The Neurotransmitters: Clinical Neurology Education

Stiff Person Syndrome

December 23, 2022 Episode 18
The Neurotransmitters: Clinical Neurology Education
Stiff Person Syndrome
Show Notes Transcript

Stiff person syndrome (SPS) is a relatively rare neurologic disorder that often causes disabling muscle spasms. After Celine Dion recently announced she was diagnosed with SPS it has received significant attention in the news. What do you need to know to answer your patients' questions about this syndrome and to potentially identify it yourself? Today we'll talk about the common symptoms, diagnostic tests, and treatments used for SPS. 

Celine Dion's Instagram Post

Stiff-Person Syndrome

Stiff-Person Syndrome: A Treatment Update and New Directions

Long-term effectiveness of IVIg Maintenance Therapy in 36 patients

Evaluation of Treatment Outcomes in Patients with Stiff Person Syndrome with Rituximab vs. Standard of Care

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Stiff Person Syndrome 

 [00:00:00] Welcome back to the Neurotransmitters, a podcast about everything related to neurology with the goal of reducing your neurophobia. I'm your host, Dr. Michael Kentris. And today I wanted to talk with you about a stiff person syndrome. So normally on this podcast, I like to talk about things that are more common that are going to show up frequently, but sometimes a rare neurologic syndrome shows up in the news. And so that may mean that you're getting questions about it or it's showing up a little bit more often in your medical practice. Or maybe you're just curious about what that entails. So I'm recording this in December of 2022, and earlier this month, Celine Dion had announced that she was diagnosed with stiff person syndrome. She had released a video on Instagram, kind of going through a little bit of her challenges with it and talking about doing some of her performance dates and things like that. 


[00:00:54] So let's dive right into it. What is person syndrome? So stiff person, what used to be called stiff man syndrome. We changed a stiff person center because actually it's a little bit more common in women, about 2 to 3 times as common in women than men. And it is it is a very rare disorder, as I mentioned earlier. So it's not something you're likely to see very often. The incidence is reported as around 1 to 2 people out of every 1 million. So definitely not something you're going to be seen around every corner. I can probably count on one hand the number of patients I've seen with sort of person syndrome. Now, as the name implies. What kind of symptoms do people usually present with? They become stiff, and as such they have muscle spasms, very painful most of the time. And these tend to preferentially affect the trunk kind of the abdomen, the back. But they can also involve the limbs. So it can be a little tricky to diagnose. So part of the problem is that not only is this person syndrome rare, but because the symptoms are a lot of times like muscle spasms, pain, difficulty walking, these patients are very often written off as kind of having psychologic issues. So there is in addition to just the rareness of the syndrome, there is also diagnostic delay, just due to preconceptions among health care workers who are potentially seeing these people. 


[00:02:24] So as I said, you know, we kind of have our classic stiff person syndrome presentation where you have the axial muscle rigidity, painful muscle spasms, etc., etc.. But I can think of three cases that I've had from residency through present day that all presented in a different fashion. So I just wanted to sit down for a little story time, kind of go through kind of these different presentations that I've encountered myself. So the first time was when I was a senior resident. We had a young man who had a preexisting diagnosis of stiff person syndrome. And so he had had it for a number of years. And he had your classic textbook muscle spasms. He was he was a younger guy in his, you know, early thirties. And he was having these, like kind of full body muscle spasms, kind of resistant to treatment. And he had come into the hospital because his home medication regimen was not able to control them. And he kind of got into a little bit of a flare up and required some I.V. therapies. Another patient had come to me. She was a more of a middle aged woman she had been having for several months, increase in muscle spasms, stiffness in her back and limbs to the point where she was unable to walk anymore. So when she came in to see me in the office, she was actually in a wheelchair and had been in that way without any treatment. No, nothing being provided by her primary care physician, because again, there was this preconception that potentially this might have a psychologic element to it, you know, So we ended up working her up. She did have a good response to therapy and we'll talk about some of those treatment options as we go. 


[00:04:02] But again, her presentation was what one would consider fairly textbook for stiff person syndrome. This last case is the one that I really wanted to talk about because it was such a learning experience for me. It was when I was a fellow and I had the chance to work with some amazing instructors. And so I had gone in to see this middle aged guy who had been coming in for, you know, some a complaining of difficulty walking, nothing severe. He had maybe just a little bit of difficulty with stairs with one of his calves. And this had been going on for a little while but hadn't really progressed, Right? No, no painful muscle spasms, no falls, just a little hitch in the giddy up, if you will. So, you know, I go in and I spend an hour talking and examining this guy, and I don't really find anything that catches my eye. I thought his exam was entirely normal. So I go out, I tell my preceptor all this information, we go in and he examines this patient. 


[00:05:00] And I just remember him like, kind of like laying his hands on, if you will. I feel this this man's calves and it's like it just feels a little stiff. And he's like, let's order GAD65 antibodies. And lo and behold, three or four weeks later, those results came back floridly positive. And that just really floored me. To see someone with such diagnostic ability is just right there at the bedside leading to getting the diagnosis in just one shot. I was just ridiculously impressed. And obviously this is years later and I still remember that story vividly. 


[00:05:38] So again, there can be, especially in the early stages, a lot of subtlety, a lot of variation, but what can we look for? So there are some diagnostic criteria. So let me run through a few this with you. One Stiffness in the limb and axial muscles, most prominent in the abdomen and thoracic a lumbar region. All right. So normally when we think about checking for stiffness or increased tone in the limbs, right, we do passive range of movements in the arms and legs. That's fairly straightforward. But when we talk about the rack, a lumbar region, we're usually looking at like having them touch their toes, checking for backward bending. Usually you'll have like one hand on their lower back, just kind of feeling for any hyper tenacity in the muscles, just with regular posture. And then like maybe having them bend back kind of with one hand on their shoulder or the other on their lower back, you know, trying to help them maintain balance and feeling like, is there a restricted range of movement there? It is a little subtle sometimes, definitely. And it is something that you kind of have to practice a little bit to get a good feel. So it is good to check that on people who you don't think they have stiff person syndrome. So you get a little more of a feeling for what it should be and someone who's not dealing with that issue. 


[00:06:51] Number two, painful spasms precipitated by unexpected, tactile and auditory stimuli. So this is the part that can sometimes maybe make people in health care think that these have a psychologic element to them. But it is important that many neurologic conditions can be precipitated by unexpected stimulation, whether that is tactile, auditory, visual, etc.. We think of like in in infants like hyper complexity, where they have a sometimes a genetic abnormality that predisposes different kinds of epilepsy. So seeing it in this condition as well should not be outside the realm of normal for people who are familiar with neurologic conditions. Right. Lots of triggers for lots of different conditions. So they can be precipitated in this case, sometimes even by emotional stimulation. And number three evidence of continuous motor unit activity in agonist and antagonist muscles demonstrated by EMG. Now, this isn't a routine lecture diagnostic technique that is used by most EMG-ers. Essentially, you need to have two needle electrodes and you are applying one to say, We're looking at the upper arm, the biceps and the triceps simultaneously. And what we're looking for is essentially this continuous motor unit activity in both muscles simultaneously. And obviously you can look at any agonist antagonist pair of muscles in any part of the body, assuming that you're able to reach those safely with your electrodes. Number four, absence of other neurological impairments that could support an alternative diagnosis. Right. So what we're really looking for is, is there evidence of like myelopathic signs that would suggest a spinal cord issue like a, you know, something in the brain, other genetic causes, etc., etc.. So you do have to initially sometimes have a broader differential looking for other competing diagnostic entities. 


[00:08:51] So things that you would think about, like I said, myelopathies, other types of paraneoplastic syndromes of which there are very many or certain kinds of motor neuron disease like primary lateral sclerosis, which presents with a more upper motor neuron predominant type of phenotype as opposed to more like ALS, which is kind of a mixed bag of upper and lower motor neuron findings. So those are a few things that you might think about in your initial workup depending on the presentation. Number five, positive serology for anti-gad 65 or anti amphiphysin autoantibodies. 


[00:09:24] So the classic one that most neurology residents will be familiar is the anti-GAD65. That's the glutamic acid D carboxyl is this enzyme is important in producing GABA. So if you have an autoimmune condition reducing gad that thereby will decrease GABA GABA being one of our primary inhibitory neurotransmitters. If we have reduced levels then we have de facto increased excitation and hence the muscle spasms in these patients. It's always nice if we can just turn our brains off and order a lab test to confirm or refute whether or not we have the correct diagnosis. However, anti-gad 65 antibodies are seen in approximately 60 to 80% of people with stiff person syndrome. So definitely not as good as we would need to be to be definitive. In addition to that, anti-GAD antibodies are also seen in a number of other autoimmune conditions, in particular type one diabetes. So with stiff person syndrome, the titer does matter. The higher the titer and the more clinically consistent the presentation of your patient, then the more confident you can be that you do in fact have the correct diagnosis. Now, you also heard me mention just a minute ago the anti-amphiphysin Autoantibodies as well. And we'll come back around to those in a minute. The last diagnostic criteria, point six and again, I'm taking this from a reference article, references will be in these show notes, is a clinical response to therapy with benzodiazepines, right? So benzodiazepines are gaba-ergic. They work on your GABA receptors, so they are going to kind of take up the slack from the decreased endogenous GABA that we are producing in this condition. So if you see people have a good response, typically we're talking diazepam, then that is also a supporting clinical feature. 


[00:11:19] So like so many things in medicine, it is rarely a straight line from point A to point B in terms of making a diagnosis, especially in a condition this rare. So some people will group different types of stiff person syndrome into different categories. And again, because this is such a rare condition, we don't necessarily this is not a particular robust classification scheme, but it does suggest that maybe we are seeing multiple different underlying pathophysiologic processes manifesting in these same a clinical phenotype. So type one is what we mentioned earlier with the anti-gas 65 autoimmune type condition associate with other autoimmune conditions like type one diabetes like Hashimoto's Thyroiditis and others. Type two is referred to as a para neoplastic syndrome. That is to say it is associated with different types of malignancies and these are the anti amplifies and positive patients. So we're typically looking for things like lung cancer, thymus, cancer, breast or lymphoma. So if there are concerns for a more systemic process, weight loss, night sweats, history of cancer, of various types, a risk factors for different types of cancer, you should certainly pursue an investigation in those patients that would be appropriate to the underlying malignancy, and especially if you do have one of these neoplastic antibodies come back positive on a panel you should definitely be considering. Does that fit clinically, first of all, because again, we can have a lot of false positives with a lot of these neoplastic antibodies. 


[00:12:54] So a strong titer certainly should prompt you to be a little suspicious in the appropriate clinical context and do an appropriate NEOPLASTIC type of workup. And then finally, type three is what is referred to as a zero negative, stiff person syndrome. This is a more of an idiopathic, presumably autoimmune, but potentially, you know, again, this is speculative, but presumably an unidentified antibody at this point in time. Again, like we mentioned earlier, the sensitivity of the GAD65 antibodies, they're okay, but they're not remarkably sensitive. So it is important to always, even if it's negative, have a high clinical suspicion based off of the clinical presentation. So let's talk a little bit about treatments. And there are essentially two broad categories. There are the symptomatic treatments, and then there are the disease modifying or immunotherapy type treatments. So talking about symptomatic treatments, we're essentially looking at things that are going to decrease that excitability. So a lot of things that work on GABA pathways. So as I mentioned earlier, benzodiazepines are kind of one of our first line symptomatic therapies. Oftentimes we're talking about diazepam. And again, depending on the person in question that kind of guides your dosing a little bit. But it is important to remember that diazepam, we always think in, you know, if you've gone to medical school, Diazepam has a very long half life, but because it is so lipophilic, the actual effective half life in the CNS is much reduced just because of the peripheral distribution. So do keep that in mind when dosing diazepam. Conversely, we have baclofen another GABA agonist, so benzodiazepines work on a back often on GABA a for Ativan and GABA B for baclofen. Obviously there is oral baclofen but when people progress and that can happen where people will start out relatively mild and their symptoms can get more advanced, more severe over time. And we see this with other types of neurologic disorders as well, like multiple sclerosis being one where we find that the oral administration of BACLOFEN is too sedating. So we'll actually put in an intrathecal BACLOFEN pump and this can help ameliorate some of those side effects that you'll see with high doses of oral baclofen. There are also reports of tizanidine being used, right. Tizanidine is one of our kind of old school muscle relaxers. It's an alpha two inhibitor and this can lead to the inhibition of a glutamate release, right? Glutamate being one of our primary excitatory neurotransmitters. So that can also help from that perspective. And then there are also some case reports of things like Levetiracetam or Keppra, one of our old seizure meds being used. It's thought to decrease spinal cord hyper excitability. Pregabalin, or Lyrica as the brand name, again thought to have some spinal inter-neuron type mechanism and in some cases propofol has also been used. So again, these are case report level evidence for these last few with some proposed theoretical mechanisms in the papers where they are referenced. But I wouldn't say the routine. 


[00:16:17] I would say usually we're talking about diazepam and baclofen as our primary ones moving to our disease, modifying therapy. One of the mainstays of therapy is IVIG or, you know, intravenous immunoglobulins for those who aren't familiar. So essentially this is kind of it binds to antibodies in the system and they are flushed out in the urine essentially. So it's a way to kind of reduce the antibody load in someone's system. And it's usually dosed on a monthly basis about every four weeks. There are some studies looking at it. One study showed about 67% of patients benefited for three years on monthly treatments. So there are some decent data there. Another, I hesitate to use the word commonly, but often considered treatment is rituximab, and rituximab is used, I would say fairly often in a variety of neurologic conditions that are thought to be antibody mediated in that same vein. Plasmapheresis is also sometimes used again to reduce that antibody load. So these three therapies, you see these used a lot in different neurologic conditions and similarly in something like stiff person syndrome, where the proposed mechanism is an antibody mediated process. 


[00:17:36] These are kind of things that have been in some cases more or less studied other things that are the case report level data are we have steroids. Mycophenolate Mofetil is a thigh heparin tacrolimus, although certainly again, not standard therapies, but things that can be considered in patients who have been refractory or progressive despite kind of these more first line types of disease modifying therapies. So those are some of the high notes that I have for you today on stiff person syndrome. 


[00:18:07] I hope you find it useful. I hope you're able to answer any questions that come your way about stiff person syndrome, and hopefully it'll at least be on your radar next time you see someone with muscle spasms. If you enjoyed this podcast, please rate review and shared on Apple, iTunes, Spotify, wherever you're getting your podcasts and please subscribe for future episodes. You can find me on Twitter at Dr. Kentris. That's D R K E N T R I S or by email at with any questions or please submit any suggestions for topics that you might be interested in. As always, thank you again for listening.