Thursday, 18 September 2014

ClinicSpeak: cognitive MS

Cognitive MS: what is it? #ClinicSpeak #MSBlog #MSResearch

"I have been heavily criticised by MSers and my colleagues for trying to redefine MS as a dementia and for focusing on brain atrophy and cognitive impairment. I am told why be negative and not everyone with MS has cognitive problems. The study below focuses on the entity of cognitive-MS, i.e. the small group of patients who present with cognitive impairment. I have several patients like this in my clinic and when you scan them they typically have large lesion loads and gross brain atrophy. I have always assumed that they have had MS for a long time before presenting. But this is not necessarily the case; for example I look after one patient who had a catastrophic disease early in the course of the disease and now has severe cognitive impairment. The latter is despite alemtuzumab treatment having switched off  the inflammatory component of the disease (relapses and focal MRI activity)."

"How common is cognitive impairment in MS? If you start at RIS (radiologically isolated syndrome) or asymptomatic MS about 25% have cognitive impairment at baseline, this increases to about 30-40% in CISer, over 50% in RRMSer and much higher levels in SPMSers. Interestingly, some studies have shown lower levels of cognitive impairment in PPMSers than SPMSers; presumably because PPMSer tend to have less brain disease and more spinal cord disease."

"What is important to realise that MS causes cognitive impairment and is largely driven by gray matter disease that is not visible on our routine MRI scanners. This is why I am a proponent of early effective treatment to slow down or stop inflammatory disease activity. The latter may not be sufficient to prevent ongoing damage, which is why we are working on neuroprotective strategies."

"Please remember that MS is a preventable dementia. Prevention needs to be stressed. If we treat MS early and aggressively I am confident we will prevent dementia. This is why we need to adopt treat-2-target of NEDA with the aim of preventing end-organ damage. Anything less is unacceptable. MSologsists now have a responsibility for protecting the brains of their patients so that they maintain their cognitive reserves for later on in life when they have to face the ravages of ageing."

"In response to some of the questions on this post you may find the following presentation I gave at ECTRIMS 2013 helpful.""




Assouad et al. Clinical and MRI characterization of MS patients with a pure and severe cognitive onset. Clin Neurol Neurosurg. 2014 Aug 20;126C:55-63.

BACKGROUND AND OBJECTIVE: Cognitive and behavioural symptoms are common in MS, but they are rarely the inaugural and predominant manifestation of the disease. Our objective is to characterize the clinical and radiological features of cognitive-multiple sclerosis(cog-MS), defined as MS subjects who entered into the disease with cognitive symptoms, which subsequently remain the predominant manifestation.

METHODS: We describe the disease course, and clinical and radiological features of 18 subjects with a cognitive form of MS.

RESULTS: Memory loss and behavioural changes were the primary symptoms at disease onset. They remained prominent and led to severe cognitive impairment during disease course. The main associated manifestations were depression, pathological laughing and/or crying, urinary incontinence and gait disturbance suggestive of high-level gait disorder. Motor, sensory or cerebellar abnormalities were uncommon. During disease course, superimposed neurological relapses occurred in 61% of cases. Brain MRI revealed multiple periventricular lesions that were extensive and confluent in half of cases, and a severe atrophy measured as an increase in the third ventricular width compared to age-matched healthy controls. Gadolinium-enhancing lesions were common (72%). The mean diagnosis delay from disease onset was 2 years. A principal component analysis on the neuropsychological results revealed that verbal memory assessment is complementary to global cognitive functioning evaluation in these patients with severe cognitive deficit. Verbal memory deficit was associated with high EDSS.

CONCLUSIONS: cog-MS patients might represent a challenging diagnosis, which needs to be individualized for an early management.

Gilenya slows nerve death

Slowik A, Schmidt T, Beyer C, Amor S, Clarner T, Kipp M. FTY720 is neuroprotective after cuprizone-induced central nervous system demyelination. Br J Pharmacol. 2014. doi: 10.1111/bph.12938. [Epub ahead of print]

BACKGROUND: The sphingosine 1-phosphate (S1P) receptor modulator is an approved treatment of relapsing multiple sclerosis (MS) because of its anti-inflammatory effect to retain lymphocytes within the lymph nodes. Here, we evaluated the potential of FTY720 (fingolimod; Gilenya™, Novartis Pharma AG) to activate pro-myelinating pathways within the brain to encourage remyelination and neuroprotection.
EXPERIMENTAL: APPROACH: In this study, we used the cuprizone model and tested pro-myelinating and neuroprotective effects of FTY720 after acute and chronic toxin-induced experimental demyelination.
KEY RESULTS: The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone-induced demyelination. Robust endogenous remyelination was evident after acute but impaired after chronic demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Gliosis parameters (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein (APP)-positive spheroids in axons was less distinct in FTY720-treated animals, indicating that this drug alleviates ongoing axonal damage.
CONCLUSIONS: We show that even during endogenous remyelination, axonal degeneration continues to progress at a low level, accumulating over time, and that this continuous neurodegenerative process is ameliorated by FTY720 treatment. This study demonstrates that FTY720 preserves central nervous system integrity by direct interaction with brain resident cells, the actions of which are still to be defined.
Gilenya is a sphingosine-1-phosphate receptor (S1PR) modulator of which there are a number of variants. S1PR one  mediates the immune effects and blocks white blood cells from creeping out of the lymph glands. S1PR5 is found on glial cells in the brain, where Gilenya can concentrate. It has been suggested that Gilenya may be promyelinating and help remyelination. We have published some data indicating that this drug can upregulate myelin genes and this study suggests it can have some effect a helping remyelination after a recent demyelinating event....This however contrasts with a competing companies data that it does nothing for remyelination. However, in established long term demyelination it did not support remyelination in this study either. So further tempering this view that repair is promoted. However, what was noted is that demyelinated axons can die and this is seen by a breakage of the axon. When this occurs a protein in the nerve that shuttles down the nerve ouses out of the cut axon and makes a bleb. There were less blebs suggesting that Gilenja can save nerves. This would therefore be good news for the primary progressive trial that is essentially complete......The investors will be told the results in one of two months time. Fingers crossed for good news.

MS Day: Progression

Today Ben Turner talks about Progression
Dr Ben Turner: Q & A

How can a neurologist see a transition from RRMS to SPMS in a patient if they don’t give you MRI scan?
I cannot predict SPMS from the MRI scan, it’s a clinical diagnosis. It’s often a retrospective question as we look at the patient over the last 6-12 months and realise that the patient has gradually changed, but haven’t had a relapse. Now this raises a very hard point to notice who is entering that progressive phase, and that’s why maybe this work about neuro-filaments may be promising. If we can have a test when we think we are not sure, let’s do lumbar puncture and measure neuro- filaments and that would suggest a patient is entering a progressive phase, than if we have an effective treatment for a progressive phase, we can treat it. We always struggled to do lumbar punctures, if we just find a treatment for a progressive phase, we just probably want to start it quite early on anyway. So don’t worry about not having MRI scan, if you have symptoms and a good communication with your neurologist, then hopefully it will be picked up on that.

If I have RRMS does it guarantee that I will definitely develop SPMS?
The key word in MS is heterogeneity. Reviewing statistics, we would say if you have RRMS at 10-15 years you have 50% chance of converting, 20 years you have 80% chance. There is nothing absolute in biology, but yes overtime you have high likelihood of developing SPMS. It can be very subtle, very gradual, and very variable.
I have been put on Tysabri, and on one of your slides it says that you treat SPMS with it. My neurologist has never termed my MS as SPMS and never discussed that I have entered SPMS stage even that I asked, is he doing this preventatively?
Well there is a trial on SPMS for Natalizumab. So we do not know the answer whether it does stop the progression. We had quite few patients on Natalizumab for many years and unfortunately we have seen some patients continue to progress. So like any treatment it is not perfect. Hopefully we can see in the study that it slows it down. I admit neurologists try to avoid the diagnosis of SPMS, because it is not good news and as there is no clear treatment. We don’t know many things, but hopefully with the new treatments we should be more honest and discuss it and be more alert to it.