The emerging roles of glutamine amidotransferases in metabolism and immune defense.

Glutamine amidotransferases (GATs) catalyze the synthesis of nucleotides, amino acids, glycoproteins and an enzyme cofactor, thus serving as key metabolic enzymes for cell proliferation. Carbamoyl-phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase (CAD) is a multifunctional enzyme of the GAT family and catalyzes the first three steps of the de novo pyrimidine synthesis. Following our findings that cellular GATs are involved in immune evasion during herpesvirus infection, we discovered that CAD reprograms cellular metabolism to fuel aerobic glycolysis and nucleotide synthesis via deamidating RelA. Deamidated RelA activates the expression of key glycolytic enzymes, rather than that of the inflammatory NF-κB-responsive genes. As such, cancer cells prime RelA for deamidation via up-regulating CAD activity or accumulating RelA mutations. Interestingly, the recently emerged SARS-CoV-2 also activates CAD to couple evasion of inflammatory response to activated nucleotide synthesis. A small molecule inhibitor of CAD depletes nucleotide supply and boosts antiviral inflammatory response, thus greatly reducing SARS-CoV-2 replication. Additionally, we also found that CTP synthase 1 (CTPS1) deamidates interferon (IFN) regulatory factor 3 (IRF3) to mute IFN induction. Our previous studies have implicated phosphoribosyl formylglycinamidine synthase (PFAS) and phosphoribosyl pyrophosphate amidotransferase (PPAT) in deamidating retinoic acid-inducible gene I (RIG-I) and evading dsRNA-induced innate immune defense in herpesvirus infection. Overall, these studies have uncovered an unconventional enzymatic activity of cellular GATs in metabolism and immune defense, offering a molecular link intimately coupling these fundamental biological processes.

The Interferon-inducible NAMPT acts as a protein phosphoribosylase to restrict viral infection.

As obligate intracellular pathogens, viruses often activate host metabolic enzymes to supply intermediates that support progeny production. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the salvage NAD+ synthesis, is an interferon-inducible protein that inhibits the replication of several RNA and DNA viruses with unknown mechanism. Here we report that NAMPT restricts herpes simplex virus 1 (HSV-1) replication via phosphoribosyl-hydrolase activity toward key viral structural proteins, independent of NAD+ synthesis. Deep mining of enriched phosphopeptides of HSV-1-infected cells identified phosphoribosylated viral structural proteins, particularly glycoproteins and tegument proteins. Indeed, NAMPT de-phosphoribosylates viral proteins in vitro and in cells. Chimeric and recombinant HSV-1 carrying phosphoribosylation-resistant mutations show that phosphoribosylation promotes the incorporation of structural proteins into HSV-1 virions and subsequent virus entry. Moreover, loss of NAMPT renders mice highly susceptible to HSV-1 infection. The work describes a hidden enzyme activity of a metabolic enzyme in viral infection and host defense, offering a system to interrogate roles of phosphoribosylation in metazoans.

Caregivers' Impression About the Effect of Subthalamic Nucleus Deep Brain Stimulation in the Treatment of Parkinson's Disease.

AIM: To determine caregivers' impressions of the impact of STN-DBS on motor and non-motor symptoms of Parkinson's disease (PD) in patients who underwent subthalamic nucleus deep brain stimulation (STN-DBS), evaluate the relationship of these changes with disease characteristics, and examine their contribution to the daily lives of patients. MATERIAL AND METHODS: The caregivers of patients who underwent STN-DBS were interviewed over the telephone. All telephone interviews were recorded, and changes in the motor and non-motor symptoms of the patients after STN-DBS were evaluated with a standardized questionnaire. RESULTS: Of the 173 patients with PD who underwent STN-DBS between 2005 and 2015, 62 who could be contacted by telephone were enrolled in the study. The mean age of the patients was 59.71 ± 9.78 years (range: 33-77 years). The mean disease duration was 15.62 ± 8.66 years (Range: 4-50 years). STN-DBS was performed on average 3.88 ± 2.6 years earlier (range: 1-11 years). According to the caregivers of the patients, there was a reduction in "off" periods in 79% of the patients, tremor in 58.1%, dyskinesia in 59.6%, depression in 46.8 %, pain symptoms in 41.9%, and improvement in sleep problems in 43.6% after STN-DBS. Moreover, 80.6% of the patients reported an improvement in their daily life activities after STN-DBS. CONCLUSION: From the caregivers' perspective, there was an improvement in the non-motor symptoms as well as the motor symptoms of patients with PD after STN-DBS, and this had a positive effect on the activities of daily lives in the majority of patients. Telephone interviews can be considered as an alternative method in the follow-up of patients with PD, especially when they cannot be assessed face-to-face.

Microsurgical anatomy of the anterior cerebral artery and the arterial supply of the cingulate gyrus.

PURPOSE: The cingulate gyrus is a potential surgical area to treat tumours, psychiatric diseases, intractable pain and vascular malformations. The aim of the study was to define the topographic anatomy and arterial supply of the cingulate gyrus located on the medial surface of the cerebral hemisphere. METHODS: We studied thirty-six hemispheres, each hemisected in the midsagittal plane. The vertical thickness of the cingulate gyrus was measured at the anterior commissure (AC), posterior commissure (PC), and genu levels of the corpus callosum. The branches of the anterior and posterior cerebral arteries supplying each zone were noted separately. The arterial pathways were transformed to digital data in AutoCAD to identify the condensation and reduction areas. RESULTS: The mean AC-PC distance was 27.17 ± 1.63 mm. The thinnest region was the genu level of the corpus callosum (10.29 mm). The superior internal parietal artery (SIPA), inferior internal parietal artery (IIPA) and pericallosal artery (PrCA) supplied all zones of the cingulate gyrus. The anterior zone received the greatest supply. The arterial condensation and reduction areas on both sides of cingulate gyrus and its x, y, and z coordinates specified. CONCLUSIONS: The target cingulotomy (TC) area was determined for anterior cingulotomy. The properties of the TC area are that the thinnest region of the cingulate gyrus is supplied relatively less than other areas and is close to the anterior cingulotomy areas in the literature. The arterial reduction area (ARA) was found to be suitable for corpus callosotomy in terms of avoiding haemorrhage.

Metabolic Enzymes in Viral Infection and Host Innate Immunity.

Metabolic enzymes are central players for cell metabolism and cell proliferation. These enzymes perform distinct functions in various cellular processes, such as cell metabolism and immune defense. Because viral infections inevitably trigger host immune activation, viruses have evolved diverse strategies to blunt or exploit the host immune response to enable viral replication. Meanwhile, viruses hijack key cellular metabolic enzymes to reprogram metabolism, which generates the necessary biomolecules for viral replication. An emerging theme arising from the metabolic studies of viral infection is that metabolic enzymes are key players of immune response and, conversely, immune components regulate cellular metabolism, revealing unexpected communication between these two fundamental processes that are otherwise disjointed. This review aims to summarize our present comprehension of the involvement of metabolic enzymes in viral infections and host immunity and to provide insights for potential antiviral therapy targeting metabolic enzymes.

SARS-CoV-2 couples evasion of inflammatory response to activated nucleotide synthesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolves rapidly under the pressure of host immunity, as evidenced by waves of emerging variants despite effective vaccinations, highlighting the need for complementing antivirals. We report that targeting a pyrimidine synthesis enzyme restores inflammatory response and depletes the nucleotide pool to impede SARS-CoV-2 infection. SARS-CoV-2 deploys Nsp9 to activate carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD) that catalyzes the rate-limiting steps of the de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. While RelA deamidation shuts down NF-κB activation and subsequent inflammatory response, it up-regulates key glycolytic enzymes to promote aerobic glycolysis that provides metabolites for de novo nucleotide synthesis. A newly synthesized small-molecule inhibitor of CAD restores antiviral inflammatory response and depletes the pyrimidine pool, thus effectively impeding SARS-CoV-2 replication. Targeting an essential cellular metabolic enzyme thus offers an antiviral strategy that would be more refractory to SARS-CoV-2 genetic changes.

Morphology of the trigeminal ganglion: anatomical structures related to trigeminal radiofrequency rhizotomy.

BACKGROUND: Trigeminal neuralgia is the most common example of craniofacial neuralgia. Its etiology is unknown and is characterized by severe episodes of paroxysmal pain. The trigeminal ganglion and its adjacent anatomical structures have a complex anatomy. The foramen ovale is of great importance during surgical procedures such as percutaneous trigeminal rhizotomy for trigeminal neuralgia. OBJECTIVE: We aimed to identify the anatomical structures associated with the trigeminal ganglion and radiofrequency rhizotomy on cadavers and investigate their relationship with the electrodes used during rhizotomy to determine the contribution of the electrode diameter and length to the effectiveness of the lesion formation on the ganglion. METHODS: Five fresh-frozen cadaver heads injected with red silicone/latex were used. A percutaneous puncture was made by inserting of a cannula through the foramen ovale to create a pathway for electrodes. The relationships between the electrodes, Meckel's cave, trigeminal ganglion, and neurovascular structures were observed and morphometric measurements were obtained using a digital caliper. RESULTS: Trigeminal ganglion, therefore the electrode in its final position, shows proximity with important anatomical structures. The electrode was inserted posteriorly into the foramen ovale in all of the specimens and was located on the retrogasserian fibers. This study revealed that the electrodes targeting the ganglion and passing through the foramen ovale may cause a radiofrequency lesion due to the contact effect of the dura itself pressing on the electrode. Pushing the cannula beyond the petroclival angle may result in puncturing of the dura propria and moving further away from the target area. CONCLUSION: The success of radiofrequency rhizotomy is directly related to the area affected by the lesion. Understanding the mechanism of action underlying this procedure will ensure the effectiveness, success, and sustainability of the treatment.

Combined Unilateral Radiofrequency Lesioning of the Motor Thalamus, Field of Forel, and Zona Incerta: A Series of Cases With Dystonia.

BACKGROUND: Dystonia is a group of disorders characterized by involuntary slow repetitive twisting movements and/or abnormal posture. Surgical options such as neuromodulation through deep brain stimulation and neuroablative procedures are available for patients who do not respond to conservative treatment. OBJECTIVE: To present our series of patients with dystonia who were treated with stereotactic combined unilateral radiofrequency lesioning of the motor thalamus, field of Forel, and zona incerta. METHODS: Medical records of 50 patients with dystonia who were treated with unilateral combined lesions were reviewed. Outcomes of the surgical procedure were evaluated using the Burke-Fahn-Marsden Dystonia Rating Scale (with movement and disability subscales) and Unified Parkinson's Disease Rating Scale-tremor items. RESULTS: Based on the symptoms, patients were categorized as having generalized dystonia (34%), hemidystonia (30%), and dystonic tremor (DT) (36%). Primary/idiopathic dystonia, primary genetic/hereditary dystonia, and secondary dystonia accounted for 16%, 4%, and 80% of patients, respectively. The mean follow-up duration was 156.2 ± 88.9 mo. The overall improvement in the Burke-Fahn-Marsden Dystonia Rating Scale scores (movement and disability, respectively) was 57.8% and 36.4% in generalized dystonia, 60.0% and 45.8% in hemidystonia, and 65.6% and 56.8% in DT. Patients with DT showed an 83.3% improvement in mean Unified Parkinson's Disease Rating Scale tremor score. Patients with cerebral palsy showed mean improvements of 66.7% in movement scores and 50.8% in disability scores. No mortality or major morbidity was observed postoperatively. CONCLUSION: Stereotactic radiofrequency unilateral combined thalamotomy, campotomy, and zona incerta lesions may be an effective surgical alternative for patients with dystonia, especially those with secondary dystonia resistant to deep brain stimulation.

SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response.

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with astonishing mortality and morbidity. The high replication and transmission of SARS-CoV-2 are remarkably distinct from those of previous closely related coronaviruses, and the underlying molecular mechanisms remain unclear. The innate immune defense is a physical barrier that restricts viral replication. We report here that the SARS-CoV-2 Nsp5 main protease targets RIG-I and mitochondrial antiviral signaling (MAVS) protein via two distinct mechanisms for inhibition. Specifically, Nsp5 cleaves off the 10 most-N-terminal amino acids from RIG-I and deprives it of the ability to activate MAVS, whereas Nsp5 promotes the ubiquitination and proteosome-mediated degradation of MAVS. As such, Nsp5 potently inhibits interferon (IFN) induction by double-stranded RNA (dsRNA) in an enzyme-dependent manner. A synthetic small-molecule inhibitor blunts the Nsp5-mediated destruction of cellular RIG-I and MAVS and processing of SARS-CoV-2 nonstructural proteins, thus restoring the innate immune response and impeding SARS-CoV-2 replication. This work offers new insight into the immune evasion strategy of SARS-CoV-2 and provides a potential antiviral agent to treat CoV disease 2019 (COVID-19) patients. IMPORTANCE The ongoing COVID-19 pandemic is caused by SARS-CoV-2, which is rapidly evolving with better transmissibility. Understanding the molecular basis of the SARS-CoV-2 interaction with host cells is of paramount significance, and development of antiviral agents provides new avenues to prevent and treat COVID-19 diseases. This study describes a molecular characterization of innate immune evasion mediated by the SARS-CoV-2 Nsp5 main protease and subsequent development of a small-molecule inhibitor.

Interleukin-7 protects CD8+ T cells from adenosine-mediated immunosuppression.

The nucleoside adenosine accumulates extracellularly in solid tumors and inhibits CD8+ T cells by activating adenosine receptors. The cytokine interleukin-7 (IL-7), which is produced by various tissues and tumors, promotes the survival and maintenance of T cells. Adenosine and IL-7 signaling are being clinically targeted separately or in combination with other therapies for solid tumor indications. Here, we found that IL-7 signaling promoted the accumulation of tumor-associated CD8+ T cells, in part, by preventing adenosine-mediated immunosuppression. Inhibition of the transcription factor FoxO1 downstream of IL-7 receptor signaling was important for protecting CD8+ T cells from suppression by adenosine. These findings have implications for the development of new approaches for cancer immunotherapies that target the adenosine pathway.

Targeting CTP Synthetase 1 to Restore Interferon Induction and Impede Nucleotide Synthesis in SARS-CoV-2 Infection.

The newly emerged SARS-CoV-2 caused a global pandemic with astonishing mortality and morbidity. The mechanisms underpinning its highly infectious nature remain poorly understood. We report here that SARS-CoV-2 exploits cellular CTP synthetase 1 (CTPS1) to promote CTP synthesis and suppress interferon (IFN) induction. Screening a SARS-CoV-2 expression library identified ORF7b and ORF8 that suppressed IFN induction via inducing the deamidation of interferon regulatory factor 3 (IRF3). Deamidated IRF3 fails to bind the promoters of classic IRF3-responsible genes, thus muting IFN induction. Conversely, a shRNA-mediated screen focused on cellular glutamine amidotransferases corroborated that CTPS1 deamidates IRF3 to inhibit IFN induction. Functionally, ORF7b and ORF8 activate CTPS1 to promote de novo CTP synthesis while shutting down IFN induction. De novo synthesis of small-molecule inhibitors of CTPS1 enabled CTP depletion and IFN induction in SARS-CoV-2 infection, thus impeding SARS-CoV-2 replication. Our work uncovers a strategy that a viral pathogen couples immune evasion to metabolic activation to fuel viral replication. Inhibition of the cellular CTPS1 offers an attractive means for developing antiviral therapy that would be resistant to SARS-CoV-2 mutation.

Viral pseudoenzymes in infection and immunity.

Pseudoenzymes are proteins that are evolutionarily related to active enzymes, but lack relevant catalytic activity. As obligate intracellular pathogens, viruses complete their life cycle fully dependent on the cellular supplies of macromolecule and energy. Traditionally, studies of viral proteins sharing high homology with host counterparts reveal insightful mechanisms by which host signaling pathways are delicately regulated. Recent investigations into the action of cellular pseudoenzymes elucidate diverse molecular means how enzymes are differentially controlled under various physiological conditions, hinting to the potential that pathogens may exploit these regulatory modalities. To date, there have been three types of viral pseudoenzymes reported and our understanding concerning their mechanism of regulation is rudimentary at best. However, it is clear that viral pseudoenzymes are emerging with surprising functions in infection and immunity, and we are only at the beginning to understand this new group of enzyme regulators. In this review, we will summarize current knowledge in viral pseudoenzymes and provide a perspective for future research.

Deamidation Shunts RelA from Mediating Inflammation to Aerobic Glycolysis.

Cell proliferation and inflammation are two metabolically demanding biological processes. How these competing processes are selectively executed in the same cell remains unknown. Here, we report that the enzyme carbamoyl-phosphate synthetase, aspartyl transcarbamoylase, and dihydroorotase (CAD) deamidates the RelA subunit of NF-κB in cancer cells to promote aerobic glycolysis and fuel cell proliferation in tumorigenesis. This post-translational modification switches RelA function from mediating the expression of NF-κB-responsive genes to that of glycolytic enzymes, thus shunting the cell's inflammatory response to aerobic glycolysis. Further, we profiled diverse human cancer cell lines and found that high CAD expression and a subset of RELA mutations correlated with RelA deamidation. And by use of inhibitors of key glycolytic enzymes, we validated the pivotal role of RelA deamidation in tumorigenesis of cancer cell lines. This work illuminates a mechanism by which protein deamidation selectively specifies gene expression and consequent biological processes.

Predictive Factors for Favorable Outcome from Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s Disease.

AIM: To investigate predictive factors for a favorable outcome from subthalamic nucleus-deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) and whether low serum vitamin B12 (vB12) levels can predict an unfavorable outcome. MATERIAL AND METHODS: Thirty-nine patients with PD who underwent bilateral STN-DBS were retrospectively analyzed. A difference of at least 30% between preoperative medication-off and postoperative medication-off stimulation-on Unified PD Rating Scale (UPDRS)-III scores was accepted to be a good outcome. Patients with good and bad outcomes were compared in terms of age, gender, levodopa responsiveness, vB12 levels, UPDRS subscores, presence of diabetes mellitus and hypertension, and presence of lacunes on cranial magnetic resonance imaging (MRI). RESULTS: Twenty-two of 39 patients (56.4%) had a good outcome postoperatively. No significant difference was observed in terms of age, gender, presence of abnormal MRI findings, and comorbid diseases between patients with good and bad outcomes. Mean preoperative bradykinesia score in patients with a good outcome was higher than those with a bad outcome. There was a positive correlation between the benefit of STN-DBS and preoperative levodopa responsiveness. In patients with low vB12 levels, 33.3% had a good outcome, whereas 55.2% of patients with normal vB12 levels had a good outcome (p = 0.589). CONCLUSION: Our results confirm that patients with better levodopa response have better outcomes. Interestingly, patients with worse bradykinesia had a better surgical outcome. A favorable surgical outcome was less frequent in patients with low vB12 levels and was not statistically significant.

Adenosine Receptor Signaling Targets Both PKA and Epac Pathways to Polarize Dendritic Cells to a Suppressive Phenotype.

Extracellular adenosine accumulates in tumors and causes suppression of immune cells. Suppressive adenosine signaling is achieved through adenosine A2A and A2B receptors, which are Gs coupled, and their activation elevates cAMP levels. Gs-coupled GPCR signaling causes cAMP accumulation, which plays an anti-inflammatory role in immune cells. Protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) are two intracellular receptors of cAMP. In this study we showed that adenosine receptor signaling polarizes activated murine dendritic cells (DCs) into a tumor-promoting suppressive phenotype. Adenosine receptor signaling activates cAMP pathway and upregulates the negative regulators of NF-κB but does not influence phosphorylation of immediate inflammatory signaling molecules downstream of TLR signaling. Pharmacologic activation of both PKA and Epac pathways by specific cAMP analogues phenocopied the effects of adenosine signaling on murine DCs, such as suppression of proinflammatory cytokines, elevation of anti-inflammatory IL-10, increased expression of regulators of NF-κB pathway, and finally suppression of T cell activation. Inhibition of effector cytokine, IL-12p40 production, and increased immunosuppressive IL-10 production by adenosine signaling is significantly reversed only when both PKA and Epac pathways were inhibited together. Adenosine signaling increased IL-10 secretion while decreasing IL-12p40 secretion in human monocyte-derived DCs. Stimulation of both PKA and Epac pathways also caused combinatorial effects in regulation of IL-12p40 secretion in human monocyte-derived DCs. Interestingly, PKA signaling alone caused similar increase in IL-10 secretion to that of adenosine signaling in human monocyte-derived DCs. Our data suggest adenosine/cAMP signaling targets both PKA/Epac pathways to fully differentiate DCs into a suppressive phenotype.

No Effect of Different Stimulation Conditions on Verbal Fluency and Visuospatial Orientation in Patients with Subthalamic Nucleus Deep Brain Stimulation.

BACKGROUND: Subthalamic nucleus deep brain stimulation is an effective treatment for the symptomatic treatment of Parkinson's disease. Apart from the obvious motor benefits, some cognitive side effects have been reported, particularly in verbal fluency. OBJECTIVES: Our aim was to evaluate the effects of the stimulation on verbal fluency and visuospatial orientation with changing stimulation conditions in 35 patients with Parkinson's disease. METHODS: Patients were randomized for their stimulation conditions as 'both on', 'both off', 'right on', and 'left on' and underwent verbal fluency and visuospatial orientation tasks during their drug-on periods. Letter and categorical fluency tasks and Benton's Judgment of Line Orientation Test were used for assessment. RESULTS: Overall, 6 patients were excluded due to dementia or depression. For verbal fluency, the number of words they produced in 1 min was similar in four stimulation conditions (p > 0.05). No significant difference was found between stimulation conditions in the spatial orientation task. CONCLUSIONS: We were unable to find any significant changes in verbal fluency and visuospatial orientation task scores with different stimulation conditions. This result suggests that either stimulation has no effect on given domains or the effect is so small that more detailed batteries are required to detect the difference.

Primary pineal glioblastoma: a case report.

Glioblastoma is very rare in the pineal region. We report a case of glioblastoma in this region. This is the 18th case of primary glioblastoma in the pineal region and the second case that survived over two years according the literature. A 60-year-old man admitted with headache and ataxia that continued for the last 3 months. Physical examination was normal. Neurological examination revealed ataxia. There was no motor or sensory deficit. Computer tomography showed triventricular hydrocephalus and isodense rounded mass in the pineal region. Magnetic resonance images revealed a regular-edged heterogeneous contrast-enhanced tumor in pineal region. A ventriculoperitoneal shunt was inserted for hydrocephalus. After surgery, the ataxia and hydrocephalus were improved. Ten days later, serial stereotactic biopsies were performed. Histopathological specimens revealed glioblastoma. The patient was recommended to undergo radiotherapy and chemotherapy. The patient is still surviving without deficit two years after biopsy and shunt operation.

A comparison between stereotactic targeting methods of the subthalamic nucleus in cases with Parkinson's disease.

BACKGROUND: Several methods are used for targeting of the subthalamic nucleus (STN) for the surgical treatment of Parkinson's disease (PD). The goal of this study is to determine the most suitable morphological method for localizing the STN in order to perform deep brain stimulation (DBS) in the treatment of PD. METHODS: Twelve cases with PD underwent bilateral STN-DBS and followed up for 5 years. Indirect calculation of the STN using AC-PC coordinates, and direct targeting of the STN using stereotactic CT/MRI fusion, were used for targeting. A microelectrode recording method was used to localize the STN. RESULTS: Direct targeting of the STN using CT/MRI fusion was very precise in every case, based upon evaluation of the intraoperative microelectrode recordings, postoperative MRI scans, and clinical follow-up of the cases. The coordinate differences obtained from these two methods were statistically significant. CONCLUSION: Direct targeting method of the STN using CT/MRI fusion provided higher precision than the indirect calculation method. This method may be used as a standard targeting technique, and may obviate the need for using complicated technologies such as microelectrode recording, which may sometimes be risky and counterproductive.

Management of bilateral trigeminal neuralgia with trigeminal radiofrequency rhizotomy: a treatment strategy for the life-long disease.

BACKGROUND: The objective of this study was to evaluate the effectiveness of percutaneous controlled radiofrequency trigeminal rhizotomy (RF-TR) in patients with bilateral trigeminal neuralgia (BTN). Patients were analyzed after RF-TR in terms of outcome, safety and complications. METHODS: Eighty-nine BTN patients underwent 186 RF-TR procedures. Eighty-seven patients had idiopathic trigeminal neuralgia (ITN) and two patients had multiple sclerosis (2.2%). Fifty-six (62.9%) were women and 33 (37.1%) were men. Ages ranged from 29 to 85 years. Anesthesia was administered at a determined optimal level, allowing patient cooperation for controlled and selective lesioning. RESULTS: The mean follow-up period was 101.71 ± 77.7 months. Familial occurrence was seen in two (2.2%) patients. Synchronized pain was observed in 25 (28.2%) patients. Pain occurrence on the contralateral side was observed with an average duration of 124.7 ± 87.13 months. Fifty-four of the 89 patients underwent 146 RF-TR procedures for both sides and 35 underwent 40 RF-TR procedures for one side. Complete pain relief or partial satisfactory pain relief was achieved on the medically treated side in 35 patients. During follow-up, 36 patients required the second procedure and 7 required the third procedure. Acute pain relief was reported in 86 (96.6%) patients. Early (<6 months) pain recurrence was observed in 11 (12.3%) and late (>6 months) recurrence in 25 (28.0%) patients. Complications included diminished corneal reflex in four (2.1%) patients, keratitis in two (1.1%), masseter dysfunction in four (2.1%), dysesthesia in two (1.1%), and anesthesia dolorosa in one (0.5%). CONCLUSIONS: RF-TR is an effective, selective, well-controlled, and effortlessly repeatable procedure for treating BTN, especially in the elderly, in terms of low morbidity and mortality rates and high rate of satisfactory pain relief.