The American Journal of Medicine (2006) 119, 577-578

IMAGES IN DERMATOLOGY
Parwathi Uma Paniker, MD, Section Editor

A Reticular Rash
Juan C. Salgado, MD, David R. Gutknecht, MD
Geisinger Medical Center, Department of General Internal Medicine, Danville, Penn.

PRESENTATION
A 68-year-old man presented to the clinic with mild ankle swelling and a reddish-brown shnet eruption on the skin of his legs and lower trunk. He had a history of treated hypothyroidism and coronary heart disease. Nonetheless, he had enjoyed generally good health except for recent difculty with Parkinsons disease, for which amantadine had been prescribed 3 months before. Physical examination conrmed mottling of the skin of his trunk and legs in a red-brown reticular pattern consistent with livedo reticularis (Figure). Aside from his mild ankle edema, the rest of his examination was normal. A review of systems revealed no symptoms suggestive of any associated systemic disease.

ASSESSMENT
A complete blood count (CBC), comprehensive metabolic panel, and urinalysis were all unremarkable. The patients thyroid-stimulating hormone levels were normal, and a test for rheumatoid factor was negative. Cryoglobulins were undetectable, testing for antiphospholipid antibodies was negative, and a comprehensive coagulation prole, including measurements of protein C and protein S, showed no abnormalities. Hepatitis C antibody was absent. A transthoracic echocardiogram showed no abnormalities and no likely cause of embolic phenomena. Computed tomography scanning, done within the preceding 6 months, indicated no signs of aortic aneurysm, and the patient had undergone no procedures likely to cause cholesterol embolization.

DIAGNOSIS
The peculiar mottling of the skin known as livedo reticularis (LR) is nonspecic and is found in a wide range of conditions and circumstances, many of which are associated with abnormalities of blood ow to the skin. Physiologic skin
Requests for reprints should be addressed to David R. Gutknecht, MD, Department of General Internal Medicine, Geisinger Medical Center, 100 N. Academy Avenue, Danville, PA 17822. E-mail address: dgutknecht@geisinger.edu

mottling on cold exposure is a common occurrence in normal children and in many adults and differs from idiopathic livedo in that it is reversible with rewarming. Still, the distinction between the 2 can be subtle, and these usually harmless conditions, taken together, very likely represent the majority of livedo cases. LR also may be caused by a wide range of systemic disorders, many of which have serious implications. Examples include systemic lupus erythematosus and Sneddons syndrome. This patients symptoms were attributed to his amantadine treatment. Both livedo reticularis and edema formation have been associated with use of that agent for the treatment of Parkinsons disease. The frequency of such complications ranges widely in the various series published.1,2 A widely accepted explanation for the characteristic blotchiness associated with LR is that the skin circulation involves 1- to 3-cm areas of arterial perfusion, each fed by a single ascending arteriole. The vein-rich skin between these well-perfused areas can take on a reddish-blue or purple reticular pattern whenever slow ow causes increased oxygen extraction and a deepening of the color of venous blood.3, 4 Although this model has been difcult to conrm, it does provide a convenient framework for understanding the LR seen with atherosclerosis and the vasculitides, as well as that occurring with vascular occlusions from cryoglobulinemia, disseminated intravascular coagulation, thrombocytosis, polycythemia, cholesterol embolization, decompression sickness, and hypercoagulable states, particularly the antiphospholipid syndrome.3 Mottling occurring with extremes of temperature also is likely related to disturbances in cutaneous blood ow. Examples of this kind of mottling include heat-induced erythema ab igne (really a reticular burn) and cold-related phenomena such as chilblains and the physiologic livedo, or cutis marmorata, mentioned above.3,4 How other disorders induce LR is harder to understand, although all would seem to similarly involve circulation effects, many of which would be mediated through autoimmune phenomena. Infections such as endocarditis, syphilis, and tuberculosis have all been associated with LR. Immunecomplex deposition may be involved.3 LR has been reported

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The American Journal of Medicine, Vol 119, No 7, July 2006 and a coagulation prole with testing for antiphospholipid antibodies.3 As illustrated in this case, a medication history is very important, since LR can be induced by certain drugs. In addition to amantadine, bismuth, catecholamines (dopamine, epinephrine, norepinephrine), diphenhydramine, and minocycline can be associated with LR. Quinidine can cause LR directly or as part of a lupus-like reaction. Mechanisms are poorly understood but frequently involve autoimmune phenomena.3,7,8 Use of amantadine for Parkinsons disease is complicated by LR in over 25% of patients in some reports, although drug information databases report incidences less than 10%.9 The mechanisms of amantadine-induced LR are not completely understood, but the drug can deplete catecholamines at peripheral nerve terminals and may thereby cause widespread changes in the skin circulation. These changes are likely causes of mottling of the skin, as well as occasional edema and, rarely, peripheral neuropathy.1,2

MANAGEMENT
Unlike most cases of LR due to systemic disease, amantadine-induced LR is reversible. Our patients problem resolved completely within 6 weeks of stopping treatment. Some patients do elect to continue treatment with amantadine, nding that the therapeutic benets outweigh the annoying but usually harmless consequences of continued use.1

References
Figure: causes. An eruption like this can stem from any of several
1. Sladden MJ, Nicolaou N, Johnston GA, Hutchison PE. Livedo reticularis induced by amantadine. Br J Dermatol. 2003;149:656-658. 2. Shulman LM, Minagar A, Sharma K, Weiner WJ. Amantadine-induced peripheral neuropathy. Neurology. 1999;53:1862-1865. 3. Fleischer AB, Resnick SD. Livedo reticularis. Dermatol Clin. 1990;8: 347-354. 4. Picascia DD, Pellegrini JR. Livedo reticularis. Cutis. 1987;39:429-432. 5. Gould JW, Helms SE, Schulz SM, Stevens SR. Relapsing livedo reticularis in the setting of chronic pancreatitis. J Am Acad Dermatol. 1998;39:1035-1036. 6. Marconi V, Mod MZ, McCall C, Eckman I, Nousari HC. Primary hyperoxaluria: report of a patient with livedo reticularis and digital infarcts. J Am Acad Dermatol 2002;46(Suppl 2):S16-18. 7. Morell A, Botella R, Silvestre JF, Betlloch I, Alfonso MR, Ruiz MD. Livedo reticularis and thrombotic purpura related to the use of diphenhydramine associated with pyrithyldione. Dermatology. 1996;193:5051. 8. Elkayam O, Yaron M, Caspi D. Minocycline-induced arthritis associated with fever, livedo reticularis, and pANCA. Ann Rheum Dis. 1996; 55:769-771. 9. Lexi-Comp Online. Lexi-Comp, Inc, Hudson, Ohio.

in patients with pancreatitis, and in that disorder, it has been linked to immune deposits in the dermal vessels.5 Endocrine causes of LR include untreated hypothyroidism and Cushings Disease.3,4 LR also has been noted among patients with calcium disorders such as hypoparathyroidism, which can cause skin ischemia and infarction, and among those with hyperoxaluria, which can damage the skin through crystal deposition.3,6 Evaluation of LR requires careful history-taking, physical examination, and judicious laboratory testing for suspected systemic conditions. A reasonable screening prole would include a CBC with platelet count; blood chemistry studies; tests for cryoproteins and antinuclear antibodies;