Low-grade gliomas associated with intractable epilepsy: seizure outcome utilizing electrocorticography during tumor resection

1993 ◽  
Vol 79 (1) ◽  
pp. 62-69 ◽  
Author(s):  
Mitchel S. Berger ◽  
Saadi Ghatan ◽  
Michael M. Haglund ◽  
Jill Dobbins ◽  
George A. Ojemann
Keyword(s):  
Antiepileptic Drugs ◽  
Seizure Control ◽  
Intractable Epilepsy ◽  
Low Grade ◽  
Complete Control ◽  
Content Type ◽  
Low Grade Gliomas ◽  
Fine Print ◽  
Seizure Foci

✓ Adults and children with low-grade gliomas often present with medically refractory epilepsy. Currently, controversy exists regarding the need for intraoperative electrocorticography (ECoG) to identify and, separately, resect seizure foci versus tumor removal alone to yield maximum seizure control in this patient population. Forty-five patients with low-grade gliomas and intractable epilepsy were retrospectively analyzed with respect to preoperative seizure frequency and duration, number of antiepileptic drugs, intraoperative ECoG data (single versus multiple foci), histology of resected seizure foci, and postoperative control of seizures with or without antiepileptic drugs. Multiple versus single seizure foci were more likely to be associated with a longer preoperative duration of epilepsy. Of the 45 patients studied, 24 were no longer taking antiepileptic drugs and were seizure-free (mean follow-up interval 54 months). Seventeen patients, who all had complete control of their seizures, remained on antiepileptic drugs at lower doses (mean follow-up interval 44 months); seven of these patients were seizure-free postoperatively, yet the referring physician was reluctant to taper the antiepileptic drugs. Four patients continued to have seizures while receiving antiepileptic drugs, although at a reduced frequency and severity. In this series 41% of the adults versus 85% of the children were seizure-free while no longer receiving antiepileptic drugs, with mean postoperative follow-up periods of 50 and 56 months, respectively. This difference was statistically significant (p = 0.016). Therefore, based on this experience and in comparison with numerous retrospective studies involving similar patients, ECoG is advocated, especially in children and in any patient with a long-standing seizure disorder, to maximize seizure control while minimizing or abolishing the need for postoperative antiepileptic drugs.

Low-grade gliomas in children: tumor volume response to radiation

1998 ◽  
Vol 88 (6) ◽  
pp. 969-974 ◽  
Author(s):  
Barbara J. Fisher ◽  
Glenn S. Bauman ◽  
Christopher E. Leighton ◽  
Larry Stitt ◽  
J. Gregory Cairncross ◽  
...  
Keyword(s):  
Ct Scan ◽  
Tumor Volume ◽  
Residual Tumor ◽  
Ct Scans ◽  
Low Grade ◽  
Tumor Shrinkage ◽  
Content Type ◽  
Low Grade Gliomas ◽  
Fine Print

Object. The authors conducted a retrospective review to examine and document the frequency, degree, and timing of the radiologically confirmed response to radiotherapy of low-grade gliomas in children. Methods. Between 1963 and 1995, 80 patients 17 years of age or younger were referred to the London Regional Cancer Centre in London, Ontario after diagnosis of a low-grade glioma. All patients underwent surgical resection or biopsy procedures and 47 underwent radiotherapy (40 postoperatively and seven at the time of tumor progression). Nineteen patients with residual measurable lesions who received radiation therapy were selected for volumetric analysis of tumor response to this treatment. The extent and timing of response to radiation were determined by the process of comparing postoperative, preirradiation computerized tomography (CT) scans with postirradiation, follow-up CT scans. For one patient the comparison was made by using serial magnetic resonance images. Residual tumor was found on postoperative CT scans in all cases. The mean preradiotherapy tumor volume was 17.1 cm3, and the postradiotherapy volume was reduced to a mean of 11.5 cm3. A reduction in tumor volume was demonstrated in eight patients by the time of their first postirradiation follow-up CT scan and in two patients a slower reduction in volume over time was shown, bringing the total number of “responders” to 10. In five of these 10 patients the tumor had shown a maximum response by the time of the first postirradiation CT scan; the median time to response was 3.3 months. A 25% or greater reduction in tumor volume was seen in eight (42%) of the 19 patients. A 50% or greater reduction was noted in five (26%) of the patients. A complete response was demonstrated at 7, 12, and 15 months, and 5 years, respectively, in four patients (21%). One responder's tumor eventually increased in size after radiotherapy and he died of his disease. The magnitude of the radiographically demonstrated response to radiation did not correlate significantly with clinical outcome (that is, survival or symptom improvement). Conclusions. On the basis of this CT scan analysis of the response of low-grade gliomas in children to radiotherapy, the authors suggest that these lesions respond to radiation, as demonstrated by tumor shrinkage on serial imaging. Major or complete responses occur occasionally. However, low-grade gliomas in children mimic other benign brain tumors such as pituitary adenomas and meningiomas in that, although growth is frequently arrested after radiotherapy, residual tumor can persist for many years, illustrating that tumor shrinkage may not be a good measure of treatment efficacy. Nevertheless, radiation therapy can result in improvement of clinical symptomatology in association with or independent of visible tumor reduction. As radiation treatment techniques become increasingly conformal and because studies indicate that lower doses of radiation may be equally effective, improvement of symptoms may be an important consideration when weighing treatment options, particularly in patients with residual or unresectable disease.

Impact of temozolomide chemotherapy on seizure frequency in patients with low-grade gliomas

2011 ◽  
Vol 114 (6) ◽  
pp. 1617-1621 ◽  
Author(s):  
Jonathan H. Sherman ◽  
Krisztina Moldovan ◽  
H. Kwang Yeoh ◽  
Robert M. Starke ◽  
Nader Pouratian ◽  
...  
Keyword(s):  
Antiepileptic Drug ◽  
Antiepileptic Drugs ◽  
Seizure Frequency ◽  
Intractable Epilepsy ◽  
Age At Diagnosis ◽  
Control Group ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Significant Difference

Object Seizures occur in approximately 80% of patients with low-grade gliomas (LGGs). The majority of patients are treated with anticonvulsant monotherapy; however, many patients require multidrug therapy, or their seizures are refractory to antiepileptic drugs altogether. The oral alkylating agent temozolomide has emerged as a potential initial treatment option for LGG. A few reports suggest an association between temozolomide and reduced seizure frequency in patients with intractable epilepsy. Methods Using their clinical database, the authors identified adult patients whose LGGs were treated using temozolomide as the initial antineoplastic therapy at the University of Virginia Health System. As a control group, the authors assessed patients whose LGGs were under observation. All patients had seizure disorders that were treated with anticonvulsants. Seizure frequency in patients with intractable epilepsy was analyzed before and after treatment with temozolomide. Age at diagnosis, sex, antiepileptic drugs, pathological subtype, surgical treatment, and follow-up until progression were also assessed. Interval seizure frequency was meticulously analyzed at each neurooncology clinic visit. A meaningful difference in seizures was defined as a reduction in seizure frequency of greater than 50% per month. Results Thirty-nine patients were identified in the temozolomide cohort and 30 patients in the control cohort. The median age at diagnosis was 46 years for the former cohort and 41.5 years for the latter. The median length of follow-up was 39 months for the temozolomide group and 37 months for the control group. There was a significant difference in reduced seizure frequency between patients receiving temozolomide (59%) and those who did not receive temozolomide (13%, p < 0.001). Seven patients (18%) in the temozolomide group displayed this improvement independent of antiepileptic drug adjustment compared with no patient in the control group (p < 0.001). Conclusions The authors' data suggest that a subset of patients with LGGs experience improvement in seizure frequency during treatment with temozolomide independent of antiepileptic drug adjustment. This decrease in seizure frequency appears independent of the natural history of seizures in patients whose tumors are under observation. Consequently, seizures in patients with LGGs may be better controlled with the combination of AEDs and temozolomide.

Seizure control following tumor surgery for childhood cortical low-grade gliomas

1994 ◽  
Vol 80 (6) ◽  
pp. 998-1003 ◽  
Author(s):  
Roger J. Packer ◽  
Leslie N. Sutton ◽  
Kantilal M. Patel ◽  
Ann-Christine Duhaime ◽  
Steven Schiff ◽  
...  
Keyword(s):  
Seizure Control ◽  
Tumor Resection ◽  
Tumor Location ◽  
Seizure Outcome ◽  
Low Grade ◽  
Tumor Surgery ◽  
Eeg Monitoring ◽  
Content Type ◽  
Low Grade Gliomas ◽  
Seizure Foci

✓ Detailed preoperative electroencephalographic (EEG) studies are now recommended for children with seizures and cortical tumors to define seizure foci prior to surgery. To develop a historical perspective for better evaluation of results from series reporting tumor removal combined with resection of seizure foci, the authors reviewed seizure outcome in 60 children with seizures and low-grade neoplasms treated consecutively since 1981 by surgical resection without concomitant EEG monitoring or electrocortical mapping. Forty-seven of the 60 tumors were totally or near-totally resected; 45 patients were seizure-free and two were significantly improved 1 year following surgery. Of the 50 children in this series with more than five seizures prior to surgery, 36 were seizure-free, two were significantly improved, and 12 were not improved. Factors associated with poor seizure control included a parietal tumor location, a partial tumor resection, and a history of seizures for more than 1 year prior to surgery. The children at highest risk for poor seizure control at 2 years had experienced seizures for more than 1 year prior to surgery and had undergone partial resection of their parietal low-grade glial tumors or gangliogliomas. In contradistinction, the best seizure control was seen in patients with totally resected low-grade gliomas or gangliogliomas who had experienced seizures for less than 1 year (concordance rates for being seizure-free ranged from 78% to 86%). Long-term seizure control remained excellent. These results suggest that seizure control can be obtained 2 years following tumor surgery in the majority of children with presumed tumors after extensive tumor resection without concomitant EEG monitoring or electrocortical mapping.

Complications of invasive subdural grid monitoring in children with epilepsy

2003 ◽  
Vol 98 (5) ◽  
pp. 1017-1026 ◽  
Author(s):  
Çagatay Önal ◽  
Hiroshi Otsubo ◽  
Takashi Araki ◽  
Shiro Chitoku ◽  
Ayako Ochi ◽  
...  
Keyword(s):  
Intractable Epilepsy ◽  
Intracerebral Hematoma ◽  
Content Type ◽  
Acceptable Risks ◽  
Grid Monitoring ◽  
Superficial Wound ◽  
Cerebrospinal Fluid Leaks ◽  
Sick Children ◽  
Fine Print

Object. This study was performed to evaluate the complications of invasive subdural grid monitoring during epilepsy surgery in children. Methods. The authors retrospectively reviewed the records of 35 consecutive children with intractable localization-related epilepsy who underwent invasive video electroencephalography (EEG) with subdural grid electrodes at The Hospital for Sick Children between 1996 and 2001. After subdural grid monitoring and identification of the epileptic regions, cortical excisions and/or multiple subpial transections (MSTs) were performed. Complications after these procedures were then categorized as either surgical or neurological. There were 17 male and 18 female patients whose mean age was 11.7 years. The duration of epilepsy before surgery ranged from 2 to 17 years (mean 8.3 years). Fifteen children (43%) had previously undergone surgical procedures for epilepsy. The number of electrodes on the grids ranged from 40 to 117 (mean 95). During invasive video EEG, cerebrospinal fluid leaks occurred in seven patients. Also, cerebral edema (five patients), subdural hematoma (five patients), and intracerebral hematoma (three patients) were observed on postprocedural imaging studies but did not require surgical intervention. Hypertrophic scars on the scalp were observed in nine patients. There were three infections, including one case of osteomyelitis and two superficial wound infections. Blood loss and the amounts of subsequent transfusions correlated directly with the size and number of electrodes on the grids (p < 0.001). Twenty-eight children derived significant benefit from cortical resections and MSTs, with a more than 50% reduction of seizures and a mean follow-up period of 30 months. Conclusions. The results of this study indicate that carefully selected pediatric patients with intractable epilepsy can benefit from subdural invasive monitoring procedures that entail definite but acceptable risks.

scholarly journals Survival and Seizure Control have improved for Adult Low-Grade Gliomas over the last eleven years

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv4-iv4
Author(s):  
Matt Solomons ◽  
Rimona Weil ◽  
Zane Jaunmuktan ◽  
Tedani El-Hassan ◽  
Sebastian Brandner ◽  
...  
Keyword(s):  
Seizure Control ◽  
Molecular Subtype ◽  
Intractable Epilepsy ◽  
Progression Free Survival ◽  
Morbidity Rate ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Tumour Location ◽  
The Cost

Abstract Background There has been a trend towards earlier and more aggressive resection for adult Low-Grade Gliomas (LGG) in the last decade. This study set out to compare seizure control and survival of unselected adults with LGG seen in the same neuro-oncology clinic over 11 years and to determine if a change in surgical philosophy has led to a corresponding improvement in outcomes. Methods Retrospective analysis using case-note review of 153 adults with histologically verified or radiologically suspected LGG, collecting data on patient, tumour and seizure characteristics in 2006 and 2017. Results We studied 79 patients in 2006 and 74 patients in 2017. There were no significant differences between the two groups in age at presentation, tumour location or histological or molecular subtype. The numbers of complete or partial resections increased from 21.5 % in 2006 to 60.8% in 2017 (p<0.05). There was a highly significant improvement in 5- and 10-year survival from 81.8% and 51.7% in 2006 to 100% and 95.8% in 2017 (p<0.001); and a similar improvement was seen in progression free survival. The proportion of patients with intractable epilepsy reduced from 72.2% in 2006 to 43.2% in 2017 (p<0.05). The neurosurgical morbidity rate was identical in both groups (11.8% in 2006 vs 11.1% in 2017). Conclusion Increasing use of surgery for LGG over the last eleven years has led to substantial improvements in survival and seizure control but not at the cost of long-term morbidity.

Neurosurgical management of low-grade astrocytoma of the cerebral hemispheres

1984 ◽  
Vol 61 (4) ◽  
pp. 665-673 ◽  
Author(s):  
Edward R. Laws ◽  
William F. Taylor ◽  
Marvin B. Clifton ◽  
Haruo Okazaki
Keyword(s):  
Neurological Deficit ◽  
Important Variable ◽  
Surgical Removal ◽  
Low Grade ◽  
Survival Times ◽  
Duration Of Symptoms ◽  
Content Type ◽  
Long Duration ◽  
Fine Print

✓ The authors conducted a retrospective review of surgically treated, histologically proven cases of low-grade (Grade 1 or 2) astrocytomas. Follow-up analysis, with survival time as the end-point, was completed using multivariant statistical analysis. In the 461 cases of supratentorial low-grade astrocytoma in this study, age of the patient at the time of surgery was by far the most important variable in predicting length of survival. Other variables correlating with increasing survival times were: gross total surgical removal, lack of major preoperative neurological deficit, long duration of symptoms prior to surgery, seizures as a presenting symptom, lack of major postoperative neurological deficit, and surgery performed in recent decades. The multi-variant regression analysis showed that radiation therapy was of clear benefit, primarily in older patients with incompletely removed tumors. For purposes of establishing prognosis and testing the results, a “score” was developed to predict survival times, based on the most important variables. The data in this study provide a basis for the analysis of future modes of management of low-grade gliomas.

Hydrocephalus associated with intramedullary low-grade gliomas

1995 ◽  
Vol 83 (3) ◽  
pp. 480-485 ◽  
Author(s):  
Giuseppe Cinalli ◽  
Christian Sainte-Rose ◽  
Arielle Lellouch-Tubiana ◽  
Guy Sebag ◽  
Dominique Renier ◽  
...  
Keyword(s):  
Spinal Tumor ◽  
Low Grade ◽  
Content Type ◽  
Low Grade Gliomas ◽  
Leptomeningeal Seeding ◽  
Secondary Implantation ◽  
Csf Hydrodynamics ◽  
Neuroradiological Examination ◽  
Subarachnoid Spaces ◽  
Fine Print

✓ Over the past 15 years, eight children affected by intramedullary low-grade gliomas associated with hydrocephalus were treated at l'Hôpital des Enfants Malades. In all cases the diagnosis of hydrocephalus was made prior to that of the spinal tumor. Neuroradiological examination of all patients revealed contrast enhancement of the intracranial subarachnoid spaces. In six cases this was progressive, suggesting subarachnoid spread of the tumor, which was confirmed in two cases by histological examination. The authors analyzed 38 cases of intramedullary low-grade glioma associated with hydrocephalus that were reported in the literature. Fifteen of the cases had intracranial leptomeningeal seeding. Several hypotheses have been proposed to explain this unusual association, such as 1) increase in cerebrospinal fluid (CSF) viscosity because of elevated fluid protein content; 2) obliteration of the cisterna magna due to a rostral extension of the tumor; and 3) blockage of the spinal subarachnoid pathways of CSF resorption. Two other theories seem of particular interest. Bamford and Labadie suggested that the abnormal presence of fibrinogen in the CSF and its transformation into fibrin at the level of the basal cisterns and Pacchioni's granulation may alter CSF hydrodynamics. This mechanism alone is sufficient to induce hydrocephalus of the communicating type. In addition, as suggested by Maurice-Williams and Lucey, the resulting leptomeningeal fibrosis might predispose secondary implantation of neoplastic elements in the subarachnoid spaces of the intracranial compartment.

Long-term outcome in 132 consecutive patients after posterior internal fixation and fusion for Grade I and II isthmic spondylolisthesis

2005 ◽  
Vol 2 (3) ◽  
pp. 289-297 ◽  
Author(s):  
Markus Wenger ◽  
Nicola Sapio ◽  
Thomas-Marc Markwalder
Keyword(s):  
Internal Fixation ◽  
Posterior Instrumentation ◽  
Neurological Dysfunction ◽  
Leg Pain ◽  
Low Grade ◽  
Isthmic Spondylolisthesis ◽  
Content Type ◽  
Fine Print

Object. The authors assessed the late outcome of patients with Meyerding Grade I and II isthmic spondylolisthesis (IS) who underwent posterior instrumentation and posterolateral fusion (PLF). Decompression and posterior internal fixation with PLF is the classic surgical treatment for painful low-grade IS. Nevertheless, outcome data are scarce and of limited value mainly because they represent small numbers of patients, short follow-up periods, or both. Methods. The authors obtained data in the cases of 132 consecutive adult patients (mean age 40.6 years, range 15.2–69.9 years) with IS who underwent treatment between 1984 and 2003. Assessment involved analysis of responses to mailed questionnaires, clinical charts and, in cases in which unsatisfactory results were suspected, results of clinical reevaluations. Spondylolisthesis was present at L3–4 in three patients, L4–5 in 14, L3–4 in one, L3–5 in one, L5—S1 in 113, and S1–2 in one. Signs and symptoms included back and leg pain (65.3%), leg pain alone (26.3%), back pain alone (8.4%), and neurological dysfunction (18%). At a mean follow-up duration of 9.9 years (range 0.5–19.4 years), favorable results were reported for back and leg pain in 91.7 and 87.1% of patients, respectively. The mean visual analog scale scores were 2.13 for back and 1.59 for leg pain. Eighty-four patients resumed full- or part-time work, and 56.8% were capable of performing housework more easily. In 45.5% of the patients analgesic medications were not required, and 43.9% required them sporadically. The majority (63.6%) of patients reported they would undergo surgery again and recommended it to others. Thirteen (9.9%) suffered adjacent-segment morbidity, and in seven (5.3%) pseudarthrosis was documented. There were two deep and one superficial infections (2.3%). Conclusions. Posterior instrumentation and PLF, with possible neurodecompression, yielded favorable long-term results in this retrospective study of 132 patients with low-grade IS.

Long-term outcome of hypothalamic/chiasmatic astrocytomas in children treated with conservative surgery

1995 ◽  
Vol 83 (4) ◽  
pp. 583-589 ◽  
Author(s):  
Leslie N. Sutton ◽  
Patricia T. Molloy ◽  
Heidi Sernyak ◽  
Joel Goldwein ◽  
Peter L. Phillips ◽  
...  
Keyword(s):  
Radical Surgery ◽  
Conservative Surgery ◽  
Low Grade ◽  
Term Outcome ◽  
Term Survival ◽  
Long Term Outcome ◽  
Content Type ◽  
Fine Print

✓ The feasibility of radical surgery for astrocytomas of the optic chiasm/hypothalamus has been reported by several groups. Such surgery carries significant risks, however, including permanent damage to the pituitary gland, optic apparatus, hypothalamic structures, and carotid arteries. The benefits of radical surgery, both in terms of efficacy and toxicity, should, therefore, be evaluated against standard therapy, as is usually done for new chemotherapeutic protocols. To this end, a retrospective review was performed of 33 patients treated at Children's Hospital of Philadelphia between 1976 and 1991 who met criteria that would have made them eligible for radical surgery in many centers today, but were treated with either no surgery or conservative surgery (< 50% resection) or biopsy followed by adjuvant therapy with local radiation therapy (29 patients) and/or chemotherapy with actinomycin-D and vincristine (18 patients). The review encompassed all children with a globular enhancing mass of at least 2 cm in the hypothalamic/chiasmatic region, no evidence of optic nerve involvement or involvement of the optic radiations by computerized tomography or magnetic resonance imaging, and follow up of at least 3 years. All but one patient had tissue confirmation of a low-grade or pilocytic astrocytoma. Thirteen of the patients were 2 years of age or younger at diagnosis. Five individuals died: three of tumor progression, one of acute shunt malfunction, and one of intercurrent infection. The remaining 28 were alive at last follow up, a mean of 10.9 years from diagnosis. Twenty-three surviving patients have functional vision in at least one eye, 12 require no endocrine replacement, and 16 are in or have completed schooling with regular academic requirements. If radical surgery is to become standard care for children with low-grade astrocytomas of the hypothalamic/chiasmatic region, long-term survival and functional outcome will have to equal or surpass those of historical controls who were treated conservatively.

Low-grade gliomas of the cerebral hemispheres in children: an analysis of 71 cases

1995 ◽  
Vol 82 (4) ◽  
pp. 536-547 ◽  
Author(s):  
Ian F. Pollack ◽  
Diana Claassen ◽  
Qasim Al-Shboul ◽  
Janine E. Janosky ◽  
Melvin Deutsch
Keyword(s):  
Overall Survival ◽  
Univariate Analysis ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Low Grade ◽  
Free Survival ◽  
Content Type ◽  
Low Grade Gliomas ◽  
Fine Print

✓ Low-grade gliomas constitute the largest group of cerebral hemispheric tumors in the pediatric population. Although complete tumor resection is generally the goal in the management of these lesions, this can prove difficult to achieve because tumor margins may blend into the surrounding brain. This raises several important questions on the long-term behavior of the residual tumor and the role of adjuvant therapy in the management of these lesions. To examine these issues, the authors reviewed their experience in 71 children with low-grade cerebral hemispheric gliomas who were treated at their institution between 1956 and 1991 and assessed the relationship between clinical, radiographic, pathological, and treatment-related factors and outcome. Only seven patients in the series died, one from perioperative complications, five from progressive disease, and one (a child with neurofibromatosis) from a second neoplasm. For the 70 patients who survived the perioperative period, overall actuarial survivals at 5, 10, and 20 years were 95%, 93%, and 85%, respectively; progression-free status was maintained in 88%, 79%, and 76%, respectively. On univariate analysis, the factor that was most strongly associated with both overall and progression-free survival was the extent of tumor resection (p = 0.013 and p = 0.015, respectively). A relationship between extent of resection and progression-free survival was present both in patients with pilocytic astrocytomas (p = 0.041) and those with nonpilocytic tumors (p = 0.037). Histopathological diagnosis was also associated with overall survival on univariate analysis; poorer results were seen in the patients with nonpilocytic astrocytoma compared to those with other low-grade gliomas, such as pilocytic astrocytoma, mixed glioma, and oligodendroglioma (p = 0.021). The use of radiotherapy was not associated with a significant improvement in overall survival (p = 0.6). All three patients who ultimately developed histologically confirmed anaplastic changes in the vicinity of the original tumor had received prior radiotherapy, 20, 46, and 137 months, respectively, before the detection of malignant progression. In addition, children who received radiotherapy had a significantly higher incidence of late cognitive and endocrine dysfunction than the nonirradiated patients (p < 0.01 and 0.05, respectively). The authors conclude that children with low-grade gliomas of the cerebral hemispheres have an excellent overall prognosis. Complete tumor resection provides the best opportunity for long-term progression-free survival. However, even with incomplete tumor excision, long-term progression-free survival is common. The findings in this study do not support the routine use of postoperative radiotherapy after an initial incomplete tumor resection: although irradiation appears to increase the likelihood of long-term progression-free survival, overall survival is not improved significantly, and long-term morbidity may be increased.

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