Psychiatry for Neurologists - part 9 pot

was the risk that the implanted seeds could migrate. Bridges et al. (18) published a retrospective report of nearly 1300 patients with “non-schizophrenic affective disorders” at The Geoffrey Knight Unit in London. Of patients who underwent subcaudate tractotomy, 40–60% went on to live normal or near normal lives. Additionally, they also demonstrated that the suicide rate was reduced to 1% postoperatively, compared with 15% in uncontrolled affectively disordered patients. Another retrospective study of 208 patients with depression, anxiety, and obsessional neuroses with a mean follow-up period of 2.5 years demonstrated significant improvement in 68% of patients with depression, 50% of patients with obsessional neurosis, and 62.5% of patients with other anxiety disorders (19). Patients with other psychiatric disorders, such as schizophrenia, substance abuse, or personality disorders responded poorly to the procedure. Adverse effects included short-term transient disinhibition syndromes, headache, confusion or somnolence; personality changes were seen in 6.7% of patients and seizures were seen in 2.2% of patients. In this study, there was one fatality resulting from migration of an Yttrium seed. Table 1 outlines early neurosurgical approaches for psychiatric indications. Neurosurgical Treatments 345 Fig. 5. Diagram by P. D. Malone of Lahey Clinic of bimedial approach. (Reprinted with permission from ref. 59.) 346 Park et al. Fig. 6. Diagram of inferior aspect of orbitofrontal lobe. Area of restricted orbital undercutting as performed and described by Knight. (Reprinted with permission from ref. 16.) Fig. 7. T 2 -weighted axial MRI of subcaudate tractotomy lesion in the subcaudate region bilaterally. One of the important technological advances that allowed for the development of more precise procedures was the ability to accurately position and localize targets in three-dimensional space. Initially done as unguided, free-hand procedures, lesion size and location were quite variable. This changed with the development of superior visualization and localization techniques. The stereotactic frame, initially designed by Sir Victor Horsley, represented an early localization system that led to marked improvement in the accuracy and precision of cerebral lesions. More sophisticated localization sys- tems in current use employ computed tomography (CT)/magnetic resonance imaging (MRI) guidance and provide optimal lesion localization. The development of an empirically based, statistically sound psychiatric nosology served as an equally important advance for psychiatric research. The earlier system of diagnosis based on Diagnostic and Statistical Manual of Mental Disorders, First Edition (DSM-I) (1952) and DSM-II (1968) served as a classification that embodied psychobiological theories of the time. DSM-III (1980) (and subse- quently DSM-III R in 1987, and DSM-IV in 1994) represented a marked departure from a theoretically based nosology to a descriptive, empirically based system. Paralleling this evolution in psychiatric diagnosis was the development of quantitatively reliable and valid instruments for assessing the sever- ity of psychiatric symptomatology. Armed with these advances, researchers were able to study a range of different targets. As part of a posited “limbic system,” the anterior cingulate gyrus was first mentioned by Fulton in 1947 as a possible target for neurosurgical intervention (20). Dr. Thomas H. Ballantine, Jr. at Massachusetts General Hospital was one of the first to use this procedure clinically, and pioneered its application for treatment of MDD, chronic pain syndromes, and OCD. The surgery is typically conducted under local anesthe- sia; one to three contiguous lesions are made bilaterally via thermocoagulation through bilateral burr Neurosurgical Treatments 347 Fig. 8. STT brachytherapy. Anteroposterior radiograph, showing yttrium seeds used in Knight’s original SST procedure. (Reprinted with permission from ref. 60.) holes. The target is within dorsal anterior cingulate cortex (Brodmann areas 24 and 32), at the margin of the white matter bundle known as the cingulum. Originally, the placement of lesions was determined by ventriculography. Currently, however, anterior cingulotomy is performed stereotactically via MRI guidance (see Fig. 9). Given the use of relatively small lesions, one major advantage of anterior cingulotomy over the other procedures is the decreased incidence of significant complications. However, given the conservative nature of the lesions, efficacy may also be decreased, with approx 40% of patients return- ing for a second procedure to extend the first set of lesions. Ballantine and colleagues (21) retrospectively reviewed 198 cases with mean follow-up of 8.6 years. They noted significant improvement in 62% of patients with affective disorders, 56% with OCD, and 79% with other anxiety disorders. A subsequent report reviewed a series of 34 patients who had undergone MRI-guided cingulotomy (22). Among patients with unipolar depression, 60% responded favorably; among patients with bipolar disorder, 40% responded favorably; and among patients with OCD, 27% were classified as responders with another 27% categorized as possible responders. Most recently, a prospective report of 44 patients with OCD was published, based on a mean follow-up period of 32 months (23). The investigators, employing stringent criteria, found that 45% had responded favorably, with no serious long-term adverse effects. Complications typically prove to be relatively minor, with short-term headache, nausea, difficulty with urination, and subjective transient problems with memory. Of the approx 1000 anterior cingulotomies performed by Ballantine, his successor G. Rees Cosgrove, and their colleagues at Massachusetts General Hospital, there have been no deaths, and the incidence of seizure remains approx 1%, with most occurring in patients with a pre-existing seizure history. Additionally, since the advent of MRI guidance, there has been only one case of stroke postoperatively. An independent analysis of a subset of these patients demonstrated no significant lasting intel- lectual or behavioral impairment or neurological or behavioral adverse effects (24). Another treatment strategy has involved a combination of two of the aforementioned lesions to maximize main effect. Desmond Kelley and colleagues (25) developed a procedure called limbic leucotomy, which combines anterior cingulotomy with subcaudate tractotomy (see Fig. 10). Theoretically, it was thought that an intervention at two different sites of the limbic system would improve efficacy. The lesions are made via thermo- or cryo-coagulation. Initially, localization of the lesion site was guided by intraoperative electrical stimulation (pronounced autonomic response designates the optimal lesion site); currently, lesion placement is stereotactically guided. The indications for limbic leukotomy include MDD, OCD, and other severe anxiety disorders. Retrospective review of patients undergoing this procedure (26) demonstrated an 89% improvement rate for OCD, 78% for MDD, and 66% for other anxiety disorders with mean follow-up of 16 months. Notably, improvement was only seen after a lag time of several months. Short-term side effects included headache, lethargy or apathy, confusion, and lack of sphincter control, which may last from a few days to a few weeks. Postoperative confusion was commonly seen, but typically resolved over several days. No seizures or deaths were reported, although 348 Park et al. Table 1 Early Neurosurgical Approaches for Psychiatric Indications Procedure Designers Year Main indications Comment Prefrontal lobotomy Moniz/Lima 1936 “Psychosis” Lateral approach, development of leukotome to sever white matter tracts Bimedial lobotomy Lyerly 1937 “Psychosis” Medial approach thought to minimize cognitive complications Trans-orbital leucotomy Freeman 1946 “Anxiety, worry, Superior orbital approach, “ice-pick” nervousness” leukotome Orbital undercutting Scoville 1948 Depression, Orbito-frontal gray matter lesions anxiety Neurosurgical Treatments 349 Fig. 9. Anterior cingulotomy. Early postoperative sagittal and coronal T1-weighted magnetic resonance images demonstrating radiofrequency thermocoagulation lesions created in the anterior cingulate gyrus bilaterally. (Reprinted with permission from ref. 55.) Fig. 10. T 1 -weighted sagittal MRI of limbic leucotomy lesions in anterior cingulate gyri and subcaudate region. one patient suffered severe memory loss as a result of improper lesion placement. More recently, another study of 21 patients who underwent limbic leukotomy for OCD or MDD demonstrated 36–50% response rate (using stringent response criteria) at mean follow-up of 26 months (27). There is also some evidence (n = 5) that limbic leucotomy may be of benefit for patients with severe self-mutilation, in the context of repetitive, self-injurious, tic-like behaviors (28). Anterior capsulotomy targets white matter tracts in the anterior one-third of the anterior limb of the internal capsule at the level of the intercommissural plane, thereby interrupting fibers of passage between prefrontal cortex and subcortical nuclei (see Fig. 11). Initially designed in France, and further developed by Leksell and colleagues in Sweden, anterior capsulotomy utilizes much smaller lesions because the density of white matter tracts in the anterior capsule is much higher than white matter tracts closer to their neurons of origin. However, given that structures are functionally con- densed, the need for precision of lesion placement is greater, as the possibility of side effects is relatively greater as well. Lesions were originally made in an open procedure via thermocoagulation. However, more recently the lesions have been made “noninvasively” through radiosurgery using the “Gamma Knife.” Gamma Knife technology utilizes a γ-radiation source and focuses multiple rays through the use of a collimator helmet to converge on a single location to create a lesion. Indications for anterior capsulotomy include MDD, OCD, and other severe anxiety disorders. Herner (29) retrospectively reported on the first 116 patients that Leksell operated on. He noted a favorable response in 50% of those with OCD and 48% of those with MDD, whereas only 20% of those with anxiety and 14% of those with schizophrenia improved. In another prospective study of 35 patients with OCD, 70% had satisfactory outcomes (30). The most significant complications include confusion, which typically resolves within 1 week postoperatively, permanent weight gain, and intracranial hemorrhage. Other short-term side effects can include transient headache, incontinence, fatigue, or memory diffi- culties. With the use of radiation ablation, recovery is typically quicker than open procedures (typi- cal hospital stay is one night postprocedure), although there is an associated risk of cerebral edema, which may present as far out as 8–12 months postprocedure. No significant long-term cognitive problems or adverse personality changes have been noted in patients undergoing anterior capsulotomy. Most recently, in an ongoing prospective study, the Butler Hospital and Rhode Island Hospital Group found that anterior capsulotomy was generally well tolerated and effective for patients with otherwise intractable OCD. Adverse events included cerebral edema and headache, small asymptomatic caudate infarctions, and possible exacerbation of pre-existing bipolar mania. There were no group decrements on cognitive or personality tests compared to presurgical baseline, although one patient developed a mild frontal syndrome, including apathy. A therapeutic response, defined conservatively, was seen in 10 of 16 patients receiving the most recent anterior capsulotomy procedure. Most therapeutic benefit was achieved by 1 year, and was essentially stable by 3 years (Rasmussen, personal communication). CURRENT USE OF NEUROSURGERY FOR PSYCHIATRIC INDICATIONS In the modern era of neurosurgery for psychiatric indications, four main procedures continue to be used; they are anterior cingulotomy, subcaudate tractotomy, limbic leucotomy, and anterior capsulotomy. All four procedures incorporate bilateral lesions and take advantage of modern stereotactic localization techniques (see Table 2). These procedures have demonstrated the best balance to minimize adverse effects yet maximize beneficial effects. Informed by the abuses of the past, the use of these procedures is tightly controlled, usu- ally by internal oversight by the institutions that perform them. Currently, only a handful of centers worldwide perform neurosurgery for psychiatric indications and the numbers of patients that receive this procedure in the United States annually ranges in the dozens. In the United States, centers in Boston, Massachusetts; Providence, Rhode Island; Gainesville, Florida; and Cleveland, Ohio have established interdisciplinary committees (consisting of neurosurgeons, neurologists, and psychiatrists) to evaluate patients for appropriateness for treatment. Criteria for appropriateness for surgery are quite stringent; 350 Park et al. Neurosurgical Treatments 351 Fig. 11. (A) Axial T1 MRI of acute and (B) axial CT of chronic anterior capsulotomy lesions. (Reprinted with permission from BMJ Publishing Group. From JNNP, 63(6), 1997.) patients must demonstrate nonresponsiveness to an exhaustive array of other available therapies. Additionally, patients are never forced or coerced into undergoing a procedure; in fact, patients (and their families) must petition these committees for consideration for surgery. International centers, in London and Stockholm, also employ the interdisciplinary committee approach, and in Britain addi- tional formal approval from the Mental Health Act Commission is required. Generally speaking, contemporary neurosurgical treatments across all psychiatric indications demonstrate significant improvement in 40–70% of cases and outstanding improvement in greater than 25% of cases. Response rates for MDD are slightly better than those for OCD. Side effects are minimal, with the most common severe complication being seizures that occur in 1 to 5% of cases. Frontal lobe syndromes, confusion or subtle cognitive deficits are relatively rare occurrences and typically mild when they do occur. In fact, overall cognitive function (as measured by standard intelligence quotient) often improves. This is attributed to the fact that cognitive compromise associated with primary psychiatric disorders resolves once the primary disease process remits. Studies have demonstrated that neurosurgery for psychiatric conditions may decrease suicide rates overall, although any individual patient who fails to respond to these “procedures of last resort” may be at higher risk for completed suicide (31). Based on the current body of outcome data, the best established psychiatric indications for neurosurgery are MDD and OCD. Patients to be evaluated for neurosurgery must demonstrate extremely severe symptomatology, refractoriness to existing treatments, and willingness and capacity to consent for such a procedure. Furthermore, patients must also demonstrate access to and a willingness to participate in long-term psychiatric follow-up care. Symptoms must be chronic, severe and debilitat- ing, and must be documented by quantifiable measures (i.e., patients with OCD typically have Yale- Brown Obsessive-Compulsive Scale scores ≥25; patients with MDD typically have Beck Depression Inventory scores of ≥30). Refractoriness to treatment refers to the failure of an exhaustive array of other available established treatment options. Patients must be free of other psychiatric conditions that would interfere with treatment effects. Psychoactive substance use or personality disorders are con- sidered significant relative contraindications. Patients must be in good medical condition, and able to tolerate a procedure of this nature. A history of significant cardiopulmonary disease, age greater than 65 years, structural brain lesions, and significant central nervous system injuries are relative contraindications. A history of past seizures is a risk factor for perioperative seizures and must be weighed in the overall risk–benefit assessment. Preoperative work-up consists of standard blood and urine lab- oratory tests, electrocardiogram, brain MRI, electroencephalogram, and psychometric testing. In the postoperative period, there is generally no immediate beneficial effect following the treatment; it may be several months before beneficial effects emerge. Side effects occur in less than one- 352 Park et al. Table 2 Current Stereotactically Guided Neurosurgical Approaches for Psychiatric Indications Procedure Designers Year Main indications Comment Anterior capsulotomy Leksell 1950 OCD, anxiety, Anterior limb of the internal capsule, MDD gamma knife Subcaudate tractotomy Knight 1964 Depression, Subcaudate (ventral striatum) lesions, anxiety, Yttrium 90 brachytherapy obsessions, schizophrenia Anterior cingulotomy Fulton/ 1967 MDD, OCD, Anterior cingulated gyrus and Ballantine chronic pain cingulum bundle Limbic leukotomy Kelley 1973 MDD, OCD, Subcaudate tractotomy + cingulotomy anxiety OCD, obsessive-compulsive disorder; MDD, major depression disorder. half of all patients and are typically transient (lasting a few days to a few weeks). Short-term side effects may include altered mental status, headache, or urinary or fecal incontinence. Special care must be taken to monitor for potential surgical complications—including infection, hemorrhage, seizures, or altered mental status. Postoperatively, patients are typically monitored in the hospital setting for 1 to 2 days (this varies by procedure and surgical team). After the immediate postoperative phase, an MRI should be obtained to document the placement and extent of the lesions. Because no immediate beneficial effect is typically observed, long-term comprehensive treatment, including psychopharmacology and psychotherapy, is required for all patients. Optimal response is thought to result from interplay between the neurosurgical intervention and traditional psychiatric therapies. Particularly for OCD, intensive behavior therapy should be initiated as soon as the patient is able, preferably within the first month postoperatively. Given the history of use of neurosurgery for psychiatric conditions in the past, and given the poten- tially compromised nature of the mental state of the psychiatric patient, informed consent is a vital aspect of the evaluation process as well. Neurosurgery today is never performed on patients against their will, whether they are competent to refuse the procedure or not. All patients undergoing a neurosurgical procedure must be able to demonstrate competency to make such a decision, and must demonstrate their desire to proceed with the treatment. For this reason, age under 18 is seen as a relative contraindica- tion, although there have been rare cases when procedures have been performed with the assent of the patient as well as the consent of the legal guardian. NEUROCIRCUITRY MODELS Evidence for neurobiological models of psychiatric conditions is gathered from various areas of research. The most basic source of information is the association between structural abnormalities in the brain and changes in mental functioning. The observation of neurosurgical lesions and their resulting functional effects is one example of this type of evidence. Additionally, the advent of neuroimaging has greatly increased our understanding of the underlying biology of mental states. Structural imaging techniques (CT and MRI) have been instrumental in associating certain biological changes with alterations in mental functioning. Improved neurochemical and neurohistological techniques have fur- thered our understanding of how the brain is wired and how it functions. Perhaps most importantly, the development of functional neuroimaging techniques has significantly advanced the field as in vivo functional physiological states can be linked with mental states. Currently, there are two major neurocircuitry models that may serve as a conceptual framework for understanding psychiatric neurosurgery for OCD and MDD. One model focuses on cortico– striato–thalamo–cortical circuitry (CSTC) and provides us with a mechanism to explain how neurosurgery may help to treat OCD and other related disorders. The other model, a network model of limbic–cortical connectivity contributes insights into how neurosurgery effectively treats MD. Cortico–Striato–Thalamo–Cortical Circuits: OCD and Related Disorders The CSTC circuitry model has been elaborated by Alexander and colleagues (32,33). This model describes five segregated CSTC circuit loops that are situated in parallel (with preservation of topo- logical relationship to each other) and have been postulated to mediate specific types of human activity and behavior (see Fig. 12). Each circuit consists of a cortical area linked to a unique striatal area, which is in turn linked to a unique part of the thalamus and then returns in a feedback loop to the original cortical area. In addition to a main, or direct, pathway, there is also an associated indirect pathway. It is thought that the balance between direct and indirect pathway may serve as the mechanism for modulating the activity in each circuit. Each circuit is referred to by its associated cortical compo- nent. The five circuits include: motor cortex, oculomotor cortex, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Interestingly, two of the circuits mediate motor activity,whereas the other three are thought to mediate aspects of mental activ- Neurosurgical Treatments 353 ity. The DLPFC has been associated with executive function; the OFC and the ACC have been associated with attention modulation, and affective function. Focusing on two of the five CSTC circuits, a theory of pathophysiology in OCD has been developed. Specifically, it has been proposed that the OFC circuit, ACC circuit, and the caudate nucleus play a central role in the pathophysiology of OCD (34,35). Furthermore, there is a convergence of evidence to suggest that some primary pathological process within the striatum might underlie the CSTC dysfunction in OCD. The prevailing theory suggests that a relative imbalance favoring the direct vs. indirect pathways within this circuitry, leads to overactivity (i.e., amplification) within OFC and ACC, caudate nucleus and thalamus, resonant with failed striato-thalamic inhibition (i.e., filtration) within this same circuitry. There is hyperactivity at rest within the OFC-caudate CSTC circuit that is exaggerated during symptom provocation and attenuated following successful treatment. A similar profile is present within ACC, although this appears to be a more nonspecific finding across different types of anxiety states. This basic scheme has been extended to provide a comprehensive model for a group of purportedly related disorders, called “obsessive-compulsive spectrum (OC spectrum) disorders.” In addition to OCD, the OC spectrum also includes Tourette’s syndrome, trichotillomania, and body dysmorphic disorder. The “striatal topography model” of OC-spectrum disorders suggests that these diseases share underlying CSTC dysfunction vis-à-vis primary striatal pathology. Moreover, each specific clinical presen- tation reflects the topography of pathology within the striatum and hence the constellation of dysfunction across CSTC circuits (36,37). To elaborate, the notion is that OCD and body dysmorphic disorder (the OC spectrum disorders characterized by intrusive cognitive and visuospatial symptoms) involve caudate pathology; whereas Tourette ‘s syndrome and trichotillomania (principally characterized by intrusive sensorimotor symptoms), involve pathology within the putamen and dysfunction of sensorimotor CSTC circuitry. 354 Park et al. Fig.12. Parallel cortico–striato–thalamo–cortical circuits as diagrammed by Alexander. (Reprinted with permission from ref. 32.) [...]... 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