Autoimmune Brain Disease (AIBD)

Timothy C. Hain, MD

Last edited: April 26, 2023

AIBD defined • How common is AIBD •Diagnosis of AIBD • Pandas• Autoimmune inner ear disease (AIED).

Autoimmune Brain disease or "AIBD" consists of a syndrome of central nervous system which is caused by antibodies or immune cells which are attacking the brain. There is considerable overlap between autoimmune disorders that attack the ear and those that attack the brain. There is also overlap between paraneoplastic syndromes, as many of these are mediated by the immune system.

The immune system is complex and there are many ways that it can damage the brain.

Traditional "autoimmune diseases"

These include Systemic Lupus Erythematosus (SLE), Sjoegren's syndrome (dry eye syndrome), the antiphospholipid antibody syndrome, Wegener's granulomatosis, and rheumatoid arthritis.

There are are also organ specific disorders such as Hashimoto's thyroiditis and Celiac disease (sprue) which occasionally are accompanied by AIBD. In Celiac disease, antibodies have been found directed against transglutamase 2 (an autoantigen in the gut), and transglutamase 6 - an antigen independent of intestinal involvement (Hadjivassilou M, et al, 2008). GAD65 is another biomarker (i.e. blood test), sometimes accompanied by "limbic encephalitis, epilepsy, cerebellar ataxia, and stiff-person syndrome (SPS), among others. " (McKeon and Tracy, 2017).

Autoimmune disease restricted to the central nervous system

Antibodies to glutamate receptors have been reported in cerebellar degenerations (Gahring et al, 1997), in patients with downbeating nystagmus (Antonini et al, 2003), and palatal myoclonus.

Antibodies to Gq1b (a ganglioside largely found in nerves), have been reported in a group of disorders including Guillain Barre, Bickerstaff's encephalitis, Miller-Fisher syndrome.

Antibodies to GAD are also reported in "stiff person syndrome", typified by muscular rigidity and episodic muscle spasms. Anti-GAD antibodies are also very common in diabetes, B12 deficiency and Hashimoto's thyroiditis.

Limbic encephalitis has been reported secondary to GABA-B receptor antibodies (Hoftberget et al, 2013).

Cerebellar ataxia as well as opsoclonus has also been reported in persons with GABA-B antibodies.

Autoimmune mechanisms have also been suggested for the opsoclonus-myoclonus syndrome (Pranzatelli 1996; Lapenna, Lochi et al. 2000; Dale 2003; Pranzatelli, Travelstead et al. 2004; Pranzatelli, Tate et al. 2005). Some of these are associated with tumors (i.e. neuroblastoma), making them also a paraneoplastic disease.

 

clippers
Clippers MRI -- source of image: https://livingwithclippers.blogspot.com/2011/10/four-week-journey-to-diagnosis.html

A disorder called "CLIPPERS" Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids was described by Pittock et al(2010),. This disorder consists of an MRI pattern of blood vessel enhancement of the pons, combined with a variety of pontine symptoms -- facial paresthesia, diplopia, dysgeusia, and ataxia, and response to steroids. (Pittock et al, 2010). It points out the value of trying steroids in mysterious CNS disorders with signs of inflammation. Somtimes there is attributution MRI like this to vascular malformations. It is possible that some of these cases actually have CLIPPERS (it would probably take an autopsy to be sure).

Balzabal-Carvello and Jancovic reviewed "Movement disorders in Autoimmune Diseases (2012). They listed Sydenham's Chorea and Pandas as examples of movement disorders associated with immune responses to Streptococci.

Pandas is an acronym for pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection. Click to find a discussion of PANDAS.

How common is autoimmune brain disease ?

AIBD is rare, probably accounting for less than 1% of all cases of central disturbances. It is also a difficult diagnosis and errors can and do occur. According to Flanagan et al (2023), misdiagnosis occurs in about 1/4 patients. They stated "A total of 393 patients were referred with an autoimmune encephalitis diagnosis... RESULTS: A total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis." So about 1 in 4 patients are misdiagnosed. "

Flanagan et al also commented "Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 [38%]). "

What causes autoimmune brain disease ?

The cause of AIBD is generally assumed to be related to either antibodies or immune cells that cause damage to the brain. There are several theories as to how these might arise, analogously to other putative autoimmune disorders. It is also possible that they don't "cause" the problem, they are just associated with it. Or in other words, a positive test shows that there is an inappropriate immune response, but doesn't necessarily mean that it is causing a particular disease.

Mistaken identity: Just because there is a positive blood test in a particular disease, does not imply that one causes the other.

It might just be a coincidence (perhaps the case with Gluten sensitivity and Hashimoto's encephalitus, as these are conditions associated with extremely common auto-antibodies). Or there might be a common underlying cause of both the antibodies and the disease. This has been suggested to be the situation for the "classic paraneoplastic antigens", as in animal models, these antibodies seem to be innocuous (Balzabal-Carvallo and Jancovic, 2012).

Examples of antibodies in the "mistaken identity" class include Anti-Yo, anti-Tr, anti-Ri, and anti-Hu. In other words, the "classic" paraneoplastic antibodies, don't seem to "cause" anything.

The anti-GAD65 antibody is also found most of the time in non-neurological conditions. According to McKeon and Tracy (2017), "Type 1 diabetes, autoimmune thyroid disease, and pernicious anemia are the most frequent GAD65 autoimmune associations. One or more of these disorders coexists in approximately 70% of patients with GAD65 neurological autoimmunity. "

On the other hand, there are also antibodies that are directed against cell-surface antigens. There is good evidence that these antibodies cause disease. These include VGKC (voltage gated potassium channel) antibodies, VGCC (voltage gated calcium channel) (Finkel and Koh), and NMDA-R antibodies.

NMDA-R

The NMDA-R syndrome is associated with teratomas primarily, and these patients respond to removal of the tumor. Thus these are also paraneoplastic disorders. According to Bertolini (2016), anti-NMDAR encephalitus is "now recognized as one of the most common forms of encephalitis". This dubious statistic came from a study of "young individuals" enrolled in the "California Encephalitis Project" -- i.e. it is likley not true in older people or in other parts of the world where there is more infectious encephalitus -- such as places with Zika virus. NMDA-R associated encephalitus acts like other types of encephalitis -- there is changes in behavior, mild changes in the spinal fluid, may have seizures and movement disorders. For NMDA-R (unlike the situation with the opsoclonus-neuroblastoma syndrome), symptoms may regress rapidly once the teratoma is removed. These patients are treated with the usual mixture of high-dose steroids and chemotherapy drugs -- such as IV methylprednisolone for 5 days and rituximab. Oddly, they do not get better with benzodiazepines.

As an example of aggressive treatment, according to Bertolini (2016), "treatment of anti-NMDAR encephalitus consists of supportive measures, immunotherapy, and tumor removal. First line is generally high-dose steroids, immunoglobulin (IVIg) and plasma exchange. Rituximab and cyclophosphamide are usually considered second-line treatments and reserved for those patients who fail the first line." There is some reason to this as the first 3 treatments are unlikely to be lethal by themselves. Rituximab and cyclophosphamide are "sharp instruments" that can cause damage.

"hyperekplexia" and antibodies.

Other pathogenic antibodies are thought to be to the glycine receptor. These  can cause an unusual condition called "hyperekplexia", essentially a very strong startle response, similar to persons poisoned with strychnine. One variant is called  PERM (progressive encephalopathy, rigidity and myoclonus). A similar syndrome is caused by antibodies against DPPX (dipeptidyl-peptidase?like protein 6) (Hara et al, 2017)  DPPX is not involved with glycine but rather it regulates potassium channels.

Hashimoto's encephalitis is also thought to be steroid responsive, suggesting that the antibodies are toxic, although the antibodies associated with Hashimotos are very common. Persons with Hashimoto's may also have anti-GAD65.

Potential mechanisms for brain injury from antibodies include:

Bystander damage: In this theory damage to the brain causes cytokines to be released which provoke, after a delay, additional immune reactions. This theory might explain the attack/remission cycle of disorders such as multiple sclerosis.

Cross-reactions: In this theory, antibodies or rogue T-cells cause accidental brain damage because the brain shares common antigens with a potentially harmful substance, virus or bacteria that the body is fighting off.

Intolerance: The brain, like the eye may be only an partially "immune privileged" locus, meaning that the body may not know about all of the brain antigens, and when they are released (perhaps following surgery or an infection), the body may wrongly mount an attack on the "foreign" antigen. In the eye, there is a syndrome called "sympathetic ophthalmia", where following a penetrating injury to one eye, the other eye may go blind. This theory is not presently in favor for the AIBD. It may account for some cases of autoimmune inner ear disease (AIED) however.

Genetic factors: There is increasing evidence that genetically controlled aspects of the immune system may increase or otherwise be associated with increased susceptibility to brain injury.

How is the diagnosis of autoimmune brain disease made?

The diagnosis is based on history, findings on physical examination, blood tests, and the results of other tests. NMDAR encephalitus is diagnosed by finding NMDAR antibodies in the CSF (i.e. with a spinal tap). Frequently it is surmised that a condition is autoimmune because it gets better after a specific treatment.

Blood tests for autoimmune disorders include:

 Blood tests for conditions that resemble autoimmune disorders include:

Note that having a positive test for an autoimmune disease does not necessarily mean that that antibody is responsible for autoimmune brain disease. Particularly problematic antibodies are the very common anti-thyroid antibodies, and also the anti-GAD antibodies.

 How is Autoimmune Brain Disease Treated ?

There are several protocols for treatment. In cases with a classic rapidly progressive impairment, a trial of steroids (Prednisone or Decadron) for 4 weeks may be tried. In persons with response to steroids, in most cases a chemotherapy type of medication such as Cytoxan or Methotrexate will be used over the long term . Plasmapheresis or IVIG (immunoglobulin infusion) may be beneficial. Newer medications are constantly being developed for immune suppression, usually aimed at tumors related to the immune system. Rituximab is now commonly combined with steroids in individuals where one is mainly treating the immune response.

According to McKeon and Tracy (2017), only about 50% of patients with anti-GAD65 neurological syndromes improve with immunotherapy.

Autoimmune brain disease is rare making it difficult to study. One can speculate that there might be effective treatments that simply have not been discovered. For example, there are numerous potential treatments that have not been tried in a formal way.

Gamma globulin infusions, given monthly, is useful in numerous autoimmune disorders. This treatment is very expensive, which limits its use.

Immune modulating drugs such as are used for treatment of MS (beta-interferon, alpha-inteferon, copaxone) are commonly used.

Rituximab has been used in opsoclonus where the eyes move too fast, as well as Miller-Fisher syndrome where the eyes don't move at all (go figure).

Other medications that have coincidental suppression of immune responses, such as minocycline, might be tried.

A gluten free diet has been suggested as being helpful in persons with anti-GAD ataxia. (Lemos and Manto, 2020)

REFERENCES: