Neurological Complications of Systemic Disease: Adults

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 59 discusses emboli from congenital heart disease, a consideration in young people with valvular heart disease.)

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, in examination of the aortic arch, and in the diagnosis of a patent foramen ovale. Transesophageal echocardiography is an important method for visualizing the ventricular apex, characterizing mitral or aortic valvular disease, and delineating left ventricular thrombus.

Transesophageal echocardiography is an appropriate method for investigating people younger than 60 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 an embolic source is high. Some have suggested that transesophageal echocardiography is appropriate in all patients with cryptogenic stroke ( ).

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 rather than chronic atrial fibrillation has not been definitively established.

Anticoagulation has established benefit in reducing the risk of stroke in persons with atrial fibrillation. Consensus supports the use of long-term therapy for atrial fibrillation in most cases. Although warfarin was traditionally the oral anticoagulant of choice, both oral direct thrombin inhibitors (e.g., dabigatran) and oral factor Xa inhibitors (e.g., rivaroxaban, apixaban) have emerged as effective and commonly used alternatives for anticoagulation in nonvalvular atrial fibrillation ( ). Risk stratification systems are helpful in deciding whether anticoagulation is warranted ( ). Aspirin (325 mg/day) is the recommended agent when anticoagulation is contraindicated. Recent studies suggest that addition of clopidogrel (75 mg/day) may also be worthwhile when anticoagulation cannot occur, although with a higher risk of bleeding over aspirin alone ( ).

Standard practice is to start warfarin at least 3 weeks before elective cardioversion in patients with atrial fibrillation of more than 2 days’ duration. Anticoagulation therapy is then 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, the stroke occurs within a week, but the risk persists for approximately 2 months. Therefore it is recommended to use heparin for those patients who are not on thrombolytic therapy after MI and to continue anticoagulation 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 intra-atrial thrombus or in patients with a history of emboli; long-term warfarin 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 for cryptogenic ischemic stroke or transient ischemic attacks (TIAs), especially when they are small or occur as an isolated cardiac abnormality. Those that are large or associated with an atrial septal aneurysm are at higher risk of causing stroke, but treatment with aspirin, warfarin, or percutaneous closure is equally effective for stroke prophylaxis. Secondary prevention after incident stroke of unknown etiology should involve percutaneous closure of patent foramen ovale only if the patient is less than 60 years of age, the infarct appears embolic, and the patent foramen ovale is moderate to large in size provided that a thorough workup has excluded other potential causes of stroke ( ).

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 or a large number of asymptomatic microhemorrhages. With small infarcts, it is good practice to initiate anticoagulation therapy when initial computed tomography (CT) shows no evidence of major hemorrhagic transformation; with large infarcts, anticoagulation should be delayed for 3 to 7 days.

Syncope

Transitory global cerebral ischemia secondary to cardiac arrhythmia often causes syncope. Nonspecific premonitory symptoms—such as visual disturbances, paresthesias, and lightheadedness—may precede the syncope. 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. 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 or external event recorders allows the recording of electrocardiographic data during spontaneous syncopal events. This strategy increases the diagnostic rate and permits appropriate treatment to be instituted. 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 ( ). Additional causes of syncope are central and peripheral dysautonomias, postural hypotension, and endocrine and metabolic disorders. (Discussions of vasovagal syncope and the syndrome of prolonged QT interval may be found in Chapter 2 .)

Cardiac Arrest

Brain function is critically dependent on the cerebral circulation. The brain receives approximately 15% of total cardiac output. Ventricular fibrillation, pulseless ventricular tachycardia, 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, the initiation of therapeutic hypothermia when appropriate, and the interval before the 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 is generally more sensitive to ischemia than white matter, and the cerebral cortex and deep nuclei are more sensitive than the brainstem. (The white matter of the premature brain has increased sensitivity to injury; see Chapter 110 .) 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 may lead to impaired cognitive function. A demyelinating encephalopathy may occur up to 10 days later, even in those who initially seem to recover fully. 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, including 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 around 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, which leads 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 may improve the neurological outcome ( ). 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 these same tests and time frames may not apply in patients treated with hypothermia ( ).

Complications of Cardiac Catheterization and Surgery

Cardiac catheterization in adults causes large cerebral emboli in less than 1% of cases; for unexplained reasons, these emboli 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. The type of surgery, symptomatic cerebrovascular disease, diabetes mellitus, and advanced age are important risk factors for neurological complications ( ). Ascertaining the degree of functionally significant cerebrovascular disease is an essential part of the preoperative evaluation. The causes of postoperative psychosis 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 more than half of such patients at discharge, and many of these changes persist indefinitely ( ). 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 ( ). Compression or traction injuries to the brachial plexus, especially the lower trunk, and the phrenic and recurrent laryngeal nerves may occur during cardiac surgery. Cerebral air embolism may require high-flow or even hyperbaric oxygen therapy combined with aggressive resuscitation.

Other common early complications of cardiac transplantation are organ rejection followed by cardiac failure and the side effects of immunosuppressive drugs. 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 the 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 Chapter 71, Chapter 73 ).

Stroke occurs in approximately 5% of patients undergoing coronary artery bypass surgery. The risk is increasing because of the higher number of procedures in older patients with more severe vascular disease; it is also increasing in complicated combined procedures such as bypass surgery plus valve replacement ( ). 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.

Those few patients who fail to recover consciousness after surgery despite the absence of any metabolic cause have probably suffered diffuse cerebral ischemia or hypoxia. Hemispheric or multifocal infarction ( Fig. 58.1 ) 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 ( ).

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; the cerebral imaging appearance may be that of the posterior reversible encephalopathy syndrome (PRES). Sirolimus is an alternative immunosuppressant in solid-organ transplantation 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 are probably associated with lupus anticoagulant and antiphospholipid antibodies. Quinidine has neurological side effects similar to those of procainamide; it also causes headache, tinnitus, and syncope.

Lidocaine and related agents may cause seizures, tremor, paresthesias, and confusional states. Calcium channel–blocking agents occasionally cause encephalopathy, as may cefepime and rarely other members of the cephalosporin class of antibiotics. Beta-blockers are associated with mental status changes, paresthesias, and disturbances of neuromuscular transmission, whereas digoxin and thiazide diuretics are associated with an encephalopathy and disturbances of color vision.

Infective Endocarditis

The incidence of infective endocarditis has increased due to the abuse of intravenous substances and the increasing use of prosthetic cardiac valves. The overall incidence of neurological complications of infective endocarditis is approximately 25% to 35%, but it varies with the type of infecting organism. Such complications are the initial sign or major complaint in 25% to 50% of patients and are associated with a substantially 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. 58.2 ) are recognized complications of infective endocarditis and may result in intracranial hemorrhage. They are generally more distally located than noninfective berry aneurysms. The pathogenesis of mycotic aneurysms is unclear. The most likely cause is impaction of infected material in the vasa vasorum of the artery, with resulting destruction of the arterial wall. Intraluminal occlusion of the vessel by infected material, with subsequent aneurysmal formation, is a less likely mechanism 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 subacute bacterial endocarditis. Their natural history is unknown.

Intracranial hemorrhage is also caused by septic arteritis, which destroys the vessel wall without causing aneurysm; it also leads to the hemorrhagic transformation of cerebral septic infarctions. Angiography distinguishes intracranial hemorrhage from mycotic aneurysm and 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 catheter-based angiography.

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 an inflammatory cerebrospinal fluid (CSF) profile. The basis of these symptoms is probably multifactorial, including infection, vascular occlusion, metabolic abnormalities, and sometimes mycotic aneurysms.

Antibiotic therapy to resolve the cardiac infection is the mainstay of treatment and is important in preventing neurological complications ( ). Neurological abnormalities usually resolve. Patients with progressive or persistent neurological deficits or abnormalities on CSF examination require imaging studies. Findings suggestive of mycotic aneurysm necessitate vascular imaging. Once mycotic aneurysms have ruptured, curative surgical or endovascular treatment is necessary to prevent repeated rupture. Management of unruptured mycotic aneurysms is less clear; many advocate conservative management with antibiotics and serial imaging. Owing to the risk of hemorrhagic transformation of embolic infarcts or rupture of an unrecognized mycotic aneurysm, anticoagulants are usually withheld from patients with infective endocarditis and cerebral embolism until after appropriate antibiotic therapy.

Aortic Aneurysms

An unusually high incidence of dissecting aneurysm of the ascending aorta is associated with Marfan syndrome, in which a dilated aortic root is present. Dissecting aortic aneurysms also occur in the absence of connective tissue disease. The neurological features usually consist of acute cerebral or spinal cord deficits from ischemia, the former often due to extension of the dissection into the carotid arteries. Acute chest pain often is an associated symptom.

Thoracic aortic aneurysms suggest a syphilitic etiology. Left recurrent laryngeal nerve palsy may result from compression or traction of the nerve, especially when the aneurysm involves the aortic arch. Horner syndrome is a rare finding caused by pressure on the sympathetic trunk and superior cervical ganglion. Cerebral emboli are a complication of thoracic aortic aneurysms.

Atherosclerosis is the usual cause of abdominal aortic aneurysms. Compression of the femoral or obturator nerve is usually due to a hematoma and rarely to the aneurysm itself. Injury to the lumbosacral plexus and nerves may occur at surgery, as may spinal cord ischemia. Occlusive disease of the terminal aorta sometimes leads to an ischemic monomelic neuropathy characterized by pain and loss of all sensation in the distal portion of the leg. Disturbances of micturition and sexual function may also result from aortic aneurysms.

Aortitis

The causes of aortitis include syphilis, Takayasu disease, irradiation, transient emboligenic aortoarteritis, rheumatic fever, ankylosing spondylitis, reactive arthritis, and several connective tissue diseases. The latter group includes giant cell arteritis (see Chapter 102 ), rheumatoid arthritis, systemic lupus erythematosus (SLE), and scleroderma. Neurological complications occur when arteries that perfuse neural tissues are involved or in relation to a secondary aortic pathological process or lesion such as an aneurysm.

Takayasu disease (pulseless disease) is primarily a disease of young Asian women. Nonspecific symptoms are fever, weight loss, myalgias, and arthralgia. Obstruction of the major vessels of the aortic arch causes loss of pulses in the neck and arms, hypertension, and aortic regurgitation. Less common signs and symptoms are headache, seizures, transient cerebral ischemic attacks, and stroke ( ). The diagnosis is established by the clinical features, and corticosteroids are the treatment of choice. Despite the severe vascular involvement, the clinical neurological course is often good in patients who receive appropriate treatment, which sometimes includes revascularization procedures.

Transient emboligenic aortoarteritis is a rare inflammatory process of uncertain etiology affecting the aorta and other central elastic arteries but sparing the more peripheral vessels. It causes stroke or TIAs in young people.

Coarctation of the Aorta

Congenital coarctation of the aorta is a narrowing of the thoracic aorta just after the origin of the left subclavian artery. Acquired coarctation may follow irradiation during infancy; the narrowing is in the irradiated region. A narrowed segment that is atypically located for congenital coarctation and unrelated to previous irradiation suggests Takayasu disease.

Headache occurs in more than 25% of patients with coarctation. Subarachnoid hemorrhage may occur with rupture of an associated cerebral aneurysm. Episodic loss of consciousness (of uncertain basis) occurs as well. Spinal cord dysfunction occurs when the lower part of the cord becomes ischemic owing to insufficient flow in vessels arising from the aorta beyond the narrowed segment. Neurogenic intermittent claudication may result from the “stealing” of blood from the cord by retrograde flow through the anterior spinal artery, a part of the collateral circulation that bypasses the narrowed segment. Marked enlargement of collateral vessels within the spinal canal may compress the cervicothoracic cord, causing myelopathy. Enlargement of the anterior spinal artery or one of its feeders may lead to aneurysmal distention and rupture, resulting in spinal subarachnoid hemorrhage. Treatment involves surgical correction of the underlying coarctation.

Subclavian Steal Syndrome

Occlusion of either the innominate or the left subclavian artery before the origin of the vertebral artery reverses the direction of blood flow in the vertebral artery on the affected side. This reversal of flow is often asymptomatic but may cause ischemia in the posterior cerebral circulation. Neurological features are weakness, vertigo, visual complaints, and syncope. The underlying cause is a small or occluded contralateral vertebral artery on a congenital or acquired basis. Typically, the pulse diminishes or disappears in the affected arm, and systolic pressure decreases by at least 20 mm Hg compared with the opposite arm. Reconstructive surgery or endovascular repair is sometimes helpful but is unnecessary in most patients.

Complications of Aortic Surgery

Spinal cord infarction remains the most serious neurological complication of aortic surgery. CSF drainage and distal aortic perfusion may be important adjuncts to corrective surgery for thoracic and thoracoabdominal aortic aneurysms, significantly reducing the incidence of paraplegia and paraparesis ( ), although the evidence is incomplete ( ). Other complications are neuropathy, radiculopathy, postsympathectomy neuralgia after surgical division of the sympathetic chain, and disturbances of penile erection or ejaculation with surgical division of the superior hypogastric plexus.

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. A painful mononeuropathy multiplex, at least in polyarteritis nodosa, usually develops during the first year. As more nerves are affected, the deficits become more confluent and may resemble a length-dependent 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 can also occur. 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 or hemorrhage. Angiography may not show the underlying vasculitis, and tissue biopsy may be needed to establish the diagnosis ( Fig. 58.3 ). 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; perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) elevations are present in over half of such cases. 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 or rituximab and has reversed the poor prognosis of 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.

Giant Cell Arteritis

Headache is the most common initial complaint of patients with giant cell arteritis; some also complain of masticatory claudication. The temporal and other scalp arteries are often erythematous, tender, and nodular but may be normal. A more serious presenting manifestation is acute transitory or permanent blindness affecting one or both eyes; arteritic ischemic optic neuropathy is the cause. Other CNS complications are rare, but neuropsychiatric disturbances, stroke, diplopia, or seizures may occasionally be the presenting feature. Peripheral neuropathies occur in up to 15% of patients, and half of these are generalized.

The ESR is typically elevated, often markedly, and polymyalgia rheumatica and anemia are often associated findings. When giant cell arteritis is suspected, high-dose corticosteroid treatment should be started immediately while waiting to perform a temporal artery biopsy; any delay increases the risk of vision loss. Treatment is monitored by the clinical response and the ESR, but the corticosteroid dose should be increased if clinical signs of disease activity appear regardless of test results. With time, the corticosteroid dose can be tapered, but treatment should continue for 18 to 24 months. Tocilizumab has recently been studied as a corticosteroid-sparing alternative treatment agent ( ).

Granulomatosis With Polyangiitis

Neurological involvement occurs in up to 50% of patients who have granulomatosis with polyangiitis. Direct involvement of the brain may occur by vasculitis or by the extension of granulomas from the upper respiratory tract. Among patients with neurological complications, peripheral neuropathy is most common. The neuropathy is usually a mononeuropathy multiplex, but symmetrical polyneuropathies sometimes occur. Cranial neuropathy may also occur (usually involving cranial nerves [CN] II, VI, and VII), and multiple cranial neuropathies sometimes develop. Other neurological features include an external ophthalmoplegia (due to orbital pseudotumor), cerebrovascular events (e.g., stroke and venous sinus obstruction), seizures (e.g., from metabolic causes, sepsis, or vasculitis), basal meningitis, and cerebritis. Treatment includes corticosteroids, often in conjunction with other immunosuppressive agents such as cyclophosphamide or methotrexate.

Isolated Angiitis of the Nervous System

A description of isolated angiitis (granulomatous angiitis) of the CNS is provided in Chapter 69 , and that of the PNS is discussed in Chapter 106 .

Rheumatoid Arthritis

Rheumatoid arthritis is the most common connective tissue disease. A discussion of juvenile rheumatoid arthritis can be found in Chapter 59 . Systemic vasculitis occurs in up to 25% of adult patients, but CNS involvement is rare. Pathological involvement of the cervical spine ( Fig. 58.4 ) or atlantoaxial dislocation may cause a myelopathy, headaches, or hydrocephalus or lead to brainstem and cranial nerve signs from compression or vertebral artery involvement. Special care with maneuvers requiring hyperextension of the neck, such as endotracheal intubation, is essential in patients with rheumatoid arthritis. Surgical fixation of subluxation is usually unnecessary unless displacement is marked or an associated myelopathy is severe or progressive. The risk of a fatal outcome with a relatively minor whiplash injury is a consideration.

Peripheral nerve involvement is common in rheumatoid arthritis. A distal sensory or sensorimotor polyneuropathy is the usual presentation; clinical or electrophysiological evidence of sensory dysfunction may be found in up to 75% of patients. Mononeuropathy multiplex and entrapment or compression neuropathies are also common. Compression injuries to the median nerve in the carpal tunnel, medial plantar nerve in the tarsal tunnel, ulnar nerve in the cubital tunnel or canal of Guyon, or the fibular (peroneal) nerve at the fibular head may also occur.

Several antirheumatic agents have adverse effects on the neuromuscular system. Gold treatment causes peripheral neuropathy in up to 1% of cases. Its onset is rapid, and the evolution of weakness and the CSF profile may suggest Guillain-Barré syndrome. Chloroquine can cause neuropathy, myopathy, or both, and d -penicillamine causes disturbances of taste, an inflammatory myopathy, and a reversible form of myasthenia gravis. Commonly used tumor necrosis factor-alpha (TNFα) inhibitors can lead to opportunistic CNS infections and a demyelinating disorder resembling multiple sclerosis.

Systemic Lupus Erythematosus

Neurological involvement occurs during the course of SLE in as many as 75% of patients, often during the first year. Neurological complications may lead to a fatal outcome. The mechanism of CNS involvement is unknown. Neither the presence of antineuronal and other autoantibodies nor the deposition of antibody in the choroid plexus correlates with CNS involvement.

The most common neurological manifestations are episodic affective or psychotic disorders that may be difficult to distinguish from corticosteroid-induced mental changes. Cognitive dysfunction is often temporary. The clinical and imaging features may mimic those of multiple sclerosis ( ). Treatment is empirical, depending on presentation and the probable underlying pathophysiology. Disturbances of consciousness sometimes occur, especially in patients with systemic infections. Focal neurological deficits may result from stroke. The pathogenesis of stroke in SLE includes cardiac valvular disease, thrombosis associated with antiphospholipid antibodies, and, less commonly, cerebral vasculitis. Anticoagulant therapy may prevent stroke recurrence in patients with the antiphospholipid antibody syndrome. Dyskinesias, especially chorea, occur in some patients with SLE, but underlying structural pathology of the basal ganglia is rare; chorea is associated with the presence of antiphospholipid antibodies. The probable causes of generalized or partial seizures are microinfarcts, metabolic disturbances, and systemic infections. (The pediatric aspects of SLE are discussed in Chapter 59 .)

PNS involvement occurs less often and is usually characterized by a distal sensory or sensorimotor polyneuropathy ( ) that is sometimes subclinical but can be detected by sensory threshold testing; it is related to reduced intraepidermal nerve fiber density ( ). Other forms of neuropathy include an acute or chronic demyelinating polyneuropathy that resembles Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy (CIDP), single or multiple mononeuropathies, and optic neuropathy. Corticosteroids, immunosuppressive agents, high-dose intravenous immunoglobulin, and plasmapheresis are beneficial in treating neuropathies caused by necrotizing vasculitis but have less certain value in other circumstances.

Sjögren Syndrome

Sjögren syndrome may be a primary disorder or secondary to other connective tissue diseases. The main features are xerostomia and xerophthalmia. Women are more often affected than men. Definitive diagnosis requires a positive result on the Rose Bengal dye test for keratoconjunctivitis, evidence of diminished salivary gland flow, abnormalities on biopsy of a minor salivary gland, and an abnormal test result for ss-A and ss-B antibodies. CNS complications are not common but include psychiatric disturbances, late-onset migrainous episodes, aseptic meningitis, meningoencephalitis, focal signs, and an acute or chronic myelopathy. Cranial MRI may show small hyperintense subcortical lesions.

Polyneuropathy is the most common peripheral manifestation, but mononeuropathy multiplex may also occur ( ). Sensory neuronopathy is unusual but is more characteristic of Sjögren syndrome than other connective tissue diseases ( ).

Progressive Systemic Sclerosis

Progressive systemic sclerosis (i.e., scleroderma) occasionally affects the nervous system. The usual syndromes are a distal sensorimotor polyneuropathy, entrapment mononeuropathy, trigeminal neuropathy, myopathy, or myositis ( ). A rare scleroderma-like illness, nephrogenic systemic fibrosis, is an exceedingly rare complication of gadolinium administration in patients with underlying renal dysfunction, especially those who are undergoing dialysis.

Behçet Disease

The combination of uveitis and oral and genital ulcers defines Behçet disease, a disorder of unknown cause. Aseptic meningitis or meningoencephalitis occurs in 20% of cases. Other findings may include focal or multifocal neurological signs caused by ischemic disease of the brain or spinal cord related to small vessel inflammatory disease; the brainstem is frequently involved. Cerebral venous sinus thrombosis is another possible complication ( ). The CSF commonly shows a mild pleocytosis, and the protein concentration may be increased. Peripheral nerve involvement is rare and takes the form of polyneuropathy or mononeuropathy multiplex. Treatment is with corticosteroids. Anticoagulation is used to treat cerebral venous sinus thrombosis (see Chapter 64 ).

Relapsing Polychondritis

Relapsing polychondritis is an infrequently diagnosed inflammatory condition of cartilage, such as that of the ears, nose, trachea, ribs, and joints. Episodes of ear or nose inflammation typically last 1 to 4 weeks and then either resolve completely or leave deformities secondary to the destruction of cartilage. The disorder affects both genders equally, with peak age at incidence between 30 and 60 years. Eye inflammation, especially episcleritis or conjunctivitis, may be associated with the attacks. Systemic vasculitis or features of other connective tissue disorders may develop. The diagnosis requires a typical clinical picture of chondritis confirmed by biopsy. The ESR is usually elevated. Although autoimmunity against type II collagen may play a role in pathogenesis, only half of affected patients have serological evidence of anti–type II collagen antibodies.

Auditory or vestibular dysfunction occurs in nearly half of patients. The pathological mechanism usually is otic rather than inflammation of CN VIII. Other cranial neuropathies, such as optic or facial neuropathy, may be associated. The cause of headache, when it occurs, more often involves extracranial chondritis than intracranial inflammation. Aseptic meningitis, which may be recurrent, and vasculitic meningoencephalitis are sometimes associated neurological conditions.

Corticosteroid therapy is the traditional treatment. The efficacy of other anti-inflammatory or immunosuppressive drugs is difficult to assess because of the remitting and relapsing pattern of the disease.

Hypoxia

The neurological manifestations of hypoxia depend on its rate of onset, duration, and severity. Acid-base imbalance may complicate hypoxia, leading to other hematological and biochemical changes that affect cerebral function. The precise mechanisms responsible for the neurological abnormalities are complex and not completely understood.

Headache, disorientation, confusion, and depressed cognitive function characterize the encephalopathies caused by chronic pulmonary insufficiency. Postural tremor, myoclonus, asterixis, and brisk tendon reflexes are common examination findings, and papilledema is sometimes present. These encephalopathies are due not only to cerebral hypoxia but also to hypercapnia, which leads to cerebral vasodilatation, increased CSF pressure, and altered pH of the CSF.

Sleep apnea syndromes cause chronic nocturnal hypoxia and become symptomatic as excessive daytime sleepiness and sometimes as cognitive dysfunction. Many affected patients are obese and plethoric and snore heavily. Sleep apnea is an independent and potentially modifiable risk factor for ischemic stroke. A summary of treatment appears in Chapter 101 .

Headache, lassitude, anorexia, nausea, difficulty in concentration, and disturbances of sleep characterize high-altitude sickness. Symptoms begin within hours or days of ascending higher than 10,000 ft. At even higher altitudes, consciousness may be disturbed; coma develops in severe cases and may eventuate in death. Cerebral edema of uncertain cause is the major underlying feature that causes papilledema, retinal hemorrhages, cranial neuropathies, focal or multifocal motor and sensory deficits, and behavioral disturbances. Corticosteroids or carbonic anhydrase inhibitors such as acetazolamide avert or relieve the syndrome, along with return to lower altitudes.

Hypercapnia

Ventilatory impairment causes hypercapnia along with hypoxemia; the neurological manifestations of each are difficult to distinguish.

Hypocapnia

The hypocapnia that results from hyperventilation causes cerebral vasoconstriction, a shift of the oxyhemoglobin dissociation curve that reduces the peripheral availability of oxygen, and an alteration in the ionic balance of calcium. The clinical features are lightheadedness, perioral paresthesias, visual disturbances, headache, unsteadiness, tremor, nausea, palpitations, muscle cramps, carpopedal spasms, and loss of consciousness.

Hyperventilation occurs in hepatic and diabetic coma, with some brainstem lesions, with cardiopulmonary diseases, as a result of acidosis from certain drugs, and on an iatrogenic basis in patients being ventilated mechanically. Episodic hyperventilation often occurs without an identifiable systemic disease.