Abby Reinhard, Assistant Editor for NeurologyLive, has covered medical news for MJH Life Sciences, NeurologyLive’s parent company, since 2021. Email her at 

Abby Reinhard

International Parkinson and Movement Disorders Society (MDS) Virtual Congress 2021

, September 17-22, suggest that subgroups of patients with Parkinson disease (PD) experienced worsening mental health and a poorer quality of life (QOL) due to a range of stressors associated with the COVID-19 pandemic. 

Investigators led by Lisanne Dommershuijsen, MSc, PhD candidate, department of epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands, further concluded that during the ongoing pandemic, interventions tailored to address COVID-19 stressors may improve mental health in patients with PD. “People with Parkinson disease might be especially vulnerable to distress, for instance, because reduced levels of physical activity have caused worsening of symptoms, or because people with Parkinson disease often have difficulties with flexible adaptations to rapid and drastic changes in daily routines, such as those introduced by the COVID-19 pandemic,” Dommershuijsen said in her presentation.

The cross-sectional study utilized baseline data from the PRIME-NL study, which included total of 883 participants with PD. Patients had an average age of 70.2 years (standard deviation, 7.9), 38.1% of whom were women (n = 317). Investigators included 8 COVID-19 stressors in analyses. Care stressors included problems accessing care, problems accessing medication, and problems accessing nursing. Social stressors included loss of social contacts, cancelled social events, and tension or conflict at home. Other stressors included inability to perform physical activity/relax and symptoms of COVID-19. Scores which were then integrated into stressors sum score. 

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The findings found that a higher stressor sum score was associated with worse depression (Beck Depression Inventory [BDI] ß, 0.04 [95% CI, 0.02-0.05]), greater anxiety (Spielberger State-Trait Anxiety Inventory [STAI] ß, 0.04 [95% CI, 0.02-0.05), as well as poorer QOL (Parkinson’s Disease Quality of Life Questionnaire [PDQ-39] ß, 0.03 [95% CI, 0.02-0.04]). 

When evaluating the associations between BDI and STAI scores and the 8 stressors, all were associated with depressive and anxiety symptoms, the largest effect of which was associated with tension or conflict at home. Subgroup effects also showed that women, patients who were highly educated, and patients with advanced PD had more pronounced association between mental health and COVID-19 stressors. Lower effects, investigators noted, were found with subgroups that had confrontive coping and planful problem solving strategies. 

“Several previous studies indeed concluded that the COVID-19 pandemic worsened depressive and anxiety symptoms and reduced quality of life of people with Parkinson disease. However, there is a lack of data on subgroup differences regarding the effect of the COVID-19 pandemic on mental health and quality of life, and this lack of insight has so far precluded the deployment of targeted interventions,” Dommershuijsen said.

When performing a hypothetic intervention that removed the COVID-19 stressors, investigators saw decreases in BDI from 11.2 (95% CI, 10.7-11.6) to 9.0 (95% CI, 8.2-9.8), STAI from 74.3 (95% CI, 73.1-75.6) to 68.0 (95% CI, 65.4-70.5), and PDQ-39 from 25.1 (95% CI, 24.2-26.0) to 20.9 (95% CI, 19.3-22.6).

A similar intervention also performed for the patient group with advanced PD, defined as an MDS-Unified Parkinson’s Disease Rating Scale II score above the median, where investigators model a 50% reduction in the sum score of all 8 COVID-19 stressors. Discussing the hypothetical reduction in her presentation, Dommershuijsen noted, “Intervening on COVID-19 stressors in people with advanced Parkinson disease could result in clinically important improvements of mental health and quality of life.” 

Dommershuijsen L, Heide A, Berg E, et al. Effect of COVID-19 stressors on mental health and quality of life in Parkinson’s disease. Presented at: MDS Congress 2021; September 17-22; Virtual. Poster 1045. 

Articles

Data from the PRIME-NL study showed stressors resulting from the pandemic impacted depression, anxiety, and quality of life.  

COVID-19 Stressors Associated With Poorer Mental Health in Parkinson Disease

A recent study concluded that computerized, home-based working memory (WM) programs may be an effective treatment method for children with neurofibromatosis type 1 (NF1) and other cognitive impairments. 

A total of 31 children were screened ahead of the pilot, open-label, prospective, pre-post-test study, and all participants were between the ages of 8 and 15 years, with a median age of 10.97 years (standard deviation [SD], 2.51). CogmedRM, the training program utilized, was completed by 27 eligible children (87%) over the course of 9 weeks. 

When evaluating for safety and feasibility for children with NF1, it was found that patients who completed cognitive training and follow-up testing (n = 20) saw significant improvements in short-term memory, attention, and executive functioning. Improvements were seen on both the Weschler Intelligence Scale for Children (WISC-IV) Digit Span (

 <.01) from baseline to post-intervention. When evaluating Reliable Change Index metrics, investigators found that no participants declined in Digit Span Forwards scores and 25.9% of participants showed clinically significant improvements. 

“Given the findings of the current pilot study, at-home cognitive training programs seems to be beneficial for children with NF1; however, continued empirical support for the intervention is still needed,” corresponding author Kristina K. Hardy, PhD, pediatric psychiatrist, division of neuropsychology, Children’s National Hospital; and associate professor, departments of psychiatry and behavioral sciences and pediatrics, the George Washington University School of Medicine, Washington, DC, et al wrote. “Future research should continue to explore the efficacy, generalizability, and maintenance of such programs.”

Improvements were also seen on in Cogstate tasks, specifically on identification speed (

 <.05). Participants further demonstrated improvements in one card learning speed (

On average, participants completed 19.65 (SD, 7.18) CogmedRM sessions, with 18 participants (69%) completing 20 out of 25 sessions (80%), deeming them adherent to training guidelines. Investigators noted that 11 participants (42%) completed all 25 training sessions and that high adherence rates were similar to that of other studies utilizing computerized cognitive intervention. 

The CogmedRM program utilizes game-like tasks, with participants expected to take about 30 to 45 minutes to complete 8 exercises during a single session. The computer-based program also integrated phone-based coaching for participants and families with trained study staff to provide support and foster both motivation and efficiency.

Over the course of the study, no serious adverse events were reported. Parents and participants also completed a feasibility and acceptability interview following the intervention, with 90% of respondents rating their child’s experience as “somewhat” or “very’ satisfactory. 

The study was limited due to its small sample size and potential limited generalizability due to children being from one specialty clinic. Investigators note future studies should be larger, further exploring the interaction between pharmacological interventions and cognitive interventions, as many children with NF1 often take stimulant medications.

“If cognitive training programs, such as CogmedRM, are found to be efficacious, either on their own or—especially—in conjunction with other medications, this intervention could and should be rapidly translated into clinical practice,” Hardy et al wrote. “In addition, the availability of home-based interventions has recently become more salient in the context of the COVID-19 pandemic; thus, interventions like CogmedRM that can be accessed remotely may be increasingly accessible and acceptable to patients and families. Such an efficacious intervention for children and adolescents at high risk for neurocognitive deficits could be included with standard of care practices for at-risk individuals, with the hope of remediating deficits and improving quality of life and everyday functioning.”

Hardy KK, Berger C, Griffin D, et al. Computerized working memory training for children with neurofibromatosis type 1 (NF1): A pilot study. 

. Published online September 2, 2021. doi:10.1177/08830738211038083

Participants in the pilot study saw improvements in short-term memory, attention, and executive functioning. 

Home-Based, Computerized Working Memory Programs Viable for Neurofibromatosis Type 1

Biogen announced plans to initiate a phase 3b trial, ASCEND, to study the safety and efficacy of higher doses of nusinersen (Spinraza; Biogen) in patients with spinal muscular atrophy (SMA) who have been treated previously with risdiplam (Evrysdi; PTC Therapeutics). 

The ASCEND trial is anticipated to begin enrolling its first patients in 2021, with the study spanning approximately 2.5 years and including 135 patients with later-onset, nonambulatory SMA between the ages of 5 and 39 years. Participants will be given 2 loading, 50-mg doses of nusinersen 2 weeks apart, and a 28-mg maintenance dose at 4-month intervals for the duration of the study. 

“We believe that lower drug exposure may be contributing to less-than-optimal treatment outcomes for some patients treated with Evrysdi,” Maha Radhakrishnan, MD, chief medical officer, Biogen, said in a statement.

“The ASCEND study seeks to understand if nusinersen may address that unmet medical need and will help inform the future of SMA treatment, with the hope of improving patients’ outcomes for the long term.”

The protocol has been submitted to the FDA, with inclusion criteria including being previously treated with the maximum 5-mg dose of risdiplam and falling within a specific Revised Upper Limb Module (RULM) measurement range, which will then be used to assess efficacy. Safety, Hammersmith Functional Motor Scale Expanded (HFMSE), and caregiver burden are additional clinical outcomes to be evaluated. 

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The global clinical study will include children, teenagers, and adults with SMA, as data suggest those treated with risdiplam may have remaining unmet needs. Data have suggested exposure to risdiplam decreases as patients grow and age, and when comparing adult patients to children, adults saw a 40% reduction in drug concertation. Once patients’ weight reaches 20 kg, dosage of the treatment is capped at 5 mg. 

“There have been significant advances in SMA treatment; however, there is still no cure and unmet medical needs remain,” Tim Hagenacker, MD, head, Neuromuscular Diseases Unit, Essen University, in Germany; and member, ASCEND study steering committee, said in a statement.

“As part of my clinical practice, we’ve observed an opportunity to potentially further improve patient outcomes. With a higher dose of nusinersen, we are positioned to explore what may be possible.”

The current approved dose of nusinersen is 12 mg, administered intrathecally, with patients seeing similar motor neuron exposure to the treatment as they age. Across patients of different ages and with varying SMA types, nusinersen has further shown safety and efficacy according to long-term data from patients treated with the drug for over 7 years. 

The long-term impact of nusinersen is currently being evaluated in 2 open-label extension studies, with recently reported findings from the phase 2, open-label, dose-escalation study (NCT01839656) finding that the treatment improved survival and attainment of motor milestones over 3 years in patients with infantile-onset SMA.

Originally approved in December 2016, nusinersen became the first FDA-approved therapy to treat SMA types 1, 2, and 3. Since the approval, several trials have been initiated to 

Datasets from those who transitioned from the CHERISH study (NCT02292537), a randomized control study of nusinersen, to the open-label SHINE extension study (NCT02594124), presented at the American Academy of Neurology 2020 Annual Meeting, also showed that the treatment has sustained efficacy and long-term safety in patients with infantile-onset SMA, as well as later-onset SMA. In that analysis, the HFMSE score at the modified maintenance dosing regimen Day 1 for patients with later-onset SMA was 26 (standard deviation, 11.01) for those who received nusinersen in CHERISH/SHINE and 21.2 (SD, 7.75) for those randomized to sham-procedure in CHERISH and then nusinersen in SHINE.

1. Biogen plans to initiate phase 3b study evaluating potential benefit of a higher dose of nusinersen in patients previously treated with Evrysdi (risdiplam). News release. Biogen. September 15, 2021. Accessed September 15, 2021. https://investors.biogen.com/news-releases/news-release-details/biogen-plans-initiate-phase-3b-study-evaluating-potential
2. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study.

. 2021;5(7):491-500. doi:10.1016/S2352-4642(21)00100-0
3. Chirboga CA, Darras BT, Farrara MA, et al. Longer-term treatment with nusinersen: results in later-onset spinal muscular atrophy from the SHINE study. 

Initiated by Biogen, the study will evaluate the effectiveness of the treatment in patients previously treated with risdiplam (Evrysdi; PTC Therapeutics). 

Phase 3b Study of Higher-Dose Nusinersen in Patients With SMA Announced

A recently published study investigated the effect of the COVID-19 pandemic on sleep patterns in children and adolescents, with sleep duration recommendations not being met by almost half of the children studied, when compared to sleep habits prior to the pandemic. 

The primary end point was the prevalence of sleep disturbances resulting from the pandemic and quarantine measures, with secondary end points consisting of effects on sleep quality, duration, and the severity of insomnia in both healthy children and those with neurobehavioral disorders.

Investigators, led by Mohit Sharma, MBBS, MD, department of psychiatry, Institute of Human Behaviour and Allied Sciences, in Delhi, India; and Shivali Aggarwal, MD, department of psychiatry, All Indian Institute of Medical Sciences, in New Delhi, India, deemed resultant sleep problems in children “alarming,” with the pooled prevalence of children experiencing sleep disturbances at 54% (95% CI, 50-57; 

 <.01) and the pooled prevalence not getting the recommended amount of sleep at 49% (95% CI, 39-58, 

Preschool children, who were evaluated in 5 studies, were found to have a lower prevalence of sleep disturbances during the pandemic, which had a risk ratio of 0.87 (95% CI, 0.58-1.30; 

 <.01) and was not statistically significant. 

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“Preschool children had a trend towards relatively fewer sleep disturbances in comparison with pre-pandemic times. Besides, the proportion of children with worsening sleep quality during the pandemic was nearly 3 times the proportion of those with improvement,” Sharma, Aggarwal, et al wrote.1 “Sleep duration recommendations were not met in nearly half of healthy children during the pandemic. However, these findings need to be seen in light of limited literature on the topic, few included studies done in heterogenous populations, and dubious quality of inferences drawn from these studies which were predominantly online surveys.”

Investigators included a total of 16 studies, following a review of 371 articles. Healthy children were evaluated in 14 studies, while those with behavioral disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) were evaluated in 2 studies. Children with both ASD and ADHD have a higher burden of sleep problems, when compared to healthy children, further reporting an increase with the onset of the pandemic. 

Limited data and studies on the pandemic were noted as an area of concern for investigators, as well as the fact that surveys were mostly conducted online. Further research will be necessitated to ascertain preventative recommendations for sleep management during similar times of crisis.

“The index study is the first systematic review capturing sleep in children during the COVID-19 pandemic,” Sharma, Aggarwal, et al wrote.1 “However, very few studies were eligible for inclusion and most of the included studies were not high quality and assessed sleep based on parental reporting who were themselves under psychological stress due to the pandemic.”

These data coincide with a recent initiative from the American Academy of Sleep Medicine (AASM), which announced the second annual 

, held from September 12-18, 2021. Transitioning from virtual learning environments associated with the COVID-19 pandemic to more “normal,” in-person settings has placed even more emphasis on the importance of sleep health in school-aged children. 

In conversation with NeurologyLive about Student Sleep Health Week, Raman Malhotra, MD, president, AASM, and associate professor of neurology, Washington University in St. Louis, explained that in this shift to a virtual world, “one thing that we did notice is that the consistent routine that in-person learning provided—needing to be at school at a certain time, getting home, and being on schedule was lost. A lot of the learning may have been done asynchronously, meaning they can learn whenever they want, they can wake up when they want, [which] in some respects, sounded appealing because they would be able to get enough sleep. But, in reality, it really altered children's schedules. So, children and adults both need a set pattern—a set bedtime and wake time, and what we noticed during the pandemic is that consistency was lost.”

The AASM recommends 9 to 12 hours of sleep for children aged 6 to 12 years and 8 to 10 hours for children aged 13 to 18 years, with a lack of sleep associated with decreased academic and extracurricular performance, mood, motivation, and a slowing of cognitive processes.

1. Sharma M, Aggarwal S, Madaan P, Saini L, Bhutani M. Impact of COVID-19 pandemic on sleep in children and adolescents: a systematic review and meta-analysis. 

. 2021;84:259-267. doi:10.1016/j.sleep.2021.06.002
2. American Academy of Sleep Medicine organizes second annual Student Sleep Health Week. News release. American Academy of Sleep Medicine. September 7, 2021. Accessed September 14, 2021. https://aasm.org/american-academy-of-sleep-medicine-organizes-second-annual-student-sleep-health-week/

Investigators found that preschool children had fewer sleep disturbances than older children during home confinement.

Abby Reinhard

Articles

COVID-19 Stressors Associated With Poorer Mental Health in Parkinson Disease

Home-Based, Computerized Working Memory Programs Viable for Neurofibromatosis Type 1

Phase 3b Study of Higher-Dose Nusinersen in Patients With SMA Announced

COVID-19 Pandemic Associated With Sleep Disturbances in Children, Adolescents