Ataxia Series: Recognizing sporadic ataxias

Dr. Divyani Garg: Hi, Orlando. Thank you for having me. It's truly a pleasure to be here and to discuss such a clinically important topic.

Prof. Orlando Barsottini: Divyani, m y first question. How do you clinically distinguish [00:01:00] sporadic from genetic ataxias at the bedside? And tell me about the diagnostic pitfalls you commonly see in the evaluation of sporadic ataxia.

Dr. Divyani Garg: That's a great starting point. At the bedside I focus on three pillars, age at onset, the temporal profile of progression of symptoms, and the family history. So genetic ataxias usually tend to have an insidious onset. They tend to be slowly progressive, and sometimes we find additional neurological features like say, neuropathy, pyramidal signs, movement disorders, vision involvement. It is also important to remember that the absence of family history does not exclude a genetic cause, which can be due to various reasons, like incomplete penetrance, inaccurate diagnosis in the family member, subtle symptoms in the family, or even a small family size or de novo mutations.

So sporadic ataxias, the clues to that are that they usually have an acute to subacute onset or [00:02:00] they may have a very rapidly progressive course, and sometimes we will find history of systemic symptoms or history of exposure to drugs, toxins, which can be great clues. And some of the common pitfalls include, assuming that chronic invariably means degenerative ataxia.

That is not true because we know for many of these sporadic ataxias, a longer history may still be a part of the clinical spectrum. Another pitfall is to miss sensory ataxia and assume that all ataxia is actually cerebellar because sensory ataxias have a different set of etiologies. Another pitfall would be to overlook medications that the patient may be on and not screening adequately for immune or metabolic causes.

So the key principle is to never label degenerative or hereditary before excluding treatable causes.

Prof. Orlando Barsottini: As you said we have many groups, many different groups of sporadic ataxias, including infectious, metabolic, and autoimmune. Could you talk [00:03:00] a little bit more about the treatable forms?

Dr. Divyani Garg: Yes, Orlando. Absolutely. And this is really the heart of the matter because sporadic ataxia should always be approached with the mindset that it may be treatable unless proven otherwise. So the treatable causes, as you have mentioned, can be broadly categorized into immune mediated causes. Particularly important in these are the anti-GAD associated ataxia, gluten ataxia, the paraneoplastic cerebellar degenerations, the infectious causes, which are continuing to be important in some parts of the world.

For example, ataxia is occurring in the setting of HIV, syphilis, Whipple's disease, and then the JC virus, which can cause progressive multifocal leukoencephalopathy. Which can occur either in immunocompromised or immunocompetent settings. And then in children, the post-infectious cerebellitis important, which can follow several viral infections, and then metabolic and nutritional causes.

Of course, we must always screen for vitamin deficiencies and some specific electrolyte disturbances. [00:04:00] Toxins are important, particularly alcohol continues to remain the most common cause globally. But it is also important to consider certain medications, particularly the anti-seizure medications, chemotherapy agents.

And last but not the least I would also mention the structural causes like the tumors, strokes, demyelinating disorders like multiple sclerosis, et cetera, because these can be remedied either surgically or medically. So if I had to summarize the approach to treatable sporadic ataxias, I would emphasize three clues, of course, the subacute or rapidly progressive temporal profile, the presence of systemic or extra cerebral features, and a disproportion between clinical severity and imaging, which we can talk about a little later.

Prof. Orlando Barsottini: Divyani, when should clinicians suspect immune-mediated cerebellar ataxia? And could you mention some clinical or radiological clues for these diagnosis? Especially immune mediated cerebellar ataxias. 

Dr. Divyani Garg: [00:05:00] Yeah, this is a crucial question because immune-mediated cerebellar ataxias are actually a very time sensitive and potentially treatable cause of sporadic ataxia. The earlier we intervene in these conditions, the better is the neurological outcome because once cerebellar atrophy becomes evident and established, reversibility tends to decline significantly.

So the clinicians should suspect immune-mediated etiologies primarily when the evolution is subacute, meaning the clinical symptoms progress over a few weeks to a few months. So a patient may report a history that they were walking normally three months ago, let's say, and they are now needing support.

So that should immediately raise concerns for a potential immune mediated etiology. Other clues could be a presence of a personal or a family history of autoimmune disorders. For example, there could be a family member who has autoimmune thyroid disorders, type-1 diabetes, vitiligo, pernicious anemia, celiac disease, et cetera.

And then if you have the presence of some other associated neurological features like seizures, [00:06:00] myoclonus, stiff person syndrome, peripheral neuropathy, behavioral changes. All of these raise clinical clues towards suspecting immune-mediated cerebellar ataxias. You also asked about the radiology. So from the radiological standpoint, there is an important teaching point that the MRI of the brain can actually be completely normal in the early stages.

So therefore, normal MRI does not exclude immune mediated etiologies.

Prof. Orlando Barsottini: Okay, great. Divyani, sometimes gluten ataxia is a controversial topic. What features suggest gluten ataxia and in your vision, what are the most important diagnostic and treatment regimen challenges in gluten ataxia?

Dr. Divyani Garg: Yes, Orlando gluten ataxia is indeed one of the most debated areas in sporadic ataxia, as I do agree with you. So basically it's an immune mediated cerebellar condition, which is triggered by gluten [00:07:00] sensitivity and can often occur independent of the gastrointestinal symptoms. In fact, many patients may not have the classic features of celiac disease.

Clinically one can suspect gluten ataxia in somebody who has a sporadic, progressive cerebellar condition with predominantly a midline ataxia. So there is predominantly gait and truncal ataxia a relatively pure cerebella syndrome, or sometimes one may have coexisting peripheral neuropathy or myoclonus.

The MRI may show vermian predominant atrophy, but as I told you earlier, the early imaging may be normal. So a good clue here becomes to look at the MR spectroscopy of the vermis, which may show a reduced NAA/creatine ratio. And like you mentioned, the challenges are actually substantial in gluten ataxia.

The antibody testing is imperfect. We rely on a whole host of antibodies, and there is a lot of debate about which antibodies are most neurologically relevant as opposed to most gastrointestinally relevant. Then there are patients who may be zero negative, but they are very clinically concerning [00:08:00] for gluten. So this may raise challenges about whether to initiate a strict gluten-free diet or not, and there are no universally standardized diagnostic criteria for gluten ataxia, so that creates a problem itself.

Prof. Orlando Barsottini: Divyani, now I have another sensitive point in the study of ataxias. What pathophysiologic mechanism explains cerebellar degeneration in nutritional deficient related ataxia, and which deficients are the most frequently overlooked in the clinical practice? 

Dr. Divyani Garg: This is a fascinating and a very important area. So the cerebellum as you know, especially the purkinje cells, they are metabolically highly active, and they're particularly vulnerable to metabolic stress. So these neurons have extensive dendritic connections when they have very high firing rates, so that makes them especially sensitive to mitochondrial dysfunction, oxidative stress, or any other form of energy deficit.

So [00:09:00] nutritional deficiencies tend to interfere either directly or indirectly with these pathways. Some of the commoner nutritional deficiencies are triggered by thymine deficiency that may occur in the setting of chronic alcohol use, but that's pretty well known. But some of the less common or overlooked deficiencies might be deficiency of vitamin B12, copper and vitamin E, all of which tend to cause sensory ataxia rather than cerebellar ataxia. And another important deficiency, which we should think of particularly when there is a setting of chronic vomiting or proton pump inhibitor use, or a GI surgery would be a deficiency of magnesium. Now this is a really important cause of cerebellar ataxia where patients can present with severe ataxia classically with a downbeat nystagmus. And the MRI may show a typical involvement of the naus, or it may show cerebellar vasogenic edema. It's really important to recognize magnesium deficiency because quick supplementation can lead to dramatic recovery.

Prof. Orlando Barsottini: Divyani, another important point [00:10:00] in sporadic ataxia are quite complex. Which toxin or drug induced ataxia are commonly overlooked in the clinical effect. I believe that this is a quite important point.

Dr. Divyani Garg: I absolutely agree with you because drug induced and toxin ataxias are probably more common than we recognize, and they're very frequently reversible if they're recognized early. So of course, chronic alcohol exposure it is difficult to overlook it, but sometimes, patients may minimize intake. So it's important to be careful and take a non-judgmental history.

It's important to recognize this because it can lead to permanent cerebellar damage, alcoholic cerebellar degeneration. But in terms of the drugs, some of the important drugs that I want to talk about are the anti-seizure medications. So we do know that the older generation anti-seizure medications like pheno and barbiturates, benzodiazepines, and all of that can result in cerebellar atrophy.

And they continue to be used in many [00:11:00] regions of the world. So chronic exposure to these can lead to permanent cerebellar atrophy. But even among the newer anti-seizure medications like gabapentin, pregabalin, lamotrigine, many of them are known to trigger ataxia, tremors as side effects.

The other group of drugs that we must not miss is antibiotics, particularly metronidazole because that is often used for gastrointestinal infections and a high cumulative dose can precipitate subacute cerebellar syndromes. And then sometimes we have clear exposures to drugs like lithium, chemotherapeutic agents like cytarabine, and immune checkpoint inhibitors increasingly that are being used for the treatment of cancer.

And then in certain occupations, one can have heavy metal exposures like mercury or lead. So these might be some of the overlooked causes, but definitely are imminently reversible with reduction of exposure.

Prof. Orlando Barsottini: And Divyani, how do sensory neuropathy [00:12:00] associated ataxia alter the diagnostic approach, compared, for example, with pure cerebellar syndromes?

Dr. Divyani Garg: This is a very relevant question clinically because profound proprioceptive loss can mimic cerebellar ataxia. But the clues there would be a worsening of the ataxia in darkness, presence of pseudo athetosis, and importantly, there would be a preservation of the eye movements in speech because these two lateral mediated directly by the cerebellum.

So we don't expect these to be abnormal in proprioceptive pathway dysfunction. Nerve conduction studies are essential, and it's important to differentiate clear clinically sensory from cerebellar ataxias because of the list of causes for sensory neuropathy. So the usual causes in fluid paraneoplastic syndromes, Jordan's syndrome, chemotherapy agents, b12 deficiency, and increasingly being recognized, the immune mediated neuropathies like the neuropathies and the para neuropathies.

So recognizing sensory ataxia actually [00:13:00] shifts the diagnostic workup towards peripheral and systemic causes.

Prof. Orlando Barsottini: And which systemic autoimmune or endrocrine disorders should be routinely bring for an explanation for sporadic ataxia?

Dr. Divyani Garg: So this really depends on the clinical context, but I would routinely screen for thyroid dysfunction, antithyroid antibodies, celiac serology, anti-GAD antibodies, and then the autoimmune markers, paraneoplastic markers, HIV serology and B12 deficiency. So these are relatively low cost tests with the high diagnostic yield in selected patients.

So this would be a very basic screening for sporadic ataxia.

Prof. Orlando Barsottini: Okay. And regarding treatment, which clinical or biomarker features predict immunotherapy response in autoimmune cerebellar ataxias, Divyani? 

Dr. Divyani Garg: This is a very important question, Orlando, because I just want to mention that time is cerebellum. So [00:14:00] when we initiate therapy early, there is a potential to salvage the cerebellar reserve and improve the neurological deficits. The predictors to response to immunotherapy as you asked, would include a shorter duration of symptoms, a subacute onset presence of an MRI being normal rather than an MRI showing cerebellar atrophy, presence of surface antibodies as compared to the intracellular onco neural antibodies, and of course early treatment initiation.

Prof. Orlando Barsottini: Okay. Divyani, this is my last question, is probably the most important question. What is the diagnostic algorithm for sporadic ataxia? That the treatable ones are not missive.

Dr. Divyani Garg: I think this is the core question. So my structured approach is to first confirm whether it's a cerebellar ataxia or a sensory ataxia, or a vestibular ataxia. This would of course, be deciphered by a good history and a clinical [00:15:00] examination. Determine the temporal profile and progression of symptoms, whether it's sort rapidly progressive, subacute.

Then take a targeted history of exposure to drugs and toxins. Don't forget this because this sometimes gets overlooked. Perform a good MRI of the brain. You must also try to see whether radiological involvement is proportionate to the degree of clinical involvement, because if you find a lot of clinical dysfunction but not so much of radiological findings, that's a good clue towards thinking of immune mediated ataxias.

Order some basic laboratory screening like we mentioned earlier. The routines, thyroid functions, vitamin levels. And then pursue targeted autoimmune para neoplastic or infectious testing, depending on the clinical context. Also, consider genetic testing only after these treatable causes are excluded. So the guiding principle is simple, exclude reversible causes before labeling the patient with a degenerative disorder.

Prof. Orlando Barsottini: Okay. Thank you Divyani for sharing these insights and thank you to our listeners for joining us. We [00:16:00] hope this episode helps you approach sporadic ataxias with greater confidence and precision. Thank you.

Dr. Divyani Garg: Thank you Orlando.