Paraneoplastic Syndromes: AnUnsolved Murder Syndromes.pdfParaneoplastic Syndromes: AnUnsolved Murder...

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Paraneoplastic Syndromes : An Unsolved Murder Michael R . Pranzatelli With neuroimmunology playing an ever greater role in child neurology, paraneoplastic syndromes-uncommon but often devastating complications of cancer-are in the forefront. Abnormalities of both humoral and cellular immunity support the immunological theory of causation . Through co-complicity of host and tumor factors, targets of immunologically mediated injury remote from the tumor may be damaged or destroyed, giving rise to discrete neurological deficits . In the nervous system, the main targets are neuronal nuclei or cell bodies, structural constituents, surface receptors, synapses, and ion channels. The clinical syndromes and response to treatment differ substantially between children and adults. Current pharmacological and biological therapies, which are nonselective, include noncytotoxic and cytotoxic drugs, intravenous immunoglobulins, plasma exchange, and immunoadsorption, some chosen for induction and others for maintenance . Tumor resection and thymectomy are surgical treatments. Combination immunotherapies allow steroid sparing, targeting of more than one immunologic effector pathway, and deploy an advantageous mixture of early- and late-acting drugs . More selective and efficacious immunotherapies are needed. Copyright © 2000 by W .B. Saunders Company C ANCER IS A staggering global problem, accounting for one tenth of all deaths annu- ally . In the United States, cancer causes 25% of deaths in adults and 10% of those in children . I With these statistics, a complication of cancer that af- flicts even a few of its victims will have a surprising collective impact. Such is the case with paraneoplas- tic syndromes (PNS) . PNS affect cancer patients of all ages .z Unlike neoplastic disorders, they occur as a remote, not direct, effect of cancer. The tumor usually resides in the chest or abdomen, far from the neurological symptoms . In their careers, clinicians may see only a few patients with PNS, therefore the syndromes are probably underdiagnosed and treatment is often delayed . The nervous system is not the only organ system subject to PNS (Table 1), but the consequences are dramatic . Whether the paraneoplastic disorder in- volves the central or peripheral nervous system or both, it may be more debilitating than the cancer. Involvement of a few organ systems, such as neurological and endocrine, in the same patient is not uncommon .z Neurological PNS, most of which also occur in the absence of cancer, precede the From the National Pediatric Myoclonus Center, Departments of Neurology andPediatrics, Southern Illinois University School of Medicine, Springfield, IL. This work is a product of the ongoing research efforts at the National Pediatric Myoclonus Center . Address reprint requests to Michael R . Pranzatelli, MD, Department of Pediatrics, SIU School of Medicine, PO Box 19658, Springfield IL 62702-9658. Copyright © 2000 by W .B . Saunders Company 1071-9091/00/0702-0006$10.00/0 doi: 10 .1053/pb.2000.6695 appearance of cancer in about 50% of cases, sometimes prompting the diagnosis .' The likeli- hood that a neurological disorder is paraneoplastic varies greatly with the disorder. Some neurological PNS are monophasic disorders : symptoms usually reach a plateau at whatever level of severity and improve, perhaps even remit, or become static . 4 Others are progressive and fatal, even before the tumor becomes large enough to be detected. This article reviews the clinical syndromes, differential diagnosis, purported autoimmune patho- physiology, and treatment of neurological PNS . Because PNS once ascribed exclusively to adults are being reported in adolescents, it is important to consider the entire spectrum of disorders even though some may be extremely rare . Most cancer epidemiologists define the upper end of the pediat- ric age range as 14 years in recognition that the spectrum of tumor types shifts toward that seen in adults thereafter. Recently, a teenager with an ovarian teratoma developed a reversible, limbic- encephalitis-like, paraneoplastic psychosis with dif- fuse slow waves .s The true incidence of neurologi- cal PNS in children is unknown . OVERVIEW OF CLINICAL SYNDROMES Differences in the PNS of children and adults are striking . Children exhibit fewer recognized neuro- logical syndromes and have different types of tumors and circulating autoantibodies . 6 In PNS of the central nervous system (CNS), children are less likely to have a progressive course . However, because of brain development at the time the PNS presents, they experience a developmental arrest that has no counterpart in adults . Even when the pediatric syndrome is nonprogressive or largely Seminars in Pediatric Neurology, Vol 7, No 2 (June), 2000 : pp 118-130

Transcript of Paraneoplastic Syndromes: AnUnsolved Murder Syndromes.pdfParaneoplastic Syndromes: AnUnsolved Murder...

Page 1: Paraneoplastic Syndromes: AnUnsolved Murder Syndromes.pdfParaneoplastic Syndromes: AnUnsolved Murder Michael R. Pranzatelli Withneuroimmunologyplayinganevergreater rolein childneurology,

Paraneoplastic Syndromes: An Unsolved Murder

Michael R . Pranzatelli

With neuroimmunology playing an ever greater role in child neurology, paraneoplastic syndromes-uncommon butoften devastating complications of cancer-are in the forefront. Abnormalities of both humoral and cellularimmunity support the immunological theory of causation . Through co-complicity of host and tumor factors, targetsof immunologically mediated injury remote from the tumor may be damaged or destroyed, giving rise to discreteneurological deficits . In the nervous system, the main targets are neuronal nuclei or cell bodies, structuralconstituents, surface receptors, synapses, and ion channels. The clinical syndromes and response to treatmentdiffer substantially between children and adults. Current pharmacological and biological therapies, which arenonselective, include noncytotoxic and cytotoxic drugs, intravenous immunoglobulins, plasma exchange, andimmunoadsorption, some chosen for induction and others for maintenance . Tumor resection and thymectomy aresurgical treatments. Combination immunotherapies allow steroid sparing, targeting of more than one immunologiceffector pathway, and deploy an advantageous mixture of early- and late-acting drugs . More selective andefficacious immunotherapies are needed.Copyright © 2000 by W.B. Saunders Company

CANCER IS A staggering global problem,accounting for one tenth of all deaths annu-

ally . In the United States, cancer causes 25% ofdeaths in adults and 10% ofthose in children . I Withthese statistics, a complication of cancer that af-flicts even a few of its victims will have a surprisingcollective impact. Such is the case with paraneoplas-tic syndromes (PNS) .PNS affect cancer patients of all ages.z Unlike

neoplastic disorders, they occur as a remote, notdirect, effect of cancer. The tumor usually resides inthe chest or abdomen, far from the neurologicalsymptoms . In their careers, clinicians may see onlya few patients with PNS, therefore the syndromesare probably underdiagnosed and treatment is oftendelayed .The nervous system is not the only organ system

subject to PNS (Table 1), but the consequences aredramatic . Whether the paraneoplastic disorder in-volves the central or peripheral nervous system orboth, it may be more debilitating than the cancer.Involvement of a few organ systems, such asneurological and endocrine, in the same patient isnot uncommon.z Neurological PNS, most of whichalso occur in the absence of cancer, precede the

From the National Pediatric Myoclonus Center, DepartmentsofNeurology andPediatrics, Southern Illinois University SchoolofMedicine, Springfield, IL.

This work is a product ofthe ongoing research efforts at theNational Pediatric Myoclonus Center.

Address reprint requests to Michael R. Pranzatelli, MD,Department of Pediatrics, SIU School of Medicine, PO Box19658, Springfield IL 62702-9658.

Copyright © 2000 by W.B . Saunders Company1071-9091/00/0702-0006$10.00/0doi: 10.1053/pb.2000.6695

appearance of cancer in about 50% of cases,sometimes prompting the diagnosis .' The likeli-hood that a neurological disorder is paraneoplasticvaries greatly with the disorder. Some neurologicalPNS are monophasic disorders : symptoms usuallyreach a plateau at whatever level of severity andimprove, perhaps even remit, or become static . 4Others are progressive and fatal, even before thetumor becomes large enough to be detected.

This article reviews the clinical syndromes,differential diagnosis, purported autoimmune patho-physiology, and treatment of neurological PNS .Because PNS once ascribed exclusively to adultsare being reported in adolescents, it is important toconsider the entire spectrum of disorders eventhough some may be extremely rare . Most cancerepidemiologists define the upper end of the pediat-ric age range as 14 years in recognition that thespectrum of tumor types shifts toward that seen inadults thereafter. Recently, a teenager with anovarian teratoma developed a reversible, limbic-encephalitis-like, paraneoplastic psychosis with dif-fuse slow waves.s The true incidence of neurologi-cal PNS in children is unknown .

OVERVIEW OF CLINICAL SYNDROMES

Differences in the PNS of children and adults arestriking . Children exhibit fewer recognized neuro-logical syndromes and have different types oftumors and circulating autoantibodies . 6 In PNS ofthe central nervous system (CNS), children are lesslikely to have a progressive course . However,because of brain development at the time the PNSpresents, they experience a developmental arrestthat has no counterpart in adults . Even when thepediatric syndrome is nonprogressive or largely

Seminars in Pediatric Neurology, Vol 7, No 2 (June), 2000 : pp 118-130

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PARANEOPLASTIC SYNDROMES

Table 1 . The Spectrum of Paraneoplastic Syndromes

Neurological

Brain and cranial nervesCarcinomatous cerebellardegeneration

EncephalomyeloneuritisOpsoclonus-myoclonus-

ataxiaOptic neuritisRetinal degeneration

Spinal cordNecrotizing myelopathyMotor neuron diseaseMyelitisStiff-person syndrome

Peripheral nervePolyneuropathy (sensori-

motor, sensory, motor)Autonomic neuropathyNeuromyotoniaFocal and multifocal neu-

ropathyNeuromuscular junction

Lambert-Eaton myasthenicsyndrome

Myasthenia gravisMuscleDermato/polymyositisMyopathies (cachectic,

carcinoid, necrotizing)

Brain and Cranial Nerves

Non-Neurological

DermatosesBullous/urticarialErythemasKeratoses/pigmented

EndocrinopathyAddison'sCushing'sMultiple endocrine neo-

plasiaSIADH

Fever syndromesGastrointestinalAnorexia/cachexiaProtein-losing enteropathyHematologicalCell-line abnormalitiesCoagulopathies

RenalGlomerulopathiesNephrotic syndrome

Rheumatic disorders

remits, the developmental consequences may bepermanent .

Opsoclonus-myoclonus-ataxia (POMA). POMAand the rarer encephalomyeloneuritis are the princi-pal PNS of the CNS common to both children andadults . The clinical features of POMA includeopsoclonus, myoclonus, ataxia, dysarthria, behav-ioral and cognitive problems (for review, see Pran-zatelli6 ) . Opsoclonus is a distinctive disorder ofconjugate saccadic gaze, which compels the eyes todart rapidly and randomly in any direction . Myoclo-nus designates rapid shocklike involuntary musclejerks originating in the brain or spinal cord andfound in the trunk or limbs . A remote neoplasmaccounts for about half of the pediatric cases and20% of the adult cases of POMA. In children,whose mean age is about 2 years at the onset, thedevelopmental impact of POMA is often the mostpermanent and disabling consequence of the syn-drome .The infrequent occurrence of other neurological

abnormalities in POMA, such as seizures, Homer's

syndrome, and palsies of facial, recurrent laryn-geal, phrenic, or peroneal nerves exemplifies theclinical heterogeneity.'-9

Paraneoplastic encephalomyeloneurilis (PEMN).PEMN is distinguished by its potential involve-ment of both the CNS and peripheral nervoussystem and association with neuroendocrine tu-mors . It occurs as a result of widespread inflamma-tion of brain, brainstem, spinal cord, dorsal rootganglia, and nerve roots .'° Limbic encephalitis,bulbar encephalitis, non-necrotizing myelopathy,subacute motor or sensory neuronopathy, auto-nomic dysfunction, cerebellar symptoms, even epi-lepsia partialis continua comprise the clinical syn-drome. II

Paraneoplastic cerebellar degeneration (PCD) .PCD, the most common central PNS of adults, is aprogressive pancerebellar syndrome that may coex-ist with Lambert-Eaton syndrome." ,"

Retinal degeneration (CAR) . Painless visualloss, photosensitivity, night blindness, and loss ofcolor vision are common symptoms of CAR inadults ." Photoreceptors and ganglion cells dropout .

Spinal CordSpinal involvement in PNS takes the form of

neuronopathy, motor neuron disease (MND), myeli-tis, or necrotizing myelopathy.' 5 Stiff-person syn-drome denotes rigidity with painful axial and lowerextremity spasms . 3

Peripheral NervesPolyneuropathy. About 10% of unexplained

peripheral neuropathies in patients with cancer areparaneoplastic . The neuropathies are autonomic,motor, sensory, or sensorimotor (PSN), affectingthe distal extremities symmetrically and resultingin weakness, loss of deep tendon reflexes, andstocking-glove sensory impairment with paresthe-sias . Monoclonal gammopathies (MAG, GDlb,GM1), especially IgM, have a tendency to inducedemyelinating polyneuropathies .' 6 Paraneoplasticacute polyradiculopathy (Guillain-Barre syndrome)is usually associated with lymphoproliferative dis-orders, such as Hodgkin's disease . Paraneoplasticautonomic neuropathies present as panautonomicsyndromes (orthostatic hypotension, anhidrosis,bladder atony, pupillary abnormalities, nausea andvomiting, impaired salivation, and lacrimation) oras intestinal pseudo-obstruction (gastroparesis) ."

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Focal and multifocal neuropathies.

Paraneo-plastic vasculitic neuropathy may present as progres-sive, mononeuropathy multiplex, an axonal polyneu-ropathy. Painful brachial neuritis may be aparaneoplastic feature of Hodgkin's disease .'Neuromyotonia (Isaacs' syndrome). Muscle

cramps, spasms, stiffness or rigidity, myokymia,and intermittent carpopedal postures are progres-sive features of paraneoplastic neuromyotonia. InMorvan's fibrillary chorea-chorea is a misnomer-neuromyotonia is accompanied by pruritis, hyperhi-drosis, insomnia, and delirium or psychosis . II

Neuromuscular JunctionLambert-Eaton myasthenic syndrome (LEMS) .

Patients with LEMS have proximal muscle weak-ness with bulbar sparing and most also suffer fromcholinergic dysautonomia . As many as 65% harboran underlying tumor. 19

Myasthenia gravis (MG) . In the peripheralnervous system, MG is the chief PNS common tochildren and adults . When the cause of MG isparaneoplastic, which occurs in about 15% ofcases, the tumor is usually a thymoma or occasion-ally Hodgkin's disease (for review, see Lovelaceand Younger2°) . About 30% of patients with athymoma will develop MG.

MuscleDermato/polymyositis .

Unlike other cutaneousPNS, dermatomyositis and polymyositis are alsomyopathic syndromes of proximal, perhaps painfulmuscle weakness with elevated blood creatinekinase . 21 The usual assertion is that dermatomyosi-tis is paraneoplastic only about 10% of the time andmore often linked to cancer with increasing patientage .Myopathies.

Although weight loss is typical ofpatients with many types of cancer, the progressionto cachexia may be associated with a specificmyopathy. 2 In other patients, the myopathy may benecrotizing without inflammation . Painful myopa-thy with diarrhea should suggest a carcinoid syn-drome.'

TUMORS : WHY THESE?

There are more than 200 different kinds ofcancer, but tumors of tissues that are derivedembryologically from neural crest cells are morelikely to be associated with neurological PNS . 22 Acertain degree of cell differentiation seems requi-

MICHAEL R . PRANZATELLI

site . Tumors produce or contain many of the samecomponents found in mature neural tissues (Table2) . 23 In children and adults, thymomas appear incentral or peripheral PNS and have a proclivitytoward autoimmune and other neoplastic disorders .In adults, a variety of cancers of the lung (espe-cially small cell lung cancer [SCLC]), gynecologi-cal organs (especially breast and ovaries), andlymphoreticular system (lymphoma) are most typi-cal .POMA illustrates the diversity of tumors that

may evoke one clinical syndrome . In children, thechief tumors are neuroblastoma, ganglioneuroblas-toma, and ganglioneuroma .24,25 A ganglioneuroblas-toma located in the chest is most common . Whenadults get ganglioneuroblastoma, which is veryrare, they do not develop POMA.26 Instead, adult-onset POMA is associated with tumors rangingfrom breast cancer to T-cell lymphoma. 2' ,28

In either age group, the biology of tumors thatgive rise to PNS may differ from those that do not .Cancers in patients with PNS tend to be moreindolent .29

DIFFERENTIAL DIAGNOSIS: THINKNEOPLASTIC FIRST

In patients with known tumors, the presence ofother potentially treatable, direct consequences of

Table 2 . Some Tumor Components or Products Relevant toParaneoplastic Syndromes

Categories

Types or Examples

Biogenic amines Homovanillic acid (HVA), vanil-lylmandellic acid (VMA)

Cell surface antigens Activation, differentiation,oncofeta I

Cytokines EGF, GM-CSF, IGF-II, TNF-aGenes Oncogenes (NMYC, HRAS),

onconeural genes, suppressorgenes (p53, APC)

Enzymes Neuron-specific enolase, thymi-dine kinase

Hormones Gastrin, GH, prolactin, PTHOnconeural antigens Cytoplasmic signalling proteins,

neuromuscular junction pro-teins, nuclear neuronal RNAbinding proteins, vesicle-asso-ciated nerve terminal proteins

Neuropeptides ACTH, chromogranin A, CRF,neuropeptide Y, pro-opiomela-nocortin, somatostatin, VIP

Receptors Neurotrophin, opiate, serotoninToxins ?Other ?

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PARANEOPLASTIC SYNDROMES

cancer must be considered : cerebrovascular compli-cations of cancer, complications of cancer treat-ment, direct extension of tumor, infections, meta-bolic encephalopathy, metastases, and nutritionaldeficiencies .' Besides serology, the differentiationof paraneoplastic and nonparaneoplastic complica-tions of cancer may require cerebrospinal fluidanalysis, electrophysiologic studies, metabolic bloodscreening, neuroimaging and various other radio-logical procedures, and neuropsychological test-ing . 3

In patients not known to have cancer, the pres-ence of neurological syndromes compatible withPNS should suggest the diagnosis . Even when athorough search reveals no underlying malignancy,patients with neurological PNS must be observedclosely with repeated investigations . Infrequently,months or a few years may lapse until the tumor isfound .

PATHOPHYSIOLOGY: AN UNSOLVED MURDER

In the tightly regulated immune network, noth-ing could be so scandalous as policing membersattacking the very constituents they were entrustedto protect . Take the case of central neurologicalPNS. Victims in the brain would claim to have donenothing wrong . The attackers would insist to havehad just cause to break and enter, then execute . Butcould they have been duped? The investigation hasbeen going on for decades . Now there are newclues and theories .

The Victim

The concept that the immune system can damagethe brain as profoundly as head trauma, stroke, or adegenerative disease is only now becoming fullyappreciated . Even the brain, once the prototype ofimmunologically privileged sites with its no-nonsense blood-brain barrier and absence of MHCclass I or 11 antigens and lymphatic drainage, ispatrolled by activated T and B cells (for review, seePranzatelli4) . T-cell trafficking is only a problemwhen T cells find their mark : a specific antigen inthe appropriate restriction molecule context (Fig 1) .In the absence of an animal model, an immunologi-cal causation of most PNS has not been proven, butevidence is strong .

The Charges

Is the immune system guilty of two crimes-oneof omission and the other of commission? The first

allows the tumor to grow, perhaps through a defectin immune surveillance due to a "stress response"or genetic vulnerability, which decreases immuneresponsiveness . The second problem appears to bean immunological over-reaction or hyper-respon-siveness on some level that damages the nervoussystem, although it does help fight the tumor.Neuroblastoma, the most common extracranialsolid tumor in children, 25 is associated with 50%spontaneous regression, the highest incidence ofany solid tumor. 3 ° Most children with neuroblas-toma and PNS survive their cancer, which isseldom metastatic . 29 By comparison, more than75% of children with neuroblastoma without PNShave metastases at the time of diagnosis .'5

At the Crime Scene

In the brain, perivascular inflammatory infil-trates of both T cells and B cells have been found inPCD and PEMN. 1 ° Cytotoxic T cells surrounddegenerating neurons and occupy the neuronalneuropil . Immunoglobulin G (IgG) has been discov-ered inside neurons . There are no immune complexor complement deposits . In CSF, there are variousimmunologic abnormalities, such as IgG and IgM,oligoclonal bands, interferon, and intrathecal IgGsynthesis . 31,32

In POMA, loss of both cerebellar Purkinje andgranule cells with gliosis or Purkinje cells alone, orlesions of the inferior olives, lower medulla, orupper cervical cord have been seen." -3s Reactivecells in the cerebellar vermis of one child werepositive for monocyte-macrophage antigens byimmunohistochemistry, but there was no infiltrationof T or B lymphocytes . 36 However, some patients withPOMA exhibit no apparent histopathology.

Suspects

Cells attacking the tumor are the likely suspectsfor the assault on brain. The enigma of PNS may beintricately linked to immune surveillance againsttumor emergence. To combat tumors, the immunesystem unleashes specific immunity by T cells andnonspecific immunity by natural killer cells (NK),lymphokine-activated killer cells (LAK), macro-phages, interleukin 2 (IL-2), and other cytokines . 23Tumor infiltrative lymphocytes (TIL) suggest afavorable oncologic prognosis . 31 The main anti-body responses to human tumor-associated anti-gens are antiheterophile antibodies, antigangliosideantibodies, and antiprotein antibodies, all products

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122

IMMUNE SYSTEM

W

Establishing a Motive

of B cells . Which is the main offender and whichare accomplices?

According to the autoimmune theory ofpathogen-esis, neural tissue-the innocent bystander-iscaught inadvertently in the crossfire between theimmune system and the tumor over shared onconeu-ral antigens . The immunologic basis for the mis-taken identity may be molecular mimicry : twomolecules close enough in structure to be regardedas identical by the immune system."What would drive immune cells to do the

unthinkable : autoaggression? Most human tumorantigens are structurally similar to normal brainproteins." Some are expressed at fetal stages whenrecognition should lead to elimination of self-

Resting T cellResting B cellActivated T cellActivated B cell (CD5+)Cytotoxic T cellHelperT cell (CD4+)SuppressorTcell (CD8+)Natural Killer cell (NK)

MacrophageTumor Infiltrative Lymphocyte (TIL)

How the Murder Was Committed

MICHAEL R. PRANZATELLI

Fig 1. Formation of an im-mune response to an onconeuralantigen in PNS. The inductionantigen produced "ectopically"by the tumor is the same as ormimics the structure of a nativebrain protein (molecular mim-icry), resulting in cross-reactiv-ity. The immune system, not pre-viously exposed to this brainantigen, has no mechanism ofinducing self-tolerance in thepresence of tumor-expressedMHC. The antigen-presenting cell(APC), which may be microgliaor astrocyte, activates T cells,leading to cytotoxic autoreactiv-ity. Alternatively, a tumor antigencould act as a "superantigen" toprovoke an immune responsethat bypasses the need for MHCpresentation and the safeguardsinherent in such a system. B-cellactivation may be T-cell depen-dent or independent. Activatedlymphocytes breach the blood-brain barrier andattack onconeu-ral antigens, producing cyto-kines or antibodies locally.

reactive clones . Sequestration of onconeural anti-gens in the brain from immune surveillance resultsin lack of immune tolerance to these proteins whenthey are "ectopically" expressed in tumor cells ."Immunization" with self-antigens also could un-mask the presence of autoreactive T cells at a clonallevel-humoral and cellular responses to differen-tiation antigens are not entirely suppressed bytolerance-and induce autoimmune disease . Imma-ture dendritic cells that engulf apoptotic tumor cellscould mature and migrate to draining lymph nodeswhere they could introduce a T-cell response totissue antigens . 39

What means do immune cells have for killingneural cells? Recent evidence suggests that apopto-

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PARANEOPLASTIC SYNDROMES

/A

Fig 2.

Mechanisms by whichautoimmunity may damage or de-stroy neural cells in PNS: apopto-sis and necrosis . Apoptosis ischaracterized by cell shrinkage,membrane blebbing, chromatincondensation and a ladder ap-pearance to extracted genomicDNA, and breakup of the cell intomembrane-bound fragments. Un-like with necrotic cell death, thereis usually no spillage of proin-flammatory cytoplasmic con-stituents and intact antigens totrigger further glial and immuneresponses in the brain. In ne-crotic cell death, the plasmamembrane is a primary target,not just a signaling mechanismfor phagocytic cells as it is inapoptosis. The immune attack

_odisrupts the neural membraneby cross-linking (X), perforation(=), or receptor blockade by anti-bodies .

APOPTOSIS

V

Q

Non-inflammatory

sis of neurons is a crucial mechanism of injury inPNS (Fig 2) .4° During embryogenesis, entire organsystems undergo apoptosis . 22 Antibodies to theprotein recoverin induce apoptosis of photorecep-tor and bipolar cells in CAR. 41 In contrast, apopto-sis of autoaggressive T cells may be an effectivemechanism for the termination of inflammation inthe CNS.

LABORATORY TESTING: FINDING A NEEDLEIN THE HAYSTACK?

Circulating Autoantibodies

With millions of circulating antibodies definingthe human condition, including ones to vital organsthat our immune systems have learned to disregard,why do a minority of people develop autoimmunedisease? The complexity and scope of the networkthat regulates cellular and humoral immunity is

IMMUNE SYSTEM RESPONSE

Neurons

NECROSIS

O o

Inflammatory

123

staggering and strikingly parallel to the nervoussystem, with which it is in bidirectional communi-cation .

Varieties .

Now, 35 years after the first descrip-tion of a paraneoplastic antibody, screening forserum autoantibodies is a routine clinical labora-tory test done by immunohistochemistry, Westernblotting, and ELISA. Several novel circulatingautoantibodies have been detected in patients withPNS, some of which suggest a specific tumor orsyndrome (Table 3) . Many have not yet beenevaluated in children . Most of the autoantibodiesare IgG (IgGI and IgG3), antineuronal, anticerebel-lar (Purkinje), and some also react with peripheralnerve . There are a few notable exceptions . Re-cently, antibodies to glial cells (anti-CV2) weredescribed in patients with PNS, including one withLEMS who did not have antineuronal paraneoplas-

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12 4

Table 3. Some Paraneoplastic Autoantibodies and Their Onconeural Antigens

tic antibodies . 46 Some antineurofilament antibodiesare IgM5 z and IgM antibodies already have a trackrecord of neurological disease in gammopathies .POMA. Antineurofilament and anti-Hu anti-

bodies (Fig 3) are found in children with POMA,y,51but anti-Hu and anti-Ri antibodies are found inadults . 17,48 In childhood POMA, anti-Hu antibodiesare rare (4%) despite positivity for Hu antigen inabout 75% of the neuroblastomas . 63 In contrast,antineurofilament antibodies and several other anti-bodies to unidentified antigens of various sizes (84,

MICHAEL R. PRANZATELLI

Abbreviations: MG, myasthemia gravis ; PCD, paraneoplastic cerebellar degeneration ; LEMS, Lambert-Eaton myasthemicsyndrome ; PSN, paraneoplastic sensorimotor neuropathy; PEMN, paraneoplastic encephalomyeloneuritis ; CAR, cancer-associatedretinopathy; POMA, paraneoplastic opsoclonus-myoclonus-ataxia ; MND, motor neuron disease; SCLC, small cell lung cancer.

80, 68, 55 MW) are common . 51 IgM but not IgGdisappeared during ACTH treatment and clinicalimprovement in one child . In other children withopsoclonus, circulating cerebellar-specific immuno-reactivity was found with antibodies of 62, 35, and27 MW.64LEMS and MG.

Seropositivity for P/Q-typecalcium channel-binding antibodies is specific (95%seropositive) for LEMS syndrome, and helps differ-entiate it from MG (5% seropositive) . 19 In MG, thecombination of seropositivity for striational anfibod-

Antibody(IgG) Protein Antigen

MW(kDa) Clinical Syndrome

AssociatedTumors References

Anti-AChR Muscle a1-subunit MG Thymoma 42Ganglionic a3-sub- Dysautonomia Lung, others 17

unitAnti-amphiphysin I Amphiphysin 128 PCD, LEMS, PSN, SCLC, breast 43,44

PEMN, stiff-personAnti-B-CK Brain-type creatine 47 PSN SCLC, others 45

kinaseAnti-CV2 Subpopulation of PCD, PEMN, LEMS Thymoma, SCLC 46

microgliaAnti-enolase-a a-enolase CAR SCLC, others 41Anti-Hu HuD, HuC, Hel-N1, 35-40 PEMN, PSN, POMA, Neuroblastoma SCLC 47,48

Hel-N2 (Elav pro- PCDteins)

Anti-Mal Testicular germ cell 37-40 PCD Breast colon, parotid 49phosphoprotein

Anti-Nb p-NAP (adaptin-like 120 PCD SCLC, others 50vesicle coat pro-tein)

Anti-NF and others Neurofilament (IgM 210 POMA (children) Neuroblastoma 51, 52and IgG)

Anti-S-100 and others S-100, NF, neuron- 100 Multiple endocrine Ganglioneuro-blas- 26specific enolase neoplasia-like tome

Anti-P/Q VGCC 13,19 P/Q-type voltage- LEMS, PEMN SCLCgated calciumchannels

Anti-P/Q VGCC p-sub- mysB, synapto- 37,64 LEMS SCLC 53unit tagminAnti-recoverin Recoverin, Hsc 70 23,65 CAR SCLC, ovarian, mela- 54

nomaAnti-R i Nova-1 55-55 POMA (adults) Breast, ovarian, 55,56? Nova-2 70-75 ?POMA/dementia bladder, other 57Anti-Tr Purkinje ? PCD Hodgkin's 58Anti-NTCC and others N-type calcium chan- Morvan's fibrillary Thymoma 18

nels, nAChR, titin, choreavoltage-gated K'channels

Anti-VGKC Voltage-gated K' Neuromyotonia Thymoma, lung can- 59channels cars, other

Anti-Yo cdr2 (leucine-zipper 56 PCD, MND Ovarian, breast, SCLC 60-62protein

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PARANEOPLASTIC SYNDROMES

Fig 3 .

Aphotomicrograph (original magnification x160) ofhuman inferior olivary neurons immunostained by anti-Huantibodies . Normal postmortem pediatric brainstem was cryo-sectioned, and immunoassays were performed using theavidin-biotin-peroxidase complex method inthe author's labo-ratory.

ies and nicotinic cholinergic receptor (nAChR)modulating antibodies is most predictive of thepresence of a thymoma .z° Paraneoplastic LEMScan be further differentiated from nonparaneoplas-tic LEMS by its higher incidence of seropositivityfor the N-type calcium channel and non-organ-specific autoantibodies and a lower incidence ofseropositivity for thyroid-gastric antibodies .

Onconeural antigens and genes.

The antigensfor autoantibodies are found in tumors and thenervous system (Table 4), and cDNAs encoding therespective onconeural antigens have been cloned .The Hu family of proteins, which are expressed innuclei and the cell surface of differentiating andmature neurons, neuroblastoma, and other cells, 61may function as regulatory RNA binding pro-teins .41 Proteins encoded by Nova may be involvedin signal transduction in neurons and tumor cells." ,"(3-NAP, a component of coat proteins, mediates thetransport of vesicle membrane proteins between

nerve cell body and terminals . 5 ° Neurofilament is acellular constituent of neuroblastoma and neuronsalike (Fig 4) .The clinicalproblem ofantibody interpretation.

Leaving aside the difficulties in nomenclature,66 theinterpretation of autoantibodies in PNS can beconfusing . 67 An autoantibody may be associatedwith different clinical syndromes, one central,another peripheral or mixed, such as anti-Hu inPOMA or PEMN.41 Autoantibodies also have beenfound in patients with no discemable tumor, some-times remaining elevated in the blood for years . Arethese false-positives or indicative of microscopictumors? Negative results of antibody testing are nottoo reassuring because cancer still may be present.Most patients presumed to have PNS do not harborrecognized autoantibodies . 3 These "seronegative"patients cannot be differentiated clinically fromthose who are seropositive .

Table 4 . Immunostained Cellular and Subcellular Targets ofSome Antineuronal Antibodies

Antibody

Subcellular/Nomenclature

Neural Target

Organelle Target

125

Anti-Hu (ANNA-1 ; Purkinje, granule,

Nuclei (not nucleoli)type Ila)

peripheral nerveAnti-Ma

Purkinje

Subnuclear (includ-ing nucleoli)

Anti-Ri (ANNA-2 ;

Purkinje

Nucleitype Ilb)

Anti-amphiphysin Purkinje, neuropil

Perikarya (granularmolecular layer,

periphery)granule cell layer(synaptic termi-nals)

The classification of paraneoplastic antibodies is based onthe pattern of immunostaining alone or in combination withWestern blotting . Immunohistochemistry, in which autoanti-bodies in patient serum are allowed to react with a slidesection of normal neural tissue, reveals the cellular localizationof antibody binding . Western blotting, the visual result of a gelfiltration assay in which autoantibodies from patient serumreact with antigens from neural extracts or cloned fusionproteins, detects the protein antigen . In one nomenclaturesystem, the terms ANNA (antineuronal nuclear antibody) andPCAb (anti-Purkinje cell cytoplasmic antibody) are used withnumerical subdivisions . A similar system divides antineuronalantibodies into type I (similar to PCA-1) and type Ila (likeANNA-1) and type Ilb (like ANNA-2) . Another system namesthe antibodies for these antigens .

Anti-NF Purkinje, granule, Cytoplasmperipheral nerve

Anti-Tr Purkinje, neuropil Cytoplasm, dendritesmolecular layer (not spines)

Anti-Yo (PCA-1 ; Purkinje Cytoplasm (granular)type 1)

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12 6

Fig 4.

Aphotomicrograph (original magnification x 160) ofa ganglioneuroblastoma from a child with POMA . The tumorhas been stained for neurofilament, revealing antigenic com-monalities between neural crest-derived tumors and neuralcells. The heterogeneous histopathologic features are charac-teristic of ganglioneuroblastoma . Nuclei have been counter-stained . (Courtesy of the National Pediatric Myoclonus Cen-ter.)

Cause or association? Autoantibodies havenot been causally linked to central PNS. 67 Althoughsome are cytotoxic (for review, see Dalmau andPosner 3 ), antibody access to intracytoplasmic orintranuclear autoantigens may be limited, Fc recep-tors are not abundant on neurons, and passivetransfer of autoantibodies does not induce paraneo-plastic disease . The situation is complex : in PSNwith anti-Hu antibodies, the pattern of epitopicreactivity was not critical to the clinical featureS61 ;Hu proteins were one antigenic target for CD4+ Tcells, 69 not the target of a demyelinating inflamma-tion involving CD8+ T cells and CD68+ macro-phages ; and the distribution of Hu antigen differedfrom that of the pathological lesions . 7° In theperipheral nervous system, the case is stronger forLEMS.

The Peripheral Lymphocyte

MICHAEL R. PRANZATELLI

Interest in cellular immune abnormalities in PNSis increasing." In children with POMA, the migra-tion of leukocytes was inhibited by neuroblastomaextract in vitro,'2 and blood lymphocytes werecytotoxic to neuroblastoma cells in culture .11,14 Aslightly elevated CD4+ helper to CD8+ suppres-sor T-cell ratio was found in one boy."

Studies of cytotoxic T cells in PCD show reactiv-ity to Yo protein . 76 In an adult patient with opsoclo-nus and breast cancer, suppressor Tlymphocytefunction was depressed" ; and the laboratory andclinical abnormalities were reversed with predni-sone . In anti-Hu-positive patients, CD4+ CD45+RO+ (memory or primed) helper T cells wereincreased .69

THE TREATMENT DILEMMA: CHOOSING THERIGHT WEAPON

ImmunotherapyTreatment controversies.

In the absence of aknown tumor, cancer chemotherapeutic agents usu-ally are not used in PNS. A treatment bias hasresulted because patients without identified tumorsare not treated with immunosuppressants as power-ful as those used against tumors yet may developsignificant neural injury. Another controversy iswhether immunotherapy, which might impair thehost's defenses against the tumor, should be startedbefore tumor removal . Delay in starting immuno-therapy may lead to irreversible nervous systemdamage .

Tumor removal. In theory, removal of thetumor before starting immunosuppressive therapyshould decrease the antigenic challenge, providesufficient treatment, and decrease the chance oftumor growth or metastasis . In practice, tumorremoval alone is unlikely to abolish the PNS andsome patients worsen when the tumor is resected,possibly because more antigen is released into thecirculation . 3 Antibody persistence probably resultsfrom immune dysregulation allowing survival ofautoreactive lymphocytes .

Choice of monotherapy.

Because the cliniciancannot predetermine which patient will remit spon-taneously or progress relentlessly, immunotherapyshould notbe delayed . Selection of a treatment plandepends on the clinical severity, rate of progres-sion, and risk of side effects . Sometimes, the tumorand the paraneoplastic syndrome respond to the

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PARANEOPLASTIC SYNDROMES

same agent, such as chemotherapy . Response totreatment does not differentiate patients with andwithout tumors .

Noncytotoxic immunosuppressants . ACTH(corticotrophin) 78 is superior to steroids in achiev-ing a remission in children with POMA,4 whereassteroids tend to be used instead in adults . 17 Inchildren, the problem is not in inducing a remissionbut in preventing relapse during drug withdrawal .Failure of response or tolerance to ACTH shouldsuggest an underlying tumor or the presence ofanti-ACTH antibodies . 79

Cytotoxic immunosuppressants.

Cancer chemo-therapy, such as cyclophosphamide, chlorambucil,and methotrexate, although applied to autoimmunediseases, has not been studied systematically inneurological PNS. In case reports, the response canbe dramatic.s° Azathioprine and cyclosporine Aalso have been underused .Intravenous immunoglobulins . The clinical

use of human IVIG has been unblinded, nonrandom-ized, and uncontrolled, but IVIG appears to be auseful treatment for POMA in children .75,81 Inadults with central neurological PNS, IVIG may ormay not be effective . 32,82,83 IVIG is highly regardedas a treatment for dermatomyositis and somepolyneuropathies . 3

Therapeutic apheresis .

Apheresis is used as ashort-term measure to stabilize the seriously illpatient by removing plasma (plasmapheresis orplasma exchange) or select blood cellular fractions,such as leukocytes (leukapheresis, leukocytapher-esis) or lymphocytes (lymphocytapheresis) . 21 Plas-mapheresis in adult-onset POMA yields mixedresults despite reduction in antibody titers . 84 .85 In afew adults with PEMN or PCD, plasmapheresisreduced the serum antibody titers to 20% of theinitial levels, but CSF autoantibody titers decreasedonly in the patient with a compromised blood-brainbarrier. In neuromyotonia, plasmapheresis was ben-eficial . Leukapheresis has been used in polymyosi-tis and dermatomyositis .2 '

Immunoadsorption.

Immunoadsorption, a typeof apheresis, uses a side column to which antibod-ies bind avidly . Protein A, a staphylococcal proteinused in immunoadsorption columns, may removeimmune complexes and facilitate antiidiotype anti-body formation . 86 Improvement in 12 adults withneurological PNS was reported after immunoadsorp-tion therapy .s'

127

Thymectomy. In the presence of thymoma,thymectomy has been beneficial in MG, neuromyo-tonia, dermato/polymyositis, LEMS, and PNS.'$

Combination therapy. The use of combina-tions of drugs or biologicals, with or withoutapheresis, is standard . Besides the practical needfor more efficacious therapy than monotherapyprovides, there is an immunological rationale forcombination therapy .4 Cell-mediated immunity issensitive to cyclosporine and antilymphocyte anti-bodies and less sensitive to azathioprine and corti-costeroids . Antibody production is sensitive toalkylating agents but insensitive to high-dose ste-roids and thiopurines . Most treatments that targetlymphocytes are more effective against T cells thanB cells . Also, current therapies have limited capac-ity to remove autoantibodies that have crossed theblood-brain barrier or bound to target neural tis-sues . 85 Azathioprine, cyclosporine, and IVIG maybe combined with steroids, often allowing the doseof steroids to be reduced (steroid-sparing) . Chemo-therapy, radiation therapy, and surgical treatmentsoften are combined . 3

Symptomatic TherapyAlthough symptomatic and supportive treat-

ments do not redress underlying immunologicabnormalities, they may be vital : cholinesteraseinhibitors, treatment of infection, and ventilatorysupport in MG2° ; guanidine hydrochloride, 4-ami-nopyridine, and 3,4-diaminopyridine in LEMS3 ;anticonvulsants and baclofen in neuromyotonia andstiff-person syndrome3 ; serotonin receptor blockersin carcinoid myopathy 3 ; and serotonin reuptakeinhibitors for the behavioral disorders of POMA inchildren . 6

FUTURE THERAPIES

New treatments for PNS will be directed selec-tively at lymphocytes, MHC, cytokines, and anti-bodies through the use of immunizations, antiidiot-ype antibodies, and biological response modifiers .4

CONCLUSIONS

Neurological PNS are heterogeneous clinicallyand immunologically. The spectrum of syndromesappears to be broader in adults than in children, butless has been written about pediatric PNS. Autoan-tibodies found in some of the disorders, by implicat-ing specific tumors, may lead to the diagnosis ofcancer . However, reduction in serum autoantibody

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12 8

titers may not predict clinical improvement. Thetherapy of central neurological PNS is poor, per-haps because permanent neurological injury occursbefore immunotherapy is instituted . Neurologicaldeficits may continue to progress despite tumorremoval or chemotherapy . Myriad immunological

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