Wednesday 27 March 2019

Interesting Things - Part 2 (diagnostic and nerve growth)

Nerve re-growth

One story caught my eye earlier, that the human brain may regrow nerve cells throughout its life. So I only see this as a news story (https://www.sciencenews.org/article/new-nerve-cells-adult-brains) Re-growth of nerves sounds very positive - of course, for HSP we'd be after the very long nerves rather than just those in the brain.

Some hunting around suggests that there is some re-growth in the spinal column as well - with one patient with SPG4 potentially showing some re-growth (https://hspersunite.org.au/huge-french-study-of-spg4-hsp/)

Diagnostic flowchart

The European Reference Network for neurological diseases (http://www.ern-rnd.eu/) has recently published a disgnostic flow-chart for HSP: http://brain-team.fr/ern-diagnostic-flowcharts/

This flow chart first asks if you have gene panels or genetic sequencing available. If you have then use this, otherwise only test for SPAST/SPG4 (unless you additionally have ataxia). Beyond this it is a diagnosis of exclusion - and a long list of tests which could be done and other things to look at have been suggested to end up with an HSP diagnosis if all other things have been excluded.


Drug re-classification

Some of you may use Gabapentin or Pregabalin for your HSP. If you're reading in the UK these two are changing their classifications, they will (from 1st April) be "schedule 3 controlled drugs" which means that you may have more difficulty getting hold of this medicine. It seems that additional information needs to be given on the prescription, the amount you can receive may be reduced, and getting repeat prescriptions may be more tricky.
https://www.england.nhs.uk/publication/rescheduling-of-gabapentin-and-pregabalin-as-schedule-3-controlled-drugs/

Friday 22 March 2019

Another interesting HSP paper

It seems like a busy time for HSP research at the moment. Readers may be aware that I published a post recently about my most interesting papers from 2018 (https://hspjourney.blogspot.com/2019/01/2018-hsp-research-overview.html). There are a number of other interesting things which have come out since then. This post covers one.

Researchers in Italy have published a review of HSP treatment approaches. You can read the full text of this here: https://www.frontiersin.org/articles/10.3389/fneur.2019.00003/full -

My summary is that there isn't much data out there which supports the approaches being used on a day-to-day basis to treat HSP. I find it interesting that there is no report of oral baclofen, tizanidine or diazepam are included, and the overall conclusions that there are not many studies is also borne out as there is no discussion on treatment of the other HSP symptoms - pain, continence or studies showing treatments like physiotherapy or walking aids improving things.

My highlights (with liberal use of copy,paste,cut) of the paper are:

Introduction

There currently exist no specific therapies for HSP, and treatment is exclusively symptomatic, aimed at reducing muscle spasticity, and improving strength and gait. The authors set out to perform a comprehensive systematic review of the available scientific literature on the treatment of HSP, Two authors independently analyzed 27 articles selected on the basis of a series of inclusion criteria. The 27 articles focused on pharmacological treatment (n = 17 articles), physical therapy (n = 5), surgical treatment (n = 5).

Pharmacological Treatments

Gabapentin
Gabapentin is an antiepileptic and antinociceptive drug. To evaluate its antispastic action, gabapentin was tested in a double-blind, prospective, crossover placebo-controlled trial in patients with SPG4-linked hereditary spastic paraplegia. Ten adult patients were included. Overall, no statistically significant clinical differences were found between gabapentin and placebo. The quality was rated as good, however the assessors urged caution, given the very small size of the sample considered.

Progabide
Progabide is a highly selective GABA receptor agonist. In a double-blind crossover trial involving two 14-day treatment periods, progabide was compared with placebo in 16 adults with spasticity, two of whom had a clinical diagnosis of HSP (with an unspecified molecular etiology). Outcome measures were: spastic hypertonia, reflex responses and flexor spasms . Progabide was found to significantly reduce spastic hypertonia, reflex responses and flexor spasms. The quality of this study was rated as moderate. However, only two patients had an HSP-related form of spasticity. Furthermore, the treatment was short-term and the selected outcomes were not clinically significant.

Dalfampridine (4-Aminopyridine)
Dalfampridine is a voltage-dependent potassium channel blocker used to improve walking ability in patients with multiple sclerosis. We reviewed two prospective, uncontrolled, open trials. The first study included 12 adult patients affected by HSP who were treated for 15 days. After treatment, patients were categorized into two groups: “responders” (n = 6 patients), who showed an improvement of >20% in any of the three tests (TWT, SPRS, and MSWS-12), and “non-responders” (n = 6 patients), who by definition recorded improvements of < 20% in all tests. However, these results must be interpreted with caution for several reasons: no control group was included and no information was given on the HSP patients' phenotype (pure/complex) or disease duration, and their molecular etiology thus remained uncertain. Overall, the quality of this trial was rated as low (8/22).

The second study enrolled five adult patients, all with definite HSP: four with an SPG4 form, and one with an SPG15 form. Dalfampridine, 10 mg, was administered orally twice daily for 15 days. Patients exhibited significantly improved assessment scores. This trial was uncontrolled and the sample size small, and overall its quality was considered low (7/22).

Recently, six patients with SPG11 received 10 mg dalfampridine twice daily for 12 months. A global improvement in motor function was observed and less fatigue was reported. The patients showed an improved ability to concentrate.

Botulinum Toxin Injection
Intramuscular injection of botulinum toxin type-A (BoNTA) is one of the primary treatments for focal spasticity. In an uncontrolled clinical trial, 15 adults with confirmed HSP were treated with BoNTA injections in each triceps. This was followed by 18 weeks of daily stretching exercises. After treatment, mean comfortable gait velocity increased significantly, whereas balance and the other functional measures remained unchanged. The quality of this study was low (6/22).

In another study  involving 19 unselected adult patients with a probable diagnosis of HSP, treated with BoNTA showed some improvements. In a retrospective study 10 patients with HSP received BoNTA and physical therapy for 5 years. Over time they showed significant improvements both in muscle tone and in baropodometric examination parameters. Overall, the quality of these latter case studies was very low.

L-Dopa
L-Dopa is an amino acid precursor of dopamine, essentially used in Parkinson's disease. Six open-label, uncontrolled studies were identified:

  • Two siblings (aged 16 and 18 years).
  • One subject with HSP and parkinsonism 
  • Two studies described five additional subjects with HSP resulted in a partial improvement of motor symptoms. 
  • A mother and a daughter with SPG8 whose spasticity improved after L-Dopa therapy. 

These studies were considered anecdotal, and of barely acceptable quality.

Cholesterol-Lowering Drugs
SPG5 is a rare subtype of HSP.  In one study, two adult siblings were treated with cholesterol-lowering agents: one received simvastatin for the first 12 months, after which ezetimibe was used in combination with simvastatin for a further year. His sibling received only ezetimibe for 12 months. In both patients an SPG5 biomarker significantly decreased, whereas muscle strength scores did not change. The quality of this study was rated as very low (2/22).

In a more complex study in SPG5, atorvastatin was used for 9 weeks in 14 patients and the primary endpoint was a reduction in serum 27-OHC levels. Atorvastatin, but not placebo, reduced serum 27-OHC by 31.5% (p = 0.001). This was deemed to be a high quality (20/22) study, despite being a short-term trial that did not consider any clinical outcome parameters and failed to clarify the long-term impact of cholesterol-lowering agents on disease severity.

A phase II therapeutic study of atorvastatin, chenodeoxycholic acid, and resveratrol was carried out in 12 SPG5 patients. Although well-conducted, the quality of this study was deemed to be moderate (9/22) due to the absence of randomization and blinding.

Collectively, these studies offer the first illustrations of a causal treatment strategy in the SPG5 form of HSP. However, aspects still needing to be investigated include the clinical efficacy of cholesterol-lowering drugs and the question of whether biochemical parameters reflect neurological impairment in vivo. On the other hand, these preliminary data suggest that it would be useful to evaluate the long-term effects of these drugs in SPG5.

Betaine and Folinic Acid
The literature search revealed two case series of patients with complicated HSP  who showed clinical improvement after treatment with betaine and vitamins. In the first report, Four patients were  described four patients. All patients were treated with vitamin B12, folic acid, folinic acid, and betaine anhydrous. Betaine treatment resulted in a rapid and sustained reduction in homocysteine levels in all the patients and, over a period of nine to 15 years, improved the conditions of three of them. However, no objective clinical tools were used to assess efficacy.

The second report described two adults treated with betaine, folinic acid, vitamin B12, vitamin B6, and ASA as prophylactic agents. One year after starting treatment, their SPRS score decreased from 14 and 15 to 12, respectively.

Overall, these clinical studies suggest that betaine and vitamin supplementation may be useful in the rare cases of HSP caused by MTHFR deficiency. However, they were open-label and uncontrolled studies, and their quality was rated as very low.

Physical Therapy

Electrical Stimulation
No RCTs have been conducted to assess the effectiveness of electrical stimulation in HSP treatment. A single published study met the inclusion criteria for this review. The case report in question described a 26-years-old man whose motor function improved after treatment with electrical stimulation of the quadriceps and anterior compartment musculature two to three times per week for 3 months. Gait analysis performed revealed a 27% increase in velocity, associated with increases in cadence, and right step length. The quality of this case report was rated as very low.

Robotic Gait Training
One uncontrolled trial aimed to test the effectiveness of a robotic-aided intensive training program in adults affected by pure HSP. The study included 13 adult patients undergoing rehabilitation treatment (three sessions per week for 6 weeks). At the end of the treatment, statistically significant improvements were observed in some measures, including quality of life. The quality was rated as low.

One study described the outcome of robot-assisted gait training combined with physiotherapy in a 28-years-old man with pure HSP. This patient underwent 25 training sessions over a period of 6 weeks, after which functional assessments showed some minor improvements in walking speed and balance. The quality of this case report was considered to be very low.

Hydrotherapy
The effectiveness of hydrotherapy treatment in improving locomotor function in patients with late-onset HSP was evaluated in a small, uncontrolled trial. Nine HSP patients underwent a 10-week course of hydrotherapy based on 45-min sessions of treatment. Significant pre- vs. post-therapy differences were observed in some measures, and the integration of these measures provides some insight into locomotor inefficiencies and compensatory gait strategies implemented by individuals with HSP. The design of this short-term trial was poor and the study was deemed to be of low quality.

Physical Therapy
There exist no clear indications on appropriate types and timing of physical therapy in HSP. One report described two adult siblings with HSP who underwent an intensive 8-weeks stretching, strengthening, and functional exercise program, administered in 60- to 90-min sessions (daily, 6 days/week). All measures showed improvements at the end of the intensive treatment program. Although the results of this study appeared promising, it lacked precise data on the improvements reported. Its quality was rated as very low (2/22).

Interventional and Surgical Therapies

Intrathecal Baclofen
Baclofen is a muscle relaxant and antispastic agent that acts by activating GABAB receptors. It can be administered orally or intrathecally. Intrathecal baclofen (ITB) has greater therapeutic efficacy and less systemic toxicity compared with oral preparations.

In an open study, 14 out of 16 adult non-responders to oral antispastic drugs were implanted with a pump for intrathecal administration of the drug. The treatment was found to reduce lower limb spasticity in all the patients. Walking ability was improved. The quality of this study was rated as low showing that there is still a lack of recommendations on the use of ITB in HSP.

Dorsal Rhizotomy
Selective dorsal rhizotomy (SDR) is a neurosurgical procedure serving to selectively destroy problematic nerve roots in the spinal cord. It can be used to relieve spasticity in cerebral palsy, but has also been tried in HSP.

In an uncontrolled prospective trial, four adults with an undefined form of HSP underwent the procedure. The average score improved after treatment, with no significant difference between the scores at 1 and 2 years after SDR. Lower limb spasm scores also improved significantly. All these improvements remained stable throughout the follow-up period, with no local or general complications appearing in any of the four patients. Overall, the quality of the study was considered low.

A retrospective study of four HSP children who underwent SDR was reviewed. All the patients showed reduced lower limb spasticity after the procedure, and this change was maintained over long-term follow-up (range 44–252 months). However, progressive functional decline was observed in two siblings diagnosed with the infantile-ascending form associated with mutations in ALS2. This study was rated low quality (2/22).

Discussion

No recommendations on new therapies are emerging, and it is depressing to note that these patients continue to be treated in the same way as they were in the “pre-genetic era.” In short, symptomatic treatment remains the cornerstone of HSP management. As things currently stand, few trials have evaluated specific HSP treatments, while there is a paucity of robust clinical trial data supporting the efficacy of even the most widely used symptomatic drugs.

There is no doubt that the search for an effective treatment for HSP needs to be stepped up. At present, several preclinical avenues of research are offering interesting findings that may open the way for specific pathogenetic therapies in selected forms of HSP and promising data are begging to be used to improve clinical efficacy. Tests or scales adopted to measure fatigue and quality of life might serve in general in HSP but could be inappropriate in more complex setting or in young children. Today well-designed clinical trials of symptomatic drugs for HSP treatment are clearly lagging behind.

There is a need for RCTs with sufficiently large samples and precise biological outcome measures, to evaluate the efficacy of the treatments already in use in current neurological practice.