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Picture: "Parts of a Neuron" by Phil Schatz. License: CC BY 4.0
Definition and etiology of multiple sclerosis
The proper name of this disease describes multiple (=multiple) scarring foci (=sclerosis) in the central nervous system. This is a chronic, progressive inflammatory CNS disease with damage to the Myelin layer and of the nerve cells.
MS is the most common inflammatory disease of the brain and spinal cord. In the EU and the USA it occurs with a frequency of about 1:1000. Every year about 2500 people in Germany learn of their disease. These people are mostly very young (20 years old). – 30. They are at a stage in life when chronic diseases are far removed from everyday life.
MS is one of the most frequent causes of permanent disability young people, whereby women are affected about 2 – 3 times more frequently. Being diagnosed with MS as a previously healthy person is an extreme burden for many people. Therefore, the conversation should be conducted accordingly empathetic, but also informed.
Etiological and histopathological features of MS
MS is a multifactorial disease. An exact cause is unfortunately still unknown, but genetic factors, environmental influences and an autoimmunity are amed for the development of the symptomatology.
Genetic factors of multiple sclerosis
So far, there is no single hereditary pathway that can be made causative for MS, but it is probably polygenetic influences. In particular, changes in the MHC class II can be associated with a 2 – 4 times increased risk of disease. Also a Interleukin receptor polymorphism seems to increase the risk (Compston& Coles, 2002). The hereditary component is shown, for example, by the increased risk of disease in children of parents with MS. These have an approximately 20-fold increased risk.
Environmental factors of multiple sclerosis
When looking at the epidemiological map of the world, one is struck by a disease distribution in which the MS prevalence increases with distance from the equator. Especially the USA, Central Europe and New Zealand are characterized with a high prevalence. In this context, different sun exposure, smoking, EBV infection and human herpes virus 6 have been discussed in many cases.
Migration studies have interestingly found that when migrating from a low to a high MS risk area, an age-dependent risk adjustment occurred: Migrants younger than 15 years underwent an adjustment for increased risk; older individuals experienced no change in MS risk.
Image: " geogr. Risk distribution of multiple sclerosis" by InvictaHOG. License: Public Domain
Autoimmune factors of multiple sclerosis
In MS, the attack of the immune system against the body's own components affects a Reaction against CNS myelin antigens. The result is a reversible inflammatory reaction with demyelination. When this response is pronounced, the neuronal system undergoes a axonal damage with subsequent irreversible nerve fiber destruction.
On the functional level, the demyelinated nerves already lose the ability to effectively transmit action potentials, and the transmission of information is slowed down. As predilection sites for these so-called demyelinating foci, one can consider the periventricular medullary camps, the N. opticus, the brainstem, the cerebellar peduncles, the Corpus callosum and the Myelon Notice.
Picture: "Parts of a Neuron" by PhilSchatz. License: CC BY 4.0
Clinical course and symptoms of multiple sclerosis
In the clinical picture of multiple sclerosis, a distinction is made between acute attacks and a general clinical course of disease. An overall picture of the disease can then be derived from these two components. This is important because the acute relapse is treated differently than the risk distribution of multiple sclerosis prophylactic continuous therapy, which in turn depends on the overall clinical course.
Picture: "Main symptoms of Multiple sclerosis." by Mikael Haggstrom.. License: Public Domain
Definition of an acute MS relapse
Inflammatory relapse is defined as temporary dysfunction, persisting for at least 24 hours and not explainable by fever or infection. Different neuronal qualities can be disturbed. Frequently occurs:
Sensory disturbances with dysesthesias, hypesthesias or neuralgiform pain. In addition to tingling paresthesias, the Lhermitte's sign (elicitation of flashes of downward abrupt sensation over the back and/or extremities by passive forward neck flexion) is often positive. motor abnormalities with (spastic) paresis and disturbed fine motor skills. Positive pyramidal tract signs, absent abdominal skin reflexes with increased muscle intrinsic reflexes and cloni. Optic neuritis (retrobulbar neuritis, neuritis nervi optici) with veil vision, central scotoma and painless loss of visual acuity for hours to days and bulbar movement pain. Thereby typically occur Double vision, the internuclearOphtalmoplegia or mononuclear visual acuity deterioration. vegetative dysfunction with urge incontinence, residual urine and sexual dysfunction. brainstem symptoms such as dizziness, gait, balance or coordination disorders and dysarthria. Charcot triad with chanting speech, intention tremor and nystagmus as an expression of an inflammatory reaction in the area of the cerebellum and cerebellar peduncles.
Since the inflammatory reaction can in principle affect the entire central nervous system, MS symptoms are correspondingly diverse. Of the true episodes, the so-called Pseudo relapses are delimited. This refers to neurological deteriorations in the context of infections, fever, physical exertion, hot baths or sauna, which are grouped together under the Uhthoff phenomenon.
Clinical course of multiple sclerosis
One divides different clinical courses of the MS. These sales are related Distribution and severity of symptoms very different, which makes MS a very heterogeneous disease. The degree of disability is determined by means of the Expanded Disability Status Scale (EDSS) determined.
As clinically isolated syndrome is the term used to describe the first or single inflammatory episode.
In 70 – 80 % of all patients the first symptom is the relapsing remitting MS before. That is, the neurological symptoms arise relatively suddenly and subsequently regress again. worsening of symptoms occurs. relapses are no longer clearly recognizable.
15 % of all patients experience from the beginning a primary progressive course. This patient group is generally somewhat older. Without sexual accumulation tendency. It should be remembered that this form of MS is very difficult to treat therapeutically.
Image: "Progressive forms of multiple sclerosis" by Vhancer. License: CC0 BY 1.0
Diagnosis of MS
The diagnosis of MS is based on history and clinical examination, on which Imaging of the entire CNS, CSF diagnostics and the electrophysiological conduction diagnostics. In particular, previous symptoms should be asked about and examined for.
Since multiple sclerosis can in principle affect any structure of the central nervous system, a comprehensive diagnosis is absolutely necessary. The thorough physical, neurological examination should include all qualities and in particular query and examine the above-mentioned, typical symptoms.
Since MS can often manifest itself in the form of visual and oculomotor symptoms, it is still Supplementary ophthalmological examinations at. In the clinic, the diagnostic criteria according to McDonald have proven to be effective. Evidence of temporal. Spatial dissemination of the disease by… – …the presence of a screw and activity detection by MRI imaging.
Imaging of multiple sclerosis
This is where the MRI a special position to. In particular, the typical predilection sites (see above) are investigated. If the clinical symptoms point to a lesion in the myelon, a spinal MRI should be performed.
Exam Tip: Do not let yourself be led astray! With spinal MRI, imaging of the cervical and thoracic spine is sufficient. In the lumbar spine, the spinal cord ends as cauda equina. Counted here to the peripheral nervous system.
Different sequences can be used to find different clues for the presence of MS:
T1 sequence from the beginning: hypointense lesions (black holes) and diminishing brain volume as a sign of tie loss
T1 sequence + contrast agent (gadolinum): Contrast enhancement of fresh active foci as an indication of acute inflammation, resolved inflammatory foci (old foci) do not take up contrast agent
T2 sequence, FLAIR sequence: hyperintense lesions as signs of inflammation, brain edema, demyelination and remyelination
Image: "Demyelination" by Marvin 101. License: CC BY-SA 3.0
CSF diagnostics of multiple sclerosis
CSF diagnostics serve on the one hand to detect the central inflammatory reaction typical of MS and on the other hand as a possibility to exclude some differential diagnoses. For example, an increase in the cell count in the cerebrospinal fluid of about 10 – 50/yl speaks for the presence of MS, whereby here an
lymphocytic and monocytic image exists. Not infrequently, however, the cell count in MS patients is normal.
Furthermore, the diagnosis should include the presence of liquor-specific, oligoclonal bands check as an indication for intrathecal IgG synthesis. The presence of oligoclonal bands in the CSF but not in the serum is indicative of MS. Likewise they find with the typical MS cerebrospinal fluid findings positive antibodies for different neurotropic viruses, like z.B. Measles, rubella, and zoster. If MS is suspected and the cerebrospinal fluid (CSF) findings are unremarkable, they should be re-evaluated after approximately one year. Overall, however: The typical MS cerebrospinal fluid findings are not specific.
Electrophysiological diagnostics of multiple sclerosis
By means of electrophysiological diagnostics the different evoked potentials investigated. These potentials can be used to draw conclusions about functional disorders in the central nervous system. If demyelination processes exist, there are lantence delays in the cortical stimulus response as a sign of slowed stimulus transmission.
Commonly used assays in this context are visual (VEP), acoustic (AEP), sensitive (SEP) or motor evoked potentials (MEP). If the clinical examination does not clarify whether the neuronal pathology is peripheral or central, the electrophysiological examination can be supplemented with, for example, neurography or electromyography for differential diagnostic purposes.
Differential diagnostic considerations for multiple sclerosis
The diagnosis of MS resembles a severe blow of fate. The term MS is widely used these days, and the idea that many people have of this disease often predicts a life of disability. All the more important is the conviction of the correctness of the diagnosis. For this, it is essential to consider the following differential diagnostic considerations:
Therapy of multiple sclerosis
The therapeutic goals of MS include preventing or Reduce recurrence of relapses, the Reduction of disease progression, the Sustaining disease activity, the clinical improvement and ultimately the improvement of the quality of life. To achieve this, a broad therapeutic regimen is available, essentially comprising three pillars:
1. Therapy of the acute MS relapse
Therapy of choice in acute inflammatory relapse includes intravenous administration of methyl-prednisolone for 3 – 5 days. In this context 1000 mg in the morning applied under additional gastric protection (Proton pump inhibitor) and thrombosis prophylaxis. Clinically, regular monitoring of blood glucose and blood prere should be performed. If there is no significant improvement in symptoms, therapy can be extended to 2000 mg of methyl prednisolone i.v. extended over 5 days or alternatively Plasma separation to be discussed.
2. The immunomodulatory stepwise therapy of MS
The beginning of a prophylactic permanent therapy must be well chosen. A few years ago a paradigm shift took place here, so that nowadays a Recommendation for permanent early therapy is pronounced. The BENEFIT study showed a delay in disease progression of about 580 days when therapy was started at the time of diagnosis. First, a distinction is made between basic therapy and therapy escalation. Interferon preparations are predominantly available as basic therapeutics. glatiramer acetate is available.
interferon beta: Endogenous cytokine, s.c. or i.m. administration, side effects: at the beginning of therapy flu-like symptoms, skin irritations, liver elevations; in some cases neutralizing antibodies are produced, which weaken the efficacy accordingly.
GLAT irameracetate: peptide mixture from
Glutamic acid, Lysin, Alanine and Tyrosine in identical molar ratios as a myelin protein, daily s.c. administration, well tolerated
If, despite basic therapy, there is increased disease activity with several (severe) relapses per year, therapy should be Therapy escalation be expanded. Natalizumad, mitoxantrone and fingolimod are approved for this purpose. These drugs are all characterized by strong efficacy, but have a wider spectrum of side effects than the basic therapeutics.
Natalizumab: Recombinant humanized monoclonal antibody to inhibit lymphocyte transmigration across the blood-brain barrier, i.v. administration every 4 weeks, generally well tolerated, but: risk of PML (=
progressive multifocal leukoencephalopathy) of 1:1000 with high mortality and lethality Mitoxantrone: cytostatic, cytotoxic for lymphocytes and macrophages, i.v. relevant side effect: cumulative cardiotoxicity, increased leukemia risk, infections; mitoxantrone is also approved for secondary progressive MS
Fingolimod: Daily oral intake, prevents lymphocyte migration to inflamed target ties, side effects: Infections, liver damage, macular edema, cardiac arrhythmias
News: In addition to these well-known pharmaceuticals, there have been some innovations in pharmacological therapy in recent years.
Dimethyl fumarate is approved as a new oral basic therapy drug. Gastrointestinal intolerance and flushing phenomena often occur at the start of therapy. Even with long-term administration, regular checks of the differential blood count should be carried out to avoid opportunistic infections.
With Alemtuzumab recently a highly active monoclonal antibody has been introduced for the therapy of active MS. Alemtuzumab, which was originally used for T-cell lymphomas, leads to a sustained elimination of T- and B-cell components of the immune system that lasts months. Advantages are treatment cycles with 5 or. 3 infusions in 1. or. 2. Year and if necessary. im 3. year and, in many patients, a very lasting effect on MS activity.
Disadvantages are slight increase of the tendency to infection in the months after infusion, the development of secondary, B-cell mediated autoimmunity phenomena or even diseases (formation of autoantibodies, ITP (M. Werlhof) as well as glomerulonephritis). This requires 48-month laboratory and urine checks in 4-week cycles after the last administration of alemtuzumab. Basic therapy. Retrospective data showed good efficacy for rituximab. Tolerance even over a longer. Retrospective data showed good efficacy for rituximab. Tolerability even over a longer period of time. The administration of MS-specific therapeutics (especially interferons, fingolimod, natalizumab) should be avoided, as worsening effects have been observed (DGN guidelines from 2014).