Alzheimer disease, frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD) are among the most recognized forms of dementia. Each of these neurodegenerative forms has distinct features. However, they also have overlapping characteristics, many of which are similar to those of non-neurodegenerative dementia, such as those with an etiology based in autoimmunity.1
Even after evaluating the potential effects of medication, infections, neoplasms, and metabolic or endocrine irregularities, quite often, autoimmune dementia is not considered when evaluating cognitive decline in patients, especially in the absence of delirium. Such assumptions may be devastating, especially since improvement and reversal of symptoms may be achieved through immunotherapy.
Limbic encephalitis and rapidly progressive dementia are terms often used to assign diagnoses; however, the spectrum continues to evolve.2 Included among rapidly progressive dementias is CJD, a relatively untreatable neurodegenerative disease. However, it shares many phenotypic characteristics with a voltage-gated potassium channel (VGKC) form of autoimmune dementia such as myoclonus, extrapyramidal dysfunction, visual hallucinations, and psychiatric disturbance. In one small study that included patients with World Health Organization criteria for CJD (60%), many obtained improvement after immunomodulatory therapy, indicating that serologic analysis of VGKC, as well as other neurologic markers, should be considered before finalizing a diagnosis and possible treatments.3 Similar findings of VGKC autoimmunity have occurred in patients originally thought to have frontotemporal as well as other types of dementia.4,5 Additionally, knowledge of autoantibody target specificity within the VGKC complex; for example, LGI1 and/or CASPR2 may inform immunotherapy.6
Paraneoplastic autoimmunity involving cognitive decline is often caused by the presence of an occult tumor which initiates an immune response whose antibodies cross react with neuronal proteins. Common autoimmune target proteins (and their respective autoantibodies) include ELAVL4 (anti-Hu), CRMP5 (anti-CV2), PNMA2 (anti-MA2), NOVA1 (anti-Ri) and NMDAR proteins.7
Anti-Hu antibodies are associated with limbic encephalitis and are often found in patients with small cell lung cancer. Encephalomyelitis with cognitive and behavioral deficits is sometimes associated with anti-CV2 antibodies with thymoma or small cell lung cancer as the underlying tumor. Testicular, breast, or non-small cell lung cancer may initiate anti-MA2 antibodies which are associated with limbic encephalitis and sleep disorders including narcolepsy. Lung and breast tumors are also associated with autoantibodies against NMDAR; mostly in women, with confusion, memory loss, and behavioral changes. Of the paraneoplastic autoantibodies mentioned, perhaps the least associated with limbic encephalitis is anti-Ri.7 Other non-paraneoplastic disorders include Hashimoto encephalopathy, anti-glutamic acid decarboxylase antibody syndrome (anti-GAD), gluten-sensitivity dementia, Sjögren encephalopathy, and systemic lupus erythematosus.7
Treatment options include immunosuppression and/or treatment of the underlying tumor in the case of paraneoplastics. Excluding the possibility of infections as a root cause of cognitive decline is an important consideration before commencing with immunomodulatory therapy, especially those involving the use of corticosteroids.7,8 Removal and treatment of tumors associated with anti-Hu, anti-CV2, anti-MA2, and NMDAR associated limbic encephalitis often result in significant improvement. Treatments involving direct immunosuppression such as antibody removal are more appropriate for conditions caused by VGKC or anti-GAD autoimmunity (7). Knowing the specific target of the antibodies may help better define the syndrome or identify the underlying cause and increase the likelihood of a positive response to treatment (9).
Medical Director Comments
The identification of potentially treatable forms of dementia due to autoimmune etiologies can dramatically affect the patient’s prognosis. It is important to consider these neuroimmunolgical disorders in the differential diagnosis of any patient with unexplained dementia.
1. Bucelli, R.C., Ances, B.M., Diagnosis and Evaluation of a Patient with Rapidly Progressive Dementia. Mo Med, 2013; 110(5); 422-428
2. Flanagan, E.P., et al. Autoimmune Dementia: Clinical course and predictors of Immunotherapy Response. Mayo Clin Proc, 2010; 85(10): 881-897
3. Geschwind, M.D., et al. Voltage-Gated Potassium Channel Autoimmunity Mimicking Creutzfeldt – Jakob disease. Arch Neurol, 2008; 65(10): 1341-1346
4. McKeon, A., et al. Potassium Channel Antibody-Associated Encephalopathy Presenting with a Frontotemporal Dementia-like Syndrome. Arch Neurol, 2007; 64(10): 1528-1530
5. Molloy, A., et al. VGKC Positive Autoimmune Encephalopathy Mimicking Dementia. BMJ Case Reports, 2011; doi: 10.1136/bcr.08.2011.4642
6. Grau-Rivera, O., et al. Determination of Neuronal Antibodies in suspected and Definite Creutzfeldt – Jakob disease. JAMA Neural, 2014; 71(1): 74-78
7. Rosenbloom, M.H., et al. Immunologically Mediated Dementias. Curr Neurol Neurosci Rep, 2009 September; 9(5): 359-367.
8. Geschwind, M.D., et al. Rapidly Progressive Dementia. Neurol Clin, 2007 Aug; 25(3): 783-807.
9. Greenlee, J.E., et al. Treatment of Paraneoplastic Neurologic Disorders. Curr Treat Options Neurol, 2010 May; 12(3): 212-230.