Saturday, 29 August 2015

ClinicSpeak: wrists weights work for cerebellar tremors

How good is your hand function? Do you need wrist weights? #ClinicSpeak #MSBlog #MSResearch

"The small study below in MSers with so called cerebellar tremor may be of interest to you. The cerebellum or 'small brain' is the structure at the back of your brain that controls motor function. It is commonly affected in MS and results in uncoordinated and slow movements. When MS lesions occur in the so called outflow pathway from the cerebellum it causes a severe tremor; this type of tremor used to be called a rubral (red) tremor as it was associated with lesions in, or near, the so called rubral (red) nucleus of the midbrain. The following YouTube video is a good example of a cerebellar outflow tremor and illustrates how disabling this type of tremor can be. This type of tremor is also socially isolating; MSers with type of tremor don't like being seen in public."

"In general this tremor responds very poorly to oral medications. The study below, however, shows that physiotherapy and the use of diving, or exercise, wrist weights improves upper limb function. This is my experience as well. By using wrist weights you dampen down the amplitude of the tremor. Increasingly we are sending patients with type of tremor for functional neurosurgery; this involves making a lesion in the thalamus (thalamotomy) using stereotactic techniques (surgical or ultrasound lesion) or inserting a stimulator into the area to block the function of an area of the thalamus. A good predictor of how well someone will be able to function after surgery is to immobilise the arm by holding it tightly, essentially to eliminate the tremor, and to then assess fine alternating finger movements. If the finger movements are still coordinated and rapid then there is a good chance that the patient will have a good result from surgery. However, if the finger movements are slow, incoordinated and inaccurate then surgery won't improve function."

"The great tragedy of this type of tremor in MS, like so many other disabilities, is that it is potentially preventable with early effective treatment."


Background: An intentional tremor is one of the most untreated symptoms in patients with cerebellar ataxia. Upper limb tremors decreases the performance of many activities of daily life Thus treatment of patients with tremor probably implies better functional ability. It is one of the major areas of concern to improve functional independence hence, this study proposed to know the effects of wrist weighing in reducing upper limb tremors in cerebellar injury patients.

Materials and Methods: A total number of 21 patients with various abnormalities of cerebellar function were selected. These patients were randomly divided into two groups. One group was treated with wrist weighing by using Velcro weight cuffs for 15 minutes along with conventional physiotherapy for 5 days a week for 2 months & the other group was treated with conventional physiotherapy for 5 days in a week for 2 months. The subjects were tested by using tremor rating scale and nine hole peg test. The values are collected before and after the treatment

Results: In the group treated with wrist weighing the improvement in the tremor rating scale is very significant (p: 0.0001) and in nine hole peg test is extremely significant (p: 0.0001). In conventional therapy group the improvement in the tremor rating scale was significant (p: 0.0051) and in nine hole peg test is very significant (p: 0.0002).

Conclusion: Incorporation of wrist weighing along with conventional therapy reduced the intensity of upper limb tremors in patients with cerebellar injuries but both the treatments are effective in improving upper limb function.

imaging grey matter loss

Freeman L, Garcia-Lorenzo D, Bottin L, Leroy C, Louapre C, Bodini B, Papeix C, Assouad R, Granger B, Tourbah A, Dollé F, Lubetzki C, Bottlaender M, Stankoff B. The neuronal component of gray matter damage in multiple sclerosis: A [11C]-flumazenil positron emission tomography study.
Ann Neurol. 2015 Aug. doi: 10.1002/ana.24468

OBJECTIVE:Using positron emission tomography (PET) with [11 C]flumazenil ([11 C]FMZ), an antagonist of the central benzodiazepine site located within the GABA-A receptor, we quantified and mapped neuronal damage in the gray matter (GM) of patients with multiple sclerosis (MS) at distinct disease stages. We investigated the relationship between neuronal damage and white matter (WM) lesions and evaluated the clinical relevance of this neuronal PET metric.
METHODS:A cohort of 18 MS patients (9 progressive and 9 relapsing-remitting) was compared to healthy controls and underwent neurological and cognitive evaluations, high-resolution dynamic [11 C]FMZ PET imaging and brain magnetic resonance imaging. [11 C]FMZ binding was estimated using the partial saturation protocol providing voxel-wise absolute quantification of GABAA receptor concentration. PET data were evaluated using a region of interest (ROI) approach as well as on a vertex-by-vertex basis.
RESULTS: [11 C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (-10%). Cortical mapping of benzodiazepine receptor concentration ([11 C]FMZ Bmax) revealed significant intergroup differences in the bilateral parietal cortices and right frontal areas. ROI analyses taking into account GM volume changes showed extensive decrease in [11 C]FMZ binding in bilateral parietal, cingulate, and insular cortices as well as in the thalami, amygdalae, and hippocampi. These changes were significant in both progressive and relapsing-remitting forms of the disease and correlated with WM T2-weighted lesion load. [11 C]FMZ cortical binding correlated with cognitive performance.
INTERPRETATION: This pilot study showed that PET with [11 C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS

Positron Emission Tomography is a method of imaging radio-active substances. Carbon 12 is the  non-radio active variant but carbon 11 is a  rapidly degraded radioactive isotope. Here they make a drug called flumazenil with carbon 11 and this will bind to the GABA-A receptor on  nerves.

The benzodiazepines had already been in wide use as anxiolytics and anticonvulsants for more than ten years before their site of action in the central nervous system, the benzodiazepine receptor, was discovered. Simultaneously, a binding site in the peripheral organs, e.g. heart, lungs and kidneys, was found. Although some benzodiazepines, such as diazepam, bind to both central and peripheral benzodiazepine receptors with a high affinity, these two binding sites exhibit quite different properties. It is already clear that the central benzodiazepine receptors are in many regions of the brain coupled with the receptors for gamma-amino butyric acid (GABA), and they mediate the acute actions of benzodiazepines in the central nervous system. 
The peripheral-type receptors are present on microglia and PET ligands against the peripheral benzodiazepine receptor are used for imaging microglia.

This study shows that grey matter nerves are lost in MS and this is associated with loss of flumazenil binding in both RR and SPMS.

Co-ordinated production and loss of factors are needed for remyelination

Zhao C, Ma D, Zawadzka M, Fancy SP, Elis-Williams L, Bouvier G, Stockley JH, de Castro GM, Wang B, Jacobs S, Casaccia P, Franklin RJ. Sox2 Sustains Recruitment of Oligodendrocyte Progenitor Cells following CNS Demyelination and Primes Them for Differentiation during Remyelination. J Neurosci. 2015 19; 35:11482-99. 

The Sox family of transcription factors have been widely studied in the context of oligodendrocyte development. Here we show that the expression of Sox2 occurs in oligodendrocyte progenitor cells (OPCs) in rodent models during myelination and in activated adult OPCs responding to demyelination, and is also detected in multiple sclerosis lesions. In normal adult white matter of both mice and rats, it is neither expressed by adult OPCs nor by oligodendrocytes (although it is expressed by a subpopulation of adult astrocytes). Overexpression of Sox2 in rat OPCs in vitro maintains the cells in a proliferative state and inhibits differentiation, while Sox2 knockout results in decreased OPC proliferation and survival, suggesting that Sox2 contributes to the expansion of OPCs during the recruitment phase of remyelination. Loss of function in cultured mouse OPCs also results in an impaired ability to undergo normal differentiation in response to differentiation signals, suggesting that Sox2 expression in activated OPCs also primes these cells to eventually undergo differentiation. In vivo studies on remyelination following experimental toxin-induced demyelination in mice with inducible loss of Sox2 revealed impaired remyelination, which was largely due to a profound attenuation of OPC recruitment and likely also due to impaired differentiation. Our results reveal a key role of Sox2 expression in OPCs responding to demyelination, enabling them to effectively contribute to remyelination.
SIGNIFICANCE STATEMENT: Understanding the mechanisms of CNS remyelination is central to developing effective means by which this process can be therapeutically enhanced in chronic demyelinating diseases such as multiple sclerosis. In this study, we describe the role of Sox2, a transcription factor widely implicated in stem cell biology, in CNS myelination and remyelination. We show how Sox2 is expressed in oligodendrocyte progenitor cells (OPCs) preparing to undergo differentiation, allowing them to undergo proliferation and priming them for subsequent differentiation. Although Sox2 is unlikely to be a direct therapeutic target, these data nevertheless provide more information on how OPC differentiation is controlled and therefore enriches our understanding of this important CNS regenerative process.

SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells. For repair to occur after demyelination you have to clear up the debris from the damage then the oligoprecursor cells  have to migrate into the areas of damage and you may need to proliferate and then the precursor cells have to differentiate into mature oligodendrocytes and become myelin forming cells. This is co-ordinated and things are turned on an off in the process. This shows that Sox2 is important in in the repopulation of demyelinated areas and gets them ready for  becoming oligodendrocytes, but this needs to be switched off before cells begin remyelinating. This shows that it may not always be a simple case of switch-on things to get effective remyelination.