Paraneoplastic neurological syndromes

Clinical information

Paraneoplastic neurological syndromes (PNS) are diseases of the central and peripheral nervous system that occur in direct association with tumours. However, they are not directly caused by the tumour or by its metastases, nor are they a side-effect of treatment with cytostatic drugs or radiotherapy. Approx. 15% of patients with malignant diseases, especially lung tumours, have PNS.

Depending on the type of tumour, tumour cells express antigens such as amphiphysin, CV2/CRMP5, PNMA2 (Ma2/Ta), Ri, Yo, Hu, ZIC4 or Tr (DNER), which can induce the formation of specific autoantibodies. These autoantibodies bind to the respective antigens found in nerve tissue and can thus cause neurological disorders.

Diagnostics

New diagnostic criteria for PNS have recently been established (Graus et al., 2020). What is new is the subdivision into high-risk phenotypes (encephalomyelitis, limbic encephalitis, rapidly progressive cerebellar syndrome, opsoclonus-myoclonus syndrome, sensory neuronopathy, gastrointestinal pseudoobstruction (enteric neuropathy), Lambert-Eaton myasthenic syndrome) and intermediate-risk phenotypes for PNS (including encephalitis, anti-NMDA receptor encephalitis, brainstem encephalitis, Morvan syndrome, isolated myelopathy, stiff-person syndrome, polyradiculoneuropathy).

The term “onconeural antibodies” has been replaced by “high-risk antibodies” for cancer (tumour in >70% of patients with these antibodies) and “intermediate-risk antibodies” for cancer (tumour in 30%–70% of patients with these antibodies). The guidelines classify three levels of evidence for PNS: “definite”, “probable” and “possible”. Each level can be identified using the PNS-care score, which assesses the clinical phenotype, the antibody type, the presence or absence of cancer and the follow-up time. With the exception of opsoclonus-myoclonus syndrome, the diagnosis of “definite PNS” requires the presence of high- or intermediate-risk antibodies.

Neuronal antibodies have been established as useful biomarkers and their detection is of paramount importance in the diagnosis of PNS. For a reliable diagnosis, the guidelines recommend that autoantibodies in PNS should always be determined using two independent methods.

Gold standard methods include indirect immunofluorescence (IFA or immunohistochemistry) based on brain sections, for example, using specific BIOCHIP Mosaics from EUROIMMUN for neurology. For confirmation, immunoblots (e.g. EUROLINE profiles) for the monospecific detection of autoantibodies, mainly against intracellular antigens, or cell-based assays (CBAs) for the detection of antibodies against cell surface or synaptic proteins are used. Neuronal autoantibodies should be tested in both serum and cerebrospinal fluid.

Techniques

Method
Parameter
Substrate
Species
IIFT
brain: grey and white matter,
Purkinje cell cytoplasm (Yo),
Hu and Ri antigen
CV2, Ma, amphiphysin
cerebellum
monkey
EUROLINE
positive control serum: IgG, human, 100x concentrated
for DL 1111-1 G, DL 1111-2 G, DL 1111-4 G and DL 1111-7 G
IIFT
Neurology Mosaic 1
Yo, Hu, Ri, CV2, Ma, amphiphysin
medullated nerves
non-medullated nerves
3 BIOCHIPs per field:
cerebellum
nerves
intestinal tissue

monkey
monkey
monkey
IIFT
Neurology Mosaic 1 EUROPattern
Yo, Hu, Ri, CV2, Ma, amphiphysin
medullated nerves
non-medullated nerves
3 BIOCHIPs per field:
cerebellum
nerves
intestinal tissue

monkey
monkey
monkey
IIFT
Neurology Mosaic14
cerebellum antigens
non-medullated nerves
2 BIOCHIPs per field:
cerebellum
non-medullated nerves

monkey
monkey
IIFT
Neurology Mosaic 14 EUROPattern
cerebellum antigens
medullated nerves
2 BIOCHIPs per field
cerebellum
intestinal tissue

monkey
monkey
IIFT
Yo, Hu, Ri, CV2, Ma, amphiphysin
medullated nerves
non-medullated nerves
cell nuclei (ANA)
cerebellum
nerves
intestinal tissue
HEp-2 cells
(4 BIOCHIPs per field)
monkey
monkey
monkey
human
IIFT
Neurology Mosaic 17
Yo, Hu, Ri, CV2, Ma, amphiphysin, NMO
cerebrum antigens, NMO
NMO, optic nerve antigens
aquaporin-4
5 BIOCHIPs per field
cerebellum
cerebrum
optic nerve
transfected cells
control transfection

monkey
monkey
monkey
EU 90
EU 90
EUROLINE
Neuronal Antigens Profile 2
(amphiphysin, CV2, PNMA2
(Ma-2/Ta), Ri, Yo, Hu separately)
EUROLINE
IIFT
Neurology Mosaic 2
Yo, Hu, Ri, CV2, Ma, amphiphysin
medullated nerves
2 BIOCHIPs per field:
cerebellum
nerves

monkey
monkey
EUROLINE
Neuronal Antigens Profile PLUS RST
(amphiphysin, CV2, PNMA2
(Ma-2/Ta), Ri, Yo, Hu,
recoverin, SOX1, titin separately)
EUROLINE
EUROLINE
positive control serum: IgG, human, 100x concentrated
for DL 1111-6 G
EUROLINE
Neuronal Antigens Profile
SOX1, titin
EUROLINE
EUROLINE
Paraneoplastic Neurologic Syndromes - 12 Ag
(amphiphysin, CV2, PNMA2 (Ma-2/Ta), Ri, Yo, Hu,
recoverin, SOX1, titin, Zic4, GAD65, Tr (DNER) separately)
EUROLINE
IIFT
Neurology Mosaic 8
Yo, Hu, Ri, CV2, Ma, amphiphysin
medullated nerves
non-medullated nerves
pancreas islets
4 BIOCHIPs per field
cerebellum
nerves
intestinal tissue
pancreas

monkey
monkey
monkey
monkey
IIFT
Neurology Mosaic 8 EUROPattern
Yo, Hu, Ri, CV2, Ma, amphiphysin
medullated nerves
non-medullated nerves
pancreas islets
4 BIOCHIPs per field:
cerebellum
nerves
intestinal tissue
pancreas

monkey
monkey
monkey
monkey
IIFT
antibodies against neuronal nuclei: Hu antigen
(Hu ab control)
Secondary reagents immunoblot (IgA)
Secondary reagents immunoblot (IgG)

Secondary reagents immunoblot (IgM)
Additional Reagents
EUROLINE (IgE)
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