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Non-paraneoplastic antibodies

This group of antigens are directly accessible to circulating antibodies (considered pathogenic) due to their extracellular location (i.e. neuronal cell surface) and are responsive to treatment.

These antibodies are detected by the staining seen on the transfected HEK cells.

Some of these include the following:-

Antibody Antigen Neurological Disorder Associated tumour(s) Target antigen
NMDAR Glutamate receptor LE Ovarian teratoma N-terminal extracellular domain of the NR1 subunit of NMDAR
LG1 VGKC protein LE with FBDS Rare LGI1
CASPR2 VGKC protein  Neuromyotonia + / - CASPR2
APAR Receptor  LE + / - Lung, breast or thymus GluR1 and GluR2 subunits of AMPAR
GABABR Receptor LE (mainly seizures) SCLC B1 receptor subunit of GABABR
Glycine Receptor PERM Rare α1 receptor subunit of Glycine receptor

Abbreviations

AMPAR - alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, CASPR2 = contactin-associated protein-like 2, GABA – Gamma amino butyric acid, LGI1 = Leucine-rich glioma-inactivated protein 1 antibody, SOX = Sex determining region Y-box,

FBDS = Faciobrachial-dystonic seizures, LE = limbic encephalomyelitis, PERM = Progressive encephalomyelitis, with rigidity and myoclonus

VGKC = Voltage gated potassium channel,

HEK = Human Embryonic Kidney

Overview of Non-Paraneoplastic Antibodies

Anti-glial nuclear antibody (AGNA) antibodies

AGNA or SOX1 antibody is directed against the Bergmann glia of the Purkinje cell layer of cerebellum. It has been described in patients with PNS (usually Lambert Eaton myasthenic syndrome) associated with SCLC. The target for this antibody is SOX1 & SOX2 protein with higher positivity seen against SOX1.

Clinical case

Patient details

  • 79yr old lady, admitted with right sided chest pain
  • Weight loss over the past few months.
  • Swallowing difficulties

Work-up

  • A chest X-ray on admission revealed a right sided lesion
  • CT thorax/abdomen revealed a large mass in the posterior mediastinum
  • Extensive metastases noted within the chest and abdomen

If SOX1 antibodies are found, they are highly predictive of a small cell lung cancer and extensive tumour screening should be undertaken (including repeat imaging, PET scans etc.), even if the initial scans are apparently normal.

NMO (aquaporin 4) antibodies

Neuromyelitis optica (NMO) associated antigen, a water channel protein, known as aquaporin 4 (AQP4) is found both in the central and peripheral tissues. Detection of AQP4 antibody is clinically useful in differentiating between NMO and other optic neuritis or myelitis.

On cerebellum, AQP4 is found in the juxtaposed pial membrane, microvessels in the white matter, molecular layer and granular layer.

 

Often, AQP4 antibody is also associated with the staining of the cytoplasm of the granular cells: Such reactivity is also found in the CSF.

 

Image showing AQP4 transfected HEK cell system considered as having higher sensitivity and specificity.

 

Clinical: Neuromyelitis optica (NMO, also known as Devic's disease, ~65%) is an immune-mediated demyelinated disorder of the optic nerve and spinal cord. The disorder was previously thought to be a sub-type of multiple sclerosis (MS) but has a completely different pathophysiology. The two can be distinguished from one another by the presence of Aqp-4 antibodies and long segment spinal cord inflammation (referred to as longitudinally extensive transverse myelitis, LETM) which are seen in NMO. NMO is a relapsing and life-long illness and antibodies often remain positive indefinitely.

Treatment is different for each disorder therefore important to distinguish it from MS. NMO is often treated with immunosuppression (steroids, Azathioprine, Mycophenolate etc) and acute treatments often include plasma exchange. Rituximab which is a B-cell monoclonal antibody is used in refractory patients and more recently several new treatment options have been found to be useful in clinical trials These include Eculizumab (complement C5 inhibitor), Satralizumab (Interleukin-6 receptor blocker), Inebilizumab (CD19 B-cell monoclonal antibody) etc.

Glutamate receptor type

N-methyl-D-aspartate Receptor (NMDAR) antibodies

NMDAR antibody is associated with treatable limbic encephalitis and its target is the NMDA receptor which comprises four NR units, with each of the subunit has a molecular size of 100 kDa and together they form an ion channel/receptor. NMDAR antibody binds to the neuropils in the molecular layer of the hippocampus as well as the granular layer of the cerebellum

MDAR antibodies can also be determined using commercially available NR1 transfected cells.

Tumours: Ovarian teratoma (56%, young women).

Syndrome: Limbic encephalitis

AMPAR (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor)

Tumours: SCLC, breast cancer, thymoma

Syndrome: Limbic encephalitis with psychiatric symptoms

Voltage-gated potassium channel associated proteins

VGKC antibodies were described few years ago and it has been established that the pathogenic targets are against the complexing proteins, mainly LGI1 and Caspr2 (see below). Testing for VGKC antibodies are no longer recommended to done in isolation, and the more specific LGI1 or Caspr2 antibodies should be checked, and correlated clinically.

LGI-1 (Leucine-rich glioma inactivated protein 1) antibody

Tumours: Thymoma

Syndrome: Limbic encephalitis with LE with Faciobrachial-dystonic seizures

CASPR2 (Contactin-associated protein 2)

Tumours: Thymoma

Syndrome: Limbic encephalitis, cerebellar ataxia, neuromyotonia, Morvan syndrome

DPPX (Dipeptidyl-Peptidase–Like Protein-6)

Tumours: Thymoma

Syndrome: Limbic encephalitis with psychiatric symptoms

GABARB1 (GABA receptors 1)

Tumours: B cell neoplasms

Syndrome: Gastrointestinal symptoms, weight loss, cognitive deficit CNS hyperexcitability

Diagnosis and treatment of autoimmune encephalitis

There are several antibodies which can give rise to autoimmune encephalitis (see diagram). In our lab this is done as a panel, helping to identify the antigenic target using a single assay. Antibodies are best identified by a combination of techniques (immunohistochemistry and immunofluorescence) to increase sensitivity and specificity. Patients often need immunosuppression, plasma exchange and in refractory patients B-cell depleting therapies like Rituximab (especially in NMDAR encephalitis).

Flowchart summarising encephalitic antibodies and their associated clinical features and syndromes.

Image description - Summary of encephalitic antibodies

Common clinical features

  • Rapid progressive memory deficit
  • Altered mental status, including:
    • Lethargy
    • Decreased level of consciousness
    • Personality changes
    • Psychiatric symptoms

Antibody-associated syndromes

NMDA receptor antibodies

Associated features:

  • Seizures
  • Orofacial dyskinesias
  • Dysautonomia

AMPAR antibodies

Associated features:

  • Seizures
  • Refractory status epilepticus

GABAB receptor antibodies

Associated features:

  • Cerebellar ataxia
  • Opsoclonus-myoclonus
  • Epilepsy

LGI1 antibodies

Associated features:

  • Faciobrachial dystonic seizures

CASPR2 antibodies

Associated features:

  • Morvan’s disease