Horizontal Tonic Conjugate Gaze Deviation in a 4-Week-Old Infant: What Can the Eyes (of the Parents) Tell?

A 4-week-old healthy infant failed to make eye contact when approached from the left. When evaluated by us at the age of 11 weeks, left tonic conjugate gaze deviation was noted. Brain MRI showed a left frontotemporal large tension arachnoid cyst causing right falcial herniation. During the insertion of an Ommaya reservoir, hemosiderin was found to be coating the inner wall of the cyst, which may indicate that the asymptomatic cyst evolved to a tension cyst due to spontaneous hemorrhage. Surgical decompression resulted in complete restoration of the horizontal gaze and considerable reduction in the size of the cyst. After 3 months a cystoperitoneal shunt was placed due to increased intracranial pressure secondary to impaired drainage of the cyst. Since then the infant has done well, with normal developmental and neurological examination during his last follow-up at the age of 5 years. Although gaze central ocular motor control is still underdeveloped and chaotic eye movements are present during early infancy, the present case report reminds us that a thorough examination of eye movements should not be overlooked during neurodevelopmental evaluation.

The role of noninvasive and invasive diagnostic imaging techniques for detection of extra-cranial venous system anomalies and developmental variants.

The extra-cranial venous system is complex and not well studied in comparison to the peripheral venous system. A newly proposed vascular condition, named chronic cerebrospinal venous insufficiency (CCSVI), described initially in patients with multiple sclerosis (MS) has triggered intense interest in better understanding of the role of extra-cranial venous anomalies and developmental variants. So far, there is no established diagnostic imaging modality, non-invasive or invasive, that can serve as the "gold standard" for detection of these venous anomalies. However, consensus guidelines and standardized imaging protocols are emerging. Most likely, a multimodal imaging approach will ultimately be the most comprehensive means for screening, diagnostic and monitoring purposes. Further research is needed to determine the spectrum of extra-cranial venous pathology and to compare the imaging findings with pathological examinations. The ability to define and reliably detect noninvasively these anomalies is an essential step toward establishing their incidence and prevalence. The role for these anomalies in causing significant hemodynamic consequences for the intra-cranial venous drainage in MS patients and other neurologic disorders, and in aging, remains unproven.

Comparison of intravascular ultrasound with conventional venography for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency.

PURPOSE: To investigate prevalence of extracranial abnormalities in azygos and internal jugular (IJ) veins using conventional venography and intravascular ultrasound (IVUS) in patients with multiple sclerosis (MS) being evaluated for chronic cerebrospinal venous insufficiency, a condition of vascular hemodynamic dysfunction. MATERIALS AND METHODS: PREMiSe (Prospective Randomized Endovascular therapy in Multiple Sclerosis) is a venous angioplasty study that enrolled 30 patients with relapsing MS. The patients fulfilled two or more venous hemodynamic extracranial Doppler sonography screening criteria. Phase I of the study included 10 patients and was planned to assess safety and standardize venography, IVUS, and angioplasty and blinding procedures; phase II enrolled 20 patients and further validated diagnostic assessments using the two invasive techniques. Venography was considered abnormal when ≥ 50% lumen-diameter restriction was detected. IVUS was considered abnormal when ≥ 50% lumen-diameter restriction, intraluminal defects, or reduced pulsatility was detected. RESULTS: No venography-related or IVUS-related complications, including vessel rupture, thrombosis, or side effects of contrast media were recorded among the 30 study patients. IVUS-detected venous abnormalities, including chronic, organized, thrombus-like inclusions were observed in 85% of azygos, 50% of right IJ, and 83.3% of left IJ veins, whereas venography demonstrated stenosis of ≥ 50% in 50% of azygos, 55% of right IJ, and 72% of left IJ veins. Sensitivity of venography for detecting IVUS abnormalities was 52.9%, 73.3%, and 80% for the azygos, left IJ, and right IJ veins, respectively. CONCLUSIONS: IVUS assessment of azygos and IJ veins showed a higher rate of venous abnormalities than venography. IVUS provides a diagnostic advantage over conventional venography in detecting extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency.

Multimodal noninvasive and invasive imaging of extracranial venous abnormalities indicative of CCSVI: results of the PREMiSe pilot study.

BACKGROUND: There is no established noninvasive or invasive diagnostic imaging modality at present that can serve as a 'gold standard' or "benchmark" for the detection of the venous anomalies, indicative of chronic cerebrospinal venous insufficiency (CCSVI). We investigated the sensitivity and specificity of 2 invasive vs. 2 noninvasive imaging techniques for the detection of extracranial venous anomalies in the internal jugular veins (IJVs) and azygos vein/vertebral veins (VVs) in patients with multiple sclerosis (MS). METHODS: The data for this multimodal imaging comparison pilot study was collected in phase 2 of the "Prospective Randomized Endovascular therapy in Multiple Sclerosis" (PREMiSe) study using standardized imaging techniques. Thirty MS subjects were screened initially with Doppler sonography (DS), out of which 10 did not fulfill noninvasive screening procedure requirements on DS that consisted of ≥2 venous hemodynamic extracranial criteria. Accordingly, 20 MS patients with relapsing MS were enrolled into the multimodal diagnostic imaging study. For magnetic resonance venography (MRV), IJVs abnormal findings were considered absent or pinpoint flow, whereas abnormal VVs flow was classified as absent. Abnormalities of the VVs were determined only using non-invasive testing. Catheter venography (CV) was considered abnormal when ≥50% lumen restriction was detected, while intravascular ultrasound (IVUS) was considered abnormal when ≥50% restriction of the lumen or intra-luminal defects or reduced pulsatility was found. Non-invasive and invasive imaging modality comparisons between left, right and total IJVs and between the VVs and azygos vein were performed. Because there is no reliable way of non-invasively assessing the azygos vein, the VVs abnormalities detected by the non-invasive testing were compared to the azygos abnormalities detected by the invasive testing. All image modalities were analyzed in a blinded manner by more than one viewer, upon which consensus was reached. The sensitivity and specificity were calculated using contingency tables denoting the presence or absence of vein-specific abnormality findings between all imaging modalities used individually as the benchmark. RESULTS: The sensitivity of CV + IVUS was 68.4% for the right and 90% for the left IJV and 85.7% for the azygos vein/VVs, compared to venous anomalies detected on DS. Compared to the venous anomalies detected on MRV, the sensitivity of CV + IVUS was 71.4% in right and 100% in left IJVs and 100% in the azygos vein/VVs; however, the specificity was 38.5%, 38.9% and 11.8%, respectively. The sensitivity between the two invasive imaging techniques, used as benchmarks, ranged from 72.7% for the right IJV to 90% for the azygos vein but the IVUS showed a higher rate of venous anomalies than the CV. There was excellent correspondence between identifying collateral veins on MRV and CV. CONCLUSIONS: Noninvasive DS screening for the detection of venous anomalies indicative of CCSVI may be a reliable approach for identifying patients eligible for further multimodal invasive imaging testing of the IJVs. However, the noninvasive screening methods were inadequate to depict the total amount of azygos vein/VVs anomalies identified with invasive testing. This pilot study, with limited sample size, shows that both a non-invasive and invasive multimodal imaging diagnostic approach should be recommended to depict a range of extracranial venous anomalies indicative of CCSVI. However, lack of invasive testing on the study subjects whose results were negative on the DS screening and of healthy controls, limits further generalizibility of our findings. In addition, the findings from the 2 invasive techniques confirmed the existence of severe extracranial venous anomalies that significantly impaired normal blood outflow from the brain in this group of MS patients.

Practical recommendations on treatment of multiple sclerosis with Cladribine: an Israeli Experts Group Viewpoint.

Cladribine tablets (Mavenclad®) were approved by the European Union in 2017 as high-efficacy therapy for highly active relapsing-remitting multiple sclerosis. In Israel, Mavenclad® was approved in 2018. Real-life experience has confirmed the efficacy of cladribine tablets over at least 4 years from the initial course. During the last years, several questions were raised concerning the management of people with MS who show disease activity during years 3 and 4 post-cladribine initiation and what treatment decisions are needed beyond year 4. A few expert boards have tried to provide insight based on research data and to suggest recommendations on the therapeutic dilemmas and treatment decisions with cladribine. However, there is currently no widely accepted consensus about these issues. The vast clinical experience gained in Israel in the past 5 years in several MS centers across the country allows for a broad perspective of the outcomes with long-term cladribine use. This article summarizes previously published recent recommendations and describes the insights of Israeli neurology key opinion leaders that convened for an advisory board meeting on January 29th, 2023, with the aim of reaching a consensus regarding cladribine long-term treatment and follow-up.

Residual striatal dopaminergic nerve terminals in very long-standing Parkinson's disease: a single photon emission computed tomography imaging study.

Molecular imaging studies of Parkinson's disease (PD) progression mostly focus on the first 5 years after disease onset, demonstrating rapid initial nigrostriatal neuronal loss. The fate of residual functional dopaminergic nerve terminals in patients with long-standing PD has not yet been specifically explored. Therefore, we performed [(123)I]-FP-CIT single photon emission computed tomography (SPECT) in 15 patients with very long-standing PD (mean disease duration 20.6 ± 6.3 years). Measurable uptake of [(123)I]-FP-CIT was still detected in the striata of all patients. As seen in early stages, reduction of tracer uptake in the putamen was more prominent than in the caudate nucleus. Asymmetry in tracer uptake between the two putamen and caudate nuclei was preserved. These findings indicate that degeneration of dopaminergic neurons in PD is not total even after many years of illness. Data should be considered in exploring underlying causes of progressive loss of nigrostriatal dopaminergic neurons and development of future novel dopaminergic therapeutic strategies in PD.

Myasthenia gravis and return to flying status.

INTRODUCTION: Myasthenia gravis (MG) is a common primary disorder of neuromuscular transmission. Although MG was once a fatal disease, today treatment with immunomodulating agents and cholinomimetic medications with good supportive care have improved the prognosis and the ability of patients to adapt to their workplaces, including the flight environment. CASES: The diagnosis of MG in two aircrew members illustrates the range of severity for MG from isolated ocular symptoms to relentlessly progressive generalized disease, as well as the unpredictability of the disease and difficulty in treatment. Nevertheless, both patients were returned to limited flying status. DISCUSSION: MG presents the potential for subtle progression with resulting effects on flight performance. In addition to the disease itself, flight surgeons must also consider problems related to treatment and its side effects. Progression and exacerbations of MG can develop during the course of the disease, requiring careful adjustments to treatment regimens. Taking all these factors into consideration, including the unpredictability of this disease, pilots with apparently stabilized MG should nevertheless be assigned only to duties during which the patient would be able to maintain and use his flying capabilities without risking the mission, himself, and other crewmembers.

Age-Related Clinical Presentation of MOG-IgG Seropositivity in Israel.

Introduction: Myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders (MOGAD) have been recognized over the past 10 years as distinct inflammatory, demyelinating diseases of the central nervous system (CNS). Antibodies against MOG are found mostly in patients with optic neuritis (ON), acute disseminated encephalomyelitis (ADEM), and aquaporin-4 antibody (AQP4-abs)-seronegative neuromyelitis optica spectrum disorders (NMOSD). However, data on the disease course and disability outcomes of these patients are scarce. Aim: To describe clinical and paraclinical features associated with MOG antibodies (abs) in a cohort of patients in Israel, and to assess baseline prognostic features of MOG-ab-associated diseases after a first acute demyelinating event. Methods: MOG-abs were identified in serum using a cell-based assay, and clinical data were collected from the patients' medical records. Results: Of 683 patients with demyelinating diseases tested for MOG-abs, 53 were positive (7.7%), with ON the most common presenting phenotype (68%). The age range of MOG-abs seropositive patients was 1-66 years, with increased prevalence in children (19% compared to 6.7% in adults) (p < 0.01). The highest prevalence of seropositivity was observed in children aged younger than 10 years (25.5%), followed by those aged 31-40 years (16.6%). Conclusions: MOGAD are distinct autoimmune diseases that occurs at all stages of life with a significantly higher prevalence in children; the main clinical presenting phenotype in the entire cohort is ON and young children most often presented with ON or ADEM. Our data highlight the need for repeated evaluation of MOG-abs in patients with acquired CNS demyelinating disorders, especially in children under 10 and adults between 31 and 40 years of age.

Paraneoplastic cerebellar degeneration mimicking acute post-infectious cerebellitis.

Acute cerebellitis is a monophasic non-progressive encephalitis restricted to the cerebellum, while paraneoplastic cerebellar degeneration is a subacute progressive disorder, which may either accompany or herald Hodgkin's disease. In the present report, we describe a young man with clinical and laboratory features of acute post-infectious cerebellitis in whom the progressive relapsing course subsequently led to the diagnosis of Hodgkin's disease. Dynamic changes observed on repeated MRIs during the protracted clinical course imply the presence of early active inflammation and subsequent neuronal atrophy.

Reduced expression of membrane-bound (m)RAGE is a biomarker of multiple sclerosis disease progression.

OBJECTIVES: This study is one in series measuring RAGE axis (receptor for advanced glycation end products, its isoforms, and ligands) as a biomarker in multiple sclerosis (MS). We identified and quantified membrane-bound RAGE (mRAGE) expression levels on freshly isolated PBMCs and its subpopulation (monocytes and T cells), and determined the relationship between mRAGE expression levels and MS disease severity. MATERIALS AND METHODS: mRAGE expression was determined for 28 MS patients and 16HCs, by flow cytometry, using fluorochrome unconjugated primary RAGE monoclonal antibody and a polyclonal secondary antibody conjugated to R-Phycoerythrin (PE). RESULTS: After adjusting for multiple comparisons and correcting for group differences in age and gender, MS patients showed higher percentages of mRAGE-positive on PBMCs (12.4±2.1 vs. 4.08±0.8, P=0.02), monocytes (37.4±5.8 vs. 20.1±5.0, P=0.08) and T cells (4.1±1.2 vs. 2.1±0.3, P=0.05). SPMS patients' showed lower percentages of RAGE-positive monocytes (13.7±5.5 vs. 49.5±6.6, P=0.0006) and RAGE-positive T cells (4.1±1.8 vs. 6.6±1.5, P=0.04) than RRMS patients. We observed a negative relationship between the percentages of mRAGE-positive PBMCs and MS severity scale (MSSS) (r=-0.39, P=0.04), monocytes and EDSS (r=-0.48, P=0.01), monocytes and MSSS (r=-0.58, P=0.001), and T cells and MSSS (r=-0.40, P=0.04). Monocytes expression of mRAGE showed 0.811 area under the curve (95% CI: 0.64-0.98) sensitivity/specificity for MSSS. CONCLUSION: The reduced mRAGE expression on PBMCs in general, and on monocytes in particular, can be used as biomarker of MS disease severity and progression.

Comparison of stress fractures of male and female recruits during basic training in the Israeli anti-aircraft forces.

BACKGROUND: In military basic training, stress fractures are a common orthopedic problem. Female recruits have a significantly higher incidence of stress fractures than do male recruits. Because the Israeli Defense Forces opened traditionally male roles in combat units to female recruits, their high risk for stress fractures is of concern. OBJECTIVE: To compare the prevalence of stress fractures during Israeli Defense Forces anti-aircraft basic training among otherwise healthy young male and female recruits, in terms of anatomic distribution and severity. DESIGN: Ten mixed gender batteries, including 375 male recruits and 138 female recruits, carried out basic training in the Israeli anti-aircraft corps between November 1999 and January 2003. Each battery was monitored prospectively for 10 weeks of a basic training course. During that time, recruits who were suspected of having an overuse injury went through a protocol that included an orthopedic specialist physical examination followed by a radionuclide technetium bone scan, which was assessed by consultant nuclear medicine experts. The assessment included the anatomic site and the severity of the fractures, labeled as either high severity or low severity. RESULTS: Stress fractures were significantly more common among female recruits than among male recruits. A total of 42 male (11.2%) and 33 female (23.91%) recruits had positive bone scans for stress fractures (female:male relative ratio, 2.13; p < 0.001). Pelvic, femur, and tibia fractures were significantly more common among female recruits than among male recruits (p < 0.005). Female recruits had significantly more severe fractures in the tibia (p < 0.05). However, there was no significant difference in the severity of stress fractures in the femur or metatarsals between male and female recruits, as assessed by radionuclide uptake. CONCLUSIONS: We recommend that different training programs be assigned according to gender, in which female recruits would have a lower level of target strain or a more moderate incline of strain in the training program throughout basic training.

Prospective randomized trial of venous angioplasty in MS (PREMiSe).

OBJECTIVE: We report the results of the investigation of safety and efficacy of venous angioplasty in patients with multiple sclerosis (MS) with findings of extracranial venous anomalies, considered hallmarks of chronic cerebrospinal venous insufficiency (CCSVI), in a 2-phase study (ClinicalTrials.gov NCT01450072). METHODS: Phase 1 was an open-label safety study (10 patients); phase 2 was sham-controlled, randomized, and double-blind (10 sham procedure, 9 treated). All study patients fulfilled venous hemodynamic screening criteria indicative of CCSVI. Assessment was at 1, 3, and 6 months postprocedure with MRI, clinical, and hemodynamic outcomes. Primary endpoints were safety at 24 hours and 1 month, venous outflow restoration >75% at 1 month, and effect of angioplasty on new lesion activity and relapse rate over 6 months. Secondary endpoints included changes in disability, brain volume, cognitive tests, and quality of life. RESULTS: No perioperative complications were noted; however, one patient with history of syncope was diagnosed with episodic bradycardia requiring placement of a pacemaker before discharge. Doppler evidence-based venous hemodynamic insufficiency severity score (VHISS) was reduced >75% compared to baseline in phase 1 (at 1 month) but not phase 2. In phase 2, higher MRI activity (cumulative number of new contrast-enhancing lesions [19 vs 3, p = 0.062] and new T2 lesions [17 vs 3, p = 0.066]) and relapse activity (4 vs 1, p = 0.389) were identified as nonsignificant trends in the treated vs sham arm over 6 months. Using analysis of covariance, significant cumulative new T2 lesions were related to larger VHISS decrease (p = 0.028) and angioplasty (p = 0.01) over the follow-up. No differences in other endpoints were detected. CONCLUSION: Venous angioplasty is not an effective treatment for MS over the short term and may exacerbate underlying disease activity. CLASSIFICATION OF EVIDENCE: This is a Class I study demonstrating that clinical and imaging outcomes are no better or worse in patients with MS identified with venous outflow restriction who receive venous angioplasty compared to sham controls who do not receive angioplasty. This study also includes a Class IV phase 1 study of safety in 10 patients receiving the angioplasty procedure.

The prevalence of the classical and non-classical cardiovascular risk factors in multiple sclerosis patients.

BACKGROUND: Inflammation is known to play a role in cererovascular risk. Multiple sclerosis (MS) is a neurodegenerative disease that is initially characterized by inflammatory changes in the brain. We hypothesized that due to chronic inflammation, MS patients would present with a higher levels of cardiovascular (CV) risk factors than non-MS patients. METHODS: We performed a retrospective chart review on 206 MS patients and 142 control patients suffering from meningiomas and acoustic neuromas, non inflammatory, non autoimmune diseases of the brain. The obtained data included fasting lipid profiles, plasma glucose, systolic and diastolic blood pressure (BP), serum levels of homocysteine and uric acid, data on iron status, smoking habit, and list of medications. In addition, data on indicators of MS disease severity was obtained for MS patients. RESULTS: MS patients had significantly higher total plasma cholesterol, p = 0.01, and plasma high density lipoprotein, P < 0.001, but lower plasma glucose, P < 0.001, and systolic BP, P = 0.001, than non-MS patients. In addition, MS patients had lower erythrocyte sedimentation rate and serum vitamin B12, but higher serum folic acid and vitamin D3 than non-MS patients. A positive correlation was observed between plasma glucose and the extended disability status scale (EDSS), P = 0.008, and between plasma glucose and the rate of clinical relapse, P = 0.001. CONCLUSION: The MS pathophysiology may be among factors for the lower CV risk factors in MS patients. Future studies should examine whether the chronic use of many pharmacological agents influence CV risk factors in MS patients.

Prospective Open-Label, Single-Arm, Multicenter, Safety, Tolerability, and Pharmacokinetic Studies of Intravenous Levetiracetam in Children With Epilepsy.

Levetiracetam given via intravenous administration has been shown to be an effective alternative in adults with epilepsy when oral administration is not feasible. This study was a prospective single-arm, multicenter study to assess tolerability, safety, and pharmacokinetics of intravenous levetiracetam in children with epilepsy. Children with epilepsy ages 1 month to 16 years requiring intravenous levetiracetam were enrolled. Assessments included vital signs, electrocardiogram, hematology, chemistry, plasma concentrations of antiepileptic medications, weight, physical/neurological examinations, and pharmacokinetics. A total of 52 patients were enrolled. Mild to moderate treatment-emergent adverse events occurred in 63%, the most frequent being pyrexia and dry mouth. Most other treatment-emergent adverse events were considered unrelated to intravenous levetiracetam administration. Therefore, intravenous levetiracetam in the acute setting was overall well tolerated in children 1 month to 16 years.

Results of stent-assisted vs non-stent-assisted endovascular therapies in 489 cerebral aneurysms: single-center experience.

BACKGROUND: Whether the addition of stenting to intracranial aneurysm coil embolization results in benefit in terms of occlusion rates or additional risk in terms of periprocedural adverse events is not clear. OBJECTIVE: To report retrospectively analyzed results of endovascular aneurysm treatment comparing stent-assisted coiling with coiling without stents at our hospital from 2005 to 2009. METHODS: In this retrospectively reviewed case series, aneurysms were grouped as intent-to-treat or initially treated with stent-assisted coiling (A) vs coiling alone (B) or as-treated-those that ultimately received a stent (C) or not (D). Complication and occlusion rates were compared between groups. Some patients crossed from group B to C after receiving stent placement at a later treatment following the initial therapeutic modality (without a stent). RESULTS: In 459 patients, 489 aneurysms were treated by group as follows: A = 181, B = 308, C = 225, and D = 264. In stent groups (A and C), there were significantly lower frequencies of ruptured aneurysms (A vs B = 11% vs 62%, P < .001; C vs D = 20.4% vs 62.5%, P < .001) and more giant aneurysms (A vs B = 7.3% vs 1.0%, P = .001; C vs D = 5.9% vs 1.1%, P < .001). There was no statistically significant difference in permanent event-related morbidity (A vs B = 4.4% vs 4.2%, P = 1.0; C vs D = 4.4% vs 4.2%, P = 1.0). Average angiographic follow-up after last treatment was 18.2 ± 15 months (median = 14). Higher rates of complete occlusion at last angiographic follow-up were observed in stented aneurysms (A vs B = 64.6% vs 49.7%, P = .001; C vs D = 62.7% vs 48.9%, P = .003). CONCLUSION: Stent-assisted aneurysm treatment resulted in higher total occlusion rates than non-stent-assisted treatment, with acceptable, comparable periprocedural event rates.

Limb ataxia originating from peri-central sulcus demyelinating lesion in multiple sclerosis.

BACKGROUND: To report the development of limb ataxia/intention tremor (LA/IT) associated with inflammatory demyelinating cortical peri-central sulcus lesions. METHODS: We describe a case series of five multiple sclerosis (MS) patients followed at the Jacobs Neurological Institute who developed LA/IT associated with contralateral cortical lesions without visible subtentorial MRI pathology. Demographics, MRI findings and tremor evolution in relation to specific therapies were recorded. RESULTS: Five patients (M=1/F=4), age range 29-51 that developed LA/IT associated with a contralateral cortical MRI lesion were identified. LA/IT developed after an average of 3.1years (range 0-8years) from disease onset. The contralateral cortical MRI lesion became visible on average 23.2months before the development of limb ataxia/intention tremor. Central sulcus widening was noted suggesting local atrophy. Median nerve somatosensory evoked potentials revealed asymmetric reductions in N20 amplitudes. Abnormalities in latencies and amplitudes were also noted in the posterior tibial somatosensory evoked potentials, ipsilateral to the lesion. Symptomatic therapeutic interventions were only partially beneficial. CONCLUSION: Limb ataxia/intention tremor can be associated with a demyelinating lesion involving cortical and adjacent subcortical white matter, in the absence of rubro-cerebellar lesions. Aggressive therapeutic intervention to control the cortical inflammatory process is recommended.

Arterial, venous and other vascular risk factors in multiple sclerosis.

PURPOSE OF REVIEW: This article reviews vascular risk factors with specific emphasis on lipid abnormalities reported to be associated with multiple sclerosis (MS). RECENT FINDINGS: The current paradigm of MS, supported only partially by MS lesion histopathology and its animal model (experimental allergic encephalomyelitis) considers MS to be a predominantly autoimmune disease. Until recently, most of the known risk factors for MS were interpreted in the context of the autoimmune theory, which still fails to explain why genetically close populations exposed to similar pathogens and/or environmental risk factors have different incidences of MS. Therapies which partially modulate the inflammatory arm of MS pathogenesis, fail to achieve similar benefits in later disease stages, when less inflammatory lesions and more neurodegeneration are present. Several studies have reported an increased cardiovascular morbidity in MS patients and that vascular comorbidity at any time during the disease course also increased the risk of progressive disability. A condition named chronic cerebrospinal venous insufficiency provided a different perspective, on the possible association of MS with the abnormalities of the venous system. Our recent findings revealed increased prevalence of chronic cerebrospinal venous insufficiency associated with MS disease progression as well as with other neurologic disorders. On the other hand, recently emerging evidence indicates that there is an association between lipoproteins and cholesterol metabolism and MS disease progression. Expanded disability status scale worsening was associated with higher baseline low-density lipoprotein and total cholesterol, and higher serum high-density lipoprotein levels were associated with lower contrast-enhancing T1-weigthed lesion volume. It is thought that apolipoprotein A-1 and paraoxonase anti-oxidant enzyme are associated with high-density lipoprotein and contribute to its anti-oxidant and anti-inflammatory properties. A significant inter-dependence was also recently demonstrated between vitamin D, one of the best known environmental risk factors for MS and MS disease progression and the serum lipid profile. Future work in this direction is required in order to better elucidate the role of lipid metabolism and vascular pathology in pathogenesis of MS.

Vitamin D and multiple sclerosis.

BACKGROUND: Epidemiological data support a potential relationship between vitamin D deficiency and an increased risk of developing multiple sclerosis (MS). In vitro studies have expanded the potential role of vitamin D and its receptor beyond calcium modulation, regulation, and maintenance of bone mineralization, to include immune modulation. REVIEW SUMMARY: Whether vitamin D immunomodulatory effects can be translated into clinical benefits in MS patients is still a matter of debate. A review of the biochemistry of vitamin D and its synthesized derivatives is discussed in the context of treating vitamin D deficiency. Animal studies, which led to some human studies, are also discussed. Future studies are pending and will likely yield conclusive results as to the benefit and possible synergistic effects of vitamin D with other disease-modifying therapies of MS. CONCLUSIONS: Further prospective studies are needed to identify vitamin D levels during the various phases of MS, including relapses, remissions and progression, and to determine whether correcting vitamin D during any or all of these phases may affect the incidence or even the course of the disease.

The nervous system's potential role in multiple sclerosis associated bone loss.

Osteoporosis is a degenerative bone disease that causes significant morbidity and mortality in multiple sclerosis (MS) patients; the pathogenesis of this disease being poorly understood in the context of MS. Osteoporosis is seen more frequently in MS patients than in healthy controls matched for age and sex. Extensively studied factors, including impaired ambulation and the use of steroids, do not appear to completely account for the phenomenon. This review summarizes common risk factors, physiologic and genetic, that may contribute to the etiology and progression of osteoporosis in MS patients as well as providing insight into nervous system control of bone metabolism and homeostasis.