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.

Connective Tissue Diseases and Vasculitides

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).