diff --git "a/notes/Ghai-Essential-Pediatrics_15.txt" "b/notes/Ghai-Essential-Pediatrics_15.txt" new file mode 100644--- /dev/null +++ "b/notes/Ghai-Essential-Pediatrics_15.txt" @@ -0,0 +1,2141 @@ +Doll's eye response. If the head is suddenly rned to one side, there is a conjugate deviation of eye in the opposite direction indicating that brainstem is intact. Doll's eye movement is not seen in normal conscious infants and is absent when brainstem centers for eye movements are damaged. +Oculovestibular response. If the external auditory canal is irrigated with cold water, the eyes normally deviate towards the stimulated side. This response is lost in pontine lesions, labyrinthitis and coma due to drugs such as sedatives and phenytoin. +The hallmark of metabolic encephalopathy consists of loss of oculocephalic and oculovestibular reflexes with preservation of the pupillary light reflex. +Motor responses. Structural lesions involving cortical or subcortical motor areas lead to contralateral hemiparesis, hemifacial weakness, partial seizures or tone changes. +Flexion of upper extremities with or without extension of the legs (decorticate posture) denotes a cerebral cortical and subcortical disturbance with preservation of brainstem structures. Decerebrate posturing (extension of all extremities) is observed in bilateral cerebral cortical disease extending to upper pons. Decerebrate rigidity can result from increased ICP originating in the posterior fossa, metabolic disease, cerebral hypoxia, hypoglycemia and liver dysfunction. +Flaccidity occurs when a lesion has abolished cortical and brainstem function. + +Investigaton s +i +Laboratory studies should be carried out to exclude hypo or hyperglycemia, uremia, hepatic dysfunction, dys- +Central Nervous System - + + + +electrolytemia and other metabolic abnormalities. Blood ammonia, lactate, acid-base disturbances, toxins and poi­ soning should be investigated on suspicion by preserving appropriate samples. Ferric chloride test shows purple color with ketones and aspirin poisoning. It gives green color with phenothiazine and isoniazid intoxication. Inflammatory causes of the CNS should be excluded by a lumbar puncture and blood/CSF culture and a sepsis screen. In febrile coma, peripheral smear should be examined for malarial parasite. Computerized tomography helps to identify intracranial bleeds, infarct, raised ICP, meningeal enhancement and hydrocephalus. + +Treatment +Airway should be kept patent and tongue prevented from falling back. Dyselectrolytemia and fluid imbalance should be corrected. Hyper and hypothermia should be managed. Bladder /bowel care and care of the eyes and back to avoid bed sores is imperative. Raised intracranial pressure should be treated. +Fever with acute onset coma of uncertain origin with no evidence of meningitis merits treatment as cerebral malaria in endemic areas. +Specific treatment should be given for hypoglycemia (IV glucose), diabetic coma, inflammatory disease of brain or meninges, metabolic causes or organ failure. Raised intracranial pressure is treated with IV infusion of manni­ tol, at a dose of 0.5 g/kg every 6-8 hr for 6 doses. Hyper­ tonic saline also may be used. In some cases especially TBM, dexamethasone (0.15 mg /kg every 6 hr) may be used. Specific therapy is instituted for hepatic coma. Exchange transfusion, plasmapheresis and peritoneal dia­ lysis are indicated in specific situations. Corticosteroids have been used in certain metabolic encephalopathies and postviral encephalopathies, they are contraindicated in cerebral malaria. Metabolic coma due to inborn metabolic errors requires specific treatment. + +suggested Reading +Halley MK, Silva PD, Foley J, Rodarte A.Loss of consciousness: when to perform computed tomography? Pediatr Crit Care Med 2004;5: 230-3 +Kirkham FJ. Nontraumatic coma in children. Arch Dis Child 2001; 85:303-12 +Ranjit 5. Emergency and intensive care management of a comatose patient with intracranial hypertension, current concepts. Indian Pediatr 2006;43:409-15 + +ACUTE BACTERIAL MENINGITIS +Acute bacterial meningitis, a major cause of morbidity and mortality in young children, occurs both in epidemic and sporadic pattern. + +Epidemiology +Age. Acute bacterial meningitis is commoner in neonates and infants than in older children because of poorer + +immunity and phagocytic functions. The common orga­ nisms in neonates are Escherichia coli, Streptococcus pneu­ moniae, Salmonella species, Pseudomonas aeruginosa, Streptococcus fecalis and Staphylococcus aureus. Three months to 3 yr, the infection is most often due to Haemo­ philus influenzae, S. pneumoniae and meningococci (Neisseria meningitidis). Beyond 3 yr, the two most common orga­ nisms are S. pneumoniae and N. meningitidis. +Host. Patients with diminished host resistance (comple­ ment, immunoglobulin or neutrophil function defects), malignancies, on immunosuppressive drugs are more susceptible to develop meningitis, by fungi, Listeria and Mycoplasma. + +Pathogenesis +The infection spreads hematogenously to meninges from distant foci, e.g. pneumonia, empyema, pyoderma and osteomyelitis. Purulent meningitis may follow head injury. Rarely, the infection may extend from contiguous septic foci, e.g. infected paranasal sinuses, mastoiditis, osteomyelitis and fracture of the base of skull. +Recurrent meningitis may be associated with pilonidal sinus, CSF rhinorrhea, traumatic lesions of the cribriform plate and ethmoidal sinus or congenital fistulae, besides immune deficiency disorders. + +Pathology +The leptomeninges are infiltrated with inflammatory cells. The cortex of the brain shows edema, exudate and pro­ liferation of microglia. Ependymal cells are destroyed and purulent exudate collects at the base of the brain, most marked in interpeduncular and chiasmatic cisterns. Exudates may block the foramina of Luschka and Magen­ die resulting in internal hydrocephalus. Thrombophlebitis of the cerebral vessels may occur leading to infarction and neurological sequelae. In cases of meningococcal meningitis, the illness may be fulminating and death may occur within a few hours because of endotoxic shock. +Subcellular pathogenetic mechanisms. Bacterial pathogens on destruction liberate cell wall and membrane active components (teichoic acids, endotoxins and peptidoglycans). In response the host cells and capillary endothelia produce tumor necrosis factor, cytokines and platelet activating factors. Their interaction with the blood brain barrier and neurons results in extensive host damage. Cerebral edema (vasogenic) results due to endothelial cell injury or cyto­ toxins, leukocyte products and toxic radicals. The role of dexamethasone in reducing host damage due to blockage of the above mechanisms has been demonstrated in both experimental and clinical settings. + +Clinical Features +The onset is usually acute and febrile. The child becomes irritable, resents light, has bursting headache either diffuse or in the frontal region, spreading to the neck and eyeballs. +__ _s_s_ _n_t_i_al_P_e_d_i_at_r_ic_s __________________________________ +E +e + + +The infant may have projectile vomiting, shrill cry and a bulging fontanel. +Seizures are a common symptom and may occur at the onset or during the course of the illness.Varying grades of alterations in sensorium may occur. Photophobia is marked. There is generalized hypertonia and marked neck rigidity. Flexion of the neck is painful and limited. Kernig sign is present, i.e. extension of knee is limited to less than 135 degrees. In Brudzinski sign, the knees show flexion as neck of the child is passively flexed. The fundus is either normal or shows congestion and papilledema. If skin of the abdomen is lightly scratched, flushing may be seen (tache cerebrale). The muscle power in the limbs is preserved. Reflexes are normal, diminished or exaggerated. Neuro­ logical deficits like hemiparesis, cranial nerve palsies and hemianopsia may develop. Respiration may become periodic or Cheyne-Stokes type often with shock in the late stages of illness. + +Meningitis in neonates and young infants. Neck rigidity and Kernig sign are seldom prominent. Symptoms and signs, which arouse suspicion of bacterial meningitis are: (i) sepsis; (ii) vacant stare; (iii) alternating irritability and drowsiness; (iv) persistent vomiting with fever; (v) refusal to suck; (vi) poor tone; (vii) poor cry; (viii) shock, circulatory collapse; (ix) fever or hypothermia; (x) tremor or convul­ sions; and (xi) neurological deficits of varying types. +The following are risk factors for neonatal meningitis: Prematurity, low birthweight, complicated labor, pro­ longed rupture of membranes, maternal sepsis and babies given artificial respiration or intensive care. + +Special Features +Meningococcal meningitis. Epidemics of meningococcal meningitis are generally caused by serotype A and less commonly by type C. Type B generally cause sporadic disease. Children living in overcrowded houses are spe­ cially predisposed. Carrier state is common in children. +Besides features of meningitis, children show petechial hemorrhages on the skin or mucosa. Meningococcemia may be associated with acute fulminant illness with adrenal insufficiency, hypotension, shock and coma. This is called Waterhouse Friderichsen syndrome and occurs due to hemorrhage and necrosis in the adrenal glands. +Chronic meningococcemia may occur with intermittent fever, chills, joint pains and maculopapular hemorrhagic rash lasting for several days. Meningococci are very fragile organisms and are destroyed very easily if there is delay in CSF culture. +Pneumococcal meningitis. While pneumococcal meningitis occurs at all ages, it is uncommon in the first few months of life. Usually follows otitis media, sinusitis, pneumonia or head injury. Exudates are common on the cortex and subdural effusion is a usual complication. +Staphylococcal meningitis. Neonatal staphylococcal meningitis is often associated with umbilical sepsis, + +pyoderma or septicemia. In older children it follows otitis media, mastoiditis, sinus thrombosis, pneumonia, arthritis and septic lesions of the scalp or skin. + +Haemophilus influenzae type B meningitis. Is frequent between the ages of 3 and 12 months. Subdural effusion should be suspected in infants in whom focal neurological signs and fever persist even after the CSF clears biochemically and microbiologically. Convulsions are common. Residual auditory deficit is a common complication. HiB vaccine is recommended to reduce the community prevalence of this infection. + +Complications +CNS complications include subdural effusion or empyema, ventriculitis, arachnoiditis, brain abscess and hydrocephalus. CNS complications should be suspected if infants and children fail to respond to treatment, or if fever, focal neurological signs and constitutional symptoms recur after a lapse of few days. Longterm neurological deficits include hemiplegia, aphasia, ocular palsies, hemianopsia, blindness, deafness, sensorineural auditory impairment (deafness) and mental retardation. Systemic complications include shock, myocarditis, status epilepticus and syndrome of inappropriate ADH secretion (SIADH). + +Diagnosis +Acute bacterial meningitis should be suspected in children presenting with a brief history of fever, irritability, photo­ phobia, headache, vomiting, convulsions and altered sensorium. Diagnosis should be substantiated by exami­ nation of the cerebrospinal fluid. The CSF should be examined promptly for cellular response and sent for culture for bacteria and stained to identify morphology. The CSF has elevated pressure, is turbid with an elevated cell count, often >1,000/mm3 with mostly polymorpho­ nuclear leukocytes. Proteins are elevated above 100 mg/ dl and sugar is reduced below 50% of blood sugar or below 40 mg/ dl. Microscopic examination of the sediment stained with gram stain helps to identify organisms. Collect the CSF for culture on a transport medium. +In partially treated meningitis, CSF may be clear with predominant lymphocytes; culture is usually sterile. Biochemistry may be variably altered. + +CT scan is not necessary for diagnosis, but is useful to exclude the presence of subdural effusion, brain abscess, hydrocephalus, exudates and vascular complications. It is also useful to distinguish partially treated pyogenic meningitis from tuberculous meningitis. + +Rapid diagnostic tests may be used to distinguish between viral, bacterial and tuberculous meningitis based on antigen or antibody demonstration, e.g. countercurrent immunoelectrophoresis, latex particle agglutination, coagglutination, ELISA and other techniques. Besides being rapid, they are unaltered by previous antibiotic +Central Nervous System - + + + +usage. Latex agglutination and ELISA have sensitivity and specificity of almost 80%. Polymerase chain reaction is used for diagnosis of infection with herpes simplex, enteroviruses, meningococci and tuberculosis. + +Differential Diagnosis +Meningism. This may occur in inflammatory cervical lesions, apical pneumonia and in toxemia due to typhoid, influenza. There are no neurological signs and the cerebrospinal fluid is normal. +Partially treated bacterial meningitis. If the child has received prior antibiotics, the cerebrospinal fluid becomes sterile. Biochemistry may be altered and pleocytosis persists, though type of cellular response changes. It poses a difficult problem in the differential diagnosis from tuberculous meningitis and aseptic meningitis. The onset, clinical course, rapid diagnostic tests and other ancillary investigations may be useful. +Aseptic meningitis. The clinical and laboratory profile is similar to pyogenic meningitis. The CSF pressure is ele­ vated, shows mild pleocytosis and moderate increase in protein with near normal sugar. The CSF lactic acid is not elevated. No organisms are cultured. +Tuberculous meningitis. The onset is insidious with lethargy, low-grade fever, irritability, vomiting and weight loss. Features of meningeal irritation are less prominent and course of the illness is prolonged. Neurological features include seizures, gradually progressive unconsciousness, cranial nerve deficits, motor deficits and visual involve­ ment. Features of hydrocephalus and decerebration are relatively common. Evidence of systemic tuberculosis and family contact should be looked for. Mantoux test may be positive and there may be evidence of tuberculosis else­ where. CSF shows 100-500 cells, with majority of lympho­ cytes; sugar is less reduced than in pyogenic meningitis and protein is elevated. +Cryptococcal meningitis. It usually occurs in an immuno­ compromised host. There is low-grade fever, mild cough and pulmonary infiltration. Meningeal involvement has a gradual onset with a protracted course. The clinical fea­ tures are not specific. The CSF shows the fungus as thick walled budding yeast cells, surrounded by a large gelatinous capsule in India ink preparation. The organism grows well on Sabouraud medium. +Viral encephalitis. Acute onset with early disturbances of sensorium, raised intracranial pressure and variable neurological deficit. The CSF is clear, may show mild pleo­ cytosis, mild elevation of protein and normal sugar. PCR for viral antigens and rising CSF antibody titers are useful diagnostic clues. +Subarac/moid hemorrhage. Sudden headache and sensorial alteration occur without preceding fever. The course of illness is rapid and signs of meningeal irritation are marked. CT scan is diagnostic. CSF reveals crenated RBCs. + +Lyme disease. It is an infection of central nervous system with Borrelia burgdorferi, a tick-borne spirochete. Patients develop encephalopathy, polyneuropathy, leukoence­ +phalitis and hearing loss. + +Treatment +Initial Empiric Therapy +Initial therapy recommended is a third generation cephalo­ sporin such as ceftriaxone or cefotaxime. A combination of ampicillin (200 mg/kg) and chloramphenicol (100 mg/ kg/24 hr) for 10-14 days is also effective as initial empiric choice. If fever or meningeal signs persist after 48 hr of therapy, a lumbar puncture should be repeated and the choice of antibiotics reviewed. All antibiotics are adminis­ tered intravenously. + +Specific Antimicrobial Therapy +Meningococcal or pneumococcal meningitis. Penicillin 400-500,000 units/kg/day q 4 hr. Cefotaxime (150-200 mg/ kg/day q 8 hr IV) or ceftriaxone (100-150 mg/kg/day q 12 hr IV) are also effective. + +H. influenzae meningitis. Ceftriaxone or cefotaxime IV is used as a single agent. The combination of ampicillin (300 mg/kg/day IV q 6 hr) and chloramphenicol (100 mg/kg/ day) is less preferred. + +Staphylococcal meningitis. Vancomycin is the treatment of choice if methicillin or penicillin resistance is suspected. Addition of rifampicin to the regime increases CSF penetrance and efficacy of these drugs. + +Listeria. Ampicillin (300 mg/kg/day IV q 6 hr) and amino­ glycoside (gentamicin, amikacin or netilmicin) are preferred. + +Gram-negative bacilli. Cefotaxime, ceftazidime or ceftriaxone, or a combination of ampicillin and aminoglycoside may be used. + +Pseudomonas. A combination of ceftazidime and an aminoglycoside is used. Ceftazidime may also be replaced with ticarcillin. Meropenem or cefepime are effective agents, if the above drugs fail. + +Duration of Therapy +Generally, patients with bacterial meningitis show quick improvement within days. The treatment is for 10-14 days. except for staphylococcal meningitis and Gram-negative infection, where it is extended to 3 weeks. Routine lumbar puncture at the end of therapy is not recommended. In delayed or partial clinical response, a repeat CSF examination is indicated. Therapy is stopped if child is afebrile, cerebrospinal fluid protein and sugar become normal, and the cell count in the cerebrospinal fluid is less than 30/mm3• +___ s e_n__tai_P_e_d_i_a_t_r_ _________________________________ +i +c_ +s +_ +i +E +_ +_ +s + + +Steroid Therapy +Dexamethasone at a dose of 0.15 mg/kg IV q 6 hr for 2-4 days is recommended. The first dose of corticosteroids is best given shortly before or simultaneously with the first dose of antibiotic. This helps to reduce the incidence of residual neurological complications, such as sensori­ neural deafness, hydrocephalus and behavioral disturbances. This is especially useful in Haemophilus meningitis. There is no role of dexamethasone in neonatal meningitis. + +Symptomatic Therapy +Increased intracranial pressure. Lumbar puncture should be done very carefully in the presence of increased intracranial pressure. Osmotic diuresis with 0.5 g/kg of mannitol as a 20% solution is administered intravenously every 4-6 hr for a maximum of 6 doses. + +Convulsions. These are treated using diazepam 0.3 mg/kg (maximum 5 mg) IV, followed by phenytoin 15-20 mg/ kg as initial treatment and continued at a dose of 5 mg/ kg/day PO or IV. Antiepileptic drugs can be stopped after 3 months. +Fluid and electrolyte homeostasis. Maintenance fluids are given, hypotonic fluids should be avoided. ADH secretion occurs in some patients. If unconscious, child may be fed through the nasogastric tube. +Hypotension. The patients are treated with intravenous fluids and vasopressors such as dopamine and dobutamine. +Nursing care. The oral cavity, eyes, bladder and bowel should be taken care of. Management of constipation pre­ vents atony of the rectum. Retention of the urine is mana­ ged by gentle suprapubic pressure or a hot water bottle. Bedsores are prevented by repeated change of posture in the bed and application of methylated spirit. Soft foam rubber mattress or air cushion is used to prevent pressure on the bony points. + +Complications +Subdural empyema is managed by drainage of the subdural space along with intensive antibiotic therapy; subdural effusions generally resolve spontaneously. +Hydrocephalus may occur in the acute phase and generally regresses. Ventriculoatrial or ventriculoperitoneal shunt is rarely required. + +Followup and Rehabilitation +Followup for early detection of residual neurological handicaps ensures appropriate rehabilitation. Auditory evaluation should be carried out at the time of discharge and 6 weeks later. + +Suggested Reading +El Bashir H, Laundy M, Booy R. Diagnosis and treatment of bacterial meningitis. Arch Dis Child 2003;88:615-20 + + +Maconochie I, Baumer H, Stewart MER. Fluid therapy for acute bacterial meningitis. Cochrane Database of Systematic Reviews 2008; 1:CD004786 +Tunkel AR, Hartman BJ, Kaplan SL. Practice guidelines for the management of bacterial meningitis. Clinical Infectious Diseases 2004;39:1267-84 +van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis. Cochrane Database of Systematic Reviews 2007; CD004405 + +TUBERCULOUS MENINGITIS +Meningitis is a serious complication of childhood tuberculosis. It may occur at any age, but is most common between 6 and 24 months of age. There is usually a focus of primary infection or miliary tuberculosis. Mortality rate has reduced but serious disabling neurological sequelae may occur. + +Pathogenesis +The tuberculous infection usually reaches the meninges by hematogenous route, less commonly through the lym­ phatics. Tubercle bacilli affect end arteries and form sub­ meningeal tubercular foci. The tubercle bacilli discharge into the subarachnoid space intermittently, proliferate and cause perivascular exudation followed by caseation, gliosis and giant cell formation. Tuberculous meningitis may occur as a part of the generalized miliary tuberculosis, with tubercles in the choroid plexus directly infecting the meninges. + +Pathology +The meningeal surface and ependyma are inflamed, covered with yellow grayish exudates and tubercles. These are most severe at the base, in the region of the temporal lobes and along the course of the middle cerebral artery. The subarachnoid space and the arachnoid villi are obliterated resulting in poor reabsorption of cerebrospinal fluid and dilation of the ventricles, resulting in hydro­ cephalus. Cerebral edema may be present. +The choroid plexus is congested, edematous and studded with tubercles. There may be infarcts in the brain due to vascular occlusion. Necrotizing or hemorrhagic leukoencephalopathy may occur in some cases. + +Clinical Manifestations +The clinical course of tuberculous meningitis is described in three stages. This differentiation is arbitrary as one-stage merges into the other. +Prodromal stage or stage of invasion. The onset is insidious and vague with low grade fever, loss of appetite and disturbed sleep. The child who was active and playful earlier becomes peevish, irritable and restless. Vomiting is frequent and the older children may complain of headache. Child may exhibit head banging and resents exposure to sunlight (photophobia). +Central Nervous System - + + + +Stage of meningitis. During this stage, neck rigidity may be present and Kernig sign may be positive. Fever may be remittent or intermittent, pulse is slow but regular. Breath­ ing may be disturbed. The patient may be drowsy or deli­ rious. Muscle tone may be increased. As the disease progresses, convulsions and neurological deficits may occur; sphincter control is usually lost. + +Stage of coma. This stage is characterized by loss of con­ sciousness, rise of temperature and altered respiratory pattern. Pupils are dilated, often unequal, with nystagmus and squint. Ptosis and ophthalmoplegia are frequent. With the progression of the disease, coma deepens; episodic decerebration is observed which progresses in severity. The respiration becomes Cheyne-Stokes or Biot type, bradycardia is common. Untreated illness is lethal in about four weeks. +Hemiplegia, quadriplegia, cranial nerve palsies and decerebrate rigidity are common findings. Some patients show monoplegia, hemiballismus, tremors, cerebellar sings and decorticate rigidity. + +Diagnosis +Lumbar puncture. Lumbar puncture should always be done in children with low grade pyrexia, unexplained recurrent vomiting, unusual irritability and lassitude. The cerebro­ +spinal fluid pressure is elevated to 30-40 cm H20 (normal 3-4 cm H20). The CSF may be clear or xanthochromic. On +standing, a pellicle or a cobweb coagulum is formed in the center of the tube. It is composed of cells and tubercle bacilli enmeshed in fibrin. CSF show lymphocytic pleocytosis (100-500 cells/mm3), elevated protein (more than 40 mg/dl), mild hypoglycorrhachia and low chloride values (less than 600 mg/dl). Cerebrospinal fluid does not confirm the etiological diagnosis, but provides adequate evidence for starting antitubercular therapy. Demonstration of acid fast bacilli by direct smear and culture yields variable results. + +CT scan. Computerized tomography is useful in tubercular meningitis and may reveal basal exudates, inflammatory granulomas, hypodense lesions or infarcts, hydrocephalus both communicating and less commonly obstructive type (Fig. 18.7). X-ray of the chest may provide supportive evidence for tuberculosis. Negative Mantoux test does not exclude the diagnosis. + +Serological tests for the diagnosis of tuberculous meningitis are not very sensitive. Bactec and PCR for tuberculosis carry better sensitivity and specificity. Tests for HIV should be performed on all suspected subjects. + +Differential Diagnosis +Purulent meningitis. The onset is acute with rapid progression. The cerebrospinal fluid is turbid or purulent with a significant increase in the number of polymorpho­ nuclear leukocytes in the CSF. CSF protein content is + + + + + + + + + + + + + + + + +Fig. 18.7: Contrast enhanced CT of brain showing communicating hydrocephalus and periventricular ooze in a child with tubercular meningitis (Courtesy: Dr Atin Kumar, Deptt. of Radiodiagnosis, AIIMS, New Delhi) +elevated and sugar level is markedly decreased. The etiological agent is demonstrated by the examination of smear, culture or serology. +Partially treated purulent meningitis. The clinical features and cerebrospinal fluid changes are often indistin­ guishable from tuberculous meningitis. Rapid diagnostic tests to rule out specific bacterial antigens should be performed PCR and Bactec provide supportive evidence for tuberculosis. MRI brain with gadolinium contrast often provides clue to the underlying etiology. +Encephalitis. The onset is acute with fever, seizures, disturbances of sensorium, drowsiness and diffuse or focal neurological signs. The cerebrospinal fluid reveals mild pleocytosis, normal or mildly elevated proteins and normal sugar. MRI brain may be normal or may show signal changes in basi frontal and temporal lobes (Herpes encephalitis); thalamic and midbrain involvement occur in Japanese B encephalitis. +Typhoid encephalopathy. Typhoid presents with severe toxemia, drowsiness without meningeal signs. Cerebro­ spinal fluid is normal. Blood culture for S. typhi and Widal test is positive. +Brain abscess. Presents with irregular low grade fever, localized neurological symptoms and features of raised intracranial pressure. A prior history of congenital cyanotic heart disease or pyogenic lesions (suppurative otitis media, mastoiditis, lung abscess or osteomyelitis) should be asked for. The cerebrospinal fluid is normal except when the abscess communicates with the subara­ chnoid space; CT scan is diagnostic. +Brain tumor. The onset is slow with history of headache, recurrent vomiting, disturbances of vision and localizing neurological signs. The patients are usually afebrile. CT or MRI helps in diagnosis. +___ _ss_e_n_ t_ a_l_P_e_d_ i_a _tr_ c_ ________________________________ _ +i +i +s +E +_ + + +Chronic subdural hematoma. There may be a history of head injury or trivial trauma, headache, vomiting, localizing neurological signs and features of raised intracranial pressure. The fundus shows papilledema or choked discs. The sutures may be separated. The cerebrospinal fluid is normal. CT scan or ultrasound is useful. The subdural tap shows fluid with high protein concentration. +Amebic meningoencephalitis. Free living amebae can cause meningoencephalitis. While Naegleria meningoence­ phalitis presents acutely, Acanthamoeba meningoence­ phalitis presents as chronic granulomatous encephalitis, chiefly in immunocompromised hosts. Nonresponse to antipyogenic or antitubercular therapy should arouse suspicion. Diagnosis is made by demonstration of motile amebae in fresh CSF preparation. Culture is confirmatory. + +Prognosis +The prognosis is poorer in younger children. Early diagnosis, adequate and prolonged therapy improves the prognosis. Untreated cases die within 4 to 8 weeks. +Recovery is a rule in stage 1 disease. The mortality in stage 2 is 20-25% and of the survivors, 25% have neuro­ logical deficits. Stage 3 disease has 50% mortality and almost all survivors have neurological sequelae. Longterm complications include intellectual disability, seizures, motor and cranial nerve deficits, hydrocephalus, optic atrophy, arachnoiditis and spinal block. + +Treatment +Antitubercular therapy. The treatment of tuberculous meningitis should be prompt, adequate and prolonged for at least 12 months. Short course chemotherapy is not recommended. At least 4 antitubercular drugs should be used for initial 2 months comprising (i) isoniazid (5 mg/ kg/ day, maximum 300 mg per day); (ii) rifampicin (10 mg/kg/orally, once empty stomach in the morning, maximum dose 600 mg/ day); (iii) ethambutol (15-20 mg/ kg/day); and (iv) pyrazinamide (30 mg/kg/day PO). Streptomycin (30-40 mg/kg/day IM) may be used initially for 2-3 weeks. The first two drugs are continued to com­ plete one year of therapy. + +Steroids. Parenteral dexamethasone (0.15 mg/kg/dose q 6 hr) is preferred in acute phase of illness and switched over to oral prednisolone. Oral corticosteroids may be continued for 6 weeks and tapered over next two weeks. Steroids reduce the intensity of cerebral edema, risk of development of arachnoiditis, fibrosis and spinal block. + +Symptomatic therapy of raised intracranial pressure, seizures, dyselectrolyternia should be done. The patient should be kept under observation for development of papilledema, optic atrophy or increasing head circum­ ference. Decerebration is common in advanced cases in the acute phase. Ventriculocaval shunt may be required + + +in cases with increasing hydrocephalus and persistent decerebration. + +Suggested Reading +Shah GV. Central nervous system tuberculosis: imaging mani­ festations. Neuroimaging Clin N Am 2000;10:355-74 +Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the +treatment of tuberculous meningitis in adolescents and adults. New +Eng J Med 2004;351:1741-51 +Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: Royal College of Physicians, 2006 + +ENCEPHALITIS AND ENCEPHALOPATHIES -----Encephalitis is defined as an inflammatory process of the brain parenchyma. The term encephalopathy implies cerebral dysfunction due to circulating toxins, poisons, abnormal metabolites or intrinsic biochemical disorders affecting neurons but without inflammatory response. +----- + +Etiopathology +Various causes of encephalitis and encephalopathies are listed in Table 18.7. +The pathological changes are nonspecific except in herpes simplex encephalitis and rabies. Gross examination of the brain usually shows diffuse edema, congestion and hemorrhages. Microscopically, there may be perivascular cuffing with lymphocytes and neutrophils. The neurons show necrosis and degeneration, associated with neuro­ nophagocytosis. + +Clinical Manifestations +The clinical manifestations depend on: (i) severity of infection; (ii) susceptibility of the host; (iii) localization of the agent; and (iv) presence of raised intracranial pressure. Clinical spectrum may range from inapparent/abortive ilness to severe encephalomyelitis. + +Onset. The onset of illness is generally sudden but may at times be gradual. + +Initial symptoms. The initial symptoms are high fever, mental confusion, headache, vomiting, irritability, apathy or loss of consciousness, often associated with seizures. Raised intracranial pressure may result in decerebration, cardiorespiratory insufficiency, hyperventilation and autonomic dysfunction. Child may develop ocular palsies, herniplegia, involuntary movements speech dysfunction and cerebellar symptoms. Extrapyramidal symptoms are common in Japanese B encephalitis and lateralization to one side with temporal or frontal involvement is common in herpes encephalitis. + +Typical features. Include increased intracranial pressure and evidence of brainstem dysfunction. Unchecked brain swelling may lead to herniation at tentorial hiatus, +Central Nervous System - + + + +Table 18. 7: Etiology of encephalitis and encephalopathies Encephalitis +RNA viruses (mumps, measles, rubella, enteroviruses) DNA viruses (herpes simplex, cytomegalovirus, Epstein- +Barr) +Arthropod borne viruses Oapanese B, West Nile, Russian spring summer, equine viruses) +HIV, rabies, lyrnphocytic choriomeningitis, dengue virus Slow virus infections, prion infections +Rickettsia; fungi (cryptococcus); protozoa (T. gondii) Bacteria (tuberculous meningitis, listeria) + +Encephalopathies +Acute disseminated encephalomyelitis Postinfectious: Typhoid, shigella, Reye syndrome Hypoxic encephalopathy, heat hyperpyrexia +Metabolic: Diabetic acidosis, uremic coma, hepatic coma, +neonatal hyperbilirubinenia, lactic acidosis, mitochondrial +disorders, inborn errors of metabolism +Fluid and electrolyte disturbances. Water intoxication, hypernatremia, hyponatremia, alkalosis, acidosis +Toxic: Heavy metals (lead, mercury, arsenic), insecticides, Cannabis indica, carbon monoxide +Post-vaccination + +compression of the midbrain causing deterioration in consciousness, pupillary abnormalities, ptosis, sixth nerve palsy, ophthalmoplegia, paralysis of upward gaze, Cheyne­ Stoke breathing, hyperventilation and bradycardia. + +Prognosis +Recovery depends on the severity of illness. Mild illness usually has a complete recovery and substantial morbidity occurs in severe forms. Metabolic encephalopathies may have an intermittent or progressive course despite treat­ ment. Inborn metabolic errors may have an intermittent course. + +Diagnosis +Every effort should be made to arrive at a precise etiological diagnosis by a careful history, systemic examination, account of recent illnesses or exposure to toxins. Lumbar puncture must always be done after excluding papill­ edema. CSF cytology, biochemistry, serology and cultures are mandatory. Serum electrolytes, blood sugar, urea, blood ammonia, metabolic screening, ABC, serum lactate, urinary ketones and urinalysis should be done. Toxicologic studies should be undertaken in suspected patients. One should exclude treatable causes such as enteric encephalo­ pathy, malaria, shigella, toxins, poisoning, diabetes mellitus and renal disease. Serum lead levels should be estimated if there is a possible exposure of the child to lead contaminated environment. +Acute disseminated encephalomyelitis (ADEM). Acute demyelination of brain and spinal cord may occur with + +insults to oligodendroglia following an infection or vacci­ nation. Damage is perivenular in location, commonly at the gray-white zone. Usually a monophasic illness, permanent deficits after the initial severe manifestation occasionally. Acute stage is characterized by seizures, altered sensorium, multifocal neurological signs, raised intra cranial pressure, visual disturbances, etc. Cerebrospinal fluid may be normal, or shows mild pleocytosis, mildly elevated protein and normal glucose. MRI brain generally reveals multiple hyperintensities in white matter, which enhance with contrast. MRI may also show spinal cord, basal ganglia lesions in addition to white matter involvement. Therapy with pulse corticosteroids is useful. + +Management +Treatment aims to save life, prevent neurological residua and relieve symptoms. +Emergency treatment. Airway should be kept patent and assisted respiration given if necessary. Hyperpyrexia should be managed with water sponging and anti-pyre­ tics. Shock is managed by infusion of appropriate fluid, or vasopressors. Dopamine or dobutamine are used to maintain blood pressure. Seizures are controlled by intravenous diazepam and phenytoin. Raised intracranial pressure is managed by IV infusion of 20% mannitol solution and corticosteroids. The role of corticosteroids in most encephalitides is not proven except in acute disseminated encephalomyelitis and autoimmune ence­ phalitis. +Herpes simplex encephalitis. Herpes simplex type I virus is the causative organism. Type II virus causes perinatal herpes infections. Clinical features includes fever of sudden onset, mental confusion, vomiting, meningeal irritation, headache and papilledema. In localizing signs (focal seizures, focal neurological deficit and EEG changes), presence of red cells in the CSF and focal involvement of the temporal lobe on CT scan are important diagnostic clues. Diagnosis can be established by CSF culture or PCR. The drug of choice is acyclovir (20 mg/kg/ dose every 8 hourly) for 21 days. Early therapy is crucial for recovery. Prognosis is variable; about half the patients recover after timely therapy. + +Suggested Reading +Amin R, Ford Jones E, Richardson SE, et al. Acute childhood encephalitis and encephalopathy associated with influenza: a prospective11-yr review. Pediatr Infect Dis J 2008;27:390-5 +Bulakbasi N, Kocaoglu M. Central nervous system infections of herpes virus family. Neuroimaging Clin N Am 2008;18:53-84 +Fitch MT, Abrahamian FM, Moran GJ, Talan DA. Emergency department management of meningitis and encephalitis. Infect Dis Clin North Am 2008;22:33-52 + +Reye Syndrome +The first description of this syndrome was probably made by Najib Khan inJamshedpur, in 1956 Oamshedpur fever). +..e_s_sia_l_P_e__tdr_ i a ______________________________ +i +c +_s +___ +_e_ +n +__t +- + + +Reye and colleagues described an entity with diffuse fatty infiltration of the liver, to a lesser extent of the kidney and cerebral edema with diffuse mitochondrial injury. + +Pathogenesis +It is an acute self limiting metabolic insult of diverse etio­ logy resulting in generalized mitochondrial dysfunction. Drugs (salicylates), toxins (aflatoxins), viral infections (varicella, influenza) and certain inborn errors of meta­ bolism (single enzyme defects of �-oxidation) can precipitate Reye syndrome. Neuroglucopenia and hyper­ ammonemia result from mitochondrial and sodium pump failure. Encephalopathy is secondary to the liver damage. + +Clinical Features +A mild prodromal illness is followed by acute onset of the disease. The child has vomiting for one or two days along with anorexia, listlessness, followed by altered sensorium, irregular breathing, decerebration, pupillary changes and rapidly developing coma. Seizures occur in more than 80% patients. There are few focal neurological or meningeal signs. Hepatomegaly is present in half the cases; jaundice is infrequent. The clinical features are described in four stages: +Stage I. Vomiting, anorexia, mild confusion, listlessness, apathy + +Stage II. Delirium, restlessness, irritability, lack of orien­ tation, frightened, agitated states +Stage III. Coma, decorticate posture which later becomes decerebrate. + +Stage IV. Flaccidity, areflexia, apnea, dilated pupils not reacting to light, severe hypotension + +Laboratory Investigations +There may be some degree of hypoglycemia with low levels of glucose in the cerebrospinal fluid. Serum ammo­ nia levels are elevated. Prothrombin time is prolonged and hepatic enzymes are increased. Liver biopsy shows fatty change and glycogen depletion but no necrosis of the liver cells. EEG shows generalized slow waves. + +Prognosis +Prognosis is poor with 25-70% mortality. Survivors may have neurological sequelae. + +Management +Hepatic failure needs appropriate management. The patient is given low protein diet with adequate calories. Intravenous infusion of mannitol (20% solution; 0.5 g/kg/ IV q 6 hr) and dexamethasone are used to reduce the brain edema. Hypoglycemia should be corrected by IV 10-25% glucose. Acidosis, hypoxia and dyselectrolytemia should be corrected. Double volume exchange transfusion has + +been used in stage III. Vitamin Kand fresh frozen plasma may be required. Surgical decompression of raised intracranial pressure may be required to save life. + +Sug ges ted Reading +Casteels Van Daele M, Van Geet C, Wouters C, et al. Reye syndrome revisited: a descriptive term covering a group of heterogeneous disorders. Eur J Pediatr 2000;159:641-8 +Glasgow JF, Middleton B. Reye syndrome-insights on causation and prognosis. Arch Dis Child 2001;85:351-3 +Schriir K Aspirin and Reye syndrome: A review of the evidence. Paediatr Drugs 2007;9:195-204 + +INTRACRANIAL SPACE OCCUPYING LESIONS +Intracranial space occupying lesions include brain tumors, masses of congenital origin and inflammatory disorders such as brain abscess, neurocysticercosis, tuberculoma and subdural fluid collection. Brain edema may also simulate space occupying lesions. Clinical features of space occupying lesion in brain are detailed below: + +Increased lntra cranial Tens oi n (ICT) +The intracranial space and its contents (brain, CSF and blood) are in a state of delicate equilibrium. After closure of sutures and fontanel the adaptive mechanisms to raised pressure in the brain are through the displacement of CSF from the intracranial cavity and compensatory hemodynamic changes. Heart rate slows, respiratory rate is altered and blood pressure rises to maintain the cerebral circulation. +The signs of raised ICT appear early in infratentorial tumors and are relatively late in supratentorial neoplasms. Common clinical features of raised ICT include either one or a combination of the following clinical features. +Increased head size and/or papilledema. In infants, there is separation of the cranial sutures, wide fontanels and increased head circumference. The fontanel should be examined with the baby relaxed and placed in the upright position. A delayed fontanel closure or a tense and non­ pulsatile fontanel is significant. Separation of the sutures compensates for increase in the intracranial pressure. +The MacEwen or crackpot sign indicates raised intracranial pressure after sutures have closed. Papilledema is unusual in infancy unless intracranial pressure is very high. The changes include loss of cupping of the disc, absent venous pulsations and raised disc margins. In severe cases, hemorrhages may be observed. +Vomiting. Unexplained projectile vomiting with or without headache should arouse suspicion of raised pressure. It is attributed to direct pressure on the medullary centers. +Headache. Persistent headache in young children, prominent in early morning is highly suspicious. +Diplopia and sixth nerve palsy. Increased pressure displaces the brainstem downwards, thus stretching the sixth nerve and resulting in paralysis of the lateral gaze and diplopia. +Central Nervous System - + + + +Localizing Signs +These signs help to detect the anatomical site of the lesion. +Cranial nerve palsies. Multiple cranial nerve palsies occur in brainstem lesions along with involvement of pyramidal tract and cerebellar pathways. Sixth nerve palsy usually has no localizing value. Combined sixth and seventh nerve involvement may suggest a pontine lesion. Pseudobulbar palsy may suggest lX and X cranial nerves involvement. In supranuclear hypoglossal paralysis, tongue is tilted to contralateral side. Nasopharyngeal masses, rhabdo­ myosarcoma, lymphosarcoma and inflammatory masses +may involve cranial nerves in their course. +Head tilt. Head tilt is seen in superior oblique paralysis, cerebellar lesions and posterior fossa tumors. +Ataxia. Ataxia occurs in cerebellar, spinocerebellar tract, frontal lobe or thalamic lesions. +Motor deficit. This may occur in cerebral, brainstem and spinal cord lesions. +Seizures. These indicate cortical or subcortical lesion. Intermittent decerebrate posturing may be due to infratentorial pathology. +Nystagmus. Both irritative and destructive lesions in any part of cerebellovestibular system may cause nystagmus with fast and slow components in opposite direction. Unilateral cerebellar lesion may produce bilateral manifestations because of compression across the midline. Brainstem lesions cause vertical nystagmus. The site of lesion is towards the side of the coarse nystagmus. +Vision. It is difficult to evaluate visual acuity and field of vision in children. Impaired vision with normal refraction should arouse suspicion of lesion near optic nerve, chiasma, optic radiations or cortical blindness. Bitemporal hemianopsia may indicate compression over chiasma. +Personality disturbances. Infants may become irritable, lethargic and show disturbances of behavior or speech. Loss of cortical sensation as described in supratentorial tumors of adults is difficult to interpret in children. There may be a decline in intellectual function. +Personality disturbances, inappropriate sphincter control and grasp response suggest localization of tumor near the frontal lobe. There may be optic atrophy in the +fundus of the same side and papilledema in the opposite eye (Foster Kennedy syndrome). + +Brain Tumors +Tumors arising from the brain are common in children. Certain genetic syndromes and familial factors increase risk of occurrence of brain tumors. Primary brain tumors may be malignant or benign. Benign tumors located near the vital areas of brain may be life-threatening. +Over two-thirds of brain tumors in children are infratentorial. About one-third to half of these are medulla- + +blastomas and one-third are astrocytomas of cerebellum. Brain­ stem gliomas and ependymomas account for the rest. Most of these tumors occur near the midline. Therefore they commonly obstruct CSF circulation and cause hydro­ cephalus early in disease. In adults, infratentorial tumors account for less than 10% of brain neoplasms. Common supratentorial tumors are astrocytomas, ependymomas, craniopharyngioma and malignant gliomas. Papillomas of choroid plexus and pineal body tumors are less common. Meningiomas, acoustic neuromas and pituitary adenomas are rare in childhood. Ataxia telangiectasia and neurocutaneous syndromes are associated with a higher +incidence of brain tumors. CT gives adequate information about ventricular size, tumor and surrounding edema. It is useful for followup. MRI provides better information +regarding mass size, infratentorial and spinal cord extension and tumor detail. + +Cerebellar Tumors +Medulloblastoma. These are midline cerebellar tumors and occur in infancy. They are fast growing and malignant. Craniospinal spread along neuraxis is common and death occurs early. They cause truncal ataxia, early papilledema, unsteadiness in sitting position and a tendency to walk with a broad base. Radiation, chemotherapy and a ventriculoperitoneal shunt are generally required. +Astrocytoma. These are common in the cerebellar hemisphere. Ataxia and incoordination are common on the side of the lesion. Nystagmus is observed on lateral gaze of the child to the affected side. Areflexia and hypotonia are present. The head is tilted to the side of lesion to relieve the increased intracranial pressure caused by herniation of tumor or cerebellar tonsils through the foramen magnum. Complete surgical excision of the tumor is often feasible. Chemotherapy with tomustin, vincristine and cisplatin is advised. Brachytherapy is now used in a variety of brain tumors to limit radiation necrosis and provide local irradiation to improve prognosis. + +Bralnstem Tumors +Signs of increased intracranial tension are minimal, yet vomiting occurs due to infiltration of medullary vomiting center. Hemiparesis, cranial nerve deficits and personality changes are common; reflexes in the lower limbs are exaggerated. The pontine tumors affect the 6th and 7th cranial nerves. + +Glioma of the brainstem causes bilateral involvement of the cranial nerves and long tracts. Cerebellar dysfunction is often present. The usual age of onset is in the later half of the first decade. Brainstem gliomas carry the worst prog­ nosis. Most children die within 18 months. Surgical exci­ sion is difficult and not very promising. Hyper­ fractionation radiotherapy is being evaluated. Chemotherapy +does not have significant role. +_ E_s_s_ _e_t_ia_l_P_e_d_ia_t_r_is___________________________________ +n +c +_ + + +Ependymoma of the fourth ventricle. It occurs in the first decade of life. The flow of cerebrospinal fluid is obstructed, causing an early rise in the intracranial pressure. These patients may present with subarachnoid hemorrhage. The tumors metastasize along the neuraxis. Surgical excision is rarely possible, patients may be treated with radio­ therapy. Survival of the child for a long period is unusual. + +Supratentorial Tumors +Craniopharyngioma. These can present at anytime during childhood. The tumor is congenital and arises from squa­ mous epithelial cell rests of the embryonic Rathke pouch. The neoplasm is usually cystic and benign. Clinical features include: (i) growth failure; (ii) bitemporal hemi­ anopsia, asymmetric or unilateral visual field defects; (iii) signs of increased intracranial pressure; and (iv) endocrine abnormalities such as diabetes insipidus and delayed puberty (in less than 10% of cases). X-ray films may show calcification. Cranial imaging reveals the extent of mass and its nature. Bone age is retarded. Surgical excision is possible but difficult. The tumor cyst may be aspirated or malignant ones are treated with radiotherapy or implants. + +Glioma of the cerebral hemispheres. These usually occur during the first and second decade of the life. The patient presents with seizures and hemiparesis. Rarely, involve­ ment of frontopontine cerebellar fibers may cause ataxia. Vomiting, headache and papilledema are relatively late features of supratentorial tumors. Incidence of gliomas is higher in children with neurocutaneous syndromes. The histological types include astrocytoma, oligodendro­ glioma and glioblastoma. + +Hypothalamic glioma. These rare tumors cause diencephalic syndrome in infants. The children fail to thrive, the sub­ cutaneous fat is lost and have sleep and respiratory distur­ bances. Older children may present with precocious puberty. Histological types observed are glioma, pinealoma, teratomas and hamartomas. + +Glioma of optic nerve. Visual disturbances, squint, proptosis, exophthalmos and optic atrophy are the usual presenting features. MRI of the orbit is diagnostic. Progression of tumor is relatively slow. Surgery is possible if the lesion is limited to one side. + +Inflammatory Granulomas +Inflammatory granulomas are an important cause of raised intracranial pressure and partial seizures in childhood. These may be tubercular, parasitic, fungal or bacterial in origin. Neurocysticercosis and tuberculomas are the commonest granulomas. + +Neurocysticercosis +It is caused by larval stage of Taenia solium. + +Pathogenesis. Evolution occurs from a nonattenuating cyst, to a ring with perilesional edema, to a disc lesion; which may disappear, persist or even calcify. Neurocysticercosis can be classified as parenchymal, intra ventricular, meningeal, spinal or ocular depending on the site of involvement. +Clinical features. Parenchymal neurocysticercosis -seizures are the commonest manifestations (80%), followed by raised intracranial pressure, focal deficits and rarely meningeal signs. Seizures may be generalized or partial. Intraventricular neurocysticercosis may present with features of raised intracranial pressure, focal neurological deficits and hydrocephalus. Visual symptoms or blindness results from cysts within the eye. Spinal neurocysticercosis presents with features of spinal cord compression or transverse myelitis. +Diagnosis. Neurocysticercosis is the most common cause of a cranial ring enhancing lesion (Fig. 18.8). The lesion is disc +or ring like image with a hypodense center. Lesion may be +single or multiple. A scolex is often present within the ring. There is often considerable edema surrounding the lesion. The midline shift is not significant. Lesion is usually supratentorial but may occur in infratentorial regions. MRI is more useful than a CT scan in doubtful cases. +ELISA for cysticercosis is positive in almost half the patients with single lesion. Cerebrospinal fluid may be examined for cells, cysticercal antigens and PCR, though its diagnostic utility is variable. +Therapy. Cysticidal therapy is not necessary for inactive and calcified lesions. There may be benefit to treat single active and multiple lesions. Cysticidal drugs commonly used include albendazole and praziquantel. Albendazole is the preferred drug because of efficacy, and is less expensive. The dose (15 mg/kg/day) may be given for varying periods from 5 to 28 days. Corticosteroids + + + + + + + + + + + + + + + + + + +Fig. 18.8: Contrast enhanced CT of brain showing a degenerating ring enhancing cyst with eccentric scolex and perilesional edema in right frontal lobe (Courtesy, Dr Atin Kumar, Deptt. of Radiodiagnosis, AIIMS, New Delhi) +Central Nervous System - + + + +(prednisolone 1-2 mg/kg/day) are started 2-3 days before initiating therapy and continued for a total of 5 days during cysticidal therapy. Symptomatic treatment includes anticonvulsants for --9 months or until resolution of the lesions. Calcified lesions require anticonvulsant therapy for 2-3 yr. + +Tuberculoma +The clinical presentation is similar to neurocysticercosis. On CT scan, there is a single or multiple ring enhancing lesions. Tuberculoma rings are usually larger. The lesion often has a thick (�20 mm) irregular wall and may be associated with a midline shift and severe perilesional edema (Fig. 18.9). Focal deficits are more frequent in tuberculomas. Presence of basal exudates should arouse suspicion of tuberculoma. The diagnosis is often suspected based on family history of contact, positive tuberculin reaction, other evidences of tuberculosis and subacute course of the illness. +Antituberculous therapy is recommended for 1 yr (2 HRZE + 10 HR) as for tubercular meningitis along with corticosteroids for initial 6-8 weeks. + +Brain Abscess +Brain abscess is an important differential diagnosis among children with unexplained fever, altered sensorium, elevated intracranial pressure, localized neurological findings and headache. +Predisposing/actors include cyanotic heart disease, immuno­ suppressed status, otitis media, sinusitis, mastoiditis, systemic sepsis and post-traumatic. + + + + + + + + + + + + + + + + + + + + + +Fig. 18. 9: Contrast enhanced MRI (sagittal view) of brain showing enhancing irregular ring like multiple tuberculomas (Courtesy, Dr Atin Kumar, Deptt. of Radiodiagnosis, AIIMS, New Delhi) + + +Etiology. Anaerobic organisms, streptococci, Staphylococcus aureus, pneumococci, Proteus and Haemophilus influenzae are common infecting organisms. The abscesses are observed more often in the cerebrum compared to infratentorial compartment. + +Clinical features of brain abscess may be described under 4 broad headings: (i) features of raised intracranial pressure; (ii) manifestations of intracranial suppuration such as irritability, drowsiness, stupor and meningeal irritation; (iii) features suggesting toxemia, e.g. fever, chills and leukocytosis; and (iv) focal neurological signs such as focal convulsions, cranial nerve palsies, aphasia, ataxia, visual field defects and neurological deficit. + +Diagnosis is established by CT scan or MRI. Lumbar puncture is avoided as the procedure may precipitate herniation of the brainstem. + +Management includes investigation for source of infection, treatment of precipitating cause, management of raised intracranial pressure and symptoms. Empirical therapy should begin with a third generation cephalosporin, vancomycin and metronidazole and continued for 4-8 weeks. Surgical drainage or excision of the abscess should be done in case of abscesses of >2.5 cm, located in posterior fossa, fungal abscess or if gas is identified nside the abscess. + +Suggested Reading +Foerster BR, Thurnher MM, Malani PN, et al. lntracrarual infections: clinical and imaging characteristics. Acta Radio! 2007;48:875-93 +Kraft R.Cysticercosis: an emerging parasitic disease. Am Fam Physician 2007;76:91-6 +Leotta N, Chaseling R, Duncan G, Isaacs D. lntracrrual suppuration. J Paediatr Child Health 2005;41:508-12 +Mazumdar M, Pandharipande P, Poduri A. Does albendazole affect seizure remission and computed tomography response in children with neurocysticercosis? A Systematic review and meta-analysis. J Child Neurol 2007;22:135-42 + +SUBDURAL EFFUSION +Subdural effusion may be acute or chronic. In infancy, subdural effusions are often associated with bacterial meningitis. These are generally acute, small and regress spontaneously. Rarely a large effusion may result in increased intracranial pressure and focal neurological signs. Chronic subdural effusion presents as raised intracranial pressure. The protein content of this fluid is high and vascular membrane forms around the subdural effusion. This may require surgical intervention. + +Clinical features are nonspecific. Convulsions, vomiting, irritability and drowsiness are present. There is persistent fever, anterior fontanel bulges and head size increases. In the newborn period, the skull may show increased transillumination. CT /MRl or subdural tap establishes the diagnosis. +__ _sse_ n_t i_ ai_ P_ _ed_ _ ia_ tr_ i_c_ _________________________________ +s +E +_ +_ + + +Treatment. Small collections are absorbed spontaneously. Large effusions may need to be aspirated every 24 to 48 hr until these become small. Surgical irrigation with indwel­ ling drains may be considered if the effusion persists for more than 2 weeks. Surgical excision of the subdural membrane is difficult and results are not encouraging. + +HYDROCEPHALUS +The CSF is secreted by the choroid plexus within the ventricles by ultrafiltration and active secretion. It passes from the lateral ventricles to the third and fourth ventricles and exits from foramen of Luschka and Magendie into the basal cisterns and then the cerebral and spinal sub­ arachnoid spaces where it is absorbed via the arachnoid villi (granulations) into the venous channels and sinuses. About 20 ml of CSF is secreted in an hour and its turnover is 3 or 4 times in a day. + +Etiology Hydrocephalus results from an imbalance between production and absorption of cerebrospinal fluid. It may be communicating or noncommunicating. + +Communicating hydrocephalus. There is no blockage in the CSF pathway but reabsorption may be affected. Excess CSF may be produced in papilloma of choroid plexus. + +Obstructive or noncommunicating hydrocephalus. The block is at any level in the ventricular system, commonly at the level of aqueduct or foramina of Luschka and Magendie (Fig. 18.10). +In obstructive hydrocephalus, the ventricles are dilated above the block. In cerebral atrophy, ventricles are dilated + + + + + + + + + + + + + + + + + + + + +Fig. 18.10: Arnold-Chiari II malformation: MRI T1W sagittal view showing obstructive hydrocephalus stretched brainstem and tonsillar herniation (patient also had a meningomyelocele) (Courtesy: Dr Atin Kumar, Deptt. of Radiodiagnosis, AIIMS, New Delhi) + +but pressure is not raised (hydrocephalus ex vacuo). Presence of periventricular ooze on CT or MR imaging helps to identify the former. Hydrocephalus may be congenital or acquired (Table 18.8). + +Table 18.8: Causes of hydrocephalus Congenital hydrocephalus +Intrauterine infections: Rubella, cytomegalovirus, toxo­ plasmosis, intracranial bleeds, intraventricular hemorrhage Congenital malformations: Aqueduct stenosis, Dandy-Walker syndrome (posterior fossa cyst continuous with fourth ventricle), Arnold-Chiari syndrome (portions of cerebellum and brainstem herniating into cervical spinal canal, blocking +the flow of CSF to the posterior fossa) Midline tumors obstructing CSF flow +Acquired hydrocephalus +Tuberculosis, chronic and pyogenic meningitis Post-intraventricular hemorrhage +Posterior fossa tumors: Medulloblastoma, astrocytoma, ependymoma +Arteriovenous malformation, in tracranial hemorrhage, ruptured aneurysm +Hydrocephalus ex vacuo + + +Pathology Ventricles are dilated, at times unevenly. Ependymal lining of ventricles is disrupted resulting in periventricular ooze and hence periventricular white matter is compressed. Cortex is generally preserved until late but cortical atrophy may occur. The process may be reversible if the treatment is initiated early. +Clinical features Hydrocephalus may manifest with enlarging head size, delayed closure of fontanel and sutures. Associated symptoms include headache, nausea, vomiting, personality and behavior disturbances such as irritability, head banging, apathy and drowsiness. +Papilledema, pyramidal tract signs and cranial nerve palsies may occur. Skull contour becomes abnormal and forehead is prominent. Scalp veins become prominent and dilated. A sunset sign is seen in the eyes, i.e. sclera above the cornea becomes visible. Upward gaze is impaired. Limbs become spastic because of stretching of cortical fibers. Distortion of the brainstem may lead to bradycardia, systemic hypertension and altered respiration rate. +Congenital hydrocephalus starts in fetal life and may manifest or even develop subsequently. The large head size at birth causes difficulty in delivery of the head during labor. There may be associated congenital malformations. +Diagnosis Accurate serial recording of the head circum­ ference is essential for early diagnosis of hydrocephalus and should be supported by serial USG. An increase in the head circumference in the first 3 months of life >1 cm every fortnight should arouse suspicion of hydrocephalus. Brain grows very rapidly in the first few weeks of life and therefore sagittal and coronal sutures may be separated up +Central Nervous System - + + + +to 0.5 cm. This physiological separation disappears after the first fortnight of life. Persistent widening of squamo­ parietal sutures is not physiological and should arouse suspicion of hydrocephalus. +Cranial ultrasound and computed tomography help to evaluate serial ventricular size while the latter gives information about cortical mantle, periventricular ooze and etiology of hydrocephalus. MRI may be necessary to deter­ mine the site of obstruction and in congenital hydrocephalus to identify associated malformations. Arnold-Chiari mal­ formation has downward displacement of cerebellum and medulla, obstruction of CSF pathway or migration defects. Dandy-Walker malformation reveals a cystic malformation, atresia of outlet foramina or any brain malformations. +Differential diagnosis +Megalencephaly refers to the increase in volume of brain parenchyma. There are no signs of increased intracranial pressure. The ventricles are neither large, nor under increa­ sed pressure. Causes include Hurler syndrome, meta­ chromatic leukodystrophy and Tay-Sachs disease. +Chronic subdural hematoma causes large head, mostly located in the parietal region without prominent scalp veins or sunset sign. Large head size is also observed in hydranencephaly, rickets, achondroplasia, hemolytic anemia and familial macrocephaly. +Treatment Management includes making a precise etio­ logical diagnosis and identification of associated malfor­ mations, clinical course and severity of hydrocephalus. +If hydrocephalus is arrested spontaneously, surgical intervention may not be necessary. Medical management should be instituted if surgery is not indicated. Acetazo­ lamide at a dose of 25-100 mg/kg/day diminishes CSF production in mild, slowly progressive hydrocephalus. Oral glycerol has also been used for similar purpose. A conservative approach is better in most cases. +If the head size enlarges rapidly, or is associated with pro­ gressive symptoms, where vision or life is endangered it is desirable to treat surgically before irreparable damage occurs. In congenital obstructive hydrocephalus, acquired hydrocephalus, periventricular ooze with hydrocephalus a ventriculoatrial or preferably a ventriculoperitoneal shunt should be done to drain the CSF directly into the circulation or into the peritoneal cavity. Third ventriculotomy by endoscopic approach is another option particularly in children with obstructive hydrocephalus. In cases of bacterial meningitis, an acute hydrocephalus may set in which is self limited. Patients with tuberculous meningitis and pro­ gressive hydrocephalus require a shunt, specially if it is obstructive. +A variety of shunts are now available. It is usually necessary to keep the shunt for the entire life. As the child grows in size it may be necessary to revise the shunt, using a longer tube. Blockage and infection are the two most common shunt complications. Shunt revision may also be necessary if there is bacterial colonization of the shunt. + +Prognosis Even with the best of treatment, prognosis is guarded. Almost two-thirds patients have variable mental and developmental disabilities. Prognosis of hydro­ cephalus associated with spina bifida is not satisfactory. + +Pseudotumor Cerebri +It is a benign self limiting disorder with generally a favorable outcome. Intracranial pressure is elevated and ventricular system is either normal or small. Generally, there are no focal neurological signs. Onset of symptoms of raised intracranial pressure may be sudden or gradual extending over a week. Visual field shows enlargement of blind spot. +Pseudotumor cerebri may follow use of outdated tetracycline, high doses of vitamin A, quinolones, lateral sinus thrombosis (following otitis media, mastoiditis especially on the right side) and obstruction of venous outflow due to pressure on superior vena cava. It may occur during withdrawal of corticosteroid therapy, Addison disease, hypoparathyroidism and systemic lupus erythematosus. EEG shows excessive slow wave activity. Isotope brain scan, CT or MRI are normal. The patient improves spontaneously after a few months. Acetazolnide or oral glycerol helps in symptomatic relief. Dexamethasone may be required. Cerebral decompression is rarely necessary. + +Suggested Reading +Duhaime AC. Evaluation and management of shunt infections in children with hydrocephalus. Clin Pediatr (Phila) 2006;45:705-13 +Matthews YY. Drugs used in childhood idiopathic or benign intracranial hypertension. Arch Dis Child Educ Pract Ed 2008;93:19-25 + +NEURAL TUBE DEFECTS +Neural tube defects (NTD) are one of the most common congenital anomalies due to failure of proper closure of neural tube and covering mesoderm and ectoderm. These defects occur in about 1.5 per 1,000 live births; the risk in second sibling is 5 per 100 births. The incidence in North India is as high as 3.9-9/1,000 live births. + +Etiology +Primary neural tube defects have multifactorial inheri­ tance. Maternal risk factors include zinc and folate defici­ ency, alcohol,radiation exposure,insulin dependent diabe­ tes mellitus (IDDM), and use of valproate and carbama­ zepine during pregnancy. Patients with trisomy 13 and 15 shows these defects. +Maternal folate deficiency is an important risk factor for development of NTD. Periconceptional folic acid supple­ mentation with 4 mg folate supplementation 1 month before conception and through first trimester decreases the occurrence and recurrence of NTD. The exact mechanism for this protective effect remains unknown. + +Clinical Features +The defect is obvious at birth or through fetal sonography. It varies in severity from an occult anomaly to severe life- +___ _s_se__a_r_P_edt_r__ __________________________________ +n +i +i +a c +_s +_t +i +E + + +threatening problem. Lumbosacral region is the commonest site, but any part of the spine may be affected. The defect may extend over a variable length of the spinal cord. +The spectrum includes spina bifida (meningocele, meningomyelocele, spina bifida occulta), anencephaly (absence of brain calvaria, total or partial), encephalocele (herniation of brain and meninges through defect in calvaria), craniorhachischisis (anencephaly associated with continuous bony defect of spine and exposure of neural tissue) and iniencephaly (dysraphism of occipital region accompanied by retroflexion of neck and trunk). +Neural tube defects may be associated with other congenital anomalies and dysfunction of organ systems. Affected children may have lower body paralysis, bladder and bowel dysfunction, learning disabilities, hydrocephalus due to Arnold-Chiari type 2 malfor­ mation and endocrine abnormalities. Anencephaly is an important cause of fetal and infant mortality. Severe cases die in utero, or in the early neonatal period. Longterm sequelae include neurological, motor, physical disability, psychosocial maladjustments and increased financial burden on family. +Spina bifida occulta constitutes about 5% cases and is asymptomatic. Meningocele or myelomeningocele, presents clinically as a raw red fleshy plaque, consists of meninges, CSF, nerve roots and dysplastic spinal cord. In meningocele, the sac is covered only by skin and generally there is no neurologic deficit. +In meningomyelocele the neurologic deficit includes varying degrees of flaccid paraparesis and sensory deficit in the trunk and legs corresponding to involved segments of the dysplastic cord. The cord distal to the site of the lesion is severely affected. Involvement of bowel and bladder results in fecal and urinary incontinence. Hydrocephalus is usually present in varying degrees. Arnold-Chiari malformation may cause facial weakness and swallowing difficulty. Tongue movements may be impaired and there may be laryngeal stridor. + +Management +Prenatal diagnosis of myelodysplasia is possible by elevated alpha-fetoprotein level in the maternal blood between 14 and 16 weeks of gestation, or in the amniotic fluid in early pregnancy where the test is more specific. Additional test in amniotic fluid includes acetyl cholinesterase estimation. Ultrasound detection is around 100%; raised maternal blood alphafetoprotein has accuracy of 60-70%, amnio­ centesis for alpha-fetoprotein and acetylcholinesterase has accuracy of 97%. + +Investigations include ultrasound of head, meningocele and the abdomen and chest and spine X-rays. + +Treatmen t +Management of NTD requires a team approach with the cooperation of pediatrician, neurologist, neurosurgeon, + +urologist and orthopedic surgeon with assistance from physiotherapist, social worker and psychiatrist. The degree of paralysis, presence of hydrocephalus, kyphosis, congenital malformation, evidence of infection of nervous system influences decisions. +Surgery includes closure of the defect and a VP shunt (if associated with hydrocephalus). Early closure prevents neurological deterioration. Open lesions draining CSF should be closed within 24 hr. Closed lesions should be operated within 48 hr. + +Lorber's criteria for selective surgery. Surgery is not recom­ mended if there is severe paraplegia at or below L3 level, kyphosis or scoliosis, gross hydrocephalus, associated gross congenital anomalies, intracerebral birth injuries and neonatal ventriculitis before closure of back. + +Prognoss +i +Delay in intervention causes increase in complications like worsening of neurologic deficit, infection (local or ventriculitis) and progressive hydrocephalus. Late complications include: hydrocephalus in 80-90% because of Chiari II malformation, urinary tract infections, enure­ sis, fecal incontinence or constipation, sexual dysfunction, intellectual deterioration, delayed neurological problems (tethered cord, intradural mass lesions), epilepsy in 10-30%, ocular problems (30%), shunt infection (25%), psychosocial problems and motor deficits. 2% die during initial hospitalization and 15% die by ten years of age. + +Prevention +Primary prevention includes periconceptional folate supplementation to all prospective mothers. Food +fortification is another possible approach. Counseling of family with a previous child with NTD is essential. The risk of recurrence is 3.5% with 1 affected child, 10% with 2 affected children and 25% with 3 affected children. MTHFR polymorphisms should be studied in case of recurrence of births with NTD. Periconceptional folate and prenatal diagnosis is advised in subsequent pregnancy. Folate supplementation reduces recurrence risk by 70%. Zinc and vitamin A supplementation is also advised. +Dose for primary prevention is 0.4 mg per day. A mother who has previously delivered a child with NTD should receive 4 mg per day of folic acid in subsequent preg­ nancies. Secondary prevention is imperative after an index case. Duration of supplementation is 2 months before and 3 months after conception. + +SuggestedReadng +i +Birnbacher R, Messerschmidt AM, Pollak AP. Diagnosis and prevention of neural tube defects. Curr Opin Urol 2002;12:461-4 +Kibar Z, Capra V, Gros P. Toward understanding the genetic basis of neural tube defects. Clin Genet 2007;71:295-310 +Pitkin RM. Folate and neural tube defects. Am J Clin Nutr 2007; 85: 285S-8S +Central Nervous System - + + + +Shaer CM, Chescheir N, Schulkin J. Myelomeningocele: a review of the epidemiology, genetics, risk factors for conception, prenatal diagnosis and prognosis for affected individuals. Obstet Gynecol Surv 2007;62:471-9 + +ACUTE HEMIPLEGIA O------------- +F CHILDHOOD +Acute hemiplegia of childhood is most often due to cere­ brovascular disorders. The exact cause often remains obscure despite extensive biochemical and radiological investigations. + +Causes +Cerebral venous sinus thrombosis. Inherited prothrombotic conditions (deficiency of antithrombin III, protein C or protein S; factor V Leiden mutation; homocysteinemia); acquired prothrombotic condition (nephrotic syndrome, antiphospholipid antibodies); infections (otitis media, mastoiditis, sinusitis, meningitis); systemic lupus erythematosus; polycythemia, thrombocytosis; head trauma; neurosurgery dehydration +Arterial thrombosis or embolism. Cyanotic congenital heart disease; infective endocarditis; paradoxical emboli through patent foramen ovale; arrhythmia; sickle cell SS or SC disease; polycythemia; thrombocytopenia; thrombocytosis antiphospholipid antibodies; inherited prothrombotic conditions (as listed above); disseminated intravascular coagulation; paroxysmal nocturnal hemoglobinuria; infec­ tions (meningitis, bacteremia, local head and neck infections); systemic lupus erythematosus; head trauma +Intracranial hemorrhage. Arteriovenous malformation; cerebral aneurysm; coagulopathy; inherited or acquired thrombocytopenia; thrombasthenia +Infections. Cerebral abscess, meningitis, encephalitis +Intracranial space occupying lesion. Cerebral tumor (primary or metastatic); inflammatory granuloma +Focal postviral encephalitis. Herpes virus, varicella Moyamoya syndrome +Transient cerebral arteriopathy. Vascular spasm; drug induced (amphetamine, cocaine), metabolic disease with stroke like episodes (MELAS, Leigh disease, homocysti­ nuria, pyruvate dehydrogenase deficiency, ornithine transcarbamoyl transferase deficiency); intracranial vas­ cular dissection +Todd paralysis Porencephaly + +Clinical Features +Mode of onset. The rapidity of onset varies with the cause. Emboli occur abruptly with maximum neurological signs at onset and improves with time. Although intracranial + +hemorrhage occurs acutely, it manifests usually after a brief lapse with headache and nuchal rigidity. Cerebrovascular thrombosis is relatively less rapid in onset. + +History and physical examination. History of ear, throat mastoid infection, intraoral or neck trauma, associated cardiac disease or hematological disorders may be helpful in determining the cause. +In mild hemiparesis, one should observe for circum­ duction of involved leg, asymmetric movements of upper extremities and cortical fisting of involved hands. If the child is pushed from sitting position the child extends his arm to protect himself from a fall, called lateral propping reaction. In spastic hemiplegia, this reaction is asymmetric. Absent propping reaction in infants after the age 8-9 months is always abnormal. +Benign intracranial hypertension occurs in lateral sinus thrombosis. Seizures, raised intracranial pressure and vomiting are common in superior sagittal sinus throm­ bosis. Arterial occlusions generally occur in the first two years of life. These may be associated with hemiparesis and seizures, which are difficult to control with medi­ cation. Hemiparesis, cerebral hemiatrophy and cerebral porencephaly may result. + +Localization +Cortical lesions. Cortical lesions are characterized by the specific pattern of motor deficit, depending on the vascular distribution of the artery involved. Seizures and cortical sensory loss are usual. +In the left-sided lesion, aphasia is a dominant clinical feature. The child has difficulty in reading, writing and comprehension. Organization of space and body image are affected. In right parietal lesions, the child exhibits lack of attention for objects on his left side. He may ignore the left side of a picture placed before him or may not even recognize his left hand. He has difficulty in copying simple figures, (indicating constructional apraxia). He gets lost easily and confuses directions given to him because of spatial disorganization. +Corona radiata. The hemiplegia is generally complete and seizures are absent. +Internal capsule. Hemiplegia is complete, often with sensory loss. +Midbrain. Hemiplegia affects the contralateral side and paralysis of 3rd and 4th cranial nerves on the same side (Weber syndrome). +Pons. Hemiplegia affects the opposite side and involves paralytic of 6th and 7th cranial nerves on the same side (Millard-Gubler syndrome). +Medulla oblongata. Contralateral hemiplegia with ipsilateral involvement of lower cranial nerves is noted. +__ E_s_s_e_ _ t_ia_l_P_e_d_ia_ t_ r-ic_ _________________________________ +n +s +_ + + +Management +Investigations for the predisposing illness should include platelet count, hemoglobin, MCV, MCH, serum iron and iron binding capacity, nitroprusside reaction for homo­ cystinuria, sickle cell preparation of blood, antinuclear anti­ body tests, protein C and S estimation, Factor V Leiden, testing for MTHFR mutations, antiphospholipid anti­ bodies, serum and CSF lactate and pyruvate, chest X-ray and echocardiography. Metabolic tests are done if indi­ cated. Investigations should include CT scan, electro­ encephalogram and MR angiography. Lumbar puncture is indicated if an inflammatory CNS disease is suspected. +Treatment. Specific treatment depends on the etiology of hemiplegia. The role of tissue plasinogen activator in childhood stroke is not established. In thrombotic stroke, low molecular weight heparin may be indicated followed by oral warfarin pending evaluation for underlying prothrombotic state. Seizures should be controlled and hydration should be maintained. Physiotherapy and speech therapy should be started early. +Treatment ofacute cerebral thrombosis is directed towards increasing cerebral perfusion, limiting brain edema, and preventing recurrences. Aspirin may be indicated to prevent recurrence. Calcium channel blockers have been found useful in some. Seizures often persist and anticonvulsants may be required. + +Prognosis +Prognosis with regard to seizures and mental retardation is worse in acute idiopathic hemiplegia below 3 yr of age. Herniplegic side may be atrophied and athetosis may be seen on the same side. Cerebral herniatrophy with flatten­ ing of the skull and porencephaly secondary to paren­ chymal damage may occur. + +Suggested Reading +Bernard TJ, Goldenberg NA. Pediatric arterial ischemic stroke. Pediatr Clin North Am 2008;55:323-38 +Carpenter J, Tsuchida T. Cerebral sinovenous thrombosis in children. Curr Neurol Neurosci Rep 2007;7:139-46 +Carpenter J, Tsuchida T, Lynch JK. Treatment of arterial ischemic stroke in children. Expert Rev Neurother 2007;7:383-92 +Jordan LC, Hillis AE. Hemorrhagic stroke in children.Pediatr Neurol 2007;36:73-80 +Mackay MT, Monagle P. Perinatal and early childhood stroke and thrombophilia. Pathology 2008;40:116-23 +Nelson KB, Lynch JK. Stroke in newborn infants.Lancet Neurol 2004;3:150-8 +Seidman C, Kirkham F, Pavlakis S. Pediatric stroke: current developments. Curr Opin Pediatr 2007;19:657-62 + +PARAPLEGIA AND QUADRIPLEGIA +Paraplegia refers to motor weakness of both lower limbs. Quadriplegia is the nomenclature used for neurological weakness of all four limbs; the involvement is more in the upper limbs as compared to the lower extremities. Neuro­ logical weakness may be (i) spastic with spasticity, exagge- + +rated tendon reflexes and extensor plantars; or (ii) flaccid with flaccidity, diminished tendon reflexes, flexor plantar response and muscle wasting. It may be acute or insidious in onset and have a variable course. Vascular, traumatic and postinfective lesions are usually acute in onset with variable gradual recovery. Compressive or neoplastic lesions have insidious onset with gradually progressive deficit. Degenerative disorders have an insidious onset with slowly progressive course. +Flaccid weakness may result from involvement of anterior horn cell, nerve roots, nerves and myopathies. Acute onset follows demyelinating polyneuropathy, polio, vascular and traumatic spinal cord insults. Chronic causes include spinal muscular atrophy, peripheral neuropathies and myopathies. Table 18.9 enlists the common causes of paraplegia and quadriplegia. + +Table 18. 9: Causes of paraplegia or quadriplegia Spastic +Compressive +Tuberculosis of spine with or without paraspinal abscess +Extradural, e.g. metastasis from neuroblastoma, leukemia, lymphoma; inflammatory process, such as epidural abscess (usually posterior to the spinal cord), bony abnormalities such as achondroplasia, Morquio disease, hemivertebrae and +occipitalization of atlas vertebra, atlantoaxial dislocation Intradural. Neurofibroma and dermoid cyst Intramedullary. Glioma, ependymoma, hemato- or hydro­ myelia +Noncompressive myelopathies +Vascular anomalies of the spinal cord: Arteriovenous malformations, hemangiomas and telengiectasia +Trauma or transection of cord +Transverse myelitis/myelopathy. Viral, neuromyelitis optica, segmental necrosis due to vascular occlusion, e.g. of anterior spinal artery +Familial spastic paraplegia +Lathyrism due to consumption of Lathyrus sativum Degenerative spinal cord disease +Supra-cord lesions Cerebral palsy Hydrocephalus Bilateral cortical disease +Bilateral white matter disease +Flaccid weakness +Spinal shock in the initial stages of spinal cord damage, e.g. after trauma, vascular, inflammatory, neoplastic lesions, or transverse myelopathy +Guillain-Barre syndrome Acute poliomyelitis Spinal muscular atrophies Peripheral neuropathies +Botulism, Riley Day syndrome +Pseudoparalysis +Surgery, osteomyelitis, fractures, myositis, metabolic myopathy +Central Nervous System - + + + +It should be remembered that symmetrically brisk tendon reflexes with flexor plantar response may be nor­ mal in children and do not necessarily indicate any patho­ logical process. In case of doubt between plantar reflex and withdrawal response, the dorsilateral aspect of the foot should be stroked (Chaddock maneuver) to obtain the plantar response. In lesions above the level of midbrain, jaw reflex becomes brisk. Abdominal reflexes should be elicited by stroking the skin over the abdomen close to the umbilicus. The patient should be examined carefully for sensory involvement, sensory level, wasting at the segments of the lesion, posterior column involve­ ment and bladder bowel involvement. + +Management +In acute myelitis, dexamethasone in high dose (5 mg/kg/ day) or IV methylprednisolone pulse (30 mg/kg/ day) for 3-5 days may be useful. Tuberculosis is managed with antitubercular drugs, corticosteroids and local manage­ ment. In acute trauma and paraplegia due to neoplasia, the treatment may be surgical. +Paraplegia is initially flaccid but later becomes spastic with development of painful flexor spasms due to the stimulation of pain fibers. Nursing on foam mattress and frequent change of position on bed would prevent decubi­ tus ulcers. Physiotherapy should be done. Bladder must be emptied regularly by compression or repeated cathe­ terization to prevent it being distended and becoming atonic. Later, the bladder may become spastic with frequent but partial reflex emptying. Urinary tract infection may supervene due to inadequate drainage of the bladder. It should be appropriately treated. In severe spasticity, drugs that reduce tone provide relief. + +Guillain-Barre Syndrome See Chapter 19 + +SYDENHAM CHOREA (RHEUMATIC CHOREA) +Choreiform movements are irregular, nonrepetitive, quasi­ purposive and involuntary movements that are usually proximal but may affect fingers, hands, extremities and face. Chorea may precede or follow manifestations of rheumatic fever. There is a significant epidemiological association of chorea with rheumatic fever. Nearly one­ third of these patients develop rheumatic valvular heart disease. Concurrent association of chorea with rheumatic polyarthritis is rare because chorea generally supervenes later in the course of rheumatic activity. Chorea is a major criterion for the diagnosis of rheumatic activity. + +Clinical Features +Sydenham chorea is more common in girls than in boys. The usual age of onset is 5 to 15 yr. The clinical picture may be variable depending on the severity of the illness. + + +The child may appear clumsy, and develop deterioration in handwriting. Movements may be limited to one side of the body as in hemiballismus. The movements are aggravated by attention, stress or excitement, but disappear during sleep. Emotional !ability, hypotonia and a jerky speech are common associations. +The following clinical maneuvers are helpful in arriving at the diagnosis: +i. When the hand is outstretched above the head, forearms tend to pronate +ii. When hands are stretched forwards, wrist flexes and fingers hyperextend +iii. The child relaxes hand grip on and off as if he is milking a cow (Milkmaid grip) +iv. The child cannot maintain tongue protrusion (darting tongue) +v. During speech an audible click is heard +vi. The knee reflex may show a sustained contraction resulting in a hung up reflex. + +Investigations. The neurological investigations are gene­ rally unrewarding. Antistreptolysin O titer may not be elevated because the onset of chorea is late. + +Prognosis. The disorder is generally self limiting and may last from a few weeks to few months (up to 2 yr). Relapses or recurrences can occur. + +Treatment. The child should be protected from injury; bedding should be well padded. These children may be treated with chlorpromazine, haloperidol, sodium valproate or carbamazepine. Drugs are maintained at minimum doses required for symptom suppression. Anti­ streptococcal prophylaxis with penicillin G should be given to prevent recurrence of rheumatic activity. + +Suggested Reading +nk JW. Paroxysmal dyskinesias. Curr Opin Pediatr 2007;19: 652-6 Pavone P, Parano E, Rizzo R, Trifiletti RR. Autoimmune neuro­ +psychiatric disorders associated with streptococcal infection: Sydenham chorea, PANDAS and PANDAS variants. J Child Neurol 2006;21:727-36 Weiner SG, Normandin PA. Sydenham chorea: a case report and +review of the literature. J Pediatr Emerg Care 2007;23:20-4 + +ATAXIA +Ataxia is not unusual in childhood. Movements of the limbs are uncoordinated even in absence of weakness. The child is unsteady and tends to sway while standing with feet together. Nystagmus, dysarthria, posterior column signs and evidence of labyrinthine or cerebellar disease or raised intracranial pressure should be looked for. A history of drug, toxins and recent infections is important. + +Acute Cerebellar Ataxia +Acute cerebellar ataxia may result from many causes: the common being postinfectious cerebellitis (varicella), drugs; brainstem encephalitis and paraneoplastic states. +__ _s s__en_t_i_ai_P_e_d_i_a t_r_i_c _________________________________ +s +E +_ +_ + + +Other causes include Miller Fisher syndrome, trauma, migraine, kawasaki disease and inherited episodic ataxia. The usual age of onset is between 1 and 5 yr. Ataxia may develop within a few hr following a febrile illness. The patient has hypotonia, dysarthria, significant ataxia of gait and some incoordination in extremities. The tendon jerks are often pendular and nystagmus is common. The cerebrospinal fluid shows mild pleocytosis. Prognosis is good. Corticosteroids are useful and a quick response is observed. Recurrence is uncommon. Postviral ataxia is an diagnosis of exclusion; other diagnoses should be +entertained if ataxia recurs or does not respond. + +Ataxia-Telangiectasia +This is an autosomal recessive disorder localized to long arm of chromosome 11, characterized by progressive cerebellar ataxia starting at 1-3 yr. A few years later, telangiectasia over the conjunctivae and skin may be observed. These children may have IgA deficiency or impaired cell mediated immunity, frequent sinopulmonary infections and increased predisposition to lymphoreticular malignancies. They have elevated alpha-fetoprotein levels and defects in DNA repair. + +Friedreich Ataxia +This autosomal recessive disorder presents in adolescence or second decade. The classical changes include degene­ ration of the dorsal, pyramidal and spinocerebellar spinal tracts. +There is loss of position and vibration sense, ataxia nysta­ gmus, dysarthria and areflexia. Plantar response is usually extensor because of pyramidal involvement. Intellect is not affected. In addition, these children show skeletal abnor­ malities such as pes cavus and kyphoscoliosis. Cardiac lesions may include hypertrophic cardiomyopathy. Optic atrophy is usually present. There is a higher incidence of diabetes mellitus. + +Occult Neuroblastoma +A child with acute cerebellar ataxia, hyperkinetic spon­ taneous movement of eyes in many directions (opso­ clonus) and myoclonic jerks of face and body should always be investigated for occult malignancy, especially neuroblastoma. + +Refsum Disease +It is due to disturbances in phytanic acid metabolism. Clinical features include ataxia, atypical retinitis pigmen­ tosa with night blindness, deafness, ichthyosis and con­ duction defects in the heart. Protein level in CSF is high. These patients should be treated by excluding green vegetables (rich in phytanic acid) from the diet. + +Demyelinating and Storage Diseases +Ataxia is an important component of disorders of demyelination. Visual involvement, pyramidal tract + +involvement and a waxing and waning course may be observed. Lipidoses can also present with cerebellar features. + +Developmental Disorders +Cerebellar ataxia may also occur due to rudimentary development of cerebellar folia. It may be associated with diplegia, both spastic and flaccid, congenital chorea and mental defect. These are nonprogressive and may appear to improve with physiotherapy. + +Suggested Reading +Bernard G, Shevell MI. Channelopathies: a review. Pediatr Neurol 2008;38:73-85 +Nandhagopal R, Krishnarnoorthy SG. Unsteady gait. Postgrad Med 2006;82:e7-8 + +INFANTILE TREMOR SYNDROME ---------Infantile tremor syndrome, as reported from Indian subcontinent, is a self limiting clinical disorder in infants and young children. It has an acute or gradual onset with mental and pychomotor changes, pigmentary disturbances of hair and skin, pallor and tremors. The disease is now encountered less frequently. +--- + +Etiopathogenesis +The clinical features suggest a disorder of the extra­ pyramidal system. Etiologic possibilities are malnutrition, vitamin B12 deficiency and viral infections but none have been conclusively proven. +Malnutrition. Due to its close resemblance with Kahn's nutritional recovery syndrome, malnutrition was postulated as a possible etiology. However, the majority of children are not malnourished, look chubby and their serum proteins are within normal range. + +Vitamin B12 deficiency. Low vitamin B12 levels, megalo­ blastic bone marrow and a prompt response to vitamin B12 therapy is described but not substantiated. + +Magnesium deficiency. Low magnesium levels in the serum and cerebrospinal fluid are reported in some cases. + +Infections. Seasonal incidence and cortical biopsy suggest that it might be a form of meningoencephalitis. The failure to isolate any viral antigen, consistently normal CSF, presence of pigmentary changes and pallor do not support this hypothesis. + +Toxin. Epidemiological evidence does not support the view that infantile tremor syndrome is due to a toxin. + +Enzyme dfect. A transient tyrosine metabolism defect might lead to interference in melanin pigment production. Depigmentation of substantia nigra may explain the tremor. This needs further confirmation. +Central Nervous System - + + + +Clinical Features +Infantile tremor syndrome occurs in apparently plump, normal or underweight and exclusively breastfed children of age 5 months to 3 yr. Boys are twice as commonly affected as girls. Most cases occur in summer months in children belonging to the low socioeconomic group. +The prodromal phase lasts for 2 weeks to 2 months. In a typical case, the onset is heralded by mental or motor regression characterized by apathy, vacant look, inability to recognize the mother, lack of interest in surroundings, lethargy and poor response to bright and colored objects. There is hyperpigmentation, especially over the dorsum of hands, feet, knees, ankles, wrists and terminal phalanges. Hair become light brown, sparse, thin, silky and lusterless. There is mild to moderate pallor. At times there may be fever, upper respiratory tract infections, diarrhea, edema, hepatomegaly and a tremulous cry. +The next phase is characterized by abrupt onset of tremors, which are usually generalized. Tremors are coarse, fast, 6-12 cycles per second, of low amplitude, initially intermittent but become continuous later on. Rate of tremors may vary from one limb to the other. Head is tossed from side-to-side and trunk may show twisting or wriggling dystonic movements. Tremors disappear during sleep and are aggravated during crying, playing or feeding. Tone is variable. Consciousness is retained. Average duration of this phase is 2-5 weeks. The condition remains static for some time before disappearing altogether. During the recovery phase, pallor and pigmentation become less, the child becomes more alert. Improvement in psychomotor function is relatively slow. This phase usually lasts for one to six months but the course may be unduly prolonged with associated infections. Mortality is never directly related to the disease but may be attributed to concurrent infections. Subnormal intelligence +is the only longterm sequelae. + +Investigations +Laboratory investigations are not pathognomonic. There is mild to moderate anemia with hemoglobin between 6-11 g/ dl. Morphology ofred cells is variable (normocytic, microcytic, macrocytic or dimorphic). Bone marrow shows normoblastic, dimorphic or megaloblastic changes. Cerebrospinal fluid is normal. Histological evaluation of liver, skin, muscle, rectum and nerve are noncontributory. Cortical biopsies reveal mild inflammatory changes. CT scan shows no abnormalities or mild atrophy. EEG may show epileptiform activity. Virological studies are negative. + +Differential Diagnosis +Kahn nutritional recovery syndrome, infection of the central nervous system, chronic liver diseases, hypo­ glycemia, hypomagnesemia, heredofamilial degenerative diseases, phenothiazine toxicity, hyperthyroidism and megaloblastic anemia may be considered in the differential diagnosis. + +Treatment +Treatment is largely empirical, and supportive. Iron, calcium, magnesium, vitamin B6 supplements and injectable vitamin B12 therapy is reported to help some patients. Tremors may diminish considerably after administration of propranolol. Phenobarbitone, phenytoin and antiparkinsonism drugs do not shorten the duration of tremors. Nutrition should be maintained with dietary supplementation. Parents should be reassured. Associated infections and secondary complications must be treated. + +Suggested Reading +Kumar A. Movement disorders in the tropics. Parkinsonism Relate Discord 2002;9:69-75 +Vora RM, Tullu MS, Bartakke SP, Kamat JR. Infantile tremor syndrome and zinc deficiency. Indian J Med Sci. 2002;56:69-72 + +CEREBRAL PALSY +Cerebral palsy (CP) is defined as a nonprogressive neuromotor disorder of cerebral origin. It includes heterogeneous clinical states of variable etiology and severity ranging from minor incapacitation to total handicap. Most of the cases have multiple neurological deficits and variable mental handicap. The term does not include progressive, degenerative or metabolic disorders of the nervous system. +It is difficult to estimate the precise magnitude of the problem since mild cases are likely to be missed. Approximately 1-2 per 100 live births is a reasonable estimate of the incidence. + +Etiopathogenesis +Factors may operate prenatally, during delivery or in the postnatal period. Cerebral malformations, perinatal hypoxia, birth trauma, chorioamnionitis, prothrombotic factors, acid base imbalance, indirect hyperbilirubinemia, metabolic disturbances and intrauterine or acquired infections may operate. Most infants have multiple risk factors. Prematurity is an important risk factor for spastic diplegia while term weight babies get quadriparesis or hemiparesis. The mechanism of CP in a large proportion of cases remains unclear and primary neurological aberrations may be unfolded in future. The importance of role of birth asphyxia has been questioned by recent data and asphyxia may be manifestation of the brain damage rather than the primary etiology. +A variety of pathological lesions such as cerebral atrophy, porencephaly, periventricular, leukomalacia, basal ganglia thalamic and cerebellar lesions may be observed. + +Types of Cerebral Palsy +Cerebral palsy is classified on basis of topographic distribution, neurologic findings and etiology. +__ _s_s_e_n_t _ia_ _P_e_d_ i_at_ ic_ _________________________________ +l +s +r +_ +E + + +Spastic Cerebral Palsy +This is the commonest form (65%) and is topographically classified into spastic quadriparesis, diplegia or hemi­ paresis. Early diagnostic features of neural damage include abnormally persistent neonatal reflexes, feeding difficulties, persistent cortical thumb after 3 months age and a firm grasp. On vertical suspension, the infant goes into scissoring due to adductor spasm with an extensor posture and does not flex his knees or thigh. The stretch tendon reflexes are always brisk. They have variable degrees of mental and visual handicaps, seizures and behavioral problems. +Spastic quadriparesis is more common in term babies and exhibits signs including opisthotonic posture, pseudo­ bulbar palsy, feeding difficulties, restricted voluntary movements and motor deficits. +Spastic diplegia is commoner in preterm babies and is associated with periventricular leukomalacia. The lower limbs are more severely affected with extension and adduction posturing, brisk tendon jerks and contractures. +Spastic hemiplegia is usually recognized after 4-6 months age. Early hand preference, abnormal persistent fisting, abnormal posture or gait disturbance may be the presen­ ting complaint. Vascular insults, porencephaly or cerebral anomalies may be associated. +A thorough screen for associated handicaps and developmental assessment is warranted. + +Hypotonic (Atonic) Cerebral Palsy +Despite pyramidal involvement, these patients are atonic or hypotonic. Tendon reflexes are normal or brisk and Babinski response is positive. They are often severely mentally retarded. In cerebellar involvement, hypotonia is not associated with exaggerated reflexes. Muscles may show fiber disproportion and delayed CNS maturation is common. + +Extrapyramldal CP +This form accounts for 30% of cases. The clinical manifes­ tations include athetosis, choreiform movements, dystonia, tremors and rigidity. Arms, leg, neck and trunk may be involved. Mental retardation and hearing deficits may be present. High tone audiometry should be performed. Cerebral damage following bilirubin ence-phalopathy is one of the causes. + +Cerebellar Involvement +This form is seen in less than 5% of the patients. There is hypotonia and hyporeflexia. Ataxia and intention tremors appear by the age of 2 yr. Nystagmus is unusual; mental status may be near normal in some of these patients. + +Mixed Type +A proportion of the patients have features of diffuse neurological involvement of the mixed type. + + +Severity of Lesion +Mild cases of cerebral palsy are ambulatory; these account for only 20% of patients. Moderately involved patients achieve ambulation by help, may be treated at outpatient level and include 50% of the patients. Severely affected children and those with multiple deficits account for the remainder. + +Evaluation +Eyes. Nearly half of the patients have strabismus, paralysis of gaze, cataracts, coloboma, retrolental fibroplasia, perceptual and refractive errors. +Ears. Partial or complete loss of hearing is usual in kernicterus. Brain damage due to rubella may be followed by receptive auditory aphasia. +Speech. Aphasia, dysarthria and dyslalia are common among dyskinetic individuals. +Sensory dfects. Astereognosis and spatial disorientation are seen in one-third of the patients. +Seizures. Spastic patients usually have generalized or focal tonic seizures. Seizures are more common in disorders acquired postnatally. These patients respond poorly to antiepileptic agents. Electroencephalograms show gross abnormalities. +Intelligence. About a quarter of the children may have borderline intelligence (IQ 80-100); and about half of them are severely mentally retarded. +Miscellaneous. Inadequate thermoregulation and problems of social and emotional adjustment are present in many cases. These children may have associated dental defects and are more susceptible to infections. + +Diagnosis +The diagnosis of cerebral palsy should be suspected in a child with low birthweight and perinatal insult; clinically has an increased tone, feeding difficulties and global development delay. Abnormalities of tone posture, involuntary movements and neurological deficits should be recorded. Evaluation includes perinatal history, detailed neurological and developmental examination and assessment of language and learning disabilities. Inborn errors of metabolism may need to be excluded by screening of the plasma aminoacids and urine organic acid, reducing substance. CT and MRI help delineate the extent of cerebral damage in a case of cerebral palsy. + +Dlfferentlal Diagnosis +Neurodegenerative disorders. Progressively increasing symptoms, familial pattern of disease, consanguinity, specific constellation of symptoms and signs are usual clues for neurometabolic disorders. Failure to thrive, vomiting, seizures are significant symptoms. Laboratory investigations are necessary. +Central Nervous System - + + + +Hydrocephalus and subdural efusion. Head size is large, fontanel may bulge and sutures may separate. +Brain tumors or space occupying lesions. Lesion is progressive and features of increased intracranial pressure are evident. +Muscle disorders. Congenital myopathies and muscular dystrophies can mimic cerebral palsy. Distribution of muscle weakness and other features is characteristic, hypotonia is associated with diminished reflexes. The enzyme creatine phosphokinase may be elevated. EMC and muscle biopsy are diagnostic. +Ataxia-telangiectasia. Ataxia may appear before the ocular telangiectasia are evident. + +Prevention +Prevention of maternal infection, fetal or perinatal insults, good maternal and neonatal care reduces prevalence. Early diagnosis, prompt adequate management plans can reduce the residual neurological and psychosocial emotional handicaps for the child and his family. + +Management +The management plan should be holistic, involve the family and be directed to severity, type of neurological deficits and associated problems. Stress on improving posture, reducing tone, preventing contractures and early stimulation is necessary. Identification of associated deficits is important for appropriate physiotherapy and occupational therapy. Symptomatic treatment is prescribed for seizures. Tranquilizers are administered for behavior disturbances and muscle relaxants may be used for improv­ ing muscle function. Baclofen and tizanidine help to reduce spasticity. Diazepam may ameliorate spasticity and athetosis. Dantrolene sodium helps in relaxation of skeletal muscles. Dynamic contractures can be managed with botulinum toxin injection or alternatively nerve block with phenol. Plastic orthoses may help to prevent contractures, surgical procedures for spasticity and contractures may be required in selected patients. +Occupational therapy. The beginning is made with simple movements of self-help in feeding and dressing with progressive development of more intricate activities like typing. +Educational. The defects of vision, perception, speech and learning are managed by adequate special education experiences. + +Orthopedic support. Tendon, muscle and bony surgeries may be required. Light weight splints may be required for tight tendo-Achilles and cortical thumb. +Social. The family should be given social and emotional support to help it to live with the child's handicap. +Rehabilitation and vocational guidance. Parents should help the child to adjust in the society and if possible to become + + +independent by proper vocational guidance and rehabili­ tation. Severe handicapped children may need to be institutionalized. + +Suggested Reading +Anttila H, Autti-Ramii I, Suoranta L et al. Effectiveness of physical therapy interventions for children with cerebral palsy: a systematic review.BMC Pediatr 2008;8:14 +Game E, Dolk H, Krageloh-Mann I, et al. SCPE Collaborative Group. Cerebral palsy and congenital malformations.Eur J Paediatr Neural 2008;12:82-8 +Jones MW, Morgan E, Shelton JE. Primary care of the child with cerebral palsy: a review of systems (part ll).J Pediatr Health Care 2007;21:226-37 +Rosenbaum P. Cerebral palsy: what parents and doctors wa11t to know. BMJ 2003;326:970-4 + +DEGENERATIVE BRAIN DISORDERS +A wide variety of hereditary and acquired disorders cause progressive degeneration of the central nervous system. In these disorders, new developmental skills are not achieved. As the disease advances, skills already acquired may also be lost. The degeneration may primarily involve the gray or white matter, resulting in corresponding clinical profile. +Late cases may have common features. A fluctuant course with recurrent seizures, mental deterioration, failure to thrive, infections, abnormal urine odor, skin and hair changes may point to inborn errors of metabolism. Some comm.on causes of neurodegeneration are described below. + +Infantile Gaucher Disease (Type II) +It is a metabolic disorder with autosomal recessive inheritance. The lysosomal enzyme glucocerebroside beta­ glucosidase is deficient. Glucocerebroside accumulates in various tissues. Foamy reticulum cells are present in the bone marrow. Acid phosphatase is raised in the blood and tissues. The deficient enzyme can be identified in leukocytes/ fibroblasts. Mortality occurs within first 3 yr of age. Clinically, these children show a characteristic triad of retroflexed head, trismus and squint. They may show hypertonia, marked feeding problems, vomiting and dysphagia. Splenomegaly and hepatomegaly are observed later. Enzyme replacement has been tried for juvenile and adult forms of this disease. + +Tay-Sachs Disease (GM2 Gangllosldosls) +Inheritance is autosomal recessive. A history of consan­ guinity is usually obtained. It was earlier reported in Ashkenazi Jews but has been reported in other racial groups also. Low serum beta-hexosaminidase level is the characteristic metabolic defect. As a result GM2 ganglio­ side accumulates in the neurons. Initially, milestones are delayed. Later, there is regression of development and death occurs by 2 to 4 yr. The baby has an abnormal startle response to noise. Convulsions, rigidity of the extensor +- E.;.;;,.:ial ;.P:.:.:.:.:.:;._______________________________ +.; +:; +ss +e +n +t +,: +;. +. +e +d +ia +t +r +i +c +s + + +group of muscles and blindness supervene after the first year. +A cherry-red spot is seen over the macular region of the retina. The head size increases. Liver and spleen are not enlarged. Sandhoff disease is described in non-Jewish people. It resembles Tay-Sachs disease clinically except for later onset, mild visceromegaly and progressive ataxia. Both hexosominidase A and B are deficient. These cases may show congestive heart failure and enlarged liver. + +Metachromatic Leukodystrophy +Inheritance is autosomal recessive and the gene is located on chromosome 22. The characteristic metabolic defect is decreased urinary or leukocyte aryl sulphatase A activity. Clinically, the illness manifests as ataxia, stiffness starting in the second year of life. A little later, signs of bulbar involvement and intellectual deterioration are observed. Initially there is hypotonia, but later spasticity supervenes. Characteristically, distal tendon reflexes are lost due to associated peripheral neuropathy. Progressive intellectual impairment, optic atrophy and loss of speech develop in the course of illness. Convulsions may occur in some cases. CT scan and MRI reveal abnormal white matter finger like projections, sural nerve biopsy may reveal metachromatic granules and the enzyme arylsulfatase A is low. + +Mucopolysaccharidoses +Group of disorders with autosomal recessive inheritance, Hurler syndrome is most common and is characterized by deficiency of L-iduronidase. Heparan and dermatan sulphate excretion in the urine is increased. Delayed milestones become apparent by the age of 1 yr. The facies is coarse. The child appears a dwarf with gibbus at the level of Ll vertebra. Liver and spleen are enlarged. Hands are short and stubby. Deafness, haziness of cornea and valvar heart disease may be there. + +Subacute Sclerosing Panencephalitis +This condition is believed to follow several months to years after an attack of measles. The usual age of onset is between 5 and 15 yr. In the early stages, minor personality changes may be observed and school performance deteriorates. Later, slow myoclonic jerks in the limbs and trunk are observed. Progressive neurologic deterioration occurs. Electroencephalogram shows stereotyped periodic slow waves with high voltage and a burst suppression pattern. Diagnosis is established by raised measles antibody titer in serum (�1:256) and/ or cerebrospinal fluid (�1:4). + +MENTAL RETARDATION +Mental retardation is defined as subaverage general intelligence, manifesting during early developmental period. The child has diminished learning capacity and does not adjust well socially. + + +Grades of Mental Handicap +Intellect comprises perception, memory, recognition, conceptualization, convergent and divergent reasoning verbal facility and motor competence. Intelligence tests devised to measure different parameters of intelligence in the different age groups include the following: +Gesell's developmental schedules, Bayley Infant Scales, Griffith's Mental Development Scale, Wechsler Preschool and Primary Scale of Intelligence (WPPSI), Wechsler Intelligence Scale for Children (WISC), Stanford-Binet Tests (Terman-Merrill revision), Raven's Matrices, Denver II Development Screening Test, Good enough Draw-a­ man Test, Adaptive Behavior Scale, DEPI and II. +Indian adaptations of some of these are: Kulshrestha or Karnath adaptations of the Stanford-Binet test, Phatak adaptation of the Bayley Scales, Malin's adaptation of the WISC, Vineland Social Maturity Scale and Bhatia's Battery of Performance Tests. +The intelligence quotient (IQ) is calculated according to the formula: mental age divided by chronological age, multiplied by 100. +The degree of mental handicap is designated mild, moderate, severe and profound, for IQ levels of 51-70, 36-50, 21-35 and 0-20, respectively. An IQ level of 71 to 90 is designated borderline intelligence and is not included in mental handicap. The terms educable and trainable are used for mild and moderate mental handicap, respectively, while the severe and profoundly handicapped are designated custodian. However, all levels of mentally retarded children are educable and trainable to some extent. + +Prevalence +In the general population, 2 to 3% of children have an IQ below 70. Nearly three-fourths of such cases are mildly handicapped. About 4 per 1,000 (or 0.4%) of the general population are more severely handicapped with an IQ below 50. + +Etiology +It is difficult to incriminate a single factor in etiology of mild mental retardation. Majority of cases are idiopathic. In moderate to severe mental retardation the cause is easier to identify (Table 18.10). + +Predisposing Factors +Low socioeconomic strata. These children are exposed to several environmental causes of mental handicap, such as inadequate nutrition of mother and child, poor antenatal and obstetric care, lack of immunization, delayed and inappropriate treatment of infections, and unsatis­ factory environmental stimulation. +Low birthweight. The small for gestational age infant has a poorer longterm prognosis for postnatal development than preterm infants of equal weight, who are appropriate for gestational age. However, even the preterm infant is +Central Nervous System - + + + +Table 18.10: Etiology of mental retardation +Chromosomal disorders: Trisomies 21, 18, 13; Klinefelter syndrome +Genetic syndromes: Fragile X, Prader-Willi syndrome, tuberous sclerosis +Inborn errors of metabolism: Phenylketonuria, Tay-Sachs disease, mucopolysaccharidoses, galactosemia, organic acidemias +Congenital infections: HIV, toxoplasmosis, rubella, CMV, syphilis, herpes simplex +Perinatal causes: Hypoxic ischemic encephalopathy, intra­ ventricular hemorrhage, periventricular leukomalacia, fetal alcohol syndrome +Postnatal causes: Trauma, meningitis, hypoglycemia, kernicterus, thrombosis of cerebral vessels +Iodine deficiency +Developmental defects: Microcephaly, craniostenosis, porence­ phaly, cerebral migration defects + +at risk for cerebral hemorrhage, anoxia and infections. The small for gestational age infant is subjected to adverse genetic or prenatal environmental influences, which may occasionally result in brain damage. +Advanced maternal age. Chromosomal anomalies such as Down syndrome as well as intrauterine factors, such as fetal deprivation and hypoxia are commoner in offspring of older mothers. Birth trauma is frequent in the infant of the older prnipara. +Consanguinity of parents is associated with a high incidence of genetically transmitted mental handicap. + +Clinical Features +The mental age is below the chronological age. Most of them present with the behavior syndrome of cerebral dysfunction, such as hyperactivity, short span of attention, distractibility, poor concentration, poor memory, impulsiveness, awkward clumsy movements, disturbed sleep, emotional instability, frustration, low tolerance and wide scatter in intellectual function. +Associated defects of the musculoskeletal system, of vision, or speech and hearing are often found in mentally handicapped children. Congenital anomalies of other systems, apart from the neurological system, may be associated. Convulsions are common in the mentally handicapped. +History should include developmental and family history. A complete physical examination will usually help in the diagnosis. It should include an examination of the fundus and a developmental assessment. +Additional investigations are necessary in some cases, depending on the probable diagnosis. These include urine tests (chromatography and screening for phenylketonuria, homocystinuria and galactosemia) and chromosomal studies, where indicated. Appropriate tests are required + +to diagnose hypothyroidism, storage disorders and intrauterine infections. Computerized tomography and MRI helps define hydrocephalus, porencephaly, absence of corpus callum, tuberous sclerosis and migration defects. + +Prevention +Genetic counseling. The risk of disorders with autosomal recessive inheritance is high in consanguineous marriages. Parents should be counseled about the risk of recurrence in inherited neurometabolic disorders. Mothers older than 35 yr should be screened for Down syndrome during pregnancy. +Vaccination of girls with rubella vaccine should be encouraged to prevent fetal rubella syndrome. During pregnancy, good antenatal care and avoidance of teratogens should be emphasized. Mothers should be protected from contact with patients suffering from viral diseases. When indicated, amniocentesis may be done for study of amniotic fluid for tissue culture, chromosome studies, alpha-fetoprotein and enzyme for prenatal diagnosis. During labor, good obstetric and postnatal supervision is essential to prevent occurrence of birth asphyxia, injuries, jaundice and sepsis. +Postnatally, neonatal infections should be diagnosed and treated promptly. Hyperbilirubinemia should be managed with phototherapy and/ or exchange transfusion. Cretinism and galactosemia, if diagnosed and treated in early infancy, have a satisfactory prognosis. Screening of newborn infants by tandem mass spectroscopy helps to diagnose metabolic disorders such as phenylketonuria, +biotinidase deficiency, organic aciduria, hypothyroidism and +homocystinuria, permits early treatment thereby averting irreversible brain damage. + +Management +The parents should be counseled together. The diagnosis, principles of early stimulation and management should be explained, emphasizing the prognosis. Parental guilt and the home situation should be discussed. Minimal criticism and high appreciation, short-term goals and structured learning results in less withdrawal, aggressive and hostile reactions. +Associated diseases and dysfunctions, e.g. of musculo­ skeletal system, vision, hearing, locomotion and feeding should be appropriately managed. Anticonvulsive medications such as phenobarbitone should be avoided. Patients with hyperactivity often respond to amphetamines including methylphenidate. +Institutionalization should be avoided. Day care centers and schools, integrated schools, vocational training centers, sheltered farms and workshops are useful. Classes should be taken to educate mothers and families in caring for the handicapped and in trying to develop their potential to the maximum, in an effort to make these children as independent as possible. +__ s_s__e_a_i_P_e_d _______________________________ +_a_tr- +i +c_ +s +_ +i +n +__t +i +E + +Suggested Reading +McDonald L, Rennie A, Tolmie Let al. Investigation of global developmental delay. Arch Dis Child 2006;91:701-5 +Moeschler JB. Genetic evaluation of intellectual disabilities. Semin Pediatr Neurol 2008;15:2-9 +Shevell M, Ashwal S, Donley D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology 2003 11;60:367 + + +NEUROCUTANEOUS SYNDROMES + +There are five major neurocutaneous syndromes, viz. (i) neurofibromatosis; (ii) tuberous sclerosis; (iii) von Hippel-Landau disease; (iv) Sturge-Weber syndrome; and (v) ataxia telangiectasia. All of these are inherited disorders except for Sturge-Weber syndrome. Clinical profile of these syndromes is diverse, varying from the mild abortive forms to severe potentially fatal disorders. + +Neurofibromatosis +Inheritance is autosomal dominant. There are two types: type NFl (von Recklinghausen disease or peripheral NFl) and type NF2 (central neurofibromatosis). Deletion or inactivation of the NF gene on chromosome 17 is responsible for NFl. Gene for NF2 is located on chromo­ some 22. + +NFl. Two or more of the following are present: (i) six or more cafe au lait spots, each over 5 mm in diameter before puberty or over 15 mm diameter in older persons; (ii) two or more neurofibromas or one plexiforrn neuroma; (iii) freckling in axillary or inguinal regions; (iv) optic glioma; (v) two or more Lisch nodules; dysplasia of the sphenoid bone or thinning of the cortex of long bones with or without pseudoarthrosis; and (vi) a first degree relative with NFl. +NF2. Presence of bilateral auditory neuroma; unilateral auditory neuroma along with a first degree relative with meningioma, schwannoma or juvenile posterior sub­ capsular lenticular opacity. +Management. Management comprises supportive care, surveillance for and treatment of new manifestations and +surgical management of spinal deformities. Genetic counseling is necessary. +Tuberous Sclerosis Complex +Tuberous sclerosis is an autosomal dominantly neuro­ cutaneous disorder. The presenting features vary with age. Cardinal features are skin lesions, convulsion and mental retardation. Early skin lesions are hypopigmented, ash leaf shaped macules (Fig. 18.11), red or pink papules (angiofibromas) called adenoma sebaceum on face. These enlarge with age. Other lesions are shagreen patches, sub­ +ungual fibromas and gingival fibromas. Retinal + + + + +Fig. 18,11: Facial skin showing multiple ash leaf spots in a child with tuberous sclerosis + +hamartoma may be present. In early life tumors in heart and kidneys may be detected on ultrasonography. Myoclonic jerks often lead to detection of this entity and are an important cause of West syndrome. Vigabatrin is a useful medication. + +Sturge-Weber Syndrome +Sturge-Weber syndrome is characterized by facial nevus flammens (usually in the distribution of first branch of trigeminal nerve but not limited to it), contralateral focal seizures, calcification of the cortex and subcortical struc­ tures and glaucoma on the same side as the skin lesions. Early surgery is recommended in symptomatic cases. + +von Hippel-Lindau Disease +In this disorder, there are retinal and cerebellar hemangio­ blastomas besides spinal cord angiomas and cystic tumors of pancreas, kidneys and epididymis. Patients may show nystagmus, ataxia and increased intracranial pressure. + +Ataxia-Telangiectasia +It is an autosomal recessively inherited disease that has been mapped to chromosome llq. The syndrome manifests with progressive cerebellar ataxia, oculocutaneous telangiectasia, choreoathetosis, pulmonary and sinus infections, immune deficiency and lymphoreticular malignancies. Telangiectasia appears by 2-7 yr on bulbar conjunctiva and even skin. Increased incidence of abnormal movements, vitiligo, abnormal glucose tolerance are observed. Investigations reveal decreased serum IgA in three-fourths of the patients. Alpha-fetoprotein is almost universally elevated. Treatment is symptomatic. + +Suggested Reading +Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis l.J Med Genet 2007;44:81-8 +Leung AK, Robson WL. Tuberous sclerosis complex: a review. J Pediatr Health Care 2007;21:108-14 + +Neuromuscular Disorders + + + + + + + +Sheffali Gulati + + + + + + + +A motor unit comprises one anterior horn cell and all the muscle fibers that it innervates. Neuromuscular disorders may be due to lesions anywhere along the motor unit. These include neuronopathies (primary disorders of ante­ rior horn cell), neuropathies (primary disorders of axon or its myelin), neuromuscular junction disorders and myo­ pathies (primary disorders of muscle). A careful history and physical examination help in localizing the disorder within the motor unit. + +APPROACH TO EVALUATION +The predominant presenting complaint of a patient with a neuromuscular disorder is weakness. Weakness may also result from disorders of the upper motor neuron, e.g. cerebral palsy. Weakness due to an upper motor neuron lesion is associated with increased tone, brisk reflexes and extensor plantar responses. Additional features that suggest central nervous system involvement include seizures and cognitive impairment. +Lower motor neuron lesions are associated with signi­ ficant weakness, hypotonia, depressed reflexes and flexor plantar responses. Anterior horn cell involvement (e.g. spinal muscular atrophy) is associated with wasting, fasciculations and hyporeflexia. Peripheral nerve involvement (e.g. hereditary sensory and motor neuro­ pathies) is associated with predominantly distal weakness, distal wasting, hyporeflexia and sensory involvement. Neuromuscular junction involvement (e.g. myasthenia gravis) classically leads to fatigable and fluctuating weakness. Muscle diseases (e.g. muscular dystrophies) are associated with proximal weakness and relatively preserved bulk and reflexes. The mode of inheritance is variable, e.g. X-linked recessive in Duchenne muscular dystrophy and Becker muscular dystrophy; autosomal dominant in facioscapulohumeral dystrophy; and autosomal recessive in sarcoglycanopathies and congenital muscular dystrophies. + +The presentation and pattern of disease over time allows definition of possible conditions. For example, muscular dystrophy is associated with inexorable weak­ ness. Metabolic disease and ion channelopathies (periodic paralysis) are associated with episodic course. Inflam­ matory disorders such as dermatomyositis are associated with waxing and waning course and pain. Cardiac disease often accompanies Duchenne muscular dystrophy and myotonic dystrophy. Skin rash is seen in dermato­ myositis, while eye involvement is noted in myotonic dystrophy, congenital muscular dystrophies and mito­ chondrial diseases. Liver involvement may be seen with mitochondrial disorders, acid maltase deficiency and carnitine deficiency. + +Laboratory Evaluation +Creatine phosphokinase (CPK), a muscle enzyme, is elevated in most muscular dystrophies. Muscle biopsy is a frequently performed test that enables diagnosis based on specific morphological features, immunohisto­ chemistry (absent or reduced staining for specific protein) and enzyme histochemistry (absent or reduced enzyme function). Electrophysiological tests, including nerve conduction studies and electromyography, help localize the lesion and assess its severity. +Other diagnostic tests include nerve biopsy, antibody testing (e.g. acetylcholine receptor antibodies in myas­ thenia gravis). Molecular genetic testing is now available for many neuromuscular disorders (spinal muscular atrophy and Duchenne muscular dystrophy). + +Suggested Reading +Steven A, Greenberg, Walsh RJ. Molecular diagnosis of inheritable neuromuscular disorders. Part I: Genetic determinants of inherited disease and their laboratory detection. Muscle Nerve 2005;31:418-30 +Steven A, Greenberg, Walsh RJ. Molecular diagnosis of inheritable neuromuscular disorders. Part II: Application of genetic testing in neuromuscular disease. Muscle Nerve 2005;31:431-51 + + +587 +___E_s_s_ _ t_ i_ i_ _ _e_d_ia_ t_r_ic_ __________________________________ +P +n +e +a +s +_ + + +Hypotonia +Hypotonia is a common sign of neuromuscular disorders. Any lesion along the motor unit can result in peripheral hypotonia, characterized by depressed muscle stretch reflexes and loss of muscle power. The common causes of floppiness in infancy are shown in Fig. 19.l. Hypotonia in utero may result in hip dislocation or multiple contrac­ tures (arthrogn;posis). The mother may give a history of reduced fetal movements or polyhydramnios. +An alert hypotonic infant with absent deep tendon reflexes, predominantly distal movements and fasci­ culations is the typical phenotype of spinal muscular atrophy. Neuropathies usually present later in childhood. Atrophy out of proportion to weakness, depressed or absent reflexes and predominantly distal weakness sug­ gests a nerve disorder. Fatigability, ptosis, proximal mus­ cle weakness and history of myasthenia gravis in the mother may indicate an underlying neuromuscular junc­ tion disorder. Predominantly proximal muscle weakness, normal or depressed tendon reflexes and static or impro­ ving course may indicate a muscle disease. Deep tendon reflexes are preserved in muscle disease or if reduced, are in proportion to the degree of muscle wasting and weak­ ness. Atrophy is less prominent in muscle disorders. +Central hypotonia is characterized by preserved muscle power and normal or brisk deep tendon reflexes. Some­ times a child may display features of both central and peripheral hypotonia; common causes of mixed hypotonia include hypothyroidism, motor unit disorders with + + + + + + + + + +Infections +Sepsis/Meningitis; intrauterine infections + + + +P eripheral Hypotonia + +Nerve +Charcot-Marie-Tooth disease Congenital hypomyelinating neuropathy Giant axonal neuropathy + + + +Neuromuscular junction Congenital myasthenia Transitory myasthenia Botulism + +superimposed hypoxia, acid maltase deficiency, mito­ chondrial disorders and infantile neuronal degeneration. + +Muscle Weakness in Older Children +Distal weakness is predominantly seen in neuropathies and some muscle disorders like myotonic dystrophy. Proximal weakness has broad differential diagnosis. The child may complain of difficulty in rising from the chair, going up and down the stairs or reaching with their arms. A clinical approach to a child to proximal weakness is summarized in Fig. 19.2. Some disorders such as chronic +inflammatory demyelinating polyneuropathy (CIDP) and +certain muscular dystrophies show both proximal and distal weakness. + +DISORDERS AFFECTING ANTERIOR HORN CELLS +Spinal muscular atrophy and poliomyelitis are the two most common anterior horn cell disorders encountered in children. Besides these, other enteroviruses (e.g. coxsa­ ckievirus and echovirus), juvenile form of amyotrophic lateral sclerosis and neurometabolic disorders like Tay­ Sach disease, neuronal ceroid lipofuscinosis and Pompe disease may also involve anterior horn cells. + +Spinal Muscular Atrophy +This is an autosomal recessive disease caused by muta­ tional in the SMN 1 gene, encoding the SMN protein essential for survival of anterior motor horn cells. Three clinical types are recognized. Patients with type 1 disease + + + + + +Neurometabolic condition Acid maltase deficiency Biotinidase deficiency GM1/GM2 gangliosidosis Lowe syndrome Peroxisomal disorders Familial dysautonomia + +Benign congenital hypotonia + + + + + +Anterior horn cell Spinal muscular atrophy + + + + +Muscle +Congenital myopathies Congenital muscular dystrophy + +Fig. 19.1: Common etiologies of 'floppy infant'. Maintenance of normal tone requires an intact central and peripheral nervous system +Neuromuscular Disorders - +yp + + ++ + Proximal muscle weakness _ +� +- +�-.-� +. +! +- +! +- +Absent deep tendon reflexes Progressive disorder Reduced or absent Ptosis Fasciculations ± calf hypertrophy deep tendon reflexes Ophthalmoplegia +I +Tremors Contractures Fatigability +I Static course Facial weakness Diurnal variation Static course + +Muscular dystrophy Myopathy Neuromuscular junction ++_ ( disorders +r Rash 1 �mic fin� +- +Systemic features J Episodic worsening1 + +Inflammatory myopathy Metabolic myopathy + +Fig. 19.2: Clinical approach to a child with proximal muscle weakness + + +(Werdnig-Hoffmann disease) present with profound h otonia, flaccid weakness and global areflexia (Fig. 19.3). Respiratory weakness, poor swallowing and tongue fasciculations are common. These children usually never learn to sit. Aspiration pneumonia is an important cause of morbidity and mortality. Patients with type 2 disease (Dubowitz disease) have onset of illness at 6-18 months of age and are usually able to sit unaided. They may develop kyphoscoliosis, tremors (polyminimyoclonus), poor swallowing and respiratory insufficiency. Patients with type 3 disease (Kugelberg-Welander disease) present later in childhood (>18 months) and are usually able to walk. These children are often misdiagnosed as limb girdle muscular dystrophy or myopathy. Global areflexia, fasciculations, tremors and electrophysiology may give a clue towards underlying anterior horn cell pathology. +Treatment is usually supportive and includes respiratory care, management of problems in feeding and swallowing, + + + + + + + + + + + + + + + +Fig. 19.3: A 5-month-old boy presented with motor delay and repeated chest infections. Examination revealed generalized hypotonia, absent deep tendon reflexes, poor muscle power and tongue fasciculations. Note the 'frog-like' posture and subcostal retractions due to respiratory muscle weakness. A diagnosis of spinal muscular atrophy type 1 was made + + +ensuring adequate nutrition, treatment for gastroeso­ phageal reflux, orthopedic care and rehabilitation, appro­ priate immunization and family education and counseling. Therapeutic agents undergoing evaluation include valproate, gabapentin, aminoglycosides and riluzole. + +Suggested Reading +Lunn MR, Wang CH Spinal muscular atrophy. Lancet 2008; 371:212--33 Wirth B, Brichta L, Hahnen E. Spinal muscular atrophy: from gene to +therapy. Sein Pediatr Neurol 2006;13:121-31 + +PERIPHERAL NEUROPATHIES +Most neuropathies are chronic. Guillain-Barre syndrome is the most common cause of acute neuropathy. A clinical approach to a child with suspected peripheral neuropathy is shown in Fig. 19.4. The clinical presentation, electro­ physiological characteristics and ancillary laboratory studies may help narrow down the differential diagnosis in a child with suspected peripheral neuropathy, as discussed below. + +Type of neuropathy. Most neuropathies are primarily axonal. Finding a demyelinating pattern narrows the differential diagnosis. Clinical pointers to a demyelinating process include: (i) presence of global areflexia; (ii) mode­ rate to severe muscle weakness with relative preservation of bulk; (iii) predominantly motor symptoms; and (iv) hypertrophy of nerves. The differentiation between the two types of neuropathy is mainly electrophysio­ logical. Electrophysiologically, demyelination is suggested by: (i) decreased conduction velocity; (ii) prolonged distal latencies and late responses; (iii) asymmetry; (iv) presence of conduction block; and (v) abnormal temporal disper­ sion (suggesting an acquired process). Axonal disorders show decreased compound muscle action potentials with preserved conduction velocity and distal latencies. + +Pattern of neuropathy. Most polyneuropathies show distal­ to-proximal gradient of symptoms and signs ('length +-._E_ss i l __P_a __irc ---------------------------------- +n +t +_ +___ _ +e a +__ +s +e +_id +_ +t + + +Suspected peripheral neuropathy + + +t Demyelinating +-i +I +---- + + +---*---.. Hereditary -*---' Mononeuropathy J �mmetric with Polyneuropathy AIDP orCIDP Charcot-Marie-Tooth +tern +! +� +_ +I +stepwise involvement +progression ( of 22 nerves) +-i +I +Acquired +Diphtheria disease 1 and 3 Mono euritis multiplex +, +Toxic, e.g. arsenic Metachromatic ! +leukodystrophy � +Krabbe'disease Trauma Vasculitis Guillain-Barre syndrome +Adrenoleukodystrophy +Focal compression Leprosy Charcot-Marie-Tooth disease type2 Entrapment Leukemia, lymphoma Human immunodeficiency virus +Porphyria Deficiency of vitamin 612 or E Cryoglobulinemia Induced by chemotherapy +Porphyria Diabetes + +Fig. 19.4: Approach to peripheral neuropathies in childhood. Mononeuritis multiplex refers to the involvement of multiple separate non­ contiguous peripheral nerves, either simultaneously or serially. AIDP acute inflammatory demyelinating polyneuropathy; CIDP chronic inflammatory demyelinating polyneuropathy + + +dependent' or'dying back' pattern). More proximal nerves may be involved rarely, e.g. inflammatory demyelinating polyneuropathy and porphyria. The presence of asym­ metry and a stepwise progression may point towards mononeuritis multiplex. Mononeuropathies are rarely encountered in pediatric practice and are usually due to trauma, focal compression or entrapment. +Typeofnervefiberinvolved.Neuropathiesthatpredoinantly affect large fibers result in sensory deficits (impaired touch or vibration), weakness and loss of deep tendon reflexes. Small fiber neuropathies present with distal sensory deficit, painful buing dysesthesias and autonomic dysfunction. Pure sensory neuropathies are unusual. + +Hereditary Neuropathy +A slowly progressive course, prominent sensory signs in absence of sensory symptoms, foot deformities and a family history point towards an inherited neuropathy. The hereditary neuropathies encountered in children are listed in Table 19.1. Charcot-Marie-Tooth disease is the most common hereditary neuropathy, and the most common peripheral neuropathy in children. +The phenotype of a child with Charcot-Marie-Tooth disease consists of distal weakness and wasting, especially of the peroneal compartment ('stork leg' appearance; Fig. 19.5), some distal sensory impairment, skeletal deformities, contractures and diminished or absent deep tendon reflexes. The clinical features, electrophysiological characteristics, inheritance pattern and, occasionally, features on nerve biopsy, suggest a specific hereditary neuropathy and guide further evaluation. + +Guillain-Barre Syndrome +This is a common cause of acute flaccid paralysis (AFP) in children. It is an immune-mediated, rapidly progressive, predominantly motor, symmetric polyradiculoneuropathy that often leads to bulbar and respiratory compromise. Many subtypes are described and include acute inflam­ matory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor and sensory neuropathy, acute sensory neuropathy, acute pan­ dysautonomia and the Miller Fisher syndrome. +The condition can occur at any age. About two-thirds patients have an antecedent infection within 6 weeks prior + + +Table 19.1: Hereditary neuropathies +Primary disease +Charcot-Marie-Tooth disease +Hereditary neuropathy with liability to pressure palsies Hereditary sensory and autonomic neuropathies +Distal hereditary motor neuropathies Hereditary neuralgic amyotrophy Familial amyloid polyneuropathy +Multisystem disorder +Lipid metabolism Leukodystrophies +Phytanic acid storage disorder Sphingomyelin lipidoses Porphyria +Dfective DNA repair: Ataxia-telangiectasia, xeroderma pigmentosa +Hereditary ataxias: Friedrich ataxia, spinocerebellar ataxia Miscellaneous: Neuroacanthocytosis, mitochondrial disorders +Neuromuscular Disorders - + + + + + + + + + + + + + + + + + + + + + + + + + + + + +Figs 19,SA and B: A 7-yr-old boy presented with progressive gait difficulties, frequent twisting of ankles, foot deformities and progressive thinning of legs. Examination revealed distal weakness and wasting, absent ankle reflexes and enlarged common peroneal nerves. (A) Note the 'stork leg' appearance of legs with foot deformities; and (B) hand deformities. A diagnosis of Charcot-Marie-Tooth disease was made + +to symptom onset, generally an upper respiratory tract infection or gastroenteritis. The clinical manifestations include acute onset of symmetrical ascending weakness that is both proximal and distal. Facial weakness is fre­ quent, and involvement of respiratory muscles occurs in one-fourth cases. Dysautonomia is common and is sugges­ ted by tachycardia, arrhythmia, ileus, bladder dysfunction, labile blood pressure and impaired thermoregulation. The weakness usually reaches a nadir 2-4 weeks after onset of symptoms and is followed by gradual recovery over weeks to months. The illness is usually monophasic but 7-16% patients may suffer from recurrent episodes of worsening after an initial improvement. As compared to demyelinating forms, the axonal form of Guillain-Barre syndrome exhibits a more rapid and severe course, with frequent involvement of respiratory muscles and cranial nerves and infrequent and mild involvement of the autonomic nervous system. The Miller Fisher syndrome is characterized by the triad of ophthalmologica1 abnor­ malities, ataxia and areflexia. +Diagnosis depends on clinical features, e1ectrophysio­ logical findings and cerebrospinal fluid examination. Electrophysiology may reveal absent F-responses or H-reflexes and reduced compound muscle action potential + +or sensory nerve action potential in axonal forms of the illness. Prolonged distal latencies, reduced conduction velocities, abnormal temporal dispersion and conduction blocks are noted in demyelinating types. The cerebrospinal fluid protein concentration is raised in 80% cases, while mononuclear cell count is either normal (albuminocyto­ logic dissociation) or below 50 cells/mm3. Electrophysio­ logical studies and cerebrospinal fluid analysis may be normal during the first week of the illness. +Immunotherapy is the mainstay of treatment. Intra­ venous immunoglobulin (IVIG, 2 g/kg over 2-5 days) should be administered or plasma exchanges performed if the child presents within 2-4 weeks of onset of symptoms. Such treatment is indicated in nonambulatory patients, but their role in mildly affected patients who are mobile is unclear. Plasma exchanges may hasten recovery compared to supportive treatment alone in adult patients. In patients with severe disease, therapy with IVIG (if initiated within two weeks from onset) hastens recovery as much as plasma exchange and is more likely to be completed than plasma exchange. Further, giving IVIG after plasma exchange did not confer significant extra benefit. Low quality evidence suggests that IVIG probably hastens recovery in children compared with supportive care alone. Information on appropriate therapy is limited for patients with mild disease and in those where treatment starts more than two weeks after onset. Patients who do not respond to initial treatment with IVIG may benefit from a second course of therapy. General supportive care includes cardiorespi­ ratory care, physical therapy, nutritional management, management of neuropathic pain, care of bladder and bowel and prevention of deep vein thrombosis. + +Chronic Inflammatory Demyelinating Polyradiculoneuropathy +This uncommon condition is slowly progressive (>4 weeks) or relapsing and has symmetric proximal and distal weakness in the upper and lower extremities with concomitant sensory loss. Asymmetric forms, distal predominant forms and sensory predominant forms also occur. The minimum duration of symptoms to reach the trough in patients with chronic inflammatory demyelinating polyradiculoneuropathy is 2 months. This helps to distinguish this condition from Guillain-Barre syndrome, which usually evolves in less than 4 weeks. Electro­ physiology and nerve biopsy help in diagnosis. Treatment modalities for chronic inflammatory demyelinating polyradiculoneuropathy include IVIG, plasma exchange and prednisolone. Spontaneous remission of chronic inflammatory demyelinating polyradiculoneuropathy is rare, and most patients require longterm immuno­ modulating therapy. + +Suggested Reading +Hughes RA. Give or take? Intravenous immunoglobulin or plasma exchange for Guillain-Barre syndrome. Crit Care 2011;15(4):174 +_ E_s_es_n_t_ia P_e_dt_r__ __________________________________ +l +_ +i +i +a +c +s +_ + + +Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculo­ neuropathy. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst 2005; 10:220-8 +Vavra MW, Rubin DI. The peripheral neuropathy evaluation in an office based neurlogy setting. Semin Neurol 2011;31:102-4 +Wilrnshurst JM, Ouvrier R. Hereditary peripheral neuropathies of childhood: a brief overview for clinicians. Neurornuscul Disord 2011;21:763-7 + +ACUTE FLACCID PARALYSIS + +Acute flaccid paralysis (AFP) is a clinical syndrome char­ acterized by rapid onset of weakness, progressing to maximum severity within several days to weeks. The term 'flaccid' refers to the absence of spasticity or other upper motor neuron signs. At the 41st World Health Assembly in +May 1988, the resolution to eradicate polio was passed. In + + +The differential diagnosis of acute flaccid paralysis varies considerably with age. The common causes are enumerated in Table 19.2. The differentiating features between the common causes of acute flaccid paralysis are summarized in Table 19.3. +Acute Flaccid Paralysis (AFP) Surveillance +All patients with acute flaccid paralysis should be reported to Surveillance Medical Officer of World Health Organi­ zation. Every case of AFP within the last 6 months has to be reported. Additionally, other conditions which need + +Table 19.2: Differential diagnoses of acute flaccid paralysis +Muscle disorders Inflammatory myopathy Periodic paralysis Hypokalemia +Infections + + + +the Global Polio Eradication Initiative, acute flaccid paralysis is defined as any case of AFP in a child aged <15 yr, or any case of paralytic illness in a person of any age +when polio is suspected. It can result from involvement at any point in the motor unit. Common causes of acute flaccid paralysis include Guillain-Barre syndrome, poliomyelitis, +transverse myelitis, traumatic neuritis, postdiphtheric neuropathy and nonpolio enteroviral illnesses. +Over the last few years the number of cases of polio­ myelitis has been going down. In 2009, there were 741 cases of poliomyelitis and in 2010, there were 42 cases. The last case of confirmed wild poliovirus (Pl type) was +reported from West Bengal in 2011. + + +Neuromuscular junction disorders + +Neuropathies + + + + +Anterior horn cell disorders +Spinal cord disease + + +Myasthenia gravis Botulism +Eaton-Lambert syndrome +Guillain-Barre s.yndrome Traumatic neuritis Postdiphtheric neuropathy Porphyria +Vasculitis +Poliomyelitis +Nonpolio enteroviruses +Transverse myelitis Spinal cord compression Trauma + + +Table 19.3: Differentiating among common causes of acute flaccid paralysis + + +Fever + +Symmetry Sensations + + +Respiratory insufficiency +Cranial nerves + +Radicular signs +Bladder, +bowel complaints Nerve +conduction Cerebrospina I +fluid + + +MRI spine + + +Poliomyelitis + +Present; may be biphasic +Asymmetric Intact; may have +diffuse myalgias + +May be present + +Affected in bulbar and bulbospinal variants +May be present + +Absent + +May be abnormal + +Lymphocytic pleocytosis; normal or increased protein +Usually normal + + +Gui/lain-Barre syndrome + +May have a prodromal illness +Symmetrical Variable + + +May be present + +Usually affected + + +Present + +Transient; due to autonomic dysfunction +Abnormal + +Albumino-cytologic dissociation + + +Usually normal + + +Transverse myelitis + +May have a prodromal illness +Symmetrical Impaired below the +level of the lesion + +May be present + +Absent + + +Absent + +Present + +Normal + +Variable + + + +Characteristic* + +Traumatic neuritis + +Absent + +Asymmetric +May be impaired in distribution of the affected nerve +Absent + +Absent + + +Absent + +Absent + +Abnormal + +Normal + + + +Normal + + +* Local enlargement of the spinal cord and increased signal intensity over several spinaJ segments +___ _s_s__n_t ai_1_P__dai t_rics _______________________________ +e +E +e +_ +_ +_ +_ +_ + +Transitory neonatal myasthenia may occur in about 15% of babies born to myasthenic mothers. Symptoms usually start within few hours afterbirth but may be delayed till the third day. These include difficulty in feeding, weak cry, hypotonia, lack of facial expression and respiratory insufficiency. Supportive care suffices in majority of the cases. Oral or intramuscular pyridostigmine, usually for 4-6 weeks, may be warranted in severe cases. +Edrophonium testing is usually the first test performed in a suspected case of myasthenia gravis. The dose used is 0.1-0.2 mg/kg [may be repeated every minute to a total maximum dose of 5 mg (weight <34 kg) or 10 mg (weight >34 kg)]. Effects are seen within 10 seconds and persist till 120 seconds. A positive result consists of transient resolution of the clinical sign (ptosis/ophthalmoplegia/ dysarthria) under observation. Edrophonium is not recom­ mended for use in infants due to high risk of arrhythmias and short duration of action which precludes objective assessment. Neostigmine can be used as a diagnostic test by intramuscular injection. The dose used is 0.125 mg/kg in an infant and 0.04 mg/kg in an older child. It is slower in action, with anticipated response in 10-15 min and maximum in 30 min (Fig. 19.6). If the result is equivocal or negative, the dose may be repeated in 4 hr. +Repetitive nerve stimulation studies are abnormal in 50-70% cases with generalized myasthenia gravis. A decrement of > 10% is characteristic. Electromyography may be normal or may show unstable or myopathic muscle unit action potentials. Single fiber electromyography is more sensitive and may show increased jitter or blocking. +Acetylcholine receptor (AChR) antibodies may be positive in children with myasthenia gravis. The positivity rates are lower in peri-and prepubertal children (50-60%). Antibodies to muscle specific kinase (Anti-MuSK) antibodies may be demonstrable in 40% seronegative + + + + + + + + + + + + + +Figs 19.6A and B: A 9-yr-old boy presented with drooping of eyelids, more in the evening than morning, and restricted eye movements. Examination revealed asymmetric ptosis, external ophthalmoplegia, normal pupils and normal motor examination. Neostigmine challenge test was performed. Note the improvement in ptosis between (A) before and (B) after administration of neostigmine. A diagnosis of juvenile myasthenia gravis was made + + +myasthenia gravis patients. X-ray chest or CT of antt mediastinum may show thymoma or thyrnic hyperpl. + +Congenital Myasthenia Syndromes +The congenital myasthenia syndromes are exception. rare. They should be suspected in seronegative myasthe gravis, floppy infant with underdeveloped muscles anc adults with childhood history of difficulties affecti cranial, respiratory, truncal or limb muscles. Common fE tures include hypotonia, limb weakness, feedi1 difficulties, respiratory difficulties, arthrogryposis, ptosi ophthalmoparesis, dysphagia and dysarthria. The clinic. presentation, electrophysiological features and geneti studies help to differentiate between these subtypes. The. do not respond to steroids and other immunosuppres sants. Conditions like endplate acetylcholinesterast deficiency and slow channel congenital myasthenia may worsen with pyridostigmine. + +Treatment +Cholinesterase inhibitors are usually the initial treatment for myasthenia gravis. Pyridostigmine is commonly used at doses of 1-7 mg/kg/day in 4 divided doses. Oral ste­ roids may also be used in a nonacute setting. Prednisolone is started at low doses (0.5 mg/kg/ day) and titrated according to clinical response. Azathioprine, cyclosporine, cyclophospharnide and mycophenolate mofetil have been used as steroid sparing drugs or for refractory cases. Drugs that interfere with neuromuscular transmission (Table 19.4) should be used with caution. Thymectomy in seropositive patients may be beneficial. +A myasthenic crisis necessitates cardiorespiratory monitoring and support. It should be differentiated from cholinergic crises due to overdosage of acetylcholine esterase inhibitors. Antecedent events, predominance of cholinergic symptoms, ice pack test and edrophonium challenge test may help to differentiate between the two entities. IVIG or plasmapheresis may be required. + +Suggested Reading +Chiang LM, Darras BT, Kang PB. Juvenile myasthenia gravis. Muscle Nerve 2009; 39:423-31 +Finsterer J, Papi-e L, et al. Motor neuron, nerve and neuromuscular junction disease. Curr Opin Neural 2011;24:469-74 +Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence­ based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neural 2012; 78:1009-15 + +MUSCLE DISORDERS Congenital Myopathies +The congenital myopathies are a diverse group of muscle disorders caused by genetic defects in the contractile apparatus of the muscle and defined by distinctive histo­ chemical or ultrastructural changes on muscle biopsy. Majority of these disorders present as 'floppy infant' +Neuromuscular Disorders - + + + +syndrome. The common presenting features include hypotonia, static or non-progressive muscle weakness and normal or decreased deep tendon reflexes. Respiratory insufficiency, feeding difficulties, contractures and 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 teristic morphological features observed on skeletal muscle 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, Goebel HH. 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 X chromosome in the Xp21 region). Duchenne muscular dystrophy is the most common dystrophinopathy with an incidence of 1 in 3500 live male births. Its allelic variant, Becker muscular dystrophy, differs from Duchenne muscular dystrophy by its later age of onset (usually >6 yr of age), later age of wheelchair confinement(> 15 yr), 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 gene can cause Duchenne muscular dystrophy or Becker muscular dystrophy. This is explained by the reading frame hypothesis, which states that mutations that 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 become symptomatic before age of 5 yr and may even have history of delayed walking.Gait disturbances often become apparent at 3-4 yr of age. Waddling gait, Gower sign and calf muscle pseudohypertrophy (Fig. 19.7) are classical findings at this stage. Neck flexor muscle weakness is early. Other muscles to show hypertrophy may be vastus lateralis, infraspinatus, deltoid, gluteus maximus, triceps and masseter. The progression of weakness may plateau between 3 and 6 yr 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 ambulation in untreated Duchenne muscular dystrophy to be between 8.8 and 10.5 yr. After loss of ambulation, there is worsening 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 turnal hypoventilation. 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 + + +Table 19.5: Classification of congenital myopathies + +Congenital myopathy +Structured congenital myopathy +Central core disease Multi-mini-core disease Nemaline myopathy +Centronuclear or myotubular Desminopa thies +Myosin myopathies +Unstructured congenital myopathy +Congenital fiber type disproportion + +Inheritance + + +AD, AR*, sporadic AD,AR +AD, AR, sporadic +X-linked, AD, sporadic AD,AR +AD,AR + + +AD, AR, X-linked + +Histopathology + + +Cores in type I muscle fibers +Both fiber types are poorly defined and with short cores Nemaline bodies on trichrome stain +Central nuclei in all muscle fibers Desmin positive myofibrillar aggregates +Variable, type I fiber predominance, hyaline bodies + + +Type I fiber predominance, small type I fibers + +• Autosomal recessive (AR); Autosomal dominant (AD) +__ _s_s_ n_t_iai_P__d___n_·s __________________________________ +e +ia +t +c +_ +e +e +_ +_ + +cardiomyopathy. Other clinical features of Duchenne muscular dystrophy include variable degree of 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 levels are 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 (MLP A) are commonly employed genetic techniques for detection of mutations. Muscle +biopsy may be required in mutation negative cases and +also to differentiate between these two dystrophinopathies. 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 clinical diagnosis immunohistochenical analysis of the muscle biopsy is usually performed. Absence of dys­ trophin(1, 2 and 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 multidisciplinry 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) are the only therapies proven + +to improve strength and prolong ambulation in children with Duchenne muscular dystrophy. Low dose prednisolone may be started with aim of preserving upper limb strength, reducing progression of scoliosis and delaying the decline in respiratory and cardiac function. Other supportive +management includes pulmonry and cardiac care, 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 in the DMPK +gene located on chromosome 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 history of decreased fetal movements and polyhydramnios in the mother. The serum crea tine kinase levels are variable. Electromyography may show myopathic pattern along with myotonia ('revving engine' sound). Genetic testing is confirmatory. +Treatment is symptomatic and wide range of drugs have been used. Drugs that block sodium channels(procainnide, disopyramide, phenytoin, quinine, mexiletine); tricyclic antidepressants (clomipramine, imipramine); diuretics + + + + + + + + + + + + + + + + + + +Figs 19. 7A and B: A child presented with progressive gait difficulties and lurching gate. Examination revealed proximal muscle weakness, more in the lower limbs, calf hypertrophy and positive Gower sign, leading to a diagnosis of Duchenne muscular dystrophy. (A) Calf pseudohypertrophy is shown; (B) examination in another child shows hypertrophy of deltoid and infraspinatus with wasting of posterior axillary fold muscles ('Valley' sign) +Neuromuscular Disorders - + + + +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 in children with 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, prednisone and beta­ 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 an autosomal dominant fashion. The clinical spectrum is wide ranging from aymptomatic children to wheelchair bound patients. 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 and contractures are rare. Side-to-side asymmetry of muscle weakness is very typical (Fig.19 .8). Extrrnuscular manifestations include high frequency hearing loss, Coats' disease (retinal telangiectasia with exudation and + + + + + + + + + + + + +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 is characterized by slowly progressive muscle wasting and weakness in humeroperoneal distribution, early contrac­ tures especially of elbows, Achilles tendon and postcervical muscles and cardiac conduction defects. Cardiac involve­ ment is the most serious aspect of the disease and may even occur before any significant muscle weakness. X-linked forms, autosomal dominant or recessive forms may 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, Bnkrant 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. Sein Pediatr Neurol 2006;13:104-14 +Wattjes MP, Kley RA, 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 Chapter 21). 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 the onset. In half 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 joints may be discolored and hypertrop1:ic (Gottron papules) (Fig. 19.9). Pruritus may be problematic. Nailfold capillaroscopy may reveal capillary 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 with juvenile dermatomyositis. One needs to examine carefully in a dark-skinned child + +mentation are other adjunctive therapies. Other therapies include intravenous immunoglobulin, cyclosporine, cyclophosphnide, mycophenolate mofetil, rirnab 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 from failed energy production related to defects in glycogen, lipid, or mitochondrial metabolism. The s ptons arise due to a mismatch between the rate of ATP utilization and the capacity of the muscle metabolic pathways to regenerate ATP. Affected older children and adults present primarily with exercise intolerance, weakness i:1d myoglo­ bin uria; 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 iflammatory 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, tandem mass spectrosco 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; part I. Pediatr Neurol 2000;22:87-97 +. . . +Darras BT, Friedman NR. Metabolic myopath1es: A cbrncal approach; part II. Pediatr Neurol 2000; 22: 171-81 + +Childhood Malignancies + + + + + + +Sadhna Shankar, Rachna Seth + + + + + + + +Childhood cancers are a rare but important cause of mor­ bidity and mortality in children younger than 15 yr of age. Malignancies in children are often difficult to detect because the 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 are known to be more aggressive 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 in children. 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 is the most common childhood malignancy accounting 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 ALL associated with a pre-B lineage (referred to 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, there is a 10-20 fold increased risk of leukemia (ALL and AML) in children with Down syndrome. Other genetic +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 (alkylating agents, 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 Genetic Environmen ta/ +Down syndrome Ionizing radiation +Fanconi anemia Alkylating agents (cyclophos­ Shwachman-Diamond phamide, ifosfamide, +syndrome carboplatin, procarbazine) Bloom syndrome Epipodophyllotoxins (etoposide, Ataxia telangiectasia tenoposide) +Diamond-Blackfan Nitrosourea (nitrogen mustard) anemia Benzene +Kostmann syndrome Li-Fraumeni syndrome Severe combined +immune deficiency Paroxysmal nocturnal +hemoglobinuria Neurofibromatosis +type 1 + + +599 +--E.s..e.nti..a•l•P•e•d•i•art. .ic· -------------------------------· +s +- + + +is currently based on rnunophenotyping, karyotyping and molecular biology techniques. ALL cells can be classified using the French-American-British (F AB) 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, accounting for 15% 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 rnunoglobulin 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 ALL constitutes 80-85% ALL, 15% are derived from T cells and 1-2% from mature B cells (Table 20.3). + +ytogeneHcs +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 leukemia is often associated with t(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 rates are higher in 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 associated with other risk factors, including high leukocyte count, mediastinal mass or disease affecting the central nervous system at diagnosis. Patients showing hyper­ diploid y 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 + + +Table 20.2: The French-American-British (FAB) classification for acute lymphoblastic leukemia + +Cytologic features Cell size + +Cytoplasm + +Nucleoli +Nuclear chromatin Nuclear shape Cytoplasmic basophilia +Cytoplasmic vacuolation + + +L1 (80-85%) +Small cells predominate; homogeneous +Scanty + +Small; inconspicuous Homogeneous +Regular; occasional clefts Variable +Variable + +L2 (15%) +Large cells; heterogeneous + +Variable; often moderately abundant +One or more; often large Variable; heterogeneous Irregular clefts; indentation Variable +Variable + + +L3 (1-2%) +Large cells; homogeneous + +Moderately abundant + +One or more; prominent Stippled; homogeneous Regular; oval to round Intensely basophilic +Prominent + + + +Table 20.3: Correlation of subtypes of acute lymphoblastic leukemia with surface markers Type Surface markers Comment + +Precursor B cell + + + +Mature Bcell +T cell + + +CD79a+, CD18+, CD19+, CD20+, HLA DR+ + + +CD19+, CD20+, CD21+, slg+ +CD3+, CD7+, CD2+ or CDS+ + +Presence of CDlO (common ALL antigen, CALLA) +represents a favorable prognosis; absence of CDlO (pro-BALL) is associated with translocations of MLL +gene, particularly t(4;11), and poor outcome Correlates with L3 leukemia; needs intensified regime +Affects older children; associated with leukocytosis, mediastinal mass and involvement of central nervous system + +slg surface immunoglobulin +Childhood Malignancies - + + +Table 20.4: Genetic abnonnalities in acute lymphoblastic leukemia (ALL) + +Chromosomal abnormality +or translocation; affected gene +Hyperdiploidy (>50 chromosomes) Hypodiploidy (<44 chromosomes) Trisomies 4 and 10 +t(12;21)(p13;q22); ETV6 (TEL) and RUNXl (AML1) fusion (hybrid gene) +t(1;19)(q23;p13); TCF3-PBX1 fusion t(4;11)(q21;q23); AF4-MLL fusion t(9;22)(q34;qll.2); ABL1- BCR fusion (Philadelphia +chromosome) +t(8;14)(q23;q32.3); MYC-IgL fusion + +Hox 11 rearrangement +Early T cell precursor phenotype + +Subtype + +Pre-B Pre-B Pre-B Pre-B + +Pre-B Pre-B Pre-B + +Mature B cell + +T T + +Frequency (%) + +20-30 1-2 20-25 15-25 + +2-6 1-2 2-4 + +2 + +7-8 12 + +Implication + +Excellent prognosis Poor prognosis Excellent prognosis Excellent prognosis + +High risk; probable CNS relapse Infantile ALL; poor prognosis Improved outcome with use of +imatinib and chemotherapy +Burkitt leukemia; favorable outcome with Burkitt lymphoma-like protocol +Good prognosis Poor prognosis + + + +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 Feature Standard risk High-risk +Age 2-10 yr Below 1 yr; >10 yr +Sex Female Male +Initial white <50,000 I mm3 >50,000/mm3 cell count +Hepatosplenomegaly Absent Massive Lymphadenopathy Absent Massive Mediastinal mass Absent Present Central nervous Absent Present +system leukemia +Phenotype Pre-B (T cell Mature B cell intermediate) +Ploidy Hyperdiploidy Hypodiploidy Cytogenetics t(12;21), trisomy t(9;22); t(4;11); +4 and 10 t(8;14) +Response to Good early Poor early response treatment response +Minimal residual Negative Positive disease after first +induction + +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. Lrnphadenopathy, 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 of leukemia. The first spinal tap must be performed ideally with platelet count close to 1,00,000/mm3. Children with CNS leukemia require intensive CNS directed therapy (Table 20.6). +The clinical profile of acute lymphoblastic leukemia may mimic many other clinical conditions like infectious mononucleosis, acute infectious lymphocytosis, idiopathic thrombocytopenic purpura, aplastic anemia and viral infections like cytomegalovirus that result in leukemoid reactions and pancytopenia. Idiopathic thrombocytopenic purpura is the most common cause of acute onset of petechiae and purpura in children. Children with ITP have no evidence of anemia and have normal total and differen­ tial leukocyte count. Bone marrow smear reveals normal hematopoiesis and normal or increased number of megakaryocytes. ALL must be differentiated from 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 cytoplasm and round or convoluted nuclei with inconspicuous nucleoli and 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 +CSF cytology ( diagnostic and to administer the first intrathecal dose of methotrexate) +FISH Fluorescence in situ hybridization; CSF cerebrospinal fluid + +arthritis in patients presenting with fever, joint symptoms, pallor, splenomegaly and leukocytosis. ALL should be distinguished from other malignancies (neuroblastoma, non-Hodgkin lymphoma, rhabdomyosarcoma, Ewing sarcoma and retinoblastoma) that present with bone mar­ row involvement. Morphologic, cytochemical, immuno­ phenotypic and cytogenetic characteristics of the malignant cells should be done. Occasionally, patient with ALL may present with hypereosinophilia or as an emergency with very high white cell count (hyperleukocytosis, TLC >1,00,000 I mm3), 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 survival more 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 +Childhood Malignancies - + + + +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%. +The treatment on ALL is divided into 4 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 with intensification therapy in both low risk 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. Induction therapy generally consists of 4 weeks of therapy. The drug regimen combining vincristine and prednisone induces remission in 80-95% patients with ALL. Since the remission rate and duration are improved by the addition of a third and fourth drug (L-asparaginase and/ 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 +Most children with leukemia have subclinical CNS involve­ ment at the time of diagnosis and this acts as a sanctuary site where leukemic cells are protected from systemic chemotherapy because of the blood brain barrier. The early institution of CNS prophylaxis is essential to eradicate leukemic cells which have passed the blood brain barrier. CNS prophylaxis has enabled increased survival rates in leukemia. Most children in the past received a combination 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 prophylaxis while minimizing neurotoxicity, experts now recommend a lower dose of cranial irradiation with intrathecal methotrexate. + + +Table 20.7: Chemotherapy protocol for acute lymphoblastic leukemia (MCP 841) + +Cycle +Induction 1 (Il) + + + + + +Induction 2 (I2) + + + +Repeat induction 1 (Rll) Consolidation (C) + + + + +Maintenance (M): 6 cycles + + +Chemotherapy +Prednisone Vincristine Daunorubicin L-asparaginase + +Methotrexate +6-mercaptopurine Cyclophosphamide Methotrexate Cranial irradiation Same as induction 1 Cyclophosphamide Vincristine +Cytosine arabinoside + +6-mercaptopurine Prednisone Vincristine Daunorubicin +L-asparaginase +6-mercaptopurine + +Methotrexate + +Dose and schedule +40 mg/m2 orally on days 1-28 +1.4 mg/m2 intravenous (IV) on days 1, 8, 15, 22 and 29 30 mg/m2 IV on days 8, 15 and 29 +6000 U/ m2 intramuscular (IM) on alternate days on days 2-20 (10 doses) +Intrathecal (IT)* on days 1, 8, 15 and 22 +75 mg/m2 orally on days 1-7 and days 15-21 750 mg/m2 IV on days 1 and 15 +IT* on days 1, 8, 15 and 22 +200 cGy for 9 days (total 1800 cGy) Doses and schedule as per I1 +750 mg/m2 IV on days 1 and 15 1.4 mg/m2 IV on days 1 and 15 +70 mg/m2 subcutaneously (SC) every 12 hours for 6 doses on days 1-3 and days 15-17 +75 mg/m2 orally on days 1-7 and days 15-21 40 mg/m2 orally on days 1-7 +1.4 mg/m2 IV on day 1 30 mg/m2 IV on day 1 +6000 U/m2 IM on days 1, 3, 5 and 7 +75 mg/ m2 orally daily for 3 of every 4 weeks for a total of 12 weeks; begin on day 15 +15 mg/m2 orally once a week for 3 of every 4 weeks for a total of 12 weeks; begin on day 15 + + +*Administered with 5-10 ml normal saline, at a dose of 8 mg at 1-2 yr, 10 mg at 2-3 yr, 12 mg for >3 yr +- 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 drug resistance. There is clear evidence that 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 continued for an additional 2-2.5 yr. Without such therapy, patients of ALL relapse within the next 2-4 months. A number of drug combination and schedules are used, some based on periodic reinduction, others on continued delivery of effective drugs. The main agents used include 6-mer­ captopurine daily and methotrexate once a week given orally, with or without pulses of vincristine and prednisone or other 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 failure and presence of minimal residual disease >1% at end of induction is 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 appropriate facilities. These children should be given cotrimoxazole as prophylaxis against Pneumocystis jiroveci 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 chromosome positivity, 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 diagnosis has 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. While children with average risk leukemia may not have many longterm complications, children with 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 of the disease. Common sites of 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, is more favorable in terms of 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. +Childhood Malignancies - + + + +Allogenic bone marrow transplantation offers a better chance of cure than conventional chemotherapy for children with ALL who enter a second remission after hematologic relapse. + +Late Effects of Treatment +Continued followup of these patients for prolonged periods is necessary. Patients who have received cranial irradiation at a younger age are at risk for cognitive and intellectual impairment and development of CNS neoplasms. There is a risk of development of secondary AML after the intensive use of epipodophyllotoxins (etoposide or teniposide) therapy. Endocrine dysfunction leading to short stature, obesity, precocious puberty, osteoporosis, thyroid dysfunction and growth retardation are reported. Patients having received treatment with an anthracycline are at risk of cardiac toxicity. + +Down Syndrome and Acute Leukemia +Children with trisomy 21 have a 15-20 fold higher risk of acute leukemia as compared to general population with a cumulative risk of developing leukemia of approximately 2.1%. The ratio of ALL to AML in Down syndrome is as for childhood acute leukemia. Approximately one half­ two-thirds of cases of acute leukemia in children with Down syndrome are ALL. The exception is during the first 3 yr of life when AML predominates and exhibits a distinctive biology. In addition, approximately 10% of children with Down syndrome develop a preleukemic clone, transient myeloproliferative disorder, with somatic mutations in hematopoeitic transcription factor GATAl. These children have a high leukocyte count, circulating blasts in peripheral blood, hepatosplenomegaly, effusions, anemia and thrombocytopenia in the neonatal period, which resolves by 3 months. About 20% of children with transient myeloproliferative disorder develop AML. Of the patients with Down syndrome and AML, two-thirds have megakaryocytic leukemia (FAB M7). Children with + +Down syndrome and AML have a superior outcome than those not having Down syndrome. The outcome of children with Down syndrome and ALL is inferior to those with ALL not associated with Down syndrome. + +ACUTE MYELOID LEUKEMIA +Acute myeloid leukemia (AML) also termed as acute non­ lymphoblastic leukemia, accounts for 15-20% of leukemia in children. AML is a more complex and resistant disease than ALL and results from clonal proliferation of hematopoeitic precursors of myeloid, erythroid and megakaryocytic lineage. + +Epidemiology +AML can occur at any age but the incidence is more during adolescence; males are affected as frequently as females. Congenital leukemia (occurring during first 4 weeks of life) is mostly AML. While the etiology of AML is not known, there is an association following exposure to ionizing radiation. Down syndrome is the most common genetic predisposing factor associated with risk of developing AML during the first three years of life. Other predisposing factors are Fanconi anemia, Blooms syndrome, Kostmann syndrome and Diamond Blackfan anemia. Medications associated with risk of AML include alkylating agents and epipodophyllotoxins. + +Pathogenesis +Genetic aberrations in AML suggest alterations that regulate self renewal and differentiation cooperate in the pathogenesis of AML. Several genetic mutations have been identified in AML (Table 20.8). These include mutations in FLT3, PTPN11, oncogenic Ras, BCR/ABL and TEL/PDGF�R. Mutations and translocation fusion products that impair differentiation and apoptosis (class II mutations) include PML/RARa fusion from t(15;17), AML-1/ETO fusion from t(8;21), CEBPa mutations and + + + +Table 20.8: Genetic abnormalities in AML + +Genetic abnormality + +Gene rearrangement +t(8;21)(q22;q22) (ETO-AML1) inv(1 6)(p13;q22) (MYH 11-CBF�) t(15;17)(q22;q 12) (PML-RARa) + +Mutations (karyotype normal) +NPM (nucleophosmin) CEBPa +FLT3-1TD WT1 Del5 q +M onosomy 7 \ No newline at end of file