Noggin contributes to brain metastatic colonization of lung cancer cells.

BACKGROUND: Brain metastasis is a common complication among patients with lung cancer, yet the underlying mechanisms remain unclear. In this study, we aimed to investigate the pathogenesis of brain metastasis in lung cancer. METHODS: We established highly colonizing metastatic lung cancer cells, A549-M2, through multiple implantations of A549 human lung cancer cells in the carotid artery of athymic nude mice. RESULTS: Compared to parental cells (M0), M2 cells demonstrated slower growth in culture plates and soft agar, as well as lower motility and higher adhesion, key characteristics of mesenchymal-epithelial transition (MET). Further analysis revealed that M2 cells exhibited decreased expression of epithelial-mesenchymal transition markers, including ZEB1 and Vimentin. M2 cells also demonstrated reduced invasiveness in co-culture systems. RNA sequencing and gene set enrichment analysis confirmed that M2 cells underwent MET. Intriguingly, depletion of Noggin, a BMP antagonist, was observed in M2 cells, and replenishment of Noggin restored suppressed migration and invasion of M2 cells. In addition, Noggin knockdown in control M0 cells promoted cell attachment and suppressed cell migration, suggesting that Noggin reduction during brain colonization causes inhibition of migration and invasion of metastatic lung cancer cells. CONCLUSIONS: Our results suggest that lung cancer cells undergo MET and lose their motility and invasiveness during brain metastatic colonization, which is dependent on Noggin.

What is the optimal prolactin cutoff for predicting the presence of a pituitary adenoma in patients with polycystic ovary syndrome?

Objective: Hyperprolactinemia (HPRL) and polycystic ovary syndrome (PCOS) are common causes of infertility in women of reproductive age. A pituitary adenoma (PA) is the most common type of brain tumor that causes HPRL. In the neurosurgical field, the co-existence of PA and PCOS is not common. However, neurosurgeons often treat patients who are referred from gynecology. Because most of these patients are young and reproductive-aged, it is difficult for a neurosurgeon to come up with a treatment plan alone. In this study, we investigated the prevalence of PAs in PCOS patients, the cutoff prolactin (PRL) level to detect PAs, and the treatment strategy, then assessed the relationship between these diseases via a literature review. Methods: Medical records from November 2009 to March 2020 were reviewed at our institute. A total of 657 PCOS patients were enrolled. Initial prolactin levels were investigated and hyperprolactinemic patients were selected. As a result of sella magnetic resonance imaging (MRI), patients were divided into 2 groups of those with hyperprolactinemia but without PAs (group A) and those with both hyperprolactinemia and PAs (group B), respectively. We then compared and analyzed each group to find the characteristics and statistical differences. Receiver operating characteristic (ROC) curve analysis was performed to determine a cutoff value of the serum PRL level that could detect PAs in hyperprolactinemic PCOS patients. Results: Of 657 patients diagnosed with PCOS, 76 patients had hyperprolactinemia (76/657, 11.6%). Sella MRI was performed in 56 patients, excluding 20 patients for various reasons. Patients in groups A and B numbered 43 and 13, respectively, and the mean serum prolactin level significantly differed between the groups (39.89 ± 41.64 vs. 108.59 ± 60.70 ng/mL, P < 0.001). Based on the ROC curve analysis of the prolactin threshold level for predicting PAs in PCOS patients, the area under the ROC curve was 0.853 (95% confidence interval, 0.733-0.934; P < 0.001), and the sensitivity and specificity were 76.9% and 86.1%, respectively. Ultimately, the cutoff value for prolactin level was 52.9 ng/mL. Conclusion: PCOS and hyperprolactinemia are common causes of infertility in reproductive-age women. PCOS patients with a PRL level of ≥ 52.9 ng/mL may need to undergo sella MRI for detecting PAs. To help ensure a favorable clinical course for these patients, systematic diagnosis, treatment, and follow-up plan should be established. Therefore, a multidisciplinary approach involving both neurosurgery and gynecology is essential.

Epidemiological Study of Malignant Gliomas in Korea Using Nationwide Dataset from 2007 to 2017.

BACKGROUND: The purpose of the study was to investigate the incidence, prevalence, and survival of malignant gliomas (MGs) using population-based Korean National Health Insurance Database (NHID) data. METHODS: Using the Korean NHID, we identified patients with MG as C71 codes in KCD 5-7 according to ICD-10 from January 1, 2007 to December 31, 2017. Epidemiological characteristics of MG, including annual incidence, prevalence, mortality rates, and survival rates, were collected and analyzed according to socioeconomic state (SES) and treatments received. RESULTS: We identified 45,066 newly diagnosed-MG patients from 2007 to 2017, for an age-adjusted incidence of 7.47 per 100,000 people. The mean age at diagnosis was 54 years. The male to female ratio was 1.11. Mortality and survival probability were analyzed among total subjects and in subgroups. The mortality rates were lower in female than that of male patients (hazard ratio, 0.69; 95% confidence interval, 0.67-0.71), and in younger age population and in higher income group. Patients operated had a slightly higher survival rate. The 1-, 3-, 5-, and 10-year survival rates were estimated at 63.4%, 46.2%, 39.4%, and 34.8%, respectively. This is the first population-based study to determine the incidence and prevalence of MG according to epidemiological characteristics in Korea using NHID. CONCLUSION: Our study found that female sex and high SES were factors that significantly lowered the mortality rate in MG, and younger groups and operated patients showed significantly higher survival rates.

Functional survival of rat pituitary gland in hypothermic storage for pituitary transplantation.

PURPOSE: Deteriorated pituitary function can lead to serious complications that might need lifelong hormone replacement therapy. However, long-term hormone administration can have significant adverse effects. Thus, it would be more desirable to restore pituitary function by pituitary transplantation. In this study, we investigated functional preservation of extracted pituitary gland in special preservation solution under hypothermic condition for pituitary transplantation. METHODS: We obtained nineteen pituitary glands from 250-300 g male Sprague-Dawley rats via parapharyngeal approach. These extracted glands were divided into three pieces and stored in histidine-tryptophan-ketoglutarate (HTK) solution at 4 °C and compared to their corresponding glands stored in phosphate buffer saline (PBS). Light and electron microscopic examinations were performed to identify morphological changes of pituitary gland at 0,3, and 7 days after storage. TUNEL assay to confirm cell viability, and adenosine-triphosphate (ATP) concentration were also serially examined. RESULTS: Tissue architecture and cellular viability of specimens preserved in HTK solution for 3 days were considerably maintained and similar to those in normal pituitary gland (0 day specimen). In contrast, specimens stored in PBS were markedly destroyed after 3 days of storage. After 7 days of storage, significant degeneration occurred in tissues stored in both HTK and PBS. However, tissue architecture was preserved more in specimens stored in HTK solution than those stored in PBS. ATP concentration decreased more rapidly in specimens stored in PBS solution, but there was no statistical significance (p= 0.055). CONCLUSIONS: Extracted rat pituitary gland supplemented with special preservation solution could be preserved for 3 days under hypothermic condition.

Thermoelectric Properties of Cu-Doped Bi2Te2.7Se0.3 Fabricated by Hot Pressing.

Owing to the energy and environmental issues, energy recovery technologies attract an increasing interest. Thermoelectric power generation is a recycling technology, which directly converts heat energy into electric energy by reusing waste heat. In this study, n-type Bi2Te2.7Se0.3 thermoelectric materials doped with Cu were fabricated by hot pressing. The Bi-Te system has excellent thermoelectric properties in the middle- and low-temperature ranges; when a certain amount of Cu dopant is added, the thermoelectric properties are improved. The thermoelectric properties of the samples doped with Cu were compared with those of the intrinsic Bi-Te-based sample without Cu doping. In addition, the effects of the Cu concentration on the thermoelectric-material structures were investigated.

Intermetallic Growth Mechanism and Mechanical Properties of Post-Annealed SAC305 Solder Joints on Cu-Based Electrode Interfaces.

Intrinsic Cu- and Ni-added Cu electrodes were prepared to study Sn-3Ag-0.5Cu lead-free solder joints. Our work focused on three categories: (1) formation and role of intermetallic compounds, (2) structural and compositional change of intermetallic compounds due to thermal aging effects, and (3) mechanical bonding strength of solder joints. A series of SEM, EDX, and bonding test analyses were performed on two electrode types to study joint morphologies, the types of intermetallic compounds formed, and bonding strengths, respectively. As a result, after heat treatments at 150 °C for 10 h, 100 h, and 300 h, Cu6Sn5 and (Ni, Cu)3Sn4 were obtained at the interfaces of the intrinsic Cu electrode and the Ni-added Cu electrode, respectively. In the Ni-added Cu electrode samples, the growth rate of the intermetallic compounds was reduced, but the mechanical bonding strength had a higher value compared to that of the intrinsic Cu electrode. The bonding characteristics under different heat treatment conditions are also discussed.

Influence of the Sintering Temperature of Al-Doped Higher Manganese Silicide for Improved Thermoelectric Properties.

Higher manganese silicide is generally used in thermoelectric devices between 700 K and 900 K. MnSi1.73Al0.005 samples were fabricated by two continuous solid-state reactions followed by hot pressing because the electrical conductivity of all the samples is strongly dependent on Al doping, showing superior thermoelectric performance to the as-synthesized higher manganese silicide. The solid-state-reaction was performed at 1173 K for 6 hours. The effects of the sintering temperature were examined by sintering at three different temperatures: 1273 K, 1323 K and 1373 K. For the surface, microstructural, and electrical properties, scanning electron microscopy, X-ray diffraction, and a series of electric conductivity, Seebeck coefficient, and thermal conductivity analyses were conducted, respectively. As a result, the optimal process temperature for Al-doped higher manganese silicide using a hot-press technique was determined.

Effects of Heat Treatment on Interfacial Behavior and Bonding Strength of Surface Activated Bonding Ti-Al Laminate.

The surface activated bonding (SAB) method generally has the advantage of high bonding strength, low contact resistance, and high microstructural stability at room temperature. In this study, Ti-Al laminates were produced by surface activated bonding with aluminum and titanium foils. Heat treatment was conducted at the temperature range from 200 to 550 °C in vacuum. The bonding strength Ti-Al laminates was measured by a peel test, and the interfacial characteristics were investigated microstructural observation. The results showed that the bonding strength was the highest with heat treatment at 400 °C, microstructure observation revealed that the bonding strength of the Ti-Al laminate was influenced by the interfacial characteristics.

Procarbazine and CCNU Chemotherapy for Recurrent Glioblastoma with MGMT Promoter Methylation.

BACKGROUND: While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the combination of only procarbazine and CCNU is comparable because vincristine adds toxicity with uncertain benefit. The purpose of this study was to evaluate the feasibility of procarbazine and CCNU chemotherapy for recurrent glioblastoma multiforme (GBM) with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. METHODS: Eight patients with recurrent GBM following concurrent chemoradiotherapy and temozolomide (TMZ) adjuvant therapy were enrolled in this trial; they received no other chemotherapeutic agents or target therapy. They received CCNU (75 mg/m2) on day 1 and procarbazine (60 mg/m2) through days 11 and 24 every 4 weeks. The median cycle of CCNU and procarbazine was 3.5 (range: 2-6). RESULTS: One patient achieved stable disease. The median progression-free survival (PFS) with procarbazine and CCNU chemotherapy was eight weeks (range: 5-73), and the PFS rates were 25% and 12.5% at 16 and 30 weeks, respectively. The median overall survival (OS) from the initial diagnosis to death was 40 months, and the median OS from the administration of procarbazine and CCNU chemotherapy to death was 9.7 months (95% confidence interval: 6.7-12.7). Serious adverse events were found at six visits, and two cases were considered to be grade 3 toxicities. CONCLUSION: The efficacy of procarbazine and CCNU chemotherapy is not satisfactory. This study suggests the need to develop other treatment strategies for recurrent and TMZ-refractory GBM. Trial registry at ClinicalTrials.gov, NCT017337346.

Similarity Analysis of Korean Medical Literature and Its Association with Efforts to Improve Research and Publication Ethics.

In the present study, the frequency of research misconduct in Korean medical papers was analyzed using the similarity check software iThenticate®. All Korean papers written in English that were published in 2009 and 2014 in KoreaMed Synapse were identified. In total, 23,848 papers were extracted. 4,050 Journal Articles of them were randomly selected for similarity analysis. The average Similarity Index of the 4,050 papers decreased over time, particularly in 2013: in 2009 and 2014, it was 10.15% and 5.62%, respectively. And 357 (8.8%) had a Similarity Index of ≥ 20%. Authors considered a Similarity Index of ≥ 20% as suspected research misconduct. It was found that iThenticate® cannot functionally process citations without double quotation marks. Papers with a Similarity Index of ≥ 20% were thus individually checked for detecting such text-matching errors to accurately identify papers with suspected research misconduct. After correcting text-matching errors, 142 (3.5% of the 4,050 papers) were suspected of research misconduct. The annual frequency of these papers decreased over time, particularly in 2013: in 2009 and 2014, it was 5.2% and 1.7%, respectively. The decrease was associated with the introduction of CrossCheck by KoreaMed and the frequent use of similarity check software. The majority (81%) had Similarity Indices between 20% and 40%. The fact suggested that low Similarity index does not necessarily mean low possibility of research misconduct. It should be noted that, although iThenticate® provides a fundamental basis for detecting research misconduct, the final judgment should be made by experts.

A new DNA aptamer which binds to SARS-CoV-2 spike protein and reduces pro-inflammatory response.

COVID-19 caused by SARS-CoV-2 spread rapidly around the world, endangering the health of people globally. The SARS-CoV-2 spike protein initiates entry into target cells by binding to human angiotensin-converting enzyme 2 (ACE2). In this study, we developed DNA aptamers that specifically bind to the SARS-CoV-2 spike protein, thereby inhibiting its binding to ACE2. DNA aptamers are small nucleic acid fragments with random structures that selectively bind to various target molecules. We identified nine aptamers targeting the SARS-CoV-2 spike protein using the systematic evolution of ligands by exponential enrichment (SELEX) method and selected three optimal aptamers by comparing their binding affinities. Additionally, we confirmed that the DNA aptamers suppressed pro-inflammatory cytokines induced by the SARS-CoV-2 spike protein in ACE2-overexpressing HEK293 cells. Overall, the DNA aptamer developed in this study has the potential to bind to the SARS-CoV-2 spike protein and inhibit or block its interaction with ACE2. Thus, our DNA aptamers can be used as new biological tools for the prevention and diagnosis of SARS-CoV-2 infection.

Temporal Analysis of Postoperative Outcomes With or Without Intraoperative Motor Evoked Potentials and Somatosensory Evoked Potentials Monitoring for Intracranial Meningioma Surgery.

BACKGROUND: This study aimed to retrospectively assess results of intracranial meningioma surgery with or without intraoperative neuromonitoring (IONM) in a single institution. METHODS: Two cohorts (a historical cohort and a monitoring cohort) were collected for the analysis. Before IONM was introduced, a total of 107 patients underwent intracranial meningioma operation without IONM from January 2000 to December 2008 by one neurosurgeon (historical cohort). After IONM was introduced, a total of 99 patients with intracranial meningioma were operated under IONM between November 2018 and February 2023 by two neurosurgeons (monitoring cohort). A retrospective comparison was made on the complications from meningioma surgery between the two groups. RESULTS: In the monitoring cohort, warning signals of motor evoked potential (MEPs) or somatosensory evoked potential (SSEPs) were alarmed in 10 patients. Two of these 10 patients aborted the operation and eight of these 10 patients with warning signals underwent tumor resection. Of these eight patients, five showed postoperative morbidity. Five of 89 patients without warning signals developed neurological deficits. In the historical cohort, 14 of 107 patients showed postoperative morbidity or mortality. CONCLUSION: Even after successful resection of intracranial meningiomas prior to the advent of IONM, integration of MEPs and SSEPs monitoring yielded valuable insights for surgical teams during operative procedures.

Guidelines for Manufacturing and Application of Organoids: Brain.

This study offers a comprehensive overview of brain organoids for researchers. It combines expert opinions with technical summaries on organoid definitions, characteristics, culture methods, and quality control. This approach aims to enhance the utilization of brain organoids in research. Brain organoids, as three-dimensional human cell models mimicking the nervous system, hold immense promise for studying the human brain. They offer advantages over traditional methods, replicating anatomical structures, physiological features, and complex neuronal networks. Additionally, brain organoids can model nervous system development and interactions between cell types and the microenvironment. By providing a foundation for utilizing the most human-relevant tissue models, this work empowers researchers to overcome limitations of two-dimensional cultures and conduct advanced disease modeling research.

Advances in Brain Metastasis Models.

To obtain achievements in addressing the clinical challenges of brain metastasis, we need a clear understanding of its biological mechanisms. Brain metastasis research is challenged by many practical scientific barriers. Depending on the purpose of the study, experimental brain metastasis models in vivo can be used. It is now possible to re-create the architecture and physiology of human organs. Human organoids provide unique opportunities for the study of human disease and complement animal models. The translation of experimental findings to clinical application has several barriers in the development of treatment for brain metastasis. A variety of models have provided significant contributions to the knowledge of brain metastasis pathology and remain pivotal tools for examining novel therapeutic strategies.

Transcranial application of magnetic pulses for improving brain drug delivery efficiency via intranasal injection of magnetic nanoparticles.

As the blood-brain barrier (BBB) hinders efficient drug delivery to the brain, drug delivery via the intranasal pathway, bypassing the BBB, has received considerable attention. However, intranasal administration still has anatomical and physiological limitations, necessitating further solutions to enhance effectiveness. In this study, we used transcranial magnetic stimulation (TMS) on fluorescent magnetic nanoparticles (MNPs) of different sizes (50, 100, and 300 nm) to facilitate MNP's transportation and delivery to the brain parenchyma. To validate this concept, anesthetized rats were intranasally injected with the MNPs, and TMS was applied to the center of the head. As the result, a two-fold increase in brain MNP delivery was achieved using TMS compared with passive intranasal administration. In addition, histological analysis that was performed to investigate the safety revealed no gross or microscopic damages to major organs caused by the nanoparticles. While future studies should establish the delivery conditions in humans, we expect an easy clinical translation in terms of device safety, similar to the use of conventional TMS. The strategy reported herein is the first critical step towards effective drug transportation to the brain.

Comparison of Single- and Multi-Echo Susceptibility-Weighted Imaging in Detecting Cerebral Arteriovenous Shunts: A Preliminary Study.

Purpose: To compare the sensitivities of T2-weighted image (T2WI) and susceptibility-weighted imaging (SWI) in detecting cerebral arteriovenous fistula (AVF), cerebral arteriovenous malformation (AVM), and carotid-cavernous sinus fistula (CCF), and to qualitatively evaluate single-echo SWI (s-SWI) and multi-echo SWI (m-SWI) in characterizing vascular lesions. Materials and Methods: From January 2016 to December 2021, cerebral angiography-proven lesions were recruited. The sensitivities of T2WI and SWI in detecting vascular lesions were compared using McNemar's test. Qualitative evaluations of s-SWI and m-SWI were categorized to be of poor, average, or good quality and compared using Fisher's exact test. Results: A total of 24 patients (mean age: 61 years, 12 female, and 12 male) were enrolled. Twenty patients underwent s-SWI or m-SWI, and four patients underwent both. AVF, AVM, and CCF were diagnosed in 10, 11, and 3 patients, respectively. SWI demonstrated higher sensitivity compared to that of T2WI (82.1% vs. 53.6%, p = 0.013). m-SWI showed better image quality compared to that of s-SWI (good quality, 83.3% vs. 25.0%, p = 0.009). Conclusion: SWI demonstrated a higher sensitivity for detecting cerebral arteriovenous shunts compared to that of T2WI. m-SWI exhibited better image quality compared to that of s-SWI in characterizing vascular lesions.

Efficacy and safety of metformin plus low-dose temozolomide in patients with recurrent or refractory glioblastoma: a randomized, prospective, multicenter, double-blind, controlled, phase 2 trial (KNOG-1501 study).

PURPOSE: Glioblastoma (GBM) has a poor prognosis after standard treatment. Recently, metformin has been shown to have an antitumor effect on glioma cells. We performed the first randomized prospective phase II clinical trial to investigate the clinical efficacy and safety of metformin in patients with recurrent or refractory GBM treated with low-dose temozolomide. METHODS: Included patients were randomly assigned to a control group [placebo plus low-dose temozolomide (50 mg/m2, daily)] or an experimental group [metformin (1000 mg, 1500 mg, and 2000 mg per day during the 1st, 2nd, and 3rd week until disease progression, respectively) plus low-dose temozolomide]. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, overall response rate, health-related quality of life, and safety. RESULTS: Among the 92 patients screened, 81 were randomly assigned to the control group (43 patients) or the experimental group (38 patients). Although the control group showed a longer median PFS, the difference between the two groups was not statistically significant (2.66 versus 2.3 months, p = 0.679). The median OS was 17.22 months (95% CI 12.19-21.68 months) in the experimental group and 7.69 months (95% CI 5.16-22.67 months) in the control group, showing no significant difference by the log-rank test (HR: 0.78; 95% CI 0.39-1.58; p = 0.473). The overall response rate and disease control rate were 9.3% and 46.5% in the control group and 5.3% and 47.4% in the experimental group, respectively. CONCLUSIONS: Although the metformin plus temozolomide regimen was well tolerated, it did not confer a clinical benefit in patients with recurrent or refractory GBM. Trial registration NCT03243851, registered August 4, 2017.

O6-methylguanine-DNA-methyltransferase promoter methylation assessment by microdissection-assisted methylation-specific PCR and high resolution melting analysis in patients with glioblastomas.

We have determined O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status by methylation-specific polymerase chain reaction (MSP) in 22 paraffin-embedded specimens of glioblastoma multiforme. A MGMT methylation-specific high resolution melting (HRM) assay was performed to compare the methylation levels of the tumorous and non-tumorous portions of each sample, which were selectively collected using a microdissection technique. MGMT methylation was detected in 10 patients using MSP, while 8 patients had both methylated and unmethylated MGMT promoters. HRM assays showed that there was no difference in the level of methylation between tumorous and non-tumorous portions of each sample. In patients with MSP-positive tumors, the overall survival (median, 22 months) was longer as compared to those with MSP-negative tumors (median, 14 months). A correlation between the methylation status of the MGMT promoter and MGMT protein expression was observed in 12 samples. This study demonstrates that MGMT methylation is not restricted to glioblastoma cells. Additionally, methylation-specific HRM is a feasible approach that can be readily applied to the methylation analysis of MGMT. A further study will be needed to determine the dynamic change of MGMT methylation in the tumor environment.

E-cadherin as a predictive marker of brain metastasis in non-small-cell lung cancer, and its regulation by pioglitazone in a preclinical model.

It remains unclear whether patients with non-small-cell lung cancer (NSCLC) develop brain metastasis during or after standard therapy. We attempted to identify biological markers that predict brain metastasis, and investigated how to modulate expression of such markers. A case-control study of patients who were newly diagnosed with NSCLC and who had developed brain metastasis during follow-up was conducted between 2004 and 2009. These patients were compared with a control group of patients who had NSCLC but no evidence of brain metastasis. Immunohistochemical analysis of expression of Ki-67, p53, Bcl-2, Bax, vascular endothelial growth factor, epidermal growth factor receptor, caspase-3, and E-cadherin was conducted. The methylation status of the genes for O(6)-methylguanine-DNA-methyltransferase, tissue inhibitor of matrix metalloproteinase (TIMP)-2, TIMP-3, and death-associated protein-kinase was also determined, by use of a methylation-specific polymerase chain reaction. A significantly increased risk of developing brain metastasis was associated with the presence of primary tumors with low E-cadherin expression in patients with NSCLC. We also investigated the effects of pioglitazone, a peroxisome proliferator-activated receptor γ-activating drug, in tumor-bearing mouse models. We found that E-cadherin expression was proportional to pioglitazone exposure time. Interestingly, pioglitazone pretreatment before cancer cell inoculation prevented loss of E-cadherin expression and reduced expression of MMP9 and fibronectin, compared with the control group. E-cadherin expression could be a predictor of brain metastasis in patients with NSCLC. Preventive treatment with pioglitazone may be useful for modulating E-cadherin expression.

Occipital nerve stimulation for medically refractory hypnic headache.

OBJECTIVE: Hypnic headache is a rare, primary headache disorder that exclusively occurs regularly during sleep. We present a case of hypnic headache successfully managed with occipital nerve stimulation. MATERIALS AND METHODS: A 64-year-old female presented with a four-year history of a right occipital headache that regularly awakened her from sleep. The headache, which was dull and throbbing, would awaken her regularly at 4:00 am, five hours after bedtime at 11:00 pm. No photophobia, nausea or vomiting, lacrimation, or other autonomic symptoms were present. The headache was refractory to various medical treatments, including indomethacin, flunarizine, propranolol. She underwent a trial of occipital nerve stimulation with a lead electrode using a medial approach. RESULTS: During the ten-day trial stimulation, she reported almost complete relief from hypnic headache. Chronic occipital nerve stimulation replicated the trial results. The attacks of hypnic headache recurred in one year with loss of stimulation-induced paresthesia; a subsequent x-ray showed electrode migration. After revision of the electrode to the original location, the effectiveness of the occipital nerve stimulation against hypnic headache was achieved again, and this effect has been consistent through 36 months of follow-up. CONCLUSION: Occipital nerve stimulation was effective in a patient with chronic, refractory hypnic headache.