CANVAS Syndrome

Last edited on August 20, 2021 by Timothy C. Hain, MD, Chicago IL.

Exciting stuff as of 2020: Some patients with CANVAS have a genetic mutation (RFC1 repeat expansion). CANVAS appears to be a subset of the genetic manifestations of the RFC1 expansion.

CANVAS is an easy to remember acronym for cerebellar ataxia (the CA), neuropathy (N), and vestibular areflexia (VA) syndrome. This was popularized by Szmulewicz et al (see below). There are only a very few patients in the population at large who have the requisite combination of two rare clinical findings (CA and VA), although there are a very large number with neuropathy (N). However, due to the power of internet assisted collaboration, it is now possible to find rare patients that have CA and VA.

Some of the CANVAS patients have a genetic abnormality, namely an RFC1 repeat expansion. This is a major breakthrough, and now we are beginning to see papers describing people who have this mutation, and their clinical findings (e.g. Cortese et al, 2020). About 2/3 of the patients who have the mutation, also have the clinical criteria for CANVAS. This paper does not comment on the other obvious question (i.e. how many patients with bilateral loss, or cerebellar ataxia, or a progressive sensory neuropathy, have the mutation). The trend right now seems to be that there are patients with the RFC1 expansion mutation, lacking the full CANVAS phenotype, or perhaps having other issues as well.

The CANVAS acronym might suggest that CANVAS is a disease. However, there are other ways to develop these symptoms other than a genetic mutation, and presumably a proportion of the CANVAS patients are"found" patients, others are diseases, such as the RFC1 or RNF170 genetic conditions, and there may also be other causes that are so far undiscovered or just rarely checked for.

The status now is that CANVAS seems to be a subset of patients with the RFC1 repeat expansion, who have the three features described originally by Szmulewicz. CANVAS does not appear to be a distinct "disease", but rather is a combination of several possible manifestations of the RFC1 mutation.

We think it is reasonable to offer the RFC1 blood test to all individuals with the most rare finding (bilateral vestibular loss), lacking another cause. We don't think it is reasonable to propose it in persons with sensory neuropathy (as there are a lot of these). These blood tests right now are being done for academic purposes -- which is good, but they don't directly help patients.

How many of these CANVAS patients are out there ?

Not very many. In our dizzy practice files of 20,000 patients, we have roughly 5 that are "diagnosed" as "CANVAS". Bilateral vestibular loss (BVL), which is a portion of CANVAS, has a prevalence of only 26/100,000 (Ward et al, 2018). Actually this is the prevalence of complaints of oscillopsia alone, which is a piece of BVL, but might have other causes, so it may overestimate the prevalence.

There must be far less CANVAS patients than BVL. We have 329 BVL patients in our practice database. As we have only 5 CANVAS among the 300 or so BVL patients, it would seem that CANVAS must be about 60 times less common than BVL. Somewhere around 5/million. So CANVAS cannot be a common condition. That is probably why nobody noticed it until recently. The BVL patients are "maybe CANVAS" however, if one redefines CANVAS as a positive genetic test for one of the alleles found so far.

The advent of genetic testing for the newly reported mutation should be helpful. What we need to do is to run the genetic test on many patients with bilateral loss. One would expect that a few of them (perhaps 1/60) will have the mutation. Hopefully people are working on this. According to Dupre et al (2020), "This pathological expansion was found in 100% of the familial form and 92% of sporadic ones when the triad was complete. " We think the phrase "triad was complete" may be a bit vague. Meindel et al (2020) commented: "As intronic repeat expansions cannot be identified by next generation sequencing methods, specific testing is necessary. " Or in other words, this genetic issue will not be detected by the usual screening for the genetic Spinocerebellar degenerations. In our opinion, there are so few patients with bilateral vestibular loss, requiring this as a prerequisite for genetic testing seems reasonable.

Costales et al (2021) reported that in an ataxia database of 500 patients, 13 were suspected as having a "complete or incomplete" syndrome, and 9/13 of these met the CANVAS criteria, while 11/13 had the mutation in RFC1. Furthermore, " The clinical diagnosis was supported by quantitative vestibular hypofunction, cerebellar atrophy, and abnormal sensory nerve conduction testing. " This suggests quite high specificity of the CANVAS criteria for this mutation. The problem here with inference concerning "how many ..." is that this was not a population wide sample, but a sample from an ataxia database.

Traschutz et al (2021) reported that 67% of persons with > 2 features of CANVAS or ataxia with chronic cough (ACC), as well as 100% of persons with ataxia with chronic cough had the RFC1 repeat expansions. We found this astounding and suspect that their findings has to do with the highlys select population that they chose to study (persons who had most other genetic causes of ataxia already excluded). Ataxia is common, and chronic cough is common. 100% of these patients have RFC1 ? Hard to understand except perhaps in the context of studying a highly selected population.

Clinical picture:

Patients with CANVAS combine cerebellar ataxia (i.e. coordination problems -- the CA), nerve damage (neuropathy - N), and loss of vestibular function (vestibular areflexia -- the VA). This combination causes major disturbances to balance as each of these systems alone contributes to balance. Of course, when all are out at the same time, balance is much worse than when only one or two happens to be malfunctioning.

Concerning the neuropathy part of CANVAS, the situation has been evolving, and criteria have changed between early papers and the present. A recent observation is that many patients have a chronic cough (like many people without CANVAS I would think).

Early on, Szmulewicz et al (2011) reported on 18 subjects, and noted that "All 18 had sensory neuropathy with absent sensory nerve action potentials, although this was not apparent clinically in 2, and the presence of neuropathy was not a selection criterion." Further, they stated that "In 5, the loss of pinprick sensation was virtually global, mimicking a neuronopathy. However, findings in the other 11 with clinically manifest neuropathy suggested a length-dependent neuropathy. " So as of 2011, the "N" in CANVAS could be either a common "length dependent neuropathy", or "loss of sensory nerve action potentials", or a "neuronopathy". In subsequent publications, there has been more emphasis on the neuronopathy idea. Szmulewicz et al (2015) said in a study of 14 patients they designated as having CANVAS "Findings revealed uniformly absent sensory nerve action potentials in all limbs, abnormal blink reflexes in 13 of 14 patients, and abnormal masseter reflexes in 6 of 11 patients." The sensory findings in the cranial nerves (i.e. blink), would point towards a neuronopathy (i.e. involving the dorsal root ganglia -- DRG). So it would seem that the "N" in CANVAS now has evolved to be a ganglionopathy disorder. We think that there proximal sensory findings should be required (other than vestibular), and prominent motor findings would be an exclusion.

If we throw out patients that lack evidence for cranial nerve sensory disturbances, we would have to "De-CANVAS" papers describing other findings -- for example, Cazzato et al (2016), where there was "sensory disturbances in the lower limbs". Many of the earlier CANVAS patients would also have to be converted into possible or probable CANVAS by stricter criteria discussed below.

Concerning the vestibular component, or "vestibular areflexia" (VA), this is also somewhat fuzzy.

There are many ways to quantify inner ear vestibular function. Basically rotatory chair, VHIT, and caloric. What does it take to be designated in a definite way as having "vestibular areflexia" ? Our position from a recent paper (Hain et al, 2018), is that VA should require a gain-TC product < 2. This is a rotatory chair test however. The more practical VHIT test, needs more study. We tentatively propose that gains of < 0.2 for both directions (i.e. left and right) would be sufficient. Caloric testing standards for bilateral vestibular loss are generally set as a total response < 20, but we would think < 10 would be a better choice.

Where do vestibular evoked myogenic potentials, VEMPs, belong here ? Well right now,we just need more data.

VEMPs are not as well established vestibular tests as caloric testing and rotatory chair, and it would not seem reasonable to us to depend on an emerging test to define CANVAS. Rust et al (2017) reported on a single 65 year old patient with bilateral vestibulopathy, slurred speech, downbeating nystagmus and GEN and "heavily impaired" position sense in the lower extremities, that was attributed to CANVAS, but who had both cVEMP and oVEMPs "preserved". From their figure 2, both cVEMP and oVEMP appear rather small but something seems to remain.

Yacovino et al (2019) reported on 5 patients who met the clinical criteria for CANVAS, and noted that "Severe reduction of function of the six semicircular canals and ocular VEMPs were observed. Only the cervical VEMPs were present and reproducible, consistent with either partial sparing of the inferior vestibular ganglia, specific embryologic resistance of the saccule to the degeneration or a mechanism for cervical VEMPs that does not require an intact vestibular ganglion."

To summarize: To our thinking, definite VA, just defining this as loss of horizontal canal function, would be any one of the three:

  • Rotatory chair: GainTC < 2
  • Caloric test: Water caloric < 10 deg/second combined with poor DIE test.
  • VHIT: Gain for both horizontal canals < 0.2

We do not think it is practical to define VA in terms of otolith function (ie VEMPs), or for that matter vertical canal function (as there is no reliable method of ascertaining this).

Concerning the cerebellar component, there are again problems.

We think that the bare minimum requirement for a definite cerebellar component should be an objective test, specific for cerebellar disease, not affected much by age, and that does not depend at all on subjective judgments by the examiner. Right now, we don't think that this exists, and this part of the CANVAS definition is faulty.

Petersen et al, 2013

Figure 1 from Case report of Petersen, Wichhmann and Weber, 2013

It was proposed by Petersen et al, in a case report (2013), that the CANVAS diagnosis requires poor VVOR. The evidence that Petersen et al presented was weak -- the figure shown above which is of a 75 year old woman (who presumably has no pursuit due to her age), and an analog type recording style. This is not quite the same as a rotatory chair test, with a formal VVOR paradigm, and including (lets say) 10 patients.

Should one require very poor VOR -- i.e. rotating in a chair with the lights on, looking for no response ? Perhaps a reasonable value would be a gain of only 0.5 (normal is 0.9-1). We would say no. This criterion is imprecise and at least in our experience, never encountered. There is actually very little quantitative data about deficient VVOR in the literature, and if one thinks about this a little bit, it would be very hard for this to happen. The VVOR test should, in theory, be resilient because without a VOR, individuals will naturally attempt to stabilize their gaze using tracking systems like OKN and pursuit. It may be so specific that it just never occurs -- OKN is very "tough" and it is nearly impossible to find any cerebellar patient with no OKN at all -- thus doing VVOR in a rotatory chair (as is the quantitative way) should nearly always fail due to preserved OKN. Unfortunately, we do not think that the VVOR can be reliably measured at the bedside with video-oculography as suggested by Szmulewicz et al (2011). Another problem is that visual tracking requires effort and can be turned on and off. One could certainly imagine an uncooperative patient.

Is downbeating nystagmus enough ? We would say no, as it is too common and it also is too subjective (as it is rare that there is quantitation of nystagmus). Perhaps with the qualifications that it has to occur with fixation, and has to be at least 5 deg/sec.

Is cerebellar atrophy enough ? Again we would say no as this can be found in persons who drink too much alcohol as well as in a myriad of other central disorders. In fact the superior vermis is typically atrophic -- this is seen frequently in persons without vestibular loss.

Lets think about this a bit more -- Assuming that CANVAS is a DRG disorder, why should the cerebellum be damaged by loss of sensory input anyway ? The dorsal root ganglia (part of neuropathy piece), are input to the cerebellum. One would not think that cutting off input to one part of the brain would necessarily affect another part of the brain. When someone goes blind, one does not expect them to lose hearing. Why would cutting off sensory input from the limbs, face and vestibular system, cause visual tracking, including OKN, to be reduced ? Logically, if this is really true, either the DRG are required for visual tracking (this is not generally thought to be true -- but see "magic hand" literature about visual proprioceptors), or there is a common source (e.g. genetic damage) that affects both the cerebellum and the DRG. Another problem is that most CANVAS patients are older, and pursuit is well known to decrease with age.

So what do we do about this messy situation ? In our opinion, we should refine the nomenclature. "Possible CANVAS" or "Probable CANVAS" might work (see below) for subtotal fits. Or perhaps "Canvas-" and "Canvas+". Another option might be to use the term "atypical CANVAS", but this implies greater certainty than would seem possible to achieve with tighter criteria. The genetic test may eventually lend a little more clarity, as those with the positive genetic test would be more likely to be more predictable. Time will tell.

Canvas minus

There are also conditions that might be viewed as "partial" CANVAS, or maybe, "CANVAS-". They wouldn't be "possible CANVAS" -- as this requires three things at the same time. The trend right now seems to be to accept that patients with the mutation (RFC1) have CANVAS even though they might lack most of the original requirements. This means that CANVAS is being viewed as less of a disease, but rather a chance combination of features from the RFC1 genetic repertoire.

Canvas plus

Pathology and Genetics of CANVAS:

While CANVAS does not require a family history for diagnosis, there are a few patients who have other family members with similar findings. Right now, it is very exciting that a mutation has been found that some patients with the CANVAS criteria do have (e.g. Cortese et al, 2020).

Genetics:

Dominik et al (2021) reviewed the genetics of CANVAS. They state "Although CANVAS is a rare syndrome, on discovery of biallelic expansions in the second intron of replication factor C subunit 1 (RFC1) gene, we and others have found the phenotype is broad and RFC1 expansions are a common cause of late-onset progressive ataxia." Note the "phenotype is broad" statement -- it fits with our discussion above about the many faces of CANVAS.

Cortese et al (2020) recently reported on 100 cases of repeat extensions of RFC1. The most common feature was sensory neuropathy. "Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients." In other words, 1/3 of the patients with the genetic abnormality didn't meet the core criteria for CANVAS (i.e. vestibular and cerebellar dysfunction).

Traschutz et al (2021) reported on about 76 "deep phenotyped patients, who had already had other common causes of genetic cerebellar ataxia excluded, as well as "walk in" patients with late onset ataxia, evidently chosen as somewhat of a control. It is difficult to know how to interpret this study, other than it shows that RFC1 expansion appears to be a multisystem disease. This lends support to the "CANVAS+ and CANVAS-" discussion above.

Cortese (2020) reported similar findings in a different mutation (RNF170), and called it a "CANVAS mimic".

Ahmad et al (2018) reported on a "British family" with a mutation in the ELF2 gene. This family was presumed autosomal dominant. As patients denoted "CANVAS" almost never have a strong AD family history, this is probably a "one off".

Similarly, Beecroft reported a Maori patient, with the usual CANVAS mutation, apparently another "one off".

As mentioned above, there is some overlap with SCA3 (Machado Joseph), another trinucleotide repeat disorder as well as SCA7. These cerebellar disorders sometimes also have bilateral vestibular loss.

Pathology of CANVAS:

Szmulewicz reported that in the 3 patients autopsied as of 2014, there was a disorder of the dorsal root ganglia (Szmulewicz, 2014). This is a similar pathology to Friedreich's ataxia. Friedreich's is autosomal recessive, it is common, and it is easily diagnosed from contemporary genetic tests which show a trinucleotide repeat.

Ishai et al (2021) reported pathology in 5 CANVAS patients. They reported "In CANVAS there is a severe cranial sensory ganglionopathy neuronopathy (ganglionopathy) involving the vestibular, facial, and trigeminal ganglia but sparing the auditory ganglia. These observations, when coupled with the known spinal dorsal root ganglionopathy in CANVAS, indicate a shared pathogenesis of its somatosensory and cranial nerve manifestations. " This report, seems to mainly document damage to sensory ganglia, in the areas examined (head). No surprise.

Treatment of CANVAS:

Only symptomatic treatment is currently available for CANVAS. Generally these patients require assistive devices early on, as they have three impediments to balance.

We have encountered some patients taking riluzole or acetazolamide. We are unaware of any data showing that these medications affect the progression of bilateral loss, sensory ganglionopathy, or most cerebellar disorders (there are a few where acetazolamide may help, such as EA2). Of course lack of data is not the same as data showing lack of efficacy, but nevertheless, these are long shots.

References