Autoimmune encephalitis: proposed best practice recommendations for diagnosis, acute-, symptomatic-, and long-term management.
March 5, 2021
We are excited to report the first international best practice recommendations for the management of autoimmune encephalitis. The papers result from the hard work and collaboration between 68 AEA Clinicians Network members from 17 countries, initiated and led by Dr. Hesham Abboud. These recommendations will be of great value to AE patients and clinicians all over the world.
AE is possibly as common as infectious encephalitis, and the rapidly advancing knowledge of new antibodies and their associated syndromes has created a new and growing field of autoimmune neurology. However, these advances have not been paralleled by advancement in clinical practice, leading to a large knowledge gap regarding the acute and long-term management of AE. Currently, the results of antibody testing panels are not available at early evaluation and management of AE, so physicians have to approach AE initially as a clinical entity when deciding on tests and treatments. Long-term management can then be modified according to the type of antibody identified.
These papers aim to evaluate available evidence for each step in the management of AE as a broad category, and to provide an expert opinion when evidence is lacking to come to best practice recommendations for management of AE. What makes these recommendations stand out is that these represent the practice of experienced clinicians from different clinical and geographical backgrounds.
In this first part of the best practice recommendations, Dr. Abboud and colleagues cover the diagnosis and acute management of AE guided by published studies and the results of the AEACN survey providing updated guidance for the management of patients with suspected AE. The second part focuses on bridging therapy, symptomatic treatment and maintenance immunotherapy.
Best practice recommendations summary for acute management of autoimmune encephalitis
- Evaluate the likelihood of AE relative to the patient’s clinical picture.
- Perform brain MRI and/or EEG to look for focal or multifocal brain abnormality.
- Perform lumbar puncture to support inflammatory etiology and rule out infective/neoplastic causes. Test oligoclonal bands, IgG index, IgG synthesis rate, and neuronal autoantibodies in the cerebrospinal fluid (CSF).
- Send blood tests to rule out other potential causes guided by neuroanatomical and clinical data. Test neuronal autoantibodies in the serum.
- Consider brain FDG-PET when there is a high clinical suspicion of AE, and other paraclinical studies are uninformative.
- Perform cancer screening with CT chest, abdomen, and pelvis with contrast in relevant cases (or MRI when CT is contraindicated or not preferred). If negative, consider further testing with mammogram/breast MRI, pelvic ultrasound, and/or whole body FDG-PET guided by the clinical presentation and each patient’s specific cancer risk factors.
- Once infection is ruled out based on basic CSF results (e.g., number of cells) and if a biopsy for primary CNS lymphoma or neurosarcoidosis is not a consideration, start acute immunotherapy with high dose corticosteroids (or IVIG or PLEX if steroids are not preferred or contraindicated).
- If there is no clinical, radiological, or electrophysiological improvement by the end of the initial treatment cycle, add IVIG or PLEX. Consider IVIG first in agitated patients and in those with bleeding disorders. Consider PLEX first in patients with severe hyponatramia, high thromboembolic (or cancer) risk, and if there is associated brain or spinal demyelination.
- Consider starting with a combination therapy of steroids/IVIG or steroids/PLEX from the beginning (as opposed to sequentially) in patients with severe initial presentation (e.g., severe NMDAR-antibody presentation, new-onset refractory status epilepticus, severe dysautonomia, etc.)
- If there is no clinical or radiological improvement 2–4 weeks after completion of combined acute therapy, consider starting a second-line agent when the clinical suspicion is high, and/or a clinically relevant antibody is present.
- Consider rituximab in known or highly suspected antibody-mediated autoimmunity (e.g., NMDAR-antibody encephalitis) and consider cyclophosphamide in known or highly suspected cell-mediated autoimmunity (e.g., classical paraneoplastic syndrome).
- If no clear objective or subjective evidence of improvement with conventional second-line therapies, consider novel approaches such as tocilizumab or bortezomib, although there is only minimal evidence to support their use.
- Start bridging therapy with gradual oral prednisone taper or monthly intravenous Ig or intravenous methylprednisolone. Avoid steroid taper or implement a shorter taper in vague cases with poor response to initial immunosuppressive therapy or when immunosuppression may impose higher risks than benefits (e.g., patients with cancer or active infection).
Best practice recommendations summary for long-term management of autoimmune encephalitis
- Positive antibody against intracellular antigen (classical onconeuronal antigens) and typical clinical picture: refer to oncology for treatment and tumour surveillance if one was found. If no tumour was found, initiate semiannual to annual cancer screening for at least 4 years. Treat neurological relapses with intravenous methyl-prednisolone and/or cyclophosphamide as necessary but avoid long-term immunosuppression.
- Positive antibody against neuronal surface antigen with high clinical relevance and typical clinical picture: consider periodic tumour screening based on the type of antibody and each patient’s cancer risk factors. Some neuronal surface antibodies with higher rates of tumour association may require more frequent screening as in gamma-Aminobutyric acid-B receptor (GABABR)-antibody encephalitis, and some may require less frequent screening as in leucine-rich glioma inactivated-1-antibody encephalitis. Consider initiating at least annual cancer screening for an average of 2–4 years based on antibody type. A more selective screening approach could be considered for antibodies with specific tumour associations. Consider long-term immunosuppression, preferably with rituximab (based on presumed antibody-mediated immunity and N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis studies) after a second attack. May consider starting long-term immunosuppression after the first attack in patients with severe initial presentation or risk factors for relapse (e.g., persistently positive oligoclonal bands). Overlap with short-term oral corticosteroids after initiation of long-term agent. The duration of long-term immunosuppression depends on relapse rate, relapse severity and tolerability of the immunosuppressive agent.
- Positive antibody against neuronal surface antigen with low clinical relevance to the clinical presentation: evaluate confidence in the clinical relevance of the positive antibody based on clinical and ancillary data. Evaluate for alternative etiologies. If the diagnosis of autoimmune encephalitis (AE) is felt to be probable and no other etiology found, then follow recommendation 2.
- Seronegative AE: confirm the diagnosis according to published criteria and exclude alternative causes. May consider initiating annual cancer screening for an average of 4 years for seronegative definite autoimmune limbic encephalitis and may consider periodic screening for an average of 2 years for all other neuroanatomical variants. Start long-term immunosuppression with rituximab, mycophenolate mofetil, or azathioprine after a second attack. Overlap with short-term corticosteroids after initiation of long-term agent. The duration of long-term immunosuppression depends on relapse rate, relapse severity, and tolerability of the immunosuppressive agent. Recommendations for seronegative AE are particularly anecdotal, and more research is needed for this subtype of AE.
- For all AE subtypes: treat residual symptoms including seizures, movement disorders, psychiatric symptoms, spasticity, sleep dysfunction, and dysautonomia. Also start de-escalation of symptomatic medications when appropriate. Start physical, occupational, and speech therapy depending on residual deficits. Strongly consider neuropsychological rehabilitation, although the value behind this intervention is in need of further research to establish scientific evidence.
AE Alliance would like to thank Dr. Hesham Abboud and all the Clinicians Network members that have worked to make the best practice recommendations possible.
