Ketamine for postoperative avoidance of depressive symptoms: the K-PASS feasibility randomised trial.

Background: Surgical patients with previous depression frequently experience postoperative depressive symptoms. This study's objective was to determine the feasibility of a placebo-controlled trial testing the impact of a sustained ketamine infusion on postoperative depressive symptoms. Methods: This single-centre, triple-blind, placebo-controlled randomised clinical trial included adult patients with depression scheduled for inpatient surgery. After surgery, patients were randomly allocated to receive ketamine (0.5 mg kg-1 over 10 min followed by 0.3 mg kg-1 h-1 for 3 h) or an equal volume of normal saline. Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale. On post-infusion day 1, participants guessed which intervention they received. Feasibility endpoints included the fraction of patients approached who were randomised, the fraction of randomised patients who completed the study infusion, and the fraction of scheduled depression assessments that were completed. Results: In total, 32 patients were allocated a treatment, including 31/101 patients approached after a protocol change (31%, 1.5 patients per week). The study infusion was completed without interruption in 30/32 patients (94%). In each group, 7/16 participants correctly guessed which intervention they received. Depression assessments were completed at 170/192 scheduled time points (89%). Between baseline and post-infusion day 4 (pre-specified time point of interest), median depressive symptoms decreased in both groups, with difference-in-differences of -1.00 point (95% confidence interval -3.23 to 1.73) with ketamine compared with placebo. However, the between-group difference did not persist at other time points. Conclusions: Patient recruitment, medication administration, and clinical outcome measurement appear to be highly feasible, with blinding maintained. A fully powered trial may be warranted. Clinical trial registration: NCT05233566.

Spontaneous spinal cord infarction: a practical approach.

Spontaneous spinal cord infarction is significantly less common than cerebrovascular disease. Because of the tight anatomical distribution of pathways in the cord, small spinal cord infarcts usually give more obvious symptoms and signs than similar lesions in the brain. Large epidemiological stroke studies have generally not included spinal cord stroke and so the incidence of vascular syndromes in the spinal cord is unknown. Management and prevention strategies for spontaneous spinal cord infarcts stem from small case series and case reports. Patient outcomes from spinal cord infarction are better with prompt recognition, timely management and prevention of associated medical complications arising from paraplegia, tetraplegia, neurogenic bladder and bowel dysfunction. The process of rehabilitation following spinal cord infarction is an evolving area.

"Can We Vaccinate Everybody?" A Rehabilitation Ward's Experience of an Inpatient COVID-19 Vaccination Program.

Gwynne Holford Ward (GHW) is an inpatient rehabilitation Unit at Queen Mary's Hospital in London, UK, which provides care for patients with amputation rehabilitation needs (10 beds) as well as Level 1 and 2 specialist neurorehabilitation needs (26 beds). The ward MDT has encouraged all inpatients to be vaccinated either during or prior to admission. We have conducted a weekly snapshot audit over a 3-week period in March 2021, which has shown an increase of the percentage of inpatients vaccinated, progressively from 68.75% to 80%, and 73% of vaccinated inpatients received the vaccine whilst on the ward. We also conducted inpatient interviews, which highlighted that: (1) opening dialogue about vaccines increased uptake of COVID-19 vaccine; (2) patients felt that all vaccination sites provided quick, efficient service; and (3) all patients who received the first COVID-19 vaccine were willing to have the second COVID-19 vaccine. Finally, although there were many hurdles faced whilst organizing the inpatient vaccination process, we have been able to cumulatively vaccinate 80% of rehabilitation inpatients making our ward a safer place to work and rehabilitate.

Therapeutic Hyperthermia Is Associated With Improved Survival in Afebrile Critically Ill Patients With Sepsis: A Pilot Randomized Trial.

OBJECTIVES: To test the hypothesis that forced-air warming of critically ill afebrile sepsis patients improves immune function compared to standard temperature management. DESIGN: Single-center, prospective, open-label, randomized controlled trial. SETTING: One thousand two hundred-bed academic medical center. PATIENTS: Eligible patients were mechanically ventilated septic adults with: 1) a diagnosis of sepsis within 48 hours of enrollment; 2) anticipated need for mechanical ventilation of greater than 48 hours; and 3) a maximum temperature less than 38.3°C within the 24 hours prior to enrollment. Primary exclusion criteria included: immunologic diseases, immune-suppressing medications, and any existing condition sensitive to therapeutic hyperthermia (e.g., brain injury). The primary outcome was monocyte human leukocyte antigen (HLA)-DR expression, with secondary outcomes of CD3/CD28-induced interferon gamma (IFN-γ) production, mortality, and 28-day hospital-free days. INTERVENTIONS: External warming using a forced-air warming blanket for 48 hours, with a goal temperature 1.5°C above the lowest temperature documented in the previous 24 hours. MEASUREMENTS AND MAIN RESULTS: We enrolled 56 participants in the study. No differences were observed between the groups in HLA-DR expression (692 vs 2,002; p = 0.396) or IFN-γ production (31 vs 69; p = 0.678). Participants allocated to external warming had lower 28-day mortality (18% vs 43%; absolute risk reduction, 25%; 95% CI, 2-48%) and more 28-day hospital-free days (difference, 2.6 d; 95% CI, 0-11.6). CONCLUSIONS: Participants randomized to external forced-air warming did not have a difference in HLA-DR expression or IFN-γ production. In this pilot study, however, 28-day mortality was lower in the intervention group. Future research should seek to better elucidate the impact of temperature modulation on immune and nonimmune organ failure pathways in sepsis.

The positive and the negative impacts of spasticity in patients with long-term neurological conditions: an observational study.

PURPOSE: To describe the positive and negative impacts of spasticity across different neurological disorders using the Patient Reported Impact of Spasticity Measure (PRISM), deduce any associations between severity of spasticity and its impact, and assess for differences across diagnostic subgroups. MATERIALS AND METHODS: PRISM, a spasticity-specific quality of life questionnaire validated in patients with spinal cord injuries, was given to 97 follow-up patients attending a spasticity clinic prior to symptom assessment using the REsistance to PAssive movement Scale (REPAS). RESULTS: Patients described a minor level of positive impact and a marked negative impact in the domains of "Psychological Agitation," "Daily Activities," "Need for Assistance/Positioning" and "Social Avoidance/Anxiety." Spasticity severity was, in general, a poor predictor of perceived impact, although severity and localisation of spasticity was modestly correlated with "Need for Assistance/Positioning" and "Social Embarrassment" levels. Despite comparable levels of spasticity severity, people with MS expressed a more substantial impact across some PRISM domains than did patients in other groups. CONCLUSION: PRISM can be useful to assess the impact of spasticity in various neurological conditions although further validation studies are needed.Implications for RehabilitationThe localisation of spasticity in both legs or the right arm can produce a significant impact on 'Need for Assistance/Positioning' and 'Social Embarrassment'.People with MS may experience a greater impact of spasticity than those with other neurological conditions, particularly in the domains of Social Avoidance/Anxiety and Psychological Agitation.Coexisting factors such as anxiety, depression, fatigue and pain should be investigated together with spasticity.PRISM can assist in goal setting and treatment of people with spasticity secondary to different neurological conditions.

Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients.

OBJECTIVE: To report on safety and effectiveness of subcutaneous cladribine (Litak®) in multiple sclerosis (MS) patients. METHODS: Litak® was offered to MS-patients irrespective of disease course. Litak® 10 mg was administered for 3-4 days during week 1. Based on lymphocyte count at week 4, patients received another 0-3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts. RESULTS: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17-72) years and EDSS 0-8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data (n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data (n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months. CONCLUSIONS: Litak® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.

Assessment of patients with lower urinary tract symptoms where an undiagnosed neurological disease is suspected: A report from an International Continence Society consensus working group.

AIM: Lower urinary tract symptoms (LUTS) are a common urological referral, which sometimes can have a neurological basis in a patient with no formally diagnosed neurological disease ("occult neurology"). Early identification and specialist input is needed to avoid bad LUTS outcomes, and to initiate suitable neurological management. METHODS: The International Continence Society established a neurological working group to consider: Which neurological conditions may include LUTS as an early feature? What diagnostic evaluations should be undertaken in the LUTS clinic? A shortlist of conditions was drawn up by expert consensus and discussed at the annual congress of the International Neurourology Society. A multidisciplinary working group then generated recommendations for identifying clinical features and management. RESULTS: The relevant conditions are multiple sclerosis, multiple system atrophy, normal pressure hydrocephalus, early dementia, Parkinsonian syndromes (including early Parkinson's Disease and Multiple System Atrophy) and spinal cord disorders (including spina bifida occulta with tethered cord, and spinal stenosis). In LUTS clinics, the need is to identify additional atypical features; new onset severe LUTS (excluding infection), unusual aspects (eg, enuresis without chronic retention) or "suspicious" symptoms (eg, numbness, weakness, speech disturbance, gait disturbance, memory loss/cognitive impairment, and autonomic symptoms). Where occult neurology is suspected, healthcare professionals need to undertake early appropriate referral; central nervous system imaging booked from LUTS clinic is not recommended. CONCLUSIONS: Occult neurology is an uncommon underlying cause of LUTS, but it is essential to intervene promptly if suspected, and to establish suitable management pathways.

Improving the Management of Post-Stroke Spasticity: Time for Action.

OBJECTIVE: To identify barriers to appropriate referral and treatment for patients with spasticity and present solutions that address these in a pragmatic way. METHODS: Using the findings of interviews conducted with UK healthcare professionals on the management of post-stroke spasticity, a consensus meeting was held involving 7 UK spasticity experts. The panel identified barriers to timely identification and referral of patients in the acute and post-acute care settings. Barriers were prioritized using a consensus framework based on impact and resolvability and a series of final recommendations were agreed. RESULTS: High-priority barriers broadly related to: insufficient awareness of spasticity symptoms and benefits of treatment, limited access to spasticity services and lack of standardized pathways for post-stroke spasticity identification. Potential solutions included the appointment of an experienced member of the acute team to gain expertise in spasticity identification, patient education of spasticity symptoms and a greater utilization of training resources for healthcare professionals. CONCLUSION: To address the barriers identified, we provide a series of consensus recommendations. As a key recommendation, we propose a set of indicators for the identification of stroke patients requiring specialist assessment and the use of the associated acronym "ACTION".

Monocyte Function and Clinical Outcomes in Febrile and Afebrile Patients With Severe Sepsis.

INTRODUCTION: Absence of fever is associated with higher mortality in septic patients, but the reason for this is unknown. Immune dysfunction may be a potential link between failure to mount a fever and poor outcomes. The purpose of this study was to evaluate monocyte function and clinical surrogates of immunity (i.e., mortality and acquisition of secondary infections) in febrile and afebrile septic patients. METHODS: Single-center, prospective cohort study of 92 critically ill septic patients. Patients were categorized into febrile (≥38.0°C) and afebrile (<38.0°C) groups based on temperature measurements within 24 hours of sepsis diagnosis. HLA-DR expression and LPS-induced TNF-α production were quantified on days 1-2, days 3-4, and days 6-8 after sepsis diagnosis. A repeated measures mixed models analysis was used to compare these markers between the two groups. RESULTS: Forty-four patients (47.8%) developed a fever within 24 h of sepsis diagnosis. There were no significant differences in HLA-DR expression or LPS-induced TNF-α production between febrile and afebrile patients at any individual time point. However, HLA-DR expression significantly increased between days 1-2 and days 6-8 (median difference 8118 [IQR 1,662, 9,878] antibodies/cell, P = 0.002) in febrile patients, but not in afebrile patients (median difference 403 [-3,382, 3,507] antibodies/cell, P = 0.25). Afebrile patients demonstrated higher 28-day mortality (37.5% vs 18.2%) and increased acquisition of secondary infections (35.4% vs. 15.9%). CONCLUSIONS: Absence of fever is associated with suppressed HLA-DR expression over time, a finding suggestive of monocyte dysfunction in sepsis, as well as worse clinical outcomes.

Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: This meta-analysis aimed to examine the impact of antipyretic therapy on mortality in critically ill septic adults. DATA SOURCES: Literature searches were implemented in Ovid Medline, Embase, Scopus, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, and ClinicalTrials.gov through February 2016. STUDY SELECTION: Inclusion criteria were observational or randomized studies of septic patients, evaluation of antipyretic treatment, mortality reported, and English-language version available. Studies were excluded if they enrolled pediatric patients, patients with neurologic injury, or healthy volunteers. Criteria were applied by two independent reviewers. DATA EXTRACTION: Two reviewers independently extracted data and evaluated methodologic quality. Outcomes included mortality, frequency of shock reversal, acquisition of nosocomial infections, and changes in body temperature, heart rate, and minute ventilation. Randomized and observational studies were analyzed separately. DATA SYNTHESIS: Eight randomized studies (1,507 patients) and eight observational studies (17,432 patients) were analyzed. Antipyretic therapy did not reduce 28-day/hospital mortality in the randomized studies (relative risk, 0.93; 95% CI, 0.77-1.13; I = 0.0%) or observational studies (odds ratio, 0.90; 95% CI, 0.54-1.51; I = 76.1%). Shock reversal (relative risk, 1.13; 95% CI, 0.68-1.90; I = 51.6%) and acquisition of nosocomial infections (relative risk, 1.13; 95% CI, 0.61-2.09; I = 61.0%) were also unchanged. Antipyretic therapy decreased body temperature (mean difference, -0.38°C; 95% CI, -0.63 to -0.13; I = 84.0%), but not heart rate or minute ventilation. CONCLUSIONS: Antipyretic treatment does not significantly improve 28-day/hospital mortality in adult patients with sepsis.

Magnetization transfer imaging in multiple sclerosis treated with alemtuzumab.

The magnetization transfer ratio reflects the integrity of tissue structure, including myelination and axonal density. Mean magnetization transfer ratio fell in 18 untreated patients with multiple sclerosis both in normal appearing grey (-0.25 pu/year, p < 0.001) and white matter (-0.12 pu/year, p = 0.004). Conversely, mean magnetization transfer ratio was stable in 20 alemtuzumab-treated patients (grey matter: -0.01 pu/year, p = 0.87; white matter: -0.02 pu/year, p = 0.51). The gradient difference in grey matter was 0.25 pu/year (p < 0.001) after age-adjustment. These data suggest that in multiple sclerosis alemtuzumab protects against tissue damage in normal-appearing grey matter, perhaps by preventing new lesion formation.

Patient inclusion in goal setting during early inpatient rehabilitation after acquired brain injury.

OBJECTIVE: To investigate the effects of patient participation in multidisciplinary goal setting during early inpatient rehabilitation after acquired brain injury. DESIGN: Case controlled retrospective study. SETTING: Regional neurological rehabilitation unit. SUBJECTS: One hundred and five patients with acquired brain injury. MAIN MEASURES: Numbers of goals set and achieved per patient before and after intervention; Barthel Index and Functional Independence Measure. RESULTS: The intervention resulted in a significant increase in the number of goals set per patient (340 versus 411 total goals, mean per patient 6.3 pre versus 8.05 post, P = 0.008). More patients had multiple goals set within each domain (P = 0.023). There was an increase in the number of patients with sleeping (0 pre, 9 post), continence (3 pre, 17 post) and leisure (15 pre, 35 post) goals set, and leisure goals achieved (60% pre and 68% post, P < 0.001). Correlations between goal achievement and change in activity-related outcome measures (Barthel Index and Functional Independence Measure) also improved with the new goal setting process. The proportion of goals achieved remained similar (60% pre and 63% post intervention), suggesting there was no evidence of inappropriate or unachievable goals set when the patient and family were included. CONCLUSIONS: Real-time engagement of brain-injured patients in the goal setting process during early inpatient rehabilitation is achievable, but requires a structured multidisciplinary assessment of need. We found it increases the number of domains in which goals are set and includes functional areas not rated by commonly used global measures of outcome during inpatient rehabilitation.

Comparison of the impact on health-related quality of life of repeated detrusor injections of botulinum toxin in patients with idiopathic or neurogenic detrusor overactivity.

STUDY TYPE: Therapy (case series). LEVEL OF EVIDENCE: 4. What's known on the subject? and What does the study add? We know that repeated injections of botulinum toxin A are effective in treating refractory detrusor overactivity particularly in NDO. This study shows that in both NDO and IDO repeated injections of the toxin improve quality of life as assessed by three validated questionnaires. The effect is most marked after the first injection in NDO patients but thereafter similar in both groups. OBJECTIVE: To compare the effect of repeated detrusor injections of botulinum toxin (BoNT-A) on health-related quality of life (HRQL) in patients with idiopathic (IDO) or neurogenic detrusor overactivity (NDO). PATIENTS AND METHODS: Between 2003 and 2009, 151 patients (109 with NDO and 42 with IDO) were treated by BoNT-A (Botox®, Allergan Inc., Irvine, CA, USA). Changes in HRQL were assessed using the validated short forms of Urogenital Distress Inventory (UDI-6), the Incontinence Impact Questionnaire (IIQ-7) and EuroQOL-5D (EQ-5D) before and 4 weeks after BoNT-A. RESULTS: The maximum number of repeated injections was five (mean±sd, 2.8±1.05). Mean±sd follow-up was 27.49±17.01 months. The UDI-6 and IIQ-7 questionnaires showed a consistent improvement after repeated injections in both groups with detrusor overactivity. The EQ-5D was not statistically different before and after each injection in either the NDO or IDO population. After repeated injections, no statistical differences in the change on the UDI-6 and IIQ-7 scores were found between NDO and IDO, except after the first treatment, when the decrease in UDI-6 was higher in NDO than in IDO. The EQ-5D anxiety and depression subscore improved in both groups after each injection and with the number of injections. In IDO, after the second injection, no patient reported extreme anxiety or depression and, after the fourth injection, none had anxiety or depression. The inter-injection interval was shorter after the first injection in those with NDO than in IDO but was similar thereafter. CONCLUSIONS: Intradetrusor injections of BoNT-A improved the HRQL of both NDO and IDO patients. Although improvement in HRQL was greater and the duration of efficacy shorter in NDO patients after the first injection, there was no significant difference after subsequent injections. Mean inter-injection interval in IDO and in NDO patients was similar from the second injection onwards and improvements in HRQL score were the same.

Method for simultaneous voxel-based morphometry of the brain and cervical spinal cord area measurements using 3D-MDEFT.

PURPOSE: To investigate whether a 3D-modified driven equilibrium Fourier transform (MDEFT)-based acquisition protocol established for brain morphometry also yields reliable information about the cross-sectional spinal cord area (SCA). MATERIALS AND METHODS: Images of brain and cervical cord of 10 controls and eight subjects with spinal cord injury (SCI) were acquired with the 3D-MDEFT-based imaging protocol and an 8-channel receive head coil. The new protocol was validated by two observers 1) comparing the SCA measured with the standard acquisition protocol (3D magnetization-prepared rapid acquisition gradient echo [MPRAGE] and dedicated spine coil) and the new protocol; and 2) determining the scan-rescan reproducibility of the new protocol. RESULTS: Scan-rescan reproducibility of SCA measurements with the MDEFT approach showed a similar precision for both observers with standard deviation (SD) <4.5 mm(2) and coefficient of variation (CV) ≤5.1%. Analysis of variance (ANOVA) revealed a main effect of observer and interaction between observer and scan protocol that could be primarily attributed to a small observer bias for MPRAGE (difference in SCA <2.1 mm(2)). No bias was observed for 3D-MDEFT vs. 3D-MPRAGE. CONCLUSION: The 3D-MDEFT method allows for robust unbiased assessment of SCA in addition to brain morphology.

Review of neurologic diseases for the urologist.

This article reviews the neurologic conditions associated with a high prevalence of bladder dysfunction and about which significant advances in understanding have occurred in recent years. The importance of the frontal lobes for bladder control has been confirmed through functional brain imaging, and recent findings in the elderly with incontinence suggest the problem may result from disconnection of important frontal areas caused by white matter disease. The very different urologic profile of the two sometimes-confused conditions, multiple system atrophy and Parkinson's disease, is clarified. The advances in treatments for multiple sclerosis in recent years have been remarkable and are briefly described.

The safety of baclofen in pregnancy: intrathecal therapy in multiple sclerosis.

Intrathecal baclofen is a GABA-receptor agonist and one of the mainstay treatments of severe spasticity due to multiple sclerosis (MS). The authors report a case on the use of intrathecal baclofen administered using a Medtronic Synchromed II infusion pump. A healthy male infant (2.68 kg, Apgars 9 and 10) was born at 36 weeks gestation by cesarean section, under general anesthetic. This is the fifth reported case of intrathecal baclofen administered during pregnancy and adds to the knowledge that thus far it is relatively safe in pregnancy and may in fact be safer for the infant than oral baclofen. This is the first case report of the use of intrathecal baclofen in pregnancy and MS.

A novel cause of intrathecal baclofen overdosage: lessons to be learnt.

CASE PRESENTATION: A serious intrathecal baclofen overdose occurred in a 45-year-old woman with primary progressive multiple sclerosis following a catheter dye study with concomitant change in baclofen concentration. The pump and catheter were emptied of baclofen 2000 microg/mL, refilled and primed with baclofen 1000 microg/mL. No correction was made for the ;dead space' between the reservoir and catheter access port, which contained baclofen 2000 microg/mL. Failure of the priming bolus to account for the residual baclofen concentration within the dead space resulted in a serious overdose.Action: Amendments are being made to both our local and the Medtronic protocols. CONCLUSION: We hope that by reporting this incident the risk of this potentially fatal error re-occurring is minimized.

Relapse rates and enhancing lesions in a phase II trial of natalizumab in multiple sclerosis.

BACKGROUND: Natalizumab, a humanized monoclonal IgG4 antibody, is an alpha4-integrin antagonist, which inhibits the migration of inflammatory cells into the central nervous system, a key pathogenic mechanism in multiple sclerosis (MS). In a six month, phase II clinical trial of patients with relapsing MS, natalizumab significantly reduced the formation of new gadolinium-enhanced (Gd+) lesions and the number of clinical relapses. OBJECTIVE: To investigate the relationship of historical relapse rate and new Gd + lesion number with subsequent MS disease activity and natalizumab treatment in the phase II study. METHODS: Patients who participated in the phase II study were stratified into subgroups according to: (i) the number of relapses in the two years prior to entry into the study: 2 relapses (n = 108), 3 relapses (n =57), and >3 relapses (n =48); (ii) the number of new Gd + lesions at baseline (Month 0): 0 (n = 129), 1-2 (n =50), and >2 (n =33). Relapses and new Gd + lesions during the treatment phase of the trial were determined and compared for each subgroup. RESULTS: Both the prestudy relapse rate and number of new Gd + lesions at baseline were related to the subsequent risk of a relapse; baseline number of Gd + lesions was related to the likelihood of subsequent new Gd + lesion formation. There was a lower proportion of subjects with an on-study relapse and fewer new Gd + lesions in all natalizumab-treated subgroups when compared with their placebo counterpart; the difference was most apparent in the subgroups of patients with >3 relapses in the two years prior to study entry and >2 new Gd -- lesions at Month 0. CONCLUSIONS: There was a lower proportion of subjects with an on-study relapse in natalizumab-treated patients, particularly in those with a more active disease at study entry. Larger ongoing phase III studies will allow more definitive investigation of these preliminary subgroup findings.

Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis.

BACKGROUND: Natalizumab, a humanized monoclonal anti-adhesion molecule antibody, reduces the frequency of new gadolinium (Gd) enhancing lesions and relapses in multiple sclerosis (MS). Its effect on evolution of new Gd enhancing lesions to T1 hypointense lesions is unknown. METHODS: 213 patients were randomized to receive 3 mg/kg or 6 mg/kg natalizumab or placebo monthly for 6 months and then followed for a further 6 months. A subset of patients who had one or more new gadolinium enhancing lesions from Month 0 to Month 6 and available electronic data were analysed. Each new Gd enhancing lesion that developed during treatment (months 1-6) was investigated for conversion to a new T1 hypointense lesion at month 12. Lesions were classified as large or small if their cross-sectional area was greater or less than 20 mm2. Because of the similarity of both doses of natalizumab on the frequency of new Gd enhancing lesions, the two natalizumab arms were combined in all analyses. RESULTS: Compared with the placebo group, the natalizumab group exhibited significant decreases in: (i) the proportion of patients with new Gd enhancing lesions that evolved to T1-hypointense lesions (10/38 [26 %] versus 27/40 [68 %]; p<0.01); (ii) the proportion of patients who developed large T1 hypointense lesions (2/38 [5 %] versus 16/40 [40 %]; p<0.01); (iii) the proportion of new Gd enhancing lesions that became T1 hypointense (11/75 [15 %] versus 118/466 [25 %]; p=0.045); (iv) the mean proportion per patient of new Gd enhancing lesions that converted to T1-hypointense lesions (0.15 versus 0.28; p=0.005), and (v) the odds ratio (OR) of converting from Gd enhancing to T1-hypointense lesions (OR=0.48; 95% CI=0.24, 0.94, p=0.031). CONCLUSION: Natalizumab significantly suppresses the evolution of new Gd enhancing to T1-hypointense lesions. This may reflect several mechanisms including reduced cell migration across the blood brain barrier, reduced T cell activation within lesions, an inhibitory effect on subsequent axonal damage within the new central nervous system lesion, and a reduced likelihood of recurrent lesion inflammation.