autoimmune paraneoplastic movement disorders

1. AUTOIMMUNE MOVEMENT DISORDERS
DR SWAPNIL SAMADHIYA
SR DM NEUROLOGY
GMC KOTA

2. • Autoimmune syndromes mimic neurodegenerative or metabolic
disorders.
• Rarely occur as isolated movement disorders, accompanying clinical
signs clue to diagnosis.
• Detailed history and careful examination often reveal clinical red
flags, help guide diagnosis
• Timely identification paramount importance, treatable.

3. The clinical approach
• Firstly
1. Recording clinical characteristics
2. Phenomenological categorization
3. Syndromic diagnosis
• Secondly
1. The Movement disorder syndrome categorized into “isolated” or
“combined” with other clinical symptoms
Balint, B., Vincent, A., Meinck, H. M., Irani, S. R., & Bhatia, K. P. (2018). Movement disorders with neuronal
antibodies: Syndromic approach, genetic parallels and pathophysiology.Brain: a journal of neurology,
141(1), 13–36

4. Cerebellar ataxia
• Older age ,multi-system symptoms ,suspect,paraneoplastic
• Subacute onset of rapidly progressive ataxia often combined with
peripheral neuropathy, dementia, hearing loss and dysphagia
• Anti-neuronal antibodies are detectable in up to 60%
• Red flags -cognitive deficits, seizures, neuropathic pain, autonomic
dysfunction and insomnia
Lim, T. T. (2017). Paraneoplastic autoimmune movement disorders. Parkinsonism & Related Disorders, 44, 106–
109

8. Chorea and Dyskinesias
• Second most common acquired cause after vascular lesions.
• Examples -sydenham’s chorea ,chorea in antiphospholipid syndrome
/ systemic lupus erythematosus
• Children -movement disorders and seizures,
• Adults -behavioral changes, psychiatric disorders or cognitive
impairment
• Red flags -Cognitive dysfunction, seizures, prominent psychiatric
disturbance, dysautonomia, optic neuritis,bulbar symptoms,weight
loss and peripheral neuropathy.
• m/c Ab. Collapsin response mediated protein-5 (CRMP-5) related to
SCLC or Thymoma
O'Toole, O., Lennon, V. A., Ahlskog, J. E., et al. (2013). Autoimmune chorea in adults.Neurology, 80(12), 1133–1144

11. Dystonia
• Might be the only clinical finding (isolated dystonia) or can be
combined with other movement disorders (combined dystonia) or
the occurrence of other neurological signs
• Orofacial dyskinesia, chorea,stereotypies,encephalopathy and
psychiatric features, NMDAR-antibody testing is mandatory
• Combination of jaw dystonia and breathing difficulties should prompt
testing for Ri antibodies
Duan, B. C., Weng, W. C., Lin, K. L., et al. (2016). Variations of movement disorders in anti-N-methyl-D-aspartate receptor
encephalitis: A nationwide study in Taiwan.Medicine, 95(37), e4365

14. Myoclonus
• Myoclonus -sudden, brief and involuntary jerks
• Myoclonus is one of the defining clinical characteristics- opsoclonus
myoclonus syndrome (OMS)
• Most cases of OMS, no underlying autoantibodies can be detected
• Myoclonus predominantly affects the limbs but can also present as
axial myoclonus
Oh, S. Y., Kim, J. S., & Dieterich, M. (2019). Update on opsoclonus-myoclonus syndrome in adults.Journal of Neurology,
266(6), 1541–1548

17. Parkinsonism
• Autoimmune rare, m/c atypical parkinsonian syndrome, reflecting
brainstem encephalitis with eye movement abnormalities or other
brainstem signs, and sleep disorders.
• Red flags -hypothalamic pituitary dysfunction, weight gain, prominent
sleep disorders including excessive daytime sleepiness, rapid eye
movement (REM) sleep behaviour disorder (RBD), narcolepsy-
cataplexy, and eye movement abnormalities(vertical gaze palsy)
• IgLON5 antibodies postural instability and gaze palsies, resembling
PSP in up to 23%
Dalmau, J., Graus, F., Villarejo, A., et al. (2004). Clinical analysis of anti-Ma2-associated encephalitis.Brain: a journal of
neurology, 127(Pt 8), 1831–1844

20. Paroxysmal movement disorders
• Paroxysmal dyskinesias and episodic ataxias -onset childhood or early
adulthood ,autosomal dominant inheritance.
• Antibody associated paroxysmal movement disorders -later in life
• Young women, painless paroxysmal dystonic posturing should prompt
consideration of NMDAR-antibody testing whereas painful tonic
spasms warrant testing for NMOSD-associated antibodies (AQP4,
MOG)
Liu, J., Zhang, Q., Lian, Z., et al. (2017). Painful tonic spasm in neuromyelitis optica spectrum disorders: Prevalence,
clinical implications and treatment options.Multiple Sclerosis and Related Disorders, 17,99–102

22. Stiff person spectrum disorders
• Rare diseases (estimated prevalence: 1/1,000,000)
• Stiffness, Spasms and Hyperekplexia
• m/c antibodies against GAD65 in the serum and cerebrospinal fluid
• Associated features and autoimmunity may indicate the underlying
antibody (e.g. GAD antibodies with type 1 diabetes)
Carvajal-Gonzalez, A., Leite, M. I., Waters, P., et al. (2014). Glycine receptor antibodies in PERM and related syndromes:
Characteristics, clinical features and outcomes.Brain: a journal of neurology, 137(Pt 8), 2178–2192

25. Tics
• Role of antibodies controversial.
• Tics -paediatric autoimmune neuropsychiatric disorders associated
with streptococcal infections (PANDAS)
• Antibodies modulating dopamine d1 and d2 receptors have been
hypothesized as being causative
• No antineuronal antibody consistently shown to underlie tic disorders
Morris-Berry, C. M., Pollard, M., Gao, S., Thompson, C., Tourette Syndrome Study G, & Singer, H. S. (2013). Anti-
streptococcal, tubulin, and dopamine receptor 2 antibodies in children with PANDAS and Tourette syndrome:Single-
point and longitudinal assessments.Journal of Neuroimmunology,264(1–2), 106–113

27. Tremor
• Isolated tremor is highly unlikely
• Isolated“whole-body tremulousness” often mistaken as generalized
tremor ,actually suffer from generalized repetitive myoclonus
• Beside the classic antineuronal antibodies ,paranodal Abs, such as
contactin-1 (CNTN1), neurofascin-155 (NF155), nodal neurofascin
(NF140/186) and contactin associated-protein-1 (CASPR1) CIDP
McKeon, A., Pittock, S. J., Glass, G. A.,et al. (2007). Whole-body tremulousness:Isolated generalized polymyoclonus.
Archives of Neurology, 64(9), 1318–1322

30. Sleep behaviour disorders
• Ma2 encephalitis, affects limbic, diencephalic and brainstem
structures, or in LGI1-antibody-associated limbic encephalitis (Iranzo
et al., 2006)
• Both RBD and non-RBD can be seen in IgLON5-antibody linked
neurodegeneration (Sabateret al., 2014)
• Periodic limb movement and ambiguous sleep are observed with
DPPX antibodies (Tobin et al., 2014)

31. • Status Dissociatus (breakdown of the boundaries, which are
wakefulness, REM sleep, and non-REM sleep, with motor
hyperactivity)
• Agrypnia Excitata (insomnia, motor and autonomic hyperactivation)
hallmark Morvan syndrome (with CASPR2 antibodies, less commonly
LGI1 antibodies), NMDAR antibodies or GABA-B R antibodies(can be)
(Frisulloet al., 2007)

33. Whispering and talking (“Good morning, your ring cakes are very nice”, "Which is the
difference?”), changing facial expressions, gesturing and complex movements, and
stridor.

34. Model of B cell activation

35. Directed against predominantly intracellular
synaptic proteins may gain access at the time
of vesicle fusion
(A) Antibody-dependent Cell-mediated Cytotoxicity (ADCC)
(B) Direct Target Modulation Through Agonist/Antagonist
Effects
(C) Complement Activation
(D) Antigen Internalization

36. Diagnosis
• Clinical
• Laboratory investigation
• Imaging
• Antibody testing

37. Lab.Investigations
• Cerebrospinal fluid abnormalities
1. Cells >5 cells/cu mm
2. Protein >0.45 g/dl
3. Elevated IgG index or oligoclonal bands

42. Imaging

46. Antibody testing
• Combination of -
1. Immunoblot
2. Enzyme-linked-immune-tests (e.G. ELISA) and/or radioimmunoassay
(RIA)
3. Cell-based assays (CBA)
4. Tissue-based assays (TBA)
• Complementery tests(research laboratories)
1. Live-cell cbas and non-permeabilized (live) cells
2. Primary hippocampal neurons
Ganesh A, Wesley SF. Practice Current: When do you suspect autoimmune encephalitis and what is the role of
antibody testing?. Neurol Clin Pract. 2018;8(1):67-73. doi:10.1212/CPJ.0000000000000423

47. Testing should follow five rules:
(a) Always use a combination of antigen-specific tests (immunoblots, ELISA/RIA,
CBAs) and tissue-based screening tests (TBA).
(b) Include immunoblots for intracellular antigens,CBAs for extracellular antigens,
and ELISA/RIA for GAD65, VGCC.
(c) Combination testing serum and CSF improves sensitivity and specificity,prevents
false positives and false-negatives (not uncommon if testing serum only).
(d) Start with common antibodies. If negative and clinical suspicion high, second
diagnostic step TBAs and CBAs in research laboratories utilized for less common
and unknown antibodies.
(e) Nevertheless, seronegativity in spite of comprehensive testing is common.

48. • Suspected AE cases, generally prefer to send both serum and CSF for
antibody testing
• Some antibodies are more sensitive when testing serum (e.g., LGI1,
AQP4) whereas more sensitive when testing CSF (e.g., NMDAR , GlyR,
GABA -A)
Ganesh A, Wesley SF. Practice Current: When do you suspect autoimmune encephalitis and what is the role of
antibody testing?. Neurol Clin Pract. 2018;8(1):67-73. doi:10.1212/CPJ.0000000000000423

49. The different test systems for antibody detection

52. MANAGEMENT

53. DRUG THERAPY FOR AUTOIMMUNE MOVEMENT
DISORDERS

57. RESPONSE & PROGNOSIS

58. FOLLOW UP

59. Future Directives
• Presently, treatment empirical or based on expert consensus, lack of
randomized controlled trials and available evidence limited to a few
observational studies (Grauset al., 2016)
• In disorders where neuronal surface antibodies are the main players,
overall response to immunotherapy is usually good, Although varied.

60. • LGI1 antibodies -response to corticosteroids,
• Half patients NMDAR antibodies respond insufficiently, first line
immunotherapy (corticosteroids, plasma exchange, intravenous
immunoglobulins) (Irani et al., 2013; Titulaer et al., 2013)
• Drawback (immunotherapies) -potentially toxic, higher risk of
infections, possibly with fatal outcomes
• Future-antigen-specific immunotherapy

61. Potential future treatment approaches with antigen-specific
immunotherapy

62. • Small blocking molecule, or ‘AQUAPORUMAB’ as a competitive and
protective antibody (Verkman et al., 2013).

63. • Different approach -Target the pathophysiological cascades
downstream from the antibody–antigen interaction.
• NMDAR antibodies disrupt the interaction between NMDAR and
ephrin-B2 receptor, eventually leads to displacement of NMDAR to
extrasynaptic sites before they are internalized.

64. CONCLUSION
• Prominent and common feature in many autoantibody-mediated
neurological diseases (Gable et al., 2012)
• It is imperative not to miss these potentially treatable disorders (Irani
et al.,2013; Titulaeret al., 2013)
• Can also be an alert to an occult neoplasia. (Irani et al.,2013;
Titulaeret al., 2013)
• Adequate treatment (Immunosuppression or Immunomodulation,
Tumour Treatment as appropriate), many patients, good recovery,
lasting deficits may occur (McKeonet al., 2013;Titulaeret al., 2013;
Balintet al., 2014a)

65. REFERENCES
1. Movement disorders with neuronal antibodies: syndromic approach,
genetic parallels and pathophysiology (Bettina Balint,Angela
Vincent,Hans-Michael Meinck,Sarosh R. Irani and Kailash P. Bhatia)
doi:10.1093/brain/awx189, BRAIN 201
2. The Clinical Features, Underlying Immunology, and Treatment of
Autoantibody-Mediated Movement Disorders,Published online 00
Month 2018 in Wiley Online Library (wileyonlinelibrary.com).DOI:
10.1002/mds.27446
3. Principles and approaches to the treatment of immune-mediated
movement disorders, https://doi.org/10.1016/j.ejpn.2017.11.010
4. Autoimmune and paraneoplastic movement disorders: An update
Journal of the Neurological Sciences 385 (2018) 175–184
5. Uptodate.com
6. Parkinson’s disease and movement disorders,j.jankovic,e.tolsa,6th
edition

66. Thank you