Goran A. Jamal

Characterisation of breathing and associated central autonomic dysfunction in the Rett disorder

AIM To investigate breathing rhythm and brain stem autonomic control in patients with Rett disorder. SETTING Two university teaching hospitals in the United Kingdom and the Rett Centre, Sweden. PATIENTS 56 female patients with Rett disorder, aged 2–35 years; 11 controls aged 5–28 years. DESIGN One hour recordings of breathing movement, blood pressure, ECG R-R interval, heart rate, transcutaneous blood gases, cardiac vagal tone, and cardiac sensitivity to baroreflex measured on-line with synchronous EEG and video. Breathing rhythms were analysed in 47 cases. RESULTS Respiratory rhythm was normal during sleep and abnormal in the waking state. Forced and apneustic breathing were prominent among 5–10 year olds, and Valsalva breathing in the over 18 year olds, who were also most likely to breathe normally. Inadequate breathing peaked among 10–18 year olds. Inadequate and exaggerated breathing was associated with vacant spells. Resting cardiac vagal tone and cardiac sensitivity to baroreflex were reduced. CONCLUSIONS Labile respiratory rhythms and poor integrative inhibition in Rett disorder suggest brain immaturity. Linking this to an early monoaminergic defect suggests possible targets for the MECP2 gene in clinical intervention. Exaggerated and inadequate autonomic responses may contribute to sudden death.

Low level exposures to organophosphorus esters may cause neurotoxicity

A large number of published studies support the notion that long term, low level (LTLL) exposure to organophosphorus (OP) esters may cause neurological and neurobehavioral effects. In order to differentiate these from other effects of OP such as the acute cholinergic episodes, intermediate syndrome and organophosphate induced delayed neuropathy (OPIDN), the term Chronic Organophosphate Induced Neuropsychiatric Disorder (COPIND) will be used purely for the ease of reference. The question addressed in this particular review is whether LTLL exposure to OP may produce neurotoxicity. The profile and the degree of overlap of the various components of COPIND have been addressed elsewhere and description of the possible mechanisms for COPIND is outside the scope of this article. COPIND can be classified under two headings; those produced following one or more acute clinical cholinergic episodes, and those produced without such preceding attacks. With regards to the first group, there are a total of 11 studies, all of which support the existence of a positive link between exposure to OP and neurotoxicity; six of these studies comprise descriptions of large numbers of cases without controls while five additional studies employ controls. Appearance of neurotoxicity does not seem to be related to the number or the intensity of acute cholinergic attacks. With regards to the second group, three types of studies can be identified. Firstly, there are five studies using experimental animals, all of which showed a positive link between OP and neurotoxicity. Secondly, a total of seven case studies without controls, some involving large numbers of patients, concluded that there is a positive link between OP and neurotoxicity. Thirdly, 19 studies investigated such a link using cases and control groups. Of these, 15 studies (about 80%) showed a positive link and only four failed to identify any link between OP and neurotoxicity. Annotation of all the 19 studies according to ideal set of criteria showed that only a few of these comply with the rules of excellence and all of these few showed a positive link. Furthermore, the only study carried out blind without the identification of subjects or controls, showed a positive link between OP and neurotoxicity. This blind study estimated the overall incidence of a form of neurotoxicity in people exposed to OP to be about 40 times higher than in the general population. The type of neurological involvement was unique and different from OP induced syndromes previously described. The profile of the neurological involvement was similar to that in COPIND whether or not preceded by acute cholinergic episodes, thus providing further evidence that these two neuropathies probably share a similar mechanism. There is a characteristic pattern of involvement of 15 functional indices of the autonomic nervous system examined in our laboratory. There are, in addition, preferential anatomical sites of target organs affected, selective preservation of cholinergic function within the same neuropathy-positive site, and evidence of mal-function of cardiac chemoreceptors in patients exposed to OP. The peripheral nerve involvement in OP exposure is predominantly sensory in nature affecting both small and large fibre populations. Neurobehavioral involvement of mainly cognitive dysfunction and other features are also described in other studies. The weight of current evidence is therefore very much in favor of the motion that chronic low-level exposure to OP produces neurotoxicity. Criticisms levelled against this motion are unfounded and probably misconceived.

Changes in a measure of cardiac vagal activity before and after epileptic seizures

In previous studies of the relationship between the cardiac autonomic activity and seizures, assessment of autonomic changes has relied on alterations in heart rate or R-R intervals. We have used a recently developed continuous index of cardiac parasympathetic activity (CIPA) to examine 20 seizures in 10 patients during pre-surgical evaluation in a video-telemetry unit. The patients had localization related seizures due to non-progressive pathology and both complex partial seizures (CPS) and complex partial with secondary generalised tonic clonic seizures (STCS) were examined. Mean CIPA prior to the onset of STCS was elevated above normal values and fell significantly to previously established normal values following the seizure. CPS were not associated with elevated mean CIPA pre- or post-seizure. STCS were associated with a reduction in anti-convulsant dosage and with elevation of pre-ictal CIPA. We propose that elevation of cardiac parasympathetic activity pre-ictally may be a marker for secondary generalisation of seizures.

Cognitive functioning in people with epilepsy plus severe learning disabilities: a systematic analysis of predictors of daytime arousal and attention

In spite of the high prevalence of epilepsy and the importance of preserving cognitive function in people with learning disabilities, this population has received relatively little research attention. This study sets out systematically to investigate possible predictive factors of inter-ictal states of arousal and attention. The daytime function of 28 people with epilepsy and severe learning disabilities was assessed by performance on a two-choice reaction time vigilance task, behavioural analysis of time-sampled video recordings taken in naturalistic settings, and carer ratings on visual analogue scales. This methodology yielded eight discrete functional measures, from which two further index measures were derived after principal components analysis. A range of clinical and psychosocial assessments was completed and subjects had 36 hour ambulatory EEG and sleep EEG monitoring. Regression models identified significant predictors of cognitive function from a range of potential explanatory variables i.e. demographic, clinical, pharmacological, background EEG rhythms and sleep parameters. Results indicated that greater severity of learning disability, longer bedtime periods, poor sleep efficiency, frequent seizures and antiepileptic drug polytherapy were significant predictor variables. Explained variance (adjusted R2) was greater than 50% for six of 10 outcome variables (range up to 85%). Furthermore, significant regression equations (P < 0.05) were obtained for all but one variable. Thus, these results appear reasonably robust. Results support an interactional model of daytime arousal and attention in people with epilepsy plus severe learning disabilities. Inter-ictal cognitive function appears to be mediated by a combination of organic, circadian (sleep wake), clinical and pharmacological factors.

Periodicity of a noninvasive measure of cardiac vagal tone during non-rapid eye movement sleep in non-sleep deprived and sleep-deprived normal subjects.

Cyclic alternating pattern (CAP) of microarousals reported in EEG studies is now regarded as an integrating mechanism for the different parts of the central nervous system including the autonomic system. A recently developed continuous index of cardiac parasympathetic activity (CIPA) can be time locked to the EEG allowing the relationship between EEG and autonomic changes to be studied in sleep. Eleven normal subjects were studied for evidence of periodicity in CIPA in non-REM sleep, five of whom had been sleep deprived. Fast Fouriers transformation of the CIPA data confirmed its periodicity with four frequency peaks in the range of 0.015 to 0.3 Hz. The frequency peaks previously reported as caused by respiration, Mayer waves and vasomotor thermoregulatory activity, were within what we called the alpha and beta rhythms of CIPA. There was an additional very slow peak not previously described and we called it the gamma rhythm. It covered the frequency range below 0.03 Hz. The gamma rhythm was the largest of all peaks in CIPA rhythms and its magnitude increased further in sleep-deprived subjects, but it invariably decreased during stage 4 sleep in both groups. Bursts of alpha waves in the EEG recorded concomitantly with CIPA in stage 1 sleep were associated with both peaks and troughs of the gamma rhythm. These results support previous proposals that cyclic alternating pattern in the EEG may be an integrating mechanism associated with functions of the central nervous system, and we have shown here its relationship with CIPA. Because cyclic alternating pattern can also be measured in CIPA, clinical exploitation of this phenomenon could include monitoring of epilepsy, studies of the effects of drug therapy, and assessment of other sleep disorders. All these are known to affect cyclic patterns of sleep EEG.

Selective defect of baroreflex blood pressure buffering with intact cardioinhibition in a woman with familial aniridia

We report a symptomatic failure of the baroreceptor blood pressure (BP) buffering mechanism in a woman with familial aniridia. Her baseline BP oscillated at 0.1 Hz, the frequency of Mayer waves, with increased amplitude on standing without orthostatic hypotension. Although sudomotor function was normal, cutaneous thermoregulatory function and BP response to Valsalvas maneuver were abnormal. The defective BP buffer mechanism suggests Mayer waves could be a sympathetic mediated cardiovascular resonance. Baroreceptor cardioinhibition was intact. We presume that the lesion is in the rostral aspect of the dorsal medulla oblongata.

Endogenous cyclo-oxygenase substrates mediate the neuroactivity of evening primrose oil in rats

The role of cyclo-oxygenase and or its substrate(s) on the neuroactivity of evening primrose oil was investigated on the basis that a blockade of cyclo-oxygenase activity using aspirin would inhibit neuroactivity of primrose oil if this effect was mediated by prostanoids. Streptozotocin diabetic rats and controls were all given large doses of aspirin, but only subgroups of them received primrose oil. Saphenous sensory A- and C-fibre, and sciatic motor conduction velocities were measured to assess neuroactivity of primrose oil. Aspirin enhanced the neuroactivity of primrose oil thus indicating that prostanoids are unlikely to mediate this neuroactivity, but also suggesting that substrates of cyclo-oxygenase are neuroactive. It is likely that cyclo-oxygenase antagonises neuroactivity of primrose oil by competing with the process for substrates. Thickly myelinated sensory A-fibres were most affected by primrose oil suggesting that the predominant sensory symptoms in diabetic neuropathy could be due to the sensitivity of sensory nerves to the metabolic aberration in diabetes. Normal nerve function is probably preserved by cyclo-oxygenase during an influx of neuroactive fatty acids from the gut, since inhibition of the enzyme rendered non-diabetic nerves vulnerable to dietary primrose oil.

Peripheral Nerve Dysfunction in Farmers Using Organophosphate Sheep Dip

Purpose : To investigate the function of the peripheral and central nervous system in farmers regularly using organophosphate (OP) compounds either after acute intoxication or following low level repeated exposure. Design : Case control and cross-sectional studies. Materials and Methods : Two groups, each of sixteen farmers regularly involved in dipping sheep, were compared with a group of sixteen healthy controls of similar age range using clinical neurological and neurophysiological assessment. Farmers in group 1 had long-term ill health following episodes of mild to moderate acute OP poisoning while farmers in group 2 had none of the above. Clinical symptoms and signs of neuropathy were recorded. Motor and sensory nerve conduction, electromyography (EMG), quantitative sensory testing and visual, brainstem auditory and somatosensory evoked potentials were measured. Results : A similar pattern of significant abnormalities of distal sensory and motor peripheral nerve axonal dysfunction was found in both f...

Complex regional pain syndrome with selective emotional sudomotor failure

We report a patient with sympathetically maintained pain following a mild limb injury. Only emotional sudomotor failure was found in the painful limb. Thermoregulatory vasomotor function was intact. However, the patient had other target‐specific sympathetic lesions, including thermoregulatory vasomotor failure in a different limb, not associated with pain. We hypothesize that the sympathetic failure preceded the symptoms and that the mild injury may have provoked collateral sprouting of emotional sudomotor fibres, coupling them with somatic sensory fibres to cause continuous pain.