A Common Occurrence

Walking impairment has long been considered a primary feature of MS, even in early historical accounts of the disease. An estimated 75% of persons with MS report mobility problems based on population-based studies. Recent data from an online survey of 1011 people with MS indicated that 41% of the sample reported having difficulty walking and 13% reported an inability to walk. Another recent study of 436 patients with MS in Europe indicated that nearly 1 in 2 patients reported experiencing mobility impairments within the first month of diagnosis, and more than 90% of patients reported experiencing mobility impairments within 10 years of diagnosis. Overall, these data suggest that walking impairment is (1) common in MS, even early in the disease, and (2) a long-term consequence that likely affects most persons living with this neurologic disease.

Primarily Caused by CNS Pathology

The pathology of MS is important in understanding the occurrence of walking impairment in this population. This discussion of pathology and its association with walking is based on an existing conceptual framework derived from the World Health Organization’s International Classification of Function. MS is a disease that involves demyelination and axonal transection in the white and gray matter, which results in dysfunction and atrophy within various regions of the CNS, including the pyramidal, cerebellar, and spinal/dorsal column pathways. This CNS pathology manifests in impairments such as muscle weakness and spasticity, ataxia, and sensory disturbances. These impairments and those of vision and cognition, along with secondary factors (eg, weight gain, fatigue, or deconditioning), can result in altered gait kinematics and spatial and temporal parameters of gait (base of support, double support, cadence, step length, and velocity), even early in the disease process. The changes in gait kinematics and spatiotemporal parameters alter the normally smooth and rhythmic sinusoidal vertical displacement of the body’s center of mass during ambulation (ie, inverted pendulum of gait). This disruption ultimately manifests as altered ambulation, quantified via performance tests, physiologic parameters, self-report questionnaires, and free-living assessments.

Important to Persons with MS

Walking is a fundamental part of life and daily existence, regardless of the presence or absence of disease and chronic conditions. Among persons with MS, ambulation represents one of the most valued functions and has direct relevance to physical function, independence, quality of life, and activities of daily living. For example, one study of 100 patients with MS reported that walking was rated as the most important domain of function compared with 12 other functions, such as vision, thinking and memory, and mood, in both early (<5 years duration) and late (>15 years duration) MS. Of further importance, one study reported that persons with MS described feeling limited, frustrated, powerless, and challenged by mobility impairment. Another study indicated that 70% of persons with MS who had difficulty walking rated it as the most challenging aspect of MS. Walking difficulty has been associated with adverse outcomes regarding employment, physical function, quality of life, and activities and participation. For example, one study of 196 persons with MS reported that being unemployed was independently associated with reduced community ambulation based on the metric of steps per day recorded in real life.

Clinically Important

Beyond concerns of personal relevance and importance, ambulatory impairment represents a defining feature of disease progression in MS and is a common component of clinical outcome measures such as the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC). These measures are often included in natural history studies and/or clinical trials in MS. The EDSS is a 10-point scale of disease severity ranging between 0 (no disability) and 10 (death from MS). Scores from 0 through 3.5 reflect changes in 1 or more of 8 functional systems, whereas scores 4.0 and greater are based primarily on changes in ambulation (walking distance up to 500 m and the need for assistive devices to walk). Based on the EDSS, natural history studies have examined the rate and predictors of disability progression in persons with MS based on benchmark scores. For example, the median times from onset of MS until the assignment of benchmark EDSS scores of 4.0 (ie, limited walking ability but able to walk more than 500 m without aid or rest) and 6.0 (ie, ability to walk with unilateral support about 100 m without rest) are approximately 10 and 20 years, respectively. The MSFC is a new, composite clinical measure based on measurement of ambulation (timed 25-ft walk [T25FW]), upper extremity function (9-hole peg test), and cognition (paced auditory serial addition test), which was developed based on the need for an outcome measure that better reflects progression of disease and clinical change in MS. The T25FW, in particular, has become a prominent stand-alone component for capturing clinically meaningful change in ambulation and disease progression among persons with MS. These assessments, and others, provide important information to clinicians for monitoring the rate of progression of MS over time and the results of treatments.

Performance and Gait Characteristics

The extent and type of walking impairment in MS can be described by considering common outcomes of this functional behavior. For example, 2 of the most common walking performance assessments include the T25FW and 6-minute walk (6MW) as measures of short- and long-distance (or endurance) ambulatory function, respectively. The T25FW involves having a patient walk 25 ft as fast and safe as possible, and the time is recorded in seconds by averaging 2 consecutive trials. The T25FW was recently recognized as the best-characterized objective measure of walking disability in persons with MS across a wide range of walking impairments. Data indicate that performance on the T25FW is compromised in persons with MS compared with controls who do not have MS or any other neurologic disease. For example, one study reported that T25FW performance was significantly worse in 141 patients with MS (median, 4.4 seconds) than in 104 healthy controls (median, 3.7 seconds), and the differences in T25FW performance existed across 3 levels of disability (EDSS, 0–2.0; median, 3.9 seconds; EDSS, 2.5–3.5; median, 4.5 seconds; and EDSS, 4.0–5.5, median, 5.8 seconds). Further evidence indicates that a 20% or greater change in T25FW performance is clinically meaningful. Overall, this indicates that compromised walking speed over a short distance is one facet of impaired ambulation in MS, and that a 20% change represents a significant worsening or improvement in one’s capacity for ambulation.

The 6MW involves having a person walk as fast and as far as possible during a 6-minute period and the distance is recorded in feet or meters. Consistent data indicate that performance on the 6MW is compromised in persons with MS compared with controls who do not have MS or any other neurologic disease. For example, the first application of the 6MW in this population indicated that persons with MS (n = 40) showed a large reduction in 6MW distance (eg, Cohen’s effect size d of ∼1.4 for first 6MW) compared with matched controls (n = 20), and the 6MW distance further differed between MS subjects who had mild (EDSS, 0–2.5), moderate (EDSS, 3.0–4.0), and severe (EDSS, 4.5–6.5) disability. The effect of disability on 6MW performance was replicated in a larger sample of 95 persons with clinically definite MS. Another study reported a similarly large difference in the 6MW distance (Cohen’s effect size d of ∼1.5) between persons with MS (n = 33) and age- and sex-matched controls (n = 33). Collectively, this indicates that compromised walking endurance capacity is another manifestation of walking impairment in persons with MS.

The impairments in T25FW and 6MW performance are likely associated with changes in spatial and temporal manifestations of gait, which along with kinematics describe (CIR Systems Inc, Haverton, PA, USA) the mechanics of walking. Spatial and temporal gait parameters were well characterized recently based on data recorded from the GAITRite electronic walkway in persons with MS. For example, one study reported that persons with MS (n = 43) who had minimal disability (ie, ambulatory without an assistive device) walked slower (ie, decreased velocity) by taking fewer (decreased cadence), shorter (decreased step length), and wider steps (increased base of support), and spent a greater portion of the gait cycle in double support than controls who were matched on age, height, weight, and sex. Another study reported differences in velocity, cadence, step length and time, double support, and swing phase among persons with MS (n = 78) as a function of disability level (ie, mild, moderate, and severe) based on EDSS scores. Those gait parameters have been associated with changes in ambulation. Taken as a whole, this indicates that the gait cycle and its descriptive parameters are compromised in persons with MS and likely contribute to impairments in walking performance.

Physiologic Characteristics

Another way of describing walking impairment that occurs in MS involves physiologic parameters. The oxygen (O ₂ ) cost of walking (ie, milliliters of O ₂ consumed per kilogram of body weight per meter traveled [mL/kg ⁻¹ /m ⁻¹ ]) is a physiologic marker that reflects the degree of locomotor impairment in pathologic conditions based on the energetic cost of movement. The O ₂ cost of walking reflects either an increase in the rate of O ₂ consumption (˙VO2)
( V ˙ O 2 )
with normal walking speed (ie, increased energy expenditure for doing the same movement) or a reduction in walking speed with a normal ˙VO2
V ˙ O 2
(ie, same energy expenditure for doing less movement). Overall, an increase in the O ₂ cost would indicate that walking is more physiologically effortful and less efficient for persons with MS, and this might explain why walking impairment has such a large effect on daily activities and participation in this population.

The examination of physiologic markers during ambulation in MS has been a recent area of interest for researchers. For example, one study examined the pattern of change in ˙VO2
V ˙ O 2
in relation to performance on the 6MW in a large sample of persons with MS (n = 95) with a wide range of disability (median EDSS, 4.5; range, 2.0–6.5). The rate of increase in ˙VO2
V ˙ O 2
during the 6MW was steeper in those with mild disability (EDSS, 2.0–3.5) than those with moderate (EDSS, 4.0–5.5) and severe disability (EDSS, 6.0–6.5), and those with mild disability had a higher overall rate of ˙VO2
V ˙ O 2
than those with moderate and severe disability. This finding seems counterintuitive but is logical, because those with mild disability walked further with a faster speed and cadence, thereby requiring greater ˙VO2
V ˙ O 2
during the 6MW. This pattern illustrates the importance of expressing ˙VO2
V ˙ O 2
during walking against speed and/or distance. Accordingly, other studies have indicated that persons with MS have a higher O ₂ cost of walking than matched controls, and this differs based on walking impairment and disability status, such that those with worse walking and disability have a higher O ₂ cost of walking. The existing data, when taken as a whole, indicate that walking is more physiologically demanding for persons with MS, particularly as a function of increasing levels of disability and walking impairment.

Free-Living Assessments

Walking impairments in MS have often been documented based on assessments performed in a laboratory or clinical setting. These measurements are accurate, reliable, and valid, but lack ecologic validity for understanding ambulation that occurs in the context of daily life. Accordingly, another way of describing walking impairments in MS involves assessing ambulation in free-living conditions using accelerometers and pedometers. These devices are motion sensors, often worn around the waist near the center of mass, and capture the vertical displacement of the body during ambulatory activity undertaken in the real world during the waking hours of the day without disrupting normal activities. The changes in this community ambulation are driven by changes in performance, gait pattern, and physiologic manifestations of walking in MS.

Consistent evidence indicates reduced community ambulation in persons with MS based on motion sensor data. For example, one study reported a large difference (Cohen’s effect size d of ∼1.0) in activity counts per day from a waist-worn ActiGraph accelerometer between persons with MS (n = 33) and a matched control sample (n = 33), indicating that the persons with MS were engaging in less community-based ambulation. This finding has been replicated in other research involving samples with MS and age-, sex-, height-, and weight-matched controls. The authors further note that impaired community ambulation is directly associated with disability status based on the EDSS in persons with MS. For example, one study reported a linear reduction in activity counts per day from a waist-worn ActiGraph accelerometer as a function of increasing disability (mild: EDSS, 0–3.5; moderate: EDSS, 4.0–5.5; and severe: EDSS ≥6.0) and differences based on ambulatory status classified by assistive device use in a sample of 70 persons with MS. The effect of disability status has been confirmed in other research using the StepWatch Step Activity Monitor and metric of steps per day in persons with MS. These reductions in activity and step counts suggest that walking impairment extends beyond the laboratory and into the community, thereby affecting one’s ambulation as part of everyday life.

Coupling with Cognition

An exciting new area of research involves examining the coupling of walking and thinking. This interest is based, in part, on the recognition that walking is not simply an automated motor behavior but rather a complex behavior with multifaceted neuropsychological influences, especially because persons with MS must make a conscious effort to walk safely despite increasing neurologic impairments. This research is further based on the idea that the extent of walking impairment can be exaggerated when performing a second task that stresses or overloads one’s neural systems. Indeed, considerable overlap exists in regions of the brain associated with walking and thinking, and MS often affects these areas. Therefore, competition exists for the same regions of the brain (ie, neural resources), and performing a cognitive task while walking should be associated with worse performance than when simply walking alone.

One of the first studies of cognitive–motor coupling in MS examined the association between neuropsychological performance (ie, processing speed and executive function) and lower-extremity performance based on the T25FW in 211 patients with MS and 120 healthy volunteers. Associations were seen between cognition and T25FW performance in persons with MS and controls, although the associations were more robust in the MS sample. Further associations were seen between cognitive and T25FW performance in the MS sample, even after controlling for confounders, including disease duration and disability status based on EDSS. This coupling was more recently demonstrated after having patients undertake a cognitive task while walking, and then examining the effect of the combined tasks versus walking alone on gait outcomes. This process and outcome has been termed the dual-task cost (DTC) of walking. One study reported an overall decline in gait with an additive cognitive task, with a range in DTC of 1.8% for step length through 12% for gait velocity in 78 persons with clinically definite MS. The DTC was significantly larger in persons with moderate (n = 25; EDSS, 4.0–5.5) and severe (n = 32; EDSS, 6.0–6.5) disability compared with those who had mild disability (n = 21; EDSS, 2.0–3.5). Additional data indicate that the DTC of walking is greater in persons with MS (n = 18) than in healthy controls (n = 18), and this detriment in walking while thinking has even been observed in persons with early MS (52 patients with clinically isolated syndrome) versus age- and sex-matched controls (n = 28). This problem with walking and thinking in MS might have practical implications for everyday activities that require cognition and ambulation (eg, walking across a busy street), and could further result in adverse events during ambulation, such as falling.