Retinal changes in multiple sclerosis: An optical coherence tomography and angiography study.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system with neuroaxonal damage. It is the principal driver of non-traumatic disability in young adults. Visual symptoms are common and optic neuritis (ON) may be the revealing feature in up to 30% of cases. Structural optical coherence tomography (OCT) represents a biomarker of central nervous system neurodegeneration in MS. OCT-angiography (OCT-A) is a noninvasive tool allowing the study of retinal vasculature and the detection of microvascular damage in neuro-retinal diseases. In this study, we aimed to assess structural and microvascular retinal changes in patients with MS with and without ON and to correlate the findings with visual function and MS disability. METHODS: We conducted a cross-sectional study including patients diagnosed with MS according to the 2017 McDonald criteria. All patients underwent complete neurological examination with evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS) and an ophthalmological examination including OCT and OCT-A. Patients were compared with age- and sex-matched healthy subjects. The primary endpoints were assessment of retinal nerve fiber layer (RNFL) thickness, ganglion cell layer (GCL+), and ganglion cell complex (GCL++) thicknesses on OCT. Vascular densities in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC) were assessed on OCT-A, as well as central avascular zone (CAZ) parameters, lacunarity and fractal dimension. RESULTS: A total of 160 MS eyes with and without a previous history of ON and 64 age- and gender-matched healthy eyes were analyzed. Among 160 eyes with MS, 69 had a history of ON. We observed a decrease in RNFL and GCL++ thickness in all 12 quadrants in MS patients when compared to healthy controls. Multivariate analysis by linear regression noted a significant correlation for temporal GCL++ and inferonasal RNFL thickness that were decreased in the MS group. A greater decrease in retinal layers thickness was identified in MS patients with a history of ON. On OCT-A, vascular density in (SCP) was significantly reduced in the MS group (P<0.002). A significant correlation between RNFL thickness and retinal vascular density was found but only in less than half of the hourly quadrants. A significant correlation was noted between visual acuity and CC density (P<0.0001). We also noted an inverse correlation between EDSS scores and CC density (P=0.02 and r=-0.275) and between MSSS and RNFL/GCL++ thicknesses. CONCLUSIONS: RNFL and GCL++ layers were thinner in MS patients with a history of ON and were reversely correlated with disease severity. Moreover, retinal vascular changes were observed in MS even in eyes without ON, and CC was reversely correlated with visual function and current disability. Thus, structural OCT coupled with OCT-A could represent a noninvasive and dynamic biomarker of MS severity and progression.

Consensus recommendations for diagnosis and treatment of Multiple Sclerosis: 2023 revision of the MENACTRIMS guidelines.

With evolving diagnostic criteria and the advent of new oral and parenteral therapies for Multiple Sclerosis (MS), most current diagnostic and treatment algorithms need revision and updating. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and time and exclude alternative diseases that can explain the findings at hand. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. Appropriate selection of MS therapies is critical to maximize patient benefit. The current guidelines review the current diagnostic criteria for MS and the scientific evidence supporting treatment of acute relapses, radiologically isolated syndrome, clinically isolated syndrome, relapsing remitting MS, progressive MS, pediatric cases and pregnant women. The purpose of these guidelines is to provide practical recommendations and algorithms for the diagnosis and treatment of MS based on current scientific evidence and clinical experience.

Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

There are several medications used to treat people with relapsing remitting multiple sclerosis, such as interferon-based therapies (Betaferon/Betaseron (US), Rebif, Avonex, Extavia), glatiramer acetate (Copaxone), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera), collectively named BRACETD. Other treatments for multiple sclerosis (MS) have a narrower use, such as natalizumab (Tysabri) or fingolimod (Gilenya), among others.This study objective was to assess how well natalizumab and fingolimod helped treating MS (clinical effectiveness) and subsequently estimate what the cost of these treatments is in comparison to the benefit they bring to people with rapidly evolving severe MS that use them in the United Kingdom (UK) (cost-effectiveness).We used an international disease registry (MSBase), which collects clinical data from people with MS in various centers around the world to compare the effectiveness of natalizumab, fingolimod and BRACETD treatments. We used a technique called propensity score matching to obtain results from comparable patient groups. People treated with natalizumab had better disease control, namely with fewer relapses and higher improvement on their disability level, than patients on fingolimod or BRACETD. Conversely, there were no differences between each group of people on a measure called disability worsening.Based on these clinical results, we built an economic model that simulates the lifetime costs and consequences of treating people with MS with natalizumab in comparison with fingolimod. We found that using natalizumab was less costly and was more effective compared to using fingolimod in UK patients.

Optineurin in patients with Amyotrophic Lateral Sclerosis associated to atypical Parkinsonism in Tunisian population.

Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous disorder and the phenotypic variability goes far beyond the used clinical stratification parameter. Evidence has emerged that ALS may coexist with distinct neurodegenerative diseases in single cases. We aim to study the clinical features of two familial cases of ALS carriers of two distinct variants harbored in the Optineurin (OPTN) gene. We included definite familial ALS followed up in the Department of Neurology of Razi University Hospital, Tunisia, and selected according to Byrne criteria. Preliminary screening for the four main ALS genes (SOD1, C9ORF72, TARDBP, FUS) was conducted. Given the negative results, we proceeded to NGS target-re-sequencing with a custom panel including genes associated with ALS-FTD, Alzheimer's, and Parkinson's diseases. Both families are carriers of two different OPTN variants and they present very different ALS clinical features. The first family comprises two siblings diagnosed with ALS and Corticobasal syndrome (ALS-CBS) at an early age of onset and carriers of OPTN p.E135X in the homozygous state. The proband for the second family was diagnosed with ALS at an early age of onset presenting as progressive muscular atrophy with rapid progression. Genetic analysis revealed the presence of the homozygous variant p.R520H. Our findings highlight the peculiarity of genetic Tunisian drift. Indeed, genes with a recessive mode of inheritance may explain part of ALS diversity in clinical features. Therefore, the screening of the OPTN gene is highly recommended among inbreeding populations such as the Tunisian one.

Arabic adaptation of the Edinburgh cognitive and behavioural Amyotrophic lateral sclerosis screen (ECAS-AR).

Current screening batteries for assessing neuropsychological function are not specific for Amyotrophic Lateral Sclerosis (ALS) and are considered as limited tools due to the physical disabilities associated with ALS. The Edinburgh Cognitive and Behavioural ALS screen (ECAS) was developed to detect the specific cognitive and behavioral changes that may occur among ALS patients. This study presents the ECAS developed for Arabic-speaking ALS patients (ECAS-AR) for use by healthcare professionals. ECAS was translated and modified to refined variety of Arabic language. Eighty-five ALS patients were included. Normative data were collected from 200 healthy controls (among them 97 were matched). Subjects were administered the ECAS-AR and two conventional cognitive screening batteries, Frontal Assessment Battery (FAB) and Mini-Mental State Examination (MMSE). ECAS-AR discriminated well between healthy controls and ALS patients. Significant differences were noted in language, executive functions, memory, and visuospatial domains between the two groups. The most prevalent deficit occurred in language and executive functions in ALS-specific functions. Whereas memory was more readily impaired in the lower and middle education groups concerning ALS non-specific functions. Verbal fluency tended to be preserved. Positive correlations were found between ECAS-AR and the standard cognitive tests supporting its full validity. The ECAS-AR version proposed will provide rapid, efficient and sensitive tools for healthcare professional to determine the cognitive-behavioural profile in Arabic-speaking ALS patients.

Tunisian version of the brief international cognitive assessment for multiple sclerosis: Validation and normative values.

BACKGROUND: The Brief International cognitive assessment for Multiple sclerosis (BICAMS) is a specific batterie used to identify cognitive impairment in Multiple Sclerosis (MS) in a reliable and easy way. To date, for the Arabic-speaking Tunisian MS patients, there is no consensus for the use of specific cognitive batteries in MS. OBJECTIVE: The aim of our work was to develop and validate the Tunisian version of the BICAMS (T-BICAMS) and to determine our own normative values. MATERIAL AND METHODS: Patients diagnosed with MS and followed up in the department of Neurology of Razi Hospital were recruited and matched to healthy controls according to age, sex and educational level. T-BICAMS validity was established by comparing MS and healthy controls for symbol digit modalities test (SDMT), brief visual memory test (BVMT-R) and Tunisian verbal learning tests (TVLT) which was used instead of the California verbal learning test (CVLT-II). RESULTS: The 104 MS patients and 104 healthy controls were comparable for age, sex and educational level. The MS group exhibited lower performances in all T-BICAMS domains compared to healthy controls: SDMT (x003Dp<10-3), BVMT-R (p = 0.002) and TVLT (p x003D<10-3). T-BICAMS Cronbach alpha value was 0.741. Normative values were identified for patients with MS: SDMT [39-40], BVMT-R [26-27] and TVLT [43-44]. Cognitive impairment was identified among 76 patients (73.1%). Males, lower educational levels and progressive MS were associated with a more severe cognitive impairment. CONCLUSIONS: The current study has established the BICAMS as a valid and reliable tool for the identification of cognitive impairment in the Tunisian MS population.

Clinical predictors of disease progression in a cohort of Tunisian progressive Multiple Sclerosis.

BACKGROUND: Knowledge about progressive Multiple Sclerosis (MS) is mainly based on Caucasian studies. In our North-African context, MS exhibits particular characteristics that are mainly related to a more severe phenotype. Given the limited data available, there is an imminent need to characterize progressive MS in our latitudes. OBJECTIVE: To describe the specificities of progressive MS and identify the inherent clinical predictors of disability accrual with a Tunisian cohort. METHODS: A retrospective, hospital-based study was conducted in the department of neurology of Razi hospital. Patients, who had been diagnosed with MS, were divided into relapsing MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). Epidemiological, clinical and paraclinical data were compared among the three groups. RESULTS: Of the 504 patients, a progressive MS was described among 115 patients. This percentage of (22.8%) is divided into 13.9% SPMS and 8.9% PPMS. During the first clinical attack, motor symptoms have revealed to be predominant during PPMS (91.1%). For SPMS onset, the median time was 10 years, and was significantly delayed for patients with visual onset or full recovery from the first relapse. Patients with progressive MS exhibited a more rapid disability accumulation. CONCLUSION: Compared to Caucasians, Tunisians exhibited a faster rate of conversion to SPMS. According to our natural progressive MS history, early clinical features are predictors of MS disability accrual.

Multiple sclerosis 2017 McDonald criteria are also relevant for Tunisians.

BACKGROUND: Validation of the 2017 revised McDonald criteria was based on data from Caucasians. Among North Africans, Multiple Sclerosis prevalence, clinical phenotype and differential diagnosis are different. Hence, verifying the relevance of the latest revised criteria applied in North Africans was recommended. The aim of our study was to investigate the applicability and reliability of the revised 2017 McDonald criteria, compared to the 2010 version, with the relevance to the diagnosis of Multiple sclerosis in a Tunisian cohort. METHODS: Data from patients, with a typical clinically isolated syndrome, were re-analyzed retrospectively. Also, clinical, immunological and imaging characteristics were reviewed, according to the 2010, then 2017, McDonald criteria. Sensitivity, specificity, accuracy, positive predictive value and negative predictive value were evaluated to analyze the impact of the new criteria in everyday clinical practice. RESULTS: A total of 98 patients were included. Eighty-eight patients developed a definite Multiple Sclerosis, while ten had a different diagnosis. With relevance to the 2010 criteria, 41 patients (42%) were diagnosed with Multiple Sclerosis, after the first clinical attack. The 2017 revised criteria allowed to diagnose 32 more cases (73 patients = 74%). Sensitivity of the 2017 criteria was higher (77% versus 44%), but specificity was lower (33% versus 63%). CONCLUSIONS: Compared to the 2010 version, the 2017 McDonald criteria highlighted higher sensitivity, but lower specificity for Tunisians.

[Eye movement recordings in children with attention deficit hyperactivity disorder]. / Étude des mouvements oculaires dans les troubles hyperactifs avec déficit de l'attention chez l'enfant.

INTRODUCTION: Attention-Deficit and Hyperactivity Disorder (ADHD) affects 3 to 5% of school-aged children. Diagnosis is based on criteria defined by the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV), and there is no specific marker for the disease. Eye movements may be altered in ADHD. The goal of this study was to identify difficulties in oculomotor tasks in children with ADHD. PATIENTS AND METHODS: Subjects were children with untreated ADHD (n=7) and age- and gender-matched healthy controls (n=7). Two different tasks (prosaccades and pursuit) were used to examine functions necessary for the planning and execution of eye movements. Student's t-test was used for the statistical analysis. RESULTS: Prosaccades were able to be recorded in five children with ADHD and in all control subjects. In two patients, no saccades could be recorded due to their hyperactivity. There were significant differences (P<0.01) in prosaccade latency, children with ADHD showing significantly longer latency on the prosaccade task than controls (299±91 ms versus 197±14 ms). Pursuit performance was saccadic with a gain of 0.4 versus 0.6 and was not significantly altered in the ADHD group with respect to controls. CONCLUSION: Oculomotor measurements can be a simple, non-invasive test, easily performed in children with ADHD. Longer latency on the prosaccade task is observed in ADHD children.

Autosomal-recessive forms of demyelinating Charcot-Marie-Tooth disease.

Autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) account for less than 10% of the families in the European CMT population but are more frequent in the Mediterranean basin and the Middle East because of more widespread consanguinity. Until now, demyelinating ARCMT was more extensively studied at the genetic level than the axonal form. Since 1999, the number of localized or identified genes responsible for demyelinating ARCMT has greatly increased. Eight genes, EGR2, GDAP1, KIAA1985, MTMR2, MTMR13, NDRG1, PRX, and CTDP1, have been identified and two new loci mapped to chromosomes 10q23 and 12p11-q13. In this review, we will focus on the particular clinical and/or neuropathological features of the phenotype caused by mutations in each of these genes, which might guide molecular diagnosis.

A recommended treatment algorithm in relapsing multiple sclerosis: report of an international consensus meeting.

An International Working Group for Treatment Optimization in MS met to recommend evidence-based therapeutic options for the management of suboptimal responses or intolerable side-effects in patients treated with disease-modifying drugs (DMDs) for multiple sclerosis (MS). Several DMDs are now available for the treatment of MS that have been shown to alter the clinical course of the disease by decreasing disease activity and delaying the progression of disability. Nevertheless, many patients continue to experience disease activity whilst on treatment, and recommendations have been made on how the success of therapy in an individual patient can be assessed. However, even after having identified criteria for a suboptimal response to current treatments, clinicians require guidance on how to improve the outcomes. This report summarizes the conclusions from a workshop at which this issue was addressed. We suggest treatment pathways for optimizing therapy for those patients with suboptimal responses to DMDs, and therapeutic options for patients with unacceptable side-effects on their current therapy.

[Cerebral tuberculomas]. / Les tuberculomes cérébraux.

We report eight cases of brain tuberculoma. The clinical presentation was polymorphous: partial epilepsy (n=4), headache (n=3), hemiplegia (n=1), meningitis (n=1), cerebellar syndrome (n=1). Six patients also had pulmonary tuberculosis, one had tuberculosis of the genital organs, and one had HIV co-infection. The brain CT scan and MRI were highly contributive to diagnosis and follow-up. Despite good compliance with an anti-tuberculosis regimen for at least 14 months, the course was favorable in only six patients. Adjunction of corticosteroids led to radiological improvement. Assessment of cell immunity demonstrated a diminished immunomodulator ratio. Cerebral tuberculoma should be searched for in patients with unexplained neurological manifestations and several intracerebral lesions, particularly if pulmonary or visceral tuberculosis and/or immunodepression is part of the clinical picture.

Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma.

Charcot-Marie-Tooth disease (CMT) with autosomal recessive (AR) inheritance is a heterogeneous group of inherited motor and sensory neuropathies. In some families from Japan and Brazil, a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma. We identified two such large consanguineous families from Tunisia and Morocco with ages at onset ranging from 2 to 15 years. We mapped this syndrome to chromosome 11p15, in a 4.6-cM region overlapping the locus for an isolated demyelinating ARCMT (CMT4B2). In these two families, we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13. The MTMR protein family includes proteins with a phosphoinositide phosphatase activity, as well as proteins in which key catalytic residues are missing and that are thus called "pseudophosphatases." MTM1, the first identified member of this family, and MTMR2 are responsible for X-linked myotubular myopathy and Charcot-Marie-Tooth disease type 4B1, an isolated peripheral neuropathy with myelin outfoldings, respectively. Both encode active phosphatases. It is striking to note that mutations in MTMR13 also cause peripheral neuropathy with myelin outfoldings, although it belongs to a pseudophosphatase subgroup, since its closest homologue is MTMR5/Sbf1. This is the first human disease caused by mutation in a pseudophosphatase, emphasizing the important function of these putatively inactive enzymes. MTMR13 may be important for the development of both the peripheral nerves and the trabeculum meshwork, which permits the outflow of the aqueous humor. Both of these tissues have the same embryonic origin.

Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease.

X-linked dominant Charcot-Marie-Tooth (CMTX) disease is a motor and sensory neuropathy caused by mutations in the connexin 32 (CX32) gene. In this study we report the clinical, electrophysiological and genetic features of 93 patients (41 males, 52 females) from 37 unrelated families with CMTX. Age at onset was 15.4 +/- 9.6 years in males (range 1-40 years) and 18.7 +/- 13.1 years in females (range 1-56 years) (P = 0.22) and the duration of disease at the time of examination was 18.3 +/- 14.6 years in males and 23.9 +/- 13.7 years in females (P = 0.11). Males were more severely affected than females, with significantly more frequent muscle weakness, amyotrophy, proprioception loss, upper limb areflexia and pes cavus. Females were more frequently asymptomatic, whereas high functional disability scores were more frequently encountered in males. The electrophysiological studies showed that motor nerve conduction velocities in CMTX females, but not males, were heterogeneous between nerves compared with Charcot-Marie-Tooth type 1A (CMT1A) patients and controls. The terminal latency index (TLI) for the median nerve was 0.37 +/- 0.08; it was similar in men and in women and a little higher than those observed in CMT1A and controls. The range of values for median TLI was wider in both male and female CMTX patients than in controls, but was similar to that of CMT1A patients, suggesting that motor conduction was relatively homogeneous within a given nerve. Twenty-seven different CX32 mutations, including missense (n = 23), nonsense (n = 2) and frameshift mutations (n = 1) and one entire deletion of the CX32 coding sequence, were observed in the 37 families. Four of these mutations are described for the first time. The phenotype of the patients, especially age at onset, is discussed in relation to the functional consequences of CX32 mutations, analysed in vitro in Xenopus oocytes and mammalian cells. CMTX patients with age at onset in the first decade mostly presented non-functional mutations, suggesting that the physiological consequences of the mutations affect age at onset in CMTX.

The frequency of 17p11.2 duplication and Connexin 32 mutations in 282 Charcot-Marie-Tooth families in relation to the mode of inheritance and motor nerve conduction velocity.

The 17p11.2 duplication and Connexin 32 (Cx32) mutations are the most frequent gene mutations responsible for Charcot-Marie-Tooth diseases. We classified 282 Charcot-Marie-Tooth families according to the median motor nerve conduction velocity of the index patient and the mode of inheritance, and screened them for 17p11.2 duplication and Cx32 mutations. Forty-seven percent of the Charcot-Marie-Tooth families had median motor nerve conduction velocity under 30 m/s (group 1), 15% between 30 and 40 m/s (group 2), and 28% over 40 m/s (group 3). Spinal Charcot-Marie-Tooth (group 4) was observed in 7% of the families. Modes of inheritance were not similarly represented among the different groups. The 17p11.2 duplication was detected in index patients of group 1 only, and accounted for 83% of the familial cases and 36% of the isolated cases. In contrast, 21 Cx32 mutations were detected to variable degrees in groups 1-3, but were most numerous by far in dominant families of group 2 (44%). This systematic approach was taken to estimate the frequency of 17p11.2 duplication and Cx32 mutations in the different Charcot-Marie-Tooth subgroups, in order to propose a practical strategy for molecular analysis.