Outcome Measures and Biomarkers for Clinical Trials in Hereditary Spastic Paraplegia: A Scoping Review

Abstract

Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb spasticity. There is no disease-modifying treatment currently available. Therefore, standardized, validated outcome measures to facilitate clinical trials are urgently needed. We performed a scoping review of outcome measures and biomarkers for HSP to provide recommendations for future studies and identify areas for further research. We searched Embase, Medline, Scopus, Web of Science, and the Central Cochrane database. Seventy studies met the inclusion criteria, and eighty-three outcome measures were identified. The Spastic Paraplegia Rating Scale (SPRS) was the most widely used (27 studies), followed by the modified Ashworth Scale (18 studies) and magnetic resonance imaging (17 studies). Patient-reported outcome measures (PROMs) were infrequently used to assess treatment outcomes (28% of interventional studies). Diffusion tensor imaging, gait analysis and neurofilament light chain levels were the most promising biomarkers in terms of being able to differentiate patients from controls and correlate with clinical disease severity. Overall, we found variability and inconsistencies in use of outcome measures with a paucity of longitudinal data. We highlight the need for (1) a standardized set of core outcome measures, (2) validation of existing biomarkers, and (3) inclusion of PROMs in HSP clinical trials.

Keywords: biomarkers; clinical trials; hereditary spastic paraplegia; outcome measures; scoping review.

Figure 1

PRISMA flow chart [27].

Figure 2

Outcome measures for hereditary spastic paraplegia according to frequency reported (Yellow 1–5 studies, Blue 6–10 studies, Red >10 studies). 4SMD or 4FMS—Four-stage functional scale of motor disability; 6MWT var—Six minute walk test and variations; ABC scale—Activities-specific Balance Confidence Scale; ACE—Addenbrooke’s Cognitive Exam; ALSFRS-R—Amyotrophic Lateral Sclerosis Rating Scale Revised; AMB—Ambulatory score; AMBUS—Distance walked in meters walked in 5 s without help; ATG9A ratio—Autophagy-related protein 9A ratio; BAEP—brainstem auditory evoked potentials; BBS—Berg Balance Scale; BDI-V—Becks Depression Inventory; BPI—Brief Pain Inventory; CANTAB—CANTAB cognitive assessment; CCFSw—Composite Cerebellar Functional Severity Score; Cognitive tests*—Verbal Learning and Memory Test, Farbe-Wort-Interferenz Test, Trail Making Test Part A and B, Frontal Assessment Battery, revised d2 Test of attention, Regensburg Word Fluency Test; CPCHILD—Caregiver Priorities and Child Health Index of Life with Disabilities; CPQoL—Cerebral Palsy quality of life questionnaire; DIS—Disability score; DTI—diffusion tensor imaging; EQ-5D—EuroQoL 5 Dimensions; FES-I—Falls Efficacy Scale-International; FIM—Functional Independence Measure; FMA-LE—Lower extremity subclass of Fugl–Meyer assessment; GMFCS—Gross Motor Function Classification Score; GMFM—Gross Motor Function Measure; HADS—Hospital Anxiety and Depression Scale; ICIQ-LUTSqol—International Consultation of Incontinence Questionnaire lower urinary tract symptoms quality of life; ICIQ-ShortF—International Consultation of Incontinence Questionnaire Short Form; Ioflupane-S—Ioflupane-single photon emission computed tomography (SPECT); Landmarks Dis—Landmarks of Disability; MAS—Modified Ashworth Scale; MEPs—motor evoked potentials; MFI-20—Multidimensional Fatigue Inventory; MFIS—Modified Fatigue Impact Scale; mGAS—Modified Goal Attainment Scale; MGFAQ—Modified version of Gillette Functional Assessment Questionnaire; MMSE—Mini-Mental State Exam; MoCA—Montreal Cognitive Assessment; MRC—Medical Research Council muscle strength; MRI—magnetic resonance imaging; MRS—magnetic resonance spectroscopy; MRScale—Modified Rankin Scale; MSIS—Multiple Sclerosis Impairment Scale; mtDNA—mitochondrial DNA load; NCS/EMG—nerve conduction studies/electromyography; NfH—Neurofilament heavy chain; NfL—Neurofilament light chain; NPRS—Numeric rating scale for pain; OHC—25 and 27 hydroxycholesterol; PADAF—protocol for evaluation of acquired speech disorder; PHQ-9—Patient Health Questionnaire; SARA—Scale for Assessment and Rating of Ataxia; scanning EM of hair shafts—scanning electron microscopy of hair shafts; SCOPA-AUT—Scale for Outcomes in Parkinson’s Disease for Autonomic Symptoms; SD-OCT—spectral domain optical coherence tomography; SF-36, SF-12—Short Form 36, Short Form 12; SPRS—Spastic Paraplegia Rating Scale; SSEP—Somatosensory evoked potentials; TUG—Timed Up-and-Go test; UHDRS-IV—Unified Huntington’s Disease Rating Scale Part IV; VAS—Visual Analogue Score; VEP—visual evoked potentials; Vestibular FT—video-oculography and rotational chair testing; WAIS-R—Wechsler Adult Intelligence Scale-revisited; Walking HS—Walking Handicap Scale; Zung DS—Zung Depression Scale.

Figure 3

Common limitations of studies of HSP outcome measures. * [66] A sample size of less than fifty participants is defined as small in the COSMIN checklist. However, a smaller sample size may be justified in the study design. For example, a randomized controlled trial of 14 patients with HSP-CYP7B1 calculated an estimate of the effect size of treatment using a pre-specified biomarker to determine the sample size required for adequate power [35].