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Paraneoplastic Antibodies in Neuromuscular Medicine and Neurology

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Paraneoplastic Antibodies in Neuromuscular Medicine and Neurology 2019 Paraneoplastic Antibodies in Neuromuscular Medicine and Neurology Yuebing Li, M.D., Ph.D., FAAN. Neuromuscular Center, Cleveland Clinic Email: [email protected] 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? 2019 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 B CC 2019 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. 2019 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)? 2019 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. 2019 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? 2019 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) Others 2015 1:15360 970 280 A 4th unknown antibody staining rat cerebellum 2016 1:960 1320 170 - 2019 What are “paraneoplastic” antibodies? A partial list Antibody name Antigen location Notable associated syndromes Anti-Hu (ANNA-1) Intracellular/non-synaptic Encephalomyelitis, cerebellar degeneration, sensory neuronopathy Anti-Ri (ANNA-2) Intracellular/non-synaptic brainstem encephalitis, cerebellar degeneration, opsoclonus-myoclonus Anti-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 2019 What are “paraneoplastic” antibodies? A partial list Antibody name Antigen Notable associated syndromes Anti-VGCC Cell surface/synaptic Lambert-Eaton, cerebellar degeneration, Anti-VGKC (LGI1 and Cell surface/synaptic Encephalitis, faciobrachial seizure, CASPR2) 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 Encephalitis Anti-AMPA receptor Cell surface/synaptic Encephalitis Anti-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 2019 Paraneoplastic syndromes with antibodies to different antigens With Ab to intracellular antigens With Ab to cell surface antigens Rarely detected Antibodies more commonly detected Elderly patients Variable age, but elderly patients more common Often associated with classical Can be associated with classical paraneoplastic neurological syndromes syndromes but can also be seen in variable conditions. Progressive course with unfavorable Usually a non-progressive course, some outcome, difficult to treat treatable High association with cancer Variable (?) association with cancer 2019 Paraneoplastic Antibody Result in 2017 CCF (N=1453) Antibody # POS (%) (intracellular) Antibody # POS (%) Reflex # POS (cell surface) ANNA1 (anti-Hu) 1 (0.1%) GAD65 45 AChR 26 (1.8%) ANNA2 0 NMDA-R 3 gAChR 50 (3.4%) ANNA3 0 AMPA-R 1 VGCC (N) 38 (2.6%) PCA1 (anti-Yo) 2 (0.1%) CRMP-5 1 PCA2 0 VGCC (P/Q) 37 (2.5%) GABAb and GAD65 1 PCATr 0 VGCC 46 (3.2%) NMDAR and other 1 AGNA1 0 Striational 40 (2.8%) GAD65 and ANA 1 Amphiphysin 0 Reflex 56 (3.9%) CRMP5G 0 • 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. 2019 • 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 2019 • Abboud et al. J Neurol 2017; 264: 2284: 401 patients, one year (2014) • 53 patients had a positive panel (clinically relevant in 17 patients). 2019 • 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 2019 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 2019 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. 2019 Classical Paraneoplastic Neurological Syndromes Notable 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 syndrome Motor neuron degeneration? Large-fiber sensorimotor polyneuropathy? Vasculitis neuropathy? Acute polyradiculopathy? 2019 • Ebright et al. Neurology 2018; 91: e2057: Increased yield with common paraneoplastic
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