A future of AI-driven personalized care for people with multiple sclerosis.

Multiple sclerosis (MS) is a devastating immune-mediated disorder of the central nervous system resulting in progressive disability accumulation. As there is no cure available yet for MS, the primary therapeutic objective is to reduce relapses and to slow down disability progression as early as possible during the disease to maintain and/or improve health-related quality of life. However, optimizing treatment for people with MS (pwMS) is complex and challenging due to the many factors involved and in particular, the high degree of clinical and sub-clinical heterogeneity in disease progression among pwMS. In this paper, we discuss these many different challenges complicating treatment optimization for pwMS as well as how a shift towards a more pro-active, data-driven and personalized medicine approach could potentially improve patient outcomes for pwMS. We describe how the 'Clinical Impact through AI-assisted MS Care' (CLAIMS) project serves as a recent example of how to realize such a shift towards personalized treatment optimization for pwMS through the development of a platform that offers a holistic view of all relevant patient data and biomarkers, and then using this data to enable AI-supported prognostic modelling.

Design of a non-interventional post-marketing study to assess the long-term safety and effectiveness of ocrelizumab in German real world multiple sclerosis cohorts - the CONFIDENCE study protocol.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease that requires lifelong treatment. A highly effective drug not only for relapsing but also for progressive forms of MS with a favorable safety profile is needed to further improve overall patient outcomes. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20-expressing B-cells, is the first drug indicated for the treatment of adult patients with relapsing forms of MS (RMS) and primary progressive MS (PPMS). Its safety and effectiveness profile has yet to be studied in a large, real-world setting. CONFIDENCE aims to further characterize the safety profile of ocrelizumab in routine clinical practice. In addition, real-world effectiveness data will be collected to complement the efficacy data documented in the pivotal clinical trials. METHODS: CONFIDENCE is a non-interventional, prospective, multicenter, long-term study collecting primary data from 3000 RMS and PPMS patients newly treated with ocrelizumab and 1500 patients newly treated with other selected MS disease-modifying therapies (DMTs). Treatment must be in accordance with the local label and follow routine practice. Data will be collected at approximately 250 neurological centers and practices across Germany. The recruitment period of 30 months started in April 2018. The observation period per patient is planned 7.5 to 10 years, depending on the date of inclusion, regardless of whether patients discontinue treatment. Visits follow routine practice and will be documented approximately every 6 months. The primary endpoint is the incidence and type of uncommon adverse events and death. Statistical analyses will be mainly descriptive and exploratory. DISCUSSION: CONFIDENCE is a large, non-interventional, post-authorization safety study that assesses long-term safety and effectiveness of ocrelizumab and other DMTs in a real-world setting. Data collected in CONFIDENCE will also be integrated into studies that have been developed to fulfil international regulatory requirements.

Reasons to switch: a noninterventional study evaluating immunotherapy switches in a large German multicentre cohort of patients with relapsing-remitting multiple sclerosis.

BACKGROUND: With a large array of disease modifying therapies (DMTs) for relapsing-remitting MS (RRMS), identifying the optimal treatment option for the individual patient is challenging and switching of immunotherapies is often required. The objective of this study was to systematically investigate reasons for DMT switching in patients on immunotherapies for mild/moderate MS, and provide real-life insights into currently applied therapeutic strategies. METHODS: This noninterventional, cross-sectional study (ML29913) at 50 sites in Germany included RRMS patients on therapies for mild/moderate MS who switched immunotherapy in the years 2014-2017. The key outcome variable was the reason to switch, as documented in the medical charts, based on failure of current therapy, cognitive decline, adverse events (AEs), patient wish, or a woman's wish to become pregnant. Expectations of the new DMT and patients' assessment of the decision maker were also recorded. RESULTS: The core analysis population included 595 patients, with a mean age of 41.6 years, of which 69.7% were female. More than 60% of patients had at least one relapse within 12 months prior to the switch. The main reasons to switch DMT were failure of current therapy (53.9%), patient wish (22.4%), and AEs (19.0%). Most patients (54.3%) were switched within DMTs for mild/moderate MS; only 43.5% received a subsequent DMT for active/highly active MS. While clinical and outcome-oriented aspects were the most frequently mentioned expectations of the new DMT for physicians, aspects relating to quality of life played a major role for patients. CONCLUSIONS: Our data indicate suboptimal usage of DMTs, including monoclonal antibodies, for active/highly active MS in German patients. This illustrates the medical need for DMTs combining high efficacy, low safety risk, and low therapy burden.

Clinical, electrophysiological, and MRI findings in patients with cerebellar ataxia and a bilaterally pathological head-impulse test.

A significant number of patients with bilateral vestibulopathy suffer from cerebellar ataxia and central vestibular symptoms and vice versa. We examined 31 patients presenting with the combination of gait and stance ataxia, cerebellar ocular motor signs, and a bilaterally pathological head-impulse test (HIT). Tests included neuro-orthoptical examination, electromyography and neurography, caloric irrigation, pure-tone audiogram, vestibular-evoked myogenic potentials, and volumetric magnetic resonance imaging (MRI). Only 17 of 31 patients had a pathological caloric irrigation. Twenty-three patients had evidence of polyneuropathy (predominantly mixed sensorimotor involving axonal loss and demyelination) and twenty of hypoacusis (1 unilateral and 19 bilateral). Voxel-based morphometry comparing local gray matter brain volume between patients and controls revealed cerebellar atrophy involving both the vermis and the hemispheres. We conclude that there is a clinically relevant combination of cerebellar ataxia with cerebellar atrophy, bilaterally pathological HIT, polyneuropathy, and hypoacusis. This multisensory syndrome is most likely caused by a neurodegenerative disorder affecting different systems, leading to severe impairment of affected patients.

Long-term course and relapses of vestibular and balance disorders.

The long-term course and the frequency of relapses for various peripheral vestibular disorders and somatoform phobic postural vertigo are discussed with respect to the clinically most important questions for thus afflicted patients. This review is mainly based on our own long-term follow-up studies and takes into consideration the most relevant literature. The following syndromes are discussed in detail. Vestibular neuritis: the recovery rate of peripheral vestibular function lies between 40-63% depending on early-onset treatment with corticosteroids; the recurrence rate within 10 years is 2%. Menière's disease} loss of auditory and vestibular function occurs mainly in the first 5 to 10 years; frequency of vertigo attacks may decline after 5 to 10 years; bilateral involvement increases with increasing duration of the condition in up to 30-50%; vestibular drop attacks may occur early or late within the course, mostly with spontaneous remission; high-dose and long-term treatment with betahistine significantly reduces attack frequency in Menière's disease, Benign paroxysmal positioning vertigo: the recurrence rate is 50% within 10 years (in females 58%, in males 39%), most recurrences (80%) being observed within the first year after initial relief; recurrence rate in the seventh decade is half of that in the sixth decade. Vestibular paroxysmia: medical treatment with carbamazepine or oxcarbazepine leads to a continuous significant reduction in attack frequency, intensity, and duration of 10-15% of baseline. Bilateral vestibulopathy: recovery of vestibular function is limited to single cases depending on their etiology. Phobic postural vertigo: within 5 to 16 years 27% of the patients are symptom-free, 48% improve, 22% remain unchanged, and 3% worsen; a detailed explanation of the mechanisms that cause and the factors that provoke attacks is imperative, as well as instructions for self-controlled desensitization within the context of behavioral therapy.

Bilateral vestibular failure as an early sign in Creutzfeldt-Jakob disease.

Bilateral vestibular failure causes dysfunction of the vestibulo-ocular reflex with consecutive symptoms like apparent movements of the visual environment during head movements (oscillopsia) and unsteady gait in darkness or on uneven ground. A definite case of Creutzfeldt-Jakob disease in which bilateral vestibular loss was one of the first clinical signs is reported. Further, in a series of 9 consecutive patients with Creutzfeldt-Jakob disease (6 probable, 3 definite), 3 had bilateral vestibular loss at initial presentation. The vestibular nuclei are known to be severely affected in animal spongiform encephalopathies. They might also be a vulnerable target in human prion diseases.

Causative factors, epidemiology, and follow-up of bilateral vestibulopathy.

Bilateral vestibulopathy (BV) is characterized by impaired or lost function of both peripheral labyrinths or of the eighth nerves. In a review of 255 patients (mean age +/- SD, 62 +/- 16 years) with BV diagnosed in the authors' dizziness unit between 1988 and 2005, 62% of the patients were male. Previous vertigo attacks had occurred in 36%, indicating a sequential manifestation. The definite cause of BV was determined in 24% and the probable cause in 25%. The most common causes were ototoxic aminoglycosides (13%), Ménière's disease (7%), and meningitis (5%). Strikingly, 25% exhibited cerebellar signs. Cerebellar dysfunction was associated with peripheral polyneuropathy in 32% compared with 18% in BV patients without cerebellar signs. In a follow-up study on 82 BV-patients (mean age at the time of diagnosis 56.3 +/- 17.6 years), the frequency and degree of recovery or worsening of vestibular function over time were determined. The patients were reexamined 51 +/- 6 months after the first examination. Electronystagmography with bithermal caloric irrigation was analyzed by measurement of the mean peak slow-phase velocity (SPV) of the induced nystagmus. Statistical analysis of the mean peak SPV revealed a nonsignificant worsening over time (initial mean peak SPV 3.0 +/- 3.5 degrees/s vs. 2.1 +/- 2.8 degrees/s). Only patients with BV due to meningitis exhibited an increasing, but nonsignificant SPV (1.0 +/- 1.4 degrees/s vs. 1.9 +/- 1.6 degrees/s). Forty-three percent of patients subjectively rated the course of their disease as stable, 28% as worsened, and 29% as improved.

Saccular function less affected than canal function in bilateral vestibulopathy.

Bilateral vestibulopathy (BV) is characterized by impaired or lost function of both labyrinths or eighth nerves. The diagnosis is routinely established by the head-thrust test, caloric irrigation and rotational testing with electronystagmography to determine the high- and low-frequency deficit of the vestibulo-ocular reflex. All three methods evaluate semicircular canal function only. Vestibular-evoked myogenic potentials (VEMPs) provide a measure of saccular otolith function. The aim of this study was to evaluate the frequency and extent of saccular dysfunction in patients with BV and to correlate saccular with horizontal semicircular canal dysfunction. A total of 84 BV-patients (23 females, mean age 62 +/- 15 (SD) years at the time of diagnosis assessment) were examined with VEMPs, electronystagmography with caloric irrigation and a standardized neuro-ophthalmological and -otological examination; 47 healthy subjects (18 females, mean 56 +/- 19 years) served as controls. Amplitudes P1-N1 were significantly lower in patients with BV compared to controls (mean P1-N1 of all ears 82.1 +/- 50.7 microV in the patients vs. 130.8 +/- 85.9 microV in healthy volunteers). VEMPs were absent unilaterally in four patients with BV and in none bilaterally. In contrast, caloric responses were absent bilaterally in 40 patients. There was no correlation between amplitude P1-N1 and caloric-induced nystagmus. The latencies P1 and N1 were not significantly different between patients and controls. Thus, in our study population saccular function appeared to be less affected than horizontal semicircular canal function.

Nicotine-induced nystagmus correlates with midpontine activation.

The pathomechanism of nicotine-induced nystagmus (NIN) is unknown. The aim of this study was to delineate brain structures that are involved in NIN generation. Eight healthy volunteers inhaled nicotine in darkness during a functional magnetic resonance imaging (fMRI) experiment; eye movements were registered using video-oculography. NIN correlated with blood oxygen level-dependent (BOLD) activity levels in a midpontine site in the posterior basis pontis. NIN-induced midpontine activation may correspond to activation of the dorsomedial pontine nuclei and the nucleus reticularis tegmenti pontis, structures known to participate in the generation of multidirectional saccades and smooth pursuit eye movements.

Long-term prophylactic treatment of attacks of vertigo in Menière's disease--comparison of a high with a low dosage of betahistine in an open trial.

CONCLUSION: Despite the considerable limitations of an open, non-masked trial, particularly in Menière's disease (MD), a higher dosage of betahistine-dihydrochloride and a long-term treatment seems to be more effective than a low dosage and short-term treatment. OBJECTIVE: To evaluate the prophylactic effects of a low versus high dosage long-term treatment with betahistine-dihydrochloride on the number of attacks in MD. PATIENTS AND METHODS: We performed an open, non-masked trial, in which patients with MD received either a low dosage of betahistine-dihydrochloride (16 or 24 mg tid) or a higher dosage of 48 mg tid for at least 12 months. The outcome measure was the number of attacks per month during a 3-month period. Non-parametric tests and a random effects model were used for statistical analysis. RESULTS: A total of 112 patients were included in the analysis: 50 received betahistine-dihydrochloride in a low dosage (16 mg tid, n=21, 24 mg, n=29) and 62 received 48 mg tid. Follow-up examination every 3 months showed that the number of attacks per month decreased in both groups over time. For instance, after 12 months the mean (median) number of attacks dropped from 7.6 (4.5) to 4.4 (2.0) (p<0.0001) in the low-dosage group, and from 8.8 (5.5) to 1.0 (0.0) (p<0.0001) in the high dosage group. The number of attacks after 12 months was significantly lower in the high dosage group than in the low dosage group (p(12M)=0.0002). The treatment was well tolerated in both groups.

Superficial cerebral and spinal haemosiderosis caused by secondary tethered cord syndrome after resection of a spinal lymphoma.

Superficial haemosiderosis results from chronic subarachnoid haemorrhage during which haemosiderin is deposited in the leptomeninges around the brain, spinal cord and cranial nerves. We describe an exceptional case of superficial haemosiderosis characterised by two special aspects. (1) The cause was a secondary tethered cord syndrome due to dural adhesions which had developed 8 years after resection of a thoracic lymphoma and (2) an explorative neurosurgical procedure with complete untethering caused normalisation of the cerebrospinal fluid and stopped disease progression.

Causative factors and epidemiology of bilateral vestibulopathy in 255 patients.

OBJECTIVE: To determine the causative factors and epidemiology of bilateral vestibulopathy (BV). METHODS: This is a retrospective review of 255 patients (mean age, 62 +/- 16 years) with BV diagnosed in our dizziness unit between 1988 and 2005. All patients had undergone a standardized neurophthalmological and neurootological examination, electronystagmography with caloric irrigation, cranial magnetic resonance imaging or computed tomography (n = 214), and laboratory tests. RESULTS: Sixty-two percent of the study population were male subjects. Previous vertigo attacks had occurred in 36%, indicating a sequential manifestation. The definite cause of BV was determined in 24% and the probable cause in 25%: The most common causes were ototoxic aminoglycosides (13%), Menière's disease (7%), and meningitis (5%). Strikingly, 25% exhibited cerebellar signs. Cerebellar dysfunction was associated with peripheral polyneuropathy in 32% compared with 18% in BV patients without cerebellar signs. Hypoacusis occurred bilaterally in 25% and unilaterally in 6% of all patients. It appeared most often in patients with BV caused by Cogan's syndrome, meningitis, or Menière's disease. INTERPRETATION: The cause of BV remains unclear in about half of all patients despite intensive examinations. A large subgroup of these patients have associated cerebellar dysfunction and peripheral polyneuropathy. This suggests a new syndrome that may be caused by neurodegenerative or autoimmune processes.

A clinical test of otolith function: static ocular counterroll with passive head tilt.

When roll-tilted around the naso-occipital axis, humans exhibit compensatory torsional rotation of the eyes in the opposite direction owing to the torsional vestibulo-ocular reflex. In the static condition (sustained head roll), the utricles act as responsible sensors for 'static ocular counterroll'. Contributions of cervico-ocular reflexes remain unknown. To find an easy, clinically useful test of utricular function, we induced ocular counterroll in 10 healthy study participants (two men, mean age 27+/-2 years) under three stimulation conditions (active/passive head tilt and passive whole body tilt in roll plane), used three-dimensional video-oculography to measure it, and compared values. Active head-tilt-induced ocular counterroll varied most and was thus less reliable than passive head and body tilt-induced ocular counterroll. Utricular function can thus be tested simply by measuring passive head tilt with video-oculography.

Assessment of potential cardiotoxic side effects of mitoxantrone in patients with multiple sclerosis.

Previous studies showed that mitoxantrone can reduce disability progression in patients with multiple sclerosis (MS). There is, however, concern that it may cause irreversible cardiomyopathy with reduced left ventricular (LV) ejection fraction (EF) and congestive heart failure. The aim of this prospective study was to investigate cardiac side effects of mitoxantrone by repetitive cardiac monitoring in MS patients. The treatment protocol called for ten courses of a combined mitoxantrone (10 mg/m(2) body surface) and methylprednisolone therapy. Before each course, a transthoracic echocardiogram was performed to determine the LV end-diastolic diameter, the end-systolic diameter and the fractional shortening; the LV-EF was calculated. Seventy-three patients participated (32 males; age 48 +/- 12 years, range 20-75 years; 25 with primary progressive, 47 with secondary progressive and 1 with relapsing-remitting MS) who received at least four courses of mitoxantrone. Three of the 73 patients were excluded during the study (2 patients discontinued therapy; 1 patient with a previous history of ischemic heart disease developed atrial fibrillation after the second course of mitoxantrone). The mean cumulative dose of mitoxantrone was 114.0 +/- 33.8 mg. The mean follow-up time was 23.4 months (range 10-57 months). So far, there has been no significant change in any of the determined parameters (end-diastolic diameter, end-systolic diameter, fractional shortening, EF) over time during all follow-up investigations. Mitoxantrone did not cause signs of congestive heart failure in any of the patients. Further cardiac monitoring is, however, needed to determine the safety of mitoxantrone after longer follow-up times and at higher cumulative doses.

Diagnostic pitfalls in patients with hypoxic brain damage: three case reports.

OBJECTIVE: Our aim was to assess the possible diagnostic pitfalls in three patients with hypoxic brain damage who had partly conflicting clinical, biochemical, and electrophysiological data and were in a persistent vegetative state (PVS) following cardiac arrest (CA). METHODS: Serum concentrations of the destruction proteins, neuron-specific enolase (NSE) and protein S-100B (S-100B), were measured on days 1-3, and 7; somatosensory evoked potentials (SEPs) were recorded within 48 h and on day 7 after CA. RESULTS: Two patients had significantly increased concentrations of NSE and S-100B during the first 3 days after CA, a finding that indicates ongoing neuronal destruction. In contrast, the SEPs of these patients were normal or showed only a diminished amplitude configuration. In the third patient the SEPs demonstrated a bilateral loss of cortical responses repeatedly, but both destruction proteins were only slightly above the upper normal values on all study days. CONCLUSION: Our findings demonstrate that a poor prognosis can only be established if either SEPs, NSE, or S-100B are very abnormal. The conflicting results in our patients indicate that variable values may reflect different patterns of neuropathological damage caused by diffuse hypoxia. We, therefore, favour a multi-modal approach with a combination of clinical, biochemical, and electrophysiological investigations in order to predict neurological outcome after CA reliably.

Mitoxantrone therapy in multiple sclerosis and acute leukaemia: a case report out of 644 treated patients.

As a rare complication of mitoxantrone (MITOX) therapy in multiple sclerosis (MS), a therapy-related acute leukaemia (TRAL) may develop. The incidence is difficult to estimate, as frequently single cases are reported, up to now a total of eight MS patients. Here we report a new case out of 644 patients. This is a 45-year-old female patient with secondary progressive MS who developed TRAL after a total dose of 48 mg/m2 MITOX. The TRAL was classified as acute myeloblastic leukaemia (AML) M4eo and showed an inversion of chromosome 16 and a partial trisomy 11. Her TRAL was treated with chemotherapy followed by allogeneic bone marrow transplantation. It responded well to the transplantation, whereas the MS symptoms initially worsened but have nearly returned to the pretransplantation level. This report brings the currently published frequency of MITOX-associated TRAL in MS therapy to five in a total of 2336 treated MS patients, representing an incidence of 0.21%.

Methylprednisolone, valacyclovir, or the combination for vestibular neuritis.

BACKGROUND: Vestibular neuritis is the second most common cause of peripheral vestibular vertigo. Its assumed cause is a reactivation of herpes simplex virus type 1 infection. Therefore, corticosteroids, antiviral agents, or a combination of the two might improve the outcome in patients with vestibular neuritis. METHODS: We performed a prospective, randomized, double-blind, two-by-two factorial trial in which patients with acute vestibular neuritis were randomly assigned to treatment with placebo, methylprednisolone, valacyclovir, or methylprednisolone plus valacyclovir. Vestibular function was determined by caloric irrigation, with the use of the vestibular paresis formula (to measure the extent of unilateral caloric paresis) within 3 days after the onset of symptoms and 12 months afterward. RESULTS: Of a total of 141 patients who underwent randomization, 38 received placebo, 35 methylprednisolone, 33 valacyclovir, and 35 methylprednisolone plus valacyclovir. At the onset of symptoms there was no difference among the groups in the severity of vestibular paresis. The mean (+/-SD) improvement in peripheral vestibular function at the 12-month follow-up was 39.6+/-28.1 percentage points in the placebo group, 62.4+/-16.9 percentage points in the methylprednisolone group, 36.0+/-26.7 percentage points in the valacyclovir group, and 59.2+/-24.1 percentage points in the methylprednisolone-plus-valacyclovir group. Analysis of variance showed a significant effect of methylprednisolone (P<0.001) but not of valacyclovir (P=0.43). The combination of methylprednisolone and valacyclovir was not superior to corticosteroid monotherapy. CONCLUSIONS: Methylprednisolone significantly improves the recovery of peripheral vestibular function in patients with vestibular neuritis, whereas valacyclovir does not.