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Vegetative State (VS) implies significant issues. The aim of the MORFEO study is to identify the most relevant complications in VS patients and to supply clinicians and policy-makers with data derived from the analysis of a cohort of patients treated in a dedicated long-term facility setting.A cohort of 22 VS patients treated between 2003 and 2007 were enrolled and followed up for 1 year. The information recorded were: Disability Rating Scale (DRS), Levels of Cognitive Functioning (LCF), pressure sores, nutritional status, neurological complications, articular complications (passive range of motion-ROM), deep-vein thrombosis and infections. The Kolmogorov-Smirnov test was used to verify the normal distribution of the variables. The indicators of complications were analysed with the Friedman test (continuous variables) and with the Cochran Q test (dichotomous variables).DRS and LCF values showed no significant variation. The number of pressure sores decreased. The nutritional status remained satisfying. The ROM worsened in lower limb joints; a trend (p = ns) towards an improved range was observed in shoulders and elbows. Fifteen infections were recorded.The data that proved significant suggest a minimum set of quality-of-care indicators in VS patients: pressure sores follow-up, nutritional status, ROM and incidence of infections.

The NMDA subtype of glutamate receptor plays an important role in the molecular mechanisms of learning, memory and excitotoxicity. NMDA receptors are highly permeable to calcium, which can lead to the activation of the calcium-dependent protease, calpain. In the present study, the ability of calpain to modulate NMDA receptor function through direct proteolytic digestion of the individual NMDA receptor subunits was examined. HEK293t cells were cotransfected with the NR1a/2A, NR1a/2B or NR1a/2C receptor combinations. Cellular homogenates of these receptor combinations were prepared and digested by purified calpain I in vitro. All three NR2 subunits could be proteolyzed by calpain I while no actin or NR1a cleavage was observed. Based on immunoblot analysis, calpain cleavage of NR2A, NR2B and NR2C subunits was limited to their C-terminal region. In vitro calpain digestion of fusion protein constructs containing the C-terminal region of NR2A yielded two cleavage sites at amino acids 1279 and 1330. Although it has been suggested that calpain cleavage of the NMDA receptor may act as a negative feedback mechanism, the current findings demonstrated that calpain cleavage did not alter [(125)I]MK801 binding and that receptors truncated to the identified cleavage sites had peak intracellular calcium levels, (45)Ca uptake rates and basal electrophysiological properties similar to wild type.

Although epilepsy is fundamentally a circuit phenomenon, the most basic manifestation of the hyperexcitability characteristic of epilepsy must be evident at the level of a single neuron. Furthermore, in the future, manipulations of surviving neurons within the epileptic focus will constitute one of the best therapeutic targets for intervention to cure this devastating disease. Therefore, the more that can be learned about epileptogenic alterations in this population of surviving focal neurons, the more potential avenues for therapeutic intervention will emerge. This chapter has summarized one aspect of postsynaptic neuronal function that undergoes dramatic alterations in the epileptic brain: the properties of inhibitory neurotransmitter (i.e., GABA) receptors in surviving focal neurons. GABARs in these neurons undergo significant alterations in their function and pharmacology, which appear to be mediated, at least in part, by alterations in the transcriptional production of GABAR subunits. These GABAR alterations fulfill many of the requirements for an epileptogenic mechanism: they are consistent with the hyperexcitability characteristic of epilepsy; the changes develop prior to the onset of recurrent spontaneous seizures; and the elevated zinc sensitivity of epileptic GABARs combined with epilepsy-associated mossy fiber sprouting (a zinc "delivery mechanism") can account for the existence of a prolonged latent period. Although GABAR alterations in DGCs of the epileptic hippocampus may be consistent with hyperexcitability and therefore contribute to epileptogenesis, many other processes undoubtedly also contribute, including (but not limited to) neuronal loss, circuit rearrangements, alterations in other membrane proteins, and birth of new neurons. Assuming any single change is both necessary and sufficient to fully account for epilepsy is undoubtedly an oversimplification. The initial precipitating events associated with the subsequent development of epilepsy are often traumatic events and associated with changes in many processes in widespread areas of the brain. Some of these processes may contribute to excitability changes, some may resist the development of epilepsy, and some may be unrelated to epileptogenesis. Characterizing the critical processes initiated during epileptogenesis remains an important and challenging research endeavor for the foreseeable future.

This chapter reviews two main aspects of the basic mechanisms of status epilepticus--acute factors, which are important in inducing status epilepticus in an in vitro brain slice model of status epilepticus, and the acute and chronic epileptogenic consequences of status epilepticus. Status epilepticus is difficult to produce in vitro in normal extracellular medium. This suggests that seizure-terminating mechanisms are normally quite robust. To produce long- duration, self-sustained epileptic discharges in vitro, we have found it necessary to include reciprocally connected entorhinal cortex with our hippocampal slices. Doing so closes the normal excitatory limbic loop in the brain. We found incorporation of the full loop in our brain-slice preparations necessary to bring about epileptic discharges of long duration that fit the definition of status epilepticus. Reentrant activation from distant sites may be necessary for maintenance of status epilepticus-like activity of long duration. Similar requirements may exist for generalized tonic-clonic status epilepticus discharges, but as yet no data support or refute this hypothesis. There are both acute and chronic consequences of an episode of status epilepticus. Acute consequences are alterations in membrane potential and membrane properties of hippocampal pyramidal cells accompanied by alterations in neurotransmitter-activated conductances and receptor expression. Some of these acute alterations in receptor and transmembrane iongradient associated with status epilepticus may be critically involved in the development of drug resistance during the late stages of status epilepticus. Long-term consequences of status epilepticus in the limbic system include alterations in patterns of expression of neurotransmitter receptors and in the function of excitatory and inhibitory synapses, cell loss, and circuit rearrangements within the limbic system. An episode of status epilepticus that involves the limbic system clearly elicits brain damage, at least among adult animals. This brain damage can contribute to the development of epilepsy, or a condition of recurrent, spontaneous seizures. Conversely, development of an epileptic condition enhances the susceptibility of the limbic system to trigger status epilepticus discharges.

The frequency with which agranulocytosis was associated with mianserin in New Zealand was calculated, by two methods, from spontaneous reports to the Intensive Medicines Monitoring Programme (IMMP)--one gave a frequency of 1 in 1354 (95% CI 1 in 3145 to 1 in 685) and the other gave a rate of 1 in 1743 (95% CI 1 in 2895 to 1 in 1116). There were 3 deaths. Age and dose seemed to be related to occurrence of agranulocytosis. The frequency of the complication seemed to be higher than that reported for other countries, perhaps because higher doses were prescribed in New Zealand but also perhaps because of a selection bias in surveys elsewhere. The occurrence of agranulocytosis with mianserin in New Zealand is higher than that of white-cell dyscrasias reported with use of chloramphenicol, phenylbutazone, and oxyphenbutazone, and although the case-fatality rate of agranulocytosis is lower with mianserin than with the other drugs, the overall mortality rate may be higher.

We reviewed medical records of inborn babies of30 gestational weeks who died before hospital discharge to identify the cause of death and age at death. We compared all surfactant-treated babies born during the first 19 months of our experience in a phase III trial of exogenous surfactant prophylaxis of respiratory distress syndrome with all untreated babies born during the 19 months immediately preceding the surfactant trial. The two groups were virtually identical in birth weight and gestational age. Mortality in all gestational age groups declined by half after the initiation of surfactant treatment. The mean age at death did not change significantly. Cases of early or late mortality did not change between the two periods. Exogenous surfactant prophylaxis does not significantly prolong the lives of extremely premature babies who are destined to die before hospital discharge.

To review reports of angiooedema and urticaria associated with angiotensin converting enzyme inhibitors (ACEI) in the New Zealand Centre for Adverse Reactions Monitoring and Intensive Medicines Monitoring Programme (IMMP) database.Adverse reaction reports describing angiooedema and/or urticaria between April 1981 and December 1994 were examined. Captopril, enalapril and lisinopril were intensively monitored on the IMMP during this period.Of a total of 116 reports there were 68 reports of angiooedema and 37 of urticaria alone and 11 where angiooedema and urticaria occurred in the same patient. The total number of patients is unknown, but cohorts of patients on captopril, enalapril and lisinopril in the IMMP were 16342, 25686 and 11235, totalling 53263 patients. There were 63 reports of angiooedema/urticaria in patients monitored on the IMMP, giving a reported rate of 1.2/1000 (0.9-1.5). Forty seven reactions occurred between 3 weeks and 4 years after commencement of therapy. Severe angiooedema occurred in 9 patients with early-onset angiooedema and 6 with late-onset angiooedema. There were no deaths. Seventeen patients had up to 12 episodes before diagnosis. Angiooedema/ urticaria occurred without gender preference. Although a dose relationship was not apparent, 3 patients developed angiooedema or urticaria after an increase in dose.Although reactions are more common shortly after initiation of ACEI therapy, late onset reactions may be less well recognised. Clinicians should be reminded, and ACEI data sheets should emphasise, that onset may be delayed for weeks or months, that patients may have multiple episodes with long symptom free intervals, and that angiooedema may occur with or without urticaria.

Numerous studies have shown that plasma carnitine levels are significantly lower in patients taking valproate than in controls. Free carnitine deficiency is not uncommon in these patients and also occurs in newborns with seizures and in patients taking other anticonvulsant drugs. Carnitine deficiency in epilepsy results from a variety of etiologic factors including underlying metabolic diseases, nutritional inadequacy, and specific drug effects. The relationship between carnitine deficiency and valproate-induced hepatotoxicity is unclear. Carnitine treatment does not always prevent the emergence of serious hepatotoxicity, but it does alleviate valproate-induced hyperammonemia. These studies suggest that specific risk factors for carnitine deficiency can be identified. Preliminary data suggest that carnitine treatment may benefit high-risk, symptomatic patients and those with free carnitine deficiency. Carnitine treatment is not likely to benefit low-risk, asymptomatic patients and those with normal carnitine levels.

The 1992 American Association on Mental Retardation's (AAMR) definition and classification of mental retardation is different from the previous classification system in that: (a) a single diagnostic code of mental retardation is used if the person meets the three criteria of age of onset (18 or under), significantly subaverage abilities in intellectual functioning, and related limitations in two or more adaptive skills areas; (b) the person's strengths and weaknesses are described in reference to four dimensions: intellectual functioning and adaptive skills; psychological and emotional well-being; health, physical well-being, and etiology; and life activity environments; and (c) a profile of needed supports is developed across the four dimensions. In this article we discussed six major implications of the 1992 System for the field of mental retardation.

To review reports of the association between fluoxetine and hyponatraemia.Reports of hyponatraemia associated with fluoxetine received over a four-year period in the New Zealand Intensive Medicines Monitoring Programme have been examined and these and other case reports in the literature, discussed.Seven patients, all women aged 68-88 years on fluoxetine 20 mg daily, developed hyponatraemia (serum sodium 114-128 mmol/L, five within 19 days of commencement of fluoxetine. The reported rate for women over 65 years was 8.5 per thousand. Withdrawal of fluoxetine was associated with recovery in all cases.Fluoxetine is associated with a significant incidence of hyponatraemia in the elderly, especially during the first weeks of therapy. It is advisable to monitor electrolytes in older patients during this period.

To evaluate the ability of the Gosset icterometer to identify the need for serum bilirubin measurement in premature infants we compared 269 icterometer readings with simultaneous serum bilirubin determinations in 90 premature infants of37 completed weeks of gestation. The relationship between serum bilirubin and icterometer values was different from that described in term infants. Mean serum bilirubin concentrations were lower at each icterometer level in premature infants than those reported in term babies. Neither interobserver variability nor the color balance of ambient light affected icterometry. Bilirubin estimates by first-time users were slightly less accurate than those made by experienced users. The icterometer provides reliable, cost-effective screening for clinically important hyperbilirubinemia in premature babies if a calibration curve specific for those infants is used. This simple device performs as well as electronic bilirubin meters when it is used in this manner.

The field of mental retardation is being changed by a paradigm shift in how mental retardation is conceptualized and in how services are provided. This new way of thinking is reflected in the 1992 AAMR definition of what mental retardation is (Luckasson et al., 1992). Prevention efforts must also reflect this new way of thinking, which focuses on the interaction between individuals and their environment. In this paper, the stage was set for adoption of a new vision of prevention that incorporates an ecological approach to understanding the causation of mental retardation. The articles in this symposium were reviewed and their relevance to this new vision discussed. A comprehensive, coordinated, and integrated prevention program is needed that includes new strategies addressing a variety of personal, social, and environmental risk factors and on the interactions among them.

Early in the monitoring of amiodarone it was evident that neurological events were unexpectedly frequent. A survey was then undertaken to measure the frequency of such events and to gain some impression of their clinical importance. The method of survey was the completion of questionnaires by doctors when patients were being reviewed. There was a 63.6% response rate and questionnaires were evaluated for 408 patients. There were 192 events assessed as being adverse reactions from a group of nine types of neurological events in 112 patients. Paraesthesiae, ataxia, vertigo and tremor were the most common (7-9%). The overall rate of neurological reactions was 27.5%. The individual reactions are examined as are dose relationships.

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Thirty three reports of cough associated with captopril and 26 associated with enalapril received by the New Zealand intensive medicines monitoring programme were reviewed. The programme is a specialised part of the New Zealand postmarketing surveillance system. Review of these reports showed that the cough was an adverse reaction to the drugs, occurred even with low dose treatment, and was severe enough to warrant withdrawal of the drugs in most of the cases reported. A significant sex difference was shown, with women predominating. The reaction seemed to be a greater problem with enalapril, and in seven patients it occurred with both captopril and enalapril. Withdrawal of treatment resulted in rapid recovery, and no long term effects were shown. The pathogenesis of the reaction is unknown, but possible mediators include bradykinin and prostaglandins.

We tested the hypothesis that parents of children with epilepsy may have unmet information needs because their physicians do not fully appreciate what those needs are. Twenty-four parents ranked 60 items of possible concern to them that reflected medical, school, socialization, personality, and family relationship issues. Five neurologists who treat children with epilepsy ranked the same 60 items to predict parental concerns. Ranking was performed using the Q-sort technique. Parents' and physicians' rankings were compared using a two-tailed Mann-Whitney U test. There was a statistically significant difference between the two groups on 17 of the 60 items. The physicians tended to overestimate the importance of medical concerns and underestimate the importance of psychosocial concerns. Poor communication may occur when physicians do not recognize parental concerns or parental levels of understanding of health and illness.

Valproic acid, used alone or in combination with other anticonvulsants in 100 children with epilepsy, improved seizure control in all age groups. Mean improvement in seizure control was 82%. Petit mal seizures responded best, but other types of seizures, even with associated mental and physical handicaps, also responded well. A substantial improvement in alertness and behavior often occurred. Leukopenia (27%) and an elevated SGOT value (44%) were frequent but transient. Other side effects included alopecia (1), gastrointestinal distress with vomiting (7), pancreatitis (1), thrombocytopenia (1), edema (2), and coma (2). Three severely retarded children with frequent seizures died while receiving valproic acid, but it is not clear that death was caused by valproic acid. Children must be monitored carefully for potential toxic effects, and drug interactions with other anticonvulsants may cause problems in treatment.

A questionnaire was distributed to doctors requesting reasons for cessation of therapy in patients on three drugs being intensively monitored. Adverse events were given as the reason in 20 percent of patients stopping treatment with perhexiline, 15 percent with sodium valproate and 43 percent with labetalol. These adverse events are listed and compared with those reported spontaneously to the medical assessor for the same period. Deaths reported do not appear to be drug related. Enquiry concerning reasons for cessation of therapy would appear to be a useful adjunct to spontaneous reporting of adverse events for drugs being monitored intensively. The number of additional adverse events derived from the questionnaires approximately equalled those from spontaneous reporting.

A barbiturate (phenobarbital or primidone) was withdrawn over a period of 3 months from 25 institutionalized residents, all of whom had had three seizures or less in the past 6 months and were maintained on a nonsedating drug (phenytoin, carbamazepine, or valproic acid). Results were compared with a matched comparison group maintained on both drugs. Subjects withdrawn from primidone, but not those withdrawn from phenobarbital, had increased seizure frequency, probably due to withdrawal. After 14 months, seizure-free subjects withdrawn from barbiturates were no more likely to have had seizures than were comparison subjects. Barbiturates appear to be unnecessary and may be withdrawn.

The Intensive Medicines Monitoring Programme (IMP), a specialised part of the New Zealand Post Marketing Surveillance system, has been used to monitor captopril since it was first approved for marketing for the treatment of hypertension and heart failure. Monitoring has consisted of (1) spontaneous reporting for which doctors have been encouraged to report all clinical events, (2) a specific event recording survey at the end of the first year and (3) a controlled patient survey of taste disturbance. The IMP gathers prescription information on about 85% of all patients. There were 4,124 patients at the end of the first 4 years. Reported events involved 4% of patients, the majority being cutaneous (1%) and gastrointestinal (0.7%). The event recording survey gave an overall rate of adverse events of 2.2 per patient year. The taste survey showed a remarkably high incidence of taste disturbance in the control population and only taste loss was significantly higher (P less than 0.01) for captopril. This ongoing study has so far demonstrated a low incidence of adverse effects due to captopril, which is reassuring in view of its increasing use for mild hypertension and early cardiac failure.