Paraneoplastic neurological autoimmunity 215 findings are nonspecific consisting of gliosis, neuronal loss, microglial proliferation, and variable infiltrates of CD8+ T lymphocytes (Scaravilli et al., 1999). Thus, biopsy of indeterminate brain lesions is not advised except to exclude alternative pathology. The search for a tumor rests primarily on traditional laboratory and computed tomographic imaging. However, in cases where there is a high index of suspicion, and the cancer search is uninformative, positron emission tomography (PET) scanning is advised (Linke et al., 2004). In cases with suspected mediastinal pathology, mediastinoscopy or endoscopic ultrasound-guided biopsy are helpful to establish a pathological diagnosis. In PCA-1-positive cases with negative mammography, gynecological cancer is strongly predicted, and exploratory laparotomy is justifiable (Hetzel et al., 1989). We have, in one case, encountered coexisting breast and ovarian adenocarcinomas. An abdominal (presumed colonic) adenocarcinoma has been encountered in rare male PCA-1-positive cases (99% are female). Therapy The cornerstones of treatment for paraneoplastic neurological autoimmune disorders are removal of the inciting antigen (i.e. tumor ablation), immuno- therapy, and supportive care. In theory, the patient is afforded the best chance for abrogation of the immune response if a tumor can be removed surgic- ally in its entirety. For highly malignant tumors like small-cell lung carcinoma, this is usually not pos- sible. A concern therefore arises when myelotoxic chemotherapy is employed to eliminate the cancer because it may abrogate the effector immune response that has limited the tumor’s growth and metastasis. Until the immunological mechanisms determining a beneficial anti-tumor immune response can be defined by monitoring appropriate biomarkers, myelotoxic chemotherapies should be employed judiciously in patients with neurological auto- immunity who have limited-stage cancer. Plasma exchange and intravenous immune globulin (IVIg) therapy, when combined with therapies directed primarily at the tumor, have yielded variable and limited success (Keime-Guibert et al., 2000; Vernino et al., 2003). In treating these patients, the clinician needs to keep in mind the following principles: 1 Antibody-mediated dysfunction in the central or peripheral nervous system is most amenable to plasma exchange or IVIg coupled with long-term immunosuppressive strategies, such as pred- nisone, azathioprine, or mycophenolate mofetil. Episodic use of a B-lymphocyte-targeted thera- peutic monoclonal IgG (e.g. rituximab) is a consideration. 2 Cytotoxic T-cell-mediated inflammation in the central nervous system and peripheral sensory, autonomic and enteric ganglia may cause severe and irreversible neuronal injury. 3 The goal of long-term immunosuppression is prevention of disease progression which may require immunosuppression for years. Agents employed most commonly today include pulse high-dose methylprednisolone, oral or pulse intravenous cyclophosphamide, mycophenolate mofetil, or azathioprine. 4 Neurological paraneoplastic autoimmunity can be severely disabling. Coordinated strategies are needed to address neurological symptoms, psy- chiatric symptoms, rehabilitation, nutrition, man- agement of pain, and palliative and hospice care. Summary Paraneoplastic neurological disorders are the mani- festation of a multifaceted immune response to a neoplasm. These disorders can be broadly conceptu- alized as being mediated immunopathologically by a plasma-membrane-directed effector antibody, or as being associated with neuronal or glial nuclear or cytoplasmic autoantibodies that serve as serological markers for cytotoxic CD8+ T-cell-mediated mech- anisms. Multiple levels of the nervous system can be affected and multiple autoantibody markers may be detected at diagnosis or as the neoplasm evolves over time. While the autoantibody profile may predict the cancer, an extensive evaluation over time may be required to establish the true nature of the neuro- logical illness and to locate an often limited stage underlying tumor. Treatment, tailored to the indi- vidual patient, should include removal of the incit- ing antigen, immunotherapy, and supportive care. The best approaches to immunotherapy remain to be defined. References Albert, M.L., Darnell, J.C., Bender, A., Francisco, L.M., Bhardwaj, N. and Darnell, R.B. 1998. 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Potentially rever- sible autoimmune limbic encephalitis with neuronal NICP_C19 04/05/2007 12:25PM Page 216 Paraneoplastic neurological autoimmunity 217 potassium channel antibody. Neurology, 62, 1177– 82. Vernino, S., Adamski, J., Kryzer, T.J., Fealey, R.D. and Lennon, V.A. 1998. Neuronal nicotinic ACh receptor antibody in subacute autonomic neuro- pathy and cancer-related syndromes. Neurology, 50, 1806–13. Vernino, S. and Lennon, V.A. 2000. New Purkinje cell antibody (PCA-2): Marker of lung cancer-related neurological autoimmunity. Ann Neurol, 47, 297– 305. Vernino, S. and Lennon, V.A. 2004. Autoantibody profiles and neurological correlations of thymoma. Clin Can Res, 10, 7270–5. Vernino, S., O’Neill, B.P., Marks, R.S., O’Fallon, J.R. and Kimmel, D.W. 2003. Immunomodulatory treat- ment trial for paraneoplastic neurological disorders. Neuro-Oncology, 6, 55–62. Vincent, A., Buckley, C., Schott, J.M. et al. 2004. Potassium channel antibody-associated encephalo- pathy: A potentially immunotherapy-responsive form of limbic encephalitis. Brain, 127, 701–12. Vitaliani, R., Mason, W., Ances, B., Zwerdling, T., Jiang, Z. and Dalmau, J. 2005. Paraneoplastic encephalitis, psychiatric symptoms, and hypo- ventilation in ovarian teratoma. Ann Neurol, 58, 594–604. Yu, Z., Kryzer, T.J., Griesmann, G.E., Kim, K., Benarroch, E.E. and Lennon, V.A. 2001. CRMP-5 neuronal autoantibody: Marker of lung cancer and thymoma-related autoimmunity. Ann Neurol, 49, 146–54. NICP_C19 04/05/2007 12:25PM Page 217 Introduction Vasculitis, defined by inflammation of arteries and veins of varying caliber, results in a variety of clinical neurological manifestations and neuropathological changes of the central and peripheral nervous system (CNS and PNS). There have been several recent reviews of this topic (Collins and Kissel, 2005; Younger, 2003, 2004, 2005b; Younger and Kass, 1997). Classification and overview Vasculitis in its various forms affects blood vessels of varying caliber from the aorta to capillaries and veins (Fig. 20.1). The diverse forms of vasculitis and autoimmune diseases are summarized in Box 20.1. Systemic necrotizing arteritis This category of systemic necrotizing arteritis includes polyarteritis nodosa (PAN), microscopic polyangiitis (MPA) syndrome, and Churg–Strauss syndrome (CSS). Polyarteritis nodosa The first American patient with PAN was described at the turn of the twentieth century by Longcope 20 Vasculitis and connective tissue diseases David S. Younger and Adam P.J. Younger VE SS EL S INV O LVE D C LINI C AL S YND RO M E VEIN S VEN U LE S E a l es ’ Dl stase Aller g i c G r a n u l o- m atos i s L y m p ho - m ato i d G r a n u l o- m atos i s We g ene r ’ s G r a n u l o- m atos i s sitivit y An g iiti s Tnk a rn su ’ s Ar te ri t i s Tem p ora l Ar te ri t i s C N S Vascu ii t i s Pol y arter - i t i s N odosa Mi c r o- sco p i c Pol y- an g iiti s Usuall y Involve d So m et im es Inv o lv ed C APILLA R IE S A R TE R I O LE S S MALL M USCU LA R A R TE R IE S (Intraor g an vessels ) MEDIUM MUSCULA R ARTERIES (Coronar y , he p atic, intracerebral ) LA RG E A R TE R IE S (Vertebral, tem p oral, carotld ) A OR T A Fig. 20.1 The pathological spectrum of the major vasculitides. Reproduced from Younger et al., 2003, with permission of the publisher. NICP_C20 03/05/2007 10:48 AM Page 218 Vasculitis and connective tissue diseases 219 (Longcope, 1908). His patient was a 35-year-old man with constitutional symptoms and subacute leg pains. Postmortem examination showed wide- spread necrotizing arteritis and nodules along small and medium sized vessels of the heart, liver, kidney, pancreas, testicles, brain, nerves, and skeletal muscles, sparing the lungs and spleen. The histological lesions consisted of mononuclear cell infiltration, necrosis of internal and external elastic lamina of the media, fibrin deposition, aneurismal dilatation, perivascular inflammation of the adventitia, and intimal prolifera- tion resulting in narrowing of arterial lumina. Later investigators (Kernohan and Woltman, 1938) sum- marized the clinical and pathological aspects of PAN. The dominant neurological picture was a peripheral neuritis that occurred in one-half of patients early in the illness with a predilection for the legs. At post- mortem examination, all had arteritic lesions along nutrient arteries of the peripheral nerves, and three- quarters had lesions in arteriae nervorum. The com- bination of acute and chronic lesions correlated with known exacerbations. Brain infarcts resulted from occlusion of cerebral vessels, but only 10% of lesions were clinically apparent. In PAN the vasculitic lesion proceeds in a charac- teristic manner, commencing with invasion of the intima, media, and adventitia by polymorphonuclear (PMN), plasma cells, eosinophils, and lymphocytes, and leading to swelling of the media, and fibrinoid necrosis that clusters around the vasa vasorum, with fragmentation of the internal elastic lamina (Fig. 20.2). There is focal deposition of perivascular connective tissue, vascular necrosis, and denuding of the endothelium, followed by vascular thrombo- sis, ischemia, aneurysm formation, rupture, and hemorrhage. Healed lesions coexist with active lesions. Neuroimaging reveals areas of focal cerebral infarction (Fig. 20.3). Arteriography and biopsy of involved vascular tissue, such as a segment of nerve or muscle in a suspected patient, is the only certain means of histological diagnosis. Microscopic polyangiitis At about the same time as PAN were being delineated, the essential features of MPA were being described (Davson et al., 1948). This disorder differed from PAN in the affliction of small arterioles, capillaries, and Systemic necrotizing arteritis Polyarteritis nodosa Microscopic polyangiitis Churg–Strauss syndrome Hypersensitivity vasculitis Drug-related vasculitis Serum sickness Henoch–Schönlein purpura Hypocomplementemic vasculitis Cryoglobulinemia Systemic granulomatous vasculitis Wegener granulomatosis Lymphomatoid granulomatosis Lethal midline granuloma Giant cell arteritis Temporal arteritis Takayasu arteritis Granulomatous angiitis of the nervous system Connective tissue disorders associated with vasculitis Systemic lupus erythematosus Scleroderma Rheumatoid arthritis Sjögren syndrome Mixed connective tissue disease Behçet disease Nonsystemic vasculitic neuropathy Infection-associated vasculitis Bacterial meningitis Mycobacterium tuberculosis Spirochetes Treponema pallidum Borrelia burgdorferi Varicella zoster virus Fungi Human immunodeficiency virus type 1 CNS vasculitis associated with amphetamine abuse Paraneoplastic vasculitis Inflammatory diabetic vasculopathy Box 20.1 Classification of vasculitis. NICP_C20 03/05/2007 10:48 AM Page 219 220 DAVID S. YOUNGER AND ADAM P.J. YOUNGER venules of the lungs and kidney with necrotizing glomerulonephritis. Circulating antinuclear cyto- plasmic autoantibodies (ANCA), usually myeloper- oxidase (MPO) or p-ANCA, are seen in up to 80% of patients, but are rarely if ever seen in PAN. Small- vessel involvement is considered the definite diag- nostic criterion of MPA, and is of the caliber involved in epineurial arteries leading to polyneuropathy in up to a quarter of patients, usually of the MNM type, and in skin nodules and purpura, which occur in the majority of patients. Churg–Strauss syndrome The disorder delineated by Churg and Strauss, and later named in their honor, included asthma, eosino- philia, extravascular granulomas, and necrotizing vasculitis of small and medium arteries, arterioles, capillaries, and veins (Churg and Strauss, 1951). The essential lesions of CSS include angiitis and extra- vascular necrotizing granulomas with eosinophilic infiltrates. The vasculitis may be granulomatous or nongranulomatous, and characteristically involves arteries and veins, as well as pulmonary and systemic vessels. The granulomas are located near small arteries and veins, and characterized by pallisading epi- thelioid histiocytes arranged around central necrotic zones in which eosinophils predominant. Pulmonary lesions reflect the combination of necrotizing vas- culitis and areas resembling eosinophilic pneumonia. There are three phases of the disease. The first is a prodromal period of constitutional symptoms that includes rhinitis and asthma. This is followed by the second phase of peripheral blood and tissue eosino- philia, and the third phase of systemic vasculitis, wherein neurological involvement occurs, typically peripheral neuropathy of the MNM type, stroke and hemorrhage in up to three-quarters of patients sim- ilar to PAN. The laboratory diagnosis is ascertained by serological investigation, primarily ANCA myel- operoxidase, MPO or p-ANCA, and tissue biopsy. Hypersensitivity vasculitis This group of vasculitis with a unique predilection for the dermis was defined by Zeek (Zeek et al., 1948). The inflammatory infiltrates in hypersensitivity vas- culitis (HSV) (Fig. 20.4) commences with extravasa- tion of erythrocytes, pronounced endothelial swelling, and infiltration by PMN and later mononuclear cells, with resultant fibrosis, and typical involvement of arterioles, capillaries, and postcapillary venules that leaves nuclear fragments or leukocytoclasia with variable necrosis and fibrinoid material termed leuko- cytoclastic vasculitis (LCV) and circulating immune complexes that deposit in the skin and in the vas- culitic lesions. In contrast to PAN, the lesions are all Fig. 20.3 MRI scan of a case of polyarteritis nodosa with cerebral involvement. Multiple small cortical and subcortical regions of increased signal reflect infarcts in the distribution of small, unnamed branch arteries. Reproduced from Younger et al., 2003, with permission of the publisher. Fig. 20.2 This small muscular artery from muscle is from a patient with polyarteritis nodosa. In the third, or proliferative, phase illustrated here, chronic inflammatory cells replace the neutrophils of the second phase; there is evidence of necrosis of the media (arrows), early intimal proliferation (arrowheads), and fibrosis. The lumen is almost completely occluded. Ultimately, in the healing phase, this process is replaced by dense, organized connective tissue (stain, hematoxylin and eosin; original magnification, ×250). Reproduced from Younger et al., 2003, with permission of the publisher. NICP_C20 03/05/2007 10:48 AM Page 220 Vasculitis and connective tissue diseases 221 in the same stage of evolution. Other organ involve- ment includes the peripheral nerves, kidney, lungs, spleen, liver, heart, and rarely the CNS or intestines, wherein microinfarction and hemorrhage can occur. The group of HSV includes drug-related vas- culitis, serum sickness, Henoch–Schönlein purpura (HSP), hypocomplementemic, and cryoglobulinemic vasculitis. Drug-related vasculitis Drug reactions are responsible for about 20% of cases of dermal vasculitis. They are classified clinically and temporally according to the extent of the allergic reaction, and according to the time that elapses from exposure to the observed reaction. There is a spectrum from urticaria, wheezing, and rhinitis, and variable serum sickness to laryngeal edema, and hypotension, respectively, over minutes, hours, or days. The rash is most often maculopapular or vesicular, less often palpable purpura, along the arms and legs without systemic involvement, and abates after drug with- drawal. More severe drug reactions develop multiple organ involvement, especially the heart, liver, kidneys, gastrointestinal tract, lungs, PNS, and CNS. This disorder results mainly from the focal deposition of immune complexes, which result from the covalent binding of the offending drug, or its metabolites, with native or foreign proteins to produce hapten mole- cules. The latter forms hapten–antibody complexes that deposit in the skin, eliciting the dermal vas- culitic response. Serum sickness Serum sickness leads to vasculitis with varying degrees of infiltration of arterioles, capillaries, and venules, with interstitial inflammation by PMN cells, eosinophils, and mononuclear inflammatory cells, with variable fibrinoid necrosis and perivascular granuloma formation. Urticaria, noted in the majority of patients, is followed by erythematous or maculo- papular rash, petechiae, palpable purpura, and lym- phadenopathy, first at the site of injection site, and later generalized with arthralgia, edema, headache, and lethargy. Nervous system involvement includes brachial plexus neuritis, mononeuritis simplex and multiplex, Guillain–Barré syndrome, cranial nerve palsies, blurring of vision, retinal and palpebral hemorrhages, meningismus, stroke, and myelopathy. The clinical presentation of serum sickness parallels the appearance of protein antigen and antibody excess and persists until immune complexes are eliminated. The reaction to injection of heterologous serum and many drugs is a complex one, and its multiple neuro- logical manifestations may be explainable on the basis of the immune complex disease with incipient cytotoxic and humoral and cell-mediated immune mechanisms. Henoch–Schönlein purpura This disorder consists of nonthrombocytopenic purpura, arthralgia, abdominal pain, and leukocyto- clastic vasculitis of skin lesions in an affected child with fever, headache, and anorexia. Palpable purpuric lesions arise along extensor surfaces of the lower extremities and buttocks, sometimes in association with migratory angioneurotic edema of the hands, scalp, face, lower legs, and genitalia. The presence of LCV suggests an immune complex-mediated patho- genesis; in that regard, deposits of immunoglobulins, particularly IgA, and C3 have been demonstrated in the kidney and blood vessel walls, and some affected patients had hereditary C2 deficiency. Hypocomplementemic vasculitis Hypocomplementemic or urticarial vasculitis includes urticaria, migratory arthralgia, and persistent or intermittent hypocomplementemia. Affected patients develop urticarial, bullous, and purpuric skin lesions, Fig. 20.4 This arteriole from muscle is from a patient with leukocytoclastic vasculitis. The entire vessel and perivascular tissue is infiltrated with polymorphonuclear leukocytes and some chronic inflammatory cells with necrosis and nuclear debris. The vascular lumen is nearly obliterated (stain, hematoxylin and eosin; original magnification, ×400). Reproduced from Younger et al., 2003, with permission of the publisher. NICP_C20 03/05/2007 10:48 AM Page 221 222 DAVID S. YOUNGER AND ADAM P.J. YOUNGER sometimes severe angioneurotic edema and life- threatening laryngeal edema, accompanied by arth- ralgia, conjunctivitis, episcleritis, uveitis, mild renal disease, pericarditis, abdominal pain, and spleno- megaly. Pseudotumor cerebri is the most common associated neurological manifestation. Hypocomple- mentemic vasculitis resembles a forme fruste of systemic lupus erythematosus (SLE). Immunological studies show a binding of IgG antibody to C1q along basement membranes, in which it activates the complement cascade. It is not known whether the autoantibody is more than a marker of the disease. Cryoglobulinemia Cryoglobulins are antibodies that reversibly pre- cipitate at temperatures below 37°C. They are composed of IgG and IgM, complement, lipoprotein, and antigenic protein moieties. They are classified into three types with implications for clinical and etiologic specificity. Type I is composed of a single monoclonal IgM or IgG antibody; type II, mixed, has monoclonal IgM, possessing activity against polyclonal IgG; and type III has mixed polyclonal and nonimmunoglobulin molecules in the form of immunoglobulin–anti-immunoglobulin immune complexes. Types I and II cryoglobulins are associ- ated with lymphoproliferative diseases, particularly multiple myeloma and Waldenström macroglobuli- nemia. Type III cryoglobulins are associated with infection and collagen vascular diseases; one sub- group, termed essential mixed cryoglobulinemia (EMC), harbors circulating HCV RNA and corres- ponding antibodies in the cryoprecipitate. Type I cryoglobulins cause the hyperviscosity syndrome. Four vascular lesions are noted in cryoglobuline- mia: (i) occlusion of small and large vessels in those with high levels of cryoglobulins of type I or II; (ii) bland thrombosis of small arteries and arterioles; (iii) endothelial swelling, proliferation, and base- ment membrane thickening; and (iv) LCV. Peripheral nerves demonstrate chronic axonopathy of large myelinated fibers. True vasculitis is occasionally seen, mainly in those with associated PAN. Dermatitis is the most conspicuous feature accom- panied by palpable purpura that persists for a week to 10 days, heralded by a sharp or burning sensa- tion. Purpura is noted in all types but is more common with type III and in EMC. PNS and CNS manifestations are more common with types II and III. Renal disease is a major feature of EMC. Hepatic disease is far more common with this syndrome by virtue of its association with HCV. The appearance of high levels of cryoglobulins in the blood of patients reporting cold sensitivity and vasomotor symptoms led to the presumption that cryoprecipitation was the cause of ischemia of arterioles and capillaries due to hyperviscosity and the direct plugging of small vessels. However, it is now known that the cryoprecipitate, when present, may be tangential to the pathogenesis of the clinical syndrome and even an artifact for several reasons. First, cryoprecipitation occurs in systemic organs of normal temperature. Second, the temperature at which precipitates occur in vitro is far below that achieved in the body. Third, symptoms do not cor- relate with serum cryoglobulin levels, viscosity, or cryoprecipitate concentration. Fourth, in EMC in which levels of cryoglobulins are typically quite low, the pathology can still be explained on the basis of immune complex deposition. Several factors that may contribute to the clinical manifestations of cryoglobulinemia include intravascular activa- tion of complement and the clotting cascade by aggregated immunoglobulin and immune complexes, secondary vessel wall damage; cold agglutination of erythrocytes; local tissue reaction to precipitated proteins; and VEC proliferation. Central nervous system manifestations in types I and II disease are related to vascular occlusion with or without vasculitis. Peripheral neuropathy is associated more frequently with epineurial vas- culitis, cryoprecipitate deposition, and microvascu- lar ischemia with resultant secondary axonopathy. In those studied, the inflammatory cell infiltrate in the nerve was mainly T cell with lesser numbers of B lymphocytes, in accordance with T-cell-dependent vasculitis. The isolation of HCV RNA in peripheral nerve biopsies has been unsuccessful in marked con- trast to cutaneous lesions. Cryoglobulinemia should be considered in patients with features of characteristic skin lesions, MNM, hyperviscosity, easily coagulable blood, IgM mono- clonal paraproteinemia, and risk factors for HCV infection. If found, the presence of cryoglobulinemia will direct the performance of bone marrow studies, nerve biopsy, and studies for HCV and HIV-1 infection, AIDS, occult cancer, infection, plasma cell dyscrasia, and collagen vascular disease. Systemic granulomatous vasculitis This group of systemic granulomatous vasculitis includes Wegener granulomatosis (WG), lympho- matoid granulomatosis (LG), and lethal midline granuloma. NICP_C20 03/05/2007 10:48 AM Page 222 Vasculitis and connective tissue diseases 223 Wegener granulomatosis Although first considered a form of PAN, WG was later termed rhinogenic pneumogenic granulo- matosis by the investigator for whom it was later named. It differed in fact from PAN in the triad of necrotizing granulomatous lesions of the sinuses and lower respiratory tract, systemic necrotizing vasculitis of small arteries and veins, and glomeru- lonephritis (Godman and Churg, 1954). Nervous system involvement was appreciated almost a decade later (Drachman, 1963). Vasculitic lesions in WG begin as small foci of granular necrosis and fibrinoid degeneration with PMN cells followed by histiocytes and giant cells along the margins of granulomas of the upper airways and in renal glomeruli. Necrotizing granulomatous lesions secondarily involve small arteries, arterioles, capil- laries, and venules with segmental fibrinoid necrosis in involved tissues (Fig. 20.5). Affected patients pre- sent with multifocal pain, sensory loss, and weakness due to MNM that ultimately can become disabling. Circulating c-ANCA directed against proteinase 3 (PR3) is predictive of the disease in the majority of patients even in the initial phase of illness. A quarter of patients demonstrate CNS and PNS involvement due to direct destruction of nerve or brain tissue by necrotizing granulomas, locally or remote from upper or lower respiratory tract granulomas, and necrotizing arteritis of cerebral and arteriae nervorum of peripheral nerves. CNS manifesta- tions, in particular, appear to depend upon whether there is vasculitic, contiguous extension, or remote granulomatous spread. Stroke, intracerebral and subarachnoid hemorrhage, and optic neuritis result from vasculitis of anterior and posterior ciliary and retinal vessels. Contiguous extension results from nasal and paranasal sinus cavity granulomas through the orbit leading to pseudotumor with exophthalmos, extraocular muscles, optic and oculomotor nerve involvement, whereas extension through the tem- poral bone can destroy the middle ear. Lymphomatoid granulomatosis This malignant lymphoreticular disorder has a strong affinity for the CNS. Patients present with constitutional symptoms and skin lesions resembling erythema nodosum. Focal neurological involve- ment occurs early including MNM, unilateral cranial nerve palsies, hemiparesis, ataxia, seizures, spinal and radicular syndromes, and even myopathy. In par- ticular, CNS complication occurs by the invasion of unifocal and multifocal necrotizing angiocentric and angiodestructive lesions of small- and medium-sized muscular arteries and their endothelia by masses of T cells, plasma cells, histiocytes, and atypical lymphoreticular cells (Fig. 20.6) with immunoblast formation in the cerebrum, brain stem, cerebellar parenchyma, and meninges. Fig. 20.5 Wegener granulomatosis. This small muscular artery is nearly completely destroyed. A large confluent area of fibrinoid degradation (arrows) is surrounded by neutrophils, palisading histiocytes, lymphocytes, plasma cells, and some giant cells (stain, hematoxylin and eosin; original magnification, ×250). Reproduced from Younger et al., 2003, with permission of the publisher. Fig. 20.6 Lymphomatoid granulomatosis. The characteristic invasion of the vessel wall (arrow) and the perivascular tissue by a polymorphocellular infiltrate consists of lymphocytes, plasma cells, and atypical reticuloendothelial cells. The vessel lumen is markedly narrowed. Notice the absence of well-formed granulomas and fibrinoid necrosis (stain, hematoxylin and eosin; original magnification, ×250). Reproduced from Younger et al., 2003, with permission of the publisher. NICP_C20 03/05/2007 10:48 AM Page 223 224 DAVID S. YOUNGER AND ADAM P.J. YOUNGER Lethal midline granuloma Historically, this disorder was likened to WG but systemic disease is not a major feature of lethal mid- line granuloma, and WG rarely if ever causes such extensive facial mutilation. It is now known to be a relentlessly invasive necrotizing process of the nose and palate that causes destruction of sinuses and all major midline structures of the head, producing grotesque facial mutilation and ultimately death. The disorder is associated with idiopathic midline granuloma, poorly differentiated diffuse small or large B-cell lymphomas, plasmacytomas, and other poly- morphic reticuloses mediate the damage. CNS com- plications most often result from direct invasion of the orbit and face, jugular vein, sigmoid and cavern- ous sinuses leading to vascular thrombosis, sepsis, meningitis, and exsanguinations. Giant cell arteritis (GCA) The concept of temporal arteritis was first described by Horton (Horton et al., 1932) and then named by Jennings ( Jennings, 1938) for the site of granuloma- tous giant cell inflammation and vessel involvement. Patients with biopsy-proven temporal arteritis and associated blindness due to vasculitic involvement of ophthalmic and posterior ciliary vessels were originally classified as cranial arteritis. Other patients had prominent constitutional and musculoskeletal complaints and typical polymyalgia rheumatica. The occasional finding of giant cell lesions along the aorta, its branches, and in other medium- and large- sized arteries at autopsy in some cases warranted the diagnosis of generalized giant cell arteritis. The pathological heterogeneity of temporal arteritis was further demonstrated by the finding of intracranial lesions in several patients who also qualified for the diagnosis of granulomatous angiitis. Peripheral nervous system lesions in GCA are exceedingly rare. The earliest lesions of GCA consist of vacuolization of smooth muscle cells of the media, with enlarge- ment of mitochondria, infiltration of lymphocytes, plasma cells, and histiocytes. With progression, there is extension inflammation into the intima and adventitia leading to segmental fragmentation and necrosis of the elastic lamina, granuloma formation, and proliferation of connective tissue along the vessel wall. This eventuates in vascular thrombosis, intimal proliferation and fibrosis (Fig. 20.7). Temporal arteritis and Takayasu arteritis Two forms of giant cell arteritis, temporal and Takayasu arteritis, are of clinical importance to neurologists. They differ epidemiologically and in the size of vessels involved. Temporal arteritis occurs in elderly Caucasians of either gender, and involves medium and large arteries. Takayasu arteritis affects the aorta and its branches in young Asian women. The clinical manifestations of temporal arteritis namely headache, scalp tenderness, thickened nodular and pulseless superficial temporal artery, unilateral visual loss, and jaw claudication are related primarily to disease along branches of the external carotid artery, and arteritis of the vertebral and carotid Fig. 20.7 Temporal arteritis. (a) In an early lesion of a large muscular artery, necrosis, inflammation, and giant cell formation (single arrow) can be seen immediately adjacent to the internal elastic lamina (arrowhead), which is undergoing degenerative changes, and there is some intimal proliferation (double arrows) (stain, hematoxylin and eosin; original magnification, ×100). (b) This more advanced lesion has complete segmental destruction of the internal elastic lamina and virtually the entire media (arrows). Marked intimal proliferation has nearly occluded the lumen, and few inflammatory cells remain (stain, hematoxylin and eosin; original magnification, ×50). Reproduced from Younger et al., 2003, with permission of the publisher. NICP_C20 03/05/2007 10:48 AM Page 224 [...]... manufacturing method was licensed in 199 2 Solvent detergent treatment, including partitioning steps and incubation at low pH in the final container has been effective in the removal and inactivation of enveloped viruses A new chromatographic purification process alleviates many labor-intensive and time-consuming intermediate steps with a more closed manufacturing process to reduce risk of contamination,... al., 199 9) The frequency of microvasculitis of 3% in this cohort was lower than the frequency of 40% described earlier by Younger and coworkers (Younger et al., 199 6a), reflecting the lesser sensitivity of routine hematoxylin and eosin studies as compared to immunoperoxidase-staining methods used in the earlier analysis by Younger and coworkers (Younger et al., 199 6a) Patients with various forms of in ammatory... ganglia are involved in fine control of movement with behavioral and emotional processing (Alexander et al., 198 6; Bhatia and Marsden, 199 4; Brown et al., 199 9; Nakano, 2000; Rolls, 199 4) Lesions in the basal ganglia are related to extrapyramidal movement disorders in addition to abulia, depression, disinhibition, and confusion (Bhatia and Marsden, 199 4) Psychiatric symptoms such as obsessive-compulsive... edema, and in ammatory cell in ltration Complement-mediated injury appears to be an important mechanism in the etiopathogenesis of in ammatory diabetic vasculopathy, however, the initiating factors are still speculative One possibility is a defect in the expression of certain regulatory membrane proteins in the walls of microvessels, including complement receptor (CR10), decay-accelerating factor (CD55),... also been described in association with basal ganglia lesions (Laplane et al., 198 9) These abnormalities might be due to damage or interruptions in basal ganglia circuits that have functional roles in oculomotor, prefrontal, and cingulate pathways which are central to attention, learning, and behavioral control (Brown et al., 199 9; Gerfen, 198 4; Haber et al., 199 5; Yamashiro et al., 199 7) Sydenham’s chorea... in ammatory lesions and related clinical and pathological findings in 20 patients with insulin and non-insulin dependent diabetes mellitus (IDDM, NIDDM) and diverse forms of neuropathy Axonal neuropathy was noted in all patients confirmed by semi-thin plastic sections and teased nerve fiber analysis A CD8 cytotoxic suppressor cell predominant microvasculitis, defined as in ammation of the epineurial vessel walls... example, in one analysis sustained benefit in PAN was obtained in patients with a minimum equivalent dosage of 31 mg of prednisone daily for seven months (Leib et al., 197 9) The beneficial effects of corticosteroids are attributed to a multiplicity of effects on the cell and humoral immune system, including inhibition of activated T and B cells, APCs, and leukocytes at sites of in ammation, IFN-γ, induced... suppression in malignancy, probably achieves similar effectiveness in peripheral nerve vasculitis The purine analog azathioprine, which metabolizes to the cytotoxic derivative 6-mercaptopurine, exerts favorable action in vasculitis by the inhibition of T-cell activation and T-cell-dependent antibody-mediated responses Azathioprine is generally considered a safe alternative to prednisone and cyclophosphamide in. .. showed mononuclear in ltration of endoneurial and epineurial blood vessels associated with fibrinoid necrosis, thrombosis, and recanalization of vessel lumina Immunoperoxidase and alkaline phosphatase stained sections showed in ltrating macrophages that expressed p24 and gp41 HIV-related antigens as well as interleukins, tumor necrosis factor, and strongly reactive C3d, C5b -9 , and IgM in the affected vessel... M et al 197 0 Necrotizing angiitis associated with drug abuse N Engl J Med, 283, 1003–11 Collins, M.P and Kissel, J.T 2005 Peripheral nerve vasculitis In D.S Younger (ed.), Motor Disorders, 2nd edn, Lippincott Williams and Wilkins, Philadelphia, pp 3 49 62 Cravioto, H and Fegin, I 195 9 Non-infectious granulomatous angiitis with a predilection for the nervous system Neurology, 9, 599 –607 Cupps, T., Moore, . directed against T- and B-cell subsets, macrophages, immunoglobu- lins, C3d, C5b -9 MAC proteins, cytokines and other Fig. 20.15 Radiographic features of cerebral vasculitis. Ectasia and beading in the. (Keime-Guibert et al., 2000; Vernino et al., 2003). In treating these patients, the clinician needs to keep in mind the following principles: 1 Antibody-mediated dysfunction in the central or peripheral. meninges composed of lymphocytes, multinucleate giant cells, and epitheliid cells, with vessel necrosis and exten- sion into the brain involving veins and arteries of varying caliber. The clinicopathological