Congenital Heart Disease

Children with congenital heart disease (CHD) are at risk for neurological complications including cerebrovascular accidents (CVAs), cerebral abscess, seizures, developmental delay, and cognitive impairment. The neurological complications, seen in as many as 25% of children with CHD, are the most common extracardiac complications of CHD. They contribute substantially to the mortality and morbidity of CHD, with many long-term consequences.

The many advances in the treatment of CHD and early correction in the first year have reduced the occurrence of developmental disabilities caused by long-term exposure to hypoxia and the neurological complications of uncorrected CHD. The focus of life has now shifted to neurological injury caused by cardiac surgery and cardiac transplantation.

Neurological Complications Unrelated to Intervention and Cardiac Surgery

Infective Endocarditis

The implementation of subacute endocarditis prophylaxis before dental and surgical procedures in patients with CHD has greatly reduced the incidence of bacterial endocarditis. Approximately one-third of cases of infective endocarditis are associated with neurological complications. These include cerebral embolization, usually in the middle cerebral artery territory, and meningitis, brain abscess, and seizures (Fig. 49B.1). Cerebral mycotic aneurysms complicate 1.2% to 5% of cases of infective endocarditis and carry a high mortality rate of 60%. The risk of hemorrhagic transformation of septic infarctions is high and associated with a mortality rate of 80% to 90%.

Fig. 49B.1 Magnetic resonance image of brain of a 12-year-old girl with congenital heart disease, subacute endocarditis, and brain abscess. The patient presented with fever, headaches, and diplopia.

Neurological Complications of Intervention and Cardiac Surgery

The risk of neurological complications with cardiac catheterization in infants and children is low. The incidence of seizures is 1%. Rare complications are focal paresthesias and injuries of the lumbar plexus or femoral nerve caused by localized hematoma.

The mortality rate associated with cardiac surgery has dramatically fallen in the past 20 years and is now less than 10%. The incidence of neurological complications after cardiac surgery in children ranges between 2% and 25%.

Fallon and associates (1995) reviewed data for 523 cardiac surgery patients and found neurological events or deficits in 31 patients in the immediate postoperative period. Seizures occurred in 16, pyramidal signs (hemiparesis-quadriparesis) in 11, extrapyramidal signs in 8, and neuro-ophthalmic deficits (gaze palsies, visual field defects) in 6. Six patients were unconscious, and four demonstrated miscellaneous neurological changes such as development of Horner syndrome secondary to brachial plexus injury, vocal cord palsy, isolated bulbar palsy, and transient ischemic episodes. A period of low perfusion pressure, either intraoperatively or postoperatively, was present in more patients who had an adverse neurological event than in those who were normal. The highest frequency of adverse neurological events was in the cardiac diagnostic group of arch anomaly. The likely pathogenesis of CNS injury is microembolization and ischemia during bypass or development of intracranial hemorrhage (Du Plessis et al., 1999). Corrective surgery for coarctation of the aorta is especially associated with CVAs.

Seizures are the most common complication after cardiac surgery, seen in up to 15% of children postoperatively. The prognosis varies with the underlying cause. Other complications include delayed recovery of mental status, (thought to be caused by hypoxic-ischemic reperfusion injury), movement disorders such as choreoathetosis, oculogyric crisis, and parkinsonism.

A postoperative encephalopathy characterized by choreoathetosis and developmental delay is a well-defined complication after cardiac surgery in children, but not after cardiac surgery in adults. The incidence has dropped from 18% to 0.6% in recent reports (du Plessis et al., 2002). A mild transitory form can follow cardiac surgery in infants. The severe form occurs in children who undergo such surgery after infancy. In the severe postpump choreoathetosis, the early mortality rate approaches 40%. Most of the patients have residual involuntary movements and severe long-term neurological disturbances years later. The mild form is associated with cognitive and behavioral disturbances despite complete resolution of choreoathetosis. The mechanisms underlying pathogenesis remain unclear, with the usual proposed explanations being deep hypothermia and intraoperative hypoxic injury (Wessel et al., 1995). Brain imaging in these cases usually reveals nonspecific changes such as cerebral atrophy. Neuropathological data are limited; however, the external globus pallidus is the most consistent locus of injury, with evidence of gliosis, neuronal loss, nerve fiber degeneration, and capillary proliferation (Kupsky et al., 1995).

Open heart surgery is associated with several risk factors for stroke (Fig. 49B.2). The risks include altered intravascular endothelial surfaces, thrombus formation facilitated by the use of prosthetic devices, gaseous emboli originating from the cardiopulmonary bypass, global hypoperfusion, inflammatory cascades and microvascular inflammatory changes, and occurrence of prothrombotic state during surgery, owing to consumptive coagulopathy and decreased protein C and antithrombin levels.

Fig. 49B.2 Magnetic resonance image of a 13-month-old child with tetralogy of Fallot and stroke in the middle cerebral artery distribution.

Spinal cord injury occurs especially after aortic coarctation repair. Peripheral neuromuscular complications include plexopathies (mostly brachial), pressure palsies (peroneal and ulnar nerves), myopathy, “critical care neuropathy,” and polyneuropathy developing after withdrawal of neuromuscular blocking agents. Dittrich et al. (2003) reviewed data for 90 patients younger than 1 year of age who underwent cardiac surgery. These patients had no brain anomalies or syndromes associated with delayed mental development, but 32% had evidence of psychomotor impairment. Neurological sequelae were more frequent after palliative surgery than after corrective surgery.

Cardiac Transplantation

In the past decades, the number of cardiac transplantation procedures performed worldwide has increased. Although the survival rate has steadily improved, the potential for significant complications remains. Such complications include graft rejection, graft arteriosclerosis, infections, malignancies, pneumonia, pericarditis, gastrointestinal hemorrhages, and drug toxicity, leading to an overall perioperative mortality rate of approximately 9%.

Perez-Miralles and associates (2005) reported neurological complications after cardiac transplantation in 13.7% of patients. Other studies, however, have reported an incidence of 50% to 70%, mostly in the perioperative period.

In the series of Cemillan and colleagues (2004), 48% of transplant recipients suffered neurological complications such as encephalopathy (16.6%), seizures (13.6%), neuromuscular disorders (10.6%), headaches (10.6%), CVA (10.1%), psychiatric problems (2.2%), and CNS infections (2.2%). Signs and symptoms of cyclosporine toxicity include tremor, seizures, and encephalopathy. Risk factors for encephalopathy were renal and hepatic failure and hemodynamic instability. Risk factors for stroke were the presence of systemic hypoperfusion, arrhythmias, coagulopathies, and hypertension.

Acquired Heart Disease

Several acquired heart diseases are associated with neurological complications. The most common entities are cardiomyopathies, arrhythmias, and hypertension. Cardiomyopathies can either be idiopathic or result from viral myocarditis or rheumatic carditis. Ventricular dilatation and hypokinesia cause stasis of intraventricular blood, resulting in thrombus formation and embolic stroke. Furthermore, poor ejection fraction can lead to arrhythmias and syncope. In rheumatic heart disease, the source of emboli to the brain is either vegetations or septic emboli due to infective endocarditis. Sydenham chorea occurs in 10% to 25% of patients with rheumatic heart disease.

Cardiac arrhythmias cause neurological symptoms secondary to impaired cerebral perfusion. These include dizziness, syncope, transient ischemic episodes, confusion, dementia, and abnormal behavior. Convulsive syncope occurs in severe cases associated with some degree of cerebral anoxia. Embolic strokes from arrhythmias are more likely to occur during or after surgical manipulation at the time of heart surgery or in the postoperative period.

The most important neurological complication of hypertension in children is hypertensive encephalopathy. This entity is discussed later in the chapter under the heading Hypertension.

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is rare in childhood and occurs most frequently in the fifth and sixth decades of life. Early reports of infantile PAN probably were severe cases of Kawasaki disease. PAN is a necrotizing vasculitis of small and medium-sized arteries. The etiology is unknown, but an association with hepatitis B and C is recognized in adults. In children, severe PAN-like vasculitis may follow cytomegalovirus (CMV) and parvovirus B19 infections. An association with a preceding group A or B streptococcal infection is questionable. Furthermore, some cases of PAN have followed drug exposure.

Signs and symptoms of systemic illness such as weight loss, fatigue, and anorexia can be prominent. Other manifestations include fever, arthralgias, rash, edema, petechiae, myalgia, painful subcutaneous nodules in the calf and foot, and livedo reticularis. Gastrointestinal vessel involvement causes abdominal pain, ulcers, and bleeding. Renal, cardiac, and pulmonary involvement can occur, with the potential for renal or heart failure. Hypertension is common.

Neurological manifestations can develop in 50% to 70% of children. Mononeuritis multiplex, a characteristic feature of the disease in adults, is much less frequent in children, whereas CNS manifestations are more frequent in children than adults. Focal neurological deficits secondary to ischemia, infarction, and hemorrhage are common. The signs and symptoms include unilateral blindness, visual field defect, seizures, headache, encephalopathy, cognitive decline, cranial neuropathies, and aseptic meningitis. In the brain, changes are mainly seen in the small meningeal arteries (Nadeau et al., 2002).

Confirmation of the diagnosis is either by the histopathological demonstration of the characteristic vascular lesions of necrotizing angiitis or by radiological documentation of aneurysms. MRI, magnetic resonance angiography (MRA), and angiography reveal segmental arterial narrowing and ischemic injuries. In the presence of a peripheral neuropathy, muscle or nerve biopsy (of the sural nerve) also may be diagnostic. Common laboratory features include leukocytosis, anemia, elevation in erythrocyte sedimentation rate, and increased C-reactive protein level and serum immunoglobulin levels. Antineutrophil cytoplasmic antibodies (ANCAs), and circulating immune complexes may be present. Detection of rheumatoid factor and antinuclear antibody (ANA) is rare.

Corticosteroid therapy improves life expectancy and decreases the incidence of hypertension and renal complications. In severe cases, lack of response to steroids is an indication for use of oral or intravenous-pulse cyclophosphamide. Plasmapheresis has not improved survival. Methotrexate, azathioprine, mycophenolate mofetil, intravenous immunoglobulin (IVIG) and more recently tumor necrosis factor (TNF) inhibitors (infliximab) and anti-CD20 monoclonal antibodies (rituximab) have been used successfully in children (Gedalia et al., 2009).

Kawasaki Disease

Kawasaki disease is one of the most common vasculitides affecting medium-sized arteries in childhood. It is also known as mucocutaneous lymph node syndrome. Some early reports of infantile PAN, in which the patient died of a ruptured or thrombosed coronary artery aneurysm, were probably severe cases of Kawasaki disease. Some 85% of affected patients are younger than 5 years of age. The etiology is unknown, but an infectious cause is thought possible. An interesting hypothesis suggests that the pathogenesis is superantigens (i.e., exotoxins from bacteria such as Streptococcus and Staphylococcus) with immunostimulatory properties.

The criteria for the diagnosis include the presence of unexplained fever for at least 5 days, with at least 4 of the following physical features: (1) nonpurulent conjunctivitis, (2) cervical lymphadenopathy, (3) rash, (4) mucosal changes (redness and fissuring of the lips, “strawberry tongue”), and (5) changes in the extremities (erythema and edema of palms and soles, with desquamation). Up to one-third of patients develop myocarditis, coronary artery aneurysms, and, less often, pericarditis or valvular disease. Aneurysms smaller than 8 mm usually resolve, whereas those larger than 8 mm rarely resolve and are usually associated with stenosis.

The most common neurological manifestations consist of extreme irritability, probably caused by aseptic meningitis, headaches, and encephalopathy. Cerebral infarction, seizures, polyneuropathy, myositis, cranial neuropathies, and retinal vasculitis are rare complications. Muneuchi and associates (2006) described a single patient with a silent right cerebellar infarct and suggested the need to consider the possibility of brain lesions in all children with Kawasaki disease with or without neurological symptoms.

Treatment consists of high-dose aspirin (80-100 mg/kg of body weight per day) and a single dose of IVIG (2 g/kg). High-dose aspirin is continued until the patient is afebrile for 3 to 7 days, then the dose is decreased to 3 to 5 mg/kg/day and continued until the inflammatory markers and thrombocytosis have resolved and the echocardiogram is normal.

Henoch-Schönlein Purpura

Henoch-Schönlein purpura (HSP) is a leukocytoclastic multisystem immunoglobulin (Ig)A-mediated vasculitis. The characteristic features are arthralgia, abdominal pain, and nonthrombocytopenic purpura mostly involving the buttocks and lower extremities. Fever, fatigue, and edema are common. Nephritis occurs in 40% of patients. HSP is the most common primary vasculitis affecting small vessels in childhood.

Headache is the most common neurological symptom, sometimes caused by hypertension. CNS vasculitis can occur, however, with the potential for development of ischemia and hemorrhage. Seizures, paralysis, chorea, Guillain-Barré syndrome, ataxia, and central and peripheral neuropathy are also reported. Permanent sequelae from CNS manifestations are rare. The long-term outcome of HSP depends on the degree of renal involvement.

Takayasu Arteritis

Takayasu arteritis, also known as pulseless disease, is a chronic inflammatory large-vessel vasculitis affecting the aorta and its major branches. In 75% of cases, the onset of symptoms is between the ages of 11 and 30 years. Onset in persons as young as 5 months of age has been described. Greater than 80% of the patients are female, who are more likely to be of Japanese origin. A suggested association with tuberculosis is unproven.

Clinical manifestations are hypertension, fever, back pain, dyspnea, chest pain, claudication, transitory visual loss, myalgias, arthralgias, abdominal pain, and congestive heart failure. The examination reveals loss of radial pulses, and sometimes a carotid bruit is present. Diagnosis is based on characteristic angiographic findings in the aorta and its major branches. More recently, MRI has been useful both in diagnosis and in monitoring disease activity by detecting early smooth-muscle thickening and signs of vascular inflammation of the vessel walls.

Cerebral hypoperfusion secondary to stenosis of the carotid and vertebral arteries and complications of hypertension cause the neurological complications. The signs and symptoms include visual loss, vertigo, syncope, seizures, hemiplegia, and headaches. Treatment consists of corticosteroids and immunosuppressive agents such as methotrexate. Small series showed usefulness of anti-TNF agents. Management of hypertension is critical, and antiplatelet agents are useful in preventing thrombosis. Surgical intervention, angioplasty, and stent placement sometimes are required.

Churg-Strauss Syndrome

Churg-Strauss syndrome, or allergic granulomatosis, affects middle-aged males and is rare in children. Cases are reported in children as young as 2 years, however. The clinical picture consists of asthma symptoms, eosinophilia, fever, allergic rhinitis, pulmonary infiltrates, sinus problems, purpura, skin nodules, and cardiac and renal involvement. Histopathological examination reveals vasculitis of small arteries and veins associated with necrotizing extravascular granulomas and eosinophilic infiltrates.

Neurological manifestations consist mainly of neuropathy, with evidence of mononeuritis multiplex, polyneuropathy, and cranial neuropathy. The optic nerve is the most frequently affected cranial nerve in this disorder. CNS features are less common, but focal neurological deficits occur secondary to infection and hemorrhage, and pseudotumor cerebri is reported. Treatment options include high-dose corticosteroids, cyclophosphamide, methotrexate, interferon-α, and plasmapheresis.

Juvenile Rheumatoid Arthritis

Chronic arthritis in childhood, characterized as juvenile rheumatoid arthritis (JRA), juvenile chronic arthritis (JCA), or juvenile idiopathic arthritis (JIA), is one of the most common rheumatic diseases of childhood. Classifying this heterogeneous group of disorders has been problematic. The definitions used are inconsistent, and the classifications vary.

JRA consists of three types: pauciarticular, polyarticular, and systemic. The age at onset must be younger than 16 years. For definitive diagnosis, objective evidence of arthritis is required in one or more joints for 6 weeks or longer, with exclusion of other causes for the arthritis. The systemic form is characterized by daily fever for at least 2 weeks, rash, arthritis, lymphadenopathy, or pericarditis.

The neurological complications of the systemic form include acute encephalopathy, which can be lethal as a result of the macrophage activation syndrome (Ueno et al., 2002). The cause of this syndrome is disruption of the macrophage-lymphocyte interaction, causing uncontrolled proliferation of highly activated macrophages and T lymphocytes, with consequent sepsis-like symptoms often resulting in multiple organ failure. High-grade fever, hepatosplenomegaly, pancytopenia, consumption coagulopathy, and low erythrocyte sedimentation rate are other features. Treatment is with high-dose steroids and cyclosporine (Stabile et al., 2006).

Reye syndrome has been described in affected patients secondary to the use of acetylsalicylic acid. Other neurological manifestations include myelopathy secondary to cervical arthritis. Myelopathy from atlantoaxial dislocation is rare in children. Motor and sensory neuropathies, such as entrapment neuropathies, are uncommon in children. One-third of patients have high serum creatine kinase concentration; however, evidence of proximal weakness or histological evidence of myositis is uncommon.

The management of JRA usually is with aspirin and nonsteroidal antiinflammatory agents. Some patients will require corticosteroids, IVIG, immunosuppressive agents, or antimalarials.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an episodic multisystem autoimmune disease characterized by the presence of ANA, especially antibodies to double-stranded DNA.

SLE accounts for 4.5% of patients seen in pediatric rheumatology clinics. The onset of SLE is uncommon before adolescence. In childhood, the ratio of affected girls to boys is 4.5 : 1.

The clinical features of SLE are constitutional (fever, weight loss), cutaneous (malar butterfly rash), musculoskeletal (myopathy, arthralgias), cardiac (pericarditis, myocarditis, endocarditis), vascular (Raynaud phenomenon, livedo reticularis), and renal manifestations (glomerulonephritis, nephrotic syndrome, hypertension). Gastrointestinal, pulmonary, and ocular signs and symptoms also may be features.

CNS involvement occurs in 30% to 60% of children with SLE during the course of their illness. Neuropsychiatric abnormalities occur in as many as 95% of patients. Patients with CNS involvement usually have a more severe clinical course. The prevalence of recurrent headaches is 71%, migraine 36%, cognitive disorders 55%, isolated seizures 47%, epilepsy 15%, acute confusional state 35%, dysesthesia or paresthesia 14%, transient ischemic attacks (TIAs) 12%, and CVA 8%. Chorea and myositis are rare (Ghosh et al., 2005). Parkinsonism has been reported in three patients (Kwong et al., 2000). Corticosteroid-related myopathy can complicate the course of the disease. Ophthalmoplegia, diplopia, sudden blindness, or ptosis can occur, and findings of papilledema, optic neuritis, retinal hemorrhage, and vasculitis (“cotton wool spots”) have been described. Possible neurological complications of SLE include ataxia, vertigo, sensorineural hearing loss, aseptic meningitis, transverse myelopathy, and peripheral neuropathy with predominantly sensory deficits. The most common clinical manifestations of neuropsychiatric lupus are depression, memory problems, emotional lability, trouble with concentration, and psychosis. Psychiatric assessment is important in the evaluation of children with SLE. Muscal et al. (2010) and others have described pediatric lupus patients presenting with seizures, altered mental status, and MRI findings suggestive of posterior reversible encephalopathy syndrome (PRES).

Vasculitis in SLE is rare and affects small arterioles and venules. Perivasculitis is more common. CVAs occur mainly in patients with hypertension or severe renal and cardiac disease (Fig. 49B.3) and have been associated with positive results on serological tests for syphilis and the presence of lupus anticoagulant (LA). Gattorno and colleagues (1995) found that 79% of pediatric patients with SLE had anticardiolipin antibodies (aCLs), and 42% had LA. These patients were at high risk for the development of deep vein thrombosis and other antiphospholipid antibody (APA)-related pathology. A statistically significant correlation also has been found between APA and neurological manifestations such as vascular events, seizures, and psychosis. Other antibody systems such as antiribosomal P antibodies, antineuronal antibodies, or lymphocytotoxic antibodies also may be associated with an increased risk for neurological involvement. The pathogenesis of neuropsychiatric lupus is likely to be multifactorial, including autoantibody production, microangiopathy, intrathecal production of proinflammatory cytokines, and premature atherosclerosis. It is possible that the autoantibodies associated with neuropsychiatric lupus may require a disrupted blood-brain barrier to exert their effect (Nishimura et al., 2008).

Fig. 49B.3 Magnetic resonance image of brain of a 16-year-old girl with lupus, antiphospholipid antibodies, Addison disease, and hypertension. Laminar necrosis of the right parietal region is evident.

Laboratory abnormalities include high erythrocyte sedimentation rate, anemia, leukopenia, thrombocytopenia, low CH50, and low C3 and C4. ANAs are present in almost all patients. Antibodies to double-stranded DNA are pathognomonic for SLE and are present in almost all patients with active disease. Antibodies to extractable nuclear antigen (Sm, Ro/SS-A, La/SS-B, RNP) and antihistone antibodies are strongly associated with SLE. Anti-Sm is highly specific for the disease. Rheumatoid factor is present in 10% to 30% of the patients. The MRI abnormalities in neuropsychiatric lupus include small periventricular and subcortical white matter lesions, cortical atrophy, ventricular dilatation, and infarction. Data from newer imaging techniques such diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), and quantitative volumetric studies are very promising in detecting CNS damage and could be used as biomarkers in clinical trials (Hughes et al., 2007).

The usual treatment of the CNS manifestations of SLE is high-dose oral or intravenous corticosteroids after an infectious process has been ruled out. Cyclophosphamide is used in the management of severe neuropsychiatric lupus unresponsive to other modalities. Some centers use azathioprine as an alternative therapy. Unfortunately no published neuropsychiatric lupus treatment trials in children exist. It remains unclear whether children require earlier or more aggressive treatment programs to prevent long-term neurological sequelae. In patients who have APA and platelet count greater than 70,000/mm³, low-dose aspirin therapy is recommended. Anticoagulation with heparin followed by warfarin is required for patients with CVA and antiphospholipid antibodies.

Wegener Granulomatosis

Wegener granulomatosis (WG) is characterized by the triad of (1) granulomatous vasculitis of small vessels in the upper and lower respiratory tract, (2) focal segmental glomerulonephritis, and (3) disseminated necrotizing vasculitis. It occurs mostly in middle-aged adults. In the young, onset is in the second decade. In some series, 3.3% of patients had disease onset before age 20. The etiology of WG is unknown, but the implication of ANCA along with an infectious process has been proposed.

Clinical manifestations include sinus problems, pulmonary disease (cough and hemoptysis), and glomerulonephritis. Nonspecific complaints of fever, malaise, and weight loss are frequent at onset.

Nervous system involvement occurs less frequently in children than in adults, but manifestations may include neuropathy (mononeuritis multiplex, polyneuropathy), myopathy, seizures, stroke, hemorrhage, dural venous thrombosis, pachymeningitis, cerebritis, and myelopathy.

The cause of neurological symptoms is either direct invasion of paranasal tissues by the granulomatous process or “metastasis” to CNS sites not contiguous with the upper airway, or necrotizing vasculitis. Orbital pseudotumors cause exophthalmos and ophthalmoplegia. Involvement of the optic nerve, seventh and eighth cranial nerves, chiasm, and pituitary gland can occur. Pituitary involvement causes diabetes insipidus.

The most helpful diagnostic laboratory test in Wegener granulomatosis is the demonstration of cytoplasmic-staining antineutrophil cytoplasmic antibody (c-ANCA) to proteinase-3 (PR3) antigen. A definitive diagnosis requires tissue diagnosis by biopsy of lung, skin, or kidney.

Induction therapy with corticosteroids in combination with cyclophosphamide leads to remission in more than 90% of patients with Wegener granulomatosis. Maintenance therapy includes methotrexate, azathioprine, leflunomide, trimethoprim-sulfamethoxazole, etanercept, and rituximab.

Behçet Disease

Definitive diagnosis of Behçet disease requires recurrent oral ulcerations (aphthous or herpetiform) plus two of the following: recurrent genital ulcerations, ocular lesions (uveitis or retinal vasculitis), skin lesions (erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules), and a positive pathergy test (skin reaction to a needle prick).

Several review studies have documented Behçet disease in childhood and adolescence. It may occur in neonates born to mothers with the disease. Both genders are equally affected. The disease is more common in Turkey and other countries in the Middle East.

The reported incidence of CNS involvement (“neuro-Behçet”) in children ranges from 5% to 15%. According to Saip and colleagues (2005), headache is the most common neurological symptom. Other neurological complications include encephalomyelitis, seizures, brainstem and basal ganglia involvement, aseptic meningitis, pseudotumor cerebri, and dural sinus thrombosis. Psychiatric manifestations include depression, psychosis, and dementia. A few children have suffered acute focal and generalized myositis. Vasculitis of both the arterial and venous systems, associated with thrombosis and arterial aneurysms, can occur.

Treatment includes corticosteroids, sulfasalazine, colchicine, and immunomodulating agents such as methotrexate, cyclosporine, azathioprine, interferon-α, and infliximab. Thalidomide is useful in treating isolated mucocutaneous Behçet disease. Azathioprine is one of the first choices for treatment of severe uveitis.

Sjögren Syndrome

Sjögren syndrome is a chronic inflammatory autoimmune disease that can be either isolated or seen in conjunction with other connective tissue diseases such as SLE, JRA, or dermatomyositis. The disease mainly affects females and can occur in children. The typical symptoms of dry eyes (xerophthalmia) and dry mouth (xerostomia) are secondary to infiltration of the salivary and lacrimal glands with lymphocytes and plasma cells. Tubular interstitial nephropathy also occurs.

The neurological problems in Sjögren syndrome include aseptic meningitis, infarction, optic neuritis, myelopathy, seizures, encephalopathy, behavioral changes, and motor and sensory neuropathy.

The main laboratory features are nonspecific anemia, leukopenia, and hypergammaglobulinemia. Several autoantibodies are positive, including ANA, anti-SSA, anti-SSB, and rheumatoid factor. Lymphocytic infiltration of the salivary glands of the lower lip is characteristic of Sjögren syndrome and confirms the diagnosis. Treatment is symptomatic. Corticosteroids are useful in severe cases.

Primary Angiitis of the Central Nervous System

Primary angiitis of the CNS (PACNS) was initially called granulomatous angiitis. The marked variation observed in this disease led to its subdivision into PACNS and benign angiitis of the CNS (BACNS). The latter is rare in children and consists of a monophasic form of the disease with good response to steroids. Clinical manifestations of PACNS include headaches, TIAs, encephalopathy, visual loss, hemiparesis, and neurocognitive changes.

Angiography is diagnostic, showing small and medium-sized vessel beading, or alternating segmental narrowing and ectasia. Cerebrospinal fluid analysis shows increased proteins and mild pleocytosis. Raised intracranial pressure also occurs. MRI can reveal bilateral or unilateral multifocal T2 hyperintensities in both white and gray matter.

Early diagnosis and treatment with corticosteroids, and in certain cases with cyclophosphamide, will reduce the high morbidity previously reported and the frequency of recurrences.

Periodic Breathing and Apnea

The periodic breathing pattern, more common in premature infants, consists of characteristic cyclic episodes during sleep, when brief apneic pauses of 5 to 10 seconds interrupt regular breathing, followed by a burst of rapid respiration. Infants who become hypoxic require supplemental oxygen. Neurological complications do not occur unless hypoxic periods are prolonged and severe. The definition of apnea is cessation of breathing for more than 20 seconds. The incidence of associated bradycardia increases with the duration of the apnea and correlates with the severity of hypoxia. Apnea can be idiopathic (idiopathic apnea of prematurity) or can be caused by intraventricular hemorrhage, seizures, obstruction, atelectasis, pneumonia, sepsis, meningitis, phrenic nerve paralysis, gastroesophageal reflux, hypovolemia and heart failure.

Undiagnosed obstructive sleep apnea (OSA) can lead to failure to thrive, pulmonary hypertension, and systemic hypertension. It also can cause long-term deleterious effects on neuronal and intellectual functioning, with behavioral changes, restlessness, aggressive behavior, memory problems, and poor test performance. Increasing evidence supports the association of OSA and symptoms of attention deficit hyperactivity disorder (ADHD). Some of the neurobehavioral deficits are not totally reversed with treatment of the apnea.

Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy that follows mechanical ventilation and oxygen therapy for acute respiratory distress or hyaline membrane disease in premature newborns. Multiple studies have shown that the neurological outcome of infants with BPD is closely associated with the presence of complications of prematurity such as intraventricular hemorrhage, periventricular leukomalacia, seizures, and prolonged ventilatory support, leading to the gross and fine motor delays and cerebral palsy seen in this population. The presence of severe BPD alone, however, poses an additional risk for neuromotor sequelae that include mild spasticity, microcephaly, and behavioral problems (Majnemer et al., 2000). When compared with a matched cohort of preterm peers, children with prematurity and BPD exhibited a higher frequency of subtle neurological signs such as involuntary movements, poor coordination, clumsiness, poor postural control, synkinesias, and dyspraxia and an increased need for special education.

In an earlier report, a syndrome characterized by rapid, random, jerky movements similar to chorea, and restless movements similar to akathisia involving the limbs, neck, trunk, tongue, and mouth, developed in a series of 10 premature infants with severe BPD. The movements, which began in the third month, were exacerbated by respiratory failure and were attenuated during sleep. The natural history was either partial or complete resolution or a static course. One patient had histopathological evidence of neuronal loss and astrocytosis in the basal ganglia and thalamus.

Cystic Fibrosis

The neurological complications in cystic fibrosis (CF) result from chronic hypoxia and hypercapnia leading to lethargy, somnolence, and sometimes coma. Brain abscess occurs in small numbers of adolescents and adults with CF, usually in association with advanced pulmonary disease and paranasal sinus disease.

Increased intracranial pressure, characterized by a bulging fontanel and irritability, may occur in malnourished infants with CF after initiation of nutritional therapy. The cause is unclear but may involve intrathoracic obstruction of venous return. Vitamin A deficiency must be excluded in this setting.

Patients with CF and pancreatic insufficiency frequently suffer from vitamin E deficiency, with the potential for development of spinocerebellar degeneration with ataxia, dysarthria, areflexia, and proprioceptive loss. Neuropathological studies reveal posterior column degeneration. Peripheral neuropathy, ophthalmoplegia, diminished visual acuity, tremor, and weakness may be neurological manifestations of CF. The use of indwelling intravenous catheters can result in venous thrombosis and cerebral thromboembolism. Other contributing factors for thrombotic complications include associated diabetes, chronic inflammation, acquired thrombophilia due to hepatic insufficiency, and cholestasis. In addition, patients with CF have an increased risk for right-to-left shunting because of chronic cough and secondary pulmonary hypertension.

Chiari type I malformation seems to be more common in patients with CF than in the general population. Needleman and colleagues (2000) described five children and adolescents with CF and Chiari type I malformations with swallowing dysfunction, syncope, numbness, headaches, and recurrent emesis.

Sarcoidosis

Sarcoidosis is an idiopathic, chronic, multisystem, granulomatous disease, uncommon in children. It predominantly affects females and African-American children. In 3% to 15% of published cases, the patients were younger than 15 years of age.

The clinical presentation varies between younger (before 4 years of age) and older children (8 to 15 years) and is different from that in the adult population (Yanardag et al., 2006). Children younger than 4 years of age present mainly with a maculopapular rash, uveitis, and arthritis. In the 8- to 15-year-old age group, signs and symptoms include fever, cough, lymphadenopathy, malaise, ocular lesions, and abnormalities on the chest radiograph. In 1985, Edward Blau described families with autosomal dominant granulomatous disease similar to early-onset sarcoidosis. Recent data have suggested that Blau syndrome and early-onset sarcoidosis may represent the same disease. They both share the same genetic mutations in the NOD2 (nucleotide binding oligomerization domain 2), also known as CARD 15 (capsule recruitment domain family member 15). CNS abnormalities, known as neurosarcoidosis, occur in 30% of children, compared with 5% to 10% of affected adults. CNS complications include encephalopathy, seizures, cranial neuropathy (with nerve VII most frequently affected), optic neuritis, mass lesions, obstructive hydrocephalus, basilar granulomatous meningitis, aseptic meningitis, peripheral neuropathy, headaches, myelopathy, and pituitary-hypothalamic lesions. Children are more likely to develop seizures and space-occupying lesions and less likely to develop cranial nerve palsies (Baumann et al., 2003).

Sarcoid granulomas are more commonly located in the cerebral hemispheres than in the posterior fossa. They probably result from extension of the inflammatory process through the Virchow-Robin spaces. The MRI appearance of neurosarcoid mass lesions is nonspecific. The lesions have a higher density than that of brain and enhance with contrast. White-matter sarcoid lesions seen on T2-weighted images can resemble the tumefactive demyelinating lesions seen in multiple sclerosis.

Histologically, the diagnostic feature of sarcoidosis is the presence of noncaseating granuloma. Serum levels of angiotensin-converting enzyme (ACE) are elevated in 80% of children with sarcoidosis. Most patients have hypercalcemia and hypercalciuria.

Corticosteroids are the standard treatment for sarcoidosis. Some cases require treatment with immunomodulating agents, mainly methotrexate, but also azathioprine, cyclosporine, cyclophosphamide, chloroquine, mycophenolate mofetil, and TNF-α inhibitors such as infliximab as well.

Hemolytic Disease of the Newborn and Kernicterus

Hemolytic disease of the newborn, or erythroblastosis fetalis, is caused by Rh incompatibility, A and B incompatibility, or other blood group incompatibility (C, E, Kell, and Duffy). The use of RhoGAM or human anti-D globulin within 72 hours of delivery or abortion has reduced the risk of initial sensitization of Rh-negative mothers.

In affected infants, jaundice develops within the first few hours of life. Serum bilirubin concentrations exceed safe limits within 48 hours. Unconjugated bilirubin can reach the CNS and injure neurons, mainly basal ganglia (globus pallidus and subthalamic nucleus), cerebellar vermis, dentate nuclei, hippocampi, and cranial nerve nuclei, especially the oculomotor and eighth cranial nerves, leading to the occurrence of kernicterus, or “nuclear jaundice.”

The clinical features include lethargy, poor feeding, rigidity, opisthotonos, high-pitched cry, fever, and convulsions. Approximately half of patients with kernicterus die. The survivors typically have choreoathetoid cerebral palsy, high-frequency deafness, and mental retardation. Fortunately, the classic clinical picture of kernicterus is rare with improved nursery care and early treatment of jaundice. However, recent studies have focused on the assessment of minor bilirubin neurotoxicity manifested later in childhood in more subtle ways, such as learning deficits and mild motor, cognitive, and behavioral disorders. Phototherapy and exchange transfusion are the major modes of therapy.

Hemorrhagic Disease of the Newborn

The cause of hemorrhagic disease of the newborn is a transitory deficiency of vitamin K–dependent factors. This may be due to poor placental transfer of vitamin K, marginal vitamin K content in breast milk, or maternal use of medications that interfere with vitamin K stores or function (e.g., phenytoin). Bleeding starts in the first postnatal week. The neurological complications are caused by subarachnoid or intraparenchymal hemorrhage. Administration of vitamin K intramuscularly at birth prevents hemorrhagic disease of the newborn.

Neonatal Polycythemia

The definition of neonatal polycythemia is a central hematocrit of 65% or higher. Hypoglycemia, hypocalcemia, and thrombocytopenia are often associated. Concurrent hypoglycemia increases the risk of a poor outcome.

The hyperviscosity may cause arterial or venous thrombosis. It can also lead to increased cerebrovascular resistance and diminished cerebral blood flow. Ischemic lesions often are complicated with hemorrhage. Neurological complications include stroke, developmental delay, tremor, spastic diplegia, hemiparesis, monoparesis, mental retardation, and learning deficits. Lethargy, poor feeding, tremor, and jitteriness are common clinical findings. Treatment consists of partial exchange transfusion, adequate hydration, and correction of associated metabolic disorders.

Sickle Cell Disease

Sickle cell disease is the most common hematological disorder associated with CVAs. The incidence of stroke in sickle cell disease ranges from 7% to 33% (Fig. 49B.5). The prevalence of silent infarcts was 21.8% among 266 patients in the Cooperative Study of Sickle Cell Disease (Kinney et al., 1999). Silent infarcts occur in the distribution of small vessels. The most common underlying lesion is an intracranial arterial stenosis or obstruction, often seen in the proximal middle cerebral and anterior cerebral arteries. Sickled erythrocytes cause chronic injury to the vessel endothelium, resulting in a narrow lumen. Subarachnoid hemorrhage and intraparenchymal hemorrhage also can occur. Spontaneous acute epidural and subgaleal hematomas are rare complications of sickle cell crises (Dahdaleh et al., 2009).

Fig. 49B.5 Magnetic resonance image of brain of an 8-year-old girl with sickle cell disease shows multiple cortical and subcortical infarcts.

The most common neurological signs are hemiparesis, speech abnormalities, focal seizures, gait dysfunction, headaches, and neurocognitive deficits. Seizures occur in 12% to 14% of patients with sickle cell disease. Triggering factors include CNS infections, chest syndrome, trauma, hypertension, nephrotic syndrome, and nocturnal hypoxemia. Seizures may be the presenting manifestation of an infarction or vascular insufficiency. In the Cooperative Study of Sickle Cell Disease, seizures were an independent risk factor for silent infarction.

Prengler and coworkers (2005) evaluated 76 patients with sickle cell disease with transcranial Doppler studies and perfusion MRI. All patients with seizures had decreased cerebral perfusion ipsilateral to an electrocardiographic abnormality, suggesting that a complex mechanism of large- and small-vessel disease and hypoperfusion plays a role in the pathogenesis of seizures.

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) reported in 1998 that long-term transfusion therapy to decrease the levels of hemoglobin S to less than 20% to 30% reduced the risk of stroke in high-risk patients (Adams et al., 1998). Silent cerebral infarction is the most frequent neurological complication in patients with sickle cell disease. It is reported in as many as 28% of children with sickle cell disease, who have suffered a clinically evident stroke and is associated with lower cognitive scores and poor academic achievement (Kwiatkowski et al., 2009). An ongoing silent cerebral infarct transfusion trial (SIT) is comparing blood transfusion versus observation, with the plan to determine new standard care practices to reduce neurological morbidity (Casella et al., 2010). Hydroxyurea has shown efficacy in preventing stroke in earlier studies. However, the pediatric hydroxyurea phase III clinical trial (BABY HUG) is facing many challenges (Thompson et al., 2010).

Children with sickle cell disease are susceptible to infections with Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae, which can involve the CNS. Sinus venous thrombosis, posterior reversible leukoencephalopathy, and acute demyelination are other complications. Moyamoya disease is a relatively uncommon neurovascular complication of sickle cell disease and is a risk factor for stroke and transient ischemic episodes despite prophylactic blood transfusion. Encephaloduroarteriosynangiosis (EDAS) procedures constitute an effective treatment option for moyamoya disease, with promising results (Fryer et al., 2003).

Partial exchange transfusion is standard therapy in the setting of occlusive crisis and ischemic injury. Indications for anticoagulation are dissection and sinus venous thrombosis, especially with coexistent prothrombotic abnormalities and recurrent stroke. Bone marrow transplantation sometimes is offered. Emerging prophylactic regimens include citrulline, arginine, aspirin, and overnight oxygen supplementation (Kirkham et al., 2006).

Hemophilia

Studies show that 42% of patients with hemophilia B and 34% of patients with hemophilia A suffer neurological complications. These include intracranial hemorrhage, peripheral nerve lesions due to intramuscular hemorrhage after minor injuries, and spontaneous hematoma formation in the groin or other closed anatomical spaces. Femoral nerve involvement is the most commonly reported. Other affected nerves are the lumbosacral plexus, median nerve, radial nerve, and lateral cutaneous nerve. Hemophilic “pseudotumor” in the spinal canal and cranium have been described, as well as spinal epidural and subdural hematomas presenting as back pain and torticollis (Cuvelier et al., 2006).

Klinge and associates (1999) reported the incidence of intracranial hemorrhage in 42.5% of patients with hemophilia A or B. Bleeding occurred within 1 week of birth in 41% of cases. Trauma, the most important factor, occurred in 57% of cases either during birth (30%) or later (27%). Sixty-three percent had seizures, and 1 of the 33 patients died. Psychomotor retardation occurred in 59% and cerebral palsy in 45% of cases. Nelson and colleagues (2000) evaluated the incidence and sequelae of 2- to 5-mm focal white-matter hyperintensities on T2-weighted images in hemophiliac patients and reported no correlation with neurological factors; the investigators concluded that the findings were incidental. Prompt performance of CT is critical for early recognition of the presence of hemorrhage and institution of therapy.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) shares many features with hemolytic-uremic syndrome. This disorder occurs mainly in adults, and understanding of the childhood form is incomplete. The diagnosis requires at least two major criteria (thrombocytopenia, Coombs-negative microangiopathic hemolytic anemia, neurological dysfunction) and two minor criteria (fever, renal dysfunction, circulating thrombi). The pathogenesis is unknown but is linked to exposure to chemotherapy agents, birth control pills, and cyclosporine; an association with infections also is recognized. The microangiopathy of TTP can affect any organ but predominantly targets the CNS, kidneys, pancreas, heart, and adrenal glands. Purpura is the initial manifestation in more than 90% of cases. Thrombosis of small arterioles, venules, and capillaries leads to cerebral microinfarctions. Petechial hemorrhages occur in the gray matter. Neurological symptoms consist of lethargy, headache, confusion, and visual and speech disturbances. Corticosteroids are useful in mild cases. Plasma exchange, performed in severe cases, has improved survival.

Hemolytic-Uremic Syndrome

Hemolytic-uremic syndrome frequently follows an episode of gastroenteritis caused by an enteropathogenic strain of Escherichia coli (O157:H7). However, it also follows Shigella, Salmonella, Campylobacter, and viral infections. The organisms release a toxin called verotoxin, causing endothelial injury. The syndrome is more common in children younger than 4 years of age and is the most frequent cause of acute renal failure in young children.

Familial hemolytic-uremic syndrome has been described with both autosomal dominant and autosomal recessive forms. Neurological complications predict a severe outcome and may include encephalopathy, seizures, stroke, behavioral changes, and blindness.

Hepatic Encephalopathy

Hepatic encephalopathy can complicate liver failure, whether acute, subacute, or chronic. The most common causes of liver failure in children are fulminant viral or autoimmune hepatitis, drug ingestion (acetaminophen, salicylates, valproic acid), Reye syndrome, mitochondrial diseases, galactosemia, tyrosinemia, and Wilson disease.

Understanding of the pathogenesis, which probably is multifactorial, is incomplete. The role of ammonia as a main causative agent has been widely studied. In 10% of patients with hepatic encephalopathy, however, serum ammonia levels are normal. Implicated agents include γ-aminobutyric acid (GABA), mercaptans, β-phenylethanolamine, tyramine, and octopamine. Ammonia has a direct effect on the neuronal membranes. Both ammonia and GABA cause postsynaptic inhibition.

Clinically evident encephalopathy in children with chronic liver disease appears to be less common than in adults. It is possible, however, that encephalopathy is underdiagnosed in children because of its more subtle manifestations. Irritability and lethargy are the most common signs. The neurological examination may demonstrate pyramidal signs changing to hypotonia, focal findings, early parkinsonian syndrome, ataxia, tremor, and dysarthria. Asterixis is a characteristic flapping tremor seen in hepatic encephalopathy but also can be seen in other metabolic encephalopathies. Seizures can occur in 10% to 30% of patients.

Hepatic encephalopathy progresses over four stages. The signs and symptoms in stages 3 and 4 are similar in adults and in children. Stages 1 and 2 carry certain modifications in the pediatric population.

Intracranial hypertension and cerebral edema are invariably present in stage 4, potentially leading to poor cerebral perfusion, anoxic injury, and brainstem herniation. The last is the most common cause of death seen on postmortem examination.

Metabolic derangements such as hypoglycemia, metabolic and lactic acidosis, hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia can complicate the course of the disease in addition to renal failure. Coagulopathy and thrombocytopenia, although uncommon, can cause intracranial hemorrhage.

The electroencephalogram (EEG) reveals very early slowing of the alpha rhythm, progressing to delta frequencies with evolution of the encephalopathy. Triphasic waves may be seen at a late stage and usually portend a poor prognosis. Brain imaging reveals edema and atrophy. Spectroscopy shows elevation in glutamine. The cerebrospinal fluid contains elevated concentrations of glutamine and α-ketoglutarate.

Management includes ammonia-lowering measures with protein restriction, lactulose, and bowel decontamination with neomycin. Flumazenil, a benzodiazepine receptor antagonist, reduces the severity of hepatic encephalopathy. Management of cerebral edema involves restriction of fluids, use of hyperosmolar agents, and hyperventilation. Interest has been increasing in the use of liver support devices such as cleansing devices or bioartificial liver support systems. The use of disease-specific therapies such as N-acetylcysteine for acetaminophen toxicity and the correction of metabolic disturbances and coagulopathy are very important measures in the management of hepatic encephalopathy.

Liver Transplantation

Advances in medical and surgical techniques in liver transplantation have improved long-term posttransplantation survival, with reported 5-year survival rates of 80% to 90%. Liver transplantation has become the accepted standard of care in children with end-stage liver disease. Congenital biliary atresia is the most common reason for liver transplantation in children. Other causes are biliary micronodular cirrhosis, viral hepatitis, Alagille syndrome, and several rare genetic disorders.

Neurological problems occur in 48% of pediatric orthotopic liver transplant recipients. A majority involve seizures, mental status changes, or coma. Three-fourths of comatose patients had significant intracerebral hemorrhage on brain imaging. Neurological complications constitute a significant source of mortality and morbidity in these patients. Ghaus and associates (2001) reviewed data for 41 adults and pediatric patients who underwent liver transplantation. Encephalopathy occurred in 62%, with either immediate or delayed onset. Seizures (multifocal myoclonus, focal, or status epilepticus) occurred in 11% and were associated with the presence of encephalopathy. Three patients had neuropathy. Other complications were headache, tremor, fatigue, restlessness, enuresis, dizziness, critical illness myopathy, and detached retina. Erol et al. (2007) found seizures to be the most common neurological complications of liver transplantation. Brain imaging revealed atrophy, subarachnoid hemorrhage, intracerebral hemorrhage, focal cerebritis, meningitis and posterior reversible encephalopathy syndrome. Drug toxicity may occur with use of cyclosporine, tacrolimus, or corticosteroids, in addition to the development of infections (from Candida albicans, Pseudomonas aeruginosa, Staphylococcus aureus, vancomycin-resistant enterococci, Mycobacterium tuberculosis, and other opportunistic pathogens such as Aspergillus fumigatus and Listeria monocytogenes). Late posttransplantation complications include infections with CMV and Epstein-Barr virus (EBV), lymphoproliferative disease, chronic rejection, biliary strictures, and hepatic artery and vein thrombosis.

Thyroid Disorders

Parathyroid Disorders

Hypoparathyroidism is the result of parathyroid hormone (PTH) deficiency secondary to either aplasia or hypoplasia of the parathyroid gland seen with some genetic syndromes (DiGeorge syndrome), PTH gene mutations, PTH receptor defects (pseudohypoparathyroidism), autoimmune parathyroiditis, infiltrative lesions, and removal or damage to the parathyroid glands surgically. The end result is hypocalcemia. The neurological signs and symptoms of hypocalcemia include muscular pain, cramps, tetany, apnea, seizures, numbness, stiffness, and increased intracranial pressure with headaches and vomiting.

Hyperparathyroidism results in hypercalcemia and can manifest with muscular weakness, anorexia, nausea, vomiting, encephalopathy, polydipsia, polyuria, and weight loss. Headaches, seizures, and psychiatric symptoms also may be features.

Adrenal Gland Dysfunction

Pituitary Disorders

Panhypopituitarism can occur with septo-optic dysplasia (De-Morsier syndrome), holoprosencephaly, and Laurence-Moon-Biedl syndrome. The neurological symptoms depend on the deficient hormones and specific features of the genetic conditions. Diabetes insipidus manifests with irritability, polyuria, and polydipsia. If left untreated, the disorder progresses to coma and death.

Pituitary adenomas can cause headaches, visual disturbances, hydrocephalus, cranial nerve palsies, and seizures. Growth hormone–secreting adenomas cause gigantism in children and adolescent acromegaly. Clinical features include headaches, visual disturbances, myopathy, and carpal tunnel syndrome.

Diabetes Mellitus

Diabetes mellitus type 1 (DM1) is the most common endocrine disorder of childhood. The chronic complications of diabetes mellitus have been increasingly studied. The incidence of diabetic neuropathy with onset of DM1 in childhood reaches 28% to 40% after 20 years of symptoms and 70% after 30 years. Clinical diabetic neuropathic pain (DNP) is uncommon in children and adolescents but are detectable by neurophysiological studies.

Nery Ferreira and colleagues (2005) evaluated 48 children with DM1 for periods ranging from 5 to 10 years. Neurological complaints such as lower extremity pain and numbness were reported by 6.3% of patients. Almost 65% exhibited abnormalities on examination consistent with neuropathy: absence of deep tendon reflexes and vibration sensation. Sixty percent showed changes in motor and sensory nerve conduction. El Bahri-Ben Mrad and colleagues (2000) reported a 10% incidence of clinical neuropathy, compared with 29% with neurophysiological evidence, predominantly in the legs.

A longitudinal epidemiological study of the evolution of diabetic microvascular disease and autonomic function revealed a substantial prevalence of microvascular and neurological abnormalities (Karavanaki and Baum, 1999). Reduced pupillary adaptation in darkness was noted in 7.9% of patients and impaired vibration sensation in the lower extremities in 6.2%. Low sensory nerve conduction and autonomic dysfunction were findings in 25% of newly diagnosed diabetic children, whose disease was not yet under good control (Solders et al., 1997). Turgut and associates (2004) suggested that monitoring of the dorsal sural sensory nerve action potential (SNAP) is a sensitive method for detection of peripheral neuropathy in early stages of diabetes in children.

Nordwall and coworkers (2006) found evidence of subclinical neuropathy in 59% of children and adolescents with duration of diabetes longer than 3 years, despite intensive insulin treatment and good control.

Cranial neuropathies (III, IV, VI) are rare in children. Polyradiculopathy, a well-documented complication of diabetes in adulthood, rarely occurs in diabetic children and adolescents. Carpal tunnel syndrome is uncommon. The incidence of stroke is higher in diabetic children than in the general population.

Diabetic ketoacidosis is the most serious complication of diabetes and the most common cause of death. Cerebral edema develops in 1% of the cases and occurs rarely in diabetics older than 20 years. The attributed etiology of cerebral edema is retention of intracellular osmolytes in the brain during hydration, causing a shift of water into the intracellular space. Signs of cerebral edema include agitation, confusion, lethargy, headache, emesis, and incontinence (Muir et al., 2004).

Prevention of cerebral edema is by gradual rehydration over 48 hours and avoidance of hypotonic fluids. Treatment consists of mannitol, fluid restriction, and hyperventilation.

Rare cases of extrapontine and central pontine myelinosis have been described after treatment of diabetic ketoacidoses and were attributed to rapid correction of hyperosmolality (Sivaswamy et al., 2007). Hypoglycemia, a known complication of diabetic treatment, usually occurs at night or during early morning hours. Shehadeh and coworkers (1998) reported that 32% of pediatric diabetic patients experienced at least one severe hypoglycemic episode. Variable neurological signs and symptoms such as confusion, tremor, seizures, behavioral changes, blurred vision, transitory hemiparesis, and coma occurred in all of the cases. One patient had permanent hemiparesis.

Renal Failure

Acute or chronic renal failure leads to multiple metabolic and vascular derangements that can affect the CNS and peripheral nervous system.

Uremic encephalopathy manifests early on with fatigue, drowsiness, restlessness, and reduced attention span. These symptoms can fluctuate. Mild headaches can exist mainly during dialysis. Severe headaches usually occur with concomitant hypertension. With the progression of azotemia, anorexia and generalized weakness develop. Dysarthria, cramps, fasciculations, twitching, and asterixis may appear. Psychiatric symptoms include confusion, hallucinations, and frank psychosis. Myoclonic jerks, seizures, stupor, and coma occur in severe untreated cases.

Other features may include transient focal neurological signs such as transient loss of vision (uremic amaurosis). Cranial nerve palsies, hearing loss, gait disturbances, ataxia, tremor, monoplegia, and hemiplegia also may develop and sometimes are associated with ischemic injuries caused by hypertensive encephalopathy, ischemic stroke, or intracerebral hemorrhage.

Overt clinical distal motor and sensory symmetrical mixed polyneuropathy, affecting mainly the legs, is unusual in early childhood. Reduced peroneal motor nerve conduction velocities, however, are common in children on dialysis, even without clinical evidence of neuropathy. Autonomic dysfunction leading to postural hypotension occurs. Neuropathy is manifested early on with the restless legs syndrome, characterized by a pricking sensation and pruritus. Other features may include marked hypersensitivity to touch and a burning sensation in the feet known as the burning feet syndrome. The neuropathy can evolve into weakness, loss of deep tendon reflexes mainly at the knees and ankles, and distal sensory loss. Histopathological changes consist of degeneration and segmental demyelination.

Psychometric studies have shown intellectual impairment in most patients with renal failure on dialysis. Hypertensive encephalopathy can occur in end-stage renal disease. Myoclonic jerks, focal or generalized seizures, and status epilepticus occur frequently in renal failure. Uremic seizures usually are myoclonic or generalized. The presence of focal seizures, therefore, suggests a structural brain lesion or coexisting pathology. The myoclonic jerks are nonrhythmical. They may be symmetrical or asymmetrical, stimulus-sensitive, and occasionally generalized. Rapid metabolic changes in blood pH and electrolytes and a rapid fall in urea levels are common antecedents. Myoclonus is best left untreated unless it is disabling. Clonazepam and valproic acid are the drugs of choice. The doses of anticonvulsant drugs will need adjustment, and frequent blood level monitoring is important in the management of seizures in patients with renal failure.

Complications of Dialysis

Renal Transplantation

Recent advances in surgical techniques and immunosuppression have greatly enhanced the outcome in renal transplantation and graft survival. Mir et al. (2004) analyzed data for 72 pediatric renal transplant recipients and reported hypertension in 31.9%, acute rejection in 27.8%, chronic rejection in 13.9%, and CMV infections in 20.8% of patients.

Rejection encephalopathy manifests with headaches, confusion, fever, irritability, and seizures. Symptoms develop within 3 months of transplantation in more than half of affected patients. Infections contribute significantly to transplantation-associated mortality and morbidity, developing in more than 80% of transplant recipients; of these, 5% to 10% are in the nervous system (meningitis, brain abscess). Three-fourths of intracerebral infections after renal transplantation are caused by Listeria. The causative organisms are Listeria monocytogenes, Cryptococcus, and Toxoplasma gondii. Aspergillosis is a more common cause of brain abscess. Infections with CMV and EBV rarely produce encephalitis.

The incidence of CNS lymphoma increases in transplant recipients and can manifest with focal neurological abnormalities, seizures, or increased intracranial pressure. Neurotoxicity secondary to the use of immunosuppressive agents such as cyclosporine, tacrolimus, and long-term corticosteroids is frequent. Clinical features include seizures, hypertensive encephalopathy, myalgia, tremor, and fatigue.

Qvist and colleagues (2002) studied neurodevelopmental outcome in 33 school-aged children who underwent transplantation before the age of 5 years; their mean IQ was 87. Neuropsychiatric testing was impaired in 6% to 24%. The children with learning problems had a greater number of hypertensive crises and seizures and a higher incidence of prematurity. Six of seven children attending a special school had evidence of brain infarcts on MRI. No significant difference existed in mean serum aluminum levels between these patients and children who had received transplants and who demonstrated normal school performance.