The diagnostic workup of the immune-mediated dementias begins with a complete history and physical examination. A detailed history should focus on clues relating to a subacute presentation, cancer risk factors, and autoimmune disease. Various historical points may be more suggestive of one condition over others. For instance, sarcoid should be considered in black Americans with respiratory problems and encephalopathy, whereas Sjögren's encephalopathy should remain high in the differential diagnosis of patients with rheumatoid arthritis, xerostomia, and/or mental status changes.
Given the overlapping clinical phenotype associated with immune-mediated dementias, we suggest broad screen serum laboratory studies for both antibody- and cell-mediated processes (). Screening laboratories should address rheumatologic causes of dementia (eg, with ESR, CRP, antinuclear antibody [ANA], antineutrophil cytoplasmic antibody [pANCA and cANCA], dsDNA, and anti-Ro/anti-La antibodies). Any of these biomarkers may be positive in SLE, Behçet's disease, or Sjögren's syndrome. Because HE and VGKC-E can present as rapidly progressive dementias mimicking CJD, they should be tested for in all patients with rapid dementia (). If paraneoplastic conditions are suspected, testing should be conducted for a panel of serum and CSF paraneoplastic antibodies. We generally recommend sending for panels of antibodies, because many of these antibodies can co-occur and some may help diagnose the underlying cancer. A reasonable panel for the more common paraneoplastic causes of LE might include anti-Hu, anti-CV2, anti-Ma, anti-amphiphysin, anti-Zic4, and possibly others. If patients exhibit ataxia, serum anti-Yo and anti-GAD antibodies should be measured.
Diagnostic workup of immune-mediated dementias
CSF analysis should be performed for any patient suspected of having an immune-mediated dementia. The typical CSF of these disorders is nonspecific, revealing inflammatory signs of lymphocytic pleocytosis, increased protein levels, an elevated IgG index, and CSF-specific oligoclonal bands. Thus, all CSF should be analyzed for protein, glucose, cell count, IgG index (for a serum–CSF ratio), and oligoclonal bands. If paraneoplastic disease is suspected, CSF can be analyzed for antineuronal antibodies, depending on the syndrome, but particularly anti-NMDAR and anti-AMPAR conditions, in which CSF antibody production is an order of magnitude higher than serum production ().
We recommend that all patients with a suspected autoimmune encephalopathy undergo MRI with intravenous gadolinium with FLAIR, T1, T2, and DWI and with apparent diffusion coefficient (ADC) sequences. Particular attention should be given to T2 and FLAIR sequences for T2-weighted hyperintensities within the brainstem and mesial temporal lobes that may suggest paraneoplastic or nonparaneoplastic LE. Because the medial temporal lobes can be susceptible to MRI artifact, we recommend acquiring T2 and FLAIR sequences in both the axial and coronal planes. MRI T2-weighted hyperintensities localized to the medial temporal lobes occur in about 80% of patients presenting with PLE [9
]. Other possible considerations include ischemic strokes, which can be associated with SLE or HE. Finally, patients with sarcoid may have evidence of thickening and enhancement of the leptomeninges on T1 postgadolinium sequences. There may be other nonspecific findings, such as enhancing or nonenhancing parenchymal or dural lesions [48
]. DWI with ADC sequences is helpful in diagnosing other causes of subacute presentations of dementia, such as CJD and strokes.
An EEG should be obtained in any patient experiencing a rapidly progressive dementia to both confirm abnormal slowing as well as screen for cortical irritability and to rule out seizures. The EEG carries particular importance in LE (particularly VGKC-E) and HE, which are commonly associated with seizures [22
Systemic inflammatory conditions may require further studies to support a given diagnosis. Patients with suspected paraneoplastic disease should undergo body imaging of the chest, abdomen, and pelvis with CT. If the x-ray or CT is negative and paraneoplastic conditions are suspected, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) should be performed. If certain paraneoplastic antibodies are found and the cancer workup is negative, serial imaging and testing every few months is recommended. If sarcoid is in the differential diagnosis, a CT scan or x-ray of the chest is helpful to screen for hilar lymphadenopathy. The diagnosis of Sjögren's disease can be confirmed with a lip biopsy. Finally, the standard workup of PACNS includes a conventional angiogram to screen for characteristic vasculitic beading.