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Paraneoplastic Neuronal Antibodies

Serum
Test performed by: LabPLUS VIM Serology


This test may be vetted by a pathologist.

The clinical information for the test must be clearly written on the request form. If clinical information is not provided, or does not provide sufficient justification for the test, the test may be declined.

Declined tests :

If a test is declined, the specimen will be held for a reasonable period (usually 3 weeks but dependant on the viability of the sample). Medical practitioners seeking approval for a declined test should email the LabPLUS Immunology Team , giving the patient's name and NHI number and the clinical justification for the test. If unable to email, call the on-call Immunologist via Lablink (09-3078995).

Test vetting policy

Requests for Neuronal antibodies MUST be accompanied by a completed Neuronal antibody request form. Please print a copy from the link below and complete before sending a sample to the laboratory.

Neuronal Antibody Request Form

Specimen Collection
SST3.5 mL SST Serum (Preferred)
Plain4 mL Plain Serum
Sterile Container4 mL Sterile Container CSF

Please note: CSF specimens will be assayed but the preferred appropriate specimen for this panel of antibodies is SERUM.


Turnaround Time: Between 2 weeks and 4 weeks

Current Methodology in use at LabPLUS for Neuronal antibodies

 

Test / Group                     Methodology                                          Manufacturer

 

NMDAR Ab                                    IFA (Transfected cells)                                       Euroimmun (Germany)

 

Limbic encephalitis

panel                                           IFA (Transfected cells)                                          Euroimmun (Germany)

 

Aquaporin-4 Ab                            IFA (Transfected cells)                                        Euroimmun (Germany)

                                 

Onconeuronal                          Line Immunoassay (LIA)                                        NOVA, USA (IFA) and LIA

antibody panel                         and IFA (Monkey cerebellum)                                  Euroimmun (Germany)  

 

AChRAb                                    ELISA                                                                            RSR, UK

 

MuSK Ab                                 RIA                                                                                 RSR, UK                                                                    

 

                                                             

 

 


Assay Method

Current Methodology in use at LabPLUS for Neuronal antibodies

 

Test / Group                     Methodology                                          Manufacturer

 

NMDAR Ab                                    IFA (Transfected cells)                                       Euroimmun (Germany)

 

Limbic encephalitis

panel                                           IFA (Transfected cells)                                          Euroimmun (Germany)

 

Aquaporin-4 Ab                            IFA (Transfected cells)                                        Euroimmun (Germany)

                                 

Onconeuronal                          Line Immunoassay (LIA)                                        NOVA, USA (IFA) and LIA

antibody panel                         and IFA (Monkey cerebellum)                                  Euroimmun (Germany)  

 

AChRAb                                    ELISA                                                                            RSR, UK

 

MuSK Ab                                 RIA                                                                                 RSR, UK                                                                    

 

                                                             

 

 


Assay Method
Diagnostic Use and Interpretation

Clinical Information

Paraneoplastic neurological syndromes (PNS) are rare disorders that are triggered by an abnormal (most likely T-cell mediated) immune response to an underlying (and usually undetected) malignant tumour. The exception found to date is anti-Amphiphysin, where, the evidence from in-vivo animal studies using intrathecal passively transferred Amphiphysin IgG implies the antibody itself is pathogenic [1].   Invariably, patients with PNS present with neurological symptoms before tumour detection. Approximately 1-3% of all cancer patients have PNS [2].

Paraneoplastic cerebellar degeneration (PCD) occurs when antibodies produced against the tumour proteins attack similar antigens present in cells within the cerebellum via an irreversible and rapid inflammatory based process accounting for both the rapid (weeks to months) progression of PNS and usual ineffectiveness of immunomodulatory treatments [3].  

PCD is characterised by cerebellar dysfunction. Usually initial symptoms are loss of co-ordination initially on one side but rapidly progressing to involve both sides equally. There is severe ataxia of arms, legs, neck and trunk with afflicted patients being unable to stand without assistance. Ocular findings are often abnormal and speech can be severely affected. Mild deterioration of mental status has been reported. After several weeks, symptoms stabilize leaving the patient in a severely disabled state [4].

The most effective treatment for PNS patients is successful treatment of the tumour.

Although approximately 1 in 3 PNS patients do not have a well characterised intracellular onconeuronal antibody, detection of antibodies remains the most useful diagnostic tool for PNS as outlined in the Table below.

 

Antibody

Neurological Syndromes

Tumours (prevalence)

 

 

Anti-Hu (ANNA-1)

Encephalomyelitis, Limbic encephalitis, Sub-acute sensory neuropathy, Paraneoplastic cerebellar degeneration, Autonomic neuropathy

 

SCLC, Neuroblastoma, Prostate

 

(84-88%)

 

 

Anti-Ri (ANNA-2)

 

Opsoclonus Myoclonus Syndrome (OMS), Brainstem Encephalitis, paraneoplastic cerebellar degeneration

 

 

SCLC, Breast

 

(86-100%)

 

 

Anti-Yo (PCA-1)

 

Paraneoplastic cerebellar degeneration

 

Ovary, Breast

 

(79-95%)

 

 

 

Anti-CV2 (CRMP5)

Sub-acute sensory neuropathy, Autonomic neuropathy, Paraneoplastic cerebellar degeneration, Encephalomyelitis, Limbic encephalitis, Optic neuritis, Chorea

 

 

SCLC, Thymoma

 

(86-91%)

 

 

Anti-Ma2 (Ta)

Encephalomyelitis, Limbic encephalitis, Paraneoplastic cerebellar degeneration, Brainstem encephalitis

 

Testicle, Lung

 

(63-89%)

 

Anti-Amphiphysin

Stiff-Person syndrome, Encephalomyelitis, Sub-acute sensory neuropathy, Sensory motor neuropathy

 

SCLC, Breast

 

(79-100%)

 

Anti-DNER (Tr)

 

Paraneoplastic cerebellar degeneration

 

Hodgkin?s Lymphoma

 

(89%)

 

 

Anti-GAD

 

 

Stiff-person syndrome, Paraneoplastic cerebellar degeneration, Limbic encephalitis

 

Lung, Neuroendocrine tumours

 

(1-9%)

 

 

Yo antibodies recognise two (34 and 62kDa) proteins expressed in the cytoplasm of cerebellar Purkinje cells. Patients with Yo antibodies are typically females where the underlying tumour is usually breast or ovarian. Mortality caused by the neurological degeneration is approximately 30% of afflicted patients. Survival is poorer in patients with ovarian (median survival: 22 months) as compared to breast cancer (median survival: 100 months) [6].

Hu antibodies recognise a family of 35-40kDa proteins found in both the cytoplasm and nucleus of all neurons. Additionally, Hu antibodies bind to cells of the stomach myenteric plexus. The most prevalent tumour association is SCLC and the associated neurological syndromes are the cause of death in almost two-thirds of patients [7].

CV2 / CRMP5 antibodies recognise a 66kDa developmentally regulated brain protein expressed, in the adult brain by a subset of oligodendrocytes. Over two-thirds of patients are male with a median age of 62 years. The most frequently associated cancer is SCLC and the most commonly expressed neurological disorders are polyneuropathy and cerebellar ataxia (both seen in approximately 60% of cases) [8].

The cerebellar reactivity pattern for Ri antibodies is identical to that seen with Hu antibodies in that the nuclei of all neurons are stained, however, unlike Hu antibodies the proteins recognised by Ri antibodies are 50 and 80kDa. Additionally, and importantly for laboratory diagnosis Ri antibodies do not react with cells of the stomach myenteric plexus. OMS and SCLC are the most prevalent neurological syndromes and tumours respectively [9].

In the cerebellum, anti-DNER / Tr antibodies attach to the cytoplasm and proximal dendrites of Purkinje cells. The presentation differs from Yo antibody staining by virtue of diffuse staining of the molecular layer and presence of multiple small dots suggestive of immunoreactivity with the dendritic spines of Purkinje cells. Hodgkin?s lymphoma and PCD are the cancer and neurological syndrome associated with Tr antibodies [10].

Amphiphysin antibodies recognise a 128 kDa antigen expressed in cerebellum axonal synapses. As previously mentioned, in vivo transmission studies with rodents implies the antibodies are pathogenic. The antibodies were first identified with stiff person syndrome and breast cancer but latterly have been associated with encephalomyelitis and sensory neuropathy when the underlying tumour is SCLC [11].  

Ma2 antibodies recognise a 40kDa protein in cerebellar sub-nuclear structures giving discrete dot staining in molecular layers. The ?dot? presentation in the nucleus of Purkinje cells mimics that of ANA nucleolar staining therefore ANA testing must be performed as a quality check if Ma2 antibody is suspected. The main clinical neurological associations are limbic and / or brainstem encephalopathies. The clinical picture is often complex with short-term memory loss, seizures, confusion, excessive daytime sleepiness, hypothalamic-hormonal deficits and vertical gaze paralysis that can progress to total opthalmoplegia. The tumour most associated with Ma2 antibodies is non-seminomatous testicular cancer [12].

References

1. Geis C, Weishaupt A, Hallermann S et al. Stiff-person syndrome associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition

Brain 2010; 133(31): 166-180

2. Graus F, Delatry JY, Antoine JC et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes

J Neurol Neurosurg Psychiatry 2004; 75:1135-1140

3. Vernino S, O?Neill BP, Marks RS et al. Immunomodulatory treatment trial for paraneoplastic neurological disorders

Neuro-oncol 2004; 6:55-62

4. Bolla L, Palmer RM. Paraneoplastic cerebellar degeneration. Case report and literature review

Arch Intern Med 1997; 157(11): 1258-1262

5. de Jongste AHC, van Rosmalen J, Gratama JW, Sillevis-Snitt PAE. Current and future approaches for treatment of paraneoplastic neurological syndromes with well-characterised onconeural antibodies

Expert Opinion on Orphan Drugs 2014; 2(5): 483-496

6. Peterson K, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration: a clinical analysis of 55 anti-Yo antibody positive patients

Neurology 1992; 42: 1931-1937

7. Graus F, Keime-Guibert F, Rene R et al. Anti-Hu associated paraneoplastic encephalomyelitis: analysis of 200 patients

Brain 2001; 124: 1138-1148

8. Rogemond V, Honnorat J. Anti-CV2 autoantibodies and paraneoplastic neurological syndromes

Clin Rev All Immunol 2000; 19: 48-57

9. Luque FA, Furneaux HM, Ferziger R et al. Anti-Ri: An autoantibody associated with opsoclonus and breast cancer

Ann Neurol 1991; 29: 241-251

10. Bernal F, Shams?ili S, Rojas I et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin?s disease

Neurology 2003; 60: 230-234

11. Antoine JC, Absi L, Honnorat J et al. Anti-amphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumours

Arch Neurol 1999; 56: 172-177

12. Dalmau J, Graus F, Villarejo A et al. Clinical analysis of anti-Ma2-associated encephalitis

Brain 2004; 127: 1831-1844


Contact Information

For further information contact the laboratory, (09) 307 4949 ext 22103 or:
Associate Professor Rohan Ameratunga , Immunopathologist: Locator 93-5724,  

Dr Richard Steele , or  The LabPLUS Immunology Team



Last updated at 15:37:54 02/09/2021