Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-ß-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.

Parkinson's Disease Multimodal Complex Treatment improves motor symptoms, depression and quality of life.

Parkinson's disease (PD) is the world's fastest growing neurological disorder disabling patients through a broad range of motor and non-motor symptoms. For the clinical management, a multidisciplinary approach has increasingly been shown to be beneficial. In Germany, inpatient Parkinson's Disease Multimodal Complex Treatment (PD-MCT) is a well-established and frequent approach, although data on its effectiveness are rare. We conducted a prospective real-world observational study in 47 subjects [age (M ± SD): 68.5 ± 9.0 years, disease duration: 8.5 ± 5.3 years, modified Hoehn and Yahr stage (median, IQR): 3, 2.5-3] aiming at evaluating the effectiveness of 14-day PD-MCT in terms of quality of life (Parkinson's Disease Questionnaire, EuroQol), motor [Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III], Timed Up and Go Test, Purdue Pegboard Test) and non-motor symptoms (revised Beck Depression Inventory). Six weeks after hospital discharge, a follow-up examination was performed. PD patients with a predominantly moderate disability level benefited from PD-MCT in terms of health-related quality of life, motor symptoms and non-motor symptoms (depression). Significant improvements were found for social support, emotional well-being and bodily discomfort domains of health-related quality of life. Sustainable improvement occurred for motor symptoms and the subjective evaluation of health state. We found a higher probability of motor response especially for patients with moderate motor impairment (MDS-UPDRS III ≥ 33). In conclusion, Parkinson's Disease Multimodal Complex Treatment improves motor symptoms, depression and quality of life. A more detailed selection of patients who will benefit best from this intervention should be examined in future studies.

Novel variants in a patient with late-onset hyperprolinemia type II: diagnostic key for status epilepticus and lactic acidosis.

BACKGROUND: Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood. CASE PRESENTATION: The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55-2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12-2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B6 serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The ALDH4A1 gene sequencing confirmed two previously unknown compound heterozygous variants (ALDH4A1 gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and ALDH4A1 gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B6 therapy no further seizures occurred. CONCLUSION: We describe two novel ALDH4A1-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation.

Hereditary defect of cobalamin metabolism with adolescence onset resembling multiple sclerosis: 41-year follow up in two cases.

The cblC defect is the most common inborn error of cobalamin (Cbl) metabolism. Clinical severity and presentation of the cblC defect ranges from death to mild disability. Only 71 cases of late-onset cblC defect have been described in the literature. We provide the 41-year follow up of two siblings with a late-onset cblC defect, first described after initial diagnosis in 1996. While one of the siblings showed initial symptoms resembling multiple sclerosis with a good response to corticosteroids, the other sister showed only subclinical signs of the disease. The course of the first case was characterized by a severe deterioration and intensive-care therapy after respiratory failure. After diagnoses and Cbl treatment, the patient survived and showed a pronounced improvement of the symptoms. Both sisters have an active life and gave birth to healthy children. The reason for the initial improvement after corticosteroids could not be explained by the classical metabolic pathways of Cbl. Recent studies have suggested that Cbl plays an important role as a regulator of the balance between neurotrophic and neurotoxic factors in the central and peripheral nervous system (CNS and PNS). This first long-term follow up revealed that ultra-high-dose intramuscular Hydroxocobalamin (OH-Cbl) treatment can effectively protect patients from disease progression. It underlines the importance of diagnostic vigilance and laboratory work up even in cases without typical hematologic signs of Cbl deficiency. Cbl-related diseases are often a chameleon and must always be considered in the differential of demyelinating diseases of the PNS and CNS. The case supports the theory that it is not only the classical biochemical pathways that play a key role in Cbl deficiency, especially with regard to neurological symptoms.

Capsaicin-enriched diet ameliorates autoimmune neuritis in rats.

BACKGROUND: Autoimmune neuropathies are common PNS disorders and effective treatment is challenging. Environmental influence and dietary components are known to affect the course of autoimmune diseases. Capsaicin as pungent component of chili-peppers is common in human nutrition. An influence of capsaicin on autoimmune diseases has been postulated. METHODS: We tested capsaicin in the animal model of experimental autoimmune neuritis (EAN) in Lewis rat. Rats were immunized with P2-peptide and were treated with capsaicin in different preventive settings. Electrophysiological, histological, and molecular biological analyses of the sciatic nerve were performed to analyze T-cell and macrophage cell count, TRPV1, and cytokine expression. Moreover, FACS analyses including the intestinal immune system were executed. RESULTS: We observed an immunomodulatory effect of an early preventive diet-concept, where a physiological dosage of oral capsaicin was given 10 days before immunization in EAN. A reduced inflammation of the sciatic nerve was significant detectable clinically, electrophysiologically (CMAPs reduced in control group p < 0.01; increase of nerve conduction blocks in control group p < 0.05), histologically (significant reduction of T-cells, macrophages and demyelination), and at cytokine level. In contrast, this therapeutic effect was missing with capsaicin given from the day of immunization onwards. As possible underlying mechanism, we were able to show changes in the expression of the capsaicin receptor in the sciatic nerve and the small intestine, as well as altered immune cell populations in the small intestine. CONCLUSION: This is the first report about the immunomodulatory effect of the common nutrient, capsaicin, in an experimental model for autoimmune neuropathies.

Effects of delayed-release dimethyl fumarate (DMF) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: an integrated analysis of the phase 3 DEFINE and CONFIRM studies.

PURPOSE: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) has been reported to have clinical and neuroradiologic efficacy in people with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. An integrated analysis of data from DEFINE and CONFIRM was conducted to estimate more precisely the therapeutic effects of delayed-release DMF. Here we describe the impact of RRMS on health-related quality of life (HRQoL) at baseline and assess the effects of delayed-release DMF on prespecified HRQoL end points over 2 years. METHODS: Patients with RRMS were randomly assigned to receive delayed-release DMF 240 mg PO BID or TID or matching placebo for up to 2 years (96 weeks). As a tertiary end point in both studies, patient-reported HRQoL was assessed using the Physical and Mental Component Summaries (PCS and MCS, respectively) of the 36-item Short Form Health Survey (SF-36); global assessment of well-being, as measured on a visual analog scale (VAS); and the EuroQoL-5D (EQ-5D) VAS, administered at baseline and at weeks 24, 48, and 96. Higher scores suggested better HRQoL. FINDINGS: The integrated analysis included 2301 patients treated with delayed-release DMF BID (n = 769) or TID (n = 761) or placebo (n = 771). The mean PCS and MCS scores at baseline were lower overall compared with those reported in the general US population and were ≥5 points lower (a clinically meaningful difference) in patients with a baseline Expanded Disability Status Scale (EDSS) score of ≥2.5 compared with those in patients with a baseline EDSS score of 0. At 2 years, mean PCS and MCS scores were increased from baseline in the patients treated with delayed-release DMF, whereas the mean PCS and MCS scores were decreased from baseline in the placebo group; the difference in PCS and MCS scores was significant for the delayed-release DMF BID and TID groups compared with placebo. SF-36 subscale scores generally remained stable or were improved relative to baseline in patients treated with delayed-release DMF and decreased in patients receiving placebo; improvements were significant for delayed-release DMF BID and TID versus placebo on most subscales. Compared with that in the placebo group, the proportions of patients in the delayed-release DMF groups exhibiting a ≥5-point improvement in SF-36 score were significantly higher. The following factors were found to be predictive of improved PCS and MCS scores at 2 years: delayed-release DMF treatment, lower baseline EDSS score, age ≤40 years (PCS only), and corresponding lower baseline PCS or MCS score. Changes from baseline in VAS and EuroQoL-5D scores were generally consistent with changes in SF-36 scores. IMPLICATIONS: These HRQoL benefits parallel the improvements in clinical and magnetic resonance imaging end points with delayed-release DMF, suggesting that delayed-release DMF treatment improves patient-perceived health status as well as neurologic and physical functioning. ClinicalTrials.gov identifiers: NCT0042012; NCT00451451.

MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study.

OBJECTIVE: RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab. METHODS: Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon ß-1a [IM IFN-ß-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks. RESULTS: Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-ß-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-ß-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%-29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4-8 weeks (n = 2 in weeks 4-8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity. CONCLUSIONS: MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.

Review of laquinimod and its therapeutic potential in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic immunological disease of the central nervous system characterized by early inflammatory demyelination and subsequent neurodegeneration. Although major progress has occurred, MS is still an incurable disease. Further, parenteral application and/or safety issues of the currently licensed drugs are associated with low patient compliance. Thus, there remains an unmet need for the development of more effective and well-tolerated oral therapies for the treatment of MS. At this point in time, different oral available substances are under investigation and hold promise in the treatment of relapsing-remitting MS (RRMS). AREAS COVERED: The physical, chemical and pharmacological properties of laquinimod , as well as its suggested mechanisms of action, clinical efficacy and side-effect profile are reviewed. EXPERT OPINION: Laquinimod is a new orally administered synthetic drug designed as an immunomodulator. Its mechanisms of action are not yet fully elucidated. Studies in mice and humans revealed different mechanisms of action, including anti-inflammatory and neuroprotective effects. So far, Phase II and Phase III clinical trials have shown its efficacy on magnetic resonance imaging based measures of disease activity, annualized relapse rate and disability progression in RRMS patients. Current data suggest a relatively modest efficacy by measures of relapse rate and there seems to be no superiority in comparison to established disease-modifying agents in relapsing-remitting MS. Further studies are necessary to evaluate both neuroprotective efficacy and optimal dosage of laquinimod in more detail.

Inflammation modulates anxiety in an animal model of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by inflammation, but also degenerative changes. Besides neurological deficits, the rate of affective disorders such as depression and anxiety is at least six fold increased. Many aspects of MS can be mimicked in the animal model of myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (MOG-EAE). Here we investigate behavioral changes in C57BL/6 mice suffering from mild MOG-EAE. In the later phase of the disease, mice were subjected to behavioral tests including the light-dark-box (LD Box), the acoustic startle response (SR) with a pre-pulse inhibition protocol as well as the learned helplessness (LH) paradigm. Behavioral data were correlated with the motor performance in an open field and rotarod test (RR). In the RR and open field, there was no significant difference in the motor performance between controls and mice suffering from mild MOG-EAE. Yet EAE mice displayed an increased anxiety-like behavior with a 23% reduction of the time spent in the bright compartment of the LD Box as well as an increased SR. In the LH paradigm, mice suffering from MOG-EAE were twice as much prone to depressive-like behavior. These changes correlate with an increase of hippocampal tissue tumor necrosis factor alpha levels and neuronal loss in the hippocampus. Modulation of monoaminergic transmission by chronic application of the antidepressant amitriptyline resulted in a decreased startle reaction and increased hippocampal norepinephrine levels. These data imply that chronic inflammation in the CNS may impact on emotional responses in rodent models of anxiety.