Dermato-neuro syndrome associated with scleromyxedema

Bedriye Karaman¹ , Ayse Guler¹ , Ilgen Ertam² , Nese Celebisoy¹

¹ Department of Neurology, EGE University, Faculty of Medicine, Bornova, Izmir, Turkey
² Department of Dermatology, EGE University, Faculty of Medicine, Bornova, Izmir, Turkey

Correspondence Address:
Ayse Guler
Department of Neurology, EGE University, Faculty of Medicine, Bornova, Izmir
Turkey

Sir,

A 50-year-old previously healthy male, presented with skin thickening and waxy papules on his forearms, face and upper aspect of trunk for 2 years [Figure - 1] and [Figure - 2]. A skin biopsy revealed diffuse mucin deposition in the dermis with significant fibroblastic proliferation suggestive of scleromyxedema. Serum protein electrophoresis and immunofixation revealed IgG lambda light chain gammopathy. Bone marrow biopsy specimen was normocellular with evidence of lambda chain gammopathy on immunohistochemical examination. The patient first developed symptoms of encephalopathy one year later in the form of a flu-like prodrome followed by fever, nausea, vomiting, disorientation and dysarthria. Cerebrospinal fluid study and cranial magnetic resonance imaging were unremarkable. He recovered completely within 24 hours on broad spectrum antibiotics and acyclovir. The encephalopathy recurred one year later and again spontaneously recovered in 20 hours. Cranial magnetic resonance imaging and cerebrospinal fluid studies were again normal. He was then started on intravenous immunoglobulin (IVIG) 1 g/kg monthly. After the fifth cycle, he experienced the third attack of encephalopathy lasting for 3 days for which he required admission in the intensive care unit. On admission, he was lethargic, confused and agitated with no motor deficits. The body temperature was 37.8°C. Laboratory investigations including biochemistry, thyroid functions and antibodies, rheumatoid factor, antineutrophil cytoplasmic antibody and antinuclear antibodies was within normal limits, except leukocytosis. The cerebrospinal fluid examination revealed pleocytosis (200 cells, lymphocytes) with high protein (53.3 mg/dl) and normal glucose levels. Microbiologic, virologic, and serologic studies including polymerase chain reaction for herpes simplex virus type 1 and 2, and serology for syphilis were negative. Cerebrospinal fluid IgG index was within normal limits. Electroencephalography and brain magnetic resonance imaging were normal. As the encephalopathy episode had recurred during IVIG treatment, intravenous methylprednisolone (500 mg/day) and plasmapheresis was started. There was no clinical improvement and plasmapheresis was stopped after the fourth session, and IVIG at a total dose of 2 g/kg was given with which the patient quickly improved. At the end of the second week of admission, he was oriented, and could speak and comprehend normally. Intravenous steroid was continued for another 10 days after which it was switched to oral prednisone, 60 mg/day.

Figure 1: Skin thickening over forearms

Figure 2: Skin thickening and waxy papules over face

Scleromyxedema is characterized by thick papular lesions resulting from dermal fibroblast proliferation and mucin deposition. ^[1] The exact pathophysiology of scleromyxedema is still unknown. The disorder usually affects middle aged adults with no gender predilection, ^[2] and monoclonal paraproteinemia (most commonly IgG-lambda) is typical. ^[3] Patients may have extracutaneous involvement, with neurologic, rheumatologic, cardiac, renal, gastrointestinal, and ophthalmologic manifestations. ^[4],[5] Neurological disorders such as encephalopathy, acute psychosis, cognitive disorders, peripheral neuropathy, and carpal tunnel syndrome are seen in 10-15% of the patients. ^[4],[5] Fever, coma, and convulsions following a flu-like prodrome is termed dermato-neuro syndrome and can be fatal. ^[6],[7]

In a recent study, Fleming et al. ^[8] presented 18 patients with findings proposed for the diagnosis of dermato-neuro syndrome, viz. fever, coma and convulsions following a flu-like prodrome and 7 patients with acute neurological deficits but not showing all the features for dermato-neuro syndrome. We believe all scleromyxedema patients with altered consciousness or other neurological deficits that cannot be explained by another disease may be named as dermato-neuro syndrome. All these findings indicate involvement of the central nervous system and no clear-cut proof for the given criteria for dermato-neuro syndrome is present in the literature. Hence, our patient with flu-like prodrome, fever and altered consciousness was diagnosed and treated as dermato-neuro syndrome.

Histopathologic findings in the brain have varied from near normal in one patient with lethal neurologic syndrome ^[4] to mild demyelination and gliosis in another patient with dermato-neuro syndrome. ^[6] Hence, the exact pathogenesis of systemic complications is not clear. One of the theories is that the increase in blood viscosity by paraproteins or leukocyte aggregation impairs the central nervous system microcirculation resulting in dermato-neuro syndrome. ^[7]

Various modalities have been tried for the treatment of scleromyxedema such as melphalan, bortezomib, intravenous immunoglobulin (IVIG), plasmapheresis, high dose dexamethasone, autologous stem cell transplantation, ^[9],[10] and a combination of these. Clinical response to melphalan and bortezomib suggests that scleromyxedema could be treated with agents which are known to be beneficial in multiple myeloma. ^[11],[12] IVIG ^[10] and plasmapheresis have been found to be effective for dermato-neuro syndrome with relatively less side effects. ^[8],[9] The mechanism of IVIG remains unclear. It may block an as-yet-unknown factor causing mucin and collagen deposition by stimulating fibroblasts.

If all acute onset neurological symptoms associated with scleromyxedema are taken into account, we found are 25 prior reports of dermato-neuro syndrome in the English literature. Although scleromyxedema is fairly rare, dermato-neuro syndrome should be considered in the differential diagnosis when a patient presents with unexplained neurologic symptoms with skin lesions suggestive of scleromyxedema.

1.	Rudner EJ, Pomann J. Scleromyxedema revisited. Int J Dermatol 2003;42:31-5. [Google Scholar]
2.	Rongioletti F, Rebora A. Updated classification of popular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol 2001;44:273-81. [Google Scholar]
3.	Gabriel SE, Perry HO, Oleson GB, Bowles CA. Scleromyxedema: A sclerodermalike disorder with systemic manifestations. Medicine (Baltimore) 1988;67:58-65. [Google Scholar]
4.	Webster GF, Matsuoka LY, Burchmore D. The association of potentially lethal neurologic syndromes with scleromyxedema (papularmucinosis). J Am Acad Dermatol 1993;28:105-8. [Google Scholar]
5.	Berger JR, Dobbs MR, Terhune MH, Maragos WF. The neurologic complications of scleromyxedema. Medicine (Baltimore) 2001;80:313-9. [Google Scholar]
6.	Godby A, Bergstresser PR, Chaker B, Pandya AG. Fatal scleromyxedema: Report of a case and review of the literature. J Am Acad Dermatol 1998;38:289-94. [Google Scholar]
7.	River Y, Levy I, Gilead L, Orbach H, Almog Y. Fever, convulsions and coma in scleromyxedema: A ′′dermato-neuro syndrome′′. Neurology 1996;46:1778-9. [Google Scholar]
8.	Fleming KE, Virmani D, Sutton E, Langley R, Corbin J, Pasternak S, et al. Scleromyxedema and the dermato-neuro syndrome: Case report and review of the literature. J Cutan Pathol 2012;39:508-17. [Google Scholar]
9.	Charles S, Hainaut E, Cante V, Valette C, Levillain P, Guillet G. Dermato-neuro syndrome during scleromyxedema: Efficacy of plasmapheresis and intravenous immunoglobulin. Ann Dermatol Venereol 2014;141:523-7. [Google Scholar]
10.	Shams SR, Goldstein DA, Kaufman JL, MacKelfresh J, Flowers CR, Langston AA. Dermato-neuro syndrome in a patient treated with autologous stem cell transplant for scleromyxedema. Clin Lymphoma Myeloma Leuk 2014;14:213-5. [Google Scholar]
11.	Cañueto J, Labrador J, Román C, Santos-Briz A, Contreras T, Gutiérrez NC, et al. The combination of bortezomib and dexamethasone is an efficient therapy for relapsed/refractory scleromyxedema: A rare disease with new clinical insights. Eur J Haematol 2012;88:450-4. [Google Scholar]
12.	Devos T, Thiessen S, Cuyle PJ, Meersseman W, Delforge M. Long-term follow-up in a patient with the dermato-neuro syndrome treated with high-dose melphalan, thalidomide and intravenous immunoglobulins for more than 7 years. Ann Hematol 2014;11:1927-8. [Google Scholar]