CRISBERT I. CUALTEROS, M.D. - Juvenile Rheumatoid Arthritis
   
DR. CRISBERT I. CUALTEROS
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CRISBERT I. CUALTEROS, M.D. (+63919)8586556

Chapter 145 - Juvenile Rheumatoid Arthritis

Michael L. Miller
James T. Cassidy

Juvenile rheumatoid arthritis (JRA) is one of the most common rheumatic diseases of children and a major cause of chronic disability. It is characterized by an idiopathic synovitis of the peripheral joints, associated with soft tissue swelling and effusion. In the classification criteria of the American College of Rheumatology, JRA is regarded not as a single disease but as a category of diseases with three principal types of onset: (1) oligoarthritis, or pauciarticular disease, (2) polyarthritis, and (3) systemic-onset disease ( Box 145–1 ). Nine distinct course subtypes have also been identified. The European League Against Rheumatism (EULAR) has also published classification criteria for a similar constellation of diseases, identified as juvenile chronic arthritis. New international criteria for the classification of seven specific types of onset of peripheral arthritis in children are being developed.
Etiology.
The etiology of the diseases classified under JRA is unknown. At least two events are considered necessary: immunogenetic susceptibility and an external, presumably environmental, trigger. Specific HLA subtypes have been identified as rendering children at risk, which may confer varying degrees of susceptibility, or indeed protection, depending on the age of the child. Possible external triggers for JRA include certain viruses (e.g., parvovirus B19, rubella, Epstein-Barr virus), host hyperreactivity to specific self-antigens (type II collagen), and enhanced T-cell reactivity to bacterial or mycobacterial heat shock proteins.
Epidemiology.
Although difficult to determine with precision, the incidence of JRA is approximately 13.9/100,000 children/yr among children 15 yr or younger, with an overall prevalence of approximately 113/100,000 children. A report from Australia, however, provided a much higher estimate of prevalence based on examination of school children by a pediatric rheumatologist. This study suggested a need for increased identification and referral of children with arthritis to pediatric rheumatology treatment centers. Different racial and ethnic groups appear to have varying frequencies of the subtypes of JRA. One study reported that black American children with JRA were older at presentation and less likely to have elevated antinuclear antibody (ANA) titers or uveitis.
Pathogenesis.
The synovitis of JRA is characterized by villous hypertrophy and hyperplasia with hyperemia and edema of the subsynovial tissues. Vascular endothelial hyperplasia is prominent and characterized by infiltration of mononuclear and plasma cells ( Fig. 145–1 ). Pannus formation occurs in advanced or uncontrolled disease and results in progressive erosion of articular cartilage and contiguous bone ( Fig. 145–2 ).
Although the etiology is unknown, studies suggest exaggerated immune reactivity of several types of cells in predisposed children, suspected but not proved to be in response to exposure to certain viruses. Thus, the onset of JRA may be triggered by a preceding infection. Although trauma may be cited by the


Box 145-1. Criteria for the Classification of Juvenile Rheumatoid Arthritis
Age at onset <16 yr

Arthritis (swelling or effusion, or presence of two or more of the following signs: limitation of range of motion, tenderness or pain on motion, and increased heat) in one or more joints

Duration of disease 6 wk or longer

Onset type defined by type of disease in first 6 mo:

Polyarthritis: 5 or more inflamed joints

Oligoarthritis: <5 inflamed joints

Systemic: arthritis with characteristic fever

Exclusion of other forms of juvenile arthritis


Modified from Cassidy JT, Levison JE, Bass JC, et al: A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum 1986;29;174.

 


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 Figure 145-1 Synovial biopsy from a 10-yr-old child with pauciarticular juvenile rheumatoid arthritis. There is a dense infiltration of lymphocytes and plasma cells in the synovium.
parents as a trigger, it is more likely the result than the cause of arthritis. Studies of T-cell receptor expression confirm recruitment of T cells specific for antigens, at present uncharacterized, which are present in joint synovium. Specific populations of


 Figure 145-2 MRI scan with gadolinium of a 10-yr-old child with juvenile rheumatoid arthritis (same patient as in Fig. 145–1 ). The dense white signal in the synovium near the distal femur, proximal tibia, and patella reflects inflammation. MRI is useful to exclude ligamentous injury, chondromalacia of the patella, or tumor.
T cells appear to change over time, sometimes with clonal expansion of cells that may be protective (e.g., those reactive toward certain heat shock proteins) and associated with improved responsiveness to medical treatment. However, resistance to treatment may result in part from the migration into synovium of T cells whose surfaces bear molecules permitting chronic activation.
The recruitment of these T cells is made possible by certain HLA types that are found with increased frequency in affected children. HLA-DR4 (particularly the DRB1*0401 allele) is associated with polyarticular disease; pauciarticular JRA has been associated with HLA alleles at the DR8 (particularly DRB1*0801) and DR5 (particularly DRB1*1104) loci.
T-cell activation results in a cascade of events leading to tissue damage in joints and other affected tissues, including B-cell activation, complement consumption, and, in particular, release of interleukin-6 (IL-6), IL-13, tumor necrosis factor-a (TNFa), and other pro-inflammatory cytokines, possibly under the control of specific genetic alleles. Inheritance of certain alleles may predispose to production of greater amounts of these cytokines, resulting in more severe disease.
Clinical Manifestations.
Initial symptoms often include morning stiffness and gelling, easy fatigability particularly after school in the early afternoon, joint pain later in the day, and joint swelling. The involved joint is often warm, lacks full range of motion, and is occasionally painful on motion but usually not erythematous.
Oligoarthritis (pauciarticular disease) predominantly affects the joints of the lower extremities, such as the knees and ankles ( Fig. 145–3 ). Involvement of upper extremity large joints, although seen, is not characteristic of this type of onset. Involvement of the hip is almost never a presenting sign of JRA. However, hip disease may occur later, particularly in polyarticular JRA, and is often the first sign of a deteriorating functional course ( Fig. 145–4 ).
Polyarthritis (polyarticular disease) is generally characterized by involvement of both large and small joints ( Figs. 145–5 and 145–6 ). As many as 20–40 separate joints are often affected, although inflammation of only five or more joints is

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 Figure 145-3 Pauciarticular juvenile rheumatoid arthritis with involvement of the left knee and hands. (Reprinted from the Clinical Slide Collection on the Rheumatic Diseases; Copyright 1991, 1995, 1997. Used by permission of the American College of Rheumatology.)
required as a criterion for classification of this type of onset or course. Polyarticular disease often resembles the usual presentation of adult rheumatoid arthritis. Rheumatoid nodules found on extensor surfaces of elbows and over the Achilles tendon are associated with a more severe course. Micrognathia reflects chronic temporomandibular joint involvement. Cervical spine involvement of the apophyseal joints ( Fig. 145–7 ) occurs frequently, with risk of atlantoaxial subluxation.
Systemic-onset disease is manifest by arthritis and prominent visceral involvement including hepatosplenomegaly, lymphadenopathy, and serositis, such as a pericardial effusion. It is


 Figure 145-4 Severe hip disease in a 13-yr-old boy with active, systemic-onset juvenile rheumatoid arthritis. X-ray shows destruction of the femoral head and acetabula, joint space narrowing, and subluxation of left hip. The patient had received corticosteroids systemically for 9 yr.
characterized by a quotidian fever with daily temperature spikes to at least 39°C, sometimes followed by mildly hypothermic temperatures, for a minimum of 2 wk. Each febrile episode is often accompanied by a characteristic faint, erythematous, macular rash; these evanescent salmon-colored lesions may be linear or circular, from 2 to 5?mm in size, distributed most commonly over the trunk and proximal extremities ( Fig. 145–8 ). Koebner phenomenon, which is cutaneous hypersensitivity to superficial trauma, is elicited by lightly running the edge of the examiner's fingernail along uninvolved skin, is suggestive, but not diagnostic, of systemic-onset disease.
Diagnosis.
The diagnosis of JRA is greatly aided by the American College of Rheumatology classification criteria and its subclassification of courses of disease and by the meticulous exclusion of other articular diseases. There is no one pathognomonic finding for these diseases in children. However, the classic intermittent fever in association with the typical rash and objective arthritis is highly suggestive of systemic-onset JRA. The diagnosis is based on a history compatible with inflammatory joint disease and a physical examination that confirms the presence of arthritis, as defined by the classification criteria (see Box 145–1 ). Laboratory abnormalities characteristic of inflammation include an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), leukocytosis, thrombocytosis, and the anemia of chronic disease support the diagnosis.
DIFFERENTIAL DIAGNOSIS.
Arthritis can be the presenting manifestation for any of the rheumatic diseases of childhood, including systemic lupus erythematosus (SLE) (see Chapter 148 ), juvenile dermatomyositis (see Chapter 149 ), sarcoidosis (see Chapter 155 ), and the vasculitis syndromes (see Chapter 157 ). The diagnosis of these diseases will depend on specifically associated manifestations. In scleroderma, the swelling along the digits early in the disease is not confined to the joints, and subsequent loss of motion occurs without articular swelling. Rheumatic fever is characterized by exquisite joint tenderness, high spiking fevers, and polyarthritis that is usually migratory but may also be additive. Autoimmune hepatitis can be associated with arthritis. Lyme disease (see Chapter 204 ) should be considered in children living in or visiting endemic areas who present with oligoarthritis. Although a history of tick exposure, preceding flulike illness, and subsequent rash should be sought, these are not always present. Joint pain and swelling of a single joint suggests trauma or infection; correlation with history, laboratory, and radiologic findings helps exclude these possibilities.

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 Figure 145-5 Hands and wrists of a girl with rheumatoid factor-negative polyarticular juvenile rheumatoid arthritis. Notice the symmetric involvement of the metacarpophalangeal joints, proximal interphalangeal joints, and distal interphalangeal joints. Both wrists are affected.
Monoarticular arthritis unresponsive to anti-inflammatory treatment may be the result of chronic mycobacterial or other infection; the diagnosis is established by synovial biopsy.
Physical findings may suggest other diagnoses. Arthritis and fluid in a single joint suggests bacterial infection, although joint fluid can be significant with JRA, including in the knee joint resulting in a ballotable patella. Chondromalacia of the patella or related femoropatellar syndromes can cause knee pain. Tenderness over insertion of ligaments and tendons raises the possibility of a spondyloarthropathy. Pauciarticular arthritis occurring in an unusual distribution (e.g., small joints of the hand and ankle) can be seen in psoriatic arthritis. However, until psoriasis develops, which may occur years after the arthritis


 Figure 145-6 Progression of joint destruction in a girl with rheumatoid factor-positive juvenile rheumatoid arthritis despite doses of corticosteroids sufficient to suppress symptoms in the interval between A and B. A, Roentgenogram of the hand at onset. B, Roentgenogram 4 yr later, showing a loss of articular cartilage and destruction changes in the distal and proximal interphalangeal and metacarpophalangeal joints and destruction and fusion of wrist bones.
presents, the diagnosis can only be suspected. Isolated hip pain with limited motion raises the possibility of suppurative arthritis, osteomyelitis, Legg-Calvé-Perthes disease, slipped capital femoral epiphysis, and chondrolysis of the hip.
Some children will have persistent arthralgia despite repeated normal physical examination. Although these children do not fulfill the diagnostic criteria for JRA initially, the diagnosis of JRA may sometimes be established as long as 2 yr after initial presentation. Until persisting joint swelling develops, other diagnoses need to be considered. Episodes of joint pain and swelling, usually lasting less than 1 wk with complete resolution between episodes, can be seen in juvenile episodic arthritis, often attributed to hypermobility syndrome. Inflammatory bowel disease may present with pauciarticular arthritis, usually affecting joints in the lower extremities. The presence of diarrhea in a child with arthritis can also follow an enteric infection (see Chapter 147 ). A fear of returning to school suggests school phobia.
Less commonly, other diseases can produce joint symptoms and abnormal joint examination. Children with leukemia may have joint pain resulting from metaphyseal expansion of malignant bone marrow, sometimes months before demonstrating peripheral blood lymphoblasts. Examination of such a child usually reveals a deeper pain to palpation of the bone; bone marrow aspiration yields the diagnosis. Some diseases, such as cystic fibrosis, diabetes mellitus, and glycogen storage diseases, have associated arthropathies. Swelling that extends beyond the joint can be seen in lymphedema, which may rarely coexist with JRA, and in Henoch-Schönlein purpura. A peripheral arthritis indistinguishable from types of JRA occurs in the presence of humoral immunodeficiency, such as common variable immunodeficiency and X-linked agammaglobulinemia. Some skeletal dysplasias associated with a degenerative arthropathy can be diagnosed by characteristic radiologic abnormalities.
Laboratory Findings.
Hematologic abnormalities often reflect the degree of systemic or articular inflammation, with elevated white blood cell and platelet counts and decreased hemoglobin concentration and mean corpuscular volume. The ESR and

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 Figure 145-7 Radiograph of the cervical spine of a patient with active juvenile rheumatoid arthritis, showing fusion of the neural arch between joints C2-3, narrowing and erosion of the remaining neural arch joints, obliteration of the apophyseal space, and loss of the normal lordosis.


 Figure 145-8 The rash of systemic-onset juvenile rheumatoid arthritis. The rash is salmon colored, macular, and nonpruritic. Individual lesions are transient and occur in crops over the trunk and extremities. (Reprinted from the Clinical Slide Collection on the Rheumatic Diseases; Copyright 1991, 1995, 1997. Used by permission of the American College of Rheumatology.)
CRP usually mirror these findings, along with elevated serum immunoglobulins. However, it is not unusual for the ESR to be normal in some children with JRA, probably when most activated lymphocytes responsible for disease have shifted from the bloodstream and entered the synovium.
Elevated ANA titers are present in at least 40–85% of all children with pauciarticular or polyarticular JRA but are unusual in children with systemic-onset disease. Detectable ANA, usually with homogeneous or speckled pattern, is associated with increased risk for the development of chronic uveitis but the precise specificities for various ANA patterns have not been determined. A positive rheumatoid factor (RF) may be associated with onset of the disease in an older child with polyarticular involvement (approximately 8%) and the development of rheumatoid nodules, and with a poor overall prognosis and eventual functional disability. Both ANA and RF can occur in association with transient events during childhood, such as viral infections, particularly Epstein-Barr virus; seropositivity must be defined at a specific titer within a laboratory in relation to accepted positive and negative controls and based on consecutive positive tests over a defined period.
Bone mineral metabolism is often abnormal in children with JRA with a history of active synovitis, relatively independent of onset type or course subtype, and predominantly affects appendicular cortical bone, with less effect upon the normal age-related development of trabecular bone. Increased levels of cytokines such as IL-6 may decrease bone formation (reflected by decreased serum levels of osteocalcin and bone-specific alkaline phosphatase) to a greater extent than bone resorption (which may also be decreased, as reflected by decreased levels of tartrate-resistant acid phosphatase). Corresponding abnormalities of skeletal growth become most prominent during the pubertal growth spurt and in postpubertal children (Tanner stages IV–V).
Early radiographic changes include soft tissue swelling, osteoporosis, and periostitis about the affected joints ( Fig. 145–9 ). Regional epiphyseal closure may be accelerated and the local bone growth increased or decreased. Continued disease may lead to subchondral erosions and narrowing of cartilage space, with varying degrees of bony destruction and fusion. Characteristic late radiographic changes of JRA are seen in the hands and cervical spine, most frequently in the neural arch joints at C2-3 (see Fig. 145–7 ). MRI studies may be helpful to evaluate both joint and soft tissues (see Fig. 145–2 ).
Treatment.
The long-term treatment of children with JRA is initiated and subsequently modified according to disease subtype, severity of the disease, specific manifestations of the illness, and response to therapy. The objectives of treatment are to establish the child in a pattern of adaptation that is as normal as possible


 Figure 145-9 Early (6-mo duration) radiographic changes of juvenile rheumatoid arthritis, soft tissue swelling, and periosteal new bone formation appear adjacent to the 2nd and 4th proximal interphalangeal joints.

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and to accomplish this goal with minimal risk of adverse effects (see Chapter 144 ).
Most children with oligoarticular JRA respond to nonsteroidal anti-inflammatory drugs (NSAIDs) alone. However, most polyarticular patients, and some oligoarticular patients with aggressive disease, require additional medications. A pyramid therapeutic approach should be considered; combination therapy should begin with the least toxic medications, usually NSAIDs, and proceeding through sulfasalazine, methotrexate, and possibly etanercept or immunosuppressive or experimental drugs ( Fig. 145–10 ). Medications that place the child's present and future health most at risk, such as azathioprine and cyclophosphamide, are reserved for the very few children who do not respond to less aggressive therapy. Newer modes of treatment, such as etanercept, may prove to be more specific for synovial inflammatory disease and potentially less toxic than other current medications.
Glucocorticoids are used for management of overwhelming inflammatory or systemic illness, for bridge therapy in lower doses for the child who has not yet responded, in addition to another drug such as methotrexate, and for ocular and intra-articular use. Corticosteroids are very powerful anti-inflammatory drugs, perhaps the most efficacious in current use for systemic disease, but they may be associated with tachyphylaxis and impose upon the child the risk of severe toxicities, including Cushing syndrome, growth retardation, and osteopenia.
Methotrexate is considered the safest, most efficacious, and least toxic of the currently available second-line agents. It may be given either orally or subcutaneously once weekly. Intramuscular gold therapy has been generally supplanted by methotrexate.
Other aspects of management include routine slit-lamp ophthalmologic examination of all patients with JRA to monitor for development of asymptomatic uveitis, dietary evaluation and counseling to ensure appropriate calcium intake, and physical and occupational therapy. Social workers can help families recognize stresses imposed by illness and identify appropriate community resources.
Prognosis.
Although the course of JRA in an individual child is unpredictable, some general statements can be made concerning onset type and outcome ( Table 145–1 ). Studies from

TABLE 145-1 -- Prognosis of Juvenile Rheumatoid Arthritis by Type of Onset
Onset Type
Course Subtype
Subsequent Clinical Manifestations
Outcome
Polyarthritis
RF-seropositive
Female
Poor


Older age

 

Hand/wrist

 

Erosions

 

Nodules

 

Unremitting


ANA-seropositive
Female
Good


Young age


Seronegative

Variable
Oligoarthritis
ANA-seropositive
Female
Excellent (except eyes)


Young age

 

Chronic anterior uveitis (iridocyclitis)


RF-seropositive
Polyarthritis
Poor


Erosions

 

Unremitting


HLA-B27–positive
Male
Good


Older age


Seronegative

Good
Systemic disease
Oligoarthritis

Good

Polyarthritis
Erosions
Poor
From Cassidy JT, Petty RE: Juvenile rheumatoid arthritis. In Textbook of Pediatric Rheumatology, 4th ed. Philadelphia, WB Saunders, 2001.

 


 Figure 145-10 The “therapeutic pyramid” of juvenile rheumatoid arthritis. (Adapted from Cassidy JT, Petty RE: Juvenile rheumatoid arthritis. In Textbook of Pediatric Rheumatology, 3rd ed. Philadelphia, WB Saunders, 1995.)
the United States indicate that, despite current management, approximately 45% of JRA patients have active disease persisting into early adulthood, often with severe limitations of physical function.
Children with oligoarthritis, particularly girls with early onset of arthritis at younger than 6 yr of age, are at risk to develop chronic uveitis. There is usually no association between the course of the arthritis and the chronic uveitis. Anterior uveitis ( Fig. 145–11 ), or iridocyclitis, in children with pauciarticular disease can result in posterior synechiae; untreated or refractory uveitis can result in blindness, which has decreased with more frequent monitoring by slit-lamp examination to exclude asymptomatic uveitis. Many of these children do well, however, with early remission.
The child with polyarticular disease often has a more prolonged course. Functional risk has been associated with older age of onset, the presence of rheumatoid factor seropositivity or

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 Figure 145-11 Chronic anterior uveitis, or iridocyclitis, of juvenile rheumatoid arthritis. Extensive posterior synechiae have resulted in a small, irregular pupil. There is a well-developed cataract and early band keratopathy at the medial and lateral margins of the cornea.
rheumatoid nodules, and the early development of specific articular disease, such as that affecting the cervical spine or hips.
The child with systemic-onset disease is often the most difficult to manage in terms of both articular and systemic manifestations. However, systemic manifestations are usually present only during the first few years after onset. The prognosis after that time is dependent on the number of joints involved and severity of the arthritis.
Anemia, common in active disease or disease of prolonged duration, is usually unresponsive to oral iron administration. Anemia may be exacerbated by gastrointestinal bleeding associated with the use of NSAIDs. Specific complications may occur in subsets of the disease, such as the development of SLE during the course of disease in children with polyarticular JRA, particularly when they develop ANAs with a high titer. Anemia associated with decreases in other blood cell lines raises the possibility of malignancy. Rarely, anemia is a result of hemolytic anemia. Anemia associated with thrombocytopenia or leukopenia with fever, lymphadenopathy, and hepatosplenomegaly suggests macrophage activation syndrome, a rare complication of systemic JRA. This diagnosis is confirmed by liver or bone marrow biopsy. Treatment with cyclosporine has been effective in many patients. A rare digital endarteritis threatening autoamputation may respond to parenterally administered prostaglandin E1 . The development of manifestations of other rheumatic diseases suggests that the diagnosis has changed to an overlapping syndrome or another specific disease, such as SLE or dermatomyositis.
Orthopedic complications include leg length discrepancy, which can be treated with a shoe lift on the shorter side to prevent a secondary scoliosis; popliteal cysts, which require no treatment if small; and flexion contractures, particularly of the knees, hips, and wrists. Contractures require medical control of arthritis, appropriate splinting, and a physical therapy program to allow stretching of affected tendons.
Psychosocial adaptation may be affected by JRA. Studies from Scandinavia and the United States indicate that, compared with control subjects, many of these children have problems with lifetime adjustments and obtaining employment. Disability not directly associated with arthritis may continue into young adulthood in as many as 20% of patients, together with continuing chronic pain syndromes in a similar frequency. Psychologic complications, including problems with school attendance and socialization, may respond to counseling by mental health professionals.

   

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