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Published: August 2014Print Record of Viewing
A number of disorders of the central nervous system previously considered neurodegenerative and untreatable are now recognized as having a treatable autoimmune cause. Improved recognition is facilitated by an expanding profile of neural-specific autoantibodies and when detected in serum or cerebrospinal fluid, these 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 autoimmune encephalopathy, dementia, and epilepsy are now available at Mayo Clinic.
Presenter: Andrew McKeon, MB, BCh, MD
Welcome to Mayo Medical Laboratories Hot Topics. These presentations provide short discussion of current topics and may be helpful to you in your practice. Our speaker for this program is Dr. Andrew McKeon, consultant in the Neuroimmunology Laboratory in the Division of Clinical Biochemistry and Immunology at Mayo Clinic in Rochester, Minnesota. Dr. McKeon describes new testing profiles for evaluation of patients suspected to have autoimmune encephalopathy, dementia, and epilepsy. Thank you Dr. McKeon for presenting with us today. On behalf of my colleagues in the Neuroimmunology Laboratory, I am going to describe new testing profiles available from Mayo Medical Laboratories for the evaluation of patients suspected to have autoimmune brain disorders, namely autoimmune encephalopathy, dementia and epilepsy. I receive research support from the Guthy-Jackson Charitable Foundation and Medimmune.
It is now recognized that many central nervous system disorders previously considered neurodegenerative or of unknown cause have an autoimmune cause. Many of these occur as an aberrant byproduct of an immune response against a systemic cancer, known as a paraneoplastic disorder. These neurological disorders are diverse, and are classified using 1 or more neural-specific IgG antibodies in serum and cerebrospinal fluid. Though individually rare, testing for a profile of antibodies in serum and CSF relevant to the disease state ensures optimum sensitivity and specificity. These new evaluations bring together comprehensive profiles of autoantibodies relevant to the 3 diseases, autoimmune encephalopathy, dementia and epilepsy. Separate serum and CSF evaluations are available for each.
Having separate evaluations for these 3 disease states permits the composition of reports that are maximally informative for the ordering clinician. However, each patient should only have one serum evaluation and one CSF evaluation requested, as determined by the neurological phenotype.
The following symptoms may be clues as you consider autoimmune encephalopathy, dementia, and/or epilepsy in your differential diagnosis: Cognitive or other neuropsychiatric symptoms of subacute onset, Treatment-resistant localization-related epilepsy of unknown cause.
Encephalopathy refers to a disorder of subacute onset usually characterized by multimodal cognitive dysfunction with altered sensorium (delirium, confusion) as a prominent feature. Encephalitis is the term often used when the CSF or MRI demonstrates evidence of inflammation. The classic form in an autoimmune context is known as limbic encephalitis, because of the predominance of symptoms referable to the limbic system, namely altered memory, mood and behavior. Delirium and sleep problems are also common. Brain imaging may demonstrate typical abnormalities, as seen on here on coronal T2-weighted MRI, namely mesial temporal high signal. The major differential diagnostic consideration is CNS infection. Serological findings of limbic encephalitis are diverse, and cannot be predicted by neurological phenotype. Thus evaluating with profiles of autoantibodies is appropriate.
In addition, or alternatively, electroencephalography may show abnormal brain function, namely slow waves of epileptiform discharges in the temporal lobes. Autoimmune encephalopathy may have a non-temporal lobe localization, and present with a syndrome not compatible with classic limbic encephalitis. The MRI figures demonstrate frontal and parietal lobe localization in one patient (seen in figure A) and frontal localization in another patient (figure B).
Autoimmune Clues include: Personal history of cancer, Personal history of autoimmunity, for example: Thyroid disease, Diabetes mellitus, SLE, Rheumatoid arthritis, Smoking history, Family history of autoimmunity or cancer.
A form of autoimmune encephalitis that is relatively common, but does not usually present with features of limbic encephalitis is NMDA receptor encephalitis. These patients present to a psychiatrist in 70% of cases with one mood and thought symptoms. Careful evaluation usually reveals comorbid neurological symptoms. If unrecognized, and untreated, this disorder evolves phenotypically into encephalopathy. Oral and upper extremity dyskinesias are common, and some patients go on to develop dysautonomia, hypoventilation and coma. Women are more commonly affected than men. Approximately half have an occult ovarian teratoma detected, removal of which can result in dramatic resolution of the neuropsychiatric symptoms. CSF testing is critical here because serum can yield false negatives and false positives. Early and aggressive immune therapy is critical to a good outcome in these patients.
Some patients do not present with such diverse symptoms, and may have an isolated rapidly progressive dementia phenotype. These disorders may mimic rapidly progressive neurodegenerative disorders such as Creutzfeldt-Jakob disease, rapidly progressive diffuse Lewy Body disease, or other neurodegenerative disorders. Similarities with autoimmune encephalitis include: The presence of coexisting neurological disorders and coexisting autoimmunity as diagnostic clues. These patients often have diverse serological possibilities emphasizing the need for testing profiles rather than selecting individual antibodies for testing. Furthermore these disorders may be paraneoplastic and so evaluation for occult cancer is needed in many of these patients and finally these neurological symptoms may reverse with immunotherapy.
Similarly, some patients present with a phenotype limited to seizures, arising in the absence of classic risk factors for epilepsy. However, more subtle cognitive and behavioral symptoms may be present also. The MRI may be normal in these patients. Patients are usually resistant to standard antiepileptic drugs, but often become seizure free with immune therapies. As is the case for autoimmune encephalopathy and dementia, coexisting autoimmunity may serve as a clue to the diagnosis and serological findings may be diverse, and evaluation for occult cancer may be required. Next I will describe the patient evaluation.
After obtaining the history, standard neurological evaluation is used to document phenotype. Neurological findings include: Impaired attention, memory, reasoning, calculation, or executive function, seizures may be witnessed by the clinician. Other signs may include: ataxia, parkinsonism, myoclonus, tremor, signs of spinal cord dysfunction know as myelopathy, and neuropathy.
Additional testing that may assist in determining the phenotype is noted on this slide and includes EEG sometimes with video monitoring to capture spells, MRI of brain, PET-CT imaging of brain and neuropsychometric testing. Basic serum and CSF testing may also reveal additional clues and includes serum testing for antinuclear antibodies and other connective tissue-related antibodies and thyroid antibodies. Standard CSF evaluations include: cell count, protein, CSF-exclusive oligoclonal bands, the IgG index and synthesis rate.
Comprehensive evaluation of serum and spinal fluid for neural antibodies can secure the diagnosis and impart information regarding the search for cancer that should be undertaken, and also give information regarding appropriate treatment. Some antibodies are detected more readily in serum such as voltage gated potassium channel-complex antibodies and some are more readily detected and more specific in spinal fluid, such as NMDA-receptor antibody. Detection of 1 or more of these antibodies supports a diagnosis of an autoimmune encephalopathy, epilepsy, or dementia, may predict an occult cancer and the type of cancer that could be found and may also guide type of immune therapy that is undertaken.
I will now review the serum and CSF profiles for autoimmune encephalopathy. As mentioned, these profiles are very similar for autoimmune dementia and epilepsy, so I will not review those here. Only 1 of the evaluations of serum and 1 of CSF should be requested in any 1 patient. Ordering should be dictated by the particular neurological phenotype encountered. First, the serum evaluation. The first round of testing consists of screening for autoantibodies by tissue immunofluorescence and some antigen-specific testing using immunoprecipitation and cell-based immunofluorescence assays. Depending on initial findings, some reflex tests may occur. Some are to confirm the presence of an antibody by Western blot. In the case of NMDA-receptor antibody, GABA-B receptor antibody or AMPA receptor antibody when detected by cell-based assay, a reflex to tissue immunofluorescence occurs to obtain an antibody value, or titer. Because neuromyelitis optica may present initially with an encephalitic phenotype, if that is incidentally identified by tissue-based immunofluorescence screening, confirmation will then occur by cell-based aquaporin-4 IgG assay.
Now the CSF evaluation. As for serum, the first round of testing consists of screening for autoantibodies by tissue immunofluorescence and some antigen-specific testing using immunoprecipitation and cell-based immunofluorescence assays. Depending on initial findings, some reflex tests may occur. Some are to confirm the presence of an antibody by Western blot. In the case of NMDA-receptor antibody, GABA-B receptor antibody, or AMPA receptor antibody detected by cell-based assay, a reflex to tissue immunofluorescence occurs to obtain an antibody value. Because neuromyelitis optica may present with an encephalitic phenotype, if that is incidentally identified by tissue immunofluorescence screening, confirmation will occur by cell-based aquaporin-4 IgG assay.
Once serum and CSF tests have been completed, if 1 or more antibodies have been detected, this may guide the cancer search. However, seronegativity does not exclude an autoimmune or paraneoplastic diagnosis, and a search for cancer may need to be undertaken with 1 or more of the modalities mentioned.
These particular autoantibodies target neuronal nuclear and cytoplasmic antigens, and have a high predictive value for cancer (70% or higher). Small-cell carcinoma, breast adenocarcinoma, thymoma, and gynecological cancers are common. PCA-Tr is associated with Hodgkin's lymphoma.
On this slide is represented the oncological association of some of synaptic antibodies that target plasma membrane proteins including ion channels receptors and water channels. Ovarian teratoma is detected in 50% of woman with NMDAreceptor encephalitis. GABA-B receptor autoantibody is usually detected in the context of small cell lung carcinoma. The cancer associations and positive predictive values for the other synaptic autoantibodies vary and include the associations seen on this slide.
The focus of this presentation is diagnostics, but I will make some key points regarding treatment. A number of disorders are reversible with immunotherapy, particularly those with synaptic autoantibodies as biomarkers as mentioned on the last slide. Early treatment is important, and may need to be sustained with multimodal therapies. In the seronegative cases, trials of treatment may be appropriate for diagnostic purposes also. Acute treatment modalities include IV steroids, intravenous immunoglobulin or IVIg, and plasma exchange. Responses to those therapies may be maintainable with longer-term immunotherapy.
In summary, autoimmune encephalopathy, dementia, and epilepsy are: not rare, they are potentially treatable, their diagnosis is aided by testing autoantibody profiles in serum and spinal fluid, and occult cancer accompaniment is not uncommon. Thank you very much.