Epileptogenic brain malformations: radiological and clinical presentation and indications for genetic testing

Malformations of cortical development (MCD) represent a major cause of developmental disabilities and severe epilepsy. Advances in imaging and genetics have improved the diagnosis and classification of these conditions. Up to now, eight genes have been involved in different types of MCD. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Additional forms are X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia associated with mutations of the ARX gene. Lissencephaly with cerebellar hypoplasia (LCH) encompass heterogeneous disorders named LCH type a to d. LCHa are related with mutation in LIS1 or DCX, LCHb with mutation of RELN gene, and LCHd could be related with TUBA1A gene. Polymicrogyria encompass a wide range of clinical, aetiological and histological findings. Among several syndromes, recessive bilateral fronto-parietal polymicrogyria has been associated with mutations of the GPR56 gene. Bilateral perisylvian polymicrogyria showed a linkage to chromosome Xq28 in some pedigrees, and mutations in SRPX2 gene in others conditions. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of BPNH with focal epilepsy in females and prenatal lethality in males. Filamin A (FLNA) mutations have been reported in some families and in sporadic patients. It is possible to infer the most likely causative gene by brain imaging studies and other clinical findings. Based on this experience, a detailed phenotype analysis is needed to develop the most efficient research on MCD in the future.     

Cortical brain malformations: effect of clinical, neuroradiological, and modern genetic classification

BACKGROUND: Malformations of cortical development (MCDs) are a major source of handicap. Much progress in understanding the genetic causes has been made recently. The number of affected children in whom a molecularly confirmed diagnosis can be made is unclear. OBJECTIVE: To evaluate the etiology of MCDs in children and the effect of a combined radiological, clinical, and syndrome classification. DESIGN: A case series of 113 children with a radiological diagnosis of MCD from January 1, 1992, to January 1, 2006. SETTING: The Erasmus Medical Center-Sophia Children's Hospital, a secondary and tertiary referral center. PATIENTS: Patients with MCD underwent a complete radiological, clinical, and neurological assessment and testing for known genes involved in the pathogenesis of MCD as appropriate for their phenotype. RESULTS: We established an etiological diagnosis in 45 of 113 cases (40%). For 21 patients (19%), this included molecular and/or genetic confirmation (Miller-Dieker syndrome; LIS1, DCX, FLNA, EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism). In 17 (15%), a syndrome with an unknown genetic defect was diagnosed. In 7 patients (6%), we found evidence of a gestational insult. Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history with multiple affected persons (12 patients), or consanguineous parents (7 patients). CONCLUSIONS: In our cohort, combining diagnostic molecular testing with clinical, radiological, and genetic classification; syndrome identification; and family study provided a diagnosis in 40% of the cases of MCD. This contributes to the possibility of prenatal diagnosis and improved patient treatment and disease management.     

Surgical removal of brain stem cavernous malformations: surgical indications, technical considerations, and results

OBJECTIVES: This study was undertaken to review the indications for surgical treatment of brain stem cavernomas and to develop strategies to minimise the complications of surgery. PATIENTS AND RESULTS: Twelve patients underwent surgical resection of a brain stem cavernoma due to symptoms caused by one or more haemorrhages. Age ranged from 18 to 47 years (mean 29.2 years). Long term follow up (mean 3.7 years) included a complete neurological examination and annual MRI studies. The annual haemorrhage rate was 6.8 %/patient/year and a rate of 1.9 rehaemorrhages/patient/year was found. Surgery was performed under microsurgical conditions with endoscopic assistance, use of neuronavigation, and neurophysiological monitoring. Navigation proved to be reliable when applied in an early stage of operative procedure with minimal brain retraction. Endoscopy was a useful tool in some cases to confirm complete resection of the lesion and to ascertain haemostasis. Ten patients had a new neurological deficit in the early postoperative period, nine of these were transient. At the last follow up the neurological state was improved in five patients, unchanged in six, and worse in one compared with the preoperative conditions. The preoperative average Rankin score was 2.2 points and had improved at the last follow up by 0.6 points to 1.6 points. CONCLUSIONS: Symptomatic brain stem cavernomas should be considered for surgical treatment after the first bleeding. Careful selection of the optimal operative approach and a meticulous microsurgical technique are mandatory. The additional use of modern tools such as neuronavigation, endoscopic assistance, and monitoring can contribute to the safety of the procedure.     

Epileptogenic temporal cavernous malformations: Operative strategies and postoperative seizure outcomes

Operative treatment of epileptogenic cavernous malformations (CM) continues under debate. Most studies focus on surgery for supratentorial CM in general. For temporal lobe CM, surgical decision-making concerns in particular whether to perform lesionectomy alone or the additional excision of mesial temporal structures. The purpose of this case series was to evaluate operative strategies used to treat epileptogenic temporal CM and to report resultant postoperative seizure outcomes.Twelve consecutive cases of patients with medically intractable epilepsy who underwent operation for temporal CM between 1996 and 2006 were retrospectively reviewed. When the temporal CM directly invaded the hippocampus or amygdala, the affected structures were resected in addition to the lesion; when the CM was located in the superficial temporal cortex, and there was no radiographic evidence of hippocampal sclerosis, lesionectomy alone was done; with CM located between the superficial temporal cortex and the mesial temporal region, other factors were considered in decision-making, such as lesion proximity to the deep mesiotemporal structures and preoperative epilepsy duration.For six of the twelve patients, extended lesionectomy (EL) alone was done; for the other six, tailored anteromedial temporal resection with hippocampectomy and/or amygdalectomy was performed in addition to EL. Postoperatively, 11 patients – all with preoperative VEM demonstrating electroclinical seizure patterns concordant with lesion location – were seizure-free. We conclude that epileptogenic temporal CM are surgically remediable, when approached with the above operative strategies and presurgical VEM. On the basis of these postoperative seizure control results, we recommend consideration of concurrent resection of mesial temporal structures with EL for certain temporal CM.     

Intracranial arteriovenous malformations in childhood: presentation, management and outcome.

Cases of true intracranial arteriovenous malformations (AVMs) presenting over a 25 year period were reviewed in order to achieve a better understanding of the behaviour and management of AVMs in children. There were 69 cases, presenting with haemorrhage (78%), seizures (13%) cardiac failure (3%) and focal signs with or without headache (6%). It was less common to present under six years of age. CT scanning, where performed, always demonstrated an abnormality, but this was suggestive of an AVM in less than one third. By contrast, angiography defined the lesion in 82% of initial studies. 59 patients underwent a surgical procedure directed at their AVM or an associated haematoma. Total AVM excision was obtained in 65%, with none of these later rebleeding. Three patients presenting solely with seizures were not operated upon initially, but underwent successful resections of their lesions after later haemorrhages. There were 6 (9%) deaths in the series, with focal deficits in 52% of survivors at last follow up. In the operative group these figures were 3% and 51%, respectively. None of the eight patients operated upon prior to a clinical bleed suffered a new neurological deficit. The role of stereotactic radiosurgery, although not used in any of our cases, is discussed. We believe that our results support an aggressive surgical approach to childhood AVMs, regardless of presentation, given the significant risk of morbidity from a later bleed, and the lack of a clearly better outcome with expectant management or irradiation.     

Tuberculous brain abscess: clinical presentation, pathophysiology and treatment (in children)

BACKGROUND: Tubercular brain abscess (TBA) is a rare manifestation of CNS tuberculosis. It is characterised by an encapsulated collection of pus, containing viable tubercular bacilli without evidence of tubercular granuloma.PRESENTATION AND HISTORY: Patients may present with features of raised intracranial pressure and focal neurological deficit commensurate with the site of the abscess. A history of pulmonary tuberculosis may be present, as documented in one of our six cases; three of our six children developed TBA despite 3-weeks to 12-month courses of antitubercular chemotherapy prescribed for post-TBM hydrocephalus.DIAGNOSIS: Contrast CT head, MRI, MR spectroscopy is helpful in making the diagnosis and planning the treatment. TBA may be unilocular or multilocular on contrast CT scan. A relatively long clinical history and an enhancing capsule with thick wall are suggestive of TBA. Pyogenic abscess, however, has a thin rim on contrast CT. The capsule of TBA is formed of vascular granulation tissue containing acute and chronic inflammatory cells, particularly polymorphs. Proof of tubercular origin must be demonstrated either by presence of acid fast bacilli in culture or staining of pus or wall.TREATMENT: Treatment options include simple puncture, continuous drainage, fractional drainage, repeated aspiration through a burr hole, stereotactic aspiration and total excision of the abscess. Total excision usually becomes necessary in multilocular noncommunicating and thick-walled abscesses. Antitubercular therapy is the mainstay of management. The development of fulminant tubercular meningitis is sometimes problematic following surgical excision of TBA, as seen in one of our four operated cases. Mortality is reported to be high despite progress in treatment, while five of the six children treated by us responded well to the treatment.     

Multiple brain infarcts: clinical and neuroimaging patterns using diffusion-weighted magnetic resonance.

The capability of diffusion-weighted (DW) magnetic resonance imaging (MRI) to identify very early ischemic brain injury better than conventional MRI is well known. This technique, which successfully discriminates acute from old infarcts, is particularly useful in patients with multiple brain infarcts (MBI). Among 142 patients with acute stroke consecutively admitted to our primary care center, we selected 43 patients with two or more brain infarcts on conventional MRI. All patients presented with clinical deficits consistent with acute cerebral ischemia and underwent conventional spin echo for T(1) (T1-WI) and T(2)-weighted images (T2-WI), T(1)-W gadolinium-enhanced images, and echo-planar technique for DW MRI sequences. Patients underwent DW MRI examinations within 15 days of stroke onset (mean +/- SD: 3 +/- 3 days). In all but 1 case, the infarcts detected on DW MRI were also visible on T2-WI. The different signal pattern on DW MRI, compared with T2-WI, facilitated the detection of acute infarcts in all patients. T1-WI with gadolinium enhancement was only helpful in 5 (11.6%) patients. DW MRI enabled precise clinicotopographic correlations in 79% of our patients and provided additional clinically relevant findings in 72% of the patients. Based on the neuroradiological findings, patients were divided into three clinicotopographic types of MBI as follows: 13 patients (30.2%) presented with multiple acute infarcts, 24 patients (55.8%) with a single acute infarct and multiple old infarcts, and 6 patients (13.9%) with multiple acute and old infarcts. In conclusion, DW MRI can easily be added to conventional MRI in order to be able to distinguish acute from old infarcts, and to identify acute multiple lesions. Therefore, a better correlation between clinical symptoms and the site of lesions can be obtained, considerably improving patient care.     

Focal brain malformations: Seizures, signaling, sequencing

Focal malformations of cortical development are highly associated with intractable epilepsy in children and adults. Most patients with focal cortical malformations and epilepsy will require epilepsy surgery. Recent studies have provided new insights into the developmental pathogenesis of cortical malformations specifically relating to alterations in cell signaling though the mammalian target of rapamycin (mTOR) pathway. Focal cortical dysplasias, hemimegalencephaly, and tubers in tuberous sclerosis complex all exhibit evidence for hyperactive mTOR signaling, suggesting that these disorders form a spectrum of malformations or "TORopathies" characterized by disorganized cortical lamination, cytomegaly, and intractable seizures. Alterations in mTOR activity in focal brain malformations provide a potential pathogenic pathway to investigate for gene mutations and to exploit for animal models. Most importantly, however, if select focal cortical malformations result from enhanced mTOR signaling, new therapeutic antiepileptic compounds, such as rapamycin, can be designed and tested that specifically target mTOR signaling.     

Parkinson's disease in Ireland: clinical presentation and genetic heterogeneity in patients with parkin mutations.

Early-onset autosomal recessive parkinsonism is associated with parkin gene mutations. Different parkin mutations occur in many ethnic backgrounds; however, the phenotype may vary. We studied 102 young-onset (age at onset <60 years) Parkinson's disease (PD) patients. From 102 patients, 40 with early-onset PD (<45 years at symptomatic onset) were selected for clinical assessment and parkin gene molecular analysis for duplications/deletions and point mutations. We identified parkin mutations in 7 of 40 early-onset patients; including novel compound heterozygotes and potential splice site changes. The mean age at onset in the 7 parkin mutation-positive patients was 33 +/- 9 years (age range, 18-42 years), marginally lower than that of the 33 parkin-negative early-onset patients, 38 +/- 7 years (age range, 17-45 years). A family history of PD was present in 4 of 7 patients with parkin mutations, compared with 6 of 33 early-onset parkin-negative patients. Overall, parkin mutations were found in 4 of 10 patients with a positive family history and 3 of 30 patients without a family history of PD. Patients with parkin mutations had more dystonia, dyskinesia, and sleep benefit compared with parkin-negative patients. We subsequently identified a single point mutation among the 62 young-onset (age at onset 45 to <60 years). Mutations in the parkin gene may account for approximately 17% of early-onset (age at onset <45 years) parkinsonism in Ireland, in agreement with previous European studies.     

Quantified flow and angioarchitecture show similar associations with hemorrhagic presentation of brain arteriovenous malformations

IntroductionThe purpose of our study was to elucidate the impact of brain arteriovenous malformation (BAVM) flow and wall shear stress (WSS) on angioarchitecture and to evaluate their association with hemorrhagic presentations.Materials and methodsForty-one patients with BAVMs were evaluated by phase-contrast MR angiography. Volume flow rate and WSS were quantified. Angioarchitectural features such as location, angiogenesis, venous stenosis, venous ectasia, venous phlebitis, venous rerouting, exclusive deep vein and venous sac were evaluated by two neuroradiologists. The correlation between BAVM flow and size was evaluated with Spearman correlation coefficients. Differences of size, flow, and WSS between the hemorrhagic and non-hemorrhagic groups, the seizure and non-seizure groups, and between the different groups based on angioarchitecture were evaluated with Mann-Whitney U tests. Accuracy in predicting hemorrhage was evaluated with receiver operating characteristic curves.ResultBAVM flow was highly correlated with volume (ρ = 0.77). Higher flow was more commonly associated with angiogenesis, venous ectasia, venous rerouting, and venous phlebitis. Flow and angioarchitecture showed similar efficacy in differentiating hemorrhagic from non-hemorrhagic BAVMs. WSS did not demonstrate differences across any clinical groups.ConclusionFlow quantification and angioarchitecture analysis of BAVMs showed similar efficacy as evaluated by associations with hemorrhagic presentation. High flow affects both arterial and venous angioarchitecture, reflecting the nature of low vascular resistance in BAVMs.     

Specificity of brain activation patterns in people at genetic risk for Alzheimer disease.

Previous studies with positron-emission tomography (PET) and functional magnetic resonance imaging (fMRI) have indicated differences in neural metabolism and activity between carriers of the APOE epsilon4 allele and those who are not at risk for Alzheimer disease (AD). Persons without dementia carrying the epsilon4 allele showed greater magnitude and extent of brain activation than noncarriers in regions required for memory, suggesting they performed additional cognitive work to accomplish the same task. To determine whether the fMRI differences were specific to a memory task or generalizable to any difficult cognitive task, the authors performed fMRI and compared images from 25 subjects with and without the APOE epsilon4 allele. In the most difficult conditions, all subjects showed increased MR signal in the prefrontal cortex, indicating increased cognitive effort. However, the two genetic groups showed no differences in activation patterns even at the most difficult task level, suggesting that additional cognitive effort in persons at genetic risk for AD is specific to episodic encoding and is not merely a reflection of task difficulty.     

Apnoea testing to confirm brain death in clinical practice.

In six patients an apnoea test was carried out to confirm brain death according to a protocol recommended in the USA. After ten minutes' apnoea the pCO2 did not reach the target value of 7.98 kPa (60 mm Hg) in any of these patients. This was caused by the low initial value and the slow increase of the pCO2. Moreover, we could not confirm the belief that the necessary duration of the apnoea test can be predicted by assuming a rise of the pCO2 of 0.33 kPa (2.5 mm Hg) per minute.     

伽玛刀治疗脑动静脉畸形

目的评估伽玛刀（γ刀）治疗脑动静脉畸形（ＡＶＭ）的疗效。方法用Ｌｅｋｓｅｌγ刀手术治疗脑ＡＶＭ２１６例并随访１２～３４个月。患者年龄１１～８３岁,ＳｐｅｔｚｌｅｒＭａｒｔｉｎ分级：Ⅰ级４２例,Ⅱ级６８例,Ⅲ级９５例,Ⅳ级７例,Ⅴ级４例。ＡＶＭ体积０３～４３．９ｃｍ３,治疗用周边剂量１２～３０Ｇｙ。结果γ刀治疗后的ＡＶＭ闭塞情况和并发症的发生与其体积、分级、定位方法、周边剂量、剂量规划及质量控制等因素有关。对体积≤５．０ｃｍ３或ＳｐｅｔｚｌｅｒＭａｒｔｉｎ分级＜Ⅲ级及周边剂量≥２０Ｇｙ者,其２年闭塞率超过７８５％。本组有４例γ刀术后再出血,９例并发有明显症状的放射性脑水肿。结论γ刀是治疗脑ＡＶＭ的一种安全、有效的方法,特别是ＳｐｅｔｚｌｅｒＭａｒｔｉｎⅠ～Ⅱ级或体积≤５０ｃｍ３的ＡＶＭ及周边剂量≥２０Ｇｙ者疗效较好。数字减影血管造影（ＤＳＡ）结合磁共振血管造影（ＭＲＡ）联合定位对提高ＡＶＭ的闭塞率、降低并发症有帮助     

Oligodendrogliomas: clinical and genetic correlations.

Oligodendrogliomas, once obscure, are now recognized as a relatively common form of primary brain tumour, and are among the most chemosensitive of all solid human malignancies. New histopathological, molecular, and genetic information has, for the first time, allowed the distinction of several subtypes of human glioma with predictable biological and clinical behaviour. Genetic markers are emerging as useful not only for the diagnosis of oligodendroglioma, but also as specific predictors of both the response to treatment and prolonged survival. This review will focus upon the past year of advances in the area of clinical-molecular genetic predictors of glioma behaviour and highlight the importance of these advances in everyday clinical practice.     

Mannosidosis. New clinical presentation, enzyme studied, and carbohydrate analysis.

Mannosidosis is a rare inborn error of metabolism characterized by deficiency of the lysosomal enzyme alpha-mannosidase and widespread storage of complex carbohydrate, which is enriched in mannose. Two affected unrelated males, aged 6 and 26 years, are reported. Both had a nonprogressive encephalopathy with moderately severe mental retardation. The older patient showed several unique features, including massive gingival hyperplasia associated with histiocytes containing large amounts of a material with the staining characteristics of glycoprotein. The best determinant of mannose storage proved to be the ratio of mannose to other carbohydrates in urinary polysaccharides. The enzyme deficiency in this disease is most convincingly demonstrated at pH values below 4.0. The ability of zinc to activate the mutant enzyme in vitro offers a possible mode of therapy for this disease. Retarded individuals with a Hurler-like appearance and gum hyperplasia of unknown cause should be screened for alpha-mannosidase deficiency.