Introduction
Amyotrophic lateral sclerosis (ALS) is a heterogeneous inherited or sporadic neurodegenerative disease characterized by the degeneration of both upper (corticospinal) and lower (spinal and bulbar) motor neurons leading to motor and extra-motor symptoms (Hardiman et al., Reference Hardiman, Al-Chalabi and Chio2017). The annual median incidence rate in Europe is 2.08/100,000 inhabitants (Chio et al., Reference Chio, Logroscino and Traynor2013). Symptom onset types are typically anatomically localized and include extremity muscle deficits, “limb onset,” and dysarthria or dysphagia symptoms, “bulbar onset,” with a small fraction presenting with respiratory or generalized weakness onset (Hardiman et al., Reference Hardiman, Al-Chalabi and Chio2017; Pfohl et al., Reference Pfohl, Kim and Coan2018). ALS subsequently spreads into other body regions with progressive muscle weakness and loss of voluntary muscle control of the bulbar, limb, thoracic, and abdominal regions, usually leading to death from respiratory failure, on average 2–5 years after symptom onset, with 5–10% of patients surviving beyond 10 years. During the course of the disease, 20–50% of patients develop cognitive and/or behavioral impairment, and 5–15% develop concomitant dementia, usually frontotemporal dementia (FTD). Other brain functions, and oculomotor and sphincter functions are relatively spared, but may occur in late stages of the disease (Andersen et al., Reference Andersen, Abrahams and Borasio2012; Gordon, Reference Gordon2013).
Multidisciplinary care is considered standard of care and associated with better quality of life (QoL) and possibly increased survival (Rooney et al., Reference Rooney, Byrne and Heverin2015; Hogden et al., Reference Hogden, Foley and Henderson2017). The severity of the illness and uncertainties regarding the time course of disability demands clinical care centered around the patient and carers, with disease-focused expertise offering a multidisciplinary approach that leverages the experience of several healthcare providers in order to control the symptoms and assist the patient to reach their fullest potential and maximum comfort during disease progression (Van den Berg et al., Reference Van den Berg, Kalmijn and Lindeman2005; Paganoni et al., Reference Paganoni, Karam and Joyce2015; Hogden et al., Reference Hogden, Foley and Henderson2017). This often involves a weekly rehabilitation treatment routine in palliative care, performed by one or more allied healthcare professionals, such as physiotherapists, speech therapists, occupational therapists, and specialized nurses. Options such as enteral nutrition, mechanical ventilation, and disease-modifying therapy drugs (such as Riluzole) are also related to prolonged survival in patients with ALS and better QoL (Hardiman et al., Reference Hardiman, Al-Chalabi and Chio2017; Ng et al., Reference Ng, Khan and Young2017; Paipa et al., Reference Paipa, Povedano and Barcelo2019).
On 12 March 2020, the World Health Organization declared “Coronavirus disease 2019” (COVID-19), caused by a virus easily spread from close contact, a global pandemic. Actions taken across the country over COVID-19 mandated social distancing measures, temporary lockdown, and closure of all non-essential rehabilitation facilities to minimize the risk of exposure, and especially for high-risk populations such as patients with ALS.
The present study assesses the effects of the lockdown on functionality rates and QoL in ALS patients, comparing data before and during the lockdown.
Methods
Patients and data collection
Thirty-three patients who were observed and evaluated in the first two weeks of January at a Neuromuscular Disease Portuguese Association were enrolled in this longitudinal study. All belong to a population of 131 patients with ALS who routinely receive or are in contact with this Association for follow-up or onsite rehabilitation, providing a convenience non-probabilistic sample.
All patients have definite ALS disease according to the revised El Escorial criteria. Data collection was conducted between 6 January 2020 and 8 May 2020. Patients were assessed three times: during the first two weeks of January (T0); 8–9 weeks later (T1, before mandatory lockdown); and 16–17 weeks after T0 (T2, during lockdown), by the following questionnaires: ALS Functional Rating Scale-Revised (ALSFRS-R) at T0, T1, and T2; Fatigue Severity Scale (FSS); and ALS-Specific Quality of Life-Short Form (ALSSQOL-SF) at T1 and T2. The first two assessments were done at the ALS association, with the latter being done online.
At T0 and T1, ALSFRS-R was assessed by a healthcare professional onsite, as opposed to T2 assessment which was conducted by phone and video call to guarantee its application, by the same professional. Onsite testing of ALSFRS-R is well correlated with online administration within clinical trials follow-up and for profiling and managing the care of patients with ALS (Kasarskis et al., Reference Kasarskis, Dempsey-Hall and Thompson2005; Maier et al., Reference Maier, Holm and Wicks2012; Proudfoot et al., Reference Proudfoot, Jones and Talbot2016; Bakker et al., Reference Bakker, Schröder and van Es2017). Regarding the FSS and ALSSQOL-SF, all patients received instructions at T1 on how to self-administer the instruments, followed by its self-application through digital support available in the Association (which allowed them to correctly fill out all the questions and used alternative/augmentative communication devices if in need). For these instruments, the same digital support was shared at T2 and self-administrated, but at their homes.
ALSFRS-R slopes between T0–T1 and T1–T2 were calculated by subtracting the ALSFRS-R score and subscores between (T0–T1) and (T1–T2) divided by time (in months) between evaluations.
To further explore the differences between the slope decays, a comparison between the values of progression was conducted. The cutoff for “slow progressors” and “fast progressors” was set at 0.77 (rate of decline of the ALSFRS-R units per month lower or higher than 0.77, respectively). Previous data reported slower progression rates when less than 0.44, moderate decline between 0.44 and 1.04, and fast when higher than 1.04 units/month (Gordon et al., Reference Gordon, Miller and Moore2004), with medium ranges reported from 0.77 to 0.81 (Maier et al., Reference Maier, Holm and Wicks2012). The last one was used as a reference for our cutoff point.
The ALSFRS-R is a 12 questions instrument designed for monitoring the progression of functional disability in patients with ALS. Each question is rated according to progressive functional impairment from 4 (normal function) to 0 (loss of function/total dependence), with 3, 2, 1 representing progressive worsening of the functional capability. Four subscores, with 3 questions each, are evaluated ranging from 0 to 12: bulbar function (BS) assessing speech, salivation, and swallowing; upper limb function (ULS) assessing handwriting, handling utensils (including for patients with gastrostomy), and dressing-hygiene; lower limb function (LLS) assessing turning in bed walking and climbing stairs; and respiratory function (RS) assessing dyspnea, orthopnoea, and respiratory insufficiency. Total ALSFRS-R score ranges from 0 to 48, resulting from the sum of the 4 subgroups, where higher scores indicate higher functionality.
The FSS assesses fatigue (ranging from 9 to 63, higher scores indicate more fatigue) (Lou, Reference Lou2012). ALSSQOL-SF is a 20-item disease-specific global QoL instrument, each rated on a Likert-type scale from 0 to 10. Six domains are calculated based on their mean scores: negative emotions (NE), interaction with people and the environment (IPE), intimacy (IN), religiosity (RE), physical symptoms (PS), and bulbar function (BF), an extra item assesses the overall self-perception (SP) of quality of life. NE, PS, and BF domains require transposing (subtracting the score of response from 10) prior to calculating a score, with lower scores indicating worse specific aspects of QoL (Felgoise et al., Reference Felgoise, Feinberg and Stephens2018; Gayoso et al., Reference Gayoso, Domingues and Franca Junior2020).
Ethical-legal procedures involved a positive opinion from the committee (n°07/2020). Data confidentiality and anonymity was guaranteed, with the respective data coding. All participants agreed to participate in the study on a voluntary basis through electronic validation of the informed consent that appears as a pre-response.
Data analysis
Descriptive statistics were used to describe participants and their weekly rehabilitation routines. To assess the normality and variance, the Kolmogorov–Smirnov test was performed. Decay between T0–T1 and T1–T2 on ALSFRS-R outcomes was assessed using the paired-sample t-test, as normal distribution was confirmed, for global decay and for different onset presentation scrutiny. For further analysis, patients were distributed between three groups, according to their functional capacities and dependency (early, medium, and late-stage patients): group A (ALSFRS-R scores ranging from [0–15], with severe to total functional dependency patients), group B (ALSFRS-R scores ranging from [16–31], moderate to severe functional dependency patients), and group C (ALSFRS-R scores ranging from [32–48], group of mild to moderate functional dependency patients), and the categorized according to the functional decay between the two time points evaluated: being “slow progressors” if the decline was lower than 0.77 units/month, or “fast progressors” if higher (Maier et al., Reference Maier, Holm and Wicks2012), using McNemar for comparing proportions for related samples.
QoL and FSS outcomes, between T1 and T2, were assessed by the Wilcoxon signed-rank test, for non-normal data distributions. Spearman correlation coefficients were used to examine associations among different variables for non-normal data distributions, and values of p < 0.05 were considered as significant. SPSS package software v. 24 was used.
Results
From the 33 patients with ALS who were evaluated at T0, one (with an ALFRS-R score of 4, total dependency) was excluded because he does not attend any type of therapy, and as per his request, only a daily personal routine of hygiene assistance is performed by a team of homecare formal caregivers. A final 32 patients, with a mean age of 56.9 (±14.2) years, were included in this study. Patients characteristics are shown in Table 1.
Characteristics of the ALS population included in the study
a Occupational therapist, specialized nurse.
b Percutaneous endoscopic gastrostomy.
c Noninvasive ventilation.
During T1–T2, two patients had to attend hospital care; the first went for respiratory testing and evaluation, with adjustments on noninvasive ventilation (NIV) parameters. The second was hospitalized for two days for a percutaneous endoscopic gastrostomy (PEG) procedure due to deterioration of bulbar function.
ALSFRS-R mean values showed a progressive decrease throughout each assessment (Figure 1): at T0 = 26.06 (±8.97), T1 = 25.53 (±8.96), and T2 = 22.81(±7.62). Comparing T0–T1 and T1–T2 ALSFRS-R slopes, decay was significantly different (p < 0.001). Significant differences were also found for ALSFRS-R subscores (Table 2): bulbar subscore (p = 0.009), upper limbs subscore (p = 0.005), and lower limbs subscore (p = 0.004), but not for respiratory subscore (p = 0.18). A separate analysis was conducted comparing bulbar (n = 7) and spinal (n = 25) onset patients, for ALSFRS-R progression (T0–T1, p = 0.145; T1–T2, p = 0.371) and its subscores (upper and lower limb, bulbar function, and respiratory function), but no significant differences were found between the decays.
ALSFRS-R values at each period (T0, T1, and T2). Total represents the mean values at each assessment, Group A — severe to total functional dependency patients at T0, Group B — moderate to severe functional dependency patients, and Group C — mild to moderate functional dependency patients.
Mean and standard deviation values for ALSFRS-R and ALSFRS-R subscores slopes during each assessment period (T0–T1, T1–T2)
BS, bulbar subscore; ULS, upper limbs subscore; RS, respiratory subscore.
* Statistically significant.
Ninety percent of the patients presented a slow progression pattern between T0 and T1, with a decline less than 0.77 units/month. This pattern percentage dropped to 45.8% between T1 and T2. For bulbar onset patients (n = 7), 28.6% showed a fast progression pattern between T0 and T1, with an increase to 57.1% between T1 and T2. For spinal onset patients (n = 25), 4% showed a fast progression pattern between T0 and T1, with an increase to 56% between T1 and T2. Paired-sample analysis performed by the McNemar test showed a significant decay for group C (p = 0.008), but not for group A (p = 1.0) and B (p = 0.07). Based on these results, we explored bulbar/spinal onset form differences in-between group B and in-between group C, for the two time points. Group C (n = 9) had only one bulbar subject with a fast progression pattern for both time-frames (T0–T1: 1.0 units/month; T1–T2: 1.5 units/month), with all the spinal patients changing from slower to fast progressions (mean values T0–T1: 0.25 units/month; T1–T2: 2.87 units/month). For group B (n = 19), no differences were found between T0–T1 and T1–T2 for bulbar (p = 0.25; mean values T0–T1: 0.63 units/month; T1–T2: 1.5 units/month) and for spinal patients (p = 0.13; T0–T1: 0.2 units/month; T1–T2: 0.73 units/month). For the bulbar patients group vs. spinal patients group, 8 spinal patients preserved the slow pattern for the different time points assessments, 6 spinal and 2 bulbar patients have accelerated the functional decline from slow to fast, and 1 bulbar patient maintained the faster progression pattern. No cases with a fast to slower pattern shift were observed.
The ALSSQOL-SF means (±SD) scores showed a significant decrease (p < 0.001) between T1 (115.31 ± 17.06) and T2 (104.31 ± 20.65) on overall QoL assessment (Figure 2). Differences were also found in four specific domains (mean ± SD): Negative Emotions [p < 0.023, T1 (7.18 ± 2.78) vs. T2 (6.39 ± 3.25)], Interactions with People and Environment [p < 0.027, T1 (6.02 ± 2.27) vs. T2 (5.60 ± 2.35)], Physical Symptoms [p < 0.001, T1 (6.52 ± 2.08) vs. T2 (5.62 ± 2.55)], and Bulbar Function [p < 0.001, T1 (7.48 ± 2.61) vs. T2 (6.80 ± 3.00)], but not on Religiosity or Intimacy domains (p > 0.05). In addition, Self-Perception of QoL also decreased (p = 0.002) between T1 (5.19 ± 2.43) and T2 (4.25 ± 2.32).
ALSSQOL-SF total scores for T1 and T2 are reported in the boxplots. The lines represent the different domains. NE, negative emotions; BF, bulbar function; PS, physical symptoms; IPE, interactions with people and environment; RE, religiosity; IN, intimacy; and SP, self-perception. *Statistically significant.
An increase in FSS total score was verified, mean values (±SD) were in T1 = 34.06 (±16.84), and at T2 = 40.09 (±17.63), significant differences were found comparing T1 vs. T2 (p < 0.001). Negative correlations were found between FSS and Negative Emotions and Physical Symptoms domains of ALSSQOL-SF, with moderate (r = −0.58, p = 0.001) and strong correlation (r = −0.71, p < 0.001), respectively.
Discussion
Several studies have been conducted on the effectiveness of different rehabilitation strategies in patients with ALS. Due to the restrictive public health measures established as a response to the COVID-19 pandemic, a longitudinal study was conducted to assess the effect of the cessation of these therapies on the progression of ALS in patients who could not perform their weekly rehabilitation therapies onsite.
Previous studies have shown that disease-specific recommendations (general mobility, physical activity, stretching, and range of motion exercises) can benefit patient's functionality (Paganoni et al., Reference Paganoni, Karam and Joyce2015; Bello-Haas, Reference Bello-Haas2018; Merico et al., Reference Merico, Cavinato and Gregorio2018). Growing evidence shows that exercise-based therapies (especially aerobic exercise and resistance exercise of the unaffected muscles) might slow functional decay, although the neuroprotective mechanisms are still not well established, and can also help to adapt and improve functionality and lessen caregiver burden (de Almeida et al., Reference de Almeida, Silvestre and Pinto2012; Lisle and Tennison, Reference Lisle and Tennison2015; Lunetta et al., Reference Lunetta, Lizio and Sansone2016; Braga et al., Reference Braga, Pinto and Pinto2018). Bulbar symptoms, which lead to a progressive loss of speech, phonation, and swallowing abilities (dysphagia and dysarthria), can also benefit from rehabilitation care such as alternative communication strategies, training, and feeding and nutrition guidance (Leveque, Reference Leveque2006; Makkonen et al., Reference Makkonen, Ruottinen and Puhto2018). Overall, there were significant differences in the rates of the decay, with a faster pattern during the T1–T2 (from 0.27 to 1.36 units/month on ALSFRS-R score) period when the rehabilitation routines were interrupted. Notably, the majority of the patients in this study presented a slow progression rate at the beginning, and the acceleration of the functional decline to a fast progression pattern was not related to the onset form, reflecting in both cases decreased functionality. It is essential to highlight that there were only 7 bulbar patients in the study, which represents a statistical limitation, although the ratio presented between bulbar/spinal patients is in agreement with previous literature (Hardiman et al., Reference Hardiman, Al-Chalabi and Chio2017).
The deterioration pattern in ALS is non-linear with early, medium, and late stages of the illness declining at different rates, and the ALSFRS-R slope and its domains follow this curvilinear progression (Gordon et al., Reference Gordon, Cheng and Salachas2010; Rooney et al., Reference Rooney, Burke and Vajda2017; Ackrivo et al., Reference Ackrivo, Hansen-Flaschen and Jones2019). This finding might be particularly worth noting considering the mean symptoms onset of the participants and the percentage of “slow progressors” at the beginning that presented a faster decline progression after the interruption of the rehabilitation treatment during lockdown. In this study, we found that the most functional patients (group C) at the beginning of the evaluation were the most prone to have an accelerated functional decline with the interruption, and therefore to experience the largest decline in function and independency, followed by the moderate dependent patients (group B), which also showed this tendency (despite not reaching the statistical significance). However, it was not verified among the severe patients (group A). The slope differences between the groups can be interpreted as separate groups of patients presenting at different stages of the disease rather than representing the progression from baseline. This reflects a change in the ALSFRS-R curve with a faster decline in the mild dependency group (scores from 32 to 48) and a preserved linearity tendency in the decline rate among severe patients (latter part of the curve). The results of this study reinforce the importance of rehabilitation in general, and physical therapy and speech therapy in particular, especially in mild and moderate dependent patients, where it can significantly contribute to slow the progression of the disease, minimizing the slope decay of ALSFRS-R. The interruption of rehabilitation treatment routines, forced by the lockdown, may have accelerated the functional decline in ALS patients’ motor skills; this might be a consequence of lack of training during this lockdown. We hypothesize that therapy routines might minimize temporary shifts from slow to fast progressors, specially in patterns, considering the increase in functional decay (bulbar function, upper and lower limbs, and fatigue) since the faster decline in certain motor functions may stabilize after resumption of rehabilitation routines. This may also be implicated in patients who might consider to dropout rehabilitation routines, during their disease journey. In that case, they should be, in some way be encouraged to keep their supervised rehabilitation routines (either through the hospital, clinics, associations, home programs, and/ or caregivers training).
Reflecting on the moderate to severe patients, it is important to consider this small subgroup sample, and also to critically adapt the multidisciplinary rehabilitation goals to be more centered in preserving wellbeing, increasing participation, and minimizing loss of function derived complications such as deformities, loss of range of motion, respiratory and nutritional management, alternative communication strategies and controls, and symptoms management (Paganoni et al., Reference Paganoni, Karam and Joyce2015; Bello-Haas, Reference Bello-Haas2018). These should be evaluated on a case-by-case basis, as many of parameters that ALSFRS-R scale evaluates do not present good sensitivity because they do not directly reflect the scale evaluation but can significantly impact the QoL of the patient and their carers.
Furthermore, the decay between T0–T1 and T1–T2 was significant in the bulbar, upper limbs, and lower limbs subdomains but not in the respiratory subdomain. This might be associated with the continuous respiratory management, which is highly supported when needed with mechanical ventilation, educational programs (on adherence and effective use), including home telemonitoring follow-up and assistance (Pinto et al., Reference Pinto, Almeida and Pinto2010; O'Brien et al., Reference O'Brien, Stavroulakis and Baxter2019). The fact that patients are confined at their homes may also generate fewer respiratory symptoms (like dyspnea) due to decreased mobility and metabolic demand (Pinto and de Carvalho, Reference Pinto and de Carvalho2015). An overlap between the natural weakness caused by ALS and the deconditioning process caused by the lack of use and stimulation may have occurred in T1–T2 period, which favored the decay on bulbar and limb functionality as well an increase in symptoms of fatigue, with a higher FSS score in T2.
QoL decreased over time. Four specific domains (Negative Emotions, Physical Symptoms, Bulbar Function, and Interactions with People and Environment) contributed the most for this decay, followed by a lower Self-perception of QoL, contradicting previous studies that have reported independence of patient QoL vs. symptom progression related to the adjustment of expectations over time (Robbins et al., Reference Robbins, Simmons and Bremer2001; Chiò et al., Reference Chiò, Gauthier and Montuschi2004; Simmons, Reference Simmons2015). These results may be related to the acceleration of disease progression (between T0–T1 and T1–T2), with lower functionality in physical and bulbar function in particular impairing participation and performance in daily living activities and routines. In fact, patients with ALS have high equipment needs that can assist them to optimize their QoL (Londral et al., Reference Londral, Pinto and Pinto2015; Connors et al., Reference Connors, Mahony and Morgan2019), and the results support that patients with ALS benefit from early strategies to support and prepare functional decay, such as adaptive equipment designed to assist mobility, hygiene, comfort, and augmentative/alternative communication devices. Additional strategies include the education of patients and carers on symptoms management and energy-conservation, anticipating the next possible stage of the disease, whether it arrives or not. The Interactions in People and Environment decay was expected as it represents the social and environmental relationships that can be affected by the lockdown imposed to combat the pandemic. We hypothesized that a combination between the perception of loss, loss of functionality, and the lockdown itself might have contributed together to the decrease in QoL, especially considering the reduction in direct multidisciplinary support that patients and carers have experienced at this time.
Furthermore, the negative correlation between fatigue and the Physical Symptoms and Negative Emotions domains of ALSSQOL-SF concurs with other authors that highlight the experience of fatigue with worse motor function and NE (Vucic et al., Reference Vucic, Krishnan and Kiernan2007; Lou et al., Reference Lou, Weiss and Carter2010; Gibbons et al., Reference Gibbons, Thornton and Young2013), reinforcing the importance of continuous multidisciplinary-care assessment and treatment of fatigue in ALS patients.
Symptom management is a major component of ALS care. Identifying and addressing problematic symptoms can minimize their effects on a person's function, health, and quality of life. This management can be enhanced by healthcare professionals using telehealth technologies in patient care and training and support of carers (Andrews et al., Reference Andrews, Berry and Baloh2020; Helleman et al., Reference Helleman, Kruitwagen and van den Berg2020; Stegmann et al., Reference Stegmann, Hahn and Liss2020) throughout disease progression. These telehealth technologies can include multidisciplinary rehabilitation programs, nutrition, ventilation and pharmacology, brain–computer interfaces and eye-tracking, augmentative communication and environment control, virtual-reality, and mobile/computer applications that can connect patients to their multidisciplinary teams daily, providing alternative dynamic connecting tools. This pandemic presents an unexpected opportunity to recognize gaps and challenges in rehabilitation and speed up the development and implementation of patient-oriented technologies, with high value for both clinical practice and the improvement in quality of daily living among patients with ALS and their caregivers.
Some study limitations should be highlighted, including the sample size and subgroup analysis (with small bulbar representation n < 10). Additionally, although the relationship between functional loss and quality of life is unquestionable, the negative effects may be enhanced by social isolation itself and increased the perceived stress levels imposed by the lockdown, so they should be analyzed and interpreted carefully. It would be interesting to follow-up these patients after the lockdown and assess the impact of returning to rehabilitation routines on QoL and functionality slopes and progression patterns.
In conclusion, rehabilitation treatment routines in palliative care, such as physiotherapy and speech therapy, appear to mitigate the ALSFRS-R slope. A sudden dropout or prolonged interruption of these interdisciplinary rehabilitation routines may have accelerated the functional decline in certain ALS patients’ motor skills (as measured by ALSFRS-R). And might have short-term effects (less than 2 months) such as increased fatigue, negative impact on QoL, poorer bulbar and limb function, with an increased decay in the ALSFRS-R subscores reflecting bulbar function, upper limb function , and lower limb funcion, but not in the respiratory subscore.
Funding
No sources of funding.
Conflict of interest
The author reports no conflicts of interest.
