Nicholas W. C. Dorsch

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.

Cerebral arterial spasm-a clinical review

A review of the literature on cerebral vasospasm after aneurysmal subarachnoid haemorrhage (SAH) has shown that angiographic vasospasm occurs in 67.3% of cases when angiography is timed for the highest likelihood, and delayed ischaemic deficit or symptomatic vasospasm in 32.6%. The presence of vasospasm has a marked effect on overall outcome of SAH, and the outcome of delayed ischaemia itself is in about one-third death and in one-third permanent deficit. Management with fluid loading or induced hypertension and with calcium antagonists has been reported widely for both prevention and treatment, and can reduce the incidence and improve the outcome of vasospasm. Other forms of treatment including tissue plasminogen activator, aminosteroids and transluminal angioplasty also appear useful. In spite of these improved therapeutic possibilities, large numbers of patients are still being reported in whom no specific treatment is used.

Early Experience with Spiral CT in the Diagnosis of Intracranial Aneurysms

ABSTRACT: WE REPORT EXPERIENCE with 16 patients undergoing spiral CT Scans for the evaluation of cerebral aneurysms. There were 10 females and six males, aged between 36 and 73 years. The three‐dimensional scanning was useful in five situations: (i) Suspicion of aneurysm on conventional scan. An aneurysm was found in one of four patients and later confirmed by angiography, and two showed arterial ectasia with no saccular aneurysm; the fourth again appeared to have an aneurysm, but this was not shown on angiography. (ii) Follow‐up of previously detected aneurysms not planned for surgery. This has been done in three patients, the spiral CT findings correlating well with previous angiography. (iii) Follow‐up of aneurysm remnants after surgery (three cases); findings correlate well with previous angiography, and clips cause no artefact problems. (iv) Detection of ruptured aneurysms. In two cases, small aneurysms were found that had been missed on angiography, and in a third, with doubtful angiographic findings, spiral CT was useful. (v) Investigation of patients with past treated aneurysms, or of relatives. Three subjects have been screened so far for that purpose; in one a small aneurysm has been found, and confirmed angiographically.

Cerebral vasomotor reactivity testing in head injury: the link between pressure and flow

Background: It has been suggested that a moving correlation index between mean arterial blood pressure and intracranial pressure, called PRx, can be used to monitor and quantify cerebral vasomotor reactivity in patients with head injury. Objectives: To validate this index and study its relation with cerebral blood flow velocity and cerebral autoregulation; and to identify variables associated with impairment or preservation of cerebral vasomotor reactivity. Methods: The PRx was validated in a prospective study of 40 head injured patients. A PRx value of less than 0.3 indicates intact cerebral vasomotor reactivity, and a value of more than 0.3, impaired reactivity. Arterial blood pressure, intracranial pressure, mean cerebral perfusion pressure, and cerebral blood flow velocity, measured bilaterally with transcranial Doppler ultrasound, were recorded. Dynamic cerebrovascular autoregulation was measured using a moving correlation coefficient between arterial blood pressure and cerebral blood flow velocity, the Mx, for each cerebral hemisphere. All variables were compared in patients with intact and impaired cerebral vasomotor reactivity. Results: No correlation between arterial blood pressure or cerebral perfusion pressure and cerebral blood flow velocity was seen in 19 patients with intact cerebral vasomotor reactivity. In contrast, the correlation between these variables was significant in 21 patients with impaired cerebral vasomotor reactivity, whose cerebral autoregulation was reduced. There was no correlation with intracranial pressure, arterial blood pressure, cerebral perfusion pressure, or interhemispheric cerebral autoregulation differences, but the values for these indices were largely within normal limits. Conclusions: The PRx is valid for monitoring and quantifying cerebral vasomotor reactivity in patients with head injury. This intracranial pressure based index reflects changes in cerebral blood flow and cerebral autoregulatory capacity, suggesting a close link between blood flow and intracranial pressure in head injured patients. This explains why increases in arterial blood pressure and cerebral perfusion pressure may be useful for reducing intracranial pressure in selected head injured patients (those with intact cerebral vasomotor reactivity).

Intracranial aneurysms: evaluation in 200 patients with spiral CT angiography.

Abstract The goal of this study was to assess the usefulness of spiral CT angiography (CTA) with three- dimensional reconstructions in defining intracranial aneurysms, particularly around the Circle of Willis. Two hundred consecutive patients with angiographic and/or surgical correlation were studied between 1993 and 1998, with CTA performed on a GE HiSpeed unit and Windows workstation. The following clinical situations were evaluated: conventional CT suspicion of an aneurysm; follow-up of treated aneurysm remnants or of untreated aneurysms; subarachnoid haemorrhage (SAH) and negative angiography; family or past aneurysm history; and for improved definition of aneurysm anatomy. Spiral CTA detected 140 of 144 aneurysms, and an overall sensitivity of 97 %, including 30 of 32 aneurysms 3 mm or less in size. In 38 patients with SAH and negative angiography, CTA found six of the seven aneurysms finally diagnosed. There was no significant artefact in 17 of 23 patients (74 %) with clips. The specificity of CTA was 86 % with 8 false-positive cases. Spiral CTA is very useful in demonstrating intracranial aneurysms.

A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage Part III: Mechanisms of action of calcium antagonists.

The possible mechanisms by which calcium antagonists are effective in the management of cerebral vasospasm are discussed. They number seven: relaxation of spastic arteries or prevention of spasm; opening up of collateral channels; neuronal protection at the membrane level; intracellular actions in neurones or vascular cells; alterations of blood rheology; antimitogenic effects; and improved fluid management of patients. A number of more minor actions may also be involved. It is likely that more than one mechanism is involved in their protective effect, especially at different periods in the time course of vasospasm.

Transcranial Doppler ultrasound in brain death: Experience in 140 patients

The interpretation of clinical tests for brain death is often complicated by the presence of facial trauma, or the use of barbiturate therapy for reduction of intracranial pressure. We propose a non-invasive technique--transcranial Doppler (TCD) sonography for the diagnosis of brain death. One hundred and forty comatose patients, 111 of whom were believed to be brain dead underwent TCD examinations. TCD assessments of the middle cerebral arteries (MCAs) and the basilar artery were performed before formal clinical testing for brain death. The TCD spectra recorded in the brain dead (BD) patients consisted of short, sharp systolic peaks followed by retrograde flow during diastole or just systolic peaks with absent flow in either direction. There were no survivors among patients who displayed these two TCD patterns. The 29 comatose control patients always showed flow throughout the cardiac cycle--no retrograde flow was ever recorded in these patients all of whom survived. Of particular interest were the basilar artery results. In nine BD patients no MCA signals could be obtained while good quality signals were recorded from the basilar artery. The TCD results agreed essentially with 100% accuracy with clinical testing and four vessel cerebral angiography. This paper illustrates the usefulness of TCD examination of the MCAs and especially the basilar artery in the diagnosis of brain death.

Spiral CT Scanning in the Detection and Evaluation of Aneurysms of the Circle of Willis

PURPOSE To assess the utility of spiral computed tomography (CT) with three-dimensional reconstruction in defining aneurysms of the Circle of Willis. METHODS Eighty-one patients with angiographic or surgical correlation were studied between 1993 and 1995, with surface rendered reconstructions of the arteries of the Circle of Willis. RESULTS Spiral CT was useful in six clinical situations: further assessment in cases with CT suspicion of an aneurysm, follow-up of known untreated aneurysms or aneurysm remnants, subarachnoid hemorrhage (SAH) with negative angiography, a past or family history of aneurysms, and improved definition of aneurysm anatomy. Ten of fifteen patients with previous surgery had no significant artifacts on the spiral study. In 66 other patients studied in search of aneurysms, the sensitivity of detection was 95% and specificity 74%. Seventeen of nineteen aneurysms 3 mm or less in size and 38 of 39 larger were detected by spiral CT. Four of thirteen patients with SAH and previous negative angiography had aneurysms identified, which were confirmed at surgery. CONCLUSIONS There is great promise in the use of spiral CT in demonstrating aneurysms of the Circle of Willis, including very small ones. Careful detailing of scan protocols and meticulous examination of multiplanar images are needed for maximum accuracy.

Cerebral autoregulation and ageing.

Little is known about the effects of ageing on cerebral autoregulation (CA). To examine the relationship between age and CA in adults, we conducted a prospective study using a non-invasive protocol without external stimuli. We studied 32 subjects, aged 23-68 years. They were assigned to a young group (28+/-5 years) and an old group (54+/-8 years). The groups were sex-matched. Transcranial Doppler ultrasonography (TCD) was used to record bilateral middle cerebral artery flow velocities (CBFV, cm/sec). Noninvasive beat-to-beat tonometric arterial blood pressure (ABP) measurement of the radial artery was used to record spontaneous blood pressure fluctuations. The Mx, an index of dynamic cerebral autoregulation (dCA), was calculated from a moving correlation between ABP and CBFV. We did not find a correlation between age and Mx. No statistically significant difference in the Mx between the groups (0.27+/-0.23, young, vs. 0.37+/-0.24, old) was demonstrated. Age does not affect dynamic cerebral autoregulation assessed by the Mx index in healthy adult subjects. This study supports findings from previous papers wherein CA was measured with protocols which require external stimuli. Further studies are needed to determine CA in subjects above 70 years of age.

Direct cerebral oxygenation monitoring—a systematic review of recent publications

This review has been compiled to assess publications related to the clinical application of direct cerebral tissue oxygenation (PtiO2) monitoring published in international, peer-reviewed scientific journals. Its goal was to extract relevant, i.e. positive and negative information on indications, clinical application, safety issues and impact on clinical situations as well as treatment strategies in neurosurgery, neurosurgical anaesthesiology, neurosurgical intensive care, neurology and related specialties. For completeness’ sake it also presents some related basic science research. PtiO2 monitoring technology is a safe and valuable cerebral monitoring device in neurocritical care. Although a randomized outcome study is not available its clinical utility has repeatedly been clearly confirmed because it adds a monitoring parameter, independent from established cerebral monitoring devices. It offers new insights into cerebral physiology and pathophysiology. Pathologic values have been established in peer-reviewed research, which are not only relevant to outcome but are treatable. The benefits clearly outweigh the risks, which remains unchallenged in all publications retrieved. It is particularly attractive because it offers continuous, real-time data and is available at the bedside.