The Neurologic Complications of Scleromyxedema

Introduction Scleromyxedema is a rare fibromucinous disorder that is difficult to treat and associated with significant morbidity and mortality (12). This dermatologic disorder, a form of papular mucinosis, is characterized by lichenoid waxy papules appearing erythematous or yellowish. These papules become confluent, forming plaques, which has led to the designation “diffuse sclerosis”(52). The skin, though thick, is not bound down (52). The face, neck, and upper arms are chiefly affected, and the forehead and glabellar region often appear deeply furrowed. The skin thickening may result in impaired joint mobility. The scalp, chest, and back are less frequently involved (60). Sparseness of hair in the eyebrow, axillary, and pubic regions is a frequent associated finding (26,70). Features suggestive of scleroderma are frequently noted, including indurated skin, restricted facial mobility, and sclerodactyly. These features often result in misdiagnosis (63); however, the entity is quite distinct from scleroderma (36). The pathogenesis of scleromyxedema remains uncertain. A proliferation of fibroblasts and an excessive deposition of acid mucopolysaccharide in the dermis are universal (66). A monoclonal paraproteinemia is frequently observed in association with the disorder. Some investigators have suggested that the paraproteinemia plays a fundamental role in the pathogenesis of the disorder, as it has been demonstrated that serum from patients with scleromyxedema stimulates hyaluronic acid and prostaglandin E production (75). Alternatively, the paraproteinemia may be a secondary immunologic phenomenon consequent to the dermal mucin deposition or other processes (26). The paraproteinemia is most often an IgG monoclonal gammopathy, and less frequently IgA (40). Lambda light chains are more commonly observed than kappa light chains (11,40). In addition to scleromyxedema, there is a spectrum of paraproteinemias that results in skin disorders (60), including amyloidosis, POEMS syndrome (p olyneuropathy, o rganomegaly, e ndocrinopathy, m onoclonal gammopathy, s kin changes), certain xanthomatous conditions, cutaneous plasmacytoma, benign hypergammaglobulinemic purpura of Waldenström, and multiple myeloma (42). Like scleromyxedema, several of these conditions may result in neurologic disability. We report a patient with self-limited encephalopathy in association with scleromyxedema and review the world’s literature on the neurologic disorders reported in association with this disease. Illustrative Case Report A 34-year-old African-American man with a history of scleromyxedema was admitted to the hospital with the sudden onset of incomprehensible speech and confusion. He had been diagnosed with scleromyxedema 5 years earlier when he developed the classic lichenoid papules of his face and thickened skin resulting in limited joint mobility, particularly of his fingers. He reported no systemic manifestations at that time. Laboratory investigation revealed a monoclonal paraproteinemia consisting of IgGκ light chains and a monoclonal B cell proliferation. Multiple medical therapies were of no benefit in ameliorating his dermatologic condition. These therapies included corticosteroids, melphalan, retinoids, and misoprostol. Minimal improvement was noted after a trial of photopheresis. Electron beam radiation resulted in slight improvement. A traveling salesman, he had been riding in the car with his partner when he suddenly grabbed his head and said “Hold on.” Immediately afterward, he was unable to speak comprehensibly. Before transfer to our hospital, computed tomography of the head without contrast in the emergency room of a local hospital was unremarkable. His general physical examination was notable for the cutaneous changes of scleromyxedema. His face was leonine in appearance and there were multiple coalescing, pink, lichenoid papules of his brow and midface (Figure 1). Scleroderma-like induration of the forearm and hands was noted (Figure 2) with limited joint mobility. He was awake and alert, but his speech was incomprehensible. He was unable to follow simple commands consistently. No cranial nerve abnormalities were observed. He moved all extremities equally and localized pain. Deep tendon reflexes were symmetrical and graded as 1+. Plantar responses were mute and no pathologic reflexes were evident.Fig. 1: Coalescing papules over nose and central face.Fig. 2: Scleroderma-like induration of forearms and hands.Standard laboratory studies were remarkable for an erythrocyte sedimentation rate of 30 mm/min. Lumbar puncture was performed and was notable for total protein of 61 mg/dL (normal, 15–40 mg/dL). Other studies performed on the cerebrospinal fluid were normal. Magnetic resonance imaging of the brain, including diffusion weighted imaging, was normal. Cerebral angiogram was normal. Echocardiogram was normal. Electroencephalogram showed generalized slowing and voltage suppression of the left hemisphere. Additional laboratory studies were remarkable for the presence of free lambda monoclonal chains on serum protein electrophoresis. Urine protein electrophoresis showed “overflow-type” proteinuria from serum acute-phase inflammatory proteins. His free protein S was 46 mg/dL (normal, 70–130 mg/dL). Other laboratory studies, including antinuclear antibody, antithrombin III, lupus anticoagulant, and factor V Leiden, were normal. The day after admission, he was alert and followed simple commands but exhibited an expressive aphasia. Dysphagia resulted in the restriction of all oral intake. He demonstrated a new right homonymous hemianopsia, right central facial nerve palsy, and a right hemiparesis (graded 3/5). Sensory perception was decreased to all modalities on the right side. Muscle stretch reflexes were uniformly depressed in the right-sided extremities when compared with those of the left side. On the fifth day of hospitalization, in the absence of a specific therapy, his right arm and leg strength began to improve spontaneously. He began to speak comprehensible, albeit isolated, words. Over the ensuing week, his language, motor, and sensory function continued to improve. Seven days after presentation, the patient was discharged to home. At discharge, he exhibited a mildly dysarthric speech with normal comprehension and mild right hemiparesis. He had no difficulty swallowing, and he ambulated well despite his right-sided weakness. Discussion Scleromyxedema was described independently by Dubreuilh (14) and Reitman in 1908 (64). Gottron introduced the term “scleromyxedema” in 1954 (24). Subsequently, Montgomery and Underwood divided the disorder into 4 separate categories on the basis of the dermatologic appearance: generalized lichenoid papules (Gottron-Arndt syndrome), discrete papules, discrete lichenoid plaques, and urticarial plaques (53). Although scleromyxedema is regarded as a rare dermatologic disorder, it often involves other organ systems (22,52), including the heart, lungs, gastrointestinal system, kidneys, joints, endocrine organs, and nervous system. The neurologic and psychiatric complications of scleromyxedema are broad (Table 1). Clearly, no part of the neuraxis appears to be uniquely spared in patients with scleromyxedema. Although scleromyxedema is a rare condition, the concurrence of scleromyxedema and disorders of the central or peripheral nervous system or muscles is probably not uncommon. Table 2 provides specifics of the neurologic disorders reported in association with scleromyxedema for which sufficient data were available to comment meaningfully. As in our patient, thorough evaluation in patients with central nervous system disease seldom results in an explanation for the neurologic disorder observed. While these neurologic deficits are generally reversible, they may persist despite the effective treatment of the skin condition. For instance, Nieves et al (56) report persistent visual symptoms in a man whose skin lesions had cleared with melphalan and plasmapheresis.TABLE 1: Neurologic and psychiatric disorders associated with scleromyxedemaTABLE 2: Examples of neurologic illness associated with scleromyxedemaTABLE 2: continuedThe etiology of scleromyxedema remains unknown. While mucin deposition appears to play a role in the pathogenesis of the disorder, it is insufficient to explain all the manifestations observed with the disorder (22). The frequent concurrence of a monoclonal paraproteinemia in patients with this disorder suggests that it plays a fundamental role in the pathogenesis. However, paraproteinemias are not an invariable component of scleromyxedema (61,74) and may not be fully responsible for the spectrum of abnormalities observed. Although scleromyxedema has been reported in association with multiple myeloma (13,54), some investigators contend that, on the basis of clinical and histologic features, this entity is distinct from scleromyxedema and refer to it as “scleredema”(42). Many of the neurologic features observed in association with scleromyxedema may be the consequence of the paraproteinemia with or without concomitant hyperviscosity. Among those conditions that could be potentially explained by the paraproteinemia are encephalopathy, transient focal neurologic disturbances, seizures, cerebrovascular events, and peripheral neuropathy. Kaufman et al (41) suggested that mucin deposition in the brain may be partially responsible for the neurologic symptoms of their patient; however, this has not been demonstrated pathologically (51,53). Atherosclerosis and hypertension have been associated with scleromyxedema (40) and, in some instances, may have been contributory to the stroke or stroke-like manifestations. Our patient experienced a neurologic deficit of sudden onset involving the left middle cerebral artery territory characterized by aphasia, right homonymous hemianopsia, and right hemiparesis. In the absence of a specific therapeutic intervention, his neurologic deficit largely, though incompletely, resolved within 1 week of onset. He had no history of migraine headache, drug abuse, fever, or seizure disorder. Cranial magnetic resonance imaging failed to reveal any abnormalities, including diffusion weighted imaging which is typically very sensitive for early brain infarction (34). Angiography failed to reveal any obstruction or features suggestive of atherosclerosis. No source of embolization was apparent on detailed evaluation. Blood studies were remarkable for a mildly elevated sedimentation rate (30 mm/min), free lambda monoclonal chains, and low protein S levels. Except for the latter, other coagulation parameters revealed no evidence of a hypercoagulable state. An electroencephalogram showed generalized slowing and voltage suppression over the left hemisphere; there was no evidence of seizures. Our patient’s history is similar to that of other patients with scleromyxedema suffering from stroke or a stroke-like disorder (1,3,6,7,9,16,41,59,62,66). As in those cases, the pathogenesis of the stroke-like manifestation remains obscure. We believe the likeliest explanation is a reversible hemodynamic abnormality consequent to the paraproteinemia associated with scleromyxedema. Conceivably, increased blood viscosity resulted in a reversible cerebrovascular event (58). The low protein S levels also raise the possibility of hypercoagulability; however, magnetic resonance studies failed to reveal findings consistent with permanent ischemic brain injury. Other possibilities, for example, vasospasm, angiitis, migraine, cerebral embolization, and thrombosis associated with accelerated atherosclerosis, appear less likely given the negative studies. Similarly, the pathogenesis of the peripheral neurologic disorders associated with scleromyxedema remains unclear. Carpal tunnel syndrome has been postulated to result from deposition of mucopolysaccharide at the wrist or a direct toxic effect on the median nerve (73). Amyloidosis may also play a role in the peripheral neuropathy. Neurologic complications may occur as a consequence of the treatment regimens, for example, peripheral neuropathy from cytotoxic agents, and may also result from a variety of other systemic illnesses associated with scleromyxedema. The latter include cardiovascular disorders (66), amyloidosis (52), and connective tissue disease (52). With respect to myopathy, it was first reported by Nagy et al in 1962 (55), but in the absence of confirmatory muscle enzyme levels or muscle biopsy. Since that time, at least 12 additional cases (2,8,15,27,28,39,45,49,72) of myopathy or myositis have been reported. The range of symptoms has varied from myalgia and slight weakness to more profound weakness. Dysphagia may be noted and is more common than in myopathy associated with polymyositis (29). Altered speech has been reported as a consequence of deposition of mucopolysaccharides in the larynx of 1 patient (10). Serum muscle enzymes vary from normal to elevated, and electromyogram shows myopathic features. Inflammatory infiltrates within the muscle are rarely observed; more common is a vacuolar myopathy with or without necrosis and without the deposition of mucopolysaccharide within the muscle fibers or vacuoles (15). In addition to disorders of the central and peripheral nervous system, scleromyxedema has been associated with dysfunction and disease in other organ systems, including cardiac (30,50), pulmonary (16), renal (27,45,51,66), gastrointestinal (45), and thyroid disease (27,54,55). Neoplasms affecting several organ systems have been reported as isolated case reports with scleromyxedema (40). With the exception of multiple myeloma, for which there have been at least 7 case reports (3,44,54,62,67), the association between neoplasm and scleromyxedema is highly questionable. Recognition of the characteristic skin lesions is fundamental to the diagnosis of this disorder. Unfortunately, on rare occasions the neurologic abnormalities have occurred before the appearance of the classical skin lesions (56). In patients with encephalopathy, an abnormal generalized slowing of the electroencephalogram has been reported (41,52). An increase in cerebrospinal fluid protein concentration may also be observed (41). Treatment of scleromyxedema has included a number of modalities, including immunosuppression, antineoplastic agents, plasmapheresis, extracorporeal photopheresis, and the retinoids. Scleromyxedema of the skin may respond to radiation therapy (31) or electron-beam therapy (48). Etretinate, an aromatic retinoid, has been successful after failure of therapy with melphalan and corticosteroids (5). PUVA (psoralen plus ultraviolet A light) has also been used successfully in isolated instances (17). These therapeutic modalities are unlikely to have any significant effect on the associated neurologic disorder. Corticosteroids and immunosuppressive agents have been considered the mainstay of treatment of the systemic complications of scleromyxedema, but with variable efficacy. Among the immunosuppressive agents reported to be useful are melphalan (Alkeran) (27) and cyclophosphamide (35). Initial favorable responses to these drugs may not be maintained consistently (52), and side effects may preclude their continuation even when deemed effective. The administration of corticosteroids, with or without methotrexate, may provide a favorable response to scleromyxedemaassociated myopathy (29). Despite aggressive treatment with immunosuppressive agents, the disease remains fatal in a high percentage of patients (12). In 1 patient who had failed to respond to prednisone, colchicine, and cyclophosphamide, improvement was observed after treatment with thiomucase, a mucopolysaccharidase extracted from testicles (10). Plasmapheresis has been recommended for patients with altered mental status (71), as hyperviscosity may be responsible for the neurologic findings. The latter may be the consequence of polymer formation through intermediate immunoglobulins or other protein chains or the altered deformability of red blood cells by binding of paraproteins (71). More recently, combination therapy of melphalan and plasmapheresis has been reported to be effective in a patient with neurologic symptoms consisting of confusion, hemiparesis, tremor, and migraine headache (6). Extracorporeal photopheresis may be therapeutically beneficial in patients with refractory cutaneous scleromyxedema (43), but its effectiveness in patients with central nervous system manifestations has not been established. Summary Scleromyxedema is a rare dermatologic disorder in which proliferation of fibroblasts and excessive deposition of acid mucopolysaccharide in the skin result in lichenoid waxy papules. It was initially described in 1908. In addition to the dermatologic manifestations, scleromyxedema may involve other organ systems, including the heart, lungs, gastrointestinal system, kidneys, joints, and the nervous system. The pathogenesis of scleromyxedema remains uncertain. It is often associated with a monoclonal paraproteinemia. While some investigators have suggested that paraproteinemia is fundamental to the pathogenesis of the disorder, others believe that it is simply the consequence of an immune response to dermal mucin deposition or other processes. We report a 34-year-old man with a 5-year history of scleromyxedema who developed sudden aphasia, right homonymous hemianopsia, and right hemiparesis that largely reversed over the ensuing 2 weeks. Extensive diagnostic evaluation for the etiology of the neurologic deficit failed to reveal an alternate etiology to scleromyxedema. In addition to reporting this illustrative case, we review the world’s literature on the topic of the neurologic complications of scleromyxedema. A wide variety of central nervous system and neuromuscular disorders accompanies scleromyxedema not uncommonly. These neurologic complications include behavioral abnormalities, encephalopathy, seizures, cerebrovascular insults, peripheral nerve disorders, and myopathy. They are generally reversible. In some instances, these complications may be the consequence of the associated paraproteinemia; however, in others the pathogenesis remains uncertain.