Outcome after surgical or conservative management of cerebral cavernous malformations.

OBJECTIVE: There have been few comparative studies of microsurgical excision vs conservative management of cerebral cavernous malformations (CCM) and none of them has reliably demonstrated a statistically and clinically significant difference. METHODS: We conducted a prospective, population-based study to identify and independently validate definite CCM diagnoses first made in 1999-2003 in Scottish adult residents. We used multiple sources of prospective follow-up to assess adults' dependence and to identify and independently validate outcome events. We used univariate and multivariable survival analyses to test the influence of CCM excision on outcome, adjusted for prognostic factors and baseline imbalances. RESULTS: Of 134 adults, 25 underwent CCM excision; these adults were younger (34 vs 43 years at diagnosis, p = 0.004) and more likely to present with symptomatic intracranial hemorrhage or focal neurologic deficit than adults managed conservatively (48% vs 26%; odds ratio 2.7, 95% confidence interval [CI] 1.1-6.5). During 5 years of follow-up, CCM excision was associated with a deterioration to an Oxford Handicap Scale score 2-6 sustained over at least 2 successive years (adjusted hazard ratio [HR] 2.2, 95% CI 1.1-4.3) and the occurrence of symptomatic intracranial hemorrhage or new focal neurologic deficit (adjusted HR 3.6, 95% CI 1.3-10.0). CONCLUSIONS: CCM excision was associated with worse outcomes over 5 years compared to conservative management. Long-term follow-up will determine whether this difference is sustained over patients' lifetimes. Meanwhile, a randomized controlled trial appears justified. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CCM excision worsens short-term disability scores and increases the risk of symptomatic intracranial hemorrhage and new focal neurologic deficits.

Seizure risk with AVM treatment or conservative management: prospective, population-based study.

OBJECTIVES: To compare the risk of epileptic seizures in adults during conservative management or following invasive treatment for a brain arteriovenous malformation (AVM). METHODS: We used annual general practitioner follow-up, patient questionnaires, and medical records surveillance to quantify the 5-year risk of seizures and the chances of achieving 2-year seizure freedom for adults undergoing AVM treatment compared to adults managed conservatively in a prospective, population-based observational study of adults in Scotland, newly diagnosed with an AVM in 1999-2003. RESULTS: We identified 229 adults with a new diagnosis of an AVM, of whom two-thirds received AVM treatment (154/229; 67%) during 1,862 person-years of follow-up (median completeness of follow-up 97%). There was no significant difference in the proportions with a first or recurrent seizure over 5 years following AVM treatment, compared to the first 5 years following clinical presentation in conservatively managed adults, in analyses stratified by mode of presentation (intracerebral hemorrhage, 35% vs 26%, p = 0.5; seizure, 67% vs 72%, p = 0.6; incidental, 21% vs 10%, p = 0.4). For patients with epilepsy, the chances of achieving 2-year seizure freedom during 5-year follow-up were similar following AVM treatment (n = 39; 52%, 95% confidence interval [CI] 36% to 68%) or conservative management (n = 21; 57%, 95% CI 35% to 79%; p = 0.7). CONCLUSIONS: In this observational study, there was no difference in the 5-year risk of seizures with AVM treatment or conservative management, irrespective of whether the AVM had presented with hemorrhage or epileptic seizures.

Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study.

BACKGROUND: Cerebral cavernous malformations (CCMs) are prone to bleeding but the risk of intracranial haemorrhage and focal neurological deficits, and the factors that might predict their occurrence, are unclear. We aimed to quantify these risks and investigate whether they are affected by sex and CCM location. METHODS: We undertook a population-based study using multiple overlapping sources of case ascertainment (including a Scotland-wide collaboration of neurologists, neurosurgeons, stroke physicians, radiologists, and pathologists, as well as searches of registers of hospital discharges and death certificates) to identify definite CCM diagnoses first made in Scottish residents between 1999 and 2003, which study neuroradiologists independently validated. We used multiple sources of prospective follow-up both to identify outcome events (which were assessed by use of brain imaging, by investigators masked to potential predictive factors) and to assess adults' dependence. The primary outcome was a composite of intracranial haemorrhage or focal neurological deficits (not including epileptic seizure) that were definitely or possibly related to CCM. FINDINGS: 139 adults had at least one definite CCM and 134 were alive at initial presentation. During 1177 person-years of follow-up (completeness 97%), for intracranial haemorrhage alone the 5-year risk of a first haemorrhage was lower than the risk of recurrent haemorrhage (2·4%, 95% CI 0·0-5·7 vs 29·5%, 4·1-55·0; p<0·0001). For the primary outcome, the 5-year risk of a first event was lower than the risk of recurrence (9·3%, 3·1-15·4 vs 42·4%, 26·8-58·0; p<0·0001). The annual risk of recurrence of the primary outcome declined from 19·8% (95% CI 6·1-33·4) in year 1 to 5·0% (0·0-14·8) in year 5 and was higher for women than men (p=0·01) but not for adults with brainstem CCMs versus CCMs in other locations (p=0·17). INTERPRETATION: The risk of recurrent intracranial haemorrhage or focal neurological deficit from a CCM is greater than the risk of a first event, is greater for women than for men, and declines over 5 years. This information can be used in clinical practice, but further work is needed to quantify risks precisely in the long term and to understand why women are at greater risk of recurrence than men. FUNDING: UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

The presentation and clinical course of intracranial developmental venous anomalies in adults: a systematic review and prospective, population-based study.

BACKGROUND AND PURPOSE: Reported risks of hemorrhage from intracranial developmental venous anomalies (DVAs) vary, so we investigated this in a systematic review and population-based study. METHODS: We systematically reviewed the literature (Ovid Medline and Embase to November 7, 2007) and selected studies of >or=20 participants with >or=1 DVA(s) that described their clinical presentation and/or their clinical course over a specified follow-up period. We also identified every adult first diagnosed with a DVA in Scotland from 1999 to 2003 and followed them in a prospective, population-based study. RESULTS: Of 2068 articles detected by the literature search, 15 met our inclusion criteria and described clinical presentation, 8 of which also described the clinical course of DVAs. In the 15 studies of 714 people first presenting with a DVA, 61% were incidental findings, the mode of presentation was unclear in 23%, 6% presented with nonhemorrhagic focal neurological deficit, 6% had caused symptomatic hemorrhage, 4% were associated with epileptic seizure, and <1% were associated with infarction. In studies of the clinical course of 422 people with a DVA, the hemorrhage rate after first presentation ranged from 0% to 1.28% per year. In the population-based study of 93 adults with DVAs, 98% were incidental, 1% presented with symptomatic hemorrhage, and 1% presented with an infarct, but there were no symptomatic hemorrhages or infarcts in 492 person-years of follow-up (0% per person-year; 95% CI, 0% to 0.7%). CONCLUSIONS: Intracranial DVAs have a benign presentation and clinical course.

Patterns of brain arteriovenous malformation treatment: prospective, population-based study.

BACKGROUND AND PURPOSE: The extent of variation in the interventional treatment of brain arteriovenous malformations (AVMs) is unknown, so we explored patterns of treatment at 4 neuroscience centers in one European country. METHODS: We included every participant with an AVM in a prospective, population-based cohort study of adults aged >or=16 years residing in Scotland at the time of AVM diagnosis in 1999 to 2003. RESULTS: Only 11 (5%) of the 229 adults were not managed at a neuroscience center. Adults who received interventional treatment were younger (median, 43 versus 54 years), more likely to have presented with hemorrhage (OR, 2.8; 95% CI, 1.6 to 4.9), and had smaller AVMs (median nidus diameter, 2 cm versus 3 cm; P=0.003) than those who did not. Adults seen at the 4 centers only differed in AVM Spetzler-Martin grade (P=0.04). The 4 centers did not differ in the proportion of adults with AVMs who received interventional treatment (P=0.16), but they differed in the Spetzler-Martin grade of the AVMs they treated (Grades III to IV, P=0.01) and the interventional treatments used (P=0.004). The 2 largest centers differed from each other in the likelihood of surgical resection (OR, 0.2; 95% CI, 0.1 to 0.6) and stereotactic radiosurgery (OR, 2.8; 95% CI, 1.3 to 6.1), and the choice of modality varied within some Spetzler-Martin grades. CONCLUSIONS: Patient characteristics and patterns of AVM interventional treatment differ between neuroscience centers in the same population necessitating careful consideration of these factors when comparing one hospital's outcome with another.

Outcome after interventional or conservative management of unruptured brain arteriovenous malformations: a prospective, population-based cohort study.

BACKGROUND: The decision about whether to treat an unruptured brain arteriovenous malformation (AVM) depends on a comparison of the estimated lifetime risk of intracranial haemorrhage with the risks of interventional treatment. We aimed to test whether outcome differs between adults who had interventional AVM treatment and those who did not. METHODS: All adults in Scotland who were first diagnosed with an unruptured AVM during 1999-2003 (n=114) entered our prospective, population-based study. We compared the baseline characteristics and 3-year outcome of adults who received interventional treatment for their AVM (n=63) with those who did not (n=51). FINDINGS: At presentation, adults who were treated were younger (mean 40 vs 55 years of age, 95% CI for difference 9-20; p<0.0001), more likely to present with a seizure (odds ratio 2.4, 95% CI 1.1-5.0), and had fewer comorbidities (median 3 vs 4, p=0.03) than those who were not treated. Despite these baseline imbalances, treated and untreated groups did not differ in progression to Oxford Handicap Scale (OHS) scores of 2-6 (log-rank p=0.12) or 3-6 (log-rank p=0.98) in survival analyses. In a multivariable Cox proportional hazards analysis, the risk of poor outcome (OHS 2-6) was greater in patients who had interventional treatment than in those who did not (hazard ratio 2.5, 95% CI 1.1-6.0) and was greater in patients with a larger AVM nidus (hazard ratio 1.3, 95% CI 1.1-1.7). The treated and untreated groups did not differ in time to an OHS score of 2 or more that was sustained until the end of the third year of follow-up, or in the spectrum of dependence as measured by the OHS at 1, 2, and 3 years of follow-up. INTERPRETATION: Greater AVM size and interventional treatment were associated with worse short-term functional outcome for unruptured AVMs, but the longer-term effects of intervention are unclear.

Assessment of 123I-FIAU imaging of herpes simplex viral gene expression in the treatment of glioma.

BACKGROUND: Herpes simplex virus 1716 (HSV1716), a selectively replication competent mutant of HSV1, is under investigation as an oncolytic viral therapy in human malignant glioma. As with similar therapies, a technique for measurement of viral replication and distribution over time following virus administration is required. Imaging expression of the HSV-thymidine kinase (HSV-tk) gene offers an opportunity for non-invasive assessment of viral distribution in living subjects. This is the first study to explore the use of HSV-tk as a reporter gene and radiolabelled thymidine analogue 5-[(123)I]iodo-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil ((123)I-FIAU) as a marker substrate to non-invasively monitor HSV1716 replication in humans during treatment of high-grade glioma. METHODS: I-FIAU brain SPECT imaging was undertaken in eight patients receiving intra-tumoural injection of HSV1716, before and after administration of the virus. Baseline images were acquired 3 days prior to virus administration and between 1 and 5 days following virus administration. Region of interest analysis was used to investigate whether there was an increase in (123)I-FIAU concentration following virus administration due to HSV-tk expression. RESULT: Increased (123)I-FIAU accumulation due to HSV-tk expression was not detected in this study. The possible explanations for this finding are explored and design options for future studies are discussed.

Involvement of apolipoprotein E in glioblastoma: immunohistochemistry and clinical outcome.

We hypothesised that apolipoprotein E (apoE) influences brain tumours by delivery of lipids to tumour cells and by analogy with other brain insults. APOE gene analysis was performed for 126 glioblastomas, the commonest primary brain tumour. Neither APOE epsilon2 nor epsilon4 alleles were significantly associated with differences in post-operative survival. However, there was apoE immunoreactivity of tumour cells, macrophages in areas of necrosis and astrocytes nearby. The immunohistochemistry findings support the hypothesis that apoE is involved in the delivery of lipids to tumour cells and in the recycling of lipids by macrophages in necrotic areas, raising the possibility that apoE-mediated lipid transport may represent a new therapeutic target in brain tumours.

Prospective, population-based detection of intracranial vascular malformations in adults: the Scottish Intracranial Vascular Malformation Study (SIVMS).

BACKGROUND AND PURPOSE: Intracranial vascular malformations (IVMs) are an important cause of intracranial hemorrhage, epilepsy, and long-term disability in adults. There are no published prospective, population-based studies dedicated to the detection of any type of IVM (cavernous malformations, venous malformations, and arteriovenous malformations [AVMs] of the brain or dura). Therefore, we established the Scottish Intracranial Vascular Malformation Study (SIVMS) to monitor detection and long-term prognosis of people with IVMs. METHODS: We used multiple overlapping sources of case ascertainment to identify adults (aged >or=16 years) with a first-ever-in-a-lifetime diagnosis of any type of IVM made between January 1, 1999, and December 31, 2000, while resident in Scotland (mid-1999 adult population estimate 4,110,956). RESULTS: Of 418 notifications to SIVMS, 190 adults (45%) were included, 181 (95%) of whom were deemed to harbor a definite IVM after review of diagnostic brain imaging and/or reports of autopsy/surgical excision pathology. The crude detection rate (per 100,000 adults per year) was 2.27 (95% CI, 1.96 to 2.62) for all IVMs, 1.12 (95% CI, 0.90 to 1.37) for brain AVMs, 0.56 (95% CI, 0.41 to 0.75) for cavernous malformations, 0.43 (95% CI, 0.31 to 0.61) for venous malformations, and 0.16 (95% CI, 0.08 to 0.27) for dural AVMs. CONCLUSIONS: In addition to providing data on the public health importance and comparative epidemiology of IVMs, continuing recruitment and follow-up of this prospective, population-based cohort will provide estimates of IVM prognosis.

Scottish Intracranial Vascular Malformation Study (SIVMS): evaluation of methods, ICD-10 coding, and potential sources of bias in a prospective, population-based cohort.

BACKGROUND AND PURPOSE: The rarity of intracranial vascular malformations (IVMs) and the infrequency of their outcomes make large, prolonged cohort studies the best means to evaluate their frequency and prognosis. METHODS: The Scottish Intracranial Vascular Malformation Study (SIVMS) is a prototype prospective, population-based study of adults resident in Scotland and diagnosed for the first time with an IVM after January 1, 1999. We evaluated the design of SIVMS using 2 complete years of data for adults with arteriovenous malformations (AVMs) of the brain. RESULTS: A collaborative network of clinicians, radiologists, and pathologists, combined with coding of hospital discharge data and death certificates, recruited a cohort distributed in proportion to the Scottish population. Coding (with International Classification of Diseases, 10th Revision [ICD-10] codes Q28.2 and I60.8) had a sensitivity of 72% (95% CI, 61% to 80%) and a positive predictive value of 46% (95% CI, 38% to 55%) for detecting incident brain AVMs. Adults who were detected by coding alone were significantly (P<0.05) younger, more likely to present with hemorrhage, more frequently investigated with catheter angiography, and more likely to be treated. Adults recruited from tertiary referral centers were significantly more likely to be investigated with catheter angiography and to be treated. Using catheter angiography as a diagnostic requirement for brain AVMs significantly biases the cohort toward younger adults presenting with hemorrhage and receiving treatment. CONCLUSIONS: Population-based studies of IVM frequency and prognosis should use multiple overlapping sources of case ascertainment, and such studies of brain AVMs should not require catheter angiography to be the diagnostic standard.

Cirugía para la enfermedad de parkinson: la nueva cara de una vieja moneda: comentarios sobre técnicas actuales en neurocirugía funcional (talamotomías y palidotomías) y experiencia en 65 pacientes / Surgery to the parkinson's disease: the new face of an old coin: commentaries about the present tecnics in funtional neurosurgery (thalamotomy and pallidotomy) and experience in 65 patients

La enfermedad de Parkinson (EP) es una enfermedad neurodegenerativa común, progresiva, cuyo manejo terapéutico puede llegar a ser muy complicado y exigente. Los pacientes después de un tiempo, frecuentemente presentan fallas en responder a las drogas anti-parkisonianas y se convierten en dependientes funcionales de las actividades diarias más comunes. La constante búsqueda de nuevas perspectivas terapéuticas, el entendimiento actual de los mecanismos neurales en la EP sugieren que una lesión adecuadamente colocada en el tálamo (talamotomía) y en el pallidum medial (palidotomía) deberían aliviar síntomas de temblor, rigidez, bradikinesias así como diskinesias inducidas por drogas. La clave para el éxito de esta cirugía y para evitar sus complicaciones, es la correcta colocación de los blancos a lesionar. Aun cuando la mejor forma de lograr esto es todavía controversial, la tecnología actual ha permitido diseñar programas computarizados que fusionan las imágenes cerebrales de la TAC con las de RMN, para definir en forma más precisa la anatomía de los ganglios basales, y con ello el blanco a lesionar en las talamotomías y palidotomías para parkinsonismo y temblor. Presentamos nuestra experiencia con esta técnica en 65 pacientes