الفهرس 
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Abstract
Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) that is characterized pathologically by inflammation, demyelination, and, ultimately, axonal loss (Frohman et al., 2006; Compston and Coles, 2008).
Axonal transection is a consistent pathological feature of acute MS lesions and the incidence of neuronal damage correlates with the extent of inflammation within the lesion. Importantly, such damage may be present in the early stages of MS (Trapp et al., 1999). It can, however, be masked by mechanisms such as recruitment of other neuronal pathways or cortical remodelling, that compensate for functional loss; hence, progressive damage may go unrecognized until it is too late for an intervention to be beneficial (Filippi and Rocca, 2007).
As the disease progresses, the balance between degenerative and reparative processes shifts, resulting in progressive neuroaxonal degeneration and increasing disability (Fig. 8) (Ziemssen et al., 2016).
Current evidence showing that there is only a limited period early in the course of MS which is critical for maintaining neurological function and preventing subsequent disability ‘windows of opportunity’. Both early intervention after diagnosis, and early treatment optimization in the event of insufficient response to initial treatment (Fig. 6), are critical to achieving a favorable outcome and reducing the progressive burden imposed by MS on the patients, their families and society as a whole (Ziemssen et al., 2015).
The point of a great importance nowadays is giving the clinical evidence that an important number of patients who are at risk of converting a first CIS to MS can benefit from immunomodulatory therapy, even before confirming the MS. This indicates the need to raise awareness of the symptoms of MS among the general population (Fernandez et al., 2010).
The earlier that MS can be diagnosed; the sooner treatment can be initiated. Ideally people with suspected MS should be referred for diagnosis to a neurologist with a special interest and experience in MS. It is currently possible to diagnose MS earlier than ever before 10 times more rapidly than in the 1980s by using evidence from magnetic resonance imaging (MRI) & clinical assessments (Zivadinov et al., 2006).
However, significant delays between the initial onset of symptoms and diagnosis of MS can last for more than 2 years (Fernandez et al., 2010).
The aim of this study was to highlight the causes of delayed diagnosis of multiple sclerosis for more than 2 years and the impact of referral delay on the disability at the initial encounter at MS specialist clinics and on initiation of DMD.
This study included a total number of 2000 MS patient attending MS unit at Ain Shams Hospital in Cairo have been screened, 500 patients of them selected to have delayed diagnosis of MS for more than 24 months . Data could be obtained from 320 patients out of 500.
In this study we find that number of factors adversely affected a timely diagnosis including the age at onset; the mean age at disease onset was nearly 26.80 ± 9.39 and it was of significant relationship to delayed diagnosis (P-value = 0.005).
Regarding denial of symptoms, i.e. a reluctance to seek medical attention with minor neurological symptoms, this was a leading cause for delayed time to first doctor consultation and delayed diagnosis of MS (P-value =0.009).
Regarding comorbidities and delayed diagnosis, 17 (3.4%) of patients has past history of DM, 15 (3.0%) has HTN, 9 (1.8%) has DM and HTN and 76 (15.2%) had other medical diseases like liver diseases, connective tissue diseases and depression. In finding the relation with delayed diagnosis P-value =0.788.
About types of MS and delayed diagnosis we found that 61.5% patients had PPMS were diagnosed after 24 months, while only 24.4% of RRMS had delayed diagnosis for more than 24 months.
Meanwhile, about symptoms at onset of the disease ;we find that sensory symptoms at onset was associated with longer diagnostic delay, median time to diagnosis was 60 while it was around 48 in other symptoms. Regarding the first specialty the patients visit, we found that the ophthalmology services received an appreciable number of cases (26.2%). Furthermore; we find that the most common Source of referral to a neurologist was Suggestion by family and media (42.1%).
About the effect of delayed diagnosis on number of relapses, EDSS and initiation of DMD; we find that the median (IQR) of the total number of relapses in patients with delayed diagnosis for more than 2 years(group 1) was 3 (2 - 5), while it was 2 (2 – 4) in patient diagnosed less than 2 years (group 2). In comparing the 2 groups in relation to the duration between onset of symptoms and diagnosis P- value = 0.000 which indicates that the number of relapses increase with delayed diagnosis.
Also, regarding EDSS; the median (IQR) of the EDSS at time of diagnosis in patients with delayed diagnosis for more than 2 years (group 1) was 4 (2.5 - 6), in patient diagnosed less than 2 years (group 2) it was 2.5 (2 – 4.5). In comparing the 2 groups in relation to the duration between onset of symptoms and diagnosis P- value = 0.000 which indicates that EDSS increase with delayed diagnosis.
About DMD, we find 343 patients of group 1 (68.7%) started their journey of treatment with first line DMD (interferons) with median time to diagnosis was (48months), 18 (3.6%) started with second line DMD (fingolimode) and this was associated with higher median time to diagnosis (54 month) and 84 (16.8%) with cytotoxic medications from the start as they were either presented with high EDSS at time of diagnosis or had SPMS with median time to diagnosis (57 month).