Neuroimmunology in Clinical Practice - part 9 pot

Younger matoid Granulo- matosis Lympho-Wegener’s Granulo- matosis sitivity Angiitis Tnkarnsu’s Arteritis Temporal Arteritis CNS Vascuiitis Polyarter- itis Nodosa scopic Poly- angiitis

findings are nonspecific consisting of gliosis, neuronal loss, microglial proliferation, and variableinfiltrates of CD8+ T lymphocytes (Scaravilli et al.,1999) Thus, biopsy of indeterminate brain lesions isnot advised except to exclude alternative pathology.

The search for a tumor rests primarily on traditionallaboratory 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 isadvised (Linke et al., 2004) In cases with suspectedmediastinal pathology, mediastinoscopy or endoscopicultrasound-guided biopsy are helpful to establish

a pathological diagnosis In PCA-1-positive caseswith 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 ovarianadenocarcinomas An abdominal (presumed colonic)adenocarcinoma has been encountered in rare malePCA-1-positive cases (99% are female)

Therapy

The cornerstones of treatment for paraneoplasticneurological autoimmune disorders are removal ofthe inciting antigen (i.e tumor ablation), immuno-therapy, and supportive care In theory, the patient

is afforded the best chance for abrogation of theimmune response if a tumor can be removed surgic-ally in its entirety For highly malignant tumors likesmall-cell lung carcinoma, this is usually not pos-sible A concern therefore arises when myelotoxicchemotherapy is employed to eliminate the cancerbecause it may abrogate the effector immune responsethat has limited the tumor’s growth and metastasis

Until the immunological mechanisms determining

a beneficial anti-tumor immune response can bedefined by monitoring appropriate biomarkers,myelotoxic chemotherapies should be employedjudiciously in patients with neurological auto-immunity who have limited-stage cancer Plasmaexchange and intravenous immune globulin (IVIg)therapy, when combined with therapies directed primarily at the tumor, have yielded variable andlimited success (Keime-Guibert et al., 2000; Vernino

et al., 2003) In treating these patients, the clinicianneeds to keep in mind the following principles:

1 Antibody-mediated dysfunction in the central orperipheral nervous system is most amenable toplasma exchange or IVIg coupled with long-term

immunosuppressive strategies, such as nisone, azathioprine, or mycophenolate mofetil.Episodic use of a B-lymphocyte-targeted thera-peutic monoclonal IgG (e.g rituximab) is a consideration

pred-2 Cytotoxic T-cell-mediated inflammation in thecentral nervous system and peripheral sensory,autonomic and enteric ganglia may cause severeand irreversible neuronal injury

3 The goal of long-term immunosuppression isprevention of disease progression which mayrequire immunosuppression for years Agentsemployed most commonly today include pulsehigh-dose methylprednisolone, oral or pulseintravenous cyclophosphamide, mycophenolatemofetil, or azathioprine

4 Neurological paraneoplastic autoimmunity can

be severely disabling Coordinated strategies areneeded to address neurological symptoms, psy-chiatric symptoms, rehabilitation, nutrition, man-agement of pain, and palliative and hospice care

Summary

Paraneoplastic neurological disorders are the festation of a multifaceted immune response to aneoplasm These disorders can be broadly conceptu-alized as being mediated immunopathologically by

mani-a plmani-asmmani-a-membrmani-ane-directed effector mani-antibody, or

as being associated with neuronal or glial nuclear orcytoplasmic autoantibodies that serve as serologicalmarkers 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 evolvesover time While the autoantibody profile may predictthe cancer, an extensive evaluation over time may

be required to establish the true nature of the logical illness and to locate an often limited stageunderlying 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

neuro-be defined

References

Albert, M.L., Darnell, J.C., Bender, A., Francisco, L.M.,Bhardwaj, N and Darnell, R.B 1998 Tumor-specifickiller cells in paraneoplastic cerebellar degeneration

Nat Med, 4, 1321– 4.

Altermatt, H.J., Rodriguez, M., Scheithauer, B.W andLennon, V.A 1991 Paraneoplastic anti-Purkinje

and type 1 anti-neuronal nuclear autoantibodiesbind selectively to central, peripheral, and auto-

nomic nervous system cells Lab Invest, 65, 412–20.

Ances, B., Vitaliani, R., Taylor, R et al 2005

Treatment-responsive limbic encephilitis identified

by neuropil antibodies: MRI and PET correlates

small-cell lung cancer Neurology, 62, 778 – 82.

Bernal, F., Shams’ili, S., Rojas, I et al 2003 Anti-Trantibodies as markers of paraneoplastic cerebellar

degeneration and Hodgkin’s disease Neurology, 60,

230 – 4

Chan, K.H., Vernino, S and Lennon, V.A 2001

ANNA-3 anti-neuronal nuclear antibody: Marker

of lung cancer-related autoimmunity Ann Neurol,

50, 301–11.

Cross, S.A., Salomao, D.R., Parisi, J.E et al 2003

Paraneoplastic autoimmune optic neuritis with

retinitis defined by CRMP-5-IgG Ann Neurol, 54,

Darnell, R.B and Posner, J.B 2003 Paraneoplastic

syndromes involving the nervous system N Engl J

Med, 349, 1543 – 54.

Fukuda, T., Motomura, M., Nakao, Y et al 2003

Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellardegeneration with Lambert–Eaton myasthenic syn-

drome Ann Neurol, 53, 21– 8.

Graus, F., Vincent, A., Pozo-Rosich, P et al 2005 glial nuclear antibody: Marker of lung cancer-related

Anti-paraneoplastic neurological syndromes J Neuroimm,

165, 166 – 71.

Greenlee, J.E and Brashear, H.R 1983 Autoantibodies

to cerebellar Purkinje cells in patients with neoplastic cerebellar degeneration and ovarian car-

para-cinoma Ann Neurol, 14, 609.

Harper, C.M and Lennon, V.A 2002 Lambert–Eaton

syndrome In H.J Kaminski (ed.), Current Clinical Neurology: Myasthenia Gravis and Related Disorders,

Humana Press, Inc., Totowa, NJ, pp 269 – 91

Hetzel, D.J., Stanhope, C.R., O’Neill, B.P and Lennon, V.A

1990 Gynecologic cancer in patients with subacutecerebellar degeneration predicted by anti-Purkinjecell antibodies and limited in metastatic volume

Mayo Clin Proc, 65, 1558 – 623.

Keime-Guibert, F., Graus, F., Fleury, A et al 2000

Treatment of paraneoplastic neurological syndromeswith antineuronal antibodies (anti-Hu, anti-Yo) with

a combination of immunoglobulins,

cyclophospha-mide, and methylprednisolone J Neurol Neurosurg

Psychiatry, 68, 479 – 82.

Lachance, D.H., Kryzer, T.J., Pittock, S.J., Chan, K.H.and Lennon, V.A 2006 Anti-neuronal nuclear anti-body type 4 (ANNA-4), a novel paraneoplastic

marker of SCLC Abstract Neurology, 66(2), A340.

Lennon, V.A 1994 Paraneoplastic autoantibodies:The case for a descriptive generic nomenclature

Neurology, 44, 2236 – 40.

Lennon, V.A 1996 Calcium channel and related neoplastic disease autoantibodies In J.B Peter and Y

para-Schoenfeld (eds.), Textbook of Autoantibodies, Elsevier

Science, The Netherlands, pp 139 – 47

Lennon, V.A., Kryzer, T.J., Griesmann, G.E., O’Suilleabhain, P.E., Windebank, A.J., Woppmann,A., Miljanich, G.P and Lambert, E.H 1995 Calcium-channel antibodies in the Lambert–Eaton syndrome

and other paraneoplastic syndromes N Engl J

Medi-cine, 332, 1467–74.

Linke, R., Schroeder, M., Helmberger, T and Voltz, R

2004 Antibody-positive paraneoplastic neurologicsyndromes: value of CT and PET for tumor diagnosis

Neurology, 63, 282 – 6.

Lucchinetti, C.F., Kimmel, D.W and Lennon, V.A 1998.Paraneoplastic and oncological profiles of patientsseropositive for type 1 anti-neuronal nuclear auto

antibodies Neurology, 50, 652– 7.

Peterson, K., Rosenblum, M.K., Kotanides, H andPosner, J.B 1992 Paraneoplastic cerebellar degen-eration I A clinical analysis of 55 anti-Yo antibody-

positive patients Neurology, 42, 1931– 7.

Pittock, S.J., Kryzer, T.J and Lennon, V.A 2004 neoplastic antibodies coexist and predict cancer,

Para-not neurological syndrome Ann Neurol, 56, 715–19.

Pittock, S.J and Lennon, V.A 2006 Paraneoplasticautoimmunity affecting the nervous system In

J Baehring (ed.), Brain Tumors – A Practical Guide

to Diagnosis and Management Informa Healthcare.

Pittock, S.J., Lucchinetti, C.F and Lennon, V.A 2003.Anti-neuronal nuclear autoantibody type 2: Para-

neoplastic accompaniments Ann Neurol, 53, 580–97.

Pittock, S.J., Lucchinetti, C.F., Parisi, J.E et al 2005.Amphiphysin autoimmunity: Paraneoplastic accom-

paniments Ann Neurol, 58, 96 –107.

Scaravilli, F., Shu, F.A., Groves, M and Thom, M 1999.The neuropathology of paraneoplastic syndromes

Brain Pathology, 9, 251– 60.

Shams’ili, S and Sillevis Smitt, P 2005 Paraneoplasia

In M Strauss, N Fernando and L Sheinis (eds.),

Principles of Neuro-Oncology, McGraw-Hill, New

potassium channel antibody Neurology, 62, 1177 –

82

Vernino, S., Adamski, J., Kryzer, T.J., Fealey, R.D

and Lennon, V.A 1998 Neuronal nicotinic AChreceptor antibody in subacute autonomic neuro-

pathy and cancer-related syndromes Neurology, 50,

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 Paraneoplasticencephalitis, 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-5neuronal autoantibody: Marker of lung cancer and

thymoma-related autoimmunity Ann Neurol, 49,

146 – 54

Vasculitis, defined by inflammation of arteries andveins of varying caliber, results in a variety of clinicalneurological manifestations and neuropathologicalchanges 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 andautoimmune 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

Vasculitis and connective tissue diseases

David S Younger and Adam P.J Younger

matoid Granulo- matosis

Lympho-Wegener’s Granulo- matosis sitivity

Angiitis

Tnkarnsu’s Arteritis Temporal Arteritis CNS

Vascuiitis Polyarter-

itis Nodosa

scopic Poly- angiitis

Micro-Usually Involved Sometimes Involved

CAPILLARIES

ARTERIOLES SMALL MUSCULAR ARTERIES (Intraorgan vessels) MEDIUM MUSCULAR ARTERIES (Coronary, hepatic, intracerebral) LARGE ARTERIES (Vertebral, temporal, carotld)

AORTA

Fig 20.1 The pathological spectrum of the major vasculitides Reproduced from Younger et al., 2003, with permission

of the publisher.

(Longcope, 1908) His patient was a 35-year-oldman with constitutional symptoms and subacute leg pains Postmortem examination showed wide-spread necrotizing arteritis and nodules along smalland medium sized vessels of the heart, liver, kidney,pancreas, testicles, brain, nerves, and skeletal muscles,sparing the lungs and spleen The histological lesionsconsisted of mononuclear cell infiltration, necrosis

of internal and external elastic lamina of the media,fibrin deposition, aneurismal dilatation, perivascularinflammation of the adventitia, and intimal prolifera-tion resulting in narrowing of arterial lumina Laterinvestigators (Kernohan and Woltman, 1938) sum-marized the clinical and pathological aspects of PAN

The dominant neurological picture was a peripheralneuritis that occurred in one-half of patients early

in the illness with a predilection for the legs At mortem examination, all had arteritic lesions alongnutrient arteries of the peripheral nerves, and three-quarters had lesions in arteriae nervorum The com-bination of acute and chronic lesions correlated withknown exacerbations Brain infarcts resulted fromocclusion of cerebral vessels, but only 10% of lesionswere clinically apparent

post-In PAN the vasculitic lesion proceeds in a teristic manner, commencing with invasion of theintima, media, and adventitia by polymorphonuclear(PMN), plasma cells, eosinophils, and lymphocytes,and leading to swelling of the media, and fibrinoidnecrosis that clusters around the vasa vasorum,with fragmentation of the internal elastic lamina(Fig 20.2) There is focal deposition of perivascularconnective tissue, vascular necrosis, and denuding

charac-of the endothelium, followed by vascular sis, ischemia, aneurysm formation, rupture, andhemorrhage Healed lesions coexist with activelesions Neuroimaging reveals areas of focal cerebralinfarction (Fig 20.3) Arteriography and biopsy ofinvolved vascular tissue, such as a segment of nerve

thrombo-or muscle in a suspected patient, is the only certainmeans 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 nodosaMicroscopic polyangiitisChurg–Strauss syndrome

Hypersensitivity vasculitis

Drug-related vasculitisSerum sicknessHenoch–Schönlein purpuraHypocomplementemic vasculitisCryoglobulinemia

Systemic granulomatous vasculitis

Wegener granulomatosisLymphomatoid granulomatosisLethal midline granuloma

Giant cell arteritis

Temporal arteritisTakayasu arteritis

Granulomatous angiitis of the nervous system

Connective tissue disorders associated with vasculitis

Systemic lupus erythematosus

SclerodermaRheumatoid arthritisSjögren syndromeMixed connective tissue disease

Behçet disease

Nonsystemic vasculitic neuropathy Infection-associated vasculitis

Bacterial meningitisMycobacterium tuberculosisSpirochetes

Treponema pallidum Borrelia burgdorferi

Varicella zoster virusFungi

Human immunodeficiency virus type 1

CNS vasculitis associated with amphetamine abuse

Paraneoplastic vasculitis Inflammatory diabetic vasculopathy

Box 20.1 Classification of vasculitis.

venules of the lungs and kidney with necrotizingglomerulonephritis Circulating antinuclear cyto-plasmic autoantibodies (ANCA), usually myeloper-oxidase (MPO) or p-ANCA, are seen in up to 80% ofpatients, but are rarely if ever seen in PAN Small-

vessel involvement is considered the definite nostic criterion of MPA, and is of the caliber involved

diag-in epdiag-ineurial arteries leaddiag-ing to polyneuropathy diag-in

up to a quarter of patients, usually of the MNM type,and in skin nodules and purpura, which occur in themajority of patients

Churg–Strauss syndrome

The disorder delineated by Churg and Strauss, andlater named in their honor, included asthma, eosino-philia, extravascular granulomas, and necrotizingvasculitis of small and medium arteries, arterioles,capillaries, and veins (Churg and Strauss, 1951) Theessential lesions of CSS include angiitis and extra-vascular necrotizing granulomas with eosinophilicinfiltrates The vasculitis may be granulomatous ornongranulomatous, and characteristically involvesarteries and veins, as well as pulmonary and systemicvessels The granulomas are located near small arteriesand veins, and characterized by pallisading epi-thelioid histiocytes arranged around central necroticzones in which eosinophils predominant Pulmonarylesions reflect the combination of necrotizing vas-culitis and areas resembling eosinophilic pneumonia.There are three phases of the disease The first is aprodromal period of constitutional symptoms thatincludes rhinitis and asthma This is followed by thesecond phase of peripheral blood and tissue eosino-philia, and the third phase of systemic vasculitis,wherein neurological involvement occurs, typicallyperipheral neuropathy of the MNM type, stroke andhemorrhage in up to three-quarters of patients sim-ilar to PAN The laboratory diagnosis is ascertained

by serological investigation, primarily ANCA operoxidase, MPO or p-ANCA, and tissue biopsy

myel-Hypersensitivity vasculitis

This group of vasculitis with a unique predilectionfor 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 ofarterioles, capillaries, and postcapillary venules thatleaves nuclear fragments or leukocytoclasia withvariable necrosis and fibrinoid material termed leuko-cytoclastic vasculitis (LCV) and circulating immunecomplexes 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.

in the same stage of evolution Other organ ment includes the peripheral nerves, kidney, lungs,spleen, liver, heart, and rarely the CNS or intestines,wherein microinfarction and hemorrhage can occur.

involve-The group of HSV includes drug-related culitis, serum sickness, Henoch–Schönlein purpura(HSP), hypocomplementemic, and cryoglobulinemicvasculitis

vas-Drug-related vasculitis

Drug reactions are responsible for about 20% of cases

of dermal vasculitis They are classified clinically andtemporally according to the extent of the allergicreaction, and according to the time that elapses fromexposure to the observed reaction There is a spectrumfrom urticaria, wheezing, and rhinitis, and variableserum sickness to laryngeal edema, and hypotension,respectively, over minutes, hours, or days The rash

is most often maculopapular or vesicular, less oftenpalpable purpura, along the arms and legs withoutsystemic involvement, and abates after drug with-drawal More severe drug reactions develop multipleorgan involvement, especially the heart, liver, kidneys,gastrointestinal tract, lungs, PNS, and CNS This disorder results mainly from the focal deposition ofimmune complexes, which result from the covalentbinding of the offending drug, or its metabolites, withnative or foreign proteins to produce hapten mole-cules The latter forms hapten–antibody complexes

that deposit in the skin, eliciting the dermal culitic response

vas-Serum sickness

Serum sickness leads to vasculitis with varyingdegrees of infiltration of arterioles, capillaries, andvenules, with interstitial inflammation by PMN cells,eosinophils, and mononuclear inflammatory cells,with variable fibrinoid necrosis and perivasculargranuloma formation Urticaria, noted in the majority

of patients, is followed by erythematous or papular rash, petechiae, palpable purpura, and lym-phadenopathy, first at the site of injection site, andlater generalized with arthralgia, edema, headache,and lethargy Nervous system involvement includesbrachial plexus neuritis, mononeuritis simplex andmultiplex, Guillain–Barré syndrome, cranial nervepalsies, blurring of vision, retinal and palpebral hemorrhages, meningismus, stroke, and myelopathy.The clinical presentation of serum sickness parallelsthe appearance of protein antigen and antibody excessand persists until immune complexes are eliminated.The reaction to injection of heterologous serum andmany drugs is a complex one, and its multiple neuro-logical manifestations may be explainable on thebasis of the immune complex disease with incipientcytotoxic and humoral and cell-mediated immunemechanisms

maculo-Henoch–Schönlein purpura

This disorder consists of nonthrombocytopenic purpura, arthralgia, abdominal pain, and leukocyto-clastic vasculitis of skin lesions in an affected childwith fever, headache, and anorexia Palpable purpuriclesions arise along extensor surfaces of the lowerextremities and buttocks, sometimes in associationwith migratory angioneurotic edema of the hands,scalp, face, lower legs, and genitalia The presence ofLCV suggests an immune complex-mediated patho-genesis; in that regard, deposits of immunoglobulins,particularly IgA, and C3 have been demonstrated inthe kidney and blood vessel walls, and some affectedpatients had hereditary C2 deficiency

Hypocomplementemic vasculitis

Hypocomplementemic or urticarial vasculitis includesurticaria, migratory arthralgia, and persistent orintermittent hypocomplementemia Affected patientsdevelop 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.

sometimes severe angioneurotic edema and threatening laryngeal edema, accompanied by arth-ralgia, conjunctivitis, episcleritis, uveitis, mild renaldisease, pericarditis, abdominal pain, and spleno-megaly Pseudotumor cerebri is the most commonassociated neurological manifestation Hypocomple-mentemic vasculitis resembles a forme fruste of systemic lupus erythematosus (SLE) Immunologicalstudies show a binding of IgG antibody to C1q alongbasement membranes, in which it activates the complement cascade It is not known whether theautoantibody is more than a marker of the disease.

life-Cryoglobulinemia

Cryoglobulins are antibodies that reversibly cipitate at temperatures below 37°C They are composed of IgG and IgM, complement, lipoprotein, and antigenic protein moieties They are classifiedinto three types with implications for clinical and etiologic specificity Type I is composed of a singlemonoclonal IgM or IgG antibody; type II, mixed, has monoclonal IgM, possessing activity againstpolyclonal IgG; and type III has mixed polyclonaland nonimmunoglobulin molecules in the form

pre-of immunoglobulin–anti-immunoglobulin immunecomplexes Types I and II cryoglobulins are associ-ated with lymphoproliferative diseases, particularlymultiple myeloma and Waldenström macroglobuli-nemia Type III cryoglobulins are associated withinfection and collagen vascular diseases; one sub-group, termed essential mixed cryoglobulinemia(EMC), harbors circulating HCV RNA and corres-ponding antibodies in the cryoprecipitate Type Icryoglobulins cause the hyperviscosity syndrome

Four vascular lesions are noted in mia: (i) occlusion of small and large vessels in thosewith high levels of cryoglobulins of type I or II;

cryoglobuline-(ii) bland thrombosis of small arteries and arterioles;

(iii) endothelial swelling, proliferation, and ment membrane thickening; and (iv) LCV Peripheralnerves demonstrate chronic axonopathy of largemyelinated fibers True vasculitis is occasionally seen,mainly in those with associated PAN

base-Dermatitis is the most conspicuous feature panied by palpable purpura that persists for a week

accom-to 10 days, heralded by a sharp or burning tion Purpura is noted in all types but is more common with type III and in EMC PNS and CNSmanifestations are more common with types II andIII Renal disease is a major feature of EMC Hepaticdisease is far more common with this syndrome byvirtue of its association with HCV

sensa-The appearance of high levels of cryoglobulins

in the blood of patients reporting cold sensitivity and vasomotor symptoms led to the presumptionthat cryoprecipitation was the cause of ischemia ofarterioles and capillaries due to hyperviscosity andthe direct plugging of small vessels However, it isnow known that the cryoprecipitate, when present,may be tangential to the pathogenesis of the clinicalsyndrome 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 relate with serum cryoglobulin levels, viscosity, orcryoprecipitate concentration Fourth, in EMC inwhich levels of cryoglobulins are typically quite low,the pathology can still be explained on the basis ofimmune complex deposition Several factors thatmay contribute to the clinical manifestations of cryoglobulinemia include intravascular activa-tion of complement and the clotting cascade byaggregated immunoglobulin and immune complexes, secondary vessel wall damage; cold agglutination

cor-of erythrocytes; local tissue reaction to precipitatedproteins; 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 culitis, cryoprecipitate deposition, and microvascu-lar ischemia with resultant secondary axonopathy

vas-In those studied, the inflammatory cell infiltrate inthe nerve was mainly T cell with lesser numbers of Blymphocytes, in accordance with T-cell-dependentvasculitis The isolation of HCV RNA in peripheralnerve biopsies has been unsuccessful in marked con-trast to cutaneous lesions

Cryoglobulinemia should be considered in patientswith features of characteristic skin lesions, MNM,hyperviscosity, easily coagulable blood, IgM mono-clonal paraproteinemia, and risk factors for HCVinfection If found, the presence of cryoglobulinemiawill 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 vasculitisincludes Wegener granulomatosis (WG), lympho-matoid granulomatosis (LG), and lethal midlinegranuloma

Wegener granulomatosis

Although first considered a form of PAN, WG waslater termed rhinogenic pneumogenic granulo-matosis by the investigator for whom it was laternamed It differed in fact from PAN in the triad ofnecrotizing granulomatous lesions of the sinusesand lower respiratory tract, systemic necrotizingvasculitis of small arteries and veins, and glomeru-lonephritis (Godman and Churg, 1954) Nervoussystem involvement was appreciated almost a decadelater (Drachman, 1963)

Vasculitic lesions in WG begin as small foci ofgranular necrosis and fibrinoid degeneration withPMN cells followed by histiocytes and giant cells alongthe margins of granulomas of the upper airways and

in renal glomeruli Necrotizing granulomatous lesionssecondarily involve small arteries, arterioles, capil-laries, and venules with segmental fibrinoid necrosis

in involved tissues (Fig 20.5) Affected patients sent with multifocal pain, sensory loss, and weaknessdue to MNM that ultimately can become disabling

pre-Circulating c-ANCA directed against proteinase 3(PR3) is predictive of the disease in the majority ofpatients even in the initial phase of illness

A quarter of patients demonstrate CNS and PNSinvolvement due to direct destruction of nerve or braintissue by necrotizing granulomas, locally or remotefrom upper or lower respiratory tract granulomas,and necrotizing arteritis of cerebral and arteriae

nervorum of peripheral nerves CNS tions, in particular, appear to depend upon whetherthere is vasculitic, contiguous extension, or remotegranulomatous spread Stroke, intracerebral andsubarachnoid hemorrhage, and optic neuritis resultfrom vasculitis of anterior and posterior ciliary andretinal vessels Contiguous extension results fromnasal and paranasal sinus cavity granulomas throughthe orbit leading to pseudotumor with exophthalmos,extraocular muscles, optic and oculomotor nerveinvolvement, whereas extension through the tem-poral bone can destroy the middle ear

manifesta-Lymphomatoid granulomatosis

This malignant lymphoreticular disorder has astrong affinity for the CNS Patients present withconstitutional symptoms and skin lesions resemblingerythema nodosum Focal neurological involve-ment occurs early including MNM, unilateral cranialnerve palsies, hemiparesis, ataxia, seizures, spinal andradicular syndromes, and even myopathy In par-ticular, CNS complication occurs by the invasion ofunifocal and multifocal necrotizing angiocentric andangiodestructive lesions of small- and medium-sizedmuscular 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, cerebellarparenchyma, 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.

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 suchextensive facial mutilation It is now known to be arelentlessly invasive necrotizing process of the noseand palate that causes destruction of sinuses and all major midline structures of the head, producinggrotesque facial mutilation and ultimately death

The disorder is associated with idiopathic midlinegranuloma, poorly differentiated diffuse small or largeB-cell lymphomas, plasmacytomas, and other poly-morphic reticuloses mediate the damage CNS com-plications most often result from direct invasion ofthe 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 byJennings ( Jennings, 1938) for the site of granuloma-tous giant cell inflammation and vessel involvement

Patients with biopsy-proven temporal arteritis andassociated blindness due to vasculitic involvement

of ophthalmic and posterior ciliary vessels were originally classified as cranial arteritis Other patients had prominent constitutional and musculoskeletalcomplaints and typical polymyalgia rheumatica

The occasional finding of giant cell lesions along theaorta, its branches, and in other medium- and large-

sized arteries at autopsy in some cases warranted the diagnosis of generalized giant cell arteritis Thepathological heterogeneity of temporal arteritis wasfurther demonstrated by the finding of intracraniallesions 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 ment of mitochondria, infiltration of lymphocytes,plasma cells, and histiocytes With progression,there is extension inflammation into the intima andadventitia leading to segmental fragmentation andnecrosis 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)

enlarge-Temporal arteritis and Takayasu arteritis

Two forms of giant cell arteritis, temporal andTakayasu arteritis, are of clinical importance to neurologists They differ epidemiologically and inthe size of vessels involved Temporal arteritis occurs

in elderly Caucasians of either gender, and involvesmedium and large arteries Takayasu arteritis affectsthe aorta and its branches in young Asian women.The clinical manifestations of temporal arteritisnamely headache, scalp tenderness, thickened nodularand pulseless superficial temporal artery, unilateralvisual loss, and jaw claudication are related primarily

to disease along branches of the external carotidartery, 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.

arteries typically at end points of dural ment The characteristic involvement of obliterativelesions in large arteries such as the aorta and itsmajor branches in Takayasu arteritis, especially late

invest-in the disease, leads to other symptoms, not typicallyseen in temporal arteritis, due to chronic ischemia such

as dizziness, syncope, subclavian steal, carotid sinussyndrome, stoke, amaurosis fugax, corneal opacifica-tion, cataracts, claudication and gangrene of thelimbs, chest and abdomen angina Whereas biopsy

of the temporal artery is easily performed in clinicallysuspected patients before commencing therapy withlong-term corticosteroids or other agents, similararterial biopsy is impractical in Takayasu arteritis

Granulomatous angiitis of the nervous system (GANS)

This rare vasculitic disorder has captured the tion of generations of neurologists and neuropatho-logists The first two patients with this disorderdescribed by Harbitz (Harbitz, 1922) had a previouslyunrecognized vasculitis with progressive headachesand mental change culminating in stupor, spasticparaplegia, coma, and death Postmortem examina-tion showed granulomatous vasculitis of the meningescomposed of lymphocytes, multinucleate giant cells,and epitheliid cells, with vessel necrosis and exten-sion into the brain involving veins and arteries ofvarying caliber The clinicopathological syndromewas delineated and so named for the distinctivepathology (Cravioto and Fegin, 1959) For two moredecades, rare affected cases were reported, but therewas no effective treatment

atten-Fauci and coworkers (atten-Fauci, 1978) transformedprevailing concepts of the disorder by suggestingangiographic criteria for the antemortem diagnosis

of so called “primary angiitis” or “isolated angiitis”

of the CNS, and emphasized the clinically restrictednature of the vasculitis rather than the granuloma-tous histology (Cupps et al., 1983) The rationalewas that giant cells and epithelioid cells, described atautopsy, were an inconsistent finding in a meningealand brain biopsy, and therefore not necessary forantemortem diagnosis, and furthermore, that treat-ment with prednisone and cyclophosphamide was agiven necessity This unfortunately led to difficulty

in comparisons of treatment efficiency and long-termprognosis of cases in the literature, which persistedfor two decades until the enthusiasm for the empir-ical treatment of cerebral vasculitis waned as a result

of several influences First, there was recognition of

the unreliability of beading in a cerebral angiogram

in histologically proven cases of granulomatousangiitis of the brain (Younger et al., 1988); similarbeading was demonstrated by young women withthe prior diagnosis of primary angiitis of the CNSwho were later diagnosed as benign angiopathy ofthe CNS but differed in spontaneous resolution(Calabrese et al., 1993) Second, interest in empiricaltherapy with cyclophosphamide waned with therecognition of permanent side effects in up to 40% ofpatients so treated with WG Subsequent historicalanalyses demonstrated an equivalent efficacy of corticosteroids and cyclophosphamide in the initialtreatment of this disorder (Younger et al., 1997).There are at least 140 well-described cases ofGANS in the literature (Younger, 2003) Diag-nostic biopsy of the brain and overlying meningesand postmortem examination shows granulomatousgiant cell and epithelioid cell inflammation withnecrotizing arteritis of cerebral vessels of all calibersfrom named cerebral vessels to medium and smallleptomeningeal vessels (Fig 20.8) The disorder has nearly exclusive neurological manifestationsincluding headache, mental change, and pleocytosisand elevated protein content in the cerebrospinalfluid (CSF), with signs of angiographic beading; whichprecedes focal seizure and stroke (Fig 20.9), and

if untreated, coma and death The clinical geneity is manifested by the occurrence of GANS inassociation with cell arteritis, sarcoidosis, varicellazoster virus, lymphoma, amyloid angiopathy, andhuman immunodeficiency virus (HIV) infection

hetero-Collagen vascular diseases

The collagen vascular diseases associated with vasculitis of the nervous system include systemiclupus erythematosus, scleroderma, rheumatoidarthritis (RA), Sjögren syndrome, mixed connectivetissue disease (MCTD) and Behçet disease, each withrecognizable clinical neurological and histopatho-logical syndromes

Systemic lupus erythematosus (SLE)

The earliest concepts of connective tissue diseasesstemmed from the appreciation of fibrinoid necrosisusing collagen staining in patients with SLE Oncethought to be an important cause of cerebral lupus,true vasculitis is present in only about 10% ofpatients at postmortem examination The vasculitis

of SLE shows fibrinoid necrosis of small arteries,

arterioles, and capillaries (Fig 20.10) As collagenswells and fragments in the course of SLE, it dis-solves to form a homogeneous hyaline and granular PAS positive material The fibrinoid material con-tains immunoglobulins, antigen–antibody complexes,complement, and fibrinogen The organ-specificresponses of the CNS, PNS, and systemic organs ofthis fibrinoid necrosis lead to recognizable clinicalsequela A number of fluorescent antibody tests provide serological support of SLE The antinuclearantibody (ANA) screen produces a homogeneouspattern in the majority of cases; with antibodies

to native double-stranded DNA (anti-ds-DNA), ivity to Sm and ribonuclear proteins (RNP), the combination of which constitutes the extractablenuclear antigen (ENA), providing the strongest supportive evidence of SLE Circulating IgG and IgM antibodies with an affinity for charged phoso-pholipids (APA), some of which have procoagulantactivity, the s-called lupus anticoagulant (LAC), and the generic anticardiolipin (aCL) antibody assayusing cardiolipin as the antigen probe for APA, are

react-an importreact-ant determinreact-ant of prothrombotic eventsespecially in the CNS wherein there is a propensity

Fig 20.9 MRI (FLAIR sequence) of a patient with biopsy-proven, unifocal central nervous system vasculitis that is largely confined to the left temporal and basal frontal regions Reproduced from Younger et al., 2003, with permission of the publisher.

Fig 20.8 Central nervous system vasculitis (a) The media and adventitia of this small leptomeningeal artery have been almost completely replaced by multinucleated giant cells (arrowheads) There is intimal proliferation with obliteration of the vascular lumen, and a dense, perivascular, mononuclear inflammatory infiltrate can be seen (stain, hematoxylin and eosin; original magnification, ×250) (b) A somewhat larger leptomeningeal vessel shows necrosis of the media and internal elastic lamina with multinucleated giant cell formation (arrows), intimal proliferation (arrowhead), and lymphocytic infiltration of the adventitia and neighboring meninges (stain, hematoxylin and eosin; original magnification, ×250) Reproduced from Younger et al., 2003, with permission of the publisher.

Fig 20.10 Systemic lupus erythematosus This small vessel within brain parenchyma is largely necrotic Abundant fibrin (darkly stained) is evident in vessel walls and surrounding tissues There are a few chronic inflammatory cells indicating the presence of vasculitis, which may be seen in 20% of patients (stain, fibrin;

original magnification, ×250) Reproduced from Younger et al., 2003, with permission of the publisher.

Fig 20.11 (a)–(c) Thrombotic-embolic cerebral microangiopathy in a patient with antiphospholipid antibody syndrome (see text for details) Reproduced from Younger et al., 2003, with permission of the publisher.

for occlusive microangiopathy In particular, tion of the serum aCL antibody titer appears to be

eleva-an independent risk factor for stroke, especially

in young patients due to vasculopathy and in situ

thrombosis To illustrate, one previously reported22-year-old man (Younger et al., 1994a) with lupusglomerulonephritis and hypertension developedright frontal headache followed by left hemiplegia

Brain CT showed a large superficial and deep infarct

in the territory of the upper and lower divisions of the right middle cerebral artery (MCA) Follow-upbrain scan showed hemorrhagic transformation

in the absence of clinical worsening Magnetic resonance angiography (MRA) revealed a proximalright MCA occlusion Serum aCL titer was 60 GPL(normal range 0 to 10) with a serum ANA titer of1:320 (homogeneous), and anti-dsDNA titer was

371 unit/ml (normal positive active range 0 to 249)

Selective angiography showed total occlusion of theright proximal MCA with retrograde filling of distalbranches (Fig 20.11) He was given intravenousheparin followed by long-term anticoagulation withwarfarin

Scleroderma

Scleroderma or systemic sclerosis is recognized bywidespread microvasular changes and diffuse fibrosisaffecting first the skin, and later systemic organs and the nervous system Vascular lesions includeincreased collagen deposition, sclerosis, and hyalin-ization, followed by proliferation of the endothelium,

fibrosis of the adventitia, and intima; duplication and fraying of the internal elastic membrane, withprogressive luminal obliteration (Fig 20.12) Themicrovascular lesions in scleroderma appear to bemediated by three autoantibodies – anticentromere,anti-SCL-70 or topoisomerase, and anti-RNA polymerase III – and the HLA-DQB1 haplotype,accompanied by autoreactive lymphocytes that produce interleukins 4 and 6, which are chemo-tactic for dermal fibroblasts and capable of inducingcollagen synthesis Necrotizing vasculitis with pro-minent neurological involvement can be indolent

Fig 20.12 Progressive systemic sclerosis This digital artery has severe intimal hyperplasia and greater than 90% luminal narrowing There is also severe adventitial fibrosis and marked telangiectasia of the vasa vasorum, but the media and internal elastic lamina are relatively spared (stain, trichrome; original magnification, ×60) Reproduced from Younger et al., 2003, with permission of the publisher.