Update on research analysis

I've been keeping myself busy over the last few weeks. Back in 2013 I had downloaded all of the papers on the PubMed database which referenced HSP, but I hadn't really done anything with them. I've now undertaken two passes through the papers getting ready to put a more in depth analysis up on a new page.

I've limited myself to papers with abstracts - so I've got some better information on what information the paper contains, there are just over 1000 of those.

My first pass was to look through the papers and give them a "usefulness" rank. Papers which I thought would be very useful were given the rank of 10, with smaller numbers for papers which were less relevant. My "default" rank for papers on HSP which aren't obviously useful is 4, which allowed me to score lower than this for papers which mention HSP in passing rather than being specifically about HSP (or some aspect of this).

My second pass has been to read all of the abstracts again and divide the papers into categories. Evan Reid had indicated at the AGM in the summer that HSP research could be divided up into three zones, and I wanted to see what these zones looked like. I began with the papers which I had ranked 10, and then worked down the list until I got to rank 4, so there are some 800 papers which I've done this for.

This post is my initial results. I used the set of results which I had previously downloaded, so this includes papers up to some point in 2013.

When I came to go through the papers and categorise them it was obvious that some of my rankings may need adjusting, and that by the time I got a reasonable way through the process my initial thoughts on what the categories should include have changed. Basically, I'm just saying that this is a work in progress.

This is the table of topics:

Topic	Earliest	Latest	Papers
Treatments	1984	2012	20
Clinical studies	1980	2012	93
Clinical and Genetic studies	1981	2013	51
Genetic studies	1996	2012	67
Genetic identification	1983	2013	241
Assessment tools	1975	2013	25
Reviews	1953	2013	34
Models	1998	2013	62
Biology	1976	2013	100
Prevalence	1985	2009	11
Multi-illness studies	1975	2013	113
Uncategorised	1946	2013	376

I've used the "biology" category as a bit of "not sure" category at times, so there may be a few papers in this topic which are not strictly to do with the biology of HSP. Other papers cover a few different topics, so there will be many papers which could easily be put into different categories.

I suspect that readers would be most interested in the treatment category. These papers comprise:

9 papers on Baclofen
3 papers on Botox
2 papers on Levodopa
1 paper each for: Gabapentin, Electrical stimulation, Progabide, Methylphenidate and Ranibizumab
There was one further paper which looked generally at matching drugs to diseases based on genetic analysis.

In addition to some of these papers, my most relevant papers covered:
Depression, bladder function, cognitive performance, sensory function, continence and the prevalence of HSP. All in all there are about 30 papers which I thought would be most useful.

This is how all of those categories look on a graph:

Next steps:

Create a page on this blog to hold such information
Add papers published since end of last trawl
Classify papers with ranks of 3 and below
Review classification and topic designations

Ultimately I'm aiming to draw out analysis for different aspect of HSP, but I'm a way off that yet.

A trip to the bowel doctor

Today I went to see the colorectal surgery team, so thats another part of the health system ticked off. As a reminder, this was suggested by the HSP specialist as I'd been experiencing bowel urgency problems, and this is not viewed as a common HSP symptom.

So, I wasnt sure what to expect on this visit, could it be about seeing if we could rule out other things, or would it be about management of the situation. It turned out to be a bit of both.

In the ruling out of other things front: I was examined, and things are not quite as expected, so I'll have a further appointment to have some nerve tests done, and then we'll hopefully know a bit more. The specialist I saw has not had any previous experience with HSP.

here's a description of things I've learnt about the bowel today:

Your bowel is controlled by two sphincter muscles, an inner one and an outer one. The inner one stays tight all of the time, and its main job is to prevent leakage. This muscle is not one which you have control over. The outer sphincter also stays closed all the time, but you control over this one, which allows you to choose when you want to go.

There are two types of incontinence - one where you know that you've got a problem - and the issue is getting to the toilet in time, and another when you dont know you've got a problem - and you end up with a mess to deal with.

On the management front:

Management strategy 1: It is possible to re-train the muscles for some people. But the general thought was that as the correct messages are likely as not failing to get through, this strategy may not work.

Management strategy 2: Use Loperamide / Imodium. Some people are on this all the time. This can help by making your stool/faeces/feces firmer, and therefore giving a bit more time to get to the toilet. However, as my urgency issue is not predictable this makes it difficult to use pro-actively. It could be taken when loose stools are noticed, or taken when it is known that you may have difficulty finding a toilet in time.

Management strategy 3: This was mentioned in passing, and not appropriate for me now. You can get a home colonic irrigation kit. Some people will use this 2-3 times a week, and others will use this after they have been once, which then makes you empty for a while, meaning that you cant have any incidents.

These are the management strategies which were mentioned, suggesting that there are some more. Perhaps I'll find out more at my next appointment. The one which springs to mind is checking that my diet helps the situation rather than hinders it.

So, in conclusion, it looks like I'll need to go to the chemist and get some imodium to add to my collection of tablets. I'll need to understand how quickly this works and how long it lasts.

Reversing Paralysis - Spinal Cord Regeneration

This week (in the UK) there has been a very interesting story in the news - A man in Poland has been able to walk after surgery to repair his spinal cord. He had been paralysed from the chest down after a knife attack in 2010.

You can read the news story here:
http://www.bbc.co.uk/news/health-29645760
http://www.theguardian.com/science/2014/oct/21/paralysed-darek-fidyka-pioneering-surgery
http://thenextstepsci.org.au/research/

This was featured in the BBC Panorama program, which you can watch on the BBC iPlayer until Oct 2015: http://www.bbc.co.uk/programmes/b04mm8zl

I watched the program after hearing about the story on the news, with a thought that this may yield a treatment for HSP. Here is my take on the story (as presented on Panorama).

Researchers had identified that the olfactory system (sense of smell) was the only system in the human body where nerves were continually regenerated throughout life. In all other systems nerves, once damaged, do not re-grow.

Much research has been done over many years to identify if the olfactory cells could be used to encourage re-growth in other nerve systems, with work being undertaken at UCL (University College London) -  Professor Geoffrey Raisman featured on the program. They had undertaken research with mice which had shown potential. Olfactory ensheathing cells (OECs) were shown to regenerate the olfactory nerves, and the research involved extracting these cells and transplanting them to examine if they would regenerate other nerves.

The research had concluded that the cells needed to be extracted from the olfactory bulb, which is located in the brain. This means that very invasive surgery is needed to extract them - the program didnt go into the details of the cell extraction.

A team in Poland, led by Dr Pawel Tabakow of Wroclaw Medical University, was keen to take this further. Darek Fidyka had been paralysed from the chest down after a knife attack in 2010. He volunteered to undergo the surgery to extract the cells from his olfactory bulbs. These cells were then grown in the lab for a couple of weeks before being injected into the spinal cord at the injury site.

The story showed the operation to implant the cells into the spinal cord. The damage site was bigger than expected from the various MRI scans - half an inch (10-15mm) rather than a nice clean slice. There was a small section of cord which was intact, but most of it had gone in the attack. The view was that whilst the cells would encourage nerve re-growth they would not bridge this gap, so a section of nerve from the ankle was inserted to form a bridge. Some cells were injected into the section of the cord which remained, but most were injected into the spinal cord either side of the bridge. They were only able to extract a very small amount of these cells, which remained a small amount even after 2 weeks growth in the lab. It was quite amazing to see the surgery.

The surgery was undertaken in 2012. After a few months intense physiotherapy there was some activity, and this developed over the next two years such that there was muscle re-growth, control from the brain and the brain was receiving feedback - i.e. there was re-establishment of 2-way communication through the spinal cord. Darek was also able to regain some bladder, bowel and sexual function again. After two years he was able to walk again and is able to drive.

This is one example. The research had been conducted to demonstrate that the surgery and cell implants had done the job, although there is still some scepticism. The next steps for this research is to repeat the process in a few more patients which give a much more robust dataset to demonstrate that it works.

The story mentioned that the results were published, so that the scientific community can scrutinise them. That article (or at least an abstract for it) can be found here:
http://www.ncbi.nlm.nih.gov/pubmed/25338642

My take on the key points are:

• Invasive surgery is needed to extract the cells
• Invasive survey is needed to inject the cells into the spine
• The procedure was shown to work at a small site where there was relatively clean damage of the cord
• Other sections of nerve can be used to act as a bridge to replace missing parts of the spinal cord
• It is a long and hard process getting movement back
• The repair seemed to have benefits in other lower body functions

So the question I consider is: how likely is it, given that our spasticity is like paralysis, that this kind of treatment could be used for HSP?

My understanding is that the degeneration of the nerves in HSP is along the nerves rather than across them, and they degenerate from the end, rather than at a place mid-way along the spinal cord. The main problem, from my limited understanding, is that in HSP the nerves degenerate from the end, so I suspect that even if a long piece of nerve could be used to bridge over the degenerated area of the spinal column the issue will be that the join between the upper motor neurons and lower motor neurons would still be missing. So my suspicion is that unless a "bridge" can be created between upper and lower motor neurons, this is unlikely to help people with HSP in the short term.

However, the program was keen to point out that this effectively showed proof of concept, and that the researchers were keen to share their knowledge. This may mean that the technique or the knowledge may be used to help understanding or provide new ideas for treatment. The comparison was made in the programme with antibiotics - we take these as a given now, but re-wind about a hundred years (to 1928) and Alexander Flemming first discovered the antibiotic effects of Penicillin. Now we have many many more antibiotics which are much more powerful than Penicillin, but that was the starting point. Perhaps that kind of path can follow from this process.

Symptoms Update (and a trip to the Doctor)

I mentioned a few months ago (in May: http://hspjourney.blogspot.co.uk/2014/05/hsp-clinic-visit.html) my visit to the HSP Clinic at the National Hospital in London. Not long after that I received a copy of a letter which had been written to my doctor in order to take further the various things which we had discussed at the HSP Clinic.

It was only after a few months had passed that I realised that nothing seemed to be happening, and I popped in to the doctors. Waiting in the box behind the counter was a prescription for Detrusitol, which had been sitting there since June, but nothing else had happened. It seems that I should have made an appointment to discuss these. So, that is what I have done.

The main function of my trip to the doctors was to move forward the various appointments that had been suggested at the Clinic, and these are now starting to come through. Readers outside the UK may be interested to know that I get a letter which allows me to go onto a website and choose my own appointment (and if it wasnt a specialist I was seeing, I'd be able to choose where I went too).

So, thats put the whole thing back by a few months, and its made me realise that I have to be the one who drives the process forward. Despite any best interests or good meaning, there is only one person who is responsible for me seeing the various specialists, and that person is myself [This is something I picked up from a seminar at work some years ago in the context of personal development - you are the only person responsible for your training and progress. There is no point trying to blame someone else/the system if you dont do what you want to do].

Back to the first part of the topic title - symptoms update....

I've now been taking Detrusitol for about 3 weeks. My prescription is for Detrusitol XL (a 4mg dose) and I take one tablet per day. The active ingredient in this medicine is tolterodine, and it is taken for overactive bladders. Other names for this medication include Detrol, My doctor said that there are other medicines available which achieve the same outcomes.

I noticed a reduction in urgency pretty immediately with this medicine, which is a good thing! I've not noticed that I've been going to the toilet any less frequently, but the drop in urgency is a real benefit.

The most common side effect is a dry mouth, which I get. Of course, my first reaction with a dry mouth is to have a glass of water, which perhaps goes somewhat against the grain of the objectives as I'm just filling my bladder up more quickly!

I havent really noticed any other side effects, which means that either they are not there, or they are not at a level which I would notice. The other common ones include tiredness, fatigue and headaches. I get bothered by these sometimes anyway, and I've not noticed them appearing more often in the last few weeks. 

The other main symptom update to report is my use of the stairs. I realise now that I'm actively using the bannister/hand-rail to get up and down to majority of stairs, whereas a few years ago I didn't need to at all. This is a subtle change. I do this more for steadiness than for balance/trips/falls, and I can still nip up and down stairs without using them. Just yesterday evening I arrived back to my nearest train station and walked up the steps to cross the footbridge - the handrails were filthy, but I still continued to use them (it had been a long day, I'd been on the go for about 17 hours). I must send the station an e-mail about this.

One final point for today on symptoms is to note that I bought a new pair of shoes the other week. I only mention this so when I next need to replace them I can find out how long I've had them.

Various Tolterodine / Detrusitol links:
http://www.patient.co.uk/medicine/tolterodine
http://en.wikipedia.org/wiki/Tolterodine
http://www.medicines.org.uk/emc/medicine/7685/SPC/Detrusitol+XL+4mg/
http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?condition=Urinary%20retention%20and%20incontinence&medicine=Tolterodine%20tartrate&preparationTolterodine%204mg%20modified-release%20capsules
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a699026.html
http://www.nhs.uk/medicine-guides/pages/selectorshow.aspx?medicine=Detrusitol
http://www.netdoctor.co.uk/seniors-health/medicines/detrusitol.html

Autumnal Survey 2014

Update: This 2014 survey is now closed. For details of the results of this survey and any current surveys, please see this page: http://hspjourney.blogspot.co.uk/p/my-on-line-resarch.html

Original Post:
After the success of my survey last year, the results of which has given me my most read page, I decided to undertake another survey this year.

My main focus for this survey is medication so that I can understand the range of medication used by people with HSP. So I've put a handful of questions together about this. I also touch on diet, exercise and relaxation to get a more complete picture.

Like last year I will collect results until around the end of the year and analyse these to publish on rare disease day 28th Feb 2015.

Also like last year, all questions are optional, and I don't collect any personal info apart from your name. If you took part last time, I'd appreciate using the same name to allow tracking.

I would appreciate any readers with HSP to complete this.
http://www.surveygizmo.com/s3/1797674/HSP-Medication-diet-and-exercise

Since I published the results of last years survey there have been a few more responses which I can analyse.

The ALS Ice Bucket Challenge

Many people have seen or heard of the ALS Ice Bucket Challenge. I watched this through facebook and it circled closer and closer to me with friends and family being challenged and then nominating on. [Feb 17 - realised I hadn't included the video, now at the bottom]


I had spotted that ALS was a mis-diagnosis for HSP in my survey last year, and so I thought about the similarities and differences between them.

So, I start with a definition:
Motor Neuron Disease can refer either to the most commonly occurring form - ALS (Amyotrophic Lateral Sclerosis) also known as Lou Gherig's disease, or to the broader spectrum of conditions.

Motor Neuron Diseases (MND) are a group of neurological disorders that affect motor neurons in adults and in children.  Motor neurons are specific types of cells that control voluntary muscle activities such as speaking, walking, and breathing.  http://www.alsconsortium.org/motor_neuron_disease.php 

Everyone who has looked up HSP on the internet must have read "Hereditary Spastic Paraplegia (HSP) is a group of rare, inherited neurological disorders" (today, copied from the SPF website). HSP is a neurological disease because the long nerves in the spine are gradually degenerating - the nerves are the neurological system (paraphrased from HSP Research Foundation).

HSP

The one paragraph description of HSP (with parts borrowed from both previous links) is:
The primary features of HSP are spasticity and weakness in the legs, varying between individuals. There is progressive difficulty walking and symptoms worsen over time. Initial symptoms are typically difficulty with balance, stubbing the toe or stumbling. Changes begin gradually. As the disease progresses, canes, walkers and eventually wheelchairs may become needed, although some people never require assistive devices. A wide variety of symptoms are observed across cases and over time, including balance, fatigue, bladder and back pain. The majority of individuals with HSP have a normal life expectancy. [Jan 2015 update - this refers to people with uncomplicated HSP]

ALS

Whereas ALS describes as (NHS: http://www.nhs.uk/conditions/Motor-neurone-disease/Pages/Introduction.aspx)

The symptoms of motor neurone disease begin gradually over weeks and months. Common early symptoms are: weakened grip, weakness at the shoulder, "foot drop", dragging of the leg, slurred speech.  As damage progresses, symptoms spread to other parts of the body and the condition becomes more debilitating. Eventually, a person with motor neurone disease may be unable to move. They may also find communicating, swallowing and breathing difficult. The condition is not usually painful. ALS is a severely life-shortening condition for most people. Life expectancy for about half of those with the condition is three to four years from the start of symptoms.

PLS

Primary lateral sclerosis (PLS) slowly gives rise to progressive weakness in voluntary muscle movement. The first symptoms are often tripping or difficulty lifting the legs. The disorder often affects the legs first, followed by the body, trunk, arms and hands, and, finally the bulbar muscles (muscles that control speech, swallowing, and chewing). PLS progresses gradually over a number of years, or even decades.  Life expectancy is normal.

Summary

I wont go further and list any other types of motor neuron disease, but note the similarities:

• Early symptoms for all three are similar.
• All three cause upper motor neurons to degenerate (those from the brain down into the spine)

And the differences:

• ALS and PLS progress to more parts of the body
• Life expectancy for ALS is reduced.

It depends where you read to see if HSP is included within the motor neurone disease list or not. I certainly found some websites which did and others which didnt.

I take the view that all this ALS ice bucket challenge activity raises awareness of diseases caused by degeneration of the nervous system, and that with all such causes it is down to the participants to personalise their message to encourage others to donate money. On this basis when I was nominated I donated to the UK HSP support group, and several friends and family who were nominated at around the same time did so as well.

Naturally, I write this with my own diagnosis safely under my belt, but having read up more about these other diseases, I can picture the trauma which people go through before getting their own diagnosis.

If there are any readers who were not lucky enough to be nominated for the ice bucket challenge and would like to make a donation, then I encourage you to do so, even if you dont empty a bucket of icy water over your own head. If you're stuck to find a relevant charity which you would like to donate to, then why not choose the UK HSP support group? http://www.hspgroup.org/ 

You can read Wikipedia's ice bucket challenge story here too: http://en.wikipedia.org/wiki/Ice_Bucket_Challenge it would seem that golfer Chris Kennedy was the first to nominate/donate for ALS on July 15 2014, and former basketball player Pete Frates who has ALS and is a patient advocate began spreading the ALS word through Twitter. 

Ataxia

I think it is worth pointing out here as well, the other major mis-diagnoses for HSP in my survey were ataxias (MS, ataxia, Spinocerebellar Ataxia)

(http://www.nhs.uk/Conditions/Ataxia/Pages/Introduction.aspx) These are diseases which affect co-ordination, balance and speech, usually as a result of damage to the brain. The symptoms of ataxia can affect every part of the body and cause difficulties with: walking, balance, speaking, vision, swallowing or tasks that require a high degree of physical control, such as writing and eating. There are currently more than 50 recorded types of ataxia, which fall in three broad categoriess.

• acquired ataxia – from trauma, stroke, multiple sclerosis (MS), brain tumour etc.
• hereditary ataxia – develops slowly over many years from underlying genetics 
• idiopathic late onset cerebellar ataxia (ILOCA) – progressively damaged over time for reasons that are still unclear

The key difference from HSP is that Ataxias affect the brain rather than the nerves, even though some of the symptoms appear the same. I note, of course, that complex forms of HSP affect the structure or functioning of the brain, and I can picture the trauma associated with difficulties getting a clear diagnosis.

It is also clear that there is a fair degree of cross-over here - some of the HSP groups on Facebook are for HSP and PLS people, and indeed that is the focus of the US SP Foundation: http://sp-foundation.org/. Also the SPATAX network groups together researchs in spastic paraplegia and ataxia: http://spatax.wordpress.com/.

Feb 2017 Video Addition

So, you want to see me getting iced? - here it is:

AGM2014: Sportability - David Heard

This post is the final one in the set of my AGM posts. Those that were there know that after this presentation Jon Marsden spoke about telehealthcare and telerehabilitation, but I've already grouped that together with the other Plymouth talk previously.

David talked about Sportability, which he was one of the founding members of. Sportability was set up about 25 years ago, with the aim of providing access to sporting events to people with paralysis. This would include not only people with HSP but also people with spinal cord injury, stroke or MS.

David shared with us some stories about people who had used Sportability and gave us examples of what people had felt after taking part. The range of sports which are on offer include riding quad-bikes, archery, canoeing, sailing, scuba diving and so on. (their website http://www.sportability.org.uk/index.php?id=3 says "archery, angling, abseiling, canoeing quad-biking, gliding, clay pigeon shooting, motor-sport and more." the list of activities also includes falconry, jet-skiing, marshall arts, tennis and blokarting)

Some people who participate in the activities may have been keen participants of those sports earlier in their lives, whereas others will be trying sports for the first time. People feel a range of emotions from this, some of which are positive - for example, there is excitement and the feeling that something can be done again, and there may also be negative thoughts - for example reinforcing the perception of being disabled.

David said that one of the main outcomes from people taking part in sport were psychological benefits. Undertaking a sport either again or for the first time can begin to re-build a persons confidence and self esteem. These activities can also help to re-define someone's horizons, and people can begin to think that if they can do this, then what else can they achieve. Overall, participation in such activities can help put some purpose back into someone's life as well as getting a good shot of adrenaline as well.

David had a good selection of photos and videos of people taking part in some of these, and it was good to hear the genuine happiness and excitement of the participants. David also shared with us how different some bookings can be, in some instances people call up with a definite idea of what they want to do and are prepared to travel to take part, whereas others are not sure and David gave examples of the "negotiation process" with some people in order that they convince themselves that they really do want to take part.

Sportability aims to remove barriers to participation. So, all activities are free of charge, and there are a number of regions all over the country offering different activities. the Sportability strap line is "taking the dis out of disability". Sportabiliy is a charity and all activities are funded by donations, so people may like to consider this as a good recipient for fundraising activities they organise or take part in.

You can find out more about Sportability here: http://www.sportability.org.uk/

Personally, I hadnt really thought about this side of things before, but I can see that this is a really good way of helping people get some self-improvements. A lot of the comments that David made tied in well with what was said at the mood management course I went on a few months ago (http://hspjourney.blogspot.co.uk/2014/04/stress-and-mood-management.html) - Exercise and being with other people reduce stress, Taking part in a new activity can help break out of the depression cycle,  Getting a rush of adrenaline in a new situation may get you a new set of symptoms and help you think about anxiety differently.

I can also picture how important the potential for allowing people to re-define their horizons is, and I think that many people will get a lot more out of doing this than they ever thought about beforehand. This sounds like an excellent thing to bear in mind down the line when I'm less able to do what I want.

AGM2014: HSP Research, the Historical Perspective - Dr Evan Reid

Dr Evan Reid gave a historical perspective on HSP research. He initially showed a graph with the number of research articles which cover HSP, ranging between 1947 and now, and described that research into HSP has fallen into three phases.

The first phase - the Clinical Phase, began with the original work of Strumpell and Lorrain, with Strumpell describing the condition initially, and Lorrain fleshing out the detail some more. Another researcher Dr Reid mentioned in this phase was Anita Harding who was working on the clinical definition of HSP until her death in 1995. [Various links with info/obituaries below].

In this Clinical Phase, which ran through till around the 1990's definitions were made of the:

• different types of HSP - pure and complex, 
• features/symptoms of HSP
• pathological anatomy
• inheritance modes
• different complex sub-types.

During the late 1980's / early 1990's the next phase started, the Genetic Phase, which ran through until the 2000's. One researcher noted was Sue (Susan) Kenwrick, who was involved with the first genetic identification of HSP in 1984, which was identified as SPG1. [Various links with info below]

In 2007 there was a leap in technology, with Next Generation Sequencing which allowed research to progress at a greater rate and at a cheaper cost than previously, now at about £5,000 per genome. [The first human genome to be sequenced cost $100m, and costs have dropped ever since, roughly following Moores Law until the advent of next generation sequencing, with costs now at $8k per genome http://www.genome.gov/sequencingcosts/]. 

Dr Reid said that new HSP genes were continuing to be identified, and suggested that overall there might be 100-200 HSP genes in total.

The next area where the sequencing is likely to go is in the investigation of modifier genes. There are some genes which are protective, and others which are enhancing of the action of a gene - i.e. the function of one gene can be helped or hindered by other genes.

In the background, we always have to remember what genes do. The function of a gene is to produce a protein. When a gene is mutated, like various genes are with HSP, then the end result is either that the protein is not produced at all, or there is an abnormality in the production (which may mean too much protein in produced, or not enough, or the protein is not produced properly).

This leads us on to the third phase of HSP research, the Biological and Treatment phase, which began around 2001. To describe this phase Dr Reid gave us a quick lesson in cell biology so we could understand what happens with HSP. This lesson takes the form of an analogy:

• Treat a cell as a company. It is semi-autonomous. 
• The nucleus of the cell is the head office, in charge of the company.
• The DNA is the CEO of the company.
• The endoplasmic reticulum (ER) and the golgi apparatus make up the manufacturing department of the company. Proteins are made by the ER and the golgi apparatus packages them up for despatch.
• The plasma membrane, at the edge of the cell is responsible for exporting the proteins that are made.
• There are also receptors on the plasma membrane which undertake market research, identifying if more (or less) proteins need to be made.
• The power for the companies operations comes from the mitochondria.
• Within the cell there are microtubules which are like rails, allowing proteins to be moved from manufacture to export
• There are special motor proteins which are used to move things along the rails.
• The packaging of various things as they move within the cell includes endosomes, which also have a sorting function sorting if things should be disposed of, recycled or sent on.

A neuron is a special type of cell. In addition to the cell described above the neuron also has an axon, which is another method of communicating with the outside world. This is a special part of the cell which can extend away from the nucleus a distance many thousands of times the size of the rest of the cell (up to ~1.5m). Within the axon are microtubules which carry information to/from the nucleus. This arrangement means that the transfer of information between parts of the body is very quick, but complex machinery is needed to support this transfer. The axon from a neuron can connect to the cell of another neuron. 

In the majority of types of HSP, the result is degeneration at the end the axon which then progresses. The different types of HSP affect different elements of the axon. Some affect the endoplasmic reticulum (ER), some affect the motor protiens, some the endosomes, and others some of these in combination.

Spastin is a protein which regulates the microtubules within a cell. Its job is to chop them up, which helps to shape or prune them. When you have spastin HSP (SPG4) less spastin is produced, and fewer microtubules are broken up. The essential questions are:

• Why do the microtubules need to break?
• When does a reduction in microtubule breakdown cause HSP? 

Perhaps the wrong receptors are on the surface of the cell, so instructions to grow/stop growing/divide/change/etc. are not received properly. This could then influence the cells behaviour. It has been noted that with HSP BMP signalling is unregulated, but it is not known if this is the cause of HSP or an effect of HSP. If it is a cause, then drugs are available for this.

There are three areas where research in HSP is being undertaken to answer these and other HSP questions:

• Cell biology - using microscopes, stem cells, genetic edits
• Animal models - principally mice, zebra fish and fruit flies
• Human studies - HSP clinics

In summary, the genetic identification of HSP is now rapid, which improves diagnosis and allows testing. Within the cell there is an increase in the knowledge of the functions of the proteins. The proteins associated with HSP have inter-related functions. The use of animal models allows quick progression, and stem cell models are also used.

Currently there are several starting points, with potential treatment avenues identified. Thorough research is required to develop treatments.

As an example of how things are progressing, Dr Reid noted Duchenne Muscular Dystrophy. This is a genetic condition which results in muscle degeneration and death by the mid-20's. Like HSP there is no treatment. However, there has been an overall improvement as a result of the use of combined therapies. In the 1960's 80% of people with Duchenne MD had died by the age of 20. In the 1970's this had improved with 60% having died by the age of 20, and with further improvements in the 1980's and beyond, with some people now living into their 30's.

For HSP, like the three areas of research there are three areas for treatment. The main area is in rehabilitation, where orthotics or FES may be used, or drugs given to mitigate the symptoms, e.g. baclofen. With genetic testing, advice can be given which provides clarity and frames likely progression. The other area is neurology, where assessments are made in clinic and can guide approaches for treatment.

After the presentation there were a few questions, some of which I've built into the text above.

It was asked if spastin could be injected as a treatment. For this to work you'd have to inject it directly into the neuron, which would be difficult to do. It is also very difficult to get spastin isolated by itself.

Stem cell research was touched on briefly, noting that it could be possible in the future to edit the DNA to remove the spastin mutation from stem cells and then re-inject them, but the issue is getting the these to the neurons. Dr Reid noted that at the moment about 10% of stem cell injections resulted in a tumour, but this may be useful in the future.

Post AGM links:

Anita Harding:
http://en.wikipedia.org/wiki/Anita_Harding
http://www.acnr.co.uk/SO09/ACNRSO09_anita_harding.pdf
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1051804/pdf/jmedgene00255-0013.pdf
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1914930/pdf/ajhg00014-0240.pdf

Sue Kenwrick:
Google was playing up, but this text was in the Google cache of the Addenbrookes hospital site, Cambridge. "Sue retrained to become a genetic counsellor after 20 years in scientific research. Her postdoctoral work was based around finding and understanding genes for X-linked monogenic diseases and she was a Lecturer and then Reader at Cambridge University. As a principal, registered genetic counsellor her main role is GC Cancer Lead but she keeps up her interest in general genetics through prenatal clinics and a general clinic at Ipswich Hospital."

SPG1:
http://omim.org/entry/303350?search=spg1&highlight=spg1

AGM2014: The effects of warming and cooling on HSP - Amanda Denton

Amanda reported some work that has recently been completed at Plymouth University. Many people with HSP report that walking becomes more difficult when they are cold, and Amanda reported some work which sought to investigate the effects of heat on nerve and muscle function..

The general symptoms that are reported are that people feel stiffer, that they have more falls, and that it seems to take longer for messages to get from the brain to the legs. This research was undertaken in two parts, and Amanda was principally reporting the second piece of work.

The first piece was undertaken in 2010/11 where participants were subjected to warming and cooling of their legs in the laboratory. These results showed that when legs were cooled there were negative effects, and when legs were warmed there were positive effects. This research can be seen http://www.plymouth.ac.uk/pages/view.asp?page=38252

This first piece of work led to a product trial of some wearable heating pads, as discussed at an HSP support group meeting in 2011. These were neoprene sleeves which could be warmed in hot water and then put on calf muscles on the front and back of the leg. These were tested being worm for periods of half an hour. The second part of the research sought to answer two questions:

1) Can external warming have the same effects as shown in the lab?
2) Is there any benefit from keeping the neoprene on?

The research sought to measure temperature, walking, tapping, blood flow, stiffness and muscle strength - all of which can be measured. Two groups were used, 21 people with HSP and a control group of 16.

The research shows that wearing the neoprene can give the same benefits as shown in the lab. Applying the warming gives a statistically significant increase in walking speed and tapping. The research also showed that there was an increase in blood flow with the neoprene, but this was also true of the control group.

As mentioned, the main part of the trials looked at the effects after applying heat with the neoprene for half an hour, and some investigations were made into keeping the neoprene on. These results showed no clear benefits. The objective is to find practical application for these findings, and Amanda discussed where the research would go next, and the thought is to undertake a case study after Christmas when it is generally cold outside. Amanda noted that people with Cerebal Plasy can report the same temperature effects as those with HSP.

Various questions were asked by the audience including simply replacing one set of warm neoprene with another. Amanda and the others noted that caution should be applied as they have not looked at issues like skin integrity which may come into play - but they did note that the wearing of tight garments may be able to retain some natural heat and affect spasticity. I note that the wearing of many layers can also retain heat, they dont have to be tight to do that then.

After Amandas presentation, Jon Marsden and Kate Winstone took questions about all three presentations.

Another area where research could be undertaken is the rehabilitation of pes cavus (arched feet). There would appear to be no previous work in this area. Pes cavus arises because some muscles become weaker and others become stiffer, and this effect can change over time.

One way of treating this is to use in shoe orthotics/insoles to change the distribution of weight when walking, although it is noted that orthortics can change peoples back postures. Other ways could include high-tech clothes (this reminded me of the high-tech swimming outfits which were "banned" from the London Olympics in 2012) - perhaps a special sock could be designed for pes cavus. Plymouth are looking to undertake research into this, and are seeking to establish focus groups. Various audience members showed their in-soles and shared their experiences.

The final point which was discussed in the question sessions was that of generalising exercises. Each person who is given a set of exercises by their physio has been given them for a reason. As it is easy to spot with a room full of HSP-ers, each has their own way of moving, and this leads me to believe that each person would potentially need a different set of exercises.

The final point, which I'll expand on more in another post was how to find a physiotherapist with a neurology specialisation and an interest in HSP.

First answer - talk to others who have used one and get a recommendation.

Second answer - look at ACPIN (the Association of Chartered Physiotherapists in Neurology) http://www.acpin.net/ There appears to be a load of useful links and resources on this site - hence a further post comingup.

From this site you can also get to the CSP (Chartered Society of Physiotherapy) which allows you to search for people near where you are (in the UK). http://www.csp.org.uk/physio2u/search/table

A quick search here shows one practice which specifically mentions HSP http://www.specialist-physiotherapy.co.uk/ who are based in Kenilworth.

AGM2014: Does physical activity improve quality of life in HSP? - Kate Winstone

Kate Winstone gave an overview of work that is currently being undertaken at Plymouth University. A number of people at the AGM took part in research on the day, and Kate was explaining.

Kate is examining the benefits of physical activity. It is known that there is a lower level of activity in people with neurological conditions, compared with the normal population. It is also known that physical activity can bring an improvement to quality of life.

The general question is would physical activity improve the quality of life? A study has shown that for people with cerebral palsy an increase in physical activity does not lead to an increase in quality of life. Kate is researching what the outcome is for people with HSP.

If her research confirms that increased physical activity does increase quality of life, then follow on work can be undertaken to establish:

• What types of physical activity? - strength or flexibility exercises, for example
• When, over the progression of HSP would this be best? - at the beginning, later on, etc.
• Which types of HSP would gain the most benefit?

Effectively, Kates research seeks to identify if there is a correlation between physical activity and quality of life for people with HSP.

This work should have the following benefits:

• An increased understanding of the importance of physical activity
• Could lead to further research being undertaken
• An increased awareness of HSP
• Provide support for finding.

Kate observed that there was limited evidence for the general benefits of physio on people, which means that it is more difficult to obtain funding for research.

Kate then went on to describe the study being undertaken. She had been contacted by 35 members of the HSP group who wanted to take part, and 22 were being investigated on the day. (I did apply, but the spaces were all full by that time).

The aim of the day was to assess participants using the Spastic Paraplegia Rating Scale (SPRS). Each person went to four different "stations" set up on the day testing:

• Speed of walking/stair climbing
• Muscle power and reflexes
• Memory
• Senses and sensations

After the assessment participants would have to complete an on-line survey, and after that the data needs to be analysed.

Kate will share the results of her research with the HSP group, with those involved with physiotherapy, and she hopes to produce abstracts and get a published paper from this work.

Post AGM Investigations: 

1) Here's one of many possible links showing the relationship between physical activity and quality of life.

http://www.nhs.uk/Livewell/fitness/Pages/Whybeactive.aspx

2) The SPRS can be seen here: http://www.neurology.org/content/67/3/430.short , which concludes: "Application of SPRS requires less than 15 minutes and does not require any special equipment, so it is suitable for an outpatient setting. Interrater agreement of SPRS was high (intraclass correlation coefficient = 0.99). Reliability was further supported by high internal consistency (Cronbach α = 0.91). SPRS values were almost normally distributed without apparent floor or ceiling effect......The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity." 

Whilst the article requires a log-in to see the full text, the SPRS scale itself can be downloaded as an attachment from here: http://www.neurology.org/content/67/3/430/suppl/DC1.

There are 14 steps. the first 13 are ranked on 5 point scale:

1) Walking distance without pause

2) Gait quality

3) Maximum gait speed

4) Climbing stairs 

5) Speed of stair climbing

6) Arising from chair

7) Spasticity in hip adductor muscles (those which bring your legs back in line with your body)

8) Spasticity in knee flexion muscles (those which cause your knee to bend)

9) Weakness in hip abduction muscles (those which move your leg out of line with your body)

10) Weakness in foot dorsiflexion muscles (those which raise your toes or foot up)

11) Contractures of lower limbs (measure of permanent shortening of hip, knee and ankle muscles)

12) Pain due to HSP symptoms

13) Bladder and bowel function

The 14th step is identifying if any of a list of complicating signs are present.

You can also see the SPRS as a part of this fuller form on the SPATAX network website. http://spatax.files.wordpress.com/2013/09/fichecliniquespatax-eurospa-2011.pdf