babinski signs and global mental decay (Mini Mental State Examination = 16/30). Further motor and mental deterioration was observed in the following 2 years. Slightly increased fibrinogen (452 mg/dl) and von Willebrand factor (216 U/dl; normal 50-l 50), reduced platelet count (100,000) and mildly increased protein in cerebrospinal fluid (77 mg%) were observed. At 43 years of age fibrinogen was again slightly high (432 mg/dl) and ERS was 40. Cerebral CT and MR showed multiple small vascular lesions in cerebral hemisphere white matter, basal ganglia, thalami and pons. The ventricular system was enlarged and cortical atrophy, more marked at the parietal lobes, was evident. Skin biopsy showed mild dilatation of the superficial plexus and direct immunofluorescence showed IgM deposits at the dermal junction. Case 5

This 47-year-old married woman was a smoker. Her paternal grandmother died in a psychiatric hospital of a progressive neurological disease with loss of motor selfsufficiency. Three of her grandmother’s brothers had shown similar disturbances and had all died in their fifth decades. Her father died at 33 with a diagnosis of multiple sclerosis. Two brothers died at 35 following a disease characterized by dementia, dysarthria, spastic tetraparesis and livedo of the trunk and limbs. The patient had had a miscarriage and had also delivered a baby stillborn because of placenta previa. At the age of 39 she showed mild hemiparesis. In the following years gait disturbances, dysarthria, and moderate mental decay

(QIT 74) developed. Cerebral CT and MR showed cortical atrophy and lacunar infarcts in white matter, basal ganglia, thalami and pons. Arteriography showed mimma1 vascular abnormalities without stenosis or obstruction. Thermography showed small hyperthermic spots in the area affected by livedo.

4. Discussion In our patients the clinical diagnosis of Sneddon’s syndrome was founded on the association of multiple cerebral ischemic lesions with livedo racemosa. All patients were female and onset of livedo racemosa or stroke occurrence was between 23 and 41 years. The criteria for juvenile stroke were met for strokes occurring before 45 years of age [23]. The course of the disease was protracted and progressive with sudden worsening of symptoms sometimes in association with pregnancy. Cerebral CT and MR showed multiple ischemic lesions more frequently localized in the white matter of the cerebral hemispheres and basal ganglia and usually having the appearance of lacunar infarcts; marked cortical atrophy was also noted. Risk factors for cerebrovascular disorders were absent except for arterial hypertension in 2 patients. Increased incidence of arterial hypertension has been reported in Sneddon’s syndrome [4,6]. Mitral valve abnormalities were noted in 3 patients and may have accounted for the embolic nature of some strokes [2,4,12,24]. Hemostasis was normal except for mild fibrinogen increase in one subject. It is therefore unlikely that coagulation abnormalities can account for cerebral ischemic lesions in Sneddon’s syndrome. The slightly high factor VIII titre in one patient was not comparable to levels observed in systemic vasculitides such as systemic lupus erythematosus (SLE) or rheumatoid arthritis [16]. Factor VIII is a glycoprotein secreted by endothelial cells following vascular damage. The mild vascular damage and reduction of vessel size can probably account for the slight increase in factor VIII in our patient. LAC and anticardiolipin antibodies were negative except for transient LAC positivity in one case (No. 1). These negative results indicate that Sneddon’s syndrome cannot be grouped as a primary antiphospholipid syndrome even though several findings are common to both conditions, viz. multiple ischemic cerebral lesions, miscarriages, gestosis and cardiac valve abnormalities [2,25,26]. Antiphospholipid antibodies have been variably reported in Sneddon’s syndrome, some series reporting 20-58% of cases positive for these antibodies [8-l 11, others reporting no cases positive [12,13]. The nosology of Sneddon’s syndrome is also uncertain with respect to other systemic vasculitides, and vasculitis secondary to collagen diseases such as SLE, since in Sneddon’s syndrome other organs are not involved,

F Fetoni et al. I Clinical Neurology and Neurosurgery 96 (1994) 310-313

there is no inflammation in the small and medium size arteries and specific antibodies which are commonly observed in those conditions are lacking [2-4,27]. Four-mm punch skin biopsies were performed in all patients. Neither histological examination nor direct immunofluores~en~e revealed focal arteriolar occlusions [S] or Ig deposits in dermal vessel walls. Mild perivascular lymphocytic infiltration and C3 deposits at the junction of the wall of some dermal vessels were diffuse. However, these were aspecific alterations; the superficial location and small size of the biopsy samples may account for the lack of more significant findings. More invasive biopsy may have provided more information [5] but this was not considered ethical in patients with clinically unambiguous Sneddon’s syndrome. Nonetheless, the biopsy findings did rule out systemic vasculitis and vascuhtis in association with connective tissue diseases f27] confirming the diagnosis of Sneddon’s disease inferred from the clinical and neuroradiological findings and negative laboratory results. In conclusion, the clinical course and obliterative arteriopathy distinguish Sneddon’s syndrome as a peculiar clinico-pathological condition that probably has several different etiologies [2,6,12,28] but in which the cause of the endothelial proliferation remain unknown [24]. Sneddon’s syndrome is distinguished from primary antiphospholipid syndrome by the inconstant presence of antiphosphoiipid antibodies in the former and by the lack characteristic obliterative arteriopathy in the latter v91. References [l] Sneddon, I.B. (1965) Cerebrovascular lesions and livedo reticuiaris. Br. J. Dermatol., 77: 180-185. [2] Bruyn, R.P.M. (1989) Sneddon’s syndrome. In: P.J. Vinken, G.W. Bruyn and H.L. Klawans (Eds.), Handbook of Clinical Neurology, vol. 1I(%): Vascular Diseases, Part III, Elsevier. Amsterdam, pp. 401-110. [3] Ellie, E., Julien, J., Henry, P., Vital, C. and Ferrer, X. (1987) Angiomatose portico-m~ning~e de Divry-Van Bogaert et syndrome de Sneddon. Rev. Neurol., 143: 798805. [4] Rebollo, M., Val, J.F., Garijo, F., Quintana, F. and Berciano, J. (1983) Livedo reticularis and cerebrovascular lesions (Sneddon’s syndrome). Brain, 106: 9655979. [S] Stockammer, G.J., Felber, S.R., Aichner, ET., Zelger, B., Sepp, N. and Fritsch, P. (1992) Sneddon’s syndrome and antiphospholipid antibodies: clarification of a controve~y by skin biopsy? Stroke, 23: 1182-1183. [B] Rumpl, E., Neuhofer, J., Pallua, A., Willeit, J., Vogl, G., Stampfel, G. and Platz, T. (1985) Cerebrovascular lesions and livedo reticularis (Sneddon’s syndrome) - a progressive cerebrovascular disorder? J. Neurol., 231: 324330. [7) Stevens. W.P. and Ferguson. I.T. (1982) Livedo reticularis and cerebto-vascular disease. Postgrad. Med. J., 58: 70-73. [8] Kalashnikova, L.A., Nasonov, E.L., Kushekbaeva, A.E. and Gracheva, L.A. (1990) Anticardiolipin antibodies in Sneddon’s syndrome. Neurology, 40: 464-467. [9] Otoyama, K., Katayama, I., Suzuki, Y., Tone, T., Nishioka, K. and Nishiyama, S. (1990) A case of Sneddon’s syndrome with

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