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), for example.
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.
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.
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.
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.
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). In these examples, an experienced clinician in autoimmune encephalitis may have a high suspicion of a specific type of AE based on your presenting symptoms and the history of how your illness began.
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. CSF studies can be normal in patients with early active autoimmune encephalitis. Combined abnormal CSF WBC count, protein, and oligoclonal bands are more likely when a shorter time between symptomatic-onset-to-Lumbar puncture occurs. 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% accurate 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. This is because not all antibodies in autoimmune encephalitis have been discovered yet. If the antibody test comes back negative and the patient has all the other findings confirming AE, the patient is considered to have seronegative AE aka antibody-negative AE.
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.
Due to the broad spectrum of initial symptoms seen in AE, data shows that the correct initial diagnosis of Autoimmune Encephalitis is often missed or delayed. Hence, clinicians in neurological and psychiatric hospitals should consider AE in the differential diagnosis of cases with atypical clinical presentations.
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When should the clinician suspect an Autoimmune Encephalitic Disorder?
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
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.
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.
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.)
AE is refractory to Antispychotics
Handout of Research Referencing this Concern
Antibody Mediated Psychosis ~ Causes and Treatment
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.
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.
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
Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.