Relapse of encephalitis was defined as the new onset or worsening of symptoms occurring after at least two months of improvement or stabilization. Patients without a tumor had a higher frequency of relapses than those with a tumor. If a tumor is found, removal is important because it expedites improvement and decreases relapses.

The frequency of clinical relapse in the encephalitides associated with antibodies against NMDAR, AMPAR, LGI1, CASPR2, or DPPX ranges from 12 to 35%. The relapse rate in NMDAR encephalitis is reported to be 12–25 %, and relapses may occur in cases of anti-LGI1 or anti-NMDAR encephalitis months to several years after the initial episode.

Relapses often occur when immunotherapy is reduced or discontinued. Relapses may herald recurrence of the associated tumor or a tumor that was missed in the initial episode. Immunotherapy and treatment of the tumor, if it was missed initially, usually result in improvement.

Relapses in NMDAR Ab encephalitis are often less severe and may be mono- or pauci-symptomatic. In children, atypical presentations such as cerebellar ataxia or brainstem signs have been described. The majority of relapses occur in patients who do not have a tumor associated with NMDAR Ab encephalitis, those who received no or limited treatment for the initial episode, and those not exposed to second-line agents. Second-line immunotherapy also appears to prevent further relapses in those with a multi relapse disease course. At present, there is no clinical or paraclinical predictive marker for relapses. Although alterations in CSF Ab titers relate well to clinical changes, it is impractical and perhaps unsafe to conduct CSF analysis for predictive purposes in well patients. Changes in serum Ab titers were not well correlated with relapses. The effects of long-term immunosuppression with oral agents such as azathioprine or CellCept(mycophenolate mofetil) on relapse rate is currently unknown.

Following antibody titers in the management of patients has several limitations and rarely helps guide therapy, which should be based on clinical findings as titers are not reliable markers of disease severity, but they can sometimes predict relapses and support the use of prolonged immunotherapy for prevention.

To prevent relapses and maximize the response to acute phase therapy, maintenance immunotherapy should be instituted especially if early relapses during steroid taper occur. Commonly used drugs in this phase include oral corticosteroids, IVIG, and steroid sparing agents such as mycophenolate mofetil, azathioprine, and rituximab. There are no guidelines regarding treatment duration; maintenance therapy is typically continuing for 3 years after stability is achieved. It is important to remember that the prolonged use of immunosuppressive medications increases the risk of lymphoproliferative disorders, and they have also been associated with progressive multifocal leukoencephalopathy.

The NEOS Score, just published December 2018, accurately predicts 1-year functional status in patients with anti-NMDAR encephalitis. This score could help estimate the clinical course following diagnosis and may aid in identifying patients who could benefit from novel therapies.

During the 24-month follow-up, 45 patients (representing a 12% risk) had clinical relapses, which in 15 patients (33%) were multiple. Compared with the initial episode, (67%) relapses were less severe (as reflected by a lower mRS score measured at the stage of maximum severity), more frequently mono-symptomatic (35%), and resulted in fewer admissions (17%) to the ICU (all p<0·0001). In 16 relapses (23%) the severity of symptoms was comparable to that of the initial episode, and in (10%) was worse.