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It is said that in dermatomyositis(DM) , proximal muscle weakness is seen earlier than distal muscle weakness. It is also said that , DM is due to damage to small blood vessels contributing to muscle injury.( from Robbin's textbook of pathology pg.no: 1238-1239, 10e)
Shouldn't the distal group of muscles being smaller show weakness earlier? Why inclusion body myositis does not follow the pattern as in DM?
Usefull links: https://www.mda.org/disease/dermatomyositis/causes-inheritance https://emedicine.medscape.com/article/332783-overview#a1
My hypothesis are
1) Since skin, is commonly involved in sunexposed areas, may be enviornmental factors do play a major role. So, Proximal Muscles are more used in day to day work, so are more favourable site for drugs, autoantibodies to act upon.
2)May be, in case of due to drugs or vaccines, proximal muscles may be are preferrential site of action of these, making these group of muscle more suceptible.
By the way correct answer would be: Its under research.
Adult and Adolescent Onset Muscular Dystrophies Part 1: Evaluation and Diagnosis
Adult and adolescent onset muscular dystrophies (MDs) are a group of disorders that cause muscle disease (myopathy) characterized by progressive muscle weakness (myasthenia) and muscle degeneration (atrophy) due to mutations in one or more genes required for normal muscle function. 1 These mutations alter the function of proteins responsible for muscle structural support and homeostasis. Other organ systems can be affected in many of these conditions as some of these proteins are not localized to just skeletal muscle. As a general rule, muscle dystrophies present with proximal and symmetric muscle weakness, though some types may present with distal or regional weakness. 2,3 They are historically categorized by patterns of weakness (regional MDs, distal MDs) and inheritance (autosomal dominant, autosomal recessive, X-linked). In some cases, a discrete mutation accounts for a specific clinical syndrome. They can also be classified by age of presentation (congenital MDs). It has been increasingly recognized that different mutations can present phenotypically similar, while conversely a specific gene mutation can lead to different phenotypes.
The most common adult and adolescent onset muscular dystrophies that will be briefly reviewed include the following: myotonic dystrophy, Emery-Dreifuss muscular dystrophy (EDMD), facioscapulohumeral dystrophy (FSHD), and limb-girdle muscular dystrophies (LGMDs).
Dystrophinopathies (Duchenne/Becker MD) are discussed as their own subcategory, as are congenital muscular dystrophies such as Merosin-deficient MD, alpha-dystroglycanopathies, and Ullrich congenital MD. These and non-dystrophic myotonic syndromes, metabolic myopathies, and channelopathies are clinically separate syndromes and are discussed elsewhere.
Most MDs are inherited disorders, but spontaneous mutations can occur. These can be X-linked (most EDMD, dystrophinopathies), autosomal dominant (myotonic dystrophies, FSHD and some LGMDs and EDMD) or autosomal recessive (other LGMDs and rare forms of EDMD). Careful history of family members must be a part of medical evaluation.
Epidemiology including risk factors and primary prevention
Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy and is estimated to affect about 1 in 8,000-20,000 in the general population. The prevalence of both DM1 and myotonic dystrophy type 2 (DM2) vary greatly across countries and ethnic groups. 4
The overall incidence and prevalence of EDMD is not known. 5 FSHD has an estimated prevalence of between 4 and 10 in 100,000 and is the third most common type of MD after the dystrophinopathies and myotonic dystrophy. 6 The LGMDs are thought to have a minimum prevalence between 10 and 23 in 100,000. 7 Approximately 250,000 people in the United States have some form of MD. 8
MDs are genetic disorders obtained by way of inheritance or spontaneous mutation. Identifying risk factors and providing primary prevention for patients is difficult due to variable inheritance patterns, possibility of spontaneous mutations, and irregular phenotypic expression. Regardless, genetic counseling should be made available for parents to understand their genetic characteristics and the risk of their offspring inheriting MD.
Though most of these MDs are inherited disorders, the specific genes and proteins affected in each varies.
Myotonic dystrophy: There are two types of myotonic dystrophy (MD), DM1 and DM2, both caused by an abnormal trinucleotide repeat within two unrelated genes. Though they exhibit a similar phenotype, in DM1 the production of a kinase is affected, whereas DM2 affects a protein abundantly expressed in muscle fibers. 9,10
Emery-Dreifuss muscular dystrophy: In EDMD, defects in one of multiple genes can lead to loss of proteins (emerin, lamin A, and lamin C) essential for proper function of a cell’s nuclear membrane. More research is needed to elucidate why malfunction of these specific proteins affect primarily skeletal muscle when emerin and the lamin proteins are found in multiple tissue types. 11
Facioscapulohumeral dystrophy: In the majority of patients with FSHD, there is reactivation of a gene (DUX4) used in fetal development but normally silenced thereafter. This gene reactivation in childhood or adulthood leads to aberrant production of a protein that is toxic to muscle cells. 12
Limb-girdle muscular dystrophies: LGMDs are phenotypically similar but genotypically diverse, with over 30 identified types. Many of the affected genes code for proteins essential to the sarcolemma, or muscle cell membrane. The LGMDs can be more aptly named depending on the particular protein that is defective or missing. For example, abnormalities in the proteins calpain, dysferlin, or sarcoglycan can lead to clinical syndromes termed calpainopathies, dysferlinopathies, and sarcoglycanopathies, respectively. 13
In some cases, many of the aforementioned proteins are important to tissues other than skeletal muscle. This leads to the manifestation of clinical features that involve the cardiac, pulmonary, gastrointestinal and central nervous systems. 14
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Although there are several types of adult-onset MDs, they generally begin with loss of strength and endurance. Patients may develop symptoms at different points in their lives. Weakness occurs mostly in the pelvic and scapular region. Patients may experience falls, difficulty ascending stairs, exercise intolerance, muscle cramps, episodic weakness, focal wasting of muscle groups, contractures and/or breathing difficulties. 15,16
Specific secondary or associated conditions and complications
Although symptoms tend to be primarily neuromuscular in nature, MDs can have manifestations in additional organ systems. Many of the LGMD subtypes are associated with cardiomyopathy and respiratory involvement. Patients with FSHD commonly have sensorineural hearing loss, cardiac conduction abnormalities, and retinal telangiectasias. 17 Individuals with EDMD can have multiple cardiac issues. Finally, those with myotonic dystrophy have learning disabilities, cataracts, cardiac conduction abnormalities, as well as gastrointestinal and pulmonary complications.
Therefore, a multi-specialty approach is essential to properly manage patients with MD and commonly includes cardiologists, pulmonologists, neurologists, orthopedists, physiatrists, audiologists, and ophthalmologists, to name a few.
What causes these disorders?
Myositis, or general muscle inflammation, may be caused by:
- autoimmune disorders in which the immune system attacks muscle
- an allergic reaction following exposure to a toxic substance or medicine
- a virus or other infectious organism such as bacteria or fungi
Although the cause of many inflammatory myopathies is unknown, the majority are considered to be autoimmune disorders, in which the body&rsquos immune response system that normally defends against infection and disease attacks its own muscle fibers, blood vessels, connective tissue, organs, or joints.
Identifying and Managing Dermatomyositis: A Case Report and Review
This detailed review desccribes the heterogeneous idiopathic inflammatory myopathies and their mimics, with criteria for classification, an overview of cardiac, pulmonary and malignant comorbidieis, and guidance for treatment.
ABSTRACT: The idiopathic inflammatory myopathies are a heterogeneous group of disorders excluding conditions that mimic them during the initial patient evaluation is essential. Classification of dermatomyositis (DM) for a definitive diagnosis requires a characteristic rash and other criteria, such as proximal muscle weakness and muscle enzyme level elevation. DM often overlaps with other connective tissue diseases. A photosensitive rash often is the initial manifestation. Cardiac and pulmonary involvement may be life-threatening. Malignancies occur in up to 25% of cases. A detailed strength examination at every visit is important for assessing treatment response. Muscle biopsy is central in establishing the diagnosis. Physical therapy and occupational therapy should be started at diagnosis. Corticosteroids are the foundation of treatment. Most patients require corticosteroid-sparing medication.
(J Musculoskel Med. 200825:415-420, 444)
Dermatomyositis (DM) is one of the idiopathic inflammatory myopathies (IIMs), a heterogeneous group of disorders that involve proximal muscle weakness and nonsuppurative skeletal muscle inflammation. Others are polymyositis (PM) and inclusion body myositis (IBM). Excluding conditions that mimic the IIMs during the initial patient evaluation is essential. 1 Not every patient who has myopathic weakness, elevated creatine kinase (CK) levels, and inflammatory muscle histology has DM or PM, and there is clinical and pathological overlap with myositis associated with collagen vascular diseases. In addition, other conditions that do not respond to immunosuppression (eg, muscular dystrophy, IBM, metabolic myopathies, and neuromuscular disorders) also may have these features.
If treatment of a patient with DM or PM is unsuccessful, the muscle biopsy should be reexamined or a second biopsy ordered to reassess the diagnosis. Elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) in patients with nonspecific symptoms often direct attention to liver disease. These enzymes also are found in muscle if levels are elevated, the CK level should be checked to evaluate for myositis. Although the CK level is helpful, the response to therapy is best appraised by monitoring muscle strength and function. "Treating" the CK level instead of the muscle weakness may lead to unnecessarily prolonged use of immunosuppressive medications and incorrect judgment about their efficacy. 2
In this article, we offer a case report of a patient with DM. Then we review the key points of diagnosis and treatment.
A 39-year-old woman, in her eighth week of pregnancy, was admitted with myalgia, proximal muscle weakness, and a rash that had developed over the course of 1 week. She experienced aching pain that worsened with activity thigh and proximal arm muscle fatigue and weakness began 3 days later. Then a mildly pruritic rash across the forehead, nose, and forearms developed. Her symptoms progressed rapidly, and within days she required assistance from 2 persons to rise from a chair she also had difficulty walking, brushing her teeth, bringing objects to her mouth, and washing her hair. She felt feverish (temperature, 37.2°C [99°F]).
One year earlier, about 3 to 4 weeks into a pregnancy, the patient had experienced similar proximal myalgia and very mild weakness without rash. The symptoms had resolved in 2 weeks without medical attention. This pregnancy ended in miscarriage at 10 weeks.
The patient smoked cigarettes, 1 pack a day for 15 years, but she denied alcohol or illicit drug use. The only medication she took was a prenatal vitamin.
Physical examination revealed a slight periorbital heliotrope rash around the eyelid margin and erythematous plaques with a thin scale overlying the forehead, scalp line, nose, cheeks, neck, and anterior chest (Figure 1). Similar plaques, in a linear pattern, were observed on the forearms (Figure 2) and on the medial aspect of the distal thighs and knees. No Gottron papules or nail fold capillary abnormalities were seen. There was symmetrical weakness: 3/5 in the neck flexors, hip flexors, and deltoids and 4/5 in the hands, quadriceps, biceps, and triceps. There was severe tenderness with palpation of the forearms, deltoids, neck, and proximal thigh muscles. Cardiopulmonary examination results were unremarkable.
A faint periorbital heliotrope rash and erythematous facial plaques were present in our patient with dermatomyositis. A heliotrope rash is pathognomonic for this condition, although it may be subtle with only mild discoloration.
Figur e 2 – Some erythematous, linear plaques were present
on the patient's forearms and medial thigh s. The patient denied
scratching these areas. The skin lesions of dermatomyositis are
photos ensitive photoprotection measures are an important
component of treatment.
Diagnostic study results were as follows: normal electrolyte levels, complete blood cell count, and thyroid-stimulating hormone levels C-reactive protein (CRP) level, lower than 0.5 mg/dL erythrocyte sedimentation rate (ESR), 8 mm/h AST level, 78 U/L (normal range, 0 to 31 U/L) LDH level, 252 U/L (normal range, 135 to 214 U/L) creatine phosphokinase level, 1730 U/L (normal range, 35 to 150 U/L) aldolase level, 11.8 U/L (normal range, 1.5 to 8.1 U/L) antinuclear antibodies (ANA) titer, lower than 1:40 and electromyography (EMG)/nerve conduction study results consistent with myositis. A skin biopsy revealed interface dermatitis (Figure 3), and a muscle biopsy revealed mild, patchy, lymphocytic perivascular inflammation in the interstitial connective tissue (Figure 4). A myositis-specific antibody panel later came back negative.
Skin biopsy of the patient's right forearm demonstrated lymphocytic inflammation at the dermal-epidermal junction and vacuolar changes at the basal layer. This is consistent with interface dermatitis, which often is found on skin biopsy in patients with dermatomyositis but is nonspecific it also is present in systemic lupus erythematosus.
A hematoxylin and eosin stained section from the patient's left quadriceps muscle is shown. Mild perivascular lymphocytic inflammation (arrows) is present in the perimysial connective tissue between fascicles (A and B) and in the epimysial fibroadipopse tissue (C).
Despite receiving prednisone, 30 mg twice daily for 2 weeks, the patient had worsening neck weakness and new dysphagia. Fiberoptic endoscopic evaluation revealed pharyngeal weakness. The addition of methylprednisolone, 1g intravenously for 3 days, provided symptomatic improvement starting 4 days after the final methylprednisolone infusion.
The patient subsequently was found to have low IgG levels, and a diagnosis of common variable immunodeficiency was made. Intravenous immunoglobulin therapy-given first at 300 mg/kg and then at 400 mg/kg, every 3 weeks-was beneficial. The patient returned to normal strength, and the rash resolved. Prednisone was tapered to 5 mg/d, and a healthy daughter was delivered. Mother and daughter did well during the first month postpartum.
For a definitive diagnosis of DM, the Bohan and Peter 3,4 classification requires a characteristic rash plus 3 of the following criteria:
• Symmetrical, subacute, proximal muscle weakness.
• Muscle biopsy abnormalities: necrosis, regeneration, fiber size variation, inflammation, and atrophy.
• Muscle enzyme level elevation: CK, aldolase, AST, ALT, and LDH.
• Electromyographic abnormalities: triad of short, small, polyphasic motor units insertional irritability, positive sharp waves, fibrillations and bizarre, high-frequency repetitive discharges.
• Rash typical of DM: heliotrope rash or Gottron papules.
Evidence of muscular dystrophy is an exclusion. Others include evidence of neuromuscular, infectious, posttraumatic, toxic, metabolic, and endocrine disease.
DM may occur in association with malignancy, immunodeficiency syndromes,and medication use. 5 It may overlap with other connective tissue diseases, especially scleroderma and systemic lupus erythematosus (SLE). Amyopathic DM (ADM) is a special subset that has classic skin findings but no clinical evidence of weakness. About 30% of cases of DM present this way clinically evident myositis develops in most persons weeks to years later. 6
The annual incidence of DM and PM is 2 to 10 cases per million,with a recent trend of increasing incidence 7 the prevalence is about 1 case per 100,000. In adult DM, the overall ratio of women to men is 2:1 when overlapping with another connective tissue disease is included, it is 10:1. DM is more common in African Americans. IIMs may occur at any age, but the onset peaks between 10 and 15 years and 45 and 60 years. Only 14% of patients with DM or PM present during childbearing years (age 15 to 30 years). 8
A photosensitive rash often is the initial manifestation it may precede muscle disease by more than a year. The severities of the rash and muscle disease may be parallel or follow disparate courses. Gottron papules (seen in 60% to 80% of patients) and the heliotrope rash (seen in fewer than 50% of patients) are pathognomonic for DM many other cutaneous lesions are characteristic but not as specific.
Gottron papules are scaly, erythematous plaques symmetrically located on bony prominences, especially the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints, although the elbows, knees and feet also may be affected. The heliotrope rash is a purplish discoloration of the upper eyelids, sometimes with periorbital edema. The discoloration may be slight, appearing as only mild discoloration of the eyelid margin (as in our patient's case). Scaling and desquamation may occur in addition to the color changes.
Poikiloderma-a combination of atrophy, dyspigmentation, and telangiectasia-often occurs over the anterior chest ("V sign"), upper back ("shawl sign"), extensor surfaces of the arms, and upper-lateral thighs ("holster sign"). 9 Nail fold changes include periungual erythema with dilated nail fold capillaries and cuticle overgrowth. Hyperkeratosis and cracking of the lateral and palmar aspects of the fingers are termed "mechanic's hands." Also reported are malar erythema, nonscarring alopecia, psoriaform dermatitis of the scalp, panniculitis, facial seborrhea, and flagellate erythema (linear streaks on the trunk and proximal extremities). Calcinosis of soft tissue is a late complication of juvenile DM, but it is uncommon in adult-onset disease.
Symmetrical, proximal muscle weakness usually is of insidious onset, although acute onset may occur. Distal muscle weakness, such as in the finger flexors, is characteristic of IBM but uncommon in DM and PM. Muscle atrophy may be indicative of IBM, but it is absent in early DM and PM. Unlike in PM, which usually is painless, significant myalgia may occur in DM (as in this patient).
Lower extremity weakness often manifests first, with difficulty in climbing stairs or rising from a chair or toilet. Upper extremity weakness leads to difficulty in combing or washing hair. Neck flexor weakness, evidenced by an inability to lift the head from the pillow, is common. Neck extensor strength remains preserved unless the disease is severe and chronic weakness suggests another diagnosis (eg, muscular dystrophy or neck extensor myopathy). Pharyngeal weakness manifested by nasal regurgitation, dysphagia, or dysphonia is less common it portends a poor prognosis. Ocular or facial weakness is rare in DM and PM and suggests other diagnoses.
Constitutional symptoms include fatigue, fever, and weight loss. Fatigue often is severe and persistent even with adequate treatment of other disease features. Fever is especially frequent with antisynthetase syndrome (occurs in a few patients with myositis, who may present with dominant symptoms and signs in tissues other than muscle [fever, mechanic's hands, arthritis, and interstitial lung disease]). Weight loss may be a manifestation of systemic inflammation but also may herald underlying malignancy.
Cardiac and pulmonary involvement could be life-threatening. Pulmonary complications include interstitial lung disease (ILD), aspiration pneumonia, and hypoventilation resulting from respiratory muscle weakness. ILD occurs in 5% to 46% of cases of DM and PM, especially in patients who have antisynthetase antibodies. 10 It may be severe and rapidly progressive, especially in ADM, 6 resulting in respiratory failure and death. Pharyngeal or esophageal muscle weakness may result in aspiration. Weakness of the diaphragm or intercostal muscles, which is uncommon, may lead to respiratory failure.
Clinically symptomatic cardiac involvement is uncommon. Manifestations include myocarditis (rarely leading to heart failure), pericarditis, valvular disease, and rhythm disturbances. Asymptomatic conduction abnormalities, such as atrial and ventricular arrhythmias, nonspecific ST-T changes, and atrioventricular and bundle-branch blocks, have been observed in up to 72% of patients with DM and PM. 11 Polyarthritis,in a rheumatoid arthritis–like distribution, may occur and usually is mild and nonerosive. 7 Raynaud phenomenon, with abnormal nail fold capillaries, is common in DM. Uncommon clinical features include smooth muscle involvement of the intestinal tract, retinopathy with vision loss, proteinuria, and CNS vasculitis. 7
Malignancy in DM
Malignancies, predominantly adenocarcinomas, occur in 20% to 25% of DM cases 9 they are more common in patients older than 50 years, but they may be seen in any age group. The risk is greatest in the first 3 years after the diagnosis of myositis, but an increased risk persists lifelong. Ovarian cancer is overrepresented in patients with DM, and the diagnosis may be made many years after the onset of the myositis. Increased associations with lung, pancreatic, stomach, colorectal cancer, and non-Hodgkin lymphoma have been reported. Cancer is seen more frequently in patients with cutaneous necrosis of the trunk, leukocytoclastic vasculitis, and ADM. 7
DIAGNOSIS AND EVALUATION
DM should be suspected in patients who have proximal muscle weakness and compatible skin findings. A detailed, well-documented strength examination at every visit is important for assessing treatment response.
CK, LDH, AST, ALT, and aldolase all are enzymes present in muscle. The level of at least 1 is elevated in most cases (except for ADM) and often all are elevated. Aldolase and CK are the most sensitive enzymes however, even their levels are normal in 4% and 5% of cases, respectively. 12 However, myoglobinuria is rare in the IIMs.
The ESR and CRP level are poor markers of disease activity and often are normal or minimally elevated in spite of severe muscle inflammation. ANAs are positive in 50% to 80% of cases. Many of the myositis-specific autoantibodies are directed against cytoplasmic antigens, explaining why ANA test results often are negative. Found in about 20% to 30% of patients with DM or PM, myositis-specific autoantibodies aid in the diagnosis and characterization of the disease and as prognostic indicators of disease severity. 13
EMG usually is performed on half of the body, preserving the contralateral side for muscle biopsy. Classic findings in myositis are noted above. Although these findings are not specific for IIM, and may be seen with any cause of myositis, they are an important component of diagnosis-EMG helps rule out neuropathic disorders. The result is abnormal in about 90% of patients with myositis thus, a normal EMG result is strong evidence against active myositis. 12 A muscle injured by needle EMG will have inflammatory histology and should not be biopsied for at least 1 month after the test. 2
The muscle biopsy is central to establishing the diagnosis, but selecting the appropriate site for biopsy may be difficult. Muscles with end-stage disease should be avoided because the pathological findings often are nonspecific, showing only atrophy and maybe inflammation. The disease is patchy, and normal muscle may be obtained despite active disease nearby.
Selection of an appropriate muscle for biopsy may be aided by the physical examination (choose a moderately but not severely weak muscle), EMG, and MRI. With short tau inversion recovery images, MRI may detect muscle edema, which may be interpreted as active myositis. 14 If possible, preference should be given to biopsy of a standard muscle site (quadriceps or deltoid) that is well characterized in a pathological sense.
DM and PM have overlapping but different pathological findings. Both have lymphocytic inflammation however, the distribution of the inflammatory infiltrate and the subset of involved lymphocytes differ. In PM, CD8 + T-cells target muscle fibers, resulting in diffuse muscle injury (predominantly endomysial inflammation) without vasculopathy. In DM, B-cells and complement target small blood vessels, causing perivascular inflammation. As a result, there is muscle microinfarction and inflammation around the muscle fascicle (perifascicular inflammation and atrophy). 7 Endomysial inflammation is much less frequent in DM.
Skin biopsy often demonstrates inflammatory changes at the dermoepidermal junction (interface dermatitis). This finding is nonspecific and also may be seen in SLE.
Further testing is needed to determine the extent of the disease and evaluate for underlying malignancy. In addition to a thorough history and physical examination, chest x-rays, pulmonary function testing with diffusion capacity, swallow studies, and electrocardiography are important.
An evaluation for cancer, based on the patient's age and sex, is necessary in all cases of DM. The evaluation should include testicular or breast and pelvic examination with Papanicolaou smear. Urinalysis, CA-125 (ovarian cancer is overrepresented in DM), stool occult blood testing, chest x-ray, mammography, and CT of the abdomen and pelvis also should be considered. The American Academy of Dermatology recommends re-evaluation for malignancy every 6 to 12 months for the first 2 years after diagnosis. 1
Physical therapy and occupational therapy should be started at diagnosis. Active disease should not prevent patient-specific graded exercise. 14 Exercise is safe and beneficial in reducing disability in patients with IIM. 15
Corticosteroids are the foundation of treatment. Oral prednisone usually is initiated at 1 mg/kg/d in divided doses to a maximum of 80 mg/d and continued until the CK level improves (often after 4 weeks). Improvement in muscle strength may lag behind enzyme improvements by 2 or 3 months. In cases with severe manifestations, pulse methylprednisolone, 1000 mg/d for 3 days (as used in this case), may help achieve a more rapid response. Prednisone is then consolidated into a single daily dose and tapered by 20% to 25% every month until 5 to 10 mg/d is achieved. 16
Low-dose prednisone usually is continued to complete a year of therapy. Patients should be evaluated for response to therapy monthly, with measurement of muscle enzyme levels, manual muscle testing, and assessment of functional status.
To ameliorate corticosteroid-induced bone loss, the use of calcium, 1500 mg/d (in divided doses with food), and vitamin D, 1000 to 2000 IU/d, is appropriate. Bisphosphonate therapy is indicated when 5 mg/d or more of prednisone is to be used for more than 2 months, but it should be avoided in pregnancy and in women of childbearing age. Chemoprophylaxis against pneumocystis pneumonia also should be initiated.
Most patients require corticosteroid-sparing medication during the course of their disease. Many experts recommend immediate initiation of a corticosteroid-sparing agent concomitant with the start of prednisone, especially in severely ill patients. In one study, 87% of patients with DM responded to corticosteroid therapy initially, but 92% had recurrence with subsequent taper. 13
Methotrexate and azathioprine are frequently used first-line corticosteroid- sparing agents. Other agents that have been used include cyclosporine, tacrolimus, cyclophosphamide, rituximab, mycophenolate mofetil, hydroxychloroquine, intravenous immunoglobulin, infliximab, and etanercept. 16,17
Most patients with DM have a chronic course with either persistent disease activity or repeated exacerbations and remissions. However, patients with DM are more likely than patients with PM to have a monophasic disease that responds to therapy initially and remains in long-term remission after all therapy is stopped. 7
Before the widespread use of corticosteroids, as many as 50% of patients with DM or PM died because of disease complications. 7 However, corticosteroid therapy has improved outcomes and survival. In one recent study, 5-year survival for adult patients with DM or PM without associated cancer was 95%. 18 A poorer prognosis is associated with older age, malignancy, delayed treatment, pharyngeal dysfunction with aspiration pneumonia, ILD, and clinically evident myocardial involvement. 7
Disability accumulates because of the inflammatory muscle disease and complications of corticosteroid and immunosuppressive therapy. Up to one-third of patients will have mild to severe functional disability, and disability increases with disease duration. 19
IIMs are systemic diseases that may be severe and involve more than the shoulder and hip musculature, evidenced by recalcitrant pharyngeal weakness in the patient discussed here. The ability to recognize rash associated with DM is important as this case illustrates, however, rash may be subtle and require careful examination. IIMs typically are characterized by painless muscle weakness, but DM occasionally presents with striking pain in addition to weakness. Muscle or skin biopsy or both play an important role in confirming the diagnosis.
1. Painless muscle weakness characterizes the idiopathic inflammatory myopathies, but dermatomyositis may include striking pain.
2. The ability to recognize associated rash is important, but rash may be subtle and require careful examination.
3. Muscle or skin biopsy or both play an important role in confirming the diagnosis.
References 1. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for dermatomyositis. American Academy of Dermatology. J Am Acad Dermatol. 199634:824-829.
2. Dalakas MC. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med. 1991325:1487-1498.
3. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975292:344-347.
4. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975292:403-407.
5. Dourmishev AL, Dourmishev LA. Dermatomyositis and drugs. Adv Exp Med Biol. 1999455:187-191.
6. Gerami P, Schope JM, McDonald L, et al. A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis sinÃ© myositis): a missing link within the spectrum of the idiopathic inflammatory myopathies. J Am Acad Dermatol. 200654:597-613.
7. Oddis CV, Medsger Jr TA. Inflammatory muscle disease: clinical features. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, eds. Rheumatology. 3rd ed. Philadelphia: Mosby 2003:1537-1554.
8. Silva CA, Sultan SM, Isenberg DA. Pregnancy outcome in adult-onset idiopathic inflammatory myopathy. Rheumatology (Oxford). 200342:1168-1172.
9. Callen JP, Wortmann RL. Dermatomyositis. Clin Dermatol. 200624:363-373.
10. Takada K, Nagasaka K, Miyasaka N. Polymyositis/dermatomyositis and interstitial lung disease: a new therapeutic approach with T-cell–specific immunosuppressants. Autoimmunity. 200538:383-392.
11. Lundberg IE. The heart in dermatomyositis and polymyositis. Rheumatology (Oxford). 200645(suppl 4):iv18-iv21.
12. Bohan A, Peter JB, Bowman RL, Pearson CM. Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore). 197756:255-286.
13. Troyanov Y, Targoff IN, Tremblay JL, et al. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine (Baltimore). 200584:231-249.
14. Coyle KM, Plotz PH, Gourley MF. Why isn't my myositis patient getting better? The Rheumatologist. 20082:18, 19, 22.
15. Alexanderson H, Lundberg IE. The role of exercise in the rehabilitation of idiopathic inflammatory myopathies. Curr Opin Rheumatol. 200517:164-171.
16. Oddis CV. Idiopathic inflammatory myopathy: management and prognosis. Rheum Dis Clin North Am. 200228:979-1001.
17. Quain RD, Werth VP. Management of cutaneous dermatomyositis. Am J Clin Dermatol. 20067:341-351.
18. Sultan SM, Ioannou Y, Moss K, Isenberg DA. Outcome in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology (Oxford). 200241:22-26.
19. Bronner IM, van der Meulen MF, de Visser M, et al. Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis. 200665:1456-1461.
Presentation and course
Symptoms of systemic amyloidosis include neuropathy, myopathy, and cardiac or renal insufficiency there is often multiple-organ involvement. Myopathy is a rare clinical manifestation in primary systemic amyloidosis, and to some extent an underdiagnosed entity ( 30 22 12 ). Proximal weakness, muscle stiffness, pseudohypertrophy, and myalgia constitute the principal features.
The initial manifestation may predominantly consist of proximal muscle weakness. Other features due to amyloid deposition at different sites may develop later ( 13 ). Pseudohypertrophy, nodular lesions of muscles, and macroglossia are often lacking. This syndrome usually develops in cases with well-recognized generalized amyloidosis ( 37 ). Carr and colleagues described the first case in literature in a patient with symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition (from sural nerve and vastus lateralis muscle) ( 03 ).
The mean onset age of amyloid myopathy is 60 years. Ninety percent of patients report proximal weakness. This may be associated with macroglossia and muscle pseudohypertrophy in almost a third of the patients. Macroglossia sometimes precludes closure of the mouth dysphagia and hoarseness may also occur. Dysphagia is present in 25% of patients ( 35 38 04 ). The clinical importance of macroglossia in a patient with dyspnea and cardiomyopathy is highlighted in a case report ( 14 ).
The most prominent findings are abnormal firmness and pseudohypertrophy of the musculature and palpable tumors within muscles ( 28 53 36 ). Muscle weakness caused by amyloid myopathy has also been described in the absence of pseudohypertrophy. It can also manifest with diffuse muscle hypertrophy on general physical examination ( 50 ). The clinical picture then comprises proximal limb weakness with pronounced atrophy. As expected, with any proximal muscle weakness, patients have difficulty raising the arms overhead or climbing stairs ( 18 ). Weakness of the neck flexors as well as shoulder and thigh muscles with atrophy is also common ( 23 53 36 ).
Muscle claudication is rare but has been recognized in patients with amyloid myopathy. It results from progressive vascular deposition of amyloid and leads to ischemia and obstruction of small vessels. These patients have been misdiagnosed as having giant cell arteritis and inappropriately treated with high dose corticosteroids ( 53 41 ).
The presence of amyloid myopathy with myeloma and lytic bone disease has been recognized. Santos and colleagues reported a patient with amyloidosis associated with multiple myeloma who showed clinical characteristics of pseudomyopathy ( 40 ). Amyloid myopathy involving the diaphragm and resulting in diaphragmatic failure requiring ventilatory support is also well recognized ( 48 39 01 ). Amyloidosis may cause adult-onset sensorimotor peripheral neuropathy. Unlike neuropathy secondary to amyloid deposition, myopathy is infrequently described ( 51 ).
Amyloid myopathy is frequently misdiagnosed as an inflammatory myopathy, especially polymyositis because of similarities in clinical, neurophysiological, and muscle biopsy findings. Both can show similar inflammatory infiltrates on muscle biopsy, especially when only the hematoxylin-eosin stain is used ( 26 16 19 08 31 ). Spuler and colleagues found that routine use of Congo red-stained sections increased the frequency of a diagnosis of amyloid myopathy almost 10-fold.
Failure to recognize amyloid myopathy precludes patients of potentially life-prolonging treatment. Congo red staining and immunohistochemical analysis of tissue could prevent misdiagnosis ( 26 ). In middle-aged or elderly patients with proximal limb weakness, the diagnosis of amyloid myopathy should be considered ( 18 ).
Tanabe and colleagues reported an autopsy-proven case of systemic secondary amyloid A (AA) amyloidosis with muscle amyloid angiopathy, possibly induced by psoriasis vulgaris ( 49 ).
Prognosis and complications
Likelihood of survival with this disease remains poor, with a median survival rate of 1 to 2 years. Congestive heart failure and nephrotic syndrome are predominant causes of death. Without early therapy, however, the disease has a dismal prognosis ( 20 ). A case report from Ohtsuka and colleagues emphasized the fact that when amyloidosis is suspected and there is evidence of muscle injury, a muscle biopsy should be performed ( 33 ).
A 71-year-old woman with a history of primary systemic amyloidosis noted worsening fatigue, claudication, and weakness in her legs more than arms and hands over the past 2 years. Neurologic examination revealed symmetrical proximal limb weakness in lower and upper extremities with preserved tendon reflexes. Examination showed no other abnormalities. EMG study revealed myopathic findings and CK values were borderline elevated. Bone marrow biopsy revealed an IgG kappa monoclonal gammopathy. MRI of the thighs revealed increased T2 signal of subcutaneous fat and tissue between muscle groups with only minimal signal intensity alteration of muscle. Muscle biopsy revealed characteristic apple-green birefringent amyloid deposits surrounding individual muscle fibers in Congo red stained sections. Electron microscopy demonstrated amyloid filaments in close apposition to muscle fibers exhibiting excessive corrugations of the sarcolemmal membrane. Treatment included prednisone 60 mg daily and cyclophosphamide 150 mg daily with improvement of symptoms.
Diagnosis and management of inflammatory muscle disease
Idiopathic inflammatory myopathy is a term applied to a group of relatively rare diseases that present with the gradual onset of weakness of shoulder and pelvic girdle muscles. These diseases include polymyositis and dermatomyositis, as well as myositis associated with neoplastic disease, myositis associated with underlying collagen-vascular disease, and inclusion body myositis.
Weakness is a common clinical complaint that can be associated with significant morbidity. Although many complaints of weakness are purely subjective, the finding of objective muscle weakness indicates an underlying myopathic or neuropathic process. With an estimated incidence of only 5 cases per million adults, 1 the idiopathic inflammatory myopathies are rare diseases.
Individual diseases included under the term “idiopathic inflammatory myopathy” are polymyositis and dermatomyositis, as well as myositis associated with neoplastic disease, myositis associated with collagen-vascular disease, and inclusion body myositis. Although dermatomyositis can be seen in both adults and children, polymyositis is seen almost exclusively in adults. Inclusion body myositis is rare in patients younger than 60 years. Polymyositis and dermatomyositis are more common in women inclusion body myositis is 3 times more common in men. Inclusion body myositis also is the most common idiopathic inflammatory myopathy. Myopathy associated with malignancy is more common in persons older than 50 years myopathy associated with collagen-vascular disease occurs at the age that is associated with the particular collagen-vascular disease that is present.
The idiopathic inflammatory myopathies must be differentiated from those caused by infections, toxins, endocrinopathies, muscular dystrophies, and inborn errors of metabolism. Understanding the epidemiology, clinical presentation, diagnostic techniques, and treatment options is important to reduce the significant morbidities related to these disease processes. In this article, we describe an approach to the diagnosis and management of the idiopathic inflammatory myopathies.
The diagnosis of an idiopathic inflammatory myopathy is made by finding a combination of a typical clinical presentation in association with elevated levels of enzymes of muscle origin, myopathic changes on electromyography, edema in muscle on MRI, and characteristic muscle histopathology. A summary of these clinical and diagnostic findings is shown in Table 1.
No single feature is diagnostic of an idiopathic inflammatory myopathy, and the diagnosis can be made only after the exclusion of other causes of these abnormalities. Although several sets of criteria have been developed to more accurately classify these diseases, none of them have been validated. 2-4
Muscle weakness is the chief complaint in patients with any of the idiopathic inflammatory myopathies. However, muscle weakness is a common symptom in many patients with other conditions, and the differential diagnosis for the complaint is extensive (Table 2). A detailed history must be obtained and a thorough physical examination must be performed to rule out more common causes, such as prescription and illicit drug toxicities, environmental exposures, infections, and other signs or symptoms suggestive of endocrinopathies. A detailed family history may suggest the presence of an inherited muscle disorder, such as a muscular dystrophy or metabolic myopathy.
The first step in diagnosing an idiopathic inflammatory myopathy is to determine the time course of the weakness. Generally, weakness begins insidiously over a period of 3 to 6 months, without a recognized precipitating event. The weakness in patients with inclusion body myositis may develop even more insidiously over the course of years.
Other diseases that may cause the insidious onset of muscle weakness include the muscular dystrophies, metabolic myopathies (glycogen and lipid storage diseases), and endocrine myopathies. Neuropathic diseases, such as amyotrophic lateral sclerosis and myasthenia gravis, also may result in the gradual onset of weakness. The acute onset of muscle weakness suggests a neuropathic or myopathic cause other than the idiopathic inflammatory myopathies.
The second step is to determine the characteristics of the weakness and the effect it has on daily life. As a rule, myopathic weakness is symmetrical and occurs mostly in the proximal muscle groups of the pelvis, thighs, shoulders, and neck. For example, patients may complain of having difficulty in standing from a seated position, climbing stairs, brushing hair, or placing objects on a high shelf. Patients with inclusion body myositis provide an exception to the rule in that they may present with distal or asymmetrical muscle weakness.
The third step is to elicit any associated symptoms. In severe cases, esophageal and pharyngeal muscle weakness can result in dysphagia, aspiration pneumonia, and dysphonia. Extraocular muscles are spared. Less frequently seen are pulmonary (interstitial lung disease [ILD], diaphragmatic weakness) and cardiac manifestations (tachyarrhythmias, dilated cardiomyopathy). Muscle pain and joint pain may be seen but are not classic symptoms of the idiopathic inflammatory myopathies. Severe muscle pain and frank synovitis are uncommon. Because the idiopathic inflammatory myopathies can overlap with neoplastic disease and collagen-vascular diseases (system lupus erythematosus, Sjgren syndrome, scleroderma, and mixed connective-tissue disease [MCTD]), a detailed review of systems looking for symptoms of these conditions should be performed.
The physician should assess all muscle groups, noting that the weakness in most idiopathic inflammatory myopathies is proximal (shoulder, neck, and pelvic girdle muscle) and symmetrical. In contrast, neuropathic diseases typically present with distal or asymmetrical weakness and may present with abnormalities on neurological examination that would not be present in myopathic disease. However, many patients with inclusion body myositis may have asymmetrical weakness or weakness and atrophy of the distal muscle groups, providing a mixed picture.
The examiner should assess the patient's ability to swallow and speak as well as the patient's cardiac and pulmonary function, because these muscles and organs also may be involved. In addition, the physician must look for signs of neoplastic or other connective-tissue diseases.
Patients with dermatomyositis have cutaneous findings that may precede or develop concomitantly with the muscle weakness or may develop after the onset of myopathy. The 2 pathognomonic skin findings of dermatomyositis are Gottron papules and the heliotrope rash. Gottron papules are pink or violaceous papular lesions that can be found symmetrically on the dorsal aspects of the distal interphalangeal joints, elbows, patellae, and malleoli (Figure 1). The heliotrope rash is a violaceous discoloration of the eyelids that may be associated with periorbital edema (Figure 2).
Other cutaneous findings in dermatomyositis include facial rash, the shawl sign, the V-sign, dystrophic cuticles, and mechanic's hands. Abnormal dilated capillaries may be seen just proximal to the cuticles. This finding is common in patients who also have Raynaud phenomenon.
Although serum elevations of aldolase, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase can be seen in myopathic disease, elevation of the creatine kinase (CK) level is thought to be the most sensitive laboratory test result related to skeletal muscle damage. However, the specificity of elevations in CK levels in regard to the idiopathic inflammatory myopathies is quite low. Severe disease may be seen with minimal elevations as well as with very high levels. In general, very high CK levels are seen more frequently as a result of medications, trauma, aerobic and isometric exercises, and other causes of muscle injury. In addition, there can be normal individual and racial variations in CK levels (highest levels in African American men), which may not be associated with a patient's complaint of weakness. 5
Although elevated CK levels are seen in most cases of inflammatory myopathy, CK levels may be minimally elevated or even normal in inclusion body myositis, myositis associated with neoplasia, and early presentations of polymyositis and dermatomyositis and when significant muscle atrophy has developed. CK levels do not necessarily correlate with disease activity. Declines in CK levels may not accurately correlate with response to therapy, and disease remission can be attained despite persistent elevations in CK levels.
The erythrocyte sedimentation rate and C-reactive protein level often are normal in patients with myositis and therefore are not diagnostically helpful. Antinuclear antibodies (ANAs) often are present in low titers in patients with inflammatory myopathies. However, the presence of a high-titer ANA or of other positive serological test results may indicate the presence of myositis in association with another collagen-vascular disease, such as anti-Smith or anti–double-stranded DNA (system lupus erythematosus), anti-SSA(Ro) and anti-SSB(La) (Sjgren syndrome), anti-SCL-70 (scleroderma), and anti-ribonucleoprotein (MCTD).
Myositis-specific autoantibodies are found exclusively in patients with the idiopathic inflammatory myopathies. The most common of these antibodies are directed toward aminoacyl-tRNA synthetase activities. Patients who carry these specific antibodies may present with certain clinical features and may not respond well to treatment, depending on the type of antibody present.
Anti-Jo-1 is the most common of the antisynthetase antibodies 73% of patients with anti-Jo-1 antibodies have ILD. These patients also are more likely to have fever, arthritis, Raynaud phenomenon, and mechanic's hands. This constellation of findings is referred to as the “antisynthetase syndrome.” 6 Anti-Mi-2 antibodies are seen in up to 30% of patients with dermatomyositis and generally are associated with a very good prognosis. Anti–signal recognition particle (anti-SRP) antibodies are associated with cardiomyopathy and portend the worst prognosis.
MRI is the most useful imaging modality for diagnosis and monitoring of myositis. MRI with T2-weighted images and fat suppression, or STIR technique, can show edema in the muscle, which is indicative of inflammation. 7 Because there often is only patchy involvement of the muscle, MRI is an effective noninvasive method for determining the optimal location for muscle biopsy.
Electromyography is most useful for distinguishing between neuropathic and myopathic disease. Electromyographic (EMG) changes in the idiopathic inflammatory myopathies include the characteristic triad of (1) increased insertional activity, fibrillations, and sharp positive waves (2) spontaneous, bizarre high-frequency discharges and (3) polyphasic motor unit potentials of low amplitude and short duration. 2 Although this triad is seen in 40% of patients with idiopathic inflammatory myopathies, 10% to 15% of patients will have normal EMG results. 8 In patients with inclusion body myositis and distal or asymmetrical weakness, an EMG also may reveal some neuropathic changes.
Muscle histology can help identify the specific type of idiopathic inflammatory myopathy however, histological changes may be minimal or nonspecific. The classic findings of muscle inflammation are seen in polymyositis, dermatomyositis, and inclusion body myositis. Biopsy also may help with diagnosis of other myopathies, for which different treatment modalities would be required.
In polymyositis, muscle fibers are seen in various stages of necrosis and regeneration. T-cell infiltrates predominate, with CD8 + cytotoxic T cells most notably surrounding and invading muscle fibers. In later stages, muscle atrophy, fat, and fibrous connective tissue may be seen in the absence of inflammation.
Inflammation in dermatomyositis is predominantly perivascular and consists of CD4 + helper T cells, plasmacytoid dendritic cells, and B lymphocytes. Perifascicular atrophy is virtually diagnostic of dermatomyositis, regardless of whether inflammation is present. Thromboses of capillaries are also seen.
The histopathology of inclusion body myositis may be identical to that seen in polymyositis. If serial biopsies are performed, the degree of inflammatory change decreases and may disappear. The characteristic histopathological abnormality is intracellular lined (rimmed) vacuoles. Filamentous, intracytoplasmic, or intranuclear inclusions may be visualized by electron microscopy. Histochemical staining may show deposition of amyloid, ubiquitin, and SMI-31 in fibers.
Dermatomyositis has a higher association with malignancies than polymyositis or inclusion body myositis. The most common cancers are those that occur most often in patients of a particular age and sex, with the exception of ovarian cancer, which is overexpressed. 9
A CT scan of the chest, abdomen, and pelvis and a thorough screening for age-appropriate cancer are recommended at the time of diagnosis. Because of the association with ILD, patients with the anti-Jo-1 or other antisynthetase autoantibodies should receive baseline pulmonary function testing and a chest CT scan.
Because the idiopathic inflammatory myopathies are relatively rare, referral to a specialist who is familiar with these diseases is recommended. Not only does medical treatment often require the use of immunosuppressive agents over long periods, but newer therapies and trials may be available that the nonspecialist may not be aware of.
Before medical therapy is started, a thorough assessment of a patient's individual muscle groups must be made so that his or her response to therapy may be measured objectively. Levels of CK and other muscle enzymes may be monitored during treatment however, a decrease in these enzymes without any improvement in muscle weakness should not be mistaken for clinical improvement. 10
Activity should be encouraged as soon as possible to prevent formation of muscle contractures. If weakness is severe, physical therapy should be prescribed to prevent flexion contractures. Otherwise, the patient should engage in regular aerobic and resistance exercise. Such exercise has been shown to not have adverse effects, and exercise has anti-inflammatory effects. 11
Generally, the earlier in the disease course medical therapy is started, the more effective and rapid improvement in symptoms it produces. Empirically, corticosteroids are used as first-line therapy to decrease inflammation. In severe cases that require hospitalization, intravenous methylprednisolone may be used. Otherwise, prednisone may be started at 1 mg/kg/d. Ninety percent of patients who have polymyositis or dermatomyositis and are treated with corticosteroids achieve some clinical response 50% to 75% achieve complete remission.
Risk factors for a poor outcome include concomitant ILD, significant esophageal dysmotility, cardiomyopathy, malignancy, and anti-SRP antibodies. However, corticosteroid myopathy, which can cause worsening muscle weakness, develops in some patients.
Prednisone should provide objective improvement in muscle weakness within 3 to 6 months. For patients who do not respond well to corticosteroids or those who present with more profound weakness, another immunosuppressive agent, such as methotrexate or azathioprine, is added next. 12 Intravenous immunoglobulin may be used in severe disease to improve symptoms, but it is not effective in the long term or as a single agent.
Hydroxychloroquine, topical tacrolimus, and topical corticosteroids may be effective for cutaneous manifestations in patients with dermatomyositis 13 however, they have no effect on the myositis. A recent systematic review highlighted the lack of quality studies assessing the efficacy and toxicity of various immunosuppressants in dermatomyositis and polymyositis. 14 However, no medication has been found that alters the course of inclusion body myositis. Although weakness progresses in an unrelenting fashion, it does so very slowly and is not associated with increased mortality.
1. Cronin ME, Plotz PH. Idiopathic inflammatory myopathies. Rheum Dis Clin North Am. 199016:655-665.
2. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975292:344-347.
3. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975292:403-407.
4. Mastaglia FL, Phillips BA. Idiopathic inflammatory myopathies: epidemiology, classification, and diagnostic criteria. Rheum Dis Clin North Am. 200228:723-741.
5. Black HR, Quallich H, Gareleck CB. Racial differences in serum creatine kinase levels. Am J Med. 198681:479-487.
6. Hengstman GJ, van Engelen BG, van Venrooij WJ. Myositis specific autoantibodies: changing insights in pathophysiology and clinical associations. Curr Opin Rheumatol. 200416:692-699.
7. Fraser DD, Frank JA, Dalakas M, et al. Magnetic resonance imaging in the idiopathic inflammatory myopathies. J Rheumatol. 199118:1693-1700.
8. Bohan A, Peter JB, Bowman RL, Pearson CM. Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore). 197756:255-286.
9. Antiochos BB, Brown LA, Li Z, et al. Malignancy is associated with dermatomyositis but not polymyositis in northern New England, USA. J Rheumatol. 200936:2704-2710.
10. Kroll M, Otis J, Kagen L. Serum enzyme, myoglobin and muscle strength relationships in polymyositis and dermatomyositis. J Rheumatol. 198613:349-355.
11. Alexanderson H, Lundberg IE. The role of exercise in the rehabilitation of idiopathic inflammatory myopathies. Curr Opin Rheumatol. 200517:164-171.
12. Oddis CV. Idiopathic inflammatory myopathies. Chapter C: Treatment and assessment. In: Klippel JH, Stone JH, Crofford LJ, White PH, eds. Primer on the Rheumatic Diseases. 13th ed. Atlanta: Arthritis Foundation 2008:375-380.
13. Callen JP, Wortmann RL. Dermatomyositis. Clin Dermatol. 200624:363-373.
14. Choy EH, Hoogendijk JE, Lecky B, Winer JB. Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis. Cochrane Database Syst Rev. 2005(3):CD003643. Update in: Cochrane Database Syst Rev. 2009(4):CD003643.
Comprehensive, up-to-date information on HIV/AIDS treatment and prevention from the University of California San Francisco
HIV is classified among the lentiviruses, a family of viruses characterized in part by their tendency to cause chronic neurologic disease in their animal hosts. It is not surprising, then, that neurologic complications of HIV infection are common and not confined to opportunistic infections. All levels of the neuraxis can be involved, including the brain, meninges, spinal cord, nerve, and muscle. Neurologic disease is the first manifestation of symptomatic HIV infection in roughly 10-20% of persons, while about 60% of patients with advanced HIV disease will have clinically evident neurologic dysfunction during the course of their illness.(1-3) The incidence of subclinical neurologic disease is even higher: autopsy studies of patients with advanced HIV disease have demonstrated pathologic abnormalities of the nervous system in 75-90% of cases.(1,4,5) In the United States and the European Union, where antiretroviral therapy is relatively available, peripheral neuropathy and HIV-associated cognitive dysfunction (including AIDS dementia) account for the greatest proportion of neurologic disease burden. In developing countries, opportunistic infections of the central nervous system (CNS) account for most of the reported neurologic morbidity and mortality in AIDS. Cryptococcal meningitis, fulminant bacterial meningitis, neurotuberculosis, toxoplasmosis, and neurosyphilis are common among HIV-infected individuals in Asia and Africa.
HIV crosses the blood-brain barrier and enters the nervous system early, probably concomitant with initial systemic infection.(6) The virus has been cultured from brain, nerve, and cerebrospinal fluid (CSF) from persons at all stages of HIV disease, including those without neurologic signs or symptoms.(7,8) Positive HIV-1 cultures in CSF do not predict the presence or development of neurologic signs or symptoms later on. The development of neuroAIDS (neurologic manifestations of AIDS) depends on a number of factors, such as antiretroviral treatment history, degree of immunosuppression, and the molecular biology of the viral strain, particularly its neurovirulence.(9) Host factors, including genetic makeup, undoubtedly play a role in selective vulnerability to neuroAIDS, but are not yet well characterized.
The initial "seeding" of the nervous system by HIV-1 is usually asymptomatic, although acute aseptic meningitis, encephalitis, and inflammatory polyneuropathy have all occurred in this setting.(4)
Despite its potential to cause disease at all levels of the neuraxis, HIV-1 does not directly infect central or peripheral neurons, astrocytes, or oligodendroglial cells. Latent or low-level HIV infection in the CNS is maintained by virus-infected cells of the monocyte/macrophage lineage. "Indirect effects" of macrophage activation--such as dysregulation of cytokines and chemokines, free-radical (oxidative stress) injury, and secretion of soluble factors that are potently neurotoxic--have been implicated as effectors of nervous system injury in HIV.
Despite evidence of early infection of the CNS, symptoms of cognitive impairment typically occur late in symptomatic HIV disease, usually in the setting of severe immunosuppression.(10,11) However, the median CD4 cell count at diagnosis of dementia appears to be increasing, from 70 cells/µL in 1992-1995 to 170 cells/µL in 1997.(12)
The role of HIV-1 proliferation itself in the development of AIDS dementia complex (ADC) is controversial. Although viral strains that are particularly efficient at replicating in brain macrophages may play a role in the pathogenesis of brain injury,(13,14) a heavy "viral burden" in brain has not been linked consistently with clinical AIDS dementia.(15)
Some investigators hold that increased HIV-1 proliferation in the brain is necessary for the development of ADC. Others propose that a macrophage-initiated cascade of events can lead to brain dysfunction and clinical dementia, even in the absence of high viral load in the brain. Activated macrophages, whether infected with HIV or not, are capable of secreting potent neurotoxins, inducing pro-inflammatory cytokines, and generating oxygen free radicals that can damage cells and lead to neuronal dysfunction or death.(16-19) A particular subtype of monocyte/macrophages derived from the peripheral blood was found to be greatly increased among patients with AIDS dementia compared with both HIV-1-infected and -uninfected controls. Soluble factors from these macrophages were found to be highly neurotoxic--that is, they killed human brain cells in culture.(20)
Although the incidence of nearly all nervous system opportunistic infections has declined dramatically in the era of potent antiretroviral therapy, the impact on incidence and prevalence of HIV-associated cognitive impairment--including frank ADC--has been low. The prevalence of ADC in HIV-infected individuals with higher CD4 counts (200-350 cells/µL) actually appears to have increased since 1996.(12) Pathologically, the prevalence of HIV-associated brain disease, or encephalopathy, is rising despite suppressive antiretroviral therapy.(21)
Poor penetration of the blood-brain barrier by many of the antiretroviral drugs, particularly the protease inhibitors, has been suggested as a reason for the persistence of ADC. Unfortunately, there is currently no effective way to monitor successful suppression of CNS HIV infection, making selection of a CNS-penetrating antiretroviral regimen a matter of guesswork rather than clinical science. Patients with ADC commonly have no detectable virus in CSF. This does not exclude high viral burden in the brain, but rather emphasizes the limitations of CSF as a "window on the central nervous system." Nonetheless, HIV-1-infected macrophages in the CNS are considered an important anatomic reservoir for HIV, one capable of reseeding of the blood with replication-competent virus. Hence, antiretrovirals that cross the blood-brain barrier may be of benefit in limiting systemic reseeding of virus from the CNS compartment.
There is some evidence that, despite the poor CNS penetration of most antiretrovirals, effective antiretroviral therapy may attenuate the neurotoxicity of circulating monocytes/macrophages. Among individuals with ADC receiving effective antiretroviral regimens, macrophage-derived soluble factors were found to be less neurotoxic than observed prior to the availability of combination antiretroviral therapy.(20,22) Rather than killing neurons outright, macrophage secretions from subjects on effective HIV therapy cause a dysregulation of proteins critical to normal function. In other words, neurons appear to be "crippled," but not killed. Such changes in macrophage neurotoxicity among treated subjects may be a molecular correlate of a clinical change in ADC noted by some clinicians. Where antiretroviral therapy is available, ADC is typically a milder, more slowly progressing deterioration in mental function among HIV-infected patients, compared with the severe, rapidly progressing dementia seen earlier in the epidemic, and still seen among untreated individuals. These molecular and clinical observations are supported by newer imaging modalities, such as proton magnetic resonance spectroscopy, which show metabolic rather than structural changes in the brains of individuals with early-stage HIV-associated cognitive impairment.(23)
Despite a more insidious onset, other changes have been observed in the "new" ADC. Some HIV-infected individuals appear to have a dementia more akin to Alzheimer disease than typical ADC, with, for example, prominent disturbances in long-term memory. Is this simply a sign of the "graying" of the HIV-seropositive population? Greater than 10% of patients with AIDS in the United States are now over the age of 50--an age at which the incidence of Alzheimer disease begins to rise. Of potential significance is that some of the newer antiretroviral drugs themselves, by virtue of their effects on lipid metabolism and processing of amyloid, might theoretically increase the risk of Alzheimer disease. Chronic, low-grade brain inflammation, such as occurs in HIV-associated brain disease, may also play a role in vulnerability to Alzheimer disease.
Looking ahead, AIDS patients with dementia should be evaluated for cortical dysfunction as well as the subcortical cognitive dysfunction of "classical" ADC, to confirm whether or not the spectrum of cognitive dysfunction is widening to include an Alzheimer-disease phenotype. Quantitative assessment of cerebral amyloid plaques and tau protein-rich tangles--the hallmarks of Alzheimer disease--should be performed postmortem in patients with AIDS. On the molecular level, the effect, if any, of antiretrovirals on the processing of amyloid and amyloid-beta proteins needs to be elucidated.
As HIV/AIDS becomes a more chronic, otherwise "manageable" disease, current evidence indicates that ADC will increase in significance as a cause of major morbidity. Clinically and pathologically, it remains a frustrating "moving target." Research efforts in ADC undoubtedly will yield insights relevant to Alzheimer disease and other devastating neurodegenerative diseases.
Apart from dementia, HIV-infected patients are at risk for a wide range of neurologic diseases. Cerebral signs and symptoms are the most common. Global cerebral disease can present with altered mental status or generalized seizures, whereas focal disease often produces hemiparesis, hemisensory loss, visual field cuts, or disturbances in language use. Fungal, viral, and mycobacterial meningoencephalitides are the most common causes of global cerebral dysfunction, and progressive multifocal leukoencephalopathy (PML), primary CNS lymphoma, and toxoplasmosis account for the majority of focal presentations. As the epidemic has progressed, the epidemiology of CNS complications has changed. In general, availability of effective antiretroviral regimens has been associated with a dramatic decline in incidence and severity of opportunistic infections of the CNS. Even before the availability of these regimens, the incidence of CNS toxoplasmosis had declined among patients receiving trimethoprim-sulfamethoxazole prophylaxis against Pneumocystis. Unfortunately, antiretroviral regimens have not demonstrably decreased the prevalence of PML, and the incidence among individuals with higher CD4 counts may be increasing. However, the prognosis of this once uniformly fatal disease has improved dramatically, with long-term remissions now fairly common among patients receiving antiretroviral therapy.(24,25)
Human herpesvirus-6 and parvovirus B19 have been recognized as pathogens in patients with AIDS, and these viruses have been linked with meningoencephalitis, or brain inflammation however, their importance in the spectrum of neuroAIDS has yet to be characterized, and is probably low.(26,27,28)
Viral and, rarely, fungal and parasitic opportunistic infections can affect the spinal cord. Systemic lymphoma can infiltrate nerve roots and meninges, occasionally causing a mass lesion within the cord. In addition, HIV itself is associated with a spastic paraparesis similar to that seen with vitamin B12 deficiency. Peripheral nerve injury is very common, particularly a painful distal neuropathy seen late in HIV infection. About 35% of hospitalized patients with advanced HIV disease have peripheral neuropathy.(29,30) Among 272 HIV-infected outpatient subjects studied over time, 55% had signs, or both signs and symptoms, of distal neuropathy. The 1-year incidence of symptomatic distal neuropathy was estimated at 36%.(31)
Although myalgias or muscle pains are a frequent complaint, frank muscle disease is less common. Both inflammatory myopathies and a toxic myopathy secondary to zidovudine have been observed. More recently, a syndrome of acute neuromuscular weakness, often associated with lactic acidosis, has been described in association with several nucleoside analogue reverse transcriptase inhibitors, including zidovudine (AZT), stavudine (d4T), didanosine (ddI), and lamivudine (3TC), either alone or in combination. The first cases were reported to the U.S. Food and Drug Administration in mid-2001. Although the pathophysiology of this potentially fatal syndrome is not yet understood, the presence of lactic acidosis suggests an acute mitochondrial toxicity, or "mitochondropathy," possibly caused by the inhibition of mitochondrial DNA synthesis by nucleoside analogues. Anecdotally, the use of cofactors against lactic acidosis, such as thiamine, riboflavin, L -carnitine, vitamin C, and other antioxidants have been associated with lower mortality among the 60 patients described as of 2002.(32) Any patient on antiretroviral therapy presenting with a "Guillain-Barré-type" picture of ascending neuromuscular weakness should be tested for lactic acidosis and evaluated with electromyography and nerve conduction studies.
Among patients infected with HIV, serious neurologic disease may present with relatively trivial symptoms and signs. Therefore, a high index of suspicion must be maintained to detect disease early in these patients. A careful neurologic examination to attempt anatomic localization is necessary to guide further laboratory and imaging studies. Because multiple neurologic diseases often coexist in patients, close follow-up is needed even if a presumptive diagnosis has been made. A change in clinical condition often necessitates a thorough reevaluation.
There is growing awareness that pain from a variety of etiologies commonly complicates HIV disease. In general, patients with AIDS have pain comparable in prevalence and intensity to pain in patients with cancer, with similar mixtures of neuropathic and visceral-somatic etiologies. However, although efforts to improve malignant pain management have benefited many patients with cancer, pain in patients with AIDS is dramatically undertreated.
Aggressive pain treatment can be the single most important and most challenging intervention in the care of patients with HIV disease. In a recent U.S. study, only 15% of ambulatory AIDS patients with severe pain received adequate pain management.(33) The principles of pain assessment and treatment in the patient with HIV/AIDS are not fundamentally different from those in the patient with cancer and should be followed.(34,35)
These principles are described in the WHO analgesic ladder,(36) a well-validated, stepwise approach to pain management related to pain severity. Therapy ranges from nonopioid analgesics and adjuvants to systemic weak and strong opioids to intraspinal drug delivery for refractory severe pain. Opioids, except in quite high doses, can be ineffective in neuropathic pain adjuvants (namely, tricyclics, anticonvulsants) are often more successful. Where neuropathic pain is refractory to such therapies, pain management specialists should be consulted.
A patient's previous substance abuse is a particularly strong risk factor for the undertreatment of pain by clinicians. Approaches to treatment in this difficult setting should be formulated with clear goals and limits, such that risks for both abuse and undermedication are minimized.(37)
A wide range of peripheral nervous system disorders develop in patients with HIV infection, leading to pain, sensory symptoms, and muscle weakness (Table 1). Both "primary" HIV-1-associated nerve disorders, and those secondary to opportunistic processes are well described. In addition, certain antiretroviral drugs may cause or exacerbate peripheral neuropathies.
Distal symmetric polyneuropathy (DSPN)
Chronic inflammatory demyelinating polyneuropathy
Progressive lumbosacral polyradiculopathy
Although there are also rare reports of motor neuron disease resembling amyotrophic lateral sclerosis,(38) its association with HIV infection is uncertain (see Table 1) and will not be discussed further in this chapter. Muscle diseases are discussed separately at the end of this chapter.
Depending on the study population and the method of case ascertainment, clinical, electrophysiologic, or pathologic evidence of peripheral neuropathy is present in about one-third to nearly 100% of patients with advanced HIV disease.(39) The incidence of neuropathy increases with declining CD4 cell count and advancing systemic HIV disease. Familiar causes of neuropathy, such as nutritional deficiency and diabetes mellitus, account for only a small percentage of the neuropathy in these patients. Toxicity of therapeutic drugs, notably ddI, zalcitabine (ddC), and d4T, is responsible for some cases of neuropathy, or for progression however, antiretroviral toxicity is probably overdiagnosed as a primary cause of HIV-associated neuropathy. Of note, among 272 HIV-infected outpatient subjects studied over time, the use of antiretrovirals often suspected to cause a dose-related neuropathy was not associated with development of symptomatic neuropathy.(31)
Proper recognition of the different types of peripheral nerve dysfunction is essential for patient management. Except for the few neuropathies with known causes, most of these disorders are characterized on the basis of clinical features alone(Table 2). The rate of symptom progression, the degree of weakness relative to sensory loss, and the severity of immunosuppression guide the differential diagnosis. The electrophysiologic features of nerve conduction and electromyographic studies remain the gold standard for diagnosis, and may lead to different therapeutic options.
Distal symmetric polyneuropathy (DSPN) is by far the most common neuropathy in HIV disease.(3,30,31,40)
In a cross-sectional study of hospitalized patients with advanced HIV disease, 35% had clinical and electrophysiologic evidence of this neuropathy. In a longitudinal study of outpatients, 55% had neuropathic signs or symptoms, and the estimated yearly incidence was 36%. Even among asymptomatic seropositive individuals, nerve conduction studies demonstrated polyneuropathy in 16%.
DSPN can disable HIV-1-positive patients who are otherwise healthy. Associated pain and hypersensitivity can be intense, and is too often undertreated by physicians. Typical symptoms are tingling, numbness, and burning pain in the toes or over the plantar surface of the feet, often ascending over time. Neurologic examination shows bilateral depressed ankle-tendon reflexes and elevated vibratory threshold in the toes. There is often decreased appreciation of temperature distally. Brisk ankle reflexes suggest a diagnosis other than neuropathy or, at the very least, the presence of coexisting upper motor neuron disease (spinal cord or brain). Weakness, if present, is mild and usually restricted to the distal muscles, where muscle atrophy may also be observed. Severe or proximal weakness points to a different type of neuropathy (eg, polyradiculopathy), myopathy, or other neurologic diagnosis. Similarly, significant asymmetry in presentation usually suggests a focal neuropathy (eg, tarsal tunnel syndrome, other mononeuropathies) or other superimposed disorders. Electromyography and nerve conduction studies may be critical to localizing pathology and suggesting etiology.
HIV-1-associated DSPN is a diagnosis of exclusion. Its pathophysiology, although not yet well characterized, is thought to be due to "indirect" effects of HIV-1 infection. HIV-1 virions are rarely detected in peripheral nerve tissue, even in patients with severe neuropathy. As in AIDS dementia and HIV-1-associated (vacuolar) myelopathy, theories of pathogenesis have focused on "friendly fire"--that is, products of immune-cell activation that may become neurotoxic. Tumor necrosis factor alpha in particular has been implicated, but other pro-inflammatory molecules are probably involved as well. The severity of neuropathy, in terms of both signs and symptoms, is associated with the levels of detectable plasma HIV RNA.(41) Pathologically, both large, myelinated fibers and small, unmyelinated fibers are damaged, accounting for the signs and symptoms of numbness, reflex loss, and pain.
The clinical syndrome of DSPN is a common manifestation of many systemic diseases. Chronic alcoholism, neurotoxicity of therapeutic drugs, uremia, vitamin B12 deficiency, and diabetes mellitus all cause a similar, sometimes painful, polyneuropathy. In patients with HIV infection, vincristine, ddC, ddI, and d4T, among other drugs, may induce or exacerbate neuropathy. A temporal relationship with development of symptoms and a relatively more rapid onset (in terms of weeks to months, rather than months to years) may help to distinguish these toxic neuropathies from HIV-associated DSPN. Several studies of patients with advanced HIV disease have reported abnormally low serum vitamin B12 levels in 15-20% of subjects.(42-44) The significance of this apparent deficiency is not known, and the vast majority of patients with AIDS and DSPN have normal vitamin B12 levels. Because vitamin B12 deficiency can cause or exacerbate both myelopathy and neuropathy, however, it should be ruled out in all patients with either of these disorders. In DSPN, electromyographic and nerve conduction studies typically show a length-dependent sensorimotor polyneuropathy. Small or absent sural nerve action potentials are the most common finding. Electrodiagnostic tests help to confirm the diagnosis and assess the severity of the disorder, but they generally cannot distinguish the idiopathic DSPN from the polyneuropathies secondary to drug toxicity, vitamin B deficiency, or other causes.
Treatment of patients with DSPN is directed toward the neuropathic pain. We use, as first-line therapy, lamotrigine (25 mg, slowly increasing up to 250 mg) or desipramine (25 mg, slowly increasing up to 250 mg at bedtime). Amitriptyline (25-150 mg at bedtime) may also be used however, sedation and anticholinergic effects may be dose limiting. Mexilitine (600-1200 mg/day) can be useful, as can phenytoin, carbamazepine, and other anticonvulsants. Gabapentin is used widely, but, in this author's experience, is relatively ineffective in more severe neuropathic pain syndromes. Potential drug-drug interactions and alterations in drug metabolism, particularly in conjunction with use of protease inhibitors, should be carefully considered. Patients should be monitored, as appropriate, for hepatotoxicity and leukopenia. Therapy is typically initiated at a low dosage and increased in increments over days to weeks until satisfactory therapeutic effect is achieved or adverse effects become limiting. These "adjuvant" agents provide partial relief in half to two-thirds of neuropathic pain patients, and dramatic relief in some. A number of "complementary" approaches to neuropathy and neuropathic pain syndromes are being tried by patients and clinicians. Although several are reasonable, none has been adequately studied. Acylcarnitine, magnesium and calcium supplementations are sometimes tried, and vitamin B12 injections given, despite normal B12 levels in blood. There is some evidence that vitamin B12 utilization pathways may be impaired in the setting of HIV disease, so that there may be a "functional" deficit in B12 despite normal serum levels.(45)
If vitamin B12 utilization is impaired, however, it is unlikely that supplementation will be of benefit. Amino acid supplements that bypass the B12 pathway, such as methionine or S-adenosyl methionine (SAM-E), theoretically could provide critical "methyl donors" needed for nerve fiber maintenance and repair. Controlled clinical trials are needed to investigate the safety and efficacy of these and other complementary approaches.
Mononeuropathy multiplex typically occurs in patients with symptomatic HIV-1 infection or in those with U.S. Centers for Disease Control and Prevention (CDC)-defined AIDS. The syndrome is uncommon, although accurate estimates of its incidence are not available.
The pathogenesis of this syndrome is poorly understood. There may be two different disorders. Patients at an earlier stage of HIV-1 infection (CD4 cells/µL) may have a self-limited mononeuropathy, usually involving only one or two nerves. An autoimmune etiology has been proposed.(46) In contrast, some evidence suggests that the mononeuropathy multiplex occurring in highly immunocompromised HIV-infected patients (CD4 អ cells/µL) is often the result of infection of nerves or their vascular supply by cytomegalovirus (CMV).(47,48)
Mononeuropathy multiplex typically presents as multifocal or asymmetric sensory and motor deficits in the distribution of peripheral nerves or spinal roots. Symptoms develop over weeks to months. Deep-tendon reflexes mediated by the affected nerves are diminished or absent, but diffuse areflexia does not occur. Cranial neuropathies may be a presenting feature. CMV-associated mononeuropathy multiplex can be extensive, involving several limbs or cranial nerves, or may preferentially involve the recurrent laryngeal nerve, resulting in hoarseness and vocal cord paresis. Electrophysiologic studies typically show a neuropathy with multifocal demyelination and axonal loss.
The asymmetric neurologic signs and the prominent weakness separate this disorder from DSPN. Besides HIV, other etiologies of mononeuropathy multiplex include hepatitis B infection, diabetes, herpes zoster, and neoplastic infiltration of nerve. Entrapment neuropathies should be considered in disorders involving the ulnar, median, or tibial nerves, as cubital, carpal, and tarsal tunnel syndromes occur commonly in patients with AIDS wasting syndrome or extensive weight loss, and may also occur when human growth hormone is used to treat wasting or fat redistribution syndromes.
In our experience, mononeuropathy multiplex in patients with CD4 cell counts cells/µL involves few nerves and follows a self-limiting clinical course. Clinical observation without specific treatment may be sufficient. Widespread and progressive weakness primarily occurs in patients with very low CD4 counts (typically អ cells/µL). Although there are only anecdotal data to support the use of ganciclovir or foscarnet in such patients, we recommend empiric therapy because of the disabling nature of the disorder and its association with CMV.(48)
Patients with HIV infection rarely may develop either acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome, GBS), or chronic inflammatory demyelinating polyneuropathy (CIDP).(49) The incidence of these neuropathies is not known GBS is probably no more common in the setting of HIV-1 than in the general population. However, GBS at seroconversion has been reported, and has been attributed to an autoimmune attack on nerves with resulting inflammation and destruction of myelin.
Patients with inflammatory demyelinating neuropathies present with progressive, usually symmetric weakness in the upper and lower extremities. There is usually generalized areflexia. If the illness is monophasic with maximal neurologic dysfunction reached within the first month, it is, by definition, GBS. Patients with clinical progression of the syndrome after the first 4 to 6 weeks have, by definition, CIDP. Nerve conduction studies may show multifocal conduction slowing and conduction block and help establish the diagnosis of a demyelinating polyneuropathy. Electromyography typically shows signs of denervation in clinically weak muscles. CSF protein is usually elevated and, unlike the demyelinating neuropathies in the general population, a mononuclear pleocytosis of up to 50 cells/µL sometimes occurs.
Although no objective data on efficacy in the HIV-1-infected population are available, most centers treat these patients with either intravenous immune globulin (400 mg/kg/day for 5 days) or plasmapheresis (5 to 6 exchanges over 2 weeks) in a manner similar to that used for non-HIV-infected patients. In patients with CIDP, repeated treatment at monthly intervals may be needed to achieve clinical stabilization.(49)
A new syndrome, which may resemble Guillain-Barré, has been described in association with several NRTIs, including AZT, d4T, ddI, and 3TC, either alone or in combination. Although the pathophysiology of this potentially fatal syndrome is not yet understood, lactic acidosis suggests an acute mitochondrial toxicity, or "mitochondropathy," possibly caused by the metabolic effects of the nucleoside analogues. Anecdotally, the use of cofactors against lactic acidosis, such as thiamine, riboflavin, L -carnitine, vitamin C, and other antioxidants have been associated with lower mortality.(32)
Any patient on antiretroviral therapy presenting with a Guillain-Barré-type picture of ascending neuromuscular weakness should also be tested for lactic acidosis and evaluated with electromyography and nerve conduction studies.
Progressive lumbosacral polyradiculopathy due to CMV infection is important to recognize because, unlike many other neurologic complications of AIDS, this serious disorder can be effectively treated if appropriately diagnosed. If unrecognized or untreated, CMV polyradiculopathy can be neurologically devastating or lethal.
CMV polyradiculopathy syndrome occurs in the setting of advanced systemic HIV disease in patients with very low CD4 cell counts (អ/µL). Even prior to the advent of effective antiretroviral therapy, the disorder was uncommon, being recognized in fewer than 2% of HIV-seropositive patients referred for neurologic consultation.(50) It is now quite rare in areas where antiretroviral therapy is generally available. A more benign or self-limited lumbosacral polyradiculopathy, without evidence of inflammation in spinal fluid, can occur in patients with higher CD4 counts.
Autopsy studies have demonstrated CMV inclusions in astrocytes, neurons, and capillary endothelial cells in areas of necrosis around the lumbosacral roots and cauda equina. CMV is often recovered from the CSF, especially in those patients with polymorphonuclear pleocytosis. Other disorders reported to mimic this syndrome include neurosyphilis, toxoplasmosis of the conus medullaris, primary CNS lymphoma, and leptomeningeal metastasis from systemic lymphoma.(51-53)
Progressive polyradiculopathy has a striking predilection for the lumbosacral roots, leading to neurologic deficits that are limited to the legs during the early stage of the syndrome. The presenting complaint is bilateral leg weakness that leads to difficulty with walking. Symptoms progress rapidly over several weeks. Flaccid paraplegia may develop within 1 to 2 weeks in some patients. Urinary retention and constipation or obstipation may be prominent, suggesting involvement of the lower sacral roots with sphincter disturbance. Deep tendon reflexes in the legs are suppressed or lost early. Back pain and subjective numbness or paresthesias are common, but sensory deficits are rarely severe. Sensory loss over the perineal or perianal areas (ie, the lower sacral dermatomes), if present, is characteristic of the syndrome.
Loss of tendon reflexes and sensory symptoms and signs (even if mild) separate this disorder from the weakness due to myopathy or wasting syndrome. Weakness in the upper extremities, if any, occurs only late in the course of disease. Sphincter disturbances and the sparing of the upper extremities distinguish this syndrome from other neuropathies, such as mononeuropathy multiplex, chronic inflammatory demyelinating neuropathy, and GBS. CMV polyradiculopathy can be diagnosed with some confidence based on characteristic CSF findings, including polymorphonuclear CSF pleocytosis in conjunction with a convincing clinical presentation and progressive, areflexic leg weakness with early bowel and bladder (sphincter) disturbance. Lumbar puncture is probably the most important diagnostic test. In about half of affected patients, the CSF studies show a white cell count in excess of 500 cells/µL, with polymorphonuclear cells constituting at least 40-50% of the cells. Elevated protein and hypoglycorrhachia are common. CMV can be cultured from CSF in half to two-thirds of such cases. In others, often with a more benign clinical course, the CSF is characterized by a predominantly mononuclear pleocytosis in the range of 5 to 50 white blood cells/µL. CMV cultures are negative in the majority of such cases. Relatively bland CSF, however, does not rule out the diagnosis, and a high index of suspicion should be maintained. CSF diagnostic studies should include viral cultures, (nontreponemal syphilis testing (RPR or VDRL titer), and cytologic examination to look for the various causes reported in association with this syndrome. Where available, nucleic acid assays for CMV should be used.(51-53) Radiologic imaging, preferably magnetic resonance imaging (MRI), should be used to exclude compressive or space-occupying lesions of the cauda equina or lower thoracic spinal cord. MRI often reveals enhancement and thickening of lower spinal roots. Electromyography and nerve conduction studies are useful to localize the lesion to the spinal roots and to exclude other neurologic causes of weakness.
There is no controlled clinical trial to document the efficacy of ganciclovir or foscarnet. In practice, however, treatment successes are seen with either regimen or their combination.(54) Many clinicians treat these patients empirically before results of diagnostic studies are known. Early, empiric treatment is justified to preserve neurologic function, especially in patients with rapidly progressive leg weakness or characteristic CSF polymorphonuclear pleocytosis. Non-CMV causes of the polyradiculopathy syndrome, if identified, should be treated accordingly.
Symptomatic primary muscle disease is uncommon in patients with HIV infection. A polymyositislike syndrome occurs rarely, with few cases encountered even in large referral centers. A secondary myopathy attributable to the muscle toxicity of AZT emerged in the latter half of the 1980s with widespread use of the drug. In a study of 86 patients receiving AZT therapy for more than 6 months, 16% had persistently elevated serum creatine kinase, and 6% had symptomatic myopathy.(55)
AZT probably causes mitochondrial dysfunction in muscle through its inhibition of the mitochondrial enzyme DNA polymerase gamma. In some myopathic patients treated with AZT, mitochondrial abnormalities are seen with either Gomori trichrome staining ("ragged-red fibers") or electron microscopy.(56,57) Little or no inflammatory infiltration occurs. The appearance of ragged-red fibers is a result of accumulation of abnormal mitochondria that were stained intensely red with trichrome. Whether the finding of ragged-red fibers is specific for the myopathy associated with AZT remains controversial.
The cause of the myopathies unassociated with AZT are unknown, but pathologic findings include rod body myopathy, both necrotizing and nonnecrotizing inflammatory myopathy, and type 2 muscle fiber atrophy found in HIV-1-associated muscle wasting syndrome. Immunologic factors likely play an important role in HIV-1-associated polymyositislike syndromes.(58-60)
The hallmark of myopathy is diffuse, symmetric weakness of "proximal" muscles--hip or shoulder girdle muscles--with a sparing of sensory and autonomic functions. Difficulty with squatting, rising from a chair, or walking upstairs is often the presenting symptom of myopathy. Some patients have myalgia and muscle tenderness, but these complaints are also common in patients without myopathy. Neurologic examination reveals predominantly proximal weakness of the upper and lower limbs, although some patients may have prominent distal weakness as well. The clinical and laboratory features of HIV-associated myopathies are indistinguishable from those seen in the general population. Serum creatine kinase is almost always abnormally elevated.(56,57,58) Electromyography of clinically weak muscles shows fibrillation potentials, positive sharp waves, complex repetitive discharges, and a full recruitment of small, short-duration motor unit action potentials. The electromyography pattern is distinctive for myopathic disorders and is invaluable in establishing a diagnosis. The interpretation, however, requires an electromyographer experienced in the diagnosis of myopathy.
Preservation of tendon reflexes and sensory function helps distinguish myopathy from CIDP and other neuropathic causes of weakness. In most, but not all cases, creatinine phosphokinase levels will be elevated. As is often the case, however, more than one neurologic problem may be present and can complicate the examination. In the majority of cases, electromyography and muscle biopsy readily confirm the presence of a primary muscle disorder. Muscle biopsy may further assist in the differentiation among the different forms of myopathy. In addition to causing a syndrome of ascending neuromuscular weakness discussed above, antiretroviral-induced mitochondrial toxicity with lactic acidosis is often associated with muscle injury. Also, treatment with HMG-CoA reductase-type lipid-lowering agents ("statins"), often used to manage metabolic complications of antiretroviral therapy, can be associated with muscle pain, weakness, and muscle damage with enzyme elevations.
In patients receiving AZT, discontinuation of the drug may result in clinical improvement of myopathy. Muscle pain and serum creatine kinase levels decrease first, followed by a more delayed improvement in strength. Some patients may tolerate rechallenging with lower doses of AZT, although the use of other antiretroviral therapy is probably preferable. Some patients, including some with ragged-red fibers on muscle biopsy, continue to deteriorate after cessation of AZT and respond only after initiation of steroid treatment,(56) suggesting a possible superimposed immunologic mechanism. Prednisone has also been used, apparently with some success, to treat those patients with polymyositis or rod body myopathy, although the natural history of these myopathies is not known and the relation of improvement to treatment is uncertain. We usually initiate prednisone at 60 to 80 mg/day and continue its administration until there is improvement in muscle strength. The dosage is then tapered to alternate-day dosing over several months, and prednisone eventually can be discontinued if there is no clinical relapse. Where lipid-lowering agents are suspected, immediate discontinuation is imperative.
Clinically significant spinal cord disorders are less common in HIV disease than are peripheral nervous system diseases. The neurologic signs of myelopathy, however, such as increased tone and hyperreflexia in the legs and Babinski signs (extensor plantar responses), may be elicited even in the absence of subjective complaints. In most cases, such asymptomatic signs reflect mild HIV-associated spinal cord disease that may or may not progress. Patients with symptomatic myelopathy usually complain first of clumsy gait and urinary hesitancy. On examination, one finds relatively symmetric leg weakness, sensory loss, particularly in vibration and position sense, spasticity and hyperreflexia of both legs, and Babinski signs. In clinical management, it is important to separate the acute from the more chronic myelopathies. More rapidly progressive neurologic deficits, especially if accompanied by back pain, spine tenderness, or a marked spinal sensory level, warrant immediate investigation with MRI or computed tomography (CT) myelogram to rule out cord compression.
Strictly speaking, vacuolar myelopathy (VM) is a pathologic diagnosis. Characteristic pathology is identified in postmortem examination in as many as 55% of patients dying from AIDS.(61,62) Clinical myelopathy is less common, but is probably underdiagnosed.
The pathologic finding of noninflammatory vacuolation of myelin, particularly in the lateral and posterior columns of the spinal cord, characterizes VM. Upper thoracic levels of the cord are affected most commonly, but cervical pathology is well described, and occasionally diffuse cord changes are seen. The physiologic mechanisms leading to these pathologic changes are unknown.(63) Direct invasion of spinal cord neural cells by HIV is not seen, even in severe cases. As in AIDS dementia, products secreted by activated macrophages have been implicated in pathogenesis. Tumor necrosis factor alpha, for example, a known neurotoxic pro-inflammatory cytokine, may play an important role in HIV-1-associated spinal cord disease.
Curiously, the myelopathy associated with HIV disease is nearly identical clinically and pathologically to that seen in severe cobalamin (vitamin B12) deficiency (subacute, combined systems disease). However, despite the fact that low vitamin B12 levels are seen in up to 20% of AIDS patients, those with HIV-1-associated myelopathy rarely have B12 deficiency. Many clinicians routinely provide monthly injections of B12 to HIV-1-positive patients with myelopathy although this practice is innocuous, evidence of clinical benefit is lacking. However, there is evidence that vitamin B12 is not utilized normally in the setting of HIV disease for the stabilization of nerve fibers. Vitamin B12-dependent transmethylation of myelin basic protein is critical to nerve fiber survival and maintenance, and this process has been shown to be deficient in HIV-seropositive subjects with myelopathy. This metabolic defect may result in a "functional" vitamin deficiency, despite normal B12 levels in blood.(45)
Vacuolar myelopathy typically presents as subacute progression of motor and sensory deficits over several months. Paresthesias or numbness of the limbs, if present, is sometimes difficult to distinguish from symptoms of peripheral neuropathy moreover, the two conditions often coexist in patients with advanced HIV disease. Brisk tendon reflexes suggest spinal cord (or brain) involvement, whereas peripheral neuropathy is associated with depressed reflexes, especially those of the Achilles tendons. A patient with both processes might have brisk knee reflexes and absent ankle jerks.
Because VM also occurs in patients with AIDS dementia complex, and both conditions cause spasticity and paraparesis, it may be clinically difficult to separate spinal cord disease from cerebral involvement of motor pathways. Brain MRI demonstrating extensive bilateral white matter changes supports a cerebral etiology. The diagnosis of VM in the setting of HIV disease is one of exclusion. The evaluation should include radiologic imaging of the spinal cord (and brain, if indicated). MRI is typically normal in patients with VM, although areas of increased T2 signal may be seen rarely. CSF studies may be normal or may show nonspecific abnormalities such as low-grade mononuclear pleocytosis and mild elevation of protein content. Such changes are also seen in asymptomatic HIV-1-seropositive patients, and so have little diagnostic sensitivity or specificity.
The clinical course is typically one of slow progression, and most patients remain ambulatory. A more fulminant course may be seen, however, with wheelchair dependence within a few months. Upper extremities are affected very late, if at all. Baclofen (10-30 mg three times daily) or tizanidine (4 mg three times daily) may attenuate leg spasticity and reduce leg cramps. Painful dysesthesias may be treated with "neuropathic pain" adjuvants, such as lamotrigine or desipramine. As noted above, the vast majority of patients with this condition have normal vitamin B12 levels however, there may be a defect in utilization of B12. Amino acid supplements that bypass the B12 pathway, such as methionine or S-adenosyl methionine (SAM-E), could theoretically provide the "methyl donors" normally supplied by B12 metabolism, which are critical for nerve fiber maintenance. Controlled clinical trials are needed so that the safety and efficacy of such complementary approaches may be better understood.
Another rare but important retroviral cause of subacute myelopathy is human T-lymphotropic virus type I (HTLV-1) infection. The diagnosis of HTLV-1-associated myelopathy (also known as "tropical spastic paraparesis") should be considered in patients from the high-risk epidemiologic groups (eg, previous transfusion, injection drug use, and residence in known endemic areas such as Japan, the Caribbean islands, and parts of Central and Latin America). Endemic areas have also been identified in the United States and include parts of Texas and New Orleans.(64,65) Serology for anti-HTLV-1 antibodies can be assayed. Interferon-alfa is being investigated for the treatment of HTLV-1-associated myelopathy.
The causes of acute myelopathies include spinal cord compression from lymphomatous metastasis,(1,66) tuberculous or bacterial spinal abscess,(67) and acute infections by herpes zoster or other DNA viruses.(68-70) In addition, a rare acute myelopathy at the time of seroconversion to HIV has been reported.(71) This is not surprising, given that acute or "transverse" myelitis can complicate a number of viral syndromes. In the experience of the author, by far the most common cause of subacute myelopathy in patients with HIV is non-HIV-associated cervical spine disease (eg, cervical spinal stenosis, disk disease, degenerative joint disease, and so on. The assumption that myelopathy in a seropositive individual "must" be HIV related can lead to missing relatively common treatable, non-HIV-related conditions.
In patients with acute back pain and rapidly developing neurologic deficits such as leg weakness and numbness, or bowel and bladder dysfunction, spinal cord compression must be ruled out. Neurologic examination, including sensory examination of the trunk for a sensory level to temperature or pinprick, should be performed to establish the probable level of the lesion for diagnostic imaging. MRI of the appropriate spinal cord segments or myelography with follow-up CT scan are the diagnostic tests of choice. If radiologic studies are negative, the CSF should be evaluated for evidence of infectious and neoplastic causes. In addition to routine CSF studies, mycobacterial cultures and cytologic examination for malignant cells should be performed. CSF nucleic acid assays for CMV, herpes varicella-zoster virus (VZV), herpes simplex virus (HSV), and tuberculosis (TB) are useful emerging tools for diagnosis of treatable conditions.(72) Prognosis for recovery depends on the neurologic function at the time of initiation of treatment.
The CNS disorders in the setting of HIV disease can be divided into four general categories: a) primary infection of the brain by HIV b) opportunistic infections by parasitic, fungal, viral, and bacterial organisms b) CNS neoplasms and d) complications of systemic disorders.
HIV-1-associated dementia complex (AIDS dementia, or ADC) has been variously called AIDS dementia complex, HIV-associated dementia (HAD), AIDS encephalopathy, HIV encephalitis, and multinucleated giant-cell encephalitis. This devastating complication of HIV-1 infection is discussed briefly above (Pathogenesis of ADC), and more completely in the chapter "AIDS Dementia Complex".
CNS toxoplasmosis has been the most common cause of intracerebral mass lesion in HIV-infected patients. Its incidence has declined dramatically among patients receiving PCP prophylaxis, and further declined among patients treated with effective antiretroviral therapy. Earlier reports described frequencies of 3-40%, reflecting the considerable regional variation in exposure to the parasite.(1,3,73) Most of the cases in the United States are probably a result of reactivation of latent infection. Toxoplasmic encephalitis in the absence of immunoglobulin G antibodies to Toxoplasma has been documented(74-76) however, this is probably quite rare with newer assays. Toxoplasmosis causes a multifocal cerebritis, and initial symptoms and signs are often both diffuse and focal. They include confusion, headache, personality change, generalized or focal seizures, hemiparesis, hemisensory loss, or other focal neurologic deficits.
CT scan of the brain usually shows multiple ring-enhancing lesions with predilection for cortex and deep gray-matter structures such as the basal ganglia. The cerebellum and brain stem are less commonly involved. Radiologic appearance can vary markedly single lesions and lesions with diffuse enhancement, as well as nonenhancing lesions can appear. In fact, other common cerebral lesions can be radiologically indistinguishable from toxoplasmosis. MRI is more sensitive than CT, which can underestimate the number of lesions.(77) If tissue diagnosis is indicated, MRI can often be helpful in localizing a lesion most accessible for biopsy. The differential diagnosis of cerebral focal lesions in patients with AIDS should include lymphoma, progressive multifocal leukoencephalopathy (rarely enhances), other masses of infectious etiology such as cryptococcal cerebritis and tuberculoma, and, in some cases, stroke. CSF examination in toxoplasmosis is nondiagnostic it can be normal, or it can show a mononuclear pleocytosis and elevated protein. CSF antibodies to Toxoplasma are not sensitive for Toxoplasma encephalitis.
The treatment of toxoplasmosis is discussed in the chapter "Toxoplasmosis and HIV".
Cryptococcus neoformans is another CNS opportunistic infection that has become rare among individuals receiving effective antiretroviral therapy. It usually presents as a subacute meningitis.(78-80) Clinical manifestations can be remarkably benign, with vague malaise or nausea alone. More commonly, headache and fever are the presenting features. An acute confusional state can be seen, as can cranial nerve palsies. Stiff neck (meningeal sign) is absent in up to 70% of cases. In fact, some patients may have a completely normal physical examination. Hence, clinicians must maintain a high index of suspicion for cryptococcal disease, particularly in the setting of new onset of headache.
CT or MRI is usually normal or reveals only atrophy. Uncommonly, cryptococcomas occur, particularly in the basal ganglia due to spread of the organisms from the basal cisterns by way of the lenticulostriate arteries. These lesions do not enhance after contrast administration. Over the past several years, we have observed severe cryptococcal cerebritis in patients previously "successfully" treated for cryptococcal meningitis. Focal meningeal and parenchymal enhancement is seen on MRI, and patients typically present with seizure or altered mental status.
CSF can be normal or show mononuclear pleocytosis, elevated protein, low glucose, and high opening pressure. India ink staining may reveal fungus, but it is relatively insensitive. Determination of CSF cryptococcal antigen (CRAG) titer is essential because this may be the only CSF abnormality latex agglutination of CSF for cryptococcal antigen has a sensitivity of 90-95%.
The treatment of cryptococcal meningitis is discussed in the chapter "Cryptococcus and HIV".
Patients with aseptic meningitis often present initially with headache, occasionally in association with altered mental status or cranial neuropathies. Many patients with this syndrome probably have primary HIV meningoencephalitis.(6,81) The meningitis can manifest at the time of seroconversion and can recur spontaneously or become chronic.(1) Because of the high incidence of CSF abnormalities in HIV-infected patients, regardless of symptoms (see Diagnostic Studies: Lumbar Puncture), interpretation of CSF in this population can be difficult. In investigating symptoms such as headache, altered mental status, and cranial neuropathy, aseptic meningitis must be a diagnosis of exclusion.
Progressive multifocal leukoencephalopathy (PML) is caused by JC virus, a ubiquitous polyoma virus that affects approximately 4-8% of patients with advanced HIV disease. With effective antiretroviral therapy, the prognosis for those who develop PML has improved dramatically, with long-term remission being fairly common. PML is a subacute or chronic progressive illness most often characterized by focal neurologic findings, such as hemiparesis, gait abnormalities, and visual field cuts, as well as changes in mental status and personality. Dementia, encephalopathy, and coma can occur with fulminant disease. Seizures are uncommon, but not rare.(82) If focal deficits are not prominent, it can be difficult clinically to distinguish PML from ADC. CT or MRI usually reveals focal or diffuse lesions in the white matter, particularly in the parieto-occipital region. The brainstem or cerebellum may be solely involved in up to 15% of cases. Single lesions are not uncommon in patients with HIV disease, however, making "multifocal leukoencephalopathy" something of a misnomer in this population and gray-matter involvement, though unusual, is well described. With rare exceptions, the lesions do not enhance, nor do they cause tissue edema or mass effect. Pathologically, infection is confined to oligodendrocytes and results in demyelination with little or no inflammation. Routine CSF evaluation is nondiagnostic and is usually normal or reveals only nonspecific changes, such as mild pleocytosis or protein elevation. CSF PCR detection of JC virus DNA has become a useful tool in the diagnosis of PML, and is available in some commercial laboratories.(83) Diagnosis should be based on clinical and radiographic features, supported by PCR. Sensitivity of PCR will vary depending on the laboratory and the primers used hence, while a positive test is confirmatory, a negative CSF PCR for JC virus should not exclude the diagnosis.
Occasionally clinical and radiographic features of PML are quite similar to those of AIDS dementia with its radiographic counterpart, HIV encephalitis. Clinically, focal findings strongly favor PML, as does rapid progression of symptoms. Radiographically, asymmetry and hypointensity of lesions on T1-weighted MRI, involvement of the subcortical U-fibers, and relative sparing of the periventricular white matter all favor a diagnosis of PML.
In the absence of antiretroviral therapy, PML is characterized by progressive decline over the course of 4 to 5 months until death. Stabilization of symptoms, either without treatment or in the setting of antiretroviral therapy, occurs in some patients with relatively high CD4 counts ( cells/µL), for whom PML is the CDC AIDS-defining illness. Improvement and stabilization for months to years is now fairly common among patients treated with antiretroviral therapy, particularly those who achieve complete suppression of HIV in the blood.(24,25)
Some patients who undergo a decline in status despite combination antiretroviral therapy or who cannot tolerate antiretrovirals may improve or stabilize on cidofovir treatment, using the same regimen as for CMV retinitis (see chapter "Cytomegalovirus and HIV"). This approach has not been studied adequately in controlled clinical trials, and remains experimental. Ocular hypotension and renal injury are important adverse events associated with cidofovir, and must be closely monitored.(84)
There have been several reports of severe worsening of PML on initiation of antiretroviral therapy, thought to be due to "immune reconstitution" syndrome. Marked inflammation--otherwise rare in PML--has resulted in rapid neurologic deterioration and, in some cases, death. Patients with PML should be monitored closely in the first 4 to 6 weeks after initiation of highly active antiretroviral therapy (HAART) for neurologic worsening. In the setting of rapid deterioration, an MRI or CT scan with contrast should be obtained. A trial of corticosteroids is reasonable in the setting of marked inflammation and mass effect.
Among the opportunistic viral infections of the CNS, the most important are the herpes viruses: herpes simplex types 1 and 2 (HSV-1 and -2), herpes varicella-zoster (VZV), and CMV. Each can cause a meningoencephalitis with mental status changes and focal neurologic findings. Diagnosis is complicated by the low yield of CSF viral cultures in herpesvirus encephalitis in general. Sensitive CSF PCR assays have been developed for each of these conditions, however, and, where available, can greatly aid diagnosis.
In general, the onset of headache, fever, and seizures should, in the absence of other clear etiologies, prompt empiric treatment for herpes simplex encephalitis with acyclovir (10.0 to 12.5 mg/kg intravenously every 8 hours). Interestingly, HSV encephalitis is rarely reported among patients with AIDS. Also, in contrast to its fulminant course in immunocompetent persons, HSV infection in patients with advanced HIV disease is often insidious in onset and chronic in duration. Skin or mucosal lesions are absent in the majority of patients. CT or MRI scans may reveal edema, focal hemorrhage, or contrast enhancement in the characteristic locations--medial temporal lobes and inferior frontal lobes--especially if coronal images are obtained. However, diffuse lesions also occur. CSF often shows a lymphocytic pleocytosis and elevated protein in addition, red blood cells may be a prominent though nonspecific finding. Glucose levels are usually normal. Electroencephalogram may show diffuse slowing, common to all encephalitides, or periodic lateralized epileptiform discharges or other focal abnormalities. Definitive diagnosis often requires brain biopsy, but CSF PCR may reduce the need for tissue diagnosis.(85)
Herpes varicella-zoster infection of the CNS is associated with meningoencephalitis, cranial nerve palsies, myelitis, leukoencephalopathy, ependymitis, or cerebral vasculitis leading to strokes and transient ischemic attacks (TIAs). Zoster encephalitis is probably underdiagnosed among patients with AIDS. Clinical suspicion should be high in AIDS patients with stroke or TIAs. Neurologic signs and symptoms can precede or follow the rash, or be unassociated with a rash, present or past. CSF usually reveals only nonspecific, mild pleocytosis and protein elevation. VZV viral cultures of CSF and CSF PCR for VZV should be performed, where available.(86) Positive PCR or culture results justify high-dose intravenous acyclovir treatment. CT or MRI scans may demonstrate cerebral ischemia or combined hemorrhagic and ischemic changes.
If skin lesions are present, immunofluorescence of biopsied tissue should be performed. Acyclovir (10.0 to 12.5 mg/kg intravenously every 8 hours) for 14 to 21 days has, in our experience, resulted in excellent recovery in zoster encephalitis. Where vasculitis is suspected, and confirmed with MR or conventional angiography, steroids or other anti-inflammatory immunosuppressants may be required.
Because CMV is ubiquitous in patients with advanced HIV disease, it can be difficult to determine what role, if any, CMV is playing in CNS disease. Cells bearing CMV inclusion bodies are a common finding in the brains of patients with HIV disease at autopsy, regardless of presence or absence of neurologic symptoms. Occasionally, severe necrotizing CMV ependymitis or meningoencephalitis is seen in tissue specimens, as is necrotizing involvement of spinal roots. CT and MRI scans are usually normal or reveal only nonspecific changes, even in biopsy-proven CMV encephalitis. Occasionally, an ependymitis is evident on imaging but is not diagnostic for CMV infection. Similarly, CSF examination is nondiagnostic and cultures are usually negative, even in pathologically proven CMV encephalitis.(87) If available, nucleic acid amplification testing (PCR or bDNA) for CMV should be performed on CSF a positive test is highly suggestive of actual CNS disease., Because CMV involvement of the brain is usually patchy, even brain biopsy may yield a false-negative result. Evidence of systemic CMV infection--retinal, gastrointestinal, or, rarely, pulmonary--should be sought aggressively in any patient with HIV infection and signs and symptoms of acute meningoencephalitis for which no other convincing etiology is found.
Therapeutic response to ganciclovir has been documented in patients with spinal root involvement.(88) A small clinical series of patients with CMV encephalitis described response to treatment with ganciclovir or foscarnet in 3 of 5 patients.(54)
Candida albicans, which commonly infects the oral mucosa of patients with HIV disease, can cause a meningoencephalitis, usually in the setting of fungemia. Microabscesses are the usual pathologic findings in the brain. Mucormycosis, especially among injection drug users, and aspergillosis have been reported causes of meningoencephalitis in patients with advanced HIV disease, as have coccidioidomycosis and histoplasmosis in patients from endemic areas, such as the southwestern United States and the Ohio Valley, respectively.(6) Diagnosis usually requires demonstration of fungus from biopsied tissues.
It is unclear whether infection with HIV is an independent risk factor for the development of neurosyphilis. Although some authors have suggested that neurosyphilis is both more fulminant and more difficult to eradicate in the setting of HIV disease,(89,90) luetic neurologic disease has always encompassed a broad spectrum of presentations and clinical courses, and clinical evidence does not support the theory that HIV alters the natural history of Treponema pallidum infection.(77) Manifestations of neurosyphilis include meningitis, cerebral arteritis, and cerebritis, as well as optic neuropathy and deafness. Evaluation of HIV-infected patients with a positive serum treponemal antibody test (FTA-ABS or MHATP) meeting diagnostic criteria for late latent syphilis or syphilis of unknown duration should include lumbar puncture to evaluate for neurosyphilis. Current CDC recommendations also suggest lumbar puncture in the setting of primary or secondary syphilis when accompanying signs or symptoms suggest ophthalmic involvement (eg, uveitis) or neurologic involvement (eg, headache, altered mental status, meningeal signs).(91)
In the absence of neurologic signs or symptoms, a positive CSF VDRL in the setting of abnormal spinal fluid establishes the diagnosis of latent neurosyphilis. Unfortunately, the sensitivity of the CSF VDRL in the setting of HIV disease is unknown but estimated at only 70% at best. A negative CSF VDRL does not exclude the diagnosis.(92) A CSF pleocytosis (usually 10-400 cells/µL) and mildly elevated protein (46-200 mg/dL) with or without a positive CSF VDRL may be the only findings. One should probably err on the side of caution, and AIDS patients with abnormal CSF and a positive peripheral syphilis serology--even with negative CSF VDRL--should receive a course of at least 10 days of intravenous aqueous penicillin G, 4 million units every 4 hours. Repeat lumbar puncture with normalization of CSF is evidence of the efficacy of treatment however, CSF abnormalities due to HIV infection alone can complicate interpretation. In contrast, a positive CSF VDRL in the setting of normal CSF poses another interpretive dilemma, particularly in a severely lymphopenic patient with advanced HIV disease. T pallidum has been recovered from CSF of patients with otherwise normal spinal fluid.(93) In patients already treated for primary or secondary syphilis, either empiric therapy for neurosyphilis or careful interval neurologic and CSF evaluations are reasonable approaches.
Although Kaposi sarcoma (KS) is the most common systemic neoplasm in HIV disease, it rarely spreads to the CNS. Among the systemic cancers, non-Hodgkin lymphoma is the most important cause of neurologic dysfunction in HIV disease and invades the CNS by spreading along the leptomeninges. Common signs and symptoms include cranial nerve palsies and polyradiculopathy, and, less commonly, myelopathy due to epidural metastasis with spinal cord compression.(94) Intraparenchymal mass lesions are uncommon. Cytologic examination of CSF, often requiring multiple large-volume (10-20 mL) taps, is essential for the diagnosis. CSF must be delivered immediately for analysis to minimize cell lysis.
Primary CNS lymphoma (PCNSL) is a fairly common cause of cerebral mass lesions in patients with advanced HIV disease.(95) The most common signs and symptoms are confusion, lethargy, and personality changes, usually with focal deficits, such as hemiparesis, hemisensory loss, ataxia, and aphasia. Seizures are less common, but not rare.
On CT or MRI, lesions can be single or multiple, and typically enhance, either diffusely or in a ring pattern, after injection of contrast. About half the lesions are associated with edema and mass effect, but the degree of swelling is often mild relative to the size of the tumor(s). The most common locations are in the periventricular white matter, and in the deep gray matter. Primary CNS lymphoma can be indistinguishable radiologically from toxoplasmosis however, a single lesion on MRI (which is more sensitive than CT for detecting multiple lesions) in a patient with AIDS favors the diagnosis of lymphoma.(96) Definitive diagnosis requires brain biopsy or positive CSF cytology. Special assays to detect clonal markers in CSF may aid in the diagnosis. Prior to the availability of effective antiretroviral treatment, a common initial approach to contrast-enhancing brain lesions in the setting of HIV was a 10- to 14-day trial of antitoxoplasma therapy with careful clinical and radiologic reevaluation. However, given the decline in incidence of toxoplasmosis where antiretroviral drugs are available, the index of suspicion for PCNSL should be higher in individuals receiving effective antiretroviral treatment, and a definitive diagnosis based on CSF or brain biopsy should be more aggressively pursued. Whole-brain radiation (4,000 to 5,000 cGy over 3 weeks) prolongs survival in some patients with advanced HIV disease.(97) The tumor is radiosensitive, but its recurrence rate is high.(94,98) In general, treated patients have modestly improved survival and often succumb to opportunistic infections rather than to lymphoma.(96) Dexamethasone, which is lympholytic as well as effective against tumor-associated edema, may be used to control symptoms. There is some evidence that prognosis of PCNSL has improved in the era of effective antiretroviral therapy, and the incidence has declined.(99)
Metabolic encephalopathy occurs frequently in patients with advanced HIV disease. Adverse reactions to therapeutic drugs, hypoxia, electrolyte imbalance, and multiorgan failure are common etiologies. Efavirenz can cause a (usually) transient encephalopathy for a few weeks after initiation of therapy. In the cachectic patient or in patients with significant liver disease or history of protracted vomiting, Wernicke encephalopathy, due to thiamine deficiency, should be considered.(100)
Cerebral infarction and TIAs are seen infrequently in HIV-1-infected patients, with a reported incidence ranging from 0.5% to 8.0%.(101) Based on a case control study, this incidence is less than that among age-matched young adults with other terminal illnesses.(102) Among patients with advanced HIV disease, cerebral ischemic disease is more common than hemorrhagic stroke. One cause of stroke is cardiac disease resulting in cardiogenic emboli. Cerebral vasculitis, particularly that due to VZV or syphilitic arteritis, as well as vasculopathies due to chronic meningitis, or amphetamine or cocaine use, may cause thrombotic stroke in patients with HIV disease. Hemorrhage is occasionally seen in the setting of zoster vasculitis, thrombocytopenia, or, rarely, metastatic KS.
Headache is a common and difficult clinical problem in patients with HIV disease. Although many patients undoubtedly have "benign" headaches, headaches may also herald a wide range of CNS disorders. Meningitis, encephalitis, cerebral vasculitis, and mass lesions can all present with headache. New headache or significant change in pattern of headache warrants evaluation including imaging by CT or MRI followed by a lumbar puncture, unless contraindicated by the presence of mass lesions. Lumbar puncture need not await CT or MRI unless the patient has altered mental status, papilledema, or a focal neurologic examination. The likelihood of HIV-related causes increases with more severe immune deficiency (current or recent CD4 cells/µL). Clinicians should measure opening CSF pressure, and special studies should include cryptococcal antigen titers and CSF VDRL. CSF can be frozen for later PCR analysis. Clinical and preliminary laboratory evaluation should guide further testing. For example, in the setting of unexplained cranial neuropathies, CSF cytology should be included among the examinations ordered, whereas an extremely low CSF glucose (ន mg/dL) should lead to stains and cultures for acid-fast bacteria.
Seizures can accompany ADC or can be manifestations of any of the opportunistic or neoplastic intracranial complications of advanced HIV disease previously discussed.(103) The most common causes, in descending order of frequency, are cerebral mass lesions, encephalitis (including HIV-associated dementia), and meningitis. In about 20% of patients, no definite etiology for seizures can be found despite thorough neurologic, radiologic, and laboratory evaluation.(103) Treatment with anticonvulsant medications such as phenobarbital, phenytoin, carbamazepine, or valproic acid, provides excellent symptomatic control, although seizures due to mass lesions can be refractory to anticonvulsant therapy. Patients with advanced HIV disease appear to have an increased risk of adverse reactions to anticonvulsants, particularly phenytoin. In addition, liver disease may be exacerbated, particularly by valproic acid, and severe lymphopenia is a contraindication to the use of carbamazepine. Protease inhibitors may markedly alter metabolism of many drugs anticonvulsant drug levels may need to be carefully monitored. A patient with seizures or episodes of confusion or loss of consciousness may need to be reported to the Public Health Department. State legislation varies on the requirements for reporting by physicians, but in some states it is mandatory. In most states, patients with seizures must not operate a motor vehicle unless seizures are controlled for at least 6 months. An exception may be granted if a reversible metabolic abnormality or drug toxicity caused the seizure and is not expected to recur.
Acute encephalopathy is distinguished from dementia by the rapid progression of symptoms and the frequent association of a depressed level of alertness. Opportunistic infections and neoplasms can present with progressive cognitive decline and personality changes similar to ADC, but focal deficits are usually more prominent and the clinical course more rapid than in ADC.
Decline in mental status in HIV-infected patients warrants full physical examination, evaluation of electrolytes and renal and hepatic function, syphilis serology, measurement of vitamin B12 level, toxicology screen, and neurologic evaluation, including diagnostic imaging of the brain and, unless contraindicated, lumbar puncture. Review of prescribed and nonprescribed medications as well as recreational drug and alcohol use is essential.
Neuropsychiatric testing should be considered where depression (pseudodementia) is in the differential diagnosis. If altered mentation is episodic and the sensorium clears within 24 hours without specific treatment, suspicion of drug toxicity or a postictal encephalopathy should be raised. An electroencephalogram can be useful if epileptiform activity is demonstrated, but a normal study does not rule out a seizure disorder.
Isolated involvement of the posterior fossa (cerebellum and brainstem) is uncommon in HIV-associated conditions, but may occur in PML, toxoplasmosis, or lymphoma. Manifestations include vertigo, diplopia, headache, cerebellar ataxia, and cranial nerve deficits. If the brainstem parenchyma is involved, hemiparesis and hemisensory loss can be prominent.
Although MRI is more sensitive than CT in detecting CNS pathology,(77) CT with double-dose contrast is an excellent alternative in the evaluation of HIV-infected patients with signs and symptoms of intracranial disease. There is no pathognomonic radiologic appearance for any of the CNS disorders seen in patients with advanced HIV disease. Several patterns, however, are clinically helpful. Widespread white-matter abnormalities without contrast enhancement or mass effect suggest either PML or HIV encephalitis. Lesions associated with the latter tend to be more diffuse, less well demarcated, and more prominent in the frontal regions, whereas lesions of PML tend to be discrete and, in patients with AIDS, to favor occipital-parietal regions of the brain. Zoster encephalitis can resemble PML radiographically.
Periventricular contrast enhancement can be seen with either CMV or zoster ventriculitis. Focal cerebral lesions with surrounding edema and mass effect are most commonly caused by either abscesses (especially those of toxoplasmosis), or primary CNS lymphoma. Either can show ring, nodular, or diffuse enhancement, and either can produce single or multiple lesions. A solitary lesion on MRI, while not definitive, would favor a diagnosis of lymphoma.(104) Enlarged ventricles are usually the result of atrophy (hydrocephalus ex vacuo) frank hydrocephalus occurs with mass lesions that obstruct CSF flow or as the result of previous meningitis, most commonly cryptococcal or tuberculous.
Abnormal CSF findings, such as mild elevations in white blood cell count and protein and mild decrease in glucose concentration, are frequent in the setting of HIV disease at all stages, including among asymptomatic HIV-infected persons with well-preserved immunologic function.(105) These nonspecific findings complicate the interpretation of CSF indices in the setting of neurologic signs and symptoms. In one large retrospective study of HIV-infected outpatients who underwent lumbar puncture for the "classic" indications of headache, fever, and altered mental status, alone or in combination, CSF abnormalities were found in 45%. Definitive diagnosis, however, was reached based on lumbar puncture in only 8%.(106) In contrast, the diagnostic yield of lumbar puncture was 40% in another study in which a specific neurologic deficit, cranial neuropathy, was the reason for CSF examination.(107)
Despite difficulties in interpretation and low yields in many instances, lumbar puncture remains unsurpassed as a means of detecting treatable CNS diseases such as cryptococcal, tuberculous, syphilitic, or lymphomatous meningitis. Recent validation of CSF PCR assays provide additional tools in the diagnosis of PML, CMV, HSV, VZV, and TB.(85)
To avoid possible herniation, lumbar puncture should not be performed in patients with altered mental status, papilledema, or a focal neurologic examination until the presence of a mass lesion has been ruled out by CT or MRI brain imaging.
Biopsy is a reliable method for making a definitive diagnosis of intracranial disorders presenting as focal lesions on brain imaging, such as toxoplasmosis, lymphoma, and PML. Because the incidence of toxoplasmosis has declined dramatically in the setting of antiretroviral therapy, it is reasonable to consider brain biopsy early, rather than pursuing an empiric course of toxoplasmosis treatment, in patients receiving effective antiretroviral therapy. Brain biopsy should be strongly considered in patients with focal brain lesions who are either neurologically unstable or have only a solitary lesion on brain MRI, or who have negative antitoxoplasma serology. Nevertheless, the risks and benefits of brain biopsy must be carefully evaluated for each individual case, taking into account not only clinical factors, laboratory evaluation, and imaging studies, but, above all, the patient's particular situation and wishes.
Congenital myotonic dystrophy
Myotonic Dystrophy is an autosomal dominant muscular dystrophy characterized by weakness and stiffness, more pronounced in facial and distal muscles, and by increased muscle excitability. Atrophy and weakness of facial muscles, ptosis, and frontal baldness produce a characteristic facial appearance. Myotonia (prolonged muscle contraction) occurs spontaneously or is elicited by voluntary activity or by mild stimulation, such as tapping on a muscle (percussion myotonia). The EMG shows characteristic repetitive discharges. In many cases, a handshake is enough to establish the diagnosis (the myotonic patient cannot let go). Symptoms appear in adolescents or young adults, but no age is spared. At times, congenital myotonic dystrophy, transmitted from the mother, causes severe, even fatal hypotonia, weakness, and respiratory insufficiency in newborn babies. In addition to muscle disease, patients with myotonic dystrophy have cataracts, cardiac arrhythmias, testicular atrophy, and diabetes. Weakness is progressive. The biopsy shows atrophy of type 1 fibers, a profusion of central nuclei (normally myonuclei are under the sarcolemma), and ring fibers. None of these changes are diagnostic individually, but their combination strongly suggests myotonic dystrophy. Congenital myotonic dystrophy is characterised by small fibers with central nuclei, similar to centronuclear myopathy.
There are two genetic forms of myotonic dystrophy, DM1, and DM2. They are similar in most respects, except that in DM1 weakness is predominantly distal and in DM2 proximal. DM1 is caused by a CTG trinucleotide expansion in the DMPK (Dystrophia Myotonica Protein Kinase) gene on chromosome 19q13. In DM1, this gene is expanded over 37 CTG repeats. The more repeats, the more severe the dystrophy and the earlier the onset of symptoms. Thus, 100-150 repeats cause myotonia and cataracts, 150-1000 cause full blown myotonic dystrophy, and over 1500-2000 repeats cause neonatal myotonic dystrophy. As with other diseases caused by trinucleotide repeats, the onset of the disease is earlier with each successive generation (anticipation). DM2 is caused by a CCTG expansion of the ZNF9 (Zink Finger Protein 9) gene on 3q21. Neither mutation affects the coding portion of these proteins and it is not kown how these mutations affect muscle and other organs.
Any condition that causes muscle inflammation can lead to myositis. Causes may include inflammatory conditions, infections, medications and drugs, injury, or a condition called rhabdomyolysis that causes muscle breakdown.
Inflammatory conditions: Conditions that cause systemic (whole body) inflammation affect the muscles and may result in myositis. Many inflammatory causes are autoimmune diseases, where the body attacks its own healthy tissues. Inflammatory causes are the most serious causes of myositis and require long-term treatment.
Infection: Viral infections are the most common infective causes of myositis. Bacteria, fungi, and other organisms can also cause myositis, but these cases are rarer. Viruses and bacteria may attack muscle tissue directly or they release substances that cause damage to muscle tissue.
Medications: Many different medications can cause muscle weakness. Medications, such as statins, colchicine, and hydroxychloroquine can induce different types of myositis. Excessive use of alcohol and illicit drugs can also cause myositis. Myositis may occur at the start of a new medication or it may occur years after taking a drug. It can also result from a reaction between two medications.
Injury: Vigorous activity can cause muscle pain, swelling, and weakness for hours or days. Inflammation is the main cause of symptoms in myositis related to injury. The good news is that myositis from mild injury or after exercise usually resolves quickly with rest and pain relievers.
Rhabdomyolysis: Rhabdomyolysis occurs when muscles break down quickly leading to the release of muscle fiber materials into the blood. These substances are harmful to the kidneys. Muscle pain, weakness, and swelling are symptoms of this condition.
How lupus affects the muscles, tendons and joints
It is not uncommon for people with lupus to experience muscle aches and pain (myalgias) or have inflammation of certain muscle groups (myositis), which causes weakness and loss of strength. More than 90 percent of people with lupus will experience joint and/or muscle pain at some time during the course of their illness. 1 More than half of the people who develop lupus mention joint pain as their first symptom.
Muscle pain and muscle tenderness, especially during periods of increased disease activity (flare), occur in as many as 50 percent of those with lupus. The symptoms may have different causes. It is important for your physician to determine the cause of your symptoms since treatments are quite varied. Rheumatologists are the physicians who specialize in the joints, muscles and bones.
Muscle aches and pain may be from symptoms that happen when your body is responding to some type of inflammation, from muscle atrophy (weakness) or from a true myositis.
Inflammation is the most common reason for muscle pain and aches. Any time that major inflammation exists ("strep" throat, hepatitis, cancer, lupus, acute heart attack, etc.), signs and symptoms often include fevers, sweats, chills, fatigue, weight loss, and various muscle aches, pains and weakness. These non-specific, non-diagnostic symptoms are signs of your body's inability to cope with whatever process has overwhelmed it. Because lupus is an inflammatory disease it may cause any of these problems. These myalgias are a secondary part of the overall disease.
Lupus arthritis causes pain, stiffness, swelling, tenderness and warmth in your joints. The joints most often affected are the ones farthest from the middle of the body, such as fingers, wrists, elbows, knees, ankles and toes. General stiffness upon awakening, which gradually improves as the day goes on, is a key feature of lupus arthritis. However, there also may be joint pain later in the day. Several joints are usually involved, and the inflammation will affect similar joints on both sides of your body.
Compared to rheumatoid arthritis, lupus arthritis is less disabling and less likely to cause destruction of the joints. Fewer than 10 percent of people with lupus arthritis will develop deformities of their hands and feet associated with weakening of cartilage and bone.
Muscle atrophy (wasting away of muscle strength) may occur if arthritis becomes chronic.
Some people with lupus develop myositis, an inflammation of the skeletal muscles that causes weakness and loss of strength. Lupus myositis often affects the muscles of your neck, pelvis, thighs, shoulders and upper arms difficulty in climbing stairs and getting up from a chair are early symptoms. Later symptoms may include difficulty lifting objects onto a shelf, lifting your arm to comb or brush your hair, getting out of the bath, and even raising your head or turning over in bed.
An exercise program supervised by a physical therapist is helpful in regaining normal muscle strength and function.
Drug-induced muscle weakness
Muscle weakness also may be a side effect of certain drugs used to treat lupus and related conditions, including prednisone and other corticosteroids, cholesterol-lowering drugs and hydroxychloroquine (Plaquenil®). Therefore, drug-induced muscle disease should be ruled out as a cause of weakness if you are taking any of these medications, as drug-induced muscle weakness usually does not produce elevated levels of muscle enzymes as is seen in lupus myositis.
Adjusting or stopping the drugs that are causing the muscle weakness usually brings about an improvement of muscle strength.
Tendonitis and bursitis
A tendon is a strong rope-like structure made of tough fibers that attaches muscle to bone. A bursa is a small sac containing a slippery fluid that is usually found near a joint and allows muscles, bones, and tendons to move easily. Tendonitis (irritation of a tendon) and bursitis (irritation of a bursa) are usually due to damage or overuse of a joint. Pain is the major symptom of both conditions. Different areas of your body may be affected common areas include the elbow (tennis elbow), the finger (trigger finger) and the shoulder. In addition, tendons and bursas are both lined with synovial membrane, which is a target for inflammation in lupus arthritis.
Carpal tunnel syndrome
Pressure on the central nerve in the wrist causes a condition called carpal tunnel syndrome. It is characterized by tingling, numbness, and pain in the fingers, which sometimes affects the entire hand. A number of medical conditions, including lupus, can cause carpal tunnel syndrome. When carpal tunnel occurs with lupus, it is usually because inflammation in your wrist is putting pressure on the nerves.