This document outlines Paraneoplastic Neurological Disorder (PND), including its history, definition, pathophysiology, clinical features, diagnosis criteria, treatment, and recommendations. PND is a neurological dysfunction associated with but not directly caused by cancer. It can affect the central, peripheral, or autonomic nervous systems. Onconeural antibodies are present in 60-70% of cases and help diagnose PND. Common PNDs include limbic encephalitis, cerebellar degeneration, and opsoclonus-myoclonus. Treatment involves treating the underlying cancer, immunotherapy like steroids, IVIg, and plasma exchange, and symptom management. Patients with suspected PND should be regularly

1. Paraneoplastic Neurological Disorder
(Clinical Spectrum & Management)
Dr Ahmad Shahir Mawardi
Neurology Department,
Hospiatl Kuala Lumpur
23rd January 2019

2. Outlines
1.History, Definition, Pathophysiology
2.Clinical features & Common PNSs
3.Diagosis criterias for PNS
4.Treatment
5.Algorithm & Recommendations

3. History...
• The first description in 1890, when the French physician
M. Auche described the cases of peripheral nervous
system disorders in patients with diagnosed cancer.
• The first antibody described was PCA-1 (Purkinje Cell
Antibody 1), by Greenlee and Brashear in 1983, in two
patients with ovarian carcinoma and paraneoplastic
cerebellar degeneration

4. Definition
• Paraneoplastic syndrome (PS) is a dysfunction of
organs or systems, associated with neoplastic disease,
but not related to the local growth of tumor, metastasis or
adverse anti-cancer drugs reactions.
• Neurological paraneoplastic syndromes (NPSs) may
affect every region of a human nervous system - both
central, peripheral, and/or autonomic nervous
system.

5. Introduction
• precede the development of cancer for months or years
• They present an autoimmune background in serum and
CSF reacting with tumor antigens and the brain, the
spinal cord and peripheral ganglia antigens.

6. Introduction
• Studies performed on large groups of patients have
confirmed the presence of PNSs before the cancer
diagnosis among 80% of cases.
• the paraneoplastic markers respond to antineoplastic
therapy and usually disappear after the treatment and
tend to be detectable again in case of the relapsing
proliferative process
Honnorat J, Antoine JC. Paraneoplastic neurological syndromes. Orphanet J Rare Dis 2(1) (2007) 22
Graus F, Dalmau J. Paraneoplastic neurological syndromes. Curr Opin Neurol 25(6) (2012) 795–801

7. PATHOPHYSIOLOGY autoimmune
Servier Medical Art website, http://smart.servier.com.

8. What should you expect in the CSF study?
• In a European study, abnormal CSF was found in 93% of
the cases;
– pleocytosis in 39%,
– elevated protein in 67%
– oligoclonal bands (OCB) in 63%.
• (OCBs were the only abnormality in 10%.)
Psimaras D, Carpentier AF, Rossi C; PNS Euronetwork Cerebrospinal fluid study in paraneoplastic
syndromes. J Neurol Neurosurg Psychiatry 2010;81:42-5.

9. How common it is?
• unknown
• rare
– Overall, it is estimated that 0.5–1% of all patients with cancer
have clinically disabling PNS.
• The prevalence varies from cancer to cancer
– 2–3% of the patients with neuroblastoma SCLC
– 30–50% of the patients with thymoma and sclerotic myeloma.

10. The classification of onconeuronal autoantibodies.

11. Lachance DH, Lennon VA. Paraneoplastic neurological autoimmunity In Neuroimmunology in Clinical Practice.
In: Kalman B, Brannagan TH 3rd, editors. Oxford: Blackwell Publishing; 2008. p. 210-7.

12. Lachance DH, Lennon VA. Paraneoplastic neurological autoimmunity In Neuroimmunology in Clinical
Practice. In: Kalman B, Brannagan TH 3rd, editors. Oxford: Blackwell Publishing; 2008. p. 210-7.

13. The limitations ?
• only 60–70% will have detectable antibodies
• Look for the entire range of antibodies than one or two
specific antibodies.
– single antibody testing can result in missing the potential cases.
– multiple antibodies, which predict the type of cancer better than
the presence of a single antibody.
• CSF antibody testing is encouraged along with serum
testing

14. Clinical features
• multiple clinical manifestations like encephalitis,
autonomic failure, peripheral neuropathy,
cerebellar ataxia, visual complains and many
others.
• There can be multiple antibodies in a patient
• onset :subacute

15. When you should consider
diagnosis of PNS?
• a subacute onset and insidiously
progressive neurologic condition where no
clear alternate diagnosis is possible

16. What are the common paraneoplastic
neurological syndromes?
1. Limbic encephalitis.
2. Subacute cerebellar degeneration.
3. Opsoclonus-myoclonus.
4. Lambert-Eaton myasthenic syndrome.
5. Dermatomyositis.

17. F Graus et al, Recommended diagnostic
criteria for paraneoplastic neurological
syndromes, for the Paraneoplastic
Neurological Syndrome Euronetwork
2004

18. Gozzard P, Maddison P. Republished: Which antibody and which cancer in which paraneoplastic
syndromes? Postgrad Med J 2011;87:60-70.

19. The clinical correlation between PNSs,
cancers and determined antibodies

20. F Graus et al, Recommended diagnostic criteria for paraneoplastic neurological syndromes,
for the Paraneoplastic Neurological Syndrome Euronetwork 2004

22. • A new serum antibody was described that appears to be
very specific for the presence of a SCLC in patients with
LEMS.
• This SOX antibody is present in
– 64% of the patients with LEMS and SCLC,
– 22% of the patients with SCLC and no clinical PNS
• specificity is high (95%), the sensitivity is moderate
(65%)
• the antibody is absent in about 1/3 of LEMS patients with
a SCLC

23. Clinical/lab clue for PNS?
Kannoth S,Paraneoplastic neurologic syndrome: A practical approach, Ann Indian Acad Neurol
2012;15:6-12

24. MRI findings in PNS?
Kannoth S,Paraneoplastic neurologic syndrome: A practical approach, Ann Indian Acad Neurol
2012;15:6-12

25. F Graus et al, Recommended diagnostic criteria for paraneoplastic neurological syndromes, for the
Paraneoplastic Neurological Syndrome Euronetwork 2004

26. Treatment of PNS
•  anti-cancer therapy
•  immunotherapy
– There are no evidence-based recommendations
available regarding the immunosuppressive therapy
– steroids, IVIg, plasma exchange, cyclophosphamide,
azathioprine and rituximab.
•  symptomatic treatment
– Analgesics, antiepileptics, antipsychotic,
dysautonomia medications and physiotherapy

27. Immunotherapy in PNS
• PNS mediated by antibody are more reversible; e.g VGKC
complex antibodies, AChR antibodies and NMDAR a/b.
• In disorders with intracellular target antigens and a strong cellular
immune reaction, damage is more severe and often irreversible.
• The common approach used (Mayo):IV MTP 1 gram OD x 5/7 followed
by weekly therapy of the same dose for 6–12 weeks.
– Other option: MMF or azathioprine.
• Second line: plasma exchange (antibody-mediated disease).
• Other options: cyclophosphamide. Rituximab may be useful in
antibody mediated diseases.
• Patient may need long-term treatment. individualized treatment

28. Immunotherapy in anti-NMDAR encephalitis
Dalmau group has proposed :
• First line: a combined treatment IV MTP with IVIgG or
plasma exchange.
– If there is good response to this, chronic immunosuppression with
azathioprine or mycophenalate is recommended for 1 year.
• Second line: rituximab or cyclophosphamide, or both
combined
• Third line: alternate immunosuppressive like oral or
intravenous methotrexate should be considered.

29. Antibodies, Neurologic Syndromes, Cancer
Associations, Treatment Response (1)

30. Antibodies, Neurologic Syndromes, Cancer
Associations, Treatment Response (3)

31. Antibodies, Neurologic Syndromes, Cancer
Associations, Treatment Response (2)

32. Flow chart showing the level of diagnostic evidence of the
neurological syndrome according to the criteria defined by the panel
F Graus et al, Recommended diagnostic criteria for paraneoplastic neurological syndromes, for the
Paraneoplastic Neurological Syndrome Euronetwork 2004

33. Algorithm for diagnosis and management of
paraneoplastic neurological syndromes

34. Recommendations
• Patients with PNS most often present with neurological symptoms
before an underlying tumour is detected.
• Onconeural antibodies should be sought in sera from patients with
suspected PNS.
• Radiological investigations for tumours, such as high - resolution CT
for the detection of SCLC, are important, but should be followed by
PDG - PET if no tumour is found.
• Patients should be followed at regular intervals, for example every 6
months for up to 4 years.

35. Recommendations
• Immune therapy (steroids, PLEX, or IVIG) usually has no or only
modest effect on PLE, SSN, or PCD.
• Children with POM may respond to immune therapy, whereas no
evidence for the effect of such therapy has been shown in adults.
• Patients with LEMS or PPNH should be treated with immune
therapy if symptomatic therapy does not give sufficient
improvement.
• Symptomatic therapy should be offered to all patients with PNS.

36. References

37. Thank you