James Wymer, MD

When risdiplam came out, it gave us a wonderful option. To date, we had had 1 medication that was FDA approved that required the intrathecal therapy and was clearly showing significant benefit. The introduction of an oral medication for patients who have complex spinal disease and were unable to get the intrathecal infusions, this gave them an option. Now we have a way of treating the disease. For other patients who had difficulties with the intrathecal injections for various reasons, this gave them a way, because the most important thing I always feel is that a patient with SMA [spinal muscular atrophy] needs to be treated with these medications to improve. These medications have an impact on the disease, and whether you go with the intrathecal or the oral, the competition is the patients who are not taking medications. We need to get people on these medications. By having an oral option for those who can’t do the intrathecal or for those who choose not to, this gives them another option. It is very well tolerated. Most patients I’ve given it to have done very well. I’ve had some infections, some GI [gastrointestinal] [adverse] effects, but we’ve been able to work with patients to try to get those addressed. There have been one or two with whom we’ve had to have the discussion about switching, but again, this is a conversation. Trying these different options, choosing which one’s going to be the best is something that as a neurologist, you develop a relationship with the patient, you know what’s going to work. And in those patients who may be particular for the oral, this does bring up a perfect option that can allow them to keep an active life, a level of activity, because this is just an oral medication you have to do. You don’t have to worry about the hospital presentation, the intrathecal injections.

The biggest unmet need in treating adult SMA has to do with disease education. We’ve got wonderful medications that can impact the disease, that can slow the decline. I’ll describe a different patient from the case, but somebody who basically as an adult developed a way to compensate for the SMA, so they weren’t interested in treatment because they had their power chair, their apartment, their job, but they came to me because after a while they started declining. Our biggest unmet need is educating these patients about the treatment before that decline occurs because if we can impact and slow that decline and then bring all the other multidisciplinary approaches to it, that person who is comfortable with where they are, we could improve their function and keep them at that functional level for a lot longer with the introduction of these medications.

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James Wymer, MD discusses his firsthand experience with risdiplam and identifies a key unmet need in the treatment of spinal muscular atrophy.   

Experience with Risdiplam and Unmet Needs in SMA 

After you’ve started the patient, either on oral therapy or the intrathecal therapy, one of the single most important issues, and it’s especially true for the oral because you’ve got to take it every day, is compliance. It’s staying on the medication if you want to get the sustained benefit. Much of your time will be spent counseling the patient on the importance of taking the medication as it’s directed and taking it for a lifetime. This becomes a problem with the teenagers because they may be reluctant to do that as they get into their teenage years. With adults, it’s easier. You monitor the compliance by periodically calling them, touching base with them. What we like to do is see our patients periodically for their comprehensive multidisciplinary meetings and then we’ll talk with them. “How are you doing on the medication? Are you having any [adverse] effects? What are those [adverse] effects? Is there a way we can help to control, to limit those adverse effects?” If it’s GI [gastrointestinal] can we adjust the timing of the medication to control that? How do we need to try to improve the adverse effects so that the patients are tolerating it because it is important to stay on those medications? If they have difficulty staying on it and we have to consider switching to a different one, we want to go through that discussion we had before. If you’re on the oral therapy and maybe you have some problems with compliance, then you have to switch to the alternative of the intrathecal, which carries its own issues, with the injections as a concern.

One of the key parts of treating spinal muscular atrophy, after you get somebody on the medication and they’re staying on the medication, which is helping to stabilize the disease, is developing a multidisciplinary approach to try to improve their function. What we will talk about with these patients is they may have some diseased nerves and muscles, but they also have some functioning nerves and muscles, and you want to enhance that functioning. For those who are having problems functioning, you want to find ways to compensate for that. That’s why it is critical that while they’re going through this treatment, they get involved with physical therapy, occupational therapy, pulmonary therapy, speech and language pathology. This type of multidisciplinary approach, which is going to be individualized to that patient, is what will help to further improve [any potential] benefit. In our clinic we do this as a group. The patient will come in on a day and will be seen by whichever of those specialists [is needed] the same day, so we can all come together as a group and discuss what is the optimal therapy for that patient. What is the individualized personal therapy that’s going to work for them? We will use other health care providers if they are needed. We talk about compliance, and if we need to get their primary care physician involved to help us out with that, we may contact them and include them in the loop. 

The way I describe it to my patients is, in the center you have the patient, and surrounding the patient is their core group of family, friends, people involved in their care. And outside of that group are all your different specialists, which include your neurologist, your primary care physician, your physical therapist, your speech and language pathologist, your occupational, your respiratory therapist. Nobody is at the top, nobody is at the bottom; we are all working together to develop this comprehensive program, and that’s what’s important in the multidisciplinary management of this disease. You develop that program, it gets the patient vested in the care, the patient is working to get better. We’re helping to develop a program that as they go through their lifetime with the different stages of the disease, we can help to address those stages, those disabilities, improve function, improve quality of life.

An expert neurologist emphasizes the importance of medication compliance and the value of multidisciplinary management in meeting patient goals of therapy for spinal muscular atrophy.  

Importance of Compliance and Multidisciplinary Management in SMA  

 With the 2 medications, you’ll see in the clinical trials that the kids lead to improvement. In adults there may be some modest improvement, but the most important thing is the stabilization we see in the disease. These have the potential in adults. For a disease that’s a gradually progressive neurodegenerative course, starting 1 of these medications can start to stabilize it. The goal of the therapy is stabilization of disease. With the other types of interventions, can they lead to improvement? 

We’ve got several very good trials that have come out. In the case of risdiplam, you have the SUNFISH trial, which was a 12-month trial that included adults. It showed clearly some benefits and some improvement, but most important, the big take-home I see is that a disease that’s gradually progressive and neurodegenerative in the adult level was showing stabilization so that we could enhance and improve recovery. As an oral therapy, it was very well tolerated. There were not many complications. A few you need to go over with your neurologist to make sure it’s the right medication for you. But it definitely was effective in the treatment, in the controlling of the disease, so you could introduce all the other therapies to try to enhance recovery.

In deciding the ideal medication for this patient, you’re going to discuss what’s going to work best for their lifestyle. You’re going to look at the options. Do you want the oral? Do you want an injection intrathecal therapy? Which is going to be quality? If the patient wants to take the oral therapy as this 1 did because of concern for the intrathecal, you’d then review with them the potential adverse effects that we can see. These include fever; GI [gastrointestinal] adverse effects, in terms of diarrhea; ear infections; and upper respiratory infections. We have to educate patients on what to follow. If these infections occur, they need to be addressed. They need to be identified. Certainly if they have respiratory involvement, as this subject does, then you must think about the concern. Are you going to develop pneumonia? Should you be getting antibiotics for treatment? Otherwise, addressing the adverse effects tended to be milder and easier to control. For the GI adverse effects, you can adjust the dosing back and gradually taper it to work toward that, just to come up with what’s ideal to get patients to tolerate. Most patients tolerated the medication well. Over time we’re able to stay on the medication and get the benefit from it.

An insight into the goals of therapy and treatment selection between oral and intrathecal medications for adult-onset spinal muscular atrophy. 

Goals of Therapy and Treatment Selection in Adult-Onset SMA 

The next question is, how do you treat SMA [spinal muscular atrophy]? You have to treat SMA with a complete comprehensive approach. There are a lot of data showing that when you look at addressing diseases like this, you think about approved medication and you think about the complementary additional therapies that are going to get involved. There’s a shift from supportive care, physical therapy, occupational therapy, because we’ve got newer medications, which we’ll talk about. But 1 of the things I want to stress is physical therapy, occupational therapy, speech and language pathology, respiratory therapy, developing exercise programs on all those are key to the treatment of spinal muscular atrophy. Patients with spinal muscular atrophy should be seen in a clinic that has this type of multidisciplinary approach that brings everybody a specialized treatment program for these patients. 

There has been a shift in the last couple of years, backing up to what we were talking about before, the SMN1 and SMN2. We know that the difference between the 2 is an abnormal splicing pattern in SMN2. Three medications have come out that have worked to replace the SMN1, 2 of them by altering the splicing in SMN2. When you do that you can increase the levels of SMN1, which can therefore treat the disease. That gets into that component that all patients should be in an FDA-approved medication, 1 of 2 that will work to try to, at the cellular level, replete the amount of SMN1. In combination with that, the best treatment plan is while you’re treating the disease and correcting it on a molecular basis with these 2 medications, you’re also working with physical therapy, occupational therapy, speech and language pathology, and the respiratory therapist to develop exercise programs to enhance any therapeutic benefit that you’re getting.

There’s a lot of thought about these new treatments, but they work only if you get them in combination with the other therapy. Getting into a real comprehensive center is what’s going to give you the best approach to doing that. That’s what your major goal of therapy is going to be: trying to improve the patient’s quality of life. When you look at the different therapies, we have a couple that I was mentioning. For adults, we have 2. We have an oral and we have an intrathecal. They both try to correct the splicing deficit that has happened in that SMN2 to enhance the level of SMN1. They each have their pluses and minuses. We neurologists—and the patients—need to think that 1 isn’t the perfect 1. You’ve got to look at both and decide which is going to work best for you. 

There are advantages to the intrathecal: It’s an antisense oligonucleotide that’s going right into the spinal cord, where the problem is and trying to correct it directly. There’s an advantage to the oral: It’s a solution that you have to take. It’s a solution that you would drink, which is a lot preferable over an intrathecal injection. But remember, if you’re drinking a medication, it’s got to go through your whole body, and there can be adverse effects. There may not be any adverse effects, in which case that may be the perfect medication. Look at the pluses and minuses of each medication and go through with the patient and neurologist as a team to come up with the best medication. One isn’t better than another. They’re equal options, and you’re deciding which is going to be the best.

A discussion of the multidisciplinary treatment approach in spinal muscular atrophy. 

Treatment Approach in SMA 

As I mentioned, SMA [spinal muscular atrophy] is a spectrum disease. It presents with this motor neuron phenotype that will come out. They’ll primarily get the weakness; it will be pure motor with limited sensory. As it’s shown in this case, it can be proximal. There can be respiratory involvement with it, and there can be even clumsiness and tremors at times because of the way the motor neurons will be involved. There will be preserved sensation, so that will be 1 of the keys. In this case, that brings up the question of why they were initially called a muscular dystrophy because they were pure motor. But when that neurologist looked at them closely and saw the pattern of thinning of the muscles going on, I’m assuming that’s what was seen in this case. That leads you to the thought that maybe it isn’t so much muscle disease as it is the nerves going to the muscles, or the motor neurons. That’s going to direct you toward that question of, is this like spinal muscular atrophy? 

When you’re seeing somebody like this, keeping in mind this can be at any age that they can present with more of this motor phenotype, you’re going to look at the differential. You may consider doing an EMG [electromyogram] nerve conduction study as a first step in the evaluation. What’s the EMG going to show you? It determines whether it’s primarily a muscle disease or more of a motor neuron disease. SMA is a typical pattern that shows chronic neurogenic changes will be present on it. That’s something that could be diagnostic. 

Nowadays genetic testing is common because it’s easy to order as a next step to go right into a genetic test. That genetic test that you would do because of this pattern of weakness would likely be for the muscular dystrophies but also the SMA, because you want to cover all your bases. In this case, that’s what the neurologist was thinking at that time. It’s a pure motor syndrome with a mildly elevated CK [creatinine kinase], and everything is pointing toward the nerve. They said, “Let’s go into 1 of these genetic tests.” Ten years ago we would have done a muscle biopsy. We would have evaluated further. But now when they put that EMG with the exam, the CK, it points toward the SMA, and that’s what led to the genetic test. That’s what’s going to lead us to that genetic testing in this particular patient. But as an adult neurologist, in any patient I’m seeing, if I get that motor neuron description—clinical, where they’re appearing, where it became early in life, I’m going to think about doing the SMA in addition to any other testing.

We don’t have a good sense of the prevalence of adult-onset SMA. The reason why I say that is because it can be such a spectrum disease. In childhood, when they’re presenting with aggressive disease, it can be easier to diagnose. But as we get into the adult and you get people with milder and milder involvement, they can have a normal life span. They may just be a little slow and aren’t able to run as much as they were before. It can be a very mild disease. It’s not that common. There may be a couple per 100,000 that we will see, but the actual prevalence needs to be sorted out. Because with genetic testing, we’re learning more about the disease and the phenotypes that it can present. That gets us to a second question: What age will it usually present? That’s going to depend on how much involvement there is. When you look at the genetics of SMA, which is an interesting pattern in which you have the SMN1 and the SMN2. Depending upon the number of copies of SMN2 that you have, you can compensate for a deficiency in SMN1. If you compensate enough, it can present very late in life. As an adult neurologist, it’s something I think about in all the patients when I’m looking at a pure motor presentation with the weakness that we were describing in this patient. With genetic testing, it’s so easy to obtain. We will look to see if we can identify it.

An overview of the diagnosis of spinal muscular atrophy, including prevalence, age of onset, and the role of genetic testing.  

Diagnosis of Adult-Onset SMA 

 I want to discuss the case of a young woman who presented for evaluation. This is a 38-year-old woman who had been previously diagnosed with what was called muscular dystrophy. This occurred around age 9 because she was having some difficulty and muscle weakness. She said she started with the weakness, that it was primarily in her hips and her thighs. She couldn’t walk that far because she was getting significant muscle fatigue and having some difficulty breathing. She then saw her primary care physician, and they sent her to a neurologist. The neurologist did some examination and ordered some blood work. In the process, when they evaluated it, they had concerns for spinal muscular atrophy [SMA]. They sent off genetic testing and it showed an absence of SMA1 with a slightly elevated creatinine kinase, or CK. Because of that and because this patient is 38 years old, they were diagnosed with type 4 SMA. The neurologist discussed the treatment options, started the patient on risdiplam because they wanted to take a pill to treat this, and then referred the patient for OT [occupational therapy], PT [physical therapy], and a pulmonary evaluation.

This classic pattern that we’re seeing led to that muscular dystrophy diagnosis. A young girl at age 9 was having some difficulty running and was having some muscle weakness. And that’s the proximal weakness that we’ll see. As a neuromuscular specialist, we’ll see this in a lot of patients who are having some form of muscular dystrophy, and that’s why these questions were initially raised about that. But what complicates it is we had this difficulty breathing there was a lot of respiratory, there was a lot of different muscle. There was fatigue that was going on, and this pointed us again towards that muscular dystrophy but also more, could it be something else because the respiratory was a little bit more involved in it? When you examine somebody at this age in the differential, you start thinking about other processes. Muscular dystrophy is a muscle disease, which this could be, but in your lab work you can see there’s talk about a slightly elevated CK, but in muscular dystrophy it’s more dramatically elevated. That’s going to point you toward other causes, of which SMA becomes a real possibility. Spinal muscular atrophy is a disease of the motor neurons, not of the muscle. Initially looking at this, you think about this being not just a muscular dystrophy but something more than that. The SMA becomes in the differential, and that’s where that testing comes up. The thing about SMA is SMA is really a spectrum disease. You can have some of the SMAs that can be severe and can present at birth. Some can present in their adulthood. And those are more of the type 4s. This symptom starting around age 9 would be more suggestive of a type 3 SMA, but type 4 would certainly be 1 thing that could come up.

James Wymer, MD, provides a case overview of a 38-year-old female diagnosed with spinal muscular atrophy.  

A 38-Year-Old Female with Spinal Muscular Atrophy 

Dr Chuquilin is Assistant Professor, Dr. Wyman is Professor, Department of Neurology, University of Florida, Gainesville, FL.

Amyotrophic lateral sclerosis (ALS) has an incidence of 1.5-2.7/100 000 and a prevalence of 3-5/100 000. The lifetime risk of ALS is approximately 1:350 for men and 1:400 for women.

 About 90% of ALS cases are sporadic, with no family history and 10% are familial (mostly dominant). The most common familial form is caused by mutations in the 

 gene causing multiple hexanucleotide (GGGGCC) repeat expansions. To date, there is no cure for ALS and treatment focuses on improving quality of life, slowing disease progression, and improving survival.

Disease progression and the effect of the disease on the patient’s daily activities is monitored using the ALS-Functional Rating Scale (ALS-FRS). This scale includes 12 questions, with scores ranging from 0 to 4 (best score is 48). It is a commonly accepted scale for use in clinical trials.

Multidisciplinary ALS evaluation and follow up

Patients with ALS benefit from an ALS multidisciplinary clinic. They receive comprehensive care from a neurologist, physical therapist, occupational therapist, speech therapist, respiratory therapist, dietician, social worker, and durable medical equipment expert. ALS patients that receive care at multidisciplinary centers have better quality of life, satisfactions with their care, and survival.

 In a multidisciplinary clinic setting, behavioral changes or cognitive impairment (present in up to 40% to 50% of cases), can be properly diagnosed and monitored.

Respiratory failure is the most common cause of death in patients with ALS. As the disease progresses the forced vital capacity (FVC) of the patient decreases. FVC value is insensitive to detect early respiratory failure, as 13 of 20 patients with an FVC higher than 70% had abnormal maximal inspiratory pressure (MIP) lower that -60 cm H20. Nocturnal desaturations lower than 90% for 1 cumulative minute is a more sensitive indicator of nocturnal hypoventilation than FVC or maximum inspiratory pressure.

Once patients develop orthopnea, FVC drops to less than 50%, MIP is lower than -60 cm or if patient has nocturnal desaturations, they should be started on noninvasive ventilation (NIV). The use of NIV has been shown to increase survival in ALS patients by a median of 205 days in one randomized controlled study.

 Findings from a case study also indicate that NIV  improved quality of life.

It is important to note that the disease continues to progress and eventually patients will require tracheostomy and full-time ventilation. This is a decision that has to be made by the patient after careful discussion with the clinical provider and family members. Not everyone decides to go this route.

Percutaneous endoscopic gastrostomy tube placement

ALS leads to inability to swallow and chew with risk of aspiration, weight loss, and dehydration. One manifestation of ALS is a hypermetabolic state, and decreased oral intake further exacerbates weight loss.

 There is an association between body-mass index (BMI) and survival in ALS patients. Low BMI (<10.5 kg/m

) is associated with shorter survival and moderate obesity (BMI 30-35) is associated with slower disease progression and longer survival.

 Frequent swallow evaluation is needed to assess if it is within functional limits or if it needs to be supplemented by other means such as altering food consistency and chin tuck maneuver.

Eventually, when swallowing is no longer functional or if the patient has lost more than 10 % of his or her weight, a discussion about percutaneous endoscopic gastrostomy tube (PEG) placement is needed. This does not eliminate oral feeding, but provides a more convenient way of administering medication and fluid and stabilizing weight.

 PEG tube helps ALS patients receive the calories they need to prevent malnourishment and dehydration and stabilizes their weight. PEG tube placement is a procedure that is better performed when vital capacity is greater than 50%, procedure risks increases with anything below that value.

Two medication are FDA-approved for ALS. They are not curative, but slow disease progression. The first is riluzole, which is a glutamate receptor antagonist. In a randomized placebo controlled trial, riluzole improved survival time (defined as time to death or tracheostomy) by an average of 3 months. The patients included in this study had symptoms for less than 5 years, FVC higher than 60%, and had not had a tracheostomy. A subgroup with bulbar symptoms showed more improvement. The dose was 50 mg PO twice a day. Adverse effects included asthenia, stiffness, nausea, abdominal pain, and elevated liver function tests.

 The benefits of riluzole were also seen in other studies.

 A larger survival effect was seen in case reports, but those studies are subject to more bias.

The most recently approved drug therapy is edaravone, which is a free-radical scavenger. In a placebo-controlled study in a selected ALS patient population (< 2 years diagnosis, FVC > 80%, score of 2 points or better in each ALS-FRS score question), edaravone slowed the rate of decline of the ALS-FRS score by 33% over 6 months compared with placebo. The authors did not comment on survival effect. This medication is administered as an infusion in 14 consecutive days for the first month, then for 10 days (in a 14 day period) from the second month thereafter. The infusion time is about 1 hour and requires the placement of a port catheter for ease of administration and can occur at home or at infusion centers.

 Adverse effects include allergic reactions, sulfite allergic reactions, bruising, and headache. This medication was approved for all ALS patients, not just those meeting study criteria.

Pseudobulbar affect (excessive or inappropriate laughing, crying, yawning) can affect 20% to 50% of ALS patients and can be socially inadequate or embarrassing. A combination of dextromethorphan/quinidine 30/30 mg BID is effective in reducing the frequency and severity of laughing and crying behaviors. Adverse effects include dizziness, nausea and somnolence.

As mentioned above, patients with ALS also develop sialorrhea. In some patients, sublingual atropine drops can help. Other options include tricyclic antidepressants such as amitriptyline or anticholinergics such as glycopirrolate. In other cases, salivary gland botulinum toxin injections have been proved to be effective.

 Fatigue is also an undertreated ALS symptom. Its origin is likely multifactorial from muscle weakness, reduced endurance and can be treated with modafinil.

Although there is no cure for ALS, there are treatments available that can improve the quality of life and prolong survival (

). A multidisciplinary approach is key in the care of this population.

1. Salameh JS, Brown RH, Berry JD. Amyotrophic lateral sclerosis: review. 

2. Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. 

3. Murphy J, Factor-Litvak P, Goetz R, et al. Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort. 

4. Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. 

5. Bourke SC, Tomlinson M, Williams TL, et al. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. 

6. Bouteloup C, Desport JC, Clavelou P, et al. Hypermetabolism in ALS patients: an early and persistent phenomenon. 

7. Paganoni S, Deng J, Jaffa M, et al. Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. 

8. Andersen PM, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS): revised report of an EFNS task force. 

9. Kellogg J, Bottman L, Arra EJ, et al. Nutrition management methods effective in increasing weight, survival time and functional status in ALS patients: a systematic review.

 Amyotroph Lateral Scler Frontotemporal Degener

10. Kasarskis EJ, Scarlata D, Hill R, et al. A retrospective study of percutaneous endoscopic gastrostomy in ALS patients during the BDNF and CNTF trials. 

11. Bensimon G, Lacomblez L, Meininger V, for the ALS/Riluzole Study Group. A controlled trial of riluzole in amyotrophic lateral sclerosis. 

12. Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). 

13. Group W, Group EM-AS. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. 

14. Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. 

15. Rabkin JG, Gordon PH, McElhiney M, Rabkin R, Chew S, Mitsumoto H. Modafinil treatment of fatigue in patients with ALS: a placebo-controlled study. 

Articles

Although there is no cure for ALS, there are treatments available that can improve the quality of life and prolong survival.