By A. Cobryn. Purdue University North Central. 2018.
Pharmacologic Approaches Based on the Correction of Neurotransmitter Abnormalities Drugs That Increase GABA GABAergic neurons in the striatum purchase 100mg suhagra visa, globus pallidus interna (GPi) purchase suhagra 100mg line, and substantia nigra pars reticulata (SNpr) have been implicated in hyperkinetic movement disor- ders such as chorea and tardive dyskinesia buy generic suhagra 100mg line. Medium-sized spiny neurons (MSSN) containing GABA are the major output pathways from the striatum discount suhagra 100mg line, and neurons in the GPi and SNpr project to the thalamus buy suhagra 100 mg with mastercard, superior colliculus, and reticular for- mation, establishing important inhibitory efferent pathways from the basal ganglia. Valproic acid is thought to act by enhancing GABA levels in the striatum and substantia nigra. In multiple small studies and case reports, valproic Table 3 Treatment of Chorea Based on Neurochemistry Pathologic mechanisms Role of medication Reduced Ach Increase Ach Lecithin? Reduced GABA Increase GABA Valproic acid Clonazepam Excess DA Diminish DA Pimozide Haldol Tetrabenazine Reserpine Carbamazepine (mechanism? In general, no serious side effects were noted, but hepatotoxicity and thrombocytopenia have been reported with valproic acid use in other disorders. Clonazepam is a long-acting benzodiazepine that has been used to treat chorea with some success. Benzodiazepines act on the GABAA receptor–chloride ion channel complex and increase the frequency of ion channel opening, acting as indirect GABA agonists. Case reports document improved chorei- form movements at relatively low clonazepam doses, 1–5 mg=day. Tolerance may develop after a period of months, necessitating dose escalation or a drug holiday. Drugs That Increase ACh Large aspiny cholinergic interneurons within the striatum innervate GABAergic MSSN and tend to counterbalance the inﬂuences of dopamine and glutamate. Trials of cholinergic precursors, such as choline and lecithin, for chorea have been limited and results modest. Reports dating back to the 1970s suggest that tetrabenazine may be helpful in selected patients with chorea. Tetrabenazine acts by preventing the presynaptic release of dopamine, so-called monoamine depletion, as well as blocking dopamine receptors on postsynaptic terminals. Tetrabenazine treatment in 5 pediatric patients with chorea signiﬁcantly improved movements in 80%, although high doses (up to 275 mg=day or 25 mg=kg=day) were often necessary (Chatterjee). Medication was continued for at least several months and side effects commonly reported in adults, such as depression, parkinsonism, hypotension, acute dystonic reaction, and neuroleptic malignant syndrome, were not present. Tetrabe- nazine is not approved for use in the United States, but can be obtained from Canada for selected cases. Reserpine, another dopamine-depleting agent, is effective for chorea in some patients. Reserpine is longer acting than tetrabenazine and side effects may include hypotension, depression, and parkinsonism. Dopamine antagonists including the typical neurolep- tics haloperidol, pimozide, and chlorpromazine have been efﬁcacious in treating chorea. Early case reports describe rapid improvement of abnormal movements within a few days, using low doses of haloperidol, from 0. Other authors have suggested that pimozide may have a lower risk of inducing neuroleptics side effects, such as sedation, parkinsonism, weight gain, school phobia, hepatocel- lular dysfunction, leukopenia, and tardive dyskinesia. Carbamazepine has also been used to treat chorea, but its mechanism of action is unknown. Some authors have postulated that it stimulates cholinergic pathways and others have implicated structural similarity to tricyclic antidepressants and phenothiazines. Surgical Therapy Surgical approaches for the treatment of chorea are unproven. Deep brain stimula- tion (DBS) of the thalamus and pallidotomy have been performed in a small number of cases with mixed results. Chorea in Children 137 Therapy in Sydenham’s Chorea Since treatment is symptomatic and not curative, the decision to initiate therapy in patients with SC is based on the degree of patient disability, whether due to chorea, behavioral, or psychiatric symptoms. Numerous neuropsychiatric problems are seen in association with SC, including emotional lability, irritability, attention deﬁcit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), and psycho- sis, and speciﬁc therapy may be required to address these issues (see appropriate chapters). Studies in patients with SC have shown improvement of chorea with the use of anticonvulsants. In limited trials, there were no signiﬁcant differences between val- proic acid and carbamazepine in the time to clinical improvement, time to complete remission, duration of therapy, or recurrence rates. Other therapies have included neuroleptics, such as haldol and pimozide. In most patients, chorea improved dra- matically and the duration of therapy, although variable, ranged from 3 to 6 months. Immunomodulatory therapies, such as corticosteroids, plasmapheresis, and intravenous immunoglobulin (IVIG), have been used to treat SC.
As with neglect purchase suhagra 100mg with mastercard, these phenomena may be classified as object- or person-centered: ● Object-centered: affecting size and spatial relationships Macropsia: objects appear larger than normal - 194 - Micrographia M Micropsia: objects appear smaller than normal Pelopsia: objects appear closer to the observer than actual Porropsia: objects appear farther away from the observer than actual ● Person centered: Micro- and macrosomatognosia: body image appears smaller or larger than normal (“Alice in Wonderland” syndrome) discount suhagra 100 mg online. Metamorphopsias are often transient and episodic discount suhagra 100 mg line, occurring for example during migraine attacks 100mg suhagra with visa, epileptic seizures buy 100mg suhagra with visa, with psychotropic drug abuse, and following petechial intraparenchymal hemorrhages. Rarely, they are long-lasting or permanent, for example following brain infarction (most commonly involving the occipito-parietal or temporo-parietal cortex: lesions on the right are more likely than those on the left to give metamorphopsia) or tumors. Retinal disease causing displacement of photoreceptors may produce metamorphopsia: micropsia due to receptor separation in retinal edema, macropsia due to receptor approximation in retinal scarring. Occasional cases of metamorphopsia have been reported with lesions of the optic chiasm, optic radiation, and retrosplenial region. Indeed, it seems that meta- morphopsia may occur with pathology at any point along the visual pathway from retina to cortex. Differing patterns of metamorphopsia may assist with clinico-anatomical correlation: ● retinal lesions: ipsilateral monocular ● chiasmal lesions: bitemporal ● occipitoparietal lesions: contralateral homonymous Metamorphopsia may be associated with visual hallucinations. Metamorphopsia and visual hallucinations restricted to the right visual hemifield after a left putaminal hemorrhage. Journal of Neurology, Neurosurgery and Psychiatry 1996; 61: 420-421 Cross References “Alice in Wonderland” syndrome; Hallucination; Illusion; Macropsia; Micropsia; Pelopsia; Porropsia; Telopsia Micrographia Micrographia is small handwriting. It is most often recognized in asso- ciation with the extrapyramidal features of idiopathic Parkinson’s dis- ease (indeed it may be the presenting sign), but may occasionally occur with other parkinsonian syndromes (e. In Parkinson’s disease, handwriting may initially be of normal size but then become progressively smaller, slower, and more illegible as writing proceeds, an example of parkinsonian fatigue, a gradual - 195 - M Micropsia decline in the amplitude and speed of initiation of voluntary move- ments. Such “slow” micrographia may be distinguished from “fast” micrographia in which letters are small throughout although written at normal speed without fatigue, which may be seen in PSP or other pal- lidal pathologies. There is a poor correlation between micrographia and the side, severity or duration of classical parkinsonian features, and its response to levodopa preparations is very variable. These observations, along with reports of isolated micrographia with cortical lesions demon- strated by neuroimaging, suggest that the anatomical basis of micro- graphia may be at the level of the cortex (dominant parietal lobe) rather than the basal ganglia. Micrographia has also been described following large right ante- rior cerebral artery infarcts and lacunar infarcts involving the putamen and genu of the internal capsule. Journal of the Neurological Sciences 1972; 15: 141-152 Scolding NJ, Lees AJ. Micrographia associated with a parietal lobe lesion in multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry 1994; 57: 739-741 Cross References Fast micrographia; Fatigue; Parkinsonism Micropsia Micropsia, or “Lilliput sight,” is an illusory phenomenon in which the size of a normally recognized object is underestimated. It is the most common form of metamorphopsia, and is most often associated with lesions of the right temporo-parietal cortex, although macular edema and optic chiasm lesions may also cause micropsia. Hemimicropsia, micropsia confined to one visual hemifield, has been recorded. The entirely subjective nature of the disorder may account for the relative rarity of reports. Seeing objects smaller than they are: micropsia following right temporo-parietal infarction. Selective deficit of visual size per- ception: two cases of hemimicropsia. Journal of Neurology, Neurosurgery and Psychiatry 1994; 57: 73-78 Cross References Metamorphopsia Microsomatognosia - see “ALICE IN WONDERLAND” SYNDROME - 196 - Mirror Agnosia M Milkmaid’s Grip Milkmaid’s grip is the descriptive term applied to the inability to main- tain a firm grip (e. Seen in Huntington’s disease, this may reflect a combination of chorea and motor impersistence. Cross References Chorea, Choreoathetosis; Impersistence; Trombone tongue Miosis Miosis is abnormal reduction in pupillary size, which may be unilateral or bilateral. Philadelphia: Lippincott Williams & Wilkins, 2002: 135-146 Cross References Age-related signs; Anisocoria; Argyll Robertson pupil; Horner’s syn- drome; Mydriasis Mirror Agnosia Mirror agnosia, or the “looking glass syndrome,” is a phenomenon observed in patients with left hemispatial neglect as a result of right parietal lobe lesions. There is inability to point to objects seen in a mirror, with repeated reaching “into” the mirror even when the actual location of the target is shown. In a milder form, known as “mirror ataxia,”patients reach in the direction of the object but with increased errors of reach and grasp, suggesting that visual information is not adequately transformed into a body-centered frame of reference. Mirror agnosia and mirror ataxia constitute different parietal lobe disorders. Annals of Neurology 1999; 46: 51-61 Ramachandran VS, Altschuler EL, Hillyer S.
It is important not to underestimate the impact of headache in the child or adolescent and their family and friends buy suhagra 100 mg on line. Recognizing migraine and instituting appropriate treatment will lead to greater patient and physician satisfaction order suhagra 100mg on-line. Ibuprofen or acetaminophen for the acute treatment of migraine in children: a double-blind order 100 mg suhagra, randomized purchase 100mg suhagra with visa, placebo- controlled buy suhagra 100 mg low cost, crossover study. Children’s ibuprofen suspension for the acute treatment of pediatric migraine. One-year tolerability and efﬁcacy of sumatriptan nasal spray in adolescents with migraine: results of a multicenter, open- label study. The International Classiﬁcation of Headache Disorders, Part 1: the primary headaches. Winner P, Rothner AD, Saper J, Nett R, Asgharnejad M, Laurenza A, Austin R, Peykamian M. A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents. INTRODUCTION Although a number of terms have been used to describe the typical clinical picture, I prefer the term pediatric pseudotumor cerebri (PPTC), rather than the alternative: idiopathic intracranial hypertension. The diagnosis of PPTC allows inclusion of indi- viduals who ﬁt the typical clinical picture, yet have a putative cause identiﬁed, to be classiﬁed as a case of associated PPTC. Another older name, benign intracranial hypertension, should be avoided because it minimizes the potential for serious ocular morbidity from this condition. DIAGNOSIS=CLINICAL FEATURES Deﬁnition Pseudotumor cerebri is deﬁned as elevated intracranial pressure ( >200 mm water), normal brain on imaging, normal or small sized ventricles, and normal CSF compo- sition. The neurological examination is usually normal, though some patients may have ocular motor problems or other minor neurological symptoms. Epidemiology Pediatric pseudotumor cerebri may develop throughout the ﬁrst two decades of life. Prior to puberty the gender ratio is 1:1, while after puberty girls outnumber boys by 2 to 1. Obesity is noted in patients with PPTC, but only in about 25% prior to puberty and 50% after puberty. Symptoms The most common symptom is headache, often posterior, which occurs in up to 86% of cases. In young children and infants, irritability and apathy have been noted, rather than headache. Less frequent symptoms include 237 238 Repka ataxia, dizziness, neck pain, paresthesias, facial and limb numbness, and tinnitus. The most common ocular symptom is decreased vision, followed by horizontal double vision. Transient visual obscurations and visual loss are rarely presenting symp- toms in children. This will be found in nearly every patient, though it can be unilateral or markedly asymmetric. Papilledema is manifested by elevation of the optic disc tissue, blurring of the disc margin, and obscuration of the retinal blood vessels as they cross the disc margin. The optic nerve swelling should be assessed not only for the elevation, but also the presence of nerve ﬁber layer infarcts, hemorrhages, exudates, and macular edema. The latter ﬁndings are evidence of chronicity and a greater likelihood of permanent damage to the visual pathways. Papilledema is occasionally seen in infants with PPTC, even among those who have open fontanelles. Visual acuity is typically normal, though about 1=3 of the children able to com- plete optotype acuity testing will present with reduced acuity in their better eye. Decreased vision should be considered a sign both of chronicity and of high pressure and often signals irreparable visual loss. This may be from paresis of one or both lateral rectus muscles from abducens nerve damage, but may also occur without clinical evidence of an ocular motor neuropa- thy. Other ocular motor ﬁndings include trochlear nerve paresis, oculomotor nerve paresis, internuclear ophthalmo- plegia, and hypertropias, all of which produce diplopia or torticollis in an attempt to fuse a vertical misalignment. Neurological signs, other than the ocular motor abnormalities, are unusual, except for a facial nerve palsy, which has been reported in a number of series.
Thoroughly exploiting the information that was developed with each potential synthesis would be a crucial step purchase suhagra 100mg with amex. The time required for conformation searching is dramatically reduced discount 100 mg suhagra overnight delivery, if similar molecules have already been investigated discount suhagra 100 mg. For example buy generic suhagra 100mg line, PM-toxin has a very compli- cated potential energy surface order suhagra 100mg fast delivery, which may be searched directly by tradi- tional methods, or which may be mutated from the conformation search of an alkane, which is easier as it is particularly susceptible to a genetic algorithm based approach. It depends how difﬁcult syntheses are (and will provide a way of quantifying this). It may be that the best possible synthesis is not required, provided that a good route is available, as assessed by total cost (including waste disposal and safety pre- cautions), by time required, by certainty of success, by ease of using robots to follow the procedure, and so on. Brute force methods of calculating new synthetic routes will not be fea- sible for a very long time, and pure literature based methods will also be very time consuming, and will be restricted by the data available. An hybrid approach provides the best hope for designing a synthetic machine, and it is likely that such programs will become increasingly useful in the new millennium. Most of the elements of these programs are available now, but they are not sufﬁciently useful that they are an essential part of every chemist’s work. An exhaustive solution may not be possible, so it is World champion chemists 57 not certain that computers will beat people. However, the odds are stacked in favour of the computer, which will be able to develop and optimise many more routes than it is possible for synthetic chemists to consider directly. We will be taught the answer by the computers which extend the art beyond the heights reached by human scientists. Macquarrie Department of Chemistry, University of York, Heslington, York YO10 5DD, UK 4. The ability of chemists to produce a wide range of different molecules, both simple and staggeringly complex, is very well developed, and nowadays almost anything can be prepared, albeit maybe only on a small scale. On an industrial scale, a great variety of products are synthesised, using chemistry which varies from simple to complex. These products go into almost all the consumer goods we take for granted – colours and ﬁbres for clothes, sports equipment, polymers which go into plastics for e. Unfortunately, many of these processes generate a great deal of waste – often more waste is produced than product. One of the major challenges for chemistry in the opening years of the new millennium is therefore the development of new methods for the clean production of these chemicals. In the last few years a new, intrinsically more powerful approach has been pioneered. Green chemis- try, as it has been called, involves the redesign of chemistry, such that the desired products from a reaction are obtained without generating waste. This massive undertaking involves a wide range of approaches, from the 59 60 D. MACQUARRIE invention of new reactions to developing new catalysts (chemicals which are themselves not used up in the reaction, but which allow the reaction partners to be transformed more rapidly, using less energy, and often more selectively, generating fewer byproducts) which allow more selective reac- tion to take place, to biotransformations and novel engineering concepts, all of which can also be used to minimise waste. Catalysts can sometimes be developed which allow inherently clean reactions to be invented. A very important part of such an undertaking is to be clear about what stages of a chemical process generate the most waste. Often this is found to be the separation stage, after the transformation of reactants to products, where all the various components of the ﬁnal mixture are separated and puriﬁed. Approaches to chemical reactions which help to simplify this step are particularly powerful. This is an area of chemistry where the catalysts used are typ- ically solids, and the reactants are all in the liquid or gas phase. The catalyst can speed up the reaction, increase the selectivity of the reaction, and then be easily recovered by ﬁltration from the liquid, and reused. One of the newest areas in the realm of catalysis is that of tailored mesoporous materials, which are ﬁnding many uses as highly selective cat- alysts in a range of applications. A mesoporous material is one which has cavities and channels (pores) in the range of 2–5nm (a nanometre is 10 9m) – for comparison, a typical chemical bond is of the order of 0.
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