Tuesday, 3 May 2016

Diagnostic parsimony

J Neurol. 2016 Apr 25. [Epub ahead of print]

Multiple sclerosis and chronic progressive external ophthalmoplegia associated with a large scale mitochondrial DNA single deletion.

Gaetani L, Mignarri A, Di Gregorio M, Sarchielli P, Malandrini A, Cardaioli E, Calabresi P, Dotti MT, Di Filippo M.

The patient had a history of progressive bilateral ptosis and ophthalmoparesis which started at the age of 7 and slowly evolved into almost complete bilateral external ophthalmoplegia. Her family history was unremarkable. At the age of 41, she experienced for 2 weeks persistent gait instability. She underwent a brain and cervical spine MRI that revealed multiple T2-hyperintense lesions in periventricular, juxtacortical and infratentorial white matter (Fig. 1a, b) and in the cervical spinal cord. Three brain lesions showed gadolinium enhancement (Fig. 1c). Cerebrospinal fluid (CSF) examination showed intrathecal IgG synthesis, and a serological screening for autoimmune and infectious conditions was negative. The patient was treated with high-dose steroids and had a complete recovery from the relapse. Given the external ophthalmoplegia, she underwent muscle biopsy that showed ragged red fibers (RRF) and 1 % of cytochrome c oxidase (COX) negative fibers (Fig. 1d).

Fig 1 a,b MRI showing bilateral periventricular hyperintense T2 lesions (inflammatory lesions). c Post-gadolinium (or contrast study) showing one enhancing lesion. d COX staining of muscle biopsy showing a COX (cytochrome C oxidase - part of complex IV which makes up a chain of enzymes that produce energy in the mitochondria)  negative fiber (asterisk). e Long-range PCR performed on the patient’s muscle mtDNA (P) compared to the normal control (C), showing the presence of a deleted mtDNA species, f (P) amplifying a single small species of about 2 kb, compared to a molecular weight marker (M). g Electropherogram showing the breakpoints of the novel 8.2 kb deletion spanning nucleotides 6902 and 15103 of the mtDNA.

Occam's razor, which is a reductionist approach in science and medicine states 'among competing hypotheses, the one with the fewest assumptions should be selected' - William of Ockham c.1287-1347. As a clinician, this is now second nature to my way of thinking, whereby I formulate a unifying diagnosis that could explain all/most of my patients symptoms (diagnostic parsimony). If the same logic is applied to this case (as the authors are doing), then logically the two presentations must be linked, i.e. 1) the mitochondrial disorder caused by a mutation in the mitochondrial DNA and 2) multiple sclerosis.

This is by no means the first case of this description. In fact, mitochondrial disorders and MS occurring together has been previously reported, in particular with Leber's hereditary optic neuropathy (LHON) - a mitochondrial disorder characterised by visual loss starting in the teens.

As we learn more about the importance mitochondrial respiratory deficient neurones in MS, based on these naturally occurring associations, we also start to question whether mutations in mtDNA can kick start MS? That is, can the degeneration in cells caused by mtDNA mutations trigger in susceptible individuals an inflammatory reaction? This is difficult to say as the incidence of mitochondrial disorders is rare in the population, as is MS.

I am also a believer of Hickam's dictum (the medical counterargument to Occam's razor), which simply states that 'patients can have as many diseases as they damn well please'! Why is this also plausible in this case? Well, attempts at searching for mtDNA mutations in progressive MS patients did not reveal an excess of those with mutations compared to age-matched controls (Campbell GR, Reeve AK, Ziabreva I et al. (2013) No excess of mitochondrial DNA deletions within muscle in progressive multiple sclerosis. Mult Scler 19(14):1858–1866).

Monday, 2 May 2016

Loss of Oligodendrocytes

Rone MB, Cui QL, Fang J, Wang LC, Zhang J, Khan D, Bedard M, Almazan G, Ludwin SK, Jones R, Kennedy TE, Antel JP. Oligodendrogliopathy in Multiple Sclerosis: Low Glycolytic Metabolic Rate Promotes Oligodendrocyte Survival. J Neurosci. 2016;36(17):4698-707.

Multiple sclerosis (MS) lesions feature demyelination with limited remyelination. A distinct injury phenotype of MS lesions features dying back of oligodendrocyte (OL) terminal processes, a response that destabilizes myelin/axon interactions. This oligodendrogliopathy has been linked with local metabolic stress, similar to the penumbra of ischemic/hypoxic states. 

Here, we developed an in vitro oligodendrogliopathy model using human CNS-derived OLs and related this injury response to their distinct bioenergetic properties. We determined the energy utilization properties of adult human surgically derived OLs cultured under either optimal or metabolic stress conditions, deprivation of growth factors, and glucose and/or hypoxia.

Baseline studies were also performed on OL progenitor cells derived from the same tissue and post-natal rat-derived cells. Under basal conditions, adult human OLs were less metabolically active than their progenitors and both were less active than the rat cells. 

Human OLs and progenitors both used aerobic glycolysis for the majority of ATP production, a process that contributes to protein and lipid production necessary for myelin biosynthesis. Under stress conditions that induce significant process retraction with only marginal cell death, human OLs exhibited a significant reduction in overall energy utilization, particularly in glycolytic ATP production. 

The stress-induced reduction of glycolytic ATP production by the human OLs would exacerbate myelin process withdrawal while favoring cell survival, providing a potential basis for the oligodendrogliopathy observed in MS. The glycolytic pathway is a potential therapeutic target to promote myelin maintenance and enhance repair in MS.
SIGNIFICANCE STATEMENT: The neurologic deficits that characterize multiple sclerosis (MS) reflect disruption of myelin (demyelination) within the CNS and failure of repair (remyelination). We define distinct energy utilization properties of human adult brain-derived oligodendrocytes and oligodendrocyte progenitor cells under conditions of metabolic stress that model the initial relapsing and subsequent progressive phases of MS. The observed changes in energy utilization affect both cell survival and myelination capacity. These processes may be amenable to therapeutic interventions to limit the extent of cumulative tissue injury and to promote repair in MS.

Glycolysis s the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO + H+. The free energy released in this process is used to form the high-energy compounds ATP (adenosine triphosphate) and NADH (reduced nicotinamide adenine dinucleotide).[
Glycolysis is a determined sequence of ten enzyme-catalyzed reactions. The intermediates provide entry points to glycolysis. For example, most monosaccharides, such as fructose and galactose, can be converted to one of these intermediates. The intermediates may also be directly useful. For example, the intermediate dihydroxyacetone phosphate (DHAP) is a source of the glycerol that combines with fatty acids to form fat.
Glycolysis is an oxygen independent metabolic pathway, meaning that it does not use molecular oxygen (i.e. atmospheric oxygen) for any of its reactions. 

However the products of glycolysis (pyruvate and NADH + H+) are sometimes disposed of using atmospheric oxygen. When molecular oxygen is used in the disposal of the products of glycolysis the process is usually referred to as aerobic, whereas if the disposal uses no oxygen the process is said to be anaerobic
The entire glycolysis pathway can be separated into two phases:
  1. The Preparatory Phase – in which ATP is consumed and is hence also known as the investment phase
  2. The Pay Off Phase – in which ATP is produced.

Sunday, 1 May 2016

ClinicSpeak & BrainHealth: Is sedentary behaviour a silent killer?

Are you a MS Sedent? Time to change your behaviour. #ClinicSpeak #MSBlog #BrainHealth

"Sedentary behaviour is well described in MS (see review below). Is sedentary behaviour a consequence of you having MS or does MS cause sedentary behaviour? It is obvious that if you are disabled it is more difficult to exercise. Similarly, if you suffer from exercise induced fatigue you may be reluctant to exercise, or exert yourself unnecessarily, so as not exacerbate your fatigue. Then there is the issue of low mood and poor motivation. MSers have a high prevalence of comorbid depression and this is associated with reduced motivation and drive; people who are depressed simply don't want to exercise. Then there is deconditioning; the less you exercise the less you are able to exercise because any exertion is tiring. All these factors create a downward spiral that leads to you becoming a sedent. It is often difficult to break the cycle unless you want to break it. What is clear that if you are a sedent you may need help to break the cycle. I suggest asking your neurologists or MS clinical nurse specialist to refer you to a physiotherapist for help. Once you start reconditioning yourself you will be surprised how good it makes you feel. Exercise is one of the most effective treatments we have for a whole range of issues MSers suffer from; low mood, obesity, poor sleep, fatigue, etc. The problem I have is how do I successfully prescribe exercise to my patients in a way that they take me seriously and adhere to the prescription? One thing I am trying to do is to practice what I preach; I personally try to get in 4-5 exercise sessions in a week. It is difficult to tell your patients to exercise if you don't exercise yourself. Exercise is one component of the Barts-MS Brain Health Challenge; have you signed-up to the challenge?"

Epub: Veldhuijzen van Zanten et al. Sedentary behaviour in people with multiple sclerosis: Is it time to stand up against MS? Mult Scler. 2016 Apr 12. pii: 1352458516644340.

Historically, people with multiple sclerosis (MS) have been considered sedentary, although the actual scientific study of sedentary behaviour in MS did not originate until 2011. Sedentary behaviour, which is conceptually distinct from physical inactivity, is defined as any waking activity characterised by an energy expenditure ⩽ 1.5 metabolic equivalents and in a sitting or reclining posture. In the general population, the volume of sitting time is associated with increased risks of morbidity and mortality, independent of physical activity, and has been suggested to carry a greater risk of mortality than smoking behaviour. There are many symptoms of MS (e.g. mobility disability and fatigue) that could increase the prevalence of sedentary behaviour, and sedentary behaviour may have considerable implications for the development of comorbid conditions prevalent in MS. This review provides a summary of the rates, correlates, consequences and interventions attempting to reduce sedentary behaviour in MS. We provide a research agenda that guides future research on sedentary behaviour in MS. This paper provides a clarion call that it is time to 'stand up against MS'.

Unrelated Blogger Comments-May2016

Sometimes you want to say something unrelated to the threads . This is the place for you

Remyelinating drug Saving nerves

Wootla B, Denic A, Warrington AE, Rodriguez M.A monoclonal natural human IgM protects axons in the absence of remyelination. J Neuroinflammation. 2016 ;13(1):94.
BACKGROUND:Whereas demyelination underlies early neurological symptoms in multiple sclerosis (MS), axonal damage is considered critical for permanent chronic deficits. Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic induced demyelinating disease (TMEV-IDD) with progressive axonal loss and neurologic dysfunction similar to progressive forms of MS. We previously reported that treatment of chronic TMEV-IDD mice with a neurite outgrowth-promoting natural human antibody, HIgM12, improved brainstem NAA concentrations and preserved functional motor activity. In order to translate this antibody toward clinical trial, we generated a fully human recombinant form of HIgM12, rHIgM12, determined the optimal in vivo dose for functional improvement in TMEV-IDD, and evaluated the functional preservation of descending spinal cord axons by retrograde labeling.
FINDINGS: SJL/J mice at 45 to 90 days post infection (dpi) were studied. A single intraperitoneal dose of 0.25 mg/kg of rHIgM12 per mouse is sufficient to preserve motor function in TMEV-IDD. The optimal dose was 10 mg/kg. rHIgM12 treatment protected the functional transport in spinal cord axons and led to 40 % more Fluoro-Gold-labeled brainstem neurons in retrograde transport studies. This suggests that axons are not only present but also functionally competent. rHIgM12-treated mice also contained more mid-thoracic (T6) spinal cord axons than controls.
CONCLUSIONS:This study confirms that a fully human recombinant neurite outgrowth-promoting monoclonal IgM is therapeutic in a model of progressive MS using multiple reparative readouts. The minimum effective dose is similar to that of a remyelination-promoting monoclonal human IgM discovered by our group that is presently in clinical trials for MS.

The TMEV model has been a model of viral induced demyelination and now it is claimed that it is a model of progressive MS. I am not sure on what grounds. It has nerve loss?

This study says that one delivery of antibody stops 40% nerve loss, which sounds great. If they had done more the mouse's immune system would have got rid of it, but one injection and it saves the brain..great 

Maybe it is time that this approach was put to the test. One injection should be all that is needed. 

I first saw this approach well over a decade ago and we are still awaiting the human results.