Limbic Encephalitis

Limbic Encephalitis

July-22-2020 | Nitsan Goldstein, PennNeuroKnow

What is limbic encephalitis?

Limbic encephalitis is a type of autoimmune encephalitis (AE) that targets the brain’s limbic system. The limbic system is a group of brain structures that underlie memory and emotion (Fig. 1). The term limbic encephalitis is slightly misleading, however. The disease does not affect all areas of the limbic system and frequently involves non-limbic regions as well1. The classification, however, can be useful to categorize several specific types of encephalitides that target similar regions of the brain and thus result in common symptoms, even though they may arise from different antibodies and underlying causes. Some of the more common types of AE that fall into this category are caused by antibodies against LGI1, the GABAB receptor, and the AMPA receptor.

The major brain structures of the limbic system include the amygdala and the hippocampus (Fig. 1). The amygdala is critical in regulating emotion while the hippocampus is primarily responsible for creating new memories. Regardless of the root cause, the different types of limbic encephalitides disproportionally affect these regions1. This is likely because these regions contain higher levels of the proteins that the antibodies target. Even when doctors cannot identify the antibody that is causing encephalitis, scientists can determine which areas of the brain have high levels of antibody activity. By exposing rodent brains to the cerebrospinal fluid (CSF) from patients containing the antibody, the scientists see that binding of the antibody to neurons is much higher in the hippocampus, for example, than other areas1.

limbic-encephalitis

Figure 1. The Limbic System. The temporal lobes (green, left) are located on the sides of the head, behind the ears. The image to the right shows the inside of the brain. The temporal lobe houses the hippocampus (blue, right), and the amygdala (purple, right) which are two of the major brain structures that make up the limbic system.

While the symptoms and progression of limbic encephalitis vary widely, there are several commonly experienced symptoms due to the similarities in affected brain regions. Patients typically become irritable, depressed, and have trouble sleeping. These signs may rapidly give way to seizures, hallucination, and severe short-term memory loss1. As the disease progresses and begins to involve other parts of the nervous system, symptoms vary even more widely based on which antibody is present. For example, patients with antibodies against an intracellular protein called Hu experience loss of sensation and even loss of reflexes due to spinal cord neuron damage2.

What causes limbic encephalitis?

There are two main causes of limbic encephalitis: viruses and an autoimmune response. An infection with a virus such as the herpes-simplex virus (HSV) can cause a disease called viral encephalitis1,3. In this case, it is the virus itself that attacks the cells in the limbic system. Thus, while it is a type of limbic encephalitis, it is not an autoimmune disease since it is a foreign agent that is attacking the brain rather than the body’s own antibodies. Viral infections can, however, trigger a patient’s own immune system to attack the brain, resulting in autoimmune encephalitis3.

Non-viral causes result from an autoimmune response involving  either cytotoxic T-cells or antibodies. Cytotoxic T-cells arise as a result of a cancerous tumor. In limbic encephalitis, these T-cells target proteins inside neurons (common proteins targeted are Hu and Ma2)2,4. In contrast, limbic encephalitis caused by antibodies rather than cytotoxic T-cells may develop in response to cancerous tumors or benign tumors. In fact, many cases of limbic encephalitis are not associated with tumors at all5. These antibodies target proteins on the surface of neurons like the GABAB receptor, the AMPA receptor or, in the case of LGI1 limbic encephalitis, the voltage gated potassium channel complex5. In either case, neuronal damage is found in limbic regions, explaining why similar symptoms may be observed with these seemingly distinct diseases1,5.

Diagnosis and treatment

When patients present with symptoms indicating a possible diagnosis of limbic encephalitis, there are several diagnostic tests that are typically performed to confirm the diagnosis. An electroencephalogram (EEG) is administered to measure electrical brain activity. EEG electrodes are placed throughout the scalp, allowing doctors to pick up seizure-like activity in the brain and often isolate where in the brain the seizures originate. EEGs from patients with limbic encephalitis frequently suggest involvement of the temporal lobe1. The temporal lobe houses the amygdala and hippocampus and is therefore often the source of seizures in limbic encephalitis. A magnetic resonance imaging (MRI) scan is also performed which gives doctors an image of the brain. Differences in contrast can indicate that the blood brain barrier is compromised in the temporal lobe, giving the antibodies access to neural tissue1. Finally, doctors can take samples of patients’ CSF, which may have increased immune cells and other markers of inflammation1. However, the findings of any one of these diagnostic tests can be normal which can make diagnosis challenging. Therefore, the results from all tests are considered when making a diagnosis.

Despite the devastating effects autoimmune limbic encephalitis may have on patients, many people are able to fully recover following treatment, though long-term recovery depends on the specific type of encephalitis1,5. The treatment involves removal of the tumor or other growths that initiated the antibody or T-cell production. In cases where antibodies against cell-surface proteins were present, removing the root cause along with a course of steroids and immunotherapy to restore the immune system can be an extremely successful treatment. In cases where cytotoxic T-cells attack intracellular proteins, patients often continue to experience symptoms even after removal of the tumor2. A variety of T-cell therapies can be tested to see if any lead to improvement in individual patients1. The hope is that future and ongoing research on treatment-resistant types of limbic encephalitis will guide individualized care and improve patient outcomes.

References:

  1. Erdem, T. & Dalmau, J. Limbic Encephalitis and Variants: Classification, Diagnosis and Treatment. The Neurologist 13, 261-271 (2007).
  2. Dalmau, J., Graus, F., Rosenblum, M.K., & Posner, J.B. Anti-Hu–associated Paraneoplastic Encephalomyelitis/Sensory Neuronopathy. A Clinical Study of 71 Patients.  Medicine (Baltimore) 72, 59‐72 (1992).
  3. Venkatesan, A. & Murphy, O.C. Viral Encephalitis. Neurol Clin. 36, 705-724 (2018).
  4. Ortega Suero, G., Sola-Vallsm, N., Escudero, D., Saiz, A., & Graus, F. Anti-Ma and anti-Ma2-associated paraneoplastic neurological syndromes. Neurologia 33, 18‐27 (2018).
  5. Dalmau, J. & Graus, F. Antibody-Mediated Encephalitis. N Engl J Med. 378, 840-851 (2018).

Figure 1 created using BioRender

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Treatments for Autoimmune Encephalitis

Treatments for Autoimmune Encephalitis

June-24-2020 | Carolyn Keating, PennNeuroKnow

As the name suggests, autoimmune encephalitis (AE) is a group of diseases in which the body’s immune system attacks the brain.  To treat it, there are a variety of therapies that target different aspects of the immune system.  The goal of these immunotherapies is to reduce brain inflammation and the resulting symptoms, as well as maintain these improvements by preventing relapses1.

Immunotherapy is most successful in patients with antibodies against cell-surface proteins (such as NMDR, LGI1, and Caspr2).  These diseases tend to be caused by B cells and autoantibodies.  In contrast, when antibodies are directed against molecules inside of cells (such as Hu, Ma, or GAD65) the disease is usually mediated by T cells, and these patients typically do not respond as well to immunotherapy.  It should also be noted that removal of any disease-associated tumors, such as the ovarian teratomas frequently seen in NMDAR encephalitis or tumors seen in patients with intracellular antigens, should be an early treatment priority as removal quickly produces improvements2.  However, there are currently no standardized treatment guidelines; at present, different regimens are used based on the patient’s particular condition and clinical status, as well as the opinion of their doctor.

iv-dripFirst-line Treatments

The first treatment for most patients is typically steroids, also calledcorticosteroids.  Corticosteroids act to broadly inhibit inflammation in multiple ways, which results in the depletion of mainly T cells.  They offer the additional benefit of restoring the blood-brain barrier (BBB), which can be impaired in

 AE. However, corticosteroids aren’t perfect.  They have many side effects, and can aggravate or even induce psychiatric symptoms associated with AE such as depression, insomnia, agitation, and psychosis.  What’s more, corticosteroids do not target B cells, the cells that go on to produce the antibodies that cause many of the symptoms of AE3.

Two other first-line therapies do target autoantibodies.  One is administration of intravenous immunoglobulin (IVIg). IVIg is a blood product prepared from the serum of more than 1,000 donors that contains a broad range of antibodies. Some of these antibodies target a patient’s autoantibodies and neutralize them, along with other pro-inflammatory aspects of the immune system3.  The other first-line treatment targeting autoantibodies is plasma exchange (PLEX, also called plasmapheresis). PLEX “cleans” the blood of autoantibodies by replacing the liquid plasma portion of a patient’s blood with that of a donor.  PLEX also changes T and B cells in favorable ways.  A more refined form of PLEX called immunoadsorption has also been used to treat AE, and selectively removes antibodies from the blood, instead of all the other components that are also in the plasma3.  However, both PLEX and immunoadsorption only remove antibodies from the blood, not from the brain; although decreasing antibodies in the blood can lead to a decrease in the brain4.  Furthermore, all first-line treatments but especially PLEX require a good deal of patient compliance, which can limit their use if the patient is agitated or displays other behavioral problems5.

Different subtypes of AE respond differently to treatment.  For instance, patients with LGI1 antibodies who are diagnosed early are often responsive to corticosteroids alone.  In contrast, only about 50% of patients with NMDAR antibodies are responsive to first-line treatments, and the remaining require second-line therapies6.

Second-line Treatments

There are two main second-line immunotherapies for AE. The first is a drug that destroys B cells called rituximab.  Rituximab is actually an antibody that targets B cells, which normally go on to become antibody-producing cells.  It is expected to work particularly well in patients with LGI1 and Caspr2 autoantibodies. However, because B cells can cross into the brain and become antibody-producing cells, but rituximab cannot cross the BBB, its effects may be limited3.

The other second-line treatment is a chemotherapy drug called cyclophosphamide. Cyclophosphamide directly prevents T and B cells from multiplying, but it affects the ability of many other cells to multiply as well.  For that reason, it has some potentially serious side effects including infertility, and instead rituximab is usually the preferred second-line therapy3.

Alternative Treatments

Sometimes second-line treatments are also not effective at treating AE.  When that happens, options include re-administration of first-line therapies, extended use of second-line therapies, or use of other non-steroid (steroid-sparing) drugs to suppress the immune system. For instance, the steroid-sparing drug mycophenolate mofetil prevents T and B cells from multiplying and has a better side-effect profile than cyclophosphamide3.

Other alternative treatments are also available.  One option interrupts the inflammatory effects of a molecule called interleukin-6 (IL-6).  Normally, when IL-6 binds to its receptors on immune cells, it causes B cells to multiply and mature into antibody-producing cells, and causes pro-inflammatory T cells to mature. The antibody drug tocilizumab targets the IL-6 receptor and prevents these inflammatory processes.  A molecule related to IL-6, IL-2, is also a target.  Instead of inhibiting this molecule, giving patients low doses of IL-2 activates a “good” type of T cell called regulatory T cells that help the body shut down autoimmune responses.  Another option, bortezomib, directly targets antibody-producing cells, instead of their immature B cell precursors3.

Maintenance Treatments

Even if AE is successfully treated, sometimes the disease can relapse.  Relapses could be caused by some antibody-producing cells that can survive for many months, which are not targeted by treatments.  Many of the therapies described above, including the first-line treatments, steroid-sparing agents, and rituximab, have been used as maintenance therapy to try and prevent this from occurring.  However, the length of time patients should continue to receive treatment is unknown, and can range from 6 months to several years depending on the patient’s condition and doctor’s opinion3.

In addition to immunotherapy, other important aspects of treatment include supportive care (particularly while in the hospital); treatment of symptoms such as seizures, spasms, and psychiatric issues; and rehabilitation1.  While responses to tumor removal and immunotherapy are often seen within a few weeks, it may take years for patients to return to normal7.  As more is discovered about which aspects of the immune system are involved in each subtype of AE, hopefully more directed treatments will become available.

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1. López-Chiriboga, A. S. & Flanagan, E. P. Diagnostic and Therapeutic Approach to Autoimmune Neurologic Disorders. Semin. Neurol. 38, 392–402 (2018).

  1. Seki, M. et al. Neurological response to early removal of ovarian teratoma in anti-NMDAR encephalitis. J. Neurol. Neurosurg. Psychiatry 79, 324–326 (2008).
  2. Shin, Y.-W. et al. Treatment strategies for autoimmune encephalitis. Ther. Adv. Neurol. Disord. 11, 1–19 (2018).
  3. Fassbender, C., Klingel, R. & Köhler, W. Immunoadsorption for autoimmune encephalitis. Atheroscler. Suppl. 30, 257–263 (2017).
  4. Damato, V., Balint, B., Kienzler, A. K. & Irani, S. R. The clinical features, underlying immunology, and treatment of autoantibody-mediated movement disorders. Mov. Disord. 33, 1376–1389 (2018).
  5. Varley, J., Taylor, J. & Irani, S. R. Autoantibody-mediated diseases of the CNS: Structure, dysfunction and therapy. Neuropharmacology 132, 71–82 (2018).
  6. Venkatesan, A. & Adatia, K. Anti-NMDA-Receptor Encephalitis: From Bench to Clinic. ACS Chem. Neurosci. 8, 2586–2595 (2017).

 

The Unique Nature of Seizures in Autoimmune Encephalitis

The Unique Nature of Seizures in Autoimmune Encephalitis

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April-29-2020 | Claudia Lopez Lloreda, PennNeuroKnow 

IAES PNK Partnership logo 300x251 - The Unique Nature of Seizures in Autoimmune EncephalitisWhat are seizures?

Seizures can be scary events both for people who suffer from them and for their loved ones. Symptoms of a seizure typically include muscle spasms; loss of consciousness; sudden, rapid eye movements; or sudden mood changes; among other symptoms, and these can last from seconds to minutes1. These are the most severe seizures, but mild seizures, with more moderate physical and behavioral symptoms — such as stiffness of the muscles, feelings of déjà vu, anxiety, temporary confusion, or nausea — can also happen and may negatively affect health. During seizures, the body parallels what is happening in the brain: uncontrolled movements of the body can result from uncontrolled bursts of electrical activity in the brain.

Seizures are a response to hyperexcitability, meaning increased activity, of neurons in the brain, and hypersynchrony, meaning more neurons fire at the same time than normal. Seizures are very different across and within conditions. They can be generalized, affecting the entire brain from the beginning of the seizure, or focal, affecting one specific area although it may later spread. Frequent, unprovoked seizures called recurrent seizures may indicate that the person has a condition called epilepsy. Epilepsy is a chronic neurological disorder in which seizures can cause periods of unusual behavior, sensations, and negative effects on cognition such as a loss of awareness. However, because abnormal electrical activity can happen in response to other alterations in the brain such as brain injury and in response to medications, seizures can also be seen in other conditions.

One of these conditions is autoimmune encephalitis (AE). In AE, the body attacks the brain by creating antibodies against important neuronal proteins. Because these proteins help neurons communicate, the antibodies alter neuronal activity. Altering neuronal activation can lead to the changes that are seen in seizures (hyperexcitability and hypersynchrony). In fact, research shows that seizures in some patients can be a common symptom during the acute phase (early on in disease) of AE2. It is believed that antibodies against the neuronal proteins contribute directly to the disease processes and the development of seizures. It’s also possible that the process of neuroinflammation associated with AE, which increases the amount of toxic inflammatory molecules in the brain, can also contribute to the development of seizures2. Even once the inflammation has been resolved, the brain can still be predisposed to seizures or developing epilepsy, especially if the inflammation resulted in neuronal death3. However, whether epilepsy, a chronic disease, is developed in response to AE is not entirely clear. Some studies suggest that the risk of developing chronic epilepsy is low, from 10-15%4.

In different types of AE, seizures appear differently. Apart from the well-known tonic-clonic seizures (associated with jerking muscle movements), seizures in AE can also show up as faciobrachial dystonic seizures. These are characterized by abrupt involuntary movements, typically on one half of the face and arm of the same side. The frequency, response to therapies, and symptoms of the seizures themselves can all vary. However, the AE that most frequently manifest with seizures and chronic epilepsy are those mediated by antibodies against the LGI1, GABABR, and GABAAR; all-important proteins involved in neuronal communication5.

 

Are seizures associated with AE treated the same way as in epilepsy?

 

Antiepileptic drugs are the standard of care for people with epilepsy. Since seizures are a result of uncontrolled electrical activity and an imbalance of excitation and inhibition in the brain, antiepileptic drugs work by trying to restore that balance. For example, the drug clonazepam prevents seizures by increasing the effectiveness of a molecule in the brain called GABA, which helps the brain dampen the uncontrolled brain activity.

Now, although the normal path for people with epilepsy is treatment with antiepileptic drugs, it may not be particularly effective for people with seizures associated with AE. A study looking at a population of AE patients found that resolution of seizures happened even after discontinued antiepileptic drugs therapy6. In these young patients with AE who experienced unprovoked seizures at the onset of the disease there was a remission rate of 94%, meaning they stopped suffering from seizures, after they stopped taking antiepileptic drugs. Rather, immunotherapy seemed to be the important factor in controlling seizures. The researchers suggested that “long-term use of antiepileptic drugs appears not to be necessary to control seizures in AE”6.

Other studies support the idea that immunotherapy is more effective in attacking seizures in AE. One study looked at three different types of autoimmune encephalitis (anti-LGI1, anti-NMDAR, and anti-GABABR) and their response to immunotherapy and antiepileptic drugs7. They found that seizure freedom was achieved faster and more frequently after the use of immunotherapy than after the use of antiepileptic drugs. However, there may be a specific window in which immunotherapy is effective at controlling seizures.

Importantly, the researchers do mention that differences in seizures characteristics and therefore response to treatment may be due to the specific type of encephalitis. For example, patients with anti-GABABR encephalitis had an increased risk of developing seizures, meaning that the development of seizures may depend on the type of encephalitis7.

 

What do these findings mean for people with AE?

 

These differences in treatment response between AE and epilepsy point to an important trait that needs to be considered: the cause of seizures. In AE, antibodies generated against important neuronal proteins make the brain go awry. Therefore, one of the most effective ways to treat seizures may be attacking the root of the problem with immunotherapy. However, due to the variable nature of AE and the seizures associated with the condition, proper treatment with immunotherapy and/or antiepileptic medication will change from patient to patient.

 

What to do if someone is having a seizure?

 

During the most severe seizures, the person may not be able to control their body movements. For this reason, you may help them clear the area around them to prevent possible injury. If possible, place them on their side and provide cushioning for their head. There are additional indications suggested by the Center for Disease Control (become familiar with these here).

Seizures in AE Handout 

 

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References

  1. Epilepsy. (2019, August 10). Retrieved March 6, 2020, from https://www.mayoclinic.org/diseases-conditions/epilepsy/symptoms-causes/syc-20350093
  2. Rana, A., & Musto, A. E. (2018). The role of inflammation in the development of epilepsy. Journal of Neuroinflammation, 15(1). doi: 10.1186/s12974-018-1192-7
  3. Vezzani, A., Fujinami, R. S., White, H. S., Preux, P.-M., Blümcke, I., Sander, J. W., & Löscher, W. (2015). Infections, inflammation and epilepsy. Acta Neuropathologica, 131(2), 211–234. doi: 10.1007/s00401-015-1481-5
  4. Steriade, C., Moosa, A. N., Hantus, S., Prayson, R. A., Alexopoulos, A., & Rae-Grant, A. (2018). Electroclinical features of seizures associated with autoimmune encephalitis. Seizure, 60, 198–204. doi: 10.1016/j.seizure.2018.06.021
  5. Spatola, M., & Dalmau, J. (2017). Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis. Current Opinion in Neurology, 30(3), 345–353. doi: 10.1097/wco.0000000000000449
  6.  Huang, Q., Ma, M., Wei, X., Liao, Y., Qi, H., Wu, Y., & Wu, Y. (2019). Characteristics of Seizure and Antiepileptic Drug Utilization in Outpatients with Autoimmune Encephalitis. Frontiers in Neurology, 9. doi: 10.3389/fneur.2018.01136
  7. Bruijn, M. A. D., Sonderen, A. V., Coevorden-Hameete, M. H. V., Bastiaansen, A. E., Schreurs, M. W., Rouhl, R. P., … Titulaer, M. J. (2019). Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology, 92(19). doi: 10.1212/wnl.0000000000007475

 

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Diagnosing autoimmune encephalitis: a role for 18F-FDG PET imaging

Diagnosing autoimmune encephalitis: a role for 18F-FDG PET imaging

March-18-2020 | Greer Prettyman, PennNeuroKnow

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Autoimmune encephalitis (AE) can be hard to diagnose because its symptoms can vary widely and may be similar to symptoms of other illnesses or disorders. When a patient is in the hospital with symptoms that may point to AE, they typically undergo a series of tests and evaluations to determine if a diagnosis of AE is likely. These test results help doctors decide whether or not to begin immunotherapy treatment, the normal standard of care for AE. Eventually, patients get antibody testing to more precisely diagnose specific types of AE and refine treatment.

Typically, an MRI scan is included in the standard battery of tests when a patient with potential AE arrives at the hospital. MRI, magnetic resonance imaging, is a technique that uses a strong magnet to identify areas of the brain that may be overly active. Particular patterns of activity that can be seen with MRI, such as increased activity in brain regions including the hippocampus, are often associated with AE1. However, many patients with AE have normal-looking MRIs, so MRI is not a perfectly accurate tool for diagnosis. A different type of diagnostic imaging called 18F-FDG PET might be able to detect certain types of encephalitis that would be missed with MRI1.

 

What is 18F-FDG PET?

 

18F-FDG PET imaging, which stands for [18F]fluorodeoxyglucose positron emission tomography, uses a radioactively labeled glucose molecule to identify parts of the body or brain that have unusual amounts of activity. Glucose is the body’s main source of energy, so PET scans allow doctors to visualize areas that have high energy metabolism, or hypermetabolism. An area that is more active uses more glucose and shows up more strongly on a PET image. FDG PET is often used in cancer diagnosis because it can be used to locate parts of the body where cancer cells are growing and using a lot of extra energy2,3.

 

FDG PET imaging is also useful for identifying patterns of activity in the brain that are often associated with AE1,4. Many patients with a specific type of AE called limbic encephalitis who receive an FDG PET scan have hypermetabolism in a part of the brain called the medial temporal lobe5,6. This part of the brain is involved with emotion and memory, which are often related to symptoms of AE. However, there is no one signature activation pattern that is consistently associated with limbic encephalitis, and other patients have shown patterns of unusually low metabolism (hypometabolism) in the medial temporal lobe or hypermetabolism in different brain regions, such as parietal and occipital lobes1,9.

 

Another subtype of AE called anti-NMDA receptor encephalitis may also be easier to diagnose with FDG PET than with MRI7. This type of encephalitis that affects NMDA glutamate receptors in the brain is often associated with hypermetabolism of glucose in the frontal and temporal lobes and hypometabolism in the occipital lobe7. A study at Johns Hopkins looked at PET and MRI scans of 5 patients with anti-NMDA receptor encephalitis and found that all 5 had abnormal FDG PET scans but no abnormalities detected with MRI scans1.

Doctors have been able to diagnose these types of AE based on FDG PET results, even when that patient’s MRI scans appear normal4. One study of AE patients found that 85% had abnormal FDG PET scans, a greater percentage than for either MRI or EEG, suggesting that FDG PET may be a more sensitive measure8. For these reasons, researchers believe FDG PET may be an important tool for getting specific and precise diagnoses of AE6.

 

PET vs MRI

 

One drawback of using PET scans for early diagnosis is that they are typically not as quick and easy to obtain as an MRI. Many hospitals require time to schedule PET imaging so it cannot be completed when a patient is in the hospital with possible AE symptoms that need to be evaluated. MRI, on the other hand, can usually be performed on an emergency basis, so these results can be obtained more quickly and guide early treatment decisions10,11.

Another argument against implementing PET imaging as part of an initial battery of tests to diagnose AE is that a small amount of radiation is injected into the body in the form of the radioactive glucose tracer. However, many patients with AE symptoms already get PET scans of the body to check for tumors, so performing a PET scan of the brain at the same time would not require any extra radiation and could help doctors to get more information on what is going on in the brain6.

More research will be needed to determine exactly how accurate FDG PET can be at diagnosing different subtypes of AE, but since PET scans offer more precise diagnostic powers than MRIs, FDG PET shows promise as another tool to help with the diagnosis of AE.

Download FDG-Pet Handout

 

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References:

  1. Solnes, L. B., Jones, K. M., Rowe, S. P., Pattanayak, P., Nalluri, A., Venkatesan, A., … Javadi, M. S. (2017). Diagnostic Value of 18 F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis. J Nucl Med, 58, 1307–1313.
  2. Gallamini, A., Zwarthoed, C., & Borra, A. (2014). Positron Emission Tomography (PET) in Oncology. Cancers, 6(4), 1821–1889.
  3. Shukla, A. K., & Kumar, U. (2006). Positron emission tomography: An overview. Journal of Medical Physics, 31(1)
  4. Deuschl, C., Rüber, T., Ernst, L., Fendler, W. P., Kirchner, J., Mönninghoff, C., … Umutlu, L. (2020). 18F-FDG-PET/MRI in the diagnostic work-up of limbic encephalitis. PloS One, 15(1).
  5. Baumgartner, A., Rauer, S., Mader, I., & Meyer, P. T. (2013). Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types. Journal of Neurology, 260(11), 2744–2753.
  6. Morbelli, S., Djekidel, M., Hesse, S., Pagani, M., Barthel, H., Committee of the European Association of Nuclear Medicine, N., … Imaging, M. (2016). Role of 18F-FDG-PET imaging in the diagnosis of autoimmune encephalitis.
  7. Leypoldt, F., Buchert, R., Kleiter, I., Marienhagen, J., Gelderblom, M., Magnus, T., … Lewerenz, J. (2012). Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease. Journal of Neurology, Neurosurgery, and Psychiatry, 83(7), 681–686.
  8. Probasco, J. C., Solnes, L., Nalluri, A., Jesse Cohen, B., Krystyna Jones, B. M., Zan, E., … Venkatesan, A. (2017). Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm, 4, 352.
  9. Lee, S. K., & Lee, S.-T. (2016). The Laboratory Diagnosis of Autoimmune Encephalitis. Journal of Epilepsy Research, 6(2), 45–50.
  10. Graus, F., Titulaer, M. J., Balu, R., Benseler, S., Bien, C. G., Cellucci, T., … Dalmau, J. (2016). A clinical approach to diagnosis of autoimmune encephalitis. The Lancet.Neurology, 15(4), 391–404.
  11. Graus, F., & Dalmau, J. (2016). Role of 18F-FDG-PET imaging in the diagnosis of autoimmune encephalitis – Authors’ reply. The Lancet Neurology, 15(10), 1010.
When Your Brain is on Fire

When Your Brain is on Fire

brain on fire

January-22-2020 | Carolyn Keating, PennNeuroKnow

Imagine you’re a bright twenty-something with a new job and a new relationship.  Everything seems to be going your way until you start becoming paranoid and acting erratically.  Then come the hallucinations and seizures.  You’re admitted to a hospital where you’re (incorrectly) diagnosed with a psychiatric disorder.  You swing from violence into a state of immobility and stupor.  And perhaps even scarier?  You don’t remember any of it.  Sound like a nightmare?  Well, it actually happened to Susannah Calahan, who details her terrifying story first-hand in her 2012 book Brain on Fire: My Month of Madness.

What caused these frightening symptoms?  The answer was a disease that had only been discovered a few years earlier (right here at Penn!): NMDAR encephalitis.  There are four main phases of the disorder.  In the prodromal phase, many but not all patients experience a flu-like illness for up to 3 weeks.  The psychotic phase is accompanied by delusions, auditory and visual hallucinations, depression, paranoia, agitation, and insomnia.  At this stage, most patients are taken to the hospital, where around 40% are misdiagnosed as having a psychiatric disorder like schizophrenia.  As this phase progresses, seizures are very common (although they can occur at any time throughout the illness), as well as involuntary muscle movements like lip-smacking or grimacing, catatonia (muscular rigidity and mental stupor), impaired attention, and memory loss.  The next phase is unresponsiveness, which includes symptoms like the inability to speak, loss of voluntary movement, and sometimes abnormal muscle contractions that cause involuntary writhing movements.  The last phase is the hyperkinetic phase and is characterized by instability of involuntary bodily functions such as breathing, blood pressure, heartbeat, and temperature.  Many patients who breathe too slowly often need to be placed on a ventilator at this stage. The decline to ventilator support can progress very rapidly after several weeks in the psychotic stage, and ultimately patients can be hospitalized for several months with the disease1–3.

What does NMDAR encephalitis actually mean?  This disease is an autoimmune disorder, meaning the body’s immune system mistakenly attacks its own healthy cells.  Normally the body identifies foreign substances by making something called an antibody that recognizes a unique part of the invader, thus targeting it for attack and destruction.  In NMDA encephalitis though, the immune system attacks the brain (that’s where to term encephalitis comes from), specifically a type of neurotransmitter receptor called an NMDA receptor (NMDAR).  These receptors bind the neurotransmitter glutamate, and play an important role in learning, memory, cognition, and behavior.  In fact, the symptoms of NMDAR encephalitis resemble those caused by drugs such as ketamine or PCP that prevent the activation of NMDARs.  For instance, at low doses ketamine and PCP cause paranoia, false perceptions, and impaired attention (like the early stages of NMDAR encephalitis), and at higher doses these drugs cause psychosis, agitation, memory and motor disturbances, and eventually unresponsiveness, catatonia, and coma2.  Several mechanisms have been proposed to explain the symptoms caused by antibodies targeting the NMDAR, but most of the evidence seems to support the idea that the receptors get removed from the cell surface and internalized.  For instance, experiments in the laboratory demonstrate that when animal neurons grown in a dish are exposed to patients’ anti-NMDAR antibodies, the number of NMDARs on the cell surface decreases as the amount of antibodies increase.  When the antibodies are removed, the number of NMDAR receptors on the cell surface returns to baseline within 4 days1.

It’s easy to remove antibodies in a dish, but how do doctors get the body to stop producing antibodies against itself?  Step one is identifying what triggers antibody production in the first case.  Interestingly, NMDAR encephalitis predominantly affects women, and ovarian teratomas (a type of tumor made up of multiple types of tissues, which can include nervous system tissue) are responsible for 50% of cases in young women2.  In patients who have some sort of tumor, removal improves symptoms in 75% of cases.  Interestingly, herpes simplex virus can also cause encephalitis (inflammation of the brain), and about 20% of these patients also develop antibodies against NMDAR2.  Treatment consists of immunotherapy: corticosteroids, IV infusion of immunoglobulins, and/or plasma exchange1, however patients with a viral trigger tend to be less responsive to treatment than those with a teratoma trigger or the 50% of patients with an unknown trigger2.  Once treatments begin improvements in symptoms start within a few weeks, though return to baseline functioning can take up to three years.  Rehabilitation is required for many patients after they leave the hospital.  Deficits in attention, memory, and executive function may linger for years, but luckily over 75% of patients with the disease recover to at or near baseline neurological functioning1.

Doctors and scientists hope to develop new treatments involving immunotherapy combined with small molecules that are able to access the brain to directly combat the effects of anti-NMDAR antibodies, ideally leading to faster control of symptoms and shorter recovery time2.  A brand new animal model of the disease was just described last week that will hopefully lead to more discoveries about how the disease is triggered and potential new therapies4.  And with increased awareness of autoimmune disorders against the brain, doctors will be able to more quickly correctly diagnose patients with this illness and get them the treatment they need.

References:

  1. Venkatesan, A. & Adatia, K. Anti-NMDA-Receptor Encephalitis: From Bench to Clinic. ACS Chem. Neurosci. 8, 2586–2595 (2017).
  2. Dalmau, J. NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture. Neurology 87, 2471–2482 (2016).
  3. Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008).
  4. Jones, B. E. et al. Anti-NMDA receptor encephalitis in mice induced by active immunization with conformationally-stabilized holoreceptors. bioRxiv 467902 (2018). doi:10.1101/467902

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How does Sleep Affect the Blood-brain Barrier?

How does Sleep Affect the Blood-brain Barrier?

December-11-2019 | Sarah Reitz, PennNeuroKnow

IAES PNK Partnership logo 300x251 - How does Sleep Affect the Blood-brain Barrier?Autoimmune encephalitis (AE) is the name for a group of conditions that occur when the body’s immune system mistakes its own healthy brain cells for invaders, leading to brain inflammation that ultimately triggers a number of other symptoms. Normally, the body’s immune system has only limited access to the brain, as it is protected by the blood-brain barrier (BBB). When this barrier is healthy, it can prevent an immune system attack by blocking immune cells and antibodies targeting brain cells from actually entering the brain. Like any fortress, however, the BBB isn’t completely impenetrable. Given that AE symptoms occur when immune cells or antibodies manage to cross the BBB, researchers think that the weakening of this barrier plays a critical role in AE and may even be a target for future therapies to reduce or prevent AE symptoms. But what causes the BBB to weaken, allowing cells, antibodies, and other molecules to invade the brain?

 

The blood-brain barrier: gatekeeper of the brain

Before discussing how the BBB becomes impaired, we need to understand how the healthy BBB functions. The BBB is often referred to as a “gateway”, made up of tightly joined endothelial cells that surround the blood vessels in the brain and spinal cord1. Outside of the brain, the endothelial cells lining blood vessels have small spaces between them, allowing for the exchange of substances between the blood and the surrounding tissue. However, the endothelial cells of the BBB are connected to each other by proteins called tight junction proteins, which squeeze the cells tightly together, blocking larger cells and molecules from freely flowing between the blood supply and the brain (Figure 1).

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Figure 1: The blood-brain barrier is made up of endothelial cells that are tightly connected to each other by tight junction proteins (purple). These tight connections prevent unwanted substances from traveling between the blood and the brain. Different types of transporter proteins (yellow & blue) shuttle only certain types of molecules between the blood and brain.

The BBB is selectively permeable, meaning it allows only certain substances to enter and leave the brain. One way that molecules can cross the BBB is by endocytosis, a process where the endothelial cells uses its cell membrane to take in a molecule on one side (say, the side facing the blood) and pass it through to the other side (facing the brain) where it is released1. The endothelial cells of the BBB also express a variety of transporter proteins, which actively move molecules between the blood and the brain (Figure 1). Additionally, small, fat-soluble molecules can cross the BBB without any help from endocytosis or transporter proteins, giving the brain access to important nutrients and energy sources1.

BBB permeability changes across the day

The permeability of the BBB is not always the same, however. Research has shown that its permeability actually changes depending on the time of day2. Like many cells in the body, BBB cells are controlled by circadian rhythms, biological processes that cycle roughly every 24 hours. These rhythms are driven by a molecular “clock” within each cell, and cells across the body are synchronized by the “master clock” located in the brain.

What do these rhythms mean for BBB permeability though? Interestingly, research in both flies and mice shows that the amount of hormones, inflammatory proteins, and other molecules that cross from the blood into the brain fluctuates across the day, with peak BBB permeability occurring at night2.

Sleep loss impairs BBB function

Circadian rhythms aren’t the only daily process that affects the integrity of the BBB. Sleep—or more appropriately, lack of sleep—is also known to affect the BBB’s protection of the brain. This relationship between sleep and the BBB is increasingly important as sleep restriction becomes more and more common in our modern society.

Sleep loss is also highly relevant to the AE community. One study found that 73% of AE patients surveyed reported sleep disturbances, including gasping/snoring and insomnia. Even further, patients with AE had decreased total sleep time and increased fragmentation of sleep compared to people without AE3. But how exactly does sleep loss affect the BBB?

Blood Brain Barrier after full sleep 300x71 - How does Sleep Affect the Blood-brain Barrier?

Figure 2: After periods of sleep loss, the blood-brain barrier is negatively affected in many ways (left). Inflammatory signaling caused by TNFα and IL-6 increases, leading to the breakdown of tight junction proteins (purple). This causes gaps between endothelial cells, allowing unwanted immune cells and antibodies to enter the brain. After sleep loss, the endothelial cells also make fewer of the transporter proteins (blue and yellow) that are required to shuttle necessary molecules between the brain and blood.

Multiple studies have now shown that sleep restriction weakens the BBB. One reason is due to the increase in inflammatory signaling that results from extended periods of wakefulness. Increases in inflammatory proteins, like TNFα and IL-6, are known to break down the tight junction proteins that keep the endothelial cells tightly joined together2 (Figure 2). Sleep-deprived mice and rats showed decreased numbers of tight junction proteins, leading to increased BBB permeability.

In addition to weakened tight junctions between endothelial cells, sleep loss also increases permeability by enhancing the rate of endocytosis across the BBB2, meaning that the endothelial cells shuttle more molecules from the blood into the brain. Relevant to AE, this increased permeability means that more immune cells and antibodies can enter the brain after sleep loss compared to after a full night’s sleep.

While these results are a bit frightening, there is good news. All of the damage to the BBB caused by sleep loss returns to normal after getting enough sleep! One study found that even an extra 1-2 hours of sleep following sleep loss restored BBB function in most brain areas4. Given even more time to sleep, the BBB throughout the brain returned to normal function5. These results suggest that treating the sleep disorders commonly associated with AE may help strengthen the BBB, increasing the brain’s protection against the immune system’s cells and antibodies and improving long-term outcomes for patients.

The BBB as a treatment target

Given that AE is caused by immune cells and antibodies infiltrating and attacking the brain, researchers are now looking at the BBB as a potential therapeutic target1. Treatments that strengthen the BBB will hopefully reduce the number of immune cells and antibodies that make it into the brain, and may also increase the effectiveness of some AE medications, such as anti-inflammatory drugs or immune-suppressants. Because these AE medications are specifically designed to cross a healthy BBB and access the brain, strengthening a weakened BBB will protect against molecules that aren’t supposed to be in the brain, while still allowing the necessary medication in.

The known circadian effects on BBB permeability can also be used in determining when to give medication that needs to cross the BBB. Medication can be given at the time of day when BBB permeability is highest to increase the amount of drug that makes it into the brain. In fact, this has already been studied with anti-seizure medication in epilepsy. For instance, in both flies and humans, when medication was given at night during peak BBB permeability, it was most effective at controlling seizures6,7.

This new strategy of “chronotherapeutic” dosing schedules has the potential to improve the efficacy of medication in many diseases. By administering drugs when it is easiest for them to enter the brain, doctors may be able to see results at lower doses of the drug, potentially reducing the risk of harmful side effects. As we continue to learn more about the BBB, scientists may identify even more ways to improve BBB health in the many disease states where it is compromised.

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Image References:  Figure 1 and 2 created with BioRender.com

References:

  1. Platt MP, Agalliu D, Cutforth T (2017) Hello from the other side: How autoantibodies circumvent the blood-brain barrier in autoimmune encephalitis. Front. Immunol. 8:442. doi: 10.3389/fimmu.2017.00442
  2. Cuddapah VA, Zhang SL, Sehgal A (2019) Regulation of the blood-brain barrier by circadian rhythms and sleep. Trends Neurosci 42(7):500-510. doi: 10.1016/j.tins.2019.05.001
  3. Blattner MS, de Bruin GS, Bucelli RC, Day GS (2019) Sleep disturbances are common in patients with autoimmune encephalitis. J Neurol 266(4):1007-1015. doi: 10.1007/s00415-019-09230-2
  4. Gomex-Gonzalez B, et al. (2013) Rem sleep loss and recovery regulates blood-brain barrier function. Curr. Neurovasc. Res. 10, 197-207
  5. He J, Hsuchou H, He Y, Kastin AJ, Wang Y, &Pan W (2014) Sleep restriction impairs blood-brain barrier function. J Neurosci 34(44)14697-14706. doi: 10.1523/jneurosci.2111-14.2014
  6. Zhang SL, Yue Z, Arnold DM, Artiushin G, Sehgal A (2018) A circadian clock in the blood-brain barrier regulates xenobiotic efflux. Cell 173(1):130-139. doi: 10.1016/j.cell.2018.02.017
  7. Yegnanarayan R, et al. (2006) Chronotherapeutic dose schedule of phenytoin and carbamazepine in epoleptic patients. Chronobiol. Int 23, 1035-1046

 

 

 

It is the Season When We Give Thanks

It is the Season When We Give Thanks

Barbara Layt Vujaklija | November 28-2019

No matter the origins in your part of the world, during the autumn or early winter there is usually some sort of harvest or thanksgiving festival. A time for people to share the earth’s bounty with friends and family and gather together to renew and strengthen the bonds we share.

Growing up in England I remember being paraded from school across the village street to the local church which was decked out with bales of sweet-smelling hay, turnips, parsnips, carrots and all manner of other foodstuffs (both fresh and canned or purchased), plus magnificent late flowering plants. The church was filled with the earth’s splendor and the folk of the village. We elementary school children dressed in our best took our place in the choir stalls. After the sermon, we were to sing a few songs that expressed everyone’s thanks for the bounty before us. The foodstuff was later distributed to the poor of the village.

Since coming to live in America at the age of 20, I have discovered a new way of giving thanks to the earth’s bounty and family and friends.  I have found the customs of Thanksgiving here in the USA to be comforting and enriching.

What am I, as someone with Autoimmune Encephalitis, thankful for?

I am thankful for my improving health, and for my family who has stayed beside me during my trials. I am especially thankful for my son-in-law and daughter who came to live with us to be my caregiver. Thanks to Toys-for-Tots and local food drives, I still have the satisfaction of helping those less fortunate than myself.

Here, at the International Autoimmune Encephalitis Society, we asked members what they were thankful for.  Their responses are below:

Thanks for understanding

For this Thanksgiving, I am a warrior who is thankful for my husband, my family, my neighbors, and IAES. These people know that despite having AE I still have a lot of knowledge and am an intelligent woman.

I am so thankful for everyone at the International Autoimmune Encephalitis Society, they help me to feel that I will make it through this, my husband who has learned to deal with my poor memory, my family who supports me, our awesome neighbours and everyone in this world who has learned in one way or another that disabled people have so much to offer.   – Mari Wagner Davis

 Thanks for loving and listening

I am thankful to have a loving kind man that has been with me every step of the way and helps me cope every day. I am also thankful for my best friend who listens and talks to me about anything and whatever I need.  – Katherine Crow

Thanks for life and a new me

Life ?? Thankful to still be alive and getting the chance at the new me. We all know the outcome could always be worse with this disease. Happy Thanksgiving.    -Dayna Burns Rudy Munoz

Thanks to the Lord

For Thanksgiving, I want to say I am very thankful for the Lord being present with me and carrying me through a three year battle with AE. Especially when I was hallucinating in the psychiatric hospital, thinking everyone was plotting to kill me. He gave me a peace that I would survive and be OK. And I was.
-Wayne L. Wall

Thanks for hope, life, love

I am thankful that despite everything I can still have some semblance of a normal life, that my husband still loves me and cares for me despite everything, and I still have hope, love, life, my children, husband and the best of my friends and family in my life. I’m thankful that the chaff has been able to be cut away, so I can enjoy and wholeheartedly love those who are genuine in my life.
-Cathy Bolton

Life and smiles

I am thankful that my son did not die when he first got sick. He was very close. I am thankful that he was given a cheerful, strong and enduring spirit that touches the lives of so many he knows. I am thankful for his smiles and that he always compliments people and wants to care for them. I am thankful for the opportunity to enjoy the gift of every day and the ability to live a full life with him. Happy Thanksgiving!
Lora Strange

This group

I’m thankful for finding this group because many of my questions have been answered here. Also because I don’t feel like a strange person anymore.
Michelle M. Caamaño

Caregivers

I’m thankful for my husband and son who are also my caregivers.
Amy Underwood-Crossley

 

Make a Comment below to share what you are Thankful for

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The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells

The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells

Nov-27-2019 | Carolyn Keating, PennNeuroKnow

The Immune System: An Explainer

When we catch a cold, get an infection, or otherwise become sick, our bodies use a natural defense mechanism called the immune system to fight off what’s attacking us.  The immune system has two ways of responding1.  The first, called innate immunity, involves physical and chemical barriers like the skin and saliva, as well as many different types of cells that “eat” and destroy whatever is causing the trouble.  While this innate response happens very quickly, then the downside is that it’s not very specific, and the immune cells can damage healthy parts of the body while trying to gobble up the foreign invaders.  In order to specifically target particular offenders, the body uses its second way of responding: the adaptive immune system.  This response can take days or weeks to develop but is also able to remember what the foreign invader looked like, so if it attacks again a targeted reaction can occur faster than the first time.  To acquire this immunity against a particular foreign substance, the body uses two types of cells that act in different ways: T cells (which develop in an organ called the thymus, that’s where the “T” comes from) and B cells (which mature in the bone marrow, hence the “B”).

 

These two cell types are able to attack so specifically because each one recognizes a particular structure, called an antigen, on a foreign substance.  For instance, one T cell might recognize a certain part of an influenza virus, while another could recognize a specific part of a bacterium; the same situation also holds true for B cells.  The T and B cells travel around between different lymphoid tissues (organs like the spleen, tonsils, and lymph nodes, the last which are spread throughout the body) until they encounter their particular antigen.  Once activated by their antigen, the T and B cells leave the lymph tissues and work in different ways to fight off the foreign invader (Figure 1).

types of T and B cells PNK - The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells

Types of T and B cells

T cells come in many varieties, but the two major types are cytotoxic and helper.  Cytotoxic T cells (sometimes referred to as CD8+ T cells due to a particular identifier on their surface) travel to the disease site to search for cells that also bear the antigen that activated them, and destroy them.  Helper T cells (sometimes referred to as CD4+ T cells), as the name might suggest, help activate other parts of the immune system.  There are many subtypes of helper T cells that activate different types of responses; for instance, some promote the cytotoxic T cell response, while others activate B cells. Another kind of CD4+ T cell called regulatory cells actually tells the immune system, not to attack2.

 

Unlike T cells, B cells do not destroy their target.  Instead, once they are activated by their antigen and T helper cells, they mature into plasma cells that produce antibodies, proteins that recognize the same antigen as the B cell.  These antibodies essentially enhance the innate immune system and act in several ways, including neutralizing toxins, signaling to other immune cells that a cell should be attacked and destroyed, or activating complement.  Complement is a group of proteins (not cells) that make up yet another arm of the immune system.  These complement proteins can recruit immune cells or directly kill foreign cells themselves1.

 

T and B Cells in Autoimmune Encephalitis

So what happens in autoimmune encephalitis (AE)?  In this and other autoimmune diseases, the body mistakenly recognizes part of itself as a foreign invader and mounts an attack. Scientists believe that AE starts when a tumor or virus causes proteins from neurons to be exposed to the immune system. The proteins get picked up by immune cells outside the brain that go on to activate T and B cells in lymphoid tissue. These activated cells then make their way into the brain where they cause AE3,4.  Which cells are responsible for causing the disease depends on what antigen sets off the immune response.

In cases where the antigen comes from inside a cell, cytotoxic T cells are the culprits.  When proteins from inside neurons like Hu, Yo, or Ma2 are the antigens, that usually indicates that the immune system first encountered the proteins in a cancerous tumor, which can express proteins from all sorts of cell types (this cancer association is why these antibodies and diseases are called “onconeural,” or “paraneoplastic”).  Cytotoxic T cells fighting the tumor can make their way into the brain and kill neurons5.  This cell death is likely part of the reason why patients with these diseases have poor recovery.  Antibodies from B cells that have matured into plasma cells can also be produced in response to the tumor, but they do not contribute to AE symptoms6.

Antibodies do have a strong role in producing AE symptoms when the antigen comes from the outside surface of a neuron, like the NMDA receptor for instance.  These antibodies can still be formed in reaction to a tumor, but this is less common.  Research on NMDAR encephalitis, in particular, has revealed the presence of B cells and antibody-secreting plasma cells in the brain7,8.  Because the antibodies have access to the surface proteins they target, they can bind to them and interfere with their function.  In the case of NMDAR encephalitis, it’s thought that the antibodies cause the receptors, which normally are exposed to the outside of the cell, to be taken back inside so that they can’t function properly.  Once the antibodies are gone the receptors can return to the cell surface, reversing many of the symptoms9.  Unlike diseases in which the antibodies target intracellular proteins, in NMDAR encephalitis there are few to no cytotoxic T cells in the brain or neuronal death5,7,8.  But while there are little to no cytotoxic T cells, there have been reports of helper T cells around blood vessels in the brain, including one type called Th17 that act to enhance the immune response10.

 

In other cases of encephalitis with antibodies again a cell surface protein, such as LGI1, CASPR2, or GABA receptors, the precise immune reaction is less certain and in some ways seems to be a little different from NMDAR encephalitis.  B cells and plasma cells are still found in the brain, and antibodies also play a major role in causing symptoms5,11.  For instance, antibodies against the GABAB receptor block it from functioning, while antibodies against LGI1 can disrupt interactions between proteins and lead to a decrease in AMPA receptors12.  The involvement of T cells is unclear and may vary depending on the disease-causing antibody. For example, cytotoxic and helper T cells have been found in the brain of anti-GABAB receptor patients11, while few T cells were found in anti-VGKC-complex patients5.  In addition, scientists sometimes observe signs of complement, the protein arm of the immune system that can kill cells5,6.  In line with the presence of cytotoxic T cells and complement, neuronal loss is sometimes reported5,13.

 

Overall, the type of immune response the body produces appears to be dependent on the specific antigen. In general, diseases with antibodies that target intracellular proteins like Hu, Yo, or Ma2 involve cytotoxic T cells that kill neurons.  In contrast, diseases with antibodies that target cell surface proteins like NMDAR, LGI1, and GABAR involve B cells in symptom production. In this second category, the role of T cells and complement may vary depending on the particular antigen.

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References

  1. Parkin, J. & Cohen, B. An overview of the immune system. Lancet 357, 1777–1789 (2001).
  2. Corthay, A. How do regulatory T cells work? Scand. J. Immunol. 70, 326–336 (2009).
  3. Venkatesan, A. & Adatia, K. Anti-NMDA-Receptor Encephalitis: From Bench to Clinic. ACS Chem. Neurosci. 8, 2586–2595 (2017).
  4. Dalmau, J. NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture. Neurology 87, 2471–2482 (2016).
  5. Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: Clues for pathogenesis. Brain 135, 1622–1638 (2012).
  6. Damato, V., Balint, B., Kienzler, A. K. & Irani, S. R. The clinical features, underlying immunology, and treatment of autoantibody-mediated movement disorders. Mov. Disord. 33, 1376–1389 (2018).
  7. Martinez-Hernandez, E. et al. Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology 77, 589–593 (2011).
  8. Tüzün, E. et al. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol. 118, 737–743 (2009).
  9. Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008).
  10. Zeng, C. et al. Th17 cells were recruited and accumulated in the cerebrospinal fluid and correlated with the poor prognosis of anti-NMDAR encephalitis. Acta Biochim. Biophys. Sin. (Shanghai). 50, 1266–1273 (2018).
  11. Golombeck, K. S. et al. Evidence of a pathogenic role for CD8 + T cells in anti-GABA B receptor limbic encephalitis. Neurol. Neuroimmunol. NeuroInflammation 3, 1–8 (2016).
  12. Dalmau, J. & Graus, F. Antibody-mediated encephalitis. N. Engl. J. Med. 378, 840–851 (2018).
  13. Shin, Y.-W. et al. Treatment strategies for autoimmune encephalitis. Ther. Adv. Neurol. Disord. 11, 1–19 (2018).

 

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Introducing the IAES and PennNeuroKnow Partnership

Introducing the IAES and PennNeuroKnow Partnership

IAES and PNK announce partnership in autoimmune encephalitis and neuroschience education

October 16-2019 | Carolyn Keating and Sarah Reitz

Hello AE Community!

 

Our names are Carolyn and Sarah, and we are happy to announce the partnership between IAES and our blog, PennNeuroKnow (PNK).  We are working with IAES to learn about topics that patients and families in the AE community have trouble understanding, in order to create handouts and blog posts that explain these issues in a way that’s easy to digest.  We’re excited to begin this alliance and to introduce our team to the AE community.

PNK is a blog we founded in early 2018 to dive into the complex field of neuroscience and simplify it so that anyone can understand.  Including the two of us, we have 6 writers creating weekly articles ranging from general topics like how the brain produces curiosity, to breaking down specific journal articles on subjects like how the bacteria in your gut may be linked to depression.  All of us are PhD students in the University of Pennsylvania’s Neuroscience Graduate Group who are committed to better communicating science.  We know that scientific studies are sometimes difficult to both access and understand, so we want to use our training as scientists to share our passion for neuroscience and make our field more accessible to everyone.

We were first introduced to IAES in July 2019, when Carolyn wrote about NMDAR encephalitis in a blog post called When Your Brain is on Fire.  IAES saw the post and shared it on their Facebook page, giving the article much greater reach than we normally experience.  The amount of positive feedback we have received from the AE community has been overwhelming, and we are truly grateful to have been able to help so many people understand the science behind the disease that has affected themselves or a loved one.  Now thanks to IAES President Tabitha Orth reaching out to us about forming a partnership, we are excited to produce more easy-to-read articles on complex topics important to the AE community.

All of our writers are looking forward to learning more about AE and the issues that are difficult for patients and families to grasp.  Already we are hard at work learning and writing about how AE relates to the immune system, memory loss, and FDG-PET scans, just to name a few topics.  We hope that we can use our strengths as neuroscientists to help translate complicated subjects and journal articles into something everyone can understand, and are excited to contribute to this wonderful community. We want to make sure we are writing about topics that are most important to you and your family members, so please do not hesitate to reach out to either Tabitha or us with topics you would like to learn more about!

Get In Touch with IAES

Get In Touch with PNK

E-mail Sarah and Carolyn Directly at PNK 

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Why the Zebra

 

Attending the Neurology and Psychiatry London Conference

Attending the Neurology and Psychiatry London Conference

July 24 | Dr. Daria Muir, IAES Medical Liaison,  and (stubborn) AE survivor

The long-awaited day has arrived – Finally. It’s Monday morning, very early in the morning, and I have a flight to catch to take me to London to attend the Converging Themes in Neurology and Psychiatry conference to be held at the Royal Society of Medicine in London.  I’ve been looking forward to attending and representing IAES for so months.  I am excited.

The aim of this meeting is to review the current clinical and basic research understanding of the diagnosis and management of a range of disorders, including Autoimmune Encephalitis, Epilepsy and Dementia, that are at the interface between neurology and psychiatry.

The first day was going to be about Autoimmune Encephalitis (mainly focus on anti- NMDAr and anti-LGI1 antibodies), seen from the perspective of two neurologists (Prof. Sarosh Irani and Prof. Christopher Butler), a psychiatrist (Prof. Belinda Lennox) and an immunologist (Prof. David Wraith) and followed by some in-depths of the neuroscience of space and time, wonderfully focused on the memory process of evolution and dissolution (Prof. Eleanor Maguire), the navigation systems after long-term memory consolidation ( Prof. Hugo Spiers) and the development of hippocampal-dependent memory in humans (Prof. Faraneh Vargha-Khadem).

london bus Daria Muir - Attending the Neurology and Psychiatry London ConferenceEver since I got AE I started to feel uncomfortable in crowded and busy places. Too much noise and lots of conversations at the same time makes me lose focus.  Brain-fog takes over and I am lost; (this literally happened at the end of the first day, when I took the wrong bus and ended up almost outside London in the middle of the night).

But arriving at the conference and seeing the presenters and the attendants, most of them eminent names in neurology and psychiatry in the U.K., leading doctors in the field who provide care for autoimmune encephalitis patients, gave me strength to gather all my energy to attend and get the most value I could from the experience!

autoimmune encephalitis

I’ll share more in a follow up blog with a more detailed story, with slides and answers to questions.  (The AE session was the most debated one!), but now that I have returned home, I wanted to give you the “fresh flavors”, in terms of objectives that were set and reached by the speakers and take home messages:

  • NMDAR-dysfunction is the hallmark of NMDAR- antibody encephalitis and hence NMDAR antibodies
  • There are several lines of evidence (clinical evidence, immunological/epitope data, electrophysiological modeling and PET imaging)
  • Down regulation (a decrease in the number of target cells in the brain caused by NMDAR) of NMDAR is key and sufficient for disease!
  • LGI1 AE has highly distinctive clinical phenotypes
  • The disease neurobiology and the underlying immunology remain poorly understood
  • mAbs (monoclonal antibodies) can offer novel insights in terms of tools and therapies and immunology
  • Autoimmune limbic encephalitis leads to acute cognitive and behavioral disruption
  • There are persistent deficits in anterograde and remote memory after treatment
  • Hippocampal atrophy is associated with network-wide structural and functional changes
  • These changes explain memory deficits better than hippocampal volumes
  • Novel disorder of pathological tearfulness in AE requires further study
  • Limbic encephalitis – a “neurological” neuropsychiatric disorder
  • There is an overlap in clinical phenotype between encephalitis and schizophrenia
  • 5-9% of patients with psychoses have antibodies against a neuronal cell surface target
  • Patients with psychoses and antibodies have an abrupt onset to illness, but do not have a distinct clinical phenotype
  • Neurology and psychiatry need to combine forces!
  • The future in immunotherapy: proteins can be replaced with apitopes, representing T cell epitopes, for effective desensitization of cells causing allergy, autoimmunity and other unwanted immune responses. Apitope therapy is already proven in a range of immune pathology. Apitope immunotherapy is a targeted approach treating the underlying disease pathology by selectively reinstating immune tolerance rather than global immune suppression. (Apitope means antigen targeting epitope).

I can’t help but reinstate one of the key messages about the management of diagnosis and treatment of Autoimmune Encephalitis:

-Neurology and psychiatry need to combine forces!

A big “Thank you” and “Congratulations” to the amazing speakers and great organizers!

Your generous Donations allow IAES to continue our important work and saves lives!

Why the zebra 2 - Attending the Neurology and Psychiatry London Conference

Our website is not a substitute for independent professional medical advice. Nothing contained on our website is intended to be used as medical advice. No content is intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for your own health professional's advice. Although THE INTERNATIONAL AUTOIMMUNE ENCEPHALITIS SOCIETY  provides a great deal of information about AUTOIMMUNE ENCEPHALITIS, all content is provided for informational purposes only. The International Autoimmune Encephalitis Society  cannot provide medical advice.


International Autoimmune Encephalitis Society is a charitable non-profit 501(c)(3) organization founded in 2016 by Tabitha Andrews Orth, Gene Desotell and Anji Hogan-Fesler. Tax ID# 81-3752344. Donations raised directly supports research, patients, families and caregivers impacted by autoimmune encephalitis and to educating healthcare communities around the world. Financial statement will be made available upon request.

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