CASE REPORTS
Systemic Lupus Erythematosus, Myasthenia Gravis, and Ehlers-Danlos Syndrome C. E. Branch, Jr, CPT, MC, USA, and T. R. Swift, MD
Clinical, electrophysiological, and laboratory data are reported on a 2 1-year-old black woman with systemic lupus erythematosus, myasthenia gravis, and EhlersDanlos syndrome. T h e first two diseases are related by similar pathogenetic mechanisms. To our knowledge, this is the first patient reported with this unusual combination of rare diseases. Branch CE Jr, Swift TR: Systemic lupus erythematosus, myasthenia gravis, and Ehlers-Danlos syndrome. Ann Neurol4:374-375, 1978
Physical examination at admission revealed a thin woman with generalized proximal muscle weakness. Bilateral ptosis appeared after repeatedly opening and closing the eyes and improved dramatically with intravenous administration of edrophonium, 8 mg. The skin had a velvety texture and was easily stretchable, particularly over the elbows and knees (Fig 1). T h e joints of her hands and feet were hyperextensible. The rest of the physical examination was unremarkable, and studies of nerve conduction velocity were normal in the upper and lower extremities. On needle examination, motor unit potentials were decreased in amplitude and duration and varied in amplitude. Single-fiber studies revealed increased jitter and blocking. Repetitive stimulation of the ulnar nerve produced a progressive decline in amplitude ofthe muscle action potential and twitch tension of the type seen in MG (Fig 2 ) . Pyridostigmine, 60 mg every 4 hours, greatly improved her strength and ability to swallow and corrected the double vision. Five months later, because of increasing weakness, high-dose oral prednisone therapy was begun. The patient's strength returned, and pulmonary function tests improved greatly.
Discussion Systemic lupus erythematosus (SLE) and myasthenia gravis (MG) occur together at a frequency greater than that expected by chance alone [9].The occurrence of these two diseases and a n even rarer third disease, Ehlers-Danlos syndrome (EDS), in a single patient forms the basis of this report.
A 2 1-year-old black woman complained of generalized muscle weakness. For one year the patient had noted drooping of' both eyelids and generalized fatigue late in the afternoon. During the three weeks before hospitalization she developed horizontal diplopia and nasal regurgitation of fluids. At age 17 she had been evaluated for complaints of joint pain, fever, and pleuritic chest pain. Laboratory values at that time revealed positive LE preparations, the presence of antinuclear antibodies (ANA) that were 4+ positive, anti-DNA binding that was 93.4%, a P C l complement level of 114 mg/dl, negative Rh factors and A N A titers, normal SMA 18 that included creatine phosphokinase and aldolase, and a normal blood count except for an elevated sedimentation rate of 40 mm per hour. A diagnosis of SLE was made. She was started o n a regimen of prednisone, 5 mg orally three times a day. She was noted to have hyperextensibility of the joints in both hands and feet, cigarette-paper scars on her knees and elbows, and poor wound healing. A diagnosis of EDS type 11 was made. No other family members were affected.
T h e similarities between SLE and MG have been noted by many authors. Both diseases occur predominantly in young women, and both are characterized by exacerbations and remissions. T h e y share t h e presence of positive fluorescent antinuclear antibodies [l] and hyperplastic changes in the thymus [4]. Thymic hyperplasia in both these diseases is asso-
F i g I . Easily stretchable skin wer the elbow.
From the Neurology Service, Fitzsimons Army Medical Center, Denver, CO, and the Department of Neurology, Electromyography Laboratory, Medical College of Georgia, Augusta, GA.
Accepted for publication Mar 7, 1978. Address reprint requests to Dr Swift, Department of Neurology, Medical College of Georgia, Augusta, G A 3090 1.
374 0364-5134/78/0004-0413$01.~0@ 1978 Iby C. E. Branch, Jr
F i g 2. Muscle action potentials (top)and twitch tensions (bottom) of adductor polliris muscle in response to d n a r nerve stimulation at 2lser-.
ciated with an increased incidence of HL-A8 tissue type [3]. Both SLE and M G appear to be diseases of altered immunity. Antibodies directed against acetylcholine receptor are present in a majority of patients with M G [7]. An animal disease resembling MG, called experimental autoimmune MG, has been developed that strongly resembles the human disease and suggests an underlying immunological pathogenesis 161. In addition, it is well known that in kidney biopsies of patients with SLE, immunofluorescent stains reveal the presence of immunoglobulins and the third component of complement (C3) in involved areas as well as in the mesangium [ 5 ] . A recent report has identified an immunoglobulin, IgG, as well as C3 at the motor end-plate in patients with M G [2]. The term collagen disease is commonly used to apply to a group of diseases including SLE, dermatomyositis, progressive systemic sclerosis, and periarteritis nodosa. In this sense, it is used to refer to a pathological arterial change, fibrinoid degeneration, and except for progressive systemic sclerosis, does not refer to a specific abnormality in the metabolism of collagen. O n the other hand, true diseases of collagen refer to a select group of conditions that exhibit abnormalities in the patient’s synthesis and structural arrangement of collagen. These include EDS, osteogenesis imperfecta, cutis laxa, and Marfan syndrome [S]. The patient reported here is unique in that she has both a “collagen disease” and a true disease of collagen in the specific sense. The seven forms of EDS can be separated by clinical, genetic, and sometimes biochemical criteria [S]. All seven types are believed to be related to biochemical and structural abnormalities in collagen. Type I1 is of intermediate severity, and these patients have hypermobile joints and stretchable skin, with a tendency to form atrophic scars. It is inherited as an autosomal, dominant trait. Neurological problems in patients with EDS have usually occurred secondary to subarachnoid hemorrhages or other acute vascular insults to the nervous system. These have arisen from multiple intracranial aneurysms, thrombotic occlusions, subdural hematomas, o r arteriovenous malformations [ 11. Other reported associated neurological problems
are neurofibromatosis, Erb’s palsy, mental retardation, severe leg cramps, amyotrophic lateral sclerosis, and muscular hypotonia in neonates with the syndrome. Easy fatigability is frequently complained of by patients with EDS, and indeed, until M G was diagnosed in this patient, her complaints of fatigability were attributed to EDS. Although M G and SLE are probably related in this patient by virtue of their similar pathogenetic mechanisms, EDS does not appear to be a disease of altered immunity and probably represents a chance association.
References 1. Adner MM, Sherman JD, Is&C , et al: An immunologic survey of 48 patients with myasthenia gravis. N Engl J Med 271: 1327-1333, 1964 2. Engel AG, Lambert E H , Howard FM: Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis. Mayo Clin Proc 52:267-280, 1977 3. Fritze D , Herrmann C, Naeim F, et al: The biologic significance of HL-A antigen markers in myasthenia gravis. Ann N Y Acad Sci 274:440-450, 1976 4. Hutchins G M , Harvey AM: The thymus in systemic lupus erythematosus. Bull Johns Hopkins Hosp 115:355-378, 1964 5 . Koffler D, Schur P, Kunkel HG: Immunological studies concerning the nephritis of systemic lupus erythematosus. J Exp Med 126:607-624, 1967 6 . Lennon VA, Lindstrom JM, Seybold ME: Experimental autoimmune myasthenia gravis: cellular and humoral immune responses. Ann N Y Acad Sci 274:283-299, 1976 7 . Lindstrom JM, Seybold ME, Lennon VA, e t al: Antibody to acetylcholine receptor in myasthenia gravis. Neurology (Minneap) 26:1054-1059, 1976 8. Uitto J, Lichtenstein JR: Defects in the biochemistry of collagen in diseases of connective tissue. J Invest Dermatol 66:597 9 , 1976 9. Wolf SM, Barrows HS: Myasthenia gravis and systemic lupus erythematosus. Arch Neurol 14:254-258, 1966
Case Report: Branch and Swift: SLE, MG, and Ehlers-Danlos Syndrome 375
Systemic Lupus Erythematosus, Myasthenia Gravis, and Ehlers-Danlos Syndrome C. E. Branch, Jr, CPT, MC, USA, and T. R. Swift, MD
Clinical, electrophysiological, and laboratory data are reported on a 2 1-year-old black woman with systemic lupus erythematosus, myasthenia gravis, and EhlersDanlos syndrome. T h e first two diseases are related by similar pathogenetic mechanisms. To our knowledge, this is the first patient reported with this unusual combination of rare diseases. Branch CE Jr, Swift TR: Systemic lupus erythematosus, myasthenia gravis, and Ehlers-Danlos syndrome. Ann Neurol4:374-375, 1978
Physical examination at admission revealed a thin woman with generalized proximal muscle weakness. Bilateral ptosis appeared after repeatedly opening and closing the eyes and improved dramatically with intravenous administration of edrophonium, 8 mg. The skin had a velvety texture and was easily stretchable, particularly over the elbows and knees (Fig 1). T h e joints of her hands and feet were hyperextensible. The rest of the physical examination was unremarkable, and studies of nerve conduction velocity were normal in the upper and lower extremities. On needle examination, motor unit potentials were decreased in amplitude and duration and varied in amplitude. Single-fiber studies revealed increased jitter and blocking. Repetitive stimulation of the ulnar nerve produced a progressive decline in amplitude ofthe muscle action potential and twitch tension of the type seen in MG (Fig 2 ) . Pyridostigmine, 60 mg every 4 hours, greatly improved her strength and ability to swallow and corrected the double vision. Five months later, because of increasing weakness, high-dose oral prednisone therapy was begun. The patient's strength returned, and pulmonary function tests improved greatly.
Discussion Systemic lupus erythematosus (SLE) and myasthenia gravis (MG) occur together at a frequency greater than that expected by chance alone [9].The occurrence of these two diseases and a n even rarer third disease, Ehlers-Danlos syndrome (EDS), in a single patient forms the basis of this report.
A 2 1-year-old black woman complained of generalized muscle weakness. For one year the patient had noted drooping of' both eyelids and generalized fatigue late in the afternoon. During the three weeks before hospitalization she developed horizontal diplopia and nasal regurgitation of fluids. At age 17 she had been evaluated for complaints of joint pain, fever, and pleuritic chest pain. Laboratory values at that time revealed positive LE preparations, the presence of antinuclear antibodies (ANA) that were 4+ positive, anti-DNA binding that was 93.4%, a P C l complement level of 114 mg/dl, negative Rh factors and A N A titers, normal SMA 18 that included creatine phosphokinase and aldolase, and a normal blood count except for an elevated sedimentation rate of 40 mm per hour. A diagnosis of SLE was made. She was started o n a regimen of prednisone, 5 mg orally three times a day. She was noted to have hyperextensibility of the joints in both hands and feet, cigarette-paper scars on her knees and elbows, and poor wound healing. A diagnosis of EDS type 11 was made. No other family members were affected.
T h e similarities between SLE and MG have been noted by many authors. Both diseases occur predominantly in young women, and both are characterized by exacerbations and remissions. T h e y share t h e presence of positive fluorescent antinuclear antibodies [l] and hyperplastic changes in the thymus [4]. Thymic hyperplasia in both these diseases is asso-
F i g I . Easily stretchable skin wer the elbow.
From the Neurology Service, Fitzsimons Army Medical Center, Denver, CO, and the Department of Neurology, Electromyography Laboratory, Medical College of Georgia, Augusta, GA.
Accepted for publication Mar 7, 1978. Address reprint requests to Dr Swift, Department of Neurology, Medical College of Georgia, Augusta, G A 3090 1.
374 0364-5134/78/0004-0413$01.~0@ 1978 Iby C. E. Branch, Jr
F i g 2. Muscle action potentials (top)and twitch tensions (bottom) of adductor polliris muscle in response to d n a r nerve stimulation at 2lser-.
ciated with an increased incidence of HL-A8 tissue type [3]. Both SLE and M G appear to be diseases of altered immunity. Antibodies directed against acetylcholine receptor are present in a majority of patients with M G [7]. An animal disease resembling MG, called experimental autoimmune MG, has been developed that strongly resembles the human disease and suggests an underlying immunological pathogenesis 161. In addition, it is well known that in kidney biopsies of patients with SLE, immunofluorescent stains reveal the presence of immunoglobulins and the third component of complement (C3) in involved areas as well as in the mesangium [ 5 ] . A recent report has identified an immunoglobulin, IgG, as well as C3 at the motor end-plate in patients with M G [2]. The term collagen disease is commonly used to apply to a group of diseases including SLE, dermatomyositis, progressive systemic sclerosis, and periarteritis nodosa. In this sense, it is used to refer to a pathological arterial change, fibrinoid degeneration, and except for progressive systemic sclerosis, does not refer to a specific abnormality in the metabolism of collagen. O n the other hand, true diseases of collagen refer to a select group of conditions that exhibit abnormalities in the patient’s synthesis and structural arrangement of collagen. These include EDS, osteogenesis imperfecta, cutis laxa, and Marfan syndrome [S]. The patient reported here is unique in that she has both a “collagen disease” and a true disease of collagen in the specific sense. The seven forms of EDS can be separated by clinical, genetic, and sometimes biochemical criteria [S]. All seven types are believed to be related to biochemical and structural abnormalities in collagen. Type I1 is of intermediate severity, and these patients have hypermobile joints and stretchable skin, with a tendency to form atrophic scars. It is inherited as an autosomal, dominant trait. Neurological problems in patients with EDS have usually occurred secondary to subarachnoid hemorrhages or other acute vascular insults to the nervous system. These have arisen from multiple intracranial aneurysms, thrombotic occlusions, subdural hematomas, o r arteriovenous malformations [ 11. Other reported associated neurological problems
are neurofibromatosis, Erb’s palsy, mental retardation, severe leg cramps, amyotrophic lateral sclerosis, and muscular hypotonia in neonates with the syndrome. Easy fatigability is frequently complained of by patients with EDS, and indeed, until M G was diagnosed in this patient, her complaints of fatigability were attributed to EDS. Although M G and SLE are probably related in this patient by virtue of their similar pathogenetic mechanisms, EDS does not appear to be a disease of altered immunity and probably represents a chance association.
References 1. Adner MM, Sherman JD, Is&C , et al: An immunologic survey of 48 patients with myasthenia gravis. N Engl J Med 271: 1327-1333, 1964 2. Engel AG, Lambert E H , Howard FM: Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis. Mayo Clin Proc 52:267-280, 1977 3. Fritze D , Herrmann C, Naeim F, et al: The biologic significance of HL-A antigen markers in myasthenia gravis. Ann N Y Acad Sci 274:440-450, 1976 4. Hutchins G M , Harvey AM: The thymus in systemic lupus erythematosus. Bull Johns Hopkins Hosp 115:355-378, 1964 5 . Koffler D, Schur P, Kunkel HG: Immunological studies concerning the nephritis of systemic lupus erythematosus. J Exp Med 126:607-624, 1967 6 . Lennon VA, Lindstrom JM, Seybold ME: Experimental autoimmune myasthenia gravis: cellular and humoral immune responses. Ann N Y Acad Sci 274:283-299, 1976 7 . Lindstrom JM, Seybold ME, Lennon VA, e t al: Antibody to acetylcholine receptor in myasthenia gravis. Neurology (Minneap) 26:1054-1059, 1976 8. Uitto J, Lichtenstein JR: Defects in the biochemistry of collagen in diseases of connective tissue. J Invest Dermatol 66:597 9 , 1976 9. Wolf SM, Barrows HS: Myasthenia gravis and systemic lupus erythematosus. Arch Neurol 14:254-258, 1966
Case Report: Branch and Swift: SLE, MG, and Ehlers-Danlos Syndrome 375
