Botulinum Toxin in Patients With Hereditary Spastic Paraplegia: a Randomized, Double-blind, Placebo-controlled, Crossover Study

Introduction

Hereditary spastic paraplegias (SPG) constitute a heterogeneous group of diseases with a common predominant feature: spasticity of the lower limbs and difficulty walking. The neurologic examination reveals spasticity, exaggerated and pathological reflexes, such as the Babinski sign, and minor hypoesthesia. Spasticity is more evident when the patient walks than during passive movement. Weakness may or may not be present, and typically is less disabling than spasticity, especially during the initial years of the disease. The increase in tonus leads to reduced amplitude of movement and abnormal posture, altogether leading to a very slow gait, falls and articular deformities. Clinically, SPG is divided into pure and complicated forms. The first one is characterized by almost exclusive dysfunction of the pyramidal tracts. Minor sensory and sphincter disturbances are also present. The complicated subtypes encompass a wide variety of associated features such as ataxia, cognitive decline and vision loss. Genetically, SPGs are divided into autosomal dominant, autosomal recessive and X-linked forms. Pure forms are mostly inherited in an autosomal dominant manner, whereas the autosomal recessive forms mostly manifest as complicated forms. Although useful clinically, this genotype-phenotype correlation is not always true. The most used SPG classification is based on the locus that harbors the mutated gene. Each subtype is designated by the initials SPG, followed by a number that corresponds to a specific gene. The gene number is established following the chronological order of identification of each locus.

The discovery of new genes and the unraveling of molecular pathways of SPGs have lead to a better understanding of the disease in the past few years. Despite that, there are very few treatment options . There is no placebo-controlled clinical trial performed to assess any therapeutic intervention for SPG. Oral anti-spastic agents such as baclofen and tizanidine are frequently employed. When the response is inadequate, or there are significant side effects, botulinum toxin injections may be attempted. The substance blocks liberation of acetylcholine from the pre-synaptic cleft. With less activation of the nicotinic receptors at the post-synaptic junction the muscle contraction is inhibited. Botulinum Toxin (Btx) is a first-line treatment for movement disorders such as cervical dystonia, blepharospasm, and spastic arm following stroke. Studies with Btx in patients with SPG are limited to small open-label case series, and there is no solid evidence that patients actually benefit from this therapy. The rationale basis for its use is based on the well established knowledge that Btx reduces muscle tonus. The functional impact on gait, on the other hand, is not well known, as well as the impact this treatment could produce over symptoms such as fatigue and pain.

Justification Spasticity is the most disabling manifestation in patients with SPG. Although there have been recent advances in the genetic and pathogenic characterization of the disease, there is scarcity of therapeutic options. The use of oral anti-spastics is limited by frequent side effects such as somnolence and drowsiness. Therefore, the investigators designed a randomized, double-blind, placebo-controlled, crossover trial to evaluate the efficacy and safety of Btx injections in patients with SPG. The primary outcome measure will be gait velocity assessed through the 10 meter walking test 8 weeks after injection. Each participant will be submitted to one injection session with Btx and one with placebo (consisting of sterile sodium chloride), each one separated by a period of 6 months.

Objectives General Objective To evaluate the effects of Btx compared to placebo injections in a cohort of patients with SPG. The primary outcome will be increase in gait velocity, a measure that reflects functional gain. Secondary outcomes will include measures of spasticity, pain and fatigue.