Multiple SclerosisMultiple Sclerosis (MS) is an autoimmune, chronic inflammatory demyelinating disease of the central nervous system. The course of the disease is highly variable, but usually relapsing. Curative therapy is not yet available.
Multiple Sclerosis : Overview
Encephalitis disseminata, encephalomyelitis disseminata, MS, ED
Multiple sclerosis, abbreviated MS, is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Neurological symptoms are due to multiple demyelinating lesions and diffuse neuronal destruction of white and gray matter. The exact cause has not yet been deciphered despite intensive worldwide research (as of 07/2021).
Multiple sclerosis usually progresses in relapses. Since the lesions can be ubiquitously localized in the CNS, virtually any neurological symptom can occur with varying severity. Considerable progress has been made in MS therapy in recent years, but a cure is still not possible.
Multiple sclerosis is the most common neurological autoimmune disease. According to the Atlas of MS, the most informative global study to date, there are approximately 2.8 million multiple sclerosis patients worldwide.  Distribution varies by region. Since 1960, the prevalence has increased significantly in most countries. This trend is most prevalent in northern industrialized countries with predominantly white populations, but also in South America, Asia, and northern industrialized countries. There are fewer MS diagnoses in the equatorial zone than in northern and southern latitudes. More and more women develop multiple sclerosis. In relapsing-remitting MS (RRMS), women are affected three times more often than men. The reasons for this development are controversially discussed. 
In Germany the number of MS patients is estimated to be 252.000 estimated. 14.600 patients are newly diagnosed per year. The annual incidence is about a quarter higher in the west than in the east (19 vs. 15 new cases per 100.000 population). 72 percent of MS patients living in Germany are women. The average age at diagnosis is 33 years (worldwide 32). However, the disease can occur at any age. 
94 percent of patients initially experience relapsing-remitting MS; the remaining 6 percent experience a progressive disease course. After 10 to 15 years, in about 30 to 40 percent of the cases, the disease changes into a secondary-chronic progressive course; after more than 20 years, up to 90 percent suffer from this form of progression. 6 percent of all MS patients are diagnosed with a progressive course of the disease right at the beginning. 
Although scientists worldwide are researching the cause of multiple sclerosis, the exact pathogenesis of MS is not yet understood. Based on the available data, a multifactorial pathogenesis with the involvement of genetic factors (30 percent) can be amed. Environmental influences (70 percent) and reciprocal multiplication effects can be amed. In this context, various theories are discussed. 
Despite familial clustering and an increased risk of disease for family members of MS sufferers, multiple sclerosis is not a hereditary disease in the classical sense. Furthermore MS is neither contagious nor a mental disease.
So far, more than 110 genetic variations have been identified, which are more frequent in MS patients than in the healthy general population. These could contribute to an increased predisposition. As in the autoimmune diseases diabetes mellitus type 1 or Crohn's disease, many conspicuous gene variants are directly related to the immune system, for example the alleles of the human leukocyte antigen system (HLA type HLA-DRB1*15:01) and the TNF/TNFR family (TNFR1 variant rs1800693).  IgG autoantibodies against the ATP-sensitive potassium channel KIR4 were detected in nearly half of MS patients (46.9%).1 have been detected on the cell membrane of glial cells. 
Several environmental influences in the pathogenesis of multiple sclerosis are currently being discussed, including sunlight exposure and associated vitamin D balance, viral and bacterial infections in childhood, dietary habits, obesity, and smoking.
Vitamin D metabolism
Several physicians are convinced of the influence of solar radiation in the development of multiple sclerosis. Proponents of the so-called vitamin D metabolism hypothesis point to the differential number of MS diagnoses in areas with different levels of UV exposure. Thus, there are actually fewer cases of the disease in sunny zones. According to the theory, a sufficiently good vitamin D supply should protect against MS. However, no clear causality has been established so far. In addition, it is not known for sure whether a vitamin D deficiency is a consequence or a cause of MS. 
It is possible that childhood infections increase the risk of developing multiple sclerosis later in life. Numerous viruses and bacteria are suspected. Indeed, there is a striking accumulation of immune responses to Eppstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) in children and juvenile patients with multiple sclerosis. However, it is still unclear whether and which role a dysregulated immune response against EBV or HHV-6 plays in the etiopathogenesis of MS. 
Environmental toxins, smoking, diet and microbiome
Whether environmental toxins such as amalgam, mercury or lead increase the risk of multiple sclerosis is still not proven. However, nicotine actually appears to be a risk factor in the development of the disease. Depending on the study, there is an increase in risk by a factor of 1.2 to 1.8. In addition, people who started smoking at a very early age seem to be more prone to chronic MS and a rapid progression of functional limitations and disabilities. 
Similarly, the influences of dietary habits, athletic activity, and obesity are being scientifically studied. A confirmed association between lifestyle. MS could not yet be ascertained. Obesity is thought to favor the development of multiple sclerosis. In particular, severely obese children and adolescents appear to be at increased risk of developing MS. Possibly the association is mediated by adipose tie hormones such as leptin and adiponectin. 
In recent years, the gut microbiome has moved into scientific focus. Microorganisms living in the gut seem to influence the development of multiple sclerosis. Also of scientific interest is the messenger substance interleukin-17, which acts via the microbiome. Conclusive data on a connection with multiple sclerosis are currently still lacking. 
Focal, chronic inflammatory demyelinating lesions of CNS nerve fibers are found in multiple sclerosis. These are accompanied by axonal damage, persistent tie scars (gliosis) and brain atrophy in the further course of the disease. 
Most likely, demyelination is initiated by different cellular and humoral factors of the innate and acquired immune system. The exact mechanisms have not yet been deciphered. [21
Histologically, four patterns could be differentiated in active MS foci. These are homogeneous in the individual MS patient, heterogeneous in different patients. Whether this changes with increasing disease duration is unclear so far. Subtypes I and II are particularly found in primary immunologically-induced demyelination, subtypes III and IV in primary damage to oligodendroglial cells. All four subtypes are associated with a predominantly T lymphocyte. Macrophage mediated inflammatory response associated. 
Clinical symptoms in multiple sclerosis depend on the extent and location of lesions and vary accordingly among MS patients. Initially, relapse-associated symptoms usually regress completely. Neurological deficits persist in the further course of the disease.
Clinically isolated syndrome
At the beginning, often an isolated clinical picture dominates: the so-called clinically isolated syndrome (CIS). Neurological dysfunction develops acutely or subacutely. Persist for at least 24 hours. If all diagnostic criteria are met, it is the first relapse. Typical are eye pain or visual disturbances due to optic neuritis as well as sensory deficits in the form of paresthesia, paresis and coordination difficulties (mostly the extremities are affected) due to demyelinating lesions in the cerebrum, cerebellum, brain stem and spinal cord – without the presence of infection and/or fever. 
Definition of an MS relapse
An MS relapse is defined as the occurrence of new or reactivated, already known neurological deficits. These must:
– persist for at least 24 hours and – occur more than 30 days after the onset of a previous episode and – are not due to heat exposure (Uhthoff's phenomenon), infection, or other physical or organic cause. 
Symptoms range from mild impairment of mobility to severe neurological functional impairment to severe disability of patients. Many people with MS suffer from cognitive deficits, manifest depression, pain, spasticity and fatigue (depending on the duration of the disease).
Typical manifestations and symptoms include:
– Optic neuritis, especially retrobulbar neuritis: central scotoma (almost always), painful eye movement, visual blur, veiling vision, visual acuity reduction, color vision disturbance – Oculomotor disturbances with eye muscle paresis, pupillary disturbances, and double vision – Affection of other cranial nerves: facial nerve paresis, trigeminal neuralgia – motor disorders: central paresis, including para- and tetraparesis (mostly distally accentuated), spastic tone elevation, spasticity, cloni – ataxia: spastic, ataxic gait – sensory disorders: paresthesias, hypesthesias, dysesthesias – cerebellar symptoms: mainly intention tremor, nystagmus and scanting speech (Charcot triad), gaze dysmetria (exaggerated eye movements with corrective jerks), dysphagia, dysarthria, ataxia – vegetative symptoms: Micturition disorders (incontinence, urinary retention, pollakiuria), Sexual function disorders (declining libido, erectile dysfunction, reduced lubrication) – Cognitive changes: concentration and memory disorders, depression – affective changes: inadequate euphoria, inappropriate/uncontrollable crying and laughing – Uhthoff phenomenon: heat-induced increase in symptoms
Pain is a common symptom in multiple sclerosis, with a prevalence of up to 80 percent.  Many MS patients suffer from paroxysmal or persistent pain of varying localization and intensity during the course of the disease. MS-associated pain in particular:
– Headache, especially tension headache, migraine, and headache without classification – Neuropathic pain such as trigeminal neuralgia and transient aching extremities – Musculoskeletal pain, especially back pain and spasticity-induced pain
Spasticity is a consequence of a lesion of descending motor pathways. In the course of the disease, up to 80 percent of all patients with multiple sclerosis are affected by it.  Typical symptoms are increased muscular tone, slowed movements, increased muscle reflexes, and pathologically disinhibited synergisms. Spasticity is often accompanied by pain (especially shooting flexor spasms), contractures, and bladder emptying problems. According to the Germany-wide multicenter MOVE study, about two-thirds of MS patients suffer from permanent spasticity, 25 percent from paroxysmal spasticity, and 6 percent from both forms. 
High levels of fatigability, marked fatigue, and a greatly increased need for sleep burden – depending on the study- up to 90 percent of all patients with multiple sclerosis. In the German MS registry, fatigue is the most common symptom (58 percent). 31 percent of patients suffer from it within the first two years. Fatigue sufferers feel extremely weak, dull and powerless, are permanently tired and can hardly motivate themselves to act anymore. any physical or mental exertion leads to pronounced exhaustion. Impairments worsen in warm and humid temperatures and with physical exertion . 
Traditionally, multiple sclerosis is divided into relapsing-remitting MS and primary and secondary progressive MS.
– Relapsing-remitting multiple sclerosis (RRMS): most common initial course; relapses are associated with complete or incomplete symptom remission – Secondary progressive multiple sclerosis (SPMS): develops from RRMS; characterized by disability progression with or without repititive relapses – Primary progressive multiple sclerosis (PPMS): disability progression from onset, isolated relapses are possible
Since 2013, the progression forms have been further differentiated based on the criteria of activity and progression. In addition to CIS, the following progression types emerge according to the McDonald criteria:
– RRMS: active/not active – SPMS: active and progressive/active and non-progressive/not active and progressive/not active and non-progressive – PPMS: active and progressive/active and non-progressive/not active and progressive/not active and non-progressive. 
The suspected diagnosis of multiple sclerosis is primarily based on the patient's history and clinical findings. If there is evidence of an inflammatory demyelinating disease of the central nervous system, laboratory tests and imaging procedures follow. Temporal and local dissemination of lesions in the CNS (dissemination in time = DIT, dissemination in space = DIS) are detected by magnetic resonance imaging (MRI). In addition, specific laboratory diagnostic findings are found, for example, liquor-specific oligoclonal bands.
Multiple sclerosis is a diagnosis of exclusion; that is, the symptomatology cannot be explained by any other, better diagnosis than MS. The diagnosis is usually made according to the internationally recognized McDonald criteria. 
Medical history and physical examination
First, evidence of past relapses and symptoms should be determined. Questions are asked, for example, about somatic and psychological complaints, psychosocial stress, previous or existing neuronal deficits and family MS diagnoses. In addition, a clinical objectification of central neurological deficits follows.
Common findings on clinical examination are:
– Marburg triad: temporal fading of optic nerve papillae, paraspasticity, and absence of abdominal skin reflexes – Lhermitt's sign (positive neck flexion sign): electrifying sensations of discomfort when the head is bent forward along the spine from cranial to caudal – loss of sensation – dysmetric pointing tests – positive Babinski sign and increased muscleigenic reflexes as evidence of damage to the 1. In addition to the clinical symptoms, the diagnosis of MS must be based on evidence of a temporal. spatial dissemination of lesions in the CNS can be provided. The most appropriate procedure for this is the MRI examination.
In addition to imaging, an examination of the cerebrospinal fluid is an important paraclinical finding and an essential component of differential diagnosis. In PPMS, CSF diagnosis according to the McDonald criteria is considered obligatory. Cell count and differential cell image, lactate, albumin and Ig quotients according to Reiber as well as liquor-specific oligoclonal bands are examined. Similarly, Borrelia and Lues serology should be performed in serum (and in CSF if positive). Analysis for intrathecal formation of antibodies against measles, rubella and varicella-zoster viruses (MRZ reaction) can be considered. In the absence of indications for possible differential diagnoses, a standard laboratory panel can be omitted. 
Electrophysiology is used to check the functionality of specific nerve tracts. In MS, the following methods are mainly used:
– visual evoked potentials (VEP) – somatosensory evoked potentials (SEP) – motor evoked potentials (MEP) – auditory evoked potentials (AEP)
Unfortunately, multiple sclerosis cannot be cured, but it is becoming easier to treat. In recent years, the drug contingent has grown steadily. Therapy measures are aimed at maintaining the patient's independence and quality of life as best as possible.
MS treatment is based on three pillars: relapse intervention, progression-modifying therapy, and symptom relief. Complications are also prevented.
Goal of relapse intervention or. Relapse therapy is the rapid. Complete regression of symptoms as far as possible. Intravenous administration of high-dose glucocorticosteroids (GKS) is the established standard of care. Treatment should be given as soon as possible after the onset of symptoms. 500 to 1.000 mg of methylprednisolone (MP) per day for three to five days.
Treatment refractory symptoms sometimes require escalation therapy with higher doses of MP (up to 2.000 mg/d for three to five days). If this form of treatment does not work satisfactorily, plasmapheresis (PE) or immunoadsorption (IA) – carried out in specialized MS centers – can be considered. In addition to glucocorticoid therapy, proton pump inhibitors such as omeprazole can be used for ulcer prophylaxis, if needed. Low-molecular-weight heparin may be useful for thromboprophylaxis.
The basis of progression-modifying therapy is immunomodulatory measures. Immunomodulators and immunosuppressants are used to reduce relapse frequency, decrease disease activity (relapses and disease progression), or. delayed and the quality of life should be maintained as long as possible.
Before starting therapy, realistic therapy goals should be agreed with the patient and advantages and disadvantages of immunotherapy should be discussed.
Depending on the relative reduction in inflammatory activity (relapse rate, MRI disease activity, relapse-related progression), immunotherapeutic agents can be divided into three efficacy categories. Mitoxantrone should be used because of the poor study record. Its high toxicity means that it should only be used as a reserve drug in exceptional cases. This is equally true for azathioprine. Intravenous immunoglobulins (IvIg) are no longer recommended in patients for course-modifying therapy of multiple sclerosis. 
Special features of RRMS
In RRMS patients, after initiation of therapy or change of drug, regular clinical controls – e.g. every three to six months – are indicated; in addition, MRI controls are indicated six and 18 months after the start of treatment . Subsequently, the frequency should be based on the course of the disease. Orient to the risk for adverse drug reactions . MRI control examinations are to be carried out without the administration of contrast media .
Patients who have an inflammatory course during therapy with drugs of efficacy category 1 should – depending on the extent of disease activity – switch to a drug of efficacy category 2 or 3 . John Cunningham virus (JCV) antibody status should be determined prior to initiation of therapy with a category 3 drug . The JC virus is prevalent. Harmless in healthy individuals . However, in the presence of a weakened immune system or immunotherapy, latent viruses could be reactivated and cause a severe , progressive brain inflammation , progressive multifocal leukoencephalopathy (PML) . Depending on JCV status, the guideline recommends:
– In JCV antibody-seropositive patients, CD20 antibodies (ocrelizumab, rituximab [off-label]) should be the first-line therapy as efficacy category 3 drugs, regardless of index level. – In JCV antibody-seronegative patients, an individual risk-benefit trade-off between natalizumab and a CD20 antibody ( ocrelizumab or rituximab ) should be made in discussion with the patient when selecting a category 3 drug . 
Special features of PPMS
According to the current guideline, only the CD20 antibodies ocrelizumab and rituximab (off-label) are recommended for the treatment of PPMS. Other agents-particularly mitoxantrone, repeated methylprednisolone pulse therapy, beta-interferons, glatirameroids, and intrathecal steroid therapy-should not be administered for immunotherapy in PPMS. 
Special features of SPMS
Treatment decisions in patients with SPMS are based on classification into active and non-active SPMS. At the time the current guideline was written, effective immunotherapeutics existed only for active SPMS. The therapy recommendations are also based on this:
– In non-treated patients with activeSPMS in the form of relapses, the use of siponimod, beta interferons, cladribine and CD20 antibodies can be considered. – Immunotherapy should not be initiated in untreated patients with non-activeSPMS. In exceptional cases, a therapy trial (initially limited to two years) with a CD20 antibody analogous to PPMS is possible. Mitoxantrone should now only be given in individual cases of active SPMS due to significant side effects. 
If patients develop inactive SPMS during therapy with drugs of efficacy category 1, the therapy should be terminated. In order to detect the development of an active SPMS and to be able to start an immunotherapy adapted to this, close-meshed clinical and MR-tomographic controls are recommended after the end of the treatment. 
If non-active SPMS occurs during therapy with cladribine and alemtuzumab, treatment should be discontinued. 
In patients who develop SPMS while on therapy with fingolimod, ozanimod, or natalizumab, discontinuation of therapy may be considered. 
Note: In early 2020, Mayzent (siponimod) – a next-generation sphingosine-1-phosphate receptor modulator – received EU approval. This is the first oral treatment option available for patients with active SPMS that slows disease progression. 
Symptom-oriented drug therapy
Drug therapy is symptom-dependent and varies from individual to individual. Therapeutic interventions target, for example, spasticity, fatigue, micturition problems, or sexual dysfunction.One of the most important goals of therapy, which applies to all symptoms, is to facilitate care. Depending on the s ymptom, different therapeutic goals are targeted . According to the current guideline, there are the following recommendations : 
– Relief of spasticity: muscle relaxants such as baclofen and tizanidine, cannabinoids, gabapentin, botulinum toxin A, and triamcinolone (intrathecal) – Gait disturbances and mobility impairment: potassium channel blockerFampridine – Ataxia and tremor: propranolol, primidone, or topiramate; if therapy is resistant, botulinum toxin – Fatigue: Therapy trial with amantadine or modafinil, selective serotonin reuptake inhibitors (SSRI) – only in case of concomitant depressive mood – Pain treatment: anticonvulsants such as carbamazepine, gabapentin or pregabalin, tricyclic antidepressants such as amitriptyline according to current guidelines and WHO recommendations – Paroxysmal symptoms:
– For trigeminal neuralgia, carbamazepine, oxcarbazepine, lamotrigine, pregabalin, gabapentin, and topiramate; in cases of treatment resistance, attempted treatment with misoprostol or mexiletine
– Other painful paroxysmal symptoms carbamazepine, gabapentin, pregabalin, and oxcarbazepine, as well as mexiletine and lidocaine
– for tonic spasms only (paroxysmal dystonia/brainstem seizures) carbamazepine and levetiracetam
– For paroxysmal dysarthria, acetazolamide, lamotrigine, and levetiracetam
– Sexual dysfunction:
– For erectile dysfunction, PDE-5 inhibitors such as sildenafil, tadalafil, or vardenafil
– Oil-, water-, silicone- or glycerin-based lubricants for lubrication disorders
– in case of decreased libido or dyspareunia, hormonal drugs such as tibolone
– Neurogenic bladder dysfunction:
– in case of spastic bladder or detrusor-sphincter dyssynergia (DSD) anticholinergics such as trospium chloride, tolterodine, oxybutynin and darifenacin (caveat: deterioration of cognitive functions, constipation),
– for stress incontinence and overactive bladder if necessary. SSRIs such as duloxetine (especially in concomitant depression)
– for urge incontinence Cannabinoids
– For overactive bladder mirabegron
– to inhibit the bladder sphincter in voiding dysfunction alpha-blockers and antispastic drugs (baclofen)
– To reduce nocturia/pollakiuria desmopressin
– For the treatment of acute urinary tract infections Antibiotics
– for prophylaxis of recurrent urinary tract infections methionine
– Neurogenic bowel dysfunction:
– for hard stools lactulose or macrogol
– for rectal emptying glycerine suppositories, if necessary. Enemas or stimulant laxatives
– For painful sphincter spasticity botulinum toxin
– in case of severe meteorism dimeticone
– after diarrhea loperamide or anticholinergics such as butylscopolamine and amitriptyline
– Eye movement disorders
– For acquired nystagmus, probational gabapentin and memantine
– for upbeat/downbeat nystagmus preferably baclofen, if necessary. also 4-aminopyridine
For non-drug symptom relief in multiple sclerosis, multifactorial treatment strategies are used. All therapy models have the goal of keeping functional limitations as low as possible, delaying everyday restrictions and ensuring the highest possible quality of life for patients.
Established treatment methods include: 
– Physiotherapy – Occupational therapy – Speech therapy – Psychotherapy – Neuropsychological therapy – Psychosocial care – Neuromodulation – Nutritional counseling – Provision of medical aids – Multimodal rehabilitation – Palliative care
Autologous stem cell transplantation (aHSCT)
Autologous stem cell transplantation (aHSCT) may soon become a treatment option for relapsing-remitting MS. However, it should still only be used in the context of studies. 
Note: In Switzerland, aHSCT in MS has been approved for coverage under mandatory health insurance since 2018, subject to certain conditions. 
Biotin is a coenzyme of carboxylases, which play an important role in cellular energy balance and fatty acid synthesis (crucial for myelination). The substance has been evaluated for several years in the treatment of progressive MS courses. To date, evidence of efficacy is lacking. Therefore, high-dose biotin should only be given within studies. 
In patients with multiple sclerosis, vitamin D levels should be checked and deficiency corrected, for example, by vitamin D supplementation with medication. In MS patients with normal vitamin D levels, vitamin D administration can be considered. A positive effect of this treatment has not yet been proven. Vitamin D ultra-high-dose therapies should be discouraged due to potential health risk. The prognosis for multiple sclerosis varies greatly from individual to individual. Cannot be predicted with certainty. A complete cure is not currently possible. However, recent cohort studies show a significantly better prognosis than in the 1980s. According to this, for example, less than 10 percent of all MS patients achieve a degree of disability (EDSS) of 6.0 after 10 or. 16 years. 
The London KIS long-term cohort found that after 30 years, less than 40 percent of patients achieved an EDSS of 6.0 or higher – although less than 10 percent ever received immunotherapy.  Furthermore, age-adjusted MS-related mortality decreased in Germany between 1990 and 2016. 
According to the current guideline, the improved prognosis is attributed to various factors, including:
– The improved therapeutic options – Dilution effects due to earlier and more sensitive diagnosis – Decrease in disease severity of MS, measured by the annual relapse rate of untreated patients
For example, unfavorable effects on the prognosis:
– male gender – late disease onset – polysymptomatic disease onset – motor, cerebellar or sphincter symptoms – incomplete remitting relapses – high frequency of relapses at onset
Since no clear cause for multiple sclerosis has been identified to date, the disease cannot be prevented with certainty. Rarely children also fall ill. Adolescents before the age of 18. The number of people diagnosed with multiple sclerosis at the age of 50 (3-7% of all MS diagnoses) is increasing. In children, the disease often begins polyfocally with a pronounced initial manifestation. Other characteristics of pediatric multiple sclerosis include: 
– more frequent occurrence of encephalopathies – increased relapse rate and lesion burden in the first six years – longer phase until relevant disability is reached – a primary progressive course is extremely rare
For the diagnosis of MS in children and adolescents, the current McDonald criteria apply as for adults . Similarly, the recommendations for relapse therapy are basically comparable to those for adults. For further information, please refer to the S1 Guideline Pediatric Multiple Sclerosis (currently under revision).
Newly approved active substances
The drug contingent in multiple sclerosis is constantly expanding. The last EU registrations or.