Eva Neumaier-Probst

Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I).

SummaryGlutaryl-CoA dehydrogenase (GCDH) deficiency is an autosomal recessive disease with an estimated overall prevalence of 1 in 100 000 newborns. Biochemically, the disease is characterized by accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine, which can be detected by gas chromatography–mass spectrometry of organic acids or tandem mass spectrometry of acylcarnitines. Clinically, the disease course is usually determined by acute encephalopathic crises precipitated by infectious diseases, immunizations, and surgery during infancy or childhood. The characteristic neurological sequel is acute striatal injury and, subsequently, dystonia. During the last three decades attempts have been made to establish and optimize therapy for GCDH deficiency. Maintenance treatment consisting of a diet combined with oral supplementation of L-carnitine, and an intensified emergency treatment during acute episodes of intercurrent illness have been applied to the majority of patients. This treatment strategy has significantly reduced the frequency of acute encephalopathic crises in early-diagnosed patients. Therefore, GCDH deficiency is now considered to be a treatable condition. However, significant differences exist in the diagnostic procedure and management of affected patients so that there is a wide variation of the outcome, in particular of pre-symptomatically diagnosed patients. At this time of rapid expansion of neonatal screening for GCDH deficiency, the major aim of this guideline is to re-assess the common practice and to formulate recommendations for diagnosis and management of GCDH deficiency based on the best available evidence.

Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I

In glutaric aciduria type I, an autosomal recessive disease of mitochondrial lysine, hydroxylysine and tryptophan catabolism, striatal lesions are characteristically induced by acute encephalopathic crises during a finite period of brain development (age 3-36 months). The frequency of striatal injury is significantly less in patients diagnosed as asymptomatic newborns by newborn screening. Most previous studies have focused on the onset and mechanism of striatal injury, whereas little is known about neuroradiological abnormalities in pre-symptomatically diagnosed patients and about dynamic changes of extrastriatal abnormalities. Thus, the major aim of the present retrospective study was to improve our understanding of striatal and extrastriatal abnormalities in affected individuals including those diagnosed by newborn screening. To this end, we systematically analysed magnetic resonance imagings (MRIs) in 38 patients with glutaric aciduria type I diagnosed before or after the manifestation of neurological symptoms. To identify brain regions that are susceptible to cerebral injury during acute encephalopathic crises, we compared the frequency of magnetic resonance abnormalities in patients with and without such crises. Major specific changes after encephalopathic crises were found in the putamen (P < 0.001), nucleus caudatus (P < 0.001), globus pallidus (P = 0.012) and ventricles (P = 0.001). Analysis of empirical cumulative distribution frequencies, however, demonstrated that isolated pallidal abnormalities did not significantly differ over time in both groups (P = 0.544) suggesting that isolated pallidal abnormalities are not induced by acute crises--in contrast to striatal abnormalities. The manifestation of motor disability was associated with signal abnormalities in putamen, caudate, pallidum and ventricles. In addition, we found a large number of extrastriatal abnormalities in patients with and without preceding encephalophatic crises. These abnormalities include widening of anterior temporal and sylvian CSF spaces, pseudocysts, signal changes of substantia nigra, nucleus dentatus, thalamus, tractus tegmentalis centralis and supratentorial white matter as well as signs of delayed maturation (myelination and gyral pattern). In contrast to the striatum, extrastriatal abnormalities were variable and could regress or even normalize with time. This includes widening of sylvian fissures, delayed maturation, pallidal signal changes and pseudocysts. Based on these results, we hypothesize that neuroradiological abnormalities and neurological symptoms in glutaric aciduria type I can be explained by overlaying episodes of cerebral alterations including maturational delay of the brain in utero, acute striatal injury during a vulnerable period in infancy and chronic progressive changes that may continue lifelong. This may have widespread consequences for the pathophysiological understanding of this disease, long-term outcomes and therapeutic considerations.

Local Intra-Arterial Fibrinolysis in Acute Hemispheric Stroke: Effect of Occlusion Type and Fibrinolytic Agent on Recanalization Success and Neurological Outcome

Background: To evaluate the effect of occlusion type and fibrinolytic agent on recanalization success and clinical outcome in patients undergoing local intra-arterial fibrinolysis (LIF) in acute hemispheric stroke. Methods: LIF was performed in 137 patients with angiographically established occlusion in the carotid circulation within 6 h of stroke onset. Retrospective analysis included recanalization success, recanalization time, type of occlusion and fibrinolytic treatment mode. Five types of occlusion were categorized: intracranial bifurcation (carotid ‘T’) of the internal carotid artery (ICA; n = 35); proximal segment of the middle cerebral artery (MCA; n = 66); distal segment of the MCA (n = 20); extracranial ICA with MCA embolism (n = 8); multiple peripheral branches of the anterior cerebral artery and the MCA (n = 8). Neurologic outcome was evaluated after 3 months by Barthel Index (BI) as good (BI >90), moderate (BI 50–90), poor (BI <50) or death. Results: Recanalization was achieved in 74 patients (54%). Mean recanalization time in recanalized patients was 91 min. Neurologic outcome was good in 48 patients (35%), moderate in 34 (25%), poor in 30 (22%) and 25 died (18%). Outcome was significantly better in recanalized than in nonrecanalized patients (p < 0.001). Treatment results were significantly better in proximal and distal MCA occlusion than in carotid ‘T’ occlusions (p < 0.001). Recanalization success hardly differed between urokinase and rt-PA. Combined treatment with rt-PA and lys-plasminogen tended toward a faster recanalization. Parenchymal hemorrhage occurred in 13 patients (9%). Conclusion: The type of occlusion is of high prognostic value for successful fibrinolysis in the anterior circulation. However, recanalization is a time-consuming process even with an intra-arterial approach. Recanalization did not differ between type or dosage of plasminogen activators. Further innovative attempts are warranted towards hastening recanalization time in endovascular acute stroke treatment.

Neuroradiological findings in glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency)

Summary: This article summarizes the magnetic resonance imaging features of glutaric aciduria type I (GA I) based on the cases presented at the 3rd International Workshop on Glutaryl-CoA Dehydrogenase Deficiency together with a review of previously reported neuroimaging characteristics of GA I. Previous reports have focused on characteristic findings, such as basal ganglia injury and frontotemporal atrophy or hypoplasia, subdural effusions and white-matter disease. Most of these findings have been demonstrated in symptomatic children, i.e. after manifestation of acute encephalopathic crises. In contrast, prospective investigations in presymptomatically diagnosed children are rare. Since more recent investigations have highlighted CNS changes in patients without encephalopathic crises, systematic prospective investigations of neuroradiological findings in this disease are indispensable for a better understanding of this disease. Based on these findings a suggestion for a MRI protocol is presented, supporting a standardized evaluation of patients with GA I.

Improvement of sensitivity and interrater reliability to detect acute stroke by dynamic perfusion computed tomography and computed tomography angiography.

Objective: To assess the benefits of additional computed tomography perfusion (CTP) and computed tomography angiography (CTA) on the detection of early stroke, vessel occlusion, estimated infarct size, and interrater reliability. Methods: Sixty-seven consecutive patients underwent nonenhanced computed tomography (CT) imaging, CTA, and CTP. The final diagnosis of stroke was made from follow-up neuroimaging. A first diagnosis was made on-site by the physician on duty. Three experienced neuroradiologists blinded to follow-up findings analyzed the data set off-line, evaluated CT for signs of acute stroke, and subsequently evaluated CTP and CTA for infarction-related perfusion deficits and vessel abnormalities. Results: Computed tomography perfusion and CTA increased the time from CT start to diagnosis from 2 minutes to 10 minutes. Sensitivity to detect acute stroke increased significantly in all investigators from 0.46-0.58 to 0.79-0.90 compared with CT (<0.005). The interrater weighted kappa value increased from 0.35 to 0.64. Estimation of infarct size was not improved. Conclusion: Computed tomography perfusion and CTA provide an effective add-on to standard CT in acute stroke imaging by significantly increasing the sensitivity and reliability of infarct detection.

Slow Progression of Juvenile Metachromatic Leukodystrophy 6 Years After Bone Marrow Transplantation

Metachromatic leukodystrophy refers to a group of genetic neurologic diseases caused by deficiencies of the enzyme arylsulfatase A and the resulting accumulation of sulfatides in white matter. Bone marrow transplantation has been advocated as a treatment in an attempt to correct the enzyme deficiency. Such a transplant was performed in 1991 in a 16-year-old girl with a form of late juvenile metachromatic leukodystrophy caused by a homozygous P426L mutation in the arylsulfatase A gene. Engraftment was prompt and resulted in constant enzymatic normalization of circulating lymphocytes. The elevated urinary excretion of sulfatides remained unaffected. Clinical findings up until transplantation consisted of gait disturbances, impairment of cognitive functioning, and deterioration in school performance over several years. During a 6-year follow-up period, the patients condition was subject to major fluctuations but, on the whole, findings showed slow neurologic and neurophysiologic deterioration. The clinical course observed after bone marrow transplantation probably more or less reflects the natural course expected in this form of late-onset metachromatic leukodystrophy. (J Child Neurol 1999; 14:222-228).

Cystic leukoencephalopathy without megalencephaly: A distinct disease entity in 15 children

Objective: To describe a distinctive syndrome of nonprogressive encephalopathy, normo- or microcephaly, and early onset of severe psychomotor impairment in 15 white patients, including two siblings and two first cousins. Methods and Results: MRI revealed bilateral cysts in the anterior part of the temporal lobe and white matter abnormalities with pericystic abnormal myelination and symmetric lesions in frontal and occipital periventricular regions. None of the usual inborn errors of metabolism/infectious diseases associated with leukoencephalopathy and bilateral anterior temporal lobe cysts were detected. Conclusions: These patients’ clinical signs and cranial MRI abnormalities are strikingly similar and may represent a distinctive disease with autosomal-recessive inheritance: cystic leukoencephalopathy without megalencephaly.

Operative or endovascular treatment of ruptured intracranial vertebral artery aneurysms

Abstract Our purpose was to evaluate the surgical and endovascular treatment outcomes of ruptured intracranial vertebral artery aneurysms (RIVAA). The outcomes of 44 patients with RIVAA treated between 1983 and 1998 surgically (26), endovascularly (20) or both (2) were evaluated. The aneurysms were clipped in 24 patients, and clipped and wrapped in two. We treated 20 by the endovascular approach, 12 with Guglielmi detachable coils (GDC), and eight by parent-vessel occlusion using detachable balloons. Three patients had endovascular treatment after a failed or inadequate surgical attempt. Post-treatment follow-up was 17–183 months (mean 101 months) for surgically treated patients. For the GDC-treated group angiographic follow-up was carried at 8–49 months (mean 19 months). The condition of seven (27 %) of the surgically treated patients worsened due to procedure-related complications, compared with 10 % in the endovascular treatment group. Of the patients initially presenting with Hunt and Hess grade IV or V, three of five (60 %) died who were treated surgically and two of eight (25 %) who were treated endovascularly. A good outcome was achieved in 17 surgically treated patients (85 % of the survivors) and in 16 of the endovascular group (89 % of the survivors). This present “same-site” report on treatment of a specific abnormality, RIVAA, treated surgically or by an endovascular approach indicates that especially in poorer Hunt and Hess grade patients, the latter may offer a clinical outcome as good as that of surgery, although long-term efficacy of GDC treatment is still to be determined.

Frequency and temporal profile of recanalization after cerebral vein and sinus thrombosis.

The temporal course of recanalization and its association with clinical outcome were analysed in our patients with cerebral sinus and/or venous thrombosis (CSVT) and follow‐up magnetic resonance imaging (MRI).

Dural arteriovenous fistulas.

Spontaneous dural arteriovenous fistulas (DAVFs) are abnormal arteriovenous shunts within the dura mater of the sinuses. The exact etiology remains uncertain. Arterial feeder derive from the meningeal branches in the region. The clinical symptoms are highly dependent on the venous drainage. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrate the epiphenomena rather than the DAVF itself. Angiography is the most important modality in evaluating a DAVF. Based on the patterns of venous drainage, a classification and a treatment strategy are possible. Therapeutic modalities include manual compression, transarterial embolization, transvenous embolization, and/or surgical resection. Recent technical advances concerning embolic material and microcatheter make endovascular treatment less dangerous and more effective.ZusammenfassungDie spontan auftretenden duralen Fisteln (DAVF) sind arteriovenöse Kurzschlussverbindungen mit einer in der Dura mater entstehenden arteriovenösen Verbindung. Der für die klinische Symptomatik ausschlaggebende venöse Abfluss erfolgt über die benachbarten Sinus und/oder kortikalen epizerebralen Venen. Zur Festlegung der Therapie und zur Bestimmung der Prognose ist eine auf der Angiographie basierende Klassifikation der DAVF entscheidend. Die therapeutischen Möglichkeiten sind die manuelle Kompression, die arterielle Embolisation, die venöse Embolisation und/oder die chirurgische Resektion. Durch neueste technische Fortschritte hinsichtlich Embolisationsmaterial und Mikrokatheter ist die endovaskuläre Behandlung von DAVF sicherer und deutlich effektiver geworden.