Botulinum toxin for hereditary spastic paraplegia: effects on motor and non-motor manifestations

<div><p>ABSTRACT Motor and non-motor manifestations are common and disabling features of hereditary spastic paraplegia (HSP). Botulinum toxin type A (Btx-A) is considered effective for spasticity and may improve gait in these patients. Little is known about the effects of Btx-A on non-motor symptoms in HSP patients. Objective To assess the efficacy of Btx-A on motor and non-motor manifestations in HSP patients. Methods Thirty-three adult patients with a clinical and molecular diagnosis of HSP were evaluated before and after Btx-A injections. Results Mean age was 41.7 ± 13.6 years and there were 18 women. Most patients had a pure phenotype and SPG4 was the most frequent genotype. The Btx-A injections resulted in a decrease in spasticity at the adductor muscles, and no other motor measure was significantly modified. In contrast, fatigue scores were significantly reduced after Btx-A injections. Conclusion Btx-A injections resulted in no significant functional motor improvement for HSP, but fatigue improved after treatment.</p></div

ROI subgroups analysis.

<p>Axial view of significant areas in the comparison of B&O versus controls. Areas described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182735#pone.0182735.t004" target="_blank">Table 4</a>. p-values in red scale colorbar, α = 0.017 (Bonferroni correction).</p

ROI analysis.

<p>ROI analysis.</p

Subjects demographics.

<p>Subjects demographics.</p

ROI subgroups analysis.

<p>Axial view of significant areas in the comparison of CD versus B&O. Areas described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182735#pone.0182735.t004" target="_blank">Table 4</a>. p-values in red scale colorbar, α = 0.017 (Bonferroni correction).</p

Literature review on previous study findings using voxel-based morphometry analysis in CCD.

<p>Literature review on previous study findings using voxel-based morphometry analysis in CCD.</p

Primary exploratory analysis.

<p>Primary exploratory analysis.</p

Clinical analysis.

<p>Clinical analysis.</p

Multimodal MRI-Based Study in Patients with <i>SPG4</i> Mutations

<div><p>Mutations in the <i>SPG4</i> gene (SPG4-HSP) are the most frequent cause of hereditary spastic paraplegia, but the extent of the neurodegeneration related to the disease is not yet known. Therefore, our objective is to identify regions of the central nervous system damaged in patients with SPG4-HSP using a multi-modal neuroimaging approach. In addition, we aimed to identify possible clinical correlates of such damage. Eleven patients (mean age 46.0 ± 15.0 years, 8 men) with molecular confirmation of hereditary spastic paraplegia, and 23 matched healthy controls (mean age 51.4 ± 14.1years, 17 men) underwent MRI scans in a 3T scanner. We used 3D T1 images to perform volumetric measurements of the brain and spinal cord. We then performed tract-based spatial statistics and tractography analyses of diffusion tensor images to assess microstructural integrity of white matter tracts. Disease severity was quantified with the Spastic Paraplegia Rating Scale. Correlations were then carried out between MRI metrics and clinical data. Volumetric analyses did not identify macroscopic abnormalities in the brain of hereditary spastic paraplegia patients. In contrast, we found extensive fractional anisotropy reduction in the corticospinal tracts, cingulate gyri and splenium of the corpus callosum. Spinal cord morphometry identified atrophy without flattening in the group of patients with hereditary spastic paraplegia. Fractional anisotropy of the corpus callosum and pyramidal tracts did correlate with disease severity. Hereditary spastic paraplegia is characterized by relative sparing of the cortical mantle and remarkable damage to the distal portions of the corticospinal tracts, extending into the spinal cord.</p></div

TBSS analyses showing microstructural damage in SPG4-HSP.

<p>TBSS results showing areas of reduced FA and increased MD, RD and AD in patients with SPG4 mutations after comparison with age and sex matched controls. Areas with reduced FA and increased MD, RD and AD are shown in yellow-red and represent cluster based values (p<0.05, corrected). Results are shown on the MNI152 1 mm template.</p