Steven Vernino Antibody testing as a diagnostic toolin autonomic disorders

Received: 19 May 2008Accepted: 2 July 2008Published online: 22 August 2008

S. Vernino, MD, PhD (&)Dept. of Neurology, University of TexasSouthwestern Medical Center5323 Harry Hines BlvdDallas (TX) 75390-9036, USATel.: +1-214/648-8816Fax: +1-214/648-9129E-Mail: steven.vernino@utsouthwestern.

edu

j Abstract Some forms of periph-eral autonomic dysfunction(especially enteric neuropathy andsubacute panautonomic failure)occur as autoimmune phenomenaeither in isolation or in the contextof cancer. Autoimmune auto-nomic ganglionopathy is anexample of a severe, but poten-tially treatable, antibody-mediatedform of autonomic failure. Diag-nostic evaluation of autonomicdisorders can be supplemented by

testing for paraneoplastic anti-bodies and antibodies againstmembrane receptors. The diag-nostic antibodies most commonlyassociated with dysautonomia areparaneoplastic antibodies (anti-Hu and CRMP-5) and ganglionicacetylcholine receptor antibodies.

j Key words paraneoplastic Æautonomic ganglia

Introduction

Causes of peripheral autonomic neuropathy includegenetic, toxic, metabolic, infectious and inflammatorydisorders. Some peripheral neuropathies have anautoimmune basis, either as a consequence of sys-temic autoimmune disease, an autoimmune disorderspecifically targeting peripheral nerve or ganglia, or aremote effect of malignancy. Many cases of acute orsubacute autonomic failure may be attributed toautoimmunity targeting the autonomic nerves and/organglia. When an autoimmune form of dysautonomiais suspected, the diagnostic evaluation can be sup-plemented with serological testing for specific neu-rological autoantibodies.

Antibody testing may help distinguish autoim-mune disorders from degenerative forms of auto-nomic failure. In the setting of peripheral autonomicdisorders, neurological autoantibodies fall into threegeneral categories, (1) paraneoplastic antibodies di-rected against one or more intracellular onconeuronalantigens, (2) autoantibodies against membrane

receptors, (3) antibodies against cell surface glyco-proteins (gangliosides). The ganglioside antibodiesare useful markers of immune-mediated neuropathies(for review see [37]). While some of the neuropathiesassociated with ganglioside antibodies have auto-nomic involvement (especially Guillain-Barre syn-drome), none of the ganglioside antibodies areuniquely associated with dysautonomia so thoseantibodies are not discussed further in this review.Antibodies against ganglionic neuronal acetylcholinereceptors (AChR) are of particular interest for thisreview since these are markers of an antibody-medi-ated and potentially treatable form of autonomicfailure.

Paraneoplastic autoantibodies

The use and interpretation of antibody testing insuspected paraneoplastic neurological disease re-mains a source of confusion due to the large numberof reported antibodies and the diversity of theirclinical associations. There are a growing number of

REVIEW ARTICLEClin Auton Res (2009) 19:13–19DOI 10.1007/s10286-008-0488-6

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paraneoplastic antibodies that can be detected rou-tinely in academic or commercial clinical laboratoriesas well as less common antibodies which have beenreported in only a small number of cases. Themajority of paraneoplastic antibodies are directedagainst intracellular antigens in the nucleus or cyto-plasm of neurons. These antibodies recognize anti-gens both in neurons and in tumor cells and areimportant surrogate markers of a specific immuneresponse to cancer. In these paraneoplastic disorders,the pathophysiological effect on the nervous systemappears to be primarily cell-mediated damage toneurons and axons [3]. As yet, a direct pathogenicrole for the antibodies appears unlikely since passivetransfer of these antibodies or immunization hasfailed to reproduce disease in animals [27].

Each of the paraneoplastic neuronal nuclear andcytoplasmic antibodies can be associated with anumber of different neurological syndromes but aretypically highly specific for the presence of cancer andpredictive of the cancer type (Table 1). Differentparaneoplastic antibodies frequently co-exist in asingle patient [24, 46]. Anti-Hu (ANNA-1) andCRMP-5 (anti-CV2) antibodies deserve special atten-tion because of their frequent association withperipheral sensorimotor or autonomic neuropathy.However, no individual neuronal paraneoplasticantibody is a very sensitive diagnostic tool. Evenwhen the most complete battery of paraneoplasticantibodies is obtained, many patients with a subacuteneurological syndrome and proven cancer have noparaneoplastic antibody detected [1, 15]. Thus, neg-ative antibody tests cannot exclude a paraneoplasticcause of neuropathy.

The titer of a serum paraneoplastic antibody doesnot correlate with the severity of the neurologicalsyndrome or with the type of symptoms. Thus, it isnot practical to use antibody titer to monitor responseto treatment. In general, antibody titers decreaseslowly after successful treatment of the underlyingmalignancy, so an increase in titer suggests persis-tence or recurrence of tumor.

j Anti-Hu (ANNA-1) antibodies

Anti-Hu antibodies (also known as anti-neuronalnuclear antibody—type 1, ANNA-1) bind to a familyof 35–40 kDa proteins expressed in the nuclei ofneurons of the central nervous system, dorsal rootganglia, autonomic ganglia, and myenteric plexus.These antigens are also expressed in certain tumorcells, most notably small cell lung carcinoma. Elevatedantibody titers are associated with a wide variety ofneurologic syndromes ranging from limbic encepha-litis to neuropathy. Peripheral neuropathy is the mostcommon initial manifestation, occurring in 70–80% ofpatients with anti-Hu antibody [20]. Half of theseparaneoplastic neuropathies are sensory. About 25%of patients with anti-Hu have some features of dys-autonomia, the most common manifestation is gas-trointestinal dysmotility (paraneoplastic entericneuropathy) [19, 20].

Upon detection of a positive serology for anti-Hu,patients should be aggressively screened for under-lying malignancy, beginning with chest CT since chestradiographs are less sensitive to mediastinal lym-phadenopathy. More than 80% of adult patients withanti-Hu antibodies will have cancer, usually small-celllung carcinoma [24]. Bronchoscopy, mediastinos-copy, or metabolic imaging with positron emissiontomography may identify occult tumors when initialradiologic studies are indeterminate [20, 43]. If achest malignancy is not found, the search should bewidened to include other tumors, including neuro-blastoma or small-cell carcinomas arising in otherorgans. Periodic follow-up imaging every few monthsis recommended if initial screening is unremarkable.

j CRMP-5 (anti-CV2) antibodies

Collapsing-response mediator proteins (CRMP) are afamily of neuronal cytoplasmic proteins present inadult central and peripheral neurons, and in small-cell lung carcinomas. Antibodies against CRMP-5 are

Table 1 Paraneoplastic autoantibodies associated with autonomic manifestations

Antibody namea Related tumor Associated autonomic syndromesb

Anti-Hu/ANNA-1 SCLC Sensory and autonomic neuropathy; Autonomic ganglionopathy; Enteric neuropathy (GI dysmotility)CRMP-5/anti-CV2 SCLC or thymoma Neuropathy, including autonomic neuropathy or enteric neuropathyanti-Yo/PCA-1 Ovarian or breast cancer Paraneoplastic cerebellar degeneration, occasionally with GI dysmotilityAnti-amphiphysin Lung or breast cancer Paraneoplastic neuropathies and stiff-person syndrome, occasionally with autonomic dysfunctionPCA-2 SCLC Various syndromes including some with autonomic neuropathyANNA-3 SCLC Various syndromes including some with autonomic neuropathy

aWhen alternate nomenclature exists, both are given. The neuronal and cytoplasmic antibodies are listed in approximate order of decreasing frequencybExcept for anti-Hu and CRMP-5 antibodies, autonomic disorders are an uncommon manifestation of paraneoplastic disease associated with these antibodiesANNA anti-neuronal nuclear antibody, PCA purkinje-cell antibody, SCLC small-cell lung carcinoma

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associated with a wide variety of paraneoplastic syn-dromes [46]. Although the reported specificity ofCRMP-5 antibody differs slightly from an earlierdescription of an antibody named anti-CV2 [9], thesetwo paraneoplastic antibodies appear to have thesame implications and are usually considered to-gether. CRMP-5 antibodies are proving to be one ofthe most common markers of paraneoplastic neuro-logical disorders.

The neurological syndromes associated withCRMP-5 antibodies are very diverse (much like thoseassociated with anti-Hu antibodies) and includeperipheral neuropathy, limbic encephalitis, ataxia, aswell as paraneoplastic chorea or optic neuritis.Peripheral neuropathy, usually axonal sensorimotortype, is present in about one-half of patients [46].Autonomic neuropathy occurs in about one-third.Lung carcinoma (small-cell type) is eventually foundin nearly 80% of seropositive patients. CRMP-5 anti-bodies can also be found in patients with thymoma,with or without neurological symptoms [33, 46].

Paraneoplastic autonomic neuropathy

Paraneoplastic autonomic neuropathy typically pre-sents as a subacute panautonomic neuropathy(indistinguishable from non-paraneoplastic autoim-mune autonomic neuropathy, discussed below).Standard autonomic testing demonstrates the auto-nomic deficits but does not differentiate paraneo-plastic autonomic neuropathy from other causes ofsevere peripheral autonomic failure. Limited presen-tations may also occur, most notably severe gastro-intestinal dysmotility without other autonomicfeatures (paraneoplastic enteric neuropathy). As withother paraneoplastic disorders, the symptoms usuallyprecede the diagnosis of cancer, and the tumors, whenfound, are limited in stage or only locally metastatic(regional lymph nodes). Hence, since the patient hasno symptoms directly referable to metastatic cancer,the autonomic symptoms cannot be attributed to di-rect effects of the tumor, non-specific consequences ofchronic illness or to chemotherapy-induced neurop-athy.

Paraneoplastic disorders often present as multifo-cal neurological disorders. When subacute autonomicfailure develops in combination with anotherperipheral or central neurological syndrome, para-neoplastic disease should be strongly considered.Common examples are paraneoplastic gastroparesisin combination with limbic encephalitis or subacuteautonomic neuropathy in combination with sensoryganglionopathy (paraneoplastic sensory and auto-nomic ganglionopathy). Paraneoplastic dysautonomia

also commonly occurs in the setting of paraneoplasticataxia or brainstem encephalitis, Lambert-Eatonsyndrome and Morvan syndrome (discussed later).The autoantibody most commonly associated withparaneoplastic autonomic neuropathy and small celllung cancer is anti-Hu (ANNA-1). Patients withoutanti-Hu antibodies may have antibodies against gan-glionic AChR.

Autonomic symptoms are not typically seen withmyasthenia gravis (MG). This may reflect the fact thatantibodies against muscle-type AChR in patients withMG rarely recognize neuronal nicotinic AChR [35].However, rare cases of subacute autonomic neurop-athy have been reported in association with thymomaor with MG [25]. In these cases, gastrointestinalsymptoms (such as intestinal pseudoobstruction)have been prominent. Some patients with thymomahave both ganglionic and muscle AChR antibodies[33].

Paraneoplastic enteric neuropathy

Gastrointestinal hypomotility is a common and dis-abling feature of paraneoplastic autonomic neuropa-thy. Quite often, the paraneoplastic syndrome can belimited to the gut and is better classified as a para-neoplastic enteric neuropathy. This syndrome canoccur in patients with known malignancy but moretypically precedes the diagnosis of cancer [2, 20].Features vary from severe gastroparesis, intestinalpseudoobstruction, severe constipation, or a combi-nation of these. Esophageal dysmotility (includingachalasia) has also been reported [18, 20, 33]. Patientspresent with nausea, early satiety, bloating, abdominalpain, constipation and resultant weight loss. Patientsmay regurgitate undigested food many hours aftereating. In severe cases, even fluid intake may becompromised leading to dehydration. Imaging studiesshow dilated loops of bowel, and motility studies re-veal delayed gastric emptying, diffuse intestinalhypomotility, and absent or incoordinated motorcomplexes. Such patients are often presumed to havebowel obstruction, but endoscopy and exploratorylaparotomy fail to identify an obstruction.

Pathologically, paraneoplastic enteric neuropathyhas been associated with inflammatory destructiveprocess affecting myenteric ganglia of the gut. Inpostmortem or surgical samples of the gut, the entericplexus shows reduction in neurons and axons, andlymphocytic infiltration [2, 11].

Among patients with ANNA-1 (anti-Hu) antibod-ies, more than 10% had a paraneoplastic syndromelimited to gastrointestinal dysmotility [20]. At leastone case of thymoma-associated gastric pseudo-

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obstruction was associated with antibodies to voltage-gated potassium channels (and associated neuro-myotonia) [38].

Membrane receptor antibodies

A distinct category of antibodies that can be found inpatients with both paraneoplastic and non-paraneo-plastic disorders are those that bind to surfacemembrane receptors (Table 2). The antigens includevoltage-gated calcium channels, voltage-gated potas-sium channels, and nicotinic and muscarinic AChR.Unlike the paraneoplastic antibodies discussed above,membrane receptor antibodies each associate closelywith a particular neurological disorder but do notpredict the presence of cancer. The best characterizedof this category of antibodies is the muscle AChRantibody associated with myasthenia gravis. Anti-bodies associated with autonomic disorders includeneuronal ganglionic AChR, voltage-gated calcium andpotassium channel and muscarinic AChR antibodies.

Because these antibodies can reach their targets onintact neurons, they have a greater potential to di-rectly affect neuronal function. For some disorders,there is convincing evidence of an antibody-mediatedpathophysiology. Patients may improve clinicallyafter plasma exchange or other immunotherapies, andthe conditions can be transferred to experimentalanimals by injection of patients’ IgG [14, 31, 39]. Also,the level of the antibody often correlates with theseverity of disease; improvement in symptoms may beassociated with a decrease in antibody level.

Autoimmune autonomic ganglionopathy

Acute pure dysautonomia was first described as adiscrete clinical entity by Young et al. [44, 45] in 1969.This disorder is characterized by subacute onset andmonophasic course with partial recovery. There issympathetic, parasympathetic and enteric failure withno significant evidence of somatic peripheral neu-

ropathy [8, 28]. Specific antibodies directed againstthe neuronal ganglionic AChR in autonomic gangliahave been found in about 50% of patients with thisdisorder [36]. This receptor is a pentameric trans-membrane complex consisting of two AChR a3 sub-units in combination with AChR b subunits. The a3-type ganglionic AChR mediates fast synaptic trans-mission in all peripheral autonomic ganglia and ishomologous but immunologically distinct from theAChR at the neuromuscular junction. These anti-bodies can inhibit the function of ganglionic AChR incultured cells and impair synaptic transmission inisolated autonomic ganglia [42]. Based on thesefindings, the term autoimmune autonomic ganglion-opathy (AAG) is used to highlight the nature of thedisorder.

The clinical features of AAG are essentially indis-tinguishable from paraneoplastic autonomic neurop-athy. The distinction may not be possible until canceris diagnosed or another neurological syndrome be-comes evident. As with the paraneoplastic form, thesymptoms of AAG reflect involvement of parasym-pathetic, sympathetic and enteric nervous systems.Less common patterns are those of selective cholin-ergic failure, selective adrenergic neuropathy, or iso-lated gastrointestinal dysmotility. The characteristicpresentation is severe pandysautonomia evolving overa few weeks in a previously healthy individual [12,28]. Common presenting symptoms are orthostatichypotension and gastrointestinal dysfunction; eachof these symptoms occurring in more than 70% ofpatients. Parasympathetic failure is also prominentwith dry eyes, dry mouth, impaired pupillary lightreflex, and disturbances of bladder and bowel func-tion. A presumed antecedent viral infection may bereported in about 60% of cases [28]. The spinal fluidprotein is often elevated [8, 28].

Although the finding of high levels of ganglionicAChR antibody is specific for the diagnosis of AAG, anegative antibody test does not rule out the diagnosis.Ganglionic AChR antibodies are not found in normalcontrol subjects but can occasionally be found inpatients with lung cancer- and thymoma-related

Table 2 Membrane receptor antibodies associated with dysautonomia

Antibody name Related tumor Associated autonomic syndromes

P/Q-type VGCC SCLC (~50%) Lambert-Eaton syndrome (LES)N-type VGCC SCLC or breast Various, including LES or sensorimotor and autonomic neuropathyGanglionic (a3) AChR SCLC (<10%) Autoimmune Autonomic Ganglionopathy, Postural tachycardia, GI dysmotilityVGKC Thymoma (<20%) or SCLC(<5%) Neuromyotonia, limbic encephalitis with autonomic hyperactivity, or

Gastrointestinal dysmotilityMuscarinic (M3) AChR Sjogren syndrome

VGCC voltage-gated calcium channel, AChR acetylcholine receptor, VGKC voltage-gated potassium channel, SCLC small-cell lung carcinoma

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paraneoplastic disorders [33, 36]. Recognition ofganglionic AChR antibodies has allowed for theserological classification of autoimmune autonomicdisorders and led to a better appreciation of thespectrum of autoimmune dysautonomia, includingthe recognition that some AAG cases have insidiousonset, initially indistinguishable from degenerativeforms of autonomic failure [5, 12]. Patients withautoimmune dysautonomia can be broadly dividedinto several groups based on the clinical presentationand the ganglionic AChR antibody level (Table 3).Patients with the classic presentation of subacutepanautonomic failure (including prominent pupil andgastrointestinal involvement) have highest antibodylevels. Moderate ganglionic AChR antibody levels arefound in patients with chronic progressive AAG andin some patients with restricted forms of autonomicfailure (such as idiopathic anhidrosis or pure cho-linergic failure). Low levels of antibody may be foundin a minority of patients with postural tachycardiasyndrome (up to 15%) or isolated gastrointestinaldysmotility (5–10%).

Lambert-Eaton myasthenic syndrome

LES is an acquired, antibody-mediated disorder ofneuromuscular junction transmission. Antibodiesagainst P/Q-type voltage-gated calcium channelscause impairment in presynaptic calcium influx and areduction in the release of acetylcholine [14, 40].Calcium channel antibodies are found in nearly 100%of patients with LEMS, but these antibodies can alsobe associated with other autoimmune neurologicaldisorders (notably paraneoplastic cerebellar ataxia)[6, 41]. Many adult LEMS patients (50–60%) havea malignancy, most commonly small-cell lung carci-noma.

Weakness and fatigability are the usual presentingcomplaints, but autonomic symptoms are present inabout three-quarters of patients. Often the autonomicsymptoms are mild, and patients do not volunteerthem unless specifically asked. Dry mouth andimpotence (in men) are extremely common. Othercholinergic autonomic symptoms may be present,including dry eyes, reduced sweating, abnormalpupillary function, and constipation [23]. Symptomsof sympathetic failure (postural hypotension) mayoccur but are less common. While autonomic com-plaints are relatively few, autonomic tests may showwidespread autonomic abnormalities.

Neuromyotonia and Morvan’s syndrome

Several other autoimmune neuromuscular disordersare associated with autonomic dysfunction. Acquiredneuromyotonia is an autoimmune disorder charac-terized by peripheral nerve hyperexcitability. Elec-tromyography shows spontaneous firing of motorunits in multiplet discharges at irregular intervalswith a high intraburst frequency. These discharges areoften characterized as myokymia or neuromyotonia.Clinical features include muscle stiffness, cramps,myokymia, hyperhidrosis and hypersalivation [7, 22].Serum from about 40% of patients contains antibod-ies (IgG) that precipitate 125I-dendrotoxin-voltage-gated potassium channels (VGKC) of the Kv1.1, 1.2and 1.6 subtypes [26, 34].

Excessive autonomic activity is suggested by newonset hypertension, piloerection, vasomotor instabil-ity in the hands and feet, tachycardia, extrasystolesand increased urinary or serum catecholamines [10,16, 17]. Paroxysms of sweating, piloerection, lacri-mation and salivation can occur. In addition toautonomic hyperactivity, patients with autoimmuneneuromyotonia may also experience autonomic fail-ure including constipation, intestinal pseudoobstruc-tion [38], orthostatic hypotension and cardiovagalfailure [10]. This disorder can be associated withthymoma and, less commonly, SCLC. It appears thatthe incidence of VGKC antibodies is higher in thosecases with a tumor [7]. VGKC antibodies can also beassociated with gastric motility defects in non-tumorcases [13].

j Neuropathy with Sjogren and sicca syndrome

The exact frequency of neuropathy associated withprimary Sjogren syndrome (SS) is unknown butestimated to be about 10% [4]. A variety of neurop-athies can be encountered, and neuropathy may bethe initial presentation of the autoimmune disease.

Table 3 Clinical disorders associated with ganglionic AChR antibodies

Clinical disorder Abfrequency

Antibody level

Subacute monophasic AAG ~50% High (>1.0 nmol/L)Paraneoplastic AAG (thymoma or SCLC) ~20% High (>0.5)Chronic AAG Unknown Moderate (0.2–1.0)Restricted AAG

(e.g. pure cholinergic failure)Unknown Moderate (0.1–0.5)

Postural tachycardia 7–15% Low (<0.5)Isolated gastrointestinal dysmotility ~10% Low (<0.5)Other autoimmune disorders

(e.g. MG, LES, neuromyotonia)<10% Low (<0.2)

Estimates of antibody level and frequency are based on the author’s experienceand references [29, 30, 32, 35, 36]AAG autoimmune autonomic ganglionopathy, LES Lambert-Eaton syndrome,MG myasthenia gravis

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Patients with SS are predominantly female. Diagnosisconsists of symptoms and objective evidence of drymouth and dry eyes along with presence of anti-Ro/SS-A and anti-La/SS-B antibodies. These antibodiesare found in about 60% of patients with SS. Otherserological findings include ANA and RF antibodies.

Autonomic features are often present, characterizedby sweating abnormalities and constipation. In aminority of cases, tonic unresponsive pupils can occur.Several studies have suggested that antibodies againstmuscarinic (M3-type) AChR are associated with theautonomic neuropathy of SS [21]. Testing for theseantibodies is not yet widely available but may eventu-ally prove to be a useful tool for evaluating patients withprimarily secretomotor autonomic deficits.

Summary

Clinicians should be aware that some forms ofperipheral autonomic dysfunction (especially entericneuropathy and subacute panautonomic failure) oc-cur as autoimmune phenomena either in isolation orin the context of cancer. Autoimmune autonomicganglionopathy is an example of a severe, butpotentially treatable, antibody-mediated form ofautonomic failure. Diagnostic evaluation of auto-nomic disorders can be supplemented by testing forparaneoplastic antibodies and antibodies againstmembrane receptors.

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