Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Dear editor 
 Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system. MS is characterized by dissemination in time and place. Dissemination can be clinically (clinically definite multiple sclerosis) or radiologically by magnetic resonance imaging (MRI). Correct diagnosis of MS needs dissemination both in time and in place and also exclusion of all other neurological diseases that can mimic MS. Clinically, dissemination in time is defined as two episodes of neurological symptoms occurrence, separated at least one month apart, and dissemination in place is characterized as the presence of symptoms or signs in at least two different parts of central nervous system (CNS) (e.g. visual, sensory, motor, etc.). Radiologically dissemination in space (DIS) was defined as the presence of clinically silent lesions in T2-weighted MRI in two of four locations including juxtacortical, preventricular, infratentorial, and spinal cord and dissemination in time (DIT) as the presence of simultaneous gadolinium enhancing and non enhancing lesions in MRI [1,2].
  There are some terminologies which are frequently used in patients with demyelinating disorders including clinically definite MS (CDMS), clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) [1-3]. CDMS is defined as two attacks of neurological symptoms in two different neurological systems (e.g. optic neuritis and myelitis) separated and apart for at least one month [1]. Radiologically isolated syndrome (RIS) was used in persons with MRI findings suggestive of MS without typical symptoms and signs [3].
 CIS is defined as the first episode of neurological symptoms and signs suggestive of MS. The onset of MS in 85% of patients presents as CIS. This terminology is widely used in clinical practice. By definition, CIS is always clinically isolated in time. Around 50-70% of patients with CIS have white matter lesions in brain or spinal MRI. On the other hand, CIS usually represents a wide clinical spectrum of diseases of CNS and can be present in a multitude of clinical manifestation [1, 2].
 At present time, MRI is the most important tool for diagnosis of MS in patients with CIS and the application of MRI for diagnosis of MS has been increased during the past few years [4]. Today, the diagnosis of MS is possible very earlier than before due to the wide integration of MRI in McDonalds’ criteria (2010). MacDonald’s criteria mostly rely on MRI findings to facilitate the early diagnosis of MS [1, 4]. By using the new MacDonald’s criteria some patients who presented with CIS can be diagnosed as MS if MRI fulfills dissemination in time and space. For patients who fulfill the criteria of both DIT and DIS, the term of CDMS is used; but for patients who have had one attack of neurological symptoms and fulfill DIT and DIS radiologically (by MRI) there is no appropriate terminology and all of them are classified as CIS [2, 4]. We know that this terminology is somewhat ambiguous, because CIS may be the first presentation of many neurological diseases including demyelinating diseases, inflammatory diseases such as vasculitis or non-inflammatory non-demyelinating diseases like vascular lesions [2].
 We recommend the term of radiologically definite MS (RDMS) for patients who have had one attack of neurological symptoms and fulfill DIT and DIS radiologically by MRI. Because many neurologists are not completely familiar with the term CIS and some are confused about it, we need an appropriate terminology to use in every day’s clinical practice. Also, early diagnosis of MS in patients with CIS is very important. Because early treatment of patients with CIS by disease modifying drugs including Beta-Interferon can delay turning into CDMS and also decreases brain atrophy and new brain lesions. All current disease modifying drugs have been shown to be effective in treating CIS [5]. But it is clear that all patients with CIS do not require these treatments and only those patients who show dissemination in time and space by MRI should be treated by these agents [2, 6].
 In conclusion, radiologicaly definite MS (RDMS) is the recommended terminology for patients who have one attack of neurological symptoms and radiologically fulfill DIT and DIS criteria and these patients should be treated by disease modifying agents as well.

The purpose of this study was to determine the value of spinal cord lesions as a predictive factor for conversion in clinically isolated syndrome (CIS) patients. Patients with CIS and without immunomodulatory treatment were prospectively included. Age at onset, sex, clinical syndrome at onset, oligoclonal bands, and presence, number and location of lesions on brain and spinal MRI were analyzed. Conversion to multiple sclerosis (MS) was the primary endpoint. Cox regression was used to compare outcomes between groups. A total of 75 patients were included: 53 (71%) women, mean age at onset 32.7 years (SD ± 7.5), mean follow-up time 72.5 months (SD ± 9; range 17-104 months). There were 11 (14.6%) patients with one focal spinal cord lesion, while 13 (17%) patients had two or more spinal cord lesions at the first scan during the onset of the disease. Of the 23 patients (30.6%) who converted to clinically definite MS (CDMS), 2 had a normal spinal cord MRI, 8 patients had one spinal cord lesion, and 13 had more than one lesion on MRI (p < 0.001). In multivariable analyses, one focal spinal cord lesion was significantly associated with increased risk of conversion to MS (p = 0.01, HR 3.5, CI 95% 2.1-6.9), while the presence of two or more focal spinal cord lesions was independently associated with a higher risk of conversion to MS (p < 0.001, HR 5.9, CI 95% 3.2-10.8). CIS patients with an abnormal baseline spinal cord MRI have a higher risk for developing clinically definite MS, independent of brain lesions as well as the presence of cerebrospinal fluid oligoclonal banding (OSF-OB) .

The diagnosis of multiple sclerosis (MS) requires evidence of both dissemination in space (DIS) and time (DIT); oligoclonal bands (OCBs) in the CSF can substitute for DIT on MRI. We investigated whether DIT (or positive CSF) is necessary to make a diagnosis of MS in patients who fulfil a high number of DIS criteria. We prospectively recruited patients with a first demyelinating event evaluated with brain and spinal cord MRI within 3 months of onset. The patients were followed up clinically and with MRI. We retrospectively applied DIS criteria requiring lesions in ≥2/4, ≥3/4, or 4/4 regions typically affected in MS (periventricular, cortical/juxtacortical, infratentorial, spinal cord) and ≥2/5, ≥3/5, ≥4/5, and 5/5 regions (including the optic nerve) to baseline assessments. We investigated the performance of each set of DIS criteria for a diagnosis of MS using the 2017 McDonald criteria, requiring both DIS (lesions in ≥2/4 regions) plus DIT on MRI (gadolinium-enhancing and nonenhancing lesions, new T2 lesions at follow-up) or CSF-specific OCBs, as the gold standard. We included 244 patients (mean age 32.5 years, 154 [63%] female); 187 (77%) patients were diagnosed with MS using the 2017 McDonald criteria over a mean follow-up of 11.2 years. DIS alone, requiring lesions in ≥2/4, ≥3/4, or 4/4 regions, exhibited reducing sensitivity (84%, 58%, and 26%, respectively) and increasing specificity (91%, 98%, 100%) for an MS diagnosis. In 112 (46%) patients with optic nerve assessment with orbital MRI or visual evoked potentials, DIS in ≥2/5, ≥3/5, ≥4/5, or 5/5 regions also resulted in reducing sensitivity (96%, 83%, 61%, 30%) and increasing specificity (44%, 83%, 100%, 100%) for MS diagnosis. We propose a diagnostic algorithm for MS in patients with a first demyelinating event based on the number of DIS regions fulfilled. In patients with a first demyelinating event, DIS in ≥4 regions typically affected in MS is highly specific, indicating an extremely low risk of false-positive results, and misdiagnosis. Using DIS in ≥4 regions would reduce the need for follow-up MRI or CSF examination in all patients with suspected MS, streamlining the diagnostic process. Limitations include an over-representation of patients with optic neuritis at onset, a low rate of CSF examination, and lack of optical coherence tomography data.

Given its potential for diffuse dissemination throughout virtually every ­portion of the central nervous system (optic nerves, brain, and spinal cord), it is perhaps not surprising that a broad array of symptoms may be reported by patients with Multiple Sclerosis (MS). Nonetheless, the majority of patients with MS will at some point present with a stereotyped constellation of symptoms and signs constituting a first clinical “attack” of demyelination, often referred to as a Clinically Isolated Syndrome (CIS). CIS typically comprises unilateral optic neuritis, partial transverse myelitis, or a brainstem–cerebellar syndrome (see below). The majority of patients presenting with CIS will also have characteristic lesions on brain MRI not accounting for their clinical presentation and indicative of prior asymptomatic episodes of inflammatory demyelination. These patients should be managed based on their risk of having a second attack and thus converting to Relapsing–Remitting MS (RRMS), also termed Clinically Definite MS (CDMS). In the Optic Neuritis Treatment Trial (ONTT) [1], the cumulative probability of developing MS by 15 years after onset of optic neuritis was 50% (95% confidence interval, 44–56%) and strongly related to presence of lesions on the baseline non-contrast-enhanced brain (MRI). Twenty-five percent of patients with no lesions on baseline brain MRI developed MS during follow-up compared with 72% of patients with one or more lesions. In longitudinal studies of a separate cohort of CIS patients, 83% (45/54) of patients with CIS who had abnormal results on brain MRI at baseline developed CDMS after a 10-year follow-up period and baseline lesion number and lesion volume increase over the first 5 years predicted the extent of clinical disability measured by the Expanded Disability Status Scale (EDSS) at the 14-year follow-up examination [2, 3]. These findings underscore the prognostic value of MRI early in MS. Using modern imaging criteria, it is now also possible to make a diagnosis of MS prior to a second clinical attack by demonstrating new asymptomatic lesions on MRI (i.e., dissemination in time), and most disease-modifying therapies (DMTs) are utilized in both RRMS and CIS with characteristic abnormal MRI findings. In this chapter, we will discuss the signs and symptoms experienced by MS patients as well as the diagnosis and differential diagnosis of MS.

Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study

Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria. In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up. We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [p = 0.002], DIS and DIT vs noDIS and noDIT [p < 0.001], and DIS and noDIT vs noDIS and noDIT [p = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]). These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.

P010 - Neuromyelitis optica: Case reports from Oman

ObjectiveIn the work-up of patients presenting with a clinically isolated syndrome (CIS), 3T MRI might offer a higher lesion detection than 1.5T, but it remains unclear whether this affects the fulfilment of the diagnostic criteria for multiple sclerosis (MS).MethodsWe recruited 66 patients with CIS within 6 months from symptom onset and 26 healthy controls in 6 MS centers. All participants underwent 1.5T and 3T brain and spinal cord MRI at baseline according to local optimized protocols and the MAGNIMS guidelines. Patients who had not converted to MS during follow-up received repeat brain MRI at 3–6 months and 12–15 months. The number of lesions per anatomical region was scored by 3 raters in consensus. Criteria for dissemination in space (DIS) and dissemination in time (DIT) were determined according to the 2017 revisions of the McDonald criteria.ResultsThree-Tesla MRI detected 15% more T2 brain lesions compared to 1.5T (p < 0.001), which was driven by an increase in baseline detection of periventricular (12%, p = 0.015), (juxta)cortical (21%, p = 0.005), and deep white matter lesions (21%, p < 0.001). The detection rate of spinal cord lesions and gadolinium-enhancing lesions did not differ between field strengths. Three-Tesla MRI did not lead to a higher number of patients fulfilling the criteria for DIS or DIT, or subsequent diagnosis of MS, at any of the 3 time points.ConclusionScanning at 3T does not influence the diagnosis of MS according to McDonald diagnostic criteria.

MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study

To compare the performance of the 2017 revisions to the McDonald criteria with the 2010 McDonald criteria in establishing multiple sclerosis (MS) diagnosis and predicting prognosis in patients with clinically isolated syndrome (CIS) suggestive of MS. CSF examination and brain and spinal cord MRI obtained ≤5 months from CIS onset and a follow-up brain MRI acquired within 15 months from CIS onset were evaluated in 785 patients with CIS from 9 European centers. Date of second clinical attack and of reaching Expanded Disability Status Scale score (EDSS) ≥3.0, if they occurred, were also collected. Performance of the 2017 and 2010 McDonald criteria for dissemination in space (DIS), dissemination in time (DIT) (including oligoclonal bands assessment), and DIS plus DIT for predicting a second clinical attack (clinically definite MS [CDMS]) and EDSS ≥3.0 at follow-up was evaluated. Time to MS diagnosis for the different criteria was also estimated. At follow-up (median 69.1 months), 406/785 patients with CIS developed CDMS. At 36 months, the 2017 DIS plus DIT criteria had higher sensitivity (0.83 vs 0.66), lower specificity (0.39 vs 0.60), and similar area under the curve values (0.61 vs 0.63). Median time to MS diagnosis was shorter with the 2017 vs the 2010 or CDMS criteria (2017 revision, 3.2; 2010 revision, 13.0; CDMS, 58.5 months). The 2 sets of criteria similarly predicted EDSS ≥3.0 milestone. Three periventricular lesions improved specificity in patients ≥45 years. The 2017 McDonald criteria showed higher sensitivity, lower specificity, and similar accuracy in predicting CDMS compared to 2010 McDonald criteria, while shortening time to diagnosis of MS. This study provides Class II evidence that the 2017 McDonald Criteria more accurately distinguish CDMS in patients early after a CIS when compared to the 2010 McDonald criteria.

Spinal cord lesions are included in the diagnosis of multiple sclerosis (MS), yet spinal cord MRI is not mandatory for diagnosis according to the latest revisions of the McDonald Criteria. We investigated the distribution of spinal cord lesions in MS patients and examined how it influences the fulfillment of the 2017 McDonald Criteria. Seventy-four patients with relapsing-remitting MS were examined with brain and entire spinal cord MRI. Sixty-five patients received contrast. The number and anatomical location of MS lesions were assessed along with the Expanded Disability Status Scale (EDSS). A Chi-square test, Fischer’s exact test, and one-sided McNemar’s test were used to test distributions. MS lesions were distributed throughout the spinal cord. Diagnosis of dissemination in space (DIS) was increased from 58/74 (78.4%) to 67/74 (90.5%) when adding cervical spinal cord MRI to brain MRI alone (p = 0.004). Diagnosis of dissemination in time (DIT) was not significantly increased when adding entire spinal cord MRI to brain MRI alone (p = 0.04). There was no association between the number of spinal cord lesions and the EDSS score (p = 0.71). MS lesions are present throughout the spinal cord, and spinal cord MRI may play an important role in the diagnosis and follow-up of MS patients.

Background: The presence of asymptomatic spinal cord (SC) lesions in patients with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS) predicts conversion to clinically definite multiple sclerosis (CDMS). The relation between asymptomatic SC abnormalities and disability progression warrants further investigation. Objective: To determine the prognostic value of asymptomatic SC lesions in CIS and early RRMS with respect to the time to disability development. Methods: Clinical and demographic data, brain and SC magnetic resonance imaging (MRI) were collected of CIS or early RRMS patients. Two main analyses were performed. For the first analysis, patients were divided into two groups: (1) patients with asymptomatic SC lesions and (2) patients without SC lesions and patients with symptomatic SC lesions. The second analysis excluded patients with symptomatic SC lesions. Incidence curves were used to analyse differences between these groups in time to the development of disability and time to a second relapse. Results: A total of 178 patients were included, and 42 patients (23.6%) had asymptomatic SC lesions. No significant differences were found on the time to disability development or the time to a second event. Conclusion: Asymptomatic SC lesions early in the disease course do not predict the time to disability development in patients diagnosed with CIS or early RRMS.

The increase in stool weight after feeding 20 g (dry weight) of bran daily was measured when this was of large particle size and after milling to small particle size. Twenty-eight investigations were carried out in 21 normal subjects. With coarse bran, stool weight was significantly greater than with the fine bran (mean 219.4 g/d coarse bran, 199-0 g/d fine bran: difference 20.4 g SE +/-6.4, P less than 00.1). The coarse bran also had a greater water-holding capacity (7.3 g water/g coarse bran, 3.9 water/g fine bran). Coarse bran was 2 1/2 times the volume of fine gran for a given weight and more fine bran will, therefore, be taken when bran is prescribed by the spoonful.

Background: The 2005, 2010, and 2017 McDonald diagnostic criteria for multiple sclerosis (MS) were compared at baseline in participants of a Canadian multicentre clinical trial of minocycline in clinically isolated syndrome (CIS). Methods: The cohort included 142 participants. Baseline clinical and imaging data were used to determine if participants met criteria for dissemination in space (DIS) and time (DIT) as required for each version of the criteria. We also explored the impact of permitting a clinical diagnosis of transverse myelitis to represent a spinal cord lesion, and for multifocal clinical onset to represent DIS. Results: The clinical trial excluded patients meeting the 2005 McDonald criteria at baseline. The 2010 criteria were met by 28.9% (41/142) of participants. If a multifocal clinical presentation was considered evidence of DIS 29.6% (42/142) met the 2010 criteria. The 2017 criteria were met by 36.7% (52/142). Allowing a clinical diagnosis of transverse myelitis to confirm a spinal lesion, or multifocal onset to confirm evidence of DIS, led to a diagnosis in 38% (54/142) and 38.7% (55/142), respectively. Conclusions: This study confirms that each revision of the McDonald diagnostic criteria allowed an MS diagnosis in more CIS patients at onset. Exploration of other modifications suggests further improvement may be possible.

Brain and spinal cord lesion criteria distinguishes AQP4-positive neuromyelitis optica and MOG-positive disease from multiple sclerosis