Lower Extremity Signs and Symptoms of Multiple Sclerosis

MARY ANN PICONE

HUNTER VINCENT

KAREN BLITZ-SHABBIR

CLOVER YOUN WEST

JEMIMA AKINSANYA

Multiple sclerosis (MS) frequently presents with deficits of the lower extremities, particularly gait disorders, motor weakness, balance problems, and spasticity. The goal of this chapter is to discuss the most common lower extremity impairments associated with MS, including their signs and symptoms, prevalence, pathophysiology, diagnosis, assessment tools, and treatment.

MS is a chronic multifocal autoimmune inflammatory demyelinating disease of the central nervous system (CNS). The pathologic hallmarks of MS lesions include breakdown of the blood-brain barrier, perivascular infiltrates of mononuclear cells, multifocal inflammation, oligodendrocyte loss, gliosis, axonal damage, and neurodegeneration.¹

It is predominantly a T cell-mediated inflammatory disorder with overproduction of proinflammatory cytokines. These cytokines weaken the blood-brain barrier, allowing T cells to enter the CNS and attack myelin. The resulting demyelination slows conduction of electrical impulses along nerve axons and decreases the speed at which information travels down them. Axonal damage occurs early on in the disease course and is considered the major cause of neurologic disability. MS clinical symptoms vary from person to person depending on the number and location of demyelinating lesions within the brain and spinal cord. Brain atrophy is the cumulative effect of demyelination and axonal loss.²

MS is the most common neurologic disorder of young adults in the United States, and is increasing in prevalence both in the United States and worldwide, with the median prevalence estimated at nearly 33 per 100,000 globally as of 2013.³ Approximately 450,000 people are diagnosed in the United States and 2.5 million people worldwide. Most people are diagnosed between the ages of 20 and 45 years. Women outnumber men in a 3:1 ratio.³

The cause of MS is still unknown. However, the development of MS is thought to involve both a genetic predisposition and exposure to environmental and infectious triggers. Exposure to Epstein-Barr virus after early childhood, low vitamin D levels, cigarette smoking, high-salt diets, and obesity have all been shown to potentially trigger a proinflammatory state, leading to a predisposition for developing MS. High-salt diets have been shown to induce pathogenic Th17 cells.³ Genetic factors seem to play a role as well. There tends to be a higher incidence of MS in Caucasians and people of Northern European descent, and genetically the strongest association maps to the HLA-DRB1 allele of the class II major histocompatibility complex region.⁴

MS Classification

MS disease course descriptions (phenotypes) are clinically important for interdisciplinary communication, treatment decision-making algorithms, clinical trial selection, and patient prognosis.

Clinically Isolated Syndrome

Clinically isolated syndrome (CIS) is characterized as the first episode of neurologic symptoms, lasting at least 24 hours, caused by an inflammatory or demyelinating lesion in the CNS, but not sufficient enough to satisfy the McDonald diagnostic criteria for MS.⁵ The neurologic symptoms can be monofocal, affecting only a single neurologic region such as the optic nerve in optic neuritis, or multifocal, affecting multiple neurologic areas of the body.⁶ The risk of CIS progressing to MS can vary depending on the presence of a CNS-occupying lesion.⁶ When CIS is present with at least one demyelinating lesion in the CNS, the patient has a 60% to 80% risk of a second neurologic episode and being diagnosed with MS.⁷ In CIS patients without a CNS lesion, the risk decreases to approximately 20%.⁸ Preliminary clinical trials show that early treatment of patients with CIS can decrease the risk of a second neurologic episode and the conversion to “clinically definite MS.”⁹,¹⁰

Relapsing Remitting MS

Relapsing remitting MS is the most common disease course, encompassing approximately 85% of initial MS diagnosis. This MS disease classification is defined by exacerbations of disease symptoms, also known as relapses, followed by periods of remission where no apparent clinical worsening or progression of the disease occurs. However, changes can still be seen on magnetic resonance imaging (MRI) examination. Neurologic symptoms often include changes in vision, numbness, fatigue, spasticity, muscle spasms, bowel/bladder problems, and cognitive difficulty.¹¹,¹² However, the presentation of relapsing remitting MS is oftentimes extremely variable between patients and unique to each individual.
Patients may experience complete recovery of function and resolution of symptoms following a relapse, or only partial, leading to increased disability.

Primary Progressive MS

Primary progressive MS is a disease course characterized by worsening neurologic status from the onset of diagnosis, usually without relapses or remissions, affecting approximately 10% to 15% of MS patients.¹³ Primary progressive MS usually affects men and women equally, and is often diagnosed later in life around the fourth or fifth decade.¹⁴ In addition, primary progressive MS tends to present with an increased number of spinal cord lesions with less inflammatory cells, versus relapsing remitting MS, which usually presents with brain lesions (“plaques”) containing a larger number of inflammatory cells.¹⁵ It is common for patients with primary progressive MS to experience difficulty with walking and mobility, which can potentially limit their ability to continue working.¹³,¹⁶

Secondary Progressive MS

Secondary progressive MS generally presents initially as a relapsing remitting disease course, upward of 90% of cases,¹⁷ but eventually transitions into a disease course defined by progressive disability that is independent of relapse activity. A majority of untreated patients with relapsing remitting MS usually transition to secondary progressive MS approximately 10 years after diagnosis.¹⁸ Although research is mixed, between 15% and upward of 50% of patients with relapsing remitting disease will advance to secondary progressive MS.¹⁴ The onset of secondary progressive MS is of large clinical significance, because it has been shown to be the most important determining factor for long-term prognosis with MS, and its prevention is a crucial primary target for treatment⁵,¹⁷,¹⁹ (Fig. 25-1).

Diagnostic Studies

Despite recent advances and improvements in imaging techniques, the diagnosis of MS remains primarily a clinical diagnosis. Signs and symptoms referable to white matter lesions disseminated in time and space within the neuraxis should be seen, whereas other MS mimics have been ruled out. In 2010, the revised version of the McDonald diagnostic criteria for MS was developed utilizing MRI much more than in the past to help identify patients earlier in the disease course²⁰ (Table 25-1).

No one laboratory test is diagnostic, but several tests may help support the diagnosis. Examination of cerebrospinal fluid (CSF) from a lumbar puncture could confirm the diagnosis and rule out other disease conditions. CSF studies usually show an increase in immunoglobulin G (IgG) index and intrathecal IgG antibody production, as well as two or more oligoclonal bands. In addition, evoked potentials of the visual, somatosensory, and auditory systems may show delayed conduction latencies. Furthermore, blood work testing is done to rule out confounding diagnoses and mimics.

MRI has made a tremendous impact in the early diagnosis of MS lesions. It is the most sensitive test that is currently available to detect MS lesions. It can help estimate lesion load and extent of disease activity, and measure brain volume and atrophy. Clinicians rely on MRI to monitor disease progression, evaluate therapeutic response, and serve as prognostic indicator of disease worsening. Typical MS lesions on MRI are ovoid in shape and tend to be located in the periventricular white matter, as well as in the posterior fossa, spinal cord, corpus callosum, and subcortical regions. They are often situated perpendicular to the ventricles. When gadolinium dye is injected, lesions may enhance in areas of acute inflammation because of disruption of the blood-brain barrier. Higher strength (7 T) MRIs can also detect lesions in normal-appearing white matter and gray matter.

Spinal cord lesions are usually located peripherally, with the dorsolateral cord being the most common plaque location. Lesions are typically less than two vertebral segments long, occupying less than half of the cross-sectional area of the cord.²¹ Lesions that occupy three or more vertebral segments in length or that are centrally located should raise suspicion for the diagnosis of neuromyelitis optica (Fig. 25-2A to C).

Functional Assessment

Mobility/Ambulation

Patients with MS can present with a wide variety of clinical symptoms depending on the number and location of MS lesions within the brain and spinal cord. Commonly, the presence and location of CNS lesions result in lower limb dysfunction, which manifests as difficulty with walking. Approximately 75% of MS patients experience significant difficulty with walking.²² In addition, lower leg function has been shown to be the most important bodily function when compared to other areas of the body for patients with MS.²³ Studies have shown that impaired mobility and ambulation are directly correlated with reduction in patient quality of life, activities of daily living, and overall productivity.²⁴ Walking limitations have also contributed to increased unemployment for MS patients, often linked to decreased productivity in the workplace.²⁵

In many cases, the source of lower limb dysfunction can be traced back to the spinal cord. It has been shown that lesions in the pyramidal tracts can contribute to weakness and spasticity, whereas dorsal column and cerebellar lesions can contribute to loss of coordination and proprioception.²⁶

Many common symptoms of MS can result in an abnormal gait pattern, most frequently exhibited as unsteadiness or a slowed cadence. Such symptoms include ataxia, sensory ataxia, imbalance, foot drop, weakness, spasticity, tremor, vertigo, visual impairment, and cognitive deficits. When a normal gait pattern is altered, it ultimately causes an increased expenditure of energy while walking. A common gait dysfunction seen in MS is foot drop. Though foot drop in
non-MS patients is typically caused by damage to the peroneal nerve, in MS patients, the foot drop is related to upper motor neuron dysfunction causing focal weakness in dorsiflexion, monoparesis, or hemiparesis. On examination, the forefoot drags and is unable to clear during the swing phase of gait.

FIGURE 25-1. 2013 Multiple sclerosis phenotype classifications. (Images created by Dr. Hunter Vincent with information from The National MS Society.)

Because of the heterogeneous presentation of MS, it is not uncommon for disability to fluctuate from day to day based on mood and environment, even without signs of disease progression.²⁷ The significance of walking and ambulation dysfunction in the course of MS disease progression should not be overlooked, and accurate assessment is needed to understand subtle changes in each patient’s unique disease presentation.

Proper measurement of a patient’s ambulation and balance is essential for assessing disease worsening, which are important indicators for disease progression. Identifying subtle changes in lower extremity dysfunction can ensure proper treatment and rehabilitation, as well as initiation of appropriate disease-modifying therapy.²⁸ There are many standardized assessments that aggregate multiple aspects of physical function to assess disease status. Some analyze ambulation or balance alone, whereas others test a hybrid of both. Table 25-2 summarizes a literature search on functional assessments of the lower extremity. The most commonly used functional exams will be explained in further detail.

Table 25-1. 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis²⁰

Clinical (Attacks)	Lesions	Additional Criteria to Make Diagnosis (DX)
2 or more	Objective clinical evidence of 2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack	None. Clinical evidence alone will suffice; additional evidence desirable but must be consistent with MS
2 or more	Objective clinical evidence of 1 lesion	Dissemination in space, demonstrated by ▪ 1 T2 lesion in at least two MS typical CNS regions (periventricular, juxtacortical, infratentorial, spinal cord); OR ▪ Await further clinical attack implicating a different CNS site
1	Objective clinical evidence of 2 or more lesions	Dissemination in time, demonstrated by ▪ Simultaneous asymptomatic contrast-enhancing and nonenhancing lesions at any time; OR ▪ A new T2 and/or contrast-enhancing lesions(s) on follow-up MRI, irrespective of its timing; OR ▪ Await a second clinical attack
1	Objective clinical evidence of 1 lesion	Dissemination in space, demonstrated by ▪ 1 T2 lesion in at least two MS typical CNS regions (periventricular, juxtacortical, infratentorial, spinal cord); OR ▪ Await further clinical attack implicating a different CNS site AND Dissemination in time, demonstrated by ▪ Simultaneous asymptomatic contrast-enhancing and nonenhancing lesions at any time; OR ▪ A new T2 and/or contrast-enhancing lesions(s) on follow-up MIR, irrespective of its timing; OR ▪ Await a second clinical attack
(From Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302. doi:10.1002/ana.22366, with permission.)

FIGURE 25-2. A: Ovoid, periventricular white matter lesions demonstrated on axial FLAIR image. B: Periventricular lesions characteristically seen as Dawson’s fingers on sagittal FLAIR image. C: Sagittal T2-weighted image of cervical spine lesion. (Images courtesy of Dr. John Morgan, Holy Name Medical Center.)

FIGURE 25-2. (continued)

Clinical Observation

Although direct observation and assessment of a patient’s walking lacks the objective grading scale of more standardized tests, it is often the initial approach to identify changes in a patient’s mobility. Regardless of whether a standardized assessment is performed, regular gait and mobility assessment should be a standard occurrence during patient visits.

Expanded Disability Status Scale

The Kurtzke Expanded Disability Status Scale (EDSS) is one of the most well-documented MS-specific functional scales. It is considered the gold standard for establishing objective disability status and monitoring disease progression. The EDSS applies a numerical value from 0 to 10 to a patient’s disability, primarily associating disease progression with ambulatory difficulty. The lower numbers on the EDSS (1 to 4.5) evaluate disease impairments, but all patients within this range are fully ambulatory without aid. The middle numbers on the scale (4.5 to 7.5) assess difficulty with ambulation. A patient’s numerical disability value is based on their ability to walk a maximum distance of 500 m and the presence and

type of assistive device needed. EDSS progression is more heavily weighted toward dependence on assistive devices. For patients within this range on the EDSS, there is often wide variability in functional disability, because many patients requiring assistive devices have the ability to walk the same maximum distances as patients not requiring assistive devices. In addition, day-to-day variations in patient symptoms can have large effects on walking distance and have been shown to cause changes of approximately 1.5 points on the scale.²⁷ For scores greater than 7.5, all patients are bedbound or confined to a wheelchair, with very severe degrees of functional disability²⁹ (Fig. 25-3).

Table 25-2. Functional Assessments Involving the Lower Extremity in Multiple Sclerosis

Type	Assessment Name	Data Measured	Limitations
Mobility/Ambulation
Direct observation	Clinical examination Kurtzke Expanded Disability Severity Scale²⁹	Physician’s clinical interpretation of walking and mobility Evaluates impairment and disability detected, followed by assessment of maximum walking distance and aids required. Scored 0-10	The use of aids is dependent on psychosocial factors²⁶
	Multiple Sclerosis Functional Composite (MSFC)³⁰	Evaluates walking with a timed 25-foot walk, upper extremity function with nine-hole peg test, and cognitive function with paced auditory serial addition test
	Dynamic Gait Index (DGI)³¹	8-part evaluation examining gait, balance, and fall risk; Functional Gait assessment (FGA) and 4-Item Dynamic Gait Index are variations
	25-ft Timed Walk²⁵	Gait speed	Only a measure of speed. Not effective for level of activity.²⁶ Poor test for patients with minimal disease severity²⁵
	Six Spot Step Test (SSST)³²	Ambulation, coordination, and balance. Patient walks from one end to the other of a delineated rectangular field, kicking cylindrical blocks out of their marked circles	Requires specific testing field with setup²⁵
	2- or 6-min walk³³,³⁴	Distance traveled and walking stamina	Highly variable depending on pain, mood, motivation²⁶
	Kinetic Gait Analysis	Computer-analyzed gait analysis	Costly, time consuming, not ideal for large groups²⁶
	Video Gait Analysis	Video-based scoring system of gait³⁵,³⁶
	Physiological Cost Index²⁶	Ambulation/mobility given a score based on change between resting and active heart rate to measure energy consumption	Not good for patients with dysautonomia related to MS³⁷
	Physiological Profile Approach (PPA)³⁸	Clinical tests of vision, cutaneous sensation of the feet, leg muscle force, step reaction time, and postural sway. Scored 0-2 to assess risk of falls	Time to perform: 30 min, equipment is needed, imprecise measure of physiologic mechanisms, not measuring functional tasks or balance control systems²⁶
Self-reported	Rivermead Mobility Index (RMI)³⁹	Mobility-derived disability, ranging from ability to turn in bed to running, and an observation of standing without aid	Relies on a patient’s subjective assessment²⁶
	Hauser Ambulation Index⁴⁰ (Hauser)	Semiquantitative scale (0-10) based on time to walk 25 feet and use of aids	Relies on a patient’s subjective assessment, and the use of aids is also dependent on psychosocial factors²⁶
	Multiple Sclerosis Walking Scale (MSWS-12)⁴¹	12 questions with five responses regarding limitations of mobility	Relies on a patient’s subjective assessment²⁶
	EuroQol-5 dimension Index (EQ-5D)⁴²	Five descriptive questions including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression with three potential responses
	UK Neurological Disability Scale (UKNDS)⁴³	12 subsections including mobility, scored 0-5 based on use of aids	Relies on a patient’s subjective assessment²⁶
	Functional Independence Measures (FIM)⁴⁴	Includes 18 items with four levels of response, with sections for mobility and locomotion	Relies on a patient’s subjective assessment²⁶
	Barthel Index⁴⁵	Assesses activity including mobility, based on use of aids and ability to walk a distance or climb stairs	Relies on a patient’s subjective assessment²⁶
	Short Form 36 (SF-36)⁴⁶	8-part questionnaire about overall quality of life, but includes physical functioning and ambulation	Relies on a patient’s subjective assessment,²⁶ not specific to MS, floor and ceiling effects⁴⁷
	Multiple Sclerosis Quality of Life Inventory (MSQLI)³⁰	Health Status Questionnaire (SF-36), plus nine symptom-specific measures: fatigue, pain, bladder function, bowel function, emotional status, perceived cognitive function, visual function, sexual satisfaction, and social relationships
	Multiple Sclerosis Quality of Life (MSQOL-54)⁴⁷	12 subscales along with two summary scores, and two additional single-item measures, including physical function, role limitations—physical, role limitations—emotional, pain, emotional well-being, energy, health perceptions, social function, cognitive function, health distress, overall quality of life, and sexual function	Relies on a patient’s subjective assessment²⁶
	Multiple Sclerosis Impact Scale⁴⁸	29 questions regarding limitations secondary to MS (each scored 1-5)	Relies on a patient’s subjective assessment²⁶
	Patient Determined Disease Steps (PDDS)⁴⁹	Scored from 0 (normal) to 8 (bedridden), with scores between 3 and 7 specifically focused on patient-reported walking limitations	Relies on a patient’s subjective assessment²⁶
	Functional Assessment of Multiple Sclerosis (FAMS)⁵⁰	44 questions divided into six subscales: mobility, symptoms, emotional well-being (depression), general contentment, thinking/fatigue, and family/social well-being	Relies on a patient’s subjective assessment
	Physical activity diary	Patient records daily activity or recalls daily activity after each week	Patient compliance can be poor, and time consuming for patients²⁶
	Activities-specific Balance Confidence Scale (ABC)⁵¹	16-item questionnaire in which respondents rate their confidence that they can maintain their balance in the course of daily activities. Scored 0-10 and averaged	Subjective, does not identify type of balance problems, and not related to falls⁵²
Activity trackers	Pedometer	Number of steps	Not effective for qualitative assessment²⁶
	Accelerometer²⁵,²⁶	Steps, distance, energy expenditure	Not effective for qualitative assessment²⁶
Balance
Direct observation	Balance Evaluation Systems Test (BESTest)⁴⁸	36 items, grouped into six systems: “Biomechanical Constraints,” “Stability Limits/Verticality,” “Anticipatory Postural Adjustments,” “Postural Responses,” “Sensory Orientation,” and “Stability in Gait.” Each item scored 0-4 and totaled	Time to perform: 30 min, no studies of fall risk, equipment is needed⁵²
	Functional Reach⁵³	Maximal distance a person can reach beyond the length of their arm while maintaining a fixed base of support in the standing position. A reach less than or equal to 6 inches predicts fall	Only one task evaluated, does not identify type of balance problem²⁶
	Tinetti Gait and Balance⁵⁴	14-item balance and 10-item gait test. Predicts the risk of having one fall in the next year	Poor specificity, ceiling effect, does not identify type of balance problem⁵²
	Timed Up and Go (TUG)⁵⁵	Time required for a person to rise from a chair, walk 3 m, turn around, walk back to the chair, and sit down	Ceiling effect, only one functional task, does not identify type of balance problem⁵²
	Berg Functional Balance Scale⁵⁶	14-item functional assessment including sitting, standing, and postural transitions. Items scored from 0 to 4 points	Poor sensitivity, does not identify the type of balance problem, ceiling effect, does not test dynamic balance⁵²
	One-Leg Stance⁵⁷	Eyes open and arms on the hips, patients stand unassisted on one leg. Participants unable to perform for at least 5 s are at increased risk for injurious fall	Only one task of static balance is evaluated, no identification of the type of balance problem, not continuously related to falls⁵²
Spasticity
	Ashworth Scale⁵⁸	Muscle spasticity on a scale from 0 to 4 depending on tone, resistance, and range of motion	Does not differentiate lower levels effectively. Evaluator error
	Modified Ashworth Scale⁵⁹	Muscle spasticity on a scale including 0, 1, 1+, 2, 3, 4 evaluating tone, resistance, spastic catch, and range of motion	Evaluator error
	Tardieu Scale⁶⁰	Muscle reaction (0-5) at three different speeds (V1, V2, V3)	Evaluator error
	Modified Tardieu Scale⁶¹	Muscle reaction (0-5) at three different speeds (V1, V2, V3), and accounts for Joint angle	Evaluator error
	Multiple Sclerosis Spasticity Scale (MSSS-88)⁶²	88 questions regarding the impact of spasticity on a patient’s overall function	Based on the patient’s subjective response