Neurolog.uni-muenster.de

Clinical Review
Received: October 18, 2001Accepted: April 15, 2002 Therapy of Sneddon Syndrome
Agnes Flöel Tanya Imai Hubertus Lohmann Florian Bethke Department of Neurology, University of Münster, Münster, Germany Key Words
Introduction
Sneddon syndrome W Epilepsy W Cognition WAnticoagulation W Antiplatelet therapy Sneddon syndrome (SNS) is characterized by the asso- ciation of ischemic cerebrovascular events with wide-spread livedo racemosa primarily on the trunk [1]. The Abstract
presence of several other organ manifestations such as We report the case of a young woman with progressive cardiac and kidney lesions suggests that it is a systemic cognitive decline and epilepsy. She showed ischemic cerebrovascular disease and proximal livedo racemosa.
Livedo racemosa is a cutaneous sign consisting of strik- Antiphospholipid antibody (aPL) could not be detected ing violaceous, netlike-patterned erythemas of the skin, and there were no microemboli on continuous transcra- with irregular, broken circular segments. It is localized on nial Doppler ultrasonography monitoring. Histology of both trunk and extremities and persists on warming [3]. It cerebral vessels showed intimal hyperplasia in small lep- results from persistent and irregular focal impairment of tomeningeal venous vessels and micronecrosis of grey the blood flow in cutaneous vessels, e.g. due to partial or and white matter. We subsequently made the diagnosis complete occlusion or to increased viscosity, and can be of aPL-negative Sneddon Syndrome (SNS). Anticoagula- found in atherosclerosis, vasculitis, or SNS.
tion with warfarin could not be initiated because of a The onset of cerebrovascular events in Sneddon syn- drug-resistant epilepsy with the risk of falls and subse- drome usually occurs before the age of 45 years. Hemipar- quent bleeding; immunosuppression with steroids and esis, hemisensory symptoms, dysphasia, and visual symp- azathioprine was ineffective, as was initial antiplatelet toms are common. As medium-sized arteries are mainly therapy with clopidogrel alone. However, when we in- affected, strokes are rarely fatal, and good recovery is tensified antiplatelet therapy by combining clopidogrel observed initially. However, recurrent events frequently and ASS, a slowing of disease progression, as assessed lead to functional disability and vascular dementia. Ap- by neuropsychological testing and magnetic resonance proximately half of the patients report of headache. Cra- imaging, was noted on a follow-up after 6 months. Ther- nial magnetic resonance imaging (MRI) detects cortical, apeutic options in SNS in both aPL-positive and aPL-neg- subcortical or cortico-subcortical abnormalities sugges- ative patients with SNS are discussed.
tive of arterial ischemic infarcts which are frequently mul- tiple [2, 4]. Usually, periventricular white matter changes Department of Neurology, University of Münster Tel. +49 251 834 9969, Fax +49 251 834 8181, E-Mail [email protected] are observed [5]. Diffuse cortico-subcortical atrophy is family history of skin lesions, cognitive dysfunction and stroke-like observed in late stages of the disease. Heart valve abnor- On physical examination, the patient (84 kg, 174 cm) was in a malities are detected in half of the patients [4]. Both aortic reduced general state of health. Her blood pressure was 140/96 mm and mitral valve lesions may occur [4]. Mild to moderate Hg. The neuropsychological assessment revealed a significant decline systemic hypertension has been found in approximately since her first neuropsychological evaluation 2 years ago (table 1, 1st 60% of patients with SNS. Venous thrombosis occurs in examination). Her main problems had then been reduced mental 15% of patients [4]. Decreased creatinine clearance and speed, reduced mental flexibility and impaired word production(‘verbal fluency’). Other functions, including long-term memory, even chronic renal failure has been reported [6].
immediate and delayed recall, language, visuospatial abilities, praxis The prevalence of antiphospholipid antibodies (aPL) and judgement had either been average or above average. Now, she in SNS has been reported to range from 0 to 85% depend- showed a predominantly dysexecutive syndrome [9], i.e. mental flex- ing upon the series [4, 6]. Patients with SNS and aPL are ibility was moderately impaired. Verbal and spatial working memory more likely to develop epilepsy (30% in aPL-positive vs.
and selective attention were severely impaired. Mild behavioralchanges were also noted. Other higher cognitive functions (language, 10% in aPL-negative cases [2]). Optimal management of visuospatial abilities, praxis, judgement) were unimpaired (table 1, patients with SNS remains an unsolved problem. Pro- spective randomized controlled trials are not available Her motor examination showed weakness and dysdiadochokine- [7]. Therapeutic management is based either on treating sia of the left arm. Her tendon reflexes were brisk but symmetrical, detectable anomalies of the coagulation system such as coordination and sensation were normal. She had livedo racemosaon the back of the upper arms and on the back of the legs (fig. 1).
aPLs (inference from treatment of single patients with These skin signs were discrete and had not been noted before. Skin aPLs), or is based on pathophysiological assumptions.
biopsy revealed small vessels in the subcutis with a reorganizing Positive effects of anticoagulation, antiplatelet therapy small thrombus, and other small vessels showed an endothelial thick- and immunosuppression, alone or in combination, have ening. There were no signs of an inflammatory process, especially no been observed, but they were often minimal at best. Slow- signs of vasculitis (fig. 2). MRI of the brain showed bihemisphericconfluent signal increases on T ing down or even reversing the cognitive decline has rare- in cortical regions and parieto-occipital subcortical white matter ly been possible [7]. Concomitant diseases which carry an increased risk of bleeding, such as epilepsy with an On MR spectroscopy, she had neuronal degeneration (N-acetyl- increased risk of falls, uncontrolled hypertension, poor L-aspartate reduction), but no lactate increase. Therefore, a mito- compliance, liver disease, peptic ulcer and previous cere- chondrial encephalopathy with lactic acidosis and stroke-like epi-sodes was highly unlikely. EMG was normal. Muscle biopsy showed bral hemorrhage have to be considered in each patient an unspecific mild type-II atrophy. Doppler ultrasonography of the intra- and extracranial arteries was normal. There were no clinically In the present study, we report on a young woman with silent circulating microemboli on 1-hour continuous transcranial aPL-negative SNS and drug-resistant epilepsy. Her clini- Doppler monitoring of both middle cerebral arteries. Transthoracic cal course under different treatment regimens is de- echocardiography showed a tricuspid aortic valve with insufficiencygrade 1, and a minimal tricuspid valve insufficiency. An MRI-guided scribed, followed by a general discussion of treatment stereotactic brain biopsy yielded only inconspicuous brain tissue.
However, a subsequent CT scan of the head revealed that the biopsyhad been taken slightly off the lesion. Therefore, a second MRI-guided stereotactic brain biopsy was performed, which showed mul-tiple, predominantly older and mostly incomplete micronecroses of Case Report
grey and white matter and a white matter degeneration. Thesechanges were due to intimal hyperplasia in small leptomeningeal A 29-year-old woman (D.N.) presented to the department of neu- veins, most likely secondary to disseminated thromboses with recan- rology with a 5-year history of focal epilepsy with secondary generali- alization (fig. 4). Extensive laboratory studies uncovered no evidence zation, which had proven pharmacoresistent despite various antiepi- of vasculitis, hypercoagulable state, or toxic metabolic disturbances.
leptic drug regimes, including carbamazepine, valproic acid, lamotri- The following tests were all normal: full blood count, coagulation gine, phenytoin, gabapentin and topiramate. Additionally, there was tests including detection of antithrombin III, protein C, and protein a progressive 3-year decline in cognitive function. She had poor con- S deficiency, homocysteine blood levels (N ^12 Ìmol/l), fasting centration, easy fatigue and increasing difficulty in word retrieval.
serum glucose, complement (CH50, C3, C4), cryoglobulins, cryofi- This had led to her quitting a secretary trainee program in August brinogen, rheumatoid factor, antineutrophil cytoplasmatic anti- 1998, and she had had no employment since then. Lately, she had bodies and serum immunelectrophoresis. Lupus anticoagulant and had difficulties coping with everyday household work and her 8- anticardiolipid antibodies (IgM and IgG) 1 and 2, and beta 2 glyco- protein I were found normal on five occasions in a 1.5-year period.
Her medical history was significant for elevated arterial blood The patient was diagnosed as having aPL-negative SNS. Antico- pressure since the age of 18, a chronic tension headache and atopic agulation, antiplatelet and/or immunosuppressive therapy were con- dermatitis. No stroke-like episodes were reported. There was no sidered. Since no coagulopathy had been detected and the patient Fig. 1. Photograph of the right upper arm of patient D.N. Her livedo
racemosa presents as a violaceous, broken rash.
Fig. 2. Skin biopsy of patient D.N. (hematoxylin-eosin, original mag-
nification: !32). Histology reveals small vessels in the subcutis with
endothelial thickening (arrow).
Table 1. Neuropsychological evaluations of patient D.N. over the course of 38 months
WMS-R = Wechsler Memory Scale – Revised; RAVLT = Auditory Verbal Learning Test; WAIS-R = Wechsler Adult Intelligence Scale – Revised; TMT = Trail Making Task; COWA = Controlled Oral Word Association.
1 Percentile: e.g., the 75th percentile is a score that is equal to or better than 75% of all subjects who were tested.
Flöel/Imai/Lohmann/Bethke/Sunderkötter/Droste Fig. 3. Axial, T2-weighted cranial MRI of
patient D.N. In the frontal and parieto-occi-
pital cortical regions and subcortical white
matter, bihemispheric confluent signal in-
creases on T2-weighted images can be seen.
Fig. 4. Small leptomeningeal blood vessels
showing marked endothelial hyperplasia (ar-
row) (hematoxylin-eosin, original magnifica-
tion: !64).
had a high risk of falls with subsequent intracranial hemorrhage of carcinomas) was stopped. Antiplatelet therapy was intensified by because of her drug-resistant epilepsy, we decided against warfarin adding aspirin (50 mg per day) to clopidogrel.
anticoagulation. An antiplatelet agent (clopidogrel, 75 mg per day) Six months later, the patient was seen in our outpatient clinic. She was given. More aggressive therapies like immunosuppression were did not complain of any further cognitive decline. Neuropsychologi- discussed with the patient and her family. Primarily because of the cal examination did not reveal any significant changes compared rapid cognitive decline over the last 2 years, a therapeutic immuno- with the testing 6 months ago (small improvement in attentional suppressive trial (steroids plus azathioprine) was started ex juvanti- tasks, deterioration in verbal learning and memory tasks) (table 1, Additionally, her antiepileptic medication was changed; most importantly, medication that caused drowsiness (carbamazepine,phenytoine) was reduced. Subsequently, under valproic acid medica- Discussion
tion only, she improved significantly on working memory and learn-ing tasks, but still showed a dysexecutive syndrome (table 1, 3rdexamination).
SNS is clinically defined as the combination of livedo She returned to hospital 6 months later because of dizziness, nau- racemosa and cerebrovascular events [1, 11]. Because no sea and diplopia that began after an increase in her antiepileptic specific test for SNS exists, clinical differentiation from medication (valproic acid) 10 days before admission, and which dis- other phenomenologically similar disorders may be diffi- appeared after reduction of valproic acid.
She also reported a further decline in memory and concentration cult and has raised controversy [2, 11–15]. Various neuro- over the past 6 months. On neurological examination, she showed logical problems have been associated with SNS and slurred speech and weakness of the left arm, which persisted after aPLs, including cerebrovascular events, chorea, seizures, reduction of her antiepileptic medication. On neuropsychological myelopathy, atypical migraine-like events, acute encepha- assessment, she had a dysexecutive syndrome with decline in mental lopathy, and dementia [3, 4, 12, 16, 17].
flexibility, working memory and selective attention (table 1, 4thexamination). An MRI of the head revealed a progression of frontal, The first manifestation of disease in our patient was occipital, temporo-occipital and cerebellar lesions. Additionally, a drug-resistant epilepsy, followed by progressive cognitive fresh lesion with blood degradation products in the right striatum decline. Skin lesions were discrete, no coagulopathy was was noted, consistent with an infarction in the previous 2–3 months.
detected. The patient did not present with acute cerebro- In summary, no slowing in disease progression was observed since vascular events. However, her cranial MRI suggested that the initiation of antiplatelet and immunosuppressive therapy 6months ago. Therefore, the potentially dangerous immunosuppres- a number of microinfarctions had taken place in the pre- sive therapy with azathioprine (increased risk of infection, induction ceding years. Neither the signal pattern nor the distribu- tion of white matter lesions were specific for SNS. Similar A recent review [2] suggests that aPL-positive and aPL- findings may be seen in other cerebrovascular disorders negative SNS patients show distinct clinical and biologi- affecting small arteries [3]. The diagnosis of SNS was ulti- cal features. In aPL-positive patients, seizures and clini- mately confirmed on brain (and skin) biopsy.
cally audible mitral regurgitation are more frequently Stereotactic brain biopsy is invasive and carries a small observed, the fishnet of the livedo is larger, and thrombo- but definite risk of morbidity and even mortality. Nev- cytopenia is present in about one third of patients [4]. In ertheless, we opted for a brain biopsy, first to exclude any comparison, thrombocytopenia has never been reported treatable disease, and second to confirm the diagnosis of in aPL-negative patients [2, 4, 14].
SNS. The options for treatment of SNS, anticoagulation, Treatment of patients with SNS is still controversial.
antiplatetelet and/or immunosuppressive medication are Categorization of SNS patients into two subsets (aPL-pos- all long-term treatments, and carry a substantial risk itive and aPL-negative), as described above, might in- themselves. Therefore, in patients without aPLs, the deci- sion about potentially harmful therapies should be based APL-positive SNS patients might be treated like pri- on a definite diagnosis. Skin biopsy, which is much less mary antiphospholipid syndrome. In primary antiphos- invasive, has been reported to yield no abnormalities on pholipid syndrome, patients with the highest titers of histological examination in the majority of patients in a aPLs seem to have the greatest risk of recurrent thrombot- study of 44 patients [4]. Not all studies agree on the validi- ic events [12, 19]. A wide variety of treatments including ty of brain biopsy in diagnosing SNS. A recent study by antiplatelet agents, anticoagulants, corticosteroids, im- Zipper et al. [18] reported inconclusive results for brain munosuppressants has been tried, but no prospective ran- biopsy. However, brain biopsy might not have been car- domized controlled trials are available to guide manage- ried out by an experienced examiner, and therefore the ment. A retrospective analysis of patients with primary biopsy might have missed the relevant area. Even a slight antiphospholipid syndrome suggested that long-term anti- deviation from the lesion area might lead to inconspic- coagulation is advisable, with the INR maintained at 3 or higher [2, 22, 24]. Therefore, in aPL-positive SNS pa- The pathogenic mechanisms in SNS and primary anti- tients, high-dose warfarin (INR 6 3) is currently mostly phospholipid syndrome are incompletely understood [12, 19]. A defective vascular endothelium, alone or in combi- Optimal management of aPL-negative SNS remains an nation with a slight or nondetectable coagulation deficit, unsolved problem [2]. In a study on aPL-negative patients might traumatize the endothelium [4, 12, 20, 21]. The with SNS, the number of cerebral events was lower with presence of aPLs, most notably anticardiolipid antibodies antiplatelet therapy; antiplatelet therapy was as effective and lupus anticoagulant, may be detected in about half of as high-dose warfarin [4]. Frances et al. [4] suggested that the SNS patients, with a range from 0 to 85% depending antiplatelet therapy might slow cognitive decline in aPL- on the series [4, 6]. Their presence suggests that SNS negative SNS patients, based on the observation that the results from a thrombotic process [4, 12]. A number of only patient in their study who developed frank dementia authors have found noninflammatory endothelial prolif- (of the vascular type) was the one who did not receive eration and fibro-mucinous changes with subsequent oc- clusion of small vessels [20]. Monitoring the middle cere- Wohlrab et al. [28] suggested the use of a triple therapy, bral artery using transcranial Doppler ultrasonography i.e. in addition to antiplatelet therapy, angiotensin-con- (TCD) showed clinically silent microembolisms in 38% of verting enzyme inhibitors (ACE inhibitors) and prosta- patients with SNS, all aPL-positive [22].
glandin E1 are to be given. ACE inhibitors are posited to In aPL-negative cases, a primary inflammatory process reduce angiotensin II-mediated proliferation and migra- has been suggested [3, 4, 21], though a number of studies tion of subendothelial vascular myocytes. Prostaglandin did not show inflammatory changes on skin and brain E1 might improve microcirculation by altering the rheo- biopsies [11, 14], and the inefficacy of immunosuppres- logical properties of the blood. The authors reported 5 sive therapies argues against a primary inflammatory vas- patients treated with the triple combination who did not show further clinical deterioration over the course of 3–5 Varying findings on microscopy might be due to differ- ent underlying disease processes in patients clinically In both aPL-positive and aPL-negative cases, limited diagnosed with SNS [2]. It might also be due to sampling effectiveness [3, 11, 14, 25] or frank inefficacy [13] of var- in different stages of the disease [23].
ious immunotherapies, including steroids and azathio- Flöel/Imai/Lohmann/Bethke/Sunderkötter/Droste prine, has been repeatedly described. The use of cortico- signals on continuous TCD monitoring does not argue steroids and immunosuppressives without antithrombot- ic agents seems to be deleterious as noted in 6 previously In summary, patients diagnosed with SNS are to be reported patients [4, 26]. A temporary improvement with screened for antiphospholipid antibodies, arterial hyper- high-dose corticosteroids and aspirin has been reported tension (24-hour blood-pressure monitoring and ophthal- moscopy), renal dysfunction (creatine clearance) and The symptom most difficult to treat in both aPL-posi- heart valve abnormalities (echocardiography).
tive and aPL-negative patients is cognitive decline [5, 29].
Therapeutically, aPL-positive patients should be start- Mental deterioration is not only one of the most common ed on high-dose warfarin (INR 63). If warfarin is con- symptoms in SNS, but also one of the most important as traindicated because of a concomitant disease, antiplate- far as quality of life is concerned. It ranges from moderate let therapy, ideally in the combination of two different cognitive impairment [3, 5, 16] to frank dementia [3, 5].
agents (ASS and clopidogrel), is the most appropriate Dementia in SNS occurs on a multi-infarct basis [16, 28].
Rare cases of more gradual cognitive decline without spe- In aPL-negative patients, antiplatelet therapy, again in cific acute cerebrovascular episodes have also been re- combination, should be administered.
ported [29, 30]. On imaging, these cases show widespread In both aPL-positive and aPL-negative patients, if dis- changes in the form of cerebral infarction.
ease is rapidly progressive despite therapy, ACE inhibi- Apart from aPLs, clinically silent microembolism has tors and prostaglandin E1 might be given. Ultimately, been posited to provide subclinical evidence of active dis- immunosuppressive agents like steroids and azathioprine ease in SNS patients, and might therefore guide thera- can be tried, but always in combination with antithrom- peutic approaches [22]. However, in our patient, no microemboli were detected; still, the disease was clearlyprogressive, both clinically (further deterioration in men-tal flexibility, working memory and selective attention) Acknowledgments
and on cranial MRI (progression of size of white matter This work was supported by the Nachwuchsgruppen-Förderung lesions, fresh lesion in the right striatum). This finding of the Ministry of Science, Nordrhein-Westfalen (516-400 01000).
argues against a mechanism of arterio-arterial or cardio- We thank Dr. C. Rickerts, Institute of Neuropathology, University of genic microembolism as the pathomechanism in our pa- Münster, Germany, for providing histological pictures of patient tient. Intravascular, in situ thrombosis seems more likely here [22]. Taken together, the absence of microembolic References
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