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Observation | ONLINE FIRST

Successful Long-term Use of Oral Isotretinoin for the Management of Morbihan Disease:  A Case Series Report and Review of the Literature FREE

Lauren A. Smith, MD; David E. Cohen, MD, MPH
[+] Author Affiliations

Author Affiliations: Department of Dermatology, New York University Langone Medical Center, New York, New York.


Arch Dermatol. 2012;148(12):1395-1398. doi:10.1001/archdermatol.2012.3109.
Text Size: A A A
Published online

ABSTRACT

Background Morbihan disease (MD) is characterized by persistent erythema and solid edema of the upper two-thirds of the face. It is generally regarded as a late-stage complication of rosacea, although its etiology is poorly understood. The standard therapeutic management includes systemic anti-inflammatory medications; however, the clinical response, if any, is often unsatisfactory. We review the current challenges and a promising new option for the treatment of MD.

Observations Five cases of MD were treated with long-term (>6 months; mean, 16 months) oral isotretinoin, with documented nonrecurrence. The mean sustained daily dose was 60 mg/d (range, 40-80 mg/d), and the mean cumulative dose was approximately 285 mg/kg (range, 170-491 mg/kg). The total treatment period ranged from 10 to 24 months, with a mean disease-free follow-up period of 9 months (range, 1-24 months). A substantial clinical improvement was not noted until 6 months of treatment in all 5 cases.

Conclusions We report 5 cases of MD that were successfully treated with long-term oral isotretinoin, with lasting results. Further research is required to better understand the pathogenesis of MD and isotretinoin's mechanism of action in this condition.

Figures in this Article

Since its first description by French dermatologist Robert Degos in 1957, Morbihan disease (MD) has remained an ambiguous entity with respect to its etiology and clinical manifestations. The word Morbihan references the French district where the condition was first reported; however, MD has gone by several other names, including rosaceous lymphedema, solid persistent facial edema, and morbus Morbihan.13 We report 5 cases of MD that were successfully treated with long-term oral isotretinoin therapy along with a literature review of current options for the treatment of MD.

CLINICAL FEATURES, DIFFERENTIAL DIAGNOSIS, AND HISTOPATHOLOGIC FINDINGS

Morbihan disease is characterized by persistent erythema and solid edema of the upper two-thirds of the face.4 Clinical examination typically reveals firm, nonpitting edema and erythema, particularly of the forehead, glabella, eyelids, nose, and cheeks.112 Facial erythema has been described as ill-defined or discrete patches or as solitary plaques.2,3,57,13 Pitting edema may be evident in its early stages; however, it is believed that fibrotic induration due to recurrent inflammation gives way to the solid edema that is typical of MD.1,3 Subjective symptoms are normally minimal; however, patients with severe periorbital edema may develop disfigurement of facial contours, with subsequent visual field narrowing.1,3,4

Morbihan disease is generally regarded as a late-stage complication of rosacea; however, documented reports of MD as an initial presentation of rosacea complicates its classification as a distinct entity or adverse outcome.3,10,1316 Nevertheless, MD remains a diagnosis of exclusion and necessitates the omission of other conditions with a similar clinical presentation.3 The differential diagnosis is varied and includes congenital, inflammatory, infectious, and neoplastic diseases.13,15 Melkersson-Rosenthal syndrome, systemic lupus erythematosus, dermatomyositis, sarcoidosis, chronic actinic dermatitis, and chronic contact dermatitis are most frequently considered in the differential diagnosis.3

Unfortunately, skin biopsies are not routinely performed in these cases, and biopsy specimens are usually obtained when other possible diagnoses are being considered. As a result, our knowledge of MD's histopathologic findings are limited, and the findings reported in the literature are rather vague. Features include dilated blood vessels, perifollicular fibrosis, perivascular and perifollicular infiltration of lymphocytes, and, rarely, an increased number of mast cells.1,3,4,13 Also, Nagasaka et al2 reported dilated and damaged lymphatic vessels with adjacent epithelioid cell granulomas and lymphatic obstruction via histocytic infiltration.

PATHOGENESIS

The clinical manifestations of MD appear to result from an imbalance between lymphatic production and drainage. Although the exact pathogenesis of MD remains poorly understood, there is a strong suggestion of an association between MD and rosacea in the existing literature.68,10,12

Morbihan disease is likely a manifestation of downstream effects from rosacea's recurrent episodes of vascular dilation and inflammation.17 In this setting, byproducts of acute and chronic inflammation eventually give rise to tissue remodeling and structural damage of both blood and lymphatic vessels.14 This vessel damage is of particular concern among individuals with frequent rosacea exacerbations, who may be susceptible to subsequent lymphatic pooling and impaired drainage.1,3,4,18 The mechanisms for lymphatic vessel destruction may vary by inflammatory trigger, which likely accounts for the variation in histologic findings.2

The stark contrast in incidence between rosacea and MD raises questions regarding the underlying factors promoting the development of MD. Wohlrab et al3 reported a preexisting lymphatic drainage defect in the affected skin of patients with MD through ultrasonography and laser Doppler flowmetry. While their findings suggest a possible cause, there is no way to ascertain whether this insufficiency preceded the diagnosis of rosacea.

TREATMENT

Reported systemic therapy for the treatment of MD includes anti-inflammatory drugs such as systemic corticosteroids, oral antibiotics, thalidomide, and antihistamines,1012,19 which generally overlap with the management of rosacea.11,13 These agents have been used alone or in combination. At best, they are associated with a reduction of facial erythema; however, more often than not, the clinical response is partial and short-lived. Generally, little to no improvement in facial edema is noted with the use of pharmacological agents, leading many clinicians to pursue more invasive, yet also unreliable, treatments such as blepharoplasty, carbon dioxide laser, and local injections.6,10,11,13,20,21

There are fewer than a handful of publications documenting the use of oral isotretinoin for the treatment of MD, which was first described by Jansen and Plewig22 in 1997; however, all publications report its use in combination with oral corticosteroids or antihistamines, and treatment duration has varied from 6 to 16 weeks, with daily dosing between 10 and 50 mg.5,10,22 Also, these treatment regimens were marked by incomplete or transient improvements in clinical findings6,10,22,23; yet the notable improvement in both facial erythema and edema was indicative of oral isotretinoin as a promising therapeutic option compared with other pharmacological agents. It is possible that the conservative dosing and brief treatment duration documented in these reports contributed to the partial success of isotretinoin therapy for MD.6,10,2224

REPORT OF CASES

A total of 5 patients (3 women, 2 men) with MD were treated with long-term (>6 months; mean, 16 months) oral isotretinoin at our institution, with documented nonrecurrence. All patients' relevant clinical characteristics are listed in the Table. The mean sustained daily dose was 60 mg/d (range, 40-80 mg/d), and the mean cumulative dose was approximately 285 mg/kg (range, 170-491 mg/kg). The total treatment period ranged from 10 to 24 months, with a mean disease-free follow-up period of 9 months (range, 1-24 months). A substantial clinical improvement was not noted until 6 months of treatment in all 5 cases. Representative clinical pictures of the response to oral isotretinoin therapy are shown in the Figure.

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Clinical response of Morbihan disease to oral isotretinoin therapy. Erythema and edema of the eyelids, glabella, nose, and cheeks (A and B) were followed by complete resolution after 12 months of oral isotretinoin therapy (C and D).

COMMENT

To date, pharmacological treatment options mostly involve systemic immunomodulators such as corticosteroids, antibiotics, and antihistamines1012; however, the clinical response with these therapies has largely been inadequate. There have been reports of more invasive interventions, including surgical reduction, carbon dioxide laser blepharoplasty, and radiography, with unpredictable outcomes.4,6,20,21 To our knowledge, this is the first case series to report the effective use of long-term oral isotretinoin for the treatment of MD with complete and lasting results.

Insight into isotretinoin's mechanism of action is limited by the undefined pathogenesis of MD. Conceivably, MD may respond to the same immunomodulatory and anti-inflammatory properties that make oral isotretinoin useful for the management of rosacea.23,2528 There is also evidence to support isotretinoin's role in the repair of structural tissue damage via alterations in cellular metabolism and its ability to inhibit fibroblast proliferation as well as the migration and proliferation of connective tissue constituents.29 As a result, isotretinoin therapy may alter the downstream effects of chronic inflammation that would otherwise result in damage to the dermal matrix.29

We treated patients with a daily dose ranging from 40 to 80 mg/d for up to 24 months (range, 9-24 months). In contrast, previous reports documenting the use of oral isotretinoin for the treatment of MD recommend doses ranging from 10 to 50 mg/d for 4 to 6 weeks, both of which are substantially lower than those that were found to be effective in our patients. The effective treatment dose in our sample appeared to be somewhat dependent on body weight, with patients who weighed more than 70 kg requiring a daily dose of 80 mg and those who weighed between 50 and 60 kg requiring 40 to 60 mg/d. All 5 patients were given a starting dose of 20 mg/d, which was titrated up until a clinical response was observed. Adverse effects, which were limited to dry lips, joint pain, and hyperlipidemia, were mild and easily managed. Clinical improvements in facial erythema and edema were noted within 4 to 6 weeks of treatment initiation, as documented in the existing literature; however, the most substantial effects were observed after 6 months of therapy. Isotretinoin therapy was continued until facial erythema and edema had completely resolved (10 to 24 months). All 5 patients described in our case series have completed therapy, with no documented disease recurrence.

Morbihan disease has long been considered a refractory condition with discouraging treatment options. The use of long-term oral isotretinoin, a treatment regimen not previously described (to our knowledge), is a promising alternative. Adverse events were minimal and easily managed; however, patients should be closely monitored given the safety profile of oral isotretinoin. Further research is required to better understand the pathogenesis of MD and isotretinoin's mechanism of action in this condition.

ARTICLE INFORMATION

Correspondence: Lauren A. Smith, MD, Department of Dermatology, New York University Langone Medical Center, 550 First Ave, New York, NY 10016 (Lauren.Smith@nyumc.org).

Accepted for Publication: July 1, 2012.

Published Online: November 19, 2012. doi:10.1001/archdermatol.2012.3109

Author Contributions: Both authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Smith and Cohen. Acquisition of data: Smith. Analysis and interpretation of data: Smith and Cohen. Drafting of the manuscript: Smith. Critical revision of the manuscript for important intellectual content: Smith and Cohen. Administrative, technical, or material support: Smith and Cohen. Study supervision: Cohen.

Conflict of Interest Disclosures: Dr Cohen has served as a consultant to and has received honoraria from Galderma.

Additional Contributions: Taylor DeFelice, MD, assisted with patient record collection.

REFERENCES

Morales-Burgos A, Alvarez Del Manzano G, Sánchez JL, Cruz CL. Persistent eyelid swelling in a patient with rosacea.  P R Health Sci J. 2009;28(1):80-82
PubMed
Nagasaka T, Koyama T, Matsumura K, Chen KR. Persistent lymphoedema in Morbihan disease: formation of perilymphatic epithelioid cell granulomas as a possible pathogenesis.  Clin Exp Dermatol. 2008;33(6):764-767
PubMed   |  Link to Article
Wohlrab J, Lueftl M, Marsch WC. Persistent erythema and edema of the midthird and upper aspect of the face (morbus morbihan): evidence of hidden immunologic contact urticaria and impaired lymphatic drainage.  J Am Acad Dermatol. 2005;52(4):595-602
PubMed   |  Link to Article
Lamparter J, Kottler U, Cursiefen C, Pfeiffer N, Pitz S. Morbus Morbihan: a rare cause of edematous swelling of the eyelids [in German].  Ophthalmologe. 2010;107(6):553-557
PubMed   |  Link to Article
Batra M, Bansal C, Tulsyan S. Granulomatous rosacea: unusual presentation as solitary plaque.  Dermatol Online J. 2011;17(2):9
PubMed
Bechara FG, Jansen T, Losch R, Altmeyer P, Hoffmann K. Morbihan's disease: treatment with CO2 laser blepharoplasty.  J Dermatol. 2004;31(2):113-115
PubMed
Hölzle E, Jansen T, Plewig G. Morbihan disease—chronic persistent erythema and edema of the face [in German].  Hautarzt. 1995;46(11):796-798
PubMed   |  Link to Article
Jansen T, Regele D, Schirren CG, Trautner B, Plewig G. Persistent erythema and edema of the face associated with rosacea and lymph vessel dysplasia [In German].  Hautarzt. 1998;49(12):932-935
PubMed   |  Link to Article
Laugier P, Gilardi S. Chronic erythematous oedema of the upper face (Degos): Morbihan disease (author's transl) [in French].  Ann Dermatol Venereol. 1981;108(6-7):507-513
PubMed
Mazzatenta C, Giorgino G, Rubegni P, de Aloe G, Fimiani M. Solid persistent facial oedema (Morbihan's disease) following rosacea, successfully treated with isotretinoin and ketotifen.  Br J Dermatol. 1997;137(6):1020-1021
PubMed   |  Link to Article
Ranu H, Lee J, Hee TH. Therapeutic hotline: successful treatment of Morbihan's disease with oral prednisolone and doxycycline.  Dermatol Ther. 2010;23(6):682-685
PubMed   |  Link to Article
Renieri G, Brochhausen C, Pfeiffer N, Pitz S. Chronic eyelid oedema and rosacea (Morbus Morbihan): diagnostic and therapeutic challenges [in German].  Klin Monbl Augenheilkd. 2011;228(1):19-24
PubMed   |  Link to Article
Romiti N. Morbus Morbihan: solid and persistent facial edema and erythema [in Portuguese].  An Bras Dermatol. 2000;75(5):599-603
Chen DM, Crosby DL. Periorbital edema as an initial presentation of rosacea.  J Am Acad Dermatol. 1997;37(2, pt 2):346-348
PubMed   |  Link to Article
Harvey DT, Fenske NA, Glass LF. Rosaceous lymphedema: a rare variant of a common disorder.  Cutis. 1998;61(6):321-324
PubMed
Scerri L, Saihan EM. Persistent facial swelling in a patient with rosacea: rosacea lymphedema.  Arch Dermatol. 1995;131(9):1071- 1074
PubMed   |  Link to Article
Crawford GH, Pelle MT, James WD. Rosacea, I: etiology, pathogenesis, and subtype classification.  J Am Acad Dermatol. 2004;51(3):327-344
PubMed   |  Link to Article
Sugaya M, Kuwano Y, Suga H,  et al.  Lymphatic dysfunction impairs antigen-specific immunization, but augments tissue swelling following contact with allergens.  J Invest Dermatol. 2012;132(3, pt 1):677-676
PubMed   |  Link to Article
Lai TF, Leibovitch I, James C, Huilgol SC, Selva D. Rosacea lymphoedema of the eyelid.  Acta Ophthalmol Scand. 2004;82(6):765-767
PubMed   |  Link to Article
Marzano AV, Vezzoli P, Alessi E. Elephantoid oedema of the eyelids.  J Eur Acad Dermatol Venereol. 2004;18(4):459-462
PubMed   |  Link to Article
Bernardini FP, Kersten RC, Khouri LM, Moin M, Kulwin DR, Mutasim DF. Chronic eyelid lymphedema and acne rosacea: report of two cases.  Ophthalmology. 2000;107(12):2220-2223
PubMed   |  Link to Article
Jansen T, Plewig G. The treatment of rosaceous lymphoedema.  Clin Exp Dermatol. 1997;22(1):57
PubMed
Nikolowski J, Plewig G. Rosacea: oral therapy with 13-cis retinoic acid [in German].  Hautarzt. 1980;31(12):660-661
PubMed
Jungfer B, Jansen T, Przybilla B, Plewig G. Solid persistent facial edema of acne: successful treatment with isotretinoin and ketotifen.  Dermatology. 1993;187(1):34-37
PubMed   |  Link to Article
Korting HC, Schöllmann C. Current topical and systemic approaches to treatment of rosacea.  J Eur Acad Dermatol Venereol. 2009;23(8):876-882
PubMed   |  Link to Article
Plewig G, Nikolowski J, Wolff HH. Action of isotretinoin in acne rosacea and gram-negative folliculitis.  J Am Acad Dermatol. 1982;6(4, pt 2):(suppl)  766-785
PubMed   |  Link to Article
Webster GF. Rosacea: pathogenesis and therapy.  G Ital Dermatol Venereol. 2011;146(3):235-241
PubMed
Gollnick H, Blume-Peytavi U, Szabó EL,  et al.  Systemic isotretinoin in the treatment of rosacea—doxycycline- and placebo-controlled, randomized clinical study.  J Dtsch Dermatol Ges. 2010;8(7):505-515
PubMed
Hein R, Mensing H, Müller PK, Braun-Falco O, Krieg T. Effect of vitamin A and its derivatives on collagen production and chemotactic response of fibroblasts.  Br J Dermatol. 1984;111(1):37-44
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Clinical response of Morbihan disease to oral isotretinoin therapy. Erythema and edema of the eyelids, glabella, nose, and cheeks (A and B) were followed by complete resolution after 12 months of oral isotretinoin therapy (C and D).

Tables

References

Morales-Burgos A, Alvarez Del Manzano G, Sánchez JL, Cruz CL. Persistent eyelid swelling in a patient with rosacea.  P R Health Sci J. 2009;28(1):80-82
PubMed
Nagasaka T, Koyama T, Matsumura K, Chen KR. Persistent lymphoedema in Morbihan disease: formation of perilymphatic epithelioid cell granulomas as a possible pathogenesis.  Clin Exp Dermatol. 2008;33(6):764-767
PubMed   |  Link to Article
Wohlrab J, Lueftl M, Marsch WC. Persistent erythema and edema of the midthird and upper aspect of the face (morbus morbihan): evidence of hidden immunologic contact urticaria and impaired lymphatic drainage.  J Am Acad Dermatol. 2005;52(4):595-602
PubMed   |  Link to Article
Lamparter J, Kottler U, Cursiefen C, Pfeiffer N, Pitz S. Morbus Morbihan: a rare cause of edematous swelling of the eyelids [in German].  Ophthalmologe. 2010;107(6):553-557
PubMed   |  Link to Article
Batra M, Bansal C, Tulsyan S. Granulomatous rosacea: unusual presentation as solitary plaque.  Dermatol Online J. 2011;17(2):9
PubMed
Bechara FG, Jansen T, Losch R, Altmeyer P, Hoffmann K. Morbihan's disease: treatment with CO2 laser blepharoplasty.  J Dermatol. 2004;31(2):113-115
PubMed
Hölzle E, Jansen T, Plewig G. Morbihan disease—chronic persistent erythema and edema of the face [in German].  Hautarzt. 1995;46(11):796-798
PubMed   |  Link to Article
Jansen T, Regele D, Schirren CG, Trautner B, Plewig G. Persistent erythema and edema of the face associated with rosacea and lymph vessel dysplasia [In German].  Hautarzt. 1998;49(12):932-935
PubMed   |  Link to Article
Laugier P, Gilardi S. Chronic erythematous oedema of the upper face (Degos): Morbihan disease (author's transl) [in French].  Ann Dermatol Venereol. 1981;108(6-7):507-513
PubMed
Mazzatenta C, Giorgino G, Rubegni P, de Aloe G, Fimiani M. Solid persistent facial oedema (Morbihan's disease) following rosacea, successfully treated with isotretinoin and ketotifen.  Br J Dermatol. 1997;137(6):1020-1021
PubMed   |  Link to Article
Ranu H, Lee J, Hee TH. Therapeutic hotline: successful treatment of Morbihan's disease with oral prednisolone and doxycycline.  Dermatol Ther. 2010;23(6):682-685
PubMed   |  Link to Article
Renieri G, Brochhausen C, Pfeiffer N, Pitz S. Chronic eyelid oedema and rosacea (Morbus Morbihan): diagnostic and therapeutic challenges [in German].  Klin Monbl Augenheilkd. 2011;228(1):19-24
PubMed   |  Link to Article
Romiti N. Morbus Morbihan: solid and persistent facial edema and erythema [in Portuguese].  An Bras Dermatol. 2000;75(5):599-603
Chen DM, Crosby DL. Periorbital edema as an initial presentation of rosacea.  J Am Acad Dermatol. 1997;37(2, pt 2):346-348
PubMed   |  Link to Article
Harvey DT, Fenske NA, Glass LF. Rosaceous lymphedema: a rare variant of a common disorder.  Cutis. 1998;61(6):321-324
PubMed
Scerri L, Saihan EM. Persistent facial swelling in a patient with rosacea: rosacea lymphedema.  Arch Dermatol. 1995;131(9):1071- 1074
PubMed   |  Link to Article
Crawford GH, Pelle MT, James WD. Rosacea, I: etiology, pathogenesis, and subtype classification.  J Am Acad Dermatol. 2004;51(3):327-344
PubMed   |  Link to Article
Sugaya M, Kuwano Y, Suga H,  et al.  Lymphatic dysfunction impairs antigen-specific immunization, but augments tissue swelling following contact with allergens.  J Invest Dermatol. 2012;132(3, pt 1):677-676
PubMed   |  Link to Article
Lai TF, Leibovitch I, James C, Huilgol SC, Selva D. Rosacea lymphoedema of the eyelid.  Acta Ophthalmol Scand. 2004;82(6):765-767
PubMed   |  Link to Article
Marzano AV, Vezzoli P, Alessi E. Elephantoid oedema of the eyelids.  J Eur Acad Dermatol Venereol. 2004;18(4):459-462
PubMed   |  Link to Article
Bernardini FP, Kersten RC, Khouri LM, Moin M, Kulwin DR, Mutasim DF. Chronic eyelid lymphedema and acne rosacea: report of two cases.  Ophthalmology. 2000;107(12):2220-2223
PubMed   |  Link to Article
Jansen T, Plewig G. The treatment of rosaceous lymphoedema.  Clin Exp Dermatol. 1997;22(1):57
PubMed
Nikolowski J, Plewig G. Rosacea: oral therapy with 13-cis retinoic acid [in German].  Hautarzt. 1980;31(12):660-661
PubMed
Jungfer B, Jansen T, Przybilla B, Plewig G. Solid persistent facial edema of acne: successful treatment with isotretinoin and ketotifen.  Dermatology. 1993;187(1):34-37
PubMed   |  Link to Article
Korting HC, Schöllmann C. Current topical and systemic approaches to treatment of rosacea.  J Eur Acad Dermatol Venereol. 2009;23(8):876-882
PubMed   |  Link to Article
Plewig G, Nikolowski J, Wolff HH. Action of isotretinoin in acne rosacea and gram-negative folliculitis.  J Am Acad Dermatol. 1982;6(4, pt 2):(suppl)  766-785
PubMed   |  Link to Article
Webster GF. Rosacea: pathogenesis and therapy.  G Ital Dermatol Venereol. 2011;146(3):235-241
PubMed
Gollnick H, Blume-Peytavi U, Szabó EL,  et al.  Systemic isotretinoin in the treatment of rosacea—doxycycline- and placebo-controlled, randomized clinical study.  J Dtsch Dermatol Ges. 2010;8(7):505-515
PubMed
Hein R, Mensing H, Müller PK, Braun-Falco O, Krieg T. Effect of vitamin A and its derivatives on collagen production and chemotactic response of fibroblasts.  Br J Dermatol. 1984;111(1):37-44
PubMed   |  Link to Article

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