Aleksandar Videnovic, MD

• Assistant Professor of Neurology, Parkinson? Disease
• and Movement Disorders Center, Department of
• Neurology, Northwestern University Feinberg School
• of Medicine, Chicago, IL, USA

A majority (>95%) of these individuals have de novo heterozygous pathogenic causative variants [11] treatment 4 anti-aging 800mg neurontin free shipping. The low yield of genetic screening is perhaps due to variable clinical presentation of individuals with tubulinopathies medications cause erectile dysfunction discount 400 mg neurontin overnight delivery. Genetic testing may play a more diagnostic role in the future as more specific genotype-phenotype correlations are established symptoms 6 year molars purchase 100 mg neurontin amex. Genetic testing for the identified pathogenic variant is recommended in the parents of affected individuals (probands) treatment 5th toe fracture purchase neurontin 300mg with mastercard. If parental testing is negative medications dictionary order neurontin us, then the proband likely has a de novo mutation and there is low risk of mutations in siblings and other family members treatment eating disorders purchase neurontin canada. Genetic counseling for the proband, specifically regarding family planning, is recommended and discussed below. Neuroimaging Irrespective of the genes involved, the diagnosis of tubulinopathy requires neuroimaging demonstrating the combination of characteristic cortical malformations. Briefly, lissencephaly in tubulinopathies can range from classic lissencephaly with agyria, characterized by marked cortical thickening more pronounced in parietal and occipital lobe, to centrally predominant pachygyria, defined by presence of a few, shallow sulci involving frontal, temporal and parietal regions, and often accompanied by abnormalities in the basal ganglia, and a hypoplastic brainstem, and dysmorphic corpus callosum. Lissencephaly can also be associated with cerebellar hypoplasia in rare forms, dysmorphic or hypoplastic corpus callosum, and subcortical band heterotopia. Polymicrogyria-like cortical dysplasia, which can be predominantly central or generalized, is characterized by unlayered polymicrogyria with neuronal heterotopias and can be associated with schizencephaly [6,16,17,19]. Typically, it resembles cobblestone lissencephaly and lacks the deep infolding characteristic of classic polymicrogyria. Simplified gyral pattern typically has normal thickness cortex with abnormal gyri and sulci. Lastly, microlissencephaly is the most severe dysplasia with the presence of both extreme microcephaly and lissencephaly. Management Following initial diagnosis, long-term care and management by a pediatric neurologist with expertise in children with developmental delay, intellectual disability and refractory epilepsy is recommended. If seizures are present, they should be treated promptly with appropriate anti-epileptic medications. Individualized care with physical therapy, occupational therapy, speech therapy, vision therapy if necessary, and developmental specialists are recommended at time of diagnosis to improve functionality. Children will need to be monitored and treated for failure to thrive, poor growth and complications of motor impairments. Owing to the autosomal dominant inheritance of most tubulinopathies, children of affected individuals have a 50% risk of inheriting the mutation. Young adults with identified pathogenic variants can consult a geneticist for family planning and prenatal testing. Molecular Genetic Testing Genetic testing is used to identify a genetic basis for observed cortical malformation. Cortical tubers, similar to other hamartomas in the body, arise from a two-hit mechanism [26]. In this model, heterozygous patients (with germline mutations) acquire a somatic mutation that inactivates the normal, second allele. The loss of heterozygosity results in the formation of hamartomas and cortical lesions [26]. Increased tuber burden is associated with a more severe phenotype, specifically poor cognitive function, refractory epilepsy and autism [27]. In cases with germline mutations, the causative mutation may be detected in all cells in the body. This suggests that epilepsy may have a causative role in cognitive decline and developmental delay [40]. Seizure onset typically occurs in early childhood in these patients and often correlates with severity of cortical dysplasia. One of the biggest challenges of pre-surgical evaluation is identifying the complete extent of the lesions and potential risk of neurological deficits following resection. Ketogenic diet and vagus nerve stimulation are treatment options for patients with refractory epilepsy who are not surgical candidates or those who have failed surgical resection [28,40,43]. Results from retrospective studies show that 34 of 40 patients had a >50% reduction in seizure frequency (reviewed in [24]). The number of patients that experienced daily seizures is reduced from 27% at baseline to 11% following treatment [46]. Other smaller clinical series, summarized in [23,24], demonstrated that greater than 61% of patients achieved 25% reduction in seizure frequency. The findings demonstrate 40% of patients treated with high-dose everolimus had a >50% reduction in seizure frequency compared to 15% in placebo (P = 0. Furthermore, the mean reduction in seizure frequency was by 29% in everolimus group compared to 15% in control (P = 0. Positive genetic testing is diagnostic and does not require additional clinical criteria. Minor features include [49]: confetti skin lesions, dental enamel pits, intraoral fibromas, retinal achromic patches, multiple renal cysts and non-renal hamartomas. This is especially important for affected individuals considering family planning. Clinical genetic testing is now more widely available for patients as either target gene panels, which include up to 500 or more candidate genes. Screening for somatic mutations found in tissue sections is currently a research application. As a result, regular screening, surveillance and monitoring are required even into adulthood. Screening at key developmental stages, which include infancy, preschool, before entering school, adolescence and early adulthood is recommended. Ophthalmological evaluation and dental assessment should be done at least every year. In none of these disorders have therapies been identified that improve intellectual disability or autism. It has also been long recognised that the risk of developing epilepsy is low following minor head injuries but higher in more severe head injuries. Because head injury is extremely common in all populations, post-traumatic epilepsy is a sizeable problem, accounting at a rough approximation for around 5% or more of all epilepsies in Western countries and 20% of symptomatic epilepsies [1]. The incidence rates are highest in young adults and lowest in middle age and vary markedly in different locations. For instance, in the Rochester study, half of all head injuries were due to motor vehicle, motorcycle and bicycle collisions, and a third due to falls; in the Bronx, violence was the cause of head injury in 34%; and in China 32% were due to motor vehicle accidents, 22% to falls and 24% to occupational accidents [2,3]. In most (but not all series) this term is restricted to cases where the dura is also breached. Loss of consciousness is not necessarily present, contrary to some earlier definitions. Military and civilian head injury are often considered separately when it comes to consider prognosis and risk factors, as the degree of force (velocity and blast) are in general much greater in military injuries, there is a higher incidence of open head injury with dural breach and pattern of epilepsy differs. However, as Jennett pointed out, there is overlap in some countries with significant numbers of gunshot and assault injuries in civilian practice (19% for instance in a study of 123 patients with refractory post-traumatic epilepsy from Texas [4]) and he preferred to distinguish between missile and non-missile injury. Whilst this is eminently reasonable, in the literature, military and civilian populations have been studied separately and so in this chapter this divide is maintained. Existing epilepsy can be occasionally worsened or improved by head trauma (emphasising the multifactorial nature of many epilepsies) but studies of post-traumatic epilepsy have usually excluded these cases and so these are not included in the statistics given below [5,6]. Severity the severity of the traumatic brain injury has been categorised in different ways. These have the advantage of being simple and clear-cut, but scales using multiple criteria are claimed to be more valid. A trivial head injury is defined as one in which there is no alteration of consciousness, confusion or amnesia and in which there is no evidence of any neurological dysfunction. It can take the form of focal, secondarily generalised and seizures generalised from the onset, and focal seizures occur with or without alteration of consciousness. Timing is very important, and post-traumatic seizures are usually subdivided into: immediate seizures, early seizures and late seizures (see Table 74. The term post-traumatic epilepsy is applied strictly speaking only to those who have two or more late posttraumatic seizures, although early seizures have been included in some published studies. The epilepsy often accompanies and complicates other signs of brain injury although it can also occur after a head injury in which other neurological deficits have resolved. Many studies have looked into the factors influencing the likelihood of developing epilepsy, and these are discussed in detail below. The features which have been repeatedly shown to be associated with the highest rates of epilepsy are: the presence of early epilepsy, depressed fracture with dural breach and intracranial haemorrhage (various types). Others have correlated the presence of epilepsy with the site and extent of radiographic abnormalities, the presence of bone or metal fragments, and psychosocial factors. An acceleration-deceleration injury occurs when the head in motion suddenly strikes an immovable object and inertia resulting in the compression of brain tissue against the bony ridges of the interior of the skull. Deceleration injuries selectively damage frontopolar and orbitofrontal areas, but also cause axonal shearing as the physical properties of different components of brain tissue have differing velocities and momentums. Depending on the position of the head and the velocity and direction of the collision, large shearing forces within brain tissue can occur distant from the site of impact. Diffuse axonal injury, in which there is extensive damage to the cerebral white matter, is due to shearing forces in the brain against the tentorium and falx following acceleration/deceleration injury, and also as a result of ischaemia. It is sometimes divided into: grade 1, axonal injury mainly in parasagittal white matter of the cerebral hemispheres; grade 2, additional lesions in the corpus callosum; and grade 3, focal lesions in the cerebral peduncle. These include immunological and mitochondrial change, oxidative damage and changes in synaptic and receptor function [8,9]. Chemical changes occur including excessive activity of excitatory amino acids causing cell swelling and neuronal death. Longer-term neogenesis and microglial and astrocytic changes with axon sprouting, gliosis and cortical atrophy, and communicating hydrocephalus can occur. More severe injuries produce diffuse axonal injury and microhaemorrhages and white matter degeneration. The deposition of iron products (especially haemosiderin) from red blood cells is one likely cause of epileptogenesis. This has been demonstrated experimentally by the injection of ferrous or ferric chloride into sensorimotor cortex of cats and rats [11,12]. In this model, seizure activity 522 Chapter 74: Epilepsy Associated With Head Injury developed within 72 hours and persisted for over the 6 weeks of observation although no clinical seizures occurred. The causes of head injury vary widely in different geographical and cultural settings and these influence the type of brain damage sustained. In the Western world, civilian head injuries are typically due to road traffic accidents (motor cars, motor cycles, bicycles), falls, industrial accidents, sportsrelated injury and assault. In military injuries, there is a higher rate of penetration of the brain by high velocity missiles, shrapnel or bullets, and blast injury. However, it is the incidence and risk factors that have been the subject of most interest. Numerous studies have been published, but from the methodological point of view many suffer from being retrospective, of selected populations, registry-based, having irregular quality of follow-up or being performed prior to modern neuroimaging. Of this mass of studies, three stand out and provide the most reliable or influential data: those of Jennett, Annegers et al. In many other studies, the findings have been largely confirmative or contribute only incremental new information to these three investigations. When other studies have added important detail on specific topics, these are also referred to below. Immediate and Early Seizures: Incidence and Risk Factors the earliest and still the most influential studies of immediate, early and late post-traumatic seizures were those carried out by Jennett over a period of more than 20 years, and these are landmarks in the field. Nevertheless, the findings from his studies in relation to both early and late seizures have very largely been confirmed in all subsequent work. Nine hundred and eighty-six had no previous epilepsy and were included in the analysis, and of these 275 were followed for 4 years or more. Jennett then extended the studies to include cases from neurosurgical facilities in other hospitals, and these later series were more selective, with a larger proportion of severe cases, and their main purpose was to identify risk factors. Jennett was the first to stress the distinction between immediate, early and late seizures. In his first series, 5% of those with significant head injuries requiring admission suffered early seizures. In half of these cases, seizures occurred within an hour of the injury and 60% occurred within the first day. In 65% of patients, further seizures occurred and status epilepticus developed in 10%. Immediate seizures have a different pathophysiology from that of late seizures, and their occurrence reflects the acute disturbances of brain homeostasis common in significant head injury. The seizures could take the form of generalised convulsions or more typically simple partial motor seizures (focal motor seizures without loss of consciousness). Early seizures also have a different pathogenic basis and a different prognosis from late seizures, and Jennett cited four strands of evidence to support this view. He followed this up in a later series of 339 patients with epilepsy in the first 8 weeks after an injury finding that the first seizures are 30x more common in the first week than in any of the next 7 weeks.

Consequently treatment of diabetes neurontin 800 mg with amex, toothbrushing can help to prevent the dysbiosis that can eventually result in gingivitis and periodontitis symptoms just before giving birth purchase genuine neurontin. Manual toothbrushing cannot remove approximal plaque which is unfortunate as the gaps between the teeth are important sites of caries formation medications just for anxiety order neurontin 400 mg otc. However treatment multiple sclerosis purchase neurontin now, some electric toothbrushes have been specially designed to be able to remove approximal as well as smooth-surface plaque medications known to cause miscarriage buy neurontin uk. A variety of antimicrobial agents have been incorporated into toothpastes in order to improve the levels of oral hygiene achievable by toothbrushing treatment neutropenia generic neurontin 600mg with amex. Such agents include chlorhexidine, triclosan, cetylpyridinium chloride, phenolic compounds, sanguinarine, fluoride, tin compounds, zinc compounds, and various enzymes. The removal of subgingival plaque can be accomplished by dentists and dental hygienists using a variety of devices ranging from simple hand instruments to ultrasonic scalers-this procedure is known as subgingival debridement. The complete removal of all subgingival plaque is rarely achieved because it is difficult to access all of the root surfaces of the teeth. A thorough debridement of the root surface removes approximately 99% of the viable bacteria present but substantial numbers (approximately 105 cfu per root) can remain. Recolonization of the root surface then takes place and viable counts can reach pretreatment levels within 3 to 7 days. However, the composition of the newly formed subgingival microbiota is often different from that which existed prior to debridement with substantially decreased proportions of periodontopathogenic species. Recolonization of the subgingival plaque by periodontopathogens occurs from sites such as the tongue and other mucosal surfaces which act as reservoirs of these organisms. The oral cavity contains various types of mucosae and the only nonshedding surfaces in the body-teeth. Gingival crevicular fluid provides microbes in the gingival crevice with a wide variety of nutrients. The oral cavity is predominantly aerobic but anatomical factors provide micro-aerophilic regions. Powerful mechanical and hydrodynamic shear forces operate in the oral cavity and hinder microbial colonization. Teeth lack an important antimicrobial defense mechanism-the shedding of surface layers with their attached microbes. The oral cavity supports a variety of microbial communities at the various locations within it. More than half of oral microbes have been grown in the laboratory-a higher proportion than for most other body sites. The oral microbiota is very diverse-bacteria from 355 genera belonging to 19 phyla have been detected. Tooth eruption and puberty result in changes in the composition of the oral microbiota. Most of the microbes in the oral cavity are present as biofilms on the tooth surface-these are known as dental plaques. The main types of plaque are interproximal, smooth surface, fissure, gingival crevicular, and subgingival. Microbes adhere to a protein coating on the tooth surface known as the acquired enamel pellicle. Biofilms provide a wide range of habitats which enables the survival of different physiological types of microbes. A variety of beneficial interactions occur between oral microbes resulting in the provision of nutrients and adhesion sites, protection from host defense systems and the creation of a favorable environment. Antagonistic interactions include the production of bacteriocins and other antimicrobial compounds, interference with adhesion, and the creation of unfavorable environments. The oral microbiota contributes to human health by inhibiting colonization of the oral cavity by pathogens, maintaining the integrity of the oral epithelium, and ensuring the effectiveness of the innate and acquired immune systems. Some members of the oral microbiota are able to cause diseases including infective endocarditis, actinomycosis, various abscesses, atherosclerosis, adverse pregnancy outcomes, and aspiration pneumonia. Probiotics have been used for the prevention and/or treatment of a number of oral diseases but with limited success. Regular mechanical removal of dental plaque can maintain oral communities in states that are compatible with oral health. Compare and contrast the main features of the environments of the tooth surface and the tongue. Describe the process of biofilm formation on the supragingival regions of the tooth surface. Compare and contrast the composition of the microbiotas of the supragingival tooth surface and the gingival crevice. Probiotics are of enormous benefit in maintaining the oral microbiota in a state that is compatible with oral health. In what ways do microbial interactions help to shape the composition of oral microbial communities Proteome data set of human gingival crevicular fluid from healthy periodontium sites by multidimensional protein separation and mass spectrometry. Salivary defense proteins: their network and role in innate and acquired oral immunity. Saliva as the sole nutritional source in the development of multispecies communities in dental plaque. Human neutrophils and oral microbiota: a constant tug-of-war between a harmonious and a discordant coexistence. Application of metagenomic analyses in dentistry as a novel strategy enabling complex insight into microbial diversity of the oral cavity. Redefining the human oral mycobiome with improved practices in ampliconbased taxonomy: discovery of Malassezia as a prominent commensal. The influence of orthodontic fixed appliances on the oral microbiota: a systematic review. The oral microbiome of children: development, disease, and implications beyond oral health. The oral microbiome in health and disease and the potential impact on personalized dental medicine. The impact of horizontal gene transfer on the adaptive ability of the human oral microbiome. Shaping the oral mycobiota: interactions of opportunistic fungi with oral bacteria and the host. Fungalbacterial interactions and their relevance to oral health: linking the clinic and the bench. The road less traveled-Defining molecular commensalism with Streptococcus sanguinis. Microbiome of periimplant infections: lessons from conventional, molecular and metagenomic analyses. Periodontal disease and periodontal bacteria as triggers for rheumatoid arthritis. Historical and contemporary hypotheses on the development of oral diseases: are we there yet From focal sepsis to periodontal medicine: a century of exploring the role of the oral microbiome in systemic disease. The oral cavity microbiota: between health, oral disease, and cancers of the aerodigestive tract. Probiotics for managing caries and periodontitis: systematic review and meta-analysis. This is particularly apparent in the oral cavity which, as well as having a more complex anatomy than other regions, also contains both shedding and non-shedding surfaces (the teeth). Diagram showing the main regions of the digestive system which consists of the intestinal tract (mouth, pharynx, esophagus, stomach, small and large intestines, rectum, and anus) and the accessory digestive organs (teeth, tongue, salivary glands, liver, gallbladder, and pancreas). Contractions of the muscularis mucosae result in folding of the mucosa, which dramatically increases its surface area thereby improving the efficiency of the digestive process and the absorption of digestive products. The submucosa is a thick layer of loose connective tissue that also contains blood vessels, lymphatic vessels, and nerves. The muscularis is arranged in two layers, an inner circular layer and an outer longitudinal layer. Contraction of these muscles mixes the food with digestive fluids and physically breaks down the food into smaller particles. Cross section through the wall of the gastrointestinal tract showing the arrangement of the five main tissue layers- the mucosa (epithelium and underlying connective tissue), muscularis mucosae, submucosa, muscularis, and serosa. It connects the laryngopharynx to the stomach and its function is to transport food between these two regions. Muscular contractions of the laryngopharynx propel food into the esophagus, and peristalsis moves the ball-shaped mass of food/saliva (bolus) along the esophagus into the stomach. It is a highly elastic organ and its volume varies widely depending on food intake-after a typical meal its volume is approximately 1 liter. Food enters the stomach from the esophagus via the cardiac orifice, which is situated below the uppermost region of the stomach (the fundus). G cells in the gastric glands secrete the hormone gastrin, which is involved in regulating the secretion of gastric juice and gut motility, into the bloodstream. Intrinsic factor, although produced in the stomach, is necessary for the absorption of vitamin B12 in the small intestine. Damage to the epithelium by the very low pH is prevented by the presence of a layer of mucus that is 0. Peristaltic movements of the stomach mix food with the gastric juice to produce a watery fluid known as chyme, small quantities of which pass through the pyloric sphincter into the small intestine. Diagram showing the main regions of the stomach and a cross section through the stomach wall. Mucosa Connective tissue with capillaries, venules and lymphatic vessels Gastric gland Submucosa (connective tissue with blood and lymphatic vessels) Muscularis mucosae Arteriole Venule the epithelium of the small intestine epithelium is highly folded and has numerous villi the small intestine is a tubular structure approximately 3 m long and 2. It is the main site of digestion and absorption and consists of three regions-the duodenum (approximately 25 cm in length), the jejunum (approximately 1. The mucosa is highly folded to produce permanent ridges (plicae circulares) that project into the lumen, and has numerous finger-like projections (0. The surface area of the mucosa of the small intestine is greatly increased by the presence of villi. The inset shows that the surface area is further increased by the presence of microvilli on each epithelial cell. The folds and villi decrease in size in the ileum; most absorption takes place in the duodenum and jejunum. Between the bases of the villi are cavities lined with glandular epithelial cells and these are known as intestinal glands (or crypts of Lieberkuhn), which secrete intestinal juice. Cholecystokinin inhibits gastric emptying, stimulates the release of digestive enzymes from the pancreas, induces bile secretion by the gallbladder, and creates a feeling of satiety. Secretin inhibits the production of gastric juice, stimulates the release of bicarbonate ions by the pancreas and stimulates bile secretion. Transmission electron micrograph of the intestinal epithelium showing a goblet cell and absorptive epithelial cells with associated microvilli. Transmission electron micrographs showing microvilli on the surface of intestinal epithelial cells at low (A) and high (B) magnifications. This absorptive phase is followed by peristalsis, which expels the chyme into the large intestine. No villi are present but there are many narrow invaginations lined with enterocytes (absorptive cells) and goblet cells. Mucin-producing cells (yellow) in the crypts produce mucus which is secreted into the colon through the crypt lumen (the white spots in the centers of the crypts) to facilitate the movement of the fecal mass through the colon. The large intestine is an important site of microbial breakdown of dietary macromolecules Although no digestive enzymes are secreted by the mucosa of the large intestine, further breakdown of dietary constituents does occur due to the activities of the resident microbiota. Between 3 and 10 h after entering the large intestine, the chyme becomes solid as a result of water absorption. This solid material (known simply as intestinal content) is transferred into the rectum from the lower, S-shaped region of the colon known as the sigmoid colon. This opening is controlled by the inner and outer sphincters and the material expelled during defecation is known as feces. The mucosa of the anal canal has a number of vertical folds known as anal columns. Because the esophagus receives saliva continuously as well as food and beverages intermittently, it is subjected to hydrodynamic and mechanical forces. A potential colonizer of this region, therefore, must be able to adhere to the epithelium and resist such forces. The most reliable source of nutrients for microbes inhabiting the esophagus is the mucus layer, which contains mucins as well as substances excreted and secreted by epithelial cells. The stomach is aerobic and can be very acidic this is an aerobic environment and the partial pressure of oxygen at the surface of the mucosa is 46. However, the pH is influenced by many factors including age, diet, and whether or not food and/or drinks have recently been consumed.

In the neonatal period it can have a variety of causes treatment urinary retention generic neurontin 800 mg, including inborn errors of metabolism such as aminoacidemias treatment urinary incontinence trusted 300mg neurontin, urea cycle disorders symptoms vs signs order genuine neurontin on line, organic acidurias treatment hypothyroidism order neurontin overnight, and fatty acid oxidation disorders medications definition purchase 800mg neurontin otc. Other causes include insulinoma treatment definition buy neurontin 100 mg with visa, primary hypothalamic dysfunction, severe alcoholism, hypothyroidism, Addison disease, fasting, gastric surgery, drug-induced hypoglycaemia. Irreversible hypoglycaemic brain damage can occur rapidly in severe hypoglycaemia in a pattern similar (but not identical) to that in cerebral hypoxemia, affecting particularly the cerebral cortex, hippocampus, striatum, and cerebellum; and hypoxia and hypoglycaemia may cause cerebral damage via common pathways. Clinical Features the major symptoms of hypernatraemia are neurological taking the form of encephalopathy. Neurologic signs generally develop with serum sodium concentrations >160 mEq/l [32], but symptoms are more common and more severe when the changes in serum sodium concentration are rapid. Chronic hypernatraemia and slow rises in sodium are more likely to be asymptomatic even to levels in excess of 170 mEq/l. Initial symptoms typically are anorexia, restlessness, irritability, lethargy, muscle weakness, and nausea. Seizures can also be precipitated iatrogenically if the hypernatraemia is corrected too rapidly. Indeed, the most common setting in which convulsions occur in relation to hypernatraemia is when a patient is treated with aggressive hypotonic fluids in the setting of prolonged hyperosmolality, and this can cause cerebral oedema, leading to coma, convulsions and death. Seizures can also be caused by iatrogenic rupture of cerebral veins and subarachnoid haemorrhage where correction has been too rapid. Treatment the aim of therapy is to replace body water and restore osmotic homeostasis and brain volume, but at a rate that does not cause complications. The speed of correction depends on the clinical urgency, and also whether the hypernatraemia was acute or chronic. Replacement with hypotonic saline or dextrose is usual, with fluids given orally in non-acute situations. Plasma sodium concentration should be reduced by 1 mmol/ l/hr with acute hypernatraemia, but in less urgent situations, the rate of correction should not exceed 0. Cautious correction of hypernatraemia with half-isotonic saline may reduce the likelihood of convulsions occurring during treatment. Clinical Features the initial symptoms of hypoglycaemia include sweating, a feeling of hunger, fatigue, weakness, and tremor, and these can progress to confusion, erratic or bizarre behaviour, stupor, coma, and seizures. Diabetic children below 6 years of age can have frequent hypoglycaemic episodes, with 90% of these episodes manifesting as seizures [36]. Insulinoma may present with all forms of seizures and with refractory epilepsy [37]. As with other endocrine disturbances, the rate of fall is important, and chronic hypoglycaemia is associated with a much lower rate of seizures. Hypoglycaemic seizures can be generalized or focal or take the form of myoclonic attacks. Typically, though, hypoglycaemic attacks are longer lasting, have a slow prodrome, and take a more bizarre form than epileptic seizures. Epilepsia partialis continua occurs when the serum glucose level is between 600 and 800 mg/dl and in the early stages when the patient is alert [48]. Seizure clustering and recurrence are more common in diabetic patients than in nondiabetic patients [45]. Diagnosis Hypoglycaemia needs to be considered in any patient presenting with seizures. Treatment is urgent and takes the form of rapid intravenous administration of 50% dextrose. Hyperglycaemia Elevated levels of blood sugar can cause seizures, although less frequently than low levels. The most common presenting symptom is repetitive seizures, which can be generalized or focal. Other causes of hyperglycaemia rarely result in seizures and include drug-induced hyperglycaemia, stress, and critical illness and sepsis. If the diagnosis is made early, a complete recovery without sequelae can be expected. Pathophysiology Experimental [42] and human studies [45] have suggested that glucose may have a proconvulsant effect. The most common are: vitamin D deficiency, hypoparathyroidism and pseudohypoparathyroidism, and renal disease. Several theories have been suggested to explain epileptogenesis in hypocalcaemia, including neuronal membrane excitability changes, hypertensive encephalopathy, and hypercalcaemia-induced vasoconstriction [56]. Hypocalcaemia may also lower the excitation threshold for seizures if the patient has pre-existing subclinical epilepsy. In chronic hypocalcaemia, especially in the absence of seizures, correction of the underlying cause and supplementation with calcium, vitamin D, or vitamin D analogues can be sufficient depending on the clinical setting. Hypercalcaemia Hypercalcaemia is defined as a total serum calcium concentration >10. It is much more common than hypocalcaemia in clinical practice, but seizures are a less prominent symptom. Aetiology Hypercalcaemia is usually caused by abnormally high bone reabsorption, and there are many causes of this including: primary hyperparathyroidism, malignancy, granulomatous disease, acute and chronic renal failure, immobilization, vitamin D or A toxicity, and hyperthyroidism. It can also result from excessive calcium absorption such as in sarcoidosis and other granulomatous diseases, or milk-alkali syndrome. It can also result from drug therapy with such drugs as lithium, theophylline, and thiazides, and from other endocrine disturbances such as Addison disease, hypothyroid-ism, and Cushing disease or from the rare genetic syndrome of familial hypocalcuric hypercalcaemia. The associated signs of congenital hypoparathyroidism or type 1A pseudohypoparathyroidism may be present. The commonest symptoms are muscle cramps, tetany, skin changes (in chronic hypocalcaemia), and seizures. Hypocalcaemic seizures are typically generalized, but partial (focal) motor or sensory seizures occur in 20% of patients and atypical absence seizures are also reported. Focal seizures are said not necessarily to correlate with localized cerebral abnormalities. Clinical Features and Pathophysiology Patients are often asymptomatic in mild hypercalcaemia. Symptoms, when they do occur, are initially predominantly gastrointestinal: constipation, vomiting, anorexia, abdominal pain, and ileus. Other symptoms include muscle weakness and lethargy, and renal stones can occur in chronic hypercalcaemia. Severe hypercalcaemia can cause neurological symptoms including confusion, delirium, psychosis, stupor, and coma. Focal seizures have been ascribed to clotting of small blood vessels within the brain [61]. Hypercalcaemic hypertensive encephalopathy and vasoconstriction may be a cause of seizures [64]. Seizures can also occur as part of the posterior reversible encephalopathy syndrome, which can be associated with hypercalcaemia. The differentiation of conditions causing abnormal vitamin D, parathyroid hormone, and calcitonin levels is outside the scope of this book, and can be complex requiring careful assessment. Paroxysmal epileptiform discharges are noted in hypocalcaemia-induced seizures [60]. Diagnosis the diagnosis is by biochemical measurement, and investigations include (depending on cause): serum calcium, parathyroid hormone, phosphate, alkaline phosphatase, other electrolytes, urea, and protein immunoelectrophoresis and imaging. Treatment In the acute situation, with seizures, treatment of hypocalcaemia should be immediate to reduce the associated morbidity and mortality [59]. In chronic hypercalcaemia, treatment is usually directed at the underlying cause though oral bisphosphonates can be given. Treatment should also be directed at the cause, and the urgency of treatment may depend on this. Treatment Rapid correction of magnesium levels with intravenous magnesium salt solutions is needed if seizures are present [74]. The usual cause is renal failure, and the symptoms are those of hypotension and respiratory and cardiac depression. Hypomagnesaemia Hypomagnesaemia occurs when the serum magnesium level falls below 1. The serum magnesium level does not necessarily reflect the whole body level as only 2% of body magnesium is extracellular, and concentrations also vary from organ to organ. Magnesium deficiency is very often associated with calcium deficiency and the symptomatology can reflect a combination of both deficiencies. Aetiology There are many causes of a low potassium level, but the most common are vomiting, diarrhoea, Cushing syndrome, or laxative or diuretic therapy. Other causes include Fanconi syndrome, hypomagnesaemia, hyperthyroidism, insulin, and some drug therapies (including terbulatine and theophylline). Aetiology the usual causes are: dietary deficiency, perturbations of calcium metabolism, drug-induced deficiencies (from loop diuretics, protein pump inhibitors (omeprazole), antibiotics (aminoglycoside, amphotericin, pentamidine, gentamicin, tobramycin, viomycin) and nephrotoxic drugs such as cisplatin, amphotericin B, cyclosporine, tacrolimus and pentamidine), primary hypomagnesaemia, stress hypomagnesaemia, alcoholism, renal disease, parathyroid disease, pregnancy (preeclampsia/eclampsia), gastrointestinal disease (diarrhoea or small-bowel bypass), diabetic ketoacidosis, and various congenital and genetic conditions and inborn errors of metabolism [71,72]. Clinical Features the commonest features are muscle weakness, cramps and twitches, and abnormalities of cardiac rhythm. Very rarely seizures and other neurological signs develop, but these are not a major feature and when seizures do occur these are either with very low potassium levels or related to comorbidities or other electrolyte disturbances. The lack of seizures is surprising, considering the importance of potassium channels in cerebral function and the fact that rare genetically determined epilepsies are due to potassium channel defects. Seizures and other neurologic symptoms are typically encountered when the serum magnesium concentration falls to <0. Chronic magnesium deficiency is also recorded as a rare cause of intractable seizures [73]. Seizures also release catecholamines, which in turn lower the magnesium level, so a low magnesium level in the setting of acute seizures can be the result as well as the cause of the seizures. In very severe hypokalaemia, including hypokalaemia complicated by seizures, intravenous potassium should be given. The usual causes are increased ingestion of potassium, renal disease, severe burns, diabetes, or metabolic acidosis. Very severe hyperkalaemia is treated with calcium, insulin, and glucose, and later by dialysis and cation exchange resin. Drake K, Nehus E, Goebel J (2015) Hyponatremia, hypo-osmolality, and seizures in children early post-kidney transplant. Bautista C (2012) Unresolved issues in the management of aneurysmal subarachnoid hemorrhage. Halawa I, Andersson T, Tomson T (2011) Hyponatremia and risk of seizures: a retrospective cross-sectional study. Lu X, Wang X (2017) Hyponatremia induced by antiepileptic drugs in patients with epilepsy. Guisado R, Arieff A (1975) Neurologic manifestations of diabetic comas: correlation with biochemical alterations in the brain. Sallman A, Goldberg M, Wombolt D (1981) Secondary hyperparathyroidism manifesting as acute pancreatitis and status epilepticus. Swash M, Rowan J (1972) Electroencephalographic criteria of hypocalcemia and hypercalcemia. Nuytten D, Van Hees J, Meulemans A, Carton H (1991) Magnesium deficiency as a cause of acute intractable seizures. Recreational and illicit drugs causing epilepsy and status epilepticus are discussed in Chapter 115. In the scientific literature there are a large number of drugs reported to be associated with seizures. However, not all the evidence for these reported associations is scientifically robust [1]. Indeed, the causal relationship between a drug administration and the appearance of seizures is sometimes difficult to ascertain with certainty. The event (seizure occurrence or aggravation) should be pharmacologically plausible, and the possibility of a drug interaction leading to seizure should also be taken into consideration. Standardized ways of reporting health events (including emergence of seizures or seizure aggravation) occurring during or after a certain treatment have been proposed to express different degrees of probability of causal relationship and of the putative mechanisms being implicated. Epidemiology It is estimated that approximately 6% of new-onset seizures [3] and up to 9% of cases of status epilepticus [4] are druginduced. Usually patients with drug-induced seizures have single seizures (45% in one retrospective study), but a relevant proportion has multiple seizures (40%) or status epilepticus (15%) [8]. Knowing which drugs are most frequently associated with seizure risk should alert clinicians to closely monitor patients receiving these drugs, as should the identification of individual features predisposing to drug-induced seizures and their complications (including status epilepticus and risk of hypotension, pulmonary aspiration, hyperthermia, anoxic brain injury, or death). Unfortunately, new drugs continuously enter the market, making it difficult for epidemiological studies to provide a stable picture of substances involved in drug-induced seizures. Changes in pharmacological prescribing pattern over time and in different geographic regions are reflected only partially by epidemiological studies, and explain their limited generalizability [9].

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Microbial metabolites are another important nutrient source for resident microbes medications for ocd cheap 600mg neurontin. Very few studies of the microbial communities resident in the urinary system of females have been undertaken symptoms of appendicitis purchase 100mg neurontin overnight delivery. In the urethra treatment plan goals and objectives discount neurontin 100mg without prescription, the microbial population density decreases with increasing distance from the external orifice medicine 8 letters buy neurontin 600 mg free shipping. The most frequently isolated organisms from the urethra of healthy females of reproductive age are Corynebacterium medications 1800 100 mg neurontin for sale, Gram-positive anaerobic cocci medications diabetes purchase 300mg neurontin free shipping, Bacteroides, coagulase-negative staphylococci, and lactobacilli. Culture-dependent and -independent studies have reported the presence of Lactobacillus, Corynebacterium, and Staphylococcus in the bladder. Many members of the urethral microbiota, particularly lactobacilli, are antagonistic to other members. Some members of the urethral microbiota, particularly lactobacilli, protect the host from sexually transmitted and urinary tract infections. Urease production by some urethral microbes can result in the formation of urinary stones. Dysbiosis of the urethral and bladder microbiotas can be induced by catheterization, sexual intercourse, and antibiotic use. A meta-analysis of studies of probiotic administration concluded that there is no evidence that probiotics are able to prevent urinary tract infections. What have culture-independent studies contributed to our knowledge of the urethral microbiota Describe those diseases of the female urinary system that are associated with dysbiosis. In what ways do the microbiotas of the female urinary system contribute to health and well-being Describe the effect of antibiotic administration on the urethral microbiota of females. Describe the sequence of events that results in the formation of a biofilm on a urinary catheter. Questions and challenges associated with studying the microbiome of the urinary tract. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. Culturing of female bladder bacteria reveals an interconnected urogenital microbiota. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Innate immunity and genetic determinants of urinary tract infection susceptibility. Dysbiosis of urinary microbiota is positively correlated with type 2 diabetes mellitus. Microflora changes with norfloxacin and pivmecillinam in women with recurrent urinary tract infection. Uropathogenic Escherichia coli virulence and innate immune responses during urinary tract infection. An integrative review of current research on the role of the female urinary microbiota in overactive bladder symptoms. Microbiota in 2016: Associating infection and incontinence with the female urinary microbiota. We will also come to understand the important impact that hormonal fluctuations during the menstrual cycle have on the environment of the reproductive system and the consequences of this for the microbial communities that reside there. We should appreciate by now that the microbiota of a body site is affected by age and, consequently, develops as we progress from infancy to adulthood. When it comes to antimicrobial defenses, we will meet, once again, mucociliary clearance as an important contributing mechanism as well as the usual mucosa-associated defense systems. Such objects include the penis and more recently, in evolutionary terms, tampons and contraceptive devices. Text in red signifies a resource with a webpage that is given in full at the end of the chapter 240 Chapter 7: the Indigenous Microbiota of the Reproductive System of Females 7. The vagina, vulva, cervix, and uterus support a resident microbiota in healthy individuals For many years it has been known that the vagina, vulva, and cervix of healthy individuals have resident microbial communities. The microbiotas present in the vagina and the cervix have been studied extensively using both culture-dependent and molecular approaches. In contrast, far less is known about the microbial communities that reside on the various regions of the vulva. The mons pubis consists of a layer of adipose tissue covered by skin and pubic hair (Table 7. The labia majora are longitudinal folds of skin which contain adipose tissue, have sebaceous and sudoriferous glands, and their outer surfaces are covered in pubic hair. They are covered with a stratified squamous epithelium (which may have a thin keratinized layer on its surface) and have numerous sebaceous glands but few sudoriferous glands. From the innermost surfaces of the labia majora to the vagina, there is a gradual transition in the structure of the epidermis as it changes from a keratinized epithelium typical of the outer body surface to the mucosal epithelium found in the vagina. The clitoris consists of erectile tissue and nerves, is covered with a thin stratified squamous epithelium and has a hood of skin known as the prepuce or foreskin (see Table 7. It extends from the vulva to the cervix and its main functions are to provide an outlet for the menstrual flow, to act as a receptacle for the penis during sexual intercourse, and to act as a passageway during childbirth. No glands are present in the vagina but the surface is lubricated by mucus produced by the cervix and by the fluid (transudate) that leaks through the epithelium from the capillaries within the vaginal wall. The innermost layer consists of basal cells which are actively undergoing cell division. Cells of the superficial layer have fewer glycogen granules but are rich in intracytoplasmic microfilaments which provide rigidity and protection to the underlying layers. The mucosa is folded into ridges known as rugae which enable the vagina to expand. Migrating lymphocytes and Langerhans cells are also present throughout the mucosa. Non-keratinized, stratified, squamous epithelium Mucus layer the anatomy and physiology of many regions of the reproductive system are dependent on the sexual maturity of the individual and vary during the reproductive cycle the epithelium is constantly undergoing remodeling during the female reproductive cycle and this involves the proliferation, maturation, and desquamation of cells. Various phases within this cycle are recognized- follicular, luteal, ovulation, and menstruation. Cross section through the wall of the vagina showing the typical stratified, squamous, non-keratinized epithelium and the mucus layer that coats the epithelium. The cultured cells form multi-layered structures similar to those seen in vaginal biopsies from healthy individuals. Diagram showing the changes that occur during the female reproductive cycle with respect to: (1) the development of an oocyte in the ovary, (2) body temperature, (3) hormone levels, and (4) the endometrium (the mucosa lining the inside of the uterus). Note that these are average values; duration and values may differ between different females or in different cycles of the same individual. Diagram illustrating the difference in thickness of the vaginal mucosa in pre-menopausal (left image) and postmenopausal (right image) females. The vagi nal mucosa is much thicker in pre-menopausal individuals than in post-menopausal individuals. This marks the boundary between the squamouslined ectocervix and the columnar-lined endocervix. The ectocervix is covered by a stratified, squamous, nonkeratinized epithelium similar to that present in the vagina. This type of epithelium extends into the cervical canal for a distance which varies depending on the age of the individual. Unlike the mucosa of the uterus, the cervical epithelium is not shed during menstruation. For example, the quantity of mucus secreted increases tenfold when the level of estrogen peaks at mid-cycle. Following ovulation, the increased level of progesterone causes less mucus to be produced and it becomes more viscous so that it forms a plug which seals the canal. Consequently, the environments within these organs are markedly dependent on the sexual maturity of the individual. These environmental fluctuations will, in turn, affect the composition of the resident microbial communities. The environments within the various regions of the vulva are also likely to be affected by hormonal fluctuations although less is known about this. The mons pubis and the labia majora have the innate and acquired defense mechanisms typically present in skin whereas the labia minora, clitoris, and vestibule have defense mechanisms similar to those found at other mucosal surfaces. The partial pressure of oxygen in the vagina of healthy individuals during menstruation is approximately 4 mm Hg which is 2% of that present in air and 10% of that found in tissue cells. However, oxygen levels in the vagina vary during the menstrual cycle, with lower levels being found in mid-cycle. The vaginal ecosystem, therefore, can be regarded as predominantly microaerophilic. For example, the insertion of a contraceptive diaphragm results in an increase in the partial pressure of oxygen to approximately 82% of that present in air. Also, the insertion of a tampon increases the oxygen content of the vagina to a level similar to that found in air-the concentration then decreases slowly and returns to normal after approximately 8 hours. This could have a profound effect on the vaginal microbiota and may encourage the growth of aerobes and facultative organisms such as Staph. The pH of the vagina correlates strongly with the sexual maturity of the individual (Table 7. In neonates the estrogen level is high due to a corresponding high level in the mother. This results in neonates having a thick vaginal epithelium with a high glycogen content and a low pH (approximately 4. The estrogen level then declines until, after approximately 3 weeks, the vaginal epithelium becomes thinner and the glycogen content lower. At the onset of menstrual flow the pH is almost neutral, it then falls during and after menstruation and reaches a minimum (<4) at mid-cycle. Pregnancy does not appear to affect the pH of the vagina which remains less than 4. Vaginal fluid is a source of a wide variety of nutrients Vaginal fluid is the main source of host-derived nutrients for the vaginal microbiota and this is produced by women of reproductive age at a rate of approximately 6 g per day with approximately 0. Consequently, it is an important source of a wide variety of nutrients and contains approximately 48 mg/g of carbohydrates, 4 mg/g of proteins, and 0. Importantly, it contains hemoglobin which could be a valuable source of iron for vaginal microbes. Although there is a plentiful and varied supply of nutrients available to microbes colonizing the vagina, certain features of the environment are unfavorable to many organisms, for example the low pH and low oxygen content. Furthermore, the range of antimicrobial mechanisms described later exert a selective effect and influence the composition of the vaginal microbiota. Like the vagina, it is predominantly a microaerophilic environment with the lowest oxygen levels (approximately 8% of that found in air) during the proliferative phase of the reproductive cycle. The pH of the cervix is generally higher than that of the vagina and ranges from 5. Both the amount of mucus produced and its water content gradually increase until mid-cycle and then decrease. For example, the immunoglobulin content is highest during the follicular phase than during the luteal phase whereas the albumin content decreases significantly prior to , and during, ovulation then increases. A large variety of proteins (approximately 200) have been identified in cervical mucus and one study has reported that 38 of these are present at all stages of the menstrual cycle. The presence of polysaccharides was revealed by staining with fluorescent wheat germ agglutinin which stains polysaccharides blue. The main nutrient sources for microbial colonizers vary with the exact location within the vulva but include vaginal secretions (see Table 7. The anatomy and physiology of the vulva depend on the degree of sexual maturity and will vary during the menstrual cycle. Consequently, the environmental determinants operating in the vulva will fluctuate in a similar manner. Other factors that affect the vulval environment, particularly with respect to the moisture content and pH, include the type of underwear worn, panty-liner use (type used, frequency of use, length of use), use of genital deodorants, and the frequency and type of hygiene practices employed. However, several studies have now demonstrated the presence of microbes in the uterus of non-pregnant and pregnant females. It is, of course, very important to maintain these upper regions devoid of pathobionts and exogenous pathogens in order to protect any fertilized ovum from infection. The cervix is the main potential entry route for microbes and has a variety of antimicrobial defense mechanisms to prevent ingress of microbes from the heavily colonized lower genital tract (Table 7. The thick layer of mucus coating the cervical epithelium is a physical barrier to microbes and hinders their access to the underlying epithelium. The carbohydrate moieties on the mucins present in mucus act as receptors for many of the adhesins present on microbes and so trap them within the mucus layer. Mucus was stained for IgA (green) and IgG (red) and also with wheat germ agglutinin (blue) to show the presence of mucus polysaccharides.

Herzog Definition symptoms rabies purchase generic neurontin on-line, Patterns and Prevalence of Catamenial Epilepsy Seizures do not occur randomly in the majority of men and women with epilepsy symptoms of the flu order neurontin with amex. The clusters treatment 02 bournemouth buy generic neurontin, in turn medicine you can give cats buy neurontin cheap online, can occur with a temporal rhythmicity in a significant proportion of men (29%) and women (35%) with epilepsy [2] symptoms zinc deficiency adults purchase discount neurontin on-line. In women medicine show cheap neurontin 400 mg otc, seizure numbers and cycle days with seizure occurrence vary across the menstrual cycle. When the periodicity of seizure exacerbation aligns with the menstrual cycle, it is commonly known as catamenial epilepsy [4]. Catamenial seizure exacerbation may be attributable to the (1) neuroactive properties of reproductive steroids, (2) variation of neuroactive steroid levels across the menstrual cycle, and (3) susceptibility of the epileptic substrate to neuroactive steroid effects [4,8]. In ovulatory cycles, seizure frequency shows a statistically significant positive correlation with the serum estradiol/progesterone ratio [9]. This ratio is highest during the days prior to ovulation and menstruation and is lowest during the early and mid luteal phase [9]. The premenstrual exacerbation of seizures has been attributed to the rapid withdrawal of the antiseizure effects of progesterone [4,9]. Mid cycle exacerbations may be due to the preovulatory surge of estrogen, unaccompanied by any rise in progesterone until ovulation occurs [4,9,10]. Seizures are least common during the mid luteal phase when progesterone levels are highest [4,9,10] except in anovulatory cycles in which the mid cycle surge of estrogen still occurs, albeit to levels not as high as in ovulatory cycles, but unaccompanied by any substantial increase in progesterone levels [4]. These three patterns can be demonstrated simply by (1) charting menses and seizures and (2) obtaining a mid luteal phase serum progesterone level to distinguish between normal and inadequate luteal phase cycles (<5 ng/ml). We propose the use of these points of inflection values in seizure frequency for the designation of catamenial epilepsy. Using the cutoffs provided by the points of inflection of the three reverse S-shaped curves for the designation of catamenial epilepsy, the 1997 investigation found that 78 of the 184 (or 42. Adoption of a standard albeit arbitrary nomenclature may provide greater uniformity to study designs for the investigation of the pathogenesis and treatment of catamenial seizure exacerbation. Pathophysiology There are three critical pathophysiological determinants of catamenial epilepsy: (1) neuroactive properties of reproductive steroids, (2) variation of neuroactive steroid levels across the menstrual cycle, and (3) susceptibility of the epileptic substrate to neuroactive steroid effects [8]. There is considerable scientific evidence at molecular biological, neuronal, experimental animal and clinical levels to indicate that reproductive steroids have neuroactive properties which play an important role in the pathophysiology of epilepsy and the pattern of seizure occurrence. Steroids act in the brain by direct membrane-mediated (short latency, cell surface receptor signaling) effects as well as genomically mediated (long latency, ligand-activated nuclear transcription) effects [12,13]. While acknowledging that hormones have complex effects that vary with their isomers. Estradiol the potential importance of estradiol in the regulation of temporolimbic function is highlighted by the presence of the estradiol synthesizing enzymes, cytochromes P45017a and P450 aromatases, in hippocampal neurones and the measurement of estradiol levels in the hippocampus that surpass serum levels [17,18]. In adult experimental animals, the thresholds of limbic seizures vary across the estrus cycle and do so inversely to serum estradiol levels [19]. The systemic administration of physiological doses of estradiol activates spike discharges [15,20,21] and lowers the thresholds of seizures induced by electroshock, kindling, pentylenetetrazol, kainic acid, ethyl chloride and other agents and procedures [15,20,23]. The topical brain application of estradiol also produces a significant increase in spontaneous electrically recorded paroxysmal spike discharges [15]. The increase occurs within seconds of application to suggest a direct membrane rather than a genomic effect and is more dramatic in animals with pre-existent cortical lesions [15,20]. The role of estrogen, however, may be more complex since there is also evidence in some models that estradiol can raise seizure thresholds in the hippocampal region and provide neuroprotection against seizure induced injury [23]. Estradiol modulates neuronal excitability by regulating neuronal development and plasticity. The dendritic spine density on these neurones correlates positively with the levels of circulating estradiol during the estrous cycle of the rat and is decreased by oophorectomy [24]. The complex role of estrogen is illustrated by evidence in some models that estradiol can raise seizure thresholds in the hippocampal region and provide neuroprotection against seizure-induced injury [23]. The resulting combined increase in excitatory synapses and restoration of inhibitory synapses leads to a wider dynamic range of neuronal responses and may contribute to the synchrony of firing that is important to the occurrence of seizures. Estradiol may affect neuronal excitability by cytosolic neuronal estrogen receptor-mediated, genomically dependent mechanisms. Receptors are particularly abundant in the temporolimbic system, especially in the medial and cortical amygdaloid nuclei, and occur in much fewer numbers in the hippocampal pyramidal cell layer and the subiculum [30]. By regulating the expression of genes affecting the activity, release and postsynaptic action of different neurotransmitters and neuromodulators, estrogens may act to increase the excitability of neurons, which concentrate estradiol. Menopausal hormone replacement with conjugated estrogen and medroxyprogesterone is associated with a dose-related increase in seizure frequency in postmenopausal women with epilepsy [35]. Progesterone In most adult female animal models, progesterone depresses neuronal firing and lessens spontaneous and induced epileptiform discharges [22,36]. Progesterone and allopregnanolone have also been shown to have neuroprotective effects on hippocampal neurons in kainic acid induced seizure models [36]. Their synthesis is region-specific and includes the cortex and the hippocampus [40]. The anticonvulsant properties of allopregnanolone resemble those of the benzodiazepine, clonazepam [38,42]. Progesterone may act via genomic mechanisms to influence the enzymatic activity controlling the synthesis and release of various neurotransmitters and neuromodulators produced by progesterone receptor containing neurons [12]. Progesterone binds specific cytosolic receptors not only to produce its own characteristic effects but also to lower estrogen receptor numbers and thereby antagonize estrogen actions [46]. Variation of Neuroactive Steroid Levels Across the Menstrual Cycle the most consistent and compelling preclinical evidence of the role of the variation of neuroactive steroid levels in catamenial epilepsy is related to allopregnanolone, a metabolite of progesterone. This might be a mechanism for perimenstrual seizure exacerbation (C1 pattern) and a rationale for treatment trials with cyclic progesterone supplement that provides gradual, rather than abrupt, progesterone withdrawal premenstrually. Assuming a proconvulsant effect of estradiol, mid cycle seizure exacerbation (C2 pattern) correlates temporally with, and could result from, the pre-ovulatory estradiol surge [4,8]. Entire luteal phase seizure exacerbation in anovulatory cycles and ovulatory cycles with high serum estradiol to progesterone level ratios (C3 pattern) could result from an unopposed estradiol effect. Effects of Epilepsy Laterality and Focality Epileptic brain substrates differ from non-epileptic brain at the molecular biological. For instance, temporal lobe foci, especially left-sided, are more susceptible to circalunar, i. This is generally accomplished using injectable progestins or gonadotropinreleasing hormone analogues. Cyclic Progesterone Therapy Synthetic oral progestins, administered cyclically or continuously, have not proven to be effective therapy for seizures [48,50], although individual successes with continuous daily oral use of norethisterone and combination pills have been reported [51]. However, open-label trials of adjunctive progesterone therapy for women with catamenial epilepsy did result in clinically important and statistically significant and enduring reductions in seizure occurrence (Table 111. Progesterone was more efficacious when administered during the entire second half of the cycle, rather than just premenstrually, and then tapered and discontinued gradually over 3 or 4 days at the end of the cycle [53]. Failure to taper gradually premenstrually can result in rebound seizure exacerbation. The principal outcomes were the proportion of 50% responders and the change in seizure Table 111. Catamenial designation was based on the demonstration of catameniality in 2 of 3 baseline cycles using the criteria of Herzog et al. The trial found that cyclic progesterone was not superior to placebo in the treatment of intractable seizures in women with partial epilepsy. A pre-specified secondary analysis found that the level of perimenstrual catameniality (C1 level) was a predictor of the efficacy of progesterone treatment. With increasing C1 levels, responder rates, when considering all seizures combined, increased progressively from 21. The separation between responder rates for all seizures combined for progesterone (27. Failure of the trial to prove the principal hypothesis might be due to the design that attempted to treat all three patterns of catamenial epilepsy which likely differ in pathophysiology with a single treatment regimen. Specifically, cyclic progesterone supplement may have greater efficacy where progesterone withdrawal (C1 pattern), rather than estrogen surge (C2) or high luteal phase estradiol/progesterone serum level ratios (C3 pattern), are causally implicated. A 60 50 40 30 20 10 0 Responder Rate and Seizure Change in Relation to C1 Level: Progesterone vs. This is a plot of 50% responders versus the level of perimenstrual seizure exacerbation (C1 level). C1 levels were determined during baseline and are expressed as multiples of the combined mid-follicular and mid-luteal seizure frequencies. Each level includes all women who had seizure exacerbation greater than or equal to that specific level of catameniality. The anticipated primary outcome that 35% of catamenial progesterone treated versus 15% of placebo treated women would show a 50% reduction in seizure frequency is realized at C1 level 3 where 37. In comparison to the responder rate of the combined placebo group, the progesterone responder rates are significantly greater at each C1 level 3. Progesterone is a naturally occurring hormone with a long history of clinical use for the treatment of reproductive disorders. The daily regimen to achieve physiological luteal range serum levels measured 4 hours after administration ranges from 50 mg to 200 mg, taken three times daily, with the usual optimal daily dose ranging from 300 mg to 600 mg [52,53,56]. The maintenance dosage and regimen should be individualized and based on a combination of clinical response and serum progesterone levels between 10 and 30 ng/ml. Progesterone is also available in micronized form in an oral capsule preparation that may also exert similar antiseizure effects although formal investigations to this effect are lacking. Theoretically, it is possible that first pass through the liver using the oral micronized form may result in the delivery of different concentrations of progesterone and its neuroactive metabolite to the brain. Progesterone use can also occasionally be associated with breast tenderness, weight gain, and irregular vaginal bleeding and sometimes constipation. Discontinuation of the hormone or lowering of the dosage resolves these side effects [52,53,56]. They remained on a stable dose of the anticonvulsant throughout the period of treatment with triptorelin. They reported that three patients became seizure-free; four showed a decrease in seizure frequency of up to 50%. The study was not a controlled study and longer term follow-up was not available for some of the patients. They reported a decrease in frequency from 10 admissions for status to three over a similar period. Reid and Gangar suggested the addition of medroxyprogesterone acetate and conjugated estrogens to goserelin to prevent this while still abolishing most of the cyclical fluctuations of ovarian hormones [61]. Suppressive Progestin Therapy Parenteral depomedroxyprogesterone may lower seizure frequency when it is given in sufficient dosage to induce amenorrhea [50,58]. In one open-label study of 14 women with refractory partial seizures and normal ovulatory cycles, parenteral depomedroxyprogesterone administration in doses large enough to induce amenorrhea. It was unclear whether the effect was due to direct anticonvulsant activity of medroxyprogesterone or to the hormonal consequences of the induced amenorrhea. Long-term hypoestrogenic effects on cardiovascular and Conclusions the practical applications of the findings from the treatment studies are that the detection of a 3-fold level of perimenstrual seizure exacerbation by charting seizures and menses might indicate the possibility of a favorable response to treatment with adjunctive cyclic progesterone supplement. The findings of the secondary analysis still require formal confirmation in an adequately powered investigation of the 818 Chapter 111: the Menstrual Cycle and Catamenial Epilepsy derived hypotheses. Investigations of these parenteral treatments, however, have been limited to small open-label trials. Finally, the role of progesterone treatment in primarily generalized epilepsy, especially juvenile myoclonic epilepsy, that is more common in women and tends to develop in adrenarchal and pubertal years, remains to be investigated. Louis Sleep is vital to brain and general health, and appears to play important roles in some clinical situations in both seizure activation and suppression, and may even contribute to epileptogenesis and the development of refractory epilepsy. Some epilepsies have a seemingly unique and intimate relationship to the sleep state, and brief partial seizures can be difficult to differentiate from non-epileptic parasomnias or sleep-related movement disorders. Furthermore, the relationship between sleep and epilepsy is bidirectional, in that sleep may influence the activation of interictal epileptiform discharges as well as the frequency of specific seizure types, while epileptic seizures in turn have been shown to have influences on sleep architecture and sleep quality, and treatments for epilepsy may also impact these features of sleep. While current International League Against Epilepsy classification schemes do not recognize sleep-related epilepsies as a distinct category, it is useful to consider organization of the sleep-related epilepsies by categories: pure sleep epilepsies (in which seizures remain confined to the sleep state), such as benign focal epilepsies of childhood or sleep-related focal epilepsies; epilepsies with diurnal seizures, but in which some seizure types or overall seizure frequency are increased during sleep, such as the epileptic encephalopathies. The frequency of co-morbid sleep disturbances and disorders in people with epilepsy is greater than controls, and even more so in refractory epilepsy populations [5]. However, sleep deprivation demonstrated no significant effect on seizure frequency in one inpatient epilepsy monitoring randomized trial [13]. Through adolescence, sleep patterns resemble that of adults, although children and adolescents still need more sleep and often have a delayed circadian preference for a later bed and rise time.