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Increased muscle tone during etretinate therapy
Volume 14 Number 5, Part 2 May, 1986
3. Domonkos AN, Arnold HL, Odom RB: Andrews' diseases of the skin. Philadelphia, 1982, W. B. Saunders Co., p. 860. 4. Glinick SE, Alper JC, Bogaars H, Brown JA: Becker's melanosis: Associated abnormalities. ,1 AM ACAD DERMATOL9:509-514, 1983. 5. Takayasu H, Ueno A, Tsukada O: Accessory scrotum: A case report. J Urol 112:826-827, 1974. 6. Hata Y: Accessory scrotum. Plast Reconstruct Surg 66:613-616, 1980.
Becker' s nevus and a c c e s s o r y scrotum
7. Daut WW, Daut RV: Accessory scrotum posteriorly located: Review of the literature and report of a case. J Iowa State Med Soc 39:194-195, 1949. 8. Azmy A, Ransley 1:'(3: Accessory scrotum. Z Kinderchir 33:373-374, 1981. 9. Redman JF, Morris WD: Accessory perineal scrotum. Urology 23:406-407, 1983.
Increased muscle tone during etretinate therapy Charles N. Ellis, M . D . , * ' * * Martin Gilbert, M . D . , * Kenneth A. Cohen, M . D . , * J a m e s W. Albers, M . D . , P h . D . , * * * ' * * * * Richard D. Ball, M . D . , P h . D . , * * * * Roger L. Albin, M . D . , * * * Alan Silverman, M . D . , * and John J. Voorhees, M . D . * A n n Arbor, M I A 40-year-old man with severe psoriasis developed painless muscle stiffness coinciding with four successive courses of etretinate therapy. Peripheral nerve block extinguished the increased muscle tone. Our patient's symptoms resembled those of the stiff-man syndrome. Increased muscle tone is a potential side effect of etretinate treatment and must be distinguished from the common musculoskeletal symptoms observed in patients taking retinoid therapy. (J AM ACAD DERMATOL14:907-909, 1986).
Etretinate (Tegison), an aromatic vitamin A derivative, has proved efficacious in the treatment of psoriasis. ~Marketed in Europe for several years, its use in the United States is restricted to experimental clinical trials. Its side effects are similar to those o f chronic h y p e r v i t a m i n o s i s A and consist m a i n l y o f xerosis of skin and mucosa, thinning of From the Clinical PharmacologyUnit of the Departmentof Dermatology,* the Department of Neurology,*** and the Departmentof Physical Medicine and Rehabilitation,****Universityof Michigan Medical School, and the DermatologyService, VeteransAdministration Medical Center.** Supported in part by the Babcock DermatologieEndowment. Reprint requests to: Dr. Charles N. Ellis, DermatologyService(110), Veterans AdministrationMedical Center, Ann Arbor, MI 48105/ 313-769-7100, ext. 781.
the hair, bone and joint pain, muscle aches, fatigue, and nausea. 2 We are reporting a case of increased muscle tone associated with etretinate therapy. CASE R E P O R T A 40-year-old white man with severe, plaque-type psoriasis of 20 years' duration had been unsuccessfully treated with conventional forms of therapy, including topical corticosteroids, modified Goeckerman regimen, psoralens with ultraviolet A, and methotrexate. After providing informed consent, the patient began etretinate therapy in July 1981 as a participant in a study approved by our institutional review board. He received an initial 6-month course of etretinate and two subsequent 9month courses and has begun a fourth course. Etretinate was discontinued for 3 months between each treatment
907
908
Journal of the American Academy of Dermatology
Ellis et al
course. Emollients were the only other form of treatment allowed at any time during this study. The patient's doses of etretinate ranged from 0.6 to 1.0 rag/ kg/day. The patient's psoriasis improved remarkably during etretinate treatment but recurred within a few weeks to a few months, when etretinate was discontinued. Known side effects of etretinate therapy, including xerosis of skin and mucosa, stickiness of skin, and palmoplantar desquamation, were observed in our patient during periods of therapy. In addition, our patient repeatedly complained of painless muscle stiffness without cramping 2 to 3 months after the initiation of each course of etretinate. This symptom was worse with each subsequent course of etretinate therapy, although it resolved within a few weeks each time he stopped taking the drug. The patient's stiffness involved primarily his axial and lower extremity muscles. It was more noticeable on relaxation of the involved extremities and improved with repeated movement. There was no history of either exerciseinduced stiffness or myoglobinuria, nor was there a family history of neurologic or muscle disease. He had no symptoms of arthritis or hypothyroidism. The patient was taking no medication other than etretinate and denied taking any vitamin supplements or phenothiazines. Radiographs of the cervical spine obtained at the termination of the patient's initial 6-month course of etretinate therapy showed only mild degenerative changes. Subsequently, radiographs of the lumbosacral spine, sacroiliac joints, and hips were obtained at the temaination of his second course of etretinate therapy. These films were normal except for minimal sclerosis of the lilac side of the left sacroiliac joint. Serum calcium levels and liver function remained normal. Neurologic examination performed during the third course of etretinate demonstrated a slow, broad-based gait with flexion at the hips and knees. The lower extremities showed a striking increase in tone of the leadpipe variety. Following volitional or passive extension at the knees, requested relaxation resulted in the legs' slowly (over seconds) returning to a relaxed position. Percussion myotonia was not present. With repetition, muscle tone approached normal. The remainder of the motor and sensory examinations had normal results, and muscle stretch reflexes were also normal. No pathologic reflexes, tetany, or contractures were present. Nerve conduction and electromyographic studies had normal results with the exception of persistent motorunit action-potential activation in the quadriceps muscle during attempted relaxation. As the limb came to rest, all motor units eventually disappeared.
On the basis of these findings, we believed that our patient's increased tone was the result of a central nervous system (e.g., spinal cord) effect similar to that seen in the stiff-man syndrome, 3 although an intrinsic mechanical abnormality of muscle could not be excluded. A femoral nerve block performed with the patient under local anesthesia resulted in a flaccid paralysis of the quadriceps muscles, demonstrating that the increased tone was neurogenic. The neurologic evaluation and electromyography were repeated 2 months after the end of the patient's third course of etretinate; both the muscle tone and the electromyogram were normal. The increased muscle tone recurred within a few weeks after our patient began his fourth course of etretinate. In an attempt to relieve his stiffness, we gave our patient baclofen, a centrally acting analog of 3'aminobutyric acid, a putative inhibitory neurotransmitter. Baclofen reduces muscle rigidity through spinal cord reflex mechanisms and is beneficial in some cases of stiff-man syndrome. 4 After the patient took baclofen, 20 mg three times daily tor 1 month, both subjective and objective improvements in his altered muscle tone were noted. Subsequently the patient again developed increased tone in the lumbosaeral paraspinal muscles, which has persisted despite an increase in his dose of baclofen to 90 mg daily. Although his lower extremity symptoms have resolved, he now has difficulty bending because of the increased tone in his back. The degree of his physical impairment has made the patient consider stopping his etretinate therapy. COMMENT In addition to demonstrating m a n y of the recognized side effects o f etretinate, our patient developed increased muscle tone initially involving primarily his lower extremities. This increase in muscle tone occurred repeatedly during four different courses of etretinate. The symptom resolved completely within a few weeks after each interruption of etretinate treatment. There was no evidence of arthritis other than the minimal degenerative changes noted on radiographs. No disturbance of calcium metabolism or evidence of hypothyroidism was noted in our patient. A femoral nerve block temporarily eliminated the increased tone, excluding an intrinsic muscle abnormality as the cause o f our patient's symptoms. Our patient's initial improvement while taking baclofen suggested that central nervous system
Volume 14 Number 5, Part 2 May, 1986
effects of etretinate were responsible for his symptoms. The clinical and electrodiagnostic findings in our patient resembled many of those seen in patients with early or mild stiff-man syndrome. Characteristic were the symmetric muscle stiffness and boardlike rigidity, the axial predilection, the absence o f corticospinal tract signs, local relief with nerve block, and during attempted rest, prolonged motor-unit action-potential activity that was indistinguishable from voluntary activation. Unlike the findings in classic stiff-man syndrome, our patient lacked the severe paroxysmal muscle spasms, the progression o f stiffness to diffuse musculature, the typical extended posture, and the indefinite persistence of motor-unit action-potential activity at rest. Muscle stiffness also may be found in chronic hypervitaminosis A . 5'6 A striking example was reported by M u e n t e r et al, 7 but these authors were unable to conclude whether the muscle stiffness was o f myogenic or neurogenic origin. Stiffness has been observed in dogs given etretinate, 8 although it is unclear whether the stiffness was muscular in nature or a consequence of pathologic bone fractures that the dogs developed. Musculoskeletal symptoms in the form of intermittent muscle aches are frequent during etretinate therapy. 2 Similarly, patients taking isotreti-
Increased muscle tone during etretinate therapy
909
noin occasionally have discomfort in their muscles. 9 To our knowledge, this is the first report of increased muscle tone induced by etretinate, a side effect that should be distinguished from the common complaint of muscle aches noted by patients taking retinoids. REFERENCES 1. Peck GL: Retinoids in clinical dermatology, in Fleischmajer R: Progress in diseases of the skin, vol. 1. New York, 1981, Gmne & Stratton, Inc., pp. 227-269. 2. Windborst DB, Nigra T: General clinical toxicology of oral retinoids. J AM AC_ADDERMATOL 6:675-682, 1982. 3. Moersch FD, Woltman HW: Progressive fluctuating muscular rigidity and spasm ("stiff-man" syndrome): Report of a case and some observations in 13 other cases. Proe Mayo Clin 31:421-427, 1956. 4. Miller F, Korsvik H: Baclofen in the treatment of stiffman syndrome. Ann Neurol 9:511-512, 1981. 5. Gerber A, Raab AP, Sobel AE: Vitamin A poisoning in adults with description of a case. Am J Med 16:729-745, 1954. 6. Fumich RM, Essig GW: Hypervitaminosis A: Casereport in an adolescent soccer player. Am J Sports Med 11:3437, 1983. 7. Muenter DM, Perry HO, Ludwig J: Chronic vitamin A intoxication in adults. Am I Meal 50:129-136, 1971. 8. KammJJ: Toxicology,carcinogenicity, and teratogenicity of some orally administered retinoids. J AM ACADDERMATOL6:652-659, 1982. 9. ShalitaAR, CunninghamWJ, Leyden IJ, et al: Isotretinoin treatment of aene and related disorders: An update. I AM ACADDERMATOL9:629-638, 1983.
3. Domonkos AN, Arnold HL, Odom RB: Andrews' diseases of the skin. Philadelphia, 1982, W. B. Saunders Co., p. 860. 4. Glinick SE, Alper JC, Bogaars H, Brown JA: Becker's melanosis: Associated abnormalities. ,1 AM ACAD DERMATOL9:509-514, 1983. 5. Takayasu H, Ueno A, Tsukada O: Accessory scrotum: A case report. J Urol 112:826-827, 1974. 6. Hata Y: Accessory scrotum. Plast Reconstruct Surg 66:613-616, 1980.
Becker' s nevus and a c c e s s o r y scrotum
7. Daut WW, Daut RV: Accessory scrotum posteriorly located: Review of the literature and report of a case. J Iowa State Med Soc 39:194-195, 1949. 8. Azmy A, Ransley 1:'(3: Accessory scrotum. Z Kinderchir 33:373-374, 1981. 9. Redman JF, Morris WD: Accessory perineal scrotum. Urology 23:406-407, 1983.
Increased muscle tone during etretinate therapy Charles N. Ellis, M . D . , * ' * * Martin Gilbert, M . D . , * Kenneth A. Cohen, M . D . , * J a m e s W. Albers, M . D . , P h . D . , * * * ' * * * * Richard D. Ball, M . D . , P h . D . , * * * * Roger L. Albin, M . D . , * * * Alan Silverman, M . D . , * and John J. Voorhees, M . D . * A n n Arbor, M I A 40-year-old man with severe psoriasis developed painless muscle stiffness coinciding with four successive courses of etretinate therapy. Peripheral nerve block extinguished the increased muscle tone. Our patient's symptoms resembled those of the stiff-man syndrome. Increased muscle tone is a potential side effect of etretinate treatment and must be distinguished from the common musculoskeletal symptoms observed in patients taking retinoid therapy. (J AM ACAD DERMATOL14:907-909, 1986).
Etretinate (Tegison), an aromatic vitamin A derivative, has proved efficacious in the treatment of psoriasis. ~Marketed in Europe for several years, its use in the United States is restricted to experimental clinical trials. Its side effects are similar to those o f chronic h y p e r v i t a m i n o s i s A and consist m a i n l y o f xerosis of skin and mucosa, thinning of From the Clinical PharmacologyUnit of the Departmentof Dermatology,* the Department of Neurology,*** and the Departmentof Physical Medicine and Rehabilitation,****Universityof Michigan Medical School, and the DermatologyService, VeteransAdministration Medical Center.** Supported in part by the Babcock DermatologieEndowment. Reprint requests to: Dr. Charles N. Ellis, DermatologyService(110), Veterans AdministrationMedical Center, Ann Arbor, MI 48105/ 313-769-7100, ext. 781.
the hair, bone and joint pain, muscle aches, fatigue, and nausea. 2 We are reporting a case of increased muscle tone associated with etretinate therapy. CASE R E P O R T A 40-year-old white man with severe, plaque-type psoriasis of 20 years' duration had been unsuccessfully treated with conventional forms of therapy, including topical corticosteroids, modified Goeckerman regimen, psoralens with ultraviolet A, and methotrexate. After providing informed consent, the patient began etretinate therapy in July 1981 as a participant in a study approved by our institutional review board. He received an initial 6-month course of etretinate and two subsequent 9month courses and has begun a fourth course. Etretinate was discontinued for 3 months between each treatment
907
908
Journal of the American Academy of Dermatology
Ellis et al
course. Emollients were the only other form of treatment allowed at any time during this study. The patient's doses of etretinate ranged from 0.6 to 1.0 rag/ kg/day. The patient's psoriasis improved remarkably during etretinate treatment but recurred within a few weeks to a few months, when etretinate was discontinued. Known side effects of etretinate therapy, including xerosis of skin and mucosa, stickiness of skin, and palmoplantar desquamation, were observed in our patient during periods of therapy. In addition, our patient repeatedly complained of painless muscle stiffness without cramping 2 to 3 months after the initiation of each course of etretinate. This symptom was worse with each subsequent course of etretinate therapy, although it resolved within a few weeks each time he stopped taking the drug. The patient's stiffness involved primarily his axial and lower extremity muscles. It was more noticeable on relaxation of the involved extremities and improved with repeated movement. There was no history of either exerciseinduced stiffness or myoglobinuria, nor was there a family history of neurologic or muscle disease. He had no symptoms of arthritis or hypothyroidism. The patient was taking no medication other than etretinate and denied taking any vitamin supplements or phenothiazines. Radiographs of the cervical spine obtained at the termination of the patient's initial 6-month course of etretinate therapy showed only mild degenerative changes. Subsequently, radiographs of the lumbosacral spine, sacroiliac joints, and hips were obtained at the temaination of his second course of etretinate therapy. These films were normal except for minimal sclerosis of the lilac side of the left sacroiliac joint. Serum calcium levels and liver function remained normal. Neurologic examination performed during the third course of etretinate demonstrated a slow, broad-based gait with flexion at the hips and knees. The lower extremities showed a striking increase in tone of the leadpipe variety. Following volitional or passive extension at the knees, requested relaxation resulted in the legs' slowly (over seconds) returning to a relaxed position. Percussion myotonia was not present. With repetition, muscle tone approached normal. The remainder of the motor and sensory examinations had normal results, and muscle stretch reflexes were also normal. No pathologic reflexes, tetany, or contractures were present. Nerve conduction and electromyographic studies had normal results with the exception of persistent motorunit action-potential activation in the quadriceps muscle during attempted relaxation. As the limb came to rest, all motor units eventually disappeared.
On the basis of these findings, we believed that our patient's increased tone was the result of a central nervous system (e.g., spinal cord) effect similar to that seen in the stiff-man syndrome, 3 although an intrinsic mechanical abnormality of muscle could not be excluded. A femoral nerve block performed with the patient under local anesthesia resulted in a flaccid paralysis of the quadriceps muscles, demonstrating that the increased tone was neurogenic. The neurologic evaluation and electromyography were repeated 2 months after the end of the patient's third course of etretinate; both the muscle tone and the electromyogram were normal. The increased muscle tone recurred within a few weeks after our patient began his fourth course of etretinate. In an attempt to relieve his stiffness, we gave our patient baclofen, a centrally acting analog of 3'aminobutyric acid, a putative inhibitory neurotransmitter. Baclofen reduces muscle rigidity through spinal cord reflex mechanisms and is beneficial in some cases of stiff-man syndrome. 4 After the patient took baclofen, 20 mg three times daily tor 1 month, both subjective and objective improvements in his altered muscle tone were noted. Subsequently the patient again developed increased tone in the lumbosaeral paraspinal muscles, which has persisted despite an increase in his dose of baclofen to 90 mg daily. Although his lower extremity symptoms have resolved, he now has difficulty bending because of the increased tone in his back. The degree of his physical impairment has made the patient consider stopping his etretinate therapy. COMMENT In addition to demonstrating m a n y of the recognized side effects o f etretinate, our patient developed increased muscle tone initially involving primarily his lower extremities. This increase in muscle tone occurred repeatedly during four different courses of etretinate. The symptom resolved completely within a few weeks after each interruption of etretinate treatment. There was no evidence of arthritis other than the minimal degenerative changes noted on radiographs. No disturbance of calcium metabolism or evidence of hypothyroidism was noted in our patient. A femoral nerve block temporarily eliminated the increased tone, excluding an intrinsic muscle abnormality as the cause o f our patient's symptoms. Our patient's initial improvement while taking baclofen suggested that central nervous system
Volume 14 Number 5, Part 2 May, 1986
effects of etretinate were responsible for his symptoms. The clinical and electrodiagnostic findings in our patient resembled many of those seen in patients with early or mild stiff-man syndrome. Characteristic were the symmetric muscle stiffness and boardlike rigidity, the axial predilection, the absence o f corticospinal tract signs, local relief with nerve block, and during attempted rest, prolonged motor-unit action-potential activity that was indistinguishable from voluntary activation. Unlike the findings in classic stiff-man syndrome, our patient lacked the severe paroxysmal muscle spasms, the progression o f stiffness to diffuse musculature, the typical extended posture, and the indefinite persistence of motor-unit action-potential activity at rest. Muscle stiffness also may be found in chronic hypervitaminosis A . 5'6 A striking example was reported by M u e n t e r et al, 7 but these authors were unable to conclude whether the muscle stiffness was o f myogenic or neurogenic origin. Stiffness has been observed in dogs given etretinate, 8 although it is unclear whether the stiffness was muscular in nature or a consequence of pathologic bone fractures that the dogs developed. Musculoskeletal symptoms in the form of intermittent muscle aches are frequent during etretinate therapy. 2 Similarly, patients taking isotreti-
Increased muscle tone during etretinate therapy
909
noin occasionally have discomfort in their muscles. 9 To our knowledge, this is the first report of increased muscle tone induced by etretinate, a side effect that should be distinguished from the common complaint of muscle aches noted by patients taking retinoids. REFERENCES 1. Peck GL: Retinoids in clinical dermatology, in Fleischmajer R: Progress in diseases of the skin, vol. 1. New York, 1981, Gmne & Stratton, Inc., pp. 227-269. 2. Windborst DB, Nigra T: General clinical toxicology of oral retinoids. J AM AC_ADDERMATOL 6:675-682, 1982. 3. Moersch FD, Woltman HW: Progressive fluctuating muscular rigidity and spasm ("stiff-man" syndrome): Report of a case and some observations in 13 other cases. Proe Mayo Clin 31:421-427, 1956. 4. Miller F, Korsvik H: Baclofen in the treatment of stiffman syndrome. Ann Neurol 9:511-512, 1981. 5. Gerber A, Raab AP, Sobel AE: Vitamin A poisoning in adults with description of a case. Am J Med 16:729-745, 1954. 6. Fumich RM, Essig GW: Hypervitaminosis A: Casereport in an adolescent soccer player. Am J Sports Med 11:3437, 1983. 7. Muenter DM, Perry HO, Ludwig J: Chronic vitamin A intoxication in adults. Am I Meal 50:129-136, 1971. 8. KammJJ: Toxicology,carcinogenicity, and teratogenicity of some orally administered retinoids. J AM ACADDERMATOL6:652-659, 1982. 9. ShalitaAR, CunninghamWJ, Leyden IJ, et al: Isotretinoin treatment of aene and related disorders: An update. I AM ACADDERMATOL9:629-638, 1983.