A catalogue of autoimmune mimics

A post from two weeks ago describes a PSP-like condition caused by antibodies against a normal protein called IgLON5. Like most autoimmune disorders, it responded to immune-modulatory treatment.  Now, six cases of an MSA-like picture with antibodies against a different protein called Homer-3 has just been published by a research group in China. (See below for a downloadable pdf.)

Those patients’ conditions looked something like MSA in featuring ataxia, slowed movement and autonomic loss, and most of them responded to steroids or other immune modulation to some degree.  That report prompted an editorial by Eoin Mulroy, Bettina Balint and Kailash Bhatia of University College London summarizing what we know about immune disorders mimicking PSP, MSA and CBD.  I subscribe to that journal, Movement Disorders Clinical Practice, but I can’t upload the editorial to this public space without paying a hefty fee to the publisher.  So I’ll summarize it for you.

Drs. Mulroy and colleagues list 13 kinds of antibodies found in blood and/or spinal fluid that can produce some of the diagnostic features of one or more atypical parkinsonian syndrome. Each of the 13 antibodies attacks one of these proteins: CASPR2, CRMP5, DPPX, GAD, glycine receptor, Homer-3, Hu, IgLON5, Kelch-like protein 11, LGI1, Ma2, Ri and Sez612. 

  • The disorders mimicked by these syndromes are PSP (12 of 13), MSA (11 of 13) or CBD (3 of 13).
    • The one not reported to cause PSP symptoms is anti-Homer-3.
    • The two not reported to cause MSA symptoms are anti-DPPX and anti-MA2.
    • The three that have been reported to cause CBD symptoms are anti-GAD, anti-glycine receptor, and anti-IgLON5.
  • Only 4 of the 13 always start before age 60. 
  • Nine of 13 show evidence of inflammation on MRI in the form of high T2 signal in various spots.  
  • Routine tests on the spinal fluid (i.e., cell count, total protein, glucose) are normal in about half of cases.
  • A malignant tumor is commonly present in an organ outside the brain in 5 of the 13 and are “uncommon” in another 6.  Detection and removal of that tumor sometimes helps the neurological issue.
  • The good news is that in only 1 of the 13 is the response to immunomodulatory treatment described as “poor.”  It’s “good” in 2 and “partial” or “variable” in the other 10.

An important piece of advice is that the symptoms of these disorders develop from nothing to a state of some disability over weeks to months.  That’s called a “subacute” course. So there’s no point in doing these tests when the symptoms have developed over a period of years, a chronic course. 

None of the lab testing companies offers all of the antibody tests listed, and not everyone’s insurance covers tests from every company.  So the doctor (or patient/family/caregiver) will have to do some homework to figure out which tests are applicable to the specific symptoms, which companies offer the required tests and which testing companies work with that person’s insurance.   

A treatable PSP mimic

Yesterday’s post updated my diagram showing relationships between PSP/CBD and the other major neurodegenerative diseases.  The only substantive change was the addition of a tauopathy called “anti-IgLON5 syndrome,” which we’ll call “AIS.”  It’s not “major” in the sense of “common,” but in the sense of “important to know about because it’s treatable, especially if diagnosed early.” 

AIS sits on the border between the autoimmune and the neurodegenerative diseases.  (In fact, multiple sclerosis does that, too, but unlike most neurodegenerative diseases, it has no known protein aggregates in the affected brain cells.)  In AIS, the blood and/or spinal fluid have antibodies directed against one type of the “cell adhesion molecules” on the surface of brain cells.  Those molecules assist in the function of the microtubules, which are the cell’s internal skeleton and transport system, and also where tau normally works.  The problem is that we don’t yet know for sure whether the antibody attack causes the cell damage or if the antibodies are merely the immune system’s reaction to damage caused by something else.

The classic symptoms of AIS are major difficulties in the control of sleep and involuntary movements called “chorea.”   But more recently, four different types of AIT have been described, and one of them mimics PSP, with severe loss of balance and milder cognitive loss and predominantly vertical eye movement problems.  As in ordinary PSP, sleep problems are present as well, but with more dream enactment and obstructed breathing than occur in PSP. 

About a quarter of those with AIT have the PSP type.  The other three types emphasize problems with sleep (the most common); speech and swallowing; and cognitive problems, respectively.  All four types also display autonomic disturbances in a majority of patients, including episodes of sweating, incontinence, and slow or fast heartrate.  Oddly, only a few have low blood pressure. Otherwise, the autonomic features are similar to those of MSA, and of course the motor features of MSA, like those of PSP, can be similar to those of AIS, but without the chorea.

An important difference between AIT and PSP, CBD or MSA is that AIT has no muscle rigidity, movement slowness or tremor. Those three things are collectively called “parkinsonism.”

AIS’s average onset age of 64 plants it firmly in the range of most neurodegenerative diseases, rather than in the younger range typical of autoimmune diseases.  Furthermore, the female predominance of most autoimmune diseases does not exist for AIS.  Also, only one case in the literature has been reported to spontaneously improve, and the course is slowly progressive rather than fluctuating.  These points favor a neurodegenerative origin.

On the other hand, all patients with AIS have a specific genetic variant in one member of a set of genes on chromosome 6 associated with autoimmune disease.  It’s called the human leukocyte antigen, or HLA system.  And here’s the most important point favoring an autoimmune origin: treatment with standard immune modulating drugs such as steroids, intravenous immunoglobulin and azathioprine, helps about two-thirds of the patients.  

It’s interesting that the classic form of AIT, where sleep disturbances predominate, is much less responsive to immune modulatory drugs than the more recently-described variants.  So maybe the different types sit slightly on one side or the other of the autoimmune/neurodegenerative fence.

Here’s a colorful (but blurred – sorry) diagram showing features in 22 patients with AIS.  It’s from the research team in Barcelona that and first described AIS in in 2014 and is probably the world’s leader in neuro-autoimmune disorders.

The four subtypes appear in the second column (where “bulbar” means speech and swallowing), the intensity of each of seven features is represented by the shade of color in the boxes, and the immunological and genetic findings are on the right. From: Gaig C, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology. 2017 May 2; 88(18): 1736–1743. PMID: 28381508

This diagram doesn’t mention that some patients with AIS exhibit hyperexcitability in the form of muscle cramps, muscle jerks and easy startle. 

I must emphasize that while AIS is a tauopathy, it’s not PSP or CBD.  It affects different parts of the brain, has both 3R and 4R tau (PSP and CBD have only 4R), it has a longer survival untreated, and it has anti-IgLON5 antibodies.

So here’s the take-home: 

  1. People in the early stages of an illness suspected of being PSP, CBD or MSA should make sure their doctor knows about AIS so that testing for the antibody can be considered.  If it’s positive, immunomodulating treatment may make a big difference, especially if two or more such drugs are used together, and if treatment is started in the first two years of the illness.  Often, rheumatologists know more about the treatment of autoimmune disorders than neurologists, especially movement disorder specialists.
  2. Even if there’s no response to immunomodulatory treatment, finding anti-IgLON5 antibodies should prompt a search for small but growing cancer. While none of the publications on AIS has examined this issue thoroughly, other autoimmune disorders in the nervous system are very often associated with cancer.  Most of the published case series either didn’t work up the patients for cancer or lost follow-up before a small cancer would have revealed itself.  Detection and removal of a small, early cancer could help the AIS, and even more important, save a life.