CASE REPORT Severe Diabetic Scleredema with Extension to the Extremities and Effective Treatment Using Prostaglandin Ex Yukio Ikeda, Tadashi Suehiro, Tomoki Abe, Toshinori Yoshida, Tomoko Shiinoki, Kiyoshi Tahara, Mitsuru Nishiyama, Tomoaki Okabayashi, Toshihiro Nakamura, Hiroyuki Itoh and Kozo Hashimoto Wereport a 49-year-old womanwith severe diabetic scleredema (DS). The patient had non- insulin-dependent diabetes mellitus (NIDDM)for 9 years and noticed thickened skin on her back 3 years previously. Her DSrapidly extended to her back and extremities with pain and immobility. Her symptomsof DSimproved dramatically after establishing strict glycemic control and intravenous administration of prostaglandin Ex (PGEX). However, the histological findings of her skin biopsy did not change even after the treatment for 12 weeks, and her symptomsworsened again after discontinuation of glycemic control and PGEt treatment. The causes of DS have been considered to be metabolic abnormalities associated with hyperglycemiaand hypoxiain the skin due to diabetic microangiopathy. PGEXwas an effective treatment for DSin our patient. Strict control ofhyperglycemia and PGEXtreatment maybe sufficient to manage DS, although a very long treatment period is necessary. (Internal Medicine 37: 861-864, 1998) Key words: non-insulin-dependent diabetes mellitus (NIDDM) Introduction she noted thickened skin on her neck, which subsequently extended to her shoulders and back along with severe pain and Diabetic scleredema (DS) is a diabetic dermopathy charac- impaired mobility of the neck. The skin lesion had extended to terized by thickened skin on the posterior neck and upper back. her upper arms and thighs in one year, therefore, she was The dermis in DS is histologically characterized by hyperplasia admitted to our hospital for treatment of her skin lesions on of collagen and increased accumulation of glycosaminoglycans October 23, 1996. Her family history showed that only her and hyaluronic acid in scleredema (1). Although DSis often father had NIDDM. seen in long-standing diabetic patients with insulin resistance, The patient was obese (height 150 cm; body weight 62 kg; its extension to the lower extremities is very rare (2, 3). body mass index 27.6 kg/m2), but did not have hypertension. Effective treatment has not yet beeen established for patients Fundoscopic examination showed proliferative retinopathy. with DS. Wereport a patient with non-insulin-dependent diabe- The skin over the neck, back, shoulder, proximal upper and tes mellitus (NIDDM),who showed severe DSextending to the lower extremities was firmly indurated, and was not pitted with extremities. Her symptoms including severe pain, immobility pressure (Fig. 1). Impaired mobility of the neck was observed of the neck, and stiffness of the extremities were markedly in all directions (Table 1 , October 1 996). All peripheral arteries improved during strict glycemic control and administration of were well palpable. Ankle pressure index was also normal. On prostaglandin Ei (PGE}). neurological examination, hypesthesia of the glove and stock- ing type was seen in her peripheral extremities. Deep tendon reflexes were also diminished in the lower extremities. Case Report Hematological examinations revealed normal findings. Her A 49-year-old Japanese womanhad a history ofNIDDMfor blood chemistry examinations showed the following: fasting morethan 9 years and had required insulin therapy (NPH plasma glucose, 177 mg/dl; hemoglobin Ale (HbAlc), insulin 32-40 unit/day) for the previous 7 years; she did not 10.0%; serum creatinine, 0.6 mg/dl; blood urea nitrogen, 15 comply well to establish glycemic control. Three years earlier, mg/dl; total cholesterol, 165 mg/dl; triglyceride, 140 mg/dl; From the Second Department of Internal Medicine, Kochi Medical School, Nankoku Received for publication December 8, 1997; Accepted for publication July 16, 1998 Reprint requests should be addressed to Dr. Tadashi Suehiro, the Second Department of Internal Medicine, Kochi Medical School, Kohasu, Okoh-cho, Nankoku, Kochi783-8505 Internal Medicine Vol. 37, No. 10 (October 1998) 861 Ikeda et al high-density lipoprotein (HDL)-cholesterol, 38 mg/dl. Creati- stimulating hormone (TSH) (2.33 juIU/ml), free T3 (3.02 pg/ nine clearance was 53.2 ml/min and urine total protein was 600 ml), free T4 (1.02 ng/dl) and plasma level of adrenocortico- mg/24h. Serum C peptide immunoreactivity (CPR) level was tropic hormone (ACTH) (23.3 pg/ml) were normal. Serum and 4.5 ng/ml and urinary CPR excretion rate was high (150 |ig/ urinary electrophoresis werenormal. C-reactive protein was day). Serum levels of cortisol (12.4 (LLg/dl), growth hormone 0.3 mg/dl, anti-streptolysin-0 (ASO) and anti-streptokinase (GH) (<0.15 ng/ml), somatomedin C (97.6 jig/ml), thyroid (ASK) were within normal limits. Rheumatoid factor, antinu- clear antibody, and anti-Scl-70 were negative. Chest X-ray film and electrocardiogram (ECG) did not show any abnormal findings. Roentogengrams of cervical vertebra, shoulder, el- bow, hip, and kneejoints also revealed no abnormal findings. A bone scintigram showed no positive finding. Computedtomog- raphy (CT) of the chest revealed markedly thickened skin (9 mm)of the back (Fig. 1). Skin biopsy specimens were obtained from her upper back and femur. Microscopic examinations of both specimens showed thickly packed collagen bundles throughout the dermis with matrix materials that were stained blue by colloidal iron (Fig. 2). These findings were consistent with scleredema. She was treated by diet and intensive insulin therapy (3 injections daily) for her hyperglycemia. Wealso started intra- venous administration of PGE1? 80 |ig/day from December 1 1 , 1996. Over the subsequent 2 weeks, neck pain decreased and the skin lesion, especially on the lower back and extremities, gradually softened. Consequently, we administered oral and intravenous PGEi (30 and 80 |Ug/day, respectively) alternately every 2 weeks. Thermographywas performed before and after 12 weeks of treatment, at the same roomtemperature (27°C). The second thermography which was done 30 hours after the last PGEj administration, revealed marked improvement of skin temperature on her back (Fig. 3). Improved cervical mobility was also observed (Table 1). CT of the chest however, did not show any change of the skin thickness. Furthermore, a second biopsy specimen from her back skin did not reveal any remarkable change histologically. At that time, diabetic control was improved (HbAlc, 7.2%). The patient was discharged from our hospital on April 15, 1997. It was difficult to control her Figure 1. Upper: View of the patient's posterior neck and blood glucose level after discharge because of her poor compli- back. The affected skin is indurated and thickened. She had ance with diet and irregular injection of insulin (HbAlc, 8.8- received acupuncture for reduction of neck and back pain. Lower: 10.4%). Although oral administration of PGE2was continued, Computedtomography of the chest revealed a markedincrease in neck pain and cervical immobility worsened gradually. There- skin thickness. fore, she has been receiving intravenous administration of Table 1. Cervical Mobility before and after the Administration of Prosta- glandin E, Direction Normal Oct., '96 Feb., '97 Apr., '97 Flexion 0-60 ° 0-20 ° 0-5 0 ° 0-55 ° Extension 0-60° 0-20° 0-20° 0-55 ° R. rotation 0-70° 0-1 5° 0-30° 0-45° L. rotation 0-70° 0- 1 0° 0-20° 0-40° R. lateral bending 0-50° 0-1 5° 0-20° 0-30° L. lateral bending 0-50° 0-10° 0-20° 0-30° Intravenous and oral PGEi were administered alternately every 2 weeks from December ll, 1996 to April 15, 1997. 862 Internal Medicine Vol. 37, No. 10 (October 1998) Severe Diabetic Scleredema Figure 2. Histologic appearance offemoral skin biopsy speci- men. Microscopic examination showedthickly packed collagen bundles throughout the dermis (upper; HE stain, x40). Colloidal Figure 3. Comparison of thermographies performed before iron stain was positive for mucopolysaccharides in the deep der- and after the administration of PGEj for 12 weeks showed a mis (lower). markedimprovementin skin temperature on the posterior neck and back after treatment with PGEj. PGEb 80 ng/day, on admission for 2 weeks every 2 months. During the PGEjtherapy, there was no undesirable event such severe in this case. as an exacerbation of retinopathy. The pathogenesis of DShas not been clarified and seems to be heterogeneous. Irreversible glycosylation of collagen in the Dis cussion skin has been suggested as a mechanismin the development of DS. Non-enzymatic glycosylation ofcollagen in diabetes causes Scleredemais classified into two types, scleredema adulto- increased cross-linking and makes the collagen fibers resistant rum of Buschke and DS (1, 4). Scleredema adultorum of to degradation by collagenase. This leads to excessive accumu- Buschke is more commonlyfound in children and is usually lation of abnormal collagen in the dermis (7, 9). The patient did preceded by an acute infection, often streptococcal infection. not control her blood glucose level for a prolonged period, Althoughthis type can involve an extensive region of the body which might have caused non-enzymatic glycosylation of col- including the extremities, the disease usually remits without lagen fibers, resulting in an accumulation of collagen in the any treatment within 1 8 months (5). In contrast, DS, the second dermis. The patient could hardly move her neck, therefore the type of scleredema, is not preceded by any infection and usually