David Paling

Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial

BACKGROUND Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis. METHODS We did a randomised, placebo-controlled, double-blind phase 2 trial at two UK academic hospitals in London and Sheffield. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratified by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifying treatment, and use of corticosteroids for acute optic neuritis. Participants and treating and assessing physicians were masked to group assignment. The primary outcome was retinal nerve fibre layer (RNFL) thickness in the affected eye at 6 months, adjusted for fellow-eye RNFL thickness at baseline, analysed in a modified intention-to-treat population of all randomised participants who were followed up at 6 months. Safety was analysed in the entire population, including those who were lost to follow-up. The trial is registered with ClinicalTrials.gov, number NCT 01451593. FINDINGS We recruited 86 participants between Feb 3, 2012, and May 22, 2014 (42 assigned to phenytoin and 44 to placebo). 29 were assigned to phenytoin 4 mg/kg and 13 to phenytoin 6 mg/kg. Five participants were lost to follow-up, so the primary analysis included 81 participants (39 assigned to phenytoin and 42 to placebo). Mean 6-month RNFL thickness in the affected eye at 6 months was 81.46 μm (SD 16.27) in the phenytoin group (a mean decrease of 16.69 μm [SD 13.73] from baseline) versus 74.29 μm (15.14) in the placebo group (a mean decrease of 23.79 μm [13.97] since baseline; adjusted 6-month difference of 7.15 μm [95% CI 1.08-13.22]; p=0.021), corresponding to a 30% reduction in the extent of RNFL loss with phenytoin compared with placebo. Treatment was well tolerated, with five (12%) of 42 patients having a serious adverse event in the phenytoin group (only one, severe rash, was attributable to phenytoin) compared with two (5%) of 44 in the placebo group. INTERPRETATION These findings support the concept of neuroprotection with phenytoin in patients with acute optic neuritis at concentrations at which it blocks voltage-gated sodium channels selectively. Further investigation in larger clinical trials in optic neuritis and in relapsing multiple sclerosis is warranted. FUNDING US National Multiple Sclerosis Society, Multiple Sclerosis Society of Great Britain and Northern Ireland, Novartis, UK National Institute for Health Research (NIHR), and NIHR UCLH/UCL Biomedical Research Centre.

Sodium accumulation is associated with disability and a progressive course in multiple sclerosis

Neuroaxonal loss is a major substrate of irreversible disability in multiple sclerosis, however, its cause is not understood. In multiple sclerosis there may be intracellular sodium accumulation due to neuroaxonal metabolic dysfunction, and increased extracellular sodium due to expansion of the extracellular space secondary to neuroaxonal loss. Sodium magnetic resonance imaging measures total sodium concentration in the brain, and could investigate this neuroaxonal dysfunction and loss in vivo. Sodium magnetic resonance imaging has been examined in small cohorts with relapsing-remitting multiple sclerosis, but has not been investigated in patients with a progressive course and high levels of disability. We performed sodium magnetic resonance imaging in 27 healthy control subjects, 27 patients with relapsing-remitting, 23 with secondary-progressive and 20 with primary-progressive multiple sclerosis. Cortical sodium concentrations were significantly higher in all subgroups of multiple sclerosis compared with controls, and deep grey and normal appearing white matter sodium concentrations were higher in primary and secondary-progressive multiple sclerosis. Sodium concentrations were higher in secondary-progressive compared with relapsing-remitting multiple sclerosis in cortical grey matter (41.3 ± 4.2 mM versus 38.5 ± 2.8 mM, P = 0.008), normal appearing white matter (36.1 ± 3.5 mM versus 33.6 ± 2.5 mM, P = 0.018) and deep grey matter (38.1 ± 3.1 mM versus 35.7 ± 2.4 mM, P = 0.02). Higher sodium concentrations were seen in T₁ isointense (44.6 ± 7.2 mM) and T1 hypointense lesions (46.8 ± 8.3 mM) compared with normal appearing white matter (34.9 ± 3.3 mM, P < 0.001 for both comparisons). Higher sodium concentration was observed in T₁ hypointense lesions in secondary-progressive (49.0 ± 7.0 mM) and primary-progressive (49.3 ± 8.0 mM) compared with relapsing-remitting multiple sclerosis (43.0 ± 8.5 mM, P = 0.029 for both comparisons). Independent association was seen of deep grey matter sodium concentration with expanded disability status score (coefficient = 0.24, P = 0.003) and timed 25 ft walk speed (coefficient = -0.24, P = 0.01), and of T1 lesion sodium concentration with the z-scores of the nine hole peg test (coefficient = -0.12, P < 0.001) and paced auditory serial addition test (coefficient = -0.081, P < 0.001). Sodium concentration is increased within lesions, normal appearing white matter and cortical and deep grey matter in multiple sclerosis, with higher concentrations seen in secondary-progressive multiple sclerosis and in patients with greater disability. Increased total sodium concentration is likely to reflect neuroaxonal pathophysiology leading to clinical progression and increased disability.

Energy failure in multiple sclerosis and its investigation using MR techniques

Energy failure is an emerging concept in multiple sclerosis research. Pathological studies have indicated that axonal modifications in response to demyelination may increase neuronal energy demand. At the same time, soluble mediators of inflammation may impair mitochondrial function, and brain perfusion may also be decreased. Insufficient energy production for demand can lead to intracellular sodium accumulation, calcium influx and cell death. Magnetic resonance (MR) is a promising technique to investigate these pathology driven hypotheses in vivo. MR spectroscopy can inform on mitochondrial function with measures of N acetyl aspartate (NAA), and requirement for extra-mitochondrial glycolysis via measurement of lactate. MR measurement of phosphorous (31P) and sodium (23Na) allows direct assessment of energy availability and axonal sodium handling. MR techniques for imaging perfusion can quantify oxygen delivery and nascent MR techniques that exploit the paramagnetism of deoxyhaemaglobin may be able to quantify oxygen utilization. This report reviews the physical principles underlying these techniques, their implementation for human in vivo imaging, and their application in neurological conditions with an emphasis on multiple sclerosis. Combination of these techniques to obtain a comprehensive picture of oxygen delivery, energy production and utilization may provide new insights into the pathophysiology of multiple sclerosis and may provide outcome measures for trials of novel treatments.

Reduced R2′ in multiple sclerosis normal appearing white matter and lesions may reflect decreased myelin and iron content

Background R2′ is an MRI measure of microscopic magnetic field inhomogeneity, and is increased by the paramagnetic effect of iron and the diamagnetic effect of myelin. R2′ may detect features of multiple sclerosis (MS) not evident with conventional MRI. Methods Multiecho T2 and T2* weighted sequences were obtained from 21 healthy controls (nine men, 12 women; mean age 36 years) and 28 MS patients (seven men, 21 women; 18 relapsing remitting, 10 secondary progressive; mean age 42 years). T2 and T2* relaxation time maps were created from the multiecho sequences, and R2′ maps were created using the formula R2′ = R2*−R2 = 1/T2*−1/T2. R2′ was measured in MS white matter lesions and in regions of interest in normal appearing white matter (NAWM) and grey matter in all subjects. Results R2′ was reduced in NAWM in MS compared with controls (9.5/s vs 10.1/s, p=0.05). R2′ was additionally reduced in lesions, both T1 isointense (8.5/s vs 9.5/s, p=0.02) and T1 hypointense (7.7/s vs 9.5/s, p=0.003) compared with NAWM. R2′ tended to be higher in the basal ganglia of MS patients compared with controls, and was significantly higher in the caudate nucleus in secondary progressive MS (12.9/s vs 10.9/s, p=0.03). Increased T2 lesion volume predicted an increase in R2′ in the caudate (β=0.412, p=0.02). Conclusions Reduction in R2′ in NAWM and lesions is consistent with a decreases in myelin, tissue iron and/or deoxyhaemoglobin. Increased caudate R2′ in patients with secondary progressive MS is consistent with increased iron deposition, as corroborated by other techniques.

Cerebral arterial bolus arrival time is prolonged in multiple sclerosis and associated with disability

Alterations in the overall cerebral hemodynamics have been reported in multiple sclerosis (MS); however, their cause and significance is unknown. While potential venous causes have been examined, arterial causes have not. In this study, a multiple delay time arterial spin labeling magnetic resonance imaging sequence at 3T was used to quantify the arterial hemodynamic parameter bolus arrival time (BAT) and cerebral blood flow (CBF) in normal-appearing white matter (NAWM) and deep gray matter in 33 controls and 35 patients with relapsing–remitting MS. Bolus arrival time was prolonged in MS in NAWM (1.0±0.2 versus 0.9±0.2 seconds, P=0.031) and deep gray matter (0.90±0.18 versus 0.80±0.14 seconds, P=0.001) and CBF was increased in NAWM (14±4 versus 10±2 mL/100 g/min, P=0.001). Prolonged BAT in NAWM (P=0.042) and deep gray matter (P=0.01) were associated with higher expanded disability status score. This study demonstrates alteration in cerebral arterial hemodynamics in MS. One possible cause may be widespread inflammation. Bolus arrival time was longer in patients with greater disability independent of atrophy and T2 lesion load, suggesting alterations in cerebral arterial hemodynamics may be a marker of clinically relevant pathology.

Carotid sinus syndrome is common in very elderly patients undergoing tilt table testing and carotid sinus massage because of syncope or unexplained falls

Background and aims: Although the incidence of falls and syncope increase with age, the underlying mechanisms are not fully understood, particularly in very old patients. We report diagnostic outcomes of tilt table and carotid sinus massage (TT/CSM) testing in a population of older old subjects (82% over 80 years of age) referred for TT/CSM from a falls clinic for assessment of syncope or unexplained falls. Methods: Prospective observational study between January 1, 2001 and January 1, 2005 involving 290 consecutive subjects undergoing TT/CSM testing according to European Society of Cardiology guidelines for the diagnosis and management of syncope. Results: Combination of TT/CSM provided a positive result in 62% of subjects, and was significantly more likely to be positive in subjects over the age of 80 (68% vs 50%, p=0.001). Carotid sinus syndrome (CSS) was the most common diagnosis, and was significantly more common in subjects over 80 (48% vs 34%, p=0.022) particularly due to a higher incidence of mixed CSS (16% vs 7%, p=0.023). There was no significant difference in the diagnosis of subjects referred due to falls and those reporting syncope (p=0.93). No cardiovascular or neurological adverse events occurred. Conclusions: In our cohort of very elderly patients, the diagnostic accuracy of tilt testing and carotid sinus massage was high and adverse incidents absent when testing was indicated by a geriatrician experienced in the assessment of falls and syncope. We advocate the use of TT/CSM testing as part of a comprehensive falls/syncope assessment for the diagnostic evaluation of older patients presenting with unexplained falls and/or syncope in whom structured assessment has not identified a cause for their symptoms.

Multiple sclerosis update: use of MRI for early diagnosis, disease monitoring and assessment of treatment related complications

MRI has long been established as the most sensitive in vivo technique for detecting multiple sclerosis (MS) lesions. The 2010 revisions of the McDonald Criteria have simplified imaging criteria, such that a diagnosis of MS can be made on a single contrast-enhanced MRI scan in the appropriate clinical context. New disease-modifying therapies have proven effective in reducing relapse rate and severity. Several of these therapies, most particularly natalizumab, but also dimethyl fumarate and fingolimod, have been associated with progressive multifocal leukoencephalopathy (PML). PML-immune reconstitution inflammatory syndrome (IRIS) has been recognized in patients following cessation of natalizumab owing to PML, and discontinuation for other reasons can lead to the phenomenon of rebound MS. These complications often provide a diagnostic dilemma and have implications for imaging surveillance of patients. We demonstrate how the updated McDonald Criteria aid the diagnosis of MS and describe the imaging characteristics of conditions such as PML and PML-IRIS in the context of MS. Potential imaging surveillance protocols are considered for the diagnosis and assessment of complications. We will explain how changes in MS treatment are leading to new imaging demands in order to monitor patients for disease progression and treatment-related complications.

MIDODRINE HYDROCHLORIDE IS SAFE AND EFFECTIVE IN OLDER PEOPLE WITH NEUROCARDIOGENIC SYNCOPE

To the Editor: Midodrine hydrochloride, an alpha 1-adrenergic receptor agonist that increases peripheral blood pressure by constricting arterial and venous beds, has been shown to be effective in the management of syncope in adults with orthostatic hypotension, vasovagal syncope, and vasodepressor carotid sinus syndrome, although its use, tolerability, and side effects have not been monitored specifically in older adults, particularly not over a prolonged period of time. Data are reported from a prospective registry of 135 consecutive elderly subjects (mean age 84) referred to a geriatric unit for assessment of syncope or unexplained falls from January 1, 2001, to January 1, 2005. All patients referred to the unit underwent investigation according to European Society of Cardiology guidelines. Patients who had a suspected diagnosis of neurally mediated syncope or had falls that remained unexplained and were severe or frequent underwent tilt table testing and carotid sinus massage maneuvers based upon a variation of a protocol established previously. Of 290 patients evaluated during the study period, 52 men and 83 women aged 64 to 97 who had a clinically significant tilt table test or carotid sinus massage and severe symptoms and remained symptomatic after standard treatments (e.g., patient education, physical counter-pressure maneuvers to abort imminent faints, advice on salt intake and hydration, avoidance of situational triggers, and standing training) were offered midodrine, initially at a dose of 2.5 mg three times a day. Dose was titrated up at clinic visits in increments of 2.5 mg, and patients were monitored for a median length of time of 2.7 years. Ninety-seven individuals (71%) reported cessation or significant reduction in their symptoms for all of the tilt table diagnoses (Figure 1), and 29% reported no benefit. Thirtyfour subjects (25%) had stopped taking the drug by the end of follow-up: failure to maintain symptom control (n 5 14), inability to keep patient appointments (n 5 7), significant clinical deterioration unrelated to midodrine (n 5 7), and adverse drug reactions (n 5 6). Of the remaining 101 individuals taking midodrine until the end of follow-up, 49% received 2.5 mg three times per day, 30% required 5 mg three times daily, and 21% required higher dosages. Incidences of adverse drug reactions were assessed at each clinic visit, and although 19 patients reported drug-related side effects, only six ceased taking midodrine, whereas 13 continued treatment. Reasons for drug discontinuation were hypertension (n 5 3), lower urinary tract obstructive symptoms (n 5 1), palpitations (n 5 1), and nausea (n 5 1). In conclusion, midodrine hydrochloride appears to be safe and well tolerated in older adults and should be considered in the management of patients with symptomatic orthostatic hypotension, vasovagal syncope, and vasodepressor or mixed carotid sinus syndrome independent of age after standard treatments have been tried. This observation requires further confirmation in randomized control studies.

SODIUM ACCUMULATION IS ASSOCIATED WITH DISABILITY AND PROGRESSION IN MULTIPLE SCLEROSIS: A 23NA MRI STUDY

Introduction Neuroaxonal loss is the major pathological substrate of irreversible disability in Multiple Sclerosis (MS). Sodium is maintained at lower concentration within the intra–axonal space by the Na/K/ATPase pump. In MS, failure of the pump secondary to neuroaxonal metabolic dysfunction increases the intracellular sodium concentration, which in turn leads to neuroaxonal loss by causing intra–axonal calcium import.1 Since sodium is at higher concentration within the extracellular space, neuroaxonal loss and replacement with extracellular fluid also increases sodium concentration. Sodium (23Na) magnetic resonance imaging enables quantitation of total sodium concentration in the brain, and could help to quantify the extent neuroaxonal dysfunction and loss in different tissue types and different MS subgroups in vivo, and their association with clinical disability. Previous studies have shown increased sodium concentration in lesions, normal appearing white matter (NAWM) and grey matter in patients with relapsing remitting MS (RRMS)2 3 however whether similar increases are seen in patients with primary progressive MS (PPMS) and secondary progressive MS (SPMS) and whether sodium accumulation is associated with disability in these patients is not known. Methods We performed 23Na MRI imaging on 27 healthy controls, 27 patients with RRMS, 23 patients SPMS and 20 patients with PPMS. Sodium concentration was quantified in segmented NAWM, cortical grey matter, basal ganglia and T2 hyperintense, T1 hypointense and T1 isointense lesions. Results Cortical sodium concentrations were significantly higher in all subgroups of MS compared to controls, and NAWM and basal ganglia sodium concentrations were higher in PPMS and SPMS compared to controls. T2 hyperintense, T1 hypointense and T1 isointense lesion sodium concentrations were higher than NAWM. Sodium concentrations were higher in SPMS compared to RRMS in cortical grey matter (mean 41.3±4.2mM vs. 38.5±2.8 mM, p=0.028), NAWM (36.1±3.5 mM vs. 33.6±2.5 mM, p<0.001), and basal ganglia (38.1±3.1 mM vs. 35.7±2.4 mM, p=0.02). Sodium concentrations were also higher in T1 hypointense lesions in PPMS (49.3±8.0 mM vs. 43.0 mM, p=0.029) and SPMS (49.0±7.0 mM vs. 43.0±8.5 mM) compared to RRMS. Multivariate analysis showed significant independent associations of basal ganglia sodium concentration with EDSS (coefficient=0.244, p=0.003) and timed 25ft walk speed (coefficient=–0.24, p=0.01), and of T1 lesion sodium concentration with the z scores of the 9 hole peg test (coefficient –0.12, p<0.001) and paced auditory serial addition test (coefficient =–0.08, p<0.001). Conclusions Significant increases in sodium were seen in lesions and normal appearing brain tissues in MS. Increased concentration of sodium in lesions, cortical grey matter, NAWM and basal ganglia in SPMS versus RRMS indicates greater neuroaxonal metabolic dysfunction and/or loss in the former group. MRI measurement of sodium concentration in vivo is likely to reflect clinically relevant neuroaxonal pathophysiology and may be a useful outcome measure in trials of putative neuroprotective treatments.