Progressive Worsening of Gait and Motor Abnormalities in Older Adults With Dravet Syndrome

Methods

Results

Twenty-nine patients were eligible for the study. Given the COVID-19 pandemic, several patients' caregivers declined to come to the hospital for this study. As a result, 18 patients were evaluated with mUPDRS (6 of them were part of the prospective study and were evaluated twice, 5 years apart [results of the first evaluation were published previously¹⁴]); 17 patients completed the IGA (Table 1). The age range was 18–51 years and mean age was 31.81 ± 9.6 years. A breakdown of the pathogenic variants is reported in Table 2. This group of adults with DS displayed a tendency to have a decrease in seizure frequency, as this group averages 2.4 convulsions per week. They also had mainly nocturnal convulsions in adulthood. Six out of 21 patients in this study were seizure-free for at least a year before the assessments were performed. Cognition was not formally evaluated, as all patients experienced moderate or severe intellectual disability. Cranial nerves were evaluated to the extent the participants collaborated for evaluation and we noted no abnormalities.

Discussion

Although DS is well studied in the pediatric population, there is little information regarding DS in adulthood.^8-12 As such, we do not know how patients with DS age. In this study, it was observed that gait measures and parkinsonian symptoms were abnormal across all ages, but clearly worse in older patients, suggesting a progressive gait disorder. This progression was confirmed in a subgroup of patients studied prospectively. In the 5-year period that patients were followed, we found evidence of a decline in gait function and increase in parkinsonian manifestations, including 2 patients who were ambulatory in the first and were no longer able to walk in this second evaluation.

In the cross-sectional IGA, all gait measures evaluated were abnormal and worse in the older patients, in keeping with a progressive course. In addition, all gait measures were worse in the DS group compared with an older healthy control group (mean age of control group was double that of patients with DS). The IGA registered a combination of increase in gait velocity, decrease in single/double time ratio, increased number of steps, and increase in eGVI. These abnormal gait findings are in keeping with gait abnormalities of patients with Parkinson disease (PD).²⁰ The cadence and stride width in adults with DS was consistent across all ages, again aligning with the literature in PD, in which stride width and cadence were reported to have no apparent relationship with age in PD.^21-23 In addition, in both DS and PD there is a progressive worsening of bradykinetic gait features (step length and velocity).

Abnormal gait has long been reported in children and adolescents with DS, although parkinsonian features per se have not been reported in pediatric cohorts. Two studies in children with DS and young adults demonstrated that patients spend a significant increased amount of time in support stance, compared with typically developing peers.^24,25 Similarly to younger patients with DS, our older adult DS population also spent a significantly increased amount of time in stance, and this time was longer with older age, thus representing a compensatory mechanism for the antero-posterior instability typical of parkinsonian gait disorders.²⁶ Another common gait pattern observed in children and young adolescents with DS is a crouch gait with increased flexion of the knees, ankles, and hips.^17,27 In addition to the parkinsonian gait, a few of our adult patients also had crouched gait. Interestingly, a gait characterized by knee flexion has been described in patients with late stage PD.²⁸

In the current study, a subgroup of adult patients with DS was evaluated prospectively, 5 years apart. At the first evaluation, using an mUPDRS, it was observed that adults with DS had parkinsonian gait (slow pace, small steps, en bloc turning, little to no arm swing, postural instability) and other motor parkinsonian features (bradykinesia, rigidity, antecollis, and camptocormia).^14,19 That group of patients was reevaluated with mUPDRS in 2019. The longitudinal data show that both gait and the other motor features have deteriorated over this 5-year period in all but 1 patient (patient 3). Two patients (patients 10 and 12) who had mUPDRS evaluation in 2014 are no longer walking in 2021. Their caregivers reported that in this period of 5 years, it became increasingly difficult to have them leave their wheelchair and even with support, their gait was too “unsafe.” The patients also started to refuse any attempts to walk. Patients 10 and 12 were started on levodopa after their first mUPDRS evaluation at the ages of 42 and 46 years, respectively. However, this medication was stopped after 2 years in both cases, as the initial benefits observed after the addition of levodopa wore off. Patient 3 was also started on levodopa after the first mUPDRS evaluation, but she was only 24 years old at that time. Patient 3 continues to derive benefits from levodopa and she is the only one who improved in the second mUPDRS evaluation. The minimal clinically important difference for motor has been reported on average to be between 2.3 and 3.3 points for the UPDRS scale.^29,30 However, these studies were based on all scale items. Our study saw an average decrease of 2.2 points in 5 of 6 individuals.^29,30

Our study has a few limitations. In particular, we had a limited sample size and were unable to enroll over a third of eligible patients. The COVID-19 pandemic was the primary cause precluding us from recruiting more patients to the hospital for their IGA and mUPDRS evaluations. This also limited the sample followed prospectively (from 11 patients in 2014 to 6 patients in 2019); however, even this limited sample provides information demonstrating the progressive nature of gait and motor deterioration in adults with DS. We also note that muscle weakness may be a potential confounding limitation in in the assessment of gait. Many patients with DS use wheelchairs to travel large distances. This may lead to a disuse of lower limbs musculature and in turn influence gait assessments.³¹

Factors such as contraindicated medications and delayed diagnosis can potentially affect adult outcomes. It was shown that long periods of contraindicated medication intake during the first 5 years of life are correlated with worse long-term cognitive outcomes of patients with DS.³² It is unknown whether these contraindicated medications play a role in abnormal gait and motor manifestations and their progression. Almost all of the participants in this study (18/21 [85.7%]) were diagnosed in adulthood. It is likely that these patients have been misdiagnosed several times during their life. As a result, they could have been exposed to a variety of contraindicated medications for long periods of time.

This is the largest gait and motor analysis in an older adult DS population (mean age 31 years) and the first prospective study, to our knowledge, of a subgroup of these older patients. Taken altogether, the results show a progressive deterioration of gait and motor function as patients with DS age. It is unclear why such deterioration happens with age and further research should help explain not only why this happens but also if it is possible to slow or avoid this progression.

Study Funding

This study received funding from Dravet Syndrome Foundation (grant 2019001) and Dravet Canada.

Disclosure

D.M. Andrade serves on the medical advisory board of Dravet Syndrome Foundation and Stoke Therapeutics, is on the speakers bureau for Eisai and Biocodex, and has participated in investigator-initiated research for Biocodex and Dravet Syndrome Foundation. A.T. Berg is on the speakers bureau for Biomarin and the advisory board for Zogenix and Neurocrin. The remaining authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.