Evaluation of leptomeningeal enhancement in patients with multiple sclerosis

INTRODUCTION

Multiple sclerosis (MS) is a devastating neurological illness that has no recognized cause. This illness has complicated and varied pathogenesis, although it is commonly characterized by multifocal demyelinated plaques, inflammation, and axonal damage.¹                                                                                               

Neurodegeneration is increasingly becoming identified as another pathogenic process that contributes to MS's progressive neurological impairment. Previously, it was considered that axonal damage was limited to persistently demyelinated lesions induced by trophic factor deficiency or maladaptive responses in chronically demyelinated axons. However, axonal injury may occur in connection with inflammation in grey matter and more diffusely in normal-appearing white matter, irrespective of white matter demylination.²                                     

A substantial neurodegenerative component begins early in the illness course, according to a number of recent investigations. Grey matter lesions and grey matter atrophy, which may be identified using the double inversion-recovery (DIR) sequence, have been demonstrated to play a role in the pathophysiology of neurodegeneration and have a greater link to impairment than white matter lesions and total brain atrophy. MS causes grey matter disease in both deep grey matter regions (thalamus, etc.) and the cortex. Advanced stages of secondary and primary progressive MS have been demonstrated to have substantial cortical damage.^.2,4

 Many investigations have shown a link between leptomeningeal ectopic lymphocytic aggregates and cortical disease. Magliozzi et al. found a gradient of necroptosis and demyelination severity in the cortex underneath these leptomeningeal aggregates, with the highest intensity in subpial regions. In another investigation, similar aggregates were seen in subarachnoid space, deep inside cortical sulci, all throughout the brain.²

Massive B cell infiltration has been shown to be a component of such aggregates in immunostaining studies. These B cell enriched aggregates are most likely associated with the development of IgG and/or IgM intrathecal oligoclonal bands (OCB) and Ig-free light chains (FLC).

Due to the tiny size of leptomeningeal infiltrates, which are generally less than 1 m, detecting leptomeningeal pathology in MS is challenging. The failure of the leptomeningeal blood-brain barrier is presumably the cause of this lymphatic follicles.³

Recently, post-contrast fluid-attenuated inversion recovery (FLAIR) MRI has sparked attention, since it may identify mild augmentation in the CSF space caused by leptomeningeal BBB malfunction when post-contrast T1W MRI fails to detect these abnormalities. This is not unique to MS, since it has been shown in a variety of illnesses linked to BBB failure, such as localized cerebral ischemia after intracerebral hemorrhage, posterior reversible encephalopathy syndrome, brain tumors, vasculitis, neurosarcoidosis, and CNS infections. In MS, post contrast FLAIR is not routinely performed. We hypothesized that BBB dysfunction might be detectable also in the leptomeningeal vascular segment of patients with MS, which points to leptomeningeal inflammation that could be used as prognostic marker for progressive disability and conversion to SPMS and could help us for more understanding the disease pathophysiology and developing efficient well controlling medical regimen.⁴

The purpose of this study to assess the value of Leptomeningeal enhancement detection in patients with various phenotypes of multiple sclerosis as a prognostic marker for the clinical course in terms of prognosis, as well as its utility in patients with clinically isolated syndrome (CIS) phenotype as a predictive marker for conversion to clinically definite multiple sclerosis.

PATIENTS AND METHODS

Study approval: The present research was authorized by the Al-Azhar University's Faculty of Medicine's ethics committee. After a thorough explanation of all research stages, all participants signed a written informed consent form.

Study design: A prospective study.

Subjects: Included 52 patients with multiple sclerosis: 35 patients with relapsing remitting multiple sclerosis, 11 patients with secondary progressive multiple sclerosis and 6 patients with CIS phenotype. They were recruited from Neurology MS clinics of Al-Azhar University– Hospitals and followed up for 16 month in the period from April 2020 to October 2021.

A clinically isolated syndrome (CIS) is described as the initial clinical event that is indicative of MS, with no prior bouts of demyelination in the patient's history or on imaging.⁵

Mcdonald criteria 2017 as used for diagnosis of Multiple sclerosis.⁶

In the absence of a relapse, secondary progressive multiple sclerosis was defined as a disability progression of 1 EDSS step in patients with an EDSS less than 5.5 or 0.5 EDSS steps in patients with an EDSS more than 6, a minimum EDSS score of 4 and pyramidal FS. With a score of 2 and a three-month track record of improvement, includes confirmation from the most powerful FS.⁷

Increases in EDSS score of ⩾ 1.5 points from an EDSS score of 0.0, ⩾ 1.0 point from an EDSS score of 1.0–5.5, or ⩾ 0.5 point from an EDSS score of ⩾ 6.0 were considered as EDSS worsening and progression events.⁸

Inclusion criteria: Patients diagnosed with different phenotypes of MS regarding McDonald criteria 2017 [6].All patients aged from18 to 50 years.

Exclusion criteria: 1 - Patients with MRI white matter abnormalities interfere with results such as: (vascular disorder - brain injury-metabolic and toxic disorders).  2- Hx of contrast contraindications (Renal impairment) and contrast hypersensitivity. 3_presence of relapse or steroid treating within 30 days of inclusion (as It may affect the enhancement pattern or mimic it).⁹

Study population and procedure: 52 subjects aged 31.83 (8.609), with females compromised 65.4% of the subjects. Most of them were Relapsing remitting multiple sclerosis phenotypes about 35 subjects (67.3%) besides 11 patients with SPMS (21.2%) and 6 (11.5%) subjects with CIS phenotypes. All of the subjects were educated, at least with above intermediated qualifications with 11.92 (1.453) years of educations. All except 8 (15.4%) subjects were on different treatment at the time of enrollment, two of them were shifted to Interferon and one was escalated to Rituximab for better control from Fingolimod. (Table 1)

The following was done to all of the patients: At baseline and at the conclusion of the trial, a detailed history was taken, a clinical examination was performed, and the illness severity was assessed using the Expanded Disability Status Scale (EDSS) and the Symbol Digit Modalities Test Arabic Version (SDMT).¹⁰ Radiological analysis

The SDMT consists of nine symbols, each of which is associated with a single number in a key at the top of a standard sheet of paper. For 90 seconds, patients must write down the digit connected with each symbol as quickly as possible. There is just one result, which is the number of right answers throughout a 90-second period. The Symbol Digit Modalities Test (SDMT) is the most sensitive neurocognitive function metric in multiple sclerosis (MS), and it's always viewed as a measure of information processing speed (IPS).¹¹

Radiological evaluation includes:

At baseline and at the conclusion of the trial, 3 Tesla routine MRI brain imaging was performed, including a post-contrast 3D FLAIR sequence and post-contrast T1 imaging. A 3.0T MRI equipment was used for all of the MRI experiments (MAGNETOM Skyra, Siemens, Erlangen, Germany, 20-channel head coil, 50-cm field of view)                                                                             

Statistical analysis: The data was organized, tabulated, and statistically analyzed using SPSS, version 24 (SPSS Inc. USA), on an IBM compatible computer. The mean and standard deviation were used to depict quantitative data (SD). Relative frequency and percentage were used to depict qualitative data. For quantitative and qualitative data, the student samples (t) test or the Chi square test were used to compare groups. If p <0.05, the result is regarded substantial; if p<0.001, the result is considered extremely substantial.

RESULTS

Table 1: Demographics.

Table 2: Clinical data.

Table 3: Radiological and lab data.

Table 4: Comparisons between leptomeningeal enhancement and age, EDSS progression, duration of illness.