Neurological Complications of Systemic Disease: Adults

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Chapter 49A Neurological Complications of Systemic Disease*

Adults

Chapter Outline

Cardiac Disorders and the Nervous System

Diseases of the Aorta

Connective Tissue Diseases and Vasculitides

Respiratory Diseases

Systemic Inflammatory Response Syndrome

Sarcoidosis

Hematological Disorders with Anemia

Proliferative Hematological Disorders

Hemorrhagic Diseases

Antiphospholipid Antibody Syndromes

Liver Disease

Pancreatic Encephalopathy

Gastrointestinal Diseases

Renal Failure

Electrolyte Disturbances

Pituitary Disease

Diabetes Insipidus

Thyroid Disease

Parathyroid Disease

Adrenal Glands

Diabetes Mellitus

Cardiac Disorders and the Nervous System

Neurological complications are an important cause of morbidity in patients with cardiac disease. Cardiogenic emboli may result from cardiac disease or its surgical treatment, and cardiac dysfunction can cause global cerebral hypoperfusion leading to syncope, stroke, anoxic encephalopathy, or death, depending on the severity and duration of the ischemia.

Cardiogenic Embolism

Cardiogenic emboli are most prevalent in patients with atrial fibrillation with or without mitral stenosis, intramural thrombi, prosthetic cardiac valves, infective endocarditis, atrial flutter, and sick sinus syndrome. Other causes include recent myocardial infarction (MI), left atrial thrombus or turbulence, atrial myxoma, mitral annulus calcification and prolapse, hypokinetic left ventricular segments, and dilated cardiomyopathy. (Chapter 49B discusses emboli from congenital heart disease, a consideration in young people with either valvular heart disease or mitral valve prolapse.)

Echocardiography is an important investigative procedure in patients with suspected cardiogenic emboli. Transesophageal echocardiography is preferable to the transthoracic approach in the evaluation of suspected atrial diseases such as myxoma or thrombus and in the diagnosis of a patent foramen ovale. Transthoracic echocardiography is an important method of visualizing the ventricular apex, characterizing mitral or aortic valvular disease, and delineating left ventricular thrombus.

Transesophageal echocardiography is an appropriate method to investigate people younger than 55 years of age with suspected cardiogenic emboli who may need anticoagulation or surgery and in those with no clear source demonstrated on transthoracic echocardiography when suspicion for embolic source is high. Some have suggested that transesophageal echocardiography is appropriate in all patients with cryptogenic stroke (de Bruijn et al., 2006).

Embolus formation is more likely when atrial fibrillation is associated with valvular heart disease. The incidence of stroke among patients with atrial fibrillation, with or without rheumatic heart disease, is increased 17-fold or 5-fold, respectively. Atrial fibrillation in the absence of cardiovascular disease or other predisposing illness carries a considerably lower risk of neurological complications. The neurological prognosis for paroxysmal atrial fibrillation is not established, unlike that of chronic atrial fibrillation.

Anticoagulation has established benefit in reducing the risk of stroke in persons with atrial fibrillation. Consensus supports the use of long-term oral warfarin therapy for atrial fibrillation in most cases. Risk stratification systems are helpful in deciding whether anticoagulation is warranted (Gage et al., 2001). Aspirin (325 mg/day) is the recommended agent when warfarin is contraindicated. Recent studies suggest that addition of clopidogrel (75 mg/day) is also worthwhile (Connolly et al., 2009). Standard practice is to start warfarin at least 3 weeks before elective cardioversion in patients with atrial fibrillation of more than 2 days’ duration. Warfarin therapy is continued at least until a normal rhythm has been maintained for 4 weeks. Myocardial infarcts, especially apical, anterolateral, or large infarcts, carry a risk of embolic stroke. In most cases, infarction occurs within a week, but the risk persists for approximately 2 months. Therefore, it is recommended to use heparin for those patients not on thrombolytic therapy after MI, and to continue warfarin for 3 months if they have an increased risk of embolism. The groups with increased risk are those with congestive heart failure, previous emboli, a mural thrombus, left ventricular dysfunction, substantial wall motion abnormalities, or atrial fibrillation.

Emboli are an important cause of death in people with rheumatic valvular disease. The risk of embolism increases in the presence of atrial fibrillation or intraatrial thrombus or in patients with a history of emboli; long-term warfarin treatment is the recommended treatment. Addition of low-dose aspirin (50-100 mg/day) is recommended for recurrent systemic emboli or left atrial thrombus despite adequate warfarin therapy.

Mitral valve prolapse is a common anomaly, especially in young women, and is a recognized source of cerebral emboli. The risk of embolism is relatively small, and long-term warfarin therapy is the recommended treatment for persons who have had previous embolic phenomena or are in atrial fibrillation. Aspirin therapy (50-325 mg/day) is the recommended treatment for patients with mitral valve prolapse and transient cerebral ischemic attacks of uncertain nature.

Patent foramen ovale is common in asymptomatic subjects and does not seem to be a risk factor with cryptogenic ischemic stroke or transient ischemic attacks (TIAs), especially when small or occurring as an isolated cardiac abnormality. Those that are large or associated with an atrial septal aneurysm are at higher risk of stroke, but whether to choose treatment with aspirin, warfarin, or surgical or percutaneous closure for stroke prophylaxis is unclear.

Among patients with a history of cardiogenic emboli, recurrent stroke is more likely in those with cardiac valve disease and congestive heart failure. Nevertheless, the main cause of death in such patients is from the heart disease itself rather than neurological complications. The conversion of a cerebral infarct into a hemorrhage is a concern when patients with stroke from cardiogenic emboli are anticoagulated. The concern is especially justified in patients with large infarcts or when imaging studies suggest preexisting hemorrhagic transformation. With small infarcts, it is good practice to initiate anticoagulation therapy only if initial computed tomography (CT) shows no evidence of major hemorrhagic transformation. With large infarcts, delay anticoagulation for 3 to 7 days, and when indicated, begin with warfarin alone without bridging heparinoids.

Syncope

Transitory global cerebral ischemia secondary to cardiac arrhythmia often causes syncope. Most normal people have fainted at least once. Nonspecific premonitory symptoms such as visual disturbances, paresthesias, and lightheadedness may precede the syncope (Soteriades et al., 2002). Syncope usually is associated with loss of muscle tone, but prolonged ischemia causes tonic posturing and irregular jerking movements that are easily mistaken for seizures (Stokes-Adams attacks). The syncopal patient is pale, and postictal confusion is absent or short lived, usually lasting less than 30 seconds. Obstructed outflow from aortic stenosis or left atrial tumor or thrombus is one cardiac cause of syncope. Other causes are arrhythmias, especially from ventricular tachycardia or fibrillation, chronic sinoatrial disorder or sick sinus syndrome, and paroxysmal tachycardia. Placement of implantable loop recorders allows the recording of electrocardiographic data during spontaneous syncopal events. This strategy increases the diagnostic rate and permits appropriate treatment to be instituted (Farwell et al., 2006). Arrhythmia is detectable in 25% to 46% of patients with syncope, and another 24% to 42% will be in sinus rhythm during a clinical event, which is therefore not attributable to a disturbance of cardiac rhythm (McKeon et al., 2006). Additional causes of syncope are central and peripheral dysautonomias, postural hypotension, and endocrine and metabolic disorders. (Discussions of vasovagal syncope and the prolonged QT-interval syndrome are in Chapter 49B.)

Cardiac Arrest

Brain function is critically dependent on the cerebral circulation. The brain receives approximately 15% of the total cardiac output. Ventricular fibrillation or asystole leads to circulatory failure, which can cause irreversible anoxic-ischemic brain damage if it lasts for more than a critical time. The prognosis generally depends on age, the duration of the arrest before institution of cardiopulmonary resuscitation, and the interval before initiation of defibrillating procedures. The prognosis is better when the cause of circulatory arrest is ventricular fibrillation rather than asystole.

The pathophysiology of neurological damage secondary to transitory interruption of cerebral blood flow is unclear. Suspected mechanisms are the accumulation of intracellular calcium, increased extracellular concentrations of glutamate and aspartate, and increased concentrations of free radicals.

In the mature brain, gray matter generally is more sensitive to ischemia than white matter, and the cerebral cortex is more sensitive than the brainstem. (The premature brain has the reverse pattern of sensitivity; see Chapter 60.) Cerebral or spinal regions lying between the territories supplied by the major arteries (watershed areas) are especially vulnerable to ischemic injury.

The severity of neurological complications of circulatory arrest correlates with the duration of the arrest. Brief arrests (<5 minutes in duration) cause temporary loss of consciousness and impaired cognitive function. A demyelinating encephalopathy may occur to 10 days later. Characteristic of the encephalopathy are increasing cerebral dysfunction with cognitive disturbances and pyramidal or extrapyramidal abnormalities that may lead to a fatal outcome. Thus, some patients regain consciousness after several hours, with the subsequent development of progressive neurological deficits affecting cognitive and cortical function: intellectual decline, seizures, visual agnosia, cortical blindness, amnestic syndromes, and personality changes. Less common residua are the locked-in syndrome, parkinsonism and other extrapyramidal syndromes, abnormal ocular movements, bilateral brachial paresis, and action myoclonus. Spinal cord dysfunction is uncommon and usually involves the watershed region at T5; flaccid paraplegia with sensory loss, areflexia, and sphincter dysfunction are the immediate findings.

Prolonged cardiac arrest causes widespread and irreversible brain damage characterized by prolonged coma leading to a persistent vegetative state. Prolonged coma and loss of brainstem reflexes indicate a poor prognosis for survival or useful recovery. Therapeutic hypothermia initiated rapidly after the arrest improves neurological outcome (Bernard et al., 2002). Absence of the pupillary response to light and absence of motor recovery better than extensor posturing at 72 hours are perhaps the most useful clinical guides to prognosis (see Chapter 5 for further discussion). These features of the clinical examination, along with measurement of neuron-specific enolase and recording of median-derived somatosensory evoked potentials (to determine whether the N20 component is absent bilaterally), can be helpful in prognostication, although recent data question whether these same tests and time frames apply in patients treated with hypothermia (Rossetti et al., 2010).

Complications of Cardiac Catheterization and Surgery

Cardiac catheterization in adults causes large cerebral emboli in less than 1% of cases; for unexplained reasons, these more often involve the posterior than the anterior circulation. The frequency of large cerebral emboli after percutaneous transluminal coronary angioplasty is less than 1% and may involve either the carotid or vertebral circulation. The risk of stroke, however, is greater in patients with acute MI treated by angioplasty.

Hypoxia and emboli are the usual causes of “post-pump” encephalopathy, seizures, and cerebral infarction after cardiac surgery. Type of surgery, symptomatic cerebrovascular disease, diabetes mellitus, and advanced age are important risk factors for neurological complications (Boeken et al., 2005). Ascertaining the degree of functionally significant cerebrovascular disease is an essential part of the preoperative evaluation (McKhann et al., 2006). The causes of postoperative psychoses or encephalopathy are metabolic disturbances, medication, infection, and multiorgan failure. Intracranial infection should be suspected when behavioral disturbances develop several weeks postoperatively in patients receiving immunosuppressive agents. The usual causes of postoperative seizures are focal or generalized cerebral ischemia, electrolyte or metabolic disturbances, and multiorgan failure. Intracranial hemorrhage is a rare complication of cardiopulmonary bypass. Cognitive changes after cardiac bypass surgery are detectable in 53% of patients at discharge, some of which persist. However, the previously described late cognitive decline that occurs years following cardiac bypass surgery is similar to that found in age-matched patients with coronary artery disease managed without surgery (Selnes et al., 2008). Compression or traction injuries to the brachial plexus, especially the lower trunk, and the phrenic and recurrent laryngeal nerves may occur during cardiac surgery. Other common early complications of cardiac transplantation are organ rejection followed by cardiac failure and the side effects of immunosuppressive drugs. Cerebral air embolism may require hyperbaric oxygen therapy combined with aggressive resuscitation (Hinkle et al., 2001). Infection (meningitis, meningoencephalitis, or cerebral abscess) secondary to immunosuppressive therapy is the most important late complication. The infecting organisms include Aspergillus, Toxoplasma, Cryptococcus, Candida, Nocardia, and viruses including JC virus. An increased risk of lymphoma and reticulum cell sarcoma has been observed in patients on long-term immunosuppressive agents. Primary central nervous system (CNS) lymphoma may be difficult to distinguish clinically or radiologically from infection, and biopsy may be necessary (see Chapters 33A and 52C).

Stroke occurs in approximately 5% of patients undergoing coronary artery bypass surgery. The risk is increasing because of the increasing number of procedures in older patients with more severe vascular disease, and in complicated combined procedures such as bypass surgery plus valve replacement (Nussmeier, 2002). Other risk factors include proximal aortic atherosclerosis, hypertension, diabetes, and female gender. The mechanism is either embolic or, less commonly, a watershed infarction from hypoperfusion. A history of previous stroke also increases the risk, but a carotid bruit or radiological evidence of atherosclerotic disease of the carotid artery does not. Carotid endarterectomy preceding cardiac surgery is not justified.

A few patients who fail to recover consciousness after surgery, despite the absence of any metabolic cause, probably have suffered diffuse cerebral ischemia or hypoxia. Hemispheric or multifocal infarction (Fig. 49A.1) is responsible in some cases. In evaluating patients with postoperative neurological deficits, diffusion-weighted magnetic resonance imaging (MRI) is more sensitive than CT to ischemic change and may reveal multiple small embolic infarcts (Wityk et al., 2001).

Neurological Complications of Medication

Infectious and neoplastic complications of immunosuppressive agents have already been discussed in previous sections. Other adverse effects associated with corticosteroid treatment are behavioral disturbances, psychoses, postural tremor, cataracts, osteoporotic fractures, and proximal weakness with type II muscle fiber atrophy. Benign intracranial hypertension may occur during treatment with or on withdrawal of corticosteroids. Neurological complications of cyclosporine and other calcineurin inhibitors include tremor, seizures, focal deficits, paresthesias, encephalopathy, and ataxia. Sirolimus is an alternative immunosuppressant in solid-organ transplant and appears to have less neurotoxicity than the calcineurin inhibitors.

Among antiarrhythmic agents, amiodarone causes tremor, sensorimotor peripheral neuropathy, myopathy, ataxia, optic neuropathy, and pseudotumor cerebri. Procainamide may unmask latent myasthenia gravis or precipitate a lupus-like syndrome with secondary vascular occlusive complications that probably are associated with lupus anticoagulant and antiphospholipid antibodies. Quinidine has neurological side effects similar to those of procainamide and causes headache, tinnitus, and syncope.

Lidocaine and related agents may cause seizures, tremor, paresthesias, and confusional states. Calcium channel–blocking agents occasionally cause encephalopathy. Beta-blockers are associated with mental changes, paresthesias, and disturbances of neuromuscular transmission, and digoxin and thiazide diuretics with an encephalopathy and disturbances of color vision.

Infective Endocarditis

The incidence of infective endocarditis has been increasing because of intravenous substance abuse and the increasing use of prosthetic cardiac valves. The overall incidence of neurological complications of infective endocarditis is approximately 25% to 35% but varies with the infecting organism. Such complications are the initial sign or major complaint in 25% to 50% of patients and are associated with a significantly higher mortality rate. Neurological manifestations are especially common in patients with mitral valve abnormalities and consist of embolic or hemorrhagic stroke and infections such as meningitis or brain abscess.

Cerebral mycotic aneurysms (Fig. 49A.2) are recognized complications of infective endocarditis and may result in intracranial hemorrhage. They are generally more distally located than congenital berry aneurysms. The pathogenesis of mycotic aneurysms is unclear. The most likely cause is impaction of infected material in the vasa vasorum, with resulting destruction of the wall of an artery. Intraluminal occlusion of the vessel by infected material, with subsequent aneurysmal formation, is less likely but has been documented in some cases. Mycotic aneurysms may be clinically silent and sometimes resolve with antibiotic therapy. They are less common but occur earlier in acute than in subacute bacterial endocarditis. Their natural history is unknown.

Intracranial hemorrhage is also caused by septic arteritis that destroys the vessel wall without causing aneurysm and by hemorrhagic transformation of cerebral infarcts. Arteriography distinguishes intracranial hemorrhage from mycotic aneurysm from septic arteritis.

Intracranial bleeding from a ruptured mycotic aneurysm can be the initial feature of an underlying cardiac disorder or may occur during the management of a recognized infective endocarditis. Every patient with infective endocarditis who has a subarachnoid hemorrhage requires four-vessel arteriography. Arteriography should be performed before initiation of anticoagulation therapy unless the neurological symptoms developed after an appropriate course of antibiotics.

Embolization of infected material causes cerebral microabscesses and meningitis. Multiple septic emboli may cause meningoencephalitis or a diffuse encephalopathy characterized by a confusional state, headache, meningismus, and a cerebrospinal fluid (CSF) profile suggesting an aseptic process. The basis of these symptoms probably is multifactorial: infection, vascular occlusion, metabolic abnormalities, and mycotic aneurysms.

Antibiotic therapy to resolve the cardiac infection is the mainstay of treatment and is important in preventing neurological complications (Heiro et al., 2000). Neurological abnormalities usually resolve. Patients with progressive or persistent neurological deficits or abnormalities on CSF examination require imaging studies. MRI findings suggestive of mycotic aneurysm necessitate arteriography. Once mycotic aneurysms have ruptured, curative surgical or endovascular treatment is necessary to prevent re-rupture. Management of unruptured mycotic aneurysms is less clear, and many advocate conservative management with antibiotics and serial imaging. Anticoagulants are usually withheld from patients with infective endocarditis and cerebral embolism until after appropriate antibiotic therapy, owing to the risk of rupture of an unrecognized mycotic aneurysm. Anticoagulation also may increase the risk of hemorrhagic transformation of embolic infarcts.

Diseases of the Aorta

The aorta supplies blood to the CNS and peripheral nervous system (PNS). Several neurological syndromes result from aortic disease, depending on the site and severity of obstruction.

Spinal cord ischemia may result from congenital aortic abnormalities such as coarctation, acquired disorders such as aortic aneurysm or occlusive atherosclerotic disease, and aortic surgery or aortography. The level of myelopathy depends to some extent on the site of aortic disease. In general, aortic pathology that causes cord ischemia is above the origin of the renal arteries; obstruction at a more distal point is less likely to affect the segmental vessels that feed the spinal cord. Risk factors for cord ischemia during aortic surgery include the presence of dissection, extensive thoracoabdominal disease, and a long cross-clamp time. The thoracic cord is more susceptible to ischemia than the cervical and lumbosacral regions.

Spinal cord ischemia from aortic disease usually causes a complete transverse myelopathy or an anterior spinal artery syndrome. Clinical features include weakness, loss of sphincter control, and impaired pain and temperature appreciation below the level of myelopathy. Spasticity, hyperreflexia, and bilateral extensor plantar responses eventually replace the initial flaccidity and areflexia. The existence of a true posterior spinal artery syndrome is doubtful, because the posterior spinal arteries have multiple feeding vessels along their length. Occasional reports of a clinical disorder resembling progressive spinal muscular atrophy have been attributed to cord ischemia from aortic disease affecting the anterior horn cells especially.

Neurogenic claudication may be caused by ischemia of the nerve roots or cauda equina (as from a protruded lumbar disk in spinal stenosis), by intermittent cord ischemia from spinal vascular malformations, or by aortic disease. Pain, weakness, or a sensory disturbance develops in one or both legs during walking or in relation to certain postures. Rest or change of posture relieves the symptoms. The distinction between neurogenic claudication and the intermittent claudication of peripheral vascular disease is important, because their treatments are different.

Disease of the aortic arch or its main branches also may lead to transient cerebral ischemic attacks or strokes. Estimates of the risk of embolization from the aortic arch have been low until recently, especially in patients older than 60 years. Transesophageal echocardiography is an important means of evaluating the aortic arch, although less invasive means such as CT or MR angiography are gaining favor. Antiplatelet drugs remain the treatment of choice for cerebral embolism due to aortic arch disease.

Connective Tissue Diseases and Vasculitides

Neurological complications may be direct consequences of connective tissue diseases or may be secondary to other organ involvement or to treatment. (The adverse effects of corticosteroids and immunosuppressive agents were discussed earlier in the chapter.) Autoimmune inflammatory responses, especially necrotizing vasculitis, characterize connective tissue disorders. The mechanism of vasculitis is uncertain but may involve the deposition of immune complexes in vessel walls or cell-mediated immunity and release of lymphokines; autoantibodies also may be important in some instances. The common direct CNS manifestations of connective tissue diseases are cognitive or behavioral changes and focal neurological deficits. Peripheral neuropathies also occur and may take the form of a vasculitic neuropathy, distal axonal polyneuropathy, compression neuropathy, sensory neuronopathy, trigeminal sensory neuropathy, acute or chronic demyelinating polyneuropathy, or plexopathy.

The cause of vasculitic neuropathy is nerve infarction from occlusion of the vasa nervorum. A mononeuropathy multiplex develops that becomes increasingly confluent with increasing nerve involvement until it resembles a distal symmetrical polyneuropathy. Nerves in watershed regions that lie between different vascular territories, such as the mid-thigh or mid- to upper arm, are more likely to be involved. Both large and small fibers are affected. Treatment with corticosteroids, often in conjunction with other immunosuppressive therapy, usually is effective (Burns et al., 2007), but intravenous immunoglobulin may be helpful in resistant cases (Levy et al., 2005).

Polyarteritis Nodosa, Churg-Strauss Syndrome, and Overlap Syndrome

Peripheral neuropathy occurs in up to 60% of patients with polyarteritis nodosa, Churg-Strauss syndrome, or overlap syndrome. Usually a painful mononeuropathy multiplex, at least in polyarteritis, develops during the first year. As more nerves are affected, the deficits become more confluent and come to resemble a polyneuropathy. A few patients exhibit only patchy hypesthetic areas; in others, a secondary polyneuropathy (e.g., from renal failure) may develop. A plexopathy, radiculopathy, or cauda equina syndrome also can develop. Electrophysiological studies and nerve histology are often abnormal even in the absence of clinical evidence of peripheral nerve involvement.

CNS involvement usually occurs later than peripheral involvement in the course of the disease. Common features are headache, which sometimes indicates aseptic meningitis, and behavioral disturbances such as cognitive decline, acute confusion, and affective or psychotic disorders. The electroencephalogram (EEG) sometimes shows diffuse slowing, but neuroimaging studies are generally normal. Focal CNS deficits are uncommon but are typically sudden in onset and may be caused by cerebral infarction (Fig. 49A.3) or hemorrhage. Angiography may not show the underlying vasculitis. Ischemic or compressive myelopathies from extradural hematomas are rare complications.

The 6-month survival rate for patients with untreated polyarteritis nodosa is only 35%. Prompt diagnosis and treatment are critical. Weight loss, fever, cutaneous abnormalities, and arthralgias are common, and hypertension and renal, cardiac, pulmonary, or gastrointestinal (GI) involvement may occur. Laboratory studies show multiorgan involvement and immunological abnormalities. Common abnormalities are an increased erythrocyte sedimentation rate (ESR), anemia, and peripheral leukocytosis. Hepatitis B surface antigen, hypocomplementemia, and uremia each occur in at least 20% of cases.

Patients with Churg-Strauss syndrome often have asthma and a marked peripheral eosinophilia; typically p-ANCA elevations are present. Nerve or muscle biopsy often shows the necrotizing vasculitis, and angiography reveals segmental narrowing or aneurysmal distention, especially in the renal, mesenteric, or hepatic vessels.

Treatment for these conditions is with corticosteroids combined with cyclophosphamide and has reversed the poor prognosis in this disease. With adequate combined therapy, approximately 60% of patients do well. Some are able to discontinue treatment by 2 years, although a subset will require lifelong therapy.

Rheumatoid Arthritis

Rheumatoid arthritis is the most common connective tissue disease. Discussion of juvenile rheumatoid arthritis is in Chapter 49B. Systemic vasculitis occurs in up to 25% of adult patients, but CNS involvement is rare. Pathological involvement of the cervical spine (Fig. 49A.4

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