Neurological Complications of Systemic Disease: Children

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Chapter 49B Neurological Complications of Systemic Disease


This chapter addresses a complex and diverse topic: the neurological complications of systemic disease in children. Although some clinical features are similar in children and in adults, others vary according to the child’s age and stage of development.

Cardiac Disorders and the Nervous System

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.

Chromosomal and Genetic Disorders

The combination of CHD and neurological disorders, mainly developmental delay, are sometimes manifestations of genetic conditions combining both cardiac and central nervous system (CNS) involvement. Such conditions include trisomy 21, trisomy 13, trisomy 18, Williams syndrome, DiGeorge syndrome, and velocardiofacial syndrome. Chromosomal microarray analysis, also known as array-based comparative genomic hybridization (CGH), has recently become an extremely valuable diagnostic tool, allowing the detection of subtle genomic imbalances undetected by conventional chromosome analysis. Lu et al. (2008) studied 101 patients with CHD with or without other malformations such as cleft palate, club foot, and polydactyly, and array-based CGH detected significant abnormalities in 21.8% of patients. Richards et al. (2008) also found that children with CHD and other anomalies, specifically neurological problems, had a higher incidence of cryptic chromosomal abnormalities detected by CGH, which were not detected by conventional karyotyping. The authors advocated screening patients with CHD and neurological abnormalities such as developmental delay with chromosomal microarray analysis.

Neurological Complications Unrelated to Intervention and Cardiac Surgery

Cerebrovascular Accidents in Uncorrected Congenital Heart Disease

The incidence of stroke (CVA) in children with CHD unrelated to surgery or endocarditis is 1.5% to 2%. The most commonly associated cardiac anomalies are tetralogy of Fallot and dextroposition of the great arteries. Children with cyanotic CHD or right-to-left shunt have a higher incidence of stroke because of relative anemia, which leads to increased blood viscosity. Strokes may be arterial or venous in origin and either embolic or thrombotic. Cardiogenic stroke can result from emboli arising from the right heart or systemic venous circulation through a right-to-left shunt (paradoxical emboli) or from an intracardiac arterial embolic source. It also can result from cerebral venous thrombosis secondary to the combination of polycythemia, venous stasis and central venous hypertension. Hemiplegia is the most frequent clinical finding, Other presenting features include sudden alteration in consciousness, seizures, and dysphasia or aphasia. Brainstem infarcts are rare; common clinical features are ataxia, dysphagia, cranial nerve palsies, and weakness.

Patients with acyanotic CHD and left-to-right shunt such as atrial septal defect (ASD), VSD, and patent ductus arteriosus (PDA) are not usually at risk for cardiogenic emboli because of the protection provided by the pulmonary vascular bed. Stroke can occur in rare cases if the direction of shunt flow reverses.

Congenital stenosis of the great vessels (e.g., aortic stenosis, pulmonary artery stenosis, coarctation of the aorta) contribute to the occurrence of CVA and neurological complications. The usual causes are bacterial endocarditis, arrhythmias, chronic hypoxia, and cerebral aneurysms, with their known association with coarctation of the aorta.

Infants who have CHD are at risk for intraventricular-periventricular hemorrhage because of vascular immaturity and systemic hemodynamic instability. Cranial ultrasound examination shows hemorrhage in 24% of term infants with CHD and an increased incidence of cerebral atrophy and linear echodensities in the basal ganglia and thalamus.

Brain Abscess

The incidence of brain abscess is higher in cyanotic CHD. Earlier report rates were 2% to 6%. In recent years, the incidence of brain abscess has decreased markedly because of earlier corrective surgery and more aggressive treatment of dehydration and infections. The occurrence of brain abscess is now largely confined to the developing world, where CHD goes uncorrected. Tetralogy of Fallot is the most common underlying cardiac lesion, followed by transposition of the great arteries. Brain abscesses are rare before the age of 2 years. In 75% of the cases, the lesion is supratentorial; in 20%, multifocal. The most common early presentation, often subtle, consists of headache in 50% of patients, vomiting in 72% of patients, personality change, and irritability. In some cases, the clinical onset can be abrupt, with seizures as the first clinical manifestation. Focal neurological signs and visual disturbances occur. Early on, as many as 75% of patients are afebrile. Eventually, papilledema and coma can occur. Computed tomography (CT) and magnetic resonance imaging (MRI) establish the diagnosis by revealing areas of hypodensity with contrast ring enhancement surrounded by edema. The usual causative organisms are mixed aerobic and anaerobic streptococci, staphylococci, Haemophilus, and occasionally gram-negative bacteria. Early detection at the stage of cerebritis allows a conservative approach with high-dose broad-spectrum antibiotic therapy for 3 to 6 weeks. Surgery sometimes is required, either by direct resection or CT-guided aspiration, depending upon the location of the abscess.

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.

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.

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.

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.

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)

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