Immune-mediated inflammatory diseases of the CNS.

In recent decades, there has been an increase in the incidence of autoimmune diseases in general. The current article briefly summarizes the most important innovations regarding etiopathogenesis, diagnosis, and therapy of the three neuroimmunological disease patterns mentioned above.

In recent decades, there has been an increase in the incidence of autoimmune diseases in general for reasons that are not yet fully understood. Environmental factors that have been discussed as possibly etiologically relevant and potentially modifiable include changes in dietary habits, obesity, smoking, and vitamin D deficiency. One of the most common chronic inflammatory autoimmune diseases of the central nervous system is multiple sclerosis (MS), for which a steady increase in incidence and prevalence has also been described, including in countries where this disease was previously very rare (e.g. Japan). In parallel, other distinct autoimmune diseases of the CNS, such as neuromyelitis optica spectrum diseases (NMOSD) or MOG-AK-associated encephalomyelitis (MOG-EM), have been distinguished from the diagnostic category “multiple sclerosis” – among others due to new developments in autoantibody diagnostics – for which an early and correct diagnosis is highly relevant from a clinical point of view due to the different therapeutic principles from MS.

The current article briefly summarizes the most important innovations regarding etiopathogenesis, diagnosis, and therapy of the three neuroimmunological disease patterns mentioned above.

Multiple sclerosis

MS is the most common chronic inflammatory immune-mediated CNS disease in Western countries and affects women two to three times more often than men [1]. In addition to genetic susceptibility (people with first-degree relatives have about a 2-4% risk of developing MS, compared with about 0.1% in the general population), environmental factors such as latitude (incidence increases with higher latitude), vitamin D deficiency, smoking, childhood and adolescent obesity, and Epstein-Barr virus infection and manifest infectious mononucleosis in childhood/adolescence are considered established risk factors [2–10]. More recently, alterations in the gut microbiome have also been discussed as a possible link between the environment and the immune system as a risk factor [11]. Although the exact immunopathogenesis of MS remains unclear, it is well established that invasion of the CNS by CD4+ and CD8+ T-lymphocytes as well as B-lymphocytes, but also cells of the innate immune system such as macrophages, from the periphery via a disturbed blood-brain barrier leads to an inflammatory reaction in the brain, the optic nerves and the spinal cord, resulting in focal lesions with demyelination and axonal damage (“axonal transection”), which are visible in magnetic resonance imaging (MRI) as typical T2-hyperintense or, in the acute stage, gadolinium-absorbing T1-hyperintense foci and which have given the disease its name. Whereas in older textbooks MS was thought to be an exclusively demyelinating disease affecting only the white matter and leaving neurons and axons largely unaffected, in the last ten years it has become accepted that MS is primarily an autoimmune-inflammatory disease, but from its onset it is a disease of the nervous system. The disease is a neurodegenerative disease in which diffuse damage to the white and gray matter occurs at an early stage, resulting in measurable brain and spinal atrophy as well as retinal damage, and which is also partly responsible for the clinical symptoms (e.g. cognitive disorders) [12–19]. It is likely that the extent of early-onset axonal and neuronal damage is of greater importance to longer-term disability than the number of focal T2 lesions. MS can cause basically any neurological symptom, but visual disturbances due to optic neuritis, sensory disturbances and paresis, and ocular motility and coordination disturbances due to infratentorial, cerebellar, and spinal lesions are particularly common. More recently, however, increasing attention has been paid to other “hidden” symptoms of MS, such as fatigue, sleep disturbances, depression, cognitive impairment, bladder dysfunction, and pain, which significantly affect quality of life and are major reasons for many patients’ early retirement [20-26]. The paraclinical diagnostics include, in addition to the CSF examination with the detection of oligoclonal bands, an MRI of the head and spinal cord, whereby the repeated administration of gadolinium-containing contrast agents (GBCA) during follow-up examinations must be viewed very critically against the background of the current discussion about the possible deposition of these in the cerebellum and the basal ganglia. [27]. Routine follow-up MRI examination with administration of GBCA should be discouraged in the absence of clinical disease activity; standardized quantification of T2 lesion burden is quite sufficient to assess radiologic disease activity. Recently, an updated version of the diagnostic criteria known as the “McDonald criteria” has been published, which are still very MRI-based, but also emphasize the importance of CSF examination, and tend to allow even earlier MS diagnosis [28]. In recent years, high-resolution retinal optical coherence tomography with determination of retinal nerve fiber layer thickness and ganglion cell layer thickness has also been increasingly used to quantify neuronal and axonal damage in MS and other diseases [29–34]. OCT may have clinical value as a marker of disability progression; whether the method can be used to assess treatment success is currently the subject of intensive research [35].

The therapy of MS rests on two pillars, a) immunotherapy (or course-modifying therapy) and b) symptomatic therapy for the treatment of the above-mentioned symptoms of the disease. Immunotherapy does not cure MS but is thought to have some effect on disability progression in the longer term, but high-quality data to support this are largely lacking. [36–38]. There are now more than 15 compounds available that have demonstrated an effect on relapse rate and, in some cases, disability progression, at least over periods of usually one to two years in clinical trials, mostly in patients with relapsing-remitting MS. For details on these preparations, please refer to the relevant literature. It is important to group therapies (at least in Germany) according to their use in patients with mild or moderate relapsing MS (e.g., β-interferons, glatiramer acetate, teriflunomide, dimethyl fumarate) or with (highly) active relapsing MS (natalizumab, alemtuzumab, fingolimod, ocrelizumab). Recently, ocrelizumab has become available for the first time as an immunotherapeutic agent for use in primary chronic progressive MS (see also the following article “News on monoclonal antibody therapy”). It should be noted that many of the preparations require close and consistent monitoring of possible side effects, including the presence of a drug. regular laboratory tests require [39]. In principle, based on the new findings on very early neurodegeneration in MS, immunotherapy as early as possible is recommended with the aim of preventing secondary tissue damage by actively combating inflammation and thus improving the long-term prognosis. In any case, a careful risk-benefit assessment must be carried out and a decision made together with the patient (“shared decision making”). In parallel, a consistent symptomatic therapy of possible distressing symptoms such as depression, bladder disorders, sleep disturbances and fatigue should be performed, although here, unfortunately, pharmacological options often do not lead to satisfactory results, so that novel non-pharmacological procedures are under clinical trials, such as deep transcranial magnetic stimulation for the treatment of fatigue [40]. Current research topics in the field of MS therapies include remyelinating therapeutic approaches, substances aimed at improving mitochondrial function (e.g., high-dose biotin), substitution with high-dose vitamin D [41], and exercise and nutrition interventions to promote endogenous repair mechanisms.

Neuromyelitis optica spectrum diseases (NMOSD)

NMOSD are rare compared to MS, but usually much more severe and usually relapsing autoimmune inflammatory diseases of the CNS with preferential affection of the optic nerves, spinal cord and brainstem [42–45]. Many patients suffer from severe impairment of visual acuity or motor skills, but pain, fatigue, and depression are also common [46]. After long being considered a rare variant of MS, since the discovery of a highly specific biomarker, antibodies against the astrocytic water channel aquaporin-4 (AQP4) in the serum of up to 80% of patients, it has become clear that this is a neuroimmunological entity immunopathogenetically distinct from MS [47–50]. Timely and correct diagnosis are critical, as many classic MS immunomodulators may not work in NMOSD or may even lead to worsening. NMOSD should be consistently treated immunosuppressively from the outset with oral prednisolone, azathioprine or mycophenolate mofetil, or B-cell depleting therapies such as rituximab, while natalizumab, fingolimod, alemtuzumab, β-interferons and glatiramer acetate should not be given [51–54]. Currently, several phase III trials are ongoing with compounds that more specifically interfere with the immune process in NMOSD (anti-CD19, anti-IL6, complement inhibition), so that specific immunotherapeutics for the treatment of NMOSD may become available in two to three years [55–57].

MOG-associated encephalomyelitis (MOG-EM).

In recent years, several publications from different countries have appeared detecting antibodies to myelin oligodendrocyte glycoprotein (MOG) in a subset of patients with an NMOSD phenotype, some of whom meet current diagnostic criteria [58], but are seronegative for antibodies to AQP4. The clinical phenotype seems to be characterized by more frequent (bilateral) optic neuritis, a more frequent monophasic course, and a slightly better prognosis compared to AQP4-NMOSD [59–65]. However, there are only few longitudinal and especially prospective data, so that a conclusive nosological classification vis-à-vis NMOSD and MS is not possible so far [66,67]. However, therapeutic caution toward MS immunotherapeutics such as β-interferons also appears to be warranted in MOG patients.

Take-Home Messages

There are new clinical findings in multiple sclerosis (MS), neuromyelitis optica spectrum disease (NMOSD), and MOG antibody-associated encephalomyelitis (MOG-EM).
MS: early stage neurodegenerative changes, low side effect diagnostics and new immunotherapeutics as well as remyelination, vitamin D substitution and lifestyle modification are some of the current topics. Alterations in the gut microbiome are discussed as a new etiologic factor.
NMOSD: Previously classified as a subtype of MS, NMOSD is nowadays differentiated from MS and many MS-specific drugs (e.g., β-interferons) are contraindicated.
MOG-EM: Detection of antibodies against myelin oligodendrocyte glycoprotein serves as a differential diagnostic differentiation from NMOSD with AQP4-AK and is associated with implications for drug therapy (e.g., avoid β-interferons). The nosological classification with respect to NMOSD has not been conclusively clarified.

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