Wednesday, 9 December 2009

Liberation therapy - CCSVI

I am a sceptic but remain open to the possibility, albeit remote, that CCSVI may be a real finding. I would definitely not recommend any surgical or radiological intervention at this stage. More research is needed to confirm of refute Zamboni's findings before any prospective randomised trials are started. You may not be aware but I have been informed that two people with MS have died from the complications of stenting for possible CCSVI.

http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20091120/W5_liberation_091121/20091121?s_name=W5

http://watch.ctv.ca/news/latest/possible-cure/#clip238089

http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20091120/W5_liberation_091121/20091121?s_name=W5

http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20091120/W5_QandA_091121/20091121?hub=WFive

http://jnnp.bmj.com/content/80/4/392.full

http://www.ncbi.nlm.nih.gov/pubmed/19958985?dopt=Abstract

Prof G

Monday, 30 November 2009

2009 European Charcot Foundation Symposium

The 2009 European Charcot Foundation Symposium gathered many world opinion leaders in MS in Lisbon for a 3 day meeting to discuss “A new treatment era in multiple sclerosis: options, challenges and risks”.

Prof Lassmann
. In brain lesions in secondary progressive MS (SPMS), about 65% of cells are clonally expanded MHC class I CD8+ T cells that seem to escape apoptosis and outnumber CD4+T cells 10:1. There was little surprise that ustekinumab (anti-p40 IL-12/IL-23 antibody) trial in MS showed no benefit.Associated with the active demyelination, activated microglia/astroglia and cellular infiltrates are found in most types of lesions, there is evidence for oxidative damage from reactive oxygen species (ROS/RNI) and involvement of the mitochondrial complex IV in acute Balo type lesions (Mahad Brain 2008). The axonal injury is characterized by dissolution of the cytoskeleton, calpainopathy and disturbance of axonal transport. Na+ overload is observed, as in a channelopathy, which is the base for trials that block Na+ as a strategy for neuroprotection: Na+/Ca++ channel blockers, GluR blockers both in low doses (Frischer Brain2009). Overall, despite integrity of BBB, there is active inflammation: compartmentalization of inflammation in SP.
Prof Comi. The use of imaging techniques such as MTR can show sequential changes in new Gad enhancing lesions. This made it possible to see that in the same patients different lesions recover differently. The enhancement with a ring distribution is associated with worse evolution than when there is nodular enhancement and periventricular lesions evolve in a worse way than subcortical lesions (could it be because of the preferential location of stem cells in the periventricular area?)
Unlike Lassmann, he thinks there is imaging evidence for dissociation between inflammation and degeneration. In MRI, one can see evidence for primary anterograde and retrograde axonal degeneration in the NAWM.
He also emphasized the role of OCT (optical coherence tomography) in optic neuritis and CIS in particular.

Prof Edan. There emphasis on the difference between neurodegeneration due to focal or diffuse inflammation.
A bigger change in T2 lesion volume in the 1st 5 years is correlated with who will progress to SP stage (Fisniku LK & Miller).
In MS with progressive onset, phase I (time from EDSS 0 to EDSS 3) is much shorter that in RR-MS.
Both PP-MS and initially RR MS start phase II (EDSS 3 to EDSS 6) at about the same age.
At the end of day, the debate could reach a consensus about whether inflammation drives or is independent of neurodegeneration. Based on brain post-mortem pathology, there is inflammation behind the BBB; this compartment is not targeted by most drugs: even drugs with BBB penetration such as cladribine only achieve a concentration of about ¼ of the peripheral blood concentration, which may explain why SP-MS trials disappointment. Based on clinical cohorts and MRI studies, there is imaging evidence for neurodegeneration very early on in disease and in locations that do not seem to be affected by focal inflammation.

Novartis sponsored a Satellite Symposium
on “Fingolimod: SP1 receptor modulation” chaired by Prof Giovannoni.
Prof Antel. Fingolimod is a pro-drug that needs a converting enzyme to be activated; this enzyme is present in the blood and in the central nervous system. This drug is thought to work both on the inflammatory component of MS but also to have CNS effects. Fingolimod is a lipophiic molecule that crosses the BBB and binds to myelin. Interestingly, this raised the question whether the myelin pool is available to act on inflammatory cells. Nevertheless, it is measurable in the CSF.
S1P1 receptor is present in neural cells and astrocytic S1P1 signalling is critical for EAE. Physiologically, it is thought to modulate endogenous repair mechanisms; in mice cerebellar cultures, the oligodendrocyte precursor cells (OPC) put out and retract processes, depending on the timing and dose of the drug, with an impact on myelin maintenance and remyelination. This effect was not always protective.
In the periphery, fingolimod prevents naïve and central memory T cells to egress from lymph nodes; only naïve T cells (CCR7+CD45RA+), central memory T cells (Tcm or CCR7+CD45RA-) and B cells are affected, but effector memory T cells (Tem or CCR7-CD45RA- and CCR7-CD45RA+) are spared. This means that only selective T cell subsets are present in the circulation and they retain their functional properties.

Prof Vermersch. In the trials with fingolimod, the primary outcomes that were assessed were T1 hypointense lesion load, general atrophy and the visual system (anterior visual pathway / RNFL / macular volume).
The OCT was used to measure retinal nerve fibre layer (RNFL) thickness, which has been associated with relapse rate and progression in 52 PwMS, as well as associated with disease activity (measured as a 1 point increase in EDSS) and disability. The OCT measures were also correlated with MRI assessment of normalised brain volume.
The OCT uses a superluminescent diode as a near-infrared light source, uses interferometry measures and is able to penetrate significantly deeper into the scattering medium, for example ~3× deeper than confocal microscopy. It measured macular thickness and volume, but can also measure retinal ganglion density of different retinal regions.
In CIS patients, the temporal area of the retina was thinner, but not the average. In most measures, it was the external areas that showed significant differences, but this is similar to all types of damage, it is not specific for CIS/MS.
In contrast with MRI general brain volume, this measure was not affected by high dose pulsed steroids.

Prof Havrdova. Clinical trials with fingolimod
Initial results from the 2-year phase III FREEDOMS 1 study (~1300 patients) show that oral fingolimod was significantly superior to placebo in reducing both relapses and disability progression in patients with RRMS. There was no significant difference in efficacy between 0.5 mg and 1.25 mg doses. It reduced the relapse rate by 54% for the 0.5 mg dose and 60% for the 1.25 mg dose compared to placebo (both p<0.001). In addition, it reduced the progression of disability by 30% for patients on 0.5 mg (p=0.024) and 32% for those on 1.25 mg (p=0.017) compared to placebo over two years. Results from the 1-year TRANSFORMS study (largest head-to-head Phase III study, vs Avonex) showed a reduction in relapse rates of 52% and 38% for fingolimod 0.5 mg and 1.25 mg respectively compared to interferon beta-1a (both p<0.001) FREEDOMS II, currently under way, is a 2-year placebo-controlled Phase III study, similar to FREEDOMS 1. INFORMS in PPMS patients in on-going.
Profs Kappos, Vermersch, Hartung and Montaban
discussed what to do in CIS or fulminant MS, the role of new drugs in RRMS and in progressive disease.
When CIS becomes MS with McDonald’s criteria through MRI in the first year, it seems reasonable to treat, as these are the patients at higher risk of developing a clinical relapse earlier.
The challenges with fulminant MS
Definition: 1. Rapid sequence of relapses with intervals shorter than 30 days or
2. A single catastrophic clinical manifestation with tumour-like MRI appearance – Marburg type – with encephalopathy that may be fatal and usually on the first attack.
Histology: greater number of T cells that recognise deiminated epitopes, increased citrullination in human MBP and developmentally immature MBP. If they have a Lassmann-Lucchinnetti type II pattern, there is good recovery with plasmapheresis (and possibly rituximab), but not if they are type I or III (Balo type). It must be stressed, however, that the existence of the Lassmann- Lucchinnetti classification has recently been questioned and is not accepted by all MS neuropathologists.
The differential diagnosis includes gliomas, multifocal gliomas, gliomatosis cerebri, lymphoma or rarely sarcoidosis. Treatment: high dose pulsed steroids: 1 to 5g of methylprednisolone daily for 5 to 10 days, followed by tapering
1. MRI shows no Gad+ve lesions and less T2 lesion load → Clinical and MRI follow-up → DMT
2. MRI with Gad +ve lesion or increased T2 lesion load → mitox 6 months → DMT
3. Clinical aggravation (15 days) → plasmapheresis (5 sessions) → mitox 6 months/rituximab (pattern II)

The future anti-B-cell therapies were mentioned: ocrelizumab (humanized anti CD20 monoclonal antibody) and ofatumumab (Arzerra - HuMax-CD20, human mab, approved for non-responsive CLL, targets a different anti-CD20 epitope); atacicept (soluble form of the TACI receptor that binds to two ligands, BLyS and APRIL, that are implicated in B-cell survival, maturation and antibody production – not good in phase II MS trial), belimumab (Benlysta or LymphoStat-B is a fully human mab that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator -BLyS, also known as B-cell activation factor of theTNF family -BAFF.

The role of the new drugs in RRMS is a matter of intense debate: while some groups would offer them as first line treatment considering increased efficacy and easier administration other groups would use them in cases of failed IFNβ/glatimer acetate because of increased potential for serious side-effects.

There are still no positive trials for progressive MS. The OLYMPOS trial of rituximab in SPMS, MAESTRO (MBP8298 or dirucotide) in SPMS, and most of the trials have got the inadequate selection of patients, and bad outcome measures to show benefits.

Prof Meinl. The group has tested for antibodies against myelin glycoproteins, in particular neurofascin – an adhesion molecule required for the clustering of voltage gated Na+ channels at the node of Ranvier – as they are targets for auto-ab in MS patients. NF 186 and NF 155 may be implicated. The ab induces axonal injury in the animal model. There are detectable contactin-2 auto-abs in MS patients and the ab mediates gray matter pathology in animals. The ELISA technique is not optimal and they developed a FACS based technique and are testing their samples.

Prof Fujihara. The identification of NMO-Ig as anti-AQP4 antibodies and their presence in the serum of patients with neuromyelitis-optica was a major step in the research of neuroinflammation. Not unlike MS patients, patients with NMO have relapses of neurological deficits, usually with worse outcome. The a-AQP4-abs have been shown to destroy the AQP4 in the foot processes of astrocytes and the disease is now an independent entity, with more aggressive treatment. The highlights were the features of pain as a typical symptom, the possibility that abs become negative after steroid treatment and the presence of the typical antibodies many years prior to clinical attacks.

Prof Hemmer
. The mechanisms of pathogenic antibodies target 1. Inactivation of extra-cellular proteins, 2. Receptor blockade, 3. Cytotoxicity (through complement deposition or NK cell activity). The pathogenic antibodies bind in a conformational way to epitopes of the target protein. They have been testing for a-MOG abs in children and the younger the children are, the more a-MOG-abs they detect.
Also, in a study of children with demyelinating disease, the ones that went on to develop MS were the ones who were a-EBV-abs positive.

Dr Monica Calado-Marta

Thursday, 12 November 2009

Fingolimod mechanism of action


Please click on the following URL

http://www.youtube.com/watch?v=sT68KZVo8-I

ProfG



 

Wednesday, 11 November 2009

CCSVI

Recently, evidence has emerged – and widely publicised – that a condition called “chronic cerebro-spinal venous insufficiency (CCSVI)” may play a role in the pathogenesis of multiple sclerosis (MS). Paolo Zamboni, professor and director of the Vascular Diseases Centre at the University of Ferrara (Italy), and co-workers detected anomalies of venous drainage from the brain and spinal cord in all 65 (100%) people with MS in their cohort (published earlier this year in the Journal of Neurology, Neurosurgery and Psychiatry). Using venous ultrasound as well as venography (where a dye or contrast agent is injected through a catheter) they reported four patterns of restricted blood flow due to narrowing in the internal jugular, azygos and superior cava vein system. In none (0%) of their 235 strong control population (i.e. people with no known disease of the nervous system and people with neurological conditions other than MS such as Parkinson’s or motor neuron disease) did they find abnormalities similar to that found in the group of 65 people with MS.


Based on these findings, Professor Zamboni and his colleagues have started treating people with MS using a technique called endovascular balloon angioplasty, which widens the blood vessels using a catheter that has a balloon attached to its tip; when the balloon is inflated the vessel is opened. In a few cases they have resorted to inserting a stent, or rigid tube, in places where narrowing had been detected. Preliminary results following treatment of 75 patients with MS were reported earlier this year at the 31st Charing Cross Symposium “Vascular and Endovascular Controversies Update”. At that point patients had been followed up for a maximum of one year. Zamboni’s team reported positive trends using a panel of outcome measures of efficacy; i.e. (i) the MS functional composite (MSFC) scale, which measures walking speed, upper limb function and cognition, (ii) quality of life (MSQoL-54) and (iii) relapse rate.


The recent collaboration of Professor Zamboni’s group with MS experts from Buffalo (NY) and Detroit (MI) has propelled “CCSVI and MS” to a new level of publicity. This group plans to investigate 1,600 adults and 100 children with a diagnosis of possible or definite MS alongside 300 healthy controls and 300 patients with autoimmune and/or neurodegenerative diseases other than MS. Apart from using doppler ultrasound of head and neck blood vessels this group will also use magnetic resonance imaging (MRI) of the brain with particular focus on brain iron levels; the effects of excess iron has been implicated for some time in the tissue destruction that occurs in various brain disorders including MS.


The “big idea” underlying the presumed link between CCSVI and MS is that narrowing in large veins outside the central nervous system (CNS) leads to stagnation of venous blood in small veins within the CNS and, subsequently, to iron deposition and inflammation around these veins with damaging knock-on effects (e.g. demyelination & axonal loss). Zamboni likens the perivascular MS lesion to a venous ulcer of the leg emerging from a varicose vein. The origin of increased iron in varicose legs is the leaking of red blood cells in conditions with stasis of blood in the veins.


Extravasation of red blood cells and thrombosis of small veins have indeed been seen in MS brain tissue, too. However, such findings are rare and far outnumberd by evidence suggesting different early abnormal events in MS lesion development including (i) migration through the blood brain barrier of autoreactive T cells or (ii) oligodendrocyte death.


There are numerous further questions that need to be addressed in order to draw any reasonable conclusion from Zamboni and co-workers’ findings: How does CCSVI explain relapses and remissions? What is the mechanism underlying apparent narrowing in large veins of people with MS? Are these vascular changes primary or secondary to MS? What is the association between these changes and apparent iron deposition in the brain of patients with MS? Is there an animal model that responds with inflammation and demyelinaton following stasis in large skull veins? Is there any evidence from people with MS who have been – for reasons other than MS – on drugs to thin the blood? And so forth…


We will follow the Ferrara/Buffalo/Detroit-collaboration on CCSVI in MS with interest, and we understand a first preliminary analysis is due within the next few months. For the time being, patients and their families should be re-assured that there is currently very little – if any – evidence in favour of endovascular treatment for MS. These procedures are invasive and carry a risk. Without firm evidence from properly conducted clinical trials we would not recommend this therapy.


Klaus Schmierer & Gavin Giovannoni

Monday, 9 November 2009

Immunology highlights ECTRIMS 2009

The highlight of ECTRIMs was the talk by the famous pathologist Prof John Prineas (Sydney, Australia), who was awarded the prestigious Charcot Prize for his unique contributions to the pathology of MS. The prize is named after the famous French neurologist also called “the Napoleon of the neuroses”. He was the first to describe multiple sclerosis as a distinct disease entity.

This talk highlighted the “astrocyte lesion” in neuromyelitis optica (NMO) and multiple sclerosis. NMO has been historically considered a subtype of MS and an autoimmune disease targeting astrocytes – star-shaped glial cells in the brain and spinal cord. Anti-aquaporin-4 antibodies, which are directed against this astrocytic water channel, are involved in the disease pathogenesis and used as diagnostic markers. Similar degenerative changes were also found in astrocytic endfeet in early MS lesions and Prof Prineas put forward the hypothesis that MS may not be a disease exclusively of oligodendrocytes and myelin, and suggested that future work should also focus on astrocytes.

One “hot topic session” of the conference was dedicated to Th17 cells. This cytokine was recently discovered and found to play a role MS and other autoimmune diseases. It is now known that axons express the IL-17 receptor and we saw very elegant experiments, using live cell imaging, looking at the trafficking capacity of these cells, which were found in close proximity to axons. This poses interesting questions about the pathogenic role of Th17 cells in MS.

Ute Meier, Post-doctoral Scientist

Label change for Natalizumab

09 November 2009

Elan & Biogen-Idec have made changes to the label on Natalizumab to reflect the increased risk of PML over a longer period of time. They are updating the label following consultation with the FDA; “risk of developing progressive multifocal leukoencephalopathy increases with longer treatment duration, and for patients treated for 24 to 36 months is generally similar to the rates seen in clinical trials. There is limited experience beyond three years of treatment”.

Source Pharma Times: http://www.pharmatimes.com/WorldNews/article.aspx?id=16874

Saturday, 24 October 2009

23 post-marketing natalizumab-related PML cases

The EMEA announced, in a press-release, on the 23 October that there are now 23 post-marketing natalizumab-related PML cases:

"Review of benefits and risks for Tysabri started -The Committee started a review of the benefits and risks of Tysabri, in view of reports of 23 cases of progressive multifocal leukoencephalopathy (PML) worldwide since Tysabri has been on the market. This review is initiated to discuss any additional measures necessary to ensure the safe use of Tysabri and how to balance the risks to the patients against the benefits of the treatment. Tysabri is indicated for patients suffering from highly active relapsing remitting multiple sclerosis with high disease activity despite treatment with a beta-interferon and for patients with rapidly evolving severe relapsing-remitting multiple sclerosis." EMEA



You need to more vigilant than ever regarding possible symptoms of PML if you have been on Natalizumab (Tysabri) more than 12 months.

Wednesday, 21 October 2009

Genetics of MS update post-ECTRIMS 2009

Studies of family members of MS patients has shown that the more closely related you are to an MS patient the higher your risk of the disease. For example, if you are a sibling or child of an MS patient your risk is about 3%. This shows that genes play a role in MS.


Studies over the last 30 years has shown that a region of DNA on chromosome 6 is the main genetic locus in MS. The main gene involved is called HLA-DRB1 and this gene has an immune function. HLA-DRB1 comes in over 400 different forms (or alleles). A common form in Europe, named 15, increases the risk of MS by 3-fold. Other alleles of this gene also play a role in the disease. For example, 14 protects individuals from getting the disease. As each person has two copies of all genes (one from your mother and one from your father), it is important as to which two copies of HLA-DRB1 you have. For example, 14 completely cancels the risk increasing effect of 15 when they are inherited together. This may explain, in part, why MS is rare in Asia; there, the 14 allele is common.


More recently, large scale studies have identified a number of other genes involved in MS, including the interleukin 7 receptor alpha (IL7RA), interleukin 2 receptor alpha (IL2RA), the c type lectin 16 a gene (CLEC16A) and interferon response factor 8 (IRF8) genes. These genes increase disease risk by a substantially smaller amount compared to HLA-DRB1, but due to their role in the immune response highlight that the key mechanism of the disease appears to be immune dysfunction.


Dr Sreeram Ramagopalan, post-doctoral scientist

Novel disease modifying therapies: data presented at ECTRIMS 2009

The 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Dusseldorf in September 2009 brought together leading international experts in MS to share and discuss recent advances in MS research. We were presented very promising new treatments evaluated in phase II and III trials.
Oral therapies have reached an advanced phase of development, with some of the molecules having completed phase III trials. Data from the cladribine and fingolimod phase III trials were presented at the congress, as well as the phase II trial with teriflunomide and new data illustrating the mechanism of action of laquinimod. Prof. Giovannoni (London, UK) presented the findings of CLARITY, the phase III trial comparing two doses of cladribine and placebo in relapsing remitting MS patients. The study showed that a short course of cladribine tablets significantly increased the proportion of patients without disease activity after two years. Prof. Barkhof (Amsterdam, The Netherlands) presented TRANSFORMS, the phase III trial of oral fingolimod compared with intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis. Twelve months of fingolimod therapy significantly reduced MRI inflammatory activity and cerebral volume reduction. The results of the phase II trial with two different doses of oral teriflunomide or placebo added to interferon beta for 6 months in patients with relapsing remitting multiple sclerosis were presented by Prof. Freedman (Ottawa, Canada). Both doses of teriflunomide were shown to decrease the inflammatory activity seen in MRI. Prof. Brück (Gottingen, Germany ) and Comi (Milano, Italy) summarized the studies evaluating laquinimod’s mechanism of action and the current data of efficacy and safety of laquinimod. They suggested dual neuroprotective and immunomodulatory properties, and promising efficacy data.
Alemtuzumab is a monoclonal antibody to CD52, a surface receptor of lymphocytes. We already know that alemtuzumab is superior over subcutaneous interferon beta 1-a (Rebif-44) in reducing relapse rate and accumulation of disability in treatment-naive relapsing-remitting MS patients for three years. In this Congress, Dr. Coles (Cambridge, UK) presented the primary efficacy outcomes of CAMMS223 at 4 years, which showed that alemtuzumab maintains its superiority to SC IFNB-1a.
Two trials with secondary-progressive MS patients were presented. Unfortunately, intravenous dirucotide failed to delay disease progression compared to placebo in a phase III study with 612 patients, as shown by Prof. Freedman.  Likewise, lamotrigine did not show any benefit in decreasing rate of cerebral atrophy and slowing disease progression in a placebo-controlled phase II trial in 120 people with secondary progressive MS, as was shown by Dr. Kapoor (London, UK).
Finally, Prof. Freedman disclosed the consensus of the mesenchymal stem cell transplantation (MSCT) experts held in Paris earlier this year. MSCT might be an important and exciting new modality for the treatment of MS. The formation of the International MSCT Study Group and the conception of a common protocol to be used worldwide will help advance this promising therapeutic line.
Overall, some new therapies seem to be clinically beneficial for MS patients. However, ongoing trials are underway to evaluate clinical benefit and safety data before these new drugs may be widely administered.


Dr Isabel Bosca, Visiting Neurologist Barts and The London

Panel recommends that FDA approves Fampridine for increasing walking speed in PwMS


Concerns:

Aminopyridines, a family of compounds to which Fampridine belongs, works by lowering the requirements for axons (the electrical cabling of nerves) by blocking a specific group of proteins on their surface called voltage-gated potassium channels. This makes it more likely for an electrical impulse or action potential to be transmitted across a demyelinated segment of an axon. Although this will improve motor function the effect on sensory and other pathways may make some problems worse, for example exacerbation of pain and increase in the frequency and severity of MS-related positive symptoms (pins & needles, muscle spasms and seizures).
Aminopyridines will almost certainly increase the energy requirements of damaged, vulnerable, demyelinated axons as they will require more energy for repolarization the process by which they get ready to transmit another electrical signal. There is now good evidence that increasing the energy requirements of axons may result in further axonal injury and loss. Essentially this is the theory underlying the use of sodium channel blockers, such as phenytoin or lamotrigine, as neuroprotective compounds in MS; by reducing transmission you reduce the energy requirements and hence protect vulnerable axons.
For these reasons I am wary about the long-term use of Fampridine in MS-related motor fatigue. I am worried that Fampridine may speed up the rate of disability progression. I stand to be proved incorrect on this; we will only find this out by doing clinical trials and following up patients with progressive MS on these medications for long periods of time using standardised methods.
I have posted Hugh Bostock’s videos, from Queen Square, on conduction in a normal nerve and a demyelinated nerve, on YouTube, to illustrate how slow and difficult it is to transmit an electrical impulse down a demyelinated nerve. When you watch the videos please try and imagine how much more effort/energy is required for conduction in demyelinated axons; aminopyridines are the chemical whips that keeps these axons firing.

Prof G