2019

Yuebing Li, M.D., Ph.D., FAAN. Neuromuscular Center, Cleveland ClinicEmail: liy@ccf.org

Paraneoplastic Antibodies in Neuromuscular Medicine and Neurology

2019

Financial Disclosure

• Has served as a consultant for Advisory Board Meeting by Argenx.• Will discuss investigational and off-label usage of treatment.

2019

Contents• Focus on discussions about limitations in interpreting results of “paraneoplastic” antibodies

• Illustrative cases

• Attempt to answer following questions: What are the commonly encountered paraneoplastic antibodies and what are their typically

associated PNS and CNS syndromes? What are the advantages and disadvantages in adopting an antibody panel approach? What to do when a particular antibody is positive but specific syndromes are absent? Do antibody titers matter? Which one should be chosen: antibody testing in the serum or cerebrospinal fluid? How to evaluate the risk of malignancy? Is there a need to scan every patient?

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Case #1 Aphasia and right sided weakness• 67-year-old woman with 2-week history of speech difficulty, muscle jerking and impaired usage of

right arm and leg. • Father died of a progressive illness with a presumptive diagnosis of ALS. • Exam: confusion, agitation, expressive aphasia, apraxia and alien limb phenomenon. • Serum VGKC complex antibody: 460 pM (normal<20pM).

A CB C

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Case #1 Genetic CJD• IVMP then IVIG treatment: no improvement. Died 4 months later. • Brain autopsy (Jammoul et al, BMJ Case Report 2014)

− No inflammation. − Intracytoplasmic vacuolation spongiform changes− Diffuse prion protein (PrP) immunostaining, confirming CJD. − Genetic analysis: E200K-129M mutation in the PrP-encoding gene.

• Father probably carried the same diagnosis.

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Case #2 Autoimmune Dysautonomia?

• 41 year-old Caucasian male:˗ Recurrent episodes of limb pain, abdominal pain, headache˗ Excessive sweating˗ Nausea˗ Trouble with concentration˗ Insomnia

• Medication: aspirin, atorvastatin, clonidine, flexeril, metoprolol, gabapentin, oxycontin, oxycodone

• Ganglionic AChR antibody: 64,600 pM (normal <20)

• ? Autoimmune autonomic ganglinopathy (AAG)?

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Case #2 Antibody positivity related to previous autoimmune condition?

• Autonomic evaluation all negative− No orthostatic hypotension or tachycardia on exam.− Cardiovascular autonomic test with tilt normal. − QSART normal. − Skin biopsy: basically normal.

• Proceeded with chronic pain rehabilitation. Never treated with immunotherapy. • All symptoms resolved except occasional headache.• Stopped all medications (except venlafaxine for headache). • Seen again five years later. No evidence of a significant neuromuscular disorder. • History of “autoimmune disorder involving spleen” as a child.

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Case #3 VGKC Complex Ab in MND• 52 year old male presented with muscle cramp and twitching for 6 months.• Exam：reduced right ankle jerk, otherwise normal. • VGKC antibody was 237 pM (normal <20 pM). Diagnosed as cramp-fasciculation syndrome. • Referred for consideration of immunotherapy. • EMG:

Sparse fasciculations seen in three limb muscles. Sparse fibrillations in the mid-thoracic paraspinal muscles.

• 4 to 5 months later, developed progressive asymmetrical hand weakness. Repeat EMG verified a diagnosis of amyotrophic lateral sclerosis.

• Repeat VGKC antibody was negative. • VGKC-Ab as acute phase reactant in MND secondary to cell death?

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Case #4 Multiple Abs in CIDP

• 76 year old male with severe weakness. Diagnosed as CIDP. Platelet count 17K.• Treated with prednisone and IVIG. Remarkable recovery in strength. Platelet count normalized. • Chest CT and body PET scan: no malignancy. Bone marrow no malignancy.• Follow up for 4 years. Currently stable with no weakness on prednisone 5mg per day. • Antibody testing at diagnosis and at follow-up

Striational Ab AChR-binding Ab (pM) VGKC Ab (pM) Others2015 1:15360 970 280 A 4th unknown antibody

staining rat cerebellum

2016 1:960 1320 170 -

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What are “paraneoplastic” antibodies? A partial listAntibody name Antigen location Notable associated syndromesAnti-Hu (ANNA-1) Intracellular/non-synaptic Encephalomyelitis, cerebellar degeneration, sensory

neuronopathyAnti-Ri (ANNA-2) Intracellular/non-synaptic brainstem encephalitis, cerebellar degeneration,

opsoclonus-myoclonusAnti-ANNA-3 Intracellular/non-synaptic Encephalomyelitis, sensory neuronopathy

Anti-Yo (PCA-1) Intracellular/non-synaptic Cerebellar degeneration

Anti-MAP1B (PCA-2) Intracellular/non-synaptic Peripheral neuropathy, cerebellar ataxia,

Anti-CV2/CRMP5 Intracellular/non-synaptic Encephalomyelitis, cerebellar degeneration, neuropathy

Anti-Ma/Ta Intracellular/non-synaptic Encephalomyelitis, cerebellar degeneration

Anti-Recoverin Intracellular/non-synaptic Cancer-associated retinopathy

Anti-Zic 4 Intracellular/non-synaptic Cerebellar degeneration

Anti-SOX1 (AGNA1) Intracellular/non-synaptic Lambert-Eaton

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What are “paraneoplastic” antibodies? A partial listAntibody name Antigen Notable associated syndromes

Anti-VGCC Cell surface/synaptic Lambert-Eaton, cerebellar degeneration,

Anti-VGKC (LGI1 and CASPR2)

Cell surface/synaptic Encephalitis, faciobrachial seizure, neuromyotonia, Morvan syndrome

Anti-ganglionic AChR Cell surface/synaptic Autoimmune autonomic ganglionopathy

Anti-AChR Cell surface/synaptic Myasthenia gravis

Anti-NMDA receptor Cell surface/synaptic EncephalitisAnti-AMPA receptor Cell surface/synaptic EncephalitisAnti-PCA Tr (DNER) Cell surface/synaptic Cerebellar degeneration

Anti-GAD65 Intracellular/synaptic Stiff person syndrome

Anti-Amphiphysin Intracellular/synaptic Stiff person syndrome

Striational antibody Intracellular/non-synaptic Myasthenia gravis

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Paraneoplastic syndromes with antibodies to different antigens

With Ab to intracellular antigens With Ab to cell surface antigens

Rarely detected Antibodies more commonly detectedElderly patients Variable age, but elderly patients more

commonOften associated with classicalparaneoplastic neurological syndromes

Can be associated with classical syndromes but can also be seen in variable conditions.

Progressive course with unfavorable outcome, difficult to treat

Usually a non-progressive course, some treatable

High association with cancer Variable (?) association with cancer

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Paraneoplastic Antibody Result in 2017 CCF (N=1453)

Antibody (cell surface)

# POS (%)

AChR 26 (1.8%)

gAChR 50 (3.4%)

VGCC (N) 38 (2.6%)

VGCC (P/Q) 37 (2.5%)

VGCC 46 (3.2%)

Striational 40 (2.8%)

Reflex 56 (3.9%)

Antibody (intracellular)

# POS (%)

ANNA1 (anti-Hu) 1 (0.1%)

ANNA2 0ANNA3 0

PCA1 (anti-Yo) 2 (0.1%)

PCA2 0

PCATr 0

AGNA1 0

Amphiphysin 0

CRMP5G 0

Reflex # POS

GAD65 45

NMDA-R 3

AMPA-R 1

CRMP-5 1

GABAb and GAD65 1

NMDAR and other 1

GAD65 and ANA 1

• Patients with positive anti-ANNA-1 (Hu) antibodies: A total of 10 cases from a five-year period (2009-2013), all having classical anti-Hu syndromes.

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• Albadareen et al. Int J Neurosci. 2017;127:531: one year (7/2012 to 6/2013). 321 samples

Antibodies to cell surface antigens

Antibodies to intracellular antigens

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• Abboud et al. J Neurol 2017; 264: 2284: 401 patients, one year (2014)• 53 patients had a positive panel (clinically relevant in 17 patients).

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• Ebright et al. Neurology 2018; 91: e2057: 500 patients, nine month (2013-2014)• 87 patients had a positive result despite using a panel testing>15 antibodies

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Ordering of “Paraneoplastic” Antibodies: A partial List of Panels

• ARUP Labs: https://arupconsult.com/content/paraneoplastic-neurological-syndromes-and-associated-disorders

• Health Lab: https://www.healthlabtesting.com/Test%20Directory• /Test%20Directory%20Item.aspx?itemGuid=7907ad3c-c704-43a7-a8f8-55cc4f8cd4d1• Mayo Clinic Labs: https://www.mayocliniclabs.com/it-

mmfiles/Paraneoplastic_Evaluation_Algorithm.pdf• Oxford: https://www.ouh.nhs.uk/immunology/diagnostic-tests/tests-

catalogue/neuronal-antibodies.aspx• Quest: https://www.questdiagnostics.com/home/physicians/testing-

services/condition/neurology/neuroimmunology/paraneoplastic-disorders.html

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Advantages and Disadvantages of a Panel Approach

• A paneled approach could increase diagnostic sensitivity. • Different antibodies can be associated with the same paraneoplastic neurologic syndrome. Examples:

57 year-old female with SCLC and encephalitis, serum anti-Hu (+) 60 year-old female with SCLC and encephamyelitis, serum and CSF anti-CRMP5 (+) 67 year-old female with encephalitis, serum VGKC-Ab (+)

• Conversely, the same antibody may be associated with different syndromes• Several paraneoplastic antibodies may co-occur on the same patient. Sometimes helpful.

• Disadvantages: Unrelated antibody positivity (especially for antibodies against cell surface antigens) can be a

common occurrence. Clinical significance is unclear when classical paraneoplastic syndromes are absent. Lead to cost increase, anxiety, unnecessary tests and unneeded treatment.

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Classical Paraneoplastic Neurological SyndromesNotable associated CNS syndromes Notable associated PNS syndromes

Encephamyelitis Lambert-Eaton myasthenic syndrome

Cerebellar degeneration Subacute sensory neuronopathy

Limbic encephalitis Chronic gastrointestinal pseudo-obstruction

Opsoclonus-myoclonus Dermatomyositis

Stiff person syndrome Necrotizing myopathy

Retinal degeneration Myasthenia gravis

Morvan syndrome Neuromyotonia and Morvan syndromeMotor neuron degeneration? Large-fiber sensorimotor polyneuropathy?

Vasculitis neuropathy?

Acute polyradiculopathy?

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• Ebright et al. Neurology 2018; 91: e2057: Increased yield with common paraneoplastic presentations

Definition of true positives:A. (+) Ab, no other etiology

AndB. Known syndrome, response

to immunotherapy or new malignancy

Definition of false positives: None of above was met or another explanation was found.

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VGKC Complex Antibody as Example

• Voltage gated potassium channels (VGKC): present on the membranes of neurons, and other excitable cells, gated by membrane voltage change.

• VGKC complex: An array of both intracellular and extracellular proteins. • LGI1, CASPR2 and Contactin-2 or in combination are antigens using cell based

assay and direct immunoprecipitation (Irani et al. Brain 2010;133: 2734; Lai et al Lancet Neurol 2010; 9:776).

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VGKC Complex Antibody

• Four unique clinical syndromes: Limbic encephalopathy/encephalitis (LE): mostly anti-LGI1 Neuromyotonia: Mostly anti-CASPR2 Faciobrachial dystonic seizure (FBDS): Mostly anti-LGI1 Morvan syndrome (MoS): CASPR2>LGI1.

• What if these classical syndromes are absent in VGKC complex antibody (+) patients?

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• Tan et al. Neurology 2008; 70: 1883: 24 of 72 (33%) had evidence of organ-specific autoimmunity: hypothyroidism or thyroid

autoantibody, diabetes, pernicious anemia, and others Coexistence of other antibodies in nearly half of the patients.

• Jammoul et al Neuro Clin Pract 2016; 6: 409: 14 of 114 (12%) patients have one or more (+) antineuronal antibody from the same panel

(striational smooth muscle, VGCC, AChR, ganglionic AChR, GAD-antibodies). 34 of 114 (30%) patients had autoimmune conditions: Optic neuritis, multiple sclerosis,

myasthenia gravis, sarcoidosis, SLE, rheumatoid arthritis, celiac disease, inflammatory bowel disease etc.

• Other antibodies seen more commonly in autoimmune disorders Striational antibody (Mckeon et al. Muscle Nerve 2013; 47: 585) VGCC antibody (Zalewski et al. Muscle nerve 2016; 54: 220)

VGKC-Ab relation to autoimmunity

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• Olberg et al. JNNP 2013; 84: 941. • VGKC complex antibodies are seen

in many autoimmune disorders: Multiple sclerosis Vasculitis AIDP Myasthenia gravis Crohn’s disease

VGKC-Ab as (non-specific) autoimmunity marker

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Antibodies observed in a variety of non-immunological presentations

• Only 11 of 114 (9.6%) patients with (+) VGKC complex antibody had specifically associated syndromes.

• Jammoul et al Neuro Clin Pract 2016; 6: 409

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VGKC complex antibody in sporadic and genetic prion disease: PNS hyperexcitability? Reaction to cell death?

Author No. of pts Serum VGKC-Ab (pM)

CSF VGKC-Ab (pM)

Final CJD category

Fujita 2012 1 603.5→0 ND (not done) Genetic

Angus-Leppan 2013

1 210 ND Sporadic

Newey 2013 1 170 ND Sporadic

Jammoul 2014 1 460 ND Genetic

Jones 2014 1 4159 (no antigen) ND Genetic (GSS)

Zuhorn 2014 1 1:2000 (CASPR2) ND Sporadic

Rossi 2015 2 210 and 113 ND Sporadic

Kim 2016 1 338 (LGI1) ND Sporadic following LGI1-LE

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• Donaldson and Li 2016: 6.9% of MND patients possesses one of the following three antibodies: VGKC, VGCC or gAChR antibodies.

Paraneoplastic Antibodies in Motor Neuron Disease

• No difference in motor neuron disease progression with positive Abs. • In literature, immunosuppression in 1 MND with VGKC-Ab and 2 MND cases with Hu-Ab

failed to alter disease course (Verma eta al 1996; Lee et al 2013; Sato et al 2014).

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• A small portion of patients with (+) VGCC-Ab has LEMS and/or SCLC: Zalewski et al. Muscle nerve 2016; 54: 220: 236 patients with (+) VGCC-Abs.

• Only 10 (4%) had neuromuscular junctional disorder (6 LEMS, 4 MG). Di Lorenzo et al. J Neurol 2018; 265: 2114: 100 patients with (+) VGCC-Abs.

• Only 8 (8%) cases had LEMS (6) or SCLC (2).

• Frequent positive in paraneoplastic cerebellar ataxia/degeneration Zekeridou et al. Thorac Cancer. 2019;10:1001 Zalewski et al. Muscle nerve 2016; 54: 220

• A variety of other CNS and PNS disorders (both immune-mediated and non-immune mediated) in the remaining majority.

VGCC-Ab Disease Spectrum

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• VGKC complex antibodies can be detected in healthy controls.− Low-level VGKC-Ab in 5% of elderly population (Vincent et al, Brain 2004; 127: 701).− 1 of 112 healthy pediatric population (Wright et al. Epilepsia. 2016; 57: 823).

• Antibody to CASPR2 (0.9%) and to LGI1( ≤0.1%)) can be seen in healthy and common neuropsychiatric illness (Dahm et al, Ann Neurol 2014; 76: 82).

• VGCC-Ab was seen in 1.7% of healthy controls (Zalewski et al. Muscle nerve 2016; 54: 220).

• Differences in the normal ranges of VGKC-Ab among labs: Normal ranges from five labs: ≤20 pM ; ≤80 pM; ≤88 pM; ≤100 pM; ≤112 pM Titers comparable between labs. Issue of the control population: Young healthy subjects as reference standard for older patients

with more than one illness?

Presence of Paraneoplastic Antibodies in Healthy Subjects

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Abnormal Paraneoplastic Antibody Result in 2017 CCF

0.01

0.1

1

10

100

0 10 20 30 40 50 60

NM

PARNEO POS RIA: 2017ACHBND ACHRGN LCABN LCABPQ NVGK

• Lower normal cutoff (such as 20 pM) used. If a cutoff of <= 100 pM is adopted, approximately 50% of patients who had blood drawn at Cleveland Clinic who are (+) for a variety of antibodies would br classified as being normal.

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Do titers matter? VGKC Complex Antibody as Example• Classically VGKC complex -Ab associated diseases may have high or low antibody titers, and higher

antibody titer has better specificity (Huda et al J Neurol 2015; 262: 418).

• Paterson et al JNNP 2014; 85: 625: Definite autoimmune condition is seem more likely in the high antibody-titer group.

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• Olberg et al. JNNP 2013; 84: 941. 32 patients with VGKC antibody

• Antigens were identified in most cases with higher antibody titers, mostly LGI1.

• In all disease-specific diagnoses (LE, PNH): VGKC-Ab > 200 pM.

• In nonspecific syndromes: VGKC-Ab ≤ 200 pM

VGKC-Abs recognizing LGI1/CASPR2 tend to exhibit higher concentration on RIA.

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• VGKC-Abs recognizing LGI1/CASPR2 clearly exhibit higher concentration on RIA than VGKC-Ab without identifiable antigen.

• ? cut-off of around 250-280 pM

Van Sonderen et al. Neurology 2016; 86: 1692: When not recognizing LGI1/CASPR2, VGKC-Ab (+) is not a marker for autoimmune inflammation.

Category LGI1(n=19)

CASPR2 (n=6)

Autoimmune VGKC(+) (n=7)

Non-autoimmune VGKC (+) (n=18)

VGKC-Ab RIA titer (pM)

936 (245-1314) 412 (385-653) 148 (105-295) 117 (102-219)

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Jammoul et al Neurol Clin Pract 2016; 6: 409

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• Klein et al. Neurology 2012; 79: 1136: positive VGKC-Ab in patients with neuropathic pain. Median Ab level of 130 pM.

• Vanli-Yavuz et al, JNNP 2016; 87:684: 15 patients with mesial temporal lobe epilepsy. All at low levels.

• Wright et al. Epilepsia. 2016: 57: 823: 17 of 178 pediatric epileptic patients have positive neuronal antibodies, mostly at low levels. 3 VGKC

complex, 4 CASPR2, 3 contactin-2, 7 NMDAR. Follow-up testing in 6 to 12 months:

• Antibodies disappeared in 6 of 7 cases who were initially positive. • Newer antibodies appeared in other 7 cases who were initially negative.

Change in antibody status was not associated with seizure frequency. None received immunotherapy. Most had a good outcome and responded to standard AEDs. Antibody developed transiently secondary to cell damage from seizures?

Low-level VGKC-Ab: doubtful clinical significance

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• McKeon et al Arch Neurol 2009:66:735: 155 patients.

>1000pM, 10 of 12 with pandysautonomia 100-990 pM, 20% with dysautonomia <100pM, non-specific neurological disorders

• Li et al Muscle Nerve 2015; 52: 386:116 patients− 21 (18%) patients with dysautonomia− The remaining 95 cases with a variety of

CNS and PNS disorders Higher antibody levels in the dysautonomia

group

Ganglionic AChR-Ab Titer and Disease Spectrum

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• Striational Antibody (Mckeon et al. Muscle Nerve 2013; 47: 585) Associated with thymoma and a variety of carcinomas. All cases with newly diagnosed

cancer had a titer of ≥1:7680

• VGCC Antibody (Zalewski et al. Muscle nerve 2016; 54: 220) More autoimmune neurological disorders are seen in the higher-level (>1,000pM)

antibody group.

Antibody Titer and Disease Spectrum: other antibodies

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Paraneoplastic syndrome: Common Cancer Association

Cancer Notable associated syndromesSmall cell lung cancer and other lung carcinoma

LEMS, sensory neuronopathy, cerebellar degeneration, retinopathy,dermatomyositis, necrotizing myopathy etc

Breast cancer Limbic encephalitis, cerebellar degeneration, retinopathy, sensory neuronopathy, dermatomyositis etc

Ovary tumor Limbic encephalitis, cerebellar degeneration, dermatomyositis

Thymoma Myasthenia gravis, neuromyotonia, stiff person syndrome

Lymphoma Cerebellar degeneration, limbic encephalitis, mononeuritis multiplex, dermatomyositis

Neuroblastoma Opsoclonus myoclonus

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Antibody Representative cancer types

Anti-Hu Small cell lung cancer, other neuroendocrine tumor

Anti-Ri Neuroblastoma, breast cancer, ovary cancer,

Anti-Yo Breast cancer, ovary cancer

Anti-Tr Hodgkin’s lymphoma

Anti-Ta Testicular tumor

Anti-Amphiphysin Small cell lung cancer, breast cancerAnti-CV2 Thymoma, small cell lung cancer

Anti-Recoverin Small cell lung cancer, breast cancer, ovary cancer

Anti-Zic4 Small cell lung cancer

Anti-SoX1 Small cell lung cancer

Anti-NMDA Ovarian teratoma

Paraneoplastic Antibody: Cancer Association (a partial list)

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Paraneoplastic Antibody: Cancer Association

• A classical syndrome and cancer that develops within five years of diagnosis of the neurologic disorder, mostly within two years:

Very true for paraneoplastic antibodies to intracellular antigens.

• Mixed results for the association between antibodies to cell-surface antigens and cancer. • High-quality prospective cohort or a good cross-sectional studies are needed to declare a true association

between antibody to cell-surface antigens and malignancy. Zalewski et al. Muscle nerve 2016; 54: 220:

• Prevalence of malignancy in VGCC-Ab (+) patients: 21%• Prevalence of malignancy in VGCC-Ab (-) patients: 17%

• The oncologic outcome of patients with antibody-associated paraneoplastic syndromes does not differ significantly from that of patients without such paraneoplastic syndromes.

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Tumor association with Ab to Cell-Surface AntigensSource No. of Ca cases/total

Ab (+) casesNo. of New Ca Cases after Ab detection

Notes

Tan et al 2008 (VGKC) 34/72 (47%) 18 Lung, thymus, prostate, breast, colon, leukemia,lymphoma, benign tumors.

Irani et al 2010 (VGKC)

9/96 (9%) ?; 6 with active cancer

Thymoma (5), prostate, breast, lung, melanoma, uterine. Mostly CASPR2 antibody.

Olberg et al 2013 (VGKC)

7/32 (22%) 2 5 (lymphoma, prostate, leukemia, lung) present > 5 years prior to symptomatic onset.

Huda et al 2015 (VGKC)

7/57 (12%) ? Thymoma (3), petrous apex cholesteatoma, SCLC, astrocytoma, epidermoid cyst..

Jammoul et al 2016 (VGKC)

30/114 (26%) 2; 20 with active cancer

Many cancer types, including many > 10-year history. Higher in older patients (>45 yo).

Zalewski et al 2016 (VGCC)

50/236 (21%) 6 Prostate (9), breast (8), uterine (4), lung (4), bladder (3), lymphoma (3), renal cell (3) etc.

• A variety of cancer/tumor types exist. Some (prostate, uterine, benign cyst) are atypical in causing paraneoplastic syndrome. • Most cancer occurrence is historical (remote or existing) rather than prospective (new). • Ab titers could not differentiate cancer versus non-cancerous condition.

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Cancer Statistics from ACS (Siegel et al): Incidence of new cancer in the remaining life expectancy (skin cancer excluded)

• If assuming a life-span of 80 years for an American of ≥70 yo, 33% male and 25% female would develop new cancer within the next 10 years.

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Paraneoplastic Antibody: Cancer Association

• Vigilance for an underlying tumor may be still needed to varying degrees.

• Cancer screening in selected patients with (+) Ab with other risk factors: − Older patients (>50 years of age)? − Smoking history? − Weight loss? − Absence of autoimmune condition?− Other markers for malignancy?− Ab (+) alone may not be an independent marker for malignancy in these patients.

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• Without intra-thecal production, CSF to serum antibody ratio would be 1 to 400 (Vincent at el. Lancet Neurol 2011; 10: 759).

• Which antibody to follow for treatment response? Probably still serum in most cases. − Limited number of antibodies can be tested in CSF. − Lower Ab concentration in CSF is difficult to monitor.− Lack of good CSF normal range. − Ebright et al Neurology 2018; 91: e2057: 64 patients had serum and CSF paraneoplastic

studies, serum (+) in 10, CSF (+) in none. • Rare situations exist that CSF antibody testing is more productive

More relevant in patients with a presentation of encephalitis (?) Some antibodies more than others: e.g, anti-GAD, anti-NMDA receptor, anti-AMPA, anti-

GFAP.

Paraneoplastic Antibody: serum versus CSF

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• Paraneoplastic antibody detection can be very helpful in confirming a diagnosis in patients presenting with known associated neurological syndromes.

• Significant differences exist between antibodies against cell-surface (common, but possibly non-specific, unclear cancer association) versus intracellular (rare, specific and unique phenotype, high cancer association) antigens.

• Paraneoplastic antibodies (those to cell surface antigens) Can be a marker of neurol or non-neurol autoimmunity in patients without classical syndromes. Higher Ab titers might be more relevant in revealing association with autoimmunity. Low-level antibodies possibly arise as an epiphenomenon following cellular death in degenerative conditions. Age-specific normal ranges are needed for a lot of antibodies. Low level background Ab in elderly?

• If unsure, could always follow up with repeated Ab testing. • Implication of immunotherapy should not be based on Ab status alone.

• A higher proportion of patients with (+) antibodies to cell-surface antigens may have cancer. Most cancers are historical, and antibody positivity rarely leads to prospective cancer detection in the majority.

− Be aware of the high cancer incidence in the elderly. − Need of cancer screening should not be based on (+) antibody result alone.

A Few Tentative Conclusions

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