Late Neurological Sequelae Research Articles

Universal Newborn Screening for Congenital Cytomegalovirus Infection - From Infant to Maternal Infection: A Prospective Multicenter Study.

Introduction:Most infants at risk for cytomegalovirus (CMV)-associated sensorineural hearing loss (SNHL) are unrecognized because of the absence of a universal neonatal CMV screening. The search of CMV-DNA by molecular methods in salivary swabs was demonstrated to be a reliable approach. This study describes the results obtained by carrying out a universal screening for congenital CMV (cCMV) infection including all live-born newborns in three Italian sites, as well as the therapeutic interventions and clinical outcome of the CMV-infected neonates. Moreover, CMV maternal infection's characteristics were evaluated.MethodsTo confirm or exclude cCMV infection, a CMV-DNA-positive result on a first salivary swab was followed by repeated saliva and urine samples collected within 21 days of age. Breast milk samples were also collected. The search of CMV-DNA was performed with a single automated quantitative commercial real-time PCR assay, regardless of the type of samples used.ResultsA total of 3,151 newborns were enrolled; 21 (0.66%) of them were congenitally infected (median saliva viral load at screening, 6.65 [range, 5.03–7.17] log10 IU/ml). Very low/low viral load in screening saliva samples (median value, 1.87 [range, 1.14–2.59] log10 IU/ml) was associated with false-positive results (n = 54; 1.7%). CMV-DNA was detected in almost half of the breast milk samples of mother–infant pairs with a false-positive result, suggesting that contamination from breast milk may not be the only explanation in the study population. cCMV infection confirmation with the search of CMV-DNA in a urine sample proved to be the gold standard strategy, since false-positive results were observed in 4/54 (7.5%) of the repeated saliva samples. Symptomatic cCMV infection was observed in 3/21 (14.3%) infants; notably, one (4.7%) developed moderate unilateral SNHL at 5 months after birth. Finally, two symptomatic cCMV infections were associated with primary maternal infection acquired in the first trimester of gestation; one newborn with severe cCMV symptoms was born to a mother with no CMV checkups in pregnancy.ConclusionWithout universal neonatal CMV screening, some infected infants who develop late neurological sequelae may not be recognized and, consequently, they are not able to benefit early from instrumental and therapeutic interventions to limit and/or treat CMV disease.

Carbon monoxide intoxication-New aspects and current guideline-based recommendations

Carbon monoxide poisoning is acommon and potentially life-threatening intoxication, showing an interindividual variety of unspecific symptoms as well as late neurological and other sequelae. Two new German guidelines (S2k guidelines diagnosis and treatment of carbon monoxide poisoning as well as S3 guidelines oxygen therapy in the acute care of adult patients) focus on current evidence-based information on diagnostics as well as therapeutic options with considerable uncertainty remaining. This review summarizes current information and presents aflow scheme for daily practical use.

Pontine demyelination as a late complication of resolved mild COVID-19 infection

Previous case reports have demonstrated COVID-19 related neurotropism. Neural infection may result from trans-lamina cribrosa invasion that allows COVID-19 to reach the brain through the olfactory tract. A wide range of symptoms from headaches, anosmia, dysgeusia to neuropathy, encephalitis, cerebrovascular stroke, and rarely demyelination has been reported. Here, we report a case of pontine demyelination causing generalized weakness as a rare neurological complication in a COVID-19 survivor. Our case highlights that even mild and moderate COVID-19 infection can have late neurological sequelae.
 Keywords: COVID-19, demyelination, neurological complications, corticosteroids

Significant Reduction in Vertebral Artery Dose by Intensity Modulated Proton Therapy: A Pilot Study for Nasopharyngeal Carcinoma.

Intensity modulated proton therapy (IMPT) with the vertebral artery (VA)-sparing technique has been initially proposed in our institution. This pilot study was conducted to compare the dose to VAs between IMPT and volumetric-modulated arc therapy (VMAT) for patients with nasopharyngeal carcinoma (NPC). A total of six patients with NPC treated by IMPT were enrolled in the study. Target volumes and organs at risk (OARs) were delineated, including 12 samples of right and left VAs, respectively, for each patient. Treatment planning by IMPT and dual-arc VMAT was carried out for comparison. The IMPT plan significantly reduced VA mean dose, V10, V20, V30, V40, and V50, compared to the VMAT plan in all 12 samples (p < 0.001). The average mean dose to VAs for IMPT was 35.2% (23.4–46.9%), which was less compared to VMAT (p < 0.001). Adequate dose coverage was achieved with both IMPT and VMAT plans for three different dose levels of target volumes for all patients. IMPT significantly reduces VA dose while maintaining adequate dose coverage of all target volumes. For patients with head and neck cancer who seek to preserve their blood flow to the brain in order to decrease late vascular and neurologic sequelae, IMPT should be considered. A prospective study with longer follow-up is ongoing to confirm our preliminary results.

Late Neurological and Cognitive Sequelae and Long-Term Monitoring of Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma Survivors: A Systematic Review by the Fondazione Italiana Linfomi.

Simple SummaryThe last 25 years have seen a significant increase in the number of lymphoma survivors. This review was carried out to examine the data currently available on the incidence of some of the consequences most reported by this population: peripheral neuropathy, cognitive impairment, fatigue, and anxiety and depression. This review also investigated any follow-up strategies or monitoring implemented. The 35 articles included in the final analysis provided an idea of what the incidence of these sequelae may be in long-term survivors of classical Hodgkin lymphoma and diffuse large B-cell lymphoma. Despite methodological limitations encountered in the literature search, the Authors attempted to summarize the available evidence and provide support to clinical practice. This systematic review represents the basis for designing future studies with a longitudinal trial design and examining more homogeneous populations to assess and monitor these dimensions over time in clinical practice and to respond promptly to the needs of lymphoma survivors.Background: The continuously improving treatment outcome for classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) over the last 25 years has led to a high number of long-term survivors. The impact of treatment, however, can sometimes be dramatic and long-lasting. Focusing on peripheral neuropathy (PN), cognitive impairment, fatigue, anxiety, and depression, researchers of the Fondazione Italiana Linfomi conducted a systematic review of the literature to collect the available data on sequelae incidence as well as evidence of follow-up strategies for long-term cHL and DLBCL survivors. Methods: The review was carried out under the methodological supervision of the Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy. The literature search was conducted on three databases (MEDLINE, Embase, and the Cochrane Library) updated to November 2019. The selection process and data extraction were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 2236 abstracts were screened, 247 full texts were analyzed, and 35 papers were included in the final analysis. Fatigue was the most extensively studied among neuropsychological sequelae, with a mean prevalence among cHL survivors of 10–43%. Although many of the papers showed an increased incidence of PN, cognitive impairment, and anxiety and depression in long-term cHL and DLBCL survivors, no definite conclusions can be drawn because of the methodological limitations of the analyzed studies. No data on monitoring and follow-up strategies of PN and other neuropsychological sequelae were highlighted. Conclusions: Based on our findings, future studies in this setting should include well-defined study populations and have a longitudinal trial design to assess the outcomes of interest over time, thus as to structure follow-up programs that can be translated into daily practice.

Haemodialysis for lithium poisoning: Translating EXTRIP recommendations into practical guidelines.

This study aimed to determine the impact on practice of applying the Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup criteria to lithium toxicity. We retrospectively examined the medical records of patients from three hospitals who presented with chronic or acute on chronic lithium poisoning with a lithium concentration ≥1.3 mmol/L (2008-2018). We determined which criteria were met by patients and their subsequent course. We developed and validated a method to predict if lithium concentration would be >1mmol/L at 36 hours. There were 111 acute on chronic and 250 chronic lithium toxic patients. Nine patients (2.5%) were treated with haemodialysis. Six chronic patients had neurological sequelae. The "estimated lithium concentration at 36 hours > 1 mmol/L" criterion required pharmacokinetic calculations. A simple nomogram was developed using Estimated Glomerular Filtration Rate (eGFR) and lithium concentration. For chronic toxicity, the nomogram would have correctly predicted lithium concentration >1.4 mmol/L at 36 hours in all except two patients. If EXTRIP criteria were followed, dialysis would have been instituted for 211 patients (58%). However, only 51 patients with chronic toxicity fulfilled both a concentration and a clinical criterion. Late neurological sequelae were observed in five out of six patients who fulfilled a concentration and a clinical criterion on admission, with the sixth meeting these criteria shortly after admission. The EXTRIP criteria are too broad, but minor modifications allow haemodialysis to be targeted to those most at risk of sequelae. Most acute on chronic poisonings do not need haemodialysis, but it might shorten hospital stay in those with very high concentrations. The nomogram accurately predicts the fall in lithium concentration for chronic poisoning.

Mice Exposed to Combined Chronic Low-Dose Irradiation and Modeled Microgravity Develop Long-Term Neurological Sequelae.

Spaceflight poses many challenges for humans. Ground-based analogs typically focus on single parameters of spaceflight and their associated acute effects. This study assesses the long-term transcriptional effects following single and combination spaceflight analog conditions using the mouse model: simulated microgravity via hindlimb unloading (HLU) and/or low-dose γ-ray irradiation (LDR) for 21 days, followed by 4 months of readaptation. Changes in gene expression and epigenetic modifications in brain samples during readaptation were analyzed by whole transcriptome shotgun sequencing (RNA-seq) and reduced representation bisulfite sequencing (RRBS). The results showed minimal gene expression and cytosine methylation alterations at 4 months readaptation within single treatment conditions of HLU or LDR. In contrast, following combined HLU+LDR, gene expression and promoter methylation analyses showed multiple altered pathways involved in neurogenesis and neuroplasticity, the regulation of neuropeptides, and cellular signaling. In brief, neurological readaptation following combined chronic LDR and HLU is a dynamic process that involves pathways that regulate neuronal function and structure and may lead to late onset neurological sequelae.

Current perspectives on neonatal hypoglycemia, its management, and cerebral injury risk

Glucose is an essential substrate for mammalian cells; in particular, the brain needs glucose continuously as a primary source of energy. Hypoglycemia is the most common biochemical finding in the neonatal period. However, despite the common occurrence, there is still controversy on the definition of hypoglycemia in the newborn period. This has led to the development of guidelines designed to identify infants at-risk and the implementation of an operational threshold for physicians to consider intervention. In healthy term infants, the optimal hormonal and metabolic adaptations during the immediate neonatal period ensure an adequate energy substrate for the vital organs, whereas the abnormal glucose homeostasis observed in preterm and growth-retarded infants is multifactorial in origin. For these high-risk infants, it is important to identify, screen, and prevent significant hypoglycemia. Detailed investigations are warranted in infants with severe and persistent hypoglycemia. Neonatal hypo- glycemia is a major cause of brain injury. The speculated mechanisms of cellular injury include excitatory neurotoxins active at N-methyl-D-aspartate receptors, increased mitochondrial free radical generation with initiation of apoptosis and altered cerebral energetic characteristics. This hypoglycemic brain injury predominantly affects parieto-occipital regions causing cognitive, sensory, psychomotor, and behavioral deficits in children. This state of the art review article covers the fetal-neonatal metabolic adaptation, glucose homeostasis in normal and abnormal conditions, management strategies, and late neurological sequelae of hypoglycemia.

Measles may be a Risk Factor for Malignant Brain Tumors.

BackgroundA possible risk factor for brain tumor might be measles, since late neurologic sequelae are part of measles pathology. Subacute sclerosing panencephalitis, a devastating neurologic illness, is prone to develop years after measles infection.MethodsBecause measles damage to the brain might increase the risk of brain tumor, we examined the relationship of measles incidence in 1960 and brain tumor incidence in 50 US States and the District of Columbia, 2004-2007. Data on number of cases of measles by state in 1960 are from the Morbidity and Mortality Weekly Report. In 1960 measles was a childhood illness. We calculated measles incidence by obtaining the population of each state from the 1960 US Census and then age adjusting our results to the cumulative percent of the state population under age 21, since this would have been the measles-infected group. Data on the percentage white population by state are from the US Census (www.census.gov). Age-adjusted incidence (to the 2000 US standard population) of brain tumors is from the Central Brain Tumor Registry of the United States 2011 report.ResultsThere was a significant correlation between 1960 measles incidence and incidence of malignant brain tumors in persons 20 and older in 2004-2007 (r=0.321, p=0.026). Because glioblastoma is more frequent in whites and males, multivariate linear regression was performed with tumor incidence as the dependent variable, measles incidence, percent white population, and sex ratio by state as independent variables. Measles incidence was significantly correlated with malignant brain tumor incidence (β=0.361, p<0.001) and independent of the effect of race (β=0.734, p<0.001) and sex ratio m/f (β=-0.478, p<0.001). There was no correlation of measles incidence with brain tumor incidence in persons younger than 20.ConclusionInflammation is a critical component of tumor development. The inflammation of measles-induced subacute sclerosing panencephalitis, even subclinical cases, could well promote tumor formation, since many tumors arise from sites of infection, chronic irritation and inflammation.

Modified single innominate artery cannulation with low flow cardiopulmonary bypass during repair of interrupted aortic arch

Results Age at time of surgery was 7 days (4-120 days) and weight 3.1 kg (2.1 to 5.8 kg). Selective cerebral perfusion was maintained in all patients throughout aortic reconstruction. During the period of selective cerebral perfusion, pump flow rate was maintained at 30 mls/kg/min. Aortic cross clamp time, low-flow, and total CPB time were 66 (42-114), 29 (18-41) and 109 (83-217) minutes, respectively. There were no deaths or neurological injury in this series. Postoperative ventilation time, and length of ICU and hospital stay were 3 (2-14), 5 (3-21), and 13 (6-27) days, respectively. Follow-up, complete at 48 months (21-156), revealed no late neurologic sequelae nor innominate artery complications. There were three late re-stenosis of the aortic arch requiring balloon dilatation in 2 and surgical repair in 1.

Prophylactic cranial irradiation for small-cell lung cancer: how, when and for whom?

Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases and improves overall survival in both limited disease (LD) and extensive disease (ED) small-cell lung cancer (SCLC), in complete and good responders to initial chemo(radio)therapy. In LD-SCLC, a standard dose of 25 Gy given in ten fractions is recommended, whereas in ED-SCLC a shorter schedule of 20 Gy in five fractions could be used. The issues of acute neurotoxicity (NT) and the potential impact of PCI on quality of life are of particular concern in ED-SCLC patients, as their expected survival is short. In LD-SCLC late neurologic sequelae may worsen quality-adjusted life expectancy for long-term survivors, as the pronounced effect of NT becomes apparent after several years. Some novel potential approaches to reduce the PCI-related late NT have recently been investigated. Despite the growing incidence of lung cancer in elderly people, there are no established standards of treatment for this subset of the population.

Distribution of human Cytomegalovirus gB genotypes in samples from pediatric patients in Parma during the period 1995-2003

Background. Human Cytomegalovirus (HCMV) infection is a leading cause of developmental disability and late neurological sequelae in children. Several literature data indicate that HCMV pericapsidic glycoprotein B (gB) is highly immunogenic and is involved in virus-cell interaction.The gB gene has hypervariable regions producing four genotypes (gB1, gB2, gB3, gB4); however, the correlation between gB genotypes and HCMV infection outcome remains unclear. Objectives. The main goal of this study was that of evaluating the distribution of HCMV gB genotypes in samples from pediatric population in Parma with congenital, perinatal or post-natal infections, in order to find a correlation between viral gB genotypes and the clinical outcome of the infection. Study design. Forty eight urine samples, selected between 1999 and 2003 and stored at -80°C, underwent DNA extraction, nested PCR amplification of a gB gene region and restriction polymorphism analysis (RFLP). Results. The gB genotypes distribution in the considered pediatric population was as follows: gB1 was the most diffused (45.83%) followed by gB2 (22.92%), gB3 (16.67%) and gB4 (14.58%). Conclusions. In the considered population, gB1 was the most represented genotype and was often found in congenital and perinatal symptomatic infections, as well as in post-natal, asymptomatic infections.

Delayed sciatic neuropathy after distal semimembranosus muscle rupture associated with tethering of the sciatic nerve by a rare distal muscular branch

Hamstring rupture usually occurs in professional athletes, but is rarely associated with sciatic neuropathy. Proximal hamstring rupture is much more often reported than distal rupture. Entrapment of the sciatic nerve from perineural scarring and muscle fibrosis is responsible for late neurologic sequelae of injury to the hamstring muscles. There is currently no literature reporting the incidence of acute or delayed sciatic neuralgia after proximal hamstring muscle rupture. The association between distal hamstring rupture and sciatic nerve injury is extremely rare. A few cases of isolated rupture of the distal semimembranosus tendon complex have been reported recently, but without neurological sequelae. We present the first case of distal semimembranosus muscle rupture with delayed sciatic neuropathy and explain its unusual cause other than perineural scarring.

A Phase I/II Study to Evaluate the Toxicity and Efficacy of Accelerated Fractionation Radiotherapy for the Palliation of Dysphagia from Carcinoma of the Oesophagus

Aims We hypothesised that accelerated fractionated radiotherapy may provide a good palliative approach for dysphagia relief in patients with incurable oesophageal cancer, significantly reducing the overall duration of treatment, while providing symptom response with an acceptable toxicity profile. A phase I/II accelerated fractionation study was conducted to evaluate the efficacy and toxicity of this approach. Materials and methods Patients with incurable oesophageal cancer, symptomatic with dysphagia, Eastern Cooperative Oncology Group performance status ≤ 3, without fistula or oesophageal stent in situ, were eligible. Treatment consisted of 40 Gy in 20 fractions, twice a day (2 Gy per fraction, ≥6 h apart), 5 days a week, over 2 weeks. Results Of the 39 evaluable patients, the dysphagia response rate was 69% (27/39) with a median response duration of 5.5 months. The median time to response was 4 weeks. Twenty-eight per cent (11/39) of patients had transient worsening in their dysphagia scores. Acute toxicity (weeks 1–8) occurred in 41% (16/39) of patients. An improvement in global quality of life by week 8 was seen in 42% of patients. There were no late neurological sequelae. The median overall survival was 8 (range 1.7–58+) months. Conclusion The ideal palliative regimen should be relatively short, with minimal toxicity, while offering a favourable response profile. Accelerated fractionation fulfils these criteria and is a suitable treatment alternative for the palliation of dysphagia, especially if the goal is to deliver a higher total biological dose within a shorter (2 week) period of time.

Severe Carbon Monoxide Poisoning Treated by Hyperbaric Oxygen Therapy—A Case Report

Carbon monoxide (CO) poisoning is an important cause of mortality and late neurological sequelae such as memory loss, personality changes, psychosis, dementia, and so on. The benefits of hyperbaric oxygen (HBO) therapy are still discussed, but the majority of trials recommend it in severe cases with coma and/or hemodynamic instability, irrespective of carboxyhemoglobin (COHb) level, to prevent permanent neurological deficits. We present a 35-yr-old woman who underwent accidental CO poisoning. Although breathing 100% oxygen by mask during transfer to the hospital, she was in deep coma, hypotensive, cyanotic, and hypoxic (arterial pO2 7,41 kPa, HbO2 87.8%), with serum COHb 26.7% on hospital admission. Orotracheal intubation, mechanical ventilation, iv fluids, dobutamin, and norepinephrine were administered. COHb level decreased to 17.2% within 1 h. To prevent severe neurological sequelae, the patient was transferred as soon as possible to an HBO center 60 km distant to perform HBO therapy twice at 3.0 and once at 2.2 atm within 24 h. After the second HBO session, the patient regained consciousness, and respiratory failure and shock resolved. She was transferred to our hospital and discharged few weeks later with discrete paresis of peripheral nerves, discrete ischemic brain lesions on computed tomography (CT) scan, and moderately abnormal electroencephalogram (EEG) without cognitive disturbances. She was able to resume her daily activities. We conclude that in severe CO poisoning, normobaric oxygen therapy and resuscitation by fluids, inotropic agents, and catecholamines is essential for survival, but additional HBO therapy seems to prevent major neurological sequelae.

Late Neurologic and Cognitive Sequelae of Inflicted Traumatic Brain Injury in Infancy

There is limited information regarding the long-term outcome of inflicted traumatic brain injury (TBI), including shaken infant syndrome. The purpose of this study was to describe the long-term neurologic, behavioral, and cognitive sequelae seen in this population. A cross-sectional and prospective longitudinal study was conducted of 25 children with inflicted TBI in Scotland between 1980 and 1999. After consent was obtained, neurologic and cognitive examinations were performed on all participants and sequentially in the prospective cohort. Two global outcome measures were used: Glasgow Outcome Score (GOS) and Seshia's outcome score. Cognitive outcome was assessed using the Bayley Scales of Infant Development, British Ability Scales, and the Vineland Adaptive Behavior Scales. The mean length of follow-up was 59 months. A total of 68% of survivors were abnormal on follow-up, 36% had severe difficulties and were totally dependant, 16% had moderate difficulties, and 16% had mild difficulties on follow-up. A wide range of neurologic sequelae were seen, including motor deficits (60%), visual deficits (48%), epilepsy (20%), speech and language abnormalities (64%), and behavioral problems (52%). There was a wide range of cognitive abilities: the mean psychomotor index, 69.9 (SD: +/-25.73); and mean mental development index, 74.53 (SD: +/-28.55). Adaptive functioning showed a wide range of difficulties across all domains: communication domain (mean: 76.1; SD: +/-25.4), Daily living skills domain (mean: 76.9; SD: +/-24.3), and socialization domain (mean: 79.1; SD: +/-23.1). Outcome was found to correlate with the Pediatric Trauma Score and the Glasgow Coma Score but did not correlate with age at injury or mechanism of injury. Inflicted TBI has a very poor prognosis and correlates with severity of injury. Extended follow-up is necessary so as not to underestimate problems such as specific learning difficulties and attentional and memory problems that may become apparent only once the child is in school. Behavioral problems are present in 52% and begin to manifest clinically between the second and third years of life, although the consequences of frontal lobe injury may be underestimated unless follow-up is extended into adolescence and early adulthood.

Effect of Prenatal Diagnosis on Outcome in Patients With Congenital Heart Disease

After completing this article, readers should be able to: 1. List the most frequent prenatally diagnosed forms of congenital heart disease. 2. List the fetal indications for echocardiography. 3. List the maternal indications for echocardiography. 4. Review the findings of studies comparing the outcome of prenatally versus postnatally diagnosed newborns who have congenital heart disease. 5. List the advantages of prenatal diagnosis of congenital heart disease. Congenital heart disease (CHD) continues to be a major source of neonatal mortality. Since the development of echocardiographic screening for fetal cardiac anatomy in the 1980s, an increasing number of affected newborns are identified prior to delivery. (1) A recent study in a population that had risk factors for CHD found that the sensitivity of fetal echocardiography was 38%, with a false-positive rate of only 0.05%. (2) However, when performed by skilled operators viewing outflow tracts in addition to the four-chamber view, an accuracy as high as 96% has been reported. (3) These prenatal diagnoses are heavily skewed toward more severe CHD, with disorders of the atrioventricular junction (endocardial cushion defects), univentricular hearts, and hypoplastic left heart syndrome (HLHS) being the most common (Table 1). | Diagnosis | Proportion of All Fetal Diagnoses | Proportion of CHD in Newborns in Study | |:-------------------------------------------:| --------------------------------- | -------------------------------------- | | Hypoplastic left heart syndrome | 31% | 15% | | Atrioventricular septal defect | 30% | 25% | | Univentricular heart | 20% | 9% | | Pulmonary atresia intact ventricular septum | 8% | 5% | | Total anomalous pulmonary venous return | 0.3% | 1% | | Tetralogy of Fallot | 9% | 28% | | Transposition of the great arteries | 1.7% | 17% | Table 1. Relative Frequencies of Congenital Heart Defects (CHD) at Fetal Diagnosis and Seen At Birth* The ability to identify the most severe forms of CHD prior to delivery has changed the population of liveborn infants who have CHD. Prenatal diagnosis allows for extensive parental counseling and coordination of care. The fetal diagnosis of CHD prompts genetic testing to identify chromosomal abnormalities, which are found in 10% of cases, and a detailed anatomic evaluation to assess associated extracardiac anomalies, which coincide in 15% of cases. (1) In cases of poor prognosis, early prenatal diagnosis gives the parents the option of terminating …

Long term neurological sequelae of high dose 3D conformal fractionated combined proton-photon therapy to the cauda equina

To report late neurological sequelae and clinical outcomes for patients treated with high dose 3D conformal fractionated combined proton-photon radiation therapy to portions of the cauda equina (L2-coccyx). From 1974 through 1995, 62 patients were treated to fields encompassing portions of the cauda equina (L2-coccyx) with high dose 3D conformal fractionated combined proton-photon radiation therapy. This report describes clinical outcomes and late neurological sequelae in 53 patients with detailed data regarding neurological follow up and dose delivered to the cauda was available. Mean patient age was 43 years (range 6–79 years). 27 patients (51%) were male. Median follow-up was 87 months (range 14–217 months); 39 patients (71%) were followed for at least 5 years. Histology in all patients was reviewed at Massachusetts General Hospital. 66% of patients had either chordomas (18 patients) or another type of sarcoma (17 patients), 3 patients had giant cell tumors, and the other 15 patients had miscellaneous tumor types. Doses were defined in terms of CGE, Cobalt Gray Equivalents (CGE = proton Gy × RBE 1.1). Prescribed GTV doses ranged from 48.4 to 84.2 CGE. Median and mean GTV doses were 69.2 CGE and 69.5 CGE ± 7.64, respectively. Median and mean cauda doses were 67.5 CGE and 64.5 ± 13.3 CGE (38.8–84.2 CGE). Daily fraction size ranged from 1.8–2.24 CGE. Follow-up clinical data regarding tumor status and date of onset of neurological symptoms were obtained from patient charts, referring physicians, or by telephone contact with the patient or their relatives. Neurological symptoms developing in the absence of evident local failure were scored as radiation toxicity. No treatment failures occurred in 27 patients, 25 of whom were alive without evidence of disease (NED) at follow-up times ranging from 50 to 217 months. 26 patients had some type of failure, including 11 with local failure only (LF), 7 with distant failure only (DF), and 8 with both local and distant failure (LFsDF). Only 2, 3, and 3 patients were alive in the groups with LF, DF, or LFsDF respectively. Local recurrence free and disease free survival rates at 5 years were 72 ± 6 % and 75 ± 6 %, and at 10 years were 56 ± 8% and 48 ± 8% respectively. Thirteen patients experienced neurological sequelae in the absence of evident local failure. 10 had pain, numbness, and weakness and 3 had pain only. Using the LENT Scale for Peripheral Nerves, 4 patients had grade 4, 2 patients had grade 3, and 7 patients had grade 2 toxicity. Evident toxicity appeared in 7 patients (54%) at least 60 months after treatment. Median and mean cauda doses in patients with neurological toxicity were 75.4 CGE and 71.9 ± 11.1 CGE, respectively, and were 66 CGE and 62.1 ± 13.2 CGE in the remaining 40 patients without neurological toxicity (p = 0.02). In patients with neither neurological toxicity nor local failure, median cauda dose was 58.7 CGE and mean dose was 57.2 ± 12.3 CGE (p = 0.002). All grade 4 toxicities were associated with cauda doses greater than 75 CGE. The probability of surviving without neurological sequelae (whether from local failure or radiation toxicity) at 5 years was 59 ± 7% at 5 years and 33 ± 7% at 10 years. The probability of surviving without radiation sequelae in patients without local failure was 78 ± 7% at 5 years and 51 ± 11% at 10 years. This study demonstrates that the traditional milestone for defining tolerance at 5 years is not appropriate for the cauda equina, since over half of the late toxicities observed occurred at least that long after treatment. Very long follow-up is required in patients such as those reported here to accurately assess neurologic damage, and then to differentiate that phenomenon from local recurrence. Both local and distant failures remain issues for these patients, even with the radical doses used in this population. Patients treated to cauda doses above 70 CGE were at significantly increased risk of neurological toxicity, and above 75 CGE at risk of Grade 4 toxicity

One step removal of dumb-bell tumors by postero-lateral thoracotomy and extended foraminectomy.

Thoracic dumb-bell tumors are rare, usually benign tumors in the posterior mediastinum, consisting of intrathoracic and intraspinal parts. Surgical removal is the treatment of choice, performed by two teams - neurosurgeons and thoracic surgeons operating in a prescribed order. Between 1994 and 1997 five patients had dumb-bell tumors removed in a one-step operation involving postero-lateral thoracotomy and extended foraminectomy. This operating method, rarely described in the medical literature, consists of intrathoracic and intraspinal parts being performed by a thoracic team independently or with the assistance of a neurosurgeon. Initially the intrathoracic part is resected, followed by an extensive widening of the intervertebral foramen to an appropriate extension and the removal of the remaining intraspinal part of the tumor. Four postero-lateral thoracotomies and one incision over a huge tumor in the thoraco-lumbal region, without entering the pleural cavity, were performed. In one patient postoperative, transient leakage of the cerebral fluid was observed. No form of late complications or neurologic sequelae have been reported within a 5-year follow-up. One-step removal of a dumb-bell tumor by postero-lateral thoracotomy and extended foraminectomy is a safe surgical procedure that can be performed by the thoracic team alone. Early and late surgical results confirm the appropriateness and usefulness of the method.

Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor study.

To describe the neurologic and neurosensory deficits in children with brain tumors (BTs), compare incidence of these deficits with that of a sibling control group, and evaluate the factors associated with the development of these deficits. Detailed questionnaires were completed on 1,607 patients diagnosed between 1970 and 1986 with a primary CNS tumor. Neurosensory and neurologic dysfunctions were assessed and results compared with those of a sibling control group. Medical records on all patients were abstracted, including radiotherapy dose and volume. Seventeen percent of patients developed neurosensory impairment. Relative to the sibling comparison group, patients surviving BTs were at elevated risk for hearing impairments (relative risk [RR], 17.3; P = <.0001), legal blindness in one or both eyes (RR, 14.8; P = <.0001), cataracts (RR, 11.9; P = <.0001), and double vision (RR, 8.8; P = <.0001). Radiation exposure greater than 50 Gy to the posterior fossa was associated with a higher likelihood of developing any hearing impairment. Coordination and motor control problems were reported in 49% and 26%, respectively, of survivors. Children receiving at least 50 Gy to the frontal brain regions had a moderately elevated risk for motor problems (RR, 2.0; P <.05). Seizure disorders were reported in 25% of patients, including 6.5% who had a late first occurrence. Radiation dose of 30 Gy or more to any cortical segment of the brain was associated with a two-fold elevated risk for a late seizure disorder. Children surviving BTs are at significant risk for both early and late neurologic or neurosensory sequelae. These sequelae need to be prospectively monitored.