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IMAGES IN DERMATOLOGYParwathi Uma Paniker, MD, Section Editor

A Reticular RashJuan C. Salgado, MD, David R. Gutknecht, MDGeisinger Medical Center, Department of General Internal Medicine, Danville, Penn.

PRESENTATIONA 68-year-old man presented to the clinic with mild ankle

swelling and a reddish-brown fishnet eruption on the skin of

his legs and lower trunk. He had a history of treated hypo-

thyroidism and coronary heart disease. Nonetheless, he had

enjoyed generally good health except for recent difficulty

with Parkinsons disease, for which amantadine had beenprescribed 3 months before.

Physical examination confirmed 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.

ASSESSMENTA complete blood count (CBC), comprehensive metabolic

panel, and urinalysis were all unremarkable. The patientsthyroid-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 profile, includ-

ing measurements of protein C and protein S, showed no

abnormalities. Hepatitis C antibody was absent. A trans-

thoracic 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.

DIAGNOSISThe peculiar mottling of the skin known as livedo reticularis

(LR) is nonspecific and is found in a wide range of condi-

tions and circumstances, many of which are associated with

abnormalities of blood flow to the skin. Physiologic skin

mottling on cold exposure is a common occurrence in nor-

mal 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 haveserious implications. Examples include systemic lupus ery-

thematosus and Sneddons syndrome.

This patients symptoms were attributed to his amanta-

dine 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 complica-

tions 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 orpurple reticular pattern whenever slow flow causes in-

creased oxygen extraction and a deepening of the color of

venous blood.3, 4 Although this model has been difficult to

confirm, it does provide a convenient framework for under-

standing the LR seen with atherosclerosis and the vasculit-

ides, as well as that occurring with vascular occlusions from

cryoglobulinemia, disseminated intravascular coagulation,

thrombocytosis, polycythemia, cholesterol embolization,

decompression sickness, and hypercoagulable states, partic-

ularly the antiphospholipid syndrome.3

Mottling occurring with extremes of temperature also is

likely related to disturbances in cutaneous blood flow. Ex-amples of this kind of mottling include heat-induced ery-

thema 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 autoim-

mune phenomena. Infections such as endocarditis, syphilis,

and tuberculosis have all been associated with LR. Immune-

complex deposition may be involved.3 LR has been reported

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

0002-9343/$ -see front matter 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.amjmed.2006.03.026

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

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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 Cush-

ings 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, physi-

cal examination, and judicious laboratory testing for sus-pected systemic conditions. A reasonable screening profile

would include a CBC with platelet count; blood chemistry

studies; tests for cryoproteins and antinuclear antibodies;

and a coagulation profile 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 (dopa-

mine, epinephrine, norepinephrine), diphenhydramine, and

minocycline can be associated with LR. Quinidine can

cause LR directly or as part of a lupus-like reaction. Mech-

anisms are poorly understood but frequently involve auto-immune phenomena.3,7,8

Use of amantadine for Parkinsons disease is compli-

cated 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 cat-

echolamines 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

MANAGEMENTUnlike most cases of LR due to systemic disease, amanta-

dine-induced LR is reversible. Our patients problem re-

solved completely within 6 weeks of stopping treatment.

Some patients do elect to continue treatment with amanta-

dine, finding that the therapeutic benefits outweigh the an-

noying but usually harmless consequences of continued

use.1

References1. Sladden MJ, Nicolaou N, Johnston GA, Hutchison PE. Livedo reticu-

laris 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 re-

ticularis in the setting of chronic pancreatitis. J Am Acad Dermatol.

1998;39:1035-1036.

6. Marconi V, Mofid 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 diphen-

hydramine associated with pyrithyldione. Dermatology. 1996;193:50-

51.8. Elkayam O, Yaron M, Caspi D. Minocycline-induced arthritis associ-

ated with fever, livedo reticularis, and pANCA. Ann Rheum Dis. 1996;

55:769-771.

9. Lexi-Comp Online. Lexi-Comp, Inc, Hudson, Ohio.

Figure: An eruption like this can stem from any of several

causes.

578 The American Journal of Medicine, Vol 119, No 7, July 2006