Lipocalin-type prostaglandin D synthase: a glymphopathy marker in idiopathic hydrocephalus.

Idiopathic normal pressure hydrocephalus in elderly people is considered a form of glymphopathy caused by malfunction of the waste clearance pathway, called the glymphatic system. Tau is a representative waste material similar to amyloid-ß. During neurodegeneration, lipocalin-type prostaglandin D synthase (L-PGDS), a major cerebrospinal fluid (CSF) protein, is reported to act as a chaperone that prevents the neurotoxic aggregation of amyloid-ß. L-PGDS is also a CSF biomarker in idiopathic normal pressure hydrocephalus and significantly correlates with tau concentration, age, and age-related brain white matter changes detected by magnetic resonance imaging. To investigate this glymphopathy, we aimed to analyze white matter changes and contributing factors in vivo and their interactions ex vivo. Cerebrospinal tap tests were performed in 60 patients referred for symptomatic ventriculomegaly. Patients were evaluated using an idiopathic normal pressure hydrocephalus grading scale, mini-mental state examination, frontal assessment battery, and timed up-and-go test. The typical morphological features of high convexity tightness and ventriculomegaly were measured using the callosal angle and Evans index, and parenchymal white matter properties were evaluated with diffusion tensor imaging followed by tract-based spatial statistics. Levels of CSF biomarkers, including tau, amyloid-ß, and L-PGDS, were determined by ELISA, and their interaction, and localization were determined using immunoprecipitation and immunohistochemical analyses. Tract-based spatial statistics for fractional anisotropy revealed clusters that positively correlated with mini-mental state examination, frontal assessment battery, and callosal angle, and clusters that negatively correlated with age, disease duration, idiopathic normal pressure hydrocephalus grading scale, Evans index, and L-PGDS. Other parameters also indicated clusters that correlated with symptoms, microstructural white matter changes, and L-PGDS. Tau co-precipitated with L-PGDS, and colocalization was confirmed in postmortem specimens of neurodegenerative disease obtained from the human Brain Bank. Our study supports the diagnostic value of L-PGDS as a surrogate marker for white matter integrity in idiopathic normal pressure hydrocephalus. These results increase our understanding of the molecular players in the glymphatic system. Moreover, this study indicates the potential utility of enhancing endogenous protective factors to maintain brain homeostasis.

Prediction of MGMT promotor methylation status in glioblastoma by contrast-enhanced T1-weighted intensity image.

Background: The study aims to explore MRI phenotypes that predict glioblastoma's (GBM) methylation status of the promoter region of MGMT gene (pMGMT) by qualitatively assessing contrast-enhanced T1-weighted intensity images. Methods: A total of 193 histologically and molecularly confirmed GBMs at the Kansai Network for Molecular Diagnosis of Central Nervous Tumors (KANSAI) were used as an exploratory cohort. From the Cancer Imaging Archive/Cancer Genome Atlas (TCGA) 93 patients were used as validation cohorts. "Thickened structure" was defined as the solid tumor component presenting circumferential extension or occupying >50% of the tumor volume. "Methylated contrast phenotype" was defined as indistinct enhancing circumferential border, heterogenous enhancement, or nodular enhancement. Inter-rater agreement was assessed, followed by an investigation of the relationship between radiological findings and pMGMT methylation status. Results: Fleiss's Kappa coefficient for "Thickened structure" was 0.68 for the exploratory and 0.55 for the validation cohort, and for "Methylated contrast phenotype," 0.30 and 0.39, respectively. The imaging feature, the presence of "Thickened structure" and absence of "Methylated contrast phenotype," was significantly predictive of pMGMT unmethylation both for the exploratory (p = .015, odds ratio = 2.44) and for the validation cohort (p = .006, odds ratio = 7.83). The sensitivities and specificities of the imaging feature, the presence of "Thickened structure," and the absence of "Methylated contrast phenotype" for predicting pMGMT unmethylation were 0.29 and 0.86 for the exploratory and 0.25 and 0.96 for the validation cohort. Conclusions: The present study showed that qualitative assessment of contrast-enhanced T1-weighted intensity images helps predict GBM's pMGMT methylation status.

Risk of Bone Wax Migration During Retrosigmoid Craniotomy for Microvascular Decompression: Case-Control Study.

BACKGROUND AND OBJECTIVES: Bone wax is a flexible hemostatic agent commonly used for surgery in the posterior cranial fossa to control bleeding from the mastoid emissary vein. A large amount of bone wax can migrate into the sigmoid sinus through the mastoid emissary canal (MEC). We aimed to identify clinical factors related to intraoperative bone wax migration through the MEC during microvascular decompression (MVD) surgery, which may result in sigmoid sinus thrombosis. METHODS: We retrospectively collected the clinical data of patients with trigeminal neuralgia, hemifacial spasm, or trigeminal neuralgia accompanied by painful tic convulsif who underwent MVD. Basic information and the residual width and length (from the bone surface to the sigmoid sinus) of the MEC on computed tomography images were collected. We compared the collected clinical data between 2 groups of cases with and without intraoperative bone wax migration in the sigmoid sinus. RESULTS: Fifty-four cases with intraoperative bone wax migration and 187 patients without migration were enrolled. The t -test revealed significant differences in the width and length of the MEC ( P = .013 and P = .003, respectively). These variables were identified as significant factors in predicting intraoperative bone wax migration using multivariate logistic regression analysis. CONCLUSION: The large size of the MEC may be related to intraoperative bone wax migration into the sigmoid sinus in MVD. Neurosurgeons should be aware of these risks. Bone wax should be applied appropriately and hemostasis should be considered to control bleeding from the mastoid emissary vein in patients with a large MEC.

Functionality and Usability of the Exoscope in Microvascular Decompression for Hemifacial Spasm and Trigeminal Neuralgia.

BACKGROUND: Studies on the functionality and usability of the exoscope in neurosurgical procedures against surgical microscopes (SMs) are limited. This study aimed to examine the functionality and usability of the exoscope during microvascular decompression (MVD) surgery. METHODS: Seven neurosurgeons evaluated the usefulness of a 4 K, 3-dimension digital exoscope in MVD by answering a questionnaire. The questionnaire inquired about the functionality and usability of the exoscope by utilizing a visual analog scale (VAS; 1-10). A score of 5 on VAS was equivalent to the corresponding quality of the SM. The learning effect of the exoscope was evaluated using mean VAS scores in the first and last 3 cases for each neurosurgeon. RESULTS: The functionality of the exoscope in MVD was superior to that in SM (P < 0.001). In the last 3 surgeries, the mean VAS scores of the exoscope were excellent in terms of ease of arm handling, exchange of surgical instruments, ease of surgical procedure, and intraoperative physical stress. The mean VAS scores of the exoscope in intraoperative asthenopia were significantly higher than those of the SM (P < 0.001). No statistical significance was found in operation time, discharge outcome, and 1-year post-surgery outcome between MVD performed using the exoscope and SM. CONCLUSIONS: Neurosurgeons may experience reduced stress levels during MVD when using the exoscope. As the outcome of MVD using the exoscope did not demonstrate a statistical difference compared with MVD using the SM, the exoscope may prove to be a useful tool for performing MVD.

Intramedullary feeder aneurysm of a cervical epidural arteriovenous fistula causing myelopathy: a case report and literature review.

While a craniocervical junction (CCJ) epidural arteriovenous fistula (EDAVF) may present with hemorrhagic myelopathy from an associated feeder aneurysm on rare occasions, non-hemorrhagic myelopathy from such an aneurysm remains unreported. A woman in her late sixties presented with cervical myelopathy due to a non-hemorrhagic intramedullary aneurysm associated with CCJ-EDAVF. The intramedullary aneurysm originated from the spinal pial artery supplied by the anterior spinal artery. Direct surgical fistula coagulation and feeder obliteration resulted in the disappearance of the aneurysm and myelopathy improvement. This report illustrates the first case of a non-hemorrhagic intramedullary aneurysm associated with CCJ-EDAVF successfully treated with direct surgery.

Resolution of Visual Field Defect in Macroprolactinoma After Treatment With Cabergoline.

We report the case of a 49-year-old woman presenting with amenorrhea and progressive visual field defect for one month. Endocrinological workup revealed a high concentration of serum prolactin, and magnetic resonance imaging (MRI) showed pituitary macroadenoma with extrasellar extension as well as compression of optic nerves. Treatment with a dopamine agonist, cabergoline, for eight weeks led to the resolution of the visual field defect accompanied by a rapid decrease in the serum prolactin level. Follow-up MRI three months after the initial diagnosis revealed alleviation of visible mechanical compression of the optic chiasm by the tumor. We considered that the absence of retinal nerve damage and prompt initiation of cabergoline contributed to the rapid recovery of the visual acuity.

Carotid Micromesh Stent for the Cervical Carotid Artery Dissecting Aneurysm in a Patient with Vascular Eagle Syndrome.

OBJECTIVES: An elongated styloid process may cause vascular Eagle syndrome that includes cervical carotid artery (CCA) dissection with stenosis and aneurysm formation. There are only four reported cases with vascular Eagle syndrome-related CCA dissecting aneurysm treated with carotid artery stenting (CAS). This is the first report of applying a dual-layer nitinol micromesh stent (CASPER) for vascular Eagle syndrome-related CCA dissecting aneurysm. CASE PRESENTATION: A 38-year-old man presented with a sudden onset of aphasia and right hemiplegia. Cerebral angiography demonstrated the left CCA dissecting aneurysm. The superior trunk of the left middle cerebral artery (MCA) was also occluded, and emergent thrombectomy was performed. Computed tomography with angiography (CTA) revealed that a 33 mm-long styloid process compressed the CCA at the aneurysm formation. Three weeks later, a CASPER stent was applied for the CCA aneurysm under the flow reversal system. Immediately after stent placement, blood flow in the aneurysm became stagnant, and postoperative CTA demonstrated regression of the aneurysm. The aneurysm did not recur for 6 months with no styloid process resection. CONCLUSIONS: The dual-layer nitinol micromesh stent (CASPER) was useful to treat vascular Eagle syndrome-related CCA dissecting aneurysm.

[Posterior Subthalamic Area, Pallidothalamic Tract, and Pedunculopontine Nucleus:Deep Brain Stimulation Targets for Parkinson's Disease and Essential Tremor].

This article reviews the stereotactic targets in the posterior subthalamic area(PSA), fields H1/H2 of Forel(pallidothalamic tract), and the pedunculopontine nucleus(PPN)to complement the preceding articles on stereotactic and functional neurosurgery for movement disorders in the present issue of No Shinkei Geka. Two regions within the subthalamus, the PSA and fields H1/H2 of Forel, are the revisited stereotactic targets to treat movement disorders. Currently, the PSA is often utilized to treat essential tremor and various types of tremor. Fields H1/H2 of Forel are investigated as a target for magnetic resonance-guided focused ultrasound to treat motor symptoms and motor complications in patients with Parkinson's disease. For the past twenty years, the PPN has been investigated to treat refractory gait freezing and fall in patients with Parkinson's disease. These revisited and novel targets may be utilized as substitutes and complements for the present standard stereotactic targets.

Thalamic Deep Brain Stimulation for Refractory Atypical Tremor after Encephalitis of Unknown Etiology: A Case Report.

Tremor associated with encephalitis is usually transient and rarely becomes chronic and refractory. Treatment for such tremor using deep brain stimulation (DBS) has not yet been reported. We report an uncommon case of chronic tremor after encephalitis of unknown etiology and its outcome treated with thalamic DBS. A 47-year-old man presented with a 6-month history of medically refractory tremor after non-infectious and probable autoimmune encephalitis. The patient showed an atypical mixture of resting, postural, kinetic, and intention tremor. The tremor significantly disabled the patient's activities of daily life (ADL). The patient underwent bilateral thalamic DBS surgery. DBS leads were placed to cross the border between the ventralis oralis posterior (Vop) nucleus and ventralis intermedius (Vim) nucleus of the thalamus. Stimulation of both the Vop and Vim using the bipolar contacts controlled the mixed occurrence of tremor. The ADL and performance scores on The Essential Tremor Rating Assessment Scale (TETRAS) improved from 47 to 0 and from 44 to 9, respectively. The therapeutic effects have lasted for 24 months. Administration of combined Vop and Vim DBS may control uncommon tremor of atypical etiology and phenomenology.

Activated leukocyte cell adhesion molecule expression correlates with the WNT subgroup in medulloblastoma and is involved in regulating tumor cell proliferation and invasion.

Cluster of differentiation (CD) 166 or activated leukocyte cell adhesion molecule (ALCAM) is a transmembrane molecule known to be an intercellular adhesion factor. The expression and function of ALCAM in medulloblastoma (MB), a pediatric brain tumor with highly advanced molecular genetics, remains unclear. Therefore, this study aimed to clarify the significance and functional role of ALCAM expression in MB. ALCAM expression in 45 patients with MB was evaluated by immunohistochemical analysis of formalin-fixed paraffin-embedded clinical specimens and the relationship between ALCAM expression and pathological type/molecular subgroup, such as WNT, SHH, Group 3, and Group 4, was examined. Eight ALCAM positive (18%), seven partially positive (16%), and 30 negative (67%) cases were detected. All seven cases of the WNT molecular subgroup were ALCAM positive and ALCAM expression strongly correlated with this subgroup (P < 0.0001). In addition, functional studies using MB cell lines revealed ALCAM expression affected proliferation and migration as a positive regulator in vitro. However, ALCAM silencing did not affect survival or the formation of leptomeningeal dissemination in an orthotopic mouse model, but did induce a malignant phenotype with increased tumor cell invasion at the dissemination sites (P = 0.0029). In conclusion, our results revealed that ALCAM exhibited highly specific expression in the WNT subgroup of MB. Furthermore, we demonstrated that the cell kinetics of MB cell lines can be altered by the expression of ALCAM.

Radiomics and MGMT promoter methylation for prognostication of newly diagnosed glioblastoma.

We attempted to establish a magnetic resonance imaging (MRI)-based radiomic model for stratifying prognostic subgroups of newly diagnosed glioblastoma (GBM) patients and predicting O (6)-methylguanine-DNA methyltransferase promotor methylation (pMGMT-met) status of the tumor. Preoperative MRI scans from 201 newly diagnosed GBM patients were included in this study. A total of 489 texture features including the first-order feature, second-order features from 162 datasets, and location data from 182 datasets were collected. Supervised principal component analysis was used for prognostication and predictive modeling for pMGMT-met status was performed based on least absolute shrinkage and selection operator regression. 22 radiomic features that were correlated with prognosis were used to successfully stratify patients into high-risk and low-risk groups (p = 0.004, Log-rank test). The radiomic high- and low-risk stratification and pMGMT status were independent prognostic factors. As a matter of fact, predictive accuracy of the pMGMT methylation status was 67% when modeled by two significant radiomic features. A significant survival difference was observed among the combined high-risk group, combined intermediate-risk group (this group consists of radiomic low risk and pMGMT-unmet or radiomic high risk and pMGMT-met), and combined low-risk group (p = 0.0003, Log-rank test). Radiomics can be used to build a prognostic score for stratifying high- and low-risk GBM, which was an independent prognostic factor from pMGMT methylation status. On the other hand, predictive accuracy of the pMGMT methylation status by radiomic analysis was insufficient for practical use.

The histone modification H3 lysine 27 tri-methylation has conserved gene regulatory roles in the triplicated genome of Brassica rapa L.

Brassica rapa L. is an important vegetable and oilseed crop. We investigated the distribution of the histone mark tri-methylation of H3K27 (H3K27me3) in B. rapa and its role in the control of gene expression at two stages of development (2-day cotyledons and 14-day leaves) and among paralogs in the triplicated genome. H3K27me3 has a similar distribution in two inbred lines, while there was variation of H3K27me3 sites between tissues. Sites that are specific to 2-day cotyledons have increased transcriptional activity, and low levels of H3K27me3 in the gene body region. In 14-day leaves, levels of H3K27me3 were associated with decreased gene expression. In the triplicated genome, H3K27me3 is associated with paralogs that have tissue-specific expression. Even though B. rapa and Arabidopsis thaliana are not closely related within the Brassicaceae, there is conservation of H3K27me3-marked sites in the two species. Both B. rapa and A. thaliana require vernalization for floral initiation with FLC being the major controlling locus. In all four BrFLC paralogs, low-temperature treatment increases H3K27me3 at the proximal nucleation site reducing BrFLC expression. Following return to normal temperature growth conditions, H3K27me3 spreads along all four BrFLC paralogs providing stable repression of the gene.

The role of FRIGIDA and FLOWERING LOCUS C genes in flowering time of Brassica rapa leafy vegetables.

There is a wide variation of flowering time among lines of Brassica rapa L. Most B. rapa leafy (Chinese cabbage etc.) or root (turnip) vegetables require prolonged cold exposure for flowering, known as vernalization. Premature bolting caused by low temperature leads to a reduction in the yield/quality of these B. rapa vegetables. Therefore, high bolting resistance is an important breeding trait, and understanding the molecular mechanism of vernalization is necessary to achieve this goal. In this study, we demonstrated that BrFRIb functions as an activator of BrFLC in B. rapa. We showed a positive correlation between the steady state expression levels of the sum of the BrFLC paralogs and the days to flowering after four weeks of cold treatment, suggesting that this is an indicator of the vernalization requirement. We indicate that BrFLCs are repressed by the accumulation of H3K27me3 and that the spreading of H3K27me3 promotes stable FLC repression. However, there was no clear relationship between the level of H3K27me3 in the BrFLC and the vernalization requirement. We also showed that if there was a high vernalization requirement, the rate of repression of BrFLC1 expression following prolonged cold treatments was lower.

Long noncoding RNAs in Brassica rapa L. following vernalization.

Brassica rapa L. is an important agricultural crop that requires a period of prolonged cold for flowering. This process is known as vernalization. Studies have shown that long noncoding RNAs (lncRNAs) play important roles in abiotic stress responses and several cold-responsive noncoding RNAs have been suggested to be involved in vernalization. We examined the transcriptome of the Chinese cabbage inbred line (B. rapa L. var. pekinensis) RJKB-T24, and identified 1,444 long intergenic noncoding RNAs (lincRNAs), 551 natural antisense transcripts (NATs), and 93 intronic noncoding RNAs (incRNAs); 549 of the 2,088 lncRNAs significantly altered their expression in response to four weeks of cold treatment. Most differentially expressed lncRNAs did not lead to a change of expression levels in mRNAs covering or near lncRNAs, suggesting that the transcriptional responses to four weeks of cold treatment in lncRNA and mRNA are independent. However, some differentially expressed mRNAs had NATs with expression altered in the same direction. These genes were categorized as having an abiotic stress response, suggesting that the paired-expression may play a role in the transcriptional response to vernalization or cold treatment. We also identified short-term cold treatment induced NATs in BrFLC and BrMAF genes, which are involved in vernalization. The lncRNAs we identified differed from those reported in Arabidopsis thaliana, suggesting the role of lncRNAs in vernalization differ between these two species.

Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors.

Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.

Characteristics and outcomes of elderly patients with diffuse gliomas: a multi-institutional cohort study by Kansai Molecular Diagnosis Network for CNS Tumors.

INTRODUCTION: This study investigates the current state of clinical practice and molecular analysis for elderly patients with diffuse gliomas and aims to elucidate treatment outcomes and prognostic factors of patients with glioblastomas. METHODS: We collected elderly cases (≥ 70 years) diagnosed with primary diffuse gliomas and enrolled in Kansai Molecular Diagnosis Network for CNS Tumors. Clinical and pathological characteristics were analyzed retrospectively. Various factors were evaluated in univariate and multivariate models to examine their effects on overall survival. RESULTS: Included in the study were 140 elderly patients (WHO grade II: 7, III: 19, IV: 114), median age was 75 years. Sixty-seven patients (47.9%) had preoperative Karnofsky Performance Status score of ≥ 80. All patients underwent resection (gross-total: 20.0%, subtotal: 14.3%, partial: 39.3%, biopsy: 26.4%). Ninety-six of the patients (68.6%) received adjuvant treatment consisting of radiotherapy (RT) with temozolomide (TMZ). Seventy-eight of the patients (75.0%) received radiation dose of ≥ 50 Gy. MGMT promoter was methylated in 68 tumors (48.6%), IDH1/2 was wild-type in 129 tumors (92.1%), and TERT promoter was mutated in 78 of 128 tumors (60.9%). Median progression-free and overall survival of grade IV cases was 8.2 and 13.6 months, respectively. Higher age (≥ 80 years) and TERT promoter mutated were associated with shorter survival. Resection and adjuvant RT + TMZ were identified as independent factors for good prognosis. CONCLUSIONS: This community-based study reveals characteristics and outcomes of elderly glioma patients in a real-world setting. Elderly patients have several potential factors for poor prognosis, but resection followed by RT + TMZ could lengthen duration of survival.

Bridging veins and veins of the brainstem in microvascular decompression surgery for trigeminal neuralgia and hemifacial spasm.

OBJECTIVE In microvascular decompression surgery for trigeminal neuralgia and hemifacial spasm, the bridging veins are dissected to provide the surgical corridors, and the veins of the brainstem may be mobilized in cases of venous compression. Strategy and technique in dissecting these veins may affect the surgical outcome. The authors investigated solutions for minimizing venous complications and reviewed the outcome for venous decompression. METHODS The authors retrospectively reviewed their surgical series of microvascular decompression for trigeminal neuralgia and hemifacial spasm in patients treated between 2005 and 2017. Surgical strategies included preservation of the superior petrosal vein and its tributaries, thorough dissection of the arachnoid sleeve that enveloped these veins, cutting of the inferior petrosal vein over the lower cranial nerves, and mobilization or cutting of the veins of the brainstem that compressed the nerve roots. The authors summarized the patient characteristics, operative findings, and postoperative outcomes according to the vascular compression types as follows: artery alone, artery and vein, and vein alone. They analyzed the data using chi-square and 1-way ANOVA tests. RESULTS The cohort was composed of 121 patients with trigeminal neuralgia and 205 patients with hemifacial spasm. The superior petrosal vein and its tributaries were preserved with no serious complications in all patients with trigeminal neuralgia. Venous compression alone and arterial and venous compressions were observed in 4% and 22%, respectively, of the patients with trigeminal neuralgia, and in 1% and 2%, respectively, of those with hemifacial spasm (p < 0.0001). In patients with trigeminal neuralgia, 35% of those with artery and venous compressions and 80% of those with venous compression alone had atypical neuralgia (p = 0.015). The surgical cure and recurrence rates of trigeminal neuralgias with venous compression were 60% and 20%, respectively, and with arterial and venous compressions the rates were 92% and 12%, respectively (p < 0.0001, p = 0.04). In patients with hemifacial spasm who had arterial and venous compressions, their recurrence rate was 60%, and that was significantly higher compared to other compression types (p = 0.0008). CONCLUSIONS Dissection of the arachnoid sleeve that envelops the superior petrosal vein may help to reduce venous complications in surgery for trigeminal neuralgia. Venous compression may correlate with worse prognosis even with thorough decompression, in both trigeminal neuralgia and hemifacial spasm.