Specimen Collection

Please note: Ideally, paired serum and CSF should be sent for testing, however, we will accept either serum or CSF specimens sent independently. CSF specimens in early stages of the disease will increase assay sensitivity.

1 mL Sterile Container CSF (Preferred)

4 mL Plain Serum

3.5 mL SST Serum
Turnaround Time: Within 2 days

Tested daily Monday to Friday.

Specimen must be in the department available for analysis by 1030 hours, otherwise testing will be deferred to the next working day

Assay Method

Limbic encephalitis panel IFA (Transfected cells) Euroimmun (Germany)

Diagnostic Use and Interpretation

Anti-NMDAR (N-methyl-D-aspartate-receptor) encephalitis has a characteristic clinical syndrome in most patients. Symptoms of psychosis and memory impairment are commonly the initial findings with abnormal movements, seizures, and depressed level of consciousness emerging later.
Patients may experience the psychotic symptoms again as they wake form coma, a phenomenon analogous to the psychotic symptoms seen after recovery from phencyclidine anaesthesia (Phencyclidine, also known as PCP or "angel dust", is an NMDAR antagonist developed as an anesthetic but is not used due to the high risk of psychosis).
Ovarian teratoma affects many female patients of reproductive age, but other tumours (and tumours outside women of reproductive age) are rare.
The response to immune therapy is generally good, particularly if the more effective treatments are used promptly. However, treatment may take many months to reach its full effects, and some patients have persistent deficits, especially in the domains of memory and cognition. The mechanisms of NMDAR antibodies have been extensively studied: these antibodies cross-link and internalize the target receptors, depleting NMDARs from synapses. The antibodies are clearly directly pathogenic; passive transfer into the brains of rodents produced neurological symptoms that correlate with reduction in surface NMDARs on neurons.

Anti-LGI1 (leucine rich glioma inactivated protein type 1) encephalitis accounts for most cases of encephalitis previously attributed to VGKC antibodies. Myoclonus, hyponatremia, and fascio-brachial dystonic seizures are common. In some cases, fascio-brachial dystonic seizures precede other symptoms of the disease by months. These seizures have characteristic appearance and respond well to immune therapy.
Respiratory failure and critical illness are less common with LGI1 than NMDAR antibodies, but the course may be slower. The median age is about 60 years, significantly older than anti-NMDAR encephalitis. LGI1 is a secreted synaptic protein that organizes AMPA receptors and VGKCs at CNS synapses. LGI1 antibodies have been shown to affect AMPA receptor localization on cultured neurons, but additional mechanisms involving the localization of potassium channels are also possible. Cancers are relatively rare in this disorder, and some of these may be chance events in this older age group.

Anti-CASPR2 (contactin associated protein type 2) is associated with encephalitis, Morvan syndrome and acquired neuromyotonia (Isaacs syndrome). The most common phenotype is Morvan syndrome, but peripheral nerve symptoms may precede or follow encephalitis by months or years. Encephalitis tends to be slower in onset than anti-NMDAR encephalitis and responds to immune therapy but is prone to relapse with taper of immune therapy. Some patients may have thymoma and this subgroup is particularly prone to comorbid myasthenia gravis and other auto immunities found in thymoma patients. The median age is about 60 years, significantly older than anti-NMDAR encephalitis. CASPR2 is a cell adhesion molecule that organizes Voltage Gated Potassium Channels s at the juxtaparanodes of myelinated axons in the central and peripheral nervous system. It is unknown why some patients have CNS versus peripheral nerve symptoms since the antigen is the same on both types of axons.

Anti-AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor encephalitis may have psychiatric symptoms on presentation like anti-NMDAR encephalitis. AMPA receptors are a widely expressed type of glutamate ionotropic receptors used for much of the rapid excitatory transmission in the brain. There is significant risk of tumours of the lung, breast, and thymus in these patients. Most patients are female, and they are mostly middle-aged and older.

Anti-GABA- _B (gamma aminobutyric-acid type B) receptor encephalitis is characterised by encephalitis with severe seizures or status epilepticus. This is logical due to the inhibitory role of the GABA-B receptor system in the brain (GABA- _B receptors are important for limiting excessive neuronal activity). About half of patients have small cell lung cancer and the patients are mostly older adults. Antibodies to the GABA- _B receptor may be the most common type of immune cause found in patients with lung cancer. Anti-GABA- _A receptor encephalitis has been reported in children and adults. At high titre these antibodies, which target the primary inhibitory ionotropic receptor in the brain, associate with severe encephalitis with status epilepticus or epilepsia partialis continua. So far only 1 of 6 patients had a tumour, Hodgkin lymphoma, but the full cancer associations will become clearer as more cases are found. There is currently no commercially available assay for GABA-A antibody detection.

DPPX (dipeptidyl aminopeptidase-like protein 6) interacts with the with the voltage gated potassium channel Kv4. DPPX is an important regulator of membrane excitability in in hippocampal CA1 pyramid cells. The main symptoms of anti-DPPX encephalitis are restlessness, forgetfulness, confusion, hallucinations, muscle spasms and tremor.

IgLON5 (immunoglobulin-like cell adhesion molecule family member 5) is a cell adhesion molecule belonging to the IgLON family. Members of the family are characterised by an N-terminal signal peptide, three immunoglobulin-like domains and a glycosylphosphatidylinositol [GPI] anchor. While the specific function(s) of IgLON5 remain unclear, the IgLON's participate in neural development, neural circuit formation, tumour inhibition, depression and obesity. Anti-IgLON5 encephalitis differs from the other autoimmune encephalitis diseases in that the progression is slower and abnormal proteins are deposited in affected brain regions like those seen in certain dementia cases. The principal clinical feature (83% of patients) is a distinctive sleep disorder including both REM and non-REM parasomnia with obstructive sleep apnoea (OSA). Other symptoms include:

• Movement disorders 60%
• Neuropsychiatric (cognitive impairment, hallucinations) 50%
• Dysautonomia 41%
• Dysarthria 38%
• PNS (Fasciculations, cramps, neuropathy) 32%
• Brain MRI and EEG are typically normal; however, brain FDG-PET CT is abnormal in 50% cases.
• Antibodies are present in both serum and CSF and presence of a tumour is rare.

References:

1. Gultekin SH, Rosenfeld MR, Voltz R et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000; 123 [7]:1481-94
2. Lai M, Huijbers MG, Lancaster E et al. Investigation of LGI 1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010; 9:776-85
3. Fukata Y, Lovero KL, Iwanaga T et al. Disruption of LGI 1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci USA 2010; 107:3799-3804
4. Andrade DM, Tai P, Dalmau J, Wennberg R. Tonic seizures: A diagnostic clue of anti-LGI 1 encephalitis? Neurology 2011; 76:1355-57
5. Rosenfeld MR, Dalmau J. Anti-NMDA-receptor encephalitis and other synaptic autoimmune disorders. Curr Treat Options Neurol 2011; 13(3):324-32
6. Irani SR, Alexander S, Waters P et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich glioma inactivated 1 protein and contractin-associated protein-2 in limbic encephalitis, Morvan?s syndrome and acquired neuromyotonia. Brain 2010; 133:2734-2748
7. Wong SH, Saunders MD, Larner AJ et al. An effective immunotherapy regimen for VGKC antibody-positive limbic encephalitis. J Neurol Neurosurg Psychiatry 2010; 81:1167-69
8. Lai M, Hughes EG, Peng X et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009; 65:424-434
9. Bettler B, Kaupmann K, Mosbacher J et al. Molecular structure and physiological functions of GABA _B receptor. Physiol Rev 2004; 84:835-67
10. Lancaster E, Lai M, Peng X et al. Antibodies to the GABA _B receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010; 9:67-76
11. Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011; 77:179-189
12. Kim T-J, Lee S-T, Shin J-W et al. Clinical manifestations and outcomes of the treatment of patients with GABA _B encephalitis. J Neuroimmunology 2014; 270:45-50
13. Rodenes-Cuadrado P, Ho J, Vernes SC. Shining a light on the CNTNAP2: complex functions to complex disorders. European journal of Human Genetics 2014; 22:171-78
14. Poliak S, Salomon D, Elhanany H et al. Juxtaparanodal clustering of shaker-like K ⁺ channels in myelinated axons depends on Caspr2 and TAG-1. The Journal of Cell Biology 2006; 162(6):1149-1160
15. Dalmau J, Rosenfeld MR. Paraneoplastic and autoimmune encephalitis. 2014. http://www.uptodate.com/contents/paraneoplastic-and-autoimmune-encephalitis
16. Irani SR, Pettingill P, Kleopa KA et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012; 72:241-255
17. Lancaster E, Huijbers MG, Bar V et al. Investigations of Caspr2, an autoantigen of encephalitis and neuromyotonia. Ann Neurol 2011; 69:303-11
18. Klein CJ, Lennon VA, Aston PA et al. Insights from LGI 1 and CASPR 2 potassium channel complex autoantibody subtyping. JAMA Neurol 2013; 70(2):229-234

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

Specimen Transport Instructions for Referring Laboratories

Send separated serum under standard cool pack refrigeration conditions

CSF can be transported under ambient temperature conditions

Last updated at 15:26:10 25/06/2025