Ghai Essential Pediatrics8th

syndrome. The common presenting features include hypotonia, static or non-progressive muscle weakness and normal or decreased deep tendon reflexes. Respiratory insufficiency, feeding difficulties,contracturesand skeletal deformities may be present.They may also present in late childhood or adulthood.

The serum creatine kinase is either normal or mildly raised. Electromyography reveals myopathic pattern. Clinically these disorders may be indistinguishable from one another, they are typically distinguished by charac­ teristicmorphologicalfeaturesobservedonskeletalmuscle biopsy with new immunohistochemical techniques and electron microscopy.Advances in molecular genetics has also improved our understanding of congenital myo­ pathies. Table 19.5 summarizes the key features of commonly recognized congenital myopathies.

Suggested Reading

North KN. Clinical approach to the diagnosis of congenital myopathies. Semin Pediatr Neurol 2011;18:216-20

Sharma MC, Jain D, Sarkar C, GoebelHH. Congenital myopathies- a comprehensive update of recent advancements. Acta Neurol Scand 2009; 119:281-92

Muscle Dystrophies

The muscular dystrophies are diseases of muscle mem­ brane or supporting proteins which are generally char­ acterized by pathological evidence of ongoing muscle degeneration and regeneration. Diagnosis of these disorders is based on clinical presentation, genetic testing, muscle biopsy and muscle imaging.

Dystrophlnopathies

Dystrophinopathies are a group of disorders resulting from mutations in the dystrophin gene (located on the short arm of Xchromosomein the Xp21 region). Duchenne musculardystrophy is the mostcommondystrophinopathy with an incidence of 1 in 3500 live male births. Its allelic variant,Beckermusculardystrophy,differsfromDuchenne muscular dystrophy by its later age of onset(usually >6 yr of age), later age of wheelchair confinement(>15yr), more incidence of myalgias, occasional rhabdomyolysis following exercise and early cardiomyopathy.

Over 4700 mutations have been reported in the Leiden Duchenne muscular dystrophy mutation database. Deletion of ;:>:1 exons is the most common mutation seen (-65%). In dystrophinopathies, 65% of the pathogenic changes are large partial deletions. Mutations in the dystrophin genecancause Duchenne muscular dystrophy or Becker muscular dystrophy. This is explained by the readingframe hypothesis, which states thatmutationsthat disrupt the reading frame (frame-shift) eventually leads to dystrophin deficiency and usually cause Duchenne muscular dystrophy. In Becker muscular dystrophy, however, mutations maintain the reading frame(inframe mutations) and generally result in abnormal but partly functional dystrophin.The reading frame rule holds true for over 92% of all dystrophinopathies.

Children with Duchenne muscular dystrophy usually becomesymptomaticbeforeageof 5yrandmay evenhave historyofdelayedwalking.Gaitdisturbancesoftenbecome apparent at 3-4 yr of age. Waddling gait, Gower sign and calf muscle pseudohypertrophy(Fig. 19.7) are classical findingsatthisstage. Neckflexormuscleweaknessisearly. Other muscles to show hypertrophy may be vastus lateralis, infraspinatus, deltoid, gluteus maximus, triceps and masseter. The progression of weakness may plateau between 3 and6yr of age.Subsequently there is increasing gait difficulty, development of contractures(initially dynamic and then fixed) and increased lumbar lordosis. Natural history studies have shown the age at loss of independent ambulationinuntreatedDuchennemuscular dystrophy to be between 8.8 and 10.5 yr. After loss of ambulation, there isworsening kyphoscoliosis, increasing upper limb weakness and bulbar dysfunction.

Weakness of intercostal and diaphragmatic muscles with spinal deformity affects the respiratory function. Dropping of vital capacity <20% of normal leads to noc­ turnalhypoventilation.Cardiomyopathy and arrhythmias are the major cardiac manifestations in Duchenne mus­ cular dystrophy. Children with deletions of exons 48 to 53 are especially prone for cardiac complications. The cause of death in Duchenne muscular dystrophy patients is usually a combination of respiratory insufficiency and

cardiomyopathy. Other clinical features of Duchenne muscular dystrophy include variabledegreeof intellectual disability and impaired gastric motility.

Around 10% of female carriers may show variable degree of weakness with elevated creatine kinase levels, calf hypertrophy, myalgias and cramps and increased risk of dilated cardiomyopathy. Full Duchenne muscular dystrophy phenotype may be present in case of complete inactivation of normal X chromosome.

The serum creatine kinase levelsare greatly elevated(>10 times upper limit of normal). It has no correlation with severity of the disease or response to treatment. Multiplex PCR and the more sensitive multiplex ligation-dependent probe amplification (MLPA) are commonly employed genetic techniques for detection of mutations. Muscle biopsy may be required in mutation negative cases and alsotodifferentiatebetween these twodystrophinopathies. The muscle biopsy shows features of muscular dystrophy which include necrosis and attempted regeneration of individual muscle fibers, increased variability of muscle fiber diameter with both hypertrophic and small fibers, and central nuclei. In an end-stage biopsy, almost the entire muscle is replaced by fibrofatty tissue. To confirm the clinicaldiagnosisimmunohistochernicalanalysisof the muscle biopsy is usually performed. Absence of dys­ trophin(1, 2and 3) staining is seen in Duchenne muscular dystrophy whereas it is reduced and patchy in Becker muscular dystrophy.

Management Management of a child with Duchenne muscular dystrophy requires a multidisciplinary team. The mainstays of management are maintenance of strengtl1 and joint range of motion by exercise, physiotherapy and avoidance of prolonged immobility. Corticosteroids (prednisone and deflazacort) aretheonly therapies proven

to improvestrengthandprolongambulation inchildrenwith Duchennemusculardystrophy. Lowdoseprednisolonemay be started with aim of preserving upper limb strength, reducing progression of scoliosis and delaying the decline in respiratory and cardiac function. Other supportive managementincludespulmonary andcardiaccare,nutrition, calcium homeostasis, appropriate immunization and orthopedic care. Table 19.6 summarizes the management in a child with Duchenne muscular dystrophy.

Myotonic Dystrophy Type I

It is the most common muscular dystrophy encountered in adults. It is a multisystem disorder transmitted by autosomal dominant inheritance and is caused by an abnormal expansion(>80) of [CTG]n repeats inthe DMPK gene located onchromosome 19. The classic form presents in childhood with myotonia, facial weakness, distal limb weakness, cataracts (iridescent spoke-like posterior capsular cataract), frontal baldness, endocrinopathies (testicular atrophy, hyperinsulinism, adrenal atrophy and growth hormone disturbances), cardiac arrhythmias and disturbed gastrointestinal motility. The congenital form may present with respiratory failure, poor feeding, hypotonia, facial diplegia, clubfoot and gastroparesis. Myotonia is absent in neonates and infants. There may be a historyofdecreasedfetalmovementsandpolyhydramnios in the mother. The serum creatine kinase levels are variable. Electromyography may show myopathic pattern along with myotonia ('revving engine' sound). Genetic testing is confirmatory.

Treatmentissymptomaticand widerangeof drugshave beenused. Drugsthatblocksodiumchannels(procainarnide, disopyramide, phenytoin, quinine, mexiletine); tricyclic antidepressants(clomipramine, imipramine); diuretics

Table 19.6: Management of Duchenne muscular dystrophy

Corticosteroids

Indication. Children >2 yr with static or declining function Dose. Prednisolone, 0.3-0.75 mg/kg/day (initially 0.3

0.6 mg/kg/day if non-ambulatory)

Deflazacort, 0.9 mg/kg/day (preferred inchildrenwith excessive weight gain or behavioral problems)

Ensure immunization against pneumococcus, influenza and varicella before starting steroids

Monitoring

Pulmonary function tests: Every 6 months if non-ambulatory; annually in ambulatory patients

Echocardiography: Once in 2 yr for <10 yr of age; annually if >10 yr)

Serum calcium, phosphate, 25(0H) vitamin 03 (biannually) EXA scan annually

Physical therapy

Effective stretching and appropriate positioning at various joints, assistive devices to prevent contractures, avoid high resistance strength training

Surgery. For fixed contractures and spinal deformities

Other components

Respiratory and cardiac care Management of gastrointestinal problems Psychosocial management

Family education and genetic counseling

Newer therapies

Exon skipping, gene therapy, cell therapy, pharmacological approaches (utrophin upregulation, read through compounds, myostatin inhibitors)

(acetazolamide, thiazides) and other drugs (taurine, nifedipine, diazeparn, carbarnazepine, prednisoneandbeta­ agonist such as albuterol) have been used. A Cochrane review concluded that it was not possible to determine whether drug treatment was safe and effective for myotonia. Larger, well-designed randomized controlled trials are needed to assess the efficacy and tolerability of drug treatment for myotonia.

Facioscapulohumeral Muscular Dystrophy

ltis inherited in anautosomal dominantfashion.The clinical spectrum is wide ranging from aymptomatic children to wheelchair boundpatients. Age at onsetis also variable. The disease may start with asymptomatic facial weakness followed sequentially by scapular fixator, humeral, truncal and lower extremity weakness. Biceps and triceps are typically involved with sparing of deltoid and forearm muscles resulting in the "popeye" arm appearance. Lower abdominal muscles are weaker than the upper abdominal muscles resulting in Beevor sign. The progression of weakness is typically slow. Extraocular and bulbar muscles are spared andcontracturesare rare.Side-to-sideasymmetry of muscle weakness is very typical (Fig.19.8). Extrarnuscular manifestations include high frequency hearing loss, Coats' disease (retinal telangiectasia with exudation and

Neuromuscular Disorders -

Figs 19.SA and B: A child with facioscapulohumeral dystrophy. (A) Note the facial weakness and inability to close the eyes completely;

(B) asymmetric scapular winging

detachment), atrial arrhythmias and restrictive respiratory disease.Serum creatine kinase levels are variable. EMC and muscle biopsy are nonspecific. Diagnosis is clinical and confirmed by demonstrating the presence of contraction of the D4Z4 repeats in one copy of 4q 35. Treatment is mainly supportive.

Emery-Dreifuss Muscular Dystrophy

It ischaracterized byslowlyprogressive muscle wastingand weakness in humeroperoneal distribution, early contrac­ tures especially of elbows, Achilles tendon and postcervical muscles and cardiac conduction defects. Cardiac involve­ ment is the mostseriousaspect of the disease and may even occur before any significant muscle weakness. X-linked forms, autosomal dominant or recessiveformsmay be seen. There is no specific treatment available currently.

Limb Girdle Muscular Dystrophy

Limb girdle muscular dystrophy is a group of clinically heterogenous syndromes consisting of different specific disease entities. They may be autosomal dominant or recessive in inheritance. Most childhood onset limb girdle muscular dystrophies are associated with lower extremity predominant weakness. The neck flexors and extensors may be involved. Facial weakness is usually mild. Cardiac or other systemic involvement is variable. Serum creatine kinase is usually modestly elevated but can be very high in the sarcoglycanopathies, dysferlinopathy and caveo­ linopathy. The autosomal recessive limb girdle muscular dystrophies generally have an earlier onset, more rapid progression and higher creatine kinase values. Treatment is symptomatic.

Congenital Muscular Dystrophy

They usually present at birth or in first year of life. The affected infant shows hypotonia, weakness, arthro­ gryposis, bulbar dysfunction or respiratory insufficiency. Weakness is static or slowly progressive. Diagnosis is supported by dystrophic myopathic features on muscle biopsy, elevated creatine kinase levels and exclusion of

- Essential Pediatrics

common myopathies of newborn. Congenital muscular dystrophies are divided into syndromic and non­ syndromic. The syndromic ones have associated neuro­ logical abnormalities.

Suggested Reading

Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and managemen of Duchenne muscular dystrophy, Part 1: Diagnosis and pharmacological and psychosocial management. The Lancet Neurol 2010;9:77-93

Straub V, Bushby K. The childhood limb-girdle muscular dystrophies. Sernin Pediatr Neurol 2006;13:104-14

Wattjes MP, KleyRA, Fischer D. Neuromuscular imaging in inherited muscle diseases. Eur Radio] 2010;20:2447-60

Inflammatory Myopathies

The inflammatory myopathies are a diverse group of disorders in which muscle appears to be injured by the immune system. Dermatomyositis is the most common pediatric inflammatory myopathy. Pol yosi s is rare in childhood and inclusion body myosihs mamly occurs above 50 yr of age.

Juvenile Dermatomyositis

It is a small vessel vasculitis which typically affects skin and muscle but may involve joints, gut, lung, heart and other internal organs (see also Chapter21). Autoantibodies are commonly seen. The mean age of onset is around 7 yr and is more common in girls. The child can have acute or insidious onset. Fever, malaise, anorexia, weight loss or irritability may be present at theonset. Inhalf of the cases, rash is concomitant with the muscle weakness but may precede the weakness. The dermatologic mani estations include 'heliotrope' rash, confluent macular v10laceous erythema over face, neck and anterior chest ('V' sign) and

upper back ('shawl' sign). The skin over metacarpal and

_

interphalangeal jointsmay bediscoloredandhypertrop1:ic (Gottronpapules) (Fig. 19.9). Pruritus may beproblematic. Nailfold capillaroscopy mayrevealcapillary drop-out and terminal bush formation.

The muscle weakness is symmetrical and proximal. Weakness of neck flexors and dysphagia is common. The serum creatine kinase is usually elevated. Electro­ myography reveals myopathic changes with occasional evidence of denervation. The muscle MRI may reveal multifocal or diffuse hyperintensities on T2-weighted images with fat suppression which is more marked in proximal limb muscles. It may also guide the ite f_or muscle biopsy. The muscle biopsy may reveal penmysial perifascicular atrophy, perivascular inflammatory cells and absence of multiple myofibers surrounded by inflammatory cells.

The primary modality of treatment for juvenile derma­ tomyositis remains corticosteroids (oral or intravenous pulses). Methotrexate and azathioprine are o er first ine agents. Physical therapy, photoprotechon, topical therapies for skin rash, calcium and vitamin D supple-

fig. 19.9: Gottron papules in a child withjuvenile dermatomyositis. One needs to examine carefully in a dark-skinned child

mentation are other adjunctivetherapies. Other therapies include intravenous immunoglobulin, cyclosporine, cyclophospharnide, mycophenolate mofetil, rituxirnab and anti-TNF-a agents.

Suggested Reading

Wedderburn LR, Rider LG. Juvenile dermatomyositis: new developments in pathogenesis, assessment and treatment. Best Pract Res Clin Rheurnatol 2009;23:665-78

Metabolic Myopathy

The metabolic myopathies are a group of muscle disorders resulting fromfailed energy production related to defects in glycogen,lipid,ormitochondrialmetabolism.Thes pto_rns arise due to a mismatch between the rate of ATP utilization and the capacity of the muscle metabolic pathways to regenerate ATP. Affectedolderchildrenand adults present primarily with exercise intolerance, weakness ai:1d myoglo­ binuria; newborns and infants present with severe multisystem disorders. Most metabolic myopathies have dynamic rather than static findings. Some children may present with progressive proximal muscle weakness mimicking a dystrophy or an inflammatory myopathy.

In patients with glycolytic/glycogenolytic defects, symptoms are induced by either brief isometric exercise, such as lifting heavy weights, or by less mtense but sustained dynamic exercise. With disorders of lipid metabolism the abnormalities are usually induced by prolonged exercise and prolonged_ fasti_ng. Plan. of investigations include serum creatme kmase, unne myoglobulin, serum ammonia, tandemmass spectroscof:'y, gas chromatography mass spectrometry, electrophysio­ logical studies, forearm ischemia exercise test, muscle biopsy and molecular studies.

Suggested Reading

Darras BT, Friedman NR. Metabolic myopathies: A clinical approach;

Darras BT, Friedman NR. Metabolic myopath1es: A cbrncal approach; part II. Pediatr Neurol 2000; 22: 171-81

Childhood cancers are a rare but important cause of mor­ bidity and mortality inchildren younger than 15 yr of age. Malignancies in children are often difficult to detect becausethe signs and symptoms are often nonspecific and mimic many common disorders of childhood. Cancers in children, when compared to adult cancers, are clinico­ biologically distinct and are considered as potentially curable; pediatric tumors areknownto bemoreaggressive but responsive to chemotherapy when compared to adult cancers. Common childhood malignancies include leukemias (30-40%), brain tumors (20%) and lymphoma (12%) followed by neuroblastoma, retinoblastoma and tumors arising from soft tissues, bones and gonads.

LEUKEMIA

Leukemia is a malignancy that arises from clonal proliferation of abnormal hematopoietic cells leading to disruption of normal marrow function leading to marrow failure. The clinical manifestations of leukemia are the result of the unregulated proliferation of the malignant clone and bone marrow failure. Leukemia is the most common cancer inchildren. There are two main subtypes, the commoner acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). A small proportion may have chronic myeloid leukemia (CML) and juvenile myelomonocytic leukemia (JMML).

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) ____

ALL isthemostcommonchildhoodmalignancyaccounting for one-fourth of all childhood cancers and three-fourths of all newly diagnosed patients with acute leukemia. Its incidence is approximately 3-4 cases per 100,000 children below 15 yr of age. There is a peak in the incidence of childhood ALL, between the ages of 2 and 5 yr, due to ALLassociatedwith a pre-Blineage (referredto as common ALL). Boys have higher rates than girls, especially in adolescents with T cell ALL.

The etiology of ALL remains unknown in a majority of cases. However, several genetic syndromes have been associated with an increased risk of leukemia. In parti­ cular,thereis a10-20 fold increasedrisk of leukemia (ALL and AML) inchildren with Down syndrome. Othergenetic syndromes associated with leukemia include Bloom syndrome, Fanconi anemia, neurofibromatosis, Klinefelter syndrome, immunodeficiency and ataxia-telangiectasia. Exposure to ionizing radiation, certain pesticides and parental smoking are associated with a higher incidence of ALL. Patients having received therapeutic irradiation and aggressive chemotherapy (alkylatingagents,epipodo­ phyllotoxins) are at higher risk of developing acute leukemia (Table 20.1).

Morphology

The classification of ALL has evolved over the years from one that was primarily morphology based to one which

Table 20.1: Risk factors for childhood leukemia

is currently based on imrnunophenotyping, karyotyping and molecular biology techniques. ALL cells can be classified using the French-American-British(FAB) criteria into morphologic subtypes (Table 20.2). L1 morphology lymphoblasts, are the most common subtype of childhood ALL (80-85%), have scant cytoplasm and inconspicuous nucleoli; these are associated with a better prognosis. Patients in the L2 category, accountingfor15%cases,show large, pleomorphic blasts with abundant cytoplasm and prominent nucleoli. Only 1-2% patients with ALL show L3 morphology in which cells are large, have deep cytoplasmic basophilia and prominent vacuolation; these cells show surface imrnunoglobulin and should be treated as Burkitt lymphoma.

lmmunophenotype

Immunophenotype classification describes ALL as either B cell derived or T cell derived. Progenitor B cell derived ALLconstitutes80-85% ALL, 15% are derived from Tcells and 1-2% from mature B cells (Table 20.3).

CytogeneHcs

Genetic abnormalities found in the leukemic clone greatly impact the therapy and prognosis of ALL. Conventional cytogenetics and fluorescence in situ hybridization should be performed on the bone marrow specimen to look for common genetic alterations in ALL.

The presence of hyperdiploidy (chromosome number >50, DNA index >1.16) is associated with good prognosis in contrast to the poor prognosis in patients with hypo­ diploidy. Specific chromosomal translocations in ALL,

including t(8;14, associated with Burkitt leukemia) in B cell ALL, t(4;11) in infant leukemia and t(9;22) trans­ location, that forms the Philadelphia chromosome, are associated with a poor prognosis. Certain chromosomal abnormalities are associated with a favorable prognosis

like t(12;21) and simultaneous presence of trisomy 4 and 10. Common genetic alterations and their clinical impact are listed in Table 20.4.

Prognostic Factors and Risk Assessment

The two most important prognostic factors include age at diagnosis and the initial leukocyte count. Children less than 1-yr-old have an unsatisfactory prognosis; infant leukemiaisoftenassociated witht(4;11)translocation and high leukocyte counts. Children between the ages of 1 and 9 yr do well. The presence of leukocyte count more than 50,000/mm3 at diagnosis is associated with a bad prognosis. Relapse ratesarehigherin boys. While patients with B cell leukemia (L3 morphology) previously had unsatisfactory outcome, the prognosis has improved with specific B cell leukemia directed protocols. The presence of T cell leukemia is not a poor prognostic factor unless associatedwith otherriskfactors,including highleukocyte count, mediastinal mass or disease affecting the central nervous system at diagnosis. Patients showing hyper­ diploidy have a good prognosis, while presence of hypodiploidy is associated with an unsatisfactory outcome. Philadelphia positive t(9;22) ALL and trans­ location t(4;11) which is present in infant leukemia are associated with poor prognosis. A lack of response to treatment with prednisone is considered a prognostic

factor; patients showing :?:1,000/mm3 blasts in peripheral blood following 7 days treatment with prednisone and an intrathecal dose of methotrexate are likely to have an adverse outcome.

B cell ALL, age between 1 and 9 yr, total leukocyte count less than 50,000/mm3 at diagnosis, female sex, absence of mediastinal widening, lymphadenopathy and organo­ megaly, absence of CNS disease, hyperdiploidy and certain chromosomal abnormalities (trisomy 4 and 10) at diagnosis constitute low risk ALL (Table 20.5). The rapi­ dity with which leukemia cells are eliminated following onset of treatment is associated with longterm outcomes. Treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics.

Table 20.5: Prognostic features in acute lymphoblastic leukemia

Clinical Presentation

The duration of symptoms in a child with ALL may vary from days to weeks and in some cases few months. The clinical features of ALL are attributed to bone marrow infiltration with leukemic cells (bone marrow failure) and extramedullary involvement. Common features include pallor and fatigue, petechiae or purpura and infections. Lyrnphadenopathy, hepatomegaly and splenomegaly are present in more than 60% patients. Bone or joint pain and tenderness may occur due to leukemic involvement of the periosteum of bones or joints. Infants and young children may present with a limp or refusal to walk. Tachypnea and respiratory distress may be present secondary to severe anemia leading to congestive heart failure or secondary to the presence of mediastinal mass leading to tracheal compression (superior mediastinal syndrome). A large mediastinal mass may sometimes cause superior vena cava syndrome with facial edema and plethora, throbbing headache, conjunctiva! congestion and dilated neck veins. Patients with high tumor burden can occasionally present with very high total white cell count (hyperleukocytosis,TLC >1,00,000/mm3) or tumor lysis syndrome with decreased urine output and azotemia secondary to uric acid nephropathy.

Few patients (2-5%) show central nervous system involvement at diagnosis; most are asymptomatic but some have features of raised intracranial pressure. The diagnosis of CNS leukemia is made on examination of the cerebrospinal fluid. Overt testicular leukemia may be seen in about 1% of cases. It presents with firm, painless, unilateral or bilateral swelling of the testes; the diagnosis is confirmed by testicular biopsy. Other rare sites of extramedullary involvement include heart, lungs, kidneys, ovaries, skin, eye or the gastrointestinal tract.

Diagnosis and Differential Diagnosis

Clinical presentation and peripheral blood counts and morphology are indicative of the diagnosis of ALL.

- Essential Pediatrics

Children may present with pancytopenia or hyper­ leukocytosis. The diagnosis is confirmed by peripheral smear examination and or bone marrow aspirate and biopsy. It is important to do both an aspirate as well as biopsy at time of initial diagnosis. Very rarely leukemic cells may be seen only in the biopsy specimen and not in the aspirate. Higher white blood cell counts are more common with T cell ALL. Bone marrow showing >25% lymphoblasts is diagnostic for ALL (Fig. 20.1). While morphology of the leukemic blasts can give important clues to the diagnosis, it needs to be confirmed by immunophenotyping of the bone marrow. Immuno­ phenotype differentiates the cellular lineages of ALL into pre-B, T cell and mature B cell. This distinction has therapeutic implications. Evaluation of CSF for leukemic blasts to determine CNS involvement is important for staging ofleukemia. Thefirstspinaltapmust be performed ideally withplatelet count close to 1,00,000/mm3. Children with CNS leukemia require intensive CNS directed therapy (Table 20.6).

Theclinicalprofileofacutelymphoblasticleukemiamay mimic many other clinical conditions like infectious mononucleosis,acuteinfectious lymphocytosis,idiopathic thrombocytopenic purpura, aplastic anemia and viral infections like cytomegalovirus that result in leukemoid reactionsandpancytopenia.Idiopathicthrombocytopenic purpura is the most common cause of acute onset of petechiaeandpurpurainchildren. Children withITPhave noevidence of anemiaandhavenormaltotaland differen­ tial leukocyte count. Bone marrow smear reveals normal hematopoiesis and normal or increased number of megakaryocytes.ALL mustbedifferentiatedfrom aplastic anemia, which may present with pancytopenia. The condition may also be mistaken for juvenile rheumatoid

Fig. 20.1: Bone marrow from a child with acute lymphoblastic leukemia shows reduced marrow elements and replacement by lymphoblasts. Neoplastic lymphoblasts are slightly larger than lymphocytes and have scant, faintly basophilic cytoplasmand round or convoluted nucleiwithinconspicuous nucleoliand fine chromatin, often in a smudged appearance

Table 20.6: Evaluation of a child with suspected leukemia

History and physical examination Complete blood count and differential count

Peripheral smear examination (morphology of cells and blasts; blast count; platelet count; immunohistochemistry; immunophenotype)

Chest X-ray (include lateral view if mediastinal mass present) Electrolytes, urea, creatinine uric acid, LDH, calcium,

phosphate, bilirubin, SGOT and SGPT Coagulation profile

Bone marrow aspirate: Morphology, immunophenotype, cytogenetics and FISH

Bone marrow biopsy

CSFcytology (diagnostic and to administer the first intrathecal dose of methotrexate)

FISH Fluorescence in situ hybridization; CSF cerebrospinal fluid

arthritisinpatientspresenting withfever,jointsymptoms, pallor, splenomegaly and leukocytosis. ALL should be distinguished from other malignancies (neuroblastoma, non-Hodgkin lymphoma, rhabdomyosarcoma, Ewing sarcoma andretinoblastoma) that present withbone mar­ row involvement. Morphologic, cytochemical, immuno­ phenotypicandcytogeneticcharacteristicsofthemalignant cells should be done. Occasionally, patient with ALL may present with hypereosinophilia or as an emergency with very high white cell count (hyperleukocytosis, TLC >1,00,000Imm3), life-threatening infections, hemorrhage, organ dysfunction secondary to leukostasis or signs and symptoms of superior vena cava or superior mediastinal syndrome.

Management

The management of acute leukemia needs the combined effort of a number of health professionals. Improvement in survival from ALL with modern therapy is one of the greatest successes in the field of pediatric oncology. Improvement in supportive care and use of combination chemotherapy has led to a survivalmore than 80% overall and greater than 95% in children with low risk ALL. Treatment is determined by the risk of relapse in each patient.

Risk based approach allows use of modest therapy for children who have historically had very good outcome thereby avoiding the toxic adverse effects of high intensity therapy. Children with historically poor survival are treated with high intensity therapy to increase cure rates. The three most important determinants of this risk are age at presentation, total WBC count at presentation and response to initial therapy. Age 1-9 yr and WBC count <50,000/mm3 is considered average risk by most study groups. Infants <1 yr of age and children >10 yr are at a higher risk and require more intensive therapy. Infants <6 months of age have extremely poor outcome. Patients with Philadelphia chromosome, t (9;22) and t(4;11) have a high-risk of relapse. Patients with slow initial response

require more intensive therapy to achieve cure than those with early response.

The treatment of ALL requires the control of bone marrow or systemic disease, as well as treatment (or prevention) of extramedullary disease in sanctuary sites, particularly the central nervous system. Different centers use different protocols for childhood ALL (Table 20.7), with 5 yr survival rates above 80-85%.

Thetreatmenton ALL is dividedinto4 stages: (i) induc­ tion therapy (to attain remission), (ii) CNS prophylaxis or CNS preventive therapy, (iii) intensification (consolidation) and (iv) maintenance therapy (continuation). The intensification (consolidation) phase, following induction of remission, may not be required in low risk patients, though recent studies suggest benefits in longterm sur­ vival withintensificationtherapyinboth lowrisk and high risk patients. The average duration of treatment in ALL ranges between 2 and 2.5 yr; there is no advantage of treatment exceeding 3 yr.

Induction Therapy

The goal of this phase is to eradicate leukemia from the bone marrow such that at end of this phase there are <5% leukemic blasts in bone the bone marrow by morphology. Patients who achieve rapid early remission (<5% blasts in bone marrow) by day 7 or 14 of induction have a better prognosis than slow responders. Failure to achieve this at

end of induction is associated with high-risk of relapse. Inductiontherapygenerallyconsists of4 weeks of therapy. The drug regimen combining vincristine and prednisone induces remission in 80-95% patients with ALL. Since the remission rate andduration are improved by the addition of a third and fourth drug (L-asparaginaseand/or anthra­ cycline), current induction regimens include vincristine, prednisone, L-asparaginase and an anthracycline, with remission achieved in 95-98% of cases. The induction therapy lasts for 4-6 weeks.

CNS Preventive Therapy

MostchildrenwithleukemiahavesubclinicalCNSinvolve­ ment at the time of diagnosis and this acts as a sanctuary site where leukemic cells are protected from systemic chemotherapybecauseofthebloodbrainbarrier.Theearly institution of CNS prophylaxis is essential to eradicate leukemic cellswhichhave passed the bloodbrain barrier. CNS prophylaxis has enabled increased survival rates in leukemia. Mostchildreninthepastreceivedacombination of intrathecal methotrexate and cranial irradiation. How­ ever, there is considerable concern regarding longterm neurotoxicity and risk of development of brain tumors following this therapy. In order to achieve effective CNS prophylaxiswhile minimizing neurotoxicity, expertsnow recommend a lower dose of cranial irradiation with intrathecal methotrexate.

- Essential Pediatrics

Intensification (Consolidation) Therapy

This is a period of intensified treatment administered shortly after remission induction with administration of new chemotherapeutic agents to tackle the problem of drugresistance. Thereis clearevidencethat intensification has improved the longterm survival in patients with ALL, especially those with high-risk disease. Commonly used agents for intensification therapy include high dose methotrexate, L-asparaginase, epipodophyllotoxin, cyclophosphamide and cytarabine.

Maintenance (Continuation) Therapy

It has been estimated that approximately two to three logs of leukemic blasts are killed during the induction therapy, leaving a leukemic cell burden in the range of 109-1010. Additional therapy is therefore necessary to prevent a relapse.

Once remission is achieved, maintenance therapy is continuedforanadditional2-2.5yr. Without such therapy, patients of ALL relapse within the next 2-4 months. A numberofdrugcombinationandschedulesare used, some basedonperiodic reinduction,othersoncontinueddelivery of effective drugs. The main agents used include 6-mer­ captopurine daily and methotrexate once a week given orally,withorwithoutpulses ofvincristineand prednisone orother cytostatic drugs. Monthly pulses of vincristine and prednisolone appear to be beneficial. In intermediate high­ risk ALL most investigators use aggressive treatment and additional drugs during maintenance therapy.

Infant ALL

Outcome of ALL remains poor in this group of patients even with very intense therapy including stem cell trans­ plant. Only 30-40% of children with MLL t(4;11) gene rearrangement are cured. Role of transplantation remains controversial. Therapy usually includes high dose cytara­ bine and methotrexate in addition to standard ALL therapy.

Philadelphia chromosome positive ALL

The 3 yr survival for Philadelphia chromosome positive ALL has improved to 80% with use of imatinib.

Other high-risk groups

Hypodiploidy (<44 chromosomes), t(17;19), remission induction failureand presence of minimal residual disease >1% at end ofinductionis associated with poor prognosis. Most such patients undergo stem cell transplantation.

Supportive Care

Because of the complications encountered with treatment and the need for aggressive supportive care like blood component therapy, detection and management of infections, nutritional and metabolic needs and psycho­ social support, these children should be treated at centers

with appropriatefacilities. Thesechildrenshouldbe given cotrimoxazoleasprophylaxis against Pneumocystisjiroveci pneumonia. They should be vaccinated against hepatitis B infection and screened for HIV infection. Oral hygiene should be taken care of. Facilities for blood component therapy should be available.

Prognosis

Hypodiploidy, Philadelphia chromosomepositivity, T cell ALL, MLL rearrangement, IKZFl gene deletion, age <1 yr and >10 yr, leukocyte count >50,000/cu mm and presence of CNS disease are poor prognostic features.

Assessment of minimal residual disease (MRD) by PCR assay using immunoglobulin/T cell receptor gene rearrangements or by flow cytometry has been shown to be an important determinant of outcome. These methods can detect one leukemic cell in 10,000 to 100,000 normal cells. Patients with MRD <0.01% on day 29 of induction are at low-risk of relapse.

More that 80% of children with ALL are longterm survivors in the developed countries. However, survival remains poor in the developing nations, chiefly due to infection related mortality.

Approximately 15-20% of patients develop bone marrow relapse with current therapy. Bone marrow relapse occurring within 18 months of diagnosishas worst prognosis. Patients with early bone marrow relapse have very poor survival even with stem cell transplantation. Late isolated CNS relapse (>18 months) can be effectively cured in most cases with cranial radiation and systemic chemotherapy.Whilechildren with average risk leukemia may nothave manylongtermcomplications,childrenwith high risk disease receive intensive therapy and are at risk for longterm complications. Significant complications include neurocognitive deficits, obesity, cardiomyopathy, avascular necrosis, secondary leukemia and osteoporosis. Children who receive cranial radiation are at risk for neurocognitive deficits, growth hormone deficiency and brain tumors.

Treatment after Relapse

Despite success of modem treatment, 20-30% of children with ALL relapse. The main cause of treatment failure in leukemia is relapse ofthe disease. Commonsitesof relapse are the bone marrow (20%), central nervous system (5%) and testis (3%). The prognosis for children with ALL who relapse depends on the site and time of relapse. Early bone marrow relapse before completing maintenance therapy has the worst prognosis and long time survival of only 10-20% while late relapses occurring after cessation of maintenance therapy have a better prognosis (30-40% survival). Relapse in extramedullary sites, particularly testes,ismore favorableintermsof survival. The treatment of relapse must be more aggressive than the first line therapy with use of new drugs to overcome the problem of drug resistance.