Neurology_Adams

Neurology_Adams. This disorder is suitably considered here because it is a chronic, recurrent vasculitis, involving small vessels, with prominent neurologic manifestations. It is most common in Turkey, where it was first described, in other Mediterranean countries, and in Japan, but it occurs throughout Europe and North America, affecting men more often than women. The disease was originally distinguished by the triad of relapsing iridocyclitis and recurrent oral and genital ulcers, but it is now recognized to be a systemic disease with a much wider range of symptoms, including erythema nodosum, thrombophlebitis, polyarthritis, ulcerative colitis, and a number of neurologic manifestations, some of them encephalitic or meningitic in nature. The most reliable diagnostic criteria, according to the International Study Group that assembled data on 914 cases from 12 medical centers in 7 countries, were recurrent aphthous or herpetiform oral ulceration, recurrent genital ulceration, anterior or posterior


Neurology_Adams

Neurology_Adams. Study Group that assembled data on 914 cases from 12 medical centers in 7 countries, were recurrent aphthous or herpetiform oral ulceration, recurrent genital ulceration, anterior or posterior uveitis, cells in the vitreous or retinal vasculitis, and erythema nodosum or papulopustular lesions.


Neurology_Adams

Neurology_Adams. The nervous system is affected in approximately 30 percent of patients with Behçet disease (Chajek and Fainaru); the manifestations are recurrent meningoencephalitis, cranial nerve (particularly abducens) palsies, cerebellar ataxia, corticospinal tract signs, and venous occlusion disease. There may be episodes of diencephalic and brainstem dysfunction resembling minor strokes. A few postmortem examinations have related these small foci of necrosis to a vasculitis, including perivascular and meningeal infiltration of lymphocytes. There may also be cerebral venous thrombosis. The neurologic symptoms usually have an abrupt onset and are accompanied by a brisk spinal fluid pleocytosis (lymphocytes or neutrophils may predominate), along with elevated protein but normal glucose values (in one of our patients, 3,000 neutrophils per cubic millimeter were found at the onset of an acute meningitis). As a rule, neurologic symptoms clear completely in several weeks, but they have a tendency to


Neurology_Adams

Neurology_Adams. of our patients, 3,000 neutrophils per cubic millimeter were found at the onset of an acute meningitis). As a rule, neurologic symptoms clear completely in several weeks, but they have a tendency to recur, and some patients are left with persistent neurologic deficits. Rarely, the clinical picture is that of a progressive confusional state or dementia (see the reviews of Alema and of Lehner and Barnes for detailed accounts).


Neurology_Adams

Neurology_Adams. The cause of Behçet disease is unknown. A pathergy skin test—the formation of a sterile pustule at the site of a needle prick—is listed as an important diagnostic test by the International Study Group, but on the basis of admittedly limited U.S. experience, we and our colleagues have found it to be of questionable value. Administration of corticosteroids has been the usual treatment, on the assumption of an autoimmune etiology. Because the episodes of disease naturally subside and recur, evaluation of treatment is difficult.


Neurology_Adams

Neurology_Adams. Thrombosis of the cerebral venous sinuses, particularly of the superior sagittal or lateral sinus and the tributary cortical and deep veins, gives rise to a number of important neurologic syndromes. Cerebral vein thrombosis may develop in relation to infections of the adjacent ear and paranasal sinuses or to bacterial meningitis, as described in Chap. 31. More common is noninfectious venous occlusion resulting from one of the many hypercoagulable states discussed below.


Neurology_Adams

Neurology_Adams. Occlusion of cortical veins that are the tributaries of the dural sinuses takes the form of a venous infarctive stroke. It may be difficult to determine if the thrombus originated in the dural sinuses and propagates to the tributary cortical veins, or the reverse. The diagnosis is difficult except in certain clinical settings known to favor the occurrence of venous thrombosis, such as the taking of birth control pills or postpartum and postoperative states, which are often characterized by thrombocytosis and hyperfibrinogenemia. Hypercoagulable conditions also occur in cancer (particularly of the pancreas and colon and other adenocarcinomas), cyanotic congenital heart disease; cachexia in infants; sickle cell disease; antiphospholipid antibody syndrome, the aforementioned Behçet disease, factor V Leiden mutation, protein S or C deficiency, antithrombin III deficiency, resistance to activated protein C; primary or secondary polycythemia and thrombocythemia; and paroxysmal nocturnal


Neurology_Adams

Neurology_Adams. factor V Leiden mutation, protein S or C deficiency, antithrombin III deficiency, resistance to activated protein C; primary or secondary polycythemia and thrombocythemia; and paroxysmal nocturnal hemoglobinuria.


Neurology_Adams

Neurology_Adams. The administration of drugs such as tamoxifen, bevacizumab, and erythropoietin, and even the hypercoagulable reaction to heparin that is associated with thrombocytopenia have all been cited as risks for cerebral venous thrombosis. The study by Martinelli and colleagues, mentioned earlier in the chapter, attributed 35 percent of cases of cerebral vein thrombosis in the context of oral contraceptive use to a mutation in the factor V or in the prothrombin gene. Averback, who reported seven cases of venous thrombosis in young adults, has emphasized the diversity of the clinical causes. Two of his patients had carcinoma of the breast and one had ulcerative colitis. A few cases will follow head injury or remain unexplained.


Neurology_Adams

Neurology_Adams. A stroke in a patient suffering from any one of these systemic conditions should suggest venous thrombosis, although in some instances—for example, postpartum strokes—arteries are occluded as often as veins. A slower evolution of the clinical stroke syndrome, the presence of multiple cerebral lesions not in arterial territories, and a convulsive and hemorrhagic character, favor venous over arterial thrombosis. The reasons for these clinical features and their variability as well as the differences from ischemic brain damage caused by arterial occlusion become apparent in the discussions below. Stam has undertaken a review of this subject. Cortical Vein Thrombosis (Superficial Thrombosis of Cortical Veins)


Neurology_Adams

Neurology_Adams. Cortical Vein Thrombosis (Superficial Thrombosis of Cortical Veins) Certain syndromes occur with sufficient regularity that they suggest thrombosis of a particular vein or sinus. The signature features of isolated thrombosis of superficial cortical veins are the presence of large superficial (cortex and subjacent white matter) hemorrhagic infarctions and a marked tendency to focal seizures. Hemiparesis, incomplete hemianopia, and aphasia, any of which may fluctuate over days, are also characteristic according to Jacobs and colleagues. These variable syndromes reflect the inconstant location of the main surface veins. Thrombosis of the vein of Labbé causes infarction of the underlying superior temporal lobe, and occlusion of the vein of Trolard implicates the parietal cortex. A concern is the propagation of the clot into the larger draining veins or dural sinuses.


Neurology_Adams

Neurology_Adams. Quite often, in our experience, the focal deficit worsens immediately after a focal seizure. The intracranial pressure is not elevated, as it is when the dural venous sinuses are occluded. The diagnosis is made by careful examination of the MRV or by the venous phase of the conventional angiogram. Cortical vein thrombosis should be suspected in the situation of multiple hemorrhagic infarctions in one hemisphere without a source of embolism or atherothrombosis.


Neurology_Adams

Neurology_Adams. Sagittal and transverse (lateral) sinus thrombosis In the case of sagittal sinus thrombosis, intracranial hypertension with headache, vomiting, and papilledema may constitute the entire syndrome; this is the main consideration in the differential diagnosis of pseudotumor cerebri (see Chaps. 9, 12, and 29) or it may be conjoined with hemorrhagic infarction. Paraparesis, hemiparesis, fluctuating unilateral or bilateral sensory symptoms, or aphasia result only if the thrombosis propagates to surface veins. Focal or odd sensory or motor seizures occur on the same basis but are not as common as with cortical vein thrombosis.


Neurology_Adams

Neurology_Adams. The transverse sinuses are usually asymmetrical; slightly more than half of individuals have a dominant right vein and approximately a quarter are symmetrical. (The larger sinus corresponds to a smaller occipital lobe on that side—a petalia). Unilateral occlusion of the nondominant transverse sinus may not be symptomatic, whereas thrombosis of the dominant side generally gives the equivalent syndrome to blockage of the sagittal sinus. Increased intracranial pressure without ventricular dilatation occurs with thrombosis of the superior sagittal sinus, the main jugular vein, and the transverse sinus or the confluence of the sinuses.


Neurology_Adams

Neurology_Adams. The common imaging feature that results from occlusion of the superior sagittal sinus is of bilateral superficial paramedian parietal or frontal hemorrhagic infarctions or edematous venous congestion. In the case of CT with contrast infusion in axial images, a lack of dye opacification in the posterior sagittal sinus can be observed with careful adjustment of the viewing window (“empty delta sign”). The spinal fluid pressure is increased, and the fluid may be slightly sanguinous. Transverse sinus thrombosis causes hemorrhagic infarction of the temporal lobe convexity, usually with considerable vasogenic edema. The enhanced CT, arteriography (venous phase), and MRV (Fig. 33-39) facilitate diagnosis by directly visualizing the venous occlusion by showing an absence of opacification of a sinus or, at times, a clot within a vein. Once a venous thrombosis becomes established for several days or longer, the tributary surface veins take on a “corkscrew” appearance that is appreciated on the


Neurology_Adams

Neurology_Adams. or, at times, a clot within a vein. Once a venous thrombosis becomes established for several days or longer, the tributary surface veins take on a “corkscrew” appearance that is appreciated on the venous phase of an angiogram.


Neurology_Adams

Neurology_Adams. Chaps. 12 and 13, in cases of cavernous sinus thrombosis there may be marked chemosis and proptosis, corresponding to a clot in the anterior portion of the sinus and there may be disordered function of cranial nerves III, IV, VI, and the ophthalmic division of V when the posterior portion is affected. If there is spread of the clot to the inferior petrosal sinus, palsies of cranial nerves VI, IX, X, and XI may result. Also involvement of the superior petrosal sinus may be accompanied by a fifth nerve palsy. Thrombosis of the venous sinuses in neonates presents special problems in diagnosis. In the series reported by deVeber and colleagues, various perinatal complications, including systemic illness such as severe dehydration or infection were common precedents; the outcome was poor. In young children the risk factors differed, in that connective tissue and prothrombotic disorders and head and neck infections were more common.


Neurology_Adams

Neurology_Adams. Occlusion of the vein of Galen and of the internal cerebral veins is the least common and clinically most obscure of the venous syndromes.


Neurology_Adams

Neurology_Adams. From the few cases that have been studied, a picture of bithalamic infarction emerges, sometimes reversible, and consisting mainly of inattention, spatial neglect, and amnesia in the case reported by Benabdeljili and colleagues, and of akinetic mutism and apathy as in the case reported by Gladstone and associates. The case series of van den Bergh and colleagues emphasizes the difficulty in diagnosis of partial syndromes of this nature. In most reports of this condition, it is the neuropsychologic aspects that are emphasized. Other cases have manifested coma and pupillary changes referable to the ischemic diencephalon and rostral midbrain. Perhaps most striking is the MRI, with a large bilobular region of signal change that encompasses the thalami. Much of the signal change probably represents reversible edema and venous congestion, because substantial clinical improvement may occur. Angiography is needed to confirm the diagnosis, most often a magnetic resonance venogram.


Neurology_Adams

Treatment of Cerebral Venous Thrombosis

Neurology_Adams. Treatment of Cerebral Venous Thrombosis


Neurology_Adams

Neurology_Adams. Anticoagulant therapy beginning with heparin or an equivalent for several days, followed by warfarin, and combined with antibiotics if the venous occlusion is infectious (it rarely is in recent times) has been lifesaving in some cases. Nonetheless, the overall mortality rate remains high, with large hemorrhagic venous infarctions found in 10 to 20 percent of cases. The clinical trial conducted by Einhaupl and colleagues only apparently settled the question of acute therapy in favor of the use of heparin, because these positive results could not be confirmed by de Bruijn and Stam, who found a minimal difference between patients who were treated with low-molecular-weight heparin compared to placebo, both followed by oral anticoagulation for 3 months. The newer anticoagulants are being considered in some cases. Most treated patients do well, but it may take weeks for the headaches to remit although administration of heparin will sometimes lead to relief of the headache. Coma and multiple


Neurology_Adams

Neurology_Adams. in some cases. Most treated patients do well, but it may take weeks for the headaches to remit although administration of heparin will sometimes lead to relief of the headache. Coma and multiple cerebral hemorrhages, on the other hand, are usually fatal.


Neurology_Adams

Neurology_Adams. The local infusion of tPA has been used, but not subjected to the same randomized testing. Thrombolytic therapy by local venous or systemic infusion has been successful in small series of cases, such as the 5 patients treated with urokinase and heparin by DiRocco and colleagues. We have reserved thrombolysis for extreme cases of dural sinus thrombosis with stupor or coma and greatly raised CSF pressure.


Neurology_Adams

Neurology_Adams. Sterile vegetations, referred to also as nonbacterial thrombotic endocarditis, consist of fibrin and platelets and are loosely attached to the mitral and aortic valves and contiguous endocardium. They are a common source of cerebral embolism (almost 10 percent of all instances of cerebral embolism according to Barron et al, but lower in the experience of other series). In past series, almost half the patients had vegetations associated with a malignant neoplasm; the remainder occurs in patients debilitated by other diseases (Biller et al). Recent experience suggests that the majority is related to systemic cancer.


Neurology_Adams

Neurology_Adams. The setting in which embolism from nonbacterial endocarditis occurs is distinctive. There may also be prototypic clinical features that permit differentiation from other forms of cerebral embolism. In particular, the strokes may be multiple, sequential over days or weeks, and generally small, imparting a picture of incomplete stroke syndromes with a superimposed encephalopathy. The sudden nature of the embolic deficits helps to distinguish this process from the usual forms of cerebral metastases. The disease is essentially a manifestation of chronic disseminated intravascular coagulation (DIC) discussed below and therefore it is not surprising that similar laboratory changes are found, including an elevation in circulating fibrin split products, specifically D-dimer and indications of microangiopathic hemolysis in the blood smear. There is typically moderate thrombocytopenia. The echocardiogram is often obtained but it is insensitive.


Neurology_Adams

Neurology_Adams. The hazards of using anticoagulants in gravely ill patients with widespread malignant disease may outweigh the benefits from this treatment, but drugs that prevent platelet aggregation, while possibly helpful, have not been studied systematically for this condition. Quite often the embolic strokes continue despite treatment. Stroke as a Complication of Hematologic Disease The brain is involved in the course of many hematologic disorders, some of which have already been mentioned. A number of the better-characterized ones are discussed here.


Neurology_Adams

Neurology_Adams. This is perhaps the most common and most serious disorder of coagulation affecting the nervous system. The basic process depends on the release of thromboplastic substances from damaged tissue, resulting in the activation of the coagulation process and the formation of fibrin, in the course of which clotting factors and platelets are consumed. Virtually any mechanism that produces tissue damage can result in the release of tissue thromboplastins into the circulation. Thus, disseminated intravascular coagulation (DIC) complicates a wide variety of clinical conditions—overwhelming sepsis, massive trauma, cardiothoracic surgery, heat stroke, burns, incompatible blood transfusions and other immune complex disorders, diabetic ketoacidosis, leukemia, obstetric complications, cyanotic congenital heart disease, and shock from many causes.


Neurology_Adams

Neurology_Adams. The essential pathologic change in DIC is the occurrence of widespread fibrin thrombi in small vessels, resulting in numerous small infarctions of many organs, including the brain. Sometimes DIC is manifest by a hemorrhagic diathesis in which petechial hemorrhages are situated around small penetrating vessels. In some cases, cerebral hemorrhage is quite extensive, similar to a primary hypertensive hemorrhage. The main reason for the hemorrhage is the consumption of platelets and various clotting factors that occurs during fibrin formation; in addition, fibrin degradation products have anticoagulant properties of their own.


Neurology_Adams

Neurology_Adams. The diffuse nature of the neurologic damage may suggest a metabolic rather than a vascular disorder of the brain. In the absence of a clear metabolic, infective, or neoplastic cause of an encephalopathy, the onset of acute and fluctuating focal neurologic abnormalities or a generalized and sometimes terminal neurologic deterioration during the course of a severe illness should arouse suspicion of DIC, and coagulation factors and fibrin split products should be measured. Platelet counts are invariably depressed and there is evidence of consumption of fibrinogen and other clotting factors, indicated by prolonged prothrombin and partial thromboplastin times.


Neurology_Adams

Neurology_Adams. In the related illness abbreviated as HELLP mentioned earlier in the sections on hypertensive and eclamptic encephalopathy, women with eclampsia develop liver failure and thrombocytopenia; the contribution of this limited form of DIC to the eclamptic effects on the nervous system have not been established (see earlier discussion of eclampsia).


Neurology_Adams

Neurology_Adams. This condition, in which TIAs, or stroke, migraine, and thrombocytopenia in various combinations, occur in young adults, has already been discussed under “Strokes in Children and Young Adults.” Phospholipids are a family of lipoproteins that influence clotting. Some of the phospholipids with which the antibodies react are shared with clotting factors, particularly prothrombin. Autoantibodies directed at the binding protein of phospholipids thereby induce blood clotting. The first of the antibodies to be described were lupus anticoagulant and anticardiolipin. Most classifications of the antiphospholipid syndrome also include the major target of antibodies, β2-glycoprotein 1, a protein that may be necessary for the binding and procoagulant effect of anticardiolipin antibody. For stroke work, the formal criteria for the diagnosis of the syndrome require that an ischemic event be accompanied by the detection of autoantibodies on two occasions at least 6 weeks apart. Approximately


Neurology_Adams

Neurology_Adams. work, the formal criteria for the diagnosis of the syndrome require that an ischemic event be accompanied by the detection of autoantibodies on two occasions at least 6 weeks apart. Approximately one-quarter of patients with lupus have antiphospholipid proteins and up to 6 percent of women with pregnancy complications have the antibodies. Some surveys indicate that it is found in 17 percent of patients with stroke who are under 50 years old.


Neurology_Adams

Neurology_Adams. In addition to the cerebrovascular effects, livedo reticularis, venous thrombosis, usually in the legs, and late pregnancy loss are other features. Eclampsia and pre-eclampsia and the syndrome of HELLP during pregnancy are the result of the autoantibodies. Often the antiphospholipid syndrome is identified in asymptomatic patients during the evaluation of elevated partial thromboplastin time (PTT) or thrombocytopenia; severe reductions in platelet count (below 20 × 109/L) are, however, uncommon.


Neurology_Adams

Neurology_Adams. Testing for this disease consists of detection of IgM, IgG, and mixed antibodies to each of these three main phospholipids (lupus anticoagulant, anticardiolipin, and β2-GP 1); there is a partial overlap in many patients, in which more than one antibody subclass is present against more than one lipoprotein—80 percent of patients with lupus anticoagulant have anticardiolipin antibody but fewer than 50 percent of those with anticardiolipin antibody have lupus anticoagulant. Antibodies to β2-glycoprotein 1 are most specific for the disease. Nonetheless, the main laboratory feature of the illness is a prolonged partial thromboplastin time. The titer of anticardiolipin broadly correlates with the risk of thrombosis and the specificity for the syndrome is higher for IgG than for IgM autoantibodies. An increased incidence of migraine has long been discussed and also disputed. A review of strokes in this condition has been given by Levine and colleagues (1990) and a overview of the topic as it


Neurology_Adams

Neurology_Adams. An increased incidence of migraine has long been discussed and also disputed. A review of strokes in this condition has been given by Levine and colleagues (1990) and a overview of the topic as it applies to in general medicine, by Garcia and Erkan.


Neurology_Adams

Neurology_Adams. These comments pertain mainly to a “primary” idiopathic autoimmune form of the disease but cases occur secondarily to lupus erythematosus, Sjögren disease, neuroleptic drugs such as the phenothiazines, butyrophenones and others drugs, and to certain infections.


Neurology_Adams

Neurology_Adams. The most frequent neurologic abnormality is a TIA, often taking the form of amaurosis fugax (transient monocular blindness), with or without retinal arteriolar or venous occlusion (Digre et al). Stroke-like phenomena are more frequent in patients who also have migraine, hyperlipidemia, or antinuclear antibodies, and in those who smoke or take birth control pills. Almost one-third of the 48 patients reported by Levine and associates (1990) had thrombocytopenia and 23 percent had a false-positive Venereal Disease Research Laboratory (VDRL) test. The vascular lesions are mainly in the cerebral white matter and are infarcts, seen well with MRI. Angiography reveals occlusions of arteries at unusual sites (Brey et al). The mechanism of stroke is not entirely clear and may derive from emboli originating on mitral valve leaflets similar to nonbacterial thrombotic endocarditis; alternatively, and more likely in our view, there is a noninflammatory in situ thrombosis of medium-sized cerebral


Neurology_Adams

Neurology_Adams. on mitral valve leaflets similar to nonbacterial thrombotic endocarditis; alternatively, and more likely in our view, there is a noninflammatory in situ thrombosis of medium-sized cerebral vessels, as suggested by the limited pathologic material studied by Briley and colleagues.


Neurology_Adams

Neurology_Adams. These circulating antibodies may be associated with a syndrome of transient bilateral chorea or hemichorea; some patients have an additional slight hemiparesis or other subtle focal signs. Almost all of the affected patients we have seen have been women with thrombocytopenia, most of whom probably have systemic lupus, at least on the grounds of laboratory studies. A direct connection of the choreic syndrome to the antibodies comparable to what is proposed in Sydenham chorea may be valid, but is unproven. Some cases display microinfarctions in the basal ganglia, perhaps on the basis of valvular vegetations. The choreic syndrome may be precipitated in these patients by the introduction of estrogen-containing birth control pills and is improved, usually promptly, by corticosteroids or antiplatelet agents. This movement disorder in the syndrome is reviewed by Asherson and colleagues.


Neurology_Adams

Neurology_Adams. The Sneddon syndrome (described by him in a 1965 article) is an arteriopathy producing deep blue-red skin lesions of livedo reticularis and livedo racemosa in association with multiple ischemic strokes. Many, but not all, patients have high titers of antiphospholipid antibodies. Although the skin lesions show a noninflammatory vasculopathy with intimal thickening, the pathology of the occlusive disease has not been adequately studied. In a report of 17 such patients by Stockhammer and coworkers, 8 had strokes and MRI showed lesions in 16 patients. The age of patients with strokes was 30 to 35 years; hence this condition is considered in young adults with cerebrovascular disease. Many of the lesions on MRI were small, deep, and multiple. Although there is a tendency for strokes to recur, many of the patients have remained well for years after a single stroke. Skin biopsy aids in diagnosis.


Neurology_Adams

Neurology_Adams. There are instances in which the radiologic changes caused by recurrent small infarctions of antiphospholipid syndrome are difficult to distinguish from multiple sclerosis, as discussed in several parts of Chap. 35, on demyelinative diseases. Associations of the antiphospholipid syndrome with transverse myelitis (see Chap. 42), hearing loss, and a number of other processes have been suspected but not proven.


Neurology_Adams

Neurology_Adams. Treatment During the period in which the diagnosis is being established by repeating the antibody tests, or after just a single arterial ischemic stroke, consensus groups have stated that it is reasonable to treat these patients with antiplatelet or anticoagulant agents (see Lim and colleagues). (Venous thrombosis is treated initially with heparin). Warfarin, perhaps the more the definitive therapy, alters the testing for antibodies and several guidelines recommend confirming the presence of antibodies after an interval of 2 weeks before starting treatment. However, warfarin has been used with greatest benefit and we have sometimes started this medication on suspicion of the syndrome. Khamashta and colleagues have found that the INR must be maintained close to 3 for effective prevention of stroke. According to the study conducted by Crowther and colleagues, an INR of 2 to 3 conferred the same degree of protection from thrombosis as did higher levels, but the number of thrombotic


Neurology_Adams

Neurology_Adams. of stroke. According to the study conducted by Crowther and colleagues, an INR of 2 to 3 conferred the same degree of protection from thrombosis as did higher levels, but the number of thrombotic events was low in both groups and there was only 1 stroke in 114 patients over a period of about 3 years. Patients with severe thrombocytopenia and with other intrinsic coagulopathies should be treated with warfarin very cautiously. Although the INR is used as a gauge of the level of anticoagulation, it is also altered by the antibodies; no ideal method for monitoring the treatment has been devised. Aspirin, on uncertain grounds, is thought not to confer protection for stroke, but in only a few small series has its effect been analyzed. In “catastrophic” cases with repetitive strokes, intravenous immunoglobulin and plasma exchange have been used with some effect.


Neurology_Adams

Neurology_Adams. Immunosuppressive agents such as azathioprine, rituximab, and mycophenolate have been tried with mixed success and side effects. Eculizumab, an anti-C5 (complement-5) antibody has been used in catastrophic cases and inhibition of the m-TORC pathway in patients with renal disease and transplant failure is being explored. Statin drugs have a theoretical basis for use but have not been extensively tested. It is important to eliminate smoking and estrogen-containing compounds, as these greatly raise the risk of stroke in this syndrome. The subject of systemic antiphospholipid antibody disease and its treatment has been reviewed by Garcia. Thrombotic Thrombocytopenic Purpura (TTP, Moschcowitz Syndrome) and Hemolytic Uremic Syndrome


Neurology_Adams

Neurology_Adams. Thrombotic Thrombocytopenic Purpura (TTP, Moschcowitz Syndrome) and Hemolytic Uremic Syndrome These are serious diseases of the small blood vessels combined with microangiopathic hemolytic anemia characterized by widespread occlusions of arterioles and capillaries involving practically all organs of the body, including the brain. It was described by Adams and colleagues (1948) and named thrombocytic acroangiothrombosis. Fibrin components have been identified by immunofluorescent techniques; some investigators have demonstrated disseminated intravascular platelet aggregation rather than fibrin thrombi. Sporadic TTP is caused by an acquired circulating IgG inhibitor of the von Willebrand factor-cleaving protease (termed “a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 [ADAMTS13]”). A rarer familial form (The Upshaw-Shulman syndrome) is caused by an inherited deficiency of ADAMTS13.


Neurology_Adams

Neurology_Adams. Clinically, the main features of this disease are fever, anemia, symptoms of renal and hepatic disease, and thrombocytopenia—the latter giving rise to the common hemorrhagic manifestations (petechiae and ecchymoses of the skin, retinal hemorrhages, hematuria, gastrointestinal bleeding, etc.). Neurologic symptoms are practically always present and are the initial manifestation of the disease in about half the cases. Confusion, delirium, seizures, and hemiparesis—sometimes remittent or fluctuating in nature—are the usual manifestations of the nervous system disorder and are readily explained by the widespread microscopic ischemic lesions in the brain. Garrett and colleagues have emphasized the presentation of nonconvulsive status epilepticus in TTP, and we have encountered two such cases. Gross infarction was not observed. In most patients who survive, recovery of the focal neurologic deficits can be expected unless there is an identifiable infarction on CT or MRI. The CSF is normal


Neurology_Adams

Neurology_Adams. Gross infarction was not observed. In most patients who survive, recovery of the focal neurologic deficits can be expected unless there is an identifiable infarction on CT or MRI. The CSF is normal except for elevated protein in some cases. To our knowledge, a mononeuritis multiplex does not occur.


Neurology_Adams

Neurology_Adams. The diagnosis is made by finding a microangiopathic hemolytic anemia in the context of the characteristic clinical picture. An assay for ADAMTS13 activity is available using an enzyme-linked immunosorbent assay but the initiation of treatment usually cannot await confirmation of the diagnosis. There is an important overlap among TTP, HUS, toxemia of pregnancy, the hemolytic anemia with elevated liver function tests and platelet count (HELLP syndrome), hypertensive encephalopathy, and other causes of the posterior reversible leukoencephalopathy syndrome (PRES, see earlier discussion). In all of them, the central nervous system problem is mediated by endothelial dysfunction with breakdown of the blood–brain barrier. The recommended treatment for TTP is plasma exchange or plasma infusion. Further details can be found in Harrison’s Principles of Internal Medicine. Polycythemia Vera, Thrombocytosis, and Thrombocythemia


Neurology_Adams

Neurology_Adams. Polycythemia vera is a myeloproliferative disorder of unknown cause, characterized by a marked increase in RBC mass and in blood volume and often by an increase in WBCs and platelets. The condition must be distinguished from the many secondary or symptomatic forms of polycythemia (erythrocytosis), in which the platelets and white cells remain normal. A high proportion of patients with polycythemia vera will have mutations in JAK2. The slightly increased incidence of thrombosis in primary polycythemia is attributed to the high blood viscosity, engorgement of vessels, and reduced rate of blood flow. The majority of patients with cerebrovascular manifestations have TIAs and small strokes, but we have seen one case of sagittal sinus thrombosis. With very high hematocrit, sludging of red cells may be seen in the retinal vessels. The cause of cerebral hemorrhage in this disease is less clear, although a number of abnormalities of platelet function and of coagulation have been described (see


Neurology_Adams

Neurology_Adams. may be seen in the retinal vessels. The cause of cerebral hemorrhage in this disease is less clear, although a number of abnormalities of platelet function and of coagulation have been described (see Davies-Jones et al).


Neurology_Adams

Neurology_Adams. Instances of platelet counts above 800,000/mm3 are considered to be a form of myeloproliferative disease allied with polycythemia vera. In some patients, there is an enlarged spleen, polycythemia, chronic myelogenous leukemia, or myelosclerosis. In several of our patients, no explanation of the thrombocytosis was found. They presented with recurrent cerebral and systemic thrombotic episodes, often of minor degree and transient. Cytapheresis, to reduce the platelets, and antiplatelet drugs (hydroxyurea anagrelide) to suppress megakaryocyte formation, are helpful in ameliorating the neurologic symptoms. In one of the cases we followed, several small lesions, presumably infarctions, were situated in the white matter and simulated multiple sclerosis. Another patient with essential thrombocytosis developed dramatic new migraine with aura when her platelet counts exceeded 1,000,000/mm3, a phenomenon commented on in the literature.


Neurology_Adams

Neurology_Adams. A wide variety of bleeding disorders—such as leukemia, aplastic anemia, thrombocytopenic purpura, and hemophilia—may also give rise to cerebral hemorrhage. Many rare forms of bleeding disease may be complicated by hemorrhagic manifestations; these are reviewed by Davies-Jones and colleagues.


Neurology_Adams

Neurology_Adams. This inherited disease is related to the presence of the abnormal hemoglobin S in the red corpuscles. Clinical abnormalities occur mainly in patients with sickle cell disease—that is, with the homozygous state, and not in those with the sickle cell trait, which represents the heterozygous state. We have seen neurologic symptoms in patients with a heterozygous mixed hemoglobinopathy, such as sickle-thalassemia, sickle-S, and sickle-D, but all are less severe and less frequent than in sickle cell anemia. The disease, which is practically limited to persons of central African and certain Mediterranean origins, begins early in life and is characterized by “crises” of infection (particularly pneumococcal meningitis), pain in the limbs and abdomen, chronic leg ulcers, and infarctions of bones and visceral organs. Ischemic lesions of the brain, both large and small, are the most common neurologic complications, but cerebral, subarachnoid, and subdural hemorrhage may also occur, and the


Neurology_Adams

Neurology_Adams. and visceral organs. Ischemic lesions of the brain, both large and small, are the most common neurologic complications, but cerebral, subarachnoid, and subdural hemorrhage may also occur, and the vascular occlusions may be either arterial or venous. Patients with sickle cell anemia may develop progressive stenosis of the supraclinoid intracranial carotid artery with consequent collateral formation, producing a syndrome akin to moyamoya disease described earlier in the chapter. These fragile collateral vessels may rupture causing intracranial hemorrhage.


Neurology_Adams

Neurology_Adams. Regular blood transfusions were shown by DeBaun and coworkers to reduce the incidence or recurrent strokes from 14 to 6 percent over 3 years in sickle cell disease. Lee and colleagues demonstrated that exchange transfusions with monitoring of the velocities of flow in the middle cerebral artery by transcranial Doppler examination reduce the risk of this important neurologic complication. In the stroke prevention trial of sickle cell anemia, the risk of first stroke was reduced by 90 percent in 63 children who received periodic transfusions as compared to 67 children who received only supportive care.


Neurology_Adams

Neurology_Adams. Inevitably, most patients are seen first by clinicians who may not be expert in all the fine points of cerebrovascular disease. Situations arise in which critical decisions must be made regarding anticoagulation, further laboratory investigation, and the advice and prognosis to be given to the family. The following are some of the situations encountered by the authors that may be of value to students and residents and to nonspecialists in the field. The Patient With a History of an Ischemic Attack or Small Stroke in the Past


Neurology_Adams

Neurology_Adams. The patient may be functioning normally when examined, but it has been ascertained by the history or radiologic procedures that a stroke or TIA occurred in the past. The problem is what measures should be taken to reduce the risk of further strokes. This is particularly problematic if a surgical procedure is planned. A brief focal TIA, several minutes or less in duration, or many stereotyped spells usually represent severe stenosis of the internal carotid artery on the side of the affected cerebral hemisphere. If the symptoms have occurred recently, these may be forerunners of complete occlusion. If the TIA was far in the past—more than several weeks previously—the immediate risks of occlusion are reduced. The initial approach is to establish the patency of the carotid arteries by ultrasonography or MRA. If there is a reduction in diameter of greater than 70 percent when compared with an adjacent normal segment of vessel, and probably if there is a severely ulcerated but not


Neurology_Adams

Neurology_Adams. ultrasonography or MRA. If there is a reduction in diameter of greater than 70 percent when compared with an adjacent normal segment of vessel, and probably if there is a severely ulcerated but not critically stenotic plaque, carotid surgery (or angioplasty with stenting) is advisable. If a single TIA lasted more than 1 h or the neurologic examination discloses minor signs referable to the region of the hemisphere affected by the TIA, a search for a source of embolus is indicated. Appropriate diagnostic studies include electrocardiography (ECG), a transesophageal echocardiogram, monitoring for cardiac arrhythmia, ultrasonography of the carotid arteries, and a CT or MRI if it has not already been performed. Control of elevated blood pressure and addressing high cholesterol levels are ancillary steps. The mistake is to ignore the potential significance of a prior small stroke or TIA.


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Neurology_Adams. The Patient With a Recent Stroke That May Not Be Complete


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Neurology_Adams. If hours have passed since the first symptoms of stroke but the syndrome is fluctuating or advancing, the basic problem is whether a thrombotic infarction (venous or arterial) will spread and involve more brain tissue; or if embolic, whether the ischemic tissue will become hemorrhagic or another embolus will occur; or if there is an arterial dissection, whether it will give rise to emboli. Therapies are controversial in most of these circumstances. In some centers, it is the practice to try to prevent propagation of a thrombus by administering heparin (or low-molecular-weight heparin) followed by warfarin, as discussed earlier. Some stroke deficits fluctuate with blood pressure, suggesting occlusion of the carotid or of another large vessel. Attention to adequate cerebral perfusion by omitting the patient’s usual blood pressure medications, ensuring adequate hydration and avoiding hemoconcentration, and potentially utilizing a head-down position may all assist in stabilizing the


Neurology_Adams

Neurology_Adams. omitting the patient’s usual blood pressure medications, ensuring adequate hydration and avoiding hemoconcentration, and potentially utilizing a head-down position may all assist in stabilizing the situation.


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Neurology_Adams. The Inevident or Misconstrued Syndromes of Cerebrovascular Disease Although hemiplegia is the typical manifestation of stroke, cerebrovascular disease may manifest itself by signs that spare the motor pathways but have the same serious diagnostic and therapeutic implications. The following stroke syndromes tend to be overlooked. Sometimes disregarded is a leaking aneurysm presenting as a sudden and intense generalized headache lasting hours or days and unlike any headache in the past. Examination may disclose no abnormality except for a slightly stiff neck and raised blood pressure. Failure to investigate such a case by imaging procedures and examination of the CSF may permit the occurrence of a later massive subarachnoid hemorrhage. Small cerebral hemorrhages, subdural hematomas, and brain tumors figure into the differential diagnosis, which is usually settled by a CT or MRI.


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Neurology_Adams. A second nonobvious stroke is one caused by occlusion of the posterior cerebral artery, usually embolic. This may not be recognized unless the visual fields are carefully tested at the bedside. The patient himself may not be aware of the difficulty or will complain only of blurring of vision or the need for new glasses. Accompanying deficits are inability to name colors or recognize manipulable objects or faces, difficulty in reading, etc. MRI or CT usually corroborates the clinical diagnosis, and therapy is directed against further emboli or extension of the thrombosis.


Neurology_Adams

Neurology_Adams. An inapparent stroke that may be mistaken for psychiatric disease is an attack of paraphasic speech from embolic occlusion of a branch of the left middle cerebral artery. The patient talks in nonsensical phrases, appears confused, and does not fully comprehend what is said to him. He may perform satisfactorily at a superficial level and offer socially appropriate greetings and gestures. Only scrutiny of language function and behavior will lead to the correct diagnosis. Infarction of the dominant or nondominant temporal lobe and rarely of the caudate may produce an agitated delirium with few focal findings. This may be mistaken for a toxic or withdrawal state.


Neurology_Adams

Neurology_Adams. Parietal infarctions on either side (usually nondominant hemisphere) are often missed because the patient is entirely unaware of the problem or the symptoms create only a subtle confusional state, drowsiness, or only subtle problems with calculation, dialing a phone, reaching accurately for objects, or loss of ability to write. Extinction of bilaterally presented visual or tactile stimuli gives a clue; marked asymmetry of the optokinetic nystagmus response is sometimes the only definite sign.


Neurology_Adams

Neurology_Adams. A cerebellar hemorrhage may at first be difficult to recognize as a stroke. An occipital headache and complaint of dizziness with vomiting may be interpreted as a labyrinthine disorder, gastroenteritis, or myocardial infarction. A slight ataxia of the limbs, inability to sit or stand, and mild gaze paresis may not have been properly tested or have been overlooked. The entire syndrome may be missed if the patient is not asked to get off the gurney and walk. Early intervention by surgery may be lifesaving; but once the syndrome has progressed to the point of coma with pupillary abnormalities with bilateral Babinski signs, surgery is usually less likely to result in a good outcome. Similarly, a lateral medullary infarction causing incessant vomiting and dizziness may be mistaken for gastroenteritis unless nystagmus and gait ataxia are appreciated. The Comatose Stroke Patient


Neurology_Adams

Neurology_Adams. The most common causes of vascular coma are intracranial hemorrhage—usually deep in the hemisphere, less often in the cerebellum or brainstem, extensive subarachnoid hemorrhage, and basilar artery occlusion. After several days, brain edema surrounding a large infarction in the territory of the middle cerebral artery or adjacent to a hemorrhage may compress the midbrain and produce the same effect. Certain remedial surgical measures are still available in these circumstances: drainage of blood from the ventricles, shunting of the ventricles in cases of secondary hydrocephalus due to obstruction of the third ventricle or aqueduct, evacuation of a cerebral hemorrhage in cases of recent decline into stupor and coma, and hemicraniectomy in the case of massive stroke edema. Also, thrombolytic therapy and anticoagulants are sometimes successful in reversing the progression of basilar artery thrombosis that has caused coma by ischemia or infarction of the upper brainstem.


Neurology_Adams

Neurology_Adams. With the exception of infarction caused by cerebral venous occlusion, convulsive seizures following stroke are not a great problem. As mentioned earlier and in other chapters of the book, seizures are quite infrequent as the initial manifestation of an ischemic stroke, and when they do occur in this fashion, an embolus is usually the causative mechanism. More often, they are delayed by months or years after the infarction or hemorrhage. In the data presented by Lamy and colleagues (who were studying stroke in young patients with patent foramen ovale), when seizures occurred not at the outset but within the first week after stroke, as they did in 2 to 4 percent of their cases, about half had another seizure, usually single, during the next several years. However, the same was true for those with a first seizure after 1 week. Perhaps not surprisingly, the rate of seizures is higher after hemorrhagic than ischemic strokes and for the latter category, larger cortical strokes were more


Neurology_Adams

Neurology_Adams. with a first seizure after 1 week. Perhaps not surprisingly, the rate of seizures is higher after hemorrhagic than ischemic strokes and for the latter category, larger cortical strokes were more likely to result in a seizure disorder. An overview of the low rate of seizures that occurred soon after a stroke can be appreciated from the report by Beghi and colleagues, about 6 percent.


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Neurology_Adams. No satisfactory study has been conducted to determine if these patients benefit from antiepileptic therapy to prevent the second or subsequent seizures. Following the practice of most other neurologists, we prescribe one of the main epilepsy medications only if there has been a seizure, and continue it for about 12 months. If the EEG shows focal sharp waves or other epileptic activity at that time, we continue the drug; if not, we may discontinue the medication. It is also clear that prophylactic anticonvulsant treatment of all stroke patients is not necessary.


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Neurology_Adams. Dementia of the Alzheimer type is often ascribed, on insufficient and conceptually incorrect grounds, to the occurrence of multiple small strokes. If vascular lesions are responsible, evidence of an acute stroke episode or episodes and of focal neurologic deficits to account for at least part of the syndrome are evident. However, there is a process in which diffuse white matter changes on the basis of vascular disease lead to a less saltatory decline in cognitive function—vascular dementia. Complicating the understanding of this syndrome is the frequent coexistence, and possibly interdependence, of the lesions of both vascular and Alzheimer disease. There may be difficulty in determining to what extent each of them is responsible for the neurologic deficits. Several studies have shown an increased incidence or an acceleration of Alzheimer dementia if there are concurrent vascular lesions.


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Neurology_Adams. ACTIVE Investigators: Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 360:2006, 2009. ACTIVE Writing Group, The: Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with Irbesartan for prevention of vascular events (ACTIVE W)—a randomized trial. Lancet 367:1903, 2006. Adams HP Jr, Butler MJ, Biller J, Toffol GN: Nonhemorrhagic cerebral infarction in young adults. Arch Neurol 43:793, 1986. Adams RD: Mechanisms of apoplexy as determined by clinical and pathological correlation. J Neuropathol Exp Neurol 13:1, 1954. Adams RD, Cammermeyer J, Fitzgerald PJ: The neuropathological aspects of thrombotic acroangiothrombosis. J Neurol Neurosurg Psychiatry 11:1, 1948. Adams RJ, McKie VC, Hsu L, et al: Prevention of first stroke by transfusion in children with sickle cell anemia and abnormal results on transcranial ultrasonography. N Engl J Med 339:5, 1998.


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Neurology_Adams. Adams RJ, McKie VC, Hsu L, et al: Prevention of first stroke by transfusion in children with sickle cell anemia and abnormal results on transcranial ultrasonography. N Engl J Med 339:5, 1998. Adler JR, Ropper AH: Self-audible venous bruits and high jugular bulb. Arch Neurol 43:257, 1986. Ahlgren E, Arén C: Cerebral complications after coronary artery bypass surgery and heart valve surgery: Risk factors and onset of symptoms. J Cardiothorac Vasc Anesth 12:270, 1998. Alamowitch S, Eliasziw M, Algra A, et al: Risk, causes, and prevention of ischaemic stroke in elderly patients with symptomatic internal-carotid-artery stenosis. Lancet 357:1154, 2001. Albers GW, Marks MP, Kemp S, et al: Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. New Engl J Med 378:708, 2018. Alema G: Behçet’s disease. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology: Infection of the Nervous System. Vol. 34: Part II. Amsterdam, North-Holland, 1978, pp 475–512.


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Neurology_Adams. Alema G: Behçet’s disease. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology: Infection of the Nervous System. Vol. 34: Part II. Amsterdam, North-Holland, 1978, pp 475–512. Alexander MP, Schmitt MA: The aphasia syndrome of stroke in the left anterior cerebral artery territory. Arch Neurol 37:97, 1980. Allen GS, Ahn HS, Preziosi TJ, et al: Cerebral arterial vasospasm: A controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 308:619, 1983. Amarenco P, Cohen A, Tzourio C, et al: Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 331:1474, 1994. Amarenco P, Hauw J-J: Cerebellar infarction in the territory of the anterior and inferior cerebellar artery: A clinicopathological study of 20 cases. Brain 113:139, 1990. Amarenco P, Lavallee P, Lereuche J, et al: One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med 374:1533, 2016.


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Neurology_Adams. Amarenco P, Lavallee P, Lereuche J, et al: One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med 374:1533, 2016. Amarenco P, Lavallee P, Tavares LM, et al: Five-year risk of stroke after TIA or minor ischemic stroke. N Engl J Med 378:2182, 2018. Ames A, Nesbett FB: Pathophysiology of ischemic cell death: I. Time of onset of irreversible damage: Importance of the different components of the ischemic insult. Stroke 14:219, 1983. Ames A, Nesbett FB: Pathophysiology of ischemic cell death: II. Changes in plasma membrane permeability and cell volume. Stroke 14:227, 1983. Ames A, Nesbett FB: Pathophysiology of ischemic cell death: III. Role of extracellular factors. Stroke 14:233, 1983. Ames A, Wright RL, Kowada M, et al: Cerebral ischemia: II. The noreflow phenomenon. Am J Pathol 52:437, 1968. Anderson CS, Arima H, Lavados P: Cluster-randomized, crossover trial of head positioning in acute stroke. N Engl J Med 376:2437, 2017.


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Neurology_Adams. Anderson CS, Arima H, Lavados P: Cluster-randomized, crossover trial of head positioning in acute stroke. N Engl J Med 376:2437, 2017. Anderson CS, Heeley E, Huang Y, et al: Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 368:2355, 2013. Anderson CS, Robinson T, Lindley RI, et al: Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med 374:2313, 2016. Andrew BT, Chiles BW, Olsen WL, et al: The effects of intracerebral hematoma location on the risk of brainstem compression and clinical outcome. J Neurosurg 69:518, 1988. Aoyagi N, Hayakawa I: Analysis of 223 ruptured intracranial aneurysms with special reference to rerupture. Surg Neurol 21:445, 1984. Asherson CR, Tikly FJ, Chamorro PL, et al: Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature. Medicine (Baltimore) 76:203, 1997.


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Neurology_Adams. Auer LM: The pathogenesis of hypertensive encephalopathy. Acta Neurochir Suppl 27:1, 1978. Averback P: Primary cerebral venous thrombosis in young adults: The diverse manifestations of an unrecognized disease. Ann Neurol 3:81, 1978. Babikian V, Ropper AH: Binswanger’s disease: A review. Stroke 18:2, 1987. Bakar M, Kirshner HS, Niaz F: The opercular-subopercular syndrome: Four cases with review of the literature. Behav Neurol 11:97,1998. Bamford J, Sandercock P, Dennis M, et al: A prospective study of acute cerebrovascular disease in the community: The Oxfordshire Community Stroke Project. 1981–1986. J Neurol Neurosurg Psychiatry 51:1373, 1988; also 53:16, 1990. Banker BQ: Cerebral vascular disease in infancy and childhood: I. Occlusive vascular disease. J Neuropathol Exp Neurol 20:127, 1961. Barnett HJM, Boughner GR, Cooper PF: Further evidence relating mitral-valve prolapse to cerebral ischemic events. N Engl J Med 302:139, 1980.


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Neurology_Adams. Barnett HJM, Boughner GR, Cooper PF: Further evidence relating mitral-valve prolapse to cerebral ischemic events. N Engl J Med 302:139, 1980. Barnett HJM, Peerless J, Kaufmann JCE: “Stump” of internal carotid artery—a source for further cerebral embolic ischemia. Stroke 78:448, 1978. Barron KD, Siqueira E, Hirano A: Cerebral embolism caused by non-bacterial thrombotic endocarditis. Neurology 10:391, 1960. Batjer HH, Reisch JW, Allen BC, et al: Failure of surgery to improve outcome in hypertensive putaminal hemorrhage. Arch Neurol 47:1103, 1990. Becker S, Heller CH, Gropp F, et al: Thrombophilic disorders in children with cerebral infarction. Lancet 352:1756, 1998. Beghi E, D’Allessandro R, Beretta S, et al. Incidence and predictors of acute symptomatic seizures after stroke. Neurology 77:1785, 2011. Benabdeljlil M, El Alaoui Faris M, Kissani N, et al: Troubles neuro-psychologiques apres infarctus bi-thalamique par thrombose veineuse profonde. Rev Neurol (Paris) 157:62, 2001.


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Neurology_Adams. Benabdeljlil M, El Alaoui Faris M, Kissani N, et al: Troubles neuro-psychologiques apres infarctus bi-thalamique par thrombose veineuse profonde. Rev Neurol (Paris) 157:62, 2001. Benavente O, Eliasziw M, Streifler JY, et al: Prognosis after transient monocular blindness associated with carotid-artery stenosis. N Engl J Med 345:1084, 2001. Bendszus M, Koltzenberg M, Burger R, et al: Silent embolism in diagnostic cerebral angiography and neurointerventional procedures: A prospective study. Lancet 354:1594, 1999. Benninger DH, Gandjour J, Georgiadis D, et al: Benign long-term outcome of conservatively treated cervical aneurysms due to carotid dissection. Neurology 69:486, 2007. Bhatt DL, Fox KA, Hacke W, et al: Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 354:1706, 2006. Biller J, Challa VR, Toole JF, Howard VJ: Nonbacterial thrombotic endocarditis. Arch Neurol 39:95, 1982.


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Neurology_Adams. N Engl J Med 354:1706, 2006. Biller J, Challa VR, Toole JF, Howard VJ: Nonbacterial thrombotic endocarditis. Arch Neurol 39:95, 1982. Investigators: The effect of low-dose warfarin in the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 323:1505, 1990. Botterell EH, Lougheed WM, Scott JW, Vandewater SL: Hypothermia, and interruption of carotid or carotid and vertebral circulation, in the surgical management of intracranial aneurysms. J Neurosurg 13:1, 1956. Breen JC, Caplan LR, DeWitt D, et al: Brain edema after carotid surgery. Neurology 46:175, 1996. Brey RL, Hart RG, Sherman DG, Tegeler CH: Antiphospholipid antibodies and cerebral ischemia in young people. Neurology 40:1190, 1990. Briley DP, Coull BM, Goodnight SH: Neurological disease associated with antiphospholipid antibodies. Ann Neurol 25:221, 1989. Britton M, DeFaire U, Helmers C: Hazards of therapy for excessive hypertension in acute stroke. Acta Med Scand 207:352, 1980.


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Neurology_Adams. Britton M, DeFaire U, Helmers C: Hazards of therapy for excessive hypertension in acute stroke. Acta Med Scand 207:352, 1980. Broderick JP, Brott TG, Buldner JE, et al: Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke 24:987, 1993. Brott T, Broderick J, Kothari R, et al: Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 28:1, 1997. Brott TG, Hobson RW, Howard G, et al: Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 363:11, 2010. Brown MM, Bevan D: Is inherited thrombophilia a risk factor for arterial stroke? J Neurol Neurosurg Psychiatry 65:617, 1998. Brust JCM: Anterior cerebral artery disease. In: Barnett HJM, Mohr JP, Stein BM, Yalsu FM (eds): Stroke: Pathophysiology, Diagnosis, and Management, 2nd ed. New York, Churchill Livingstone, 1992, pp 337–360.


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Neurology_Adams. Livingstone, 1992, pp 337–360. Brust JCM, Behrens MM: “Release hallucinations” as the major symptom of posterior cerebral artery occlusion: A report of 2 cases. Ann Neurol 2:432, 1977. Byrom FB: The pathogenesis of hypertensive encephalopathy. Lancet 2:201, 1954. Call G, Fleming M, Sealfon S, et al: Reversible cerebral segmental vasoconstriction. Stroke 19:1159, 1988. Campbell B, Mitchell PJ, Churilov L, et al: Tenecteplase versus alteplase before thrombectomy for ischemic stroke. New Engl J Med 378:1573, 2018. Caplan LR: Binswanger’s disease—revisited. Neurology 45:626, 1995. Caplan LR: Intracranial branch atheromatous disease: A neglected, understudied, and overused concept. Neurology 39:1246, 1989. Caplan LR: Stroke: A Clinical Approach, 2nd ed. Boston, Butterworth-Heinemann, 1993. Caplan LR: “Top of the basilar” syndrome. Neurology 30:72, 1980. Caplan LR, Schmahmann JD, Kase CS, et al: Caudate infarcts. Arch Neurol 47:133, 1990.


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Neurology_Adams. Butterworth-Heinemann, 1993. Caplan LR: “Top of the basilar” syndrome. Neurology 30:72, 1980. Caplan LR, Schmahmann JD, Kase CS, et al: Caudate infarcts. Arch Neurol 47:133, 1990. Caplan LR, Sergay S: Positional cerebral ischemia. J Neurol Neurosurg Psychiatry 39:385, 1976. Castaigne P, Lhermitte F, Buge A, et al: Paramedian thalamic and midbrain infarcts: Clinical and neuropathological study. Ann Neurol 10:127, 1981. CAVATAS Investigators: Endovascular versus surgical treatment in patients with carotid stenosis in the carotid and vertebral artery transluminal angioplasty study (CAVATAS): A randomised trial. Lancet 357:1729, 2001. Chajek T, Fainaru M: Behçet’s disease: Report of 41 cases and a review of the literature. Medicine (Baltimore) 54:179, 1975. Chase TN, Rosman NP, Price DL: The cerebral syndromes associated with dissecting aneurysms of the aorta. A clinicopathologic study. Brain 91:173, 1968.


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Neurology_Adams. Chase TN, Rosman NP, Price DL: The cerebral syndromes associated with dissecting aneurysms of the aorta. A clinicopathologic study. Brain 91:173, 1968. Chen Y, Patel NC, Guo JJ, Zhan S: Antidepressant prophylaxis for poststroke depression: A meta-analysis. Int Clin Psychopharmacol 22:159, 2007. Chester EM, Agamanolis DP, Banker BQ, Victor M: Hypertensive encephalopathy: A clinicopathologic study of 20 cases. Neurology 28:928, 1978. Chimowitz MI, Lynn MJ, Derdyn CP, et al, for the SAMMPRIS Trial investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 365:993, 2011. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al: Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 352:1305, 2005. Churg J, Strauss L: Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol 27:277, 1951.


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Neurology_Adams. Churg J, Strauss L: Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol 27:277, 1951. Claassen J, Jetté N, Chum R, et al: Electrographic seizures and periodic discharges after intracerebral hemorrhage. Neurology 69:1356, 2007. Cogan DG: Visual hallucinations as release phenomena. Graefes Arch Clin Exp Ophthalmol 188:139, 1973. Collins R, Peto R, MacMahon S, et al: Blood pressure, stroke, and coronary heart disease. Lancet 335:827, 1990. Connor MD, Lammie GA, Bell JE, et al: Cerebral infarction in adults AIDS patients. Observations from the Edinburgh HIV autopsy cohort. Stroke 31:2117, 2000. Cordonnier C, Salman RA, Wardlaw J: Spontaneous brain microbleeds: Systematic review, subgroup analyses and standards for study design and reporting. Brain 130:198, 2007. Corrin LS, Sandok BA, Houser W: Cerebral ischemic events in patients with carotid artery fibromuscular dysplasia. Arch Neurol 38:616, 1981.


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Neurology_Adams. Corrin LS, Sandok BA, Houser W: Cerebral ischemic events in patients with carotid artery fibromuscular dysplasia. Arch Neurol 38:616, 1981. Coull BM, Williams LS, Goldstein LD, et al: Anticoagulants and antiplatelet agents in acute ischemic stroke. Neurology 59:13, 2002. Crawford PM, West CR, Chadwick DW, et al: Arteriovenous malformations of the brain: Natural history in unoperated patients. J Neurol Neurosurg Psychiatry 49:1, 1986. Crowther MA, Ginsberg JS, Julian J, et al: A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome. N Engl J Med 349:1133, 2003. Dashe JF, Pessin MS, Murphy RE, Payne DD: Carotid occlusive disease and stroke risk in coronary artery bypass graft surgery. Neurology 49:678, 1997. Davies-Jones GAB, Preston FE, Timperley WR: Neurological Complications in Clinical Haematology. Oxford, England, Blackwell, 1980.


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Neurology_Adams. Davies-Jones GAB, Preston FE, Timperley WR: Neurological Complications in Clinical Haematology. Oxford, England, Blackwell, 1980. de Bruijn SF, Stam J: Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 30:484, 1999. DeBaun MR, McKinstry RC, Noetzel MJ, et al: Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med 371:699, 2014. Decroix JP, Graveleau R, Masson M, Cambier J: Infarction in the territory of the anterior choroidal artery. Brain 109:1071, 1986. deVeber G, Andrew M, Adams C, et al: Cerebral sinovenous thrombosis in children. N Engl J Med 345:417, 2001. Devinsky O, Petito CK, Alonso DR: Clinical and neuropathological findings in systemic lupus erythematosus: The role of vasculitis, heart emboli, and thrombotic thrombocytopenic purpura. Ann Neurol 23:380, 1988.


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Neurology_Adams. Digre KB, Durcan FJ, Branch DW, et al: Amaurosis fugax associated with antiphospholipid antibodies. Ann Neurol 25:228, 1989. Diringer MN, Edwards DF, Zazulia AR: Hydrocephalus: A previously unrecognized predictor of poor outcome from supratentorial intra-cerebral hemorrhage. Stroke 29:1352, 1998. Diringer MN, Ladenson PW, Stern BJ, et al: Plasma atrial natriuretic factor and subarachnoid hemorrhage. Stroke 19:1119, 1988. DiRocco C, Ianelli A, Leone G, et al: Heparin-urokinase treatment in aseptic dural sinus thrombosis. Arch Neurol 38:431, 1981. Donnan GA, Davis SM, Chambers BR, Gates PC: Surgery for prevention of stroke. Lancet 351:1372, 1998. Donnan GA, O’Malley HM, Quang L, et al: The capsular warning syndrome: Pathogenesis and clinical features. Neurology 43:957, 1993. Douketis JD, Spyropoulos AC, Kaatz S, et al: Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 373:823, 2015.


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Neurology_Adams. Douketis JD, Spyropoulos AC, Kaatz S, et al: Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 373:823, 2015. Drake CG: Giant fusiform intracranial aneurysms: Review of 120 patients treated surgically from 1965 to 1992. J Neurosurg 87:141, 1997. Ducros A: Reversible cerebral vasoconstriction syndrome. Lancet Neurol 11:906, 2012. Einhaupl KM, Villringer A, Meister W: Heparin treatment in sinus venous thrombosis. Lancet 358:597, 1991. Eng JA, Frosch MP, Choi K, Rebeck GW, Greenberg SM. Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol 55:250, 2004. ESPRIT Study Group, The: Aspirin plus dipyridamole versus aspirin alone after cerebra ischemia of arterial origin (ESPRIT): Randomized controlled trial. Lancet 367:1665, 2006. European Carotid Surgery Trialists’ Collaborative Group: Risk of stroke in the distribution of an asymptomatic carotid artery. Lancet 345:209, 1995.


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Neurology_Adams. European Carotid Surgery Trialists’ Collaborative Group: Risk of stroke in the distribution of an asymptomatic carotid artery. Lancet 345:209, 1995. Feigen V, Roth GA, Naghavi M, et al: Global burden of stroke and risk factors in 188 countries, during 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet Neurol 15:913, 2016. Ferguson GG: Physical factors in the initiation, growth, and rupture of human intracranial saccular aneurysms. J Neurosurg 37:666, 1972. Fessler RD, Esshaki CM, Stankewitz RC, et al: The neurovascular complications of cocaine. Surg Neurol 47:339, 1997. Fisher CM: A lacunar stroke: The dysarthria-clumsy hand syndrome. Neurology 17:614, 1967. Fisher CM: A new vascular syndrome: “The subclavian steal.” N Engl J Med 265:912, 1961. Fisher CM: Binswanger’s encephalopathy: A review. J Neurol 236:65, 1989. Fisher CM: Capsular infarct: The underlying vascular lesions. Arch Neurol 36:65, 1979.


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