Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy

To study the frequency of additional cerebral demyelination in Dutch patients with adrenomyeloneuropathy (AMN). Consecutive patients with AMN from the Dutch X-linked adrenoleukodystrophy cohort without cerebral demyelination on MRI at inclusion, seen between January 1, 1992, and January 1, 1999, were included. Primary endpoints were brain involvement, death, or the end of follow-up on January 1, 2011. Three levels of certainty were used for cerebral demyelination: (1) signs and symptoms reported by relatives and treating physicians, confirmed by brain MRI; if follow-up MRIs were not available, (2) based upon information from treating physicians and relatives, and (3) based upon information obtained from relatives only. Results were compared with a study published in 2001, in which 13/68 (19.1%) patients with AMN developed cerebral demyelination in 9.5 ± 5.5 years. Differences of the proportions of patients with cerebral demyelination and their 95% confidence intervals (CIs) were calculated. Of 27 patients with AMN, 17 (63%) developed cerebral demyelination 10.2 ± 6.9 years after onset of myelo(neuro)pathy. Mean survival was 3.4 ± 2.9 years. Brain involvement was higher in Dutch patients with AMN (difference 44%, 95% CI 0.23-0.64). Cerebral demyelination in AMN may be more frequent than previously reported. Survival is as poor as in childhood cerebral adrenoleukodystrophy. Therapies that can halt cerebral demyelination in these patients are neede

Hematopoietic cell transplantation does not prevent myelopathy in X-linked adrenoleukodystrophy: a retrospective study

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder. Male patients develop adrenocortical insufficiency (80 % before 18 years), a chronic myelopathy (adrenomyeloneuropathy (AMN); all in adulthood), or progressive cerebral demyelination (cerebral ALD; 40 % before 18 years). Cerebral ALD is treated with haematopoetic cell transplantation (HCT). It is unknown if AMN still develops in patients with X-ALD that underwent HCT for cerebral ALD in childhood. A retrospective observational study was performed by selecting all adult patients with X-ALD in our cohort that underwent HCT in childhood. This retrospective study found that three out of five patients in our cohort who underwent HCT in childhood developed signs of myelopathy in adulthood. These data suggest that HCT for cerebral ALD in childhood does not prevent the onset of AMN in X-ALD in adulthoo

Progression of myelopathy in males with adrenoleukodystrophy: towards clinical trial readiness

Males with adrenoleukodystrophy develop progressive myelopathy causing severe disability later in life. No treatment is currently available, but new disease-modifying therapies are under development. Knowledge of the natural history of the myelopathy is of paramount importance for evaluation of these therapies in clinical trials, but prospective data on disease progression are lacking. We performed a prospective observational cohort study to quantify disease progression over 2 years of follow-up. Signs and symptoms, functional outcome measures and patient-reported outcomes were assessed at baseline, 1 and 2 years of follow-up. We included 46 male adrenoleukodystrophy patients (median age 45.5 years, range 16-71). Frequency of myelopathy at baseline increased with age from 30.8% (50 years). Disease progression was measured in the patients who were symptomatic at baseline (n = 24) or became symptomatic during follow-up (n = 1). Significant progression was detected with the functional outcome measures and quantitative vibration measurements. Over 2 years of follow-up, Expanded Disability Status Score increased by 0.34 points (P = 0.034), Severity Scoring system for Progressive Myelopathy decreased by 2.78 points (P = 0.013), timed up-and-go increased by 0.82 s (P = 0.032) and quantitative vibration measurement at the hallux decreased by 0.57 points (P = 0.040). Changes over 1-year follow-up were not significant, except for the 6-minute walk test that decreased by 19.67 meters over 1 year (P = 0.019). None of the patient-reported outcomes were able to detect disease progression. Our data show that progression of myelopathy in adrenoleukodystrophy can be quantified using practical and clinically relevant outcome measures. These results will help in the design of clinical trials and the development of new biomarkers for the myelopathy of adrenoleukodystrophy.10.1093/brain/awy299_video1awy299media15995811923001

Evaluation of the yield of 24-h close observation in patients with mild traumatic brain injury on anticoagulation therapy: a retrospective multicenter study and meta-analysis

Patients with mild traumatic brain injury (mTBI) on anticoagulants have an increased risk of intracranial hemorrhage (ICH). However, consensus is lacking on whether to admit them after normal initial cranial CT. We evaluated the yield of 24-h neurological observation. Retrospective multicenter study including adult patients admitted over a 5-year period with mTBI on anticoagulation [therapeutic dose heparin, direct oral anticoagulant, or vitamin K antagonist (VKA) with international normalized ratio (INR) ≥ 1.7] and reportedly normal cranial CT obtained within 24 h after trauma. Primary endpoint was symptomatic ICH within 24 h of injury. Literature on delayed ICH in patients with mTBI and anticoagulation use was reviewed. Of 17.643 mTBI patients, 905 met the inclusion criteria (median age 82 years). 97% used VKA (median INR 2.9). None developed delayed ICH within 24 h. Nine patients deteriorated neurologically due to ICH, four within 24 h (0.4%, 95% CI 0.1-1.2) and five on day 2, 18, 22, 36 and 52, respectively. In six patients, including all four that developed symptoms within 24 h, ICH was found upon reevaluation of initial imaging. The meta-analysis comprised of 9 studies with data from 2885 patients. The estimated pooled proportion of symptomatic delayed ICH or delayed diagnosis of ICH within 24 h was 0.2% (95% CI 0.0-0.5). Delayed (diagnosis of) ICH within 24 h is very rare in mTBI patients on anticoagulants after reportedly normal initial CT. Routine hospitalization of these patients seems unwarranted when the initial cranial CT is scrupulously evaluate

Hematopoietic cell transplantation does not prevent myelopathy in X-linked adrenoleukodystrophy : a retrospective study

Background X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder. Male patients develop adrenocortical insufficiency (80 % before 18 years), a chronic myelopathy (adrenomyeloneuropathy (AMN); all in adulthood), or progressive cerebral demyelination (cerebral ALD; 40 % before 18 years). Cerebral ALD is treated with haematopoetic cell transplantation (HCT). It is unknown if AMN still develops in patients with X-ALD that underwent HCT for cerebral ALD in childhood. Patients and methods A retrospective observational study was performed by selecting all adult patients with X-ALD in our cohort that underwent HCT in childhood. Results This retrospective study found that three out of five patients in our cohort who underwent HCT in childhood developed signs of myelopathy in adulthood. Conclusion These data suggest that HCT for cerebral ALD in childhood does not prevent the onset of AMN in X-ALD in adulthood

Disease progression in women with X-linked adrenoleukodystrophy is slow

Background: Over 80% of women with X-linked adrenoleukodystrophy (ALD) develop spinal cord disease in adulthood for which treatment is supportive only. For future clinical trials quantitative data on disease progression rates are essential. Moreover, diagnosis can be challenging in ALD women, as the most important diagnostic biomarker is normal in 15-20%. Better biomarkers are needed. The purpose of this single centre cross-sectional follow-up study in women with ALD was to assess whether Expanded Disability Status Scale (EDSS), AMC Linear Disability Scale (ALDS) and Short Form (36) Health Survey (SF-36) can detect disease progression and to model the effect of age and duration of symptoms on the rate of progression. Moreover, we performed a pilot study to assess if a semi-targeted lipidomics approach can identify possible new diagnostic biomarkers. Results: In this study 46 women (baseline clinical data published by our group previously) were invited for a follow-up visit. Newly identified women at our center were also recruited. We analysed 65 baseline and 34 follow-up assessments. Median time between baseline and follow-up was 7.8 years (range 6.4-8.7). Mean age at baseline was 49.2 ± 14.2 years, at follow-up 55.4 ± 10.1. EDSS increased significantly (+ 0.08 points/year), but the other outcome measures did not. Increasing age and duration of symptoms were associated with more disability. For the pilot study we analysed plasma of 20 ALD women and 10 controls with ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry, which identified 100 potential biomarker ratios with strong differentiating properties and non-overlapping data distributions between ALD women and controls. Conclusions: Progression of spinal cord disease can be detected with EDSS, but not with ALDS or SF-36 after a follow-up period of almost 8 years. Moreover, age and the duration of symptoms seem positively associated with the rate of progression. Although a significant progression was measurable, it was below the rate generally conceived as clinically relevant. Therefore, EDSS, ALDS and SF-36 are not suitable as primary outcome measures in clinical trials for spinal cord disease in ALD women. In addition, a semi-targeted lipidomics approach can identify possible new diagnostic biomarkers for women with ALD

Hypothermia after CPR prolongs conduction times of somatosensory evoked potentials

To investigate the effect of mild hypothermia on conduction times and amplitudes of median nerve somatosensory evoked potentials (SEP) in patients after cardiopulmonary resuscitation (CPR). Patients treated with hypothermia after CPR who underwent SEP recording during hypothermia and after rewarming were selected from a prospectively collected database. Latencies and amplitudes of N9 (peripheral conduction time, PCT), N13, and N20 were measured. The central conduction time (CCT) was defined as peak-peak latency N13-N20. Recordings of 25 patients were assessed by a second observer to determine the intraclass correlation coefficient (ICC). A total of 115 patients were included. The mean body temperature at SEP during hypothermia was 33.1 °C (SD 0.8) and after rewarming 37.1 °C (SD 0.8). Mean latencies of N9, N13, and N20 and mean CCT were longer during hypothermia. There were no consistent differences in amplitudes. There was an almost perfect ICC for assessment of latencies and amplitudes. This study showed that PCT and CCT of median nerve SEP were prolonged during treatment with hypothermia after CPR compared with after rewarming. Amplitudes did not differ consistentl

Work-related questions.

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Correlations between confounding variables and HRQoL, and working hours.

<p>Max., maximum;</p><p>*P<0.005;</p><p>**P<0.05.</p