Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.

Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.

Carrier-frequency estimation for digital holograms of phase objects.

Accurate estimation of carrier fringe frequency is essential for the demodulation of off-axis digital holograms. The fringe frequency is often associated with the amplitude peak of the cross-term in the two-dimensional Fourier transform of a digital hologram. We point out that this definition of carrier frequency is not valid in general for holograms associated with phase objects. We examine the carrier-envelope representation for digital holograms from the viewpoint of Mandel's criterion [J. Opt. Soc. Am.57, 613 (1967)10.1364/JOSA.57.000613]. An appropriate definition of carrier frequency is observed to be the centroid of the power spectrum associated with the cross term. This definition is shown to apply uniformly to holograms associated with phase objects, is robust to noise, and leads to the smoothest (or least fluctuating) envelope representation for the demodulated object wave. The proposed definition is illustrated with simulated as well as experimentally recorded off-axis holograms.

High-Definition Transcranial Direct Current Stimulation-Primed Intermittent Theta Burst Stimulation in Treatment-Resistant Depression: A Controlled Study.

OBJECTIVES: The aim of this study was to evaluate whether high-definition transcranial direct current stimulation (HDtDCS) priming improves the efficacy of intermittent theta burst stimulation (iTBS) in improving TRD. METHODOLOGY: A prospective hospital-based, randomized control study where the participants were divided into active or sham HDtDCS-primed iTBS stimulation groups for a total of 10 sessions and were assessed on clinical parameters at baseline, end of week 1, and end of week 2 was done. Primary outcome of the study was the difference in Hamilton Depression Rating Scale (HDRS) scores over 2 weeks of HDtDCS-primed iTBS. RESULT: A significant effect of time was seen over HDRS scores in both active and sham groups with a large effect size. Significant effect of time was also found over the Clinical Global Impressions-Severity Scale scores of patients with a large effect size. The difference in the improvement in depressive severity as measured using HDRS and Clinical Global Impressions-Severity Scale scores between active and sham groups was also found to be significant with large effect sizes. CONCLUSION: High-definition tDCS-primed iTBS is superior to normal iTBS in patients with depression who have failed a trial of 2 antidepressants, whereas both mechanisms are of benefit to the patients.

Brain activation alterations with adjunctive deep transcranial magnetic stimulation in obsessive-compulsive disorder: an fMRI study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is one of the most common neuropsychiatric disorders with lifetime prevalence higher than that of schizophrenia and bipolar disorders. Inadequate response to available pharmacological and psychotherapeutic interventions is common in OCD. Adjunctive brain stimulation methods to address the inadequate treatment response in OCD have found a special interest in research. This study aimed to examine the efficacy of adjunctive deep transcranial magnetic stimulation (dTMS) in ameliorating the symptoms of OCD and the effect of dTMS on activation of brain regions while performing the Stroop task using functional magnetic resonance imaging (fMRI). METHODS: A total of 41 patients were assessed for the study out of which 15 OCD patients received 10 sessions of high-frequency dTMS using the H7 coil to target the anterior cingulate cortex and the medial prefrontal cortex over a period of 2 weeks. The Yale-Brown Obsessive-Compulsive Scale, the Hamilton Anxiety Rating Scale, and the Hamilton Depression Rating Scale were used for the pre- and post-stimulation clinical assessment. fMRI was used to measure the activation of brain regions while performing the Stroop task. RESULTS: There was a significant improvement in the obsessive-compulsive, anxiety, and depressive symptoms after the 2 weeks of the dTMS treatment. A significant decrease in the activation of left caudate nucleus and adjacent white matter was noted while performing the Stroop task after the dTMS treatment. CONCLUSION: The study provides preliminary evidence for functional correlates of effectiveness of dTMS as an adjunctive treatment modality for OCD.

Adjunctive neuronavigated accelerated continuous theta-burst stimulation in obsessive-compulsive disorder: a randomized sham-controlled study.

BACKGROUND: Approximately 40% of patients treated for obsessive-compulsive disorder (OCD) do not respond to standard and second-line augmentation treatments leading to the exploration of alternate biological treatments. Continuous theta burst stimulation (cTBS) is a form of repetitive transcranial magnetic stimulation inducing more rapid and longer-lasting effects on synaptic plasticity than the latter. To the best of our knowledge, only one recent study and a case report investigated the effect of cTBS at the supplementary motor area (SMA) in OCD. OBJECTIVE: This study aimed to examine the effect of accelerated robotized neuronavigated cTBS over SMA in patients with OCD. METHODS: A total of 32 patients with OCD were enrolled and randomized into active and sham cTBS groups. For active cTBS stimulation, an accelerated protocol was used. Bursts of three stimuli at 50 Hz, at 80% of MT, repeated at 5 Hz were used. Daily 2 sessions of 900 pulses each, for a total of 30 sessions over 3 wk (weekly 10 sessions), were given. Yale-Brown Obsessive-Compulsive Rating Scale (YBOCS), Clinical Global Impressions scale (CGI), Hamilton Depression Rating Scale (HAM-D), and Hamilton Anxiety Rating Scale (HAM-A) were administered at baseline and at end of weeks 3 and 8. RESULTS: A total of 26 patients completed the study. Active cTBS group showed significant group × time effect in YBOCS obsession (P < .001, η2 = 0.288), compulsion (P = .004, η2 = 0.207), YBOCS total (P < .001, η2 = 0.288), CGI-S (P = .010, η2 = 0.248), CGI-C (P = .010, η2 = 0.248), HAM-D (P = .014, η2 = 0.224) than sham cTBS group. CONCLUSIONS: Findings from our study suggest that adjunctive accelerated cTBS significantly improves psychopathology, severity of illness, and depression among patients with OCD. Future studies with larger sample sizes will add to our knowledge.

Adjuvant Priming Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Obsessive-Compulsive Disorder: In Search of a New Paradigm!

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is used as a therapeutic option for obsessive-compulsive disorder (OCD) in both clinical and research settings. There has been no consensus with regard to target area and other parameters, although 1-Hz rTMS over the supplementary motor area (SMA) is found to be promising. Priming stimulation, which involves high-frequency followed by low-frequency rTMS, has been shown to enhance neural response to low-frequency rTMS. Hence, this study was conducted to investigate the effect of adjunctive priming rTMS over the SMA in treatment-resistant OCD. METHODS: Thirty patients with OCD who were symptomatic after an adequate selective serotonin reuptake inhibitor trial were randomized into 2 groups: one group receiving active priming stimulation (6-Hz rTMS at 80% resting motor threshold) followed by 1-Hz rTMS (priming rTMS group) and the other receiving sham stimulation followed by 1-Hz rTMS (rTMS-only group). Both groups received 10 sessions of such interventions for 2 weeks. Both the rater and patients were blind to the treatment allocation. Assessments were done using the Yale-Brown Obsessive Compulsive Scale, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, and Clinical Global Impression-Improvement scale at baseline, 2 weeks, and 4 weeks. RESULTS: Both groups showed a significant improvement in all domains of psychopathology over time. The priming rTMS group was better than the rTMS-only group in reducing the Yale-Brown Obsessive Compulsive Scale compulsion score (P < 0.023) as well as scores of the Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression, and Clinical Global Impression-Improvement scale. None developed any adverse effects requiring medical attention. CONCLUSIONS: Priming rTMS over the SMA is safe and has favorable effects in OCD. It seems to have a predominant effect on the reduction of compulsions, presumably rectifying the impaired response inhibition in patients with OCD.

Adjunctive High-Definition Transcranial Direct Current Stimulation in Brain Glutamate-Glutamine and γ-Aminobutyric Acid, Withdrawal and Craving During Early Abstinence Among Patients With Opioid Use Disorder on Buprenorphine-Naloxone: A Proton Magnetic Resonance Spectroscopy-Based Pilot Study.

OBJECTIVE: Our study aimed to (1) examine the effect of adjunctive high-definition transcranial direct current stimulation (HD-tDCS) in craving and withdrawal among patients with opioid use disorder on buprenorphine-naloxone, and (2) examine effect of HD-tDCS changes in glutamate-glutamine and γ-aminobutyric acid (GABA) at the left dorsolateral prefrontal cortex (DLPFC) among patients with opioid use disorder on buprenorphine-naloxone. METHODS: This was a pilot randomized double-blind, sham-controlled parallel-group study. A total of 28 patients on buprenorphine-naloxone (6/1.5 mg/d) were randomly allocated into 2 groups for active and sham HD-tDCS stimulation. High-definition transcranial direct current stimulation was administered twice daily for consecutive 5 days, from days 2 to 6. The Clinical Opiate Withdrawal Scale (COWS), the Desire for Drug Questionnaire (DDQ), the Obsessive-Compulsive Drug Use Scale (OCDUS), and glutamate-glutamine and GABA at DLPFC via proton magnetic resonance spectroscopy were measured at baseline and on day 7. RESULTS: Both active and sham groups had comparable changes in DDQ, OCDUS (except 2 subcomponents), COWS, and glutamate-glutamine and GABA at DLPFC. In the active HD-tDCS group, statistically significant reductions were observed in DDQ, OCDUS, and COWS but not in glutamate-glutamine and GABA. CONCLUSIONS: The adjunctive active HD-tDCS group showed comparable changes in craving and withdrawal, and glutamate-glutamine and GABA at DLPFC compared with sham HD-tDCS. Craving and withdrawal but not glutamate-glutamine and GABA at DLPFC decreased significantly with adjunctive HD-tDCS. Future studies with larger sample size and online assessment of glutamate-glutamine and GABA would enhance our knowledge.

CSF Oculorrhea Presenting as "Tearing" following the Repair of Fronto-Ethmoidal Encephalocele.

INTRODUCTION: Cerebrospinal fluid (CSF) oculorrhea is extremely rare, and very few cases have been reported mostly following trauma. There is only 1 case in the published literature where oculorrhea occurred following the repair of fronto-nasal encephalocele. CASE DESCRIPTION: A six-year-old girl presented with gradually increasing fronto-ethmoidal encephalocele with secondary papulo-nodular changes. She underwent bi-frontal craniotomy with excision of encephalocele sac and herniated gliotic brain followed by dural closure using peri-cranial graft. One month later, she presented again with swelling over the operative site and "tearing" from both her eyes. She was diagnosed with CSF oculorrhea. After failing conservative management, lumbar drain was inserted and kept on continuous drainage. Oculorrhea stopped with lumbar drain but restarted with its removal. Therefore, theco-peritoneal shunt was placed, following which oculorrhea stopped. She is doing well at 5 months' follow-up. CONCLUSION: CSF oculorrhea must be considered by the pediatric neurosurgeons in any patient who presents with "tearing" following the repair of an anterior encephalocele.

Adjuvant High-Definition Transcranial Direct Current Stimulation for Negative Symptoms in Schizophrenia: A Pilot Study.

OBJECTIVE: In schizophrenia, negative symptoms account for a substantial amount of the comorbidity resulting in poor performance in social interaction, interpersonal relationships, economic functioning, and recreational activities. Research has implicated hypofrontality in the pathogenesis of negative symptoms of schizophrenia. Conventional transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex has attracted significant interest as an add-on treatment for negative symptoms in schizophrenia. High-definition tDCS (HD-tDCS), an optimized form of tDCS, has the potential for more focalized neuromodulation. Hence, we aimed to evaluate the efficacy of HD-tDCS over the left dorsolateral prefrontal cortex in the improvement of negative symptoms in schizophrenia. METHODS: Fourteen patients with schizophrenia with predominantly negative symptoms were enrolled for this pilot, randomized, sham-controlled, double-blind trial. Each participant received 10 sessions of HD-tDCS at 2 mA for 20 minutes twice daily over 5 days. Negative symptoms were assessed with the Scale for Assessment of Negative Symptoms and Positive and Negative Syndrome Scale for Schizophrenia. The Calgary Depression Scale for Schizophrenia was used to rule out depressive symptoms. Assessments were carried out at baseline and at 2 weeks. RESULTS: The improvement in negative symptoms in the active group was statistically significant at P value of 0.05 as compared with the sham group. CONCLUSION: These results suggest that HD-tDCS may lead to improvement in negative symptoms of schizophrenia. Its use as an adjunct to pharmacological treatment of negative symptoms may be worth considering.

Neurosurgery training in India during the COVID-19 pandemic: straight from the horse's mouth.

OBJECTIVE: The COVID-19 pandemic has forced medical professionals throughout the world to adapt to the changing medical scenario. The objective of this survey was to assess the change in neurosurgical training in India following the COVID-19 pandemic. METHODS: Between May 7, 2020, and May 16, 2020, a validated questionnaire was circulated among neurosurgical residents across India by social media, regarding changes in the department's functioning, patient interaction, surgical exposure, changes in academics, and fears and apprehensions associated with the pandemic. The responses were kept anonymous and were analyzed for changes during the COVID-19 pandemic compared to before the pandemic. RESULTS: A total of 118 residents from 29 neurosurgical training programs across 17 states/union territories of the country gave their responses to the survey questionnaire. The survey revealed that the surgical exposure of neurosurgical residents has drastically reduced since the onset of the COVID-19 pandemic, from an average of 39.86 surgeries performed/assisted per month (median 30) to 12.31 per month (median 10), representing a decrease of 67.50%. The number of academic sessions has fallen from a median of 5 per week to 2 per week. The survey uncovered the lack of universal guidelines and homogeneity regarding preoperative COVID-19 testing. The survey also reveals reluctance toward detailed patient examinations since the COVID-19 outbreak. The majority of respondents felt that the COVID-19 pandemic will hamper their operative and clinical skills. Fear of rescheduling or deferring of licensing examinations was significantly higher among those closest to the examination (p = 0.002). CONCLUSIONS: The adverse impact of the pandemic on neurosurgical training needs to be addressed. While ensuring the safety of the residents, institutes and neurosurgical societies/bodies must take it upon themselves to ensure that their residents continue to learn and develop neurosurgical skills during these difficult times.

Detection of Depression and Scaling of Severity Using Six Channel EEG Data.

Depression is a psychiatric problem which affects the growth of a person, like how a person thinks, feels and behaves. The major reason behind wrong diagnosis of depression is absence of any laboratory test for detection as well as severity scaling of depression. Any degradation in the working of the brain can be identified through change in the electroencephalogram (EEG) signal. Thus detection as well as severity scaling of depression is done in this study using EEG signal. In this study, features are extracted from the temporal region of the brain using six (FT7, FT8, T7, T8, TP7, TP8) channels. The linear features used are delta, theta, alpha, beta, gamma1 and gamma2 band power and their corresponding asymmetry as well as paired asymmetry. The non-linear features used are Sample Entropy (SampEn) and Detrended Fluctuation Analysis (DFA). The classifiers used are: Bagging along with three different kernel functions (Polynomial, Gaussian and Sigmoidal) of Support Vector Machine (SVM). Feature selection technique used is ReliefF. Highest classification accuracy of 96.02% and 79.19% was achieved for detection and severity scaling of depression using SVM (Gaussian Kernel Function) and ReliefF as feature selection. From the analysis, it was found that depression affects the temporal region of the brain (temporo-parietal region).It was also found that depression affects the higher frequency band features more and it affects each hemisphere differently. It can also be analysed that out of all the kernel of SVM, Gaussian kernel is more efficient to other kernels. Of all the features, combination of all paired asymmetry and asymmetry showed high classification accuracy (accuracy of 90.26% for detection of depression and accuracy of 75.31% for severity scaling).

Fungating Growth of Squamous Cell Carcinoma in Long-Standing Meningocele.

Squamous cell carcinoma is known to occur as a serious complication of chronic burns, scars, and ulcers, but very rarely has it been reported to occur in a long-neglected meningocele. The authors wish to present the case of a 21-year-old man who presented to us when a previously asymptomatic meningocele developed a squamous cell carcinoma on the meningocele sac. The squamous cell carcinoma was excised in toto, followed by excision of the redundant meningocele sac. The neural placode was closed and dural closure done with an artificial dural patch. Reconstruction of the defect thus created was performed by a lumbar perforator-based reverse latissimus dorsi myocutaneous flap. The patient did not develop any postoperative neurological deficits and made an uneventful recovery in the postoperative period. He received adjuvant radiation therapy and is doing well at 4 months' follow-up.

Safety and Efficacy of Adjunctive Θ Burst Repetitive Transcranial Magnetic Stimulation to Right Inferior Parietal Lobule in Schizophrenia Patients With First-Rank Symptoms: A Pilot, Exploratory Study.

BACKGROUND: First-rank symptoms (FRS) in schizophrenia have been found to be associated with various cognitive and biological markers. Repetitive transcranial magnetic stimulation (rTMS) has been shown to modulate such factors. We hypothesized that rTMS adjunctive to antipsychotics will be safe and effective in treatment of FRS in schizophrenia. METHODS: Schizophrenia patients with FRS randomly received either active or sham-magnetic resonance imaging navigated continuous Θ burst stimulation (cTBS)-rTMS to right inferior parietal lobule for 2 weeks; assessments were repeated. While primary outcome variables were safety profile, FRS and overall psychopathology; secondary outcomes were γ oscillatory activity, brain-derived neurotrophic factor levels, and self-monitoring function. RESULTS: No significant adverse events were reported in either group. None of the outcome measures showed sufficient power on the time by group analysis. CONCLUSIONS: This study fails to demonstrate whether or not adjunctive cTBS to right inferior parietal lobule could significantly alleviate FRS. We also fail to provide evidence for whether this protocol has any effect on brain-derived neurotrophic factor levels, self-monitoring function, and right hemispheric γ oscillations.

Intracranial germ cell tumors: a multi-institutional experience from three tertiary care centers in India.

OBJECTIVE: Central nervous system germ cell tumors (CNS GCTs) are relatively rare neoplasms. Incidence of CNS GCTs in Western literature is low (0.3-0.6 %) as compared to East Asia (3-4 %). No large study is available on CNS GCTs from India. METHODS: Intracranial GCT cases were retrieved from databases of three tertiary care institutes in India; clinicopathological data was reviewed. RESULTS: Ninety-five intracranial GCT cases were identified, accounting for 0.43 % of CNS tumors. Median age was 12 years (range, birth to 48 years); male preponderance was noted (66 %). Most patients (86.3 %) were aged <18 years. Pineal location was most common (45 %) and was associated with male gender and age >14 years. Germinoma was the commonest histopathological type (63.2 %), followed by teratoma (20 %). Suprasellar location was associated with germinoma histology. Follow-up was available for 71 patients (median, 15 months). Of these, 48 received adjuvant chemotherapy and/or radiotherapy. At the last follow-up, 44 patients showed no evidence of disease. Age >10 years, male gender, pineal location, and germinoma histology were associated with favorable outcome. CONCLUSION: This is the first multicentric study from India establishing that incidence of CNS GCT in India is similar to that in the West and differs from that in East Asian countries. However, similar to both, germinoma is the commonest histological type, and pineal location is most frequent. Studies on molecular alterations based on ethnicity and geographical location are necessary to provide clarity on differences in incidence. Attention needs to be focused on decreasing treatment heterogeneity and minimizing treatment-related morbidity and mortality, improving the cure rate of these highly treatable tumors.

Evaluation of resting state gamma power as a response marker in schizophrenia.

AIMS: An abnormal activity in the electroencephalography (EEG) gamma band (>30 Hz) has been demonstrated in schizophrenia and this has been suggested to be reflecting a deficit in the development and maturation of the basic cognitive functions of attention, working memory and sensory processing. Hypothesizing gamma oscillatory activity as a potential EEG biomarker to antipsychotic response in schizophrenia, the present study aimed at measuring baseline spontaneous gamma activity in schizophrenia patients, and evaluating its response to antipsychotic treatment over 8 weeks. METHODS: Fifteen drug-free/naïve patients were recruited, compared at baseline with 15 age-, sex- and education-matched healthy controls, and were followed up for 8 weeks' treatment on antipsychotics. Resting state EEG waves were recorded using high (192-channel) resolution EEG at admission, 4 weeks and 8 weeks. Spectral power was calculated using fast Fourier transformation, Hanning window. The power was averaged region-wise over nine regions in three frequency ranges (30-50 Hz, 50-70 Hz, 70-100 Hz). RESULTS: Patients and controls differed significantly at intake in terms of left temporal and parietal high (70-100 Hz) gamma power. Consequently, no significant differences were seen over the course of antipsychotic treatment on gamma spectral power in any of the regions. CONCLUSIONS: Lack of significant effect of treatment on gamma power suggests that these gamma oscillations may be trait markers in schizophrenia.

Resting State Dense Array Gamma Oscillatory Activity as a Response Marker for Cerebellar-Repetitive Transcranial Magnetic Stimulation (rTMS) in Schizophrenia.

BACKGROUND: As cerebellum and its abnormalities have been implicated in the pathophysiology of schizophrenia, repetitive transcranial magnetic stimulation (rTMS) of this alternate site has been suggested as a novel target for treating patients with this disorder. As resting state gamma activity measures functional brain connectivity, it could be used as a specific treatment marker. AIM: To investigate the effect of cerebellar-rTMS on resting state gamma activity, while studying its efficacy in recent onset schizophrenia patients. METHODS: This rater-blinded prospective study was completed by 11 schizophrenia patients. They received 10 sessions of high-frequency (theta patterned) rTMS to midline cerebellum over 2 weeks. Resting state EEG was recorded using high (192-channel) resolution EEG at baseline and post rTMS. Gamma spectral power was calculated using fast Fourier transformation, Hanning window averaged over 8 scalp segments corresponding 8 lobes. Clinical improvement rated on the Positive and Negative Syndrome Scale and depressive symptoms assessed using the Calgary Depression Scale for Schizophrenia were other outcome variables. Nonparametric statistics were used. RESULTS: Over the treatment course, significant reduction was seen on negative syndrome and depression scores. Gamma spectral power in left frontal and temporal segments reduced significantly. Spearman correlation analysis showed that percentage reduction in psychopathology scores had significant positive correlation with percentage reduction in gamma spectral power. CONCLUSIONS: Cerebellar-rTMS might be an effective adjunct to treat intricate and lingering negative and affective symptoms. Resting state gamma spectral power in frontal and temporal regions might be used as a biomarker for treatment response.

Meningeal hemangiopericytomas: a clinicopathological study with emphasis on MGMT (O(6) -methylguanine-DNA methyltransferase) promoter methylation status.

Meningeal hemangiopericytomas (HPCs) are aggressive dural-based tumors, for which no prognostic or predictive marker has been identified. Gross total resection is treatment of choice, but not easily achieved; hence, alkylating agents like temozolomide (TMZ) are now being tried. O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation has proven prognostic and predictive value in glioblastomas. This study evaluates MGMT promoter methylation in meningeal HPCs to determine its role in HPC oncogenesis and its association with patient outcome. Meningeal HPCs diagnosed between 2002 and 2011 were retrieved and clinicopathological features reviewed. MGMT promoter methylation status was assessed by methylation-specific polymerase chain reaction (MSP) and immunohistochemistry (IHC) for MGMT protein. HPCs accounted for 1.1% of all CNS tumors. Forty cases were analyzed; the majority were adults (mean age = 41.4 years). Seventy percent were primary and 30% were recurrent tumors; 60% were grade II and 40% were grade III. MGMT promoter methylation was identified in 45% of cases, including Grade II (54.2%) and Grade III (31.3%) (P = 0.203). Promoter methylation was significantly (P = 0.035) more frequent in primary (57.1%) than in recurrent (16.7%) tumors. No correlation was noted between MGMT promoter methylation by MSP and MGMT protein expression by IHC, or with progression-free survival. Thus, a significant proportion of HPCs demonstrate MGMT promoter methylation, suggesting possible susceptibility to TMZ. As promoter methylation is more frequent in primary tumors, TMZ may serve as a therapeutic option in residual primary tumors. Epigenetic inactivation of MGMT in HPCs necessitates the assessment of prognostic and predictive value of MGMT promoter methylation in HPCs in larger clinical trials.