Georg Norén

Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues

Intractable OCD and depression cause tremendous suffering in those affected and in their families. The impaired ability to function of those affected imposes a heavy burden on society as a whole. Existing data suggest that lesion procedures offer benefit to a large proportion (ranging from about 35%-70%) of patients with intractable OCD and depression. The literature also suggests that although serious long-term adverse events have occurred, these are relatively infrequent overall. Methodologic limitations of the earlier reports on any of these procedures were described previously in this article. The major academic centers conducting this work have since been obtaining systematic prospective data using modern assessment tools. Nevertheless, even with improved methodologies, more recent studies confront some remaining issues that have been difficult to overcome fully. First, the number of patients who have received any one procedure has been relatively small, constraining statistical power. This limits the ability of researchers to enhance patient selection based on clinical characteristics. This is important, because patients with intractable OCD and depression referred for neurosurgery have high rates of comorbid Axis I diagnoses, personality disorders, and functional impairments, which may have value in predicting response. Other features, such as age of onset, chronicity, and symptom subtypes, may be likewise useful. Another key factor in response may be postoperative management, which has varied most over time but also across patients enrolled in trials. As noted previously, randomized controlled trials of neurosurgical treatment for intractable psychiatric illness have not been reported, although one has been proposed for gamma knife capsulotomy in intractable OCD [23]. The development of deep brain stimulation has also made sham-controlled studies possible and also allows within-patient designs to be considered. Bearing these problems in mind, the literature does provide important guidance on a number of key points, including approaches to referral, patient selection, and the need for long-term prospective follow-up and postoperative management. Nevertheless, important gaps in knowledge remain in all these areas. Research is expected to narrow these gaps in a number of ways, including patient selection, optimizing the procedures themselves, and understanding the mechanisms of therapeutic action. Neuroimaging studies will play a key role in achieving these aims (see the article by Rauch in this issue). So will cross-species translational research on the anatomy and physiology of the pathways implicated in the pathophysiology and response to treatment in these disorders. Future research in psychiatric neurosurgery must proceed cautiously. A recent editorial statement of the OCD-DBS Collaborative Group [26] recommends a minimum set of standards for any multidisciplinary teams contemplating work in this domain. The rationale for those standards is found throughout this issue and is especially developed in the article by Fins. The need for safe and effective therapeutic options for people suffering with these severe illnesses is just as clear. The experience over the last several decades provides grounds for careful optimism that refined lesion procedures or reversible deep brain stimulation may relieve suffering and improve the lives of people with these devastating disorders.

Randomized treatment of brain metastasis with gamma knife radiosurgery, whole brain radiotherapy or both

Results: The overall median survival was 7, 5 and 9 months for the GK, GK + WBRT and WBRT arms respectively. The local control was 87%, 91%. and 62% for GK, GK + WBRT and WBRT alone arms respectively, suggesting that the two radiosurgery arms were superior. However. the occurrence of new brain lesions was lower (43%, 19% and 23% for GK, GK + WBRT and WBRT alone respectively) in the two arms receiving WBRT. Regardless of treatment group, the local control and survival for patients who had surgical resection of brain metastases was 88% and 9 months compared to 73% and 6 months for those without resection suggesting some benefit of surgery. This survival benefit for surgery was not seen in patients who received GK as part of their treatment. Survival of patients by primary site was 6, 9.5 and 7 months for NSCLC. breast and colorectal cancers respectively. Patients with resected primary tumors had a median survival of 9 months compared with 5.5 months for those whose primary tumors were treated with radiation i- chemotherapy respectively. Conclusions: Local control of treated metastatic lesions is superior with the radiosurgery arms. However, the risk of developing new brain lesions is higher for patients not receiving whole brain radiotherapy. There was no difference in overall survival between the three arms. Resection of metastatic lesions did add to overall survival, but not for those receiving radiosurgery. Patients with breast and colorectal cancer faired better than those with lung cancer. Survival was better for patients with resected primary tumors compared to those treated with radiation i- chemotherapy.

Vestibular schwannoma management in the next century: a radiosurgical perspective.

PURPOSE To discuss how the evolution of vestibular schwannoma radiosurgery, changes in health care delivery, and patient accessibility to medical information will affect the management of vestibular schwannomas in the future. CONCEPT In comparison with microsurgical resection of vestibular schwannomas, radiosurgery has a lower morbidity rate, a similar risk of requiring further surgery, and higher patient satisfaction. As this information becomes more widely available to patients and third-party payors, radiosurgery may replace surgical resection as the preferred management strategy for patients with small to medium sized vestibular schwannomas in the United States. RATIONALE It is estimated that 2500 patients are diagnosed with vestibular schwannomas each year in the United States. Assuming that 80% undergo surgery, 2000 operations are performed annually for newly diagnosed vestibular schwannomas. Data available since 1987 regarding the number of cases for which gamma knife radiosurgery was performed were used to predict the number of patients who will undergo vestibular schwannoma radiosurgery in the future. If the current trend continues, an equal number of patients will undergo surgical resection and radiosurgery to treat their vestibular schwannomas (approximately 1000/yr) sometime between 2005 and 2010. Moreover, it is predicted that by 2020, two-thirds of the patients who are newly diagnosed with vestibular schwannomas will undergo radiosurgery, with surgical resection being reserved for patients with large tumors associated with symptomatic brain stem compression. DISCUSSION Early data regarding vestibular schwannoma radiosurgery predicted an exponential growth curve. Although it is premature to assume that the current trend will continue, it is likely that an ever increasing percentage of patients will undergo radiosurgery as accessibility to this alternative increases, and more data are published regarding long-term tumor growth control rates. If the mathematical model proves to be accurate, then stereotactic radiosurgery will replace surgical resection as the preferred management strategy for the majority of patients with vestibular schwannomas.

xROLE OF GAMMA KNIFE THERAPY IN THE MANAGEMENT OF PITUITARY TUMORS

1. Gamma knife therapy is an effective method of delivering radiation to pituitary tumors that have failed surgery and may be used as primary treatment in circumstances in which the patient refuses or is unsuitable for a transsphenoidal procedure. 2. Stereotactic radiosurgery with the gamma knife unit is generally administered in a single session unlike fractionated radiotherapy, which is administered four to five times per week over a 6-week period. 3. Preliminary data suggest that resolution of pituitary hypersecretion is faster with gamma knife therapy than with conventional radiotherapy. 4. Because of the nature of the gamma knife therapy and the fact that the radiation dose conforms to the tumor shape, there is a steep fall-off of radiation to surrounding tissue. Accordingly, the radiation dose to extrapituitary brain is substantially less with gamma knife radiosurgery than with conventional radiotherapy. This suggests that the development of second brain tumors and neurocognitive complications, which are significant risks with conventional radiotherapy, is much less likely with gamma knife surgery. 5. Gamma knife radiosurgery can be used to ablate tumors invading the cavernous sinus. 6. Gamma knife radiosurgery is safe as long as the dose of radiation to the optic structures is kept under 10 Gy. 7. Long-term follow-up is required for pituitary tumors treated by gamma knife therapy so as to determine its efficacy as well as its effects on pituitary function and any resultant complications.

Stereotactic radiosurgery for functional disorders

Stereotactic radiosurgery (SRS) with the Gamma Knife and linear accelerator has revolutionized neurosurgery over the past 20 years. The most common indications for radiosurgery today are tumors and arteriovenous malformations of the brain. Functional indications such as treatment of movement disorders or intractable pain only contribute a small percentage of treated patients. Although SRS is the only noninvasive form of treatment for functional disorders, it also has some limitations: neurophysiological confirmation of the target structure is not possible, and one therefore must rely exclusively on anatomical targeting. Furthermore, lesion sizes may vary, and shielding adjacent radiosensitive neural structures may be difficult or impossible. The most common indication for functional SRS is the treatment of trigeminal neuralgia. Radiosurgical treatment for epilepsy and certain psychiatric illnesses is performed in several centers as part of strict research protocols, and radiosurgical pallidotomy or medial thalamotomy is no longer recommended due to the high risk of complications. Radiosurgical ventrolateral thalamotomy for the treatment of tremor in patients with Parkinson disease or multiple sclerosis, as well as in the treatment of essential tremor, may be indicated for a select group of patients with advanced age, significant medical conditions that preclude treatment with open surgery, or patients who must receive anticoagulation therapy. A promising new application of SRS is high-dose radiosurgery delivered to the pituitary stalk. This treatment has already been successfully performed in several centers around the world to treat severe pain in patients with end-stage cancer.

Retreatment of vestibular schwannomas with Gamma Knife surgery

OBJECT The response rate of vestibular schwannomas (VSs) to radiosurgery has reached the 97% level in several published series. When failure rarely occurs, some controversy has existed as to whether the tumor has to be resected or can be safely retreated with radiosurgery. The authors retrospectively studied the outcome of retreating 11 patients with Gamma Knife surgery (GKS). METHODS The authors studied 11 patients at the New England Gamma Knife Center who had undergone GKS as a second radiosurgical treatment for VS from 1994 to 2007. One patient underwent proton-beam radiotherapy as the first treatment, and the other 10 patients had undergone GKS initially. Tumor control (size before and after the first and the second treatment) was evaluated using MR imaging to demonstrate the course after the 2 treatments. Facial nerve function (House-Brackmann grading system), trigeminal nerve function, hearing (Gardner-Robertson classification), and any adverse radiation effects were evaluated. The prescription dose was 12 Gy (11-13.2 Gy) for both treatments. RESULTS Of the 11 patients, 2 showed increase, 1 had no change, and, in 8, the VS decreased in size after the retreatment. One tumor remained unchanged over the first 6 months, but demonstrated signs of internal necrosis. All patients demonstrated stable facial nerve function. Regarding facial numbness, 2 patients experienced increases, 8 no change, and 1 decreased numbness. There was no functional hearing prior to the second treatment in 10 patients, and hearing was impaired in 1 patient. Adverse radiation effects (slight peduncular edema) were seen in 2 patients after the second treatment, and 1 patient had edema after the first treatment as well. CONCLUSIONS Vestibular schwannomas can be retreated with GKS with good tumor control response and low risk of toxicity.

Survival among patients with 10 or more brain metastases treated with stereotactic radiosurgery

OBJECT The goal of this study was to evaluate outcomes in patients with ≥ 10 CNS metastases treated with Gamma Knife stereotactic radiosurgery (GK-SRS). METHODS Patients with ≥ 10 brain metastases treated using GK-SRS during the period between 2004 and 2010 were identified. Overall survival and local and regional control as well as necrosis rates were determined. The influence of age, sex, histological type, extracranial metastases, whole-brain radiation therapy, and number of brain metastases was analyzed using the Kaplan-Meier method. Univariate (log-rank) analyses were performed, with a p value of < 0.05 considered significant. RESULTS Fifty-three patients with ≥ 10 brain metastases were treated between 2004 and 2010. All had a Karnofsky Performance Status score of ≥ 70. Seventy-two percent had either non-small cell lung cancer (38%) or breast cancer (34%); melanoma, small cell lung cancer, renal cell carcinoma, and testicular, colon, and ovarian cancer contributed the remaining 28%. On average, 10.9 lesions were treated in a single session. Sixty-four percent of patients received prior whole-brain radiation therapy. The median survival was 6.5 months. One-year overall survival was 42% versus 14% when comparing breast cancer and other histological types, respectively (p = 0.074). Age, extracranial metastases, number of brain metastases, and previous CNS radiation therapy were not significant prognostic factors. Although the median time to local failure was not reached, the median time to regional failure was 3 months. Female sex was associated with longer time to regional failure (p = 0.004), as was breast cancer histological type (p = 0.089). No patient experienced symptomatic necrosis. CONCLUSIONS Patients with ≥ 10 brain metastases who received prior CNS radiation can safely undergo repeat treatment with GK-SRS. With median survival exceeding 6 months, aggressive local treatment remains an option; however, rapid CNS failure is to be expected. Although numbers are limited, patients with breast cancer represent one group of individuals who would benefit most, with prolonged survival and extended time to CNS recurrence.

Visuospatial Memory Improvement after Gamma Ventral Capsulotomy in Treatment Refractory Obsessive-Compulsive Disorder Patients.

Gamma ventral capsulotomy (GVC) radiosurgery is intended to minimize side effects while maintaining the efficacy of traditional thermocoagulation techniques for the treatment of refractory obsessive–compulsive disorder (OCD). Neuropsychological outcomes are not clear based on previous studies and, therefore, we investigated the effects of GVC on cognitive and motor performance. A double-blind, randomized controlled trial (RCT) was conducted with 16 refractory OCD patients allocated to active treatment (n=8) and sham (n=8) groups. A comprehensive neuropsychological evaluation including intellectual functioning, attention, verbal and visuospatial learning and memory, visuospatial perception, inhibitory control, cognitive flexibility, and motor functioning was applied at baseline and one year after the procedure. Secondary analysis included all operated patients: eight from the active group, four from the sham group who were submitted to surgery after blind was broken, and five patients from a previous open pilot study (n=5), totaling 17 patients. In the RCT, visuospatial memory (VSM) performance significantly improved in the active group after GVC (p=0.008), and remained stable in the sham group. Considering all patients operated, there was no decline in cognitive or motor functioning after one year of follow-up. Our initial results after 1 year of follow-up suggests that GVC not only is a safe procedure in terms of neuropsychological functioning but in fact may actually improve certain neuropsychological domains, particularly VSM performance, in treatment refractory OCD patients.

RADIATION-INDUCED EPILATION DUE TO COUCH TRANSIT DOSE FOR THE LEKSELL GAMMA KNIFE MODEL C

PURPOSE To determine the cause of epilation at the top of the head for 2 patients with acoustic neuromas after undergoing fractionated radiosurgery with the Leskell Gamma Knife model C. This epilation was unexpected, because the treatment planning program stated the dose at this location was <0.1 Gy. METHODS AND MATERIALS The radiation dose along a central axis, parallel to the couch, from the helmets focus to the helmet cap was measured during couch transit. RESULTS Transit doses of 4.4 cGy/shot at 10 cm and 5.6 cGy/shot at distances >15 cm from the helmets focus were measured. It was estimated that the 2 patients with epilation received approximately 6-7 Gy to the scalp. A shield was constructed and shown to reduce the transit dose by as much as 60%. CONCLUSION The design of the helmet allows the uncollimated beams to reach areas of the patient, superior to the target, just before and after couch docking with the housing. For treatment involving a large number of shots (i.e., fractionation), off-target doses < or = 8 Gy can result. For these cases, the transit dose should be considered and some form of additional shielding should be used.

Notice of Retraction and Replacement. Lopes et al. Gamma ventral capsulotomy for obsessive-compulsive disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71(9):1066-1076

In Reply We agree that our results are based on a small number of respondents who met criteria for major depressive disorder and mood disorders. We were transparent about this and noted sample size as the study’s primary limitation. As stated in our article,1 the National Survey of American Life (NSAL) remains one of the best data sets for this study. We considered using National Comorbidity Survey Replication data; however, it contained a limited number of rural cases. Given the sample size limitation, our article1 emphasized the importance of future research examining major depressive disorder and mood disorders among rural African American individuals with other samples. Second, Keyes and colleagues’ statement that “the national sample weights cannot be assumed to be appropriate for approximating regional-specific estimates...” is not a valid statement for the NSAL. Because the nonresponse adjustment factors in the NSAL weights are computed separately for NSAL respondents from the South region and primary stage sampling units with the design strata representing the South, the weights (including the implicit nonresponse) are uniquely determined for the South and the weight computation process is not influenced by the response experience or the patterns of depression in other regions of the country. We are confident that the NSAL weights are computed “appropriately” for both national estimates and analyses for subpopulations. Third, Keyes et al criticize us for speculating on our findings. However, that is the purpose of a Discussion section. They minimize the importance of religiosity as a potential mechanism to explain lower rates of major depressive disorder among African American women. However, research consistently reports higher rates of religiosity among African American individuals,2 and that religiosity is protective for depression.3 Krause’s4 extensive body of work suggests religion and churchbased social support are protective of mental and physical health, including mortality. Most of his studies demonstrate that older African American individuals are more likely than older white individuals to reap mental and physical health– related benefits of religion owing to higher levels of religious participation and church-based support networks. Additionally, Reese et al5 found that when controlling for religious service attendance, the black-white difference in depression was no longer significant. Clearly, our speculation about the importance of religious participation is not “fraught with problematic assumptions lacking empirical support” as stated by Keyes et al. Last, Keyes et al argue that our focus on religiosity and social ties risks minimizing “the role of structural, economic, and sex discrimination experienced by African American women, while potentially reifying stereotypes.” This is by no means the case. In fact, much of the contemporaneous and historical research on black-white differences in the social sciences has taken a deficit approach and has not adequately considered African American women’s strengths. That is, despite a history of slavery and Jim Crow laws, high levels of poverty, segregated and low-quality education, and substandard housing, African American women in the rural South continue to cope. We take a strengths-based approach and argue that low rates of depression among rural African American women are potentially owing to their high levels of religiosity and their family ties.