The generalist can make a difference in therapeutic success
The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.
Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.
General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”
This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.
Dr. Daniel J. Macgowan
“Waiting for 100% certainty – this could actually harm our patients,” Dr. Maiser said. The tendency to avoid delivering bad news, he said, “is human nature, and it is not easy to tell people that ALS is the potential cause, but it’s important for early treatment.”
Some evidence suggests that the incidence of ALS is increasing3 but this is not necessarily evident at the clinical level. “It is not my impression that the incidence of ALS is increasing,” Dr. Macgowan said, “so much as I think we are getting better at making the diagnosis.”
Where we stand: Pathophysiology, diagnosis, treatment
Pathophysiology. ALS is characterized by muscle denervation.4 In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.2,5,6
Dr. Samuel Maiser
Approximately 10% of patients have a known gene associated with ALS.7 The rest have what is considered sporadic ALS, although some experts estimate that heritability will eventually be confirmed in 50% or more of cases that have been given the “sporadic” label.8,9 More than 30 genes have been linked to ALS in genomewide association studies. Among patients whose disease carries a known familial link, four genes – SOD1, TARDBP, FUS, and C9orf72 – account for approximately 70% of cases.2
Diagnosis. Genetic testing in patients with suspected or confirmed ALS is the standard of care at most, if not all, comprehensive ALS treatment centers, according to the four experts interviewed by Neurology Reviews 2023 Rare Neurological Disease Special Report for this article. Such testing was routine for years because of its potential for helping researchers to understand subtypes of disease; today, testing has assumed even greater practical value with recent approval of the first ALS gene therapy: Tofersen (Qalsody, Biogen), licensed in 2023, is an antisense oligonucleotide therapy that targets SOD1 mRNA to reduce production of the SOD1 protein, a mediator of disease progression.
“Genetic testing has been useful for telling us something about the disease and its prognosis,” Dr. Maragakis said, “but an approved gene therapy means it can have a direct effect on treatment.”
ALS therapeutics. Other gene therapies are in development. Gene signatures are likely to provide even more opportunities for clinical trials in the future.
Following three loading doses of tofersen at 14-day intervals, the maintenance regimen, administered intrathecally by lumbar puncture, is every 28 days. In the phase 3 trial, tofersen reduced levels of SOD1 protein and neurofilament light chain, a biomarker of axonal injury.10 Tofersen is appropriate only in patients with SOD1-associated ALS; the drug’s favorable clinical impact, including a positive effect, if any, on survival has not been demonstrated. Extension studies are underway.
Tofersen joins three other FDA-approved ALS therapies:
• Riluzole, an oral drug available since 1995 that slows disease progression by blocking glutamate.
• Edaravone, an antioxidant approved in 2017, administered orally or intravenously.
• An orally administered combination of sodium phenylbutyrate and taurursodiol marketed as Relyvrio and formerly known as AMX0035, that was introduced in 2022.
“We offer riluzole, which is safe in combination with other therapies, to most patients,” said Dr. Scelsa, who noted that treatment trials often test experimental drugs on top of riluzole. He moves to edaravone or Relyvrio, which are far more expensive, selectively. Tofersen, which is also expensive, is reserved for patients with SOD1-associated disease; however, not all eligible patients opt for this therapy after reviewing its benefits and risks.
“There is not yet a guarantee that tofersen will improve outcomes, and it requires intrathecal injections for life,”
Dr. Maiser said. “Some patients, particularly my older patients, have said, ‘No thank you,’ based on the available data.”
Dr. Macgowan pointed out that lumbar puncture repeated indefinitely can be “challenging.” He, too, discusses all available treatment options with every patient, including riluzole, which he agreed is associated with a meaningful benefit, particularly when started early.
Because of the safety of riluzole, Dr. Maragakis takes early treatment a step further. For neurologists who have a high level of suspicion of ALS in a given patient, “my advice would be to treat aggressively from the get-go. Even if not 100% certain of the diagnosis, I would start them on riluzole while waiting for confirmation.” Like the other experts interviewed here, he acknowledged that referral to a busy comprehensive ALS center often takes time, making it reasonable to initiate treatment when suspicion is high.
On the front lines, “the neurologist can tell the patient that ALS is just one of several potential explanations for symptoms but there is concern,” said Dr. Maragakis, proposing a strategy to introduce the possibility of ALS and start treatment that might slow disease while waiting for confirmation of the diagnosis. “My biggest concern is that no one is making that call,” he said, trying to address at least one reason for the current delay in making referrals.