Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions.

The genetic basis of the many progressive, multi systemic, mitochondrial diseases that cause a lack of cellular ATP production is heterogeneous, with defects found both in the mitochondrial genome as well as in the nuclear genome. Many different mutations have been found in the genes encoding subunits of the enzyme complexes of the oxidative phosphorylation system. In addition, mutations in genes encoding proteins involved in the assembly of these complexes are known to cause mitochondrial disorders. Here we describe two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits. Whole exome sequencing revealed a homozygous nonsense mutation resulting in a premature stop codon in the gene encoding Pet117, a small protein that has previously been predicted to be a complex IV assembly factor. PET117 has not been identified as a mitochondrial disease gene before. Lentiviral complementation of patient fibroblasts with wild-type PET117 restored the complex IV deficiency, proving that the gene defect is responsible for the complex IV deficiency in the patients, and indicating a pivotal role of this protein in the proper functioning of complex IV. Although previous studies had suggested a possible role of this protein in the insertion of copper into complex IV, studies in patient fibroblasts could not confirm this. This case presentation thus implicates mutations in PET117 as a novel cause of mitochondrial disease.

Outcome after intracranial haemorrhage from dural arteriovenous fistulae; a systematic review and case-series.

Dural arteriovenous fistulae (DAVFs) are a rare cause of intracranial haemorrhage. We aimed to investigate outcome of patients with intracranial haemorrhage from a DAVF. We performed a systematic literature search for studies reporting outcome after intracranial haemorrhage caused by a DAVF. We used predefined selection criteria and assessed the quality of the studies. In addition, we studied outcome in all patients with DAVF who had presented with intracranial haemorrhage at two university centers in the Netherlands, between January 2007 and April 2012. We calculated case fatality and proportions of patients with poor outcome (defined as modified Rankin Scale ≥ 3 or Glasgow Outcome Scale ≤ 3) during follow-up. We investigated mean age, sex, mid-year of study and percentage of patients with parenchymal haemorrhage as determinants of case fatality and poor outcome. The literature search yielded 16 studies, all but two retrospective and all hospital-based. Combined with our cohort of 29 patients the total number of patients with DAVF-related intracranial haemorrhage was 326 (58% intracerebral haemorrhage). At a median follow-up of 12 months case fatality was 4.7% (95% CI 2.5-7.5; 17 cohorts) and the proportion of patients with poor outcome 8.3% (95% CI 3.1-15.7; nine cohorts). We found no effect of mean age, sex, mid-year of the cohorts and percentage of patients with parenchymal haemorrhage on either outcome. Hospital based case-series suggest a relatively low risk of death and poor outcome in patients with intracranial haemorrhage due to rupture of a DAVF. These risks may be underestimated because of bias.

Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain.

BACKGROUND: In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM. METHODS: We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method. RESULTS: In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08). CONCLUSIONS: Our meta-analysis of two Caucasian cohorts did not show an association between five aneurysm-associated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation.

Improved arterial visualization in cerebral CT perfusion-derived arteriograms compared with standard CT angiography: a visual assessment study.

BACKGROUND AND PURPOSE: Invasive cerebral DSA has largely been replaced by CTA, which is noninvasive but has a compromised arterial view due to superimposed bone and veins. The purpose of this study was to evaluate whether arterial visualization in CTPa is superior to standard CTA, which would eliminate the need for an additional CTA scan to assess arterial diseases and therefore reduce radiation dose. MATERIALS AND METHODS: In this study, we included 24 patients with subarachnoid hemorrhage for whom CTA and CTP were available. Arterial quality and presence of superimposed veins and bone in CTPa were compared with CTA and scored by 2 radiologists by using a VAS (0%-100%). Average VAS scores were determined and VAS scores per patient were converted to a 10-point NRS. Arterial visualization was considered to be improved when the highest rate (NRS 10, VAS > 90%) was scored for arterial quality, and the lowest rate (NRS 1, VAS < 10%), for the presence of superimposed veins and bone. A sign test with continuity correction was used to test whether the number of cases with these rates was significant. RESULTS: Average VAS scores in the proximal area were 94% (arterial quality), 4% (presence of bone), and 7% (presence of veins). In this area, the sign test showed that a significant number of cases scored NRS 10 for arterial quality (P < .02) and NRS 1 for the presence of superimposed veins and bone (P < .01). CONCLUSIONS: Cerebral CTPa shows improved arterial visualization in the proximal area compared with CTA, with similar arterial quality but no superimposed bone and veins.

The contribution of posterior circulation to memory function during the intracarotid amobarbital procedure.

The purpose of this study was to evaluate the contribution of posterior circulation to memory function by comparing memory scores between patients with and without a foetal-type posterior cerebral artery (FTP) during the intracarotid amobarbital procedure (IAP) in epilepsy patients. Patients undergoing bilateral IAP between January 2004 and January 2010 were retrospectively included. Pre-test angiograms were assessed for the presence of a FTP. Memory function scores (% correct) after right and left injections were obtained. Functional significance of FTP was affirmed by relative occipital versus parietal EEG slow-wave increase during IAP. Memory and EEG scores were compared between patients with and without FTP (Mann-Whitney U test). A total of 106 patients were included, 73 with posterior cerebral arteries (PCA) without FTP ('non-FTP'), 28 patients with unilateral FTP and 5 with a bilateral FTP. Memory scores were lower when amytal was injected to the hemisphere contralateral to the presumed seizure focus (on the right decreasing from 98.3 to 59.1, and on the left decreasing from 89.1 to 72.4; p < 0.001). When IAP was performed on the side of FTP memory scores were significantly lower (70.8) compared to non-FTP (82.0; p = 0.02). Relative occipital EEG changes were 0.44 for FTP cases and 0.36 for non-FTP patients (p = 0.01). A relationship between vasculature and brain function was demonstrated by lower memory scores and more slow-wave activity on occipital EEG during IAP in patients with foetal-type PCA compared to patients with non-FTP. This suggests an important contribution of brain areas supplied by the PCA to memory function.

Intramedullary femoral nailing through the trochanteric fossa versus greater trochanter tip: a randomized controlled study with in-depth functional outcome results.

PURPOSE: In a level 1 university trauma center, an explorative randomized controlled study was performed to compare soft tissue damage and functional outcome after antegrade femoral nailing through a trochanteric fossa (also known as piriform fossa) entry point to a greater trochanter entry point in patients with a femoral shaft fracture. MATERIALS AND METHODS: Nineteen patients were enrolled and randomly assigned to two nail insertion groups; ten patients were treated with an Unreamed Femoral Nail(®) (UFN, Synthes(®), Solothurn, Switzerland) inserted at the trochanteric fossa and nine patients were treated with an Antegrade Femoral Nail(®) (AFN, Synthes(®), Solothurn, Switzerland) inserted at the tip of the greater trochanter. The main outcome measures were pain, gait, nerve and muscle function, along with endurance. Magnetic resonance imaging (MRI), electromyography (EMG), and Cybex isokinetic testings were performed at, respectively, 2 and 6 weeks and at a minimum of 12 months after surgery. RESULTS: The MRI and EMG showed, in both groups, signs of iatrogenic abductor musculature lesions (four in the UFN group and four in the AFN group) and superior gluteal nerve injury (five in the UFN group and four in the AFN group). The isokinetic measurements and the patient-reported outcomes showed moderate reduction in abduction strength and endurance, as well as functional impairment with slight to moderate interference with daily life in both groups, with no appreciable differences between the groups. CONCLUSIONS: Anatomical localization of the entry point seems to be important for per-operative soft tissue damage and subsequent functional impairment. However, the results of this study did not show appreciable differences between femoral nailing through the greater trochanter tip and nailing through the trochanteric fossa.

Contralateral MRI abnormalities affect seizure and cognitive outcome after hemispherectomy.

OBJECTIVE: To explore whether EEG and MRI abnormalities in the "healthy" hemisphere influence seizure and cognitive outcome after functional hemispherectomy. METHODS: This is a retrospective consecutive cohort study of 43 children who underwent functional hemispherectomy between 1994 and 2008. Results of preoperative EEG recordings were reviewed for the existence of (inter)ictal epileptic or background abnormalities in the contralateral hemisphere. Preoperative MRIs were reexamined for the existence of unequivocal contralateral abnormalities. Postoperative seizure status was assessed, and of 34 children, IQ or mental developmental index (MDI) scores were obtained preoperatively and postoperatively. Seizure freedom was defined as Engel 1A. Contralateral EEG and MRI abnormalities were studied in relation to seizure and cognitive outcome. RESULTS: Thirty-three children achieved seizure freedom (77%). Of the 11 patients with contralateral MRI abnormalities, only 45% were seizure free, compared with 88% of the 32 patients without contralateral MRI lesions (p = 0.030). Children with contralateral MRI abnormalities more often were severely retarded after surgery (MDI/IQ <55; 90% vs 42%, p = 0.030). Postoperative MDI/IQ scores improved in none of the children with, but in 38% of those without contralateral MRI abnormalities (p = 0.034). Contralateral epileptic or background EEG abnormalities did not affect seizure outcome or postoperative cognitive performance. Four of 6 children with bilateral epileptic encephalopathy reached seizure freedom. CONCLUSION: Unambiguous contralateral MRI abnormalities are significantly associated with seizure recurrence, severe mental delay, and lack of cognitive improvement and may be considered a relative contraindication for hemispherectomy. Contralateral EEG abnormalities do not negatively influence postsurgical outcome.

Lymph node detection by MRI before and after a systematic pelvic lymphadenectomy.

OBJECTIVE: Pelvic lymphadenectomy is considered the gold standard to diagnose and possibly treat lymphatic metastases in gynaecological cancer patients. The aim of this study is to evaluate whether all presurgical MRI detected lymph nodes were removed during the systematic pelvic lymph node dissection (PLND) in cervical cancer patients. METHODS: 21 consecutive cervical cancer patients who were scheduled to undergo a PLND were evaluated by a MRI scan prior to surgery and 6 weeks afterwards. All patients had tumour metastasis negative lymph nodes at histopathological examination. RESULTS: On average, 10 pelvic lymph nodes (range 5-17) per patient were detected by presurgical MRI. Postsurgical MRI scans showed that on average 1 (range 0-3) pelvic node per patient was not removed by surgery. In total, 14% of the presurgical MR detected nodes were not removed by surgery (31/225). Approximately half of all lymph nodes that remained after surgery were located in the obturator region. In spite of the remaining nodes, surgery and histopathological examination did detect more nodes than MRI: on average 21 lymph nodes per patient (range 9-59) were removed. Another 2 lymph nodes (range 0-6 per patient) were judged to be newly developed after surgery. CONCLUSION: Although surgery was able to remove many more lymph nodes than those detected by presurgical MRI, 14% of presurgical MRI detected lymph nodes were not removed by PLND. The value of MRI prior to surgery for the detection of pathological lymph nodes is a subject of further research.

MR angiography follow-up 5 years after coiling: frequency of new aneurysms and enlargement of untreated aneurysms.

BACKGROUND AND PURPOSE: Patients with intracranial aneurysms are at risk for future development of new aneurysms and growth of additional untreated aneurysms. Because in previous long-term studies duration of follow-up varied widely, the time interval after which screening could be effective remains largely unknown. The purpose of this study was to assess the incidence of de novo aneurysm formation and the growth of additional untreated aneurysms in patients with coiled aneurysms followed up with MR angiography (MRA) after a fixed period of 5 years. MATERIALS AND METHODS: In 65 patients with coiled intracranial aneurysms, high-resolution 3T MRA was performed 5.1 +/- 0.2 years after coiling. MRA follow-up imaging was compared with MRA or CT angiography at the time of coiling. Additional aneurysms detected at MRA follow-up were classified as unchanged, grown, de novo, or incomparable with previous imaging. RESULTS: In 13 of 65 patients (20%), 24 additional aneurysms were found. Four aneurysms were incomparable with previous imaging and 2 of these were clipped. Of the remaining 20 additional aneurysms, 1 was de novo, 1 had grown slightly, and 18 were unchanged. The incidence of de novo aneurysm formation after 5 years was 1.54% (95% confidence interval, 0.01-9.0%). For additional aneurysms known at the time of initial coiling and for the 1 de novo aneurysm, no treatment was indicated. CONCLUSIONS: MRA screening 5 years after coiling for detection of de novo aneurysms and growth of additional untreated aneurysms has a low yield in terms of finding aneurysms that need to be treated.

[Persistent renal bleeding treated with selective vascular embolisation with preservation of renal function]. / Persisterend renaal bloedverlies behandeld door selectieve vasculaire embolisatie, met behoud van nierfunctie.

In three patients with persistent blood loss from bleeding or abnormal renal vessels, kidney function was preserved by treatment with selective embolisation. The first patient, a 42-year-old woman, suffered from persistent haematuria after undergoing percutaneous nephrolithotripsy on the left side. Because conservative methods had failed and renal artery bleeding as a result of the lithotripsy was suspected, angiography with selective coil embolisation of a segmental branch of the lower pole artery of the kidney was performed. The second patient, a 40-year-old man with severe haemophilia A had been suffering from recurring macroscopic haematuria for a few months. CT showed an arteriovenous malformation in the right kidney. Angiography in combination with embolisation with two detachable balloons resulted in occlusion of the malformation. The third patient, a 23-year-old woman with tuberous sclerosis, presented with left abdominal pain, haematuria and decreasing haemoglobin concentrations. CT revealed a left renal angiomyolipoma, 10 cm in size, with a large internal haematoma. Three pathological branches of the upper pole renal artery were successfully occluded with Gianturco coils. At follow-up after 2, 2.5 and 2.5 years respectively, no recurrence of bleeding had occurred. Selective embolisation should be attempted as means of treatment for persistent renal bleeding if conservative treatment fails. Selective embolisation is minimally invasive and has the important advantage of preserving renal function.