Paraneoplastic syndrome (PNS) is the term used to refer to the disorders that accompany the benign or the malignant tumors and are not caused by mass effect or invasion / metastasis. These disorders are triggered by an immune system response to neuronal proteins expressed by the tumor(onconeural proteins). These PNS also occur due to substances secreted by the neoplasm itself.

1. Paraneoplastic syndromes
- CNS manifestations
Dr. Aminur Rahman
FCPS(Med), MD(Neuro) ,FINR (Switzerland),
MACP (USA) , Member AAN (USA)
Fellow Interventional Neuroradiology (Thailand)
Assistant Professor
Department of Neurology
Sir Salimullah Medical College

2. Learning objectives
 Definition
 Introduction
 Pathogenesis
 Classification
 Paraneoplastic cerebellar degeneration (PCD)
 Paraneoplastic encephalomyelitis / sensory neuronopathy (PEM/PSN)
 Paraneoplastic opsoclonus myoclonus (POM)
 Lambert-Eaton myasthenic syndrome (LEMS)
 To know the antineural antibodies associated with the syndromes
 Differentiations of different syndromes

3. Definition
 Paraneoplastic syndrome (PNS) is the term used to
refer to the disorders that accompany the benign or
the malignant tumors and are not caused by mass
effect or invasion / metastasis.
 These disorders are triggered by an immune system
response to neuronal proteins expressed by the
tumor(onconeural proteins).
 These PNS also occur due to substances secreted
by the neoplasm itself.

4. Introduction
 PNS may be the first presentation of the underlying
neoplasm (often tumor is unknown). – Neurological
involvement in PNS often produces rapid and severe
deficits in short period of time. – Prompt tumor control
improves neurological outcome.
 Complications of cancer and cancer therapy are not
considered as PNS (e.g. coagulopathy, stroke, metabolic
and nutritional conditions, infections and side effects of
cancer

5. Introduction- Continued
 Heterogeneous group of disorders
 Associated with systemic cancers
 Mechanisms other than…
 Metastases
 Metabolic and nutritional deficits
 Infections
 Coagulopathy
 Side effects of treatment

6. Introduction- Continued
 Occur in < 1% of pts with systemic cancer
 Heralds diagnosis of cancer in up to 60%
 Highly specific antineuronal antibodies
 Most common (presence overlaps)
 Paraneoplastic cerebellar degeneration (PCD)
 Paraneoplastic encephalomyelitis / sensory neuronopathy
(PEM/PSN)
 Paraneoplastic opsoclonus myoclonus (POM)
 Lambert-Eaton myasthenic syndrome (LEMS)

7. Pathogenesis
 Most PNS are mediated by immune responses triggered by
neuronal proteins (onconeural antigens) expressed by
tumors.
 Both humoral (antibodies) and cell mediated immunity
(CD4 & CD8)are activated. Subsequently microglial
activation leads to gliosis and neuronal loss.
 These Immune responses have complex mechanism hence
these PNS are resistant to therapy .

8. Pathogenesis- Continued
 Cell mediated immunity acts against intracellular antigens
and is less responsive to therapy than antibody mediated.
 Antibody mediated acts primarily at the neuronal surface
antigens and neuromuscular junctions.
 Classic PNS occur with cancer association.
 Non classical PNS may or may not occur with cancer
association and they are commonly seen in children.

9. Classification of PNS
 Classic PNS
 Non classical PNS

10. Examples of classic PNS
 Encephalomyelitis
 Limbic encephalitis
 Cerebellar degeneration
 Opsoclnus-myoclonus
 Subacute sensory neuronopathy
 Gastrointestinal paresis / pseudo obstruction
 Dermatomyosistis
 Lambert Eaton Myasthenic Syndrome
 Cancer or melanoma associated retinopathy

11. Examples of non classical PNS
 Brain stem encephalitis
 Stiff person syndrome
 Necrotizing myelopathy
 Motor neuron disease
 Guillian Barre syndrome
 Subacute or chronic mixed neuropathies
 Neuropathy associated with plasma cell dycrasias
 Vasculitis of nerve or muscle
 Pure autonomic neuropathy
 Acute necrotizing myopathy
 Optic neuropathy

12. Paraneoplastic cerebellar degeneration (PCD)
 This is characterized by symptoms such as dizziness,
oscillopsia, blurry or double vision, nausea, and vomiting.
 Most commonly develops in women
 Pathology – extensive degeneration of Purkinje cells in
cerebellum occasionally in cortex.

13. PCD- continued
 After few weeks diseases progresses patient usually
severely disabled
 Gait and limb ataxia
 Severe dysarthria
 Patients usually have downbeating nystagmus and
opsoclonus

14. PCD- continued
 50% have nonspecific CSF analysis
 Lymphocytic pleocytosis
 Elevated protein levels
 MRI reveals cerebellar atrophy.
 These tumors are involved in SCLC(anti VGCC), ca
breast, ca ovary(anti Yo ), Hodgkin's lymphoma(anti Tr ).

15. Paraneoplastic encephalomyelitis /
sensory neuronopathy (PEM/PSN)
 Most commonly associated with lung cancer
 Onset of symptoms precedes diagnosis of cancer
 PEM symptoms (limbic involvement)
 Rapidly progressive dementia
 Seizures
 PSN symptoms
 Progressive paresthesias
 Profound sensory ataxia
 Multimodality sensory loss

16. PEM/PSN (continued)
 Neuroimaging is normal
 CSF findings reveal nonspecific inflammation
 Lymphocytic pleocytosis
 Elevated protein level
 Nerve conduction studies in PSN reveal markedly reduced
or absent sensory nerve potentials

17. PEM/PSN (continued)
 Careful malignancy evaluation indicated
 CT chest/abdomen/pelvis
 Testicular U/S and mammography
 Natural history
 Progresses rapidly over weeks
 Causes severe disability
 Stabilizes

18. Paraneoplastic opsoclonus myoclonus
(POM)
 Opsoclonus is a disorder of eye movement
characterized by involuntary, chaotic
saccades that occur in all directions of gaze;
it is frequently associated with myoclonus and
ataxia. Rarely they present with laryngeal
spasms and autonomic dysfunctions.
 In adults, most commonly associated with…
 Small cell lung cancer
 Breast cancer
 Develops prior to diagnosis of cancer

19. POM - continued
 Pathology – disinhibition of fastigial nucleus in cerebellum.
 Associated antibodies – anti Ri antibodies
 Manifestations
 Rapidly progressive cerebellar ataxia
 Opsoclonus
 Myoclonus
 Treatment
– control of tumour and
– immunotherapy(glucocorticoids , plasma exchange and
IVIG)

20. Lambert-Eaton myasthenic syndrome (LEMS)
Incidence
 Uncommon, true incidence unknown
 Occurs much less frequently than myasthenia gravis
 Middle-aged adults
 50% of LEMS associated with a malignancy (small cell lung
cancer (SCLC)
 3% of SCLC have LEMS
 Other tumors are lymphoproliferative disorders (Hodgkin
lymphoma), "atypical" carcinoid and malignant thymoma
 27% have other autoimmune disorders (DM Type 1 or Thyroid)
 +FHx - Families of pts with non-paraneoplastic LEMS have an
increased frequency of autoimmune diseases, while families of
patients with paraneoplastic LEMS do not.

21. Pathophysiology LEMS
 Antibodies directed against the voltage-gated calcium
channel (VGCC) interfering with the normal pre-
synaptic calcium influx required for Ach release
 Among these, the L-type, N-type, and P/Q-type
VGCC are the most important.
 P/Q-type VGCCs make up more than 95 percent of
the functioning receptors at the neuromuscular
junction (NMJ) and probably represent the main
immunologic target in LEMS
 The expression of functional VGCCs in the surface
membrane of small cell lung cancer (SCLC) cells is
probably responsible for most if not all cases of
paraneoplastic LEMS

22. Clinical features of LEMS
 Usual manifestations
 Proximal upper and lower extremity weakness
 Symptoms of autonomic dysfunction
 Dry eyes and mouth
 Orthostatic hypotension
 Bowel and bladder dysfunction

23. Clinical features of LEMS
 Signs
 Deep Tendon Reflexes (DTRs )are almost always
depressed or absent.
 Postsynaptic /post exercise facilitation
 10sec Maximal isometric contraction may lead to
temporary reappearance of previously depressed or
absent DTRs/temporary improvement of muscle
weakness.

24. LEMS (continued)
 Voltage gated calcium channel (VGCC)
 Helps release acetylcholine at NMJ
 Antagonized by anti-VGCC antibodies
 Produce clinical disease
 Blockade  muscle weakness  facilitation
 Blockade at other sites  autonomic dysfunction
 90% of affected patients are seropositive

25. LEMS (continued)
 Nerve conduction studies
 Low-amplitude motor potentials
 Increased amplitude with…
 Exercise
 Rapid repetitive stimulation
 Most closely associated with SCLC
 50-60% of patients have underlying cancer
 Careful evaluation indicated

26. LEMS- Treatment
 Aggressive search for a primary underlying malignancy
(SCLC) is central
 Guanidine - inhibits voltage-gated K channels and enhances
the release of ACh. Significant toxicity limits use. SE
include bone marrow suppression and renal toxicity.
 Aminopyridines (Dalfampridine) - significant prolongation
of the nerve terminal membrane depolarization enhancing Ca
entry and improving Ach release.
 AChEI (Pyridostigmine) - Reduce the metabolism of ACh.
 Intravenous immune globulin (IVIG) - Useful with MG and
LEMS reducing the mass of voltage-gated Ca channel
antibodies

27. Summary

28. THANK YOU