Cerebral Infarction, Leukomalacia and HIE

Today we welcomed a nearly 3 year old little girl and her family back to Snowdrop for her fourth assessment. She had suffered a cerebral infarction, leukomalacia and HIE, but she also has retinal dysplasia which curtails visual ability markedly. For those of you who are unfamiliar with these terms, please allow me to explain.

(1). Cerebral Infarction. - This refers to a loss of brain tissue in an area, caused by lack of oxygen.

(2).  Leukomalacia. - This is loss of white matter, (the myelin sheath which surrounds axons and enables the electro-chemical signal created in the neuron to travel at great speed).

(3). Hypoxic Ishaemic Encephalopathy, (HIE) is a type of brain damage that occurs when an infant's brain doesn't receive enough oxygen and blood. So really it is another way of framing an infarction.

Even though she has retinal dyslpasia, she made eye contact, pulled my glasses off, (a favourite pastime of children) and I noticed her follow my wife, who was a short distance away. Auditory cognition is now above age level with her previous sound sensitivity having been resolved. Her tactile processing issues also seem to be resolved and socially she is an absolute delight, performing at near age level. Such a friendly, playful little twee, it is so nice to see her making progress.

Snowdrop. - A Week of Developmental Assessments. Week beginning 9th May 2016

We began the week by seeing a 7 year old little boy with ADHD for his second assessment. Such an intelligent, gentle little boy caught up in a whirlwind of his own hyperactivity, but definitely calmer than his first assessment and his attention definitely easier to capture. Sometimes it can take time to slow hyperactive kids down, but I feel we are making progress.

On Tuesday we saw a 4 year old little girl who has PVL and developmental delay. Today was her 7th assessment and although she still has significant problems, she is streets ahead of that 1 year old I first saw who was locked away within herself. She is using her vision beautifully to explore her environment, understanding more language, making choices, crawling on all fours and we are not far away from standing. Like me though, she is totally motivated by food!

On Wednesday we welcomed a 4 year old little boy for his 9th assessment. He has a diagnosis of severe cerebral palsy and was forecast not to live. Yes he still has many problems, but he is absolutely streets ahead of where he would have been and is thriving. His visual and auditory cognition have risen to where they will soon be at the top of the developmental profile, - he can sit, can stand with support and his tactile processing issues are resolved, as is his inner anxiety. His muscle tone is much improved and we now have 3 words of speech, (with many more to come I think). There is a massive difference in his awareness of and engagement with his environment and the people in it. It has taken a while and a great deal of hard work, battling against epilepsy too, to achieve all this, - but look how far he has come in comparison to that initial prognosis, which was as bad as it can get!

On Thursday, we welcomed a 7 year old little girl back for her 3rd assessment. Her diagnosis is cerebral palsy and CVI. Today I watched her visually steering her hands, taking the top off a pen and replacing it with great precision, which is great because hand function is also a problem. Visually and auditorially she is now 'switched on' and has visual and auditory abilities at the top of the profile, is trying to get herself into the 4 point crawling position and has an expanding vocabulary of words. A super assessment with a highly intelligent little girl.

We finished the week by meeting a great new family with a 20 month old little boy who has no formal diagnosis but what the medical people feel looks like developmental delay / cerebral palsy. He is such a bright gregarious little chap, I could have stayed there all day with him. Again, a little one with huge things going for him despite his developmental problems. A lovely way to end the week.

Antihistamine Promotes Remyelination

With thanks to Medscape, a fascinating piece of research about antihistamine and remyelination which will also be applicable to children on the Snowdrop programme who have myelination issues.  

--------------------------------------------------------------

A common antihistamine available over the counter has shown evidence of remyelination in patients with multiple sclerosis (MS) in a double-blind, placebo-controlled trial.

The study showed that clemastine — at a dose just a little higher than that approved for allergies — reduced the transmission delay in the optic nerve seen in patients with MS and chronic demyelinating optic neuropathy.

"We are extremely excited about these results," lead author, Ari Green, MD, medical director, University of California San Francisco (UCSF) MS Center, commented to Medscape Medical News. "Our main message is that it appears to be possible to repair injury to nerve cells in MS by remyelination. We have been taught that the brain can't repair itself, but our results suggest that this is not true. This could have consequences for many other neurodegenerative diseases as well as MS."

The results were released April 12 in advance of their presentation at the upcoming American Academy of Neurology (AAN) 2016 Annual Meeting.

The phase 2 crossover study — which is said to be the first randomized controlled trial documenting efficacy for a candidate remyelinating agent in MS — compared twice-daily oral clemastine to placebo in 50 patients with MS and chronic demyelinating optic neuropathy. The study period was 150 days.

The primary efficacy endpoint, latency delay on visual evoked potential (VEP; the time for transmission of signal from the retina to the visual cortex), was reduced by 1.9 ms/eye for the period on treatment with clemastine (P = .003).

Dr Green explained that VEP records the speed of transmission in the optic nerve from the visual stimulus to the processing of the image in the visual cortex of the brain.

"Good myelination of the nerve enables the signal to travel faster. For example, in an unmyelinated fiber, the signal would travel at a speed of 1 m/s. In contrast, a myelinated fiber would transmit the signal at about 100 m/s, 100 times faster. Demyelination as seen in MS-related optic neuritis can delay transmission by 30 to 50 ms. Clemastine seems to restore some of this loss."

The researchers also looked at a functional endpoint — low-contrast visual acuity — and saw a strong trend for improvement, but this did not reach statistical significance (P = .089).

In terms of side effects, clemastine treatment was associated with mild worsening of fatigue on the Multidimensional Assessment of Fatigue scale (P = .017).

Reflection of Nerves Throughout the CNS

Dr Green said that although this study just focused on the optic nerve, it probably reflects what is going on throughout the central nervous system. "We are using vision as a method of testing the principle of remyelination. The optic nerve is an obvious place to start as it is logistically practicable. We believe, however, that it should reflect nerve condition generally and acts like a surrogate marker for the rest of the CNS [central nervous system]."

But he urged caution to patients with MS. "I do not want to make false promises, and I am not advocating that MS patients take clemastine on the basis of this one study. But if they chose to do so, they should have the supervision of a physician and preferably enroll in a clinical study."

Clemastine was identified as a potential remyelinating agent in a screening program developed by a UCSF team led by Jonah Chan, PhD, using precursor cells of oligodendrocytes (the cells that make myelin).

"These oligodendrocyte precursor cells are present in the brain but don't seem to mature and make oligodendrocytes," Dr Green explained. "We are looking for agents which stimulate the precursor cells to differentiate into oligodendrocytes and produce new myelin to repair the damaged neurons. Chan et al tested many different existing drugs and found that clemastine did just that."

The researchers have identified a specific muscarinic receptor at which clemastine is acting to bring about this effect. "It is probable that the drug is only partially saturating the receptor, so we may not be seeing the full effect," Dr Green said.

But because clemastine also acts at many other receptors, his group is looking into developing new agents that act specifically at this receptor, which may be more appropriate for myelin repair. "We also know that there are other nonmuscarinic receptors that appear to bring about similar results, so there are a few possibilities under investigation," he added.

"The screening method has identified the biology. Now we have to fine-tune that biology," Dr Green commented.

Biogen is also developing a compound known as anti-LINGO, which has shown evidence of remyelination. Dr Green noted that the anti-LINGO study recently reported involved patients with a current episode of optic neuritis. "So they showed an acute action, whereas patients in our study had not had a recent episode of optic neuritis and so we have shown evidence of benefit in the chronic phase."

Commenting on the study for Medscape Medical News, Lily Jung Henson, MD, chief of neurology, Piedmont Healthcare, Atlanta, Georgia, said, "This is really exciting preliminary news. The results seem to suggest that clemastine may be effective in remyelination, for which we have no therapies."

She cautioned that larger studies will be needed with patients treated for longer periods of time for confirmation. "As clemastine is an anticholinergic, it will be interesting to see if it causes any worsening of some MS symptoms, such as cognitive difficulties, urinary hesitancy, or constipation," she added.

The study was funded by the University of California, San Francisco.

American Academy of Neurology (AAN) 2016 Annual Meeting. Emerging Science Abstract 008. To be presented April 19, 2016.

Keane. - A Case Study From the Snowdrop Programme.

Keane had been born with his twin brother prematurely, he had suffered a bleed to the white matter of his brain around the ventricles, commonly known as ‘periventricular leukomalacia.’ His cerebral aqueduct was also blocked which meant that there had been a build up of cerebrospinal fluid which had caused hydrocephalus.  This had created pressure on the brain which had caused further injuries.  A shunt had been successfully inserted to drain the excess fluid, but to top it all, the hospital had allowed infection to seep in and Keane had contracted severe meningitis.  This had caused even more injuries.

When I first saw Keane, he was 8 months old.  I had been contacted by his mother and had made the trip from Devon to London to assess his developmental problems.  I walked through the front door and into the kitchen where Keane was sitting in a baby bouncing chair and simply staring into space, - he was totally disconnected from what was happening around him, - it was as though someone had found his ‘standby’ button and pressed it.  Mum confirmed that he was like this most of the time.

The diagnosis and prognosis given by the medical professionals was dire.  There had been massive damage to the white matter of the brain, to parts of the cortex, (especially the visual cortex, meaning that Keane was cortically blind) and to parts of the upper brainstem.  The forecast was that Keane would be very severely handicapped for the rest of his life and would be totally dependent in every way for every aspect of his care.

I knew we had no time to lose here and set about designing a programme of developmental stimulation there and then in the family’s front room, which I duly taught to them that same afternoon.  The programme was designed to attack Keane’s problems in every area of development and to stimulate and direct the natural plasticity of the brain.  I knew from both mum and dad’s attitude that they would follow the programme unstintingly every day.

Two months later, I received a telephone call from mum telling me that she thought Keane was beginning to see and that he had become much more alert.  Obviously I was pleased, but I persuaded her that it was still ‘early days’ and that we should keep our feet on the ground and just continue with the programme.

The time quickly came for Keane’s four – monthly reassessment and the family had elected to come and see me in Devon.  I was delighted at what I saw when they walked through the door of the village hall where I see my families.  Keane was clearly scanning his environment and actually made eye contact with me.  As I put him through his paces it was clear that we had woken this little boy from his stupor.  He had made significant gains in every area of development.  I designed a new programme and sent the family home.

Three years down the line, and over those months and years I have received several telephone calls from mum.  The first was to tell me that Keane had begun speaking and that one of his first words was a very well known expletive!  Wonder where he got that one from, - any ideas dad?  The next was to tell me that not only was Keane now walking but that they couldn’t shut him up and he was driving them potty!  Good old Keane.  Recent phone calls complain of him placing himself on the naughty stair after purposefully being naughty and getting into a fight with another child at a family wedding after a child made impolite reference to his red hair.  Mum often makes him talk to me on the phone himself to explain his escapades. 

Keane is now developmentally superior to his twin brother in every area.  It has been a long journey for the family, who have dragged their son out of the depth of his disabilities by working relentlessly every day for three years.  The programme is relentless and is repetitive, but it shows what it is possible to achieve. 

Keane starts at school next year, but it won’t be the special school that everyone expected, - it will be at a mainstream school with his twin brother.  He is now described as ‘precociously intelligent.’  His doctors are amazed and have no explanation for his recovery.  The main thing is that he has his life back.  Instead of what would have been a life of suffering and problems he has a life of hope and opportunity.  That is how powerful brain plasticity can be.

Anyone who would like more information about the Snowdrop programme should go to our website at http://www.snowdrop.cc  or email us at snowdrop_cdc@btinternet.com or you can call for a chat on 01884 38447