Safety of anticoagulation after hemorrhagic infarction

Cerebral hemorrhagic infarction visualized on CT, secondary to embolic stroke in an anticoagulated individual, is usually associated with clinically stable or improving neurologic signs; fear of transforming the hemorrhagic infarction into a hematoma, however, usually prompts cessation of anticoagulation until the blood has cleared on CT, despite the recognized risk of recurrent embolism during this non-anticoagulated period. We now report our experience with 12 patients with hemorrhagic infarction who remained anticoagulated. Eleven men and one woman, ages 33 to 77, developed hemorrhagic infarction while on heparin, warfarin, or both, for prevention of recurrent embolism. Patients were either continued on uninterrupted anticoagulation from stroke onset (n = 6), or anticoagulation was withheld for several days and then resumed (n = 4), or it was withheld for 5 and 14 days (n = 2) after stroke onset and then continued uninterrupted despite the CT appearance of hemorrhagic infarction. Eleven patients had a definite cardioembolic source for stroke (atrial fibrillation, seven; ventricular thrombus, two; and ventricular dyskinesia, two). One patient had carotid occlusion with local intra-arterial embolism. Hemorrhagic infarcts varied in size and were located in the middle cerebral artery territory in 11 patients and posterior cerebral artery territory in one. All patients remained clinically stable or improved on anticoagulation. Serial CTs showed fading hemorrhagic areas. When the risk of recurrent embolism is high, anticoagulation may be safely used in some patients with hemorrhagic infarction.     

Carbamoylation of glutathione reductase by N,N-bis(2-chloroethyl)-N- nitrosourea associated with inhibition of multidrug resistance protein (MRP) function

The physiopathology of radiation-induced bone damage is no completely elucidated. Ionizing radiation may induce an inhibition or an impairment of growing bone. This fact is of particular importance in children, and represents one of the most important dose-limiting factors in the radiotherapeutic management of children with malignant diseases. Scoliosis, epiphyseal slippage, avascular necrosis, abnormalities of craniofacial growth may be observed after radiation. Child's age at the time of treatment, location of irradiated bone and irradiation characteristics may influence the radiation-related observed effects. In adults, pathological analysis of mature bone after ionizing radiation exposure are rare, suggesting that it is difficult to draw a clear feature of the action of radiation on the bone. Osteoporosis, medullary fibrosis and cytotoxicity on bone cells lead to fracture or necrosis. Various factors can influence bone tolerance to radiation such as bone involvement by tumor cells or infection, which is frequent is mandibulary osteoradionecrosis. Technical improvements in radiation techniques have also decreased radio-induced bone complications: the volume, fractionation and total dose are essential to consider. The absence of a consistent radiation-induced late effects evaluation scale has hampered efforts to analyze the influence of various therapeutic maneuvers and the comparison of results from different reported series. The currently proposed evaluation scale may help harmonizing the classification of radiation-induced bone late effects.     

Intestinal intussusception as an unusual complication of oral anticoagulation therapy

Hyponatremia is a common neuromedical problem seen in survivors of central nervous system injury. The etiology of this hyponatremia is often diagnosed as syndrome of inappropriate diuretic hormone (SIADH). Fluid restriction is usually the first line of treatment. However, this can exacerbate vasospasm and produce resultant ischemia. Cerebral salt wasting is a syndrome of renal sodium loss that may occur commonly after central nervous system injury, yet remains unrecognized. Treatment of cerebral salt wasting consists of hydration and salt replacement. This article uses a case report to discuss the importance of recognition of this syndrome, and treatment concerns are reviewed.     

Central nervous system involvement in hepatitis C virus infection

Few well-documented cases of central nervous system involvement in patients with hepatitis C virus infection have been reported. We describe three patients (two men and one woman) with cerebral involvement (ischemia and/or hemorrhage). Hepatitis C virus infection was confirmed in all patients by polymerase chain reaction detection of hepatitis C virus RNA. These three cases document the occurrence of central nervous system involvement in patients with hepatitis C virus infection and mixed cryoglobulinemia. Cerebral involvement may be the initial manifestation of hepatitis C virus infection.     

Second cancers after medulloblastoma: population-based results from the United States and Sweden

Medulloblastoma, one of the most common central nervous system (CNS) tumors in children, requires aggressive multimodality therapy including surgery, radiation therapy, and occasionally chemotherapy. Given its intensive treatment regimen and improved survival during the past 20 years, it is likely that a cohort of survivors will result who may incur consequences of therapy, including a second cancer. We used population-based data from the United States and Sweden to estimate risks of second neoplasms in patients with histologically confirmed medulloblastoma (n = 1,262). Overall, there was a 5.4-fold excess of second neoplasms (95 percent confidence interval = 3.3-8.4) based on 20 observed and 3.7 expected cancers. The second cancers occurred eight to 432 months after initial diagnosis (median, 73 months) with significantly elevated ratios for all intervals examined except for less than one year after initial diagnosis. Significantly elevated risks were seen for cancers of the salivary glands, cervix uteri, brain and CNS, thyroid gland, and acute lymphoblastic leukemia. Of the 15 second cancers with treatment data, seven occurred in the radiation field or within areas of scatter while two others may have been radiation-related. Although based on small numbers of second cancers, the results suggest that as survival increases, some patients with medulloblastoma will have an increased risk of a second cancer, particularly a radiation-related cancer. Thus, as survival improves, late-occurring consequences of diagnosis and treatment will need to be carefully assessed. Identification of patients hypersensitive to radiation therapy, such as those with Gorlin Syndrome, should also be attempted in order to reduce the sequelae from intensive radiation exposure.     

Flow diagram or prose: does the format of practice guidelines matter?

BACKGROUND: Hematopoietic and organ transplantations are increasing worldwide with more patients receiving immunosuppressive therapy. Neurological problems may complicate the posttransplant period. Possible causes include the conditioning regimen (e.g., seizures with busulfan), central nervous system infections (viral, bacterial, and fungal), or factors secondary to the immunosuppressive therapy and side effects of drug treatment (e.g., cyclosporine and tacrolimus). Sinus venous thrombosis, the occlusion of a cerebral venous vessel or a sinus, is an unusual cause of neurologic symptoms in patients after transplantation, and this has not been reported in the literature previously. METHODS: Three patients presenting with various neurological symptoms after allogeneic bone marrow transplantation underwent computed tomography scans and magnetic resonance imaging as a primary diagnostic procedure. RESULTS: In all patients, sinus venous thrombosis was found as the cause for seizures; it was the cause of disturbance of consciousness in two patients and headaches in two patients. All symptoms resolved without any neurologic deficiency after anticoagulation therapy with heparin followed by dicumarol. CONCLUSION: We conclude that sinus venous thrombosis should be considered as a cause of neurological symptoms in patients after transplantation under immunosuppressive therapy. Diagnosis is rapidly confirmed by noninvasive magnetic resonance imaging angiography. Therapeutic heparinization is the treatment of choice.     

Can an extremely elevated radiosensitivity in patients be recognized by the in-vitro testing of lymphocytes?

BACKGROUND: We have examined the in-vitro radiosensitivity of lymphocytes in patients with extreme acute and chronic reactions after curative radiotherapy under the assumption of increased genetic radiosensitivity. PATIENTS AND METHODS: 16 patients (14 females, 2 males, age 40 to 69 years) were retrospectively examined 1 to 108 months after radiotherapy. All had undergone definitive or postoperative curative radiotherapy for cancer (12 breast cancer, 2 lung, 1 bladder, and 1 head and neck cancer). None of them had known genetic disorders with increased radiosensitivity. Four patients were considered as having probably increased radiosensitivity; they had shown poor tolerance to radiotherapy (1 severe acute reaction with cessation of radiotherapy in bladder cancer and subsequent bladder shrinkage after 45 Gy, 1 acute skin reaction well above average with subsequent fibrosis after irradiation for regional recurrence of breast cancer, 1 radiation myelitis after palliative irradiation with 5 x 5 Gy for lung cancer, 1 severe acute reaction after mediastinal irradiation for lung cancer). Twelve patients were considered as having normal tolerance to radiotherapy. They had tolerated radiotherapy well with normal acute reactions and no or minimal signs of late radiation sequelae. Lymphocyte cultures were prepared from all patients and irradiated with 0.7 and 2 Gy, respectively; 1 culture served as control (0 Gy). Chromosomes 1, 2, and 4 were stained using fluorescence in-situ hybridization (FISH) with a 3-colour-chromosome-in-situ suppression technique. Chromosomal breaks were counted in 200 to 1000 mitoses. Radiation sensitivity was expressed as radiation-induced breaks per mitoses corrected for breaks at 0 Gy. The probes were coded and the examiner did not know the clinical course. RESULTS: Significant differences in interindividual radiation sensitivity were detectable. The frequency of radiation-induced breaks/1000 mitoses ranged from 70 to 556 after 0.7 Gy and from 420 to 1210 after 2 Gy. The 4 patients with increased clinical radiation sensitivity showed also increased chromosomal radiation-induced damage as compared to the 12 patients with normal radiation tolerance (469 +/- 103 vs. 126 +/- 79 breaks/1000 mitoses induced by 0.7 Gy, p = 0.0011, and 864 +/- 258 vs. 574 +/- 119 breaks/1000 mitoses induced by 2 Gy, p = 0.019). CONCLUSIONS: Patients with increased clinical radiosensitivity exhibited increased chromosomal damage in lymphocytes in vitro measured with chromosome painting with a FISH-technique. This technique may be useful to detect patients with severely enhanced radiosensitivity. The results suggest that if radiosensitivity is abnormally elevated this may be present and detectable in different organs.     

Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system

Ataxia telangiectasia (AT) is characterized by progressive neurodegeneration that results from mutation of the ATM gene. However, neither the normal function of ATM in the nervous system nor the biological basis of the degeneration in AT is known. Resistance to apoptosis in the developing central nervous system (CNS) of Atm-/- mice was observed after ionizing radiation. This lack of death occurred in diverse regions of the CNS, including the cerebellum, which is markedly affected in AT. In wild-type, but not Atm-/- mice, up-regulation of p53 coincided with cell death, suggesting that Atm-dependent apoptosis in the CNS is mediated by p53. Further, p53 null mice showed a similar lack of radiation-induced cell death in the developing nervous system. Atm may function at a developmental survival checkpoint that serves to eliminate neurons with excessive DNA damage.     

Differential activation of right superior parietal cortex and intraparietal sulcus by spatial and nonspatial attention

Malignant brain tumors (primary and metastatic) are apparently resistant to most therapeutic efforts. Several randomized trials have provided evidence supporting the efficacy of radiation therapy. Attempts at improving the results of external beam radiotherapy include altered fractionation, radiation sensitizers and concomitant chemotherapy. In low-grade gliomas, all clinical studies with radiotherapy have employed conventional dose fractionation regimens. In high-grade gliomas, hypofractionation schedules represent effective palliative regimens in poor prognosis subsets of patients; short-term survival in these patients has not allowed to evaluate late toxicity. In tumors arising within the central nervous system, hyperfractionated irradiation exploits the differences in repair capacity between tumour and late responding normal tissues. It may allow for higher total dose and may result in increased tumor cell kill. Accelerated radiotherapy may reduce the repopulation of tumor cells between fractions. It may potentially improve tumor control for a given dose level, provided that there is no increase in late normal tissue injury. In supratentorial malignant gliomas, superiority of accelerated hyperfractionated over conventionally fractionated schedules was observed in a randomized trial; however, the gain in survival was less than 6 months. At present no other randomized trial supports the preferential choice for altered fractionation irradiation. Also in pediatric brainstem tumors there are no data to confirm the routine use of hyperfractionated irradiation, and significant late sequelae have been reported in the few long-term survivors. Shorter treatment courses with accelerated hyperfractionated radiotherapy may represent a useful alternative to conventional irradiation for the palliation of brain metastases. Different considerations have been proposed to explain this gap between theory and clinical data. Patients included in dose/effect studies are not stratified by prognostic factors and other treatment-related parameters. This observation precludes any definite conclusion about the relative role of conventional and of altered fractionation. New approaches are currently in progress. More prolonged radiation treatments, up to higher total doses, could delay time to tumor progression and improve survival in good prognosis subsets of patients; altered fractionation may be an effective therapeutic tool to achieve this goal.     

The intrinsic radioresistance of glioblastoma-derived cell lines is associated with a failure of p53 to induce p21(BAX) expression

Radiation is the primary modality of therapy for all commonly occurring malignant brain tumors, including medulloblastoma and glioblastoma. These two brain tumors, however, have a distinctly different response to radiation therapy. Medulloblastoma is very sensitive to radiation therapy, whereas glioblastoma is highly resistant, and the long-term survival of medulloblastoma patients exceeds 50%, while there are few long-term survivors among glioblastoma patients. p53-mediated apoptosis is thought to be an important mechanism mediating the cytotoxic response of tumors to radiotherapy. In this study, we compared the response to radiation of five cell lines that have wild-type p53: three derived from glioblastoma and two derived from medulloblastoma. We found that the medulloblastoma-derived cell lines underwent extensive radiation-induced apoptotic cell death, while those from glioblastomas did not exhibit significant radiation-induced apoptosis. p53-mediated induction of p21(BAX) is thought to be a key component of the pathway mediating apoptosis after the exposure of cells to cytotoxins, and the expression of mRNA encoding p21(BAX) was correlated with these cell lines undergoing radiation-induced apoptosis. The failure of p53 to induce p21(BAX) expression in glioblastoma-derived cell lines is likely to be of biologic significance, since inhibition of p21(BAX) induction in medulloblastoma resulted in a loss of radiation-induced apoptosis, while forced expression of p21(BAX) in glioblastoma was sufficient to induce apoptosis. The failure of p53 to induce p21(BAX) in glioblastoma-derived cell lines suggests a distinct mechanism of radioresistance and may represent a critical factor in determining therapeutic responsiveness to radiation in glioblastomas.     

Managing atrial fibrillation to prevent its major complication: ischemic stroke

Atrial fibrillation is an acute or chronic arrhythmia that occurs postoperatively or during intense emotional stress, exercise, or acute alcohol intoxication. More than 10% of Americans aged 75 and older have atrial fibrillation, which is common in elderly patients with cardiopulmonary disorders. During atrial fibrillation, uncoordinated electrical activity leads to ineffective atrial contraction, reduced atrial filling time, and decreasing cardiac output. Blood flow stasis may cause thrombi to form in the quivering atria. Cardioversion may be indicated to convert an unstable patient into sinus rhythm. However, if cardioversion converts the patient's status to sinus rhythm, thrombi may become dislodged and propelled into the bloodstream as emboli. Occlusion of a cerebral blood vessel often follows, leading to stroke. Because patients with longstanding atrial fibrillation are predisposed to stroke, anticoagulation therapy (usually with heparin, warfarin, or aspirin) should be initiated 3 weeks prior to cardioversion. Proper anticoagulation can usually prevent ischemic stroke.     

Neurological form of cryptococcosis. Apropos of 2 atypical cases in non HIV-infected patients

Cryptococcal infection is the most common fungal infection of the central nervous system. More than 50% of the cases of cryptococcal infection are superimposed on an immunosuppressive or other general debilitating condition. Cerebral cryptococcosis usually presents as meningitis or meningoencephalitis, although cerebral granuloma has also been reported. Hydrocephalus is the most common neurosurgical complication of cerebral cryptococcosis. The majority of patients require only medical treatment with antifungal drugs. However, when complications ensue, surgical intervention is mandatory. We suggest that chronic meningitis be ruled out in all patients prior to the placement of shunts. In the two cases reported here treatment of cryptococcal meningitis was a combination of amphotericin B and flucytosine for six weeks. Fluconazole is a new alternative and at least as effective as amphotericin B.     

Gut feelings about recovery after stroke: the organization and reorganization of human swallowing motor cortex

Swallowing problems can affect as many as one in three patients in the period immediately after a stroke. In some cases this can lead to serious morbidity, in particular malnutrition and pulmonary aspiration. Despite this, swallowing usually recovers completely in the vast majority of patients within weeks. This impressive propensity for recovery is likely to relate to how the area of the motor cortex concerned with swallowing is organized and then reorganized after cerebral injury. Recent studies have indicated that swallowing has a bilateral but asymmetric inter-hemisphere representation within motor and premotor cortex. Damage to the hemisphere that has the greater swallowing output appears to predispose that individual to swallowing problems. However, because there is additional substrate for swallowing in the undamaged hemisphere, the capacity for compensatory reorganization in the contralateral motor cortex might be increased, leading to a greater likelihood of recovery. Swallowing might be an excellent system for studying cortical plasticity, and might prove useful in the development of new therapies aimed at accelerating reorganization in the undamaged hemisphere after unilateral cerebral injury.     

Peripheral afferents with common function cluster in the median nerve and somatotopically innervate the human palm

We have examined the role of serotonin, a neurotransmitter, in the development of normal embryos and embryos irradiated in utero at different stages of morpho- and organogenesis. We have found that serotonin is capable of attenuating radiation-induced disturbances of development; serotonin therapeutic action varied depending on the age of the embryo, severity of the original radiation damage, and the time that serotonin was administered after irradiation. All data provide evidence that the window of serotonin's therapeutic effect is strictly timed to a certain stage of prenatal ontogenesis, specifically, to neurogenesis. This conclusion is in agreement with the view that serotonin serves as a morphogenetic signal for the developing nervous system, the state of which is important for the viability and functionality of fetuses in the normal state and after exposure to ionizing irradiation.     

Cerebral artery dissection

The main symptom of arterial dissection is intense acute unilateral headache. The pain is commonly located around the eye, in the temple or the front with a carotid artery dissection [CAD] and in the posterior neck and occiput with a vertebral artery dissection [VAD]. Transient or persistent cerebral ischemic symptoms are similarly frequent but usually occur later in the time course. Horner's syndrome indicating a lesion of perivascular sympathetic fibres represents the third leading symptom and occurs in more than one third of the patients. Compression of local structures such as lower nerve or radicular palsies is rare. This constellation of symptoms in a young patient without vascular risk factors should rise suspicion of a dissection, in particular, if there is a preceding 'trivial' trauma. Characteristic features on Doppler/duplex sonography provide the diagnosis of dissection in almost all CAD and the majority of VAD. MRI demonstrating the mural hematoma allows reliable confirmation of the suspected diagnosis. Angiography is necessary only in selected cases, more often in VAD than in CAD. Brain infarction may be prevented, if premonitory symptoms, which occur in 60 to 80% of the patients, are recognized as such. Therefore, if there is clinical and sonographic suspicion of CAD or VAD, anticoagulation therapy with heparin should should be started before other imaging procedures finally prove the diagnosis. Because immediate anticoagulation may prevent cerebral embolism, this treatment strategy seems appropriate, although its efficacy has not been established by a controlled study. Anticoagulation should be continued until resolution of the dissection.     

The role of PET-FDG in questionable diagnosis of relapse in the presence of radionecrosis of brain tumors

INTRODUCTION: Although CT and MR are sensitive techniques for the detection of cerebral tumours, both have limitations in distinguishing between tumour relapse (TR) and post-treatment radionecrosis (RN). PATIENTS AND METHODS: In this study we have determined the usefulness of metabolic imaging with PET-FDG in such situations. We assessed 70 patients with CNS tumours (22 low grade astrocytomas, 25 high grade astrocytomas, 3 oligodendrogliomas, 13 metastatic tumours and 7 other tumours. All had been treated with radiotherapy and other treatments such as radiosurgery, chemotherapy or different types of surgery, and presented clinical pictures which made it necessary to decide the differential diagnosis of relapse or radionecrosis. RESULTS: In the PET-FDG study visual and semiquantitative analysis was done by SUV (Standardized Update Value). Confirmation of the findings was obtained in 44 cases (24 TR and 20 RN). MR was doubtful or inconclusive in most cases, whilst with PET correct diagnosis was made in all cases. CONCLUSIONS: Metabolic imaging with PET-FGD is better than anatomostructural imaging techniques for differential diagnosis between tumour relapse and radionecrosis in CNS tumours which have been treated. Prospective studies are necessary for evaluation of SUV as a factor for prognosis of survival.     

Auricular fibrillation, systemic embolism and anticoagulant treatment

The risk of arterial embolism, specially cerebral, in patients with mitral stenosis associated atrial fibrillation is seventeen fold greater than that of the general population and five fold greater than that of non rheumatic atrial fibrillation. The usefulness of oral anticoagulant therapy in patients with atrial fibrillation and mitral stenosis is clear. In patients with non rheumatic atrial fibrillation, the controversy about its usefulness has been cleared with five recent reports showing a significant benefit or oral anticoagulation. We believe that these results may be applied to the routine management of these patients provided an adequate patient selection, consideration of contraindications and the use of a low anticoagulation range. Aspirin effectiveness in these patients is unsettled. One study showed benefits of 375 mg/day in patients younger than 75 years. The embolic risk in patients with atrial fibrillation must be stratified. High risk patients require the use of oral anticoagulation with an INR range between 3 and 4.5; those with medium risk require an INR between 2 and 3 and in some, aspirin use may be an alternative. When electrical cardioversion is indicated, oral anticoagulation must be used when atrial fibrillation has lasted for more than two days. In these cases, it is advisable to postpone cardioversion for three weeks after oral coagulation has started and to maintain this treatment for 3 or 4 additional weeks after cardioversion.     

Frontal foramina in pediatric skull in cases of congenital hydrocephalus

PURPOSE: To describe a new observation, frontal calvarial foramina, in pediatric patients with congenital hydrocephalus secondary to central nervous system malformation. MATERIALS AND METHODS: Frontal foramina were initially identified in three female patients with Chiari II malformation. Subsequently, head computed tomographic (CT) scans in 99 patients with congenital hydrocephalus were retrospectively reviewed. CT scans in a control group of 116 patients without hydrocephalus were also retrospectively reviewed. RESULTS: Frontal foramina were found in eight of 61 (13%) patients with Chiari II malformation, in one child with Dandy-Walker malformation, and in one child with occipital horn dilatation (colpocephaly), but not in control patients. Sequential CT examinations in three patients with frontal foramina depicted gradual closure after ventriculoperitoneal shunt placement. CONCLUSION: Frontal foramina may represent an abnormality variably expressed in certain central nervous system malformations that cause congenital hydrocephalus. The presence of frontal foramina palpated or visualized on plain radiographs may help in the diagnosis of congenital hydrocephalus and central nervous system malformation.     

Calf vein thrombosis in spinal cord injured patients: conservative management of two cases

Several studies have suggested that if a calf vein thrombosis does not propagate above the knee when followed up with serial diagnostic studies, full anticoagulation may not be necessary. These studies have not included spinal cord injured patients. Two patients with spinal cord injury were diagnosed with acute calf vein thrombosis after admission to a spinal cord injury rehabilitation unit. Both patients refused intravenous heparinization. Serial duplex Doppler studies were performed on both patients to evaluate for propagation of thrombus. Neither patient developed propagation of thrombus, pulmonary embolus, or persistent thrombophlebitis. Full anticoagulation including intravenous heparinization is costly, subject to complications, and interferes with intensive rehabilitation therapies. Observation of calf vein thrombosis with appropriate serial follow-up studies may be a viable alternative to anticoagulation in spinal cord injured patients. Further studies need to be done with this unique patient population.     

Prevention of pain

Pain is a multistep process originating in the peripheral nervous system at the site of injury, transmitted by the peripheral nervous system, processed at several levels within the central nervous system, and finally perceived at the level of the cerebral cortex. Each of these steps in pain transmission is subject to intervention, with the possibility of reducing or blocking the nociceptive information to result in decreased pain. In general, therapeutic strategies that attempt to prevent the initiation or transmission of nociceptive information are more effective and safer than attempts to minimize pain after it occurs. Analgesic strategies based on knowledge of pain processes and results of controlled clinical trials should result in the prevention of pain in most patients, with fewer adverse effects than traditional analgesic therapy.