Many disorders of the central nervous system (CNS) previously considered neurodegenerative and untreatable are now recognized as having an autoimmune cause.1,2 Autoimmune disorders of the CNS may be paraneoplastic (occurring in the setting of an occult systemic cancer) or idiopathic. Improved recognition of these disorders has been facilitated by an expanding profile of neural-specific autoantibodies discovered and validated for clinical use in academic neuroimmunology laboratories. When detected in serum or cerebrospinal fluid (CSF), these immunoglobulin G (IgG) biomarkers reliably predict an autoimmune cause for neurological dysfunction in patients presenting with rapidly progressive brain disorders. New testing profiles relevant to the evaluation of 3 neurological disease states (autoimmune encephalopathy, dementia, and epilepsy) are now available from the Neuroimmunology Laboratory at Mayo Clinic, Rochester, Minnesota. Testing profiles, available for both serum and CSF, include neural antibodies that have been clinically validated as biomarkers of these 3 disorders. (Table 1) Negative results for these antibodies do not exclude an autoimmune basis for encephalopathy, dementia, or epilepsy, so in seronegative cases, a diagnostic trial of immunotherapy should be considered.
Precise frequency data for autoimmune encephalopathies, dementias, and epilepsies are not available. These disorders are clearly underrecognized. A recent review of over 1000 brain autopsy cases referred as Creutzfeldt-Jakob disease to the United States National Prion Disease Pathology Surveillance Center demonstrated a treatable cause for dementia in 7% of cases.3 Most common among these treatable dementia cases were autoimmune disorders. Among Mayo Clinic patients diagnosed with and treated for autoimmune encephalopathy or dementia, 35% were initially misdiagnosed with a neurodegenerative disorder.1
Symptoms and Other Clues from the Clinical History
Symptoms are almost always of subacute onset (evolving over days to weeks). Encephalopathies, typically characterized by confusion, seizures, memory loss, and behavioral change, traditionally have been well recognized by neurologists as having an autoimmune cause. In contrast, patients with recent-onset idiopathic epilepsy or rapidly progressive dementia without delirium have usually been classified as having an underlying genetic or neurodegenerative cause. Clinical features suspicious for an autoimmune cause of encephalopathy, dementia, or epilepsy are outlined in Table 2.
Limbic encephalitis is the classically recognized autoimmune encephalopathy syndrome. It is characterized by a confusional state with loss of orientation (delirium), and usually occurs with 1 or more signs of cognitive decline (generally memory problems), seizures, altered mood and personality, and sleep disorders. Magnetic resonance imaging (MRI) of the head often reveals T2 signal abnormality in one or both hippocampal regions. Electroencephalogram (EEG) may reveal unilateral or bilateral temporal slowing or epileptiform discharges. The main excludable differential diagnosis is viral encephalitis caused by herpes simplex virus. Encephalitis may also have an extratemporal localization, affecting 1 or more of the frontal, parietal, and occipital regions.4
Autoimmune dementia phenotypes may resemble Creutzfeldt-Jakob disease, which classically is a rapidly progressive neurodegenerative disorder accompanied by ataxia and myoclonus. Rapidly progressive forms of Alzheimer disease and diffuse Lewy body disease also are difficult to distinguish clinically from an autoimmune dementia. Tremulousness and headache at presentation, marked fluctuations in the clinical course, and spontaneous remission suggest an autoimmune cause.1
Patients with autoimmune epilepsy may present with seizures alone or with a seizure-predominant disorder.2 All patients reported to date have had seizures of focal or multifocal brain origin rather than generalized seizures. The seizures are usually resistant to 2 or more standard antiepileptic medications. A mesial temporal (limbic) onset focus is most common, but extratemporal and multifocal seizure localizations have been described. Additional less prominent manifestations may include memory and cognitive difficulties, personality changes, and depression or anxiety.
In addition to the time course, clues to an autoimmune diagnosis include a personal history of cancer or autoimmunity (eg, autoimmune thyroid disease, insulin-dependent diabetes, systemic lupus erythematosus, rheumatoid arthritis, or vitiligo). Smoking history, review of systemic symptoms, and a family history of autoimmunity or cancer might also be informative.
Impairments in 1 or more categories of attention, memory, reasoning, calculation, and executive function can be documented using brief bedside evaluations such as the mini mental state examination (MMSE), or the Kokmen short test of mental status. A seizure may be witnessed by the examiner. Autoimmune neurological disorders are often multifocal, thus it is important to note any subtle neurologic symptoms and signs accompanying cognitive impairment or seizures. These signs may include ataxia, brainstem abnormalities, parkinsonism, myoclonus, tremor, myelopathy, or a peripheral nervous system disorder.
Testing for Markers of an Autoimmune Diagnosis in Serum and Cerebral Spinal Fluid
Neural-Specific Autoantibody Profiles
Detection of 1 or more neural autoantibodies in serum or CSF is consistent with a diagnosis of an autoimmune encephalopathy, epilepsy, or dementia, and helps direct a search for cancer. Screening tests for these autoantibodies include immunofluorescence (Figure 1, tissue-based or cell-based) and immunoprecipitation assays. In some instances, reflex testing may be indicated to confirm antigen specificity (by Western blot) or to quantitate an endpoint value or titer. The testing algorithms for the 3 disease states are similar. Serum and CSF algorithms for autoimmune encephalopathy are demonstrated in Figures 2A, 2B, 3A, 3B, 4A, and 4B. Oncological accompaniments of the individual autoantibodies are detailed in Table 3. Some autoantibodies are more readily detected in serum (eg, voltage-gated potassium channel [VGKC]-complex IgG) and others in CSF (N-methyl D-aspartate [NMDA] receptor antibody). Therefore, the diagnostic yield is maximized by testing both serum and CSF, simultaneously or sequentially.5
Diagnostic Clues from Conventional Serum and CSF Testing
Seropositivity for nonneural antibodies warrants detailed investigation for an autoimmune pathogenesis for encephalopathy, dementia, or epilepsy. Informative non-neural autoantibody specificities may be organ specific (such as thyroid autoantibodies) or nonorgan specific (such as antinuclear, anti-smooth muscle, or antimitochondrial antibodies). However, these markers per se lack specificity for neurological autoimmunity. In addition, the detection in CSF of elevated protein, white blood cell count, CSF-exclusive oligoclonal bands, IgG index or IgG synthesis rate also supports an autoimmune etiology. However, these parameters also lack specificity for an autoimmune cause, and may be detected in other inflammatory CNS disorders for which there are no specific biomarkers (eg, multiple sclerosis, sarcoidosis).
In many instances, an autoimmune encephalopathy, dementia, or epilepsy may be a byproduct of an immune response directed against a systemic cancer. A paraneoplastic autoantibody profile reliably predicts the cancer type. In contrast, serological and oncological associations are not readily predicted by the neurological phenotype.6 Thus, algorithmic testing for autoantibody profiles is a more sensitive diagnostic strategy than nominal physician-selected single antibody testing. For example, seropositivity for amphiphysin IgG predicts either small-cell lung carcinoma or breast adenocarcinoma, but the presence or absence of coexisting antibodies narrows that differential diagnosis. Among 63 Mayo Clinic patients with amphiphysin antibody and a known history of cancer, 33 had small-cell lung carcinoma. Of those patients, 27 had 1 or more coexisting neural-specific autoantibodies that also predicted small-cell lung carcinoma. In contrast, no coexisting autoantibody was detected among 30 amphiphysin-IgG-positive patients in whom breast adenocarcinoma or other cancer type was found.7
The frequency of cancer detection in antibody-positive patients (pulmonary or extra-pulmonary small-cell lung carcinoma in almost all cases) varies from 20% for VGKC-complex IgG to 80% for antineuronal nuclear antibody type 1 (ANNA-1). Suspicion for a paraneoplastic cause may be raised by risk factors obtained from the clinical history. This suspicion may be honed to a search for a specific cancer based on the profile of autoantibodies detected. A thorough physical examination and computerized tomography (CT) of chest, abdomen, and pelvis are commonly undertaken as primary screening tests. Other tests may be required depending on age, sex, and other risk factors. Pelvic ultrasound (including transvaginal imaging) or MRI and gynecological examination are required to evaluate for ovarian carcinoma or teratoma. Mammography and breast examination are required to evaluate for breast carcinoma. Testicular ultrasound, prostate-specific antigen testing, and prostate examination by digital rectal examination are required to evaluate for testicular and prostate carcinomas, respectively. When neuroblastoma is suspected, and CT body imaging is negative, a radiolabeled metaiodobenzylguanidine (MIBG) body scan should be considered. Endoscopic examination of the upper and lower gastrointestinal tracts and bronchial tree should also be considered where appropriate. Positron emission tomography (PET) coregistered with CT (PETCT) imaging increases the diagnostic yield by 20% for patients in whom standard evaluations have not revealed cancer.8
Implications for Treatment
The profile of antibodies detected may guide immunotherapy and be informative for neurological prognosis.9 (Table 3) Studies suggest that autoimmune neurological disorders for which the antigens of marker IgG antibodies are intracellular are caused by neural peptide-specific CD8-positive cytotoxic T cells. An example includes encephalitis occurring in patients seropositive for ANNA-1. This autoantibody predicts with 80% certainty the presence of small-cell lung carcinoma. The target antigen is nuclear and, therefore, inaccessible in intact cells to circulating antibody. The neurological deficit rarely improves with antibody-depleting or tumoricidal therapies. On the other hand, IgG antibodies targeting neural cell surface receptors and channels do have a pathogenic role in effecting autoimmune CNS disorders that may be improved by antibody-depleting immunotherapy. For example, patients with antibodies targeting the GluN1 subunit of the NMDA ionotropic glutamate receptor present clinically with encephalopathy that improves (sometimes completely) with early teratoma removal and antibody-depleting and immunosuppressant therapy.
Serial trial of corticosteroids, intravenous immune globulin, and plasma exchange are considered first-line treatments to establish immunotherapy responsiveness. Some patients, such as those with autoimmune NMDA receptor encephalitis, may require many months of treatment. Immunosuppressants such as rituximab or cyclophosphamide may be required to maximize recovery.
Antibody values tend to decrease with immunotherapy regardless of outcome, and have a limited role in the adjudication of a treatment trial. However, a rise in antibody titer from a posttreatment baseline, accompanied by neurological deterioration, may indicate relapse of the autoimmune neurological disorder or a persistent systemic cancer.
Objective clinical, behavioral, neuroradiological, or electrophysiological measures undertaken pretreatment may be compared to posttreatment findings. Testing recommended for this purpose includes clinical examination, brain imaging (structural [MRI] or functional [PET]), detailed (4 hour) neuropsychological testing, and EEG. Resolution of neuropsychological, EEG, MRI, or functional imaging abnormalities after immunotherapy supports improvements and supports treatment continuation.
It is critically important to recognize treatable and potentially reversible autoimmune encephalopathies, dementias, and epilepsies in neurological practice. Rapid diagnosis is facilitated by testing for neural-specific autoantibody profiles in serum and CSF. When detected, 1 or more positive antibody result may direct the cancer search and prompt the timely initiation of immunotherapy.
Dr Andrew McKeon, Dr Sean J. Pittock, Dr Vanda A. Lennon
Glossary of Terms
|Aerodigestive carcinoma: cancer of the combined organs and tissues of the respiratory tract and the upper part of the digestive tract (including the lips, mouth, tongue, nose, throat, vocal cords, and part of the esophagus and windpipe)|
|Ataxia: a lack of muscle coordination during voluntary movements, such as walking or picking up objects|
|Dementia: a mental illness that causes someone to be unable to think clearly or to understand what is real and what is not real|
|Encephalitis: inflammation of the brain|
|Encephalopathy: a disease of the brain; especially one involving alterations of brain structure|
|Epilepsy: a disorder of the nervous system that can cause people to suddenly become unconscious and to have violent, uncontrolled movements of the body known as seizures|
|Epileptiform discharges: distinctive electroencephalogram (EEG) waves or complexes, distinguished from background activity, observed in those with seizure disorders.|
|Extratemporal and multifocal seizure localizations: rare brain locations for seizures to arise outside of the temporal lobes.|
|Hippocampus: a major component of the brain that plays an important role in the consolidation of information from short-term memory to long-term memory and spatial navigation.|
|Hyperintensities: small regions of abnormalities on MRI|
|Hypermetabolism on functional imaging: increased rate of metabolic activity in the brain|
|Hypometabolism on functional imaging: lower energy levels, or metabolism, of neurons in certain areas of the brain|
|Idiopathic: of unknown cause|
|Immunotherapy: the treatment of disease by inducing, enhancing, or suppressing the body’s own immune response|
|Limbic encephalitis: an inflammation of 1 or both temporal brain lobes caused by auto-immunity: an abnormal state where the body produces antibodies against itself. Some cases are associated with cancer and some are not|
|Limbic system: is a complex set of brain structures that lies on both sides of the thalamus, directly under the cerebrum. The limbic system supports a variety of functions, including emotion, behavior, motivation, long-term memory, and olfaction. It appears to be primarily responsible for emotional life, and it has a great deal to do with the formation of memories.|
|Mesial temporal: the part of the temporal lobe closest to the midline. Contains most of the limbic system|
|Myelopathy: any disorder of the spinal cord|
|Myoclonus: a quick, involuntary muscle jerk|
|Neoplasia: an abnormal mass of tissue as a result of abnormal growth or division of cells|
|Neural-specific autoantibodies: an antibody active against a tissue constituent of the individual producing it, relating to, or involving a nerve or the nervous system|
|Neuroblastoma: a cancer that develops from immature nerve cells found in several areas of the body|
|Neurodegenerative disorder: A disease state relating to or characterized by degeneration of nervous tissue|
|Neuroendocrine neoplasm: a tumor that begins in the hormone-producing cells of the body’s neuroendocrine system, which is made up of cells that are a cross between traditional endocrine cells (or hormone-producing cells) and nerve cells|
|Nonneural antibodies: an antibody not relating to the nervous system, such as thyroid antibodies|
|Oligoclonal bands: bands of immunoglobulins that are seen when a patient’s serum, plasma, or cerebrospinal fluid (CSF) is analyzed|
|Paraneoplastic: occurring in the setting of an occult systemic cancer|
|Parkinsonism: any of a group of nervous disorders similar to Parkinson’s disease, marked by muscular rigidity, tremor, and impaired motor control and often having a specific cause|
|Pleocytosis: an abnormal increase in the number of white cells (as lymphocytes) in the cerebrospinal fluid|
|CSF index: CSF IgG to CSF albumin ratio compared to the serum IgG to serum albumin ratio. The CSF index is, therefore, an indicator of the relative amount of CSF IgG compared to serum. Any increase in the index is a reflection of IgG production in the CNS|
|Radiolabeled metaiodobenzylguanidine (MIBG) body scan: a scan used to image tumors of neuroendocrine origin|
|Seronegative: a negative serum reaction especially in a test for the presence of an antibody|
|Teratoma: an encapsulated tumor with tissue or organ components resembling normal derivatives of more than 1 germ layer|
|Thymoma: a thymic epithelial tumor in which the epithelial component exhibits no overt atypia and retains histologic features specific to the normal thymus|
|Tremor: An involuntary trembling or quivering|
|Tremulousness: Marked by trembling, quivering, or shaking|
|Tumoricidal: destroying tumor cells|
|Unilateral or bilateral temporal slowing: an EEG finding suggesting brain dysfunction|
|Vitiligo: a skin disorder, of unknown cause, characterized by patches of unpigmented skin|
- Flanagan EP, McKeon A, Lennon VA, et al: Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc 2010 Oct;85(10):881-897
- Quek AM, Britton JW, McKeon A, et al: Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012 May;69(5):582-593
- Chitravas N, Jung RS, Kofskey DM, et al: Treatable neurological disorders misdiagnosed as Creutzfeldt-Jakob disease. Ann Neurol 2011 Sep;70(3):437-444
- McKeon A, Ahlskog JE, Britton JW, et al: Reversible extralimbic paraneoplastic encephalopathies with large abnormalities on magnetic resonance images. Arch Neurol 2009 Feb;66(2):268-271
- McKeon A, Pittock SJ, Lennon VA: CSF complements serum for evaluating paraneoplastic antibodies and NMO-IgG. Neurology 2011 Mar;76(12):1108-1110
- Pittock SJ, Kryzer TJ, Lennon VA: Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004 Nov;56(5):715-719
- McKeon A, Pittock SJ, Lennon VA: Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 2009 Dec;73(24):2132; author reply 2133
- McKeon A, Apiwattanakul M, Lachance DH, et al: Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol 2010 Mar;67(3):322-329
- McKeon A, Pittock SJ: Paraneoplastic encephalomyelopathies: pathology and mechanisms. Acta Neuropathol 2011 Oct;122(4):381-400