In the closing days of 2016, the FDA approved nusinersen (Spinraza; Biogen) for the treatment of spinal muscular atrophy (SMA). It was the first drug approval for the debilitating neuromus- cular condition after decades of research by clinicians and investigators for a better understanding of how to help patients with SMA, many of whom face a tragically shortened life span.

Since then, development of therapies that act on the SMN gene has exploded. With several treatments in the pipeline and an improved understanding of options for patients with SMA, clinicians are now in a better position to make a difference.

To discuss how the treatment landscape has shifted and provide some insight into future developments, Nancy L. Kuntz, MD, a pediatric neurologist at the Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois, joined 

 to lead a panel of expert clinicians in a discussion of these agents.

Kuntz began by highlighting how clinicians can optimize care in the evolving SMA treatment model, noting several questions that remain unanswered, including whether gene therapies will be used in combination with one another or in tandem with other supportive treatments. Kuntz also mentioned the need to improve newborn screening and the perspective that current treatments and therapies provide in promoting it.

Claudia Chiriboga, MD, MPH, professor of neurology and pediatrics at Columbia University Medical Center in New York, New York, shared her insight.

“All the studies that have been discussed show that even if it’s later-onset SMA or infant SMA, early treatment is important, and there’s a differential response to early treatment, with [anti-sense oligonucleotide] treatment showing the best response and possibly normal development,” Chiriboga said. “It’ll be very exciting to see on an equal playing field these presymptomatic studies that are ongoing [and]... comparing the small molecule risdiplam with AVXS-101, in the SPR1NT study as well as the NURTURE study, to see whether there’s any benefit or advantage to one over the other.”

The biggest differentiator, Chiriboga noted, is whether the therapy in question is a central nervous system (CNS)—restricted treatment, such as nusinersen, rather than a more widely disseminated treatment. She explained that in her approach to the symptomatic child or infant, a treatment such as Zolgensma (previously AVXS-101; AveXis) has been very effective in those younger than 5 months.

“The response would come to flat once they got past a certain age, which may reflect a critical number of neurons that you need. If you’re more advanced, there’s not enough gene to produce it,” Chiriboga said. She added that currently with CNS restriction, if clinicians start therapy early enough, it might make a difference. The jury is still out, however, on whether presymptomatic chil- dren with SMA will need the combination therapy.

“When they’re symptomatic, it’s a different story because you want to maximize SMN, and then combination therapy with a gene transfer and an SMN to a slicing modulator—either risdiplam or an antisense oligonucleotide&mdash;may make sense, if we’re permitted to do so,” Chiriboga said. “The studies in the pipeline now that are using ancillary drugs that are not SMN specific but that enhance muscle are another option to use in combination with an SMN-modifying therapy. It will be exciting to see how much benefit is given.”

Basil Darras, MD, director of the Neuromuscular Center and the Spinal Muscular Atrophy Program at Boston’s Children’s Hospital in Massachusetts, noted that in addition to preventing the disease, clinicians need to understand that they may be able to diminish the

“It’s not just [about] having a child who has more normal development but also having a child who does not have to be admitted to the hospital multiple times and sometimes into the intensive care unit, which we all know can be quite expensive.”

“We [also] tend to forget the value of the preconception carrier screening, which aims at diminishing the number of babies who are born with SMA,” Darras continued. “One in 50 people in the general population [is a carrier] of this mutation, which means it’s quite common, and it will help enormously, and it prevents the disease if prospective parents are screened for carrier status around the world.”

Elizabeth Kichula, MD, PhD, a clinical assistant professor of neurology at Penn Medicine and a pediatric neurologist at Children’s Hospital of Philadelphia in Pennsylvania, mentioned that even with the inclusion of SMA screening in the American College of Obstetricians and Gynecologists recommendations update in 2017, limits to carrier screening still exist.

“It’s important to remember that that’s screening and not testing, but I think sometimes not everyone is aware of that,” Kichula said. “Primarily, it tests for the deletion and not for sequence variance, which would miss about 5% of patients.”

Additionally, she pointed out that in certain cases, a higher percentage of individuals will have 2 copies of the SMN1 gene on 1 chromosome—particularly in black patients. The sensitivity of carrier testing in these patients is only between 70% and 80% compared with well over

“Really trying to think about those limitations and the interpre- tation of this, I think, is also important. And newborn screening could help fill in some of those holes, although it will still miss some of them,” Kichula said.

"It's not just (about) having a child who has more normal development, but also having a child who does not have to be admitted to the hospital multiple times... which we all know can be quite expensive," said Basil Darras, MD. 

Data for Zolgensma, which the FDA approved in May 2019,

have demonstrated rapid motor function gains and milestone achievements with intrathecal delivery in the phase 1 STRONG trial, prolonged event-free survival in addition to motor function increases and milestone achievement in the phase 3 STR1VE trial, and age-appropriate motor milestone accomplishments in the SPR1NT trial.

AveXis’ gene transfer strategy includes the commonly used adeno-associated virus 9. Kichula was involved in the trials and shared her experience with the novel treatment.

“It is a virus that doesn’t integrate its DNA into the human genome, so we shouldn’t run into issues that arose in clinical trials from decades ago, where there was an increased cancer risk with certain gene therapies,” Kichula said. “Rather, the viral caps just sit there in the cell but can continually express SMN. The choice of the virus is a really important thing when you’re talking about gene therapies because every virus has particular cells that it likes to infect.”

She also shared some of the clinical findings with Zolgensma. The initial phase 1 study included 15 patients, of whom the first 3 received a lower dose to evaluate basic safety, whereas the other 12 received a higher dose.

“A lot of the outcomes that they looked at had significant overlap with things that you’ve already heard about,” Kichula said. “The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND] test scores had significant improvement and really improved quite rapidly over the first several months following infusion. In addition, none of the patients required any full-time ventilatory support. None of the patients died during the trial--all things that in the untreated SMA type 1 population we would have anticipated to see during that [time period].”

In addition, continuous and drastic improvements were observed in feeding, bulbar involvement, speech, and the ability to walk independently.

“It’s important for me to backtrack a little bit and note that in these phase 1 patients, they are giving the medication intravenously, so the virus completely crossed the blood—brain barrier,” Kichula said. “We don’t run into those issues that we get with nusinersen, so it is a onetime intravenous injection. Then the virus has to just sit there and will continue to express the protein.”

Kuntz then inquired about the idea of promoting the development or production of SMN2 and the SMN protein, particularly outside the available genetic approaches. Chiriboga, who was involved in the clinical development of risdiplam, discussed the advantages and findings regarding the agent thus far.

“It’s an oral medication given once a day that works in a very similar fashion as nusinersen does, in that it increases alternative slicing of the SMN2 gene so that more SMN is produced,” Chiriboga said. “A difference, other than that it’s administered orally, is that it also penetrates systemically. It goes uniformly into the CNS with a 1-to-1 penetration, at least in many species, including monkeys, so that blood levels are thought to reflect concentrations in the brain.”

The treatment was shown to be successful in the recently announced results of the FIREFISH and SUNFISH studies. In FIREFISH, investiga- tors determined the proper dose and are now assessing it in a pivotal open-label trial. In the dose-finding portion, even though the pediatric participants were older than those included in the ENDEAR study or with Zolgensma, they showed notable improvements.

“A significant proportion of them improved at least 3 points on their CHOP INTEND; if they didn’t have swallowing difficulties, they didn’t develop swallowing difficulties; and they didn’t reach the end point,” Chiriboga said. “Similar to the ENDEAR study, in which the outcome with survival included an end point of survival or permanent ventilation—defined as 16 hours on a ventilator or a tracheostomy&mdash;if they didn’t have these issues, they did not develop them, which was very striking given that they were a bit older.”

Chiriboga added that given the success that risdiplam demonstrated in trials, Hoffmann-La Roche now plans to submit the agent for FDA approval.

To close the discussion, Kuntz brought up the translational research that has led to new treatments in SMA, brought on in part by the approval of nusinersen. “This is truly a new generation,” she noted, asking Darras to detail what the field learned from the development of this treatment.

“The SMN2 gene is a major phenotypic modifier but also has become the target of pharmaceutical research, and the effort is that they’re trying to increase projection of full-length SMN protein from the SMN2,” Darras said. Nusinersen is designed to improve the splicing of the SMN2 gene.

“It binds to a particular site in intron 7 next to exon 7, and by doing so, it does displace a particular protein that binds to the same site, which is a splicing repressor. And by inhibiting this particular repressor protein binding, it increases the splicing of the inclusion of exon 7 to the splicing events,” Darras said. “This, in turn, can up the production to 90% of the full-length protein—though this oligonucle- otide does not cross by the brain barrier, so it must be given by intrathecal injection.”

Ultimately, after nusinersen showed a number of successes in the ENDEAR study in SMA type 1, Biogen submitted an application to the FDA, including the results of the open-label studies dating back to 2012. That led to the approval of nusinersen as the first treatment for all types of SMA, regardless of age.

“Although the approval was based primarily on type 1 results, [the FDA] decided to approve it for all types of SMA. And we started treating all types of patients, from very severe to less severe, from babies with severe forms to the sitters or walkers,” Darras said. “We learned that the theoretical idea that you can correct the splicing of the SMN2 can work in humans, but it’s not actually a cure for SMA; it’s only a treatment with different types of responses from mild improvement to significant improvement or only to stabilization of function.”

Kuntz concluded by pointing out that by comparing outcomes and change over time in various treatment groups, it appeared “very clearly” that patients with the same number of copies of SMN who were treated earlier did better, which prompted “a lot of the impetus for early identification and newborn screening.”

1. AveXis receives FDA approval for Zolgensma, the first and only gene therapy for pediatric patients with spinal muscular atrophy (SMA) [news release]. Basel, Switzerland: Novartis; May 24, 2019. https://www.novartis.com/news/media-releases/avexis-receives-fda-approv- al-zolgensma-first-and-only-gene-therapy-pediatric-patients-spinal-muscular-atrophy-sma. Accessed June 15, 2019.

2. AveXis presented robust data at AAN demonstrating efficacy of Zolgensma in broad spectrum of spinal muscular atrophy (SMA) patients [news release]. Basel, Switzerland: AveXis; May 5, 2019. novartis.com/news/media-releases/avexis-presented-robust-data-aan-demonstrating-efficacy-zol- gensma-broad-spectrum-spinal-muscular-atrophy-sma-patients. Accessed July 9, 2019.

3. PTC Therapeutics announces risdiplam (RG7916) is well tolerated at all dose levels with no drug-re- lated safety findings [news release]. Dallas, TX: Cure SMA; June 19, 2018. www.curesma.org/news/ ptc-therapeutics-update-june2018.html. Accessed February 19, 2019.

4. Baranello G, Servais L, Day J, et al. FIREFISH part 1: early clinical results following a significant increase of SMN protein in SMA type 1 babies treated with RG7916. Presented at: 23rd Annual Congress of the World Muscle Society; October 2-6, 2018; Mendoza, Argentina. Poster 258. wms2018.com/wp-content/uploads/2018/full-congress-%20issue-final_28_9.pdf. 

Articles

Clinical Insights

In this Peer Exchange, experts discussed current SMA therapies, what they have learned, and what the future holds for treatment of this devastating disease.

Optimizing Care of Spinal Muscular Atrophy in an Advancing Treatment Era

Focused ultrasound (FUS) technology is a highly promising treatment for tremors and Parkinson disease (PD), movement disorders that are currently managed via pharmacologic interventions and invasive surgery.

 Surgery for PD includes deep brain stimulation (DBS) of the subthalamic nucleus and thalamotomy. However, DBS has several limitations, such as risks associated with device implantation and electrical stimulation. Additionally, it has relatively high maintenance costs and requires continual follow-up. Therefore, DBS is not suitable for immunocompromised patients or those for whom regular follow-up is difficult. Lesioning procedures may serve as a suitable substitute or complement to DBS in certain cases, but lesioning by radiofrequency techniques is associated with risks due to lack of control over lesion size, which can lead to irreversible adverse effects.

Clinicians can use FUS to create lesions in the deep brain tissue in a noninvasive manner. Additionally, FUS can target specific regions of the brain. In this technique, thermal ablation is achieved by focusing high-frequency ultrasound on the target area, which leads to cell death through localized heat generation while causing minimal damage to surrounding tissue. Clinicians can monitor the ablation through magnetic resonance imaging (MRI). FUS-mediated ablation can treat multiple brain disorders, such as epilepsy, neuropathic pain, and movement disorders associated with PD.

Thermal ablation is not the only application of FUS in movement disorders. “FUS can currently be used in 2 ways, depending on the frequency of ultrasound applied,” explained Nir Lipsman, MD, PhD, of Sunnybrook Research Institute in Ontario, Canada. “High-frequency ultrasound can be used to generate noninvasive lesions in the brain for a wide variety of conditions [in which] making a lesion could be effective. Essential tremor is a good example, and FUS to generate a permanent lesion in the thalamus for essential tremor patients who are no longer responsive to medications is currently a standard of care.” He added that the second approach is to use low-frequency ultrasound, which can open the blood-brain barrier to improve drug delivery to the brain. This application is not approved by the FDA but is under clinical investigation.

In July 2016, the FDA approved the MRI-guided FUS (MRgFUS) device Exablate Neuro from INSIGHTEC for the treatment of essential tremor in patients who are nonresponsive to medication.

“It’s too early to tell how the procedure will compare with current surgical approaches, but we hope it will one day provide a safe and effective option for patients. For essential tremor, FUS provides an alternative that is less invasive than standard surgical approaches but is just as effective,” said Lipsman. “FUS for essential tremor is well tolerated by patients, and they generally go home the same or next day after their procedure. Each FUS procedure involves a head shave and placement of a stereotactic frame under local anesthetic. The procedure itself takes about 3 hours in the MRI scanner. Because FUS is less invasive than standard surgical approaches for tremor, does not involve an implant, and is image guided, many patients are interested in finding out whether they would be eligible.”

Regarding the application of FUS in PD therapy, Lipsman said, “FUS for Parkinson is still in the experimental stages. We are determining its safety profile in phase 1 trials before expanding to larger, late-phase trials.”

Investigators have conducted considerable research on applications of FUS beyond ablative treatment and thalamotomy. These therapeutic applications are under varying stages of development, ranging from early research to the clinical stage (FIGURE)

. Tim Meakem, MD, chief medical officer of the Focused Ultrasound Foundation (FUSF), told 

 that “delivery of therapeutics facilitated by FUS-induced blood—brain barrier opening is a promising area of research with strong preclinical evidence that is being translated to the clinic. Neuromodulation and immunomodulation are other exciting areas of research, although more work is needed to fully understand how these biomechanisms can be tools for treating Parkinson disease.”

In addition to movement disorders, FUS may also be effective for various other neurological disorders. For example, FUS-mediated thermal ablation has been evaluated for the treatment of epilepsy and brain tumors. This method may be particularly effective for targeting deeply located tumors. For epilepsy, FUS has the potential to achieve ablation in the epileptogenic foci or to disrupt the epilepsy network. In addition, preclinical studies are evaluating nonthermal ablation using FUS for these conditions. To achieve nonthermal lesioning, FUS is used at a lower frequency of 250 KHz (as opposed to 650 KHz for thermal ablation), which induces excitation of gas bubbles that are trapped inside tissues and results in lesioning. This process is called histotripsy or cavitation.

FUS can also be used to temporarily open the blood—brain barrier, through cavitation, at specific locations to improve the delivery of drugs to the brain. Clinical studies are evaluating this application in brain tumors and neurodegenerative disorders such as Alzheimer disease.

 Cavitation induced by FUS or FUS-mediated targeted drug delivery to the brain could also be utilized to induce thrombolysis in the treatment of stroke; this application is being evaluated in preclinical studies.

FUS ablation could further offer benefits for mental health conditions such as depression and obsessive-compulsive disorder (OCD).

 Indeed, in one clinical trial, FUS ablation of the anterior limb of the internal capsule showed an improvement in OCD symptoms without any complications. However, the sonication target needs to be further refined for this condition.

FUS-mediated ablation in the thalamus may be used for the treatment of neuropathic pain. This application is under clinical evaluation in the United States.

 The use of FUS for the treatment of neuropathic pain has been approved in Europe, Russia, and Korea.

FUS is also being evaluated in disorders of the consciousness, which include coma, vegetative state, and minimally conscious state. In an ongoing clinical study at the University of California, Los Angeles, application of low-intensity FUS pulsation to the thalamus improved the condition of a comatose patient through neuromodulation.

Current and Future Clinical Applications of Focused Ultrasound (FUS) Technology

After ablative therapy, facilitating drug delivery to the brain is the next application of FUS in the pipeline for movement disorders such as essential tremor and PD. A major challenge in the treatment of brain disorders is circumventing the blood—brain barrier

so that drugs can enter the brain and reach their targets. Over the years, clinicians have used various approaches to achieve this aim, including mannitol-mediated blood—brain barrier disruption, intranasal administration of drugs, and novel drug delivery vehicles such as liposomes and magnetic nanoparticles.

FUS-mediated opening of the blood—brain barrier is one such novel approach. Significantly, the technique is a noninvasive, targeted approach, unlike other methods of disrupting the blood–brain barrier.

 “Low-frequency ultrasound can be used to open the blood— brain barrier, and we are interested in investigating whether this strategy can be used to enhance the delivery of compounds to the brain, including in Parkinson, which otherwise cannot pass through the blood–brain barrier,” Lipsman said.

With low-frequency focused ultrasound, pulses of sonication are directed in a controlled manner at gas-filled microbubbles in the blood. This leads to excitation of the microbubbles, stretching the endothelium, increasing the vascular permeability, and leading to the localized opening of the blood—brain barrier. This allows therapeutics to enter the brain.

Because this procedure uses pulses of low-frequency ultrasonic beams, it generates less localized heat compared with FUS-mediated ablation. This reduces the risk of adverse events at the focus site. Furthermore, because low-frequency FUS does not require an increase in localized temperature, clinicians can use it to target a wider range of regions compared with FUS for ablation.

Results from studies have shown the procedure to be safe and reversible, with any disruption lasting approximately 24 hours. During this time, therapeutics with high molecular weight can enter the blood—brain barrier. Additionally, it improves the odds of treating the root cause of PD by improving the delivery of therapeutics that could restore damaged neurological function. Therapeutics of particular interest include gene therapies, neurotrophic factors, adeno-associated viral vectors, and antibodies against α-synuclein, the accumulation of which is known to contribute to neuronal death in PD.

Additionally, practitioners can combine opening of the blood— brain barrier with the release of drugs from their delivery vehicle, speci cally at the target location, without affecting the nontarget regions of the brain. “You can use small microbubbles, encapsulating the required therapeutic, that can circulate through the body with no impact,” Meakem explained. “But in areas where they receive FUS stimulation, those bubbles will burst and release their payload in that local region, targeting the delivery of the drug right where you need it.”

To optimize the blood—brain barrier opening using FUS, clinicians must consider various factors, including frequency, pulse rate, characteristics of the microbubbles, and, most important, control of the cavitation process.

 Indeed, a major technical challenge of this approach is monitoring cavitation throughout the procedure. Another challenge is determining the power required to target specific brain regions, which depends on the skull, the target area, and tissue composition.

This application might complement therapy using drugs currently under research for PD that are known to have beneficial effects but are limited by their inability to reach their target in the brain. One such example is the glial cell line—derived neurotrophic factor, which is hypothesized to improve the function of striatal dopaminergic neurons in PD. However, direct infusion of glial cell line–derived neurotrophic factor failed to achieve the expected outcome in a clinical trial, possibly due to ineffcient delivery.

Another application of using FUS to open the blood—brain barrier is in gene therapy. Currently, therapeutic genes are surgically implanted into the brain; however, surgery poses increased risk, and for patients whose cognition is impaired, intracerebral gene delivery is not an option. However, clinicians could make gene therapy available to these patients using FUS-mediated gene delivery because it is a noninvasive method.

Current studies are focused on determining clinical safety and opti- mizing technical aspects of the procedure. One goal is to control pore size during blood—brain barrier disruption. Efforts are under way to measure and predict the dose of the drug delivered and the cavitation dose. Additionally, INSIGHTEC hopes to achieve automatic control of the acoustic parameters. The company is developing an Exablate system speciffically to open the blood–brain barrier, as the currently marketed device is intended for thermal ablation.

Clinicians have used radiofrequency pallidotomy for improving levodopa-associated dyskinesia in PD by lesioning the posteroventral portion of the globus pallidus.

 Investigators are evaluating the safety and efficacy of pallidotomy via MRgFUS as a noninvasive alternative. Studies have demonstrated that the efficacy of unilateral pallidotomy in PD is comparable with that of DBS and radiofrequency lesions. A complication associated with this procedure is impairment of vision, speech, and motor skills; however, this is transient.

Investigators have conducted pilot trials of FUS pallidotomy in multiple locations, including the United States and South Korea. The procedure has demonstrated a better safety profile compared with radiofrequency lesions as well as improvements in Unified Parkinson’s Disease Rating Scale scores.

 A large, international, prospective, 2-arm, randomized, multicenter pivotal study is also evaluating the safety and efficacy of unilateral FUS pallidotomy using the ExAblate 4000 MRgFUS system in advanced idiopathic PD.

 Investigators anticipate the study will lead to FDA approval.

Once the safety and efficacy of this procedure have been more firmly established, the next logical step for FUS pallidotomy would be to evaluate bilateral pallidotomy, as most patients have bilateral disease. Furthermore, in addition to the subthalamic nucleus and the globus pallidus, investigators are also considering the substantia nigra and the striatum, among other targets, for ablative treatment.

Studies have demonstrated that FUS activates the body’s immune response. For example, in Alzheimer disease models, FUS has been shown to activate microglia and increase phagocytosis of amyloid-β deposits in the brain by microglia and astrocytes.

Investigators speculate that FUS also induces the entry of immune cells into the brain and an inflammatory response, which might facilitate the clearance of amyloid-β plaques.

 Similarly, this FUS-mediated immune response could aid in clearing the accumulation of α-synuclein in PD.

 Importantly, however, clinicians must control the activated immune response, instead of allowing it to proceed in a prolonged manner, to tap its beneficial effects.

Results from other studies have shown that FUS at a lower intensity than that used for opening the blood—brain barrier safely modulates neuronal activity in animals and healthy humans.

 This application of FUS can induce reversible stimulation and inhibition of neurons in multiple regions of the brain, including the thalamus. Animal trials have demonstrated that ultrasound delivery parameters such as sonication duration determine the neuromodulation effect; short sonication times appear to increase neural activity in the motor pathway, whereas long durations suppress it.

Investigators are evaluating FUS-mediated neuromodula- tion by administering weekly stimulations in animal models, with the observed effects of a single sonication lasting 2 hours.

 Investigations are under way to determine the mechanism underlying this effect. In vitro and in vivo studies have hypothesized various mechanisms, such as presence of mechanosensitive ion channels within the neural membrane, dissolved gas bubbles oscillating within the lipid bilayer of neurons, and radiation forces.

Investigators are unsure of how the topology and density of the skull affect ultrasound focusing on the target region, so studies are needed to improve the understanding of this effect and to determine the long-term effects of FUS on neuronal tissue. Further studies are also required to determine the individual effects of frequency, pulse timing, intensity, and total sonication time on neuromodulation.

In addition to the discussed applications of FUS for treating tremors and PD, investigators are exploring several other therapeutic effects. “There are a lot of interesting ways that we can use FUS, and there is research going forward in every one of these applications,” said Meakem. “Other possibilities include sonodynamic therapy, where you can administer medications that are not active in their native state but turn from inactive to active when targeted with FUS.”

Meakem added that histotripsy is another potential application of FUS, as “it damages cells more from a mechanical impact of the ultrasound energy in a very short burst.” This is different from thermal ablation, in which cell damage occurs through localized generation of heat.

Despite its advantages and treatment possibilities, FUS has its share of challenges. Although improved penetration of the blood— brain barrier is a boon for drug delivery, it increases the risk of unwanted substances, including foreign matter and inflammatory agents, entering the brain. Importantly, clinicians must understand the significance of tissue responses that have been observed following FUS, including localized edema, hemorrhage, ischemia, and glial activation. A greater understanding of the risks associated with administration of microbubbles and cavitation is also needed.

 As with every new treatment approach, extensive research is critical to further improving the therapy, expanding its applications, and determining its long-term effects. However, lack of funds for clinical trials is a roadblock. “As with other areas in the biomedical field, funding for clinical trials is a challenge, particularly once trials move past phase 1. Many of our trials are funded by the foundation, whose support for our work has allowed us to significantly accelerate FUS research over the past 5 to 10 years,” Lipsman said.

Meakem also cited a lack of awareness of FUS. “Even in the medical community, people are generally unaware of FUS,” he said, “but we are trying to work against that.” In this regard, a need exists to educate patients, clinicians, and scientists about this technology.

“FUS is a standard treatment for patients with severe, treatment-resistant essential tremor, and our hope is to provide this option to as many eligible patients as possible,” Lipsman said. “In Parkinson disease, we are hoping to demonstrate that opening the blood—brain barrier is safe, technically feasible, and ultimately effective at delivering therapeutics to the brain that would otherwise not be possible to deliver. In this way, we hope to move the dial on this and other challenging and disabling conditions where delivering therapeutics to the brain is a major challenge.”

Because FUS is a noninvasive approach that can target specific brain regions, it has been a source of hope for clinicians and patients alike. Although further research is required, particularly long-term studies on optimizing the technical aspects of the procedure, this technology looks set to make its mark in movement disorders and beyond.

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. 2018;130(6):1853-1861. doi: 10.3171/2018.2.JNS172514.

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4. Focused Ultrasound Foundation. Focused ultrasound opening of the blood-brain barrier for the treatment of Parkinson’s disease. 

fusfoundation.org/images/pdf/Focused-Ultrasound-Foundation-Parkinsons-Disease-BBB-Workshop-2018-Report.pdf

. Published October 21, 2018. Accessed June 10, 2019.

5. FDA approves first MRI-guided focused ultrasound device to treat essential tremor [news release]. Silver Spring, MD: FDA; 

. fda.gov/news-events/press-announcements/fda-approves-first-mri-guided-focused-ultrasound-device-treat-essential-tremor. Accessed June 15, 2019.

6. INSIGHTEC for neurosurgery. INSIGHTEC website.

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2018;75(2):246—254. doi:10.1001/jamaneurol.2017.3129

8. Global Registry: ExAblate Neuro MR Guided Focused Ultrasound (MRgFUS) of Neurological Disorders.  https://clinicaltrials.gov/ct2/show/NCT03100474. Updated June 2019. Accessed July 10, 2019.

9. Thalamic Low Intensity Focused Ultrasound in Acute Brain Injury (LIFUP). https://clinicaltrials.gov/ct2/show/NCT02522429. Updated March 2018. Accessed July 10, 2019.

10. LeWitt PA, Lipsman N, Kordower JH. Focused ultrasound opening of the blood—brain barrier for treatment of Parkinson’s disease [published online May 28, 2019]. 

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fusfoundation.org/the-foundation/overview

Cover Story

The implementation of focused ultrasound has been practice changing in tremor, but the various arenas in which this technology can be used opens up new treatment avenues for a range of neurological disorders.

The Future of Focused Ultrasound: Movement Disorders and Beyond

Although substantial evidence suggests that cognitive impairments can emerge or worsen with acute and progressive neurologic changes in epilepsy, experts are also increasingly recognizing that comorbidity does not indicate causality. Indeed, cognitive impairments warrant distinct assessment and mitigation from the diagnosis and treatment of epilepsy.

Christoph Helmstaedter, PhD, and Juri-Alexander Witt, PhD, both of the Department of Epileptology at the University of Bonn in Germany, and others have suggested that a bidirectional relationship between cognitive and behavioral problems and epilepsy can exist. They have acknowledged, however, the difficulty in untangling the etiologies of cognitive problems in epilepsy and noted the need to consider these within multifactorial and neurodevelopmental models.

“Cognitive problems in epilepsy can have multiple causes, which, when viewed individually or in combination, determine the course of cognitive development and, when taken as symptoms, are not disease specific,” Helmstaedter and Witt wrote.

The proposition of a bidirectional nature of epilepsy comorbidities represents a paradigm shift in the neuropsychology of epilepsy, according to David Loring, PhD, director of neuropsychology in the Department of Neurology and a professor of neurology and pediatrics at the Emory University School of Medicine in Atlanta, Georgia, and colleagues.

 “The paradigm shift that we described addressed the proposition that both the behavioral—particularly depression&mdash;as well as some of the cognitive issues are not necessarily the result of active epilepsy but in fact can predate and actually be associated with factors prior to the seizures emerging,” Loring explained to 

Investigations into mechanisms of epilepsy and comorbidities including cognitive impairment have identified alterations in both signaling pathways and neuronal network function, as well as indications that comorbidity can occur without shared causality, according to Gregory L. Holmes, MD, of the Department of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington. In his review of the roles of network abnormalities in cognitive impairment with epilepsy, Holmes acknowledged that current understanding of processes underlying comorbidities lags behind knowledge about the mechanisms of epilepsy.

 He found, however, that “the biological underpinnings of cognitive impairment can be distinct from the pathophysiological processes that cause seizures.”

Helmstaedter and Witt estimated that about 70% to 80% of patients with chronic epilepsies have cognitive deficits, and they noted that mood and behavioral problems are also common, with depression found in up to 60%.

 Cognitive impairments are prevalent in children with epilepsy, with one large population study finding intellectual disability in 17% of pediatric patients, disorders in psychological development in 21.3%, and unspecified developmental delay in 7.5%.

“The causal relationship between epilepsy and its behavioral comorbidities was first challenged in epidemiological studies showing that psychiatric comorbidities may well precede the onset of epilepsy and that they may even be viewed as a biomarker for developing epilepsy,” observed Helmstaedter and Witt.

The most recent epidemiologic evidence of a bidirectional association emerged from the first longitudinal investigation of an association between early-life cognitive ability and risk of incident epilepsy, conducted by Merete Osler, MD, PhD, DMSc, of the Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, and the Department of Public Health at the University of Copenhagen in Denmark, and colleagues.

This large, population-based cohort study included records for over 1 million men from 3 Danish databases, including 22,364 patients (1.9%) who had developed epilepsy. A supplementary analysis with approximately 14,000 female patients corroborated the initial findings across gender.

The investigators ascertained cognitive ability using the Børge Priens Prøve intelligence test, which they indicated correlates well with the full-scale Wechsler Adult Intelligence Scale. They obtained the diagnosis of epilepsy from Danish hospital patient registers.

Osler and colleagues found that cognitive ability in young adulthood was inversely associated with the risk of epilepsy. Also, an epilepsy diagnosis during childhood and adolescence was associated with an approximately 0.25 SD lower cognitive ability in young adulthood. A limitation of the study was that the cognitive measure had not been repeated, leaving the investigators unable to determine whether a lower cognitive ability had been present before disease onset or had decreased because of the e ect of epileptic seizures or treatment.

“The cognitive impairment seen in adult patients with epilepsy may reflect combined effects of epileptic processes and lower premorbid cognitive ability, which might be a marker of brain dysfunction inherited or acquired early in life,” Osler and colleagues opined.

Although the epilepsy-centric view of cognitive changes has held that cumulative neurologic damage in chronic epilepsy contributes to poorer cognitive status over time, Helmstaedter and Witt pointed out that such decline is relatively slow, with not more than 1 SD over a period of approximately 30 years.

A possible alternative to an accumulating negative effect, they suggested, is that an initial impairment negatively affects mental development or that it interacts with normal aging. “Accordingly, it is essential to examine cognition at the time of epilepsy onset in order to understand when the problems occur and what effects the course of the disease and its treatment will have on cognition,” they advised.

Performing cognitive screening in new-onset epilepsies in children and adults, they indicated, “enables the physician to monitor the course of the disease and to attribute the potential changes [that] may occur to either the treatment’s success or failure, AED [antiepileptic drug] [adverse] effects [AEs], and the dynamics of the underlying pathology.”

Loring and colleagues agree with the importance of such screening at the time of new-onset epilepsy, noting that adults with new onset often display a pattern of mild diffuse cognitive impairment at diagnosis and prior to AED treatment. They pointed out that children often have elevated rates of behavioral problems, including attention-deficit/hyperactivity disorder, and early-life histories of academic struggles, with a pattern of distributed cognitive anomalies.

Screening is important for many neurologic conditions and certainly for epilepsy and particularly for the younger patient, Loring emphasized. “Identifying some cognitive issues that can be addressed while [patients are] still in the school system can enable some compensatory remediation and other sorts of special services to be provided, to maximize their developmental and cognitive outcomes,” Loring said.

Although clinicians have traditionally used clinical neuropsychology to guide epilepsy surgery, Helmstaedter and Witt argued that it is past time to more fully integrate it into the routine care of patients with epilepsy.

 Experts generally agree on the functional domains that should be assessed, but Helmstaedter and Witt noted that clinicians agree far less on the particular tests that should be used.

“No standardized protocols for dominance assessment and [surgical] outcome prediction are in sight,” Helmstaedter and Witt observed, “and the choice of particular tests in epilepsy is still very much determined by general neuropsychological considerations and individual preferences rather than by published evidence in epilepsy.” 

A recent report from a European pilot network of reference centers, also based at the Department of Epileptology at the University of Bonn, identified 186 different tests in use throughout the 26 participating epilepsy centers.

 The investigators also discovered, however, a smaller “core” set of tests that are frequently chosen based on the clinicians’ experience as well as on published evidence.

In lieu of recommending particular tests for “an evidence-based diagnostic toolbox for use in epilepsy,” Helmstaedter and Witt offered in the following list what they described as a question-guided and modular diagnostic approach (excerpted and edited for brevity and omitting surgery-specific testing)

The approach that Loring takes is to offer screening widely to clinicians, before the more time-intensive and specialist-applied neuropsychological testing is considered. “We can do a screen for cognition with a collection of tests that are designed to take on the order of 1 hour, and it includes the NIH [National Institutes of Health] cognition toolbox,” he said.

 as different tests and measures were being used and it was hard to get a common metric across different studies,” Loring noted. “The NIH battery is in the public domain, so it does not have to be paid for, in contrast with a lot of the neuropsychological tests that are proprietary and have a per-use fee.”

Loring pointed out that the NIH cognition assessment battery is also designed for use by staff who are not formally trained to administer neuropsychological testing. “We give it on an iPad platform that takes about 30 minutes, and supplement it with tests of processing speed and other attention measures that can be applied in clinics,” Loring said.

Consider AED Adverse Effects on Cognition

When selecting and dosing AED treatments, one might consider choosing a treatment not only for efficacy but also to minimize AEs, which can include cognitive impairment. Kees Braun, MD, PhD, of the Department of Child Neurology at University Medical Center Utrecht in The Netherlands, found that vigilance, attention, psychomotor speed, memory, and learning are most affected.

“High-dose regimens and polypharmacy increase the chance of [adverse] effects, and children appear to be most susceptible,” Braun warned. “The cumulative cognitive consequences of chronic AED use during a critical stage of development can permanently affect educational progress and eventual functioning.”

In addition to selecting an AED with a favorable AE profile when possible, Braun recommended minimizing the dosage to that required for symptom control, trying to prevent polypharmacy, switching drugs when cognitive AEs are suspected, and discontinuing the medication whenever it is safe to do so. “Many parents will report an increased alertness and improved learning capacity once an AED is discontinued in their seizure-free child, even if they had not recognized the [AE] during its use,” Braun observed.

A recent study discerned differences in cognitive and behavioral function based on particular AED effects in children with partial epilepsy who were seizure controlled on AED monotherapy for 1 year.

 Thomas Burns, PsyD, ABPP, CN, of Children’s Healthcare of Atlanta in Georgia, and colleagues identified a cohort of 98 seizure-controlled children on AED monotherapy with either topiramate, divalproex sodium, lamotrigine, levetiracetam, or oxcarbazepine. The groups did not differ on age, region of focal epilepsy, or full-scale IQ.

Measures included the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV), with verbal attention and working memory examined using standard scores from the scale’s Digit Span Forward and Backward tasks. The investigators measured a broad range of executive skills with the Delis-Kaplan Executive Function System, with verbal fluency and motor processing speed assessed with the Verbal Fluency and Trail Making motor speed subtests, respectively.

Measures of maladaptive behaviors such as irritability and hyperactivity included the parent-reported Behavior Assessment System for Children, Second Edition, and the parent-reported Behavior Rating Inventory of Executive Function. Burns and colleagues explained that maladaptive behaviors have been associated with some AED treatments and that executive function deficits in everyday living may contribute to these behaviors and emotional changes.

The investigators reported that children treated with divalproex sodium or topiramate demonstrated weaker working memory and verbal uency compared with those on other AEDs. In addition, parents of children receiving topiramate reported greater deficits in executive function and adaptive skills.

“The pattern of findings suggests that children prescribed divalproex sodium or topiramate generally demonstrated a higher risk of cognitive and behavioral impairments compared [with] the other AEDs,” Burns and colleagues reported.

 of investigations of the AEs of AEDs in cognition and behavior in children with epilepsy, Adriana Ulate- Campos, MD, of the Department of Neurology at National Children’s Hospital, in San Jose&#769;, Costa Rica, and Iva&#769;n Sa&#769;nchez Ferna&#769;ndez, MD, MPH, of the Department of Neurology at Boston Children’s Hospital, Harvard Medical School, in Massachusetts, found that lamotrigine and levetiracetam demonstrated favorable cognitive profiles but that levetiracetam was also associated with prominent behavioral AEs. Oxcarbazepine was not associated with cognitive impairment, and they found some suggestion of improvement. Ethosuximide also appeared to have minimal behavioral and cognitive AEs.

Among older AEDs, Ulate-Campos and Ferna&#769;ndez found that carbamazepine reportedly had a better cognitive and behavioral profile than phenobarbital and phenytoin but with deficits in the memory domain. The reviewers found that divalproex sodium was associated with mild behavioral changes, including irritability, hyperactivity, and aggression, and with mild impaired attention and cognition.

Clobazam was linked to behavioral AEs including irritability and aggression, but the reviewers noted that these AEs tended to improve over time or with dose reduction, and they deemed clobazam to generally have a more acceptable AE profile than other benzodiazepines.

The reviewers also found extensive literature associating topiramate with cognitive and behavioral deterioration but indicated that the association appeared stronger in children with preexisting intellectual disability and that the adverse drug effect could be reduced by dose adjustment. Rufinamide was associated with mood changes and behavioral problems, and they described gabapentin as frequently causing prominent behavioral AEs.

Ulate-Campos and Ferna&#769;ndez offered a summary recommendation: “In children in whom deterioration of cognitive function may be a concern when initiating a new AED, PB [phenobarbital] and TPM [topiramate] are generally to be avoided, and choices like ETX [ethosuximide], OXC [oxcarbazepine], or especially LTG [lamotrigine] and LEV [levetiracetam] might be better. In children in whom behavioral deterioration may be a concern when initiating a new AED, CLB [clobazam], LEV [levetiracetam], RFM [rufinamide], GBP [gabapentin], [and] TPM [topiramate] are generally to be avoided, and LTG [lamotrigine] might be better.”

A long-term follow-up study of patients following temporal lobe epilepsy surgery, conducted by Helmstaedter and colleagues, revealed that cognitive course is usually stable and may even improve if epilepsy symptoms remain controlled and AED regimens can be reduced.

 Although recovery occurred more frequently than continuing decline when surgery successfully controlled seizures, Helmstaedter and colleagues cautioned that “recovery takes time and that age is a limiting factor.”

In a review of studies with the ketogenic diet, which has been applied to control seizures in some patients with drug-refractory epilepsy, Annemiek van Berkel, a PhD candidate in the Department of Functional Genomics at the Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, in The Netherlands, and colleagues found that the intervention can lead to cognitive benefits. Although the putative cognitive benefit could have been linked to seizure reduction, it appeared independent of reduced AED.

Van Berkel and colleagues found that studies using subjective measures had identified improvements in the domains of alertness, attention, and global cognition. When objective measures were applied, benefits on alertness were confimed but without improvement in global cognition.

“There are indications that these improvements are caused by both seizure reduction and directs effects of ketogenic diet on cognition,” van Berkel and colleagues related.

Interventions that have been investigated for possible direct enhancement of cognitive outcomes in epilepsy include pharmacologic agents as well as neuromodulatory interventions. In a recent review, Claire Jacobs, MD, PhD, of the Division of Epilepsy, Department of Neurology, at Massachusetts General Hospital and Harvard Medical School, in Boston, and colleagues considered the potential cognition benefit of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) and of agents in 3 pharmacologic classes: the acetylcholinesterase inhibitors donepezil and galantamine, the N-methyl-D-aspartate noncompetitive antagonist memantine, and the psychostimulant methylphenidate.

They reported that no efficacy on cognitive performance in epilepsy had been found with the acetylcholinesterase inhibitors, which they attributed to the memory dysfunction in epilepsy being mediated by mechanisms other than loss of cholinergic neurons. Although a trial with memantine suggested some benefit, the investigators noted that it might have reflected the effect of study participation and that it would need to be replicated before any conclusions could be drawn.

Methylphenidate appeared to improve mood and processing speed without increasing seizure activity, but Jacobs and colleagues cautioned that the risks of increased seizure frequency with long-term use remain to be determined. They also found that TMS appeared to have some beneficial effect on the Stroop test for selective attention capacity but not on any other cognitive measures. The tDCS was associated with some improvement in declarative memory in a group who took a nap after the procedure but not in those without the nap.

“Research into noninvasive neuromodulation is ongoing,” Jacobs and colleagues indicated, “and it may still have a role in cognitive enhancement through reduction in frequency of epileptiform discharges, sleep-dependent memory consolidation, or other mechanisms.” 

Helmstaedter and Witt agreed with the need for further research into assessing and enhancing cognition in epilepsy that focuses on targets other than the processes underlying seizures. Research directed primarily on the seizures, they indicated, assumes that the patient’s other problems would be resolved if the seizures were controlled.

“However, this is not the case, and just focusing on the seizures may prevent the search for any underlying, active, or past disease process [that], when treated, may improve the patient’s overall condition, including cognitive and behavioral problems,” Helmstaedter and Witt advised.

Loring opined that “there [may be] some sort of common, underlying brain substrate that predisposes a person to express...either some behavioral problems, cognitive problems, or actually the seizures themselves.”

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9. Braun KPJ. Preventing cognitive impairment in children. 

Targeting research in cognitive impairment in epilepsy primarily on seizures themselves suggests that a patient’s comorbid problems will resolve with seizure control, though that is not always the case.

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