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).

Fig. 49A.1 A, Noncontrast computed tomographic (CT) scan of brain performed to evaluate confusion and left-sided weakness in a 76-year-old man 3 days post coronary artery bypass. B, Multiple bilateral ischemic lesions can be seen on diffusion-weighted magnetic resonance imaging (MRI) that are not conspicuous on CT scan.

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.

Fig. 49A.2 Carotid angiogram, lateral view with subtraction. Patient was a 48-year-old man with multiple peripheral mycotic aneurysms (arrows) verified at autopsy.

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.

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 usually is due to a hematoma and rarely is from the aneurysm itself. Injury to the lumbosacral plexus and nerves may occur at surgery. 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 also may result from aortic aneurysms.

Aortitis

The causes of aortitis include syphilis, Takayasu disease, irradiation, transient emboligenic aortoarteritis, rheumatic fever, ankylosing spondylitis, Reiter syndrome, and several connective tissue diseases. The latter group includes giant cell arteritis (see Chapter 69), 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 women. Nonspecific symptoms are fever, weight loss, myalgias, and arthralgia. Obstruction of 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 (Ringleb et al., 2005).

Transient emboligenic aortoarteritis is an inflammatory process 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 bypassing 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 is by 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 often is 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 sometimes is 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 (Hnath et al., 2008). Other complications are neuropathy, radiculopathy, post-sympathectomy neuralgia after surgical division of the sympathetic chain, and disturbances of penile erection or ejaculation with surgical division of the superior hypogastric plexus (Dougherty and Calligaro, 2001).

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.

Fig. 49A.3 A, Proton density–weighted magnetic resonance imaging scan of brain shows bilateral areas of patchy high signal intensity in the basal ganglia. B, Microscopic section of a biopsied blood vessel shows marked thickening and inflammatory infiltrates indicative of vasculitis in a patient with polyarteritis nodosa (hematoxylin and eosin, ×120).

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.

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 often are erythematous, tender, and nodular. A more serious presenting manifestation is acute transitory or permanent blindness affecting one or both eyes; ischemic optic neuropathy is the cause. Other CNS complications are rare, but neuropsychiatric disturbances, strokes, diplopia, or seizures occasionally may be the presenting feature. Peripheral neuropathies occur in up to 15% of patients, and half of these are generalized.

The ESR is elevated in over half of patients, and polymyalgia rheumatica and anemia are often associated findings. When giant cell arteritis is suspected, high-dose corticosteroid treatment should be started immediately, without 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 is 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.

Wegener Granulomatosis

Neurological involvement occurs in up to 50% of patients with Wegener granulomatosis. Peripheral involvement is usually a mononeuropathy multiplex; less often, a symmetrical polyneuropathy develops. Direct involvement of the brain may occur by vasculitis or by extension of granulomas from the upper respiratory tract. The associated clinical syndromes are basal meningitis, temporal lobe dysfunction, cranial neuropathies, cerebral infarction, and venous sinus obstruction.

Among patients with neurological complications, peripheral neuropathy is most common. The neuropathy usually is a mononeuropathy multiplex, but symmetrical polyneuropathies sometimes occur. Cranial neuropathy also may occur (usually involving II, VI, and VII), and multiple cranial neuropathies sometimes develop. Other neurological features include an external ophthalmoplegia (due to orbital pseudotumor), cerebrovascular events, seizures (e.g., metabolic, sepsis, vasculitis), and cerebritis. Treatment includes corticosteroids, often in conjunction with other immunosuppressive agents such as cyclophosphamide or methotrexate.

Isolated Angiitis of the Nervous System

The description of isolated angiitis (granulomatous angiitis) of the CNS is in Chapter 51E, and that of the PNS is discussed in Chapter 76.

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) 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 usually is unnecessary unless displacement is marked or an associated myelopathy is severe or progressive. The risk of a fatal outcome with a minor whiplash injury is a consideration.

Fig. 49A.4 Magnetic resonance imaging of craniocervical region in patient with rheumatoid arthritis. Gadolinium-enhanced images with T2-weighted (A) and T1-weighted (B) techniques. Two contiguous sagittal slices are shown. Arrows indicate pannus formation at the C1 spinal level causing narrowing of subarachnoid space, with a suggestion of posterior displacement of the upper cervical cord.

Peripheral nerve involvement is common in rheumatoid arthritis. A distal sensory or sensorimotor polyneuropathy is common; clinical or electrophysiological evidence of sensory dysfunction may be found in up to 75% of patients. Mononeuropathy multiplex and entrapment or compression neuropathies also are 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 peroneal nerve at the fibular head also may 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 (TNF) inhibitors can lead to opportunistic CNS infections.

Systemic Lupus Erythematosus

Neurological involvement occurs during the course of SLE, often during the first year, in as many as 75% of patients. Neurological complications may lead to a fatal outcome. The mechanism of CNS involvement is unknown. Neither the presence of antineuronal and antiastrocytic antibodies 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 often is temporary. The clinical and imaging features may mimic those of multiple sclerosis (Theodoridou and Settas, 2006). 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. (Chapter 49B discusses the pediatric aspects of SLE).

PNS involvement occurs less often and usually is characterized by a distal sensory or sensorimotor polyneuropathy (Rosenbaum, 2001) that sometimes is subclinical but can be detected by sensory threshold testing; it is related to reduced intraepidermal nerve fiber density (Tseng et al., 2006). Other forms of neuropathy include an acute or chronic demyelinating polyneuropathy that resembles Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy, 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. Neurological complications are not common but include psychiatric disturbances, late-onset migrainous episodes, aseptic meningitis, meningoencephalitis, focal neurological deficits, and an acute or chronic myelopathy. Cranial MRI may show hyperintense small subcortical lesions.

Polyneuropathy is the most common peripheral manifestation, but mononeuropathy multiplex also may occur (Goransson et al., 2006). Sensory neuronopathy is unusual but is more characteristic of Sjögren syndrome than other connective tissue diseases (Rosenbaum, 2001).

Progressive Systemic Sclerosis

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

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 venous inflammatory disease; the brainstem is frequently involved. Cerebral venous sinus thrombosis is another possible complication (Siva and Fresko, 2000). 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 51A).

Relapsing Polychondritis

Relapsing polychondritis is an infrequently diagnosed inflammatory condition of cartilage such as that of the nose, ears, 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 cartilage destruction. 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 usually is 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 eighth nerve inflammation. Other cranial neuropathies such as optic or facial neuropathy may be associated. The cause of headache, when it occurs, more often is extracranial chondritis than intracranial inflammation. Aseptic meningitis, which may be recurrent, and vasculitic meningoencephalitis sometimes are associated pathological conditions.

Corticosteroid therapy is the traditional treatment. The efficacy of other antiinflammatory 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 affecting cerebral function. The precise mechanisms responsible for the neurological abnormalities are complex.

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 sometimes is 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. Many affected patients are obese and plethoric and snore heavily. Chapter 68 summarizes treatment.

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 feet. 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 and hypoxemia, and 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 on ventilators. Episodic hyperventilation often occurs without an identifiable systemic disease.

Megaloblastic Anemia

Vitamin B₁₂ deficiency causes myelopathy, encephalopathy, optic neuropathy, peripheral neuropathy, or some combination of these disorders. The neurological complications do not necessarily correlate with the presence or severity of associated megaloblastic anemia. Folic acid masks the anemia without preventing the neurological complications. Nitrous oxide anesthesia may unmask a subclinical cobalamin deficiency (Marie et al., 2000). Folic acid fortification of the grain supply in the United States began in 1994 to prevent spina bifida; consequently, anemia is no longer a reliable marker of vitamin B₁₂ deficiency. Increased levels of homocysteine and methylmalonic acid may indicate intracellular B₁₂ deficiency even in the setting of normal serum B₁₂ levels.

The Schilling test is an important means of diagnosing the most common cause of vitamin B₁₂ deficiency, impaired absorption from deficiency of intrinsic factor. Vitamin B₁₂ is absorbed exclusively by the terminal ileum, and deficiency occurs in patients with ileal resection or urinary intestinal diversion. Treatment with intramuscular injections of vitamin B₁₂ corrects the deficiency, with reversal of the neurological changes. The extent of residua correlates with the severity and duration of symptoms before treatment.

Sickle Cell Disease

Sickle cell disease, the result of a genetic point mutation in the beta-globin gene, causes a vasculopathy of both large and small vessels (Prengler et al., 2002). Sickled cells adhere to the vascular endothelium, and a cascade of activated inflammatory cells and clotting factors leads to a nidus for thrombus formation. Hypoxia, infection, inflammation, dehydration, and acidosis increase sickling.

The most common neurological complication of sickle cell disease is stroke, which occurred more often in children than in adults before the routine use of transfusion therapy. Other complications are convulsions, intracranial (usually subarachnoid) hemorrhage, behavioral disturbances, and alteration in consciousness. The cause of intracranial hemorrhage cannot always be determined, despite detailed investigation, but rupture of an aneurysm, which may be surgically accessible, is sometimes responsible. Blindness sometimes results from proliferative retinopathy; retinal detachment or infarction also occurs. Spinal cord infarction is rare.

Thalassemias

Extramedullary hematopoiesis occurs in the liver, spleen, and lymph nodes of patients with severe forms of β-thalassemia. It also may occur in the spinal epidural space, causing a compressive myelopathy. Treatment includes local irradiation, surgical decompression, corticosteroids, and repeated blood transfusions. Bone marrow hypertrophy also causes facial deformity, nerve root compression, and auditory impairment. Surgical decompression or radiation therapy sometimes is beneficial.

Acanthocytic Syndromes

Acanthocytes, or spiny red cells, are associated with abetalipoproteinemia (see Chapter 57), neuroacanthocytosis (see Chapter 71), and McLeod syndrome (see Chapter 79).

Leukemias

Leukemic infiltration of the nervous system, hemorrhage, infection, electrolyte disturbances, hyperviscosity, and adverse effects of treatment cause the neurological complications of leukemia. Localized leukemic deposits are more likely to affect the brain than the spinal cord; peripheral nerve involvement is rare.

The clinical features of meningeal leukemia are headache, nausea and vomiting, somnolence, irritability, convulsions, and coma. Obstructive or communicating hydrocephalus, papilledema, or meningismus may be associated. Cranial neuropathies and spinal radiculopathies are common, and their multifocal distribution should always suggest meningeal leukemia. Examination of the CSF shows abnormal leukemic cells, especially if cytospin techniques are used, but a normal examination result does not exclude the diagnosis of meningeal leukemia. Treatment consists of intrathecal chemotherapy.

Intracerebral hemorrhage is more common than subarachnoid or subdural hemorrhage. It tends to occur when the platelet count is less than 20,000 cells per mL. The hemorrhage often is multifocal and ranges in severity from microscopic to fatal. Spinal subdural or subarachnoid hemorrhage is less common than intracranial bleeding but is a potentially serious complication of lumbar puncture, sometimes requiring surgical decompression.

A hyperviscosity syndrome occurs when the high white blood cell count markedly increases resistance to blood flow, impairing the transit of blood through the microcirculatory system. It is characterized by headache, somnolence, impaired consciousness, stroke or transient cerebral ischemia, and visual disturbances. Venous sinus thrombosis, nonbacterial thrombotic endocarditis, and disseminated intravascular coagulation (DIC) (discussed later) also may occur. The most common cause of this syndrome is an increase in the concentration of circulating gamma globulins, discussed in the following section.

Infection is a common complication of chemotherapy or corticosteroid therapy. The use of broad-spectrum antibiotics often encourages infection by unusual organisms. Progressive multifocal leukoencephalopathy is an uncommon complication of leukemia (see Chapter 53B).

Plasma Cell Dyscrasias

The basis for the classification of plasma cell dyscrasias is the protein synthesized. Complicating these disorders are paraneoplastic syndromes (see Chapter 52G) and an increased susceptibility to CNS infections.

Lymphoma

Neurological complications of lymphoma can be due to direct spread of tumor, compression of the nervous system by extrinsic tumor, and paraneoplastic syndromes (see Chapter 52G).They also may result from irradiation or chemotherapy, thrombocytopenic hemorrhage, or opportunistic infections. Primary CNS lymphoma is a known complication of immunosuppression and occurs most often in patients with acquired immunodeficiency syndrome (see Chapter 53A) and less frequently in transplant recipients.

Polycythemia

The thrombotic and hemorrhagic complications of polycythemia often affect the nervous system. Occlusion of small or large arteries or venous channels may cause cerebral infarctions, which sometimes are recurrent and fatal. Possible causes of the thrombotic tendency are increased blood viscosity, thrombocytosis, and possibly chronic disseminated intravascular clotting. Intracranial hemorrhage is caused by abnormalities of clot retraction, thromboplastin generation, and platelet function. Spinal cord infarction is rare. Patients with polycythemia often complain of headache, poor concentration, unsteadiness, tinnitus, blurred vision, dysesthesias, and other nonspecific symptoms. The basis of such symptoms is unclear, but disturbances in the retinal circulation may account for the visual complaints. Pseudotumor cerebri and chorea may occur with polycythemia. Chorea reverses when the underlying hematological disorder is treated. Low-dose aspirin (75-100 mg/day) is recommended for prophylaxis of thrombotic complications in those patients who do not have a history of major bleeding.

Hemophilia

Intracranial hemorrhage is a major cause of death in patients with hemophilia. Hemorrhages may be epidural, subdural, subarachnoid, or intracerebral and may occur spontaneously or follow trivial head injury. Neurological symptoms may not develop for several days after injury. The severity of bleeding generally correlates with the severity of coagulopathy. Spinal subdural or epidural hemorrhage may occur but is uncommon; the clinical features are back or neck pain and a progressive painful paraparesis or quadriparesis. Surgical decompression is necessary to preserve neurological function. Replacement of the deficient factor VIII is required to perform any invasive procedures.

Peripheral neuropathies secondary to compression of individual nerves by intramuscular or retroperitoneal hematomas are a common complication. Urgent operative decompression may be needed to preserve function.

Seizures may result from brain injury caused by previous intracranial hemorrhage. Their control with anticonvulsant agents helps prevent further bleeding.

Other Hemorrhagic Disorders

Other coagulopathies are associated with a lower frequency of neurological complications than hemophilia, but complications are similar to those already described.

Portal-Systemic Encephalopathy

Chronic liver disease causes a portal-systemic encephalopathy characterized by an abnormal mental status. Points to emphasize are that (1) the encephalopathy may have an insidious onset, delaying its clinical recognition and treatment, (2) a flapping tremor (asterixis) may be the only other neurological sign, and (3) liver function test results, other than the fasting arterial ammonia concentration, do not always correlate with the severity of the clinical disturbance. Focal neurological signs may be present but have no prognostic significance (Cadranel et al., 2001). EEG abnormalities also correlate with the severity of encephalopathy. MRI may show abnormal signal intensity in the basal ganglia on T1-weighted images (Fig. 49A.8). The mechanism of the encephalopathy is unknown. Treatment is discussed in Chapter 56.

Fig. 49A.8 This patient had chronic liver disease related to Hepatitis B. T1-weighted magnetic resonance imaging scan obtained without contrast shows bright signal in region of globus pallidus bilaterally (arrows).

Chronic Non-Wilsonian Hepatocerebral Degeneration

In some patients with chronic liver disease, a permanent neurological deficit develops, even in the absence of previous portal systemic encephalopathy. The neurological features are similar to those of Wilson disease (see Chapter 71): intention tremor, ataxia, dysarthria, and choreoathetosis are common. As with portal systemic encephalopathy, the severity of the neurological disorder correlates best with the fasting arterial ammonia level. Neuroimaging findings may be abnormal. Specific treatment is not available.

Liver Transplantation

The neurological consequences of liver transplantation are similar to those of transplantation of other organs. The earliest postoperative disturbances are caused by organ rejection (with worsening hepatic encephalopathy), cerebral anoxia, cerebrovascular disease, or the side effects of immunosuppressant drugs, especially cyclosporine and tacrolimus. Seizures are common and may result from metabolic disturbances, cerebrovascular disease, CNS infections, or adverse effects of treatment. Coagulopathies also may develop and can cause fatal cerebral hemorrhage. The causes of late complications are usually infections or malignancies affecting the nervous system.

Gastric Surgery

Neurological complications occur in 10% to 15% of patients after gastric resection. Because of the loss of gastric intrinsic factor, impaired vitamin B₁₂ absorption may be responsible in part for neuropathy or myelopathy (Chaudhry et al., 2002). Postgastrectomy neuropathy, however, does not usually respond to vitamin B₁₂ replacement alone. The myopathy that sometimes occurs probably is caused by vitamin D deficiency.

Gastric plication (bariatric surgery) has been associated with encephalopathy, myelopathy, polyneuropathy, Wernicke syndrome, and a nutritional amblyopia, but the precise nutritional deficiencies responsible remain to be established. Complications are especially likely in the context of recurrent vomiting. Appropriate vitamin supplementation and monitoring after surgery is essential to prevent these deficits.

Small-Bowel Disease

Neuropathy and myelopathy are associated with the malabsorption syndromes caused by small-bowel disease, biliary atresia, or blind loop syndrome, or with previous extensive GI resection. The findings may include pigmentary retinal degeneration, external ophthalmoplegia, dysarthria, peripheral neuropathy, and pyramidal and cerebral signs in the limbs. Ataxia may be an especially conspicuous feature, so the neurological disorder resembles a spinocerebellar degeneration with an associated polyneuropathy. Vitamin E deficiency causes the disorder, which responds to supplementation.

Celiac Disease

Chronic gluten enteropathy may cause a progressive and sometimes fatal CNS disorder that includes some combination of encephalopathy, myelopathy, and cerebellar disturbance. Peripheral neuropathy may be an associated, relatively underrecognized, finding (Hadjivassiliou et al., 2006). An axonal neuropathy also occurs alone and without a measurable vitamin deficiency; restriction of dietary gluten leads to gradual resolution of neuropathic symptoms.

Whipple Disease

Whipple disease is a multisystem disorder caused by infection with the bacillus Tropheryma whippelii. The clinical features are steatorrhea, abdominal pain, weight loss, arthritis, lymphadenopathy, and a variety of systemic complaints. Neurological involvement is rare but may occur in the absence of GI symptoms. The most common neurological feature is dementia (Manzel et al., 2000). Less common are cerebellar ataxia, seizures, myoclonus, clouding of consciousness, visual disturbances, papilledema, supranuclear ophthalmoplegia, myelopathy, and hypothalamic dysfunction. A characteristic movement disorder, oculomasticatory myorhythmia, is peculiar to Whipple disease; pendular vergence oscillations of the eyes, with concurrent contractions of the masticatory muscles, occur and persist during sleep. Oculofacial-skeletal myorhythmia also is pathognomonic. When present, it resembles oculomasticatory myorhythmia but also involves nonfacial muscles. Postmortem examination shows abnormalities of the gray matter of the hypothalamus, cingulate gyrus, basal ganglia, insular cortex, and cerebellum.

Small-intestine biopsy establishes the diagnosis. Patients with neurological involvement also show cells that stain positively with periodic acid–Schiff stain in the CSF and brain parenchyma (Fig. 49A.9). Polymerase chain reaction analysis of intestinal tissue or CSF sometimes is helpful. Treatment is prolonged, with antibiotic drugs such as trimethoprim-sulfamethoxazole, penicillin, tetracycline, or erythromycin. Patients who have a compatible clinical syndrome should receive treatment even when the biopsy result is negative.

Fig. 49A.9 Photomicrograph showing macrophages in brain tissue and around blood vessels, with prominent astrogliosis in involved brain in a patient with Whipple disease (hematoxylin and eosin, ×40).

Overview of Related Neurological Complications

Renal failure is associated with several neurological manifestations. Uremic encephalopathy is discussed in Chapter 56. Its clinical features resemble those of other metabolic encephalopathies, and its severity does not correlate well with any single laboratory abnormality. The mechanism of encephalopathy is not established but has been attributed to accumulation of toxic organic acids in the CNS or to direct toxic effects on the CNS of parathyroid hormone. It may be associated with asterixis and myoclonus. Characteristics of so-called twitch-convulsive syndrome are asterixis and myoclonic jerks accompanied by fasciculations, muscle twitches, and seizures (Brouns and De Deyn, 2004). Chorea may result from basal ganglia dysfunction. Stroke incidence increases in chronic renal failure. Ischemic stroke may relate to atherosclerosis, thromboembolic disease, or hypotension during dialysis. Atherosclerosis generally is more diffuse than in the age-matched general population, probably because of a combination of traditional risk factors and factors related to the renal failure, such as the accumulation of endogenous guanidino compounds. Hyperhomocysteinemia also is common; this condition, of uncertain etiology, may predispose affected persons to ischemic stroke and responds to enhanced dialysis over superflux membranes (Brouns and De Deyn, 2004). The incidence of intracranial hemorrhage is increased; hypertension, polycystic kidney disease, uremic platelet dysfunction, and the use of anticoagulation or antiplatelet agents are probable risk factors.

A length-dependent, symmetrical, sensorimotor polyneuropathy is a common complication of uremia. It usually worsens over several months but may progress more rapidly until the patient is profoundly disabled. Dysesthesias, muscle cramps, and restless legs are common early features. The neuropathy may stabilize or improve with long-term dialysis. Renal transplantation produces progressive improvement over the following year or longer, and complete recovery is possible. The accumulation of metabolites with a molecular weight of 500 to 2000 daltons is the probable cause of neuropathy, but the precise pathogenesis is not established.

Autonomic dysfunction leads to postural hypotension, sudomotor abnormalities, impotence, and GI disturbances. Dysautonomia may be important in the development of hypotension during hemodialysis, but other factors such as volume depletion are undoubtedly involved as well.

Uremic optic neuropathy causes a rapidly progressive vision loss that responds to hemodialysis and corticosteroid treatment. Isolated peripheral mononeuropathies occur in uremic patients from compression or entrapment or from intramuscular hemorrhage. Hyperkalemia sometimes is responsible for a flaccid quadriparesis that responds to electrolyte correction. Treatment with aminoglycoside antibiotics in uremic patients can lead to cochlear, vestibular, or neuromuscular junction disturbances, and a myopathy sometimes results from electrolyte disturbances, corticosteroid treatment, or the end-stage kidney disease itself (Campistol, 2002).

Neurological Complications of Dialysis

Hemodialysis requires an arteriovenous shunt in the forearm that sometimes causes a carpal tunnel syndrome attributed either to ischemia and venous congestion or to β₂-microglobulin amyloidosis.

The probable cause of dialysis disequilibrium syndrome is shift of water into the brain. Headache, irritability, agitation, somnolence, seizures, muscle cramps, and nausea occur during or after hemodialysis or peritoneal dialysis. Less common features are exophthalmos, increased intraocular pressure, increased intracranial pressure, and papilledema.

In patients undergoing dialysis for longer than 1 year, a fatal encephalopathy called dialysis dementia may develop. Hesitancy of speech, leading to speech arrest, is a characteristic early feature. Intellectual function declines with time, and delusions, hallucinations, seizures, myoclonic jerking, asterixis, gait disturbances, and other neurological abnormalities ultimately develop. Death usually occurs within 6 to 12 months of onset of signs and symptoms. Increased cerebral concentrations of aluminum at postmortem examination suggested aluminum intoxication as the cause of dialysis dementia. Dialysis dementia has become much less common since removal of aluminum from dialysates (Rob et al., 2001). Deferoxamine, a chelating agent that binds aluminum, treats dialysis dementia, but the optimal duration of treatment is unclear. Deferoxamine may actually exacerbate or precipitate encephalopathy in patients with very high serum aluminum concentrations, and it also causes visual and auditory disturbances.

Another cause of encephalopathy in patients undergoing dialysis is Wernicke disease. Dialysis removes thiamine, a water-soluble vitamin, and thiamine supplementation is essential.

Neurological Complications of Renal Transplantation

The placement of the transplanted kidney close to the inguinal ligament increases the risk of retraction injury or hematoma formation around the femoral nerve. The result can be a postoperative femoral neuropathy, which often resolves completely. Retraction or hematoma also causes dysfunction of the ipsilateral lateral femoral cutaneous nerve. Stroke occurs in 5% to 8% of renal transplant recipients; underlying causes may relate to hypertension, diabetes, and accelerated atherosclerosis. The neurological complications associated with long-term immunosuppressive treatment are the same as those for transplantation of other organs.

Headache, confusion, or convulsions in patients with evidence of acute graft rejection are a feature of rejection encephalopathy. In most cases, onset of this condition is within 3 months of transplantation; complete recovery occurs rapidly after treatment of the rejection episode. A possible cause is cytokine production related to the rejection process.

Sodium

Serum sodium concentration determines serum osmolarity. Rapid changes in serum sodium concentration cause CNS dysfunction by altering the osmotic equilibrium between the brain and body fluids. The typical clinical features are disturbances of cognition and arousal that can progress to coma. Myoclonus, asterixis, and tremulousness are common. Seizures, when they occur, often are refractory to anticonvulsant medications until the underlying metabolic disturbance has been corrected. Focal signs and symptoms (e.g., hemiparesis) may manifest during hyponatremia, without any demonstrable structural basis, but may indicate a prior or subclinical focal abnormality that is aggravated by the metabolic disturbance.

Focal abnormalities associated with hypernatremia often reflect subdural hemorrhage. The cause of hemorrhage is brain shrinkage from osmotic forces, with secondary tearing of blood vessels. Hypernatremia, a common consequence of dehydration, may develop in patients receiving inadequate parenteral fluid replacement. It also occurs with diabetes insipidus, pathological involvement of the hypothalamic thirst center by tumor, and excessive salt intake.

Hyponatremia, defined as a serum sodium concentration less than 132 mEq/L, is associated with hypoosmolarity, except in patients with hyperlipidemia or hyperglycemia. It occurs in several pathological states: excessive salt loss from the kidney or GI tract, impaired water excretion, the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), adrenocortical insufficiency, and iatrogenic water intoxication. Often thought to be secondary to SIADH in patients with acute brain syndromes (e.g., subarachnoid hemorrhage), hyponatremia is more likely to be the result of salt wasting (“cerebral salt wasting”) than of SIADH. Patients have a reduced plasma volume rather than a normal or increased plasma volume as expected with SIADH. In such cases, fluid restriction further exacerbates the hypovolemia, which may cause cerebral ischemia, and sodium supplementation is necessary to avoid complications of severe hyponatremia.

Rapid correction of hyponatremia may cause central pontine myelinolysis, a disorder initially associated with alcoholism or malnutrition but now more often iatrogenic in origin. Neurological deterioration due to central pontine myelinolysis may obscure or follow the resolution of hyponatremic encephalopathy. Spastic or flaccid quadriparesis, pseudobulbar palsy, and decreased states of consciousness characterize severe cases. In some patients, the clinical features are minimal compared with the abnormalities seen on MRI. Central pontine myelinolysis is prevented when hyponatremia is corrected at a rate of less than 12 mEq/L/day, especially in patients in whom hyponatremia is long-standing.

Potassium

The difference in the concentrations of intracellular and extracellular potassium creates the resting membrane potential of nerve and muscle cells. Disturbances of serum potassium adversely affect cardiac and neuromuscular function. The hereditary periodic paralyses are discussed in Chapter 79.

Hyperkalemia usually causes cardiac arrhythmia before neurological function is disturbed. The arrhythmia sometimes is associated with rapidly progressive flaccid paralysis and depressed tendon reflexes. Weakness, which may last for several hours, may be preceded by burning paresthesias and sometimes is accompanied by mental changes. The underlying cause, the severity of the hyperkalemia, and the electrocardiographic findings determine the treatment.

Hypokalemia usually causes neuromuscular disturbances rather than encephalopathy. Mild hypokalemia causes myalgia, fatigability, and proximal weakness that spares the bulbar muscles. Severe hypokalemia causes rhabdomyolysis and myoglobinuria, and hypokalemic alkalosis causes tetany. All signs and symptoms remit when normokalemia is reestablished.

Calcium

Hypercalcemia is associated with metastatic bone disease, myeloma, paraneoplastic syndromes, primary or secondary hyperparathyroidism, vitamin D intoxication, and milk-alkali syndrome. The main CNS complication is an encephalopathy, characterized by altered state of consciousness, apathy or agitation, depression or mania, headache, and in rare instances, seizures, which may be a result of vascular occlusive complications. PNS manifestations include muscle weakness and fatigability, especially in patients with hyperparathyroidism, in whom a myopathy may develop.

Hypocalcemia may follow thyroid or parathyroid surgery and is a recognized feature of hypoparathyroidism, malabsorption syndromes, vitamin D deficiency, and acute pancreatitis. Tetany is the main manifestation of hypocalcemia. Perioral and distal limb paresthesias are initial features and are followed by muscle cramps, a feeling of muscle spasms, and then actual spasm of the hands and feet (carpopedal spasms).

CNS complications of hypocalcemia are focal or generalized seizures and an encephalopathy characterized by hallucinations, delusions, psychosis, altered states of consciousness, and cognitive impairment. The seizures respond poorly to anticonvulsant drugs but stop after correction of the hypocalcemia. Other CNS complications are parkinsonism or chorea that responds to correction of the calcium abnormality, increased intracranial pressure (in patients with hypoparathyroidism), and myelopathy.

Magnesium

Intracellular magnesium is involved in the activation of several enzymatic reactions, and extracellular magnesium is important in synaptic transmission.

The cause of hypomagnesemia is reduced intake or impaired absorption of magnesium or excessive loss from diuretics, kidney disorders such as renal tubular acidosis, and diabetic acidosis. Serum concentrations do not accurately reflect the severity of magnesium depletion, because magnesium is predominantly an intracellular ion.

The neurological complications of hypomagnesemia are similar to those of hypocalcemia, and the two often coexist. The possibility of concurrent hypomagnesemia should be considered in the management of hypocalcemia, especially when parenteral calcium supplementation fails to provide the expected response. The cause of complaints of weakness in patients with hypomagnesemia may be magnesium deficiency alone or with other electrolyte abnormalities. The treatment of hypomagnesemia is with magnesium sulfate given orally, unless an absorptive defect necessitates intramuscular or intravenous administration.

The cause of hypermagnesemia is either excessive intake or impaired excretion of magnesium. The usual cause is renal failure or magnesium administration to treat preeclampsia. Clinical features are drowsiness and diminished responsiveness, confusion, and depressed or absent tendon reflexes. Other features are hypotension, respiratory depression, and weakness from impaired neuromuscular transmission. Severe hypermagnesemia results in coma and may be fatal.

Pituitary Adenomas

The initial features of prolactin-secreting pituitary adenomas are amenorrhea and galactorrhea in women and impotence in men. Often, however, symptoms of increased intracranial pressure originating in the sella region develop before prolactinoma becomes a consideration. The treatment choices are transsphenoidal surgery and administration of dopaminergic agonists such as bromocriptine. Radiation therapy can be used when these choices are either unhelpful or not feasible. Tension pneumocranium is a rare complication of transsphenoidal surgery. Impaired mental status, seizures, and headaches, sometimes associated with systemic hypertension and bradycardia, occur in the early postoperative period and necessitate surgical drainage of the pneumocranium. Serum sodium measurements exclude the possibility of iatrogenic central diabetes insipidus postoperatively (see later).

Growth hormone–secreting pituitary tumors cause acromegaly; gigantism occurs in children, and enlargement of the jaw, extremities, and skull in adults. Approximately 50% of patients have a myopathy, which improves over many months when the underlying hormonal disorder is treated. Carpal tunnel syndrome in patients with acromegaly results from hypertrophy of the transverse carpal ligament. Symptoms usually resolve 2 to 3 months after surgical excision of the pituitary tumor, but electrophysiological abnormalities may persist longer. In patients with acromegaly, a mild (usually subclinical) polyneuropathy also may develop.

Cushing Disease and Syndrome

The cause of Cushing disease is excessive secretion of adrenocorticotropic hormone from the pituitary gland. The clinical features are truncal obesity, hypertension, acne, hirsutism, osteoporosis, diabetes mellitus, and menstrual irregularities. Mental changes are common and include anxiety, agitation, insomnia, depression, euphoria, mania, and psychoses. Proximal muscle weakness and wasting are common, especially in the legs. Muscle biopsy shows type II fiber atrophy, a characteristic feature of muscle in patients who receive long-term corticosteroid therapy (see Chapter 79); electromyographic findings generally are normal. The constellation of clinical features that constitutes Cushing syndrome is also a feature of the paraneoplastic syndrome of ectopic secretion of ACTH, and occurs in association with adrenal adenomas and after long-term corticosteroid treatment as well.

An enlarging pituitary adenoma may cause a visual field defect (Fig. 49A.10). Treatment of Cushing disease by bilateral adrenalectomy sometimes leads to rapid expansion of the underlying pituitary adenoma (Nelson syndrome), with compression of other cranial nerves, especially cranial nerve III. Intracranial hypertension is a recognized complication of Cushing syndrome and occurs particularly after resection of the pituitary adenoma.

Fig. 49A.10 T1-weighted magnetic resonance imaging with gadolinium enhancement. A, Sagittal view. B, Coronal view. A heterogeneously enhancing mass arises out of the sella turcica and extends up to involve the region of the optic chiasm. Surgery confirmed a growth hormone–secreting pituitary adenoma.

Hypopituitarism

Hypopituitarism results from diseases of the pituitary gland or hypothalamus. The neurological features depend on the severity of secretory impairment and on the hormones affected. Common features are apathy and intellectual decline, which often are difficult to attribute to a single hormone deficiency because of concurrent dysfunction of several glands.

Hyperthyroidism

The features of hyperthyroidism are anxiety, restlessness, irritability, emotional lability, impaired concentration, headaches, mental slowing, and insomnia. Elderly patients may become depressed and lethargic, a condition designated apathetic hyperthyroidism. An enhanced physiological tremor and generalized hyperreflexia are common. Hyperthyroidism itself may cause seizures or may trigger a preexisting seizure disorder. Chorea and paroxysmal choreoathetosis also occur.

Confusion and agitation leading to coma characterize thyrotoxic crisis. Additional features include fever, cardiac arrhythmias, diarrhea and vomiting, and other systemic disturbances. Treatment consists of hydration and cooling, beta-blocking drugs, corticosteroids, and in some cases plasmapheresis.

Dysthyroid orbitopathy (ophthalmic Graves disease) characterized by exophthalmos and ophthalmoplegia is common. Orbital edema, particularly involving the extraocular muscles, and infiltration by inflammatory cells lead to orbital fullness, conjunctival edema and hyperemia, proptosis, and some limitation of ocular movement. The cause of eyelid retraction may be sympathetic overactivity affecting Müller muscle in the upper lids and fibrosis of the levator muscle. The occasional occurrence of optic neuropathy relates to infiltration of the optic nerve, crowding of the orbital apex, and enlargement of the extraocular muscles. Dysthyroid orbitopathy may occur in patients without a history of thyroid disease or clinical signs of hyperthyroidism. Treatment options include corticosteroids, radiation therapy, and orbital decompression.

Compression of the recurrent laryngeal nerve or cervical sympathetic fibers by an enlarged thyroid gland, commonly neoplastic, may lead to vocal cord paralysis or Horner syndrome, respectively.

Several neuromuscular disorders are associated with hyperthyroidism. Most common is a proximal myopathy accompanied by fasciculations. Its mechanism is unknown, but the severity of myopathy does not correlate with the severity of thyroid abnormality. Serum creatine kinase levels generally are normal. Improvement occurs with treatment of the underlying thyroid disorder. Hyperthyroidism and myasthenia gravis often coexist. Both are immune-mediated disorders (see Chapter 78). Treatment of one disorder, however, does not have any predictable effect on the other.

Thyrotoxic periodic paralysis is similar to familial hypokalemic periodic paralysis (see Chapter 79). It is most common in persons of Asian heritage, and the hyperthyroidism may be clinically silent. Episodes of weakness occur after activity or after meals with high carbohydrate content. Potassium administration treats the acute attacks, and nonselective beta-blockers may both help alleviate the acute attack and prevent recurrence of paralytic attacks (Kung, 2006). Correction of the thyroid disorder cures the periodic paralysis.

One report of a sensorimotor polyneuropathy in hyperthyroidism may represent a fortuitous association.

Hypothyroidism

Mental changes are common in hypothyroidism. Apathy, somnolence, and impaired concentration are typical and often are attributed to depression. Confusion, delirium, and psychosis (myxedema madness) also may occur and remit with treatment of the underlying thyroid disorder. In severe hypothyroidism, decreased states of consciousness are associated with hypotension, hypothermia, respiratory failure, hypoglycemia, and other metabolic derangements; untreated, the disorder progresses to coma and sometimes death.

Other features of hypothyroidism are an increased incidence of seizures, truncal ataxia due to cerebellar degeneration, hearing loss, and cranial neuropathies. Structural changes in the vocal cords cause voice hoarseness rather than neurological disease. The neurological complications of hypothyroidism usually resolve with thyroid replacement, especially if the deficiency is not long-standing.

The PNS often is involved in hypothyroidism. Most common is a proximal myopathy accompanied by myalgia and muscle stiffness. The affected muscles may be enlarged (Hoffmann syndrome) and exhibit myoedema (transient local mounding of a muscle in response to percussion).

Carpal tunnel syndrome occurs in as many as 30% of patients and usually responds to correction of the thyroid disorder. Screening most patients with carpal tunnel syndrome for occult hypothyroidism is reasonable. Less common is a sensory or sensorimotor neuropathy, for which evidence implicates both segmental demyelination and axonal degeneration. Slow relaxation of tendon reflexes also may be noted. An association with myasthenia gravis is recognized but is less common than with hyperthyroidism.

Hashimoto Thyroiditis

Hashimoto thyroiditis is a chronic autoimmune-mediated thyroiditis, probably related to both genetic and environmental factors. An association exists with myasthenia gravis and less clearly with giant cell arteritis and vasculitic peripheral neuropathy. In addition, a relapsing encephalopathy may occur in association with Hashimoto thyroiditis and high titers of antithyroglobulin and antithyroperoxidase antibodies. Confusion, altered level of consciousness, and seizures are common presenting features. Tremulousness occurred in 80%, transient aphasia in 80%, and myoclonus in 65% of the patients in the series reported by Castillo and associates (2006). Gait ataxia (affecting 65% of the patients) and sleep abnormalities (reported by 55%) also are common. The EEG is diffusely abnormal, and CSF protein concentration is increased without an associated pleocytosis, but often accompanied by markers of inflammation including an elevated Ig index or unique CSF oligoclonal bands. MRI or isotope brain scan results may be abnormal but often are unremarkable. The diagnosis of Hashimoto thyroiditis should be a consideration, even in the presence of a normal serum thyroid-stimulating hormone concentration and ESR. Treatment is with corticosteroids. The long-term prognosis is good, but relapses are expected and steroid-sparing immunosuppressive drugs are often necessary.

Hyperparathyroidism

Neurological manifestations of hyperparathyroidism are common. They are essentially those of hypercalcemia (described earlier in the chapter). A mild proximal myopathy also may occur and improves with surgical treatment of the parathyroid disorder. A clinical syndrome that mimics amyotrophic lateral sclerosis also may occur.

Hypoparathyroidism

Hypoparathyroidism commonly follows thyroidectomy or has an idiopathic basis. The etiological disorder in pseudohypoparathyroidism is peripheral resistance to the effects of parathyroid hormone, rather than deficiency of hormone secretion. The neurological manifestations of these disorders relate primarily to the effects of hypocalcemia on the nervous system. Intracranial calcification is common in patients with hypoparathyroidism, occurring especially in the basal ganglia. These calcifications are usually asymptomatic, but they can occasionally lead to seizures and progressive mental changes. Benign intracranial hypertension also may be associated with hypoparathyroidism, and correction of the underlying metabolic disorder reverses the hypertension.

Pheochromocytoma

Pheochromocytoma is associated with neurofibromatosis and von Hippel-Lindau disease (see Chapter 65). The initial features of pheochromocytoma are paroxysmal clinical features of excessive catecholamine secretion: headache, hyperhidrosis, palpitations, cardiac arrhythmias, tremulousness, and anxiety. Most patients have hypertension, and seizures occur in approximately 5%. Malignant pheochromocytomas are rare, and metastatic tumors may respond to radiation therapy.

Addison Disease

Adrenal failure results from diseases of the pituitary or adrenal gland or from adrenal suppression from long-term use of exogenous corticosteroids. The major features are generalized weakness, fatigability, lassitude, depression, headache, weight loss, anorexia, and hyperpigmentation of the skin. Increased intracranial pressure may be present. Adrenal failure is a feature of X-linked adrenomyeloleukodystrophy.

Peripheral Nervous System

In developed countries, diabetes is the most common cause of polyneuropathy (see Chapter 76). The mechanism of neuropathy is not established but may be either metabolic or vascular. Between 10% and 20% of newly diagnosed diabetic patients exhibit evidence of neuropathy. Prediabetes, as diagnosed by a glucose tolerance test demonstrating impaired glucose handling, can be associated with a painful sensory polyneuropathy. Exclude the diagnosis of diabetes in all patients presenting with an otherwise idiopathic sensory-predominant neuropathy (Singleton et al., 2005).

Diabetic polyneuropathy features both axonal degeneration and demyelination. It may be asymptomatic; depressed tendon reflexes and impaired vibratory sense in the legs will suggest the diagnosis. Symptoms are more common in the feet than in the hands. The initial symptom is pain, paresthesia, or numbness. Profound weight loss sometimes precedes the development of an acute painful neuropathy. Progressive neuropathy is characterized by distal sensory loss and weakness in the limbs, as well as areflexia. Severe impairment of pain and temperature appreciation occasionally develops and results in distal ulceration and arthropathy (acrodystrophic neuropathy).

Autonomic neuropathy is an important feature of diabetes mellitus. Clinical features range from lack of symptoms to a syndrome that includes postural hypotension, abnormal cardiovascular and thermoregulatory control, and impotence. Other possible clinical features are pupillary abnormalities, gastroparesis, diarrhea from intestinal dysmotility, and a blunted response to hypoglycemia.

Diabetic polyradiculoneuropathy is characterized by pain and asymmetrical limb weakness, usually involving the thighs and often accompanied by weight loss. A diabetic plexopathy or polyradiculopathy, rather than a femoral neuropathy, probably accounts for most cases of diabetic amyotrophy (Dyck and Windebank, 2002). Symptoms are rapidly progressive but stabilize after a few weeks; gradual but often incomplete recovery occurs over the following months or years.

The typical syndrome of diabetic thoracoabdominal polyradiculopathy consists of nonradicular truncal pain that initially may suggest intraabdominal or intrathoracic pathology necessitating surgical exploration. Sensory loss and weakness are mild.

Diabetic mononeuropathy multiplex has a vascular basis. Simple mononeuropathies also are common in diabetic patients. Entrapment neuropathies, especially carpal tunnel syndrome, occur with an increased incidence. Cranial neuropathies, usually isolated involvement of nerves III, IV, and VI, cause a painful extraocular palsy. Sparing of the pupillary reflex differentiates a diabetes-induced palsy of cranial nerve III from compressive lesions. Disturbances of cranial nerve VII cause unilateral facial weakness.

A specific treatment for diabetic neuropathy is not available, but complete control of the diabetes is imperative. In recipients of pancreatic islet transplants, diabetic neuropathy may stabilize or even regress (Lee et al., 2005). Painful neuropathies may respond to standard pharmacological measures to treat neuropathic pain (Chapter 44). Care of the feet is important, especially in patients with sensory neuropathy, to prevent ulceration.

Central Nervous System

Stroke is more common in persons with diabetes than in the general population, because of an increased incidence of hypertension and atherosclerosis in the former. Diabetes increases stroke severity and mortality and predisposes affected persons to deep subcortical infarctions. Hyperglycemia at the time of acute stroke leads to worse outcome, but lowering blood glucose in the setting of acute stroke does not improve this outcome.

Diabetic ketoacidosis, an important cause of morbidity and mortality, may be the presenting feature of previously unrecognized diabetes. Severe hyperglycemia and a metabolic acidosis cause an osmotic diuresis that dehydrates the patient. Clinical presentation includes an altered state of consciousness that progresses to coma. Focal or lateralizing signs usually are absent unless the patient has underlying brain disease. The pathogenesis of diabetic coma is poorly understood and probably multifactorial. Serum hyperosmolality and acidosis probably are important contributing factors. Postmortem examination in some patients with severe diabetic ketoacidosis shows evidence of DIC. This contributes to the altered level of consciousness. Potential contributory factors are other metabolic derangements, infection, vascular occlusive phenomena, and cerebral edema.

An acute medical complication such as an infection or MI often precipitates nonketotic hyperosmolar coma in diabetic patients. Affected patients typically are elderly with mild disease. Hyperglycemia and hyperosmolality occur without significant ketosis. Progressive obtundation is the principal feature, but seizures and focal deficits may develop. Some patients develop chorea and other hyperkinetic movement disorders, typically associated with hyperintensity of the putamen and caudate on T1-weighted MRI. Treatment of diabetic ketoacidosis and nonketotic hyperosmolar coma includes fluid, potassium, and phosphate replacement as necessary and correction of hyperglycemia by administration of insulin. Cerebral edema may complicate therapy; often, it is an incidental CT finding.

Hypoglycemia

Hypoglycemia can cause an acute metabolic encephalopathy with initial features of tremulousness, anxiety, confusion, stupor, or coma, depending on the level of hypoglycemia. Later features are brainstem dysfunction and transitory focal neurological deficits that resemble those associated with strokes but either resolve or alternate from side to side. Seizures sometimes are the only manifestation of hypoglycemia. Administration of glucose reverses the symptoms. Severe hypoglycemic cerebral injury causes MRI abnormalities localized to the basal ganglia, cerebral cortex, substantia nigra, and hippocampus, suggesting a particular vulnerability of these areas. Neuromuscular syndromes resembling a peripheral sensorimotor polyneuropathy or lower motor neuron degeneration occur in patients with insulinomas or those who receive excessive insulin for therapeutic purposes.