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and CSF from 250 patients with anti-NMDAR encephalitis does not usually improve the clinical symptoms. If, in
and 100 controls tested with three different assays showing contrast, cell surface structures are the target of the humoral
that, while autoantibodies are always detected in CSF, reaction, early immunosuppression, if applicable, tumor
serum testing with any type of cell-based assay (live or resection is indicated. In these cases substantial recovery
[26]
fixed cells) led to false negative results in at least 13% of is possible. The European Federation of Neurological
[21]
the patients. Similarly, in another study, 23% of patients Societies developed a useful guideline regarding tumor
[27]
with anti-NMDAR encephalitis tested negative when only screening in AIE. For screening of the thoracic region, a
serum samples were evaluated by live CBA. Moreover, computed tomography (CT)-thorax is recommended, which
[22]
Dahm et al. recently reported that approximately 10% if negative is followed by fluorodeoxyglucose-positron
of patients with diverse neuropsychiatric disorders and emission tomography. Breast cancer is screened for using
healthy individuals may have IgA, IgM or IgG autoantibodies mammography, followed by MRI. For possible pelvic and
to the NR1 subunit of the NMDAR in the peripheral gastrointestinal malignancies, ultrasound scanning (US) of
blood. However they found a prevalence of IgA and IgM the pelvic region followed by CT is recommended in women
at low titer, whose detection has no utility for diagnosing (especially for ovarian teratoma), while US of the testes
NMDAR encephalitis. Using commercial tests, IgA, IgM should be considered in men under 50 years of age, and
and IgG anti-NMDAR autoantibodies, at low titer, showed colonoscopy in both men and women over 50. If primary
a broader distribution and can be detected in the serum of screening is negative, it should be repeated after 3-6 months
[23]
a considerable percentage of healthy subjects. These data and then every 6 months up till 4 years.
suggest that CSF anti-NMDAR autoantibody titers show a
much better correlation with clinical symptoms than blood CONCLUSION
autoantibody titers. In contrast, LGI1-antibodies seem to be
more prevalent in serum, although most patients have also Ongoing research on AIE constantly increases the number
CSF autoantibodies. [13] of novel autoantibodies and expands the spectrum
of neurological syndromes, which is crucial in the
In general, these findings suggest that multicenter studies differential diagnosis. Identification of the specific AIE is
are needed to determine the sensitivity and specificity of the important in the complex management of these patients
different methods of autoantibody detection. To minimize as these disorders may have different co-morbidities or
errors of interpretation and misleading diagnoses, in all associated tumors. Moreover, the discovery of new AIE
suspected cases of AIE both serum and CSF should always has led to unsuspected links with other CNS diseases (e.g.
be tested for autoantibodies. antiepileptic-drug-resistant epilepsy, relapsing encephalitis
post-HSV, demyelinating disease) making the diagnosis an
Tumor screening interdisciplinary challenge for the treating physicians. [28-30]
CNS dysfunction sometimes reflects an effective immune
response to an underlying neoplasm. Paraneoplastic Given the abundance of antibodies that have been reported
neurological disorders should be suspected when the so far, physicians face the dilemma of which antibody to test
onset is subacute, with rapid progression not explained first, especially if TBA gives inconsistent results. In terms of
by more common disorders. Neurological symptoms priority, it is important to consider first NMDAR and voltage-
generally precede the diagnosis of cancer that may remain gated potassium channel (VGKC-complex) which comprises
unsuspected and undetectable both clinically and by LGI1 and contactin-associated protein-like 2 autoantibodies,
conventional radiology for long after neurological symptom because they are the most frequent antibodies associated
onset. [24] with AIE.

Although certain neural-specific autoantibodies frequently The clinical spectrum of autoimmune encephalitis is
associate with distinctive neurological presentations, broad, but prompt recognition and treatment often leads to
none of the antibodies is specific for a unique syndrome. excellent outcome. Yet, despite being a potentially reversible
Autoantibodies that are highly predictive of cancer, however, neurological condition, no clear guidelines for diagnosis and
are tightly associated with a limited number of tumors that treatment of AIE exist.
express the antibody-target antigen [Table 1]. Therapeutic
intervention in these cases consists of searching for and Prospective population-based studies to evaluate the impact
treating the associated tumor in order to eliminate the disease- of different immunotherapies in AIE as well as to standardize
[25]
triggering stimulus. In addition, the detection of onconeural the different diagnostic tests are needed in order to improve
or neuronal surface antibodies is crucial in the diagnosis the management of these complex disorders.
of an immune condition, thus in the therapeutic decisions
[Figure 1]. In the case of onconeural antibody positivity, the Acknowledgments
neuronal tissue damage is thought to be initially mediated The author thanks Prof. Amelia Evoli and Dr. Paolo Alboini for
by T-cells and consequently, an immunosuppressive therapy their critical revisions of the manuscript and the flowchart. A

96 Neuroimmunol Neuroinflammation | Volume 3 | April 19, 2016