Bilateral anterior capsulotomy for patients with refractory obsessive-compulsive disorder: A multicenter, long-term, follow-up study
Keywords: Bilateral anterior capsulotomy, obsessive-compulsive disorder, psychosurgery, stereotactic surgery
Obsessive-compulsive disorder (OCD) is a severe psychiatric disease characterized by compulsive thoughts and behavior, such as cleaning, checking, counting, and hoarding. The morbidity of OCD is seen in approximately 1–3% of the subjects assessed., However, nearly 20% of OCD patients do not respond well to pharmacological and behavioral therapy. These patients are considered as refractory OCD patients. At present, it is difficult to treat this disease. Some clinicians have attempted to treat OCD utilizing stereotactic surgery and have achieved some success. At present, several surgical methods, such as anterior capsulotomy,, anterior cingulotomy,, subcaudate tractotomy,, and limbic leucotomy,, have been used to treat OCD. Among these methods, anterior capsulotomy and anterior cingulotomy are the most commonly applied methods to treat OCD. Despite the current availability of various surgical methods to treat OCD, each method has a distinct rate of efficacy and side effect profile. Therefore, we aimed to accurately identify the optimal target of stereotactic surgery for OCD. The present study analyzed all characteristics of 37 OCD patients who underwent stereotactic anterior capsulotomy in West China Hospital of Sichuan University or Mian Yang Central Hospital, and the short-term and long-term effects and complications of capsulotomy were evaluated.
Patient selection and preparation
Between October 2007 and June 2010, 37 patients with OCD underwent anterior capsulotomy in West China Hospital of Sichuan University or Mian Yang Central Hospital [Table 1]. Patients were enrolled in the study if they met the following criteria: (1) They had been diagnosed as suffering from OCD by two psychiatrists according to The Diagnostic and Statistical Manual of Mental Disorders (DSM), and had received standard anti-obsessive drugs, primarily including clomipramine tablets and selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, fluvoxamine) at a dosage selected by a psychiatrist, for at least 5 years, and had exhibited no effect of treatment for more than 3 years; (2) there was no significant improvement in clinical symptoms, or there was gradual worsening of symptoms, or the severity of symptoms seriously affected the normal work or life of the patient; (3) the patients were more than 18 years old; (4) they had no other associated organic brain syndrome based on imaging assessment; (5) they had no existing contraindications for surgery, such as a serious liver or kidney insufficiency; and, (6) a signed consent was available from the patient and family members to undergo the operation. The operation was authorized by the bioethics committee of the corresponding hospital.
Target designation and operative process
The Leksell Gamma Knife model C stereotactic system (Elekta Instrument, Stockholm, Sweden) was positioned with the patient under local anesthesia, and then, the doctor maintained the patient's head parallel to the anterior commissure–posterior commissure (AC–PC) line. For magnetic resonance imaging (MRI) targeting, a 1.5 T Sigma unit was used to obtain T2 proton-weighted spin echo sequences in the axial and coronal planes. The slice thickness was 2 mm, without an interval gap. For determination of the target coordinates, it was necessary that the images obtained be parallel to one of the axes of the AC–PC line. Both the target coordinates and the electrode penetration angles were calculated at the MRI workstation. The anterior capsule target was located as follows: 22–25 mm anterior to the middle of the AC–PC line, horizontal to the AC–PC line, and 18–20 mm lateral to the midline [Figure 1]. Under local anesthesia, the patient's skin, skull, and meninges were sequentially incised vertically along the sagittal suture and anterior to the coronal suture. The electrodes used for capsulotomy were placed on the skull at the predetermined targets, one on each side, after localization using the Leksell stereotactic system and after achieving hemostasis. Then, high-frequency (100 Hz) stimulation and impedance measurements were obtained to verify the appropriate placement of the radiofrequency electrode. After each electrode was placed at the target, 100-Hz stimulation was applied, and rigidity of the patient was measured to confirm the position of the electrode relative to the internal capsule, and to avoid excessive penetration of the electrode into the genu of the internal capsule or the posterior limb. After confirming the placement of the electrodes at the targets, lesions were generated using radiofrequency energy (Radionics, Elekta) at 70°C and 80°C for 60 s and 70 s, respectively.
Evaluation of clinical effects
The clinical effects of the surgery were evaluated by a direct neuro-psychiatric assessment by an independent psychiatrist preoperatively and 1 week and 1, 3, 6, 12, 36, and 60 months postoperatively, to detect for changes in the clinical symptoms. The main parameters evaluated were scores on the Y-BOCS, HAMA, and HAMD scales [Table 2]. The results were interpreted based on the total scores: a score of 0–7 was considered as subclinical; 8–15 as mild; 16–23 as moderate; 24–31 as severe; and 32–40 as extreme. On comparing the scores obtained at various time points, the effects of the surgical treatment were classified as follows: (1) significant improvement (decrease in the Y-BOCS score by ≥50%), (2) partial improvement (decrease in the Y-BOCS score between 20% and 50%), or (3) no improvement (decrease in the Y-BOCS score by <20%). Moreover, patients with a Y-BOCS score of ≤8 were classified as recovered and those with a Y-BOCS score ≤16 were classified as in remission.
Positron emission tomography scanning and image analysis
All patients fasted for 4 h, and the blood glucose concentration was maintained below 6.7 mmol/L. A positron emission tomography (PET) brain scan (ECAT HR+, Siemens, Knoxville, TN, USA) was performed 40 min after 185–370 MBq of 18-fluorodeoxyglucose (FDG) was injected. For standardized quantitative analysis, a region of interest (ROI)-based method was used. ROIs such as the orbitofrontal cortex (OFC), anterior cingulate gyrus (ACG), caudate nucleus, and thalamus were selected by a PET technician who did not participate in this project. The ratios of glucose metabolism in each ROI relative to the ipsilateral hemisphere (ROI/Hem) were calculated. FDG-PET was performed preoperatively and at 3 and 6 months postoperatively. We compared the changes in regional glucose metabolism in bilateral frontal cerebral lobes and basal ganglia of the preoperative period with that obtained at the 3 and 6 month postoperative assessment using statistical parametric (SPM) analysis software to evaluate the effects of capsulotomy on OCD. A 3T Sigma MRI unit (Siemens) was used for conducting the diffusion tensor imaging (DTI) preoperatively, and at 6 months postoperatively. We compared the preoperative and postoperative images to evaluate the lesioning of the transverse fibers in bilateral anterior limb of the internal capsule.
All variables were summarized using standard descriptive statistics (mean, range, and standard deviation). The results were statistically analyzed using Statistical Package for the Social Sciences (PSSS) 22.0 software (IBM Corporation, Chicago, IL, USA). The Y-BOCS, HAMA, and HAMD scores at various time points postoperatively were compared with the respective preoperative scores using Wilcoxon tests. The FDG-PET data collected at various time-points were compared using t-tests. All tests used P< 0.05 as the level of significance.
Patients' perception of symptoms
The patients who underwent an anterior capsulotomy had different perceptions of their symptoms 5 years post-operatively. The results were as follows: 2 patients perceived that their compulsive symptoms had disappeared; 31 patients perceived improvement in their clinical symptoms; and, 4 patients perceived no improvement in their symptoms. All the patients received anti-obsessive drugs after surgery. According to the patient's recovery after surgery, we generally reduced the drug dosage after the state of illness remained stable for at least 6 months. At the last follow-up, the drug dosage had been reduced in 31 patients and the drugs had been withdrawn in 2 patients.
Changes in clinical rating scale scores
At various time points post-operatively, the scores on the three rating scales revealed a significant decrease compared with the preoperative scores based on the Wilcoxon test (P < 0.05) [Table 2].
The Y-BOCS scores of all 37 patients decreased by 5.26–100.00% (mean: 67.82 ± 26.56%) in the fifth year postoperatively compared with the preoperative score. Among the 37 patients with OCD who underwent the operation, the Y-BOCS scores decreased by more than 50% in 27 (73.0%) patients, decreased between 20% and 50% in 6 (16.2%) patients, and decreased by less than 20% in 4 (10.8%) patients [Figure 2].
The HAMD scores obtained in the fifth year postoperatively were compared with the preoperative scores. The results were as follows: The scores of 1 (2.7%) patient increased, and the scores of 36 patients decreased by 4.17–100% (mean: 72.35 ± 23.44%). Specifically, the scores of 28 (75.7%) patients decreased by greater than 50%, the scores of 7 (18.9%) patients decreased between 20% and 50%, and the score of 1 (2.7%) patient decreased by less than 20% [Figure 2].
The HAMA scores obtained in the fifth year postoperatively were compared with the preoperative scores. The results were as follows: the scores of 2 patients increased; the scores of 1 (2.7%) patient remained unchanged; and, the scores of 34 patients decreased by 5.56–100.00% (mean: 75.17 ± 22.39%). Specifically, the scores of 29 (78.4%) patient decreased by greater than 50%, the scores of 4 (10.8%) patients decreased between 20% and 50%, and the scores of 1 (2.7%) patient decreased by less than 20% [Figure 2].
The mean YBOCS score decreased significantly from a preoperative scores of 26.78 ± 4.92 to a score of 8.30 ± 6.76 after 60 months (P < 0.05) [Table 2]. The mean HAMD score significantly declined from a preoperative value of 22.95 ± 3.64 to 6.65 ± 5.60 at 5 years after surgery (P < 0.05) [Table 2]. The HAMA score, reflecting anxiety symptoms, significantly decreased from a preoperative value of 22.68 ± 5.58 to 6.32 ± 5.39 at 5 years postoperatively (P < 0.05) [Table 2]. The complications occurring after the procedure are summarised in [Table 3] and [Figure 3].
Changes in imaging findings
There were obvious differences between the patients and controls with respect to changes in the regional glucose metabolism. Moreover, there was a marked difference in the FDG-PET findings that were obtained before the surgery and those that were obtained at 3 or 6 months after the operation. Furthermore, another finding that was distinctive was that the glucose metabolic rate further decreased at 6 months postoperatively when compared to the value that existed at 3 months postoperatively [Table 4]. The FDG-PET showed that the regional glucose metabolic rate of the patients with refractory OCD was higher than that of the controls (P < 0.05). This finding suggests that OCD patients exhibit hypermetabolism in specific regions of the brain, especially in the ACG, OFC, and caudate nucleus. As shown in [Table 4], stereotactic capsulotomy significantly decreased the relative glucose metabolic rate in the ACG, OFC, and caudate nucleus (P < 0.05). The regions of most evident decreases in glucose metabolic rate are shown in [Figure 4].
DTI showed that the transverse fibers at the location of the lesion in bilateral anterior limbs of the internal capsule were disconnected in the third month postoperatively. This phenomenon persisted at the sixth month postoperatively [Figure 5].
The main complications included emotional apathy, executive dysfunction, hypomnesia, childish acts, and urinary incontinence. All complications and their timing of disappearance are shown in [Table 3].
Three patients developed cerebral hemorrhage [Figure 6]; hemorrhage occurred at the location of the lesioning in 2 of these patients, and the other patient experienced a hemorrhagic infarct in the prefrontal cortex.
The goals of this multicenter, retrospective, long-term follow-up study were to evaluate the short-term and long-term effects and complications of stereotactic anterior capsulotomy in patients with refractory OCD and to discuss the advantages and disadvantages of stereotactic anterior capsulotomy. The proportion of OCD patients who undergo capsulotomy is typically small, and studies of this approach are typically performed at a single center according to several published reports. To the best of our knowledge, this is the first follow-up study of a surgical treatment for OCD that used a large sample size and multiple centers.
In a 35-patient study, Liu et al., noted that the Y-BOCS scores decreased by >20%, 3 years after the operation, in 86% of the patients. In addition, approximately 72% of the patients exhibited a >20% decrease in the Y-BOCS score in the study by Ruck et al. The mean decrease in the Y-BOCS score was 67.82 ± 26.56%. Specifically, 72.97% of the patients exhibited a >50% decrease in the Y-BOCS score and 16.22% exhibited a 20–50% decrease. In 2 patients, the compulsive symptoms had completely disappeared 5 years after the operation. In addition to compulsive symptoms, comorbid anxiety and depression are observed in most OCD patients.,, In our study, all 37 OCD patients exhibited anxiety and depression. After bilateral anterior internal capsulotomy, in addition to achieving a significant decrease in the Y-BOCS scores, significant decreases in the HAMA and HAMD scores were also observed (P < 0.05) [Table 2]. In our study, the HAMD and HAMA scores decreased by >50% in the fifth year postoperatively compared with the preoperative scores among 75.68% and 78.38% of the OCD patients, respectively. Research showed that anxiety, depression, and OCD may involve similar neural circuits., Therefore, we propose that anterior capsulotomy could also be used to treat refractory depressive and anxiety disorders.,,
At present, our understanding of the pathogenesis of OCD is incomplete. Previous research has established that OCD is related to dysfunction of the cortico-striatal-thalamo-cortical circuit, which connects several structures, such as the prefrontal cortex, basal ganglia, ACG, thalamus, and striatum.,,,, The primary intent of the technique of anterior capsulotomy is to disconnect the fibers connecting the OFC with the thalamus. In addition, during the operation, we interfered with the projection fibers of the striatum in the frontal lobe. In our patients, we used DTI technology to reconstruct images of these fibers across the anterior internal capsule; we found that transverse fibers were clearly disconnected after the operation [Figure 5]. Brain PET scanning of OCD patients showed that these fibers were clearly altered when compared with the pre- and postoperative images, in the prefrontal cortex, basal ganglia, ACG, thalamus, and striatum. Hypermetabolism of glucose in these areas decreased after a bilateral anterior internal capsulotomy., In our patients, the glucose metabolic rate in the prefrontal cortex, caudate nucleus, and ACG significantly decreased after the operation. Moreover, PET showed that the glucose metabolic rate was distinctly lower at 6 months postoperatively than at 3 months postoperatively [Table 4]. These phenomena occurred in OCD patients whose symptoms showed a definite improvement after the operation. We assumed that because all these fibers connecting the OFC, caudate nucleus, and ACG were completely disconnected, certain functions that rely on these fibers would be affected. The PET study showed that the glucose metabolic rate gradually decreased because these disconnected fibers were unable to regenerate. It was evident that most of the locally present transverse fibers were disconnected completely, thus, emphasizing the success of the proceudre. In 10.81% of our patients, compulsive symptoms only partially improved (<20% decrease in the Y-BOCS score) at the fifth year following surgery. In these patients, the 6-month postoperative DTI showed that there were fewer fibers in the anterior internal capsule to be lesioned. In addition, the PET scan of these patients showed that the glucose metabolism rate in the frontal lobe and basal ganglia were less extensively decreased. We analyzed these cases of treatment failure and inferred several possible reasons. We considered that because MRI could not clearly show the anterior internal capsule preoperatively, we were obliged to calculate the target lesion coordinates using a coordinate graph. Moreover, the predetermined target moved because of cerebrospinal fluid loss. Interestingly, the clinical symptoms of these patients significantly improved 1 week after the operation, but subsequently, gradually worsened over time. Perhaps the reason for this short-term improvement in the initial phase was due to physiological dysfunction caused by the hematoma and edema formation at the location of the lesion, affecting the fibers connecting the OFC with the thalamus. In fact, those fibers were not completely disconnected. Thus, when the hematoma and edema had completely disappeared, the functions of those fibers gradually recovered in up to 6 months time, postoperatively. Correspondingly, the patients' symptoms gradually recurred and then persisted. Postoperatively, we evaluated the extent of fiber lesioning using DTI and assessed the changes that occurred in the location of the cerebral lesioning using a PET scan to indirectly determine the extent of fiber lesioning. Moreover, we analyzed the rating scale scores and the perceived symptom severity of all our patients. Finally, we confirmed that OCD generation is related to the activity of certain fibers that connect the anterior internal capsule with the frontal lobe, ACG, and caudate nucleus. Therefore, lesioning these fibers can treat OCD.
Stereotactic lobotomy causes irreversible damage to the brain. Therefore, there are various complications after such an operation. Among these complications, hemorrhage is the most dangerous, and frontal lobe functional disorders such as personality changes, emotional apathy, and executive dysfunction are the most common side effects of the procedure. Ruck et al., reported that 4 out of 16 patients who underwent an anterior capsulotomy developed frontal lobe deficit syndrome. Another report by Ruck et al., showed that 10 out of 25 patients who underwent an anterior capsulotomy suffered from significant frontal lobe functional disorders. The complications induced by the lobotomy are closely related to the surgical technique and targeting accuracy. Previously, surgeons utilized ventriculography to locate target lesion coordinates. However, with the development of MRI, we can now clearly detect the target on MRI. To accurately select the final target coordinates for our patients, we combined the MRI study with coordinate mapping to calculate the target coordinates. In this study, 14 patients developed frontal lobe functional disorders within the first week after the operation. However, some symptoms gradually disappeared within 6 months after the operation. One patient developed a hemorrhagic infarct in the prefrontal cortex [Figure 6]b. We attributed this complication to the selected target location, which was too close to the anterior cerebral artery. Moreover, the warm-up and rewarming rates were so high that the anterior cerebral artery spasm induced a prefrontal hematoma. Therefore, we advise that, while performing ablation, the rates of warm-up and rewarming should be reduced to minimize the anterior cerebral artery stimulation.
We found that the incidence of complications was higher at 1 week postoperatively than at subsequent time points. Most complications gradually disappeared within 3 or 6 months after the operation, and there was no significant change in the severity of complications beyond 6 months following the surgery [Figure 3]. In our 37 patients, compared with the Y-BOCS, HAMA, and HAMD scores at the first week after the operation, the scores at first month postoperatively showed an increase. However, these scores gradually decreased thereafter and gradually stabilized beyond 6 months of the procedure [Figure 3]. We propose that the functioning of many fibers, including some unlesioned ones, were interfered with by the small local hematoma and edema formation in the short-term period after the procedure. Therefore, there were more complications within the 1 week after the procedure. However, as the hematoma and edema resolved, the function of the unlesioned fibers gradually recovered. Consequently, many of the complications gradually disappeared and, the rating scale scores gradually increased over time. As the disconnected fibers cannot recover, patients with OCD can experience varying degrees of improvement following their surgical treatment. When the hematoma and edema had completely subsided, the glucose metabolism of the brain had stabilized and there was no remarkable fluctuation in the efficacy of the improvement obtained after surgery. Therefore, we believe that it is most appropriate to evaluate the effects and complications of this operation at 6 months postoperatively.
Deep brain stimulation (DBS) is a promising treatment for therapy-refractory OCD, and this method has been gradually emphasized owing to its advantages in causing reversible damage to the brain and its adjustability in terms of treatment efficacy and complications. Although there are several studies of DBS for OCD,,,,,, the published experience is limited and the literature is somewhat unclear regarding the use of different targets. Additional successful reports are needed to demonstrate the beneficial effects of DBS.
MRI-guided bilateral capsulotomy clearly improved the symptoms of OCD, as well as anxiety and depression. The Y-BOCS score of approximately 72.9% patients in our cohort was decreased by >50% at the fifth year postoperatively. Frontal lobe functional disorder often occurred in the earlier stage after the operation but gradually decreased within 6 months postoperatively and gradually stabilized thereafter. No evident complications were observed at the fifth year postoperatively. Therefore, it is most appropriate to evaluate the effects and complications of this operation at 6 months postoperatively. As our study had a follow up that was limited to 5 years after the procedure, a long term study that performs a continuous evaluation of the patients after the procedure is needed to further establish the efficacy of this therapy.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]