Nirmeen A. Kishk

Case Control Series of Intrathecal Autologous Bone Marrow Mesenchymal Stem Cell Therapy for Chronic Spinal Cord Injury

Background: Autologous bone marrow mesenchymal cells that include stem cells (MSCs) are a clinically attractive cellular therapy option to try to treat severe spinal cord injury (SCI). Objective: To study the possible value of MSCs injected intrathecally to enhance rehabilitation. Methods: This case control, convenience sample included 64 patients, at a mean of 3.6 years after SCI. Forty-four subjects received monthly intrathecal autologous MSCs for 6 months and 20 subjects, who would not agree to the procedures, served as controls. All subjects received rehabilitation therapies 3 times weekly. Subjects were evaluated at entry and at 12 months after completing the 6-months intervention. By the ASIA Impairment Scale, ASIA grading of completeness of injury, Ashworth Spasticity Scale, Functional Ambulation Classification, and bladder and bowel control questionnaire. Results: No differences were found in baseline measures and descriptors between the MSC group and control group. Although a higher percentage of the MSC group increased motor scores by 1-2 points and changed from ASIA A to B, no significant between-group improvements were found in clinical measures. Adverse effects of cells included spasticity and, in 24 out of the 43 patients developed neuropathic pain. One subject with a history of post-infectious myelitis developed encephalomyelitis after her third injection. Conclusion: Autologus MSCs may have side effects and may be contraindicated in patients with a history of myelitis. Their utility in treating chronic traumatic SCI needs further study in pre-clinical models and in randomized controlled trials before they should be offered to patients.

Possible induction of acute disseminated encephalomyelitis (ADEM)-like demyelinating illness by intrathecal mesenchymal stem cell injection

We report a 27-year-old woman with an episode of encephalitis and optic neuritis, followed by autologous bone marrow mesenchymal stem cell transplants and possible induction of acute disseminated encephalomyelitis-like demyelinating illness.

Intrathecal Transplantation of Autologous Adherent Bone Marrow Cells Induces Functional Neurological Recovery in a Canine Model of Spinal Cord Injury.

Spinal cord injury (SCI) results in demyelination of surviving axons, loss of oligodendrocytes, and impairment of motor and sensory functions. We have developed a clinical strategy of cell therapy for SCI through the use of autologous bone marrow cells for transplantation to augment remyelination and enhance neurological repair. In a preclinical large mammalian model of SCI, experimental dogs were subjected to a clipping contusion of the spinal cord. Two weeks after the injury, GFP-labeled autologous minimally manipulated adherent bone marrow cells (ABMCs) were transplanted intrathecally to investigate the safety and efficacy of autologous ABMC therapy. The effects of ABMC transplantation in dogs with SCI were determined using functional neurological scoring, and the integration of ABMCs into the injured cords was determined using histopathological and immunohistochemical investigations and electron microscopic analyses of sections from control and transplanted spinal cords. Our data demonstrate the presence of GFP-labeled cells in the injured spinal cord for up to 16 weeks after transplantation in the subacute SCI stage. GFP-labeled cells homed to the site of injury and were detected around white matter tracts and surviving axons. ABMC therapy in the canine SCI model enhanced remyelination and augmented neural regeneration, resulting in improved neurological functions. Therefore, autologous ABMC therapy appears to be a safe and promising therapy for spinal cord injuries.

Urinary 6-sulphatoxymelatonin levels and sleep disorders in children with migraine.

We conducted the present study to assess melatonin secretion in a sample of children with migraine, to describe their sleep patterns and problems, and to examine the impact of sleep problems on migraine disability. The parents of 18 children with migraine completed the Childrens Sleep Habits Questionnaire and Pediatric Migraine Disability Assessment Score in Arabic. The parents of 18 healthy controls also completed the Childrens Sleep Habits Questionnaire. Urinary 6-sulphatoxymelatonin levels were determined with the enzyme-linked immunosorbent assay method. There was no significant difference in urinary 6-sulphatoxymelatonin between the migraine and control groups (Z = –0.127, P = .889). There were no significant differences between groups in Childrens Sleep Habits Questionnaire subscales or total scores. There were significant correlations between bedtime resistance, parasomnias subscales, and migraine disability. Our findings indicate that nocturnal production of melatonin is not reduced in children with migraine, and sleep disturbances impact the degree of migraine disability.

Extracellular miR-145, miR-223 and miR-326 expression signature allow for differential diagnosis of immune-mediated neuroinflammatory diseases

BACKGROUND Although misdiagnosis of neuromyelitis optica spectrum disorder (NMOSD) with neuropsychiatric systemic lupus erythematosus (NPSLE) or multiple sclerosis (MS) is not infrequent, reliable biomarkers remains an unmet need. Extracellular microRNAs (miRNAs) represent a worthy avenue to identify biomarkers for differential diagnosis. We aimed to explore the potential role of some selected circulating miRNAs as biomarkers for the differential diagnosis in immune-mediated neuroinflammatory diseases. METHODS A total of 80 subjects were enrolled in the present study, including 37 patients with MS (relapsing-remitting MS [RRMS; n=18] and secondary progressive MS [SPMS; n=19]), 10 patients with NMOSD and 10 patients with NPSLE as well as 23 healthy subjects. Serum expression levels of three selected miRNAs (miR-145, miR-223 and miR-326) were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Whole blood expression levels of cellular immune response-relevant target genes, including signaling mother against decapentaplegic peptide 3 (SMAD3) and specificity protein 1 (SP1), were also measured using qRT-PCR. RESULTS In comparison to healthy subjects, only miR-145 and miR-223 were significantly up-regulated in MS patients, whereas, all the analyzed miRNAs revealed insignificant upregulation in NMOSD patients. All the examined miRNAs were significantly down-regulated in NPSLE patients compared to healthy subjects. miR-145, miR-223 and miR-326 expression profile is a promising diagnostic biomarker for MS and NPSLE, but not for NMOSD. This expression profile is capable of differentiating not only among MS, NMOSD and NPSLE, but also between RRMS and SPMS. CONCLUSION Specific circulating miRNAs expression signature may have the potential to differentially diagnose immune-mediated neuroinflammatory diseases.

Stem Cell in Neurological Disorders

1.2 Adult stem cells Adult stem cells (ASCs) play a critical role in tissue maintenance and repair (Stem Cell Basics, 2010). Research on adult stem cells began in the 1950s with the discovery of multipotent hematopoietic and mesenchymal stem cells in bone marrow, which can generate a number of tissues (Stem Cell Basics, 2010). Bone Marrow-Derived Mesenchymal Stem Cells can be expanded and differentiated in vitro using various media formulations and culture surface conditions to direct them to different cell lineages (Ho et al., 2006). BMSCs have the ability to migrate to areas of injury, even crossing the blood-brain barrier (Akiyama et al., 2002; Tang et al., 2007). Although the reproducibility of BMSC therapies needs to be thoroughly examined, these early experiments suggest that BMSCs can be administered intravenously to CNS targets. (Rice & Scolding, 2008)

Interictal cardiac repolarization abnormalities in people with epilepsy

BACKGROUND AND OBJECTIVE The occurrence of cardiac electrical abnormalities such as repolarization disorders in patients with epilepsy was previously documented and may, in part, clarify the mechanism of sudden unexpected death in those patients. The aim of this study was to investigate the frequency of cardiac repolarization disorders among patients with epilepsy and whether specific demographic- or disease-related features were associated with their occurrence. SUBJECTS AND METHODS This cross-sectional study was carried out on 1000 subjects with epilepsy who were compared with age- and sex-matched 2500 subjects without epilepsy. Clinical assessment, which included careful history taking and examination, was carried out for all participants in addition to resting 12-lead electrocardiogram (ECG) recording. Electrocardiograms were reviewed by experienced cardiologists. Electrocardiogram intervals were measured, and morphological abnormalities were identified using standard guidelines. RESULTS Repolarization abnormalities were found in 142 (14.2%) patients with epilepsy. A statistically significant elevation in percentage of corrected QT interval (QTc) prolongation (both severe and borderline) among patients with epilepsy compared with controls was documented (8.4% vs 2%, P<0.001). Epilepsy increased the likelihood of hosting prolonged QTc more than 4 times (95% confidence interval: 3.175-6.515; odds ratio: 4.548; P<0.001). Affected patients were significantly older (95% confidence interval: 1.012-1.044; odds ratio: 1.027; P=0.001), and the abnormality was significantly more prevalent among those with poor seizure control (95% confidence interval: 1.103-2.966; odds ratio: 1.809; P=0.019). On the other hand, early repolarization (ER) pattern and Brugada type ECG pattern (BP) were significantly more prevalent in subjects without epilepsy. CONCLUSIONS Corrected QT interval prolongation (both severe and borderline) was more prevalent among patients with epilepsy, especially if uncontrolled or elderly. Electrocardiogram should be established as a part of the diagnostic workup of epilepsy in order to identify such electrocardiographic abnormality.

Characteristics and predictors of progression in an Egyptian multiple sclerosis cohort: a multicenter registry study

Background Multiple sclerosis (MS) is a complex autoimmune disease with a heterogeneous presentation and diverse disease course. Recent studies indicate a rising prevalence of MS in the Middle East. Objective To characterize the demographics and disease features of Egyptian patients attending four tertiary referral MS centers in Cairo. Materials and methods This was a retrospective, observational study on 1,581 patients between 2001 and 2015. Medical records were reviewed and data were identified and extracted in a standardized electronic registry. Results The mean age of disease onset was 26.6±7.8 years, with the majority being female (2.11:1). Relapsing–remitting MS was the most common type (75.1%). The main presenting symptom was motor weakness (43.9%), which was also the most frequent symptom during the disease course. Family history of MS was found in 2.28%. Higher initial Expanded Disability Status Scale score, black holes, and infratentorial lesions on initial magnetic resonance imaging were independent factors for disease progression by univariate analysis (OR 3.87 [95% CI 1.84–6.51], 4.14 [95% CI 3.08–5.58], 4.07 [95% CI 3.21–4.99], respectively); however, in multivariate analysis, only infratentorial lesions were an independent risk for disease progression (OR 6, 95% CI 2.99–12.02; P=0.0005). Conclusion The results from this registry – the largest for MS in the Arab region to date – are comparable to other registries with slight differences.

Pediatric-onset multiple sclerosis in Egypt: a multi-center registry of 186 patients

Introduction Although the frequency of pediatric-onset multiple sclerosis (POMS) has increased in recent decades, it is still highly uncommon, which creates a need for the involvement of more registries from various clinical centers. Objective To characterize the demographic, clinical, and paraclinical features of Egyptian patients with POMS. Patients and methods A retrospective chart review study was undertaken on 237 Egyptian patients with demyelinating events which started before the age of 18 years who attended one of five tertiary referral centers in Cairo, Egypt. Results Multiple sclerosis was diagnosed in 186 patients, 47 (25.27%) patients had disease onset before the age of 12 years; “early-onset pediatric multiple sclerosis (EOPMS)”. The mean age of disease onset was (14.13±2.49 years), with a female:male ratio of 1.62:1, none of the enrolled patients had a primary progressive course (PPMS), whereas 10 patients (5.38%) had a secondary progressive form. Approximately two-thirds of the patients had monofocal disease onset, and less than 10% presented with encephalopathy; most of them had EOPMS. Motor weakness was the presenting symptom in half of the patients, whereas cerebellar presentation was detected in 34.95%, mainly in EOPMS. Seizures (not related to encephalopathy) were more frequent in those with EOPMS. Initial brain magnetic resonance images were positive in all patients, with detected atypical lesions in 29.03%, enhanced lesions in 35.48%, black holes in 13.98%, and infratentorial in 34.41%. Cervical cord involvement was found in 68.28%. More than two-thirds of the patients received either immunomodulatory or immunosuppressant (IS) treatment throughout their disease course, and about half of them received their treatment within the first year from symptoms onset, with a more favorable outcome, and patients with highly active disease received natalizumab, fingolimod, or other IS. Conclusion The results from this registry – the largest for MS in the Arab region to date – are comparable to other registries. Immunomodulatory therapies in POMS are well tolerated and efficacious and they can improve the long-term outcome in children.

Sonographic assessment of optic nerve and ophthalmic vessels in patients with idiopathic intracranial hypertension.

ABSTRACT Background: Early diagnosis and proper monitoring of intracranial pressure (ICP) in idiopathic intracranial hypertension (IIH) could reduce morbidity. Objectives: The objective was to explore and monitor reflection of raised ICP in IIH on optic nerve sheath diameter (ONSD), papillary height and ophthalmic vessels hemodynamics, using transorbital sonography (TOS). Methods: The study included 24 IIH patients and 30 controls. Patients were compared to controls (phase I) then reassessed twice; 1 week and 4 weeks later (phase II). Both groups underwent clinical evaluation and TOS to measure ONSD, papillary elevation, and color Doppler indices of the ophthalmic vessels. Patients underwent lumbar puncture (LP) to measure cerebrospinal fluid (CSF) pressure. Results: ONSD was significantly higher in patients compared to controls (p < 0.001). The cut-off value was 6.2 mm. Papillary elevation (p = 0.006) and ONSD (p = 0.006) were significantly reduced 4 weeks following LP. Baseline color Doppler indices of the ophthalmic vessels were comparable between both groups and the changes observed during the follow-up visits in the patients were insignificant. Conclusion: Reflected ICP changes on ONSD and papilla, measured by TOS, could be a valuable noninvasive additional tool to diagnose and monitor IIH patients. IIH insignificantly influences ophthalmic vessels hemodynamics. Abbreviation BMI: Body mass index. CSF: Cerebrospinal fluid. EDV: End diastolic velocity. ICP: Intracranial pressure. IH:intracranial hypertension. IIH: Idiopathic intracranial hypertension. LP: Lumbar puncture. MI: Mechanical index. MRI: Magnetic resonance imaging. MRV: Magnetic resonance venography. OA: Ophthalmic artery OND: Optic nerve diameter. ONSD: Optic nerve sheath diameter. OV: Ophthalmic vein. PIs: Pulsatility indices. PSV: Peak systolic velocity. ROC: Receiver operator characteristic. TOS: Trans-orbital sonography.