Severe disease reactivation in seropositive neuromyelitis optica spectrum disorders patients after stopping eculizumab treatment.

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune, inflammatory disease of the central nervous system affecting the optic nerves and spinal cord. Most NMOSD patients have autoantibodies against the astrocyte water channel protein aquaporin-4 (AQP4). Eculizumab treatment is used effectively and safely in AQP4-IgG+ NMOSD. Our study evaluated the prognosis and outcomes of all clinical trial (PREVENT) patients from Turkey who received eculizumab treatment for AQP4-IgG+ NMOSD. METHOD: Clinical and demographic data of all patients enrolled in the PREVENT and OLE clinical trial in Turkey were analyzed during the study period and after the study ended. Clinical follow-up results were recorded in detail in patients who had to discontinue eculizumab treatment. RESULTS: The study included 10 patients who participated in PREVENT and OLE. Seven patients completed the studies, three patients did not continue the study and were switched to other treatments. Only one of the seven patients was able to continue treatment after eculizumab was approved in AQP4-IgG+NMOSD. The other six patients could not continue treatment due to reimbursement conditions. Four of the six patients who could not continue eculizumab treatment experienced early relapse (within the first three months after stopping the drug). All of these patients had high disease activity before eculizumab and had never relapsed under eculizumab treatment over the long term. CONCLUSION: Eculizumab was used effectively and safely in Turkish AQP4-IgG+NMOSD patients with high disease activity. Disease reactivation and relapse may occur after discontinuation of eculizumab treatment in patients with a long-term stable course. In these cases, close monitoring for disease reactivation is recommended.

Use of follow-on fingolimod for multiple sclerosis: Analysis of effectiveness and patient reported outcomes in a real-world clinical setting.

BACKGROUND: Follow-on disease modifying therapies (FO-DMTs) do not always require Phase III studies. There are concerns that cheaper FO-DMTs are only used to reduce healthcare costs. However, the well-being of people with MS (pwMS) should be a priority. We aimed to evaluate the efficacy, safety and treatment satisfaction of one of the FO- Fingolimod (FTY) used in Turkey with the approval of Turkish Ministry of Health. METHODS: PwMS under FTY were recruited from 13 centers and real-world data and answers of satisfaction and adherence statements of pwMS on FTY treatment were analyzed. RESULTS: Data of 239 pwMS were obtained. The duration of FTY treatment was 2.5 ± 0.8 (1-4) years in pwMS who were included in the study and whose treatment continued for at least one year. Significant decreases in annual relapse rate (p < 0.001), Expanded Disability Status Scale (p < 0.001) and neuroimaging findings (p < 0.001) were observed. While 64% of the patients were satisfied and 71.5% were found to adherent with this FO-FTY. CONCLUSION: This multicenter retrospective study found that the efficacy, safety and treatment adherence of a prescribed FO-FTY were consistent with the results of real-world studies. Studies including real-world data may provide guidance to address issues related to FO-FTY use.

Retrospective analysis of effectiveness of fingolimod in real life setting in Turkey (REFINE).

BACKGROUND: During multiple sclerosis (MS) treatment different modes of action such as lateral (interferon beta to glatiramer acetate or glatiramer acetate to interferon beta) or vertical (interferon beta/glatiramer acetate to fingolimod) drug switch can be performed. This study aims to investigate the clinical effectiveness of switching from the first-line injectable disease modifying treatments (iDMTs) to fingolimod (FNG) compared to switching between first-line iDMTs. METHODS: This is a multicenter, observational and retrospective study of patients with relapsing-remitting MS who had lateral and vertical switch. The observation period included three key assessment time points (before the switch, at switch, and after the switch). Data were collected from the MS patients' database by neurologists between January 2018 and June 2019. The longest follow-up period of the patients was determined as 24 months after the switch. RESULTS: In 462 MS patients that were included in the study, both treatments significantly decreased the number of relapses during the postswitch 12 months versus preswitch one year while patients in the FNG group experienced significantly fewer relapses compared to iDMT cohort in the postswitch 12 months period. FNG cohort experienced fewer relapses than in the iDMT cohort within the postswitch 2 year. The mean time to first relapse after the switch was significantly longer in the FNG group. DISCUSSION: The present study revealed superior effectiveness of vertical switch over lateral switch regarding the improvement in relapse outcomes. Patients in the FNG cohort experienced sustainably fewer relapses during the follow-up period after the switch compared the iDMT cohort. Importantly, switching to FNG was more effective in delaying time to first relapse when compared with iDMTs.

The effect of cognitive performance on self-management behavior of multiple sclerosis patients.

BACKGROUND: Difficulties of self-management in people with MS (pwMS) is considered as one of the most important factors contributing to low rehabilitation efficacy, more severe long-term complications and increase in healthcare costs. Despite the emergence of research in the last decade documenting causes, types, and course of cognitive difficulties in MS disease subtypes, limited evidence is available in the literature for direct comparison of self-management and cognitive deficits. In this study we aimed to investigate the relationship between cognitive performance and self-management in pwMS. METHODS: PwMS who applied to neurology out-patient clinics of seven different centers were included into study. Multiple Sclerosis Self-Management Scale- Revised (MSSM-R) was used for the assessment of self-management behaviors and Multiple Sclerosis inventory cognition scale (MUSIC) was used for the assessment of cognitive performance and fatigue. RESULTS: In this study, 194 (144 female and 50 male) pwMS participated (mean age = 38.9 years). The course of the disease was RRMS in 173 patients and mean EDSS was 2.0. 68.5% of the participants were married, 32.5% were employed, and 57.2% had secondary education. The MSSM-R mean score of the study group was 42.6 ± 10.4 (1-81). There was a positive correlation between MSSM-R and MUSIC-cog scores (r = 0.21, p = 0.003). A hierarchical multiple regression revealed that income level (ß = 0.196, t = 2.692, p = 0.008) and cognitive performance (ß = 0.167, t = 2.063, p = 0.041) together with control variables (gender, age, educational status, employment status, duration of disease, EDSS and fatigue) explained 5.5% of the variance in self-management. CONCLUSION: Cognitive performance is a predictor of self-management in pwMS. Better self-management behavior is also related with employment and income level in pwMS. Studies evaluating patients' cognitive abilities and evaluating the effectiveness of adapted self-management training programs are needed.

Cognitive Impairment in Neuromyelitis Optica.

INTRODUCTION: There are few studies on cognitive impairment in neuromyelitis optica (NMO). The purpose of this study is to assess the factors that may be related with the frequency and level of cognitive impairment in Turkish NMO patients. METHODS: 22 patients with the diagnosis of NMO are evaluated retrospectively. Cognitive function was evaluated with Brief Repeatable Battery of Neuropsychological tests (BRB-N), Beck Depression Inventory (BDI) and Addenbrooke Cognitive Evaluation (ACE-R). The groups with and without cognitive impairment were compared according to age, sex, level of education, pathologic findings on cranial MRI, NMO Ig existence and EDSS score. The relation of the clinical, radiological and demographic values and patients' depression level was evaluated. The specificity and sensitivity of ACE-R test on detecting cognitive impairment were assessed through ACE-R test results. RESULTS: The mean age of the patients was 42.8±10.9.45.5% (n=10) of the patients had cognitive impairment and 50% (n=11) had depression. The group with cognitive impairment had significantly older age, lower educational status, higher EDSS and BDI scores (p<0.05). The mostly affected cognitive domains were memory impairment, attention and processing dysfunction. When the specificity and sensitivity of ACE-R test on NMO patients were evaluated, diagnostic level of the test was found to be statistically good since it could detect cognitive impairment with a sensitivity of 88% and specificity of 75% on a cut off level of 82.5. CONCLUSION: In our study, cognitive impairment and depression were detected in approximately half of the patients with BRB-N and BDI tests. It can be concluded that ACE-R test can be used to detect cognitive impairment in NMO patients. Since cognitive impairment and depression are frequent in NMO patients, it is important to assess the patients' cognitive functions and arrange the treatments to improve their quality of life, .

Autoimmune Encephalitis After Treatment of Hodgkin's Lymphoma with the Immune Checkpoint Inhibitor Nivolumab.

In recent years, by the usage of new immune therapeutic agents for cancer treatment, the neurologic adverse events began to be seen more frequently. Nivolumab, one of the immune checkpoint inhibitor, is a human IgG4 antibody that blocks programmed cell death protein 1 and is approved against metastatic melanoma, squamous cell lung cancer, renal cell carcinoma, and Hodgkin's lymphoma after failure of prior line of chemotherapy. Here, we present a 40-year-old patient developing encephalopathy after treatment of Hodgkin's lymphoma with the immune checkpoint inhibitor nivolumab. In literature, cases of autoimmune encephalitis after receiving combination therapy of immune checkpoint inhibitors ipilimumab and nivolumab were described before. As far as we know, this is the unique case of encephalopathy reported after monotherapy with nivolumab treatment used for Hodgkin's lymphoma.

Neurogenic heterotopic ossification in Guillain-Barre syndrome: a rare case report.

Neurogenic heterotopic ossification (NHO) is an abnormal development of bone in extra-skeletal tissues, related to neurological disease. NHO is frequently seen after traumatic brain injury or spinal cord injury. NHO may also occur as a rare complication of Guillain Barre Syndrome (GBS). Here, we present a 39 year old man with an acute onset of GBS who developed NHO around both hips two months after the disease onset. Our patient had a history of mechanical ventilation, incomplete tetraplegia and prolonged immobilisation. The pathogenesis of NHO is unclear. Various risk factors have been associated with the development of NHO; prolonged coma, long-term sedation, spasticity, degree of paralysis. NHO is a rare complication of GBS and physicians should be aware that it can develop especially in patients with severe paralysis and in need of mechanical ventilation. Pain and restriction of movements, especially in the hips, should bring NHO to the mind.

Impact of fingolimod on CD4+ T cell subset and cytokine profile of relapsing remitting multiple sclerosis patients.

Fingolimod inhibits the egress of lymphocytes from lymphatic tissues and also directly affects their functions by modulation of the sphingosine-1-phosphate receptor 1 (S1P1). Our aim was to evaluate the impact of fingolimod on diverse CD4+ T cell subsets, and cytokines. Sixty-six relapsing remitting multiple sclerosis (RRMS) patients were treated with oral fingolimod (0.5 mg) for 6 months, and blood samples were collected at baseline, 3 months, and 6 months. Serum levels of seven cytokines and five chemokines were measured by multiplex immunoassay, and frequencies of peripheral blood mononuclear cell subsets were assessed by flow cytometry, and compared with those of 60 healthy controls. CCL2 (p = 0.039), and CCL5 (p = 0.001) levels were significantly higher in fingolimod-treated patients than healthy controls, whereas end-of-study serum levels of IL-6, IL-8, IL-17A, IL-22, IL-23, TNF-α, CXCL10, and CXCL13 were comparable to the baseline levels. Six months of fingolimod treatment reduced CD3+ T cell (mean ±â€¯standard deviation, 72.9% ±â€¯5.5 vs. 60.1% ±â€¯11.1, p < 0.001), CD4+ T cell (62.2% ±â€¯8.5 vs. 24.6% ±â€¯12.9, p < 0.001), CD4+CD25hi regulatory T cell (Treg) (3.4% ±â€¯1.3 vs. 2.0% ±â€¯1.4, p < 0.01), and CD19+ B cell (13.2% ±â€¯5.8 vs. 5.3% ±â€¯2.7, p < 0.001) frequencies, while CD8+ T cells (31.8% ±â€¯7.8 vs. 57.8% ±â€¯13.2, p < 0.001) were increased, and NK and NKT cells remained unchanged. The proportions of intracytoplasmic IL-4, IL-10, IFN-γ, and TNF-α-producing T cells were increased, whereas IL-17-producing cells remained relatively constant as measured by flow cytometry. Fingolimod appears to primarily diminish lymphocyte subsets involved in antigen presentation (CD19+ B and CD4+ T cells) rather than immune cells (CD8+ T, NK, and NKT cells) in charge of host defense against pathogens. In contrast, a relative increase is observed in pro- and anti-inflammatory cytokine-producing T helper subsets (IFN-γ, TNF-α, IL-4, and IL-10-producing CD4+ T cells), suggesting that effector T cells are suppressed to a lesser degree by S1P1 modulation.

Comparative analysis of fingolimod versus teriflunomide in relapsing-remitting multiple sclerosis.

BACKGROUND: Fingolimod and teriflunomide are commonly used in the treatment of relapsing-remitting multiple sclerosis (RRMS). These have not been compared in controlled trials, but only in observational studies, with inconclusive results. Comparison of their effect on relapse and disability in a real-world setting is therefore needed. OBJECTIVES: The objective of this study was to compare the efficacy of fingolimod and teriflunomide in reducing disease activity in RRMS. METHODS: This multicenter, retrospective observational study was carried out with prospectively collected data from 15 centers. All consecutive RRMS patients treated with teriflunomide or fingolimod were included. Data for relapses, Expanded Disability Status Scale (EDSS) scores and brain magnetic resonance imaging (MRI) scans were collected. Patients were matched using propensity scores. Annualized relapse rates (ARR), disability accumulation, percentage of patients with active MRI and treatment discontinuation over a median 2.5-year follow-up period were compared. RESULTS: Propensity score matching retained 349 out of 1388 patients in the fingolimod group and 349 out 678 in the teriflunomide group for final analyses. Mean ARR decreased markedly from baseline after 1 and 2 years of treatment in both the fingolimod (0.58-0.17 after 1 year and 0.11 after 2 years, p < 0.001) and teriflunomide (0.56-0.29 after 1 year and 0.31 after 2 years, p < 0.001) groups. Mean ARR was lower in fingolimod-treated patients than in those treated with teriflunomide at years 1 (p = 0.02) and 2 (p = 0.004). Compared to teriflunomide, the fingolimod group exhibited a higher percentage of relapse-free patients and a lower percentage of MRI-active patients after 2.5-year follow-up. Disability worsening was similar between the two groups. Patients were less likely to discontinue fingolimod than teriflunomide (p < 0.001). CONCLUSION: Fingolimod was associated with a better relapse control and lower discontinuation rate than teriflunomide. The two oral therapies exhibited similar effects on disability outcomes.

Intravenous Immunoglobulin Treatment for Recurrent Optic Neuritis.

INTRODUCTION: Recurrent optic neuritis neuritis (rON) is an autoimmune inflammatory condition of unknown cause. Intravenous immunoglobulin (IVIg) treatment is used for many autoimmune disorders; however we do not have any information about its effect in rON, other than case reports. We aimed to evaluate our patients with rON who were treated with IVIg. METHODS: Data from all our patients with rON with or without anti aquaporin4 (AQP4) seropositivity, seen between April 2011 and October 2015, who received IVIg treatment were retrospectively evaluated. RESULTS: Nine patients (all female) with rON had received IVIg. These patients were aged between 34 and 65 years, and had started receiving monthly IVIg from 6 to 58 months after onset of disease. In three out of nine rON patients serum AQP4 antibody were positive. Under current treatments the patients had continued to have attacks, therefore monthly IVIg was given in addition to the existing immunosuppressant drug. The follow up duration was between 6 to 31 months. Three patients, each suffered one relapse under IVIg treatment. Mean number of relapses in the year prior to treatment was 1.4±0.72, whereas it was 0.3±0.5 during the year after IVIg therapy. During follow-up with IVIg administration only one patient had fever and no other adverse events were reported. CONCLUSION: Monthly IVIg is well-tolerated and safe and it seems to be effective in rON as an add on treatment. However, since our study is a retrospective case series, future randomized controlled trials with IVIg are needed.

Characteristics of optic neuropathy in Behçet disease.

OBJECTIVE: We present the clinical profile, features, and neuroimaging findings of 25 patients with Behçet disease (BD), and optic neuropathy (ON), which has been rarely reported in BD. METHODS: Data from 5 university hospitals were retrospectively reviewed, and patients with BD and ON were evaluated. There were 2 groups: (1) those already diagnosed with BD when ON developed (BD→ON group) and (2) those diagnosed with BD during the evaluation of ON (ON→BD group). RESULTS: There were 25 BD patients with ON (13 males). Among these, 13 had ON→BD, and 12 had BD→ON. Seventeen patients had unilateral ON, and 7 patients had recurrent ON. BD→ON patients were older. Disc edema was seen more in ON→BD than in BD→ON patients (10 vs 3). Fourteen patients also had uveitis, 7 with BD→ON and 7 with ON→BD. There was other neurologic involvement in 8 patients; in the BD→ON group, 4/4 had MS-like disease, in the ON→BD group, 3 had typical parenchymal BD, and 1 had MS-like disease. Twenty of 21 patients received immunosuppressive medications, corticosteroids, or both. Prognosis was favorable in most: vision improved in 20 patients, more often in those receiving combined therapies. CONCLUSION: BD may be diagnosed earlier if it is considered and investigated during the assessment of ON, particularly in high-risk regions. Prognosis of ON related to BD seems to be favorable. Immunosuppressants should be given along with corticosteroids. MS-like presentations should also be kept in mind in patients with BD and ON.

Repetitive transcranial magnetic stimulation in restless legs syndrome: preliminary results.

Our aim was to compare the effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) over supplementary motor area with that of sham stimulation in restless legs syndrome (RLS). In this prospective study, patients were randomly assigned to either real stimulation group (11 patients), or sham stimulation group (8 patients) in a double-blinded fashion. Five patients, who were initially in the sham stimulation group, received real stimulation 1 month after the sham stimulation. One session of intervention was performed once every 3 days and total of ten sessions were done in each group. The International RLS-Rating Scale (IRLS-RS) was assessed at baseline and after 5th and 10th sessions in both groups and also in five patients in whom both sham and real stimulation were performed. A statistically significant difference was seen in the IRLS scores between real (n = 11) and sham stimulation (n = 8) after 5th and 10th sessions. The real stimulation significantly improved the IRLS-RS scores although they were unaffected by the sham stimulation. In five patients, in whom both sham and real stimulation were performed, a statistically significant improvement was seen in the IRLS-RS scores with the real stimulation and a statistically significant difference was seen in the IRLS scores between real and sham stimulation after 10th session. In conclusion, this method is safe and non-invasive, and the results of this pilot study may support that rTMS has the potential to be used in the treatment of RLS, which should be verified in larger series.

The relationship of cognitive impairment with neurological and psychiatric variables in multiple sclerosis patients.

OBJECTIVE: Cognitive impairment (CI) in multiple sclerosis (MS) can develop any time. CI is associated with the degree of neuronal loss, but disease duration, fatigue, comorbid affective disorder, and drug dose may also affect cognition. Our aim was to assess which cognitive domain was disturbed primarily in mild MS patients and to see whether CI was related with clinical and psychiatric features. METHOD: Neurological and psychiatric evaluation of 31 MS patients and 31 age, sex, and education-matched healthy controls were made with Structured Clinical Interview for Axis I Disorders (SCID-I). Depression, anxiety, functionality, fatigue, and disability scoring were determined with Hamilton Depression-Anxiety scales, Global Assessment of Functionality, Fatigue Severity and Expanded Disability Status Scales. Cognitive functions were assessed using Mini Mental, Serial Digit Learning, Verbal and Nonverbal Cancellation, Stroop and Rey Auditory Verbal Learning tests. RESULTS: Retrieval from long-term memory and psychomotor speed were significantly worse in MS group. CI was correlated with disease duration, number of attacks, and physical disability but not with depression and anxiety severity. Disease duration predicted disturbances in recall and psychomotor speed, whereas fatigue and disability predicted depression. CONCLUSION: Psychomotor speed and memory were primarily impaired in MS patients, and CI was closely associated with clinical aspects of MS rather than with depression and anxiety.

Transcutaneous electrical posterior tibial nerve stimulation for chronic anal fissure: a preliminary study.

PURPOSE: Recent studies showed that sacral nerve stimulation might be an effective treatment option for chronic anal fissure. We aimed to evaluate the efficacy of transcutaneous electrical nerve stimulation as a noninvasive alternative treatment for chronic anal fissure by stimulating the sacral nerve in the ankle via the posterior tibial nerve. METHOD: In this prospective study, transcutaneous electrical nerve stimulation was applied for 10 days in addition to conventional medical treatment in ten patients. Wexner's constipation score, visual analog scale for pain, quality of life (Short Form-36), Hamilton anxiety and depression scores, symptom relief, compliance, fissure healing, and side effects were evaluated before and after treatment (days 0, 5, and 10). RESULTS: Ten patients (eight females/two males) with a mean age of 50.7 ± 18.5 years were enrolled in the study. Pain and bleeding resolved in all patients 2 days after the treatment, and mucosal healing was observed in six patients 10 days after the treatment. Wexner's constipation and visual analog scale scores for pain decreased significantly (p = 0.001 and p = 0.002, respectively). Hamilton anxiety and depression scores decreased as well (p = 0.001 and p = 0.01, respectively). Among Short Form-36 subscales, only mental health score increased significantly (p = 0.003). One patient underwent surgery at follow-up due to recurrence of symptoms, and rubber band ligation was applied to another patient who had internal hemorrhoidal rectal bleeding at the end of 10 days. CONCLUSIONS: Transcutaneous electrical nerve stimulation application to the posterior tibial nerve has the potential to be an alternative treatment option for chronic anal fissure patients who seek noninvasive treatment modality.

Sympathetic skin responses from the scalp evoked by electrical stimulation in seborrheic dermatitis.

Although the role of autonomic nervous system in seborrheic dermatitis (SD) is still unclear, seborrhea is sometimes accepted as a sign of autonomic dysfunction in several nervous system diseases. Therefore, we aimed to investigate the sympathetic nervous system (SNS) activity in SD by recording sympathetic skin responses (SSR) from the scalp (S-SSR). Thirty-one control subjects and 22 SD patients were studied by evoking right and left S-SSR with electrical stimulation of the right median nerve at the wrist. Mean latencies and maximum amplitudes were calculated for both sides in each group. In seven out of 31 control subjects and in 13 out of 22 patients, the S-SSR could not be elicited on either side. There were four subjects with unilateral response in the patient group. There were significantly more non-responders among the patients with SD (P < 0.000). This study suggests that in SD, the autonomic nervous system may be involved. The S-SSR is a new site for recording SSR. The responses are relatively symmetrical and can be evoked easily by electrical stimulation, and may be used to evaluate the SNS function in SD patients and also in healthy subjects.

Salivary alpha amylase activity in migraine patients.

OBJECTIVE: Salivary alpha amylase levels were measured to investigate sympathetic nervous system activity in migraine patients during attack, post-attack and interval periods of headache since salivary alpha amylase levels have been suggested as a potential indirect marker of sympatho-adrenal medullary activity in recent studies. METHODS: 50 patients with migraine headache (13 patients in attack, 26 patients in post-attack and 11 patients in interval period) and 60 healthy volunteers were taken into the study. In all participants, the presence of anxiety was measured by using Hamilton Anxiety Rating scale. The visual analog scale scores for pain level estimation were obtained in the attack group. RESULTS: The salivary alpha amylase levels were significantly lower in attack period (p<0.01) and higher in post-attack period (p<0.01) when compared with the control group. There was not any significant difference in salivary alpha amylase levels between interval period and control group (p>0.05). There was a weak negative correlation between the salivary alpha amylase levels and the visual analog scale scores. CONCLUSIONS: This is the first study showing the dynamic nature of sympathetic nervous system activity by evaluating the salivary alpha amylase levels-a noninvasive, reliable and an easy method-in different periods of migraine headache.