Melkersson-Rosenthal Syndrome in Neuro-ophthalmology

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Article initiated by:
Andrew Go Lee, MD, Evan Wotipka, MD, Harrison D. Marsh, MD, Kais M. Karowadia, Nagham Al-Zubidi, MD, Noor Laylani, M.D., Pamela Davila-Siliezar, MD
All contributors:
Andrew Go Lee, MD, Evan Wotipka, MD, Harrison D. Marsh, MD, Kais M. Karowadia, Nagham Al-Zubidi, MD, Pamela Davila-Siliezar, MD, Nagham Al-Zubidi, MD, Noor Laylani, M.D.
Assigned editor:
Osama Al Deyabat, MBBS
Review:
Assigned status Update Pending
 by Osama Al Deyabat, MBBS on August 18, 2022.


Disease Entity

Melkersson-Rosenthal Syndrome (MRS) is a rare disorder, involving non-caseating chronic granulomatous neurocutaneous disease.[1] This syndrome belongs to a group of conditions that have clinical and pathological similarities called “orofacial granulomatosis,” which, as the name suggests, display oral and lip edema with granulomatous inflammation on biopsy.[2] Some researchers suggest that this syndrome is actually only a manifestation of the other diseases in the group, particularly sarcoidosis or Crohn’s disease, rather than it being its own individual disease entity.[2][3] It is characterized by recurrent, long-lasting swelling of the face (edema), particularly of one or both lips (granulomatous cheilitis), facial muscle weakness (palsy) and deep grooves on the tongue (fissured tongue).[1][2]

First Description

The presence of recurrent facial paralysis and edema was first detailed as MRS in 1928 by Dr. Enst Melkersson.[1][4][5] The disease process is eponymous with the first two doctors to describe the clinical manifestations: Dr. Ernst Melkersson and Dr. Curt Rosenthal, who described the plicated tongue (lingua plicata) in 1931. However, several others highlighted disease characteristics around the turn of the 20th century.[4]

Etiology

Its etiology and pathogenesis are still unknown. However, some factors that are thought to be implicated include stress, immunodeficiency, infections, atopy, and genetic factors.[5] Dietary and other allergens have been considered in some cases to be involved in the development of MRS. Some studies have even demonstrated the role of hormonal changes triggering the onset of inflammatory episodes.[6][7][8] However, there are no strong associations explaining what causes MRS. The condition is considered to have autosomal dominant inheritance with the culpable gene at the short arm of the ninth chromosome.[1][3] However, some reports have implicated several genes to be associated with MRS, but the majority of literature demonstrates that this condition is both clinically and genetically variable.[3][9][10] MRS is thought to be associated with underlying disorders including a spectrum of orofacial granulomatosis such as cheilitis granulomatosa, sarcoidosis, or Crohn’s disease.[3][11]

Disease Manifestation

The diagnosis is made if the classical triad of recurrent or persistent orofacial edema, recurrent peripheral facial nerve palsy, and a fissured or plicated tongue (lingua plicata) is present.[1][9][12] Most affected individuals will have only one or two symptoms, while some may present with all three. These manifestations may develop all at once or at different times and the classic triad is seen in only 8-25% of the cases. Thus, cases with a monosymptomatic form of MRS are described as cheilitis granulomatosa.[3][6]

Histopathology

Histopathological features that are characteristic of MRS include non-caseating epithelioid cell granulomas, multinucleated Langerhans-type giant cells, lymphedema, and perivascular mononuclear inflammatory infiltration and fibrosis.[3][5][12] Histopathologic evidence has been suggested to be not necessary. However, biopsy may help to diagnose MRS.[3] Although non-caseous perivascular granulomas can be very important for the diagnosis, the absence of this finding does not rule out the diagnosis of MRS.[12]

Clinical Presentation

MRS is described as recurrent episodes of edema involving several facial features such as the upper lip, lower lip, one or both cheeks, eyelids, or less commonly, one side of the scalp. It is also characterized by recurrent muscle weakness or facial palsy and deep grooves, cracks, or fissures in the tongue.

MRS can affect people of all ages and some literature suggests that MRS seems to have a clear female predominance affecting significantly more females than males.[2][10][13][14] A retrospective review showed the mean age at presentation to be 39 years with a range of 8-79 years old.[2][6][9][10] The symptoms frequently begin in young adulthood, but also occur well into adulthood. MRS is estimated to occur in 0.08% of the general population and is most frequently seen in the second or third decade of life.[1][3][10][12]

The most common feature is the orofacial edema and has been documented to occur in 80-100% of reported cases.[1][5][10] It is often considered the characteristic symptom of MRS. It may be the first or only symptom that initially occurs and could resolve in a matter of hours or days. The orofacial edema most commonly is unilateral, nonpainful, non-pitting, and involves the upper lip. It is unusual for the edema to involve the palate, tongue, pharynx, larynx, cheek, and periorbital region. Early in the disease the edema tends to appear more intermittently but can shift to a continuous process later in some cases.[3][11] Clinically, the orofacial edema can appear very similarly to angioedema, but it seems to be much more persistent, it does not appear to respond to antihistamine, and can eventually lead to tissue fibrosis.[3][11][15]

The next most common finding is facial paralysis. This is found in about 50-60% (up to 90% in some studies) of the cases and can be recurrent in 3-11% of them.[1][3][8] Facial paralysis seems to develop several years before or after the orofacial edema.[8][12] It most commonly occurs after the first few episodes of edema. However, it can sometimes be the first and only symptom and in 13-50% of affected individuals, facial palsy is associated with facial edema.[9] This weakness in the face or facial paralysis can be both unilateral or bilateral and can initially resolve or become permanent. The duration of the facial palsy seems to increase as the disease progresses.[8][12] If a child presents with recurrent facial palsy, MRS should be considered since this can occur in about 10% of those diagnosed with MRS.[9][16]

The least common finding of the triad is a fissured tongue. It is present in 30-35% of the cases and may be present at birth.[1][3][16] Therefore, an isolated finding of a fissured tongue cannot be used to diagnose MRS. Despite the other components of the triad, fissured tongue is also present in the normal population at 5%. Fissures in the tongue are described as grooves measuring about 2mm (0.07 in) deep and 15mm (0.6 in) long.[9][16]

Some additional reported symptoms from people dealing with MRS include headaches, migraines, hearing problems such as tinnitus or deafness, dizziness, dry mouth, facial pain, difficulty swallowing, dry eyes, blurred vision, diarrhea, and excessive tearing.[9] MRS also is associated with inflammatory symptoms such as diverticulitis and uveitis, which supports the consideration that MRS may be a manifestation of Crohn's disease or sarcoidosis by some researchers.[6][17]

Diagnosis

Melkersson-Rosenthal syndrome is diagnosed clinically based on the history and physical exam findings. Although biopsy is not necessarily needed for diagnosis, the presence of one or two symptoms associated with granulomatous cheilitis in the biopsy material is adequate for diagnosis.[5][12][17] Albeit, a clear diagnosis is rare. The presentation of MRS was shown in a retrospective study to occur throughout a person’s lifespan, requiring consistent, long-term observation, to make the diagnosis.[10][14]

Differential diagnosis

MRS has many differential diagnoses that merit being ruled out. The diagnosis of MRS is often missed because of the overlap of clinical symptoms with other more common conditions such as sarcoidosis or Crohn's disease. A multidisciplinary team may be required to do this. Some of the different medical specialties that should be involved to help rule out some of the more common conditions with symptoms overlapping with MRS include ophthalmology, dermatology, immunology, and gastroenterology.

A clinical manifestation of Crohn’s, Orofacial Crohn’s disease, can present with granulomatous lesions of the oral cavity and face. However, sarcoidosis can also present with facial granulomatous inflammation. From a histological standpoint, these disorders display mixed perivascular inflammation and dermal edema.[10][14][18] A biopsy of the lips may be necessary to help arrive at the diagnosis and rule out recurrent angioedema, as well as other conditions such as Crohn’s disease, sarcoidosis, cancers, or possible infectious causes.

An important differential diagnosis of MRS is angioedema.[3][14][19] The differential for angioedema with features of recurrent facial paralysis and persistent orofacial edema should include MRS and vice versa. The chronic nature of the orofacial swelling in MRS along with the typically normal complement titers can usually distinguish it from angioedema.[11][20]

When creating a differential diagnosis for recurrent facial palsies, some potential causes to consider are allergic diseases presenting with orofacial edema, hypothyroidism, dental issues, superior vena cava syndrome, lymphangioma, erysipelas, lymphoma, and herpes simplex labialis.[7][8][15][20] MRS is also commonly misdiagnosed as Bell’s palsy.[20] Bell’s palsy is a condition that causes sudden weakness in the muscles on one side of the face. In most cases, the weakness is temporary and significantly improves over weeks. However, it does not involve any orofacial swelling which, as mentioned early, occurs in 80-100% of cases of MRS.[1][5][13][20]

Management

Unfortunately, there is no cure for MRS. There is also no current standard of care for management. Nevertheless, treatment in MRS is possible, but recurrences are unavoidable.[5][21] However, spontaneous remission of MRS has also been reported.[16][21] Many of the symptoms of the disease resolve spontaneously and without treatment. However, symptomatic episodes may recur more frequently and for longer durations if no treatment is offered.[2][8][17][21]

Treatment regimens for MRS may begin with nonsteroidal anti-inflammatory agents, corticosteroid injections, antihistamines, and antibiotics.[3][17][21] The most commonly utilized treatment modality are steroids in an attempt to resolve the edema. Notably, intralesional steroid injections have been shown to be just as effective as systemic steroids.[17][21] Other treatment options that have been attempted in MRS including minoxicillin, clofazimine, methotrexate, dapsone, danazol, sulfasalazine, penicillin, tetracycline, and clindamycin.[5][12][16][21] When used together, minoxicillin and clofazimine have been shown to be as effective as steroids when attempting to decrease orofacial edema and granuloma formation.[1][17][18][21] If needed, it also may be appropriate in some cases to treat with a short course of immunosuppressants. Interestingly, due to the many similarities between Crohn's disease and MRS, some physicians have had success managing MRS by utilizing treatments that have exhibited effectiveness in orofacial Crohn's disease, such as Infliximab.[6][17][21] Another procedure that has been attempted is helium-neon laser radiation. This treatment was reported to provide a significant benefit to patients with a disease burden of less than 4 years.[18][22]

Finally, surgery and/or radiation are sometimes the recommended treatment options for refractory symptoms. However, radiotherapy has not been consistently found to be beneficial.[19][21][23] Surgery is usually recommended to help decompress the affected facial nerves when patients are experiencing persistent and recurrent symptoms of facial paralysis. When medical treatment fails, surgical techniques like facial nerve decompression or chelioplasty should be preferred.[5][21][23]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Melek H, Koken R, Bukulmez A. Melkersson-Rosenthal Sendromu: Bir Olgu Sunumu. Guncel Pediatri. 2007;5:82-84.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Jamil RT, Agrawal M, Gharbi A, et al. Cheilitis Granulomatosa. [Updated 2022 Jun 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 Sozener, Z., Ozguclu, S., Aydin, O., Heper, A., Soyyigit, S., & Sin, A. (2014). A Rare Syndrome in the Differential Diagnosis for Angioedema. Journal Of Medical Cases, 5(11), 579-582.
  4. ↑ 4.0 4.1 Scully C, Langdon J, Evans J. Marathon of eponyms: 13 Melkersson-Rosenthal syndrome. Oral Dis. 2010;16(7):707-708. doi:10.1111/j.1601-0825.2009.01545.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Aktar F, Sal E, Acikgoz M. Melkersson-Rosenthal Sendromu: Bir Olgu Sunumu. Van Tip Dergisi. 2011;18:57- 60.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Kakimoto C, Sparks C, White AA. Melkersson-Rosenthal syndrome: a form of pseudoangioedema. Ann Allergy Asthma Immunol. 2007;99(2):185-189.
  7. ↑ 7.0 7.1 McKenna KE, Walsh MY, Burrows D. The Melkersson-Rosenthal syndrome and food additive hypersensitivity. Br J Dermatol 1994;131(6):921-2
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Zimmer WM, Rogers RS 3rd, Reeve CM, Sheridan PJ: Orofacial manifestations of Melkersson-Rosenthal syndrome. A study of 42 patients and review of 220 cases from the literature. Oral Surg Oral Med Oral Pathol 1992; 74(5):610-9.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Sencen, L. (2020, November 19). Melkersson-Rosenthal syndrome. NORD (National Organization for Rare Disorders).
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 Feng S, Yin J, Li J, Song Z, Zhao G. Melkersson-Rosenthal syndrome: a retrospective study of 44 patients. Acta Oto-Laryngologica. 2014;134(9):977-981.
  11. ↑ 11.0 11.1 11.2 11.3 Masson F, Barete S, Fremeaux-Bacchi V, Szpirglas H, Agbo-Godeau S, Chosidow O, Piette JC, et al. Melkersson-Rosenthal syndrome and acquired C1 inhibitor deficiency. Dermatology. 2008;217(2):114-120
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 Senel E, Gulec T. Melkersson-Rosenthal Syndrome. Successfully Treated with Intralesional Corticosteroid; A case Report. Turk J Dermatol. 2009;3:16-18.
  13. ↑ 13.0 13.1 Ozgursoy OB, Karatayli Ozgursoy S, Tulunay O, Kemal O, Akyol A, Dursun G. Melkersson-Rosenthal syndrome revisited as a misdiagnosed disease. Am J Otolaryngol. 2009;30(1):33-37.
  14. ↑ 14.0 14.1 14.2 14.3 Elias MK, Mateen FJ, Weiler CR. The MelkerssonRosenthal syndrome: a retrospective study of biopsied cases. J Neurol. 2013;260(1):138-143
  15. ↑ 15.0 15.1 Cancian M, Giovannini S, Angelini A, et al. Melkersson–Rosenthal syndrome: a case report of a rare disease with overlapping features. Allergy, Asthma & Clinical Immunology. 2019;15(1):1.
  16. ↑ 16.0 16.1 16.2 16.3 16.4 Talabi OA. Melkerssons-Rosenthal syndrome: a case report and review of the literature. Niger J Clin Pract. 2011;14(4):477-478.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 Perez-Calderon R, Gonzalo-Garijo MA, Chaves A, de Argila D. Cheilitis granulomatosa of Melkersson-Rosenthal syndrome: treatment with intralesional corticosteroid injections. Allergol Immunopathol (Madr). 2004;32(1):36- 38.
  18. ↑ 18.0 18.1 18.2 Banks T, Gada S. A comprehensive review of current treatments for granulomatous cheilitis. Br J Dermatol. 2012;166(5):934-937.
  19. ↑ 19.0 19.1 Dutt SN, Mizra S, Irving RM, et al. Total decompression of facial nerve for Melkerrson-Rosenthal syndrome. J Laryngol Otol 2000;114:870-873.
  20. ↑ 20.0 20.1 20.2 20.3 Zewde, Y.Z. Melkersson–Rosenthal syndrome misdiagnosed as recurrent Bell’s palsy: a case report and review of literature. Allergy Asthma Clin Immunol 17, 8 (2021).
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 21.9 Dhawan SR, Saini AG, Singhi PD. Management Strategies of Melkersson-Rosenthal Syndrome: A Review. Int J Gen Med. 2020;13:61-65. Published 2020 Feb 26.
  22. ↑ Gavioli CF, Florezi GP, Lourenço SV, Nico MM. Clinical Profile of Melkersson-Rosenthal Syndrome/Orofacial Granulomatosis: A Review of 51 Patients. J Cutan Med Surg. 2021;25(4):390-396.
  23. ↑ 23.0 23.1 Wehl G, Rauchenzauner M. A Systematic Review of the Literature of the Three Related Disease Entities Cheilitis Granulomatosa, Orofacial Granulomatosis and Melkersson - Rosenthal Syndrome. Curr Pediatr Rev. 2018;14(3):196-203.
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