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CASPR2

Contactin associated protein 2

Description

Anti-CASPR2 antibodies are of the IgG1 and IgG4 isotypes directed against a component of the VGKC in the central and peripheral nervous systems. They are more often associated with peripheral than central manifestations.

Thymoma is present in 20-50% of cases. Anti-CASPR2 antibodies may coexist with anti-LGI1 antibodies.

Mechanism of action

CASPR2 is expressed throughout the central and peripheral nervous systems.

  • In the CNS: it is expressed in the cerebellum, CA1 and CA3 hippocampal and pyramidal cells, olfactory bulb, and white matter tracts.
  • In the PNS: it is found in the juxtaparanodes of myelinated axons. Anti-CASPR2 antibodies disrupt CASPR2 or internalise the VGKC complex.
  • At other times: the antibody will disrupt CASPR2 interactions with neighbouring proteins. Some patients show reduced CMAP and SNAP amplitudes.

Associated clinical features

  • Seizures in 49% (predominantly complex partial)
  • Epileptiform EEG
  • Limbic encephalitis
  • Cognitive decline
  • Abnormal neuropsychological examination
  • Personality change
  • Hallucinations
  • Depression
  • Insomnia
  • REM sleep behaivour disorder
  • Abnormal polysomnogram
  • Hyponatraemia in 7%
  • Morvan's syndrome
  • Neuropathic pain
  • Sweat abnormalities
  • 8:1 male to female
  • EMG hyperexcitability
  • EMG neuropathy
  • Cramps
  • Sensory and motor symptoms
  • Nerve conduction abnormalities
  • Tilt test positive
  • MRI abnormal
  • PET abnormal
  • CSF may be normal

Associated neoplasia

Thymoma in 20-50% of cases. (1) Risk of malignancy very low in other neurological syndromes associated with this autoantibody.

  1. Particularly in cases of Morvan's syndrome and neuromyotonia.

Laboratory method

Cell based assay

Indirect immunofluoresence on rat brain

In cases of negative above assays and strongly characteristic clinical features then live hippocampal neuronal assays could be considered if accessible (1)

  1. May need to have a list of labs here, or S Irani's lab if none other available

Notes of performance characteristics

Commercial CBA (Euroimmun) using CSF has a sensitivity of 66.7% and specificity of 100% for anti-CASPR2 antibodies.

Grade

Next steps

Warning

Do not order with anti-VGKC antibodies due to low clinical yield of 'double negative anti-VGKC' results.

  1. Graus, Francesc, Alberto Vogrig, Sergio Muñiz-Castrillo, Jean-Christophe G. Antoine, Virginie Desestret, Divyanshu Dubey, Bruno Giometto, et al. “Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes.” Neurology - Neuroimmunology Neuroinflammation 8, no. 4 (July 2021): e1014. https://doi.org/10.1212/NXI.0000000000001014. ↩

  2. Michael, Sophia, Patrick Waters, and Sarosh R Irani. “Stop Testing for Autoantibodies to the VGKC-Complex: Only Request LGI1 and CASPR2.” Practical Neurology 20, no. 5 (October 2020): 377–84. https://doi.org/10.1136/practneurol-2019-002494. ↩

  3. McCracken, Lindsey, Junxian Zhang, Maxwell Greene, Anne Crivaro, Joyce Gonzalez, Malek Kamoun, and Eric Lancaster. “Improving the Antibody-Based Evaluation of Autoimmune Encephalitis.” Neurology - Neuroimmunology Neuroinflammation 4, no. 6 (November 2017): e404. https://doi.org/10.1212/NXI.0000000000000404. ↩

  4. Gadoth, Avi, Sean J. Pittock, Divyanshu Dubey, Andrew McKeon, Jeff W. Britton, John E. Schmeling, Aurelia Smith, et al. “Expanded Phenotypes and Outcomes among 256 LGI1/CASPR2-IgG-Positive Patients: LGI1/CASPR2-IgG + Patients.” Annals of Neurology 82, no. 1 (July 2017): 79–92. https://doi.org/10.1002/ana.24979." ↩

Last update: 2022-04-01
Created: 2021-12-17