Primary lateral sclerosis (PLS) is a neurodegenerative motor neuron disease characterized by slowly progressive upper motor neuron (UMN) dysfunction causing substantial disability. ^{Reference Turner, Barohn and Corcia1} It is associated with progressive muscle stiffness, spasticity, cramps, weakness and corticobulbar dysfunction. PLS is diagnosed clinically and distinguished from the more common amyotrophic lateral sclerosis (ALS) by a lack of lower motor neuron involvement over 2–4 years. ^{Reference Turner, Barohn and Corcia1}

In PLS, spasticity, cramps and stiffness can interrupt sleep, exacerbate fatigue, cause pain and impair gait with an increased risk of falls. ^{Reference Vacchiano, Bonan, Liguori and Rizzo2} Loss of ambulation is common. These UMN symptoms may be treated with oral medications (e.g., baclofen, tizanidine, diazepam), intrathecal baclofen or physical therapies (e.g., stretching); however, no interventions have demonstrated improvements in gait.

Levetiracetam is an anti-epileptic medication with a complex array of mechanisms of action including inhibiting presynaptic calcium channels, thereby reducing neurotransmitter release and providing a neuromodulatory effect. ^{Reference Vogl, Mochida, Wolff, Whalley and Stephens3,Reference Rogawski4} One previous open-label trial in motor neuron disease (including 17 patients with ALS and 3 patients with PLS) demonstrated a reduction in muscle spasms and cramps following treatment with levetiracetam. ^{Reference Bedlack, Pastula, Hawes and Heydt5} There were no objective assessments related to motor function or gait in that trial, and no data specific to the PLS subgroup are available.

Given these promising data related to UMN symptoms in motor neuron diseases broadly, and the fact that PLS is marked by ‘pure’ UMN dysfunction, it was our objective to explore any potential benefit of levetiracetam on ambulatory function in PLS. In this case series, we report two patients with PLS with objective measures of ambulatory function at baseline and following 4 weeks of oral levetiracetam therapy.

Institutional Review Board approval and patients’ written informed consent were not obtained or deemed necessary for this small retrospective case series. Two patients with definite PLS were included. Both PLS patients received oral levetiracetam therapy for their UMN syndrome and underwent objective ambulatory function testing with a physical therapist before treatment initiation and 4 weeks post-treatment. Two additional PLS patients (for a total of four) trialed levetiracetam for cramps and spasms and noted subjective benefit to their ambulation but were not formally assessed for motor or gait function and thus are not included here.

Patient characteristics, including duration of symptoms and levetiracetam dosages, were documented. Both patients underwent objective gait assessment including 6-min walk test (6MWT), timed up and go (TUG) and a single patient completed the 10-m walk test (10MWT). The 6MWT is a sub-maximal exercise test used to assess ambulatory function by measuring the distance walked on a flat surface over 6 min. The TUG involves measuring the time taken for a patient to rise from a chair, walk 3 m, turn around and walk 3 m back to the chair and return to a seated position. The 10MWT is performed by measuring gait speed in meters per second over a 10-m distance at two speeds: (1) the patient’s self-selected speed and (2) as fast as possible. These tests were performed by a physical therapist. Relative change (%) in outcome measures was calculated.

The clinical characteristics of the two female patients are reported in Table 1. Patient 1 was 73 years old and experienced PLS symptoms for 15 years, whereas Patient 2 was 68 years old and experienced PLS symptoms for 5 years. Patient 1 was taking baclofen both prior to and after the addition of levetiracetam. Both patients met diagnostic criteria for definite PLS, ^{Reference Turner, Barohn and Corcia1} and mimicking conditions were ruled out with imaging, electromyography and laboratory testing (e.g., genetic testing for hereditary spastic paraplegia). Both patients were community ambulators with gait aids (i.e., 4-wheeled walkers).

Table 1. Patient characteristics

FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; PLS = primary lateral sclerosis; PO = per os (orally); PRN = as required; QHS = at bedtime; TIA = transient ischemic attack; TID = three times daily.

Patient 1 maintained a stable regimen of levetiracetam 500 mg PO twice daily. Patient 2 started on levetiracetam 500 mg PO twice daily but did not tolerate that dosage due to fatigue and thus continued at a lower dose of 250 mg twice daily. Following the dose reduction for Patient 2, both patients tolerated levetiracetam well without any other apparent adverse effects.

Four weeks following initiation of oral levetiracetam, Patient 1 experienced an improvement in distance walked on the 6MWT from 148.5 m to 189 m (27.3%), time to complete TUG from 23 s to 17 s (26.1%) and faster preferential walking speed on the 10MWT from 0.51 m/s to 0.76 m/s (49%; see Table 2). On the patient-specific scale for walking (0–10, with 0 representing the most effort required to walk and 10 representing no effort at all), the patient’s rating improved from as effortful as 3/10 at baseline to 6/10 (“relatively easy”) following treatment.

Table 2. Functional gait parameters at baseline and following 4 weeks of levetiracetam

6MWT = 6-min walk test; TUG = timed up and go test; 10MWT = 10-m walk test.

Patient 2 experienced improvement in distance walked on the 6MWT from 90 m to 112 m (18%) and time to complete TUG from 46 s to 41 s (10%). At the baseline visit, Patient 2 reported being unable to complete the 10MWT due to muscle tightness and spasticity, whereas she indicated intolerance to that outcome measure at reassessment due to dyspnea associated with her asthma.

Following levetiracetam treatment, both patients reported subjective improvements in their muscle cramps, stiffness and spasticity, which they attributed to underlying improvements in their ambulatory function. However, no formal assessment of spasticity was undertaken.

This limited retrospective case series is the first to demonstrate improvements in objective gait parameters associated with levetiracetam treatment in patients with PLS. Moreover, to our knowledge, it is the first to show any improvement in ambulatory function in PLS attributed to pharmacologic intervention. Although the data are limited, this marks an important consideration for further study and managing gait impairment caused by UMN dysfunction in PLS, particularly given the lack of effective interventions to date.

Our results are consistent with the findings from the lone trial of levetiracetam on UMN symptoms in motor neuron disease, which included participants with ALS, PLS and primary muscular atrophy (PMA). ^{Reference Bedlack, Pastula, Hawes and Heydt5} That trial was a small, open-label study that showed levetiracetam provided a benefit regarding cramp severity, cramp frequency and phasic spasticity (but not tonic spasticity). ^{Reference Bedlack, Pastula, Hawes and Heydt5} However, that study featured a majority of participants with ALS (3/20 patients had PLS), and the outcome measures were related directly to cramps and spasticity rather than to motor function in the form of gait or other functional tasks. As there are significant challenges associated with assessing spasticity directly, there may be some utility in examining functional motor tasks in PLS as well. ^{Reference He, Luo and Yu6} Furthermore, given that levetiracetam is purported to improve UMN symptoms specifically, and PLS is a ‘pure’ UMN disorder (unlike ALS), then perhaps PLS may represent a patient population who may obtain more benefit from this medication compared to other forms of motor neuron disease (i.e., ALS and PMA).

The mechanism of action by which levetiracetam may improve the UMN syndrome and gait in PLS is not clear. It may be related to the inhibition of burst firing through effects on gamma-aminobutyric acid (GABA) and glycine receptors or through suppression of high-voltage-activated calcium currents by inhibiting N-type calcium channels. ^{Reference Lynch, Lambeng and Nocka7–Reference Contreras-García, Cárdenas-Rodríguez and Romo-Mancillas9} A centrally mediated mechanism of action is postulated based on both levetiracetam’s pharmacology and the clinical symptoms it has been shown to benefit, aside from seizure disorders. Indeed, past studies have shown that levetiracetam may have some benefit regarding spasms in stiff-person syndrome, ^{Reference Rüegg, Steck and Fuhr10} phasic spasticity in multiple sclerosis ^{Reference Hawker, Frohman and Racke11} and spasms in isolated hemi-facial spasm. ^{Reference Kuroda, Saito and Fujita12,Reference Pascual, Adiao and Prado13} However, it is important to also consider other factors that may impact gait in a patient with spasticity, including fatigue, pain, illness and prior physical activity, which were not controlled in these cases.

Importantly, levetiracetam is relatively well tolerated, even in vulnerable populations. ^{Reference Briggs and French14} Common adverse effects include disordered mood, drowsiness and somnolence (although it is usually less sedating than baclofen), and while one of our two patients did not tolerate the starting dose due to fatigue, once a dose adjustment was made, it was tolerated well. This safety and tolerance profile may offer some advantages over other anti-spasticity medications that may be associated with other undesirable effects (e.g., weakness in baclofen, hepatotoxicity with tizanidine). ^{Reference Mbizvo, Dixon, Hutton and Marson15} However, it is uncertain what the combined effects of baclofen and levetiracetam in this population may be in terms of adverse effects or benefits.

Although the results from these two cases are intriguing and encouraging, this does not provide sufficient evidence to change treatment practices. However, given these present findings and a single previous open-label trial ^{Reference Bedlack, Pastula, Hawes and Heydt5} showing the benefit of levetiracetam on UMN symptoms in motor neuron disease, we believe larger, prospective randomized controlled trials of levetiracetam in PLS are warranted, with particular emphasis on gait function as a key outcome measure.