Mycoplasma-induced minimally conscious state

Mycoplasma pneumoniae (M. pneumoniae) frequently causes community-acquired respiratory tract infection and often presents as atypical pneumonia. Following airborne infection and a long incubation period, affected patients mostly suffer from mild or even asymptomatic and self-limiting disease. In particular in school-aged children, M. pneumoniae is associated with a wide range of extrapulmonary manifestations including central nervous system (CNS) disease. In contrast to children, severe CNS manifestations are rarely observed in adults. We report a case of a 37 year-old previously healthy immunocompetent adult with fulminant M. pneumoniae-induced progressive encephalomyelitis who was initially able to walk to the emergency department. A few hours later, she required controlled mechanical ventilation for ascending transverse spinal cord syndrome, including complete lower extremity paraplegia. Severe M. pneumoniae-induced encephalomyelitis was postulated, and antimicrobial, anti-inflammatory and immunosuppressive therapy was applied on the intensive care unit. Despite early and targeted therapy using four different immunosuppressive strategies, clinical success was limited. In our patient, locked-in syndrome developed followed by persistent minimally conscious state. The neurological status was unchanged until day 230 of follow-up. Our case underlines that severe M. pneumoniae- related encephalomyelitis must not only be considered in children, but also in adults. Moreover, it can be fulminant and fatal in adults. Our case enhances the debate for an optimal antimicrobial agent with activity beyond the blood-brain barrier. Furthermore, it may underline the difficulty in clinical decision making regarding early antimicrobial treatment in M. pneumoniae disease, which is commonly self-limited.

Valor da enolase neuroespecífica (NSE) como marcador prognóstico neurológico, em doentes pediátricos, no contexto de hipoxia-isquémia cerebral

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Neurological drugs and opioids for pain management

20.1 Epilepsy and an introduction to drugs used to treat 20.1.1 Introduction to epilepsy 20.1.2 Treatment of partial seizures 20.1.3 Treatment of generalised seizures 20.1.4 Treatment of status epilepticus 20.2 Neurodegenerative disorders; principles of treatment 20.2.1 Introduction to neurodegenerative disorders 20.2.2 Parkinson’s disease 20.2.2.1 Introduction to Parkinson’s disease 20.2.2.2 Dopaminergic system 20.2.2.3 Treatment to enhance the dopaminergic system 20.2.2.4 Treatment to inhibit the cholinergic system 20.2.3 Dementia/Alzheimer’s disease 20.2.3.1 Introduction to Alzheimer’s disease 20.2.3.2 Treatment of Alzheimer’s disease 20.2.4 Amyotrophic lateral sclerosis 43.4.1 Introduction 43.4.2 Treatment 20.3. Pain and opioid analgesics 20.3.1 Introduction to pain and analgesia 20.3.2 Introduction to opioids 20.3.3 Tolerance and physical dependence 20.3.4 Effects of opioids 20.3.5 Agonists at opioid μ receptors 20.3.6 Toxicity to opioids This section deals with the neurologic drugs. The neurologic drugs are used to treat epilepsy and neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. The opioids for pain management are also discussed in this section.

Nutritional status in Parkinson's disease patients undergoing deep-brain stimulation surgery : a pilot study

People with Parkinson’s disease (PD) are at higher risk of malnutrition due to PD symptoms and pharmacotherapy side effects. Poorer outcomes are associated with higher amounts of weight loss (>5%) and lower levels of fat free mass. When pharmacotherapy is no longer effective for symptom control, deep-brain stimulation (DBS) surgery may be considered. People with PD scheduled for DBS surgery were recruited from a Brisbane neurological clinic (n=11 out of 16). The Scale for Outcomes of Parkinson’s disease –Autonomic (SCOPA-AUT), Modified Constipation Assessment Scale (MCAS), and a 3-day food diary were mailed to participants’ homes for completion prior to hospital admission. During admission, the Patient-Generated Subjective Global Assessment (PG-SGA), weight, height and body composition were assessed. Mean(±s.d.) PD duration from diagnosis and time since occurrence of PD symptoms was 9.0(±8.0) and 12(±8.8) years, respectively. Five participants reported unintentional weight loss (average loss of 15.6%). PD duration but not years since symptom onset significantly predicted PG-SGA scores (β=4.2, t(8)=2.7, p<.05). Both were positively correlated with PG-SGA score (r = .667, r=.587). On average, participants classified as well-nourished (SGA-A) (n=4) were younger, had shorter disease durations, lower PG-SGA scores, higher body mass (BMI) and fat free mass (FFMI) indices when compared to malnourished participants (SGA-B) (n=7). They also reported fewer non-motor symptoms on the SCOPA-AUT and MCAS. Three participants had previously received dietetic advice but not in relation to PD. These findings demonstrate that malnutrition remains unrecognised and untreated in this group despite unintentional weight loss and a high prevalence of malnutrition.

Nutritional status in Parkinson’s disease patients undergoing deep brain stimulation surgery : a pilot study

Objectives: People with Parkinson’s disease (PD) are at higher risk of malnutrition due to PD symptoms and pharmacotherapy side effects. When pharmacotherapy is no longer effective for symptom control, deep-brain stimulation (DBS) surgery may be considered. The aim of this study was to assess the nutritional status of people with PD who may be at higher risk of malnutrition related to unsatisfactory symptom management with optimised medical therapy. Design: This was an observational study using a convenience sample. Setting: Participants were seen during their hospital admission for their deep brain stimulation surgery. Participants: People with PD scheduled for DBS surgery were recruited from a Brisbane neurological clinic (n=15). Measurements: The Patient-Generated Subjective Global Assessment (PG-SGA), weight, height and body composition were assessed to determine nutritional status. Results: Six participants (40%) were classified as moderately malnourished (SGA-B). Eight participants (53%) reported previous unintentional weight loss (average loss of 13.3%). On average, participants classified as well-nourished (SGA-A) were younger, had shorter disease durations, lower PG-SGA scores, higher body mass (BMI) and fat free mass indices (FFMI) when compared to malnourished participants (SGA-B). Five participants had previously received dietetic advice but only one in relation to unintentional weight loss. Conclusion: Malnutrition remains unrecognised and untreated in this group despite unintentional weight loss and presence of nutrition impact symptoms. Improving nutritional status prior to surgery may improve surgical outcomes.

Current status of pharmacogenomics testing for anti-tumor drug therapies : approaches to non-melanoma skin cancer

Skin cancer is one of the most commonly occurring cancer types, with substantial social, physical, and financial burdens on both individuals and societies. Although the role of UV light in initiating skin cancer development has been well characterized, genetic studies continue to show that predisposing factors can influence an individual's susceptibility to skin cancer and response to treatment. In the future, it is hoped that genetic profiles, comprising a number of genetic markers collectively involved in skin cancer susceptibility and response to treatment or prognosis, will aid in more accurately informing practitioners' choices of treatment. Individualized treatment based on these profiles has the potential to increase the efficacy of treatments, saving both time and money for the patient by avoiding the need for extensive or repeated treatment. Increased treatment responses may in turn prevent recurrence of skin cancers, reducing the burden of this disease on society. Currently existing pharmacogenomic tests, such as those that assess variation in the metabolism of the anticancer drug fluorouracil, have the potential to reduce the toxic effects of anti-tumor drugs used in the treatment of non-melanoma skin cancer (NMSC) by determining individualized appropriate dosage. If the savings generated by reducing adverse events negate the costs of developing these tests, pharmacogenomic testing may increasingly inform personalized NMSC treatment.

Peritoneal dialysis and neurological outcome in infants and small children

Although improved outcomes for children on peritoneal dialysis (PD) have been seen in recent years, the youngest patients continue to demonstrate inferior growth, more frequent infections, more neurological sequelae, and higher mortality compared to older children. Also, maintain-ing normal intravascular volume status, especially in anuric patients, has proven difficult. This study was designed to treat and monitor these youngest PD patients, which are relatively many due to the high prevalence of congenital nephrotic syndrome of the Finnish type (CNF, NPHS1) in Finland, with a strict protocol, to evaluate the results and to improve metabolic balance, growth, and development. A retrospective analysis of 23 children under two years of age at onset of PD, treated between 1995 and 2000, was performed to obtain a control population for our prospective PD study. Respectively, 21 patients less than two years of age at the beginning of PD were enrolled in prospective studies between 2001 and 2005. Medication for uremia and nutrition were care-fully adjusted during PD. Laboratory parameters and intravascular volume status were regu-larly analyzed. Growth was analyzed and compared with midparental height. In a prospective neurological study, the risk factors for development and the neurological development was determined. Brain images were surveyed. Hearing was tested. In a retrospective neurological study, the data of six NPHS1 patients with a congruent neurological syndrome was analyzed. All these patients had a serious dyskinetic cerebral palsy-like syndrome with muscular dysto-nia and athetosis (MDA). They also had a hearing defect. Metabolic control was mainly good in both PD patient groups. Hospitalization time shortened clearly. The peritonitis rate diminished. Hypertension was a common problem. Left ventricular hypertrophy decreased during the prospective study period. None of the patients in either PD group had pulmonary edema or dialysis-related seizures. Growth was good and catch-up growth was documented in most patients in both patient groups during PD. Mortality was low (5% in prospective and 9% in retrospective PD patients). In the prospective PD patient group 11 patients (52%) had some risk factor for their neuro-development originating from the predialysis period. The neurological problems, detected be-fore PD, did not worsen during PD and none of the patients developed new neurological com-plications during PD. Brain infarcts were detected in four (19%) and other ischemic lesions in three patients (14%). At the end of this study, 29% of the prospectively followed patients had a major impairment of their neurodevelopment and 43% only minor impairment. In the NPHS1+MDA patients, no clear explanation for the neurological syndrome was found. The brain MRI showed increased signal intensity in the globus pallidus area. Kernic-terus was contemplated to be causative in the hypoproteinemic newborns but it could not be proven. Mortality was as high as 67%. Our results for young PD patients were promising. Metabolic control was acceptable and growth was good. However, the children were significantly smaller when compared to their midparental height. Although many patients were found to have neurological impairment at the end of our follow-up period, PD was a safe treatment whereby the neurodevelopment did not worsen during PD.

Management and prognosis of status epilepticus according to hospital setting: a prospective study.

BACKGROUND: The treatment of status epilepticus (SE) is based on relatively little evidence although several guidelines have been published. A recent study reported a worse SE prognosis in a large urban setting as compared to a peripheral hospital, postulating better management in the latter. The aim of this study was to analyse SE episodes occurring in different settings and address possible explanatory variables regarding outcome, including treatment quality. METHODS: Over six months we prospectively recorded consecutive adults with SE (fit lasting five or more minutes) at the Centre Hospitalier Universitaire Vaudois (CHUV) and in six peripheral hospitals (PH) in the same region. Demographical, historical and clinical variables were collected, including SE severity estimation (STESS score) and adherence to Swiss SE treatment guidelines. Outcome at discharge was categorised as "good" (return to baseline), or "poor" (persistent neurological sequelae or death). RESULTS: Of 54 patients (CHUV: 36; PH 18), 33% had a poor outcome. Whilst age, SE severity, percentage of SE episodes lasting less than 30 minutes and total SE duration were similar, fewer patients had a good outcome at the CHUV (61% vs 83%; OR 3.57; 95% CI 0.8-22.1). Mortality was 14% at the CHUV and 5% at the PH. Most treatments were in agreement with national guidelines, although less often in PH (78% vs 97%, P = 0.04). CONCLUSION: Although not statistically significant, we observed a slightly worse SE prognosis in a large academic centre as compared to smaller hospitals. Since SE severity was similar in the two settings but adherence to national treatment guidelines was higher in the academic centre, further investigation on the prognostic role of SE treatment and outcome determinants is required.

Investigating the Contribution of Personality and Neurological Disruption to Postinjury Outcome in Athletes with Mild Head Injury

Despite the increase in research regarding mild head injury (MHI), relatively little has investigated whether, or the extent to which, premorbid factors (i.e., personality traits) influence, or otherwise account for, outcomes post-MHI. The current study examined the extent to which postinjury outcome after MHI is analogous to the outcome post-moderate or- severe traumatic brain injury (by comparing the current results to previous literature pertaining to individuals with more severe brain injuries) and whether these changes in function and behaviour are solely, or primarily, due to the injury, or reflect, and are possibly a consequence of, one’s preinjury status. In a quasi-experimental, test-retest design, physiological indices, cognitive abilities, and personality characteristics of university students were measured. Since the incidence of MHI is elevated in high-risk activities (including high-risk sports, compared to other etiologies of MHI; see Laker, 2011) and it has been found that high-risk athletes present with unique, risk-taking behaviours (in terms of personality; similar to what has been observed post-MHI) compared to low-risk and non-athletes. Seventy-seven individuals (42% with a history of MHI) of various athletic statuses (non-athletes, low-risk athletes, and high-risk athletes) were recruited. Consistent with earlier studies (e.g., Baker & Good, 2014), it was found that individuals with a history of MHI displayed decreased physiological arousal (i.e., electrodermal activation) and, also, endorsed elevated levels of sensation seeking and physical/reactive aggression compared to individuals without a history of MHI. These traits were directly associated with decreased physiological arousal. Moreover, athletic status did not account for this pattern of performance, since low- and high-risk athletes did not differ in terms of personality characteristics. It was concluded that changes in behaviour post-MHI are associated, at least in part, with the neurological and physiological compromise of the injury itself (i.e., physiological underarousal and possible subtle OFC dysfunction) above and beyond influences of premorbid characteristics.

Who knows best? Awareness of divided attention difficulty in a neurological rehabilitation setting

Objective: To explore whether patients relearning to walk after acquired brain injury and showing cognitive-motor interference were aware of divided attention difficulty; whether their perceptions concurred with those of treating staff. Design: Patients and neurophysiotherapists (from rehabilitation and disabled wards) completed questionnaires. Factor analyses were applied to responses. Correlations between responses, clinical measures and experimental decrements were examined. Results: Patient/staff responses showed some agreement; staff reported higher levels of perceived difficulty; responses conformed to two factors. One factor (staff/patients alike) reflected expectations about functional/motor status and did not correlate with decrements. The other factor (patients) correlated significantly with dual-task motor decrement, suggesting some genuine awareness of difficulty (cognitive performance prioritized over motor control). The other factor (staff) correlated significantly with cognitive decrement (gait prioritized over sustained attention). Conclusions: Despite some inaccurate estimation of susceptibility; patients and staff do exhibit awareness of divided attention difficulty, but with a limited degree of concurrence. In fact, our results suggest that patients and staff may be sensitive to different aspects of the deficit. Rather than 'Who knows best?', it is a question of 'Who knows what?.

The Integrated European Project "GEHA - GEnetics of Healthy Aging": recruitment, health status assessment and survival of the Italian 90+ sibpairs

The present study is part of the EU Integrated Project “GEHA – Genetics of Healthy Aging” (Franceschi C et al., Ann N Y Acad Sci. 1100: 21-45, 2007), whose aim is to identify genes involved in healthy aging and longevity, which allow individuals to survive to advanced age in good cognitive and physical function and in the absence of major age-related diseases. Aims The major aims of this thesis were the following: 1. to outline the recruitment procedure of 90+ Italian siblings performed by the recruiting units of the University of Bologna (UNIBO) and Rome (ISS). The procedures related to the following items necessary to perform the study were described and commented: identification of the eligible area for recruitment, demographic aspects related to the need of getting census lists of 90+siblings, mail and phone contact with 90+ subjects and their families, bioethics aspects of the whole procedure, standardization of the recruitment methodology and set-up of a detailed flow chart to be followed by the European recruitment centres (obtainment of the informed consent form, anonimization of data by using a special code, how to perform the interview, how to collect the blood, how to enter data in the GEHA Phenotypic Data Base hosted at Odense). 2. to provide an overview of the phenotypic characteristics of 90+ Italian siblings recruited by the recruiting units of the University of Bologna (UNIBO) and Rome (ISS). The following items were addressed: socio-demographic characteristics, health status, cognitive assessment, physical conditions (handgrip strength test, chair-stand test, physical ability including ADL, vision and hearing ability, movement ability and doing light housework), life-style information (smoking and drinking habits) and subjective well-being (attitude towards life). Moreover, haematological parameters collected in the 90+ sibpairs as optional parameters by the Bologna and Rome recruiting units were used for a more comprehensive evaluation of the results obtained using the above mentioned phenotypic characteristics reported in the GEHA questionnaire. 3. to assess 90+ Italian siblings as far as their health/functional status is concerned on the basis of three classification methods proposed in previous studies on centenarians, which are based on: • actual functional capabilities (ADL, SMMSE, visual and hearing abilities) (Gondo et al., J Gerontol. 61A (3): 305-310, 2006); • actual functional capabilities and morbidity (ADL, ability to walk, SMMSE, presence of cancer, ictus, renal failure, anaemia, and liver diseases) (Franceschi et al., Aging Clin Exp Res, 12:77-84, 2000); • retrospectively collected data about past history of morbidity and age of disease onset (hypertension, heart disease, diabetes, stroke, cancer, osteopororis, neurological diseases, chronic obstructive pulmonary disease and ocular diseases) (Evert et al., J Gerontol A Biol Sci Med Sci. 58A (3): 232-237, 2003). Firstly these available models to define the health status of long-living subjects were applied to the sample and, since the classifications by Gondo and Franceschi are both based on the present functional status, they were compared in order to better recognize the healthy aging phenotype and to identify the best group of 90+ subjects out of the entire studied population. 4. to investigate the concordance of health and functional status among 90+ siblings in order to divide sibpairs in three categories: the best (both sibs are in good shape), the worst (both sibs are in bad shape) and an intermediate group (one sib is in good shape and the other is in bad shape). Moreover, the evaluation wanted to discover which variables are concordant among siblings; thus, concordant variables could be considered as familiar variables (determined by the environment or by genetics). 5. to perform a survival analysis by using mortality data at 1st January 2009 from the follow-up as the main outcome and selected functional and clinical parameters as explanatory variables. Methods A total of 765 90+ Italian subjects recruited by UNIBO (549 90+ siblings, belonging to 258 families) and ISS (216 90+ siblings, belonging to 106 families) recruiting units are included in the analysis. Each subject was interviewed according to a standardized questionnaire, comprising extensively utilized questions that have been validated in previous European studies on elderly subjects and covering demographic information, life style, living conditions, cognitive status (SMMSE), mood, health status and anthropometric measurements. Moreover, subjects were asked to perform some physical tests (Hand Grip Strength test and Chair Standing test) and a sample of about 24 mL of blood was collected and then processed according to a common protocol for the preparation and storage of DNA aliquots. Results From the analysis the main findings are the following: - a standardized protocol to assess cognitive status, physical performances and health status of European nonagenarian subjects was set up, in respect to ethical requirements, and it is available as a reference for other studies in this field; - GEHA families are enriched in long-living members and extreme survival, and represent an appropriate model for the identification of genes involved in healthy aging and longevity; - two simplified sets of criteria to classify 90+ sibling according to their health status were proposed, as operational tools for distinguishing healthy from non healthy subjects; - cognitive and functional parameters have a major role in categorizing 90+ siblings for the health status; - parameters such as education and good physical abilities (500 metres walking ability, going up and down the stairs ability, high scores at hand grip and chair stand tests) are associated with a good health status (defined as “cognitive unimpairment and absence of disability”); - male nonagenarians show a more homogeneous phenotype than females, and, though far fewer in number, tend to be healthier than females; - in males the good health status is not protective for survival, confirming the male-female health survival paradox; - survival after age 90 was dependent mainly on intact cognitive status and absence of functional disabilities; - haemoglobin and creatinine levels are both associated with longevity; - the most concordant items among 90+ siblings are related to the functional status, indicating that they contain a familiar component. It is still to be investigated at what level this familiar component is determined by genetics or by environment or by the interaction between genetics, environment and chance (and at what level). Conclusions In conclusion, we could state that this study, in accordance with the main objectives of the whole GEHA project, represents one of the first attempt to identify the biological and non biological determinants of successful/unsuccessful aging and longevity. Here, the analysis was performed on 90+ siblings recruited in Northern and Central Italy and it could be used as a reference for others studies in this field on Italian population. Moreover, it contributed to the definition of “successful” and “unsuccessful” aging and categorising a very large cohort of our most elderly subjects into “successful” and “unsuccessful” groups provided an unrivalled opportunity to detect some of the basic genetic/molecular mechanisms which underpin good health as opposed to chronic disability. Discoveries in the topic of the biological determinants of healthy aging represent a real possibility to identify new markers to be utilized for the identification of subgroups of old European citizens having a higher risk to develop age-related diseases and disabilities and to direct major preventive medicine strategies for the new epidemic of chronic disease in the 21st century.

Spastin in the human and mouse central nervous system with special reference to its expression in the hippocampus of mouse pilocarpine model of status epilepticus and temporal lobe epilepsy

In the present in situ hybridization and immunocytochemical studies in the mouse central nervous system (CNS), a strong expression of spastin mRNA and protein was found in Purkinje cells and dentate nucleus in the cerebellum, in hippocampal principal cells and hilar neurons, in amygdala, substantia nigra, striatum, in the motor nuclei of the cranial nerves and in different layers of the cerebral cortex except piriform and entorhinal cortices where only neurons in layer II were strongly stained. Spastin protein and mRNA were weakly expressed in most of the thalamic nuclei. In selected human brain regions such as the cerebral cortex, cerebellum, hippocampus, amygdala, substania nigra and striatum, similar results were obtained. Electron microscopy showed spastin immunopositive staining in the cytoplasma, dendrites, axon terminals and nucleus. In the mouse pilocarpine model of status epilepticus and subsequent temporal lobe epilepsy, spastin expression disappeared in hilar neurons as early as at 2h during pilocarpine induced status epilepticus, and never recovered. At 7 days and 2 months after pilocarpine induced status epilepticus, spastin expression was down-regulated in granule cells in the dentate gyrus, but induced expression was found in reactive astrocytes. The demonstration of widespread distribution of spastin in functionally different brain regions in the present study may provide neuroanatomical basis to explain why different neurological, psychological disorders and cognitive impairment occur in patients with spastin mutation. Down-regulation or loss of spastin expression in hilar neurons may be related to their degeneration and may therefore initiate epileptogenetic events, leading to temporal lobe epilepsy.

Iron status in early life and associations with developmental outcomes

Infants and young children are at particular risk of iron deficiency and its associated consequences for growth and development. The main objectives of this thesis were to quantify iron intakes, status and determinants of status in two year olds; explore determinants of neonatal iron stores; investigate associations between iron status at birth and two years with neurodevelopmental outcomes at two years and explore the influence of growth on iron status in early childhood, using data from the Cork BASELINE (Babies after SCOPE: Evaluating Longitudinal Impact using Neurological and Nutritional Endpoints) Birth Cohort Study (n=2137). Participants were followed prospectively with interviewer-led questionnaires and clinical assessments at day 2 and at 2, 6, 12 and 24 months. At two years, there was a low prevalence of iron deficiency and iron deficiency anaemia in this cohort, representing the largest study of iron status in toddlers in Europe, to date. The increased consumption of iron-fortified products and compliance with recommendations to limit unmodified cows’ milk intakes in toddlers has contributed to the observed improvements in status. Low serum ferritin concentrations at birth, which reflect neonatal iron stores, were shown to track through to two years of age; delivery by Caesarean section, being born small-for-gestational age and maternal obesity and smoking in pregnancy were all associated with significantly lower neonatal iron stores. Despite a low prevalence of iron deficiency in this cohort, both a mean corpuscular volume <74fl and ferritin concentrations <20μg/l were associated with lower neurodevelopmental outcomes at two years. An inverse association between growth in the second year of life and iron status at two years was also observed. This thesis has presented data from one of the largest, extensively-characterised cohorts of young children, to date, to explore iron and its associations with growth and development.