ARTICLE IN BRIEF
Researchers attempted to develop milestones for staging the progression of amyotrophic lateral sclerosis (ALS). ALS experts who were not involved with the analysis praised the study authors for making a strong attempt to identify milestones that describe the trajectories possible along the ALS disease pathway. But they noted the challenge is often that the disease is unpredictable and symptoms might overlap, making definable stages difficult to quantify.
When patients are diagnosed with an ongoing disease, they want to know where they are in the progression. Are they at the beginning of the marathon? Is the finish line in sight? And what can they expect to find ahead in the course of the disease?
In a paper published in the Jan. 23 online edition of Brain, researchers attempted to develop milestones for one of the most hard-to-track neurodegenerative diseases, amyotrophic lateral sclerosis (ALS).
ALS experts who were not involved with the analysis praised the study authors for making a strong attempt to identify milestones that describe the trajectories possible along the ALS disease pathway. But they noted the challenge is often that the disease is unpredictable and symptoms might overlap, making definable stages difficult to quantify. They worried that patients would cling to a stage diagnosis without understanding the variability of the path ahead. This problem is reflected in the wide confidence limits for each stage presented in the Brain paper.
For the analysis, researchers from King's College in London followed 1,471 patients with ALS between 1993 and 2007. Patients were classified as having limb, bulbar, or diaphragmatic onset ALS. They identified ALS milestones or potential staging criteria based on symptoms that were observed and routinely noted on clinical visits and which occurred at specific points in the disease course. For example, they defined symptom onset (stage 1) as functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one CNS region defined as bulbar, upper limb, lower limb or diaphragmatic; diagnosis (stage 2A); functional involvement of a second CNS region (stage 2B); functional involvement of a third CNS region (stage 3); the need for gastrostomy (4A); and the need for non-invasive ventilation (stage 4B).
Researchers also tracked the time between milestones, standardizing them as proportions of time elapsed through the disease in patients who had died. [See “Times to Reach Each Milestone in Patients Who Died.”] They reported that diagnosis occurred at 35 percent through the disease course, involvement of a second CNS region at 38 percent; a third CNS region was involved at 61 percent, the need for gastrostomy at 77 percent; and noninvasive ventilation at 80 percent. Providing the staging in the context of months, for example, diagnosis occurred between 11.3-15.7 months and the need for noninvasive ventilation occurred between 26.4-34.2 months.
Several ALS experts, who were not involved with the Brain paper, offered tempered enthusiasm for the analysis. The greatest challenge in outlining definitive stages, said Hiroshi Mitsumoto, MD, professor of neurology at Columbia University Medical School and director of the Eleanor and Lou Gehrig MDA/ALS Research Center, is that it creates an expected progression of the disease. But some patients first experience ALS as speech impairment while others might have respiratory dysfunction.
“Many patients ask what stage they're in, because they have heard about staging repeatedly with cancer,” said Dr. Mitsumoto, who was not involved with the Brain paper. “Now, having this first staging of ALS in hand, we have to work together to validate this staging in future patients with ALS. It's a great start.”
The staging offers clear benefits to select patients in clinical trials but Dr. Mitsumoto said he did not think it could be used as the outcome and needs to be validated by prospective studies.
“If the medication can keep the patients in the same stage significantly longer, that will be used as an outcome, but again, we need a validation study,” he said.
S. Ausim Azizi, MD, PhD, professor of neurology at Temple Medical School and chair of the department of neurology, said the study would help create a common language for investigators doing drug trials and allow patients and families of patients with ALS to understand where they are in the progression of the disease. Dr. Azizi cautioned, however, that it was important to articulate that the progression of the disease would not always follow the expected route.
“An important predictor of disease progression is how the disease progresses initially from point A to point B,” he said. “That's a telling speed to see how fast the disease will progress. Some people will rapidly deteriorate and others will not.”
Dr. Azizi said other factors that needed to be included in future staging analysis are comorbidities. In Alzheimer disease, for example, diabetes accelerates the functional decline.
Jeremy M. Shefner, MD, PhD, chair of neurology and associate vice president for clinical and translational research at State University of New York Upstate Medical Center, said he was uncertain if ALS is appropriate for a linear staging criterion.
“Patients do ask where they are in their disease course. However, I find that the answer usually has more to do with where the disease burden lies,” said Dr. Shefner. “Sometimes you will have someone who is completely paralyzed from the neck down, but they will have another decade if they are swallowing and talking normally.
“Someone can just go from one stage to another three levels down without passing through the other two. So in patient-terms, staging doesn't say very much in terms of what's going to happen to you next.”
“This paper attempts to try and come up with one number that will help define the course of the disease and it's a great theoretical step forward that needs to be considered by the ALS community of neurologists and patients,” said Benjamin Rix Brooks, MD, director of the Carolinas Neuromuscular/ALS-MDA Center at the University of North Carolina Medical School, who was not involved with the analysis.
But, he added, “one concern here is that the paper does not give room for the issue of cognitive involvement or behavioral changes in ALS. Considering depression and pseudobulbar affect, for example, there might be other treatments that would be important and domain-specific stages that might be better.”
Dr. Brooks, who is developing his own “ALS dashboard” system, said that it's important to include all domains of disease involvement, including cognition and behavior, when determining a patient's domain-specific stage that is presented as a matrix of numbers describing the patient overtime. These issues could be addressed in future studies, he added, and tested over time and in different clinics.
“The fact that we're talking about staging is a sign of maturity in the ALS community's approach to assessing the trajectories of this disease in different patients,” Dr. Brooks said.