Clinical and Experimental Dermatology (1986) 11, 173-178.

Clofazimine—an eflFective treatment forMelkersson-Rosenthal syndrome or Miescher's cheilitis

P.PODMORE AND D.BURROWS

Skin Department, Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland

Accepted for publication 3 July 1985

Summary

Three cases of histological proven Miescher's granulomatous cheilitis and one case of

Melkersson-Rosenthal syndrome were treated over a 4-month period. All cases showed

histological improvement with clearance of granulomata but persistence of oedema. No side-

effects were reported. Biopsy changes in al! four cases are presented.

Melkersson-Rosenthal syndrome (MR) is a rare condition which was initially described in 1928

hy Melkersson who detected a relationship between facial palsy and swelling of the face. The

triad is completed by lingua plicata which was described by Rosenthal in 1931. Cases have been

reported and the condition reviewed by Graff-Radford, (1981); Azaz and Nitzan, (1984);

Wadlington, Riley and Lowbeer (1984).

Miescher's granulomatous cheilitis, in which there is only swclhng of one of both lips, isaccepted as an oligosymptomatic form of MR (Graff-Radford, 1981; Worsaae et aL, 1982;Wadlington et aL, 1984).

Infection, bacterial or viral, allergic response, basal arachnoiditis and vasomotor disturbance

ofthe vasa vasorum ofthe facial nerve are among the many postulated but unproven aetiologies

of this condition. As 6",> ofthe sufferers give a positive family history of MR, inheritance may be

a factor (Graff-Radford, 1981).

Clinically there is swelling of the lip, usually the upper lip, and it is initially fluctuant.

Eventually there is permanent bilateral or unilateral swelling with fissuring ofthe surface and

reddish-brown discoloration. Other areas ofthe face may swell—check, lower lip, nose, eyelids

and alveolar process, in that order of frequency (Graff-Radford, 1981; Worsaae et aL, 1982;

Wadlington et al., 1984). The facial palsy may precede the lip swelling and may be unilateral or

Correspondence: P.Podmore, Skin Department, Royal Victoria Hospital, Belfast BT12 6BA, NorthernIreland.

173

174 P.Podmore and D.Burrows

bilateral, partial or complete, but is ofthe lower motor neurone type and resolves completely.Lingua plicata or fissured tongue is a variable finding which only occurs in 20-40" „ of cases(Graff-Radford, 1981; Worsaae et aL, 1982). Swelling of the tongue itself causes tastedisturbance. There may be decreased salivary, lacrimal and nasal gland secretion. Systemicsymptoms such as fever, migraine, headache and visual disturbance are rare but may occur(Graff-Radford, 1981; Worsaae et aL, 1982). The condition may start at any age but shows apeak in the second decade and has an equal sex incidence (Worsaae et aL, 1982).

Histologically, granulomatous changes are seen around the vessels in the lamina propria andmuscle. The inflammatory infiltrate may be non-specific or there may be Langhan's giant cellswith sarcoidal or tuberculoid granulomas present (Worsaae et aL, 1982; Wadlington et aL,1984).

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Clofazimine 175

The condition usually follows a relentless course of fluctuant swelling progressing topermanent distortion ofthe normal anatomical architecture ofthe face. Spontaneous recoverymay occur but relapse can also occur many years after the condition has cleared (Worsaae et al.,1982; Wadlington et al., 1984).

Neuhofer and Fritsch (1984) described seven cases who were treated with clofazimine(Lamprene) in a dosage of 100 mg daily for 10 days, then 200-400 mg weekly. Ofthe seven cases,three had the complete triad and four the cheilitis only. There was an excellent initial responseafter 2 weeks in those patients in whom the swelling was still fluctuant, but in those cases withpersistent swelling the response was slower, continuing for up to 3 months. Three cases relapsedon discontinuing treatment, but responded on re-introduction of clofazimine. The duration oftreatment was 5-7 months.

Materials and methods

Three patients with biopsy proven Miescher's cheilitis and one patient with MR were treatedaccording to the above dosage regime. They were reviewed monthly, full blood count and liverfunction tests were checked and clinical photographs taken to assess progress. Any untowardeffects were recorded and repeat biopsies were carried out after 4 months. Case histories aregiven in Table i.

Results

In Case number i, treatment was stopped following a bout of nausea and vomiting with aresultant recurrence of swelling i month later. Recommencement of therapy had a similar goodtherapeutic response with no recurrence of nausea and vomiting. Case number 2, a fit, activeyoung man during the summer months, developed a reddish-brown skin pigmentation whichfaded when clofazimine was stopped at the end of his course. Although it was difficult todemonstrate muscle weakness Case number 4 had subjective right-sided facial weakness whichdid not improve during her course of treatment. She also complained or persistent numbness onthe right side of her upper lip. This symptomatology led to investigations to exclude thepresence of an acoustic neuroma; these were all normal.

All four patients have not taken clofazimine for approximately 6 months and have shown noclinical deterioration.

Discussion

Four cases of biopsy proven MR treated with clofazimine are presented. Three of these cases aremore correctly termed Miescher's cheilitis, the oligosymptomatic form of the Melkersson-Rosenthal syndrome. Crohn's disease and MR may have very similar histological and clinicalfeatures. However, in their study of the patients with MR, Worsaae and colleagues (1980)showed that there were no clinical, radiological or biochemical findings to substantiate such arelationship, and they therefore felt that in the absence of symptoms, extensive investigationsfor Crohn's disease were not indicated in MR patients. Previous treatments for MR have

176 P.Podmore and D.Burrows

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Clofazimine 177

including long-term antibiotic, antifungal and anti-inflammatory drugs, orat and intralesionalsteroids and surgical filleting, with little therapeutic effect (Azaz & Nitzan, 1984).

Clofazimine is a phenazine iminoquinone derivative which is metabolized to a red dye-stuffwith oxygen. It is taken up by the reticulo-endothelial system and fatty tissue on prolongedadministration which results in accumulation and produces the reddish-brown pigmentationnoted with patient number 2. This effect is dose-related and is increased by ultraviolet lightexposure. The mechanism of action of clofazimine is not fully known but is thought to be relatedto its ability to stimulate phagocytosis (Neuhofer & Fritsch, 1984). In the original paper, allseven patients (three with complete MR four with Miescher's cheilitis) benefited fromtreatment with clofazimine, particularly if the swelling was still fluctuant. At this stage theswelling was essentially oedema and this showed rapid clearance after 2 weeks. As the conditionprogressed the swelling became more permanent with histological granuloma formation. At thisstage (four patients) response was slow and incomplete over a period of 3 months. Ondiscontinuing treatment, four patients remained clear over a time period of 5-45 months, butthree relapsed between 3 and 18 months. These three patients responded to a second course ofclofazimine.

Clofazimine has also proved effective in the treatment of pyoderma gangrenosum, discoidlupus erythematosis, leprosy and pustular psoriasis, in which the mechanism of action may alsobe due to enhanced macrophage phagocytosis (Sarracent & Finlay, 1982). It is a relatively safedrug if used in short courses and in low dosages. The only notable side-effect, at this low dose-range, being the red discoloration of the skin. However, there have been reports of splenicinfarction and tissue accumulation of crystals at high prolonged dosage levels, such as300-400 mg daily over several months (Ohman, 1975). Similarly, at this dosage level, somepatients developed reversible corneal pigmentation.

There have been some reports of more serious side-effects; eosinophilic enteritis after 3 yearsof clofazimine at 600 mg daily (Mason, EUis-Pegler & Arthur, 1977), and at autopsy, severeenteritis with a striking colour change in the skin and internal organs at 300 mg daily for4 months (Desikan, Ramanauyan & Balakrishar, 1975). In the latter case death was thought tohave been due to adrenal failure following rapid amyloid deposition in the adrenal glands. Tworeports from India have described nine leprosy patients on clofazimine who developedgastrointestinal symptoms and hypocalaemia. Seven of these patients died but their deaths werenot directly related to clofazimine therapy (Personal Communication, Fr Ahmed, Ciba Geigy).

We conclude that in our experience of four cases of this rare syndrome, clofazimine, in lowdosage and in the absence of gastrointestinal symptoms, appears to be a relatively safe,therapeutically effective drug.

Acknowledgments

We thank Mr T.G.Emerson and Mr T.Swinson who performed the biopsies, ProfessorF.O'Brien who advised on pathology, and Dr R.Fulton who allowed us to treat his patient.

References

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178 P.Podmore and D.Burrows

DESIKAN, K.V., RAMUNUJAM, G . R . & BALAKRISHAN, S. (1975) Autopsy findings in a case of lepromatousteprosy treated with clofazimine. Leprosy Review, 46, 181-189.

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Reveiw, 48, 175-180.NEUHOFER, J. & FRITSCH, P. (1984) Cheititis granulomatosa: therapy with clofazimine. Hautarzt, 35,459-

463OHMAN, L . (1975) Ocutar side-effects of ctofazimine. Lancet, ii, 933-934-SARRACENT, J. & FINLAY, C M . (1982) The action of clofazimine on the level of tysosomal enzymes of

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