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Stroke. 1995;26:492-495

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(Stroke. 1995;26:492-495.)
© 1995 American Heart Association, Inc.

Articles

Sneddon's Syndrome With Granulomatous Leptomeningeal Infiltration

Richard L. Boortz-Marx, MD; H. Brent Clark, MD, PhD; Saul Taylor, MD; Kathleen M. Wesa, MD David C. Anderson, MD

From the Departments of Neurology (R.L.B.-M., D.C.A.), Radiology (S.T.), and Medicine (K.M.W.), Hennepin County Medical Center, and the Departments of Neurology (R.L.B.-M., H.B.C., D.C.A.) and Laboratory Medicine and Pathology (H.B.C.), University of Minnesota Medical School, Minneapolis.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowCase Report
 down arrowDiscussion
 down arrowReferences
 
Background There is limited neuropathologic information available from cases of Sneddon's syndrome in which strokes are associated with livedo reticularis. Pathogenesis of the syndrome is controversial, although current opinion favors a coagulopathy, often with antiphospholipid antibodies. We describe a case lacking antiphospholipid antibodies but having a granulomatous infiltration of the leptomeninges.

Case Description The patient presented at age 29 with stroke, livedo reticularis, essential hypertension, and Raynaud's phenomenon. Assessment uncovered no underlying disease, including absent antiphospholipid antibodies. A leptomeningeal biopsy showed granulomatous infiltration.

Conclusions The findings suggest that an inflammatory process plays a role in at least some cases of Sneddon's syndrome.


Key Words: skin disease • Sneddon's syndrome • vasculitis • young adults


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowCase Report
 down arrowDiscussion
 down arrowReferences
 
The association of livedo reticularis, essential hypertension, and cerebrovascular lesions, although described by Champion and Rook in 1960,1 is known as Sneddon's syndrome after his report of six patients with stroke and livedo reticularis in 1965.2 The pathogenesis of the cerebrovascular component was a "mystery" to Sneddon, and histopathologic data from such cases are still meager.3 4 5 6 Current opinion favors a systemic prothrombotic state, sometimes associated with antiphospholipid antibodies, as a unifying pathogenetic mechanism.7 We care for a young woman with the clinical syndrome described by Sneddon but with granulomatous infiltration of cerebral leptomeninges. It is uncertain whether the association of dermatologic and neurological phenomena in this case is coincidental or whether these phenomena are manifestations of a single generalized process. If the latter, inflammatory vasculopathy may play a part in the cerebrovascular mechanisms causing some cases of Sneddon's syndrome.


*    Case Report
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 *Case Report
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A 29-year-old, right-handed woman presented in August 1992 with focal seizures, left leg weakness, dizziness, and difficulties with gait. Symptoms began abruptly during physical exertion. The patient also reported a right frontal headache earlier on the day of admission.

She reported that she had been troubled for several years with similar headaches. At least two previous headaches were accompanied by left-sided weakness, numbness, and tingling, which resolved. The patient had been aware of a purplish mottled appearance of the skin over her trunk and limbs the previous 2 years. Although more conspicuous in the cold, mottling persisted with warming. Also in recent years, the fingers of both hands became blanched, cool, numb, and painful on exposure to cold. She had been told that her blood pressure was "borderline elevated," although pharmacotherapy had not been prescribed. Her brother and her two children had similar but less extensive skin mottling. There was no family history of brain ischemia. She had one miscarriage in February 1992. She smoked 10 cigarettes daily but denied use of oral antiovulants, alcohol, or illicit drugs.

Admission blood pressure was 160/98 mm Hg. Striking livedo reticularis was present over extremities and trunk. She was alert and oriented with labile affect and weakness of the left leg. Left arm and leg were clumsy, and she was unsteady afoot. Several focal motor convulsions limited to the arm were observed.

Among normal or unremarkable laboratory results were the following: complete blood count, erythrocyte sedimentation rate, serum calcium, various indicators of antiphospholipid antibodies (a sensitive activated partial thromboplastin time screen for a lupus anticoagulant,8 9 platelet count, VDRL, and antiphospholipid antibody survey [antibodies against cardiolipin, phosphatidylserine, phosphatidylcholine, and phosphatidic acid]), antithrombin III, protein C and protein S electrophoresis, total complement, cryoglobulins, cryofibrinogen, fluorescent antinuclear antibody titer, and angiotensin-converting enzyme level. Also normal were a skin biopsy, chest radiograph, and cerebrospinal fluid analysis (cells, protein, glucose, cytology, and bacterial and fungal cultures).

Electroencephalography demonstrated bilateral slowing and epileptiform discharges from the right. Head computed tomography and magnetic resonance imaging (Fig 1Down) demonstrated findings of subacute infarction in the anterior right precuneus. Enhancement showed vascular enhancement confirming an ischemic etiology. Transthoracic echocardiography with color-flow Doppler and echo contrast demonstrated fibrocalcific changes of the mitral annulus and no evidence for a transcardiac communication. Three-vessel angiography showed extensive medium- and small-vessel stenoses and irregular vessel caliber (Fig 2Down). There was obliteration of distal cortical vessels associated with a blush from leptomeningeal collaterals. A focal stenosis was seen to be the cause of the infarct.



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  		Figure 1. Axial T2-weighted magnetic resonance image shows increased signal in the anterior precuneus consistent with infarct (black arrow).



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  		Figure 2. Right carotid angiogram shows stenosis of the pericallosal and callosal marginal arteries (short white arrow), irregular caliber of multiple vessels, and absence of several anterior sylvian (open arrow) and distal cortical vessels with blush from collaterals (thin white arrows).

A cerebral and leptomeningeal biopsy was carried out. Sections of the brain biopsy contained areas of granulomatous inflammation, primarily involving the leptomeninges (Fig 3Down). There were large numbers of epithelioid cells but no giant cells and few lymphocytes and plasma cells. The granulomatous inflammation was not obviously associated with vascular structures. Only rare mononuclear cells were seen in the perivascular spaces of cerebral parenchymal blood vessels. Special stains for fungi and acid-fast organisms were negative. The pathological changes were consistent with granulomatous angiitis or sarcoidosis.



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  		Figure 3. Photomicrograph of right frontal lobe biopsy shows granulomatous leptomeningeal infiltration (area above the broken line) with numerous epithelioid cells (small arrow) and occasional smaller mononuclear cells. Meningeal vessels (large arrow) appear to be uninvolved by the inflammatory process (hematoxylin-eosin, x180).

The patient was discharged on nifedipine, high-dose prednisone, and scheduled pulsed cyclophosphamide therapy for inflammatory cerebral vasculopathy. On postdischarge day 11 she was readmitted with an angiographically proven pulmonary embolism. Lower extremity venous ultrasound examination was normal. She was anticoagulated with heparin and continued on warfarin. During the next 11 months she was treated with warfarin, prednisone, and triweekly pulses of cyclophosphamide. Although occasional episodes of left extremity numbness and tingling occurred, she developed no new persisting neurological deficits. Dermatologic findings did not noticeably change. In August 1993 the patient was reevaluated, including studies for antiphospholipid antibodies as before (negative), cerebrospinal fluid examination (normal), electroencephalography (improved), magnetic resonance imaging (no new lesions), repeated skin biopsy taken central to an area of bluish discoloration to maximize yield (normal),10 11 12 13 and cerebral arteriography (unchanged). Cyclophosphamide and prednisone were discontinued. The patient remains on warfarin.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowCase Report
 *Discussion
down arrowReferences
 
We report this case because of the dearth of neuropathologic information available on patients with Sneddon's syndrome. The findings do not support a strictly coagulopathic basis for vascular occlusions in this case.

Multiple systemic diseases of potential relevance in a patient with focal cerebral ischemia may be accompanied by mottled skin. These include systemic inflammatory vascular diseases (eg, leukocytoclastic and livedoid vasculitis, polyarteritis nodosa, and lupus erythematosus), septic emboli, and processes associated with mechanical vessel obstruction (eg, cryoglobulinemia and macroglobulinemia, polycythemia, thrombotic thrombocytopenic purpura, thrombocythemia, atheromatous emboli, and disseminated intravascular coagulation).14 Identification of any of these diseases would properly supersede the designation of Sneddon's syndrome and guide specific management.

It is unclear whether a single disease is responsible for those cases of Sneddon's syndrome that remain after these primary processes are stripped away. The uniformity of clinical features suggests a common pathogenesis, ie, the relative youthfulness of affected individuals, female predominance, familial predisposition, and associated hypertension and Raynaud's syndrome. Cerebral arteriography has shown abnormalities, typically occlusions of medium-sized vessels, in approximately half of studied cases. Recently antiphospholipid antibodies have been found in some patients with stroke and livedo, suggesting that Sneddon's may be another face of the primary antiphospholipid syndrome.15 16 17 18 19 20 21 22 23 24 It has been argued that the latter term should be applied in place of Sneddon's syndrome when the antibodies are identified.17 19 However, puzzles remain: Not all cases of Sneddon's syndrome have antiphospholipid antibodies, and not all patients with antiphospholipid antibodies have Sneddon's syndrome.

A progressive course leading to severe deficits, including dementia, is described in many cases with long-term follow-up.* It has been suggested that those with antiphospholipid antibodies may have a worse prognosis than others.6 22 Given the current uncertainty about pathogenesis, it is not surprising that management is unstandardized and empirical. Cofactors for cerebrovascular disease, such as use of birth control pills, smoking, and hypertension, should be addressed.10 30 Reported "specific" treatments include the following: anticoagulation,1 24 29 31 antiplatelet agents,{dagger} corticosteroids,1 11 14 15 28 30 other immunosuppressive medications,6 11 26 30 and vasodilators.28 Clear superiority for any approach does not emerge from these anecdotes, and controlled data are unavailable.

Extensive information regarding dermatologic histopathology exists. Yield is highest when the apparently normal skin and subcutaneous tissue central to the discolored areas have been biopsied.10 11 12 13 Noninflammatory thrombotic occlusions are typical.1 11 14 20 Intimal hyperplasia22 23 27 30 33 and proliferation of medial smooth muscle cells10 have also been described. Inflammatory features have been observed infrequently,18 25 26 and the absence of vasculitic features is usually emphasized. Two recent reports, however, describe an evolving vascular lesion in Sneddon's cases, including an initial endotheliosis with infiltration of inflammatory cells from the lumen.12 13 Neuropathologic data are limited to four cases,3 4 5 6 in three of which no inflammatory abnormalities were observed. In the last, granulomatous infiltration of occasional small cerebral vessels was noted, although chronic fibrotic changes predominated.3

Where does this case fit? Histopathology documents a granulomatous leptomeningeal inflammatory process. The features of a systemic disease (livedo reticularis) argue against isolated angiitis of the nervous system as an explanation.34 Cerebrospinal fluid angiotensin-converting enzyme level was not measured to further exclude isolated neurosarcoidosis; however, no other evidence of that disease has become apparent in more than 2 years of follow-up, and stroke is a rare manifestation of neurosarcoidosis.35 Nevertheless, neither of these recognized granulomatous processes can be totally excluded by the data available in this patient's case. Perhaps the striking skin manifestations are then unrelated. This would argue that livedo reticularis with stroke is an insufficiently specific syndrome to omit biopsy in cases with clinical and angiographic features similar to this patient's, especially when laboratory evidence for a procoagulant state is absent.

Did our patient have a hypercoagulable state? It was not confirmed in the laboratory, although the use of Russell's viper venom time or kaolin clotting time might have further increased sensitivity for detecting a lupus anticoagulant. There was, however, clinical suggestion of such a state in that the patient sustained a pulmonary embolism. Perhaps the coagulopathy was primary, and the inflammatory features were an epiphenomenon. In his monograph on cerebral thromboangiitis obliterans, Fisher36 argued that the vasculitic features giving that entity its name occur subsequent to proximal stenosis, stagnation, and thrombosis, with secondary infiltration by inflammatory cells. The biopsy specimen in our patient did not, however, contain thrombotic occlusions.

We believe that a unique inflammatory process was primary in our patient and may be the basis of other cases of Sneddon's syndrome. Based on observation of skin biopsy material, Zelger et al12 postulated that Sneddon's syndrome is due to a primary vasculopathy with an evolving life history. In the initial stages, an inflammatory component, an endotheliosis, is present. We suspect that cerebral vessels are also affected by an evolving process. We "caught" a stage of inflammation, although the infiltrate in our case did not appear to be derived from the lumen of leptomeningeal vessels. The strong evidence that coagulopathy is also a contributor to cases of Sneddon's syndrome, including ours, cannot be ignored. It may be that the peculiar clinical association of skin and brain involvement by vessel occlusion is determined by a specific vasculopathy that is compounded in some cases by a systemic coagulopathy.


*    Footnotes
 
Reprint requests to David C. Anderson, MD, Department of Neurology, Hennepin County Medical Center, 701 Park Ave S, Minneapolis, MN 55415.

1 References 2, 6, 11, 13, 17, 18, 22, 25-29. Back

2 References 5, 11, 15, 16, 18, 23, 25, 27, 28, 32. Back

Received August 1, 1994; revision received November 29, 1994; accepted December 12, 1994.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowCase Report
 up arrowDiscussion
 *References
 

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