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. There is no known direct pathogenic effect of these autoantibodies. Instead, a T-cell-mediated immune response is involved in the neuronal degeneration. This also results in patients responding poorly to B-cell-based immunotherapy.

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The term “onconeural antibodies” has been replaced by “high-risk antibodies” for cancer (tumour in 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.

Methods

EUROLINE (6)

IIFT (12)

Technology	Parameter	Substrate	Species	Ig Class	Format	Order No.
EUROLINE	EUROLINE Anti-SOX1, -Titin (IgG)	EUROLINE		IgG	16 x 01	DL 1111-1601-6 G
IIFT	brain: grey and white matter, Purkinje cell cytoplasm (Yo), Hu and Ri antigen CV2, Ma, amphiphysin	cerebellum	monkey	IgAGM IgAGM	10 x 05 10 x 10 10 x 05 10 x 10	FA 1111-1005 FA 1111-1010 FB 1111-1005 FB 1111-1010
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	IgAGM IgAGM	10 x 05 10 x 10 10 x 05 10 x 10	FA 1111-1005-1 FA 1111-1010-1 FB 1111-1005-1 FB 1111-1010-1
IIFT	Neurology Mosaic14 cerebellum antigens non-medullated nerves	2 BIOCHIPs per field: cerebellum intestinal tissue	monkey monkey	IgAGM IgAGM	10 x 05 10 x 10	FA 1111-1005-14 FA 1111-1010-14
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	IgAGM IgAGM	10 x 05 10 x 10 10 x 05 10 x 10	FA 1111-1005-16 FA 1111-1010-16 FB 1111-1005-16 FB 1111-1010-16
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	IgG IgG IgG	10 x 05 10 x 10 20 x 05 10 x 05 10 x 10 20 x 05	FA 1111-1005-17 FA 1111-1010-17 FA 1111-2005-17 FB 1111-1005-17 FB 1111-1010-17 FB 1111-2005-17
IIFT	Neurology Mosaic 2 Yo, Hu, Ri, CV2, Ma, amphiphysin medullated nerves	2 BIOCHIPs per field: cerebellum nerves	monkey monkey	IgAGM IgAGM	10 x 05 10 x 10	FA 1111-1005-2 FA 1111-1010-2
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	IgAGM IgAGM	10 x 05 10 x 10 10 x 05 10 x 10	FA 1111-1005-8 FA 1111-1010-8 FB 1111-1005-8 FB 1111-1010-8
IIFT	Neurology Mosaic14 cerebellum antigens non-medullated nerves	2 BIOCHIPs per field: cerebellum non-medullated nerves	monkey monkey		10 x 05 10 x 10	FB 1111-1005-14 FB 1111-1010-14
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	IgG IgG	10 x 05 10 x 10	FC 1111-1005-1 FC 1111-1010-1
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	IgG IgG	10 x 05 10 x 10	FC 1111-1005-8 FC 1111-1010-8
IIFT	Neurology Mosaic 14 EUROPattern cerebellum antigens medullated nerves	2 BIOCHIPs per field cerebellum intestinal tissue	monkey monkey	IgG IgG	120 x 10 20 x 10	FC 1111-12010-14 FC 1111-2010-14
EUROLINE	EUROLINE Paraneoplastic Neurologic Syndromes 12 Ag (IgG) (amphiphysin, CV2, PNMA2 (Ma-2/Ta), Ri, Yo, Hu, recoverin, SOX1, titin, Zic4, GAD65, Tr (DNER) separately)	EUROLINE		IgG IgG IgG	16 x 01 50 x 01 64 x 01	DL 1111-1601-7 G DL 1111-5001-7 G DL 1111-6401-7 G
IIFT	antibodies against neuronal nuclei: Hu antigen (Hu ab control)			IgG	05 x 02	CA 1116-0502
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			IgG	05 x 07	CL 1111-0507 G
EUROLINE	positive control serum: IgG, human, 100x concentrated for DL 1111-6 G			IgG	05 x 07	CL 1111-0507-6 G
EUROLINE	EUROLINE Neuronal Antigens Profile 2 (IgG) (amphiphysin, CV2, PNMA2 (Ma-2/Ta), Ri, Yo, Hu separately)	EUROLINE		IgG	16 x 01	DL 1111-1601-2 G
EUROLINE	EUROLINE Neuronal Antigens Profile PLUS RST (IgG) (amphiphysin, CV2, PNMA2 (Ma-2/Ta), Ri, Yo, Hu, recoverin, SOX1, titin separately)	EUROLINE		IgG	16 x 01	DL 1111-1601-4 G
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