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Toxic effects were graded according to the National Cancer Institute Common Toxicity Criteria antibiotic resistance nursing implications order sumycin 250 mg otc, version 2 antibiotic 4 uti discount sumycin 250mg free shipping. The trial was supported by an unrestricted educational grant from Schering-Plough antimicrobial liquid soap cheap sumycin 250mg online, which also provided the study drug; however antibiotics for pustular acne order 250 mg sumycin mastercard, Schering-Plough was not involved in trial design or analysis infection process cheap sumycin 500mg online. Janzer in Lausanne zinc vs antibiotics for acne buy 250 mg sumycin with mastercard, Switzerland [chair]; Peter Wesseling in Nijmegen, the Netherlands; and Karima Mohktari in Paris) and a single neuropathologist in Canada (Samuel Ludwin, Kingston, Ont. Stupp with support from a medical writer and coauthors; all authors reviewed the manuscript. Radiotherapy (N=286) Radiotherapy plus Temozolomide (N=287) results patients Characteristic Age - yr Median Range Age - no. The characteristics of the patients in the two groups were well balanced at baseline (Table 1). Slightly more patients in the radiotherapy group than in the radiotherapy-plus-temozolomide group were receiving corticosteroids at the time of randomization (75 percent vs. A performance status of 0 denotes asymptomatic, 1 symptomatic and fully ambulatory, and 2 symptomatic and in bed less than 50 percent of the day. Unplanned interruptions in radiotherapy were usually brief (median, four days) and interruptions due to the toxicity of therapy occurred in only 3 percent of the radiotherapy group and 4 percent of the radiotherapy-plus-temozolomide group. One patient randomly assigned to radiotherapy alone received radiotherapy plus temozolomide. Among the 287 patients who were assigned to receive concomitant radiotherapy plus temozolomide, 85 percent completed both radiotherapy and temozolomide as planned. Thirty-seven patients (13 percent) prematurely discontinued temozolomide because of toxic effects (in 14 patients), disease progression (in 11), or other reasons (in 12). After radiotherapy, 223 patients in the radiotherapy-plus-temozolomide group (78 percent) started adjuvant temozolomide and received a median of 3 cycles (range, 0 to 7); 47 percent of patients completed 6 cycles. The new england journal of medicine beginning or not completing adjuvant temozolomide therapy was disease progression. Only 8 percent of patients discontinued adjuvant temozolomide because of toxic effects. Beginning with cycle 2, the dose of temozolomide was increased to 200 mg per square meter in 67 percent of patients. Only 9 percent of patients did not receive the higher dose because of hematologic toxicity. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group as compared with the radiotherapy group was 0. These data indicate a 37 percent relative reduction in the risk of death for patients treated with radiotherapy plus temozolomide, as compared with those who received radiotherapy alone. The two-year survival rate was 100 Probability of Overall Survival (%) 90 80 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 Radiotherapy plus temozolomide 26. The hazard ratio for death was adjusted by fitting the Cox proportional-hazard models. The adjusted hazard ratio for death in the radiotherapy-plus-temozolomide group as compared with the radiotherapy group - 0. Radiotherapy plus temozolomide was associated with a significant improvement in median overall survival in nearly all subgroups of patients (see. The hazard ratio for death among patients treated with radiotherapy plus temozolomide, as compared with those who received radiotherapy alone, was 0. We analyzed adverse events separately during radiotherapy (with or without concomitant temozolomide), the adjuvant-therapy period, and the entire study period (from study entry until disease progression or last follow-up). No grade 3 or 4 hematologic toxic effects were observed in the radiotherapy group. During concomitant temozolomide therapy, grade 3 or 4 neutropenia was documented in 12 patients (4 percent), and grade 3 or 4 thrombocytopenia occurred in 9 patients (3 percent) (Table 4). Overall, 19 patients (7 percent) had any type of grade 3 or 4 hematologic toxic effect. During adjuvant temozolomide therapy, 14 percent of patients 992 n engl j med 352;10 During the radiotherapy period, severe infections occurred in 6 patients in the radiotherapy group (2 percent) and in 9 patients in the radiotherapy-plus-temozolomide group (3 percent); during adjuvant temozolomide therapy, 12 patients (5 percent) had severe infections. The most common nonhematologic adverse event during radiotherapy was moderate-to-severe fatigue in 26 percent of patients in the radiotherapy group and 33 percent in the radiotherapy-plus-temozolomide group (Table 2 in the Supplementary Appendix). Thromboembolic events occurred in 28 patients (5 percent) - 16 in the radiotherapy group and 12 in the radiotherapyplus-temozolomide group. Two patients in the radiotherapy-plus-temozolomide group died of cerebral hemorrhage in the absence of a coagulation disorder or thrombocytopenia. Pneumonia was reported in five patients in the radiotherapy group and three in the radiotherapy-plus-temozolomide group. Opportunistic infections occurred in two patients; one patient treated with radiotherapy alone had suspected P. The outcome for patients treated with radiotherapy alone in our trial compares favorably with the outcome in other trials. At the cutoff date (May 10, 2004), 512 patients - 268 in the radiotherapy group (94 percent) and 244 in the radiotherapyplus-temozolomide group (85 percent) - had disease progression. At the time of progression, 23 percent of patients in both treatment groups underwent a second surgery, and 72 percent of patients in the radiotherapy group and 58 percent in the radiotherapy-plus-temozolomide group received chemotherapy. Salvage chemotherapy consisted of temozolomide in 60 percent of patients in the radiotherapy group and 25 percent of patients in the radiotherapy-plus-temozolomide group. The new england journal of medicine 100 Probability of Progression-free Survival (%) 90 80 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 Radiotherapy plus temozolomide Radiotherapy Months No. The hazard ratio for death or disease progression among patients treated with radiotherapy plus temozolomide, as compared with those treated with radiotherapy alone, was 0. Concomitant Temozolomide Therapy (N=284) Adjuvant Temozolomide Therapy (N=223) Entire Study Period* (N=284) Toxic Effect number of patients (percent) Leukopenia Neutropenia Thrombocytopenia Anemia Any 7 (2) 12 (4) 9 (3) 1 (<1) 19 (7) 11 (5) 9 (4) 24 (11) 2 (1) 32 (14) 20 (7) 21 (7) 33 (12) 4 (1) 46 (16) * the entire study period was defined as the period from study entry to seven days after disease progression. The relatively long survival after disease progression (approximately seven months in both groups) is also noteworthy. This extended survival may reflect either patient selection or the early detection of tumor progression by means of regular radiographic assessment. Furthermore, 72 percent of patients in the radiotherapy group and 58 percent of patients in the radiotherapy-plus-temozolomide group received salvage chemotherapy at the time of progression. This trial was designed to determine whether the addition of temozolomide to radiotherapy early in the course of treatment prolongs survival among patients with glioblastoma, but it was not designed to distinguish between the effects of concomitant therapy with radiotherapy plus temozolomide and adjuvant treatment with temozolomide. At the time the trial was conceived, it was deemed most important to administer chemotherapy early in the course of the disease, for a sufficiently long time, and concurrently with radiotherapy. Temozolomide was given concomitantly with radiotherapy on a continuous schedule for several reasons. First, daily administration of low doses makes possible an increase by almost a factor of two in dose intensity, as compared with the standard regimen, without an increase in toxicity. In the context of palliative care, chemotherapyinduced toxic effects should be manageable. Severe myelosuppression was observed in 16 percent of patients, leading to the early discontinuation of chemotherapy in 5 percent. Whether the addition of chemotherapy increases the risk of radiotherapyinduced cognitive deficits cannot be assessed at this time. However, long-term monitoring and observational studies of late toxic effects will be important to guide treatment recommendations in the future. Furthermore, prolonged chemotherapy with alkylating agents has been associated with myelodysplastic syndromes and secondary leukemia occurring years after therapy. The contents of this article are solely the responsibility of the authors and do not necessarily represent the terms of survival. In conclusion, the addition of temozolomide to views of the National Cancer Institute. Stupp, Mason, van den Bent, Brandes, Cairncross, and Miriradiotherapy early in the course of glioblastoma pro- manoff report having received consulting and lecture fees from vides a statistically significant and clinically mean- Schering-Plough; Dr. Eisenhauer consulting fees from Scheringremains to improve clinical outcomes further. Bogdahn lecture fees from Scheringthis reason, the regimen of radiotherapy plus tem- Plough. Wurm); Centre Hospitalier Rйgional de BesanзonHopital Jean Minjoz, Besanзon, France (M. Kobierska); Centre Hospitalier Rйgional de GrenobleLa Tronche, Grenoble, France (M. Kortmann); Universitair Medisch CentrumAcademisch Ziekenhuis, Utrecht, the Netherlands (M. Wong); British Columbia Cancer AgencyCancer Centre of the Southern Interior, Kelowna, B. Whitlock); Hфpital Notre-Dame du Centre Hospitalier Universitaire de Montreal, Montreal (K. Thiessen); British Columbia Cancer AgencyVancouver Island Cancer Centre, Victoria, B. Baumert) - all in Switzerland; Tasmanian Radiation Oncology Group: Peter MacCallum Cancer Institute, Melbourne, Australia (G. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas: a joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma: Brain Tumor Cooperative Group trial 8001. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. Chemotherapy in adult highgrade glioma: a systematic review and metaanalysis of individual patient data from 12 randomised trials. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Current and future developments in the use of temozolomide for the treatment of brain tumours. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. Survival of human glioma cells treated with various combination of temozolomide and X-rays. Prevention of irradiation-induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Left unrepaired, chemotherapy-induced lesions, especially O6-methylguanine, trigger cytotoxicity and apoptosis. All patients provided written informed consent for molecular studies of their tumor, and the protocol was approved by the ethics committee at each center. Unmethylated cytosine, but not its methylated counterpart, is modified into uracil by the treatment. The investigators who selected and analyzed the glioblastoma samples were blinded to all clinical information. All treatment comparisons are presented on an intention-to-treat basis according to the randomized assignment. Hegi ceived the alkylating agent temozolomide (Temodal designed and supervised the translational study or Temodar, Schering-Plough) at a dose of 75 mg and wrote the manuscript, with input from the coper square meter of body-surface area daily during authors. Treatment assignments among the 307 patients with evaluable tumor specimens was equally distributed, with 152 patients (49. Overall survival did not vary significantly according to whether or not the test was attempted (P=0. The proportion of methylated tumors was similar in the two treatment groups (Table 1). Glioblastoma numbers 549 and 527 contain a methylated promoter, whereas 555, 569, and 529 harbor only an unmethylated promoter. KaplanMeier estimates of overall survival in these two subgroups were significantly different (P=0. However, this result was not unexpected, since neither the clinical trial nor this study was powered to test the interaction. In addition, a probable confounding factor in the analysis of overall survival was the administration of temozolomide or other alkylating chemotherapy as salvage or second-line treatment after disease progression. More than 70 percent of the patients in the radiotherapy group received salvage chemotherapy; 59. Kaplan Meier curves are also shown for progression-free survival (Panel B) in a similar manner. Hegi and Stupp); by Award 2002 from the Jacqueline Seroussi Memorial Foundation for Cancer Research (to Dr. Hegi) from the Swiss National Science Foundation; and by a grant (1123/1124-2-2001, to Dr.
Hospital audits and linkage of cases to vital records or to specialized diagnostic centres can help evaluate the completeness of case ascertainment antibiotic 7 days to die sumycin 500mg generic. Approaches to help ensure data accuracy include: re-abstraction of information antibiotics rash discount 500 mg sumycin overnight delivery, validity audits antimicrobial over the counter buy sumycin 500mg with amex. Timeliness refers to the extent to which data are collected and analysed in a timely manner herbal antibiotics for dogs order 500mg sumycin free shipping. It is measured by time that elapses between the date of diagnosis and date of abstraction; the date of abstraction and the date information is sent to the office; and the date of arrival in the office to the date entered in the system antibiotics and yogurt cheap 250mg sumycin free shipping. Protocols usually include reviews of the information in the data sources bacteria 1710 generic sumycin 250 mg on line, to verify that data are being recorded in a standardized way. Also, if feasible, having a process whereby a sample of the medical records can be reviewed will ensure that information in the abstraction forms reflects the information on the medical record. Poor-quality data can lead to erroneous conclusions about the occurrence of a congenital anomaly among a population and could have a substantial effect on the decision-making process of public health authorities. Data analysis and interpretation Prevalence In surveillance of congenital anomalies, the word "incidence" is not commonly used to describe the occurrence of congenital anomalies. Because spontaneous abortions cannot be counted accurately, the suggested measure of occurrence of congenital anomalies is "live birth prevalence", "birth prevalence" or "total prevalence". In a population-based surveillance programme, the prevalence of congenital anomalies is calculated by aggregating the number of unduplicated existing cases. For hospital-based surveillance, the prevalence of congenital anomalies is calculated by aggregating the number of unduplicated hospital cases as the numerator, and the total number of hospital live births as the denominator for a specific hospital. Note: it is important to remember that hospital-based prevalence estimates can be biased, in that they give the prevalence of a condition only for the participating hospital. Prevalence estimates based on hospital data are not true estimates of the prevalence of a condition among a population. When measuring the prevalence of congenital anomalies, it is important to note what is being counted in the numerator and in the denominator. Usually, the prevalence of congenital anomalies is calculated and presented as prevalence per 10 000 live births. This prevalence can be calculated for all congenital anomalies, for a specific individual anomaly, or for groups of anomalies. The following expression is used to calculate the birth prevalence of congenital anomalies, with the assumption that both live births and fetal deaths are being captured: Birth prevalence = a/b Ч 10 000 a: Number of live births and fetal deaths (stillbirths) with a specific congenital anomaly. Live birth prevalence of congenital anomalies = live birth cases total live births x 10 000 2. Birth prevalence of congenital anomalies = live birth cases + fetal death (stillbirths) cases total live births + fetal deaths (stillbirths) x 10 000 3. The numerator includes live births and known fetal deaths (stillbirths) with congenital anomalies, and pregnancy terminations with congenital anomalies (if these data are available), or all. The denominator comprises only live births and fetal deaths (stillbirths) (if these data are available), because it is practically impossible to assess the total number of pregnancy losses. Because the number of pregnancy losses is relatively small, compared with the number of live births, its exclusion has little effect on the prevalence estimate. Spontaneous abortions (also called miscarriages) are not included in the numerator or in the denominator because it is practically impossible to assess the total number of spontaneous abortions. Case counts and crude prevalence are common measures of burden that are often presented with respect to time, geographic area, demographic characteristics, or various combinations. Many factors could affect the prevalence of a health event: population changes due to migration, improved diagnostic procedures, enhanced reporting techniques, and changes in the surveillance system or methods. A comparison of the number of case reports collected during a particular time period may help identify differences in the number of cases for a current time period compared with time periods in previous years. The number of cases can vary by geographic location, and analysis by place can help identify where an increase in cases is occurring. In the case of rare congenital anomalies, the size of the geographic unit to be considered is important in order to provide stable estimates. The analysis of demographic characteristics provides information on the characteristics of those individuals with particular congenital anomalies. The most frequently used demographic variables for analysis are age, sex, and race and ethnicity. Knowing only the number of cases (numerator data), without having information about the denominator, can result in a misinterpretation of the true burden of a congenital anomaly. Example of calculating prevalence and the importance of the denominator Numerator: total number of cases of congenital anomalies per year Country (example A) 100 Denominator 100 000 (total live births per year in region or total catchment area) 10 000 (total live births per year in eight hospitals of the total catchment area) 1000 (total live births per year in one referral hospital of the total catchment area) Prevalence 0. The surveillance programme will be population based and will include all fetuses or neonates identified with congenital anomalies in the region. Example B A country decides to start a congenital anomalies surveillance programme in all maternity hospitals in one region, and eight hospitals will participate. Only fetuses or neonates with congenital anomalies born in one of the eight participating hospitals will be counted. The total number of births per year in the eight hospitals is estimated to be 10 000. After one year, the programme identifies 100 fetuses or neonates with congenital anomalies. This hospital is where prenatally identified fetuses with congenital anomalies are usually referred for delivery. After one year, the hospital identifies 100 fetuses or neonates with congenital anomalies. Without knowing the denominator for each example, the prevalence estimate could be misinterpreted. The prevalence estimate for example C might indicate that this country has a high prevalence of congenital anomalies, when in reality the estimate resulted from a small denominator and the site is a referral hospital. The prevalence estimates for examples B and C represent the prevalence for eight hospitals and one referral hospital, respectively. The prevalence estimate for example A is based on the total number of live births for a population and, thus, it yields the most accurate prevalence estimate. Diagnosing and coding congenital anomalies Initial list of congenital anomalies to consider for monitoring Surveillance programmes can be developed to capture a variety of conditions. Although some countries may have more developed programmes than others, for the purpose of this manual, the following are suggested as an initial list of congenital anomalies to consider for monitoring. They were chosen because they are relatively easy to identify at birth, have significant public health impact, and, for some of them, the potential for primary prevention. However, high-quality data on a smaller number of congenital anomalies will be more useful for public health than poor-quality data on all congenital anomalies. It is important that decisions on which defects to include are evaluated based on available resources. If the fetus or neonate 41 has at least one eligible congenital anomaly, this and any other observable major and minor congenital anomalies are described in detail and included on the abstraction form (see Appendix G). When coding the congenital anomalies, it is important to be as specific as possible and avoid using codes that are nonspecific or too general. Congenital anomalies of the nervous system Neural tube defects affect the brain and spinal cord, and are among the most common of the congenital anomalies (see. The most prevalent types of neural tube defects are anencephaly, encephalocele and spina bifida. Neural tube defects Source: reproduced with permission of the publisher from Botto et al. In addition to the term anencephaly, two other terms are used, although rarely, to describe this anomaly. One is holoanencephaly, in which the bone defect extends through the foramen magnum, affecting the entire skull; in the other, meroanencephaly, the bone defect is limited to the anterior part of the skull. Two additional terms that are occasionally used as synonyms of anencephaly may be sources of confusion, because they also are used to describe other conditions. One is acrania, often used to refer to acalvaria, or absence of the neurocranium (calvarial bones, dura mater, and associated muscles) and believed to be unrelated to neural tube defects. The other is acephaly, which literally means "absence of the head" and is part of a pattern of anomalies observed in acardiac twins. These two terms acrania and acephaly are not coded as anencephaly; a diagnosis of acrania can be scrutinized to determine whether the diagnosis of anencephaly is more appropriate. Neonates with craniorachischisis may also have spinal retroflexion resembling the body habitus of neonates with iniencephaly. This fact helps to differentiate iniencephaly from cases of anencephaly with spinal retroflexion. The anomaly is coded as the code for the specific congenital anomaly, as well as the Q79. Encephaloceles can contain herniated meninges and brain tissue (encephalocele or meningoencephalocele) or only meninges (cranial meningocele). Most frequently, they are located in the occipital area, but in South-East Asia, the anterior location (frontal or nasofrontal) is most common (see. Encephaloceles also are observed in the amniotic band sequence with entrapment of the head. Hydrocephalus is a common complication, especially among children with open (membrane-covered) meningomyeloceles. Specific types of spina bifida include: · Meningocele: this type of spina bifida is characterized by herniation of the meninges through a spine defect, forming a cyst filled with cerebrospinal fluid. This is the most common type of spina bifida, constituting about 90% of all cases. Myelocele: in this type of spina bifida, the open spinal cord, covered by a thin membrane, protrudes through the defect in the vertebral column. To aid understanding of the individual conditions, the structure of a normal palate is shown in. Laterality of cleft palate is difficult to ascertain and some believe it does not exist. Cases of cleft lip with a cleft of the primary palate (anterior to the incisive foramen) is coded as cleft lip alone, because clefts of the primary palate involve only the alveolus, and are embryologically related to cleft lip and different from clefts of the secondary palate. It is commonly classified into one of three categories, according to the location of the urethral meatus (see. Second degree: the urethral meatus is located in the shaft of the penis (distal penile, midshaft and proximal penile hypospadias). Third degree: the urethral meatus is located in the scrotum (penescrotal or scrotal hypospadias) or the perineum (perineoscrotal, perineal, or pseudovaginal hypospadias). The shortening of the ventral side of the penis found in hypospadias can result in a penile curvature, also known as chordee. This is present more commonly in severe cases, but can also occur independently of hypospadias. However, orthopaedic specialists use it as a synonym for talipes equinovarus (see. The condition, which has a wide spectrum of severity, is characterized by adduction of the forefoot and midfoot, adduction of the heel or hind foot, and a fixed plantar flexion (equinus position) of the ankle (29). In other words, the foot points downward and inward and is rotated outward axially. Other defects of the foot and ankle include talipes calcaneovalgus (in which the ankle joint is dorsiflexed and the forefoot deviated outwards) and talipes calcaneovarus (in which the ankle joint is dorsiflexed and the forefoot deviated inwards). They are classified into three large groups: longitudinal, transverse and intercalary limb deficiencies. Some cases will have multiple limb defects, and therefore will be classified in more than one of these groups. They typically involve specific components of the limbs: preaxial (first ray: thumb or radius in the arm(s), or both, or first toe or tibia in the leg(s), or both); postaxial (fifth ray: fifth finger or ulna in the arm(s), or both, fifth toe or fibula in the leg(s), or both); or central components (typically, third or fourth rays in the hand(s) (also called split hand or lobster-claw hand) or foot (also called split foot), or both. In contrast to gastroschisis, in which the abdominal defect is lateral to the umbilicus, in omphalocele the abdominal contents are herniated through an enlarged umbilical ring and the umbilical cord is inserted in the distal part of the membrane covering the defect. The extruded abdominal contents can be matted and covered by a thick fibrous material, but this membrane does not resemble skin. Gastroschisis and omphalocele can be confused with one another when the membrane covering the omphalocele has ruptured. However, careful examination demonstrating the position of the abdominal opening lateral to the umbilical cord insertion helps confirm the diagnosis of gastroschisis. Coding Coding of congenital anomalies One of the essential aspects of a congenital anomalies surveillance programme is its ability to efficiently generate information. Central to this process is the proper and accurate coding of the recorded diagnostic information. Coding of diagnostic information using a disease classification system allows a surveillance programme to capture and classify cases with congenital anomalies in a standardized way. Entering coded information into an electronic system makes it easier to retrieve and analyse the data. It is important to understand and follow a standardized coding system, in order to accurately and consistently classify and code the various types of congenital anomalies. The more precise the clinical description of congenital anomalies present in a fetus or neonate is, the more accurate the classification and coding that can be achieved. For example, not knowing the lesion level of spina bifida (such as cervical, thoracic or lumbar) or whether hydrocephalus is present, or both, would result in coding the congenital anomaly as "spina bifida, unspecified". It is important to obtain the best possible clinical description, carefully review and classify the congenital anomaly, and assign the right code(s) based on the description. To the extent possible, the database can preserve both the codes and the detailed clinical description. Photographs of the external congenital anomalies present can supplement the clinical description and help to ensure that the proper code is assigned. Although it is relatively easy to take photographs, it requires some training to obtain the best photographs. Please refer to Appendix J for suggestions for taking photographs of fetuses or neonates with congenital anomalies. Privacy issues also need to be considered and appropriate measures to ensure confidentiality should be in place.
They should be equal in size and about the same size as those of normal individuals in the same light (8% to 18% of normal individuals have anisocoria greater than 0 virus on macbook air generic 500mg sumycin. Unequal pupils can result from sympathetic paralysis making the pupil smaller or parasympathetic paralysis making the pupil larger virus january 2014 quality 500mg sumycin. Unless there is specific damage to the pupillary system virus mac proven sumycin 500mg, pupils of stuporous or comatose patients are usually smaller than normal pupils in awake subjects antibiotic eye drops safe 250mg sumycin. The eyelids can be held open while the light from a bright flashlight illuminates each pupil antimicrobial use buy discount sumycin 250mg line. Shining the light into one pupil should cause both pupils to react briskly and equally antibiotic induced fever generic 250 mg sumycin amex. Because the pupils are often small in stuporous or comatose patients and the light reflex may be through a small range, one may want to view the pupil through the bright light of an ophthalmoscope using a plus 20 lens or through the lens of an otoscope. Most pupillary responses are brisk, but a tonic pupil may react slowly, so the light should illuminate the eye for at least 10 seconds. Moving the light from one eye to the other may result in constriction of both pupils when the light is shined into the first eye, but paradoxically pupillary dilation when the light is shined in the other eye. In a comatose patient, this usually indicates oculomotor nerve compromise either by a posterior communicating artery aneurysm or by temporal lobe herniation (see oculomotor responses, page 60). However, the same finding can be mimicked by unilateral instillation of atropinelike eye drops. Occasionally this happens by accident, as when a patient who is using a scopolamine patch to avert motion sickness inadvertently gets some scopolamine onto a finger when handling the patch, and then rubs the eye; however, it is also seen in cases of factitious presentation. Still other times, unilateral pupillary dilation may occur in the setting of ciliary ganglion dysfunction from head or facial trauma. In most of these cases there is a fracture in the posterior floor of the orbit that interrupts the fibers of the inferior division of the oculomotor nerve. The denervated pupil will respond briskly, whereas the one that is blocked by atropine will not. A normal ciliospinal response ensures integrity of these circuits from the lower brainstem to the spinal cord, thus usually placing the lesion in the rostral pons or higher. Pathophysiology of Pupillary Responses: Peripheral Anatomy of the Pupillomotor System the pupil is a hole in the iris; thus, change in pupillary diameter occurs when the iris contracts or expands. The pupillodilator muscle is a set of radially oriented muscle fibers, running from the edge of the pupil to the limbus (outer edge) of the iris. When these muscles contract, they open the pupil in much the way a drawstring pulls up a curtain. The pupillodilator muscles are innervated by sympathetic ganglion cells in the superior cervical ganglion. These axons pass along the internal carotid artery, joining the ophthalmic division of the trigeminal nerve in the cavernous sinus and accompanying it through the superior orbital fissure, into the orbit. Sympathetic input to the lid retractor muscle takes a similar course, but sympathetic fibers from the superior cervical ganglion that control facial sweating travel along the external carotid artery. The sympathetic preganglionic neurons for pupillary control are found in the intermediolateral column of the first three thoracic segments. Two summary drawings indicating the (A) parasympathetic pupilloconstrictor pathways and (B) sympathetic pupillodilator pathways. The parasympathetic neurons that supply the pupilloconstrictor muscle are located in the ciliary ganglion and in episcleral ganglion cells within the orbit. The preganglionic neurons for pupilloconstriction are located in the oculomotor complex in the brainstem (Edinger-Westphal nucleus) and they arrive in the orbit via the oculomotor or third cranial nerve. The pupilloconstrictor fibers travel in the dorsomedial quadrant of the third nerve, where they are vulnerable to compression by a number of causes (Chapter 3), often before there is clear impairment of the third nerve extraocular muscles. As a result, unilateral loss of pupilloconstrictor tone is of great diagnostic importance in patients with stupor or coma caused by supratentorial mass lesions. Pharmacology of the Peripheral Pupillomotor System Because the state of the pupils is of such importance in the diagnosis of patients with coma, it is sometimes necessary to explore the origin of aberrant responses. Knowledge of the pharmacology of the pupillomotor system is essential to properly interpret the findings. The sympathetic terminals onto the pupillodilator muscle in the iris are noradrenergic, and they dilate the pupil via a beta-1 adrenergic receptor. In the presence of a unilateral small pupil, it is possible to determine whether the cause is due to failure of the sympathetic ganglion cells or is preganglionic. The pupil can then be dilated by instilling a few drops of 1% hydroxyamphetamine into the eye, which releases norepinephrine from surviving sympathetic terminals. Because the postsynaptic receptors have become hypersensitive due to the paucity of neurotransmitter being released, there is brisk pupillodilation after instilling the eye drops. Conversely, if the pupil is small due to loss of postganglionic neurons or receptor blockade, hydroxyam- phetamine will have little if any effect. Denervated receptors are hypersensitive and there is brisk pupillary dilation, but a pupil that is small due to a beta blocker does not respond. The parasympathetic ganglion cells, by contrast, activate the pupilloconstrictor muscle via a muscarinic cholinergic synapse. In the presence of a dilated pupil due to an injury to the third nerve or the postganglionic neurons, the hypersensitive receptors will constrict the pupil rapidly in response to a dilute solution of the muscarinic agonist pilocarpine (0. However, if the enlarged pupil is due to atropine, even much stronger solutions of pilocarpine (up to 1. Preganglionic sympathetic neurons in the C8-T2 levels of the spinal cord, which regulate pupillodilation, receive inputs from several levels of the brain. The main input driving sympathetic pupillary tone derives from the ipsilateral hypothalamus. Neurons in the paraventricular and arcuate nuclei and in the lateral hypothalamus all innervate the upper thoracic sympathetic preganglionic neurons. Thus, the sympathoexcitatory pathway remains ipsilateral from the hypothalamus all the way to the spinal cord. Inputs to the C8-T2 sympathetic preganglionic column arise from a numЁ ber of brainstem sites, including the KollikerFuse nucleus, A5 noradrenergic neurons, C1 adrenergic neurons, medullary raphe serotoninergic neurons, and other populations in the rostral ventrolateral medulla that have not been chemically characterized in detail. Brainstem sympathoexcitatory neurons can cause pupillodilation in response to painful stimuli (the ciliospinal reflex). As a result, lesions of the pontine tegmentum, which destroy both these ascending inhibitory inputs to the pupilloconstrictor system and the descending excitatory inputs to the pupillodilator system, cause the most severely constricted pupils seen in humans. Preganglionic parasympathetic neurons are located in the Edinger-Westphal nucleus in primates. In rodents and cats, most of the pupilloconstrictor neurons are located outside the Edinger-Westphal nucleus, and the nucleus itself mainly consists of the spinally projecting population, so that extrapolation from nonprimate species (where the anatomy and physiology of the system has been most carefully studied) is difficult. The main input to the Edinger-Westphal nucleus of clinical interest is the afferent limb of the pupillary light reflex. The retinal ganglion cells that contribute to this pathway belong to a special class of irradiance detectors, most of which contain the photopigment me- lanopsin. Although these ganglion cells are activated by the traditional pathways from rods and cones, they also are directly light sensitive, and as a consequence pupillary light reflexes are preserved in animals and humans with retinal degeneration who lack rods and cones. This is in contrast to acute onset of blindness, in which preservation of the pupillary light reflex implies damage to the visual system beyond the optic tracts, usually at the level of the visual cortex. The brightness-responsive retinal ganglion cells innervate the olivary pretectal nucleus. Neurons in the olivary pretectal nucleus then send their axons through the posterior commissure to the Edinger-Westphal nucleus of both sides. As a result, lesions that involve the posterior commissure disrupt the light reflex pathway from both eyes, resulting in fixed, slightly large pupils. Descending cortical inputs can cause either pupillary constriction or dilation, and can either be ipsilateral, contralateral, or bilateral. Unilateral pupillodilation has also been reported in patients during epileptic seizures. However, the pupillary response can be either ipsilateral or contralateral to the presumed origin of the seizures. Because so little is known about descending inputs to the pupillomotor system from the cortex and their physiologic role, it is not possible at this point to use pupillary responses during seizure activity to determine the lateralization, let alone localization, of the seizure onset. However, brief, reversible changes in pupillary size may be due to seizure activity rather than structural brainstem injury. We have also seen reversible and asymmetric changes in pupillary diameter in patients with oculomotor dysfunction due to tuberculous meningitis and with severe cases ґ of Guillain-Barre syndrome that cause autonomic denervation. Bilateral, small, reactive pupils are typically seen when there is bilateral diencephalic injury or compression, but also are seen in almost all types of metabolic encephalopathy, and therefore this finding is also of limited value in identifying structural causes of coma. A unilateral, small, reactive pupil accompanied by ipsilateral ptosis is often of great diagnostic value. Although hypothalamic unilateral injury can produce this finding, lesions of the lateral brainstem tegmentum are a more common cause. Midbrain injuries may cause a wide range of pupillary abnormalities, depending on the Diffuse effects of drugs, metabolic encephalopathy, etc. Summary of changes in pupils in patients with lesions at different levels of the brain that cause coma. Bilateral midbrain tegmental infarction, involving the oculomotor nerves or nuclei bilaterally, results in fixed pupils, which are either large (if the descending sympathetic tracts are preserved) or midposition (if they are not). However, pupils that are fixed due to midbrain injury may dilate with the ciliospinal reflex. It is often thought that pupils become fixed and dilated in death, but this is only true if there is a terminal release of adrenal catecholamines. The dilated pupils found immediately after death resolve over a few hours to the midposition, as are seen in patients who are brain dead or who have midbrain infarction. More distal injury, after the oculomotor nerve leaves the brainstem, is typically unilateral. Either of these lesions may compress the oculomotor nerve from the dorsal direction. Because the pupilloconstrictor fibers lie superficially on the dorsomedial surface of the nerve at this level,92 the first sign of impending disaster may be a unilateral enlarged and poorly reactive pupil. However, the simultaneous injury to both the descending and ascending pupillodilator pathways causes near maximal pupillary constriction. Metabolic and Pharmacologic Causes of Abnormal Pupillary Response Although the foregoing discussion illustrates the importance of the pupillary light response in diagnosing structural causes of coma, it is critical to be able to distinguish structural causes from metabolic and pharmacologic causes of pupillary abnormalities. Nearly any metabolic encephalopathy that causes a sleepy state may result in small, reactive pupils that are difficult to differentiate from pupillary responses caused by diencephalic injuries. However, the pupillary light reflex is one of the most resistant brain responses during metabolic encephalopathy. During or following seizures, one or both pupils may transiently (usually for 15 to 20 minutes, and rarely as long as an hour) be large or react poorly to light. During hypoxia or global ischemia of the brain such as during a cardiac arrest, the pupils typically become large and fixed, due to a combination of systemic catecholamine release at the onset of the ischemia or hypoxia and lack of response by the metabolically depleted brain. If resuscitation is successful, the pupils usually return to a small, reactive state. Pupils that remain enlarged and nonreactive for more than a few minutes after otherwise successful resuscitation are indicative of profound brain ischemia and a poor prognostic sign (see discussion of outcomes from hypoxic/ischemic coma in Chapter 9). Although most drugs that impair consciousness cause small, reactive pupils, a few produce quite different responses that may help to identify the cause of the coma. Opiates, for example, typically produce pinpoint pupils that resemble those seen in pontine hemorrhage. However, administration of an opioid antagonist such as naloxone results in rapid reversal of both the pupillary abnormality and the impairment of consciousness (naloxone must be given carefully to an opioid-intoxicated patient, because if the patient is opioid dependent, the drug may precipitate acute withdrawal). Muscarinic cholinergic antagonist drugs that cross the blood-brain barrier, such as scopolamine, may cause a confused, delirious state, in combination with large, poorly reactive pupils. Lack of response to pilocarpine eye drops (see above) demonstrates the muscarinic blockade. Glutethimide, a sedative-hypnotic drug that was popular in the 1960s, was notorious for causing large and poorly reactive pupils. Hence, it is unusual for a patient with a structural cause of coma to have entirely normal eye movements, and the type of oculomotor abnormality often identifies the site of the lesion that causes coma. Functional Anatomy of the Peripheral Oculomotor System Eye movements are due to the complex and simultaneous contractions of six extraocular muscles controlling each globe. In addition, the muscles of the iris (see above), the lens accommodation system, and the eyelid receive input from some of the same central cell groups and cranial nerves. Each of these can be used to identify the cause of an ocular motor disturbance, and may shed light on the origin of coma (Figure 28). Note the intimate relationship of these cell groups and pathways with the ascending arousal system. Examination of the Comatose Patient 61 der the control of the abducens or sixth cranial nerve. The superior oblique muscle and trochlear or fourth cranial nerve have more complex actions. Because the trochlear muscle loops through a pulley, or trochleus, it attaches behind the equator of the globe and pulls it forward rather than back. When the eye turns medially, the action of this muscle is to pull the eye down and in. When the eye is turned laterally, however, the action of the muscle is to intort the eye (rotate it on its axis with the top of the iris moving medially). All of the other extraocular muscles receive their innervation through the oculomotor or third cranial nerve. These include the medial rectus, whose action is to turn the eye inward; the superior rectus, which pulls the eye up and out; and the inferior rectus and oblique, which turn the eye down and out and up and in, respectively.
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