Back, Joint, and Extremity Pain


CHAPTER 5 BACK, JOINT, AND EXTREMITY PAIN


MEGAN AYLOR


DEFINITION OF THE COMPLAINT


Back, joint, and extremity pain are worrisome symptoms in children. Although benign musculoskeletal disease accounts for many cases, more sinister diagnoses should be ruled out. The inability of young children to clearly describe the location and nature of the pain contributes to diagnostic difficulties. Since the diverse complaints of back, extremity, and joint pain frequently share a common etiology, a uniform approach to such symptoms facilitates accurate diagnosis.


COMPLAINT BY CAUSE AND FREQUENCY


Back pain, or discomfort anywhere along the spinal and paraspinal area, reflects potential pathology in a wide range of organ systems, including musculoskeletal, central nervous system, pulmonary, vascular, and intraabdominal or retroperitoneal structures (Table 5-1). Young children who cannot accurately localize pain require indirect symptom assessment. For example, refusal to walk, irritability with repositioning, and reluctance to participate in specific activities often provide the earliest clues to identifying back pain.



TABLE 5-1. Causes of back pain in childhood by etiology.







Infectious/Inflammatory


Vertebral ostemyelitis


Spinal epidural abscess


Diskitis


Paraspinal pyomyositis


Pneumonia


Pyelonephritis



Orthopedic


Scheuermann (juvenile) kyphosis


Spondylolysis/spondylolisthesis


Scoliosis


Intravertebral disk herniation


Trauma


Muscle strain



Rheumatologic


Juvenile ankylosing spondylitis


Juvenile rheumatoid arthritis



Neoplastic


Osteoid osteoma


Neuroblastoma


Ganglioneuroma


Lymphoma


Leukemia


Eosinophilic granuloma



Miscellaneous


Sickle cell disease


Nephrolithiasis






Alteration in gait or changes in the use of a limb also suggest an underlying extremity or joint disorder (Table 5-2). Examining one joint above and below the site of the chief complaint can prevent missing a diagnosis in cases of referred pain. For example, knee pain may be the presenting symptom for hip pathology. Joint and extremity symptoms can also represent referred pain from a spinal or paraspinal process. The radicular symptoms of nerve root entrapment in the lumbar spine may present as foot pain.



TABLE 5-2. Causes of joint or extremity pain in childhood by etiology.







Infectious/Inflammatory


Bacterial arthritis


Lyme arthritis


Disseminated Neisseria gonorrhoeae


Osteomyelitis


Pyomyositis


Acute rheumatic fever


Reactive/postinfectious arthritis


Immunization



Orthopedic


Trauma


Osteochondritis dessicans


Chondromalacia patella


Overuse syndromes


Osgood-Schlatter



Rheumatologic


Systemic juvenile idiopathic arthritis


Systemic lupus erythematosus


Dermatomyositis



Neoplastic


Leukemia


Lymphoma


Bone/soft tissue tumors


Metastatic malignancy



Hematologic


Sickle cell disease


Hemophilia



Miscellaneous


Kawasaki disease


Serum sickness


Behçet disease


Sarcoidosis


Henoch-Schönlein purpura


Guillain-Barré syndrome






Evaluation of back, extremity, and joint pain requires an understanding that extensive interplay of symptoms, findings, and etiologies exists among these diagnostic groups. Any patient with pain that interferes with activity, has associated neurologic symptoms (weakness, changes in reflexes, or bowel/bladder control), or has worrisome associated symptoms (weight loss, fever, worsening pain over time) should prompt a diagnostic evaluation.


CLARIFYING QUESTIONS


Routine inquiry into the onset, location, duration, character, radiation, and intensity of the pain may help clarify the diagnosis. Caretaker observations may supplement the history, especially in nonverbal patients. The timing of symptom onset relative to a traumatic injury can pose a particular diagnostic challenge. Many children with nontraumatic abnormalities will first notice a symptom following an insignificant injury. For example, a child with a spinal tumor may fall off a bicycle and complain of leg pain, when in fact the tumor was present for weeks, and the progressive paresis caused the child to fall from the bike. Incidental injuries are present in almost all children’s recent history and may be associated with the underlying problem, but may not necessarily be the primary cause.


Some particularly helpful questions are listed below:


What is the age of the patient?


—In younger children, especially those under 5 years of age, back pain is often a manifestation of a serious underlying disorder. In contrast, older adolescents are more likely to have nonspecific musculoskeletal disorders similar to adults with back pain.


What is the timing of the pain?


—Mechanical strains and stresses are often improved at night, and resolve within several weeks. However, spondylolysis, spondylolithesis, and Scheuermann disease may also improve with rest. Pain that worsens at night is more typical of neoplastic or infectious etiologies.


Are there systemic symptoms?


—Fever, malaise, and weight loss are more suggestive of an inflammatory, neoplastic, or infectious etiology.


Are there any neurologic findings?


—Bowel or bladder dysfunction, weakness, and changes on deep tendon reflexes are worrisome for spinal pathology such as syringomyelia, ruptured disc, or spinal cord tumor.


Is there decreased range of motion of the back?


—Stiffness of the spine is an unusual finding in young children and may indicate infection, inflammation, or tumor. In adolescents, muscle spasm from overuse injuries limit the range of motion, but this finding resolves quickly.


Is a deformity of the back noticeable?


—Deformity of the normal spinal curvature may represent primary spinal pathology, a congenital or idiopathic process, or muscular abnormalities that contribute to progressive scoliosis or kyphosis. Splinting during acute pneumonia leads to transient abnormal lateral curvature of the thoracic spine. Midline skin lesions such as a hemangioma, sacral dimple, or hairy patch may be useful clues to underlying spinal dysraphism.


CASE 5-1


Two-Year-Old Boy


SANJEEV K. SWAMI


HISTORY OF PRESENT ILLNESS


A 2-year-old boy presented to the emergency department for evaluation of back pain. Three days prior to admission he began complaining of abdominal pain, refused to eat lunch that day, and spent most of the afternoon watching television rather than playing outside with his siblings. At that time, he was taken to a nearby hospital for evaluation. On examination, he had mild diffuse abdominal tenderness but no rebound tenderness or involuntary guarding. Abdominal radiographs showed significant stool in the rectum and distal colon. He was diagnosed with constipation, given a glycerin suppository, and discharged after producing a moderate amount of stool.


On the day of admission, he returned to the hospital with persistent abdominal pain and a new complaint of low back pain. His oral intake had been poor over the past few days. There had been minimal response to a glycerin suppository earlier that day. He also seemed particularly uncomfortable while his diaper was being changed. There was no fever, cough, hematemesis, hematochezia, dysuria, or urinary frequency. There were no ill contacts and no known trauma. The only pet was an elderly dog that had been euthanized earlier in the week.


MEDICAL HISTORY


Tympanostomy tubes had been placed at 15 months of age for recurrent otitis media. He had only one episode of otitis media after the tubes were placed. He did not have a prior history of constipation. He was not taking any medications on a regular basis. His family history was remarkable for a paternal uncle who had a myocardial infarction at 55 years of age.


PHYSICAL EXAMINATION


T 38.9°C; HR 130 bpm; RR 36/min; BP 115/55 mmHg; SpO2 99% in room air


Weight 18.0 kg (>95th percentile)


The child appeared uncomfortable and refused to stand. The eyes, nose, and oropharynx were clear. The neck was supple. The abdomen was mildly distended and diffusely tender, particularly in the right lower quadrant. However, there was no rebound tenderness or involuntary guarding. There was no costovertebral angle tenderness. There was discomfort with passive flexion of the right hip. There was mild edema and tenderness to percussion along the right paraspinus muscle at the level of the L1 vertebrae. There was no kyphosis, scoliosis, or abnormal lordosis. There were no apparent sensory or motor neurologic deficits, though the degree of back and abdominal pain made assessment of muscle strength in the lower extremities difficult. There was no muscle atrophy. Rectal tone was normal. The deep tendon reflexes were symmetric and appropriately brisk. The remainder of the examination was normal.


DIAGNOSTIC STUDIES


Complete blood count revealed the following: 19 700 white blood cells/mm3 (67% segmented neutrophils, 29% lymphocytes, and 3% monocytes); hemoglobin, 11.4 g/dL; and platelets, 390 000/mm3. Serum electrolytes were remarkable for a bicarbonate level of 19 mEq/L and for blood urea nitrogen and creatinine levels of 7 mg/dL and 0.3 mg/dL, respectively. Urinalysis revealed a specific gravity of 1.020 and 3+ ketones but normal microscopy. Serum albumin and transaminases were normal. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were elevated at 7.9 mg/dL and 65 mm/h, respectively. Abdominal obstruction series revealed scattered air fluid levels and a small amount of stool in the rectum.


COURSE OF ILLNESS


Magnetic resonance imaging (MRI) of the spine localized the abnormality (Figure 5-1) and the definitive diagnosis was made by an interventional study.



Image


FIGURE 5-1. Magnetic resonance of the spine.


DISCUSSION CASE 5-1


DIFFERENTIAL DIAGNOSIS


Back pain is a relatively common complaint among children though fewer than 2% of children with back pain require specific medical evaluation. In a young child, neoplastic, infectious, and inflammatory disorders should be considered. Traumatic injury is usually clear based on the history prior to presentation. Malignant causes may be primary or metastatic and include osteoid osteoma, neuroblastoma, Wilms tumor, and leukemia. Infectious or inflammatory causes include pyelonephritis, vertebral osteomyelitis, spinal epidural abscess, and pyomyositis. Diskitis in children usually involves the lower thoracic or lumbar spine. The presence of fever, if related to the back pain, makes diskitis less likely. Local tenderness and elevated CRP and ESR can be seen with many infectious and neoplastic causes. MRI of the spine readily differentiates diskitis, vertebral osteomyelitis, and spinal epidural abscess. Rheumatologic conditions include systemic juvenile rheumatoid arthritis and ankylosing spondylitis. Mechanical disorders, such as muscle strains and intervertebral disk herniation, are less likely in children, although spondylolysis and spondylolisthesis do present in this age group. The absence of neurologic findings, while reassuring, does not exclude any of the above entities.


DIAGNOSIS


MRI of the spine revealed an abnormal heterogeneous enhancing mass (Figure 5-1, arrows) in the epidural space at the L1-L3 vertebral level. There was associated compression of the thecal sac. Urine homovanillic acid and vanillylmandelic acid levels were normal, making neuroblastoma less likely. Gram-stain of purulent material drained during biopsy of the mass revealed many white blood cells and Gram-positive cocci. Group A Streptococcus subsequently grew from culture. The diagnosis was spinal epidural abscess due to group A Streptococcus. The demise of the pet dog did not appear to be related to this patient’s diagnosis.


EPIDEMIOLOGY AND INCIDENCE


Spinal epidural abscesses occur rarely in children with one series reporting an incidence of 0.6 per 10 000 hospital admissions over a 15-year period at a free standing children’s hospital. Most patients are previously healthy but predisposing risk factors include sickle cell disease (SCD), hematologic malignancy, and spinal surgery. Spinal epidural abscess occasionally complicates serial lumbar punctures and varicella infection. In adult patients, additional risk factors include trauma and invasive procedures (i.e., spinal aneasthesia). Staphylococcus aureus causes more than two-thirds of cases; additional pathogens have been reported (Table 5-3). With the emergence of community acquired methicillin-resistant Staphylococcus aureus (MRSA), the incidence of MRSA epidural infections has increased over recent years.



TABLE 5-3. Etiologies of epidural abscesses.


Image


The infection is usually acquired by hematogenous spread and occasionally by direct extension from an adjacent site of infection. Associated osteomyelitis is present in approximately 50% of cases. In one case series, 7 of 8 children with spinal epidural abscess had an associated psoas or para-spinal abscess.


CLINICAL PRESENTATION


Most children develop fever early during the course of infection. Common presenting complaints include back pain, limp, and refusal to walk. Hip pain is an unusual presenting complaint though it may be difficult to differentiate back from hip pain in an ill and irritable child. Depending on the level of involvement, progression of infection can cause spinal cord compression, muscle weakness, and bowel and bladder incontinence followed by paralysis. On examination, there may be tenderness over the vertebra or paraspinal tissues. Some children develop protective paraspinal muscle spasm. There may also be loss of normal curvature of the spine (usually decreased lumbar lordosis) and limited lumbosacral mobility. Abdominal pain is relatively common and can indicate radicular pain or associated psoas abscess.


DIAGNOSTIC APPROACH


Spinal epidural abscesses can present with a range of clinical and laboratory findings and a high level of suspicion is required to make the diagnosis early in the course of infection. Surgical aspiration should always be performed since identification of a specific pathogen permits optimal antibiotic selection. Other studies may increase the level of suspicion for spinal epidural abscess.


Complete blood count. The complete blood count typically reveals the nonspecific findings of acute infection. The peripheral white blood cell count is elevated in approximately 50% of cases. There may be a predominance of neutrophils or an increased percentage of immature polymorphonuclear cells. Thrombocytosis may be present.


CRP and ESR. These markers of inflammation are usually elevated, especially when there is an associated vertebral osteomyelitis. These markers of inflammation may also be elevated in noninfectious conditions such as malignancy. CRP and ESR have also been used to assess response to antibiotic therapy. The timing of their normalization has not been studied with epidural abscesses but likely parallels their trends in osteomyelitis where the CRP peaks within the first 2 days of treatment and returns to normal within 7-10 days and the ESR peaks within the first 5-7 days of treatment and returns to normal within 4 weeks.


Blood culture. Organisms are isolated from blood culture in approximately 10% of cases. When positive, the blood culture is invaluable in guiding specific antibiotic therapy.


Spine radiographs. Radiographs of the spine exclude other causes of back pain. Associated vertebral osteomyelitis may be evident in children with a prolonged duration of symptoms.


Spine MRI. MRI of the spine demonstrates the abscess, though definitive diagnosis requires biopsy. MRI reveals concomitant vertebral osteomyelitis in 20% to 50% of cases.


Tuberculin skin testing. Tuberculin skin testing should be performed if a bacterial organism has not been isolated from blood or abscess culture since Mycobacterium tuberculosis can cause spinal epidural abscesses.


Other studies. At the time of diagnostic biopsy, specimens should be sent for stains and cultures of aerobic and anaerobic bacteria, fungi, and myco-bacteria. Radionuclide bone scans to detect osteomyelitis at sites distant from the abscess should be considered in cases where the abscess occurred as a consequence of hematogenous seeding. Cerebrospinal fluid (CSF) abnormalities are common with spinal epidural abscesses. In one case series, 33 (78%) of 42 children with spinal epidural abscess had findings consistent with meningeal infection (mild to moderate pleocytosis or hypoglycoracchia). In 12%, elevated CSF protein was the only CSF abnormality. Examination of the CSF was completely normal in 10% of children with spinal epidural abscess. Lumbar puncture should not be performed when the abscess is located in the lumbar region.


TREATMENT


Standard management of epidural abscesses includes antibiotic therapy and surgical drainage. Sporadic cases reported in the literature have been treated with antibiotics alone. Candidates for antibiotic therapy without surgical drainage may include patients without neurologic deficits and those with numerous abscesses that would be technically difficult to drain. In those children treated with antibiotics without surgical drainage, diagnostic surgical aspiration to identify the infecting organism should be strongly considered. This decision is usually made in consultation with infectious diseases and neurosurgical colleagues. The empiric antibiotic regimen should include agents with activity against Staphylococcus aureus such as oxacillin or vancomycin. Vancomycin should be the initial antibiotic when (1) MRSA accounts for more than 10% to 15% of local S. aureus isolates, (2) a household member works in a nursing home or other facility with high rates of MRSA colonization, and (3) the patient lives with someone known to be colonized with MRSA. Cefotaxime and metronidazole should be added if Gram-negative or anaerobic organisms are suspected. With increasing rates of Gram-negative resistance to third generation cephalosporins, many practitioners now recommend cefepime rather than cefotaxime. Ultimate antibiotic selection depends on results of blood and abscess culture. The duration of antibiotic treatment is usually determined by a combination of clinical (e.g., improved pain and function), laboratory (e.g., normalization of ESR and C-reactive protein levels), and radiologic imaging (e.g., resolved epidural fluid collection on MRI) improvement, but 6 weeks is usually the minimal duration of therapy.


Mortality rates for adults with spinal epidural abscesses range from 5% to 25%. Mortality rates are substantially lower in children. There were no deaths among the 34 children reviewed in one series. Approximately 75% to 85% of children treated for spinal epidural abscess will have normal neurologic function at the completion of therapy. Risk factors for persistent deficits include patients with multiple medical problems, previous spinal surgery, and severe neurologic deficit at presentation.


SUGGESTED READINGS


1. Auletta JJ, John CC. Spinal epidural abscesses in children: a 15-year experience and review of the literature. Clin Infect Dis. 2001;32:9-16.


2. Grewal S, Hocking G, Wildsmith JA. Epidural abscesses. Bri J. Anaesth. 2006;96:292-302.


3. Darouiche RO. Spinal epidural abscess. N Engl J Med. 2006;355:2012-2020.


4. Bair-Merritt MH, Chung C, Collier A. Spinal epidural abscess in a young child. Pediatrics. 2000;106:e39. (www.pediatrics.org/cgi/content/full/106/3/e39)


5. Yogev R. Focal suppurative infections of the central nervous system. In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases. 3rd ed. Philadelphia: Churchill Livingstone; 2008:324-335.


6. Rubin G, Michowiz DS, Ashkenasi A, Tadmor R, Rappaport H. Spinal epidural abscess in the pediatric age group: case report and review of the literature. Pediatr Infect Dis J. 1993;12:1007-1011.


7. Tunkel AR. Subdural empyema, epidural abscess, and suppurative intracranial thrombophlebitis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 7th ed. Philadelphia: Churchill Livingstone; 2010:1279-1287.


CASE 5-2


Two-Year-Old Boy


MAYA A. JONES


HISTORY OF PRESENT ILLNESS


A 2-year-old boy presented with a 2-week history of difficulty walking. Initially, the parents noticed that he would no longer run while playing with his siblings. Then during the past week he began walking with a limp and refused to climb stairs. The patient has had no fever, cough, rhinorrhea, throat pain, diarrhea, trauma, and there are no sick contacts. The patient lives with his parents and siblings and they have one dog.


The parents brought the patient to his pediatrician who detected splenomegaly and tenderness over the right hip on physical examination. Therefore, hip radiographs and laboratory studies were obtained after which the patient was immediately referred to the emergency department.


MEDICAL HISTORY


The patient was born at term without complications. He had one hospitalization at 4 months of age for wheezing and had pneumonia at 12 months of age which was treated as an outpatient. He was not receiving any medications and had no allergies. Family history was remarkable for a maternal aunt with rheumatic heart disease.


PHYSICAL EXAMINATION


T 37.3°C; P 104 bpm; RR 34/min; BP 98/43 mmHg


Height and Weight both 25th percentile for age


On examination the child was pale and appeared tired. His sclerae were anicteric. The heart and lung sounds were normal. On abdominal examination, the spleen tip was palpable just below the left costal margin and the liver edge was palpable 3 cm below the right costal margin. There was mild discomfort with passive flexion of the right hip but he had full range of motion and there was no overlying erythema or warmth. The left hip was unremarkable. The testes were in normal position and were not enlarged, swollen, or tender. There were numerous petechiae scattered on his lower extremities bilaterally. There were multiple small lymph nodes palpable in the anterior cervical and inguinal regions.


DIAGNOSTIC STUDIES


Complete blood count revealed a white blood cell (WBC) count of 4300/mm3 with 3% band forms, 8% segmented neutrophils, and 85% lymphocytes, and an absolute neutrophil count of 473/mm3. The hemoglobin was 8.0 g/dL with a reticulocyte count of 1.3%, platelet count was 31 000/mm3. C-reactive protein and erythrocyte sedimentation rate were 2.6 mg/dL and 60 mm/h, respectively. Serum lactate dehydrogenase (LDH), uric acid, transaminases, and electrolytes were normal. The hip radiographs performed earlier were reviewed (Figure 5-2A).



Image


FIGURE 5-2. A. Hip radiograph. B. Peripheral blood smear.


COURSE OF ILLNESS


Results of the hip radiographs combined with results of the peripheral blood smear (Figure 5-2B) suggested a diagnosis.


DISCUSSION CASE 5-2


DIFFERENTIAL DIAGNOSIS


Infectious causes of hip pain in a young boy include septic arthritis of the hip, osteomyelitis of the femur or pelvis, and psoas abscess. The prolonged duration of symptoms with recent worsening in conjunction with an elevated C-reactive protein and erythrocyte sedimentation may indicate osteomyelitis of the femur with extension of infection into the hip joint. However, the mild rather than severe hip pain on examination and the subacute rather than acute nature makes septic arthritis of the hip unlikely. Children with pancytopenia in the context of osteomyelitis are usually critically ill. Toxic synovitis can cause hip pain in this age group. While pancytopenia can be caused by viral-mediated bone marrow suppression, the mild degree of pain is not consistent with joint effusion.


Causes of pancytopenia, hepatosplenomegaly, and bone pain include leukemia, epiphyseal tumors, neuroblastoma, infectious mononucleosis, hemophagocytic syndrome, and Gaucher disease. The normal uric acid and lactate dehydrogenase (LDH) do not exclude malignancy.


DIAGNOSIS


The hip radiographs revealed dense metaphyseal lines bilaterally with adjacent metaphyseal lucency, a finding suggestive of leukemia (Figure 5-2A). The peripheral blood smear revealed numerous cells with scant cytoplasm and finely dispersed to variably condensed chromatin morphologically consistent with lymphoblasts (Figure 5-2B). Morphologic, cytochemical, and immunophenotypic features of the bone marrow aspirate were diagnostic of acute lymphocytic leukemia. The child was initially treated with vincristine, dexamethasone, and intrathecal ara-C.


EPIDEMIOLOGY


Leukemia results from malignant transformation and clonal expansion of hematopoietic cells that have stopped at a particular stage of differentiation and are unable to progress to more mature forms. Leukemias are divided into acute and chronic subtypes and further classified on the basis of leukemic cell morphology into lymphocytic leukemias (lymphoid lineage cell proliferation) and nonlymphocytic leukemias (granulocyte, monocyte, erythrocyte, or platelet lineage cell proliferation). Acute leukemias constitute more than 95% of all childhood leukemias and are subdivided into acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia, also known as acute myelogenous leukemia (AML). The following discussion focuses on ALL.


ALL, the most common pediatric malignancy, accounts for approximately 25% of all childhood cancers and 75% of all childhood leukemias. Most children are diagnosed between 2 and 5 years of age. In the United States, the incidence of ALL is higher in whites compared to blacks and in boys compared to girls. Genetic factors also affect the risk of ALL which occurs in siblings of children with ALL two to four times more often than in unrelated children. The concordance of ALL in monozygotic twins is approximately 25%. Children with chromosomal abnormalities, including trisomy 21, and syndromes characterized by chromosomal fragility, such as Bloom syndrome and Fanconi anemia, also have a substantially higher risk of leukemia.


CLINICAL PRESENTATION


The presenting signs and symptoms of children with ALL reflect both the degree of bone marrow infiltration with leukemic cells and the extent of extramedullary disease spread. Symptoms may be present for days or months and include fever, anorexia, fatigue, and pallor. Bone pain occurs with leukemic involvement of the periosteum and bone. Young children often develop a limp or refuse to walk. Headache, vomiting, and seizures suggest central nervous system (CNS) involvement. Rarely, children present with oliguria due to acute renal failure precipitated by hyperuricemia.


On examination, painless lymphadenopathy (50%) and hepatosplenomegaly (68%) result from extramedullary spread of the disease. Pete-chiae and purpura are more common but some children may also have subconjunctival and retinal hemorrhages. Children may also have focal bone tenderness. Testicular enlargement due to leukemic infiltration is present in 5% of boys. In addition to these physical examination findings, there are three life-threatening presentations of ALL, infection/neutropenia, tumor lysis syndrome, and hyperleukocytosis (summarized in Table 5-4) which require immediate attention and intervention.



TABLE 5-4. Life-threatening presentations of ALL.


Image


DIAGNOSTIC APPROACH


Complete blood count. The WBC is between 10 000/mm3 and 50 000/mm3 in 30% of children with ALL and greater than 50 000/mm3 in approximately 20%. Neutropenia, defined as an absolute neutrophil count less than 500/mm3, is common at presentation. Other findings include moderate to severe anemia and an inappropriately low reticulocyte count. The platelet count is less than 100 000/mm3 in approximately 75% of patients, however isolated thrombocytopenia rarely occurs. Leukemic cells may be noted on the peripheral blood smear, particularly if the WBC count is normal or high.


Bone marrow aspirate or biopsy. A bone marrow aspirate or biopsy definitively establishes the diagnosis of ALL since the morphology of blasts seen on peripheral smear may not reflect the true bone marrow morphology. Monoclonal antibody testing of the bone marrow for specific cell surface antigens identifies lymphocytes and granulocytes at different stages of development. When this immunopheno-typing is combined with cytochemical staining and molecular genotyping, the diagnostic classification, treatment, and prognosis become more specific.


Other laboratory studies. Other laboratory abnormalities reflect either leukemic cell infiltration or excessive proliferation and destruction of leukemic cells. Serum transaminases may be mildly abnormal with liver infiltration but coagulation abnormalities are uncommon. Hypercalcemia results from leukemic infiltration of bone. Cell lysis leads to elevated phosphorus, LDH, and serum uric acid, reflecting increased purine catabolism.


Radiographs. Long bone radiograph abnormalities include transverse radiolucent metaphyseal growth arrest lines, periosteal elevation with reactive subperiosteal cortical thickening, and osteolytic lesions.


Computed tomography (CT). CT may reveal diffuse lymphadenopathy and hepatosplenomegaly. Approximately 5% to 10% of newly diagnosed patients have an anterior mediastinal mass detected on chest imaging.


TREATMENT


Although specific treatment strategies may vary between hospitals, all modern approaches treat leukemia, the complications of leukemia, and manage treatment-related complications. Acute management involves blood product transfusions and treatment of infection, hyperviscosity, compressive symptoms, and metabolic abnormalities. Tumor lysis syndrome describes the constellation of metabolic abnormalities resulting from spontaneous or treatment-induced tumor necrosis. Acute tumor cell destruction releases intracellular contents into circulation leading to hypocalcemia, hyper-phosphatemia, hyperkalemia, and hyperuricemia. Management of tumor lysis syndrome includes vigorous hydration, urine alkalinization, uric acid reduction, and diuretic therapy.


Specific therapy for ALL is instituted in three distinct phases. Remission induction therapy lasts approximately 4 weeks during which most children have a complete remission, defined as the absence of clinical signs and symptoms of disease, recovery of normal blood cell counts, and recovery of normocellular bone marrow. Agents currently used for remission induction include dexamethasone or prednisone, vincristine, and L-asparaginase. Other agents may be used if the patient is considered high-risk or has CNS involvement. Consolidation therapy aims to kill additional leukemic cells with further systemic therapy and prevent CNS relapse with intrathecal chemotherapy. Maintenance therapy continues remission achieved by the first two phases. It is required because shorter treatment protocols are associated with a high rate of relapse. Methotrexate and 6-mercaptopurine are often used for consolidation and maintenance therapy.


Children with high WBC counts (>50 000/mm3), younger than 2 years of age, or older than 10 years of age at the time of diagnosis have the worst prognosis. However, between 95% and 98% of children diagnosed with ALL achieve complete remission after induction therapy. Relapse occurs in 20% to 30% either during subsequent treatment or within the first 2 years after its completion. Relapse affects virtually any site of the body, though bone marrow relapse is most common. Since the introduction of effective CNS-directed therapy, the frequency of CNS relapse has decreased to approximately 5%. Isolated testicular relapse occurs in 1% of boys. Bone marrow relapse is often treated with intense chemotherapy combined with bone marrow transplantation. The event-free survival rate after relapse ranges from 30% to 60%.


Late sequelae of ALL therapy include second neoplasms, neuropsychologic effects, endocrine dysfunction, and other organ-specific complications. Second neoplasms occur in 2.5% of patients, CNS tumors being the most common. Children less than 5 years of age at ALL diagnosis and those who received cranial irradiation are at highest risk of second neoplasms. Short stature occurs due to cranial irradiation-induced growth hormone deficiency. Some late complications are related to specific chemotherapeutic agents such as cardiomyopathy from anthracycline or bladder fibrosis from cyclophosphamide therapy. Chemotherapy may also have long-term effects on the child’s immune system. Recovery of the immune system usually occurs within 1-2 years after the completion of chemotherapy; however, some children may have low antibody titers of clinically significant viruses to which they have been previously immunized.


SUGGESTED READINGS


1. Hermiston ML, Mentzer WC. A practical approach to the evaluation of the anemic child. Pediatr Clin N Am. 2002;49:877-891.


2. Margolin JF, Poplack DG. Acute lymphoblastic leukemia. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 3rd ed. Philadelphia: Lippincott-Raven Publishers; 1997:409-462.


3. Meister LA, Meadows AT. Late effects of childhood cancer therapy. Curr Probl Pediatr. 1993;23:102-131.


4. Neglia JP, Meadows AT, Robison LL, et al. Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;325:1330-1336.


5. Pui CH, Crist WM. Biology and treatment of acute lymphoblastic leukemia. J Pediatr. 1994;124:491-503.


6. Rubnitz JE, Look AT. Molecular genetics of childhood leukemias. J Pediatr Hematol Oncol. 1998;20:1-11.


7. Sanders JE. Bone marrow transplantation for pediatric leukemia. Pediatr Ann. 1991;20:671-676.


CASE 5-3


Fourteen-Year-Old Boy


MEGAN AYLOR


HISTORY OF PRESENT ILLNESS


A 14-year-old boy presented to the emergency department complaining of left knee pain. Three days prior to this visit he noted left knee pain after playing basketball and began to limp. This knee pain improved over the next few days. However, on the day of presentation, he slipped and fell while walking across a wooden floor. As soon as he stood up, he again noted pain in his left knee that occasionally radiated to the left hip. There was no other bone pain. He did not strike his head and did not report headache, blurry vision, or loss of consciousness. There was no fever, weight loss, myalgias, or malaise.


MEDICAL HISTORY


The patient required overnight hospitalization at 8 years of age for disorientation following a car accident. His symptoms resolved fully. At the age of 10, he developed poststreptococcal glomerulonephritis and was treated with a short course of corticosteroids. He did not report taking any medications, currently. There was no family history of endocrine or autoimmune disorders.


PHYSICAL EXAMINATION


T 37.1°C; HR 105 bpm; RR 24/min; BP 125/80 mmHg


Weight 101 kg


Physical examination revealed an obese boy without visible evidence of head trauma. He was alert and cooperative. Heart and lung sounds were normal. The abdomen was soft without organomegaly. There was no deformity of either lower extremity. Passive flexion of the left hip accompanied by internal and external rotation significantly worsened the left knee pain. Internal rotation of the left hip was limited compared to the right hip. There was no tenderness, swelling, or erythema of the left knee. There was full range of motion of the left knee without discomfort when this joint was tested in isolation. There was no sign of knee ligament instability. The right lower extremity was normal. He had an antalgic gait and preferred not to place weight on the left leg due to pain.


DIAGNOSTIC STUDIES


The complete blood count revealed the following: 8600 white blood cells/mm3 (65% segmented neutrophils, 30% lymphocytes, and 5% monocytes); hemoglobin 13.1 g/dL; and 204 000 platelets/mm3. C-reactive protein was 0.7 mg/dL and the erythrocyte sedimentation rate (ESR) was 12 mm/h. Serum electrolytes and calcium were normal.


COURSE OF ILLNESS


Radiographs of the left knee were normal. Hip radiographs revealed the diagnosis (Figure 5-3).



Image


FIGURE 5-3. Antero-posterior (AP) radiographs of the hip.

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