Katrina Cannon, MD

• Veterans Affairs Quality Scholar and Geriatric Fellow
• Center for Research in the Implementation of Innovative
• Strategies in Practice (CRIISP)
• Iowa City Veterans Affairs Medical Center and
• Division of General Internal Medicine
• Roy J. and Lucille A. Carver College of Medicine
• University of Iowa
• Iowa City, Iowa

Anaemia occurs in about 90% of adult cases 10 medications buy septra 480mg line, due to folate deficiency alone in 30 to 50% treatment plans for substance abuse cheap septra 480mg amex, and to mixed iron and folate deficiency in the remainder medicine in ukraine buy cheap septra 480mg on line. Mild vitamin B12 deficiency may also occur symptoms flu order septra line, but it is not a cause of anaemia in uncomplicated cases medicine 831 discount septra 480mg with mastercard. A gluten-free diet produces a spontaneous rise in serum and red cell folate in those patients who respond medicine 3x a day best buy for septra. In children with gluten-induced enteropathy, anaemia is most often due to combined iron and folate deficiency. Patients with dermatitis herpetiformis almost all show some degree of gluten-induced duodenal and jejunal abnormality; the severity of folate malabsorption and deficiency correlates with the severity of the intestinal lesion. Malabsorption of folate occurs in all severe, untreated patients in the acute phase and megaloblastic anaemia due to folate deficiency may develop within a few months. Not only does the anaemia respond to folate therapy but in many patients all the clinical features, and malabsorption of fat, vitamin B12, and other substances, improves on folate therapy alone. Long-standing cases are more likely to be vitamin B12 deficient and thus to require vitamin B12 as well as folate and antibiotic therapy. Congenital specific malabsorption of folate this is a rare, autosomal recessive abnormality. Affected children show features of damage to the central nervous system (mental retardation, fits, athetotic movements) and present with megaloblastic anaemia responding to physiological doses of folic acid given parenterally but not orally. In the intestinal stagnant-loop syndrome, folate levels tend to be high due to absorption of bacterially produced folate. Alcohol, anticonvulsants, oral contraceptives, antituberculous drugs, nitrofurantoin, and sulfasalazine have been suggested, on variable evidence, to cause malabsorption of folate in some subjects but none is definitely established except sulfasalazine. Increased folate utilization A general mechanism of increased folate utilization in conditions of increased cell turnover has emerged. Pregnancy This, associated with poor nutrition, is probably the most common cause of megaloblastic anaemia world-wide, unless folic acid Folate deficiency Clinical features the main clinical features of megaloblastic anaemia due to folate deficiency are similar to those seen when the anaemia is due to vitamin B12 deficiency, except that a neuropathy does not occur and the underlying aetiology tends to be different. Cognitive changes and depression may be caused by the deficiency, and neurological abnormalities do occur with inborn errors of folate metabolism and may be precipitated by antifolate drugs. Nutritional folate deficiency Minor degrees of nutritional folate deficiency are frequent in most countries. Potentially millions of people in northern China, Bangladesh, Burma, Malaysia, Africa, or India have low levels of folate due to a poor dietary intake and nutritional folate deficiency is the main cause of megaloblastic anaemia, often presenting in pregnancy. In many countries-for example, Caribbean islands, Sri Lanka, and South-East Asia-tropical sprue (see Chapter 15. Severe folate deficiency has been estimated to account for about 17% of all cases of megaloblastic anaemia in the United Kingdom, where it occurs mainly in the context of a poor diet and/or alcoholism. In some cases, barbiturates or consumption of spirits or cough mixtures or a physical abnormality such as rheumatoid arthritis, or tuberculosis may aggravate the effect of a poor diet. A few cases have developed because a special diet is taken, such as for phenylketonuria or for slimming. Malabsorption (Also see Diseases of the gastro-intestinal tract described in Section 15. Serum and red cell folate tend to fall as pregnancy progresses, and to rise spontaneously about 6 weeks after delivery. Lactation may prove an additional cause of folate deficiency, however, which may precipitate megaloblastic anaemia postpartum. Folate transfer to the fetus may play a minor part; in a few, megaloblastic anaemia of pregnancy is the first sign of gluteninduced enteropathy. The statistical association of iron and folate deficiencies in pregnancy is probably due to a poor quality of the diet in certain women. Prematurity Newborn infants have higher serum and red cell folate concentrations than adults. In premature infants, the decline is particularly steep and megaloblastic anaemia may develop, particularly if infections, feeding difficulties, or haemolytic disease with exchange transfusion have occurred. Malignant diseases Mild folate deficiency is frequent in patients with cancer (Table 22. In general, the severity correlates with the extent and degree of dissemination of the underlying disease. However, patients with megaloblastic anaemia due to folate deficiency are unusual and, supplementation tends to be avoided in the absence of a categorical indication for its use. Blood disorders Chronic haemolytic anaemia Requirements for folate are increased in patients with increased erythropoiesis, particularly when there is ineffective erythropoiesis with a high turnover of primitive cells. Occasional patients, presumably those with a poor folate intake, develop megaloblastic anaemia, particularly in sickle cell anaemia, thalassaemia major, hereditary spherocytosis, and warmtype autoimmune haemolytic anaemia; prophylactic folic acid is usually given in these disorders. Primary myelofibrosis Megaloblastic haematopoiesis has been reported in as many as one-third of patients. Circulating megaloblasts, increased transfusion requirements, severe thrombocytopenia, or pancytopenia may be the first indication that folate deficiency has developed. The degree of deficiency is related to the extent and severity of the underlying disorder. Increased demand for folate probably is a factor but reduced appetite is also important in those who develop megaloblastic anaemia. Metabolic Homocystinuria Patients with the most common form of this disorder, due to cystathionase deficiency, may show folate deficiency, possibly due to excess conversion of homocysteine to methionine and thus excess utilization of the folate coenzyme concerned (see Chapter 12. Trimethoprim, used as an antibacterial agent, may aggravate pre-existing folate or vitamin B12 deficiency but does not in itself cause megaloblastic anaemia. The main factor is poor nutrition and it is likely that alcohol interrupts the enterohepatic circulation for folate. It also has a direct effect on haematopoiesis, causing vacuolation of normoblasts, impaired iron utilization, sideroblastic changes, macrocytosis, megaloblastosis, and thrombocytopenia, even in the absence of folate deficiency. Beer drinkers usually avoid folate deficiency because of the high folate content of beer. The usual red cell macrocytosis in nonanaemic alcoholics is not related to folate deficiency. Anticonvulsants and barbiturates Diphenylhydantoin, primidone, and barbiturate therapy may be associated with folate deficiency. The more severe deficiency is associated with poor dietary intake of folate and prolonged drug therapy at high doses. The mechanism of the deficiency is unknown and double-blind trials have shown no effect of folic acid supplementation on the frequency of seizures. Other drugs Nitrofurantoin, triamterene, proguanil, and pentamidine have been reported to cause folate deficiency. Laboratory investigation of megaloblastic anaemia this consists of three stages: (1) recognition that megaloblastic anaemia is present; (2) distinction between vitamin B12 or folate deficiency (or rarely some other factor) as the cause of the anaemia; and (3) diagnosis of the underlying disease causing the deficiency (Table 22. Hypersegmented neutrophil, oval macrocytes, and a small lymphocyte to show size of macrocytes. The reticulocyte count is low for the degree of anaemia, usually of the order of 1 to 3%. General tests Peripheral blood film and count Bone marrow Serum bilirubin, iron, lactate dehydrogenase 2. Tests for cause of vitamin B12 or folate deficiency Serum vitamin B12 and folate; red cell folate Serum homocysteine and methylmalonic acid levels Vitamin B12 deficiency: Serum antibodies to parietal cell, intrinsic factor Serum gastrin Gastric secretion; intrinsic factor, acid Endoscopy, gastric biopsy Upper gastrointestinal endoscopy Proteinuria, fish tapeworm ova, intestinal flora, etc. Folate deficiency: Transglutaminase, endomysial antibodies Small-intestinal function Duodenal biopsy Barium follow-through Tests for many underlying conditions than 1. The direct antiglobulin test is weakly positive in some patients, due to complement. Bone marrow the bone marrow is hypercellular in moderate or severely anaemic cases. The erythroblasts are larger than normal and show asynchronous maturation of nucleus and cytoplasm, nuclear chromatin remaining primitive with an open, lacy, fine granular pattern despite normal maturation and haemoglobinization of the cytoplasm. Because of death (by apoptosis) of later cells, there is a disproportionate accumulation of early cells. Bone marrow aspirate showing megaloblasts at different stages and giant metamyelocytes. In patients with severe anaemia but only mild megaloblastic changes, some additional cause for the anaemia should be sought. Chromosomes Changes found in marrow and other proliferating cells include (1) random chromatin breaks; (2) exaggeration of centromere constriction; and (3) thin, elongated, uncoiled chromosomes. Ineffective haematopoiesis the increased cellularity of the marrow with degenerate forms, and the low reticulocyte count suggest that many developing cells are dying in the marrow. The raised unconjugated serum bilirubin, lactic dehydrogenase, and lysozyme are all due to ineffective haematopoiesis. Differential diagnosis Other causes of macrocytosis include a high reticulocytosis. If a bone marrow biopsy has been performed, the principal differentiation is from other causes of megaloblastosis, particularly myelodysplasia. Other causes of megaloblastic anaemia not due to vitamin B12 or folate deficiency are listed in Table 22. Some patients with rapidly developing megaloblastic anaemia, particularly due to folate deficiency, may develop almost complete aplasia of the red cell series, and the peripheral blood and bone marrow may resemble that of acute myeloid leukaemia. In the elderly, low serum vitamin B12 concentrations usually in the range 100 to 200ng/litre may occur in the absence of anaemia or macrocytosis. Raised haptocorrin also occur in association with some tumours, especially hepatoma and fibrolamellar tumour of the liver. In active liver diseases, vitamin B12 leaks from the liver with saturation of the serum vitamin B12 binders. Rare cases of congenital methylmalonic aciduria have been described, due to a variety of enzyme defects. Randomized trials are needed to assess the value of preventing or treating putative vitamin B12 deficiency in these subjects. Raised levels occur after folate therapy and also in vitamin B12 deficiency and in the stagnant-loop syndrome. Red cell folate is not now recommended for routine diagnostics but may be useful in some patients with probable folate deficiency in whom the serum folate is found to be normal. It is low in a proportion of patients with megaloblastic anaemia solely due to vitamin B12 deficiency. Serum homocysteine levels are usually raised in folate and vitamin B12 deficiency and many other situations. Diagnosis of vitamin B12 or folate deficiency the peripheral blood and bone marrow appearances are identical in folate or vitamin B12 deficiency. Vitamin B12 deficiency the assay of serum vitamin B12 content of serum is by competitive binding of intrinsic factor and immunochemiluminescencebased assays. The reference range, depending on the assay, is from 160 to 200 mg/litre to 960 to 1200ng/litre. It is difficult to determine a normal range and each laboratory should establish this independently. The concentrations are low in vitamin B12 deficiency, being extremely low in patients with neurological disease. Unfortunately, using competitive-binding assays, false-normal results have been reported in some patients with untreated pernicious anaemia and intrinsic factor antibodies in serum, which interfere with the test. A brief dietary history will rapidly establish whether or not the patient is a vegan or takes a very inadequate diet. Endoscopy and gastric biopsy will show features of gastric atrophy and help to exclude gastric carcinoma. Followthrough radiographic examination of the small intestine will help to exclude a small-intestinal lesion. Diagnosis of the cause of folate deficiency An inadequate diet is usually at least partly implicated, but an exact estimate of dietary intake from the clinical history is impossible because of variation in folate content of foods, losses in cooking, and size of portions. Many underlying inflammatory or malignant diseases may exaggerate the tendency to folate deficiency in patients with inadequate diets. The main cause of malabsorption of folate is gluteninduced enteropathy; in patients with severe folate deficiency, tests for transglutaminase and endomysial antibodies and a duodenal biopsy are usually necessary. In certain tropical countries, sprue may cause a generalized malabsorption syndrome in which folate deficiency commonly occurs. Prophylaxis Vitamin B12 therapy should be given from the time of operation after total gastrectomy or ileal resection. Routine endoscopy is not warranted but these diseases must be particularly borne in mind if relevant symptoms or signs develop. It is unclear whether vitamin B12 should be given orally or parenterally to those with biochemical (subclinical) vitamin B12 deficiency without anaemia or macrocytosis or clinical symptoms. Treatment of megaloblastic anaemia Therapy is aimed at correcting the anaemia, completely replenishing the body of whichever vitamin is deficient, treatment of the underlying disorder, and prevention of relapse.

Lateral view of the cerebral cortex and mfdAglttal view of the brain stem show the approximate location of structures involved in controlllng smooch pursuit eye mowments symptoms zoloft withdrawal order septra 480 mg on-line. The medial vestibular nudeua medicine jar cheap generic septra canada, with a lesser contribution from the mperior and inferior vestibular nuclei medications ranitidine order septra in united states online, gives rise to the medial vestibulospinal tract medications via g-tube septra 480 mg amex, for head and neck control medications 377 cheap septra 480mg otc. The vestibular nuclei also give rise to bilateral ascending projections to the thalamus treatment yeast infection women order 480 mg septra amex. This nucleus helps to coordinate eye and head movements, espedally vertical and torsional movements. This nucleus contains neurons that project axons to the spinal cord (termed the interstitiospinal tract), for axial muscle control. Paramedian and short circwnferential branches of the po6lterlor cerebral artery supply the ventral midbrain, and when these branches become occluded. Trocblear motor axons course caudally along the lateral margin of the cerebral aqueduct and fourth ventricle, in the perlaqueductal gray matter. Lesion of the trochlear nerve paralyzea the superior oblique muscle, resulting in slight outward rotation ofthe eye (or extortion) because of the unopposed action of the inferior oblique muscle. The eye elevates slightly because of the unopposed action of the superior rectu5 muscle. Myelin-stained section through the midbrain-diencephalic junction (A) and a semischematic view of the rostral mldbraln (8). Signals from the optic nerve are transmitted to neurons In the pretectal nudel at the level of the mldbraln-dlencephalon juncture. The pretectal nuder project bilaterally to parasympathetic pregangllonlc neurons In the Edlnger-westphal nucleus. The next connection In the circuit ls In the clllary g1nglla, where parasympathetic postgangllonlc neurons are located. The dalk green arrow is a reminder that somatic motor neurons are located in the oculomotor nucleus, which innervates the listed muscles. Second, the 3n:I nerve Is located between the superior cerebellar artery and posterior cerebral artery. An aneurlsm In either artery, especially the posterior cerebral artery, can press on the nerve and Impact Its function. The abducens nerve fibers course toward the ventral brain stem surface and exit the pons at the pontomedullary junction, medial to the facial nerve. Lesion of the abducens nerve paralyzes the ipsilateral lateral rectw muscle and results in the inability to abduct that eye. As described earlier, the abducens nucleus also contain internuclear neurons for horizontal eye muscle control Parasympathetic Neurons In the Mldbraln Regulate Pupil Size the Edinger-Westphal nucleus mediates two reflexes: pupil constriction in response to light and pupil constriction together with lens accommodation in response to near focusing. The pupillary light reflex is the constriction of the pupil that occurs when light hits the retina. The pretectal nuclei project bilaterally to the Edinger-Westphal nucleus, which contains parasympathetic preganglionic neurons; pretectal axons cross to the contralateral side in the posterior commissure. Axons from the Edinger-Westphal nucleus travel with the oculomotor fibers in their path to synapse in the clliary ganglion in the periphery. The bilateral projection of pretectal neurons to the parasympathetic preganglionic neurons in the Edinger-Westphal nucleus ensures that illumination of one eye causes constriction of the pupil on the ipsilateral side (direct response in the lighted eye) as well as on the contralateral side (consensual response). Pupillary reflexes are an important component of assessing brain stem function during clinical examination, including examination of the comatose patient. Pupillary dilation is mediated either by inhibition of the circuit for pupillary constriction or by the separate control of the iris by the sympathetic component of the autonomic nervous system (see Chapter 15). As a consequence of this organization, damage to exiting fibers of the third nerve, such as by occlusion of a branch of the posterior cerebral artery, will spare the dilator fibers. Such a lesion produces pupillary dilation because of the unopposed action of the pupillary dilator fibers of the sympathetic nervous system, which are spared by the lesion. Parasympathetic preganglionic neurons in the EdingerWestphal nucleus of the midbrain participate in a second visual reflex. This reflex is usually part of the accommodation-convergence reaction, a complex response that prepares the eyes for near vision by increasing lens curvature, constricting the pupils, and coordinating convergence of the eyes. These responses involve the integrated actions of the visual areas of the occipital lobe, along with motor neurons in the oculomotor nucleus that innervate the extraocular muscles and parasympathetic preganglionic neurons. Central nervous system pathology can distinguish different components of the visual reflexes. For example, in neurosyphilis the accommodation reaction is preserved but the light reflex is impaired. Patients with this condition have a classic neurological sign, the Argyll Robertson pupils: Their pupils are small and unreactive to light but get smaller when the patients accommodate to near focusing. The action of levator palpebrae superioris muscle, an eyelid elevator, is assisted by the tarsal muscle, a smooth muscle under sympathetic nervous system control. Conditions that impair the functions of the sympathetic nervous system (see Chapter 15) can produce a mild drooping of the eyelid (pseudoptosis) resulting from weakness of the tarsal muscle. True ptosis is produced by weakness of the levator palpebrae muscle, the principal eyelid elevator. This effect can result from third nerve lesions or neuromuscular diseases, such as myasthenia gravis, an autoimmune disease that attacks the neuromuscular junction. The unopposed action of the medial rectus muscle can sometimes cause the affected eye to be adducted at rest (not shown in the figure). As with the nerve lesion, the ipsilateral eye cannot be abducted because of destruction of the lateral rectus motor neurons. Here, too, the resting position of the eye may be adducted because of the unopposed action of the medial rectus muscle. The nuclear lesion has a second effect: the patient cannot contract the contralateral medial rectus muscle on horizontal gaze in the same direction as the side of the lesion. With this lesion, the axons of internuclear neurons from the contralateral abducens nucleus become damaged. This lesion produces a lateral gaze palsy when looking to the lesioned side and an internuclear ophthalmoplegia when looking to the other side (ie, the medial rectus does not adduct). The neural mechanisms that coordinate convergence involve the visual cortex and midbrain integrative centers, not the internuclear cells of the abducens nucleus. The Ventral Posterior Nucleus of the Thalamus Transmits Vestibular Information to the Parietal and Insular Cortical Areas the vestibular nuclei project bilaterally to the thalamus. Unlike the auditory and somatic sensory systems, there is no single tract through which the ascending vestibular projection travels. The red blocks Indicate sites of leslon, producing the eye movement defldts shown In 8. The four pairs ofeyes lllusuate eye position when an lndMdual Is asked to look to the right: (from top to bottom row) normal control of eyes, with a leslon of the right abducens nerve Oeslon 1), with a lesion of the right abducens nucleus (lesion 2), and with a left medlal longltudlnal fasclculus leslon (leslon 3. Coronal myelln-stalned section through the ventral posterior lateral nucleus, lateral posterior nucleus, and caudate nucleus. The rostral region of the nucleus, adjacent to the ventral lateral nucleus (for motor control; see Chapter 10), receives vestibular input and projects to area 3a of the somatic sensory cortex, to integrate proprioceptive vestibular information. There does not seem to be a single "primary" vestibular cortex, like some of the other sensory modalities. Rather, the vestibular cortical areas are interconnected to form a network that integrates vestibular inputs with joint proprioceptive information such as posture, orientation, and perception (eg, acceleration, vertigo). Many of these areas have descending projections to the vestibular nuclei, which, in tum, project to the spinal cord for controlling axial and proximal muscles. Vestibulospinal tract neurons terminate on motor neurons that innervate proximal limb and axial muscles as well as on interneurons that synapse on these motor neurons. Multiple Areas of the Cerebral Cortex Function in Eye Movement Control Eye movements are not controlled by the primary motor cortex but rather by multiple regions in the frontal and parietal lobes. Two nearby areas, the middle temporal and middle superior temporal, which are also part of the where pathway, transmit visual information for guiding pursuit movements. The superior and inferior rectus muscles elevate and depress the eyes, respectively, but particularly when the eye is abducted. Finally, the superior and inferior oblique muscles depress and elevate the eye, especially when the eye is adducted. The oculomotor nucleus innervates the media~ inferior, and superior rectus muscles; the inferior oblique muscle; and the levator palpebrae superioris muscle. Receptor cells, located in specialized regions of the vestibular apparatus, are innervated by the distal processes of bipolar neurons located in the vestibular ganglion. Thalamic connections of the vestibular cortical fields in the squirrel monkey (Saimiri sciureus). A direct projection from the medial vestibular nucleus to the cervical spinal dorsal horn of the rat, as demonstrated by anterograde and retrograde tracing. An autoradiographic study of the pathways from the pontine reticular formation involved in horizontal eye movements. Corticovestibular interactions: anatomy, electrophysiology, and functional considerations. Eyelid dysfunction in neurodegenerative, neurogenetic, and neurometabolic disease. Collateralization of brainstem pathways in the spinal ventral horn in rat as demonstrated with the retrograde fluorescent double-labeling technique. Anatomy and physiology of the primate interstitial nucleus ofCajal I: efferent projections. Primary vestibular afferent projections to the ipsilateral abducens nucleus in cats. Functional neuroanatomy of the human premotor oculomotor brainstem nuclei: insights from postmortem and advanced in viva imaging studies. Projections of the vestibular nuclei to the thalamus in the rat: a Phaseolus vulgaris leucoagglutinin study. Vestibular cortical area in the periarcuate cortex: its afferent and efferent projections. Movement of the two eyes during horizontal saccad:ic eye movements are coordinated by which of the following brain stem regions What pathway is important for transmitting vestibular information from the vestibular nuclei to the oculomotor nucleus The ascending vestibular pathway projects to the nucleus of the thalamus, where information is integrated with vestibular sensory messages for perception. Ocular depression is produced by contraction of which of the following extraocular muscles Which of the following best describes the position of the affected eye in this person His parents reported that recently he began to have difficulty standing still, is constantly shifting his position, and difficulty running. On examination, he was observed to have a wide-based gait with occasional shifting of position to maintain balance. He was referred to a child neurologist who noted upper extremity ataxia, dysdiadochokinesia, and intention tremor. When the child was asked to maintain a standing posture with his eyes closed, he began to sway and lose his balance (positive Romberg sign). After his lnltlal workup, he was seen regularly by his neurologist who noted a progression In his motor signs. Answer the following questions based on your reading of the case, this chapter, and readings In prior chapters. What Is a posltlve Romberg slgn and how Is this related to the loss of tendon reflexes Conclusion: After further workup and genetic testing, the child was diagnosed with Friedreich ataxia, a progressive spinocerebellar disease. In Friedreich ataxia there is a loss of lower extremity proprioception because of degeneration of large-diameter mechanoreceptive atrerents. Friedreich ataxia patients often have cardiomyopathy, and most patients die as a result of cardiac arrhythmia or congestive heart failure. Inhibitory Cln:uitry afthe Cerebellum Summary Selected Readings Referettces Key neurological signs and corresponding damaged brain structures Proprioceptive and reflex signs the cervical spinal cord in the patient is thin compared with that of the healthy person. Thinning is produced primarily by degeneration of the central branches of the large-diameter somatic sensory afferents in the dorsal columns. Otner arrow points to the base of the pons, which contillins pontine nuclei thitt project axons to the cerebellum. With this large-diameter fiber loss, there is associated loss of tendon reflexes and limb proprioception. To compensate for both the balance impairment and impaired lower extremity coordination, patients adopt a broad-based, slowed gait. Interestingly, Friedreich ataxia patients may not show extensive cerebellar degeneration for most of the course of the disease. In this way, it is similar to motor disturbances in neurosyphilis (see Clinical Case in Chapter 4). This absence of early cerebellar degeneration contrasts with other cerebellar conditions, such as olivopontocerebellar atrophy, which show extensive degeneration. The cerebellum is a fascinating brain structure; more so than I many because several of its properties and organizational principles are unexpeaed. That so much of the central nervous system is devoted to the cerebellum means that iu functions are particularly important or complex, requiring so much neural processing power; indeed, it is likely both. Iu microscopic laminar structure is nearly crystalline in its organization and the basic neural circuit is the same throughout the entire cerebellum.

Diagnosis the condition should be suspected in any patient with polycythaemia associated with a left-shifted oxygen dissociation curve 5 medications related to the lymphatic system septra 480 mg generic. Treatment In asymptomatic patients with high oxygen affinity haemoglobin variants no treatment is necessary treatment thesaurus 480mg septra overnight delivery. The difficulty arises if the patient has associated vascular disease with symptoms of coronary or cerebral artery insufficiency treatment 2 prostate cancer buy 480 mg septra with mastercard. These patients require a high haemoglobin level for oxygen transport; half their haemoglobin is physiologically useless medications derived from plants cheap septra 480 mg on line. Venesection is therefore not usually recommended for these patients medications to treat bipolar order 480 mg septra overnight delivery, though there is insufficient evidence to support categorical statements how these patients should be managed medications with codeine generic septra 480 mg without a prescription. Low oxygen affinity variants At least 60 haemoglobin variants with reduced oxygen affinity have been reported. The first to be described, haemoglobin Kansas, was found in a mother and son with unexplained cyanosis. The subjects were asymptomatic and had normal haemoglobin levels without any evidence of haemolysis. Like many of the high affinity variants, the amino acid substitution in this variant was at the interface between the and globin chains. This condition should be thought of in any patient with an unexplained congenital cyanosis; the differential diagnosis is considered later in this chapter. Haemoglobin variants which cause abnormal oxygen binding the first high-affinity haemoglobin identified was haemoglobin Chesapeake, detected as an abnormal haemoglobin band in a patient with otherwise unexplained polycythaemia. Since then, over 90 haemoglobin variants of this type have been defined, all associated with familial polycythaemia. Pathophysiology the high oxygen affinity variants have a left-shifted oxygen dissociation curve with a reduced P50, which may be detected using a standard blood gas analyser. This leads to tissue Methaemoglobinaemia, carboxyhaemoglobinaemia, and sulphaemoglobinaemia Methaemoglobinaemia is a condition characterized by increased quantities of haemoglobin in which the iron of haem is oxidized to the ferric (Fe3+) form. Carboxyhaemoglobinaemia (carbonmonoxyhaemoglobinaemia) results from the binding of carbon monoxide to the haem molecules. Sulphaemoglobinaemia is a rare condition in which there is a mixture of haemoglobin derivatives whose structure is poorly characterized but which can be defined by their specific spectral characteristics. Pathogenesis As mentioned earlier, each haemoglobin molecule has four haem moieties. At first sight it is not clear why the oxidation of a proportion of the iron atoms, or the fact that they are liganded to carbon monoxide, 22. However, oxidation of 30% of the haem molecules has a much more serious effect on tissue oxygenation than a reduction of the haemoglobin level by the same amount. This is because, if a single haem is oxidized, it so alters the conformation of the haemoglobin molecule that the oxygen affinity of the other three haems is increased. Thus methaemoglobin, carboxyhaemoglobin, and cyanmethaemoglobin all have very high oxygen affinities with left-shifted oxygen dissociation curves, and hence are associated with impaired unloading of oxygen to the tissues. It should be suspected in any patient with significant central cyanosis in whom there is no evidence of cardiorespiratory disease. The degree of cyanosis produced by 50 g/litre of deoxygenated haemoglobin can be produced by 15g/litre methaemoglobin and 5g/litre of sulphaemoglobin. It is useless as an oxygen carrier; levels above this are thus often associated with dyspnoea and headache. Many patients with lifelong methaemoglobinaemia are asymptomatic, while individuals who have accumulated a similar level of methaemoglobin acutely may be acutely dyspnoeic. For reasons that are not clear, it is unusual for patients with chronic methaemoglobinaemia to have an increased haemoglobin level or red cell count. Methaemoglobinaemia may arise as a result of a genetic defect in red cell metabolism or haemoglobin structure, or may be acquired following the ingestion of various oxidant drugs and toxic agents. Heterozygotes do not have elevated levels of methaemoglobin but seem to be unusually susceptible to the oxidant action of drugs. For example, severe cyanosis has been precipitated by the use of antimalarial drugs. There are several abnormal haemoglobin variants which are associated with genetic methaemoglobinaemia, all of which are designated haemoglobin M, and further identified by their place of discovery. These variants may affect either the or chain, but usually result from amino acid substitutions near the haem pocket. Normally, haem lies between two histidine residues, one called the proximal histidine to which it is attached, and the other called the distal histidine. If the latter is substituted by tyrosine, as occurs in the chain variant haemoglobin M Boston and in the chain variant M Saskatoon, a stable bond is formed between the haem iron and the phenolic ring of the tyrosine. In the case of the chain variants it is present from birth, while the chain haemoglobin variants only produce cyanosis after the first few months of life as adult haemoglobin synthesis becomes established. Thus the diagnosis of genetic methaemoglobinaemia and even the affected globin chain can be ascertained by a good clinical history. The diagnosis is confirmed by spectroscopic examination of the blood and by determination of methaemoglobin levels. On the other hand, the genetic methaemoglobinaemias due to structural haemoglobin variants do not respond to ascorbic acid, methylene blue, or any other treatment. Acquired methaemoglobinaemia Acquired methaemoglobinaemia usually results from the administration of drugs or exposure to chemicals which cause oxidation of haemoglobin. Nitrite, often used as a preservative, is one of the most common methaemoglobinforming agents. Nitrates, after conversion to nitrites in the gut, may cause serious methaemoglobinaemia in infants. Other agents which commonly cause methaemoglobinaemia include phenacetin, primaquine, sulfonamides, and various analine dye derivatives. If any of the agents listed previously is given in low dose over a long period of time it may lead to chronic methaemoglobinaemia with or without a haemolytic anaemia. However, after exposure to a large amount of these agents, and the development of in excess of 50 to 60% methaemoglobin, the symptoms of acute anaemia develop because methaemoglobin lacks the capacity to transport oxygen. Thus the clinical picture may be characterized by vascular collapse, coma, and death. Methaemoglobinaemia with haemolytic anaemia the haemolytic action of oxidant drugs is described elsewhere (see also Chapter 22. Chronic methaemoglobinaemia with haemolytic anaemia, characterized by Heinz body formation and fragmented red cells, occurs commonly in patients receiving dapsone, salazopyrine, or phenacetin. This condition is usually innocuous and can be modified by adjusting the dose of the drug. Occasionally, acute intravascular haemolysis associated with methaemoglobinaemia and disseminated intravascular coagulation occurs. It usually follows the ingestion or infusion of a strong oxidizing agent such as chlorate or arsine. There is gross intravascular haemolysis and methaemoglobinaemia together with evidence of disseminated intravascular coagulation. The haemoglobin level may fall very rapidly and may be complicated by renal failure. Methylene blue should be administered in a dose of 1 to 2mg/kg intravenously over a 5-min period. Toxicity is uncommon, although doses of over 15mg/kg may cause haemolysis in young infants. The drug should not be used if the methaemoglobinaemia is due to chlorate poisoning, as it may convert the chlorate to hypochlorite which is an even more toxic compound. In cases of acute methaemoglobinaemia with intravascular haemolysis, haemodialysis with exchange transfusion is the treatment of choice. The molecular basis of alpha-thalassaemia: a model for understanding human molecular genetics. Carboxyhaemoglobinaemia Carbon monoxide has an affinity for haemoglobin approximately 210 times that of oxygen. Following acute exposure, it is so tightly bound that it takes about 4h for an individual with normal ventilation to expel half of it. At levels of 5 to 10% there may be no symptoms, but above 20% there is usually headache and weakness. Sulphaemoglobinaemia this poorly defined condition derives its name from the fact that it can be produced in vitro by the action of hydrogen sulphide on haemoglobin. It is usually associated with the administration of drugs, particularly sulfonamides or phenacetin. It has also been reported in patients with chronic constipation or malabsorption syndromes (enterogenous cyanosis) although its relationship to these disorders is far from clear. Other acquired abnormalities of the structure or synthesis of haemoglobin Glycosylated haemoglobin, haemoglobin A1c Haemoglobin may undergo post-translational modification in patients with diabetes. The abnormal haemoglobin, haemoglobin A1c, is formed by the nonenzymic combination of glucose with the N-terminus of the chain, first forming a Schiff base which then undergoes a rearrangement to form a stable ketoamine. The level of haemoglobin A1c is raised in diabetics and is related to the blood sugar level over the previous weeks. The value of the estimation of haemoglobin A1c as an index of the control of diabetes is considered elsewhere. Fetal haemoglobin production in adult life A number of haematological disorders are associated with a reversion to fetal haemoglobin production after the neonatal period. These include juvenile myelomonocytic leukaemia and congenital hypoplastic anaemias. Diagnosis is confirmed by finding ring sideroblasts (erythroblasts containing five or more iron-positive granules arranged in a perinuclear location around one-third or more of the nucleus) on a bone marrow aspirate stained with Prussian blue iron reagent. Aside from supportive care with blood transfusion and iron chelation, a trial of pyridoxine is generally indicated (25% of hereditary cases- but few acquired cases- show some response). Sideroblastic anaemias Introduction Erythroid cell maturation is specialized towards the coordinated synthesis of large amounts of haem and globin necessary to attain the high concentration of haemoglobin found in the mature red cell. Hereditary or acquired defects in the production of either of these cause a maturation block, which leads to ineffective erythropoiesis in which many of the developing nucleated erythroblasts are destroyed in the marrow before they can reach the circulation. Thus in thalassaemia, defective synthesis of either - or -globin leads to unbalanced production of the other chain, which precipitates and leads to destruction of the precursor erythroblast. Defective haem synthesis in the sideroblastic anaemias also leads to an anaemia which is characterized by ineffective erythropoiesis (Box 22. Ineffective erythropoiesis may be recognized by the characteristic erythroid hyperplasia of the bone marrow with normal or only slightly increased reticulocyte numbers. Some other features of ineffective erythropoiesis may be variably present: a mild increase in bilirubin, a decrease in haptoglobin, and increased serum lactic dehydrogenase activity. As a result, iron absorption is increased, serum iron and ferritin become elevated, and, after many years, iron overload develops which is indistinguishable from idiopathic haemochromatosis. The sideroblastic anaemias are a group of hereditary or acquired anaemias of varying severity diagnosed by the finding of ring sideroblasts in the bone marrow aspirate. Normochromic and normocytic red cells are also present which gives the film a dimorphic distribution of red cell sizes. The diagnostic procedure is bone marrow aspirate followed by staining of the smear with Prussian blue iron reagent. A number of drugs have been associated with reversible sideroblastic anaemia, chiefly in patients with alcohol abuse (Box 22. In humans, mutations affecting the first enzyme of this pathway produce hereditary sideroblastic anaemia. These hereditary sideroblastic anaemias consist of two nonsyndromic forms, which have a similar phenotype to X-linked sideroblastic anaemia and five rare syndromic forms where haem synthesis is affected in nonhaematopoietic tissues in addition to red cells (Box 22. Clinical and laboratory features Typically the anaemia presents in infancy or childhood, but when the condition is mild the diagnosis may not be made until adult life. Occasionally, such patients may present with features of iron overload such as diabetes or cardiac failure. Others may be found in family surveys, which should be undertaken when this anaemia is diagnosed. The blood film shows a population of cells with hypochromic, microcytic morphology. In X-linked sideroblastic anaemia, female carriers may show the characteristic red cell dimorphism. White cell counts are normal, while platelet counts are normal or slightly elevated. Serum iron and ferritin concentrations are invariably increased and transferrin shows an increased percentage saturation with iron. The differential diagnosis includes idiopathic haemochromatosis, since both diseases have evidence of iron overload. Electron microscopy reveals that the iron-containing granules are mitochondria containing precipitated ferric phosphate and ferric hydroxide. Most sideroblastic anaemias are acquired as a clonal disorder of erythropoiesis, classified as a subtype of myelodysplasia. Four molecules of this are converted by porphobilinogen deaminase to a linear tetrapyrrole, hydroxymethylbilane. The defective steps associated with specific porphyrias and X-linked hereditary sideroblastic anaemias are shown. The syndromic forms of hereditary sideroblastic anaemia present with anaemia in combination with either muscle, neurological, or pancreatic tissue involvement (Box 22. Treatment and prognosis A trial of pyridoxine, 100 to 200mg/day taken orally, is indicated for 3 months in all patients with proven or suspected hereditary sideroblastic anaemia. This vitamin should be continued lifelong in responders but at a lower maintenance dosage.

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During these periods medications quetiapine fumarate generic septra 480mg without a prescription, patients remain at high risk: prompt access to blood product support and robust procedures to prevent and manage neutropenic infections are vital treatment 3 degree heart block cheap septra 480 mg free shipping. Blood product support By the time of initial disease presentation symptoms stiff neck buy discount septra 480mg, the ability of most patients to produce red cells and platelets is severely impaired medications qid order septra pills in toronto. Due to the often rapid onset of anaemia treatment of hemorrhoids purchase septra 480 mg on-line, there may be little time for haemodynamic compensation making many patients symptomatic due to acute impairment of oxygen-carrying capacity treatment quotes and sayings buy generic septra on-line. Following intensive chemotherapy, patients will inevitably be dependent on regular transfusion support until bone marrow recovery. Patients treated with cytotoxic regimens containing purine analogues (fludarabine or clofarabine) should receive irradiated blood products to minimize the risk of transfusion-associated graftversus-host disease. Antifibrinolytic agents such as tranexamic acid may be useful for local mucosal bleeding but are contraindicated in the presence of haematuria due to the potential for ureteric clot formation. Changes to the bacterial flora as a consequence of broad-spectrum antibiotic use, and poor nutritional status following prolonged periods of hospitalization also contribute significantly. Sepsis should be suspected in the presence of any sudden nonspecific clinical deterioration; inflammatory responses may be muted in the neutropenic setting and may be associated with hypothermia, declining mental status, myalgia, or increasing lethargy. Potential portals of bacterial entry include indwelling lines and chemotherapy-induced breaches in the integrity of the bowel mucosa. Neutropenic patients should be advised to pay particular attention to personal hygiene and dental care. Careful hand-washing and decontamination before patient contact is mandatory for healthcare workers. Data from studies of adults with leukaemia, and stem cell transplantation, suggest that prophylaxis with fluoroquinolone antibiotics reduces the risk of neutropenic sepsis and this approach is recommended in National Institute for Health and Care Excellence guidance but with the corollary that rates of antibiotic resistance and infection patterns within individual institutions should be monitored. Patients should be made aware of their susceptibility to infection and provided with emergency contact details to allow rapid clinical assessment. In the presence of neutropenic sepsis, the prompt institution of broad-spectrum antibacterial therapy is potentially life-saving. Patterns of infection and pathogen isolation will vary between hospitals, and clear written guidelines for the emergency management of patients with febrile neutropenia should be decided in discussion with local microbiologists. Examples of empirical antibiotic regimens include monotherapy with a third-generation cephalosporin or carbapenem, or combination therapy with a broad-spectrum antipseudomonal penicillin and aminoglycoside. Vancomycin or teicoplanin may be added to broaden Grampositive coverage if there are particular clinical concerns regarding indwelling line infection. Mandatory investigations include central and peripheral blood cultures, cultures of urine and stool, and a chest radiograph. Further modifications to the initial antibiotic regimen should be based on culture results and regular clinical examination, although surveys demonstrate that the rate of proven bacteraemia during episodes of febrile neutropenia has remained between 20 and 25% for many years. Persistent infection or blood culture isolation of Gram-negative organisms or candida should prompt indwelling central line removal. The diagnosis of invasive fungal infection should be confirmed wherever possible, and there is an increasing move away from the empirical use of antifungal agents as treatment of fever of unknown origin. Posaconazole is the drug of choice in this setting and has activity against a broader spectrum of fungal organisms than fluconazole which is inactive against moulds including aspergillus species. Large controlled trials show variable effects on the incidence of severe infection and no clear overall survival benefit. The diagnosis is made on morphology with a typical hypercellular marrow with characteristic heavily granulated promyelocytes. However, treatment is associated with an increased risk of bleeding in these patients, particularly in the first 3 or 4 weeks of treatment, and intense support of the coagulation system is required with blood products. Restarting treatment at the time of molecular detection of disease recurrence improves overall outcome. Minimal/measurable residual disease measurement Techniques for sensitive measurement of residual disease beyond the sensitivity of the microscope or cytogenetics are developing in haematological cancer and in some circumstances are approved as a surrogate endpoint for testing new treatments. Aberrant phenotypes can also be defined at diagnosis by immunophenotyping using several antibodies. This is demanding technology requiring a high level of standardization, but it is applicable to most patients depending how many antibodies are in the panel. There is little doubt that tests on marrow which is clearly in morphological remission will detect residual disease at a level of 1 cell per 1000. This is usually a reliable predictor of imminent relapse thus enabling pre-emptive treatment to be given. While this approach is attractive for individualizing patient choices, at present it may not be ready for routine practice. It is prognostic, probably adding additional information to what is already known to enable refinement of current treatments, but the predictive value will require prospective confirmation. The platelet count and coagulation profile should be checked at least twice daily during the early stages of treatment. Cryoprecipitate or fibrinogen concentrates should be used to maintain a fibrinogen level close to 2g/litre. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Standard treatment on first suspicion of retinoic acid syndrome is dexamethasone 22. The resulting oncoprotein is a constitutively active tyrosine kinase and appears to operate as an initiator for the development of the leukaemia. Though the disease was first described in 1845 and characterized by the 1920s, it was a further 60 years before the unravelling of initiating molecular events paved the way to define specific targets for treatment. Clinical features, diagnosis, and (historical) prognosis Clinical features-many patients are asymptomatic at diagnosis, which is made following a routine blood test. Others present with signs and symptoms including fatigue, sweats, fever, weight loss, haemorrhagic manifestations, and abdominal discomfort (due to splenomegaly). Diagnosis-this is typically made by the examination of a peripheral blood film (revealing features including increased numbers of neutrophils, eosinophils, basophils, immature myeloid cells, and, in some cases, platelets) and the demonstration of the Ph chromosome by conventional cytogenetics in a bone marrow aspirate or peripheral blood sample. It induces durable complete cytogenetic responses in the majority of patients and prolongs overall survival substantially. Imatinib, however, does not totally eradicate the leukaemia in most cases and therapy is usually lifelong. These studies are currently being extended worldwide with results eagerly awaited. In the Western world, the median age of onset is 50 to 60 years, and there is a slight male excess. In contrast, the median age of onset may be considerably younger in some other countries, such as India. It was usually diagnosed in the chronic phase, which typically lasted 3 to 6 years; the leukaemia then spontaneously progressed to blast transformation. About 70 to 80% of patients had a myeloid blast transformation, and they usually survived 2 to 6 months; the 20 to 30% of patients with a lymphoid blast transformation had a slightly better survival. About half the patients in the chronic phase transformed directly into blast transformation, and the remainder did so following a period of accelerated phase. Patients presenting in the late chronic phase appear to fare less well, and those in the advanced phases, particularly the blast phase, generally do poorly, including those who did initially respond to imatinib. Most patients will have leucocytosis due to increased numbers of myeloid cells at all stages of maturation; basophilia is almost universal, and some patients have an eosinophilia (Box 22. The anaemia tends to be mild and normochromic normocytic in nature; some patients have Box 22. These findings have not yet been analysed in large clinical studies, however, so it is not clear if they are independent criteria for accelerated phase. A further 5% of patients have variant translocations in which chromosomes 9, 22, and other additional chromosomes are involved. The break in the major breakpoint cluster region (M-bcr) occurs in the intron between exon e13 and e14 or in the intron between exon e14 and e15 (toward the telomere). Occasionally patients may present with extramedullary disease, such as a chloroma. Classical clinical features include sweats, weight loss, haemorrhagic manifestations, such as spontaneous bruising and retinal haemorrhages, abdominal discomfort due to splenomegaly, fatigue (often but not always related to anaemia), and fever (Box 22. The diagnosis is typically made by the examination of a peripheral blood film and the demonstration of the Ph chromosome by conventional cytogenetics on a bone marrow aspirate sample. Most haematologists also carry out a bone marrow trephine examination; this is often hypercellular with complete or near complete loss of fat spaces and a high myeloid to erythroid ratio. A third breakpoint location is found in patients with the very rare Ph-positive chronic neutrophilic leukaemia. A variety of such substrates, which can be tyrosine phosphorylated, have now been identified. Much remains to be learned about the significance of tyrosine phosphatases in the transformation process. Even longer-term follow-up with assessment of side effects is needed to address the issue of preferred first-line therapy. Such studies also suggest better Prognostic factors Various efforts have been made to establish criteria definable at diagnosis, both prognostic (disease related) and predictive (treatment related), that may help to predict survival for individual patients. The Euro or Hasford system is an updated Sokal index, which includes consideration of basophil and eosinophil numbers. Stratifying patients into good-, intermediate-, and poor-risk categories may assist in the decision-making process regarding appropriate treatment options. Recent observations, however, suggest that age per se might not influence the biology of the disease, but rather increases the probability of treatment-related adverse effects by virtue of potential comorbid conditions. The safety analysis of imatinib is also quite impressive, with very few potentially serious long-term side effects. When imatinib is used at the standard starting dose of 400mg/day, side effects include nausea, headache, various skin reactions, infraorbital oedema, bone pains, and sometimes, generalized fluid retention. Significant cytopenias and hepatotoxicity occur less commonly and usually in the first 6 to 12 months of therapy. One study assessing outcomes in 125 of 180 study patients exposed to the agent during pregnancy concluded that about half of the offspring born were normal; 28% of the study cohort elected to undergo termination of pregnancy, including three after identification of fetal abnormalities. In total, there were 12 infants in whom abnormalities were identified, including three who had strikingly similar complex malformations. However, there appear to be no risks of fetal malformations of children from men taking imatinib at the time of conception. Dasatinib and nilotinib received regulatory approval for first-line therapy following the initial results in 2010. Overall, the results reported suggest that frontline therapy with dasatinib, nilotinib (at either dose) or bosutinib, renders higher response rates with a comparable toxicity profile compared to imatinib with up to 60 months of follow-up. It remains unknown whether these higher rates of early response will translate into improved event-free and/or overall survival. Thus far, no statistically significant differences in survival have been observed. The challenge of how long to continue imatinib in optimally responding patients remains unresolved at present. Interestingly, the majority of relapses in both studies occurred within the first 6 months of stopping imatinib. The best initial treatment for children is still uncertain, though most paediatric haematologists would now advocate the use of imatinib in the first instance. In addition to the expected side effects also encountered in adults, imatinib can cause significant growth retardation in children. Primary resistance or refractoriness to the drug appears to be very rare and when seen may be related to poor drug compliance, poor gastrointestinal absorption, cytochrome P450 polymorphisms, interactions with other medications, and abnormal drug efflux and influx at the cellular level. A somewhat larger proportion of patients, about 20% in the chronic phase, respond initially to imatinib and then lose their response. Such point mutations code for amino acid substitutions that may impede binding of imatinib but do not impair phosphorylation of downstream substrates that mediate the leukaemia signal. The precise position of the mutation appears to dictate the degree of resistance to imatinib; some mutations are associated with minor degrees of drug resistance, whereas one notorious mutation, the replacement of threonine by isoleucine at position 315 (T315I), is associated with near-total unresponsiveness to imatinib, dasatinib, nilotinib, and bosutinib. Currently, ponatinib should be reserved for third-line therapy or those with a demonstrable T315I mutation in which case it should be considered for any line of therapy. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. Preclinical studies showed that dasatinib is 300-fold more potent than imatinib and is active against 18 of 19 tested imatinib-resistant kinase domain mutant subclones, with the notable exception of the T315I 22. Nonhaematological toxicities include diarrhoea, headaches, superficial oedema, pleural effusions, occasional pericardial effusions, and pulmonary arterial hypertension (rare, c. Grade 3/4 side effects are rare, and grade 3/4 pleural effusions occur in less than 10% of patients. In vitro studies suggest that nilotinib is about 30- to 50-fold more potent than imatinib. The most common treatment-related toxicity is myelosuppression, followed by headaches, pruritus, and rashes.