Risk assessment of vascular complications following manual therapy and exercise for the cervical region: diagnostic accuracy of the International Federation of Orthopaedic Manipulative Physical Therapists framework (The Go4Safe project).

QUESTION: What is the diagnostic accuracy of the International Federation of Orthopaedic Manipulative Physical Therapists (IFOMPT) framework to assess the risk of vascular complications in patients seeking physiotherapy care for neck pain and/or headache? DESIGN: Cross-sectional diagnostic accuracy study. PARTICIPANTS: One hundred and fifty patients seeking physiotherapy for neck pain and/or headache in primary care. METHODS: Nineteen physiotherapists performed the index test according to the IFOMPT framework. Patients were classified as having a high, intermediate or low risk of vascular complications, following manual therapy and/or exercise, derived from the estimated risk of the presence of vascular pathology. The reference test was a consensus medical decision reached by a vascular neurologist and an interventional neurologist, with input from a neuroradiologist. The neurologists had access to clinical data and magnetic resonance imaging of the cervical spine, including an angiogram of the cervical arteries. OUTCOME MEASURES: Diagnostic accuracy measures were calculated for 'no contraindication' (ie, the low-risk category) and 'contraindication' (ie, the high-risk and intermediate-risk categories) for manual therapy and/or exercise. Sensitivity, specificity, predictive values, likelihood ratios and the area under the curve were calculated. RESULTS: Manual therapy and/or exercise were contraindicated in 54.7% of the patients. The sensitivity of the IFOMPT framework was low (0.50, 95% CI 0.39 to 0.61) and its specificity was moderate (0.63, 95% CI 0.51 to 0.75). The positive and negative likelihood ratios were weak at 1.36 (95% CI 0.93 to 1.99) and 0.79 (95% CI 0.60 to 1.05), respectively. The area under the curve was poor (0.57, 95% CI 0.49 to 0.65). CONCLUSION: The IFOMPT framework has poor diagnostic accuracy when compared with a reference standard consisting of a consensus medical decision.

[18F]Fluoride PET provides distinct information on disease activity in ankylosing spondylitis as compared to MRI and conventional radiography.

PURPOSE: To relate [18F]fluoride uptake on PET with abnormalities on magnetic resonance imaging (MRI) and conventional radiography (CR) in ankylosing spondylitis (AS) patients. METHODS: Ten clinically active AS patients (female 6/10, age 38 ± 11 years) were included, and both spine and SI-joints were examined. PET scans were dichotomously scored for enhanced [18F]fluoride uptake, MRI scans were scored for fatty lesions, erosions, ankylosis, and bone marrow edema (BME), and CR was scored for erosions, syndesmophytes, and ankylosis. The overlap of lesions across all modalities was evaluated through univariate and multivariate analyses using a generalized mixed model. RESULTS: In the spine, 69 lesions with enhanced [18F]fluoride uptake, 257 MRI lesions, and 88 CR lesions were observed. PET lesions were mostly located in costovertebral and facet joints, outside the field of view (FOV) of the MRI and CR. However, PET lesions inside the FOV of MRI and CR partially showed no abnormality on MRI and CR. In lesions with abnormalities on multiple modalities, both univariate and multivariate analysis showed that PET activity had the strongest association with BME on MRI and ankylosis on CR. In the SI joints, 15 lesions (75%) with PET uptake were found, with 87% showing abnormalities on MRI and CR. CONCLUSION: [18F]fluoride PET lesions are often found outside the scope of MRI and CR, and even in the same location show only partial overlap with abnormalities on MRI (especially BME) and CR (especially ankylosis). This suggests that [18F]fluoride PET partially visualizes aspects of AS separate from MRI and CR, providing novel information. CLINICAL TRIAL REGISTRATION: NL43223.029.13 registered at 02-05-2013.  https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=C1257BA2002CC066C1257B4E0049A65A.

Risk factors of late lesion growth after acute ischemic stroke treatment.

Background: Even days after treatment of acute ischemic stroke due to a large vessel occlusion, the infarct lesion continues to grow. This late, subacute growth is associated with unfavorable functional outcome. In this study, we aim to identify patient characteristics that are risk factors of late, subacute lesion growth. Methods: Patients from the MR CLEAN trial cohort with good quality 24 h and 1-week follow up non-contrast CT scans were included. Late Lesion growth was defined as the difference between the ischemic lesion volume assessed after 1-week and 24-h. To identify risk factors, patient characteristics associated with lesion growth (categorized in quartiles) in univariable ordinal analysis (p < 0.1) were included in a multivariable ordinal regression model. Results: In the 226 patients that were included, the median lesion growth was 22 (IQR 10-45) ml. In the multivariable model, lower collateral capacity [aOR: 0.62 (95% CI: 0.44-0.87); p = 0.01], longer time to treatment [aOR: 1.04 (1-1.08); p = 0.04], unsuccessful recanalization [aOR: 0.57 (95% CI: 0.34-0.97); p = 0.04], and larger midline shift [aOR: 1.18 (95% CI: 1.02-1.36); p = 0.02] were associated with late lesion growth. Conclusion: Late, subacute, lesion growth occurring between 1 day and 1 week after ischemic stroke treatment is influenced by lower collateral capacity, longer time to treatment, unsuccessful recanalization, and larger midline shift. Notably, these risk factors are similar to the risk factors of acute lesion growth, suggesting that understanding and minimizing the effects of the predictors for late lesion growth could be beneficial to mitigate the effects of ischemia.

Time Since Stroke Onset, Quantitative Collateral Score, and Functional Outcome After Endovascular Treatment for Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: In patients with ischemic stroke undergoing endovascular treatment (EVT), time to treatment and collateral status are important prognostic factors and may be correlated. We aimed to assess the relation between time to CT angiography (CTA) and a quantitatively determined collateral score and to assess whether the collateral score modified the relation between time to recanalization and functional outcome. METHODS: We analyzed data from patients with acute ischemic stroke included in the Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke Registry between 2014 and 2017, who had a carotid terminus or M1 occlusion and were treated with EVT within 6.5 hours of symptom onset. A quantitative collateral score (qCS) was determined from baseline CTA using a validated automated image analysis algorithm. We also determined a 4-point visual collateral score (vCS). Multivariable regression models were used to assess the relations between time to imaging and the qCS and between the time to recanalization and functional outcome (90-day modified Rankin Scale score). An interaction term (time to recanalization × qCS) was entered in the latter model to test whether the qCS modifies this relation. Sensitivity analyses were performed using the vCS. RESULTS: We analyzed 1,813 patients. The median time from symptom onset to CTA was 91 minutes (interquartile range [IQR] 65-150 minutes), and the median qCS was 49% (IQR 25%-78%). Longer time to CTA was not associated with the log-transformed qCS (adjusted ß per 30 minutes, 0.002, 95% CI -0.006 to 0.011). Both a higher qCS (adjusted common odds ratio [acOR] per 10% increase: 1.06, 95% CI 1.03-1.09) and shorter time to recanalization (acOR per 30 minutes: 1.17, 95% CI 1.13-1.22) were independently associated with a shift toward better functional outcome. The qCS did not modify the relation between time to recanalization and functional outcome (p for interaction: 0.28). Results from sensitivity analyses using the vCS were similar. DISCUSSION: In the first 6.5 hours of ischemic stroke caused by carotid terminus or M1 occlusion, the collateral status is unaffected by time to imaging, and the benefit of a shorter time to recanalization is independent of baseline collateral status.

The Role of Edema in Subacute Lesion Progression After Treatment of Acute Ischemic Stroke.

Background: Ischemic lesions commonly continue to progress even days after treatment, and this lesion growth is associated with unfavorable functional outcome in acute ischemic stroke patients. The aim of this study is to elucidate the role of edema in subacute lesion progression and its influence on unfavorable functional outcome by quantifying net water uptake. Methods: We included all 187 patients from the MR CLEAN trial who had high quality follow-up non-contrast CT at 24 h and 1 week. Using a CT densitometry-based method to calculate the net water uptake, we differentiated total ischemic lesion volume (TILV) into edema volume (EV) and edema-corrected infarct volume (ecIV). We calculated these volumes at 24 h and 1 week after stroke and determined their progression in the subacute period. We assessed the effect of 24-h lesion characteristics on EV and ecIV progression. We evaluated the influence of edema and edema-corrected infarct progression on favorable functional outcome after 90 days (modified Rankin Scale: 0-2) after correcting for potential confounders. Lastly, we compared these volumes between subgroups of patients with and without successful recanalization using the Mann-Whitney U-test. Results: Median TILV increased from 37 (IQR: 18-81) ml to 68 (IQR: 30-130) ml between 24 h and 1 week after stroke, while the net water uptake increased from 22 (IQR: 16-26)% to 27 (IQR: 22-32)%. The TILV progression of 20 (8.8-40) ml was mostly caused by ecIV with a median increase of 12 (2.4-21) ml vs. 6.5 (2.7-15) ml of EV progression. Larger TILV, EV, and ecIV volumes at 24 h were all associated with more edema and lesion progression. Edema progression was associated with unfavorable functional outcome [aOR: 0.53 (0.28-0.94) per 10 ml; p-value: 0.05], while edema-corrected infarct progression showed a similar, non-significant association [aOR: 0.80 (0.62-0.99); p-value: 0.06]. Lastly, edema progression was larger in patients without successful recanalization, whereas ecIV progression was comparable between the subgroups. Conclusion: EV increases in evolving ischemic lesions in the period between 1 day and 1 week after acute ischemic stroke. This progression is larger in patients without successful recanalization and is associated with unfavorable functional outcome. However, the extent of edema cannot explain the total expansion of ischemic lesions since edema-corrected infarct progression is larger than the edema progression.

Posttreatment Ischemic Lesion Evolution Is Associated With Reduced Favorable Functional Outcome in Patients With Stroke.

Background and Purpose: Ischemic lesion volume can increase even 24 hours after onset of an acute ischemic stroke. In this study, we investigated the association of lesion evolution with functional outcome and the influence of successful recanalization on this association. Methods: We included patients from the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) who received good quality noncontrast CT images 24 hours and 1 week after stroke onset. The ischemic lesion delineations included infarct, edema, and hemorrhagic transformation. Lesion evolution was defined as the difference between the volumes measured on the 1-week and 24-hour noncontrast CTs. The association of lesion evolution with functional outcome was evaluated using unadjusted and adjusted logistic regression. Adjustments were made for baseline, clinical, and imaging parameters that were associated P<0.10) in univariate analysis with favorable functional outcome, defined as modified Rankin Scale score of ≤2. Interaction analysis was performed to evaluate the influence of successful recanalization, defined as modified Arterial Occlusion Lesion score of 3 points, on this association. Results: Of the 226 patients who were included, 69 (31%) patients achieved the favorable functional outcome. Median lesion evolution was 22 (interquartile range, 10­45) mL. Lesion evolution was significantly inversely correlated with favourable functional outcome: unadjusted odds ratio, 0.76 (95% CI, 0.66­0.86; per 10 mL of lesion evolution; P<0.01) and adjusted odds ratio: 0.85 (95% CI, 0.72­0.97; per 10 mL of lesion evolution; P=0.03). There was no significant interaction of successful recanalization on the association of lesion evolution and favorable functional outcome (odds ratio, 1.01 [95% CI, 0.77­1.36]; P=0.94). Conclusions: In our population, subacute ischemic lesion evolution is associated with unfavorable functional outcome. This study suggests that even 24 hours after onset of stroke, deterioration of the brain continues, which has a negative effect on functional outcome. This finding may warrant additional treatment in the subacute phase.

Interexaminer Agreement and Reliability of an Internationally Endorsed Screening Framework for Cervical Vascular Risks Following Manual Therapy and Exercise: The Go4Safe Project.

OBJECTIVE: Clinicians are recommended to use the clinical reasoning framework developed by the International Federation of Orthopaedic Manipulative Physical Therapists (IFOMPT) to provide guidance regarding assessment of the cervical spine and potential for cervical artery dysfunction prior to manual therapy and exercise. However, the interexaminer agreement and reliability of this framework is unknown. This study aimed to estimate the interexaminer agreement and reliability of the IFOMPT framework among physical therapists in primary care. METHODS: Ninety-six patients who consulted a physical therapist for neck pain or headache were included in the study. Each patient was tested independently by 2 physical therapists, from a group of 17 physical therapists (10 pairs) across The Netherlands. Patients and examiners were blinded to the test results. The overall interexaminer agreement, specific agreement per risk category (high-, intermediate-, and low-risk), and interexaminer reliability (weighted κ) were calculated. RESULTS: Overall agreement was 71% (specific agreement in high-risk category = 63%; specific agreement in intermediate-risk category = 38%; specific agreement in low-risk category = 84%). Overall reliability was moderate (weighted κ = 0.39; 95% CI = 0.21-0.57) and varied considerably between pairs of physical therapists (κ = 0.14-1.00). CONCLUSION: The IFOMPT framework showed an insufficient interexaminer agreement and fair interexaminer reliability among physical therapists when screening the increased risks for vascular complications following manual therapy and exercise prior to treatment. IMPACT: The IFOMPT framework contributes to the safety of manual therapy and exercise. It is widely adopted in clinical practice and educational programs, but the measurement properties are unknown. This project describes the agreement and reliability of the IFOMPT framework.

Case report: Candida krusei spondylitis in an immunocompromised patient.

BACKGROUND: Invasive infections with Candida krusei are uncommon and rarely complicated by spondylitis. Previous described cases were solely treated with antimycotic therapy, despite guidelines recommending surgical interventions. CASE PRESENTATION: We describe a case of C. krusei spondylitis in a patient treated with chemotherapy for acute myeloid leukemia. After induction chemotherapy, the patient developed a candidemia, which was treated with micafungin. One month after the candidemia, the patient was admitted with severe lumbar pain. Spondylitis of the L4 and L5 vertebra was diagnosed on MR-imaging, with signs suggesting an atypical infection. The patient was treated with anidulafungin combined with voriconazole. Despite maximal conservative management symptoms gradually worsened eventually requiring surgical intervention. CONCLUSIONS: In contrast to previous case reports, antimycotic treatment alone could be insufficient in treating C. krusei spondylitis.

Case report: chronic relapsing cryptococcal meningitis in a patient with low mannose-binding lectin and a low naïve CD4 cell count.

BACKGROUND: Cryptococcal meningitis is most commonly found in HIV-infected patients. In HIV-negative patients, its low incidence can lead to prolonged time to diagnosis. Detailed case reports of chronic cryptococcal meningitis are scarce, but could provide clues for earlier diagnosis in this patient category. CASE PRESENTATION: A 60-year old man presented June 2015 with intermittent headaches for several months without any fever. Initial work-up showed a leukocytosis, raised CSF opening pressure and raised leukocytes and protein in the CSF. An MRI revealed leptomeningeal contrast enhancement and cerebellar oedema. While malignancy and various infectious causes were excluded, the patient had a spontaneous clinical and radiological recovery. One year later, the patient returned with complaints of headaches. Also, cerebellar oedema and leptomeningeal contrast enhancement had recurred. Eventually in March 2017, the novel cryptococcal antigen lateral flow assay (CrAg LFA) was positive on CSF, and one colony of Cryptococcus neoformans was cultured from CSF. The patient was treated with the standard antifungal regimen which resulted in resolution of his headaches. In retrospect, the cryptococcal antigen test was already positive on a serum sample from June 2015. Interestingly, post-treatment immunological analysis revealed both a low mannose-binding lectin (MBL) concentration and low naïve CD4 counts. CONCLUSIONS: We present a patient with cryptococcal meningitis in an HIV-negative patient with low MBL and low naïve CD4 count suffering a chronic relapsing meningo-encephalitis with relatively mild symptoms for around 2 years. In patients with an unexplained meningo-encephalitis such as this case, early performance of CrAg LFA on serum and/or CSF is an inexpensive and rapid method to reduce time-to diagnosis.

Impact of single phase CT angiography collateral status on functional outcome over time: results from the MR CLEAN Registry.

BACKGROUND: Collateral status modified the effect of endovascular treatment (EVT) for stroke in several randomized trials. We assessed the association between collaterals and functional outcome in EVT treated patients and investigated if this association is time dependent. METHODS: We included consecutive patients from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN) Registry (March 2014-June 2016) with an anterior circulation large vessel occlusion undergoing EVT. Functional outcome was measured on the modified Rankin Scale (mRS) at 90 days. We investigated the association between collaterals and mRS in the MR CLEAN Registry with ordinal logistic regression and if this association was time dependent with an interaction term. Additionally, we determined modification of EVT effect by collaterals compared with MR CLEAN controls, and also investigated if this was time dependent with multiplicative interaction terms. RESULTS: 1412 patients were analyzed. Functional independence (mRS score of 0-2) was achieved in 13% of patients with grade 0 collaterals, in 27% with grade 1, in 46% with grade 2, and in 53% with grade 3. Collaterals were significantly associated with mRS (adjusted common OR 1.5 (95% CI 1.4 to 1.7)) and significantly modified EVT benefit (P=0.04). None of the effects were time dependent. Better collaterals corresponded to lower mortality (P<0.001), but not to lower rates of symptomatic intracranial hemorrhage (P=0.14). CONCLUSION: In routine clinical practice, better collateral status is associated with better functional outcome and greater treatment benefit in EVT treated acute ischemic stroke patients, independent of time to treatment. Within the 6 hour time window, a substantial proportion of patients with absent and poor collaterals can still achieve functional independence.

Bone formation in ankylosing spondylitis during anti-tumour necrosis factor therapy imaged by 18F-fluoride positron emission tomography.

Objectives: Excessive bone formation is an important hallmark of AS. Recently it has been demonstrated that axial bony lesions in AS patients can be visualized using 18F-fluoride PET-CT. The aim of this study was to assess whether 18F-fluoride uptake in clinically active AS patients is related to focal bone formation in spine biopsies and is sensitive to change during anti-TNF treatment. Methods: Twelve anti-TNF-naïve AS patients [female 7/12; age 39 years (SD 11); BASDAI 5.5 ± 1.1] were included. 18 F-fluoride PET-CT scans were performed at baseline and in two patients, biopsies were obtained from PET-positive and PET-negative spine lesions. The remaining 10 patients underwent a second 18F-fluoride PET-CT scan after 12 weeks of anti-TNF treatment. PET scans were scored visually by two blinded expert readers. In addition, 18F-fluoride uptake was quantified using the standardized uptake value corrected for individual integrated whole blood activity concentration (SUVAUC). Clinical response to anti-TNF was defined according to a ⩾ 20% improvement in Assessment of SpondyloArthritis international Society criteria at 24 weeks. Results: At baseline, all patients showed at least one axial PET-positive lesion. Histological analysis of PET-positive lesions in the spine confirmed local osteoid formation. PET-positive lesions were found in the costovertebral joints (43%), facet joints (23%), bridging syndesmophytes (20%) and non-bridging vertebral lesions (14%) and in SI joints (75%). After 12 weeks of anti-TNF treatment, 18F-fluoride uptake in clinical responders decreased significantly in the costovertebral (mean SUVAUC -1.0; P < 0.001) and SI joints (mean SUVAUC -1.2; P = 0.03) in contrast to non-responders. Conclusions: 18F-fluoride PET-CT identified bone formation, confirmed by histology, in the spine and SI joints of AS patients and demonstrated alterations in bone formation during anti-TNF treatment.

Angiogenesis in steno-occlusive vasculopathies as a common pathway for intracranial haemorrhage. A report of six cases.

Vasculopathies, including vasculitis of the central nervous system, can lead to stenosed, cicatrized vessels and the development of arterio-arteriolar collateral vessels. Bleeding due to these vascular changes, although rare, does occur. We describe six patients (all female, age range, 21-52 years; mean age, 42 years) with steno-occlusive lesions of intracranial vessels who presented with an acute intracranial haemorrhage. All had arterial steno-occlusive changes in conjunction with extensive leptomeningeal and arterio-arteriolar collaterals. Within the collaterals, focal dilatations could be identified, which were in close spatial relationship with the intracranial haemorrhage. Cause of bleeding was depicted on CT angiography in four out of six patients. One patient presented in childhood with acute stroke, one patient was diagnosed with Buerger's disease and one with sickle cell disease; the other three patients had no relevant history and the exact cause remained unclear. Outcome was favourable in all patients. Despite focal vascular weaknesses, no recurrent haemorrhage was seen during follow-up, supporting, at least in this small patient group, a conservative wait-and-see policy.

Direct orbital puncture of the cavernous sinus for the treatment of a carotid-cavernous dural AV fistula with a concomitant venous/lymphatic malformation.

A 37- year old male with a long history of a left orbital venous/lympathic malformation presented with ocular injection, increased proptosis and reduced left vision. Angiography demonstrated a carotid cavernous dural AV fistula combined with a concomitant venous/lymphatic malformation. After attempts at transvenous embolization, a direct uncomplicated transorbital puncture of the cavernous sinus via a lateral orbitotomy was performed with complete resolution of ocular symptoms.

Clinical outcome after repeated radiosurgery for brain arteriovenous malformations.

INTRODUCTION: We assessed the clinical and radiological outcome after repeated radiosurgery for brain arteriovenous malformations (bAVMs) after failure of initial radiosurgery. MATERIALS AND METHODS: Fifteen patients underwent repeated radiosurgery. The mean bAVM volume at first radiosurgery (S1) was 4.6 +/- 4.3 ml and that at second radiosurgery (S2) was 2.1 +/- 2.5 ml. The median marginal dose was 18 Gy at S1, and 21 Gy at S2. Modified Rankin Scale (MRS) score was determined in all patients at last follow-up (FU). RESULTS: Complete obliteration was reached in nine patients (60%). Median time to obliteration was 50 months after S2. An excellent outcome (no new neurologic deficiencies, complete obliteration) was reached in seven patients (47%). Eleven patients (73%) showed a MRS1. Radiation-induced complications occurred in 20%, of which 13% occurred after S2. Radiological complications included cyst formation (n = 1), radiation-related edema (n = 4), and radiation necrosis (n = 1), resulting in an increasing mean MRS of 0.5 at S1, 0.6 at S2, to 0.8 at FU. No (re-)bleedings were encountered during 137-patient years at risk. DISCUSSION: Repeated radiosurgery is a viable option for the treatment of small remnant bAVMs. We report 20% permanent radiation-induced complications. Such complications were mainly seen in relatively large, and therefore difficult to treat, bAVMs.

Functional connectivity in the brain before and during intra-arterial amobarbital injection (Wada test).

We explored the effect of unilateral intracarotid sodium amobarbital injection during the Wada test (intra-arterial amobarbital procedure, IAP) on functional connectivity in the brain assessed by synchronization analysis of the EEG. Patients suffering from pharmaco-resistant epilepsy who were selected for epilepsy surgery and underwent a preoperative IAP to determine language dominance and contralateral memory capacity were eligible. All patients had brain abnormalities (mostly tumors) or mesial temporal sclerosis. Ipsilateral intrahemispheric, contralateral intrahemispheric, and interhemispheric synchronization likelihood (SL) was calculated in seven frequency bands before and during the IAP. Forty-two patients who underwent the IAP (34 left carotid injections, 32 right carotid injections) were included. In the delta and theta bands, SL increased over the hemisphere ipsilateral to injection, while contralateral and interhemispheric SL decreased. The SL increased in the beta band. In the gamma bands, differences between patients with right-sided and left-sided lesions were observed. When a left hemisphere lesion was present, SL increased after injection, while a more unequivocal pattern of change was present in patients with right hemisphere lesions. Our results indicate that amobarbital injection has effects on functional connectivity of both the anaesthetized and non-anaesthetized hemispheres. Synchronization consistently increases in the injected hemisphere. Functional connectivity in the contralateral hemisphere decreases in the lower frequency bands, while it tends to increase in the beta and gamma bands (depending on lesion lateralization). These results indicate that functional connectivity in both the injected as well as in the contralateral hemisphere is strongly influenced by the IAP.

Longitudinal brain volume measurement in multiple sclerosis: rate of brain atrophy is independent of the disease subtype.

BACKGROUND: In multiple sclerosis (MS), brain atrophy depicted by magnetic resonance imaging reflects overall tissue loss, including axonal loss. OBJECTIVE: To determine the course of atrophy by studying the rate of development of brain atrophy in patients who have different subtypes of MS. METHODS: Eighty-three patients with MS (42 with relapsing-remitting, 21 with secondary progressive, and 20 with primary progressive) were studied longitudinally, with an interval of 2 to 4 years. Magnetic resonance imaging included T1- and T2-weighted images to obtain 2 brain volume measurements: (1) the parenchymal fraction as a marker of global brain atrophy and (2) the ventricular fraction as a marker of central atrophy. The annualized rate of global and central brain atrophy was compared between those with different subtypes of MS and related to clinical characteristics, including sex, age, disease duration, and disability. RESULTS: There was a significant decrease of the parenchymal fraction (-0.7% per year; SEM, 0.11% per year) and a significant increase of ventricular fraction (3.7% per year; SEM, 0.54% per year) in the total group. Significant tissue loss was also seen in all 3 subtypes of MS; the decrease in parenchymal fraction was not different between subtypes, whereas the increase in ventricular fraction tended to be larger in patients with secondary progressive MS compared with patients with primary progressive MS. Marginal associations were found between clinical determinants and the rate of brain atrophy. Annualized increase in the ventricular fraction was correlated with age (r = -0.26) and duration of symptoms (r = -0.22): younger patients (mainly patients with relapsing-remitting MS who have a limited disability) displayed a larger increase in ventricular fraction compared with older patients. CONCLUSIONS: The rate of development of brain atrophy is largely independent of the course of the disease and other clinical characteristics. The relentless loss of tissue occurring in MS is not restricted to later (progressive) phases of the disease, thereby stressing the need for early neuroprotective treatment in MS.