Melih Tutuncu

Radiologically Isolated Syndrome: 5-Year Risk for an Initial Clinical Event

Objective To report the 5-year risk and to identify risk factors for the development of a seminal acute or progressive clinical event in a multi-national cohort of asymptomatic subjects meeting 2009 RIS Criteria. Methods Retrospectively identified RIS subjects from 22 databases within 5 countries were evaluated. Time to the first clinical event related to demyelination (acute or 12-month progression of neurological deficits) was compared across different groups by univariate and multivariate analyses utilizing a Cox regression model. Results Data were available in 451 RIS subjects (F: 354 (78.5%)). The mean age at from the time of the first brain MRI revealing anomalies suggestive of MS was 37.2 years (y) (median: 37.1 y, range: 11–74 y) with mean clinical follow-up time of 4.4 y (median: 2.8 y, range: 0.01–21.1 y). Clinical events were identified in 34% (standard error = 3%) of individuals within a 5-year period from the first brain MRI study. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age [hazard ratio (HR): 0.98 (95% CI: 0.96–0.99); p = 0.03], sex (male) [HR: 1.93 (1.24–2.99); p = 0.004], and lesions within the cervical or thoracic spinal cord [HR: 3.08 (2.06–4.62); p = <0.001] were identified as significant predictors for the development of a first clinical event. Interpretation These data provide supportive evidence that a meaningful number of RIS subjects evolve to a first clinical symptom. An age <37 y, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset.

Relapses and disability accumulation in progressive multiple sclerosis

Objective: We examined the effect of relapses—before and after progression onset—on the rate of postprogression disability accrual in a progressive multiple sclerosis (MS) cohort. Methods: We studied patients with primary progressive MS (n = 322) and bout-onset progressive MS (BOPMS) including single-attack progressive MS (n = 112) and secondary progressive MS (n = 421). The effect of relapses on time to Expanded Disability Status Scale (EDSS) score of 6 was studied using multivariate Cox regression analysis (sex, age at progression, and immunomodulation modeled as covariates). Kaplan-Meier analysis was performed using EDSS 6 as endpoint. Results: Preprogression relapses (hazard ratio [HR]: 1.63; 95% confidence interval [CI]: 1.34–1.98), postprogression relapses (HR: 1.37; 95% CI: 1.11–1.70), female sex (HR: 1.19; 95% CI: 1.00–1.43), and progression onset after age 50 years (HR: 1.47; 95% CI: 1.21–1.78) were associated with shorter time to EDSS 6. Postprogression relapses occurred in 29.5% of secondary progressive MS, 10.7% of single-attack progressive MS, and 3.1% of primary progressive MS. Most occurred within 5 years (91.6%) after progressive disease onset and/or before age 55 (95.2%). Immunomodulation after onset of progressive disease course (HR: 0.64; 95% CI: 0.52–0.78) seemingly lengthened time to EDSS 6 (for BOPMS with ongoing relapses) when analyzed as a dichotomous variable, but not as a time-dependent variable. Conclusions: Pre- and postprogression relapses accelerate time to severe disability in progressive MS. Continuing immunomodulation for 5 years after the onset of progressive disease or until 55 years of age may be reasonable to consider in patients with BOPMS who have ongoing relapses.

Protein biomarkers for multiple sclerosis: semi-quantitative analysis of cerebrospinal fluid candidate protein biomarkers in different forms of multiple sclerosis

Background: The complex pathogenesis of multiple sclerosis, combined with an unpredictable prognosis, requires identification of disease-specific diagnostic and prognostic biomarkers. Objective: To determine whether inflammatory proteins, such as neurofilament light chain, myelin oligodendrocyte glycoprotein and myelin basic protein, and neurodegenerative proteins, such as tau and glial fibrillary acidic protein, can serve as biomarkers for predicting the clinical subtype and prognosis of MS. Methods: Cerebrospinal fluid and serum samples were collected from patients with a diagnosis of clinically isolated syndrome (n = 46), relapsing–remitting MS (n = 67) or primary-progressive MS (n = 22) along with controls having other non-inflammatory neurological disease (n = 22). Western blot analyses were performed for the listed proteins. Protein levels were compared among different clinical subtypes using one-way analysis of variance analysis. The k-nearest neighbour algorithm was further used to assess the predictive use of these proteins for clinical subtype classification. Results: The results showed that each of tau, GFAP, MOG and NFL protein concentrations differed significantly (p < 0.001) in multiple sclerosis clinical subtypes compared with the controls. Levels of the proteins also differed between the multiple sclerosis clinical subtypes, which may be associated with the underlying disease process. Classification studies revealed that these proteins might be useful for identifying multiple sclerosis clinical subtypes. Conclusions: We showed that select biomarkers may have potential in identifying multiple sclerosis clinical subtypes. We also showed that the predictive value of the prognosis increased when using a combination of the proteins versus using them individually.

Poor early relapse recovery affects onset of progressive disease course in multiple sclerosis

Objective: To evaluate the relationship between early relapse recovery and onset of progressive multiple sclerosis (MS). Methods: We studied a population-based cohort (105 patients with relapsing-remitting MS, 86 with bout-onset progressive MS) and a clinic-based cohort (415 patients with bout-onset progressive MS), excluding patients with primary progressive MS. Bout-onset progressive MS includes patients with single-attack progressive and secondary progressive MS. “Good recovery” (as opposed to “poor recovery”) was assigned if the peak deficit of the relapse improved completely or almost completely (patient-reported and examination-confirmed outcome measured ≥6 months post relapse). Impact of initial relapse recovery and first 5-year average relapse recovery on cumulative incidence of progressive MS was studied accounting for patients yet to develop progressive MS in the population-based cohort (Kaplan-Meier analyses). Impact of initial relapse recovery on time to progressive MS onset was also studied in the clinic-based cohort with already-established progressive MS (t test). Results: In the population-based cohort, 153 patients (80.1%) had on average good recovery from first 5-year relapses, whereas 30 patients (15.7%) had on average poor recovery. Half of the good recoverers developed progressive MS by 30.2 years after MS onset, whereas half of the poor recoverers developed progressive MS by 8.3 years after MS onset (p = 0.001). In the clinic-based cohort, good recovery from the first relapse alone was also associated with a delay in progressive disease onset (p < 0.001). A brainstem, cerebellar, or spinal cord syndrome (p = 0.001) or a fulminant relapse (p < 0.0001) was associated with a poor recovery from the initial relapse. Conclusions: Patients with MS with poor recovery from early relapses will develop progressive disease course earlier than those with good recovery.

CSF Proteomics Identifies Specific and Shared Pathways for Multiple Sclerosis Clinical Subtypes

Multiple sclerosis (MS) is an immune-mediated, neuro-inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS) with a heterogeneous clinical presentation and course. There is a remarkable phenotypic heterogeneity in MS, and the molecular mechanisms underlying it remain unknown. We aimed to investigate further the etiopathogenesis related molecular pathways in subclinical types of MS using proteomic and bioinformatics approaches in cerebrospinal fluids of patients with clinically isolated syndrome, relapsing remitting MS and progressive MS (n=179). Comparison of disease groups with controls revealed a total of 151 proteins that are differentially expressed in clinically different MS subtypes. KEGG analysis using PANOGA tool revealed the disease related pathways including aldosterone-regulated sodium reabsorption (p=8.02x10-5) which is important in the immune cell migration, renin-angiotensin (p=6.88x10-5) system that induces Th17 dependent immunity, notch signaling (p=1.83x10-10) pathway indicating the activated remyelination and vitamin digestion and absorption pathways (p=1.73x10-5). An emerging theme from our studies is that whilst all MS clinical forms share common biological pathways, there are also clinical subtypes specific and pathophysiology related pathways which may have further therapeutic implications.

Factors Predictive of Severe Multiple Sclerosis Disease Reactivation After Fingolimod Cessation

Background: Fingolimod withdrawal may trigger the return of pretreatment disease activity. It is difficult to identify patients at risk of disease reactivation. We compared the demographic and clinical features of patients experiencing severe disease reactivation (SDR) after fingolimod cessation with those of patients who did not. Methods: All patients who commenced fingolimod and who continued therapy for at least 6 months were included. The demographic and clinical features of the 2 groups (SDR vs. no SDR) were assessed. Results: Forty-four of 303 patients discontinued fingolimod for various reasons. Among these, 31 fulfilled our inclusion criteria and 8 (25.8%) exhibited SDR after drug cessation. The mean time for SDR was 2.6 months (range, 2 to 3 mo). The annualized relapse rate before fingolimod therapy was higher in the SDR than in the non-SDR group (1.59 vs. 0.81) (P=0.018). Although statistical significance was not attained, the mean Expanded Disability Status Scale score at the time of fingolimod cessation was higher in the non-SDR than in the SDR group (2.5 vs. 1.12) (P=0.074). Conclusions: SDR may develop within the first 3 months after cessation of fingolimod. Patients with higher annualized relapse rates and lower Expanded Disability Status Scale scores before commencing fingolimod treatment were more likely to exhibit SDR.

Electrophysiological Investigations in Orthostatic Myoclonus: Preliminary Findings

We report the clinical and electrophysiological findings in seven patients with orthostatic myoclonus (OM) associated with gait initiation failure and falls. OM is one of the causes of unsteadiness of stance and gait, and it may develop as a symptom of neurodegenerative disorders. Both positive myoclonic bursts and negative myoclonus may be seen in electrophysiological recordings, and electrophysiological analysis suggests a subcortical origin for OM.

Auditory evoked blink reflex in peripheral facial paresis.

Purpose: The auditory blink reflex (ABR) is a teleceptive reflex consisting of an early brief muscle contraction of the orbicularis oculi in response to sound stimuli. Constriction of the orbicularis oculi in response to auditory stimulation is accepted as a part of the startle reaction. The blink reflex and ABR might share a final common pathway, consisting of facial nerve nuclei and the facial nerve and may have common premotor neurons. Methods: In this study, the authors evaluated the value of the ABR in patients with peripheral facial palsy (PFP), cross-checking the results with commonly used blink reflex changes. Results: In total, 83 subjects with PFP and 34 age-matched healthy volunteers were included. Auditory blink reflex was elicited in all control subjects and in 36 PFP cases on the paralytic sides (43.3%), whereas it was asymmetric in 30.1% of the patients. Auditory blink reflex positivity was significantly lower in PFP cases with increasing severity. Blink reflex results were largely correlated with ABR positivity. Conclusions: Auditory blink reflex is a useful readily elicited and sensitive test in PFP cases, providing parallel results to blink reflex and being affected by disease severity.

F27. Myoclonus in demyelinating polyneuropathies: Preliminary results

Introduction The reports on tremor and different types of polyneuropathies have been increasing and it was suggested to be associated with cerebellar involvement in chronic inflammatory demyelinating polyneuropathy (CIDP). Apart from specific syndromes, the co-existence of polyneuropathy and myoclonus is exceptional. We previously observed cortical myoclonus in cases with inflammatory polyneuropathy who were referred for tremor analysis and aimed to analyze presence of myoclonus and its relation with clinical features in demyelinating polyneuropathies. Methods We prospectively included all patients with inflammatory polyneuropathy who were admitted between January 2017 and June 2017 and had tremor-like, regular or irregular involuntary movements on clinical examination. All patients underwent neurological examination and multichannel surface electromyography which included upper extremity muscles as well as lower extremity and facial or neck muscles in selected cases. We also recorded long latency reflexes and somatosensory evoked potentials (SEPs) to categorize myoclonus. Results We identified eight patients with demyelinating polyneuropathy who matched the inclusion criteria: four patients with CIDP, three patients with Guillain–Barre syndrome and one patient with Charcot-Marie-Tooth disease. The mean age was 50.5 ± 19.6 years (range: 26–81 years) and there were seven male patients. Seven out of eight patients had myoclonus, two of which were in the form of polyminimyoclonus. Others had myoclonus on both proximal and distal parts of upper extremities. Negative myoclonus was observed in four of them. Duration of myoclonus was between 30 and 100 ms. only one had duration of 200 ms. Most patients (five out of seven) had cortical myoclonus (with high-amplitude C reflex or SEPs). Conclusion Myoclonus in the patients with polyneuropathy was irregular tremor-like, however, the electrophysiological characteristics was similar to a cortical subtype. Therefore, it would be interesting to investigate a bigger cohort of inflammatory polyneuropathies for the presence and subtypes of myoclonus and to determine associated clinical features.

A comparative analysis of speech signal processing algorithms for Parkinson’s disease classification and the use of the tunable Q-factor wavelet transform

Abstract In recent years, there has been increasing interest in the development of telediagnosis and telemonitoring systems for Parkinson’s disease (PD) based on measuring the motor system disorders caused by the disease. As approximately 90% percent of PD patients exhibit some form of vocal disorders in the earlier stages of the disease, the recent PD telediagnosis studies focus on the detection of the vocal impairments from sustained vowel phonations or running speech of the subjects. In these studies, various speech signal processing algorithms have been used to extract clinically useful information for PD assessment, and the calculated features were fed to learning algorithms to construct reliable decision support systems. In this study, we apply, to the best of our knowledge for the first time, the tunable Q-factor wavelet transform (TQWT) to the voice signals of PD patients for feature extraction, which has higher frequency resolution than the classical discrete wavelet transform. We compare the effectiveness of TQWT with the state-of-the-art feature extraction methods used in diagnosis of PD from vocal disorders. For this purpose, we have collected the voice recordings of 252 subjects in the context of this study and extracted multiple feature subsets from the voice recordings. The feature subsets are fed to multiple classifiers and the predictions of the classifiers are combined with ensemble learning approaches. The results show that TQWT performs better or comparable to the state-of-the-art speech signal processing techniques used in PD classification. We also find that Mel-frequency cepstral and the tunable-Q wavelet coefficients, which give the highest accuracies, contain complementary information in PD classification problem resulting in an improved system when combined using a filter feature selection technique.