 Lucas Clark, he's a fourth year neurology resident and Lucas and I started the internship together. We suffered together for a year before we got to separate on our ways. So, he's going to talk to us about nystagmus and ataxia. I don't know how to flip this. Is it? Good morning. It's a pleasure being here today. It may be a question for most of you what relevance this topic may have to your own clinical practice. But I feel like it is quite relevant in the sense that many of the patients that we'll be talking about here will first present to an ophthalmologist probably before seeing a neurologist because of their eye complaints. And it's also quite possible that the neurologist that you might be working with in the community may not be familiar with these syndromes and would be a good basis for discussion with them. So, I'd like to present to you first a man, 78 years old, who is a retired obstetrician who has a history of actually seeing the ophthalmologist for a long time because of fuchs dystrophy in both of his eyes as well as developing binocular dyplopia later on in his career, which was a significant limitation to his practice. But the reason why he came to see us in the neuroophthalmology clinic was because he had these episodes usually lasting about five days and about four times per year where he'd wake up in the middle of the night and he couldn't walk to the bathroom. He'd stagger to the bathroom and had a very difficult time with ataxia. And this would usually last for a few days and then he'd get back to his baseline. But never quite perfect, his baseline was usually a little off. So, significantly his family is also affected with, or his sisters also had problems with ataxia, only ones that we're aware of and he couldn't really identify any triggers for this problem. So, his physical examination was very significant for limited upgays as well as psychotic pursuit and a 10-prism diopter, isotropia on the left side, as well as this is the most significant finding and I wish I could have found a good video of this or I could have videotaped him while he was in the clinic with us but he had variable nystagmus. It was not a gaze evoked nystagmus and it changed all around in whatever position he was and he didn't notice it at all and he had actually had hearing and balance testing where they noted that as well but couldn't really identify any vestibular problem prior to coming to CS. He also had a very wide-based gait and difficulty hitting a target at 15 feet and he had a terminal tremor in his right arm more than his left. So, this is an MRI image of his brain that he had prior to coming to CS and you'll notice very prominently that there's significant midline atrophy of his cerebellum as well as actually generalized atrophy of his brain but that's significant for his ataxic problem. So, this brings me to the discussion of these episodic ataxic syndromes that are primary in nature. So, they usually consist of these spells of incoordination as well as it can sometimes also have weakness and dystonia associated with them and in certain cases seizures as well. The incidence is fairly rare about one in a hundred thousand people and at least for the episodic ataxia is one and two. Now, there are at least six known episodic ataxias but the other three or four are not really clinically relevant. They've only been described in one or two families each. So, there are also other people with episodic ataxia that don't have any interectal signs and usually or it's thought that these probably represent other entities. And they think that the pathology mostly lies in the Purkinje cells of the cerebellum where there are multiple different cellular synaptic inputs there. So, unfortunately this got cut off a little bit but we can see kind of the spectrum of the episodic ataxia is here and I want to focus on highlighted in red one and two. You can see very clearly that the duration of the episodic episodes is much shorter in type one than in type two and the age at onset is much lower in type one than type two as well but both of them seem to occur in young adulthood. It's also significant that there's a difference in genes that EA1 is a potassium channel problem and EA2 is a calcium channel problem. We'll go into this in a little bit more detail. So, they're both autosomal dominant diseases and in EA1 it's usually actually in childhood that they present and it's thought that the potassium channel that's affected is in the or is predominantly expressed in the cerebellum and the hippocampus but also is in the motor neurons. Now what you want to think about with this disease besides it being brief multiple episodes at a time and it starts at a young age is that they will also present with neuromyotonia or myokymion which is discharges of the muscles underneath the skin that gives sort of a rippling appearance of the skin on the surface. And this disorder may also present with epilepsy and is sometimes responsive to Cedizolamine. Sorry that the citation isn't showing up on the bottom very well. And in terms of episodicate to haxia 2, this disorder is actually very interesting because the gene that it's located at and we'll talk about this in a second is the calcium channel alpha 1 subunit which co-locates with two other disorders familial hemiplegic migraine 1 as well as spinal cerebellar ataxia 6 and they're different alleles of this that are associated with the different disorders. It's a lot more common than EA1 and it's usually actually a truncation mutation that'll be important in a second. So the episodes of ataxia are usually a lot longer and they're also triggered by physical or emotional stress and there's usually interictal nystagmus in these patients and can be very responsive to Cedizolamine. So the episodes that they have are usually very or can be very different depending on the patient and actually even within families the penetration of this disorder can be very different but usually has vertigo, nausea, and vomiting and headache associated with it. And also usually you don't see spontaneous nystagmus interictally but there is gaze evoked nystagmus so it's important in these patients to examine whether you can provoke the nystagmus by having them lean forward in the chair. Usually it also has a prominent progressive ataxia and evaluation with an EMG can also be very helpful in assessing whether the syndrome is at play. So also in this at the same allele is a missense mutation that can cause hemiplegic migraine and I don't want to really emphasize this too much just that the entity exists and actually can present in the same family as the patients with episodic ataxia. And sometimes can actually present in the same person that they can have ataxic episodes and hemiplegic migraine episodes with Spino cerebellar ataxia type 6. This is actually what I think our patient presented with. They usually present at a much older age. It's usually a much milder disease than all of the other Spino cerebellar ataxias and it's usually only an ataxia rather than a combined disorder. It can be fluctuating and episodic just like we saw in this patient and there can be a decrease in vibration and position sense or usually more distally. The eye movement findings which are very important are that they in some cases range from difficulty fixating on moving objects to dyplopia or without marked adductional deficits. So they also have very prominent interrapial nystagmus and it's thought that this disorder is actually due to alternative splicing associated with the long polyglutamine expansion. And that's why it's thought that it probably presents much later in life. So basically the key points in thinking about these episodic ataxic disorders are that the age at onset varies quite considerably. If the patient is elderly in presentation, you definitely want to think about Spino cerebellar ataxia type 6. The other two present much earlier in life and usually are associated with more severe symptoms and other disorders. You want to ask about precipitating factors for it. The aura of falling is not path mnemonic but is classic for episodic ataxia 1. There may also be or you also want to make sure that you test whether the patient has up gaze limitation, whether there's gaze evoked nystagmus and spontaneous nystagmus. And then ultimately the patient should be referred for an EMG for additional evidence. And a lot of these patients will respond well to acetazolamide so it's a treatable neurologic disorder. That concludes my presentation. Are there any questions? That's a good question so acetazolamide is a carbonic acid reductase inhibitor and the thought is that it actually stabilizes the membrane so it doesn't actually interact with the potassium channel or the calcium channel directly but by increasing that membrane potential it decreases the... I think essentially it is the change in pH in the sense that there are more cations present there. That's a really interesting question. I think there definitely are imaging characteristics that are nonspecific of cerebellar degeneration that you see in these especially as the disease progresses that the lack of neuroimaging findings does not tell you that this is not a spinal cerebellary taxia or episodic taxia but clearly if the imaging findings are present they help in cinching your diagnosis.