Journal of Neuro-Ophthalmology, December 1988, Volume 8, Issue 4

Sneddon's disease presenting with visual loss and dementia.

A 51-year-old woman with Sneddon's disease presented with transient right hemifield loss of vision and transient right-sided weakness. Over the preceding decade she had experienced a slow decline in mental function. She also had hypertension, migraine, and a mixed seizure disorder. She had skin changes typical for generalized livedo reticularis but she did not have Raynaud's phenomenon or winter ulcerations. Her disease was not understood until the stroke-related symptoms were associated with the skin abnormalities. We review the neuro-ophthalmic manifestations of Sneddon's disease and add data from our case to the growing body of fact that suggests that Sneddon's disease may be an immunologically mediated vasculopathy.

!ounuJl of Clinical Neuro-ophthalmology 8(4): 255-261, 1988. © 1988 Raven Press, Ltd., New York Sneddon's Disease Presenting with Visual Loss and Dementia W. Bruce Wilson, M.D., Don B. Smith, M.D., Roy R. Wright, M.D., and Charles E. Seibert, M.D. A 51-year-old woman with Sneddon's disease presented with transient right hemifield loss of vision and transient right-sided weakness. Over the preceding decade she had experienced a slow decline in mental function. She also had hypertension, migraine, and a mixed seizure disorder. She had skin changes typical for generalized livedo reticularis but she did not have Raynaud's phe­nomenon or winter ulcerations. Her disease was not un­derstood until the stroke-related symptoms were asso­ciated with the skin abnormalities. We review the neuro­ophthalmic manifestations of Sneddon's disease and add data from our case to the growing body of fact that suggests that Sneddon's disease may be an immunolog­ically mediated vasculopathy. Key Words: Sneddon's disease-Stroke­Hemianopia- Hypertension-Livedo reticularis­Immunology. From the Departments of Ophthalmology (W.B.W.) and Neurology (D.B.5., R.R.W.), University of Colorado School of Medicine, and Department of Radiology, Porter Memorial Hos­pital (C.E.S.), Denver, Colorado. Address correspondence and reprint requests to W. Bruce Wilson, M.D., 850 E. Harvard (535), Denver, CO, 80210, U.S.A. 255 Even though some 30 cases of Sneddon's disease have been reported to date, there is only scattered fragmentary information about the visual system changes seen in this problem. We report a well­documented case that had early, prominent changes in visual function and review the litera­ture in regard to neuro-ophthalmic findings in this disease. In 1965, Sneddon (1) saw the significance of the combination of hypertension, stroke, and the skin changes known as livedo reticularis and the disease now bears his name, even though there had been a few cases reported before that time (2-4). Livedo reticularis is a synonym for some of the older terms, such as livedo racemosa, livedo annularis, and asphyxia reticularis. It is characterized by a mottled, blotchy, or reticulated pattern of skin color-blue to red. CASE STUDY A 51-year-old woman with generalized livedo reticularis, transient neurological symptoms, labile hypertension, classical migraine, and absence and focal motor seizures was examined in consultation by the authors (Fig. 1). The university Department of Dermatology had classified her skin problem as typical for livedo reticularis. Over the 10-12 years since the beginning of her disease, she had a num­ber of transient symptoms but most Significantly three episodes of loss of her right hemifields of vision associated with weakness of her right arm and leg. She had another visual problem that had been slowly progressive. It was not related to read­ing small letters, but apparently to recognizing words and also to remembering what words she had just read for more than just a few minutes. She also had had a steady decline in mental function and motor coordination, with impairment of her ability to remember recent events and to perform 256 W. B. WILSON ET AL. FIG. 1. Photo of the legs illustrate severe generalized livedo reticularis. reasoning in regard to math or abstract parables. She had depression, which was occasionally asso­ciated with anger. She often had inappropriate laughter. More slowly progressive changes had been seen in regard to her ability to dress herself and her ability to write. Both had degenerated with time. Her livedo reticularis was generalized, but she did not have ulcerations of her skin, pe­ripheral neuropathy, or Raynaud's phenomenon. On examination the patient had mild hyperten­sion, ranging between 145 and 155 mm Hg systolic and 95 and 105 mm Hg diastolic. She was not able to do simple mathematical functions at first- or sec­ond- grade level and had little concept of abstract reasoning. Her memory for what had taken place in the first part of the examination was essentially gone by the end of the examination. She appeared inappropriately euphoric with seemingly little con­cern for her problem. She was not able to read a simple sentence, she did not know what day it was, and her general fund of knowledge was poor. Writing was done with great difficulty, and only a few words could be formed. Her speech was hes­itant, nonfluent, and marked by occasional para­phrasic errors. She had increased deep tendon re­flexes and mild weakness in the right arm and leg. Tandem walking was poor. Sensation was normal. Her visual acuity was 20/25 on the right and 20/200 on the left because of amblyopia of the left eye. She • !""''''0l'hthalm"l, Vol. 8, No, 4, 1988 had a left homonymous hemianopia that was nearly total and dense but difficult to map. because of difficulty with fixation and concentration. The right hemifields were probably n.o.rmal. There were no objective ocular abnormahtIes. She had color agnosia but no anomia or left-right confu­sion. The computed tomography (CT) scan of the head had a number of peripheral radiolucencies consistent with small infarcts, located predomi­nantly in the parietooccipital areas bilaterally. There was also significant diffuse cerebral atrophy (Figs. 2 and 3). The cerebellum and brainstem ap­peared unaffected. Four-vessel cerebral angiogra­phy and digital angiography of the left hand doc­umented the diffuse loss of small- to medium- FIG. 2. Computed tomography of the head of this pa­tient. A: An image through the lateral ventricles, which demonstrates enlarged ventricles (short arrow), large sulci (curved arrow), and focal enlarged cerebrospinal fluid spaces consistent with small peripheral infarcts (long arrow). B: The cerebral convexity, which has en­larged cortical sulci spaces (arrow) secondary to at­rophy (compare with Fig. 3) . SNEDDON'S DISEASE WITH VISUAL LOSS AND DEMENTIA 257 FIG. 3. Normal computed tomography (CT) of the head taken at the ventricular level (A) and at the con­vexity level (B). This CT is age-matched to the patient and has no evidence of sulci enlargment or ventricular enlargement (compare with Fig. 2). sized arteries ("pruning effect"). Magnetic resonance imaging also demonstrated the severe atrophy and the multiple small infarcts (Fig. 4). A skin biopsy was taken to include normal­appearing skin adjacent to an area of livedo retic­ularis. Some of the small arteries and capillaries of the dermis had endothelial proliferation. There was some perivascular mononuclear infiltrate. Normal values were reported for complete blood count, urinalysis, chemistry panel, thryroid screen, rheumatoid arthritis test, Westergren erythrocyte sedimentation rate, serum protein electrophoresis, serum and plasma antithrombin III activity, fibrinogen, activated partial thrombo­plastin time, Von Willebrand's factor, prothrombin time, protein C and S, platelet aggregation, C3/C4 complement studies, and cerebrospinal fluid (no bands, normal gamma globulin) except for C1q binding of 17.4 U (normal 0-11). However, there was a false-positive RPR and a mildly elevated ANA (1:160 homogeneous) but a normal ANA panel, an increase in factor VIII antigen at 323 (nor­mal 65-150%), a high Raji cell assay (335 with nor­mal 0-12.5 U, AHGE-M), marked elevation of an­ticardiolipin antibodies and immunoglobulins IgM, IgG, and IgA (e.g., IgM 50 and 70 U on two occasions with normal <2), and elevated serum lupus anticoagulant (weakly positive). DISCUSSION A female bias and a preponderance in the fourth and fifth decades are reported in Sneddon's dis­ease (1,5). Early neurological changes are charac­teristically transient and include aphasia and am­nesia, even of a global nature (1,6-8). While tran­sient visual field defects have also been noted in previous reports, the type is not always specified and they were probably not the presenting com­plaint (1,4,6-8). Hemiparesis and hypesthesia are also reported to be transient (6,8-11). The excep­tion might be dementia, which seems to be slowly progressive, even though it might be due to mul­tiple continuing small infarcts. The visual loss and visual field defects are prob­ably all related to stroke (1,4,6,7). While some re­port transient defects, many permanent defects have been noted. Since many of the "transient" field defects reported are large, it seems likely that some are permanent but hard to verify because of the dementia and lack of full patient cooperation. As in our patient, it may be that dementia makes it difficult to assess the visual field loss accurately and therefore these defects may seem to come and go. The type of defect seems to be either a hom- J Clin Neuro-ophthalmol, Vol. 8, No.4. 1988 258 W. B. WILSON ET AL. FIG. 4. Magnetic resonance imaging scans of the head of this patient (0.5 Picker). A and B: Taken at about the same levels as A and B in Figs. 2 and 3, these are inversion recovery T,-weighted images that confirm severe atrophic changes (arrows). C: A T2 ­weighted spin echo image, TR 2,500 ms, TE 80 ms. High signal abnormalities (white) in the white matter are consistent with deep white matter infarcts (arrows). onymous quandrantanopsia or a hemianopia. Only the association with the typical skin changes of Sneddon's disease makes the visual loss un­usual (Table 1). Permanent visual field and other fixed focal neu­rologic defects seem to occur with more frequency as the time of follow-up increases (4-7,10-14). Loss of communication skills seems to be a prominent feature. As in our patient, they involve difficulties with higher function in which recent memory is severely affected. Remote memory may be remark­edly intact on occasion. Recent memory even in­volves words read just a few minutes before. Rea­soning abnormalities are also noted, in which SNEDDON'S DISEASE WITH VISUAL LOSS AND DEMENTIA 259 TABLE 1. Sneddon's disease (reported in the English literature) (total 55 cases) No. cases CT/MRI, A Author and reported Other yr of (age at Loss Visual Visual CN neurologic publication onset, yrs) VA field agnosia PCAO MCAO CRAO abn deficits Barker et al. 2 (31 M) NR NR NR NR NR NR NR NR (1941) (40 F) NR NR NR NR NR NR NR NR Champion (1960) 1 (33 M) NR NR NR NR NR NR NR No Church (1962) 1 (33 F) Tra L hemi NR NR NR NR NR No Sneddon (1965) 6(42 M) No No NR NR NR No No He,dys (20 F) No No NR NR L No No He,dys,sei (35 F) No No NR NR NR No No He,dys (45 F) No L hemi NR NR NR No NR He (31 F) No L hemi NR NR NR NR NR No (39 F) No No NR NR NR NR No He,dys Quimby and Perry 1 (42 F) No R quad NR UA R/CT &A NR No He,dys (1980) Thomas et al. 2 (37 F) Yes Yes NR NR R,UCT NR NR He (1981) (13 F) NR R quad NR NR NR NR NR No Stephens and 3(35 M) No R hemi Yes NR NR No No He,dys Ferguson (1982) (42 M) No No Yes NR NR No No He,dem (63 M) Tra L quad Yes NR NR No No He,dem Lubach and Stamm 19(-) Not much specific data but 12 cerebral infarctions (1983) Rebollo et al. 8(-) NR NR NR NR NR NR NR Str (1983) (16 F) NR L hemi NR NR Yes NR NR Dem,sei,dys,he Mean age 19 yrs (33 F) NR NR NR NR Yes NR NR Dem,str (-F) NR NR NR NR Yes NR NR Dem,str (-F) NR NR NR NR NR NR NR Dem,str (-F) NR NR NR NR NR NR NR NR (-M) NR NR NR NR NR NR NR Sei (10 F) NR NR NR NR NR NR NR Str Marsh and 2 (36 F) Tra NR NR NR NR NR NR Hemiplegia Muckelmann (29 F) NR NR NR NR NR NR NR Hemiplegia (1985) Rumpl et al. 4 (52 F) No R hemi NR UCT R,UCT NR L7 Amn,sei,he,dysa (1985) (32 M) Yes No NR R/CT R,UCT NR L7 Dys,se,he,dysa (31 F) NR NR NR No R,UCT NR R7 He,dysa (32 M) NR NR NR NR R,UCT NR L3 He Jonas et al. 1 (22 F) Yes Tra hemi No NR R,UCT Yes NR He,dys (1986) Bruyn et al. 1 (36 F) No No NR Yes/MRI Yes No No Dys (1987) Deffer et al. 1 (38 F) No R hemi Yes NR NR NR No He,dys (1987) Pauranik et al. 1 (34 M) R,L L NR No Yes Yes Dipl He,dys (1987) Scott and Boyle 1 (24 F) No No NR NR NR NR NR Dem,dys (1987) Wilson (current paper) 1 (51 F) No R hemi Yes Pruning/A R,UCT, No No Dem,sei MRI A, angiography; abn, abnormality; Amn, amnesia; CN 1-12, 1-12 cranial nerves; CRAO, central retinal artery occlusion; CT, computed tomography; dem, dementia; dipl, diplopia; dys, dysphasia; dysa, dysarthria; F, female; he, hemiparesis; hemi, quad, hemianopsia (quadrant); L, left; M, male; MCAO, middle cerebral artery occlusion; MRI, magnetic resonance imaging; No, none; NR, not reported; PCAO, posterior cerebral artery occlusion; R, right; sei, seizures; str, stroke; tra, transient; VA, visual acuity. mathematics and abstract reasoning are poor, as problems related to space and time are occasion-demonstrated in our patient. Whether these are, in ally seen. Completed strokes also involve motor fact, evidence of a slowly progressive problem or and sensory signs. Occasionally cranial nerve of multiple small strokes may be difficult to deter- signs and seizures are noted (4--6,10). Even when mine in any single patient, but all the evidence multistroke dementia is the primary evidence for would favor the latter (15--17). Our patient had sig- stroke, if it is accompanied by livedo reticularis, nificant abnormalities of her psyche, although the Sneddon's disease should be suspected. articles reviewed do not report a high incidence of The hypertension does not seem to be unusual this type of problem. Alexia and other agnosia and is often noted to be labile and not severe (1,8). I Clin Neuro-ophthalmol, Vol. 8, No.4, 1988 260 W. B. WILSON ET AL. Only rarely is any underlying organ disease poten­tially related (9). Angiography of the central nervous system shows that strokes may involve any of the major circulations: anterior, middle, and/or posterior ce­rebral arteries (5,9,11). Even two cases of central retinal artery occlusion are reported (8,14). Some reported cases with good clinical evidence for stroke apparently did not have angiographic ab­normalities (7). This may be because the authors were looking for major vessel occlusion and the more subtle pruning effect, as seen in our case, was overlooked. CT also demonstrates the strokes­some say with even greater facility (5-7,9). Angiography of the hands reveals obstruction in the small arteries in some patients, together with the skin changes, probably explains Raynaud's phenomenon (5,10,12). It would seem unusual if the vascular disease were limited to the brain and hands. However, evidence that the arterial vascu­lar disease may involve other circulations is only occasional, e.g., the patient with myocardial in­farction or obstructive vascular disease in a limb (2,6). Livedo reticularis is a constant sign in all of the patients with Sneddon's disease and is always generalized or diffuse. It probably represents di­lated small blood vessels in response to a sluggish microcirculation. Our patient did not have Raynaud's phenomenon or winter ulcerations, but many patients do (1,2). Livedo reticularis probably occurs in several forms depending on the presence or absence of associated disease. A simple form has been called cutis marmorata and involves only skin changes in which there is bluish mottling or blotchiness or reticular patterns in skin that is cold. These become more reddish or purplish and tend to disappear as the skin warms. This is usually limited in area and not associated with other dis­ease. A more complex type is one in which the reticular pattern of the skin is more severe (even racemose) and associated with Raynaud's phe­nomenon and ulcerations (1,2). Here the pattern may change on warming the skin, but still other disease association is rarely noted. A "third type" is like the second except it is more diffuse and associated with a specific disease, such as Sned­don's syndrome (1-4). Our patient had this type. It has also been said that autoimmune vasculitis may be related to the appearance of generalized livedo reticularis. In reports to date, laboratory evidence for ath­erosclerosis or immune vascular disease has been remarkably negative. A mildly elevated erythro­cyte sedimentation rate is seen occasionally (7,9). , "/;,/ Nroro-ophthalmol. Vol. 8, No.4, 1988 More recently Raji cell analysis and the Clq bind­ing assay for circulating immune complexes have begun to show abnormalities (12). Antiphospho­lipid antibodies (anticardiolipin), suggesting a pos­sible tie-in with autoimmune clotting abnormali­ties such as seen in lupus erythematosis, have also been noted in some patients (8). Our case adds more data to support the idea of an immunologi­cally mediated vasculopathy. While biopsies of skin vessels in some of these patients have been said to be normal (7), others have reported two problems: endothelial prolifer­ation and proliferation and migration of smooth muscle cells into the subendothelial space (5,9,10). No pathologic data for intracranial vessels are re­ported in the literature. It appears that the site of the biopsy is important and must be made in nor­mal skin adjacent to a streak of livedo reticularis. This may explain why some studies report normal histopathology (10). Since these patients have hypertension and are in their fourth and fifth decade, an argument might be made that the central nervous system changes are merely those of atherosclerosis. How­ever, the unusual arterial skin changes, the specific biopsy findings, and the normal large vessels sug­gest that, in fact, this is a different type of arteri­opathy. The specific biopsy finding in Sneddon's disease even excludes other arteriopathies that may be associated with livedo reticularis (9). The concomitant occurrence of stroke, skin changes typical for livedo reticularis, and hyper­tension in a young woman should alert both those dealing with the dermatologic problems and those dealing with central nervous system problems to consider Sneddon's disease in the differential. Editor's Note This paper by Dr. Wilson and associates on Sneddon's disease is an extremely interesting topic. When they state that their patient had a "false-positive RPR" and ~ls~,had a "marked elevation of anti-cardiolipin antibod­Ies, of course, that began to eat into an editor's brain "like a rat." One would wonder what the RPR and/or VDRL titer really was? One would wonder if the "false negative RPR" was based on a nonreactive serum FTA­ABS, or a nonreactive TPHA, or both? These points would make one really want to know more about the patient'~ p~pillary reactions and also the appearance of her OptiC diSCS. One would want to know if there was any p~ripheral fundus pigmentation or perivascular sheathmg. One would even like to know this patient's serum ~yme IFA and ELISA titers. These points would be particularly interesting in a 51-year-old woman with such evidence of organic brain disease as she showed (de~entia, m~mory loss, del?ression, episodic anger, and mappropnate anger). It did not appear appropriate to hold. up ~he paper to get these extra points because the baSIC pomt of neurovascular changes in patients with SNEDDON'S DISEASE WITH VISUAL L055 AND DEMENTIA 261 livedo reticularis deserves emphasis on its own merit. Thank you, Dr. Wilson, for bringing this to our attention, and if you have any additional information concerning the above points, that would be interesting, too. REFERENCES 1. Sneddon I. Cerebro-vascular lesions and livedo reticularis. Br 1 DermatoI1965;77:180-5. 2. Barker NW, Hines EA, Craig WM. Livedo reticularis: a pe­ripheral arteriolar disease. Am Heart 1 1941;21:592-{j04. 3. Champion RH, Rook A. Livedo reticularis. Pro R Soc Med 1960;53:961-2. 4. Church RE. Reticular livedo with cerebro-vascular lesions. Br 1 Dermatol 1962;74:156-7. 5. Rebollo M, Val J, Garijo F, et al. Livedo reticularis and cerebro-vascular lesions. Brain 1983;106:965-79. 6. Stephens W, Ferguson I. Livedo reticularis and cerebrovas­cular disease. Postgrad Med 11982;58:70--3. 7. Rumpl E, Neuhofer J, Pallua A, et al. Cerebrovascular le­sions and livedo reticularis. 1 NeuroI1985;231:324-30. 8. Jonas J, Kolble K, Volcker HE, et al. Central retinal artery occlusion in Sneddon's disease associated with antiphos­pholipid antibodies. Am 1 OphthalmoI1986;102:37--40. 9. Quimby S, Perry H. Livedo reticularis and cerebrovascular accidents. 1 Am Acad Dermatol 1980;3:377-83. 10. Marsch W, Muckelmann R. Generalized racemose livedo with cerebro-vascular lesions (Sneddon syndrome). Br 1 DermatoI1985;112:703-8. 11. Thomas D, Kirby J, Britton K, et al. Livedo reticularis and neurological lesions. Br 1 DermatoI1982;106:711-2. 12. Green K, Lynfield Y, Davis D. Livedo reticularis with ulcers and circulating immune complexes. Cutis 1983;31;312-5. 13. Deffer TA, Berger TG, Gelinas-Sorell D. Sneddon's syn­drome. 1 Am Acad DermatoI1987;16:1084-7. 14. Pauranik A, Parwani S, Jain S. Simultaneous bilateral reti­nal artery occlusion in a patient with Sneddon's syndrome: case history. Angiology 1987;38:158-63. 15. Lubach D, Stamm T. Generalized racemose livedo and neu­rologicallesions. Br 1 DermatoI1983;108:501. 16. Scott lA, Boyle RS. Sneddon's syndrome. Aust NZ 1 Med 1986;16:799-802. 17. Bruyn RPM, Van der Veen JPW, Donker AM, Wolters E Ch. Sneddon's syndrome. Case report and review of the literature. 1 Neurol Sci 1987;79:243-53. JOin Neura-ophthalmol, Vol. 8, No.4, 1988