Persistent Placoid Maculopathy Complicated by Cerebral Vasculitis.

Persistent placoid maculopathy (PPM) is a bilateral inflammatory chorioretinopathy characterized by long-standing plaque-like macular lesions. No systemic manifestations have been reported to date. We describe a case of PPM complicated by cerebral vasculitis, suggesting that neurological symptoms, including headache, should be enquired about in all PPM subjects.

Multiple Sclerosis patients carry an increased burden of exceedingly rare genetic variants in the inflammasome regulatory genes.

The role of rare genetic variation and the innate immune system in the etiology of multiple sclerosis (MS) is being increasingly recognized. Recently, we described several rare variants in the NLRP1 gene, presumably conveying an increased risk for familial MS. In the present study we aimed to assess rare genetic variation in the inflammasome regulatory network. We performed whole exome sequencing of 319 probands, comprising patients with familial MS, sporadic MS and control subjects. 62 genes involved in the NLRP1/NLRP3 inflammasome regulation were screened for potentially pathogenic rare genetic variation. Aggregate mutational burden was analyzed, considering the variants' predicted pathogenicity and frequency in the general population. We demonstrate an increased (p = 0.00004) variant burden among MS patients which was most pronounced for the exceedingly rare variants with high predicted pathogenicity. These variants were found in inflammasome genes (NLRP1/3, CASP1), genes mediating inflammasome inactivation via auto and mitophagy (RIPK2, MEFV), and genes involved in response to infection with DNA viruses (POLR3A, DHX58, IFIH1) and to type-1 interferons (TYK2, PTPRC). In conclusion, we present new evidence supporting the importance of rare genetic variation in the inflammasome signaling pathway and its regulation via autophagy and interferon-ß to the etiology of MS.

Could cytokines levels or adhesion molecules expression be predictor of IFN-beta treatment response in multiple sclerosis patients?

OBJECTIVE: Some patients with relapsing-remitting multiple sclerosis (RRMS) do not respond to treatment with interferon-beta and continue to have relapses and new enhancing lesions on MRI. The markers which would predict the treatment response are still not known. The objectives of the study were to compare cytokines levels (IFN-gamma, IL-4, IL-6, IL-10) and expression of adhesion molecules before and during treatment in responders and nonresponders to IFN-beta treatment. METHODS: Twenty-nine patients with RRMS were enrolled in the study. Cytokine levels were evaluated by ELISA in supernatants of IONO/PMA activated PBMC cultures (IFN-gamma, IL-4, IL-6, IL-10), and by flow cytometry (intracellular IFN-gamma, IL-4 and IL-2R expression) before and during treatment. Expression of adhesion molecules (VLA-4, ICAM-1) was evaluated by flow cytometry (CD49+ and CD54+) before and during treatment. RESULTS: Only 9 of 29 patients were responders to treatment according to definition (no relapse in the first 2 years of treatment). We found significant differences in the expression of IL-2R after 1 month of treatment, intracellular IFN-gamma after 6 months of treatment and IL-10 level in nonactivated PBMC cultures after 1 week of treatment. CONCLUSION: We concluded that the differences we had found between responders and nonresponders are most probably incidental and not predictive of treatment response. Our study shows that cytokines levels and expression of adhesion molecules cannot be used as markers for treatment response.

Presence of central veins and susceptibility weighted imaging for evaluating lesions in multiple sclerosis and leukoaraiosis.

PURPOSE: The process of demyelination in multiple sclerosis (MS) is reflected in lesions of the central nervous system (CNS), which are found in an abundance of different diseases and are frequently radiographically indistinguishable. Our aim was to determine whether the perivenous distribution of MS lesions identified on susceptibility weighted images (SWI) could be used as a specific radiographic sign for MS, and also to determine whether the visibility of the central vein (CV) is affected by the activity of MS lesions. METHODS: We retrospectively examined 34 subjects with MS and 19 subjects with ischemic lesions, which underwent a 3T MRI investigation. According to FLAIR and T2-weighted sequences the lesions were categorized regarding location. The presence of CVs was determined on SWI. Gadolinium enhanced T1-weighted sequence was included for the evaluation of MS lesion activity. RESULTS: A total load of 601 MS and 204 ischemic lesions was identified. We found significantly more lesions with CVs in the group with ischemic lesions compared to the group with MS lesions (p<0.001). Similarly, significantly more supratentorial peripheral ischemic lesions had CVs (p=0.011), whereas in supratentorial periventricular and intratentorial lesions we found no significant difference between the two groups (p=0.377 and p=0.615). Comparing the active and inactive MS lesions regarding CVs, we found no significant difference between the groups (p=0,472). CONCLUSIONS: We can conclude that the presence of a CV is not a specific radiographic sign for MS. CVs can also be identified in lesions caused by various other diseases.

Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis.

The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1ß production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.

Anaplastic oligodendroglioma and gliomatosis type 2 in interferon-beta treated multiple sclerosis patients. Report of two cases.

The concurrence of multiple sclerosis (MS) and brain tumors has been reported, but it is not known whether MS patients are at greater risk of harbouring the latter. The most common cerebral neoplasms reported in MS patients were oligodendroglioma, astrocytoma, glioblastoma and gliomatosis. MS can also present as a mass lesion that mimics a brain tumor. To establish the correct diagnosis radiological follow-up and/or histological confirmation is needed. Two cases of coincidental MS and brain tumors are reviewed. One is a 26-year-old woman with relapsing-remitting MS and an anaplastic oligodendroglioma, the other a 49-year-old woman patient with relapsing-remitting MS and gliomatosis type 2. Both patients were treated with interferon-beta1b and both died from the tumor. The concurrence of MS and brain tumors could be purely coincidental, or the result of neoplastic transformation of reactive glial cells in the areas of demyelination. The combination of a brain tumor and MS, and interferon-beta treatment could also be pure coincidence or an unknown side effect of treatment. Although interferon-beta has been said to function as a tumor-suppressor protein, the influence of long-term treatment of MS patients on cancer development is not known.

Short-term impact of fampridine on motor and cognitive functions, mood and quality of life among multiple sclerosis patients.

OBJECTIVE: Previous studies have predominantly investigated the effect of fampridine on lower extremities motor functions while data on its impact on other symptoms of multiple sclerosis (MS) are scarce. The aim of our study was to assess the impact of fampridine on walking, arm/hand function, fatigue, cognitive function, mood and quality of life among responders. METHODS: Our prospective non-randomized study included 30 patients with different types of MS, aged 35-70, EDSS value 3.5-6.5. They were treated with 10mg of fampridine twice daily. The examinations were performed before the treatment, after 14 days, when responders were defined by T25FW (Timed 25-Foot Walk) and 2-min walk test (2MWT) was performed, and after 28 days of treatment, when only the responders were examined. Standardized protocols and questionnaires were used to evaluate the impact of fampridine on walking speed (T25FW, 2MWT), arm/hand function (9-HPT - Nine-Hole Peg Test), cognitive function (PASAT - Paced Auditory Serial Addition Test), total MSFC score (Multiple Sclerosis Functional Composite), fatigue (MFIS - Modified Fatigue Impact Scale), mood (BDI - Beck Depression Inventory) and quality of life (EQ-5D index, EQ-VAS - Euro Quality of Life - 5 Dimension questionnaire and visual analogue scale) in responders. RESULTS: Response rate was 56.7%. Average improvement of T25FW and 2MWT after 14 days of treatment in responders was 3.6s (34.5%) and 37.4m (42.3%), respectively. This improvement persisted after 28 days of treatment. In non-responders there was no significant improvement of T25FW after 14 days (p=0.689), but there was improvement of 2MWT for 13.4m (14.3%) (p=0.000). After 28 days of treatment significant improvement among responders occurred in total MSFC score (p=0.001), 9-HPT (p=0.002), BDI (p=0.005), MFIS total score (p=0.003), physical (p=0.001), cognitive (p=0.008) MFIS subscales, and EQ-5D index (p=0.012). There were implied trends towards improvement in EQ-VAS and psychosocial MFIS subscale, yet not significant (p=0.057 and p=0.127, respectively). There was no statistically significant improvement of PASAT (p=0.432). CONCLUSIONS: The results of our study highlight the potential of fampridine for improving not only walking speed but also arm/hand function, physical and cognitive fatigue, mood and quality of life. There was no objective improvement of cognitive function. Further placebo-controlled studies will be needed for precise definition of fampridine's action beyond its impact on walking.

IFN-beta1a and IFN-beta1b have different patterns of influence on cytokines.

Multiple sclerosis is characterized by elevated levels of proinflammatory cytokines produced by Th1 cells and decreased levels of anti-inflammatory cytokines produced by Th2 cells. IFN-beta treatment shifts the immune response from the Th1 to Th2 pattern, thus enhancing the production of anti-inflammatory Th2 cytokines such as IL-4, IL-10, and decreasing the production of proinflammatory Th1 cytokines such as IFN-gamma. To determine which IFN-beta has the stronger immunomodulatory effect we compared the levels of IL-4, IL-10, and IFN-gamma of 12 relapsing-remiting MS patients treated with IFN-beta1b (Betaferon) with those of 10 patients treated with IFN-beta1a (Avonex). There were no statistically significant differences in duration of disease, number of relapses before and during treatment, and in EDSS after 2 years of treatment. After 1 year of treatment the concentration of IFN-gamma was significantly lower in the Betaferon group, and concentrations of IL-4 and IL-10 were significantly higher in the Avonex group. It appears that IFN-beta1b has a downregulatory effect on both Th1 and Th2 cytokines, while IFN-beta1a causes a shift of the cytokine profile toward the Th2 phenotype. These two IFN have different influences on the pattern of cytokines in MS: IFN-beta1a enhances the production of anti-inflammatory cytokines IL-4 and IL-10 and IFN-beta1b decreases the production of the proinflammatory cytokine IFN-gamma.

Profile of depression, experienced distress and capacity for coping with stress in multiple sclerosis patients--a different perspective.

Multiple sclerosis (MS) can result in significant changes in psychological functioning. Depression and cognitive deficits are commonly present. In addition personality changes have been described. A growing body of research is showing negative impact of psychological stress on disease course. Our study focused on the profile of depression, capacity for coping with stress and experienced distress in patients with MS measured by a performance based method for personality assessment-the Rorschach Inkblot Method (RIM). We included 95 patients with MS and 44 healthy controls. RIM was used with all participants and was scored by the Exner Comprehensive system. Compared to healthy controls MS patients had statistically significantly lower capacity for coping with stress, complexity of information processing, body image, willingness to process emotional stimulation and interpersonal interest. Surprisingly patients had lower experienced distress than controls. We propose that the profile of depression in advanced MS disease might be better described in terms of negative symptoms such as emotional withdrawal and apathy and less with the profile of positive symptoms such as rumination and worry. RIM variables were not significantly associated with the EDSS. Interventions from which patients could benefit are discussed.

Adherence to disease-modifying therapies and attitudes regarding disease in patients with multiple sclerosis.

Although currently there is no cure for MS the course of the disease can be influenced by disease modifying therapy (DMT). For therapy to be sufficiently efficient, it is crucial that patients take their medication regularly as prescribed. Adherence describes the extent to which a patient acts in accordance with the prescribed timing, dosing, and frequency of medication administration. To date, there are no known data about adherence rates among patients with MS in Slovenia. We wanted to assess adherence in patients with MS, who are treated with first line DMTs and discover reasons for non-adherence. A number of 451 patients were invited to participate. They received two questionnaires via post mail. The adherence rate and putative reasons for non-adherence were assessed by the use of standardized self-report Multiple Sclerosis Treatment Experience Questionnaire (MSTEQ). Patients' attitudes regarding disease, therapy and relationship with their physician were assessed by another questionnaire. The analysis of results included 299 patients. Among the patients 18.5% missed at least one medication dose in the past 28 days. Patients taking Avonex were significantly more adherent then patients on other DMTs (p=0.005). Our study showed a higher then expected adherence among Slovenian patients with MS (81.5%). Our research did not confirm the influence of side effects or patients' attitudes regarding illness and therapy on adherence. However we found unexpectedly high percentage (71.8%) of patients belief that psychological factors are involved in MS aetiology.

Personality characteristics of multiple sclerosis patients: a Rorschach investigation.

OBJECTIVE: There are many studies examining cognitive deficits in patients with multiple sclerosis (MS), while significantly less attention has been given to emotional and personality changes. A chronic neurological disorder brings many life stresses and affects the patient's ability to cope with them. This study explored the personality characteristics in a sample of MS patients. METHODS: 51 MS patients (13 male and 38 female, mean age: 42.6 years, mean EDSS: 3.2). All participants were administered the Rorschach Test coded by the Comprehensive System. RESULTS: Our findings show that the patients in our sample perceive themselves as being less competent than others, at some cost to their self-esteem. A large percentage relies on an avoidant style of coping with problems. CONCLUSION: These findings imply that MS patients might have special needs in terms of communication with healthcare providers, decision making and adherence to their treatment plans because of their simplifying style of information processing. We argue that it is important to consider personality as well as cognitive changes in neurological disorders such as MS.