Diagnosis
&
Treatment
Through evaluations and testing, the clinician will eliminate the possibilities of what disease process is occurring with the patient. Many diseases of the central nervous system present similarly to Autoimmune Encephalitis. As a complete diagnostic work-up is done, possibilities of the cause are ruled out. Infectious forms of encephalitis present similarly at onset to autoimmune encephalitis so a lumbar puncture is performed and testing is done in the cerebral spinal fluid (CSF) to rule out all possible infectious causes; such as leading viral infections which include herpes simplex virus(HSV), Varicella-zoster virus (VZV), enterovirus, West Nile virus (WNV) and Japanese encephalitis (JE).
Once viral infections have been excluded, bacterial causes are investigated and eliminated as possible culprits through testing spinal fluid. Bacterial causes of encephalitis include: listeria, atypical presentations of streptococcus, syphilis, Lyme disease, and tuberculosis. Fungal causes such as Cryptococcus or aspergillis are particularly likely in immune compromised patients.
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Due to the diversity of potential infections, recent research by Dr. Eric Lancaster at UPENN suggests advanced genetic techniques occur (e.g., metagenomic deep sequencing of cerebral spinal fluid) which have been proposed to screen for thousands of pathogens rapidly and efficiently. This approach should assume a wider role in diagnosing unusual central nervous system (CNS) infections in the coming years. At this point in the investigation, the clinician has been able to rule out if the patient has a viral encephalitis or bacterial encephalitis and the investigation continues to determine if the patient could have autoimmune encephalitis.
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What makes the diagnosis of autoimmune encephalitis unlikely (ruled out)?
Time. If the patient doesn’t develop neurological symptoms within 4 weeks after onset of psychiatric symptoms, then the diagnosis of Autoimmune Encephalitis becomes very unlikely.
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Next, other medical causes are excluded some that present similarly to autoimmune encephalitis are Wernicke encephalitis, Intoxications such a neuroleptic malignant syndrome and serotonin syndrome, lymphoma or carcinomatous meningitis may present similarly to autoimmune encephalitis.
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The syndromes that the patient presents with, are clues to the clinician as to what is occurring as is the age and gender of the patient. For example, Approximately 60% of patients with autoimmune encephalitis have prodromal low-grade fever, malaise, or headache. Some prodromal symptoms are characteristic of particular types of autoimmune encephalitides. Faciobrachial dystonic seizures and paroxysmal dizzy spells occur with LGIl. Severe diarrhea and weight loss occur in the prodromal phase of anti-DPPX encephalitis. Myoclonus (sudden, involuntary jerking of a muscle or group of muscles) can occur with LGI1, DPPX antibody and the paraneoplastic antibody Anti-Ri (Anna 2).
At symptom presentation, about 80% of patients with autoimmune encephalitis have mild-to-moderate CSF lymphocytic pleocytosis (usually <100 white blood cells/μl), 30% have mild-to-moderate increase of protein concentration, and 50–60% have oligoclonal bands. These bands can be present even when routine CSF studies are normal. In contrast to most autoimmune encephalitis, the limbic encephalitis associated with LGI1-specific antibodies frequently occurs with normal or minimal CSF findings.
Diagnosis is confirmed through lab testing for antibodies known to cause these disorders; it is recommended that blood (serum) be tested at the same time as the spinal fluid is tested. However, some of these tests have been found to be less reliable than CSF testing. Cerebral spinal fluid (CSF) is 100% sensitive and 100% specific when testing for NMDA. For example, where blood or serum testing can give a false reading as the sensitivity of finding Anti-NDMA antibodies in serum is only ~75% with a 97%+ specificity. This means you may miss about 25% of cases. So, if there is a high index of suspicion, even if the serum test is negative, a CSF sample should be acquired and evaluated. Negative results in antibody testing does NOT rule out a diagnosis of autoimmune encephalitis.
Other testing: Magnetic resonance imaging (MRI) of the brain with and without contrast for abnormalities suggestive of autoimmune encephalitis is very useful in patients with limbic encephalitis, usually showing increased FLAIR/T2 signal involving one or both temporal lobes. It is possible that the MRI may be read as normal. FDG-PET is suggested to be more sensitive than MRI and 18fluorodeoxyglucose (18F-FDG) PET imaging has been reported to typically reveal medial temporal lobe hypermetabolism even in MRI-negative or inconclusive cases. The FDG-Pet is particularly important for patients with limbic encephalitis who often have normal or non-specific MRI findings. EEG (often sleep deprived so the neurologist can see how your brain is functioning when it is tired or a 24 hour EEG) possibilities include: low wave activity in temporal lobes, diffuse slowing, epileptic activity or extreme delta brush pattern. Any one of these are a possible finding of evidence. Cat scan may be performed for a tumor search, Lumbar puncture for any signs of inflammation or disease in the central nervous system.
When should the clinician suspect an Autoimmune Encephalitic Disorder?
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If the patient is presenting with rapidly progressive encephalopathy of unclear etiology they will most often have multi-focal symptoms. Pure symptoms of just abnormal movement or just psychosis is rarely seen. They can present like this but usually the progression is rapid and multiple neurological symptoms are present. Inflammatory findings in the Central spinal fluid (CSF) such as mild to moderate pleocytosis and oligoclonal bands can be present when routine studies are negative. This is supportive of an inflammatory autoimmune process. It doesn’t give you a diagnosis as a viral process and other disorders can have this finding but it is a piece of evidence. In some cases, the MRI can be helpful. MRI with FLAIR-T2 changes in hippocampus are seen in LGI1, GABA (B), and AMPA. If you have a bilateral medial temporal lobe flair signal and the viral studies are negative, it is not necessary to have an identified antibody to start treatment. The doctor should begin treatment at that time. - Dr. Josep Dalmau
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The development of extrapyramidal symptoms (EPS) when placed on antipsychotics should alert the team to consider this diagnosis. Of course, EPS is a known side effect of antipsychotics, but is just another reminder to consider the possibility of Autoimmune Encephalitis.
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Delayed recognition of the disease can result in inadequate use of neuroleptics. Patients who develop psychosis as an initial symptom may be treated with neuroleptics, then later show catatonia, rigidity, autonomic instability and altered level of consciousness and possible coma; this pattern of findings may be mistaken for neuroleptic malignant syndrome. Patients with anti-NMDAR encephalitis may be particularly sensitive to strong dopamine antagonist medications such as Risperdal (risperidone), Haldol and these should be avoided. For this reason, benzodiazepines are preferred for initial management of behavioral disturbance and catatonia in suspected autoimmune encephalitis.
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Autoimmune encephalitis therefore should enter into the differential diagnosis of any case of suspected/new onset of possible Neuroleptic Malignant Syndrome (especially if the Creatine Kinase (CK) is normal, or CK normalizes after treatment, but without improvement.)
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Encephalopathy, Autoimmune Evaluation, Serum Antibody Testing
​Encephalopathy, Autoimmune Evaluation, Spinal Fluid Antibody Testing
The ground breaking position paper, A clinical approach to diagnosis of autoimmune encephalitis was a collaborative work by some of the most renown medical researchers and clinician in the field of Autoimmune Encephalitis today. It was published in the Lancet in February 2016 and outlined how to diagnose autoimmune encephalitis with the technology available in all general hospitals and NOT to wait to treat until the antibody test results have come back. Best outcomes are achieved when treatment is begun immediately and antibody test results can take 7 to 10 days to receive.
Listen to the Lancet Podcast: Clinical Approach to Diagnosis of Autoimmune Encephalitis
Mayo Clinic Webinar: The Spectrum of Autoimmune CNS Disorders
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Webinar: The Emerging and Evolving Field of Neuroimmunology
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Recognizing Autoimmune-Mediated Encephalitis in the Differential Diagnosis of Limbic Disorders
 AE mimics |  Evidence for Diagnosis |  Diagnosis criteria for possible AE |
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 Diagnosis criteria for limbic encephalitis |  Diagnosis criteria for acute disseminated Encephalomyelitis |  Diagnosis criteria for anti-NMDAR |
 Diagnosis criteria for Bickerstaff brainstem encephalitis |  Diagnostic criteria for Hashimoto's encephalopathy |  Criteria for autoantibody-negative but probable AE |
 Understanding Hashimoto's Encephalopathy |  Paraneoplatic Syndrome |
Exclusion of other causes/cause of encephalitis, not AE
Autoantibody testing is extremely important for the proper diagnosis of autoimmune encephalitis. In the correct clinical context, these antibodies can be diagnostic. However, the tests have complexities that require consideration, and taking certain test results as conclusive evidence of autoimmune encephalitis can be a mistake.
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NMDAr and other cell surface antibody tests are most sensitive and specific with CSF. Serum may offer a low false positive rate and a higher false negative rate. Commercial tests for autoantibodies to NMDAR, LGI1, Caspr2, AMPAR (GluR1, GluR2 subunits), and GABA-B-R are widely available. Newer cell surface antigens like GABAA-R and DPPX are more difficult to test clinically. Have your physician contact Mayo Clinic Rochester, MN or UPENN in the Untied States to inquire about antibody testing through research resources. Contact Neuroimmunology Program in Spain if in Europe.
 |  Immunotherapies |  Mayo Appointment |
|---|---|---|
 Mayo Clinic paraneoplastic |
Autoimmune Encephalitis is treated with immunotherapy. Immunotherapy slows down the over excited immune system. By slowing down the immune system it slows down and attempts to stop the attack that is occurring. Initially, high dose steroids are used to slow down the immune system and bring down the inflammation in the brain in a broad way.
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Immunotherapy treatment is the combination of treatments that include first-line therapies: steroids, IVIG, plasma exchange (plasmapheresis) and second -line therapies: Rituxamab (Rituxan) and cyclophosphamide (Cytoxan), followed in many cases by steroid-sparing agents such as cellcept or azathioprine in the long-term. The fact that patients who receive second line immunotherapies have fewer relapses, is leading many physicians to use rituximab initially as a first line treatment.
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Memes about Autoimmune Encephalitis
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If the clinician suspects autoimmune encephalitis, treatment is often given without delay based on clinical observations of symptoms, a history of how the disease developed, and the results of medical evaluations and tests performed. Prompt treatment and escalation of treatment in patients who remain ill, is associated with better outcomes.
In the case, of ‘probable’ or ‘possible’ autoimmune encephalitis being suspected, treatments may include steroids and/or IVIG.
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IVIG offers an important advantage of being unlikely to make infectious encephalitis worse. Plasmapheresis is also unlikely to significantly worsen infectious encephalitis. Clinicians need to also consider that treatment with steroids, rituximab, or cyclophosphamide could complicate tumor diagnosis in the case of tumors like lymphoma.
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If a cell-surface/synaptic antibody disorder is diagnosed, (remember those are the extracellular antibodies which are exposed on the OUTSIDE of the brain cell it is attacking). Initial immunotherapy treatments may include IVIG, plasmapheresis, and/or steroids. Immunotherapy is mostly targeting the B cell response which is why positive outcomes are seen in these more commonly occurring antibodies in autoimmune encephalitis.
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The response to immune therapy is generally good, particularly if the more effective treatments are used promptly. However, powerful immune suppression may be needed for weeks or months in difficult cases and treatment may take many months to reach its full effects. Some patients, an estimate of 35-42% have persistent deficits, especially in the domains of memory and cognition. Autoimmune encephalitis may relapse, so follow-up care is important.
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Many forms of autoimmune encephalitis are paraneoplastic, and each of these conveys a distinct risk profile for various tumors. Tumor screening and, if necessary, tumor removal is essential to proper management of treatment.
Special Thanks to Autoimmune Encephalitis Alliance who sponsored
the symposium from which this video was taken.
As of 2016, experts in the field of autoimmune encephalitis did not yet have any really good immunotherapy treatments for patients with intracellular antibodies. Researchers know that conventional therapies are not effective.
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Help is on the horizon as researchers work to identify effective treatments. Some very preliminary small studies in immunology are looking at medications like the immune suppressant, Tacrolimus. Tacrolimus has been used in other types of neurological syndromes and is being explored for patients with intracellular antibodies in paraneoplastic autoimmune encephalitis. Tacrolimus is a potent inhibitor of lymphocyte proliferation that is commonly used to suppress the immune system for transplant patients to prevent rejection. Tocilizumab is showing some promise in research as a good treatment strategy for treating AE refractory to conventional immunotherapies and rituximab.
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Intracellular antibodies (those that are INSIDE the cell and involve aggressive T-cell responses targeting the neuronal brain cells) are mostly mediated by cytotoxic CD8+ T cells that cause functional and structural neuronal damage and this is why there is a likelihood that a response to immunotherapy is not seen in these patients.
At this time, plasmaphereses, Rituxamab (Rituxan) and the chemotherapy drug, Cyclophosphamide (Cytoxan) is used to treat various types of paraneoplastic autoimmune encephaladies.
New Treatments for Refractory Cases:
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As research continues to unfold, alternative treatments for cases that have been resistant to the prior mentioned immunotherapies have come to the forefront. More prominently: Bortezomib, Tocilizumab, Ofatumumab and Inebilizumab.
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​Early Treatment and Outcomes:
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The speed of recovery, degree of residual deficit, and frequency of relapse vary according to the type of autoimmune encephalitis. The case that early treatment provides the best outcomes, has been made in several studies. A small case series reported that 4 of 5 children treated with combinations of first-line immunotherapy within 6 days of symptom onset recovered fully with no relapses. The strongest evidence in favor of early treatment comes from the largest observational cohort published, Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis.
In that study, 53% had clinical improvement within 4 weeks, and 81% had substantial recovery (i.e., mild or no residual symptoms) at 24 months. Approximately 50% of patients respond to first line immunotherapies (intravenous immunoglobulins (IVIG), steroids, or plasma exchange) and the other 50% require second line therapies, such as rituximab or a combination of rituximab and cyclophosphamide. Relapses occur in 12–20% of cases (12% during the first 24 months of the disease), often presenting as fragments of the syndrome (perhaps due to prompt diagnosis), and respond to immunotherapy. Patients who do not respond to treatment, or who have relapses, should be reassessed for the presence of an underlying contralateral (opposite side) or recurrent teratoma with anti-NMDAr and tumor search in other variants where this may occur.
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In the July 2016 study, Anti-LGI1-associated cognitive impairment: Presentation and long-term outcome, Drs. Dalmau and Graus were surprised to discover in their study of the most common Limbic encephalitis, at follow up after 2 years shows patients had a more rapid response but that only 70% had substantial recovery. 35% of patients were fully recovered but not able to return to their previous jobs or function as they had previously due to lasting brain injury. Of the patients who received treatment within 3 months 27% relapsed. Relapse usually occurs when immunotherapies are tapered early. The final outcome for those with LGI1 antibodies is far from optimal. Improvement occurs but they acknowledge that there is a lot more that needs to done to get better improvement for these patients.
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The associated syndromes often respond to immunotherapy, resulting in substantial or complete recovery particularly if the more effective treatments are used promptly. However, treatment may take many months to reach its full effects, and some patients have persistent deficits, especially in the domains of memory and cognition.
The frequency of clinical relapse in the encephalitides associated with antibodies against NMDAR, AMPAR, LGI1, CASPR2, or DPPX ranges from 12 to 35%. Relapses often occur when immunotherapy is reduced or discontinued. Relapses may occur due to a recurrence of the associated tumor or identifying a tumor that was missed in the initial evaluation. Immunotherapy and treatment of the tumor usually result in improvement.
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Prior to these disorders being identified, and taking into account the severity and duration of symptoms, the clinical recovery of similar patients was not expected. Unaware of how the disorders worked and that they could respond to a treatment, they were thought to be untreatable and the disease was allowed to progress. These patients eventually died of status epilepticus or coma. The discovery of the first antibody, NMDAr, and subsequent antibodies since, has changed the concepts about supportive therapy today in cases that would have been considered futile in the past.
Modified Ranking Scale:
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Most studies have used the modified Rankin Scale (mRS) to measure outcome. The is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered an illness that caused neurological disability. The Dalmau and Lancaster co-hort study of 577 patients, demonstrated that early treatment, the lack of need for intensive care admission, and maximum mRS score of ≤ 3 were independently associated with good outcome. In that study, about half the patients who received first-line immunotherapy improved within 4 weeks of treatment, and 97 % of these patients went on to have a good outcome (mRS 0–2) at 24 months of follow-up.
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Even in those patients classified as having good outcome in Autoimmune Encephalitis, (mRS 0–2), incomplete recovery with deficits in executive function and memory are common and are more severe in those with delayed treatment. This would suggest that the initial part of the illness may be critical in terms of neuronal damage and long-term disability which is why it is so important to be aware of this syndrome during its earlier psychiatric presentation. As it progresses into the the later neurologic stages, the potential for a long term deficit increases.
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In addition, the associated syndromes often respond to immunotherapy, resulting in substantial or complete recovery in 70–80% of the patients. Physicians should be aware that isolated psychiatric symptoms can last for months before neurological symptoms and should remain hopeful for a good prognosis because continuous immunotherapy can achieve a favorable outcome despite delayed diagnosis. Owing to the severity and duration of symptoms, before these disorders were known the clinical recovery of similar patients was not expected, thus changing our concepts about supportive therapy today in cases that would have been considered futile in the past.
