A 6 year old girl presents to your office complaining of progressive weakness for the past two days. Her mother was alarmed this morning when her daughter had difficulty getting out of bed. Yesterday, she slept through most of the day and had a decreased appetite. She developed a low-grade temperature over night. For the past week, she has had a facial rash, which initially began as a reddish raised rash over both cheeks that has expanded to include the bridge of the nose. Coincidentally, her mother has also noticed a dry rash which developed over her daughter's elbows and knees, which she attributed to eczema. The child's medical history is unremarkable and she has been growing and developing appropriately. She is not on any prescribed or over-the-counter medications. Family history is negative for any connective tissue diseases or congenital disorders.
Exam: VS T 37.8, P 120, RR 18, BP 100/50. Wt 20 kg (50%tile), Ht 115 cm (50%tile). She appears subdued and weak. An erythematous plaque encompasses the cheeks and bridge of nose with diffuse borders, resembling a butterfly pattern. You notice a purplish-reddish hue over the upper eyelids along with some periorbital edema. There are several erythematous, scaly, and atrophic papules over her elbows and knees. A similar rash is seen over her interphalangeal joints of the hands. Examination of the nails reveals nailfold telangiectasias and erythema at the cuticles. She has trouble getting to the sitting position, and extreme difficulty getting to the standing position. No hypertrophy or atrophy of any muscle is noticed. Your examination confirms that she has profound symmetrical proximal muscle weakness. Cranial nerve testing and deep tendon reflexes are normal. Muscle fasciculations and infantile reflexes are absent.
Laboratory results: Antinuclear antibodies of (ANA) 1:640 speckled (normal range <1:160), sedimentation rate (ESR) 60 mm/hr (normal range 4-20), creatine kinase (CK) 490 IU/L (normal range 10-55), aspartate aminotransferase (AST) 500 IU/L (normal range 0-35), alanine aminotransferases (ALT) 250 IU/L (normal range 1-30).
Her initial symptoms are nonspecific except for the malar rash and eczema-like lesions on the flexor surfaces. Although this clinical picture is similar to systemic lupus erythematosus (SLE), the cutaneous findings along with the profound proximal muscle weakness make juvenile dermatomyositis (JDM) the more likely diagnosis. Treatment with prednisone (2mg/kg/d) is initiated and within days, she has resolution of her weakness. Her dermatologic symptoms gradually improve and the prednisone is gradually tapered over the course of several weeks.
The approach to the classification of neuromuscular disorders has aimed at distinguishing primary disorders of the muscle (myopathies and myositis) from disorders affecting peripheral nerves (peripheral neuropathies) (1). The spectrum of myopathies ranges from predominantly muscle disorders such as the muscular dystrophies, congenital myopathies, and myositis to multisystem disorders with muscle tissue involvement such as metabolic myopathies and myotonic dystrophy. Fortunately, the incidence of myopathies and myositis is rare. Myositis, which is the inflammation of muscle tissue, makes up the majority of these cases, with JDM as the dominant clinical entity.
In 1903 Steiner defined JDM as an acute, subacute or chronic disease of unknown origin, characterized by a gradual onset with vague and indefinite prodromata followed by edema, dermatitis, and multiple muscle inflammation (1). It is now classified as a rheumatologic condition whereby vasculitis is the etiology of the pathologic condition. JDM occurs in 3-4 cases per 1,000,000 with a predilection for females (2:1) and Caucasians (2). The peak age is 6 years, although there is a bimodal distribution of 5-9 and 10-14 years of age (2). Increased cases of JDM have been reported during the months of February through April (3). Familial cases of JDM are rare but there may be an immunogenetic predisposition among individuals who have the human leukocyte antigens HLA B8 and DR3 (4). The incidence of familial autoimmune diseases is not increased in cases of JDM. Although more common in adult dermatomyositis, JDM is not associated with underlying malignancy (5,6).
Myopathy and myositis commonly present as muscle weakness. The proximal muscles are usually involved although generalized weakness can be seen, especially in infants. Delayed motor milestones can be attributed to myopathic conditions, whereas delayed language and social adaptive behavior, and sensory impairment suggest a cerebral or neuropathic etiology. Myositis is often associated with muscle tenderness over the affected muscles. The clinical presentation of JDM is insidious, often initiating as only fever and malaise. The clinical hallmarks of JDM are the characteristic dermatologic manifestations and profound weakness of the proximal muscles. An erythematous malar rash is commonly found, along with periorbital edema and violaceous discoloration of the upper eyelids (referred to as a heliotrope rash). Pathognomonic of JDM is the finding of Gottron papules, which are erythematous, scaly, atrophic plaques that occur symmetrically over the extensor surfaces of large and small joints. As seen with other vasculopathies, erythema at the cuticles and nailfold telangiectasias may be noted. Palpable and radiographically visible subcutaneous calcinosis is a common finding, occurring in 30-70% of cases (3). The muscle weakness is symmetrical and typically begins at the thighs, and later becomes generalized. A typical presentation entails difficulty in walking up stairs, difficulty in getting up from a chair or bed, and difficulty in combing one's hair. The Gowers sign (where the patient has difficulty rising to a standing position, using his/her hands to "climb up the legs") may be present. In the younger age group, generalized weakness often presents as the initial symptom. Prolonged muscle weakness may eventually lead to muscle contractures. Weakness of the oral muscles can result in nasal speech and dysphagia. Oral ulcers and abdominal pain stemming from vasculitis of the GI tract have been reported. Sun exposure may exacerbate JDM episodes.
Myopathic conditions such as JDM should be considered when evaluating patients with progressive muscle weakness. A methodical assessment of the patient's history and clinical examination is essential in determining the level of the lesion. Hypotonia can be broadly subdivided into myopathies (in which the pathology is confined to the muscle itself, with no associated abnormality in peripheral nerve) and neuropathies (in which muscle weakness is secondary to an abnormality along the peripheral nerve, such as the anterior horn cell to the neuromuscular junction). Myopathies typically present with muscle weakness that is accompanied with proximal atrophy with and without distal pseudohypertrophy, absent muscle fasciculations and infantile reflexes, normal to decreased deep tendon reflexes, and normal sensation (7).
Other hypotonic conditions can be distinguished from myopathies, using several clinical and electromyographic (with nerve condition studies) criteria. Deep tendon reflexes are usually hyperreflexic in upper motor neuron conditions (brain and spinal cord dysfunction), while they are hyporeflexic in anterior horn cell, peripheral nerve, neuromuscular junction and myopathy conditions. A Babinski sign and other primitive reflexes are likely to be present in upper motor neuron (brain and spinal cord) conditions, but they would likely be absent in most other conditions. Muscle fasciculations are likely to be seen in upper motor neuron and anterior horn cell conditions, but not likely to be seen in muscle or neuromuscular junction conditions. Electromyography (EMG) and nerve conduction studies can usually distinguish myopathic conditions from neuropathic conditions.
Inflammatory myopathies (myositis), which includes JDM, polymyositis, inflammatory myopathy associated with other connective tissue diseases, and acute viral myositis, can present with mild to severe muscle weakness. These disorders often have a bacterial, parasitic or viral origin, and have been linked with connective tissue diseases. The common feature of inflammatory myopathies is the involvement of the muscle through an inflammatory process. The above case is a classic presentation of JDM, where the dermatologic and progressive proximal muscle weakness are characteristic of the disease. Exact criteria for the diagnosis of JDM is as follow:
1) Characteristic rash.
2) Progressive symmetrical proximal muscle weakness.
3) Elevated muscle derived enzymes.
4) EMG changes - myopathic pattern.
5) Muscle histopathology - inflammatory changes.
Consistent clinical and laboratory findings are often enough to initiate therapy, sparing the patient from the invasive EMG and muscle biopsy procedures. EMG and muscle biopsy are beneficial when clinical and laboratory findings are inconsistent, or if initial therapy fails to resolve symptoms. Increased antibody titers and viral isolation of Coxsackie virus has led many investigators to consider it to be the causative agent for JDM (3).
The clinical presentation of polymyositis is identical to JDM except for the lack of the dermatologic manifestations. Polymyositis is predominantly a disease of adults, and is thought to have a rheumatologic etiology. In contrast to JDM, polymyositis has less primary vessel involvement seen on muscle biopsy and soft tissue calcifications are rare (3). Viral myositis can also present with proximal muscle weakness, but differs from other inflammatory myopathies by its propensity to affect calf muscles. Severe pain over affected muscle is typical and more pronounced than in JDM. Viral myositis usually occurs 1-2 days after an upper respiratory infection and is commonly attributed to influenza A and B infections (8). Rapid resolution occurs within weeks. Inflammatory myopathy in SLE is rare, especially in children. In rare cases of SLE induced myopathy, there is elevated double stranded DNA, reduced serum levels of complement, and presence of immune complexes much higher than that seen in JDM (3).
Hereditary myopathic disorders, such as muscular dystrophy and metabolic myopathies, can present as proximal muscle weakness. They typically manifest at birth but can present later in life. As discussed in the muscular dystrophy chapter, the neurologic findings of muscular dystrophies are consistent with a myopathic pattern, presenting as hypotonia in infancy or progressive weakness of proximal to distal muscles in childhood. Muscular dystrophies, however, lack the dermatologic changes seen in JDM and are gradual and progressive in nature. Some hereditary metabolic myopathies are not detected until late in childhood. Metabolic myopathies are rare and frequently fatal. They result from specific metabolic defects of glycogen, lipid, or energy metabolism, often due to mitochondrial dysfunction. These diseases, such as glycogenoses disorders, carnitine deficiencies, Kearns-Sayre syndrome, and myoclonic epilepsy and ragged red fibers (MERRF), often involve multi-organ systems such as the skeletal muscular, hepatic and nervous systems. Patients with hereditary metabolic myopathies report exercise intolerance, and muscle weakness/pain after exercise or stress. Dermatologic findings are absent.
Endocrinopathies can induce myopathic conditions, although the clinical symptoms associated with endocrine induced myopathies are typically that of muscle cramps and contractures. Derangements in thyroid and adrenal functions are the common endocrinopathies associated with myopathy. Thyrotoxicosis causes proximal weakness and wasting through the binding of thyroxine to myofibrils, which impair contractility. Hyperthyroidism may also induce myasthenia gravis and hypokalemic periodic paralysis (9). Likewise, hypothyroidism can cause muscle weakness, diffuse muscle hypertrophy ('myoedema') and inflammation (10). The correction of thyroid function results in the resolution of the myopathic condition. Corticosteroid induced myopathy (Cushing disease and Cushing syndrome) is associated with a nonspecific proximal myopathy with selective type 2 fiber atrophy (3). Adrenal failure produces nonspecific muscle weakness and in chronic cases, muscle contractures. Myopathy associated with diabetes and hyperparathyroidism have been described but are rare.
Hypokalemic periodic paralysis is an inherited autosomal disorder with full penetrance. The etiology of this paralysis is thought to be an abnormality of the muscle cell membrane, particularly an impairment of the calcium ion channel. Attacks of profound generalized weakness begin suddenly during the first and second decade of life. These episodes usually last for several hours and are triggered by vigorous exercise, heavy carbohydrate meals, or anxiety. These patients present with profound hypokalemia (often less than 2.0). Potassium replacement usually results in fairly rapid recovery. Compared to JDM, patients with hypokalemic periodic paralysis are usually asymptomatic prior to and after these attacks.
Non-myopathic conditions should also be considered in patients with proximal muscle weakness. Guillain-Barre Syndrome (GBS) is an inflammatory polyradiculopathy, whereby the nerve roots and peripheral nerves are involved. Weakness follows an ascending pattern, progressing for several days to weeks, reaching a plateau, and then recovers over a period of several months. Reflexes are diminished, and patients can experience sensory abnormalities and severe back pain. There are no dermatologic findings in GBS. Lesions of the neuromuscular junction, such as myasthenia gravis, Lambert-Eaton myasthenic syndrome and botulism, can result in proximal muscle weakness. The weakness, often presenting as ptosis and diplopia, worsens with use and recovers with rest. In JDM, extraocular and facial muscles are rarely involved. Abnormalities of the peripheral nerve and neuromuscular junction do not have elevations in muscle derived enzymes and EMG findings are characteristic of the level of the lesion. Metabolic abnormalities such as hypophosphatemia and hypokalemia can result in muscle weakness but these symptoms are generalized.
Muscle derived enzymes (CK, myoglobin, AST, aldolase and lactic dehydrogenase) are elevated in JDM, representing damage to the muscle either through reduction in vascular supply or by direct immunogenic cytotoxicity. The CK elevation in JDM is usually in the range of several hundred, versus the much higher elevations in muscular dystrophies. Inflammatory markers such as ESR, white blood cell count, and ANA are commonly elevated. Von Willebrand factor-related antigen, a sensitive indicator of endothelial cell damage, has recently been used as a marker for JDM therapy (3).
EMG is a valuable tool in differentiating between myopathies and neuropathies, but is limited in further delineating the diagnosis. An EMG is performed by inserting a fine needle electrode into affected muscle to record its contractions. The procedure is painful and should be avoided in areas where future muscle biopsy may be planned. The typical EMG pattern in myopathies is that of low amplitude, polyphasic, potentials of short duration. Nerve conduction velocity is normal and unchanged with repetitive stimulation. These myopathic features suggest a myopathy as opposed to neuropathic findings which suggest a neuropathy.
A muscle biopsy can be beneficial in establishing the definitive diagnosis, especially in hereditary or congenital myopathies. Muscle biopsy is limited in that it is invasive and painful. It may not provide a specific diagnosis, if the muscle biopsied is not significantly affected by the disease process or if it not obtained appropriately. The quadriceps or biceps are typically biopsied in accessing proximal muscle weakness. The muscle histopathology of JDM shows infiltration with inflammatory cells, perifascicular atrophy, and capillary necrosis. Besides the usual histologic examination of the muscle tissue, specific staining procedures should be employed in differentiating JDM from hereditary disorders. Biochemical analyses on dystrophin protein levels assist in evaluating muscular dystrophies. Hereditary metabolic disorders should be evaluated with assays for glycolytic enzyme activity, respiratory chain enzyme complexes (i.e., oxidative phosphorylation enzymes largely found in mitochondria), carnitine levels, and fatty acid chain transport substrates. Electron microscopy can assist in evaluating mitochondrial abnormalities.
The treatment of JDM consists of immunosuppression and supportive care. Prompt initiation of corticosteroids reduces the long term complications of calcinosis and muscle contractures. Initial therapy can control muscle inflammation and gastrointestinal bleeding that results from vasculitis of the GI tract. Not uncommonly, the elevated muscle derived enzymes will normalize after the initial doses of corticosteroids. A maintenance dose of corticosteroids is titrated to normalize creatinine kinase levels and this is continued for approximately 1-2 years when re-occurrences, though rare, may develop (1,6). Other immunosuppressive agents, such as methotrexate, cyclosporin, and azathioprine are employed if corticosteroids are unable to reduce the inflammatory process. Nasogastric tube feedings may be necessary to protect the airways and in cases of severe dysphagia. Malabsorption of nutrients and medications can occur in cases of severe GI vasculitis, thus requiring parenteral nutrition and medication. Physical and occupational therapy programs are employed to avoid excessive deconditioning and to reduce muscle contractures.
Questions
1. True/False: Can sun exposure result in flare-ups in JDM?
2. What is the rate of recurrence in JDM?
3. Myopathies are most likely to cause:
. . . . . a. Delayed language skills.
. . . . . b. Sensory impairment.
. . . . . c. Delayed developmental motor milestones.
. . . . . d. Delayed social adaptive behavior.
4. Each of the following is true about myopathies, except:
. . . . . a. Distal weakness suggests a myopathic condition.
. . . . . b. Weakness is the primary symptom.
. . . . . c. Weakness or pain following exercise is a common feature of metabolic myopathies.
. . . . . d. Pain is not usually a feature of muscular dystrophies.
5. Which of the following (may be more than one) are typical of acute viral myositis but not JDM?
. . . . . a. Acute onset.
. . . . . b. Pain.
. . . . . c. Biceps involvement.
. . . . . d. Elevated CPK.
. . . . . e. Elevated ESR.
. . . . . f. Spontaneous resolution.
References
1. Dubowitz V. Muscle Disorders in Childhood. 1995, London: WB Saunders Co.
2. Pachman LM. Juvenile dermatomyositis. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Co., pp. 717-720.
3. Pachman LM. Juvenile dermatomyositis: A clinical overview. Pediatr Rev 1990;12:117-125.
4. Turner TL, Boom JA. Index of Suspicion: Case 1 Presentation. Pediatr Rev 2000;21:389-390.
5. Buchbinder R, Forbes A, Hall S, et al. Incidence of malignant disease in biopsy-proven inflammatory myopathy. Ann Intern Med 2001;134:1087-1095.
6. Spiro AJ. Childhood dermatomyositis and polymyositis. Pediatr Rev 1984;6:163-172.
7. Vannucci RC. Differential diagnosis of diseases producing hypotonia. Pediatr Ann 1989;18:404-438.
8. Miller G. Myopathies of infancy and childhood. Pediatr Ann 1989;18:439-453.
9. Sarnat HB. Neuromuscular disorders. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Co., pp. 1867-1893.
10. Patterson MC. Muscle disease in children: A practical approach. Pediatr Rev 1990;12:73-82.
Answers to questions
1. True. Sun exposure can exacerbate JDM dermatologic lesions and myositis, even during therapy. It is important to advise patients with JDM about appropriate sun protection - large rimmed hat, clothing over majority of body in sun, sunblock with a SPF of 15 or higher.
2. Unknown, but thought to be low. The risk of recurrence of JDM is highest in the first year after diagnosis, therefore maintenance prednisone is usually continued for 2 years.
3. c.
4. a
5. a, b and f are correct. Pain is typically greater in viral myositis than in JDM. Acute viral myositis has a propensity to affect the calf region, rather than the biceps. Both viral myositis and JDM have elevated CPK and ESR so these tests do not distinguish the two.