John Laidlaw

Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm

Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.

Does Treatment of Ruptured Intracranial Aneurysms Within 24 Hours Improve Clinical Outcome

Background and Purpose— The purpose of this study was to analyze whether treating ruptured intracranial aneurysms within 24 hours of subarachnoid hemorrhage improves clinical outcome. Methods— An 11-year database of consecutive ruptured intracranial aneurysms treated with endovascular coiling or craniotomy and clipping was analyzed. Outcome was measured by the modified Rankin Scale at 6 months. Our policy is to treat all cases within 24 hours of subarachnoid hemorrhage. Treatment delays are due to nonclinical logistical factors. Results— Two hundred thirty cases were coiled or clipped within 24 hours of subarachnoid hemorrhage and 229 at >24 hours. No difference in age, gender, smoking, family history of subarachnoid hemorrhage, aneurysm size, or aneurysm location was found between the groups. Poor World Federation of Neurological Surgeons clinical grade patients were overrepresented in the ultra-early group. Increasing age and higher World Federation of Neurological Surgeons clinical grade were predictors of poor outcome. Eight point zero percent of cases treated within 24 hours of subarachnoid hemorrhage (ultra-early) were dependent or dead at 6 months compared with 14.4% of those treated at >24 hours (delayed), a 44.0% relative risk reduction and a 6.4% absolute risk reduction (&khgr;2, P=0.044). A total of 3.5% of cases coiled within 24 hours were dependent or dead at 6 months compared with 12.5% of cases coiled at 1 to 3 days, an 82% relative risk reduction and a 10.2% absolute risk reduction (&khgr;2, P=0.040). These groups did not differ in age, World Federation of Neurological Surgeons clinical grade, aneurysm size, or aneurysm location. Conclusions— Treatment of ruptured aneurysms within 24 hours is associated with improved clinical outcomes compared with treatment at >24 hours. The benefit is more pronounced for coiling than clipping.

Current intracerebral haemorrhage management

Primary intracerebral haemorrhage (ICH) refers to spontaneous bleeding from intraparenchymal vessels. It accounts for 10-20% of all strokes, with higher incidence rates amongst African and Asian populations. The major risk factors are hypertension and age. In addition to focal neurological findings, patients may present with symptoms of elevated intracranial pressure. The diagnosis of ICH can only be made through neuro-imaging. A CT scan is presently standard, although MRI is increasingly important in the evaluation of acute cerebrovascular disease. A significant proportion of intracerebral haematomas expand in the first hours post-ictus and this is often associated with clinical worsening. There is evidence that the peri-haematomal region is compromised in ICH. This tissue is oedematous, although the precise pathogenesis is controversial. An association between elevated arterial pressure and haematoma expansion has been reported. Although current guidelines recommend conservative management of arterial pressure in ICH, an acute blood pressure lowering trial is overdue. ICH is associated with a high early mortality rate, although a significant number of survivors make a functional recovery. Current medical management is primarily aimed at prevention of complications including pneumonia and peripheral venous thromboembolism. Elevated intracranial pressure may be treated medically or surgically. Although the latter definitively lowers elevated intracranial pressure, the optimal patient selection criteria are not clear. Aggressive treatment of hypertension is essential in the primary and secondary prevention of ICH.

Involuntary movements caused by phenytoin intoxication in epileptic patients.

The case histories of four patients who developed choreoathetoid movements during intoxication with phenytoin are presented. Drug intoxication was confirmed in each case by measuring the serum phenytoin concentration. Drug interactions were, in part, responsible for the occurrence of intoxication in three of them. Phenytoin intoxication is not always easy to recognize, particularly when nystagmus is minimal or absent, as in these four patients. The estimation of the serum phenytoin concentration is invaluable in this situation.

Gender differences in outcome in patients with hypotension and severe traumatic brain injury

BACKGROUND Animal studies have identified hormonal influences on responses to injury and recovery, creating a potential gender effect on outcome. Progesterone and oestrogen are thought to afford protection in the immediate post-injury period, suggesting females have an advantage, although there has been limited evidence of this in human outcome studies. METHODS This study examined the influence of gender on outcome in 229 adults (151 males), aged >17 years, with severe blunt head trauma, initial GCS <9 and hypotension, recruited into a randomised controlled trial of pre-hospital hypertonic saline resuscitation versus conventional fluid management. Outcome was measured by survival and Glasgow Outcome Scale-Extended version (GOS-E) scores at 6 months post-injury. RESULTS Females recruited into the study had a higher mean age. Females were more likely to be injured as passengers and pedestrians and males as drivers or motorcyclists. There were no gender differences in GCS or injury severity scores, ICP, cerebral perfusion pressure, gas exchange (PaO2/FiO2 ratio), or duration of mechanical ventilation. After controlling for GCS, age and cause of injury, females had a lower rate of survival. They also showed a lower rate of good outcome (GOS-E score >4) at 6 months, but this appeared to reflect the lower rate of initial survival. Those females surviving had similar outcomes to males. CONCLUSIONS The study provides no evidence that females fare better than males following severe TBI, suggesting rather that females may fare worse.

Aggressive surgical treatment of elderly patients following subarachnoid haemorrhage: management outcome results.

This report presents 74 consecutive cases of subarachnoid haemorrhage (SAH) in patients aged 70 years or older, compared with the 317 consecutive younger patients treated during the same period. An ultra-early surgical strategy for all SAH cases was used throughout the study period. Management outcome for all grades of elderly patients was independent in 38%, dependent in 14% and death in 49%. Surgical 3-month outcome of good grade elderly patients was independent 53%, dependent 19% and death 28%; and for poor grades was independent 35%, dependent 15% and death 50%. Elderly poor grade patients had similar outcome to younger patients, although good grade patients had better outcome in the younger group than the elderly group. Despite ultra-early surgery, rebleeding (<12 h of SAH) occurred in 9% of the elderly series. Aggressive, ultra-early treatment is likely to benefit elderly SAH patients, the potential benefit being greater for poor grade elderly patients.

THE ELECTROENCEPHALOGRAPHIC DIAGNOSIS OF MANIFEST AND LATENT `DELIRIUM' WITH PARTICULAR REFERENCE TO THAT COMPLICATING HEPATIC CIRRHOSIS

In a previous paper in this journal (Laidlaw, 1959), one of us discussed the potential value of assessing the generalized electroencephalographic (EEG) abnormalities which were found in those general medical disorders which did not affect the brain primarily, and described a visual method of expressing these abnormalities in the form of frequency patterns. Although it was felt that there was a place for this simple method, particularly in small EEG departments, it was admitted that it took time, was dependent on the experience of the observer, and provided only a limited amount of information. It was proposed that future work should be based on some form of automatic analysis. This paper explains the system which was developed for quantifying and grading information about the rhythmic background activity of the EEG, whether normal or abnormal, obtained from a modified and simplified electronic waveform analyser, and describes the application of this system to a particular clinical problem. The system of analysis has been applied to a variety of those general medical conditions in which the EEG is affected and it is clear that the changes which occur are not specific to any particular condition. One may postulate that there is a disorder of the metabolism of deeply placed structures of the brain. The EEG follows a fairly well-defined series of changes over a continuum from normal consciousness to deep coma (Laidlaw, 1959). There is at first a gradual reduction in the frequency of the rhythmic activity which may be preceded, accompanied, or immediately followed by a partial failure of alerting conditions to reduce or maintain the reduction of this rhythmic activity. Later, when the background rhythms have fallen to between 4 and 6 cycles per second (c/s) larger slower waves

Comparison of microsurgery and endovascular treatment on clinical outcome following poor-grade subarachnoid hemorrhage

Poor-grade (World Federation of Neurological Surgeons [WFNS] clinical grading scale grades IV and V) subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality. However, the correlation between the timing, modality of intervention (clipping or coiling) and the clinical outcome is not clear. This study aims to examine this correlation. Patients presenting with WFNS grades IV and V aneurysmal SAH between 1997 and 2008 to a single centre were studied. An aggressive policy of early intervention was followed, and the selection of endovascular versus microsurgical intervention was made according to angiographic rather than clinical features. Clinical outcomes were graded using the modified Rankin scale (mRS) at 6 month follow-up. One hundred and forty-three poor-grade patients (23.9% of all 598 aneurysmal SAH patients) were studied. Treatment was microsurgical in 83 (58.0%) and endovascular in 60 (42%) patients. Twenty patients (14.0%) were lost to follow-up. Good outcome (mRS 0-2) at 6 months was found in 45 microsurgical patients (63.3%) and 24 endovascular patients (46.1%). This trend towards better clinical outcomes in the microsurgical group was not statistically significant. With an aggressive early treatment policy more than half of the poor-grade SAH patients demonstrated a good clinical outcome. Microsurgery and endovascular treatment, when selected primarily according to angiographic features, were equally likely to achieve good outcome.

Evaluation of management of road trauma survivors with brain injury and neurologic disability in Victoria

BACKGROUND Victoria recently established a new trauma care system following the Consultative Committees findings on frequent preventable deaths after road crash injury. This study investigates the contribution to neurologic disability of preventable deficiencies in health care in survivors of road crashes occurring from 1998 to 1999. METHODS The emergency and clinical management of 60 road crash survivors with head Abbreviated Injury Scale score > or = 3 and residual neurologic disability were evaluated by analysis and multidisciplinary discussion of their complete prehospital, hospital, and rehabilitation records. RESULTS The mean number of potentially preventable errors or inadequacies per patient was 19.2 +/- 7.5, with 10.5 +/- 7.2 contributing to neurologic disability. The mean number contributing to neurologic disability was greatest in the emergency room (3.5 +/- 3.2), followed by the intensive care unit (2.2 +/- 2.7) and the prehospital setting (1.8 +/- 2.0). Eighty-four percent of the deficiencies were management errors/inadequacies and 7% were system inadequacies. Fifty-five percent of deficiencies contributed to neurologic disability. In patients with a systolic blood pressure less than 90 mm Hg with hypovolemia consequent to inadequate resuscitation, the frequency of severe neurologic disability was increased almost twofold (p < 0.05). Deficiencies contributing to neurologic disability were significantly less frequent in university teaching hospitals with neurosurgical units. CONCLUSION Improvement in neurologic outcomes can be achieved through appropriate triage and increased attention to basic principles of trauma and head injury care.

Dysembryoplastic neuroepithelial tumor (DNT)-like oligodendrogliomas or DNTs evolving into oligodendrogliomas: Two illustrative cases

A review of dysembryoplastic neuroepithelial tumors (DNTs) in 14 patients over a 12‐year period revealed four patients re‐operated because of changes on magnetic resonance imaging (MRI) suggesting tumor recurrence or progression. In three of these, the histological features were identical to the initial DNT. In the fourth patient, persistent DNT was surrounded by WHO grade 2 oligoastrocytoma. In one of the other 10 patients, WHO grade 2 oligodendroglioma was present in white matter deep to and completely separate from a cortically based DNT. Fluorescence in situ hybridization showed codeletion of 1p and 19q in both the DNT and oligodendroglioma and oligoastrocytoma components. Deletions were not identified in any other tumor. Our findings corroborate other studies that 1p and 19q deletions are uncommon in DNT. These two unusual tumors also raise the possibility that rare DNTs may evolve into oligodendroglioma or oligoastrocytoma. DNTs with this altered biology can be identified by 1p and 19q deletion analysis.