Table 1.

Completed clinical trials for HSPs.

Intervention	Outcome measures	Results	PubMed ID	Patients (n)	Controls (n)	Study design
Atorvastatin at 40 mg/day for 9 weeks in adults and children under 18 received 20 mg/day (13)	Primary outcome: Change of 27-OHC in serum after 9 weeks. Secondary outcomes: change of 27-OHC in CSF, reduction of 24-OHC, 25-OHC and 3β-CA levels in serum and CSF	Statistically significant reduction in serum 24S-OHC, 25-OHC, and 27-OHC. No statistically significant change in other measures tested, notably in CSF.	29126212	7 enetically confirmed SPG5 patients	7 genetically confirmed SPG5 patients	Randomized, placebo-controlled trial
Atorvastatin 20 mg b.i.d, CDCA 500 mg b.i.d, resveratrol 40 mg b.i.d; three periods of 2 months of treatment separated by a 4-month washout. (14)	Primary outcome measure: Plasma 27-OHC levels Secondary outcome measures: plasma 25-OHC levels, plasma oxysterols to total cholesterol ratio, serum bile acids profile, safety profile of study drugs	Statistically significant reduction in plasma 27-OHC and 24S-OHC and cholesterol with Atorvastatin. Plasma oxysterols were not altered by CDCA or resveratrol.	29228183	12 genetically confirmed SPG5 patients	Three-period crossover study	Three-period, three-treatment crossover study.
Intrathecal baclofen (32)	Spasticity measured on the Ashworth scale (30), walking ability assessed with Gillette Functional Assessment Questionnaire (31)	Reduction of lower limbs' spasticity as measured by modified Ashworth scale from 2.6 (±0.8) to 0.7 (±0.9) (p = 0.000). Walking ability improved in modified version of functional walking scale of Gillette Functional Assessment questionnaire from 5.9 (±1.7) to 7.4 (±2.0) (p = 0.001).	24973568	14 patients clinically diagnosed with HSP	0	Open-label, prospective study with 14/16 patients who responded to baclofen trial.
Intrathecal baclofen pump for 3 months of continuous infusion (49)	Ashworth scale, reflexes, and spasm score 3 months after continuous infusion of baclofen pump	Ashworth scale decreased from 3.96 ± 0.81 to 1.92 ± 0.58, reflexes decreased from 4.25 ± 0.45 to 2.00 ± 0.0, and spasm score decreased from 2.50 ± 0.55 to 1.83 ± 0.41.	1514885	3	0	Open label
Botulinum toxin type A (500 MU in each leg with calf muscle tone MAS1 or 750 MU in each leg with calf muscle tone MAS2 with injections over the 3 heads of triceps surae and heads of gastrocnemius) and daily stretching exercises for 18 weeks (26)	Primary outcome: change in 10 m comfortable gait velocity gait velocity(28, 29) 8 weeks after injections (averaging three trials) and calf muscle tone Secondary outcome: change in SPRS (24, 25); change in Ashworth spasticity scale (30); Medical Research Council (MRC) strength scale; Quantitative Muscle Assessment (QMA) fixed myometry testing; brief pain inventory scale, modified fatigue impact scale; Fugl-Meyer scale (33) and timed up and go testing (34).	Mean comfortable gait velocity increased from 0.90 m/s (SD = 0.18) to 0.98 m/s (SD = 0.20) at 4 weeks after treatment which persisted to 18 weeks after treatment. Calf muscle tone decreased from median 2, range 1–2 to median 1, range 0–1 at 4 weeks, which partially persisted at 18 weeks with median 1, range 0–2.The change in MRC, QMA, maximum gait velocity, Activities-specific Balance Confidence Scale change post treatment was not statistically significant. Other functional measure remained unchanged after treatment.	25325386	15 autosomal dominant pure HSP genetically proven SPG4, 3A and 8, or based on family history	0	Open label
Dalfampridine 10 mg twice daily for 2 weeks (50)	The Timed 25-foot walk test (51), the Spastic Paraplegia Rating Scale (SPRS) (24) and the 12-item Multiple Sclerosis Walking Scale (MSWS-12) (52) performed before and after treatment.	SPRS score improved from 21 ± 9.6 to 19.1 ± 9.6 (p = 0.0195) and MSWS-12 improved from 70.3 ± 19.6 to 61 ± 22.7 (p = 0.0429)	25808501	12 patients: SPG4 (n = 6); SPG7 (n = 1); SPG10 (n = 2); adrenomyeloneuropathy (n = 2), history of childhood onset pure spastic paraplegia (n = 1)	0	Prospective, uncontrolled, proof-of- concept open trial.
Gabapentin (53) Placebo or gabapentin 2400 mg daily titrated up to 4000 mg daily over 10 days, maintained for 2 months, then washout of 10 days and drug free for 1 month, followed by crossover to treatment or placebo.	MS impairment scale (35), Visual Analog Scale score of current life quality, paired transcranial magnetic stimulation	No statistically significant differences comparing gabapentin with placebo. No evidence of altered intracortical excitability.	17539946	10 SPG4 patients (6/10 genetically confirmed)	Crossover study	Prospective double-blind, randomized, placebo-controlled, crossover trial
L-Threonine (54) 7 patients took 1.5 g t.i.d and 9 patients took 2 g t.i.d and 2 additional patients took both doses by completing the double-blind study twice.	Spasticity variables: Leg strength; leg tone, leg deep tendon reflexes, clonus, walk, hop on foot, run	Mean spasticity score went from 1.64 ± 0.17 to 1.40 ± 0.16 on L-threonine and from 1.56 ± 0.16 to 1.54 ± 0.18 on placebo. However, clinical assessments and patients' self-evaluations of response did not show significant differences.	1742749	18 familial spastic paraparesis patients	Double-blind, crossover design	Double-blind, crossover design; 2 treatment periods lasting 2 weeks interrupted by 2-weeks washout period
22 patients treated with 60 mg methylphenidate daily for 6 months (55)	Gait analysis by computerized three-dimensional infrared movement analysis system at baseline, 6 weeks of treatment and 6 months of treatment. Ashworth spasticity scale (30); MRC scale	No statistical difference between baseline and 6 weeks and 6 months of methylphenidate treatment as assessed by Ashworth spasticity scale and MRC Scale. A small increase in gait velocity from 2.56 ± 1.07 km/h to 2.85 ± 0.97 km/h, p = 0.019), which decreased back to baseline at 6 months.	16705687	22 SSP or HSP patients based on clinical dianosis. 6/22 were genetically confirmed to have SPG4 mutations.	0	Open-label study with a longitudinal follow-up