Search

One hundred cases of children in Edinburgh who underwent ventricular pressure monitoring for diverse indications have been discussed in detail and examples of their pressure tracings illustrated. This and other studies have now established that I.C.P. monitoring is a useful clinical tool. The technique employed has been justified from both a theoretical and practical standpoint and other methods of monitoring I.C.P. reviewed from the medical literature with their relative advantages and disadvantages. There is a place for I.C.P. measurement in suspect neonates by means of fontanometry; in hydrocephalic children by monitoring from ventriculostomy reservoirs; in head injury by way of the epidural or subarachnoid space; in childhood encephalopathies and other causes of brain swelling by epidural monitoring and for the continual assessment of the child in whom R.I.C.P. may be an on-going problem by means of a teletransducer. This work has afforded me the opportunity also to report related areas of interest. Firstly, the effect of I.C.P. on monoamine metabolites in children's C.S.F. with little correlation being found but a probable additional increase in one metabolite. Secondly, the effect of various types of seizures increasing the I.C.P. had not been previously reported. And, thirdly, the fascinating effect of sleep in I.C.P. with cyclical pressure variations occurring in all cases and exaggerated pressure responses and wave forms when there is existing R.I.C.P. I have put forward an hypothesis for this sleep effect based on pressure and polygraphic recordings. Lastly the chapter on anaesthesia adds some weight to other studies that caution the use of ketamine in cases of R.I.C.P., but confirms its use otherwise. These studies have however raised doubts about its convulsant action and I have shown the previously overlooked effect of intubation on I.C.P. and described a momentary pressure reflex associated with spreading the vocal cords, which together with the sleep effect, may be related to the Sudden Infant Death Syndrome.

Epileptic seizures are often un-witnessed and can result in hypoxic brain damage or can be fatal due to injuries, status epilepticus or sudden unexpected death in epilepsy (SUDEP). The first aim of this thesis was to investigate some of the physiological parameters that accompany an epileptic seizure and may be useful in a seizure alarm system. The second aim was to investigate aspects of cardiac dysfunction during clinical and sub-clinical seizures that may be potential contributing factors in SUDEP. Percentage heart rate change and oxygen saturation were studied prospectively during 527 epileptic seizures in 50 patients aged from one-day full term neonate to 60 years with a variety of seizure types (absences, generalised tonic clonic seizures, myoclonic seizures, tonic seizures and focal seizures) and in normal physiological events (e.g. coughing, turning in bed). Higher percentage heart rate change occurred during epileptic seizures (21.8%) than during normal physiological events (16.4%) p<0.001. Diagnostic testing of clinically significant seizures i.e seizures that could potentially lead to serious consequences if left undetected (n=61) had a sensitivity of 91% and specificity of 75% when percentage heart rate change and hypoxaemia parameters were combined. Percentage heart rate change and oxygen saturation could be used as reliable indicators of a seizure when set at specific levels and distinguish clinically significant seizures from normal physiological events. These parameters can now be used to develop a reliable alarm system to detect epileptic seizures at night. Prolongation of QTc and increased vagal tone may be possible mechanisms underlying SUDEP. Corrected Q-T cardiac repolarisation time 5 minutes before and throughout 156 epileptic seizures were analysed using four corrective formulae (Bazett, Hodge, Fridericia and Framingham). All formulae indicated statistically significant lengthening of the corrected Q-T during epileptic seizures (p<0.001) compared to pre-seizure values. All formulae agreed that the greatest lengthening of the corrected QT beyond normal limits occurred during right temporal lobe seizures in two patients. Reflex and tonic vagal activity utilising R-R intervals was assessed in 33 sub-clinical seizures occurring during stages 3 or 4 sleep and was compared to matched counts of R-R interval non-ictal baseline studies from the same stage of sleep in each patient. Altered vagal activity occurred during total sub-clinical seizures compared to baseline studies (p<0.001). Lengthening of the corrected Q-T and changes in cardiac vagal tone during epileptic seizures may have a role in the patho-physiology of SUDEP.

The commonest reproductive disorders of young men (namely low sperm counts, testicular germ cell cancer) may originate in fetal life similar to established disorders (cryptorchidism, hypospadias) that manifest at birth. These disorders are interlinked and may comprise a testicular dysgenesis syndrome (TDS), a concept supported by animal model studies. The latter have identified the likely time-frame within which TDS disorders may be induced, namely within the so-called masculinisation programming window (MPW). During this critical period, sufficient testosterone (androgen) must be produced by the fetal testis to program the male reproductive tract so that it will differentiate and grow normally after the MPW. Impaired androgen production or action within the MPW can result in smaller reproductive organs and their abnormal formation and function (e.g. cryptorchidism, hypospadias). The MPW is thus of fundamental importance in determining normal, or abnormal, male reproductive development and function for later life. There are two big unanswered questions about the MPW. First, what determines its timing? Second, what mechanisms are controlled by androgens specifically within this time-window and not at later time points? Three approaches were undertaken to address the first question experimentally in rats. First, investigation of whether the availability of androgens and or androgen receptors (AR) plays a role in determining the onset or ‘opening’ of the MPW. Second, investigation of whether the expression of AR co-regulators was a factor in determining androgen sensitivity during the MPW. Third, investigation of whether prostaglandins played a role in mediating androgen action in the MPW, as studies in the 1980s had suggested this possibility. To address what mechanisms are controlled by androgens specifically within the MPW, the expression of selected genes in the genital tubercle was investigated before, during and after the MPW in fetuses that had been exposed to treatments that modulated androgen action. Selection of genes was based on microarray studies and data reported in the literature (ie candidate genes). The studies reported in this thesis show that neither availability of androgens nor the AR are important in determining onset of the MPW, and providing exogenous androgens either prior to or during the MPW does not advance or enhance masculinisation. These studies also showed that females may have a slightly different window of susceptibility to androgen action than do males. Key AR co-regulators have been characterized in the male reproductive tract for the first time, two of which (BRG1, CBP) show changes in expression through development of the testis consistent with a role in Sertoli cells. Another AR co-regulator, RWDD1, was found to switch off in the absence of androgen action in the genital tubercle, pointing to a potential role during and/or after the MPW. Studies involving gestational exposure to indomethacin (a compound which inhibits prostaglandin synthesis) during the MPW showed no detectable effect on masculinisation. Finally, evaluation of candidate genes for mediating androgen action in the genital tubercle during the MPW, failed to identify their key involvement, thus they are unlikely to be involved in penis development and disorders such as hypospadias.

Perimetry is essential to identify visual field defects in disorders of the visual pathways. In compliant adults, automated static perimetry (ASP) is the preferred method of visual field assessment. However, children under 10 years have difficulty with the visuo-motor task and constant fixation required. Manual kinetic perimetry is often used for children as it can be adapted to a child’s age. However, it suffers from many of the problems inherent to ASP. In infants perimetry is limited to the “confrontation” technique which can be imprecise and does not generate quantitative data. The lack of reliable ASP in children and quantitative perimetry in infants is a longstanding clinical problem. The aims of this research were to (i) develop, and (ii) clinically evaluate, a technique for ASP in children which utilises “eye tracking”. The first part of this research was concerned with the development of the technique, termed “Saccadic Vector Optokinetic Perimetry” (SVOP). The system comprises a personal computer, display screen, and an X50 eye tracker (Tobii Technology, Sweden). The eye tracker is noncontact and provides data on (i) eye position in 3D space, and (ii) the point of gaze. This allows the screen position of “test stimuli” to be calculated, and eye gaze responses to the “test stimuli” to be assessed in “real time”. A software algorithm was developed to determine if “test stimuli” have been perceived based on the direction, amplitude and latency of a subject’s gaze response. A feasibility study was conducted with 29 subjects comprising 4 groups: (i) healthy adults, (ii) healthy children, (iii) adult patients with visual field defects, and (iv) child patients with visual field defects. Subjects performed SVOP tests which replicated the Humphrey Field Analyser (HFA) C-40 screening test with a stimulus size of Goldmann III and intensity of 14dB. Subjects able to do so also performed equivalent HFA C-40 tests for comparison. In healthy subjects 99.1% of SVOP test points were in agreement with a healthy visual field. In patients with visual field defects, 89.8% of test points were in agreement with HFA equivalent tests. The visual field defects identified using SVOP in the child patients were consistent with their clinical findings. A clinical evaluation of SVOP was undertaken in the second stage of this research with 122 subjects comprising the same four subject groups as in the feasibility trial. An “ideal” test protocol resulted in 8 uniocular visual field tests for each subject comprising 4 SVOP tests and 4 HFA tests. In children where uniocular testing was not tolerable, two binocular SVOP tests were performed. The sensitivity and specificity of the SVOP tests were computed using a direct comparison with reliable HFA tests, and repeatability of SVOP and HFA tests were assessed using Cohen’s kappa coefficient. In child patients unable to provide a reliable HFA test, their clinical history, other clinical findings and the repeatability of their SVOP tests were used to assess the SVOP results. The overall sensitivity and specificity of the SVOP testing was 72.7% and 96.8% respectively. The sensitivity had a greater variation than the specificity amongst the different subject groups. The repeatability of SVOP tests was slightly reduced as compared to the HFA tests across all groups with kappa coefficient’s of 0.65 and 0.74 for SVOP and HFA respectively. In child patients without reliable HFA equivalent tests the SVOP results could commonly be associated with other clinical findings and repeatable testing added to the confidence in the reliability of these cases. The developed SVOP technique performs well with accurate eye tracking data and an attentive child. It has proved extremely useful in identifying and monitoring visual field defects in several child patients who required regular visual field assessment.