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Biomedical subjects

Douglas Kondziolka

Publications and source records attributed to Douglas Kondziolka.

At least 19 recordsLinked to original sources

Analysis of tumor control and toxicity in patients who have survived at least one year after radiosurgery for brain metastases.

PURPOSE: To better evaluate tumor control and toxicity from radiosurgery for brain metastases, we analyzed these outcomes in patients who had survived at least 1 year after radiosurgery. METHODS AND MATERIALS: We evaluated the results of gamma knife stereotactic radiosurgery (SRS) for 208 brain metastases in 137 patients who were followed for a median of 18 months (range 12-122) after radiosurgery. The median patient age was 53 years (range 3-83). Ninety-nine patients had solitary metastases. Thirty-eight had multiple tumors. Sixty-nine patients underwent initial SRS with whole brain radiotherapy (WBRT), 39 had initial SRS alone, and 27 patients had failed prior WBRT. The median treatment volume was 1.9 cm(3) (range 0.05-21.2). The median marginal tumor dose was 16 Gy (range 12-25). The most common histologic types included non-small-cell lung cancer, breast cancer, melanoma, and renal cell carcinoma, which comprised 37.0%, 22.6%, 13.0%, and 9.13% of the lesions, respectively. Forty-five tumors were associated with extensive edema. RESULTS: At 1 and 5 years, the local tumor control rate was 89.6% +/- 2.1% and 62.8% +/- 6.9%, distal intracranial relapse occurred in 23% +/- 3.6% and 67.1% +/- 8.7%, and postradiosurgical sequelae developed in 2.8% +/- 1.2% and 11.4% +/- 3.5% of patients, respectively. Multivariate analysis found that local control decreased with tumor volume (p = 0.0002), SRS without WBRT (p = 0.008), and extensive edema (p = 0.024); distal intracranial recurrence correlated with younger patient age (p = 0.0018); and postradiosurgical sequelae increased with increasing tumor volume (p = 0.0085). CONCLUSION: Long-term control of brain metastases and complication rates in this selective series of patients surviving >or=1 year after radiosurgery were similar to previously reported actuarial estimates. Large metastases and metastases associated with extensive edema can be difficult to control by radiosurgery, particularly without WBRT.

Actuarial Analysis↗

Gamma knife radiosurgery of imaging-diagnosed intracranial meningioma.

PURPOSE: To evaluate tumor control and outcome from radiosurgery of meningiomas diagnosed by imaging without pathologic verification. METHODS AND MATERIALS: A total of 219 meningiomas diagnosed by imaging criteria underwent gamma knife radiosurgery to a median marginal tumor dose of 14 Gy (range 8.9-20), a median treatment volume of 5.0 cm(3) (range 0.47-56.5), and a median maximal dose of 28 Gy (range 22-50). The median follow-up was 29 months (range 2-164). RESULTS: Tumor progression developed in 7 cases, 2 of which turned out to be different tumors (metastatic nasopharyngeal adenoid cystic carcinoma and chondrosarcoma). One tumor was controlled, but the development of other brain metastases suggested a different diagnosis. The actuarial tumor control rate was 93.2% +/- 2.7% at 5 and 10 years. The actuarial rate of identifying a diagnosis other than meningioma was 2.3% +/- 1.4% at 5 and 10 years. The actuarial rate of developing any postradiosurgical injury reaction was 8.8% +/- 3.0% at 5 and 10 years. No pretreatment variables correlated with tumor control in univariate or multivariate analysis. The risk of postradiosurgery sequelae was lower (5.3% +/- 2.3%) in patients treated after 1991 (with stereotactic MRI and lower doses; p = 0.0104) and tended to increase with treatment volume (p = 0.0537). CONCLUSION: Radiosurgery of meningioma diagnosed by imaging without tissue confirmation is associated with a high rate of tumor control and acceptable morbidity but carries a small risk (2.3%) of an incorrect diagnosis.

Adolescent↗

The effect of radiosurgery during management of aggressive meningiomas.

BACKGROUND: Aggressive (atypical or malignant) meningiomas are difficult tumors to manage. We review the local control and survival rates of patients with aggressive meningiomas after multi-modality therapy that included stereotactic radiosurgery (SRS). METHODS: Thirty patients had SRS for treatment of malignant (n = 12) or atypical (n = 18) meningiomas. There were 17 (57%) males and 13 (43%) females with an average age of 58 years. The mean number of prior surgical resections was two. The median imaging follow-up was 2.3 (0.1-11.4) years; median clinical follow-up was 3.8 (0.25-11.5) years. RESULTS: After SRS, the overall median time until progression of neurologic signs was 48.0 (+/-6.51) months. Median time to neurologic progression was significantly worse for patients treated late after recurrence versus early after craniotomy. Atypical meningiomas had 5- and 10-year overall actuarial survival rates of 59% (+/-13), while malignant meningiomas had 5- and 10-year overall actuarial survival rates of 59% (+/-16) and 0%. These curves were not significantly different from one another. Atypical meningiomas had a 5-year progression-free survival (PFS) of 83% (+/-7%), while malignant meningiomas had a 5-year PFS of 72% (+/-10) (p = 0.018). On multivariate analysis, early SRS and smaller tumor volumes were associated with better PFS, while younger age was associated with better survival. One patient had an adverse radiation effect after SRS. CONCLUSIONS: Stereotactic radiosurgery is an important adjuvant management strategy for residual tumors identified early after craniotomy and partial resection. Aggressive use of early boost radiosurgery following craniotomy and radiation therapy is recommended for patients with malignant meningiomas.

Actuarial Analysis↗

Stereotactic radiosurgery for brain metastases from gastrointestinal tract cancer.

BACKGROUND: Outcomes in patients with brain metastases from gastrointestinal tract cancers are not well defined. In this study we used precise, single-session, focal tumor irradiation (radiosurgery) in patients with brain metastases and evaluated the results. METHODS: Thirty-nine patients had brain metastases from gastrointestinal tract cancer and were treated with radiosurgery. Thirty-two also had whole brain radiotherapy. Primary lesions included colorectal cancer (n = 25), esophageal cancer (n = 11), cholangiocarcinoma (n = 1), duodenal cancer (n = 1), and jejunal cancer (n = 1). Seventy-two tumors were treated. RESULTS: The overall median survival was 9 months after diagnosis of metastatic brain disease and 5 months after radiosurgery. The 1-year survival rate after radiosurgery was 19%. The last imaging study of 49 tumors showed complete remission (CR) in 3 tumors (6.1%), partial remission (PR) in 27 tumors (55.1%), no change (NC) in 11 tumors (22.4%), and progression in 8 tumors (16.3%). The local tumor control rate (CR, PR, NC) was 84%. Two patients (5.1%) had a new or worsening neurologic deficit after radiosurgery. CONCLUSIONS: Stereotactic radiosurgery provides reasonable local control of brain metastases from gastrointestinal tract cancer with few side effects. However, it should be used judiciously in patients with active extracranial cancers since the expected survival may be limited.

Adult↗

Neuronal transplantation for motor stroke: from the laboratory to the clinic.

Laboratory studies have established the potential for neuronal transplantation to be of benefit to patients. Experimental studies in normal animals indicate that brain implantation of neurons seems safe. Implanted neurons integrated with the host brain, sent out axonal processes to communicate with other nerve cells, released transmitters (the chemical messengers of nerve cell communication), and demonstrated typical neuronal proteins. This article discusses phase I and II trials of neuronal transplantation in humans with small strokes in critical brain locations such as the basal ganglia region. More work is needed to confirm safety and to identify optimal measures of efficacy in this setting.

Adult↗

Long-term results after radiosurgery for benign intracranial tumors.

BACKGROUND: Stereotactic radiosurgery is the principal therapeutic alternative to resecting benign intracranial tumors. The goals of radiosurgery are the long-term prevention of tumor growth, the maintenance of patient function, and the prevention of new neurological deficits or adverse radiation effects. Evaluation of long-term outcomes more than 10 years after radiosurgery is needed. METHODS: We evaluated 285 consecutive patients who underwent radiosurgery for benign intracranial tumors between 1987 and 1992. Serial imaging studies were obtained, and clinical evaluations were performed. Our series included 157 patients with vestibular schwannomas, 85 patients with meningiomas, 28 patients with pituitary adenomas, 10 patients with other cranial nerve schwannomas, and 5 patients with craniopharyngiomas. Prior surgical resection had been performed in 44% of these patients, and prior radiotherapy had been administered in 5%. The median follow-up period was 10 years. RESULTS: Overall, 95% of the 285 patients in this series had imaging-defined local tumor control (63% had tumor regression, and 32% had no further tumor growth). The actuarial tumor control rate at 15 years was 93.7%. In 5% of the patients, delayed tumor growth was identified. Resection was performed after radiosurgery in 13 patients (5%). No patient developed a radiation-induced tumor. Eighty-one percent of the patients were still alive at the time of this analysis. Normal facial nerve function was maintained in 95% of patients who had normal function before undergoing treatment for acoustic neuromas. CONCLUSION: Stereotactic radiosurgery provided high rates of tumor growth control, often with tumor regression, and low morbidity rates in patients with benign intracranial tumors when evaluated over the long term. This study supports radiosurgery as a reliable alternative to surgical resection for selected patients with benign intracranial tumors.

Adolescent↗

Stereotactic radiosurgery for CNS nongerminomatous germ cell tumors. Report of four cases.

In this study, we evaluated the results in four patients with nongerminomatous germ cell tumors (NGGCT) of the pineal region. All underwent radiosurgery in conjunction with surgical resection, fractionated radiotherapy or chemotherapy. Four male patients with pineal region NGGCT were treated with radiosurgery. The mean age was 16.5 years. Three patients had histological confirmation by stereotactic biopsy or craniotomy prior to radiosurgery. One patient was diagnosed by serum and CSF tumor markers. The mean tumor volume was 10.5 cm(3). Radiosurgery was performed with mean maximum and marginal doses of 28 and 14 Gy, respectively. At last follow-up, three patients were alive and one was dead. The mean follow-up after diagnosis and after radiosurgery was 34 and 25 months, respectively. At last follow-up, two tumors had regressed, one was unchanged and one had progressed. No patient had complications after radiosurgery. Radiosurgery can play an important adjuvant role for NGGCT patients who also undergo multimodal management. In the case of prepubertal patients, radiosurgery may play an important role by reducing the radiation dose to the surrounding normal brain.

Adolescent↗

Radiobiological analysis of tissue responses following radiosurgery.

Stereotactic radiosurgery provided clinicians the ability to administer high single-doses of radiation to intracranial targets with relative safety. Analysis of clinical outcome from radiosurgery calls into question some of the radiobiological principles that have guided conventional fractionated radiotherapy in the past. The response of the tumor or target tissue being irradiated, as well as the response of the surrounding normal tissue, seems predominantly determined by the tumor or target vasculature. Injury to the tumor or target vasculature appears to contribute to the probability of developing normal tissue complications. Estimations of alpha/beta values from radiosurgical dose-response data consistently yield values that conflict with values from fractionated radiotherapy and with linear-quadratic theory. This indicates that projections from high-dose single-fractions to fractionated dose-equivalents made using the linear-quadratic formula are unreliable. Radiobiological analysis of clinical data from radiosurgery provides models for guiding treatment to achieve desired effects and provide reliable estimates of complications.

Dose Fractionation, Radiation↗

Brain metastases treated with radiosurgery alone: an alternative to whole brain radiotherapy?

OBJECTIVE: Whole brain radiotherapy (WBRT) provides benefit for patients with brain metastases but may result in neurological toxicity for patients with extended survival times. Stereotactic radiosurgery in combination with WBRT has become an important approach, but the value of WBRT has been questioned. As an alternative to WBRT, we managed patients with stereotactic radiosurgery alone, evaluated patients' outcomes, and assessed prognostic factors for survival and tumor control. METHODS: One hundred seventy-two patients with brain metastases were managed with radiosurgery alone. One hundred twenty-one patients were evaluable with follow-up imaging after radiosurgery. The median patient age was 60.5 years (age range, 16-86 yr). The mean marginal tumor dose and volume were 18.5 Gy (range, 11-22 Gy) and 4.4 ml (range, 0.1-24.9 ml). Eighty percent of patients had solitary tumors. RESULTS: The overall median survival time was 8 months. The median survival time in patients with no evidence of primary tumor disease or stable disease was 13 and 11 months. The local tumor control rate was 87%. At 2 years, the rate of local control, remote brain control, and total intracranial control were 75, 41, and 27%, respectively. In multivariate analysis, advanced primary tumor status (P = 0.0003), older age (P = 0.008), lower Karnofsky Performance Scale score (P = 0.01), and malignant melanoma (P = 0.005) were significant for poorer survival. The median survival time was 28 months for patients younger than 60 years of age, with Karnofsky Performance Scale score of at least 90, and whose primary tumor status showed either no evidence of disease or stable disease. Tumor volume (P = 0.02) alone was significant for local tumor control, whereas no factor affected remote or intracranial tumor control. Eleven patients developed complications, six of which were persistent. Nineteen (16.5%) of 116 patients in whom the cause of death was obtained died as a result of causes related to brain metastasis. CONCLUSION: Brain metastases were controlled well with radiosurgery alone as initial therapy. We advocate that WBRT should not be part of the initial treatment protocol for selected patients with one or two tumors with good control of their primary cancer, better Karnofsky Performance Scale score, and younger age, all of which are predictors of longer survival.

Adolescent↗

Intracranial Rosai-Dorfman disease treated with microsurgical resection and stereotactic radiosurgery. Case report.

Sinus histiocytosis or Rosai-Dorfman disease (RDD) is a rare idiopathic histioproliferative disorder typically characterized by painless cervical lymphadenopathy, fever, and weight loss. Extranodal, intracranial disease is uncommon. In this report the authors describe the first case of intracranial RDD treated with stereotactic radiosurgery after resection. This 52-year-old man with known RDD presented with a 7-day course of fever, headache, diplopia, left facial paresthesias, and difficulty swallowing. No cranial nerve deficits were evident on examination, but right submandibular and inguinal node enlargements were noted. On neuroimaging, the patient was found to have a homogeneously contrast-enhancing petroclival lesion with extension into the left cavernous sinus. The patient underwent a combined left petrosal craniotomy and partial labyrinthectomy with duraplasty for biopsy sampling and partial microsurgical resection of the lesion. Microscopic examination of the biopsy specimen revealed the presence of a mixed cellular population with predominant mature histiocytes consistent with RDD. The residual tumor was treated with stereotactic radiosurgery 2 months after resection. On follow-up imaging the lesion had regressed significantly, with only slight dural enhancement remaining. Microsurgical resection for histological diagnosis, followed by stereotactic radiosurgery for residual tumor represents one treatment alternative in the management of intracranial RDD in which a complete resection carries the potential for excess morbidity.

Brain Diseases↗

Radiosurgery in patients with renal cell carcinoma metastasis to the brain: long-term outcomes and prognostic factors influencing survival and local tumor control.

OBJECT: Renal cell carcinoma is a leading cause of death from cancer and its incidence is increasing. In many patients with renal cell cancer, metastasis to the brain develops at some time during the course of the disease. Corticosteroid therapy, radiotherapy, and resection have been the mainstays of treatment. Nonetheless, the median survival in patients with renal cell carcinoma metastasis is approximately 3 to 6 months. In this study the authors examined the efficacy of gamma knife surgery in treating renal cell carcinoma metastases to the brain and evaluated factors affecting long-term survival. METHODS: The authors conducted a retrospective review of 69 patients undergoing stereotactic radiosurgery for a total of 146 renal cell cancer metastases. Clinical and radiographic data encompassing a 14-year treatment interval were collected. Multivariate analyses were used to determine significant prognostic factors influencing survival. The overall median length of survival was 15 months (range 1-65 months) from the diagnosis of brain metastasis. After radiosurgery, the median survival was 13 months in patients without and 5 months in those with active extracranial disease. In a multivariate analysis, factors significantly affecting the rate of survival included the following: 1) younger patient age (p = 0.0076); 2) preoperative Karnofsky Performance Scale score (p = 0.0012); 3) time from initial cancer diagnosis to brain metastasis diagnosis (p = 0.0017); 4) treatment dose to the tumor margin (p = 0.0252); 5) maximal treatment dose (p = 0.0127); and 6) treatment isodose (p = 0.0354). Prior tumor resection, chemotherapy, immunotherapy, or whole-brain radiation therapy did not correlate with extended survival. Postradiosurgical imaging of the brain demonstrated that 63% of the metastases had decreased, 33% remained stable, and 4% eventually increased in size. Two patients (2.9%) later underwent a craniotomy and resection for a tumor refractory to radiosurgery or a new symptomatic metastasis. Eighty-three percent of patients died of progression of extracranial disease. CONCLUSIONS: Stereotactic radiosurgery for treatment of renal cell carcinoma metastases to the brain provides effective local tumor control in approximately 96% of patients and a median length of survival of 15 months. Early detection of brain metastases, aggressive treatment of systemic disease, and a therapeutic strategy including radiosurgery can offer patients an extended survival.

Adult↗

Acoustic tumors: operation versus radiation--making sense of opposing viewpoints. Part II. Acoustic neuromas: sorting out management options.

Patients with acoustic neuromas have several options available to them. Large tumors with significant brain stem compression usually require surgical resection. For patients with small or medium-sized tumors, radiosurgery has become a common treatment, with excellent long-term results being reported. Patients must be comfortable with the concept of tumor control rather than tumor removal. Most seem to be satisfied with this concept if it allows them to avoid brain surgery. Surgeons should strive to educate their patients with information from the peer-reviewed literature. Confusion exists among patients, because the information from Internet sources, newsletters, support groups, and physicians has not always been validated and supported by outcomes data. Although we are asked to provide our opinions, our comments should not be based on myth, conjecture, training bias, or socioeconomic concerns.

Decision Making↗

External beam irradiation of craniopharyngiomas: long-term analysis of tumor control and morbidity.

PURPOSE: To delineate the long-term control and morbidity with external beam radiotherapy (EBRT) of craniopharyngiomas. METHODS AND MATERIALS: Between 1971 and 1992, 24 craniopharyngioma patients underwent EBRT at the University of Pittsburgh. Most (19 of 24) were treated within 1-3 months after subtotal resection. The other prior surgical procedures were biopsy (n = 2) and gross total resection (n = 1); 2 patients did not undergo any surgical procedure. The median follow-up was 12.1 years. The median patient age was 29 years (range 5-69). The total radiation doses varied from 36 to 70 Gy (median 59.75). The normalized total dose (NTD, biologically equivalent dose given in 2 Gy/fraction [alpha/beta ratio = 2]) varied from 28 to 83 Gy (median 55.35). RESULTS: The actuarial survival rate at 10 and 20 years was 100% and 92.3%, respectively. The actuarial local control rate at 10 and 20 years was 89.1% and 54.0%, respectively. No local failures occurred with doses >or=60 Gy (n = 12) or NTDs >or=55 Gy. The complication-free survival rate at 10 and 20 years was 80.1% and 72.1%, respectively. No complications were noted with an NTD of <or=55 Gy. The actuarial survival free from any adverse outcome (recurrence or complication) was 70.1% and 31.8% at 10 and 20 years, respectively. The adverse outcome-free survival appeared optimized (at 73%) with an NTD of 55-63 Gy. Multivariate analysis found that tumor control correlated significantly with the total dose (p = 0.02), treatment complications with NTD (p = 0.008), and adverse outcome with hypopituitarism on presentation (p = 0.03). CONCLUSION: We recommend treating craniopharyngioma with 1.6-1.7-Gy dose fractions to 60 Gy to optimize outcome from EBRT.

Adolescent↗

Analysis of repeat stereotactic radiosurgery for progressive primary and metastatic CNS tumors.

PURPOSE: To identify and evaluate the pretreatment and patient factors that would predict for complications after repeat radiosurgery. METHODS AND MATERIALS: The data from 26 patients who underwent re-irradiation with Gamma Knife surgery after a previous procedure in the same or subjacent location were available for evaluation. The range of follow-up was 1-45 months (mean 10). The mean minimal and maximal initial dose and volume for all 26 patients was 16.2 Gy (range 12-22), 31.0 Gy (range 22.2-40.0), and 12.4 cm(3) (range 1.20-70.84), respectively. The mean marginal and maximal repeated radiosurgery dose and volume for all 26 patients was 14.9 Gy (range 12-22.5), 29.7 Gy (range 18.0-45.0) and 12.8 cm(3) (range 1.10-39.20), respectively. RESULTS: Tumor control was significantly better statistically (p = 0.0129) for benign tumors (6 of 6, 100% actuarial rate at 4 years) compared with malignant tumors (7 of 20, 35% actuarial rate at 3 years, 3 of 4 metastatic tumors and 2 of 10 primary malignant gliomas). The retreatment volume for radiosurgery correlated significantly with the probability of neurologic decline (any cause) (p = 0.0181). CONCLUSION: Repeat radiosurgery can be performed for recurrent tumors with minimal central nervous system toxicity, especially for benign tumors, with reasonable tumor control.

Adolescent↗

Glioma-associated hyaluronan induces apoptosis in dendritic cells via inducible nitric oxide synthase: implications for the use of dendritic cells for therapy of gliomas.

As a means of enhancing immunity to gliomas, we investigated local delivery of rat, bone marrow-derived dendritic cells (DCs) into rat 9L gliosarcoma tumors and into 9L tumors induced to undergo apoptosis by gamma knife radiosurgery. Contrary to other tumors, local delivery of DCs had no therapeutic effect on 9L gliomas, even when tumor apoptosis was induced via radiosurgery, which leads to efficient "loading" of the DCs with tumor antigen. To determine whether antigen-presenting cells, such as DCs, were viable in tumors, we carried out multiparametric staining of 9L tumors, using phycoerythrin-conjugated OX6 (MHC class II) or OX62 (DC specific) and FITC-labeled Val-Ala-Asp-fluoromethyl ketone (FITC-VAD-FMK; activated caspases). It was determined that DCs were undergoing apoptosis in these tumors. We therefore sought to determine which glioma cell surface receptors or components of the extracellular matrix in gliomas influenced DC viability. Hyaluronan (HA) is a major component of glioma extracellular matrix and has been found to support tumor cell migration and metastasis. However, its influence on the immune system, and particularly on DCs, via its receptor CD44 is not well documented. Using reverse transcription-PCR, Northern blot, and Western blot analyses, we determined that HA stimulated production of inducible nitric oxide synthase (iNOS) in DCs. NO production by HA-stimulated DCs was then verified biochemically. NO production was dependent on the size of HA; intermediate HA fragments had the greatest capacity to induce NO production in DC, whereas completely digested HA oligosaccharides failed to induce NO. Furthermore, N-monomethyl-L-arginine, an inhibitor of iNOS, completely blocked HA-induced NO production by DCs. Because induction of NO results in the induction of apoptosis in macrophages as well as other cells, DCs treated with HA were examined for apoptosis in terminal deoxynucleotidyl transferase (TdT)-mediated dUTP biotin nick-end labeling assays. It was demonstrated that HA induced apoptosis in DCs and that induction of apoptosis was dependent on the production of NO because it was entirely inhibited by N-monomethyl-L-arginine. Using flow cytometric analyses with FITC-VAD-FMK, which is specific for activated caspases, we also determined that induction of apoptosis in DCs with HA could be titrated. Coincubation of 9L tumor cells with DCs was found to induce apoptosis in DCs as indicated by fluorescent staining with FITC-VAD-FMK. Specificity of this reaction for CD44-HA interactions was determined by pretreatment of DCs with anti-CD44 or pretreatment of 9L tumor cells with hyaluronidase, which blocked the induction of apoptosis in DCs. These data indicate that HA expressed by gliomas may contribute to their immunosuppressive effects by promoting apoptosis among professional antigen-presenting cells such as DCs via iNOS induction after CD44-HA interactions.

Animals↗

Acoustic Neuromas.

Patients with acoustic neuromas have several treatment options that include observation, surgical resection, stereotactic radiosurgery, and fractionated radiotherapy. Resection is indicated for patients with larger tumors that have caused major neurologic deficits from brain compression. Surgeons perform stereotactic radiosurgery as the main alternative to acoustic tumor resection with the goals of preserved neurologic function and prevention of tumor growth. The long-term outcomes of radiosurgery, particularly with gamma knife technique, have proven its role in the primary or adjuvant management of this disease. Radiotherapy can be offered to selected patients with larger tumors in whom radiosurgery may not be feasible. Patients with neurofibromatosis type-2 pose specific challenges, particularly in regard to preservation of hearing and other cranial nerve function. The primary clinical issues include avoiding tumor-related or treatment-related mortality, prevention of further tumor-related neurologic disability, minimizing treatment risks such as spinal fluid leakage, infections, or cardiopulmonary complications, maintaining regional cranial nerve function (facial, trigeminal, cochlear, and glossopharyngeal/vagal), avoiding hydrocephalus, maintaining quality of life and employment, and reducing cost. All treatment choices should strive to meet all of these goals.

Journal Article↗