CSF Studies



First Aid Tool Kit for Autoimmune Encephalopathy (AE)This is a resource guide compiled by persons who have had a diagnosis of Autoimmune Encephalitis to help educate, prepare and assist with symptom progression if this should occur. It is not meant to be medical guidance which should be sought out by consultation with one of the physicians on our Doctor’s list. IAES, does not advise in medical matters, and as such, we are not liable for you medical or behavioral health decisions. This is our collective experience, strength and hope. The diagnostic code for Autoimmune Encephalitis is G04.81. There are 16 types of cell surface and synaptic antibodies and 9 more paraneoplastic antibodies which occur and have been identified in Autoimmune Encephalitis to date (1-2017). ?The illness is relapsing and remitting and can be progressive in some types. ?Brain injury or damage can result in approximately 42% of non-paraneoplastic cases leaving the patient with a permanent deficient. ?Treatment is headed by a Neurologist or Neuroimmunologist (often a team of medical professionals are involved including, Immunologists and Rheumatologists), yet most neurologists have never seen a case or heard of these disorders. ?Insurance covers this disease when the doctor is knowledgeable, codes it correctly, and articulates the treatments for this disease with accompanied research. Not everyone can maintain their employment with this disease and many go on Social Security Disability as a result. It all depends on the severity of the illness and treatment outcomes.ArticlesIf your clinician is evaluating for the possible diagnosis of Autoimmune Encephalopathy, it can be difficult for the patient to understand the process. Your physician will be running tests to rule out possible causes of your medical condition. This is how an accurate diagnosis is arrived at; to rule out what it is not and gather evidence of what is occurring. Autoimmune Encephalitis can be a challenging diagnosis to make and there is no ‘cookie cutter’ protocol. Guidelines for treatment protocol are included in these peer-reviewed studies. Best outcomes for an accurate diagnosis and aggressive treatment plan occur when the patient seeks an expert in the field who has published on these disorders. Provided to help you, your family and your provider are the following articles:A clinical approach to diagnosis of autoimmune encephalitis Domingo Escudero, Francesc Graus, Josep Dalmau. ??The Diagnosis and Treatment of Autoimmune Encephalitis by Eric Lancaster, Department of Neurology University of Pennsylvania . Autoimmune encephalopathies?by: Frank Leypoldt, Thaís Armangue, Josep Dalmau Paraneoplastic and Other Autoimmune Disorders of the Central Nervous System?by: Andrews McKeon (make sure to see The treatment algorithm Figure 2,?Table 4) Neuropsychiatric symptoms in autoimmune encephalopathies: a clinician’s guide Fátima Carvalho1, Jo?o Massano1,2, and Rui Coelho1,3 Important to KnowMany of us who are further along the path on our health journey have found that even in the early stages of Autoimmune Encephalitis, these things were helpful.Do not attempt to manage this on your own. Educating a few family members,friends and/or your Power of Attorney (POA) is essential and a loving and caring thing to do for yourself and others. Cognitive problems associated with AE can occur in a few days or weeks of becoming ill; some types take a relapse-remitting course while other types can be progressive. We know stress exacerbates these disorders. Encephalopathy is a symptom, not the root cause. Autoimmune disease where the immune system has created an antibody that sees healthy brain cells as foreign, is the root cause. ?In Autoimmune Encephalitis, encephalopathy can present as mild, moderate or severe and not necessarily in that order. ?Outside of autoimmune encephalitis clinics, full neurological evaluations, testing of the central nervous system, antibody testing, (negative result does not rule out AE), EEG, MRI with and without contrast, Ultrasounds and Cats cans for tumor searches, FDG-PET scan to show hypometabolism can take many months and requires patience. ?If you do not have a Power of Attorney (POA), start the process by determining who you want to make medical decisions for you if your cognition becomes impaired. Some, who did not do this and were not aware they had AE, have found themselves in Psychiatric Hospitals, misdiagnosed and had to take psych meds which did not help their condition, exacerbated symptoms and delayed accurate medical treatment. ?It is not unusual for a patient to be put on a psych hold for their safety. If your adult child is transferred to a psych ward, you as their parent may not be informed that this has occurred. Any adult placed on a psych hold is no longer able to make their own treatment decisions. Medical information or input from family is not considered and family does not have to be informed of the patient’s treatment plan or anything about their case unless the parents/spouse/family member/or advocate get a POA. If you are in a crisis and do not have a POA in place, you can file for that and obtain emergency medical guardianship. Acquiring guardianship for your adult loved one must be urgently addressed. In a medical emergency when the patient is rendered unable to make their own medical decisions, this can be acquired very quickly. Board members of IAES have witnessed patient’s families not address this need and the patient was legally committed and did not receive appropriate medical/neurological evaluations for their condition. Autoimmune encephalitis is under recognized due to lack of awareness of these disorders in the medical community. It is complicated by the fact that it can mimic psychiatric disorders such as bipolar or schizophrenia. Other symptoms such as hallucinations, autoimmune based depression, loss of memory and stupor can result in misdiagnosis. ?AE is thought to be more common than originally realized due to those who go/have gone undiagnosed. ?Due to the combinations of a rare/uncommon illness and the complexity of the diagnostic criteria, misdiagnosis routinely occurs delaying appropriate first line treatments in suppressing the immune system that can bring the disease under control. ?AE is highly treatable and best outcomes occur with early diagnosis and aggressive immunotherapy. Free Power of Attorney (POA) forms and guidance on this process can be found at . Complete the forms even if you can’t afford the attorney and have your POA keep the forms and keep a copy in your Notebook, which will be discussed below. Should you need a POA, the hospital has a process to execute this quickly, but if you are misdiagnosed, you will need your advocate to make your decisions and to ask the very important questions which will help you to get the care you will need.Find a Neurologist who specializes in Autoimmune Encephalopathy. The International Autoimmune Encephalitis Society (IAES) has a Doctor’s list of experts who treat AE on their?Web site: . Many of us have had to travel far to find a such a specialist. In some cases, your current provider may need to make the referral. Your insurance may have to approve this which is covered later, in the Insurance part of this kit. Delay in proper identification and aggressive treatment will result in a poorer health outcome and possibly lasting disability that could have been avoided. Be sure to ask your current provider about flying if you opt for this. Air pressure changes associated with flying can impact encephalopathy symptoms in some cases. Ask your neurologist to try and keep your services, labs, testing, etc. at the same facility if possible. Some of us have many specialists spread out all over multiple offices/clinics/hospitals/facilities which uses vital energy and creates a barrier to collaboration of care. Many of us who are ill, are positive for autoimmune disease but continue to show normal labs, MRI’s. This can be confusing. The neurologist will take a full medical history and documentation of the onset of your illness, order tests and labs to gather evidence of what is occurring, rule out possibilities so an accurate diagnosis can be arrived at. ??If your physician is not an expert in autoimmune encephalitis, unnecessary delay and expense will be spent resulting in poorer health outcomes and unwarranted financial strain.Do your best self care. A structured lifestyle is important. Having a routine and a process for everything can make AE easier to manage. Some of us have a notebook we carry around and write everything down or rely on our cell phones by using notes, memory or calendar apps, to support our memory loss issues. (Week Calendar for iPhone to assist with memory and ‘Symple’ app for iPhone to assist with symptoms and medications are good examples). Many of us have had to re-evaluate what is important to stay well. Rest and minimal stimulation helps the brain to heal. Your neurologist will emphasize the importance of getting 8 hours of sleep and napping when tired to help your brain function at its current best. Your body will not have the stamina it once had. Be mindful when pushing it. Exercise such as walking 45 minutes daily is also highly recommended by neurologists. Re-evaluate your expectations and help your loved ones and employer understand these have changed. You will have to ask for and need help. ?You will have to say no, sometimes. Explain to loved ones they should be mad at this disease, not you. Understand all will be grieving the loss of the ability you used to have. You will be grieving too. Many of us have found counseling and spiritual connection helpful. Develop a ‘support circle’ of friends and family. Use your windows of good days or time during a good day to batch cook and freeze healthy meals, work on projects important to you and socialize. Some have found that describing Autoimmune encephalitis in simple terms to family and friends to be helpful. ??An easy explanation is that the immune system is attacking the brain. ?Autoimmune Encephalitis is considered a neurological autoimmune disease. ?To clarify, the immune system creates an antibody that sees healthy brain cells as foreign and attacks them. ?This occurs throughout the brain. ?The brain now malfunctions. ?All areas of brain function can be affected. ?Because these attacks are relapse/remitting, (remitting not to be confused with remission) and can target different areas of the brain and the brain function that area is responsible for, a fluctuation of symptoms is seen due to the relapse/remitting nature of its presentation. ?We can change in how our symptoms present from day to day and different times of day. An acquired brain injury due to neuronal brain damage/death can occur. ?Atrophy and injury or damage can be seen on scans or slowing seen on EEG. The many symptoms associated with AE often confuse the practitioner who is unfamiliar causing them to modify your report of symptoms to fit into a diagnostic criteria they are familiar with. ?Misdiagnosis commonly occurs which will be costly in your time, money and recovery. ?AE is a rare disease which means it is still under recognized by even some of the very best providers in neurology. ??This is why International Autoimmune (Encephalitis Society strongly advocates that patients see an expert in this emerging subspecialty of Autoimmune Encephalitis who has published in the field. ?This First Aid kit was designed to help with these issues. For some of us it takes years to get these issues sorted out.Safety. ???AE can diminish our cognitive ability. Since our symptoms can relapse/remit, (again, when symptoms remit this is not remission but a fluctuation of the disease) pre-empting with safety planning is a way we can stay responsible for our care and make choices for ourselves. Keep an ongoing assessment of safety issues in your journal or cell phone app. Neurological deficits can cause risks for driving, caretaking others, falling, financial issues, safety for appliances and home security and medication administration. ?An Occupational therapist and Physical therapist can assist in these areas. ?Plan safety precautions based on your worst days. ?People cannot see encephalopathy outwardly and often providers cannot determine this without thorough neurological testing and neuropsychiatric evaluations. You will not likely look different, if you do not have need of a cane, walker or scooter/wheelchair, so some of us have experienced not being believed that our symptoms are impacting the quality of our daily lives to the level we are reporting. Or our deficits may be under recognized by the clinician inexperienced in AE or misdiagnosed as psychiatric in origin. This occurs when a neurologist is not a specialist in autoimmune encephalitis, remember misdiagnosis is common. Use structure and a process that mitigates your risks. For example, some of us batch cook and freeze meals for the freezer on our good days or when we have a friend or family member with us to guide and support us in the kitchen for safety and assist with our memory deficits or issues around following a recipe. ??This way, we can avoid safety hazards around forgetting to turn the stove or oven off. Or to remember to turn the stove on and have an uncooked meal. ??Use of visual reminders and instructions are helpful. Incorporating the use of crock pots and rice cookers as a cooking alternative to ensure kitchen safety are examples of alternate solutions. ?If care giving for very young children, an elderly person, if your work requires care givingfind someone who will tell you when you are not capable to care for others or make good decisions. Find a way to be accountable to this. There is no shame in this as this is how responsible people mitigate their risks. Driving is another safety concern. Many of us are no longer able to drive or are highly restricted in our ability to drive. Error on the caution of safety as this is not just your life but the safety of others in the community when driving is involved. Many cities have door to door lift bus services for people with disabilities, look into that as an option and ask your provider about this. ?If affordable, Uber is another service you can take advantage of regarding alternate transportation. ?Having a Plan B and a back up plan for important things is helpful when you cannot attend to it yourself. Wear a medical I.D. bracelet. There are many types available and some allow space for listing multiple diagnoses. ?Wearing more than one in different colors is also an option. Carry a medical I.D. card. Here is a link to a free medical I.D. card: List emergency contacts in your cell phone and include an up-to-date list of your current medications in the ‘notes’ section. ?Discuss emergency care with your neurologist and have him provide an emergency treatment protocol for you to be entered into the computer data base and include that in your emergency contacts on your phone. You may also include links to the above articles in your ‘notes’ section under emergency contacts in your cell phone that an ER attendings can access during emergency room visits, although they will need your permission or be given access by a person accompanying you. ?Have close family and friends keep this information in their phones as well. Post emergency medical telephone numbers and contact information along with emergency medicine to be given or treatment protocol in several visible places in your home. EMTs will usually look on the Refrigerator for such medical information.Behavioral Health. AE can at times be very debilitating. When the brain is under attack and you are in a symptom/disease flare, this can present or mimic a behavioral health problem such as bipolar disorder or schizophrenia. ??Psychosis, delirium, hallucination, depression, and catatonia can over shadow the neurological symptoms occurring. Your behavior may require hospitalization. This tool kit, the articles and your health notebook or cell phone should go with you to the ER or hospital to help your providers understand your health problem. Your POA, legal guardian or family member should be asking for a neurologist to do an evaluation and the attending doctor to review the articles, computer patient information, as well as putting a call into your neurologist. ?Your medical id bracelet is key in ER visits. Every effort to educate the Emergency Room medical staff of your diagnosis should be made. ?Advocate that a hospital admission should be to the neurology floor. ?There are times when patients are referred to the psych ward if their behavior is such that there is a concern for safety for themselves and safety of others. ?All effort should be made to ensure that the patient’s medical records, which you should have copies of and be contained in your notebook/journal are provided to ensure admittance to neurology. ?We try and support that AE patients belong in a neurological bed with first line treatments that are outlined in the above articles and included in our notebook journal ordered to arrest the disease flare. If all aspects of your safety and emergency efforts are in place, there is a higher likelihood of success. ?However, if you are a danger to yourself or others, you will meet criteria for a psychiatric bed. ?Family members, friends and your POA will be in place to ensure neurology is consulted in your treatment plan. Once released from the hospital, you should have a neurological appointment within 7 days to follow up. ?You can ask the Social Worker at the hospital to make that appointment for you or make sure a member of your ‘support circle’ takes that job and makes the appointment for you. Depression. The most URGENT symptom in some of the more common autoimmune encephalitis types is suicidal ideation. Suicidal ideation is not uncommon in anti-NMDAr encephalitis and other autoimmune encephalitis types affecting the limbic system. ?It is the most tragic symptom and requires URGENT emergency immunotherapy treatment. Suicide is especially tragic as it is a preventable death in autoimmune encephalitis. ?Suicidal ideation often goes unreported by the patient and when patients are no longer in a symptom flare, and do discuss their experience they have trouble relating to those thoughts as even being a part of who they are as they are that foreign in nature to them. ?Patients who have no memory of an attempted suicide while in a flare of autoimmune encephalitis are also stunned at what family, physicians or friends later recount about the events that unfolded. The symptoms of depression and suicidal ideation is caused when auto antibodies attack the area of the brain that controls these emotions. ?It can come on quickly and without warning in its severity and has resulted in successful suicide when sufficient suppression of antibodies was not provided. Most AE patients are seen to emerge from severe depression and/or suicidal ideation 3 days after beginning a course of 60mg daily of prednisone or even one gram of IV solumedrol. Educate your POA and family to watch for symptoms of depression: sad mood, restlessness, irritability, sleep disturbance, ?loss of interest and suicidal thoughts. This is a critical part of your safety and self care. Normally, suppression of antibodies can resolve an autoimmune based depression in a short period of time, therefore, discussing emergency treatment protocol with your neurologist is of vital importance. ?Many AE patients have a prescription on file at their pharmacy for prednisone including a taper down for this exact situation of a dramatic symptom flare. ?Others have taken the step to have their prescription filled with directions of how much to take for how many days to bring them out of this type of flare. ?The directions for filling this prescription should be included in your journal or notebook and posted in a specific location in your home. ?Family members, friends and advocates should know where to look for this information. AE may disrupt your lifestyle, relationships and how you knew yourself to be. Compounding being ill, if you do not have a neurologist who specializes in autoimmune encephalitis, you are likely to be undiagnosed or misdiagnosed or under treated. ?(Please refer to our Doctor’s list on our website which is constantly being updated). ?This leaves you in a more vulnerable situation of having to provide evidence to a medical doctor or psychiatrist who is not informed about AE. ?The symptoms of the disease leave you vulnerable to not being able to advocate for yourself. ?Facing daily challenges with cognitive disability and other neurological symptoms is a high stress life. ?Especially if you ?are fighting a particularly aggressive and/or refractory case of autoimmune encephalitis. ?Due to these factors of additional stress the patient is prone to being more vulnerable to symptoms flares as stress is a trigger. We can experience clinical depression that needs to be addressed with your neurologist. ?Often medications are given to augment immunosuppression and facilitate emotional stability on the short term until treatment for the disease is managed and then these medications are tapered off. There are occasions when medications addressing the symptom of depression are an appropriate treatment in addition to treating the cause which is AE itself. Since some neuroleptic medications and medications used to treat some neuropsychiatric symptoms can act as antagonists with autoimmune encephalitis it is important that the neurologist prescribe as they know what medications will not exacerbate your symptoms or AE. Serious depression and thoughts of suicide are mainly rooted and linked to the disease course and how it is manifesting. ?However, the patient is made more fragile by having to contend with the above described daily life. ?We would encourage you seek out support from a local ER as they have many treatments to help with this and help you feel better soon. If you have autoimmune encephalitis and feel depressed, see your neurologist right away, and be sure to tell them you are feeling depressed or suicidal. International Autoimmune Encephalitis society also runs a support group available on Facebook. ?The link to that location is: ?the group was nominated in 2016 for “Best in Show” and “Best Health Activist” in the WEGO HEALTH AWARDS.You are not alone and IAES can assist you in overcoming many of the challenges in living with AE and receiving the best possible treatment plan for the disorder. ?Insurance assistance, overcoming treatment denials and many other hurdles a patient faces are addressed as well as emotional and personal support. Keep a health notebook that includes: Providers, address, phones and faxes. Insurance information.Pharmacy address, phone and fax.Copies of the articles in your tool kit.Emergency Treatment protocol from your Neurologist and stated diagnosisMedications and supplements and doses and schedule to administer. Medications you are allergic to and other allergies.POA and emergency contacts with a written release of information for the people who may assume your care. Disc Copy of EEG, MRI, or any scans (you can request copies and include the most recent copy in a plastic protective holder)Create separate sections for labs, specialty, and a daily journal that will read as a time line. The journal should have the date, symptoms, medication changes, provider/hospital visits, daily vitals if you keep these, ?accidents, job loss etc. Time Line. If you can recreate on a time line your whole medical history this will be helpful. Some keep this electronically as an email file that can be easily accessed. When you attend testing, or have labs, get a diagnosis, etc. be sure to get a copy and keep that in your notebook. The notebook can speak for you when you can’t, can’t remember clearly or ensure that your record is not going to take weeks to transfer from the multiple providers you have seen so will help to expedite your care. InsuranceYour insurance company will want to spend as little money as possible on your care. If medical evaluations are currently being done for Autoimmune Encephalitis as a differential diagnosis, call the number on the back of your insurance card and ask to have a nurse case manager assigned to you. Send them the articles in this tool kit and tell them you want your Autoimmune Encephalitis problem addressed correctly and do not want to waste your time or their money on incorrect diagnoses or treatments. Have your neurologist be prepared with showing your insurance company the tests which have been done such as FDG-PET, EEG, Lumbar puncture, MRI with and without contrast, antibody testing for AE, paraneoplastic panel, anti-NMDAr antibody tests in blood and spinal fluid, which will support the diagnosis of Autoimmune Encephalitis. Physician documentation of treatments received, such as a six day trial/short course of 60mg steroid with a finding that suppression of antibodies resulted in improvement, can assist in differentiating an autoimmune basis compared to other disease. Most insurance companies do not understand autoimmune encephalitis. This disorder is often incorrectly coded by staff at the hospital, infusion center or doctor’s office which leads to treatment denials. ?Please be aware that a treatment denial stated as ‘investigational’ or ‘experimental’ is often the result of a clerical error with an incorrect diagnostic code being used on a prior authorization for treatment. ?This occurs frequently because autoimmune encephalitis is not a common illness and medical staff in charge of putting prior authorizations through to insurance companies for treatment have often never done so for this disorder. ?Additionally, there are a few diagnostic codes for AE to choose from resulting in an increased chance of error resulting in a treatment denial. The specific diagnostic code for Autoimmune Encephalitis that should be used is: G04.81 (in the United States). ?This code includes Limbic encephalitis, ADEM and paraneoplastic autoimmune encephalitis. ?There is an abundance of research showing these disorders improve with Cellcept, Imuran (Azathioprine), IVIG, plasmapharesis, Rituxan, and Cytoxan and that these treatments are safe and effective in the treatment of autoimmune encephalitis. ?It is for this reason that the G04.81 will not be denied while other diagnostic codes will. ?(Please contact IAES for a list of research addressing these treatments individually as safe and effective for Autoimmune Encephalitis when you know your physician will be putting in for a prior authorization for one of these treatments or if you are faced with a denial). Confirming that this diagnostic code, G04.81, is being used in your prior authorization (the neurologist often uses several diagnostic codes G04.81 is the main one. Most patients have a few other conditions as a result of their AE) and that the peer-reviewed research showing the treatment to be safe and effective for autoimmune encephalitis is included with the prior authorization will prevent the insurance company from denying your treatment is many cases. Autoimmune Encephalitis is a life-threatening disease and requires urgent care aggressive treatment for the best documented outcomes. ?Just as Type 1 diabetes destroys the pancreas, in time, antibodies attacking the brain’s healthy brain cells can and does cause neuronal injury and/or death. ??If your insurance company denies you access to a specialist, then you must ask them to refer you to a Neuroimmunologist or neurologist who has a documented history in treating autoimmune encephalitis through their published work or mention on their bio. ?Since experts in the field are few, given that the first antibody in AE was only identified in 2005, the insurance company will be obligated to cover the cost of an expert out of network since they cannot provide you with one that is in network. ?The insurance company may not want to risk the liability of being wrong and may pay for the consult or out of network provider. If they will not, we encourage you to find a way to get to a specialist and complete the assessment for Autoimmune Encephalitis. International Autoimmune Encephalitis Society can refer you to organizations who provide free air transportation and low cost accommodations. You can also ask that the insurance company staff your case in their grand rounds. Specifically request insurance consult a neurologist in their rounds to provide your neurologist guidance on why a specialist neurologist/Neuroimmunologist in autoimmune encephalitis is not needed. Have your neurologist request this in writing and ask insurance to respond in writing. Continue weekly calls for support with your Nurse Case Manager as they have to document your progress or lack of progress in each call. They can also be a good resource for records, services, and ongoing support.Finances/Paying for CareIf you are working and have AE, you are likely having some challenges working or are not able to work. Be sure to document this along with your symptoms in your journal or app. Getting an AE diagnosis is difficult and time consuming due to long appointment waiting times and the amount of testing involved. Often, we are deemed “sick” but do not yet meet a diagnostic category that confirms a disability. Having a rule out of G04.81 diagnosis (a diagnosis is arrived at by ruling out what it is not to confirm what it is) may be enough to qualify you for FMLA or not, as criteria for this are different state to state. Your county should have a Department of Vocational Rehabilitation, which is a federal program to help disabled persons with employment. Google Department of Vocational Rehabilitation and add your state and county to the search. They offer support, testing, job training for persons with disabilities. Be prepared to show proof of your financial circumstance. ?Be prepared for more testing and the process to take several months. Be prepared to request help or ask if there is a social worker or patient advocate available to assist you in filling out the required forms as these tasks are daunting if you’re contending with a cognitive problem.Generally, Insurance companies, Medicaid, and Medicare cover encephalitis of all types. It is necessary to have proper coding and expert articulation written by the treating neurologist. When it comes to hospital bills one no longer needs to sign a repayment plan. ?Based on your income under the 2015 Law named financial assistance or charity care, any families with a household income under $70,000 a year qualify under the new law. This new law only applies to non-profit hospitals and not providers. This law can also be used to decrease copays and deductibles depending on your income and after insurance has paid. 26 USC 501 ? (3) (5) Limitation on charges.An organization meets the requirements of this paragraph if the organization— (A) limits amounts charged for emergency or other medically necessary care provided to individuals eligible for assistance under the financial assistance policy described in paragraph (4)(A) to not more than the amounts generally billed to individuals who have insurance covering such care, and(B) prohibits the use of gross charges.It normally requires the Hospital bill be written off in total if the family yearly income is under 200% of the poverty level depending on that hospitals Financial Assistance Policy published on the Internet. Contact the hospital’s Chief Financial Officer. By law they are mandated to do this if you ask for it. Know they will have to use your last year’s income record and this will work against you if your finances changed drastically from when you were well to when you were ill. ?Be prepared to show your records of this. Often the price the Hospital would charge insurance is greatly reduced when you’re paying out of pocket, no matter what your earnings. The provider does not have to abide by the minimum services rendered rule because insurance is not paying so service quality and treatment may be better and more efficacious.Department of Assistive and Rehabilitative Services (DARS) is where the process starts to apply for disability. This is a long process even for partial disability and a decision to apply should be discussed with your doctor. You will need their recommendation and an attorney.Brief by Josep Dalmau, Domingo Escudero, Francesc Graus Lancet Neurology 2016 Apr; 15(4):391-404 Position Paper A clinical approach to diagnosis of autoimmune encephalitis Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, H?ftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J. Acute encephalitis is a debilitating disorder that develops as a rapidly progressive encephalopathy (less than 6 weeks) caused by brain inflammation. The estimated incidence is 5-10 patients per 100000 inhabitants per year. The most frequent recognized causes of encephalitis are infectious and thus the existing diagnostic criteria and consensus guidelines are focused on an infectious origin. In the past ten years a growing number of non-infectious, mostly autoimmune, encephalitis have been identified. These newly identified forms of autoimmune encephalitis frequently associate with antibodies against neuronal cell-surface or synaptic proteins. Some of them can develop with core symptoms resembling infectious encephalitis, and also with neurological and psychiatric manifestations without fever or CSF pleocytosis. It is not realistic to include antibody status as part of the early diagnostic criteria of autoimmune encephalitis in view of the fact that: antibody testing is not readily accessible in many centers, or it can take weeks to obtain results absence of antibodies does not exclude an autoimmune origin Moreover, response to immunotherapy as part of diagnostic criteria is not practical because many patients with autoimmune encephalitis do not respond to the most frequently used first line immunotherapies (steroids, IVIg plasma exchange) or the response may take several weeks potentially delaying the diagnosis. Clinical facts and reported evidence suggesting that early immunotherapy improves outcome were considered in the development of the current guidelines, in which conventional neurological examination and standard diagnostic tests prevail in the initial assessment. This approach should allow the initiation of preliminary treatment while other studies and antibody tests are processed and used to refine the diagnosis and treatment. Panel 1. Diagnostic criteria for possible autoimmune encephalitis All three of the following: 1.- Subacute onset (less than 3 months) of working memory deficits, altered mental status or psychiatric symptoms. 2.- At least one of the following: - New focal CNS findings Seizures (new onset) CSF pleocytosis (more than five cells per mm3 in white cell count) MRI features suggestive of encephalitis 3.- Reasonable exclusion of alternative causes: CNS infection, septic encephalopathy, metabolic encephalopathy, drug toxicity (including seizures by drugs, posterior reversible encephalopathy, serotoninergic syndrome, neuroleptic malignant syndrome, drug withdrawal), cerebrovascular disease, neoplastic disorders, Creutzfeldt-Jakob disease, epileptic disrodersdisorders, rheumatologic disorders (lupus, sarcoidosis, others), Kleine-Levin, Reye syndrome (in children), mitochondrial diseases, inborn erroserrors metabolism (children) These guidelines should be applied with caution in children, particularly in they are younger than 5 years. Panel 2. Diagnostic criteria for definite autoimmune limbic encephalitis All four of the following criteria: 1.- Subacute onset (less than 3 months) of working memory deficits, seizures or psychiatric symptoms. 2.- Bilateral MRI brain abnormalities on medial temporal lobes (PET may be more sensitive) 3.- At least one of the following: CSF pleocytosis (more than 5 white cells per mm3) EEG with epileptic or slow wave activity in temporal lobes 4.- Reasonable exclusion of alternative causes: Lupus, Sj?gren's, Kikuchi, Beh?et, glioma, herpes, syphilis, Whipple. If one of the first three criteria is not met diagnosis of definite LE can be made only by the detection of antibodies against cell-surface, synaptic or onconeural proteins. Panel 3. Diagnostic criteria for definite acute disseminated encephalomyelitis (International Pediatric MS Study Group) All five of the following: 1.- A first multifocal clinical CNS event of presumed inflammatory demyelinating cause 2.- Encephalopathy that cannot be explained by fever 3.- Abnormal brain MRI: Diffuse, poorly demarcated large (1-2 cm) lesions in white matter T1 hypointense lesions in white matter in rare cases Deep gray matter abnormalities (thalamus, basal ganglia) can be present 4.- No new clinical or MRI findings after 3 months of symptom onset 5.- Reasonable exclusion of alternative causes Panel 4. Diagnostic criteria for anti-NMDA receptor encephalitis (antiNMDAR) Probable anti-NMDAR All three of the following: 1.- Rapid onset (less 3 months) of at least four of the six following major groups of symptoms: Abnormal (psychiatric) behaviour or cognitive dysfunction Speech dysfunction (pressured speed, verbal reduction, mutism) - Seizures Movement disorder, dyskinesias, or rigidity/abnormal postures Decreased level of consciousness Autonomic dysfunction or central hypoventilation 2.- At least one of the following lab study results: Abnormal EEG (focal or diffuse slow, epileptic activity or extreme delta brush pattern) CSF with pleocytosis or oligoclonal bands 3.- Reasonable exclusion of other disorders Diagnosis can also be made in the presence of three of the above groups of symptoms accompanied by a systemic teratoma Definite anti-NMDAR Diagnosis can be made in the presence of one or more of the six major groups of symptoms and IgG anti-GluN1 antibodies after reasonable exclusion of other disorders. Antibody testing should include CSF. If only serum is available, confirmatory test should be included (live neurons or tissue immunohistochemistry in addition to cell-based assay) Panel 5. Diagnostic criteria for Bickerstaff's brainstem encephalitis Probable: When both of the following criteria have been met: 1.- Subacute onset (less than 4 weeks) Decreased levels of consciousness Bilateral external ophthalmoplegia - Ataxia 2.- Reasonable exclusion of alternative causes Definite: Diagnosis can be made in the presence of positive IgG anti-GQ1b antibodies even if bilateral external ophthalmoplegia is not complete or ataxia cannot be assessed or if recovery has occurred within 12 weeks after onset Panel 6. Diagnostic criteria for Hashimoto's encephalopathy All six of the following: 1.- Encephalopathy with seizures, myoclonus, hallucinations or stroke-like episodes 2.- Subclinical or mild overt thyroid disease (usually hypothyroidism) 3.- Brain MRI normal or non-specific abnormalities 4.- Presence of serum thyroid (TPO, TGB) antibodies (no disease-specific cutoff) 5.- Absence of well characterized neuronal antibodies in serum or CSF 6.- Reasonable exclusion of alternative cause Panel 7. Criteria for autoantibody-negative but probable autoimmune encephalitis All four of the following: 1.- Rapid progression (less than 3 months) of working memory deficits (shorttermshort-term memory loss), altered mental status, or psychiatric symptoms 2.- Exclusion of well definedwell-defined syndromes of autoimmune encephalitis (Bickestaff's brainstem, typical limbic, acute disseminated encephalomyelitis) 3.- Absence of well characterized autoantibodies in serum and CSF, and at least two of the following: MRI abnormalities suggestive of autoimmune encephalitis (excluding some mitochondrial or metabolic causes with symmetrical patterns) - CSF pleocytosis, CSF-specific oligoclonal bands or elevated CSF IgG index, or both Brain biopsy showing inflammatory infiltrates and excluding other disorders (eg. tumor) 4.- Reasonable exclusion of alternative causes Clinical key points A substantial number of patients with autoimmune encephalitis (AE) do not present with a well-defined syndrome but in some cases, demographic information and some comorbidities (diarrhea, ovarian teratoma, faciobrachial dystonic seizures) might initially suggest the underlying disorder (DPPX, NMDAR or LGI1 autoantibodies), although these features are not pathognomonic and might be absent in some patients. In such cases, the diagnosis of definite autoimmune encephalitis depends on the results of autoantibody tests. In other patients, the clinical syndrome and MRI findings allow for classification as probable or definite AE before the autoantibody status is known (limbic encephalitis, acute disseminated encephalomyelitis). In limbic encephalitis (LE) there is a rapid development of confusion, working memory deficit, mood changes and often seizures. The subacute memory loss is a hallmark of the disorder but it can be overlooked easily because of the presence of other symptoms. CSF analysis shows mild to moderate lymphocytic pleocytosis in 60-80% of patients (usually less than 100 white cells per mm3) and elevated IgG index or oligoclonal bands in 50%. Among all the subtypes, patients with LGI1 antibodies present with a lower frequency of CSF pleocytosis (41%). In these patients, the absence of inflammatory changes in the CSF might initially suggest a non-inflammatory encephalopathy. MRI often shows increased signal on T2 FLAIR in the medial aspect of the temporal lobes. LE can present with unilateral involvement or with normal MRI and then the diagnosis requires positive antibodies. The onconeural antibodies that more frequently occur with LE are antiHu and anti-Ma2. The neuronal cell-surface antibodies more frequently involved are LGI1, GABARb, and AMPAR. Patients with antibodies against GAD (an intracellular antigen) may also develop limbic encephalitis. Acute disseminated encephalomyelitis (ADEM) is a monophasic, inflammatory disease of the CNS that mainly occurs in children and adults younger than 40 years. ADEM can be preceded by an acute systemic infection or vaccination. There is a variable encephalopathy along with focal neurological deficits. The CSF usually shows mild pleocytosis (≤ 50 cells/mm3). Oligoclonal bands are uncommon (less than 7% of patients). Criteria of ADEM require absence of new clinical and MRI findings 3 months after symptom onset. Transient detection of MOG (myelin oligodendrocyte glycoprotein) antibodies occur in 50% of children with ADEM, but these antibodies are not part of the criteria. In Susac's syndrome, a rare autoimmune vasculopathy, there is microvessel involvement of the brain, retina, or inner ear and up to 75% of the patients develop encephalopathy. Typical findings include branch retinal occlusions and MRI abnormalities involving the corpus callosum and periventricular regions. Anti-NMDAR encephalitis is frequently recognizable on clinical grounds and is associated with CSF IgG antibodies against the GluN1 subunit of the NMDA receptor. In a series of 577 patients by Titulaer et al., 95% of the patients were younger than 45 years, and 37% younger than 18 years. The ratio female:male was 4:1. An underlying ovarian teratoma was identified in 58% of women older than 18 years. Patients usually develop abnormal behaviour (psychosis, delusions, hallucinations, agitation, aggression or catatonia) along with irritability, insomnia, speech dysfunction, dyskinesias, memory deficits, autonomic instability, and decrease of the level of consciousness. Seizures can occur at any time during the disease, but tend to occur earlier in males. Young children more frequently present with abnormal movement or seizures. When the diagnostic criteria shown in Panel 4 were applied, 80% of the patients fulfilled these criteria within the first month of symptom onset. The criteria were fulfilled by 75% of patients without teratoma and 90% of patients with teratoma. Antibody studies should include CSF analysis; a risk of false-negative or false-positive diagnoses exist if only serum is used. Findings from three other studies have suggested that serum testing is less consistent, or showed antibodies in patients without anti-NMDAr or immune-mediated disorders. Analysis of CSF for the presence of anti-NMDAr antibodies is mandatory in patients with relapsing symptoms after herpes simplex encephalitis. This complication occurs in 20% of patients with this viral encephalitis, and manifests with new-onset choreoathetosis (in children) or psychiatric symptoms (adults and teenagers), a few weeks (rarely months) after the viral infection. Bickerstaff's encephalitis is usually preceded by an infectious event, runs a monophasic course, and has a good outcome. In addition to symptoms of brainstem dysfunction (pupillary, facial, bulbar), patients develop generalized limb weakness, which overlaps with features of Guillain-Barré syndrome. CSF pleocytosis occurs in 45% of the patients, and FLAIR brain MRI abnormalities in up to 20%. Anti-GQ1b antibodies are highly specific for this disorder and the related Miller-Fisher syndrome, facilitating the diagnosis in patients with incomplete, atypical symptoms or with associated encephalopathy. The differential diagnosis includes Listeria, enterovirus EV71, paraneoplastic or infectious brainstem encephalitis, CLIPPERS, neurosarcoidosis, and primary CNS lymphoma. Antibody testing Detection of specific autoantibodies establishes a definite diagnosis of AE, identifies immunological subtypes of LE, and assists in the differential diagnosis of atypical clinical cases. Therefore, antibody testing is a crucial step in the definite diagnosis of many types of AE. Several concepts that apply to classic onconeural or GAD antibodies are not applicable to antibodies against neuronal cell-surface proteins. Onconeural and GAD antibodies target intracellular proteins and because these antibodies are present in serum and CSF, and their epitopes are linear, they are detectable with many techniques including ELISA, immunoblotting, and immunohistochemistry. By contrast, antibodies against neuronal cell-surface proteins have different properties that should be considered for a better understanding of the most appropriate test to use and interpretation of the results. Conformational antigens. Most antibodies against neuronal cell-surface proteins recognize target epitopes only if they are expressed in their native conformation. Techniques that meet this requirement are cell-based assays (most clinical laboratories), immunohistochemistry of brain sections adapted to membrane proteins (commercially available; sometimes used as a confirmatory test) and immunohistochemistry of cultures of dissociated rodent live hippocampal neurons (only used in research laboratories). Molecular precision. The NMDA receptor is a heterotetramer comprised of two GluN1 subunits and two GluN2/3 subunits. Detection of IgG antibodies against the GluN1 subunit is a signature of anti-NMDAr encephalitis. By contrast, antibodies against linear epitopes of GluN2 have been reported in different disorders, providing an uncertain clinical significance (e.g. lupus). Antibodies considered against VGKC (voltage-gated potassium channels) do not target these channels; they are direceted against LGI1 or CASPR2 proteins. These antibodies have well defined syndrome associations. By contrast, antibodies named “VGKC complex antibodies” that do not target LGI1 or CASPR2 are not syndrome specific and should not be used as demonstration of an immunemediated pathogenesis. Immunoglobulin class. The antibodies associated with autoimmune encephalitis are IgG antibodies. IgA or IgM antibodies against any of the indicated antigens have unclear significance. CSF Studies The investigation of CSF antibodies is important: 1.- Most patients with AE have CSF antibodies, and relevant antibodies might be found only in CSF. In anti-NMDAr, up to 14% of patients have antibodies in the CSF, but not in the serum. 2.- The repertoire of antibodies in the CSF and serum can be different in the same patient (eg, NMDAr in serum and CSF and GABARb only in serum), and in this setting, the antibody found in CSF usually determines the clinical picture. 3.- For some disorders, like anti-NMDAR encephalitis, the titer of CSF antibodies correlates better with the clinical course than the titer in serum. 96652175115424.- Neuronal antibody testing using serum and cell-based assays could lead to false positive or false-negative results; this problem rarely occurs with CSF analysis. While awaiting larger studies with autoantibodies, our recommendation is to include both CSF and serum for neuronal antibody testing in patients with suspected AE. The approach of first testing serum and subsequently testing CSF (if the serum is found negative), should be avoided because it can delay the diagnosis If serum is positive and CSF negative or if the clinical picture does not fit with the antibody identified, the possibilities of a result unrelated to the syndrome or a false-positive should be considered. The laboratories should be contacted in order to reassess the samples or use confirmatory tests like brain immunohistochemistry or cultured neurons. Treatment decisions during the course of the disease should rely more on clinical assessment than on antibody titers. Although the titers might correlate with the clinical course, this correlation is imperfect, and antibodies often remain detectable after clinical recovery. Seronegative AE After excluding all well characterized syndromes of AE (with or without autoantibodies) and other syndromes accompanied by well-defined autoantibodies, there is still a subgroup of possible AE that remains without a final diagnosis (panel 1). Patients in this group can be regarded as having probable AE if they fulfill criteria of Hashimoto's encephalopathy (panel 6) or the criteria shown in panel 7. Patients with Hashimoto's encephalopathy are classically considered to show a good response to steroids. The disorder is considered immune mediated despite the unclear physiopathology and the absence of response to prednisone in the patient of the original report. Most patients are women with a wide age range. About 60-70% of the patients have thyroid dysfunction. Patients usually develop seizures, myoclonus, hallucinations, and stroke-like episodes. MRI and CSF studies are normal or with non-specific findings. Because most patients respond to corticosteroids, the disorder has been recently re-named as steroid-responsive encephalopathy with autoimmune thyroiditis (SREAT). Thyroid antibodies are not specific for Hashimoto's encephalopathy because they are present in up to 15% of healthy individuals (25% in women older than 60 years). Other poorly defined syndromes with no antibodies can be regarded as probable AE if they fulfill the criteria shown in panel 7. 9665218991099665219477451 The absence of CSF pleocytosis does not rule out AE (60% of LGI1 encephalitis do not have pleocytosis). Normal routine CSF studies do not imply that there is no intrathecal IgG synthesis or an absence of CSF antibodies. AE can occur with normal or atypical MRI findings In children, several genetic disorders, mitochondrial diseases or leukodystrophies can develop with CSF and MRI abnormalities similar to those found in AE and might also respond to steroids. Patients who meet criteria of probable AE but do not have well-characterized autoantibodies (panel 7) should be investigated for new antibodies in serum and CSF. The importance of these studies surpasses the clinical significance of inflammatory infiltrates in a brain biopsy, which may suggest an inflammatory process but cannot establish the autoimmune etiology. There are several autoimmune CNS disorders that can be considered in the differential diagnosis of AE. These are summarized in the appendix, including Rasmussen's encephalitis, primary CNS angiitis, Morvan's syndrome and other disorders of unclear cause like FIRES (febrile infection-related epilepsy syndrome). Implications and directions for future research This position manuscript demonstrates that it is possible to proceed through a logical differential diagnosis of AE using criteria based on conventional clinical neurological assessment and standard diagnostic tests (MRI, EEG and CSF studies). Levels of evidence can be achieved early and therapies implemented quickly, with the possibility of fine-tuning the diagnosis and treatment when antibody results become available. The stepwise escalation of immunotherapy, which includes first-line therapy (steroids, IVIg, plasma exchange, or both) followed, if there is no clinical response, by second-line therapy (rituximab, cyclophosphamide, or other), is often used in the treatment of anti-NMDAR encephalitis and other types of AE, but rituximab is increasingly being considered as a first-line therapy. Not all AE need a similar approach. Patients with LE and LGI1 antibodies appear to respond faster and better to steroids than patients with anti-NMDAR encephalitis, yet the long-term outcome is better in the last group. Seronegative AE.____________________________________________________________Neuropsychiatric symptoms in autoimmune encephalopathies: a clinician’s guide Fátima Carvalho1, Jo?o Massano1,2, and Rui Coelho1,3 Features that should raise the suspicion of autoimmune etiology in case of atypical psychiatric presentation, particularly in first episode of psychosis or mania.Recent flu-like syndrome No past psychiatric illness Rapid onset of psychosis and/or catatonia Seizures/neurological dysfunction Known history of malignancy, especially if SCLC, teratoma or thymus cancer Signs of autonomic dysfunctionWorsening of symptoms after antipsychotic therapy Refractory hyponatremiaLong history of smokingPersonal/family history of auto-immune disease Differential diagnosis of suspected autoimmune encephalopathies:Paraneoplastic encephalitis Non-paraneoplastic autoimmune encephalitis Viral encephalitis Dementia, including neurodegenerative diseases (e.g. Alzheimer disease, Frontotemporal dementia) Malignancy (glioma, lymphoma) Temporal lobe seizuresWilson’s DiseaseHuntington’s disease Endocrine dysfunction (hypothyroidism) Toxic-metabolic encephalopathy (e.g. sepsis, liver failure) Vitamin deficiency (Wernicke-Korsako encephalopathy, B12 or folic acid defi ciency) Autoimmune systemic disorder (lupus erythematosus, vasculitis, Sj?gren’s syndrome) Neurosyphilis Creutzfeldt-Jakob disease Primary psychiatric disorder Management and follow-up Once other relevant causes have been ruled out, immuno- therapy should be considered in all cases. Since most disorders are rare and/or were recently classified, there are no robust randomized clinical trials providing evidence-based data. Current treatment options are based on case reports and uncontrolled case series. Cancer treatment should al- ways be carried out, when applicable [56, 62], since combined treatment typically results in more favorable out- come than immunotherapy alone [97]. Treatment includes high-dose corticosteroids (CSTs), intravenous immunoglobulin (iv-Ig) and plasma exchange as first line immunotherapy. Rituximab, azathioprine, and cyclophosphamide are considered second line therapeutic interventions, thus prescribed when individuals fail to respond to first line drugs. Due to the high occurrence of re- lapsing disease, chronic immunosuppressant therapy with mycophenolate mofetil or azathioprine can also be considered. It has been suggested that the response to treatment could be evaluated with the modified Rankin Scale (mRS); Table 4. Suggested auxiliary exams according to suspected underlying malignancy. Suspected malignancy SCLCNon-SCLC Thymoma Testicular cancer Teratoma Breast cancer Suggested diagnostic exams Chest CT; if negative FDG-PET Ultrasonography; if negative pelvic CT Pelvic ultrasonography; if negative CT/MRI of pelvis/abdomen; if negative chest CT Mammography; if negative MRI; if negative FDG-PET CT = Computed tomography; FDG-PET = Fluorodeoxyglucose positron emission tomography; MRI = Magnetic resonance imaging; SCLC = Small cell lung cancer.First Aid Tool Box for persons undergoing a diagnosis for Autoimmune Encephalopathy and their families. ................
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