Arun S. Varadhachary, MD, PhD 

 My personal experience with Nusinersen has been positive, partially because it has changed the dynamic of conversations that I have with my patients. When patients recognize that there's a treatment available for their condition, it gives them a tremendous sense of empowerment and optimism for the future. Thus, when I can engage patients in a discussion about a treatment that might stabilize their function, and, if we're lucky, maybe even improve their function, that is very different than the kinds of conversations that we have had for many, many years prior. Consequently, instead of physicians somewhat dreading the experience of having a patient come to their clinic and having to tell them that there's nothing new to offer, the conversation now is, “Tell me what you can do now that you weren't able to do a year ago or 2 years ago.” Or, “How have things evolved, and how have things changed?” and have the patients be able to say, “You know, things are stable. Instead of me worrying about going downhill, now I feel that I can do things that I was able to do a couple years ago, and that hasn't changed. I'm happy with that.” That's what my experience has been with the medication. From the patients’ perspective, I think what they relate the most is the feeling that they are being taken care of in a way that they hadn't felt previously. 

Now, they feel that there's a great deal of interest in their condition, and people are working hard to try to come up with better tools, better solutions, which gives them a great sense of optimism for the future and improves their overall sense of well-being. The advances over the last 5 years have been really tremendous. It's an exciting time to be a neuromuscular neurologist, not only with SMA treatments that are available. The technologies that are being unlocked will find applications in a whole host of other conditions. Although these technologies and therapies are a giant leap forward, our patients still have weakness, and that means that they're still going to be suffering from the long-term, chronic adverse effects of weakness. The unmet need for this population is to recognize that we still need to improve their strength. Being able to stabilize them may be good, but since many of them come to medical attention after they've already began to accumulate side effects and consequences of weakness, we still need help to try to improve their strength further. 

We need to find ways to unwind some of the long-term negative consequences of chronic weakness. Many of our patients have weakness of their paraspinal muscles, which means that they have scoliosis and kyphosis. Many of these patients suffer from chronic backache [or] back pain as a consequence of that weakness. Many of them develop contractures, which reduces their overall range of motion. Thus, [we must find ways to] improve postural strength and range of motion and reduce the effect of contracture. These are areas [to which] we still have to pay a lot of attention. [We must recognize] that although we can stabilize their downward trajectory, and hopefully flatten that out now, we still have to work to try to improve function. It’s also important to recognize that it still requires a team approach to care for these patients. Despite the fact that we have treatments that are available, being able to optimize the outcome for these patients will require that all clinicians who interact with SMA patients work together to help [them] meet their maximum potential. It's been gratifying to recognize that the role of the neurologist has evolved so dramatically over a relatively short period of time. There used to be a time when the adage about neurology was, “Diagnosed, and Adios.” However, we now have a whole number of conditions for which we can play a role of real positive impact in these patients’ long-term care and trajectory. That's extremely satisfying and very gratifying for an individual clinician. Thus, the field of neurology is poised to make even greater inroads on a whole host of conditions, and SMA is just one example.

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Arun S. Varadhachary, MD, PhD shares insights into clinicians’ and patients’ experiences with medical therapy, comments on unmet needs for adult patients, and speculates about the future of SMA care. 

Unmet Needs and the Future of SMA Care 

Starting a medication like Nusinersen is a very personal decision, because patients have different goals and expectations for treatment. However, starting on a medication such as Nusinersen implies that patients are going to be fully engaged in their care plans and want to be active participants with their multidisciplinary team to optimize function. We tend to discuss the motivations of patients to make sure that they are able to fully engage with a plan that we can put together for them.

When we specifically discuss starting therapy with Nusinersen, we explain that the first couple of months are a lot of work because of the loading dose schedule for this medication. Within the first 2 months, a total of 4 injections are given in fairly rapid succession. After the loading doses are completed, patients enter a maintenance phase, in which they undergo repeated treatment every 4 months. At that point, most patients become used to a pattern of seeing their doctor every couple of months. They actually begin to look forward to those visits to check in, report their symptoms, and share what they believe are the benefits of undergoing treatment.

The safety profile of Nusinersen has been studied across a large range of patients. Most of the adverse effects that patients experience relate to its administration via lumbar puncture, which can sometimes lead to headaches, backache, etc. In terms of the actual safety profile of the medication itself, the drug is very well tolerated. However, as with all medications, there are some adverse events, and data from the initial studies demonstrated that patients should be monitored for kidney function and coagulation problems that can result from medications in the same class as Nusinersen.

Some efficacy data regarding [Nusinersen] come from a series of clinical trials. The pivotal clinical trial is relevant for older-onset SMA [spinal muscular atrophy] patients—specifically, patients who would fall within the type 2 or type 3 category—observed in the CHERISH study. This was a study with 126 patients with type 2 or type 3 SMA who were 2 to 9 years of age. After 15 months of treatment, primary outcome school performance was measured using the Hammersmith Functional Motor Scale–Expanded (HFMSE). Patients who were receiving Nusinersen showed an improvement of 3.9 points on their [HFSME] score over that 15-month time period when compared with the placebo control group. The improvement was considered both statistically and clinically significant. Some other outcomes of that CHERISH study included performance in the revised upper limb module, which also showed improvement among individuals on treatment as compared with those who were not. For the individuals able to walk, the CHERISH study also demonstrated an improvement in the 6-minute walk test performance.

That said, the CHERISH study did look at a quite young population. Subsequently, we were waiting for was some data that was more specific for older patients who would fall within the adult category of SMA patients. We had two observational studies following large cohorts of patients published in 2020, one in the spring, and the other later in the fall. One group studied patients in Germany, and another studied a group in Italy. Adult patients were followed for 14 months and assessed using rating scale scores also used in the pivotal studies, namely the Hammersmith score, the upper limb module test, and the 6-minute walk test. The adults showed improvement or stabilization in their Hammersmith scores over this time period. In aggregate, patients who were receiving Nusinersen experienced stabilized or improved motor function. This is encouraging news for those of us who care for adult patients, because we want data that we can cite to let them know that this medication is, in fact, doing what we think it's doing, and that the benefits that they see are comparable to the benefits observed in the younger population of patients.

A specialist in the care of patients with spinal muscular atrophy reviews the CHERISH trial of nusinersen and examines the drug’s safety and efficacy profiles.  

The Safety and Efficacy of Nusinersen for SMA 

The idea of a multidisciplinary team to care for patients receiving a diagnosis of a neurologic disorder has evolved over the past 15 years or so. The multidisciplinary team consists of clinicians from a variety of backgrounds who work together within the areas of their specialty to try to improve the health and functioning of patient. There is a growing body of evidence that a multidisciplinary team can help improve outcomes for patients with complex disorders, including spinal muscular atrophy (SMA). By working in a collaborative manner, individual parts of the patient's functioning can be addressed by experts in those areas. 

The multidisciplinary team may include the neurologist, who can help orchestrate a lot of care for the patient. However, other medical specialties are actively involved in the care of SMA patients, including pulmonologists to help improve respiratory function and orthopedic surgeons and physiatrists to help improve skeletal abnormalities that can develop as a consequence of weakness. Occasionally, we also work with our GI [gastrointestinal] colleagues to help optimize nutritional status in SMA patients. In addition to specific physician specialists, we also rely heavily on our colleagues in the physical therapy and occupational therapy realms. These professionals work regularly with patients to try to optimize function using stretching or strengthening exercises and other tools to help leverage their strength and compensate for areas of weakness. The goal of medication therapy is to try to address the underlying biology of the condition. That we now have treatment to address an underlying genetic disorder is a fantastic step forward. However, these medications are not perfect, and they need to work within the context of the overall care group. Thus, the goal of therapy is to try to optimize biology and work with more traditional strategies for care at the same time. The overall goal of therapy is, of course, to help the individual function at maximum potential. Since SMA affects multiple aspects of function, treating each one of those compromised aspects is necessary to maximize a patient's function.

A key opinion leader in neurology highlights the value of a multidisciplinary approach to care for patients with spinal muscular atrophy in order to maximize a patient’s function through physical and medical therapy.  

A Multidisciplinary Approach to Managing SMA 

Evaluation of a patient with spinal muscular atrophy (SMA) must begin at a higher cognitive level. Rather than focus immediately on SMA, the clinician should evaluate the patient for weakness. From the neuromuscular perspective, evaluating a patient for weakness localizes the symptoms to some aspect of the motor system, which consists of the brain, the spinal cord, the motor neurons in the spinal cord, the nerves, and, eventually, the muscles. By initiating the workup, the neurologist must recognize that the patient has weakness localized to the motor neurons within the spinal cord using electrode diagnostics, which can help distinguish nerve disorders from muscle disorders. The next step in the evaluation might be something traditional, like a muscle biopsy to help distinguish weakness between muscle and nerve to a higher degree of specificity. Finally, based upon the combined results of the muscle biopsy and the electrode diagnostics, the clinician likely would recognize that this patient has SMA. The neurologist then would confirm the diagnosis with a genetic test specifically seeking a mutation within the 5q SMN genes. The problem [of diagnosis taking a long time] has more to do with recognition of a problem. Specifically, in patients with type 3 SMA, the idea that there's something wrong may actually delay [medical consultation]. 

Many times, the progression of the disorder is relatively slow, which allows an individual to compensate. Only when that ability to compensate is exceeded does a [patient or family] seek medical attention. Without recognition of a problem, a diagnostic workup can't be initiated. The second problem is that later onset SMA is actually underappreciated. Although the prevalence of SMA types 2 and 3 is high, these conditions are not appreciated as a disorder that presents later, and many pediatricians and internists don't consider it. When a problem of weakness or the motor system is recognized and the individual begins working with a neurologist, the diagnosis should be made relatively quickly. The importance of early diagnosis gets to the heart of what it means to provide care for an individual. So many patients do not recognize that their functioning is not optimal and delay seeking medical help. If a diagnosis is made early, the individual has access to the tools and the resources that medical science has developed over the last number of years to assist optimal functioning. A neurologist is well positioned to recognize and understand the trajectory of the disorder, provide anticipatory guidance, and marshal the resources necessary to help that patient.

An expert neurologist, Arun S. Varadhachary, MD, PhD considers the diagnostic process for SMA and emphasizes the importance of early diagnosis to optimize care.   

The Importance of Early Diagnosis of SMA 

 This is a case of a 28-year-old young man who received a diagnosis of with SMA [spinal muscular atrophy] at the age of 16. Initially, he sought help with physical therapy to help improve function, but he didn't perceive any major improvements and was lost to follow up. When he sought medical care, we received an updated social history. He works as a computer programmer, and he enjoys playing video games in his spare time. Recently, he's noticed that he's developed more weakness in his hands, which is interfering both with his work responsibilities and his recreational activities. He went to his primary care physician, who recognized his past medical history of SMA [and advised that he] engage the input of a neurologist. The neurologist noticed that there was weakness in the hands and muscle groups, particularly in the hips and thighs, which represented progression of the patient's long-standing SMA. The neurologist then educated the patient about what had transpired over the past number of years in the treatment of SMA and began to understand the patient's personal goals for physical function and starting his own family. As a consequence of that discussion, the patient decided to begin treatment for SMA with some exciting available therapies and to reengage with physical therapy and occupational therapy to try to improve his overall level of function. After a discussion with the neurologist, the patient decided to begin treatment with Nusinersen, a drug approved in 2016 to treat SMA. This type of a presentation is actually pretty common. Frequently, patients are given a diagnosis SMA at a point during their youth but believe that they can compensate well enough or that there isn't any direct benefit in interacting with the medical system. 

Suddenly, they are lost to follow up. However, they return to medical attention some years later when they’ve had enough erosion in their symptoms and wish to pursue available treatment or anything to help them maintain their level of function. Historically, SMA has been grouped into 4 main types. Although the genetic underpinnings of the disease are the same, the phenotype is based upon the patient’s age at symptom onset. The most severe is type 1 SMA [infantile-onset or Werdnig-Hoffmann disease], which presents at infancy and is very frequently diagnosed at birth in a very weak infant who fails to feed properly or cry. The other types of SMA are designated based upon the highest motor milestones that the individual can reach. Thus, in contrast to type 1 SMA, in which the individual never achieves the ability to sit independently, type 2 SMA [Dubowitz disease] tends to come to medical attention after the infant reaches that first milestone of sitting independently after 6 months of age. Type 3 SMA [juvenile-onset or Kugelberg-Welander disease] is defined by the ability of the individual to reach the walking milestone; medical attention is sought when the child has difficulties walking or begins to lose the ability to walk. That initial presentation doesn't necessarily occur right at the typical time of independent walking (age, 12-18 months) but can occur during the toddler through teenaged years. Type 4 SMA is defined as symptoms that begin after 20 years of age. This type is relatively rare, and the frequency of this particular presentation remains unclear. From the epidemiologic standpoint, the incidence is probably highest for type1 SMA. However, because of the severity of its prognosis and the many individuals who die before 2 years of age, the prevalence of SMA tends to cluster around patients with type 2 and 3 disease.

Arun S. Varadhachary, MD, PhD provides an overview of the case of a 28-year-old male with spinal muscular atrophy, describes the 4 main phenotypes of SMA, and considers how average age of onset impacts patient prognosis.   

Arun S. Varadhachary, MD, PhD

Articles

Unmet Needs and the Future of SMA Care

The Safety and Efficacy of Nusinersen for SMA

A Multidisciplinary Approach to Managing SMA

The Importance of Early Diagnosis of SMA

A 28-Year-Old Male With SMA

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