AAN 2026 | Red flags for genetic demyelinating conditions and risks of misdiagnosing as MS

We frequently get patients that may seem like they have multiple sclerosis, but there are several red flags that point away from that. In particular, if it’s a rapidly progressive clinical course with marked disability within five years of disease onset, that can include cognitive impairment, rapidly progressive paraparesis to paraplegia. And then radiographically, that can be T2 flare hyperintensities that are quite symmetric and confluent. There can be persistent gadolinium enhancement beyond three months, as well as microhemorrhages and potentially tumefactive lesions that may have calcifications and cysts associated with them. So these are all red flags in addition to having negative oligoclonal bands. And then having a very strong familial history is also a red flag. There is a small genetic component in multiple sclerosis, but if you’re getting several family members in a patient’s history, that can also be a red flag. But it’s also, if there is a negative family history of a neurologic condition, that doesn’t exclude a genetic condition. So in one of my presentations later this week, I reported a patient with a genetic condition and she had no family history. So it doesn’t mean that it is not possible. So you really have to keep a broad differential early on.

So if it’s a genetic demyelinating condition, what commonly happens is a patient will be empirically tried on a disease-modifying therapy for multiple sclerosis. And unfortunately, in those instances, the risk of the DMT may outweigh the benefit. So what can happen is that a patient who has maybe a phenotype of progressive multiple sclerosis may be treated with B-cell depleting therapies, which can have a risk of urinary tract infections and urosepsis since they also have neurogenic bladder. So subjecting someone to that level of risk when it might actually be genetic is one unfortunate consequence. The other is that you’re missing an opportunity to treat for the correct diagnosis. One example would be in cerebrotendinous xanthomatosis, where the radiographic features might look like MS, and they might have spasticity, which is a very treatable condition and the outcomes tend to be better if you treat early on so you’re also missing an opportunity to treat correctly. And then thirdly having a correct diagnosis for the families is very important and also for the medical community we need to be able to report these so that others can refer to our cases and better understand the disease course.

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