Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). Historically management has been palliative or supportive care. Hematopoietic stem cell transplantation is poorly effective in early-onset MLD and benefit in late-onset MLD remains controversial. Hematopoietic stem cell gene therapy, Libmeldy (atidarsagene autotemcel), was recently approved by the European Medicines Agency for early-onset MLD. Treatment benefit is mainly observed at an early disease stage, indicating the need for early diagnosis and intervention. This study contributes insights into the caregiver language used to describe initial MLD symptomatology, and thereby aims to improve communication between clinicians and families impacted by this condition and promote a faster path to diagnosis. RESULTS: Data was collected through a moderator-assisted online 60-min survey and 30-min semi-structured follow-up telephone interview with 31 MLD caregivers in the United States (n = 10), France (n = 10), the United Kingdom (n = 5), and Germany (n = 6). All respondents were primary caregivers of a person with late infantile (n = 20), juvenile (n = 11) or borderline late infantile/juvenile (n = 1) MLD (one caregiver reported for 2 children leading to a sample of 32 individuals with MLD). Caregivers were asked questions related to their child's initial signs and symptoms, time to diagnosis and interactions with healthcare providers. These results highlight the caregiver language used to describe the most common initial symptoms of MLD and provide added context to help elevate the index of suspicion of disease. Distinctions between caregiver descriptions of late infantile and juvenile MLD in symptom onset and disease course were also identified. CONCLUSIONS: This study captures the caregiver description of the physical, behavioral, and cognitive signs of MLD prior to diagnosis. The understanding of the caregiver language at symptom onset sheds light on a critical window of often missed opportunity for earlier diagnosis and therapeutic intervention in MLD.

A Longitudinal Analysis of Early Lesion Growth in Presymptomatic Patients with Cerebral Adrenoleukodystrophy.

BACKGROUND AND PURPOSE: Cerebral adrenoleukodystrophy is a devastating neurological disorder caused by mutations in the ABCD1 gene. Our aim was to model and compare the growth of early cerebral lesions from longitudinal MRIs obtained in presymptomatic patients with progressive and arrested cerebral adrenoleukodystrophy using quantitative MR imaging-based lesion volumetry. MATERIALS AND METHODS: We retrospectively quantified and modeled the longitudinal growth of early cerebral lesions from 174 MRIs obtained from 36 presymptomatic male patients with cerebral adrenoleukodystrophy. Lesions were manually segmented using subject-specific lesion-intensity thresholding. Volumes were calculated and plotted across time. Lesion velocity and acceleration were calculated between sequentially paired and triplet MRIs, respectively. Linear mixed-effects models were used to assess differences in growth parameters between progressive and arrested phenotypes. RESULTS: The median patient age was 7.4 years (range, 3.9-37.0 years). Early-stage cerebral disease progression was inversely correlated with age (ρ = -0.6631, P < .001), early lesions can grow while appearing radiographically stable, lesions undergo sustained acceleration in progressive cerebral adrenoleukodystrophy (ß = 0.10 mL/month2 [95% CI, 0.05-0.14 mL/month2], P < .001), and growth trajectories diverge between phenotypes in the presymptomatic time period. CONCLUSIONS: Measuring the volumetric changes in newly developing cerebral lesions across time can distinguish cerebral adrenoleukodystrophy phenotypes before symptom onset. When factored into the overall clinical presentation of a patient with a new brain lesion, quantitative MR imaging-based lesion volumetry may aid in the accurate prediction of patients eligible for therapy.

Pathophysiology of X-linked adrenoleukodystrophy.

Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset, leading to death within a few years, to adults remaining pre-symptomatic through more than five decades. There is no general genotype-phenotype correlation in X-ALD. The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy. In about 60% of male X-ALD patients, either in childhood (35-40%) or in adulthood (20%), an initial, clinically silent, myelin destabilization results in conversion to a devastating, rapidly progressive form of cerebral inflammatory demyelination. Here, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur. Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon-glial interactions seem pertinent to the dying-back axonopathy. Various dynamic mechanisms may underlie the initiation of inflammation, the altered immune reactivity, the propagation of inflammation, as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation. An improved understanding of the molecular mechanisms involved in these events is required for the development of urgently needed therapeutics.

FOXP3 expression in cancer cells and anthracyclines efficacy in patients with primary breast cancer treated with adjuvant chemotherapy in the phase III UNICANCER-PACS 01 trial.

BACKGROUND: Predictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors. PATIENTS AND METHODS: Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells. RESULTS: Four hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline-taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy. CONCLUSION: FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer.

Metachromatic leukodystrophy: a scoring system for brain MR imaging observations.

BACKGROUND AND PURPOSE: Metachromatic leukodystrophy (MLD) is a devastating demyelinating disease for which novel therapies are being tested. We hypothesized that MR imaging of brain lesion involvement in MLD could be quantified along a scale. MATERIALS AND METHODS: Thirty-four brain MR images in 28 patients with proved biochemical and genetic defects for MLD were reviewed: 10 patients with late infantile, 16 patients with juvenile, and 2 patients with adult MLD. All MR images were reviewed by experienced neuroradiologists and neurologists (2 readers in Germany, 2 readers in the United States) for global disease burden, as seen on the T2 and fluid-attenuated inversion recovery images. A visual scoring method was based on a point system (range, 0-34) derived from the location of white matter involvement and the presence of global atrophy, analogous to the scoring system developed for adrenoleukodystrophy. The readers were blinded to the neurologic findings. RESULTS: Thirty-three of 34 MR images showed confluent T2 hyperintensities of white matter. The inter-rater reliability coefficient was 0.988. Scores between readers were within 2 points of each other. Serial MR imaging studies in 6 patients showed significant progressive disease in 3 patients (initial score average, 4; mean follow-up, 24.3) and no change or 1 point progression in 3 patients (initial score average, 12; mean follow-up, 12.66). Projection fibers and the cerebellum tended to be involved only in advanced stages of disease. CONCLUSIONS: The MLD MR severity scoring method can be used to provide a measure of brain MR imaging involvement in MLD patients.

Cortical demyelination in PML and MS: Similarities and differences.

OBJECTIVE: To characterize pathologic changes in the cerebral cortex of patients with multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML). METHODS: Autopsy brain tissue was obtained from 13 patients with PML, 4 patients with MS, 2 patients with HIV encephalopathy, and 1 subject without neurologic pathology. Immunohistochemistry for myelin proteins, inflammatory cells, and neurofilaments was performed to evaluate the distribution of cortical lesions, their inflammatory activity, and neuritic pathology. Confocal microscopy was applied to examine pathologic changes in neurites in PML cortex. RESULTS: Leukocortical, intracortical, and subpial patterns of cortical demyelination were represented in MS brain tissue. In PML brain tissue intracortical and leukocortical but not subpial lesions were observed. Cortical lesions in PML and MS contained fewer inflammatory cells than demyelinated areas in the white matter. Neuritic pathology in cortical PML lesions was represented by dystrophic and transected neurites. Pathologic modifications in neuritic processes in PML were more evident in highly inflamed white matter than in gray matter areas of demyelination, reminiscent of previous reports of neuritic pathology in MS. JC virus-infected cells were associated with PML white matter, leukocortical and intracortical lesions. CONCLUSIONS: Cortical pathology represents a distinct feature of progressive multifocal leukoencephalopathy. Similarities and differences with regard to multiple sclerosis cortical pathology were noted and may be informative regarding the pathogenesis of both disorders.

[Rupture of a splenic aneurism in an emergency situation]. / Ruptur eines Milzarterienaneurysmas im Notarztdienst.

We report on a 36 year old patient who collapsed at home and was resuscitated by prehospital medical emergency services. He presented on scene unconscious with severe ST-elevations on the ECG and hardly palpable pulses. His previous medical history included only idiopathic hypertension and his professional background as manager of a company was associated with high stress levels. The prehospital diagnosis was myocardial infarction with cardiogenic shock. A hypovolemic shock was excluded from the differential diagnosis because of the age of the patient, lack of a precipitating trauma and inconsistent symptoms. The patient died after terminating prolonged resuscitation. A post mortem showed as cause of death the rupture of a splenic artery aneurysm. We emphasize that a cardiovascular collapse in a young patient without specific history or trauma still can be caused by hypovolemic shock due to intra-abdominal or -thorac bleeding.

[Efficacy and safety of 0.1 mg of intrathecal morphine in arthroscopic knee joint surgery]. / Spinalanästhesie bei der Arthroskopie des Kniegelenks. Effektivität und Sicherheit von Morphin 0.1 mg als Zusatz--Eine doppelblinde, randomisierte Untersuchung.

BACKGROUND AND OBJECTIVE: Intrathecal morphine provides effective postoperative analgesia but is associated with the risk of respiratory depression. A dose of only 0.1 mg has been shown to be optimal for effective and safe pain relief after abdominal surgery. This study was designed to determine whether the addition of 0.1 mg of morphine to the local anesthetic for spinal anesthesia produces adequate analgesia following arthroscopic knee joint surgery. METHODS: A prospective, randomized, placebo-controlled, double-blind clinical trial was performed. Forty ASA I/II patients undergoing knee arthroscopy under spinal anesthesia were randomized to receive either mepivacaine 4% with 0.1 mg of morphine or mepivacaine 4% with saline (placebo) intrathecally. Postoperative analgesia consisted of intravenous morphine delivered by patient-controlled analgesia (bolus: 2 mg, lockout time: 5 min). During the study period of 24 h, pain intensity at rest and on movement (visual analogue scale, 0: no pain, 100: maximum pain), vigilance, and vital parameters were recorded every hour. RESULTS: There were no statistically significant differences between the two groups in postoperative pain scores, morphine requirements, vigilance, blood pressure, heart rate, and breathing frequency. The patients of the morphine group required 12.3+/-10.2 mg (mean+/-SD) and those of the placebo group 11.6+/-8.4 mg of intravenous morphine from patient-controlled analgesia. The pain scores at rest and on movement were 10.0+/-8.1 and 16.0+/-12.6 in the morphine group and 8.2+/-7.9 and 11.7+/-11.3 in the placebo group. We did not observe severe side effects in any of the patients. CONCLUSION: Intrathecal administration of 0.1 mg of morphine does not contribute to postoperative analgesia after arthroscopic knee joint surgery.

Proton MR spectroscopic imaging predicts lesion progression on MRI in X-linked adrenoleukodystrophy.

BACKGROUND: The phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progressive childhood cerebral form to the milder adrenomyeloneuropathy in adults. It is not possible to predict phenotype by mutation analysis or biochemical assays. Multislice proton MRS imaging (MRSI) has previously detected more extensive brain abnormalities in X-ALD than conventional MRI, which has been suggested to predict impending demyelination. However, the significance of these changes is unclear. OBJECTIVE: The purpose of this study was to determine the long-term sensitivity and specificity of MRSI for disease progression in X-ALD. METHODS: Twenty-five patients with X-ALD were investigated (average age, 15 years; range, 2-43 years) with MRI and proton MRSI at baseline and follow-up MRI over a mean period of 3.5 years. Eight patients had normal MRI findings at baseline and on follow-up (noncerebral group), 11 had abnormal MRI at baseline and no change on follow-up (cerebral nonprogressive group), and 6 had progressive MRI abnormalities (cerebral progressive group). On MRSI, voxels were analyzed in the normal MRI-appearing perilesional white matter, or in the corresponding area in the noncerebral group. RESULTS: The concentration ratio of N-acetylaspartate (NAA) to choline was the most sensitive indicator of disease progression. The average NAA/choline ratio was 5.99 for the noncerebral group, 5.75 for the cerebral nonprogressive group, and 3.74 for the cerebral progressive group (p = 0.002). At a cut-off point of 5.0, the NAA/choline ratio predicted disease progression in all patients with six cerebral progressive disease (sensitivity 100%). The specificity was 83%, the positive predictive value was 66%, and the negative predictive value was 100%. CONCLUSIONS: Multislice proton MRS imaging is able to identify impending or beginning degeneration in white matter that still appears normal on conventional MRI. Multislice proton MRSI may be a suitable technique for the prediction of lesion progression on MRI in X-linked adrenoleukodystrophy.

Position dependent changes of cerebral blood flow velocities in premature infants.

UNLABELLED: The supine or prone positioning of infants has been a cause of much controversy. Recently it has been postulated that the position dependent hypoperfusion of the brainstem represents a possible cause of sudden infant death. To demonstrate position dependency and maturational changes of cerebral perfusion in premature newborn infants we investigated cerebral blood flow velocities (CBFV) in the main supratentorial and brainstem cerebral arteries. Measurements of CBFV were done with transfontanellar colour-coded Doppler sonography in the internal carotid artery (ICA), basilar artery (BA), and vertebral artery (VA) in the prone (head centered-baseline) and supine positions (maximal rotation to both sides) in 23 premature infants aged between 3-5 days of life. We performed follow-up measurements in 17 infants 7-10 days later and in 16 infants at the corrected age of 1 month. There was no difference in mean CBFVs between the prone and supine position at the first investigation. At the third investigation, CBFVs were significantly higher in the supine compared to the prone position. The CBFVs of the ICA were higher than in the BA and VA. This difference was not influenced by the body position but increased with post-natal age more in the VA (159%) than in the BA (129%) and ICA (128%). Position dependency was not seen in the ICA perfusion. In the prone position, five infants showed an incomplete steal effect in the contralateral VA. There was no significant side difference in the CBFVs of the ICA and VA, but in the resistance indices in the VA (left > right). CONCLUSION: in premature newborns, position dependent changes of cerebral blood flow velocity develop with maturation and are most pronounced in the vertebrobasilar system. These changes are possibly due to compression of the vertebral artery by neck movement and suggest an individual risk of brainstem perfusion deficits that may be aggravated with age and head rotation in a prone position.

Diffusion tensor brain MR imaging in X-linked cerebral adrenoleukodystrophy.

Brain diffusion tensor MRI of 11 boys with X-linked adrenoleukodystrophy was performed. The authors determined quantitative isotropic apparent diffusion coefficient (ADC(i)) and fractional anisotropy (FA) values in the white matter. ADC(i) and FA values in the affected white matter were significantly different from those in normal-appearing white matter. Zonal ADC(i) and FA gradations, which might originate from well-established histopathologic zonal changes, existed within affected white matter.

[Evaluation of the cardiorespiratory monitor SpiroGuard C for infants. Improved registration of respiratory events by new sensors and intelligent alarm management system]. / Evaluierung des Herz-Atem-Uberwachungsgerätes SpiroGuard C für Säuglinge. Verbesserte Erfassung von respiratorischen Ereignissen durch neue Sensorik und intelligentes Alarmmanagement?

OBJECTIVES: The SpiroGuard C is a commercially available cardiorespiratory monitor working with field plethysmography, wireless signal transmission and a novel alarm management system. In order to determine the recognition rates for central, mixed and obstructive apneas, a prospective clinical trial was performed comparing frequency and kind of signals from the monitor with those simultaneously registered by polysomnographic studies. DESIGN: Normal respiratory and alarm signals of the monitor under investigation were integrated into a polysomnographic setting. All central, mixed and obstructive apneas lasting more than 10 seconds as well as all alarms obtained from the monitor were evaluated. RESULTS: 47 series of monitor recordings could be evaluated in parallel to polysomnographic studies: the detection rate for central apneas was 298/328 (90.85%), for mixed apneas 9/41 (21.95%) and for obstructive apneas 0/36 (0%). Out of the total of 708 registered alarms 359 (50.71%) were false alarms, 307 (43.36%) were apnea-related and 42/708 (5.93%) were alarms due to technical problems. 177 of the 359 false alarms (49.30%) occurred during apneas that were shorter than 10 seconds, 119 (33.15%) were related to bad signal quality, and 55 (15.32%) were caused by movement artifacts. CONCLUSION: The recognition rate for central apneas was high (> 90%), while sensitivity for mixed and obstructive apneas was not satisfactory. Approximately half of the alarms were false alarms. These could be reduced by setting the apnea detection time to > 15 seconds, by tighter fastening of the respiration belt (improving the signal transmission), and by turning off the instrument when the child is awake and physically active. The wireless system renders the SpiroGuard C an attractive alternative for home monitoring.

Cerebral blood flow velocities in an infant with moyamoya disease.

Moyamoya disease is a progressive cerebrovascular disorder with bilateral occlusion of the basal circulation and development of collateral blood supply. In a 6-month-old female with multifocal ischemic infarctions, transcranial pulsed Doppler sonography revealed extremely high and low cerebral blood flow velocities, dampened waveforms, reversed flow, and musical murmurs. Magnetic resonance angiography revealed different degrees of vascular stenosis and an abnormal collateral network. Moyamoya disease was confirmed by conventional angiography at the age of 10.5 months. Pulsed-wave transcranial Doppler sonography is a noninvasive screening method in infants at risk of moyamoya disease.

Cerebral Doppler sonography of the neonate. A résumé after 20 years and future aspects.

Up until recently the evaluation of CVR (analysis of pulsatility) had been a priority in Doppler sonography. In preterm and term infants with open fontanels and sutures this information is restricted despite its value in extreme situations. Continuous Doppler sonography allows a new approach to monitoring pathophysiologic processes. In connection with improved data recording and processing as well as progress in monitoring blood pressure and central venous pressure, new noninvasive methods of surveillance become possible. Thanks to these methods experimental and clinical research has increasingly gained insight on the autonomic nervous system over the last few years (e.g., m- and r-wave analysis during continuous measurement of arterial blood pressure and heart rate). Already well-known and newly developed functional tests (e.g., tilting test, CO2-reactivity, phase shift, and so forth) will further improve our understanding of physiologic processes and help us develop individual therapy concepts for the newborn.

Paclitaxel-anthracycline combination chemotherapy in relapsing advanced ovarian cancer after platinum-based chemotherapy: a pilot study.

Despite high response rates with platinum-based front-line chemotherapy, the prognosis for advanced ovarian carcinoma (AOC) is poor. Salvage chemotherapy for recurrent AOC was of little benefit before paclitaxel as single-agent therapy showed appreciable efficacy. Anthracyclines are effective, but are not often part of first-line therapy. In this pilot study, we investigated the feasibility of an anthracycline plus paclitaxel combination therapy for recurrent AOC. Twenty-four patients received 150 mg/m2 paclitaxel on day 1, with either 50 mg/m2 doxorubicin on day 1 or 75 mg/m2 epirubicin on day 1 every 3 weeks. A 27% overall response rate was obtained. Myelosuppression was the major toxicity, but was manageable. No myocardiac toxicity was observed. We conclude that paclitaxel-anthracyclines is a promising salvage combination therapy in AOC that should be investigated further.

[Anesthesia for cesarean section in Germany. A survey]. / Anästhesieverfahren zur Sectio caesarea in Deutschland. Eine Umfrage.

AIM OF STUDY: Goal of this survey is to give an overview of anaesthesia for caesarean section in Germany. METHOD: In 1994 and 1995, we sent a questionnaire to the chief-anaesthetists of all German hospitals with departments of gynaecology/obstetrics to find out the routine anaesthetic procedures for caesarean section. RESULTS: We obtained data from 409 hospitals (response rate 46.4%) with 321,816 births--50,123 of which were sections (mean caesarean section rate 16.6%). The mean general anaesthesia rate for elective caesarean sections was 66.5%, for non-elective sections 90.8%. The mean epidural anaesthesia rate for caesarean section was 22.6% and the mean spinal anaesthesia rate was 9.8%. For general anaesthesia most hospitals used antacids and/or histamine2-receptor antagonists (64.6% of responding hospitals). Anaesthesia was induced with intravenous barbiturates (82%), succinylcholine for intubation (98.2%) and no opioids before clamping of the cord (94.8%). For regional anaesthesia bupivacaine was the most common local anaesthetic (spinal 84.0%, epidural 96.8%). Opioids were added to local anaesthetics for epidural anaesthesia at 21.4% of the hospitals. CONCLUSIONS: General anaesthesia is the commonest practice for caesarean sections at German hospitals. Nowadays regional anaesthesia gains more importance compared to previous German surveys and in agreement with foreign data.