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Australia: Melbourne Researchers Find Botox Eases Multiple Sclerosis Tremors

Posted: July 3rd, 2012 | Author: | Filed under: Cankler Science News, Chemically Engineered, Medicated | Tags: , , , , | Comments Off on Australia: Melbourne Researchers Find Botox Eases Multiple Sclerosis Tremors

Australia - Melbourne Researchers Find Botox Eases Multiple Sclerosis TremorsResearchers have found that Botox can significantly reduce the severity of tremors in patients with the debilitating inflammatory disease, Multiple Sclerosis.

Researchers injected 23 patients with either Botox or a placebo over six months during the trial at the Royal Melbourne Hospital. They then videoed the volunteers to see if the botox made a difference.

Multiple sclerosis (MS), also known as “disseminated sclerosis” or “encephalomyelitis disseminata”, is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms.

Disease onset usually occurs in young adults, and it is more common in women. It has a prevalence that ranges between 2 and 150 per 100,000. MS was first described in 1868 by Jean-Martin Charcot ::::

Australia-Melbourne Researchers Find Botox Eases Multiple Sclerosis Tremors

The study’s author, Dr Anneke van der Walt says there was a reduction in the severity of tremors in 40 per cent of the patients.

“Anything else that has been tried generally doesn’t work very well at all, so an improvement of 40 per cent with a trial drug is very significant,” Dr van der Walt said. “We found also quite importantly that there was improvement in a lot of functional activities for the patients. The most important of those was probably an improvement in writing and drawing on paper, with an improvement seen of about 30 per cent.”

The volunteers described improvements in their ability to eat and drink, write and use a computer.

The researchers say the effects could be life-changing for many people with MS, and they hope Botox could eventually put an end to the debilitating shaking.

Australia - Melbourne Researchers Find Botox Eases Multiple Sclerosis Tremors - Wiki

Multiple sclerosis (MS), also known as “disseminated sclerosis” or “encephalomyelitis disseminata”, is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms.

Disease onset usually occurs in young adults, and it is more common in women. It has a prevalence that ranges between 2 and 150 per 100,000. MS was first described in 1868 by Jean-Martin Charcot.

MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other effectively. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are contained within an insulating substance called myelin. In MS, the body’s own immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals.

The name Multiple Sclerosis refers to scars or scleroses, plaques or lesions, particularly in the white matter of the brain and spinal cord, which is mainly composed of myelin.

Although much is known about the mechanisms involved in the disease process, the cause remains unknown. Theories include genetics or infections. Different environmental risk factors have also been found.

Almost any neurological symptom can appear with the disease, and often progresses to physical and cognitive disability. MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). Between attacks, symptoms may go away completely, but permanent neurological problems often occur, especially as the disease advances.

There is no known cure for multiple sclerosis. Treatments attempt to return function after an attack, prevent new attacks, and prevent disability.

MS medications can have adverse effects or be poorly tolerated, and many people pursue alternative treatments, despite the lack of supporting scientific study. The prognosis is difficult to predict; it depends on the subtype of the disease, the individual’s disease characteristics, the initial symptoms and the degree of disability the person experiences as time advances.

Life expectancy of people with MS is 5 to 10 years lower than that of the unaffected population.

Symptoms

A person with MS can suffer almost any neurological symptom or sign, including changes in sensation such as loss of sensitivity or tingling, pricking or numbness (hypoesthesia and paresthesia), muscle weakness, clonus, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia); problems in speech (dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis including phosphenes, or diplopia), fatigue, acute or chronic pain, and bladder and bowel difficulties. Cognitive impairment of varying degrees and emotional symptoms of depression or unstable mood are also common.

Uhthoff’s phenomenon, an exacerbation of extant symptoms due to an exposure to higher than usual ambient temperatures, and Lhermitte’s sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS although not specific. The main clinical measure of disability progression and symptom severity is the Expanded Disability Status Scale or EDSS.

Symptoms of MS usually appear in episodic acute periods of worsening (called relapses, exacerbations, bouts, attacks, or “flare-ups”), in a gradually progressive deterioration of neurologic function, or in a combination of both.

MS relapses are often unpredictable, occurring without warning and without obvious inciting factors with a rate rarely above one and a half per year. Some attacks, however, are preceded by common triggers. Relapses occur more frequently during spring and summer. Viral infections such as the common cold, influenza, or gastroenteritis increase the risk of relapse.

Stress may also trigger an attack. Pregnancy affects the susceptibility to relapse, with a lower relapse rate at each trimester of gestation. During the first few months after delivery, however, the risk of relapse is increased.

Overall, pregnancy does not seem to influence long-term disability. Many potential triggers have been examined and found not to influence MS relapse rates. There is no evidence that vaccination and breast feeding, physical trauma, or Uhthoff’s phenomenon are relapse triggers.

Causes

Most likely MS occurs as a result of some combination of genetic, environmental and infectious factors, and possibly other factors like vascular problems.

Epidemiological studies of MS have provided hints on possible causes for the disease. Theories try to combine the known data into plausible explanations, but none has proved definitive.

MS is not considered a hereditary disease. However, a number of genetic variations have been shown to increase the risk of developing the disease.

The risk of acquiring MS is higher in relatives of a person with the disease than in the general population, especially in the case of siblings, parents, and children.

The disease has an overall familial recurrence rate of 20%. In the case of monozygotic twins, concordance occurs only in about 35% of cases, while it goes down to around 5% in the case of siblings and even lower in half-siblings. This indicates susceptibility is partly polygenically driven. It seems to be more common in some ethnic groups than others.

Apart from familial studies, specific genes have been linked with MS. Differences in the human leukocyte antigen (HLA) system—a group of genes in chromosome 6 that serves as the Major Histocompatibility Complex – MHC – in humans, increase the probability of suffering MS. The most consistent finding is the association between multiple sclerosis and alleles of the MHC defined as DR15 and DQ6. Other loci have shown a protective effect, such as HLA-C554 and HLA-DRB1.

Environmental Factors

Different environmental factors, both of infectious and non infectious origin have been proposed as risk factors for MS. Although some are partly modifiable, only further research – especially clinical trials – will reveal whether their elimination can help prevent MS.

MS is more common in people who live farther from the equator, although many exceptions exist. Decreased sunlight exposure has been linked with a higher risk of MS. Decreased vitamin D production and intake has been the main biological mechanism used to explain the higher risk among those less exposed to sun.

Severe stress may be a risk factor although evidence is weak. Smoking has also been shown to be an independent risk factor for developing MS.

Association with occupational exposures and toxins – mainly solvents – has been evaluated, but no clear conclusions have been reached. Vaccinations were investigated as causal factors for the disease; however, most studies show no association between MS and vaccines.

Several other possible risk factors, such as diet and hormone intake, have been investigated; however, evidence on their relation with the disease is “sparse and unpersuasive”.

Gout occurs less than would statistically be expected in people with MS, and low levels of uric acid have been found in people with MS as compared to normal individuals. This led to the theory that uric acid protects against MS, although its exact importance remains unknown.

Infections

Many microbes have been proposed as potential infectious triggers of MS, but none have been substantiated. Moving at an early age from one location in the world to another alters a person subsequent risk of MS.

An explanation for this could be that some kind of infection, produced by a widespread microbe rather than a rare pathogen, is the origin of the disease.

There are a number of proposed mechanism including the Hygiene Hypothesis and the prevalence hypothesis. The hygiene hypothesis proposes that exposure to several infectious agents early in life is protective against MS, the disease being a response to a later encounter with such agents.

The prevalence hypothesis proposes that the disease is due to a pathogen more common in regions of high MS prevalence where in most individuals it causes an asymptomatic persistent infection. Only in a few cases, and after many years does it cause demyelination. The hygiene hypothesis has received more support than the prevalence hypothesis.

Evidence for viruses as a cause includes the presence of oligoclonal bands in the brain and cerebrospinal fluid of most people with MS, the association of several viruses with human demyelination encephalomyelitis, and induction of demyelination in animals through viral infection.

Human herpes viruses are a candidate group of viruses linked to MS. Individuals who have never been infected by the Epstein-Barr virus have a reduced risk of having the disease, and those infected as young adults have a greater risk than those who had it at a younger age.

Although some consider that this goes against the hygiene hypothesis, since the non-infected have probably experienced a more hygienic upbringing, others believe that there is no contradiction since it is a first encounter at a later moment with the causative virus that is the trigger for the disease. Other diseases that have also been related with MS are measles, mumps and rubella.

MS - Structure of a typical neuron

Pathophysiology

MS is a condition in which the Central Nervous System – CNS – of a person present a special kind of distributed lesions (sclerosis) whose pathophysiology is complex and still under investigation. It is considered a pathological entity by some authors and a clinical entity by some others. MS is believed to be an immune-mediated disorder mediated by a complex interaction of the individual’s genetics and as yet unidentified environmental insults. Damage is believed to be caused by the person’s own immune system attacking the nervous system, possibly as a result of exposure to a molecule with a similar structure to one of its own.

Damage occurs in two phases. First some MRI-abnormal areas with hidden damage appear in the brain and spine, followed later by leaks in the blood–brain barrier where immune cells infiltrate causing the known demyelination.

MS is mainly a white matter disease, and lesions appear mainly in a peri-ventricular distribution (lesions clustered around the ventricles of the brain), but apart of the usually known white matter demyelination, also the cortex and deep gray matter (GM) nuclei are affected, together with diffuse injury of the normal-appearing white matter. MS is active even during remission periods. GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS.

At least five characteristics are present in CNS tissues of MS patients: Inflammation beyond classical white matter lesions, Intrathecal Ig production with oligoclonal bands, An environment fostering immune cell persistence, Follicle-like aggregates in the meninges and a disruption of the blood–brain barrier also outside of active lesions.

Demyelination Process & Specific Areas of Damage

Damage occurs in two phases. First some MRI-abnormal areas with hidden damage appear in the brain and spine, followed later by leaks in the blood–brain barrier where immune cells infiltrate causing the known demyelination.

According to the view of most researchers, a special subset of lymphocytes, called T helper cells, specifically Th1 and Th17, play a key role in the development of the lesion. A protein called Interleukin 12 is responsible for the differentiation of naive T cells into inflammatory T cells. An over production of this protein is what causes the increased inflammation in MS patients.

Under normal circumstances, these lymphocytes can distinguish between self and non-self. However, in a person with MS, these cells recognize healthy parts of the central nervous system as foreign and attack them as if they were an invading virus, triggering inflammatory processes and stimulating other immune cells and soluble factors like cytokines and antibodies. Many of the myelin-recognizing T cells belong to a terminally differentiated subset called co-stimulation-independent effector-memory T cells.

Recently other type of immune cells, B Cells, have been also implicated in the pathogenesis of MS and in the degeneration of the axons. The axons themselves can also be damaged by the attacks.

Often, the brain is able to compensate for some of this damage, due to an ability called neuroplasticity. MS symptoms develop as the cumulative result of multiple lesions in the brain and spinal cord. This is why symptoms can vary greatly between different individuals, depending on where their lesions occur.

Repair processes, called remyelination, also play an important role in MS. Remyelination is one of the reasons why, especially in early phases of the disease, symptoms tend to decrease or disappear temporarily. Nevertheless, nerve damage and irreversible loss of neurons occur early in MS.

The oligodendrocytes that originally formed a myelin sheath cannot completely rebuild a destroyed myelin sheath. However, the central nervous system can recruit oligodendrocyte stem cells capable of proliferation and migration and differentiation into mature myelinating oligodendrocytes.

The newly-formed myelin sheaths are thinner and often not as effective as the original ones. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons. Under laboratory conditions, stem cells are quite capable of proliferating and differentiating into remyelinating oligodendrocytes; it is therefore suspected that inflammatory conditions or axonal damage somehow inhibit stem cell proliferation and differentiation in affected areas

Brain Lesions Distribution

MS is considered a disease of the white matter because normally lesions appear in this area, but it is also possible to find some of them in the grey matter.

Using high field MRI system, with several variants several areas show lesions, and can be spacially classified in infratentorial, callosal, juxtacortical, periventricular, and other white matter areas. Other authors simplify this in three regions: intracortical, mixed gray-white matter, and juxtacortical.

Others classify them as hippocampal, cortical, and WM lesions, and finally, others give seven areas: intracortical, mixed white matter-gray matter, juxtacortical, deep gray matter, periventricular white matter, deep white matter, and infratentorial lesions. The distribution of the lesions could be linked to the clinical evolution.

Post-mortem autopsy reveal that gray matter demyelination occurs in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord. Cortical lesions have been observed specially in people with Secondary Progressive MS – SPMS – but they also appear in Relapsing Remitting MS – RRMS – and clinically isolated syndrome. They are more frequent in men than in women and they can partly explain cognitive deficits.

It is known that two parameters of the cortical lesions, Fractional Anisotropy – FA – and Mean Diffusivity – MD – are higher in patients than in controls.

They are larger in SPMS than in RRMS and most of them remain unchanged for short follow-up periods. They do not spread into the subcortical white matter and never show gadolinium enhancement. Over a one-year period, lesions can increase their number and size in a relevant proportion of MS patients, without spreading into the subcortical white matter or showing inflammatory features similar to those of white matter lesions.

Due to the distribution of the lesions, since 1916 they are also known as Dawson’s Fingers. They appear around the brain blood vessels.

Spinal Cord Damage

Cervical spinal cord has been found to be affected by MS even without attacks, and damage correlates with disability. In RRMS, cervical spinal cord activity is enhanced, to compensate for the damage of other tissues. It has been shown that Fractional Anisotropy of cervical spinal cord is lower than normal, showing that there is damage hidden from normal MRI.

Progressive tissue loss and injury occur in the cervical cord of MS patients. These two components of cord damage are not interrelated, suggesting that a multiparametric MRI approach is needed to get estimates of such a damage. MS cord pathology is independent of brain changes, develops at different rates according to disease phenotype, and is associated to medium-term disability accrual.

Spinal cord presents grey matter lesions, that can be confirmed post-mortem and by high field MR imaging. Spinal cord grey matter lesions may be detected on MRI more readily than GM lesions in the brain, making the cord a promising site to study the grey matter demyelination.

Retina & Optic Nerve Damage

There is axonal loss in the retina and optic nerve, which can be meassured by Optical coherence tomography or by Scanning laser polarimetry. This measure can be used to predict disease activity and to establish a differential diagnosis from Neuromyelitis optica.

In vertebrate embryonic development, the retina and the optic nerve originate as outgrowths of the developing brain, so the retina is considered part of the central nervous system (CNS). It is the only part of the CNS that can be imaged non-invasively in the living organism.

The retina is unique within the CNS in that it contains axons and glia but no myelin, and it is, therefore, an ideal structure within which to visualize the processes of neurodegeneration. Tissue-bound IgG was demonstrated on retinal ganglion cells in six of seven multiple sclerosis cases but not in controls.

Uveitis and retinal Phlebitis are manifestations of MS. Trypsin digestion with microscopic examination is a method of testing for phlebitis and the frequency found in this series is higher than in others. These lesions are similar to the perivenular cuffing that occurs in the central nervous system in MS.

Retinal vessels show narrower arterioles and wider venules even in absence of optic neuritis, possibly as a consequence of subclinical swelling of optic nerve axons, together with a higher than normal rigidity.

Neural & Axonal Damage

The axons of the neurons are damaged probably by B-Cells, though currently no relationship has been established with the relapses or the attacks. It seems that this damage is a primary target of the immune system, i.e. not secondary damage after attacks against myelin, though this has been disputed.

Proton magnetic resonance spectroscopy has shown that there is widespread neuronal loss even at the onset of MS, largely unrelated to inflammation.

A relationship between neural damage and N-Acetyl-Aspartate concentration has been established, and this could lead to new methods for early MS diagnostic through magnetic resonance spectroscopy.

Axonal degeneration at CNS can be estimated by N-acetylaspartate to creatine (NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy.

Though MS is defined as a CNS condition, some reports link problems in the peripheral nervous system with the presence of MS plaques in the CNS.

Lesion Structure

MS is a condition defined by the presence of a special kind of lesions in the brain and spinal cord. Therefore it is very important to establish what those “lesions typical of MS” are. They mainly consist in demyelination and scarring in the fatty myelin sheaths around the axons of the brain and spinal cord. According with the most recent research, an active lesion is composed of different layers:

  • NAWM border with the lesion: These areas contained activated microglia, antibodies binding to astrocytes, axons, oligodendrocytes and dendritic cells along blood vessels. No T or B cells are present.
  • Lesion external layer: Number of oligodendrocyte cell bodies decreases. Remaining oligodendrocytes are sometimes swollen or dying. Myelin sheaths are still intact but swollen. Small increase in microglia and T cells.
  • Active layer: Phagocytic demyelinating areas: There is myelin debris taken up by local microglia and phagocytes entering from the bloodstream. More T cells in these areas, and in the space adjacent to blood vessels.
  • Recently demyelinated tissue: Tissues were full of myelin-containing phagocytes. Signs of early remyelination together with small numbers of oligodendrocytes. Large numbers of T cells, B cells, and other immune cells concentrated around blood vessels.
  • Inactive layer: Again activated microglia and dendritic cells were also found around blood vessels.

Blood-brain Barrier Disruption

A healthy blood-brain barrier – BBB – should not allow T-cells to enter the nervous system. BBB disruption is the moment in which T-cells cross the barrier and has always been considered one of the early problems in the MS lesions. For unknown reasons, leaks appear in the BBB during the course of MS.

Recently it has been found that BBB damage happens even in non-enhancing lesions. MS has an important vascular component.

The BBB is built up of endothelial cells lining the blood vessel walls. After its breakdown several problems appear, such as swelling, activation of macrophages, and more activation of cytokines and other proteins such as matrix metalloproteinases which are destructive.

Whatever the demyelination process is, currently it is possible to detect lesions before demyelination, and they show clusters of activated microglia and leukocyte infiltration, together with oligodendrocytes abnormalities.

As lesions appear – using MRI – in “Normal-appearing white matter” – NAWM – there is supposed to be the cause that finally triggers the BBB disruption. The damaged white matter is where lesions appear. These lesions form in NAWM before blood–brain barrier breakdown.

BBB can be broken centripetally or centrifugally, the first form being the most normal. Several possible biochemical disrupters have been proposed. Some hypothesis about how the BBB is compromised revolve around the presence of different compounds in the blood that could interact with the vascular vessels ony in the NAWM areas. The permeability of two cytokines, IL15 and LPS, could be involved in the BBB breakdown.

The BBB breakdown is responsible for monocyte infiltration and inflammation in the brain. Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1alpha through Lyn kinase.

Using iron nanoparticles, involvement of macrophages in the BBB breakdown can be detected. A special role is played by Matrix metalloproteinases. These are a group of proteases that increase T-cells permeability of the blood–brain barrier, specially in the case of MMP-9, and are supposed to be related to the mechanism of action of interferons.

Whether BBB dysfunction is the cause or the consequence of MS[74] is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins.

Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins. (Adhesion molecules could also play a role in inflammation) In particular, one of these adhesion proteins involved is ALCAM (Activated Leukocyte Cell Adhesion Molecule, also called CD166), and is under study as therapeutic target. Other protein also involved is CXCL12, which is found also in brain biopsies of inflammatory elements, and which could be related to the behavior of CXCL13 under methylprednisolone therapy. Some molecular biochemical models for relapses have been proposed.

Normally, gadolinium enhancement is used to show BBB disruption on MRIs.  Abnormal tight junctions are present in both SPMS and PPMS. They appear in active white matter lesions, and gray matter in SPMS. They persist in inactive lesions, particularly in PPMS.

A deficiency of uric acid has been implicated in this process. Uric acid added in physiological concentrations (i.e. achieving normal concentrations) is therapeutic in MS by preventing the breakdown of the blood brain barrier through inactivation of peroxynitrite.

The low level of uric acid found in MS victims is manifestedly causative rather than a consequence of tissue damage in the white matter lesions, but not in the grey matter lesions. Besides, uric acid levels are lower during.

Damage Before BBB Disruption

Special MRI Methods

Before BBB disruption, brain tissues present normal aspect under normal MRI (Normal appearing white matter, NAWM and normal appearing grey matter, NAGM), but show several abnormalities under special MRI technologies.

Magnetization transfer multi-echo T(2) relaxation. Subjects with Long-T(2) lesions had a significantly longer disease duration than subjects without this lesion subtype. It has been found that grey matter injury correlates with disability and that there is high oxidative stress in lesions, even in the old ones.

Diffusion tensor MRI or Magnetic Transfer MRI are two options to enhance MRI-hidden abnormalities discovery. This is currently an active field of research with no definitive results, but it seems that these two technologies are complementary.

Other methods of MRI allow us to get a better insight of the lesions structure. Recently MP-RAGE MRI has shown better results than PSIR and DIR for gray matter lesions. Susceptibility weighted imaging (SWI-MRI) has shown iron (hemosiderin) deposition in lesions, and helps to detect otherwise invisible lesions.

Normal Appearing Brain Tissues

The cause why the normal appearing areas appear in the brain is unknown. Historically, several theories about how this happens has been presented.

Venous pathology has been associated with MS for more than a century. Pathologist Georg Eduard Rindfleisch noted in 1863 that the inflammation-associated lesions were distributed around veins. Some other authors such as Tracy Putnam have pointed to venous obstructions. Others have proposed a mechanical damage procedure based on violent blood reflux. Later the focus moved to softer hemodynamic abnormalities, which were shown that precede changes in sub-cortical gray matter and in substantia nigra.

However, such reports of a “hemodynamic cause of MS” are not universal, and possibly not even common. At this time the evidence is largely anecdotal and some MS patients have no blood flow issues. Possibly vascular problems may be an aggravating factor, like many others in MS. Indeed the research, by demonstrating patients with no hemodynamic problems actually prove that this is not the only cause of MS.

Using several texture analysis technologies, it is possible to classify white matter areas into three categories: normal, normal-appearing and lesions. Currently, it is possible to detect lesions before they present demyelination, and they are called pre-active lesions.

A fourth area called DAWM – Diffusely Abnormal White Matter – has recently been proposed and can help to differentiate PPMS and SPMS. Abundant extracellular myelin in the meninges of patients with multiple sclerosis has been found.

Brain tissues with MRI-hidden problems are usually named Normal Appearing. Exploring the normal-appearing corpus callosum has been found a possible primary hypoperfusion, according with other findings in this same direction. Also iron – in hemosiderin deposits and as well as in ferritin-like structures inside the macrophage – accumulation has been reported.

Several findings in these areas have been shown. Post-mortem studies over NAWM and NAGM areas – Normal Appearing White and Gray Matters – show several biochemical alterations, like increased protein carbonylation and high levels of Glial Fibrillary Acidic Protein – GFAP – which in NAGM areas comes together with higher than normal concentration of protein carbonyls, suggesting reduced levels of antioxidants and the presence of small lesions.

The amount of interneuronal Parvalbumin is lower than normal in brain’s motor cortex areas, and oxidative injury of oligodendrocytes and neurons could be associated with active demyelination and axonal injury.

Normal Appearing White Matter

The white matter with hidden but MRI-visible damage is known as “Normal-appearing white matter” (NAWM) and is where lesions appear.

BBB disruption takes place on NAWM areas. This can be read in different ways. Maybe some hidden changes in White Matter structure trigger the BBB disruption, or maybe the same process that creates the NAWM areas disrupts the BBB after some time.

Pre-active lesions are lesions in an early stage of development. They resolve sometimes without further damage, and not always develop into demyelinating lesions. They present clusters of activated microglia in otherwise normal-appearing white matter.
Oligodendrocyte abnormalities appear to be crucially involved.

The earliest change reported in the lesions examined is widespread oligodendrocyte apoptosis in which T cells, macrophages, activated microglia, reactive astrocytes, and neurons appear normal. This observation points to some change in the local environment (NAWM) to which oligodendrocytes are especially susceptible and which triggers a form of apoptosis.

Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls.

MS CitrullinationCitrullination appears in SPMS. It seems that a defect of sphingolipid metabolism modifies the properties of normal appearing white matter. Related to these, peptidylarginine deiminase 2 is increased in patients with MS, and is related to arginine de-imination.

NAWM shows a decreased perfusion which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread astrocyte dysfunction, possibly related to a deficiency in astrocytic beta(2)-adrenergic receptors and a reduced formation of Cyclic Adenosine Mono-phosphate. CAMP, resulting in a reduced uptake of K(+) at the nodes of Ranvier and a reduced release of K(+) in the perivascular spaces.

This would be consistent again with cases of Chronic cerebrospinal venous insufficiency.

White matter lesions appear in NAWM areas and their behavior can be predicted by MRI parameters as MTR – Magnetization Transfer Ratio. This MTR parameter is related to axonal density.

It also seems that Myelin Basic Protein – MBP – from MS patients contains lower levels of phosphorylation than normal individuals.

Gray Matter Damage & Normal Appearing Gray Matter

Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disability. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS. Epstein-Barr Virus could be involved, but is not likely. Involvement of the deep gray matter (DGM), suggested by magnetic resonance imaging, is confirmed, and most DGM lesions involve both GM and white matter. Inflammation in DGM lesions is intermediate between the destructive inflammation of white matter lesions and the minimal inflammation of cortical lesions. Iron depositions appear in deep gray matter by magnetic field correlation MRI

Read more on the pathology of MS at Wikipedia: en.wikipedia.org/Pathophysiology_of_multiple_sclerosis

Diagnosis

Multiple sclerosis can be difficult to diagnose since its signs and symptoms may be similar to other medical problems.  Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process especially in the first stages of the disease. Historically, the Schumacher and Poser criteria were both popular.

Currently, the McDonald criteria focus on a demonstration with clinical, laboratory and radiologic data of the dissemination of MS lesions in time and space for non-invasive MS diagnosis, though some have stated that the only proved diagnosis of MS is autopsy, or occasionally biopsy, where lesions typical of MS can be detected through histopathological techniques.

Clinical data alone may be sufficient for a diagnosis of MS if an individual has suffered separate episodes of neurologic symptoms characteristic of MS.

Since some people seek medical attention after only one attack, other testing may hasten and ease the diagnosis. The most commonly used diagnostic tools are neuroimaging, analysis of cerebrospinal fluid and evoked potentials. Magnetic resonance imaging of the brain and spine shows areas of demyelination (lesions or plaques). Gadolinium can be administered intravenously as a contrast to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation.

Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation of the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS.

The nervous system of a person with MS responds less actively to stimulation of the optic nerve and sensory nerves due to demyelination of such pathways. These brain responses can be examined using visual and sensory evoked potentials.

Classification

Several subtypes, or patterns of progression, have been described. Subtypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for therapeutic decisions.

In 1996 the United States National Multiple Sclerosis Society standardized four clinical courses:

  • Relapsing Remitting – RRMS
  • Secondary Progressive – SPMS
  • Primary Progressive – PPMS
  • Progressive Relapsing -PR MS

The relapsing-remitting subtype is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits suffered during attacks may either resolve or leave sequelae, the latter being more common as a function of time.

This describes the initial course of 80% of individuals with MS. When deficits always resolve between attacks, this is sometimes referred to as benign MS, although people will still accrue some degree of disability in the long term. The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis. However only 30 to 70% of persons experiencing CIS later develop MS.

Secondary progressive MS – often referred to as Galloping MS – describes around 65% of those with an initial relapsing-remitting MS, who then begin to have progressive neurologic decline between acute attacks without any definite periods of remission.

Occasional relapses and minor remissions may appear. The median time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years. The primary progressive subtype describes the approximately 10–15% of individuals who never have remission after their initial MS symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.

The age of onset for the primary progressive subtype is later than for the relapsing-remitting, but similar to mean age of progression between the relapsing-remitting and the secondary progressive. In both cases it is around 40 years of age.

Progressive relapsing MS describes those individuals who, from onset, have a steady neurologic decline but also suffer clear superimposed attacks. This is the least common of all subtypes.

Atypical variants of MS with non-standard behavior have been described; these include Devic’s disease, Balo concentric sclerosis, Schilder’s diffuse sclerosis and Marburg multiple sclerosis. There is debate on whether they are MS variants or different diseases. Multiple sclerosis also behaves differently in children, taking more time to reach the progressive stage. Nevertheless they still reach it at a lower mean age than adults.

Management

Several therapies for multiple sclerosis (MS) exist, although there is no known cure. Multiple sclerosis is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS).

The most common initial course of the disease is the relapsing-remitting subtype, which is characterized by unpredictable attacks (relapses) followed by periods of relative remission with no new signs of disease activity. After some years, many of the people who have this subtype begin to experience neurologic decline without acute relapses. When this happens it is called secondary progressive multiple sclerosis. Other, less common, courses of the disease are the primary progressive (decline from the beginning without attacks) and the progressive-relapsing (steady neurologic decline and superimposed attacks). Different therapies are used for patients experiencing acute attacks, for patients who have the relapsing-remitting subtype, for patients who have the progressive subtypes, for patients without a diagnosis of MS who have a demyelinating event, and for managing the various consequences of MS.

The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS may have several adverse effects, and many possible therapies are still under investigation. At the same time different alternative treatments are pursued by many patients, despite the paucity of supporting, comparable, replicated scientific study.

This article focuses on therapies for standard MS; borderline forms of MS have particular treatments that are excluded.

Management of Acute Attacks

During symptomatic attacks, patients may be hospitalized. As of 2007, administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the routine therapy for acute relapses. This is administered over a period of three to five days, and has a well-established efficacy in promoting a better recovery from disability.

The aim of this kind of treatment is to end the attack sooner and leave fewer lasting deficits in the patient. Although generally effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery: steroids produce a rapid improvement from disability, but this improvement only lasts up to thirty days following a clinical attack and is not evident thirty-six months after the attack. This treatment does not reduce the number of patients who subsequently develop a clinical relapse.

Potential side effects include osteoporosis and impaired memory, the latter being reversible.

Recent studies suggest that steroids administered orally are just as effective at treating MS symptoms as intravenous treatment. However, short-term treatment with high-dose intravenous corticosteroids does not seem to be attended by adverse effects, whereas gastrointestinal symptoms and psychiatric disorders are more common with oral corticosteroids.

Disease-modifying Treatments

As of 2011, six disease-modifying treatments have been approved by regulatory agencies of different countries, including the U.S. Food and Drug Administration – FDA – the European Medicines Agency – EMEA –  and the Japanese PMDA.

The six drugs are interferon beta-1a (Avonex, Rebif), interferon beta-1b (Betaseron), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri) and fingolimod (Gilenya), the first oral drug available. Most of these drugs are approved only for the Relapsing-Remitting course.

Clinically Isolated Syndrome

The earliest clinical presentation of relapsing-remitting MS (RRMS) is the clinically isolated syndrome (CIS), that is, a single attack of a single symptom. During a CIS, there is a subacute attack suggestive of demyelination but the patient does not fulfill the criteria for diagnosis of multiple sclerosis. Several studies have shown that treatment with interferons during an initial attack can decrease the chance that a patient will develop clinical definite MS.

These results support the use of interferon after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.

Relapsing-remitting MS

The two approved interferons are the interferon beta-1a (with two commercial formulations, with trade names Avonex and Rebif; the first injected weekly, the latter three times a week), and the interferon beta-1b (U.S. trade name Betaseron, in Europe and Japan Betaferon), injected every second day.

The other approved drugs are Glatiramer acetate or Copaxone, injected daily, which is a mixture of polypeptides which may protect important myelin proteins by substituting itself as the target of immune system attack. Mitoxantrone is an immunosuppressant also used in cancer chemotherapy. Natalizumab, marketed as Tysabri is a monoclonal antibody  and finally Fingolimod (trade name Gilenya) is a sphingosine-1-phosphate receptor modulator.

All six approved medications differ in their efficacy rate and studies of their long-term effects are still lacking.

The percentage of non-responsive patients to each medication also varies, being around 30% with interferons. Comparisons between immunomodulators (all but mitoxantrone) show that the most effective is natalizumab in terms of relapse rate reduction.

Preliminary data points to an effect in disease progression, but studies on the long-term effect are needed. Mitoxantrone is probably the most effective of them all in the short term; however, its use is limited by severe cardiotoxicity, and it is not considered as a long-term therapy. This is the reason why it is mainly used to treat patients who have advanced relapsing-remitting or secondary progressive multiple sclerosis.

Not all the patients are responsive to all these therapies. In particular, a subset of RRMS patients with specially active MS, sometimes called “Rapidly Worsening MS” are normally non-responders to all immunomodulators and are treated with immunosuppressants, in particular, Mitoxantrone. To speak about degree of response to treatment, the concept has to be defined first.

Several measures have been proposed but none is widely accepted. Nevertheless, the concept is widely used. For example, it is known that 30% of MS patients are non-responsive to Beta interferon. They can be classified in genetic, pharmacological and pathogenetic non-responders.

Even with appropriate use of medication, to varying degrees most patients with relapsing-remitting MS still suffer from some attacks and many suffer subsequent disability.

Secondary Progressive MS & Progressive Relapsing MS

Treatment of advanced forms of MS is more difficult than relapsing-remitting MS. A wide range of medications have been used to try to slow the progression of the disease, with results that have been at best fair.

Mitoxantrone has shown positive effects in patients with a secondary progressive and progressive relapsing courses. It is moderately effective in reducing the progression of the disease and the frequency of relapses in patients in short-term follow-up.

In 2007 it was the only medication approved in the USA for both secondary progressive and progressive relapsing multiple sclerosis; however, it causes dose-dependent cardiac toxicity which limits its long-term use. It is also not approved in Europe.

Natalizumab or Tysabri has shown efficacy and has been approved for secondary progressive MS with relapses. It can help the immune system to fight against bacteria.

Interferon-beta-1b (Betaseron or Betaferon) slowed progression of the disease in one clinical trial for secondary progressive MS, but not in another. However, both studies demonstrated that interferon recipients had fewer relapses and less disease activity, as assessed by magnetic resonance imaging (MRI). Therefore, interferons show promise in treating secondary progressive MS, but more data is needed to support their widespread use.

Primary Progressive MS

Treatment of primary progressive multiple sclerosis (PPMS) is problematic as many patients do not respond to any available therapy, and no treatment has been approved specifically for use in this form of the disease.

Several trials have been designed specifically for PPMS, including trials with interferons and mitoxantrone, a phase III trial of glatiramer acetate, and an open-label study of riluzole.

Patients with PPMS have also been included in trials of azathioprine, methotrexate, cladribine, intravenous immunoglobulin, cyclophosphamide, and studies of hematopoietic stem cell transplantation. However, no treatment in these trials has been shown to modify the course of the disease.

Side Effects of Treatments

Both the interferons and glatiramer acetate are available only in injectable forms, and both can cause irritation at the injection site. Also over time, a visible dent at the injection site due to the local destruction of fat tissue, known as lipoatrophy, may develop.
Interferons are produced in the body during illnesses such as influenza in order to help fight the infection.

They are responsible for the fever, muscle aches, fatigue, and headache common during influenza infections. Many patients report influenza-like symptoms when using interferon to fight MS. This reaction often lessens over time and can be treated with over-the-counter fever reducers/pain relievers like paracetamol (known in the U.S. as acetaminophen), ibuprofen, and naproxen.

Rare, but potentially serious, liver function abnormalities have also been reported with interferons, requiring that all patients treated regularly be monitored with liver function tests to ensure safe use.

Interferon therapy has also been shown to induce the production of anti-IFN neutralizing antibodies (NAb), usually in the second 6 months of treatment, in 3 to 45% of treated patients. However, the clinical consequences of the presence of antibodies are presently unclear: it has not been proved that these antibodies reduce efficacy of treatment. Therefore, any treatment decision should be based only on the clinical response to therapy.

Glatiramer acetate is generally considered to be better tolerated than the interferons, although some patients taking glatiramer experience a post-injection reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes.

Mitoxantrone therapy may be associated with immunosuppressive effects and liver damage; however its most dangerous side effect is its dose-related cardiac toxicity. Careful adherence to the administration and monitoring guidelines is therefore essential; this includes obtaining an echocardiogram and a complete blood count before treatment to decide whether the therapy is suitable for the patient or the risks are too great. It is recommended that mitoxantrone be discontinued at the first signs of heart damage, infection or liver dysfunction during therapy.

In the phase III studies for both MS and Crohn’s Disease, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leukoencephalopathy (PML), a rare progressive demyelinating disease of the brain that typically causes permanent disability or death, were identified in patients; two who had received it in combination with interferons, the other a Crohn’s Disease patient who had received it in combination with multiple other immuno-suppressants. As a result of a safety evaluation showing that no such cases had occurred in patients treated with natalizumab alone, it was approved as a monotherapy for MS patients.

In August 2008, two further cases of PML were reported, one of which had not taken any other immunomodulatory treatment before.

Managing the Effects of MS

Disease-modifying treatments only reduce the progression rate of the disease but do not stop it. As multiple sclerosis progresses, the symptoms tend to increase. The disease is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and handicap.

Management of these deficits is therefore very important. Both drug therapy and neurorehabilitation have shown to ease the burden of some symptoms, even though neither influence disease progression. For other symptoms the efficacy of treatments is still very limited.

Neurorehabilitation

Although there are relatively few studies of rehabilitation in MS, its general effectiveness, when conducted by a team of specialists, has been clearly demonstrated in other pathologies such as stroke or head trauma.

As for any patient with neurologic deficits, a multidisciplinary approach is key to limiting and overcoming disability; however there are particular difficulties in specifying a ‘core team’ because people with MS may need help from almost any health profession or service at some point. Neurologists are mainly involved in the diagnosis and ongoing management of multiple sclerosis, and any exacerbations.

The comprehensive rehabilitation process for patients with multiple sclerosis is generally managed by physiatrists. Allied treatments such as physiotherapy, speech and language therapy or occupational therapy can also help to manage some symptoms and maintain quality of life.

Treatment of neuropsychiatric symptoms such as emotional distress and clinical depression should involve mental health professionals such as therapists, psychologists, and psychiatrists, while neuropsychologists can help to evaluate and manage cognitive deficits. Multidisciplinary approaches have been shown to be effective in increasing activity levels and participation in multiple sclerosis.

Due to the paucity of randomized controlled studies, there is limited evidence of the overall efficacy of individual therapy disciplines, though there is good evidence that specific approaches, such as exercise, psychology therapies, particularly cognitive behavioral approaches and energy conservation instruction are effective.

More specifically psychological interventions seem useful in the treatment of depression, while evidence on effectiveness for other uses such as the treatment of cognitive impairments or vocational counseling is less strong.

In regards to well-being, physical therapy focused on gait training can be vital to maximizing MS patient participation via reduction of fatigue during walking and activities of daily living (ADLs).

Most gait training is performed over-ground (i.e., in a gym room or outside on uneven ground), on treadmills or, less commonly, using robotic-assisted devices. Robotic-assisted body weight-supported treadmill training may be an effective therapeutic option in MS patients with severe walking impairments.

In contrast, over-ground gait training may be most effective in improving gait speed in MS patients with less severe impairments. Equine-assisted therapies such as therapeutic horseback riding and hippotherapy are additional treatments that can positively influence gait, balance and quality of life in people with MS.

In regards to physical activity, it is important that the patient remains cautious when their core temperature elevates above normal levels due to the resulting transient increase in symptoms.

An elevated core temperature, leading to increased symptom presentation has been noted during exercise, due to variations in circadian body temperature throughout the day, and due to heat exposure including warm temperatures, warm showers, sun bathing, etc.

The interaction between an elevated core temperature and the pathological demyelination can cause a transient nerve conduction block that leads to temporarily impaired physical and cognitive function.

These effects translate to reduced patient safety and performance of ADLs, however there are viable prevention strategies. Behavioral strategies to minimize heat exposure include performing outdoor physical activity when temperatures are cooler, or installing an air conditioner. Some studies have found other cooling strategies to be beneficial: cold showers, cold water limb immersion, applying ice packs, and drinking cold beverages. These strategies are effective when attempting to decrease core temperature post-exercise, and as a method of pre-cooling prior to physical activity or heat exposure.

Despite the preceding suggestions it must be noted that the long term benefits from physical activity far outweigh abstaining from activity to reduce the occurrence of these transient effects.

Medical Treatments for Symptoms

Multiple sclerosis can cause a variety of symptoms including changes in sensation (hypoesthesia), muscle weakness, abnormal muscle spasms, impaired movement, difficulties with coordination and balance, problems in speech (known as dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis, or diplopia),fatigue and acute or chronic pain syndromes, bladder and bowel difficulties, cognitive impairment, or emotional symptoms (mainly depression). The most common clinical measure of disability progression and severity of the symptoms is the Expanded Disability Status Scale or EDSS. At the same time for each symptom there are different treatment options. Treatments should therefore be individualized depending both on the patient and the physician.

  • Bladder: pharmacological treatments for bladder problems vary greatly depending on the origin or type of dysfunction; however, some examples of medications used are: alfuzosin for retention, anticholinergics such as trospium and flavoxate for urgency and incontinence, or desmopressin for nocturia. Non-pharmacological treatments include pelvic floor muscle training, stimulation, biofeedback, pessaries, bladder retraining, and sometimes intermittent catheterization.
  • Bowel: people with MS may suffer bowel problems in two ways: reduced gut mobility may follow from immobility and from the drugs used to treat various impairments; and neurological control of defecation may be directly impaired. Pain or problems with defecation can be helped with a diet change, oral laxatives or suppositories and enemas.
  • Cognitive and emotional: neuropsychiatric symptomatology is common in the course of the disease. Depression and anxiety appear in up to 80% of patients, and can be treated with a variety of antidepressants; selective serotonin reuptake inhibitors (SSRIs) are the most frequently employed. Other neuropsychiatric symptoms are euphoria and disinhibition. This dyad was called “euphoria sclerotica” by the first authors that described the disease during the 19th century, and affects 10% of patients Anticholinesterase drugs such as donepezil, commonly used in Alzheimer disease, although not approved yet for multiple sclerosis, have shown efficacy in improving cognitive functions. Memantine, which is also used in Alzheimer’s disease, has been reported to induce reversible neurological impairment that led to stop an ongoing clinical trial. Psychological interventions are also useful in the treatment of cognitive and emotional deficits.
  • Dysphagia and dysarthria: dysphagia is a difficulty with eating and swallowing which may cause choking and aspiration of food or liquid into the lungs, whiledysarthria is a neurological motor speech disorder characterized by poor control over the subsystems and muscles responsible for speech (“articulation”). A speech and language therapist may give advice on specific swallowing techniques, on adapting food consistencies and dietary intake, on techniques to improve and maintain speech production and clarity, and on alternative communication approaches. In the case of advanced dysphagia, food can be supplied by anasogastric tube, which is a tube that goes through the nose directly to the stomach; or a percutaneous endoscopic gastrostomy (PEG), which is a procedure for placing a tube into the stomach and therefore administering food directly to it. This second system, although more invasive, has better results in the long term than nasogastric intake.
  • Fatigue: fatigue is very common and disabling in MS, and at the same time it has a close relationship with depressive symptomatology. When depression is reduced fatigue also tends to improve, so patients should be evaluated for depression before other therapeutic approaches are used. In a similar way, other factors such as disturbed sleep, chronic pain, poor nutrition, or even some medications can contribute to fatigue; medical professionals are therefore encouraged to identify and modify them. A few medications have been studied to treat MS-related fatigue, such as amantadine or pemoline (which is apsychostimulant also used for attention-deficit hyperactivity disorder and narcolepsy), as well as psychological interventions of energy conservation, but the effects of all of them are small. Fatigue is therefore a very difficult symptom to manage for which no drugs are recommended.
  • Pain: acute pain is mainly due to optic neuritis (with corticosteroids being the best treatment available), as well as trigeminal neuralgia, Lhermitte’s sign, or dysesthesias. Subacute pain is usually secondary to the disease and can be a consequence of spending too long in the same position, urinary retention, and infected skin ulcers, amongst others. Treatment will depend on cause. Chronic pain is very common and harder to treat as its most common cause is dysesthesias. Acute pain due to trigeminal neuralgia is usually successfully treated with anticonvulsants such as carbamazepine or phenytoin. Both Lhermitte’s sign and painful dysesthesias usually respond to treatment with carbamazepine, clonazepam, or amitriptyline. Sativex is approved for treatment of pain in MS in different countries, but due to its derivation from cannabis, it is currently not available in others, such as the USA. This medication is also being investigated for the management of other MS symptoms, such as spasticity, and has shown long-term safety and efficacy.
  • Spasticity: spasticity is characterized by increased stiffness and slowness in limb movement, the development of certain postures, an association with weakness of voluntary muscle power, and with involuntary and sometimes painful spasms of limbs. A physiotherapist can help to reduce spasticity and avoid the development of contractures with techniques such as passive stretching. There is evidence, albeit limited, of the clinical effectiveness of baclofen,[131]dantrolene, diazepam, and tizanidine. In the most complicated cases intrathecal injections of baclofen can be used. There are alsopalliative measures like castings, splints or customized seatings.
  • Vision: different drugs as well as optic compensatory systems and prisms can be used to improve the symptoms of nystagmus or diplopia (double vision). Surgery can also be used in some cases.
  • Walking capacity: dalfampridine (ampyra) improves walking ability and is approved by the FDA.

Unfortunately, other symptoms, such as ataxia, tremor or sensory losses, do not have proven treatments.

Prognosis

The prognosis (the expected future course of the disease) for a person with multiple sclerosis depends on the subtype of the disease; the individual’s sex, age, and initial symptoms; and the degree of disability the person experiences. The disease evolves and advances over decades, 30 being the mean years to death since onset.

Female sex, relapsing-remitting subtype, optic neuritis or sensory symptoms at onset, few attacks in the initial years and especially early age at onset, are associated with a better course.

The life expectancy of people with MS is 5 to 10 years lower than that of unaffected people. Almost 40% of people with MS reach the seventh decade of life. Nevertheless, two-thirds of the deaths in people with MS are directly related to the consequences of the disease. Suicide also has a higher prevalence than in the healthy population, while infections and complications are especially hazardous for the more disabled ones.

Although most people lose the ability to walk prior to death, 90% are still capable of independent walking at 10 years from onset, and 75% at 15 years.

Epidemiology

Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person–time at risk (usually number of new cases per thousand person–years); while prevalence is the total number of cases of the disease in the population at a given time. Prevalence is known to depend not only on incidence, but also on survival rate and migrations of affected people. MS has a prevalence that ranges between 2 and 150 per 100,000 depending on the country or specific population.

Studies on populational and geographical patterns of epidemiological measures have been very common in MS,[22] and have led to the proposal of different etiological (causal) theories.

MS usually appears in adults in their thirties but it can also appear in children. The primary progressive subtype is more common in people in their fifties. As with many autoimmune disorders, the disease is more common in women, and the trend may be increasing. In children, the sex ratio difference is higher, while in people over fifty, MS affects males and females almost equally.

There is a north-to-south gradient in the northern hemisphere and a south-to-north gradient in the southern hemisphere, with MS being much less common in people living near the equator. Climate, sunlight and intake of vitamin D have been investigated as possible causes of the disease that could explain this latitude gradient.[18] However, there are important exceptions to the north–south pattern and changes in prevalence rates over time;[1] in general, this trend might be disappearing.

This indicates that other factors such as environment or genetics have to be taken into account to explain the origin of MS.

MS is also more common in regions with northern Europe populations. But even in regions where MS is common, some ethnic groups are at low risk of developing the disease, including the Samis, Turkmen, Amerindians, Canadian Hutterites, Africans, and New Zealand Māori.

Environmental factors during childhood may play an important role in the development of MS later in life. Several studies of migrants show that if migration occurs before the age of 15, the migrant acquires the new region’s susceptibility to MS. If migration takes place after age 15, the migrant retains the susceptibility of his home country.

However, the age–geographical risk for developing multiple sclerosis may span a larger timescale.  A relationship between season of birth and MS has also been found which lends support to an association with sunlight and vitamin D. For example fewer people with MS are born in November as compared to May.

History

Medical Discovery

The French neurologist Jean-Martin Charcot (1825–1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868.

Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease sclerose en plaques. The three signs of MS now known as Charcot’s triad 1 are nystagmus, intention tremor, and telegraphic speech (scanning speech), though these are not unique to MS. Charcot also observed cognition changes, describing his patients as having a “marked enfeeblement of the memory” and “conceptions that formed slowly”.

Prior to Charcot, Robert Carswell (1793–1857), a British professor of pathology, and Jean Cruveilhier (1791–1873), a French professor of pathologic anatomy, had described and illustrated many of the disease’s clinical details, but did not identify it as a separate disease. Specifically, Carswell described the injuries he found as “a remarkable lesion of the spinal cord accompanied with atrophy”.

Under the microscope, Swiss pathologist Georg Eduard Rindfleisch (1836–1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels.

After Charcot’s description, Eugène Devic (1858–1930), Jozsef Balo (1895–1979), Paul Ferdinand Schilder (1886–1940), and Otto Marburg (1874–1948) described special cases of the disease. During all the 20th century there was an important development on the theories about the cause and pathogenesis of MS while efficacious treatments began to appear in 1990.

Historical Cases

There are several historical accounts of people who lived before or shortly after the disease was described by Charcot and probably had MS.

A young woman called Halldora, who lived in Iceland around 1200, suddenly lost her vision and mobility, but after praying to the saints, recovered them seven days after. Saint Lidwina of Schiedam (1380–1433), a Dutch nun, may be one of the first clearly identifiable MS patients. From the age of 16 until her death at 53, she suffered intermittent pain, weakness of the legs, and vision loss—symptoms typical of MS. Both cases have led to the proposal of a ‘Viking gene’ hypothesis for the dissemination of the disease.

Augustus Frederick d’Este (1794–1848), son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and the grandson of George III of the United Kingdom, almost certainly suffered from MS. D’Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it remained unknown until 1948. His symptoms began at age 28 with a sudden transient visual loss (amaurosis fugax) after the funeral of a friend. During the course of his disease, he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and erectile dysfunction. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life.

Another early account of MS was kept by the British diarist W. N. P. Barbellion, nom-de-plume of Bruce Frederick Cummings (1889–1919), who maintained a detailed log of his diagnosis and struggle with MS. His diary was published in 1919 as The Journal of a Disappointed Man.

Research Directions

Therapies

Research directions on MS treatments include investigations of MS pathogenesis and heterogeneity; research of more effective, convenient, or tolerable new treatments for RRMS; creation of therapies for the progressive subtypes; neuroprotection strategies; and the search for effective symptomatic treatments.

A number of treatments that may curtail attacks or improve function are under investigation. Emerging agents for RRMS that have shown promise in phase 2 trials include alemtuzumab (trade name Campath), daclizumab (trade name Zenapax), rituximab, dirucotide, BHT-3009, cladribine, dimethyl fumarate, estriol, laquinimod, PEGylated interferon-β-1a, minocycline, statins, temsirolimus and teriflunomide.

In 2010, an FDA committee recommended approving fingolimod for the treatment of MS attacks, and on September 22, 2010, fingolimod (trade name Gilenya) became the first oral drug approved by the Food and Drug Administration to reduce relapses and delay disability progression in people with relapsing forms of multiple sclerosis.

Clinical trials of fingolimod have demonstrated side effects, including cardiovascular conditions, macular edema, infections, liver toxicity and malignancies.

Much interest has been focused on the prospect of utilizing vitamin D analogs in the prevention and management of CIS and MS, especially given its possible role in the pathogenesis of the disease. While there is anecdotal evidence of benefit for low dose naltrexone, only results from a pilot study in primary progressive MS have been published.

Disease Biomarkers

The variable clinical presentation of MS and the lack of diagnostic laboratory tests lead to delays in diagnosis and the impossibility of predicting diagnosis. New diagnostic methods are being investigated. These include work with anti-myelin antibodies, analysis of microarray gene expression and studies with serum and cerebrospinal fluid but none of them has yielded reliable positive results.

Currently there are no clinically established laboratory investigations available that can predict prognosis. However, several promising approaches have been proposed.

Investigations on the prediction of evolution have centered on monitoring disease activity. Disease activation biomarkers include interleukin-6, nitric oxide and nitric oxide synthase, osteopontin, and fetuin-A.

On the other hand since disease progression is the result of neurodegeneration the roles of proteins indicative of neuronal, axonal, and glial loss such as neurofilaments, tau and N-acetylaspartate are under investigation.

A final investigative field is work with biomarkers that distinguish between medication responders and nonresponders.

Chronic Cerebrospinal Venous Insufficiency

In 2008, Italian vascular surgeon Paolo Zamboni reported research suggesting that MS involves a vascular disease process he referred to as chronic cerebrospinal venous insufficiency (CCSVI, CCVI), in which veins from the brain are constricted. He found CCSVI in the majority of people with MS, performed a surgical procedure to correct it and claimed that 73% of people improved.

Concern has been raised with Zamboni’s research as it was neither blinded nor controlled and further studies have had variable results. This has raised serious objections to the hypothesis of CCSVI originating multiple sclerosis. The neurology community currently recommends not to use the proposed treatment unless its effectiveness is confirmed by controlled studies, the need for which has been recognized by the scientific bodies engaged in MS research. Read more on Chronic cerebrospinal venous insufficiency at Wikipedia.

Support Groups:

Argentina: ALCEM – Asociación de Lucha Contra la Esclerosis Múltiple

Australia: MSA – Multiple Sclerosis Australia

Brazil: ABEM – Associação Brasileira de Esclerose Múltipla

Canada:

France: NAFSEP – Nouvelle Association Française des Sclérosés en Plaques

Germany: DMSG – Deutsche Multiple Sklerose Gesellschaft

Israel: Israel Multiple Sclerosis Society

Italy: AISM- Italian MS Society

New Zealand: MSSNZ – Multiple Sclerosis Society of New Zealand

United Kingdom

United States:

DMOZ: Conditions & Diseases MS

ATLASOFMS: Database of Epidemiology

NIH Clinical Trials: Related to MS

Chochrane: Abstract Index

MORE on MS: “The Patients Journey” M. Langgartner


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