The long-term consequences of adenovirus-mediated conditional cytotoxic gene therapy for gliomas remain uncharacterized. We report here detection of active brain inflammation 3 months after successful inhibition of syngeneic glioma growth. The inflammatory infiltrate consisted of activated macrophages/microglia and astrocytes, and T lymphocytes positive for leucosyalin, CD3 and CD8, and included secondary demyelination. We detected strong widespread herpes simplex virus 1 thymidine kinase immunoreactivity and vector genomes throughout large areas of the brain. Thus, patient evaluation and the design of clinical trials in ongoing and future gene therapy for brain glioblastoma must address not only tumor-killing efficiency, but also long-term active brain inflammation, loss of myelin fibers and persistent transgene expression.
Chronic Brain Inflammation and Persistent Herpes Simplex Virus 1 Thymidine Kinase Expression in Survivors of Syngeneic Glioma Treated by Adenovirus-Mediated Gene Therapy: Implications for Clinical Trials
Dewey RA, Morrissey G, Cowsill CM, Stone D, Bolognani F, Dodd NJ, Southgate TD, Klatzmann D, Lassmann H, Castro MG, Lowenstein PR
William T. Couldwell
William T. Couldwell
, transsphenoidal surgery fails to produce remission of symptoms in a significant percentage of patients, and repeated surgery or the institution of adjuvant therapy must be considered in such cases. In this issue of Neurosurgical Focus , a series of papers has been selected to provide a comprehensive overview of the diagnosis and management of this complicated disease. Papers involving the contemporary diagnostic workup and pitfalls, as well as success rates and outcomes following transsphenoidal surgery, are presented. Authors present various treatment options for patients
Brian T. Ragel, William T. Couldwell, Robert D. Wurster and Randy L. Jensen
C omplete resection is the treatment of choice for intracranial meningiomas but may not be possible when the tumor invades critical structures such as the cavernous sinus or sagittal sinus. This is confounded even more by the fact that up to 20% of meningiomas exhibit an aggressive phenotype that does not respond to standard therapies. 19 Thus, adjuvant therapies are critical for patients with this subset of meningiomas. Radiation therapy and stereotactic radiosurgery are good adjuvant therapies but are limited by radiation neurotoxicity, tumor size
Amol Raheja, Howard Colman, Cheryl A. Palmer and William T. Couldwell
greater risk of recurrence compared with benign WHO Grade I meningiomas and by the considerably increased risk of mortality in atypical meningiomas in age- and sex-matched controls. 9 Recurrence rates of atypical meningioma can exceed 50%. 5 , 9 Currently, the management options for meningioma include surgery and radiation therapy primarily, with only a limited role for medical management (chemotherapy/targeted therapy). 3 This approach is effective in achieving tumor control of most WHO Grade I meningiomas as well as for a subset of patients with WHO Grade II tumors
Christina M. Sayama, James K. Liu and William T. Couldwell
✓Cerebral vasospasm remains a major source of morbidity and death in patients with aneurysmal subarachnoid hemorrhage (SAH). When vasospasm becomes refractory to maximal medical management consisting of induced hypertension and hypervolemia and administration of calcium channel antagonists, endovascular therapies should be considered. The primary goal of endovascular treatment is to increase cerebral blood flow to prevent cerebral infarction. Two of the more frequently studied endovascular treatments are transluminal balloon angioplasty and intraarterial papaverine infusion. These two have been used either alone or in combination for the treatment of vasospasm. Other pharmacological vasodilating agents currently being investigated are intraarterial nimodipine, nicardipine, verapamil, and milrinone. Newer intraarterial agents, such as fasudil and colforsin daropate, have also been investigated. In this article the authors review the current options in terms of endovascular therapies for treatment of cerebral vasospasm. The mechanism of action, technique of administration, clinical effect and outcomes, and complications of each modality are discussed.
James K. Liu and William T. Couldwell
features, tumor type, visual and cranial nerve outcome, and endocrinological outcome. All patients underwent an endocrinological workup at the time of admission and were started on a regimen of intravenous corticosteroid drugs. Patients with prolactin-secreting adenomas were considered for dopamine agonist therapy. Each MR image was evaluated for the presence of thickening and enhancement of sphenoid sinus mucosa. The thickness of the sphenoid sinus mucosa adjacent to the sellar floor was measured on T 1 - or T 2 -weighted MR images obtained after addition of Gd. The
James K. Liu and William T. Couldwell
Prolactin-secreting pituitary adenomas—prolactinomas—are the most common type of functional pituitary tumor. Treatment of hyperprolactinemia is indicated because of the consequences of infertility, gonadal dysfunction, and osteoporosis. Making the correct diagnosis is important because the first line of therapy is medical management with dopamine agonists. Medical therapy is effective in normalizing prolactin levels in more than 90% of patients, but long-term treatment may be required in some patients. Transsphenoidal surgery is usually indicated in those patients in whom medical therapy fails or cannot be tolerated, or in patients who harbor microprolactinomas. In experienced hands, a hormonal and oncological cure can be achieved in more than 90% of patients after transsphenoidal removal of microprolactinomas with minimal risks. Thus, surgery may be an option for microprolactinomas in a young patient who desires restoration of fertility and avoidance of long-term medical therapy. The authors review the diagnosis and management of prolactinomas, including medical therapy, surgical therapy, and stereotactic radiosurgery.
William T. Couldwell and Roukoz Chamoun
Dorsal variant proximal carotid blister aneurysms are treacherous lesions to manage. It is important to recognize this variant on preoperative angiographic imaging, in anticipation of surgical strategies for their treatment. Strategies include trapping the involved segment and revascularization if necessary. Other options include repair of the aneurysm rupture site directly. Given that these are not true berry aneurysms, repair of the rupture site involves wrapping or clip-grafting techniques. The case presented here was a young woman with a subarachnoid hemorrhage from a ruptured dorsal variant blister aneurysm. The technique used is demonstrated in the video and is a modified clip-wrap technique using woven polyester graft material. The patient was given aspirin preoperatively as preparation for the clip-wrap technique.
It is the authors' current protocol to attempt a direct repair with clip-wrapping and leaving artery sacrifice with or without bypass as a salvage therapy if direct repair is not possible. Assessment of vessel patency after repair is performed by intraoperative Doppler and indocyanine green angiography. Intraoperative somatosensory and motor evoked potential monitoring is performed in all cases.
The video can be found here: http://youtu.be/crUreWGQdGo.
Daniel R. Fassett and William T. Couldwell
Only 1% of all pituitary surgeries are performed to treat tumors that have metastasized to the pituitary gland; however, in certain cases of malignant neoplasms pituitary metastases do occur. Breast and lung cancers are the most common diseases that metastasize to the pituitary. Breast cancer metastasizes to the pituitary especially frequently, with reported rates ranging between 6 and 8% of cases.
Most pituitary metastases are asymptomatic, with only 7% reported to be symptomatic. Diabetes insipidus, anterior pituitary dysfunction, visual field defects, headache/pain, and ophthalmoplegia are the most commonly reported symptoms. Diabetes insipidus is especially common in this population, occurring in between 29 and 71% of patients who experience symptoms.
Differentiation of pituitary metastasis from other pituitary tumors based on neuroimaging alone can be difficult, although certain features, such as thickening of the pituitary stalk, invasion of the cavernous sinus, and sclerosis of the surrounding sella turcica, can indicate metastasis to the pituitary gland. Overall, neurohypophysial involvement seems to be most prevalent, but breast metastases appear to have an affinity for the adenohypophysis. Differentiating metastasis to the pituitary gland from bone metastasis to the skull base, which invades the sella turcica, can also be difficult. In metastasis to the pituitary gland, surrounding sclerosis in the sella turcica is usually minimal compared with metastasis to the skull base.
Treatment for these tumors is often multimodal and includes surgery, radiation therapy, and chemotherapy. Tumor invasiveness can make resection difficult. Although surgical series have not shown any significant survival benefits given by tumor resection, the patient's quality of life may be improved. Survival among these patients is poor with mean survival rates reported to range between 6 and 22 months.
William T. Couldwell, Martin H. Weiss and Edward R. Laws Jr
Whether the withdrawal of treatment in patients with nontumoral hyperprolactinemia, microprolactinomas, or macroprolactinomas is safe and effective has been unclear. We performed an observational, prospective study of cabergoline (a dopamine-receptor agonist) withdrawal in such patients.
The study population included 200 patients—25 patients with nontumoral hyperprolactinemia, 105 with microprolactinomas, and 70 with macroprolactinomas. Withdrawal of cabergoline was considered if prolactin levels were normal, magnetic resonance imaging (MRI) showed no tumor (or tumor reduction of 50 percent or more, with the tumor at a distance of more than 5 mm from the optic chiasm, and no invasion of the cavernous sinuses or other critical areas), and if follow-up after withdrawal could be continued for at least 24 months.
Recurrence rates two to five years after the withdrawal of cabergoline were 24 percent in patients with nontumoral hyperprolactinemia, 31 percent in patients with microprolactinomas, and 36 percent in patients with macroprolactinomas. Renewed tumor growth did not occur in any patient; in 10 female patients (22 percent) and 7 male patients (39 percent) with recurrent hyperprolactinemia, gonadal dysfunction redeveloped. In all diagnostic groups, prolactin levels at the time of recurrence were significantly lower than at diagnosis (p < 0.001). The Kaplan–Meier estimated rate of recurrence at five years was higher among patients with macroprolactinomas and those with microprolactinomas who had small remnant tumors visible on MRI at the time of treatment withdrawal than among patients whose MRI scans showed no evidence of tumor at the time of withdrawal (patients with macroprolactinomas, 78 percent vs. 33 percent, P = 0.001; patients with microprolactinomas, 42 percent vs. 26 percent, P = 0.02).
Cabergoline can be safely withdrawn in patients with normalized prolactin levels and no evidence of tumor. However, because the length of follow-up in our study was insufficient to rule out a delayed increase in the size of the tumor, we suggest that patients be closely monitored, particularly those with macroprolactinomas, in whom renewed growth of the tumor may compromise vision.