Keywords
obsessive compulsive disorder - refractory - thermocoagulation - neurosurgery
Palavras-chave
transtorno obsessivo-compulsivo - refratário - termocoagulação - neurocirurgia
Introduction
Obsessive-compulsive disorder (OCD) is a debilitating chronic neuropsychiatric disorder
that is marked by distress and anxiety. The diagnosis is based on the presence of
obsessions (recurrent and persistent thoughts, urges, behaviors, intrusive and unwanted
images) and/or compulsions (repetitive behaviors or mental acts the individual feels
driven to perform, following rigid rules, to reduce or neutralize the discomfort),
which are strictly regulated, demand time from the person, cause impaired social behavior,
and are not explained by the physiological effects of any substance in use or an existing
medical condition.[1]
[2]
[3]
[4]
The symptoms of OCD usually start from the middle of the third to the early fourth
decades of life, and the proportion of women affected is slightly higher than that
of men. However, the adolescent-onset disease inverts this trend, and its prevalence
is three times higher in males than in females.[1]
[5]
International multicentric studies suggest annual and lifetime prevalences ranging
from 1.1% to 1.8% and from 1.9% to 2.5% respectively,[5] making it the fourth most common psychiatric disorder in the world.[1] It is estimated that 50 million people suffer from OCD worldwide.[6]
The disorder may be accompanied by other psychiatric syndromes such as generalized
anxiety disorder and major depressive disorder. In addition, OCD has a high mortality
rate, given that 10% to 27% of the people that have this illness attempt suicide at
some point in life. It corresponds to the tenth cause of health-related absenteeism
due to incapacity to work. This reduces the active workforce and increases the costs
in the areas of social security and health.[3]
The annual costs of treatments for OCD in the United States reach ∼ 10.6 billion dollars,
but one third of this budget is not efficiently used. Additionally, ∼ 40 billion dollars
are annually invested by the American government in sickness insurance coverage for
OCD patients on leave.[6]
The pathophysiology of OCD has not yet been fully elucidated. It is currently considered
a multifactorial disorder (with genetic alterations standing out) associated with
neuroimmunological disorders. A literature review[7] showed agreement on the importance of genetic factors for the expression of OCD,
which ranges from 52% to 80% in monozygotic twins against 21% to 25% in dizygotic
twins, contributing to the genetic hypothesis in the pathogenesis of OCD. This hypothesis,
which is still under analysis, questions the participation of polygenic modifiers,
involved polymorphisms, and linkage mechanisms in serotonergic genes such as HTR2A and 5-HTTLPR, as well as dopaminergic receptor genes such as DRD2 and DRD3. In a systematic review,[8] autoimmune diseases were related to the outbreak of OCD, in particular group A β-hemolytic
streptococcal infection in children, in addition to systemic lupus erythematosus and
thyroid dysfunction in adults. The autoantibodies related to these disorders may cause
immunomodulation of cytokines, mainly tumor necrosis factor α and interferons γ and
α, which activate enzymes in the tryptophan cycle, therefore reducing the production
of serotonin.[7]
[8]
The first-line treatment for OCD includes the use of selective serotonin reuptake
inhibitors (SSRIs) or tricyclic antidepressants associated with cognitive-behavioral
therapy. Nevertheless, this psychiatric disorder has the highest refractoriness to
non-invasive treatment (40% to 60%).[9] The symptoms are more prominent in refractory patients, who are characterized by
not showing improvement in the condition and presenting with all of the following
refractoriness criteria: use of at least three SSRIs at full dose for at least 12
weeks; use of at least two atypical antipsychotics; and combined psychotherapeutic
treatment over a period of more than 30 hours.[3]
In the late 1930s, ablative psychosurgeries emerged in the United States for the treatment
of psychiatric disorders, especially OCD and major depressive disorder, in patients
resistant to conventional treatments.[10] This technique has been improved with the use of a stereotactic approach and imaging
tests such as positron emission tomography (PET) and single photon emission computed
tomography (SPECT). These advances made the scenario favorable to conduct studies
that prove the efficacy and few adverse effects of the procedures, which have already
crossed the experimental barrier.
The ablative thermocoagulation technique is based on strong evidence for the involvement
of the corticostriatopallidothalamocortical tract in pathophysiological changes, especially
the orbitofrontal cortex, anterior cingulate cortex, ventral striatum, anterior limb
of the internal capsule, and medial dorsal thalamic nucleus. Postoperative images
acquired using a PET/SPECT/computed tomography (CT) scanner were employed to evaluate
the metabolism of brain areas, and showed that previous anomalous activities in specific
brain circuits improved as a result of the neurosurgery.[11] Such findings contribute to reiterate the targets recommended in the four main ablative
surgeries performed for OCD: anterior capsulotomy, anterior cingulotomy, subcaudal
tractotomy, and limbic leucotomy.[12]
In the long run (more than 2 years), 43% to 75% of the patients who undergo these
procedures show improvements and satisfactory results.[10] Most adverse effects, such as headache, weight gain, urinary incontinence, cognitive
dysfunctions, neurological focal deficits, hemorrhages, and seizures, are transient,
lasting from 3 to 6 months.[10] Permanent and severe adverse effects are restricted to 5.6% of the cases.[3] Thus, ablative neurosurgery is an effective and extremely advantageous method for
the treatment of refractory OCD, with few adverse effects.
Therefore, the present systematic review aimed to identify validated protocols to
observe the effectiveness of ablative neurosurgeries in the treatment of severe and
treatment-refractory OCD, their possible adverse effects, and clinical/imagological
predictors of response and secondary benefits.
Methods
A systematic review was performed to investigate the use of ablative neurosurgical
techniques for the treatment of refractory OCD. The search was carried out by four
independent researchers, and followed the steps proposed in the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
The search was performed on the Medical Literature, Analysis, and Retrieval System
Online (MEDLINE) and on the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
(CAPES, in Portuguese) databases. The following descriptors, retrieved from the Medical
Subject Heading (MeSH) terms, were combined in each database using Boolean operators:
(obsessive-compulsive disorder or obsessive compulsive disorder) and (ablative or cingulotomy or capsulotomy or tractotomy or leucotomy) and (neurosurgery or psychiatric surgery or neurofunctional surgery).
For the selection of the articles, the following inclusion criteria were adopted:
1) studies that correlate refractory OCD and ablative surgery as a treatment strategy,
and studies that present OCD treatment using ablative techniques by thermocoagulation
and other techniques, as long as the participants who underwent non-ablative surgery
can be excluded; 2) human studies that evaluate the efficacy of ablative techniques
by thermocoagulation in OCD based on changes in the Yale–Brown Obsessive Compulsive
Scale (Y-BOCS); 3) individuals diagnosed with OCD according to the Diagnostic and Statistical Manual of Mental Disorders
[1] and the International Statistical Classification of Diseases and Related Health Problems;[2] and 4) minimum follow-up time of 12 months.
Additionally, the following exclusion criteria were applied: 1) duplicate studies;
2) articles exclusively on other surgical interventions; 3) articles exclusively on
other psychiatric disorders; 4) editorials; 5) reviews on the use of ablative thermocoagulation
techniques for OCD that do not provide results for new patients; 6) comments; 7) discussions
on related ethical issues; 8) case reports; 9) studies that do not use the Y-BOCS;
and 10) articles on indications for ablative techniques other than OCD.
As a primary outcome, the clinical improvement of OCD symptoms after the intervention,
measured by a change in the Y-BOCS score, was analyzed. The secondary outcomes included
changes in depression and anxiety scores, and we also retrieved additional information
that each article could contribute to the theme. Such secondary outcomes did not affect
the eligibility of the studies.
Results
A total of seven articles were selected for the present systematic review ([Fig. 1], [Table 1]). The studies selected included 149 patients, with a mean age at surgery of 34.6
years (range: 28.9 years to 40.8 years; standard deviation [SD]: 4.2 years), who had
the diagnosis of OCD following the international criteria,[1]
[2] and were considered refractory to the conventional treatment. In four[4]
[13]
[14]
[17] of the six studies that specified the gender of the patients, males predominated
slightly in the sample, while in the two other studies, females represented 66.6%[16] and 63.1%[3] of the participants. Only one study[15] comprised two types of surgical procedure and did not specify the gender of the
patients. The participants were individualized according to the type of surgery performed,
and the number of patients lost to follow-up was reported for each of the types.
Fig. 1 Articles selected for the systematic review.
Table 1
Articles selected for the systematic review
|
Country
|
Experimental design
|
Number os samples
|
Surgical procedure
|
Follow-up (months)
|
Mean age at surgery (years) [SD]
|
Female patients (%)
|
Average pre-operative Y-BOCS score (SD)
|
Y-BOCS mean 12 months (SD)
|
Average post-operativd Y-BOCSa score (SD)
|
Average reduction in the Y-BOCS score (%)
|
Responders (%)
|
Authors
|
|
South Korea
|
Prospective cohort
|
17
|
Bilateral cingulotomy
|
24
|
36.1 [9.4]
|
41.2
|
35 (3.9)
|
22.4 (6.5)
|
18.2 (4.35)
|
48
|
47.0
|
Jung et al.[13]
|
|
China
|
Prospective cohort
|
35
|
Bilateral anterior capsulotomy
|
36
|
29.6 [10.6]
|
37.1
|
21.2 (4.0)
|
5.4 (2.1)
|
4.4 (2.3)
|
79.2
|
85.7
|
Liu et al.[14]
|
|
Sweden
|
Retrospective cohort
|
3b
|
Unilateral anterior capsulotomy
|
12
|
37.3 [11.1]
|
NA
|
34.3 (3.2)
|
18 (12)
|
18 (12)
|
47.5
|
66.6
|
Rück et al.[15]
|
|
10c
|
Bilateral anterior capsulotomy
|
12
|
39.7 [8.7]
|
NA
|
34 (2.6)
|
19 (9.6)
|
19 (9.6)
|
44.1
|
60.0
|
|
Hungary
|
Prospective controlled cohort
|
5
|
Bilateral anterior capsulotomy
|
24
|
32.2 [6.3]
|
66.6
|
38.2 (1.8)
|
19.6 (8.5)
|
18.2 (9.95)
|
52.3
|
NA
|
Csigó et al.[16]
|
|
Canada
|
Prospective cohort
|
19
|
Bilateral anterior capsulotomy
|
24
|
40.8 [11.6]
|
63.1
|
34.9 (4.8)
|
22.9 (NA)
|
22.9 (NA)
|
34.3
|
36.8
|
D'Astous et al.[3]
|
|
United States
|
Prospective cohort
|
7
|
Bilateral anterior capsulotomy and bilateral cingulotomy
|
12
|
32.4 [6.1]
|
42.8
|
32.9 (4.7)
|
20.6 (5.3)
|
20.6 (5.3)
|
37.3
|
71.4
|
Zhang et al.[4]
|
|
China
|
Long-term follow-up
|
53
|
Bilateral anterior capsulotomy
|
60
|
28.9 [9.1]
|
39.6
|
24.7 (4.0)
|
6.7 (5.4)
|
6.5 (5.9)
|
73.6
|
77.3
|
Zhan et al.[17]
|
Abbreviations: NA, not available; SD, standard deviation; Y-BOCS, Yale–Brown Obsessive Compulsive
Scale.
Notes:
aY-BOCS applied in the last month of the evaluation of the patient. bInclusion of four patients, but one was lost to follow-up. cInclusion of 12 patients, but two were lost to follow-up.
Regarding the thermocoagulation techniques performed, 122 patients underwent bilateral
anterior capsulotomy; 3, unilateral anterior capsulotomy; 17, bilateral cingulotomy;
and 7, a combination of bilateral anterior capsulotomy and bilateral cingulotomy.
After the surgeries, the participants were followed for an average of 25.5 months
(range: 12 to 60 months; SD: 15.2 months). The total follow-up time was considered
the moment of the last evaluation of the patients.
Clinical improvement was analyzed using the Y-BOCS. The mean preoperative score on
the Y-BOCS was of 31.9 (range: 21.2 to 38.2; SD: 5.4). A significant decrease in Y-BOCS
scores was observed 12 months after surgery, with a mean value of 16.8 (range: 5.4
to 22.9; SD: 6.4). The final Y-BOCS score, that is, the one evaluated at the end of
the proposed follow-up period, continued to decrease, reaching an average of 15.9
(range: 4.4 to 22.9; SD: 6.3). This determined an average reduction of 52% (range:
34.3% to 79.2%; SD: 15.1%) in the Y-BOCS at the end of the evaluation, based on an
average of 63.5% of responders (range: 36.8% to 85.7%; SD: 15.8%). The lowest percentage
of responders (36.8%) and the lowest percentage of decrease in the Y-BOCS score (34.3%)
were found by D'Astous et al.[3] In contrast, they reported the highest average age among the participants (40.8
years). The lowest average ages were registered by Liu et al.[14] and Zhan et al.:[17] 29.6 years and 28.9 years respectively, while they had the highest rates of responders
(85.7% and 77.3% respectively).
Csigó et al.[16] evaluated and implemented neuropsychological tests in their research to assess whether
the cognitive functions of OCD patients who underwent ablative neurosurgery improved
or worsened after the procedure. They observed a significant recovery of cognitive-functional
deficits that refractory OCD patients characteristically have, mainly related to attention
and spatial memory. In addition, a significant improvement in executive functions
such as verbal fluency, decision making, and intelligence was registered. However,
they found an increase in intrusion errors. These findings are corroborated by the
results obtained by Jung et al.,[13] who did not identify any neurofunctional deficit in the areas of learning, verbal
memory, and visuospatial construction, but observed an improvement in perseveration
errors.
Rück et al.[15] confirmed the efficacy of thermocoagulation in the treatment of refractory OCD,
but emphasized that multiple or very large lesions should be avoided due to the increased
risk of side effects. In turn, Zhang et al.[4] attributed the response of the participants in their study to the association of
bilateral cingulotomy and capsulotomy.
Discussion
Thermocoagulation for the treatment of refractory OCD is a non-experimental technique
that is effective and has been validated by previous studies. This perspective was
confirmed in the present review, since the articles selected showed significant clinical
improvement documented by changes in the Y-BOCS score. This surgical technique may
be the last tool available for these patients to achieve functionality.
In the present review, the average number of responders was of 63.5%, very satisfactory,
considering the severity and chronicity of the disease. Mostly, the scores on the
Y-BOCS 12 months postoperatively and in the longest follow-up (60 months) were similar.
This shows that the 12-month results are close to the permanent results, and also
indicates a stable response to treatment over time.
A greater response to the neurosurgical approach was perceived in younger patients
compared with a lower response in older patients, which raises the hypothesis of an
ideal time window to propose this approach. Comparing responders and non-responders,
D'Astous et al.[3] concluded that the effectiveness of the surgery is inversely proportional to the
duration of the disease. Neuroimaging studies have demonstrated hypermetabolism profiles,
especially in the anterior cingulate gyrus, orbitofrontal cortex, and caudate nucleus,
areas related to the pathophysiology of OCD which have shown statistically significant
improvements in the postoperative follow-up.[14]
[17]
The comorbidities associated with OCD, such as anxiety and depression, have already
been well specified applying the Hamilton Depression Rating Scale (HAM-D) and the
Hamilton Anxiety Rating Scale (HAM-A). They have also been analyzed in the postoperative
period, showing significant improvement. This fact becomes relevant, considering that
these comorbidities have an impact on the quality of life of these patients.[12] In general, an improvement was also observed in the neurophysiological and cognitive
aspects in subjects who underwent this type of surgical treatment, with few long-term
adverse effects resulting from the procedure.[16] However, one study[15] showed a mild impairment in executive functions in the group studied as a whole.
Despite the reduced number of studies selected, the current systematic review included
a significant number of patients (149), and a certain standardization was noticed
with regard to the inclusion criteria (every study enrolled refractory patients who
had the diagnosis of OCD based on the international criteria),[1]
[2] the criterium for responders (patients showing an improvement rate of > 35% in the
Y-BOCS in the longest follow-up were considered responders), the rating scale (all
of them used the Y-BOCS), the total of follow-up time (all of them included a 12-month
cutoff), as well as the analysis of secondary outcomes such as depression and anxiety
(the studies that performed it used the HAM-A and HAM-D). In addition, the definition
of refractory OCD is currently well-established.
The interinstitutional heterogeneity in the surgical technique employed was evident
in the studies, such as the amplitude of the lesion and the time and temperature used,
even regarding the same type of approach. This fact must be taken into account when
generalizing the findings, since this lack of standardization may affect the responses.[12] Thus, the results of the present systematic review must be interpreted in the context
of the strengths and weaknesses of the studies included here.
Conclusion
Obsessive-compulsive disorder is a debilitating disorder with the highest refractoriness
rates among psychiatric disorders. Even with the limited number of studies selected
in the present systematic review, the results show that thermocoagulation is a safe
and effective method for the regression of the symptoms of this disease. Considering
the proportion of responders, both for the primary outcome and for the comorbidities,
determining safe clinical predictors of response would be of great value in the application
of targeted approaches. Nonetheless, to this date, no evidence is available to determine
reliable predictors of imaging studies or the clinical response to the treatment for
those patients who are known to have a surgical indication due to severe and refractory
OCD. Systematic, double-blinded, controlled studies are feasible (considering the
similar response to the different techniques employed) and necessary to overcome this
barrier and take a new step toward individualizing surgical indications, especially
within the spectrum of those already validated.
