A Case of Hyperglycemia-Induced Epileptic Homonymous Hemianopsia.

Hyperglycemia sometimes initially presents with neurological manifestations, including seizures, visual hallucinations, choreoathetosis, hemiballismus, myoclonus, tremor, and consciousness disturbance. Epileptic seizures induced by hyperglycemia are reported to occur predominantly in the occipital lobe, and the epileptic form is mainly epilepsia partialis continua. Of the two patterns of hyperglycemia (ketotic or nonketotic), nonketotic hyperglycemia is more commonly associated with seizures because ketosis has an anticonvulsive effect, so hyperglycemia-induced seizures are generally seen in nonketotic patients. Here, we report a 51-year-old Japanese male with intermittent homonymous hemianopsia who presented high hemoglobin A1c (19.1%). He had been drinking 3 L of the sugared soft beverage every day. After admission, he showed left-sided hemiconvulsion. Anti-seizure medications and insulin treatment were administered, and his seizure was aborted. The magnetic resonance imaging (MRI) showed a high-intensity lesion in the diffusion-weighted image and fluid-attenuated inversion recovery with gadolinium enhancement in the occipital lobe. In hyperglycemic convulsions, MRI sometimes shows leptomeningeal or parenchymal gadolinium enhancement. In addition, most hyperglycemic seizures are associated with nonketotic hyperglycemia and show occipital-dominant imaging abnormalities. We report this case by reviewing the differential diagnosis.

Discovery of a potent, selective, and orally available EGFR C797S mutant inhibitor (DS06652923) with in vivo antitumor activity.

The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Herein, we describe the discovery of DS06652923, a novel, potent, and orally available EGFR-triple-mutant inhibitor. Through scaffold hopping from the previously reported nicotinamide derivative, a novel biaryl scaffold was obtained. The potency was successfully enhanced by the introduction of basic substituents based on analysis of the docking study results. In addition, the difluoromethoxy group on the pyrazole ring improved the kinase selectivity by inducing steric clash with the other kinases. The most optimized compound, DS06652923, achieved tumor regression in the Ba/F3 allograft model upon its oral administration.

Serum perampanel levels in patients with seizures are not affected by hemodialysis.

Perampanel belongs to a novel class of antiseizure medications (ASMs). Studies examining the effect of hemodialysis on perampanel serum levels in clinical settings are lacking. We aimed to evaluate the changes in serum perampanel levels during hemodialysis. We studied patients with seizures who received oral perampanel between April 2020 and March 2023 and whose serum concentration of perampanel was measured before and after hemodialysis. We analyzed the serum concentrations of levetiracetam and lacosamide for comparison. Fourteen patients, with a mean age of 76.1 ± 7.88 years, were included. The dose of perampanel was 2.14 ± 1.27 mg. The hemodialysis clearance rate of perampanel, levetiracetam, and lacosamide was 0 ± 13%, 69 ± 11%, and 59.6 ± 8.2%, respectively. The post-dialysis CD ratio decreased significantly with levetiracetam but not with perampanel. Adverse but acceptable effects of perampanel were observed in two patients. The serum concentrations of several ASMs have been shown to be reduced during hemodialysis. Our study revealed that the serum perampanel concentration does not decrease during hemodialysis. Owing to the low rate of adverse effects and the stability of perampanel serum concentration during hemodialysis, perampanel could be a favorable choice as an ASM for patients with seizures undergoing hemodialysis. PLAIN LANGUAGE SUMMARY: Our study looked at how hemodialysis affects the serum levels of perampanel, a new type of medication for seizures. In 14 patients who started treatment between April 2020 and March 2023, perampanel serum levels did not decrease during hemodialysis, unlike other seizure medications. This shows that perampanel can be a good option for patients with seizures who need hemodialysis, with fewer side effects compared to other medications.

Bilateral Phrenic Nerve Palsy Associated With Neuralgic Amyotrophy.

Neuralgic amyotrophy (NA) is a multifocal inflammatory neuropathy accompanied by acute pain and muscle atrophy. NA commonly affects the upper extremities, but rarely affects the phrenic nerve. Here, we report a male with neck pain, orthopnea, difficulty sleeping in the supine position, and inability to slurp. His saturated oxygen level decreased from 97% to 86% in the supine position. His right shoulder showed muscle atrophy. Chest X-ray examination in the supine position and a nerve conduction study showed phrenic palsy. We diagnosed it as bilateral phrenic nerve palsy associated with NA. NA sometimes causes phrenic nerve palsy and may cause slurping difficulty.

Lumbar Subarachnoid-Peritoneal Shunting Deteriorates Superficial Siderosis Associated with a Dural Defect.

Superficial siderosis is a disease in which hemosiderin is deposited under the leptomeninges and subpial layers of hindbrain structures, e.g., the cerebellum, brainstem, and eighth cranial nerve. The main symptoms of superficial siderosis are cerebellar ataxia, hearing loss, cognitive decline, and myelopathy. The activities of daily living of patients with superficial siderosis are severely impaired due to the progressive symptoms. Here, we report a patient with superficial siderosis whose symptoms deteriorated after lumbar subarachnoid-peritoneal (L-P) shunt surgery. She received L-P shunt surgery based on the diagnosis of idiopathic normal pressure hydrocephalus at another hospital. The patient had a history of cervical surgery, and a dural defect was identified at the C4-5 level by a detailed magnetic resonance imaging study. We hypothesized that the L-P shunt reduced cerebrospinal pressure and increased bleeding from the fragile vessels in the dural defect, which might have increased hemosiderin deposition.

Highly potent, orally active novel small-molecule HPK1 inhibitor DS21150768 induces anti-tumor responses in multiple syngeneic tumor mouse models.

Augmenting T-cell activity is a promising approach to enhance the efficacy of cancer immunotherapy treatment. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in immune cells and negatively regulates T-cell receptor signaling. It is reported that inhibition of the kinase function of HPK1 results in tumor growth suppression by enhancing cancer immunity. Thus, developing HPK1 inhibitors has attracted considerable attention as a future cancer immunotherapy approach. However, despite recent progress in HPK1 biology and pharmacology, various challenges still remain, such as developing HPK1 inhibitors with favorable pharmacological profiles and identifying tumor characteristics that can be applied to define susceptibility to HPK1 inhibition. Here, we present the identification and pharmacological evaluation of DS21150768, a potent small-molecule HPK1 inhibitor with a novel chemical scaffold. DS21150768 shows remarkable inhibition of HPK1 kinase activity, and in vitro studies demonstrated its potent activity to enhance T-cell function. DS21150768 is orally bioavailable and shows sustained plasma exposure, which leads to enhanced cytokine responses in vivo. We conducted a comparison of the anti-tumor efficacy of DS21150768 alone or in combination with anti-PD-1 antibody in 12 different mouse cancer cell models, and observed that the treatments suppressed tumor growth in multiple models. Furthermore, Gene Set Enrichment Analysis demonstrated significant enrichment of immune-related gene signatures in the tumor models responsive to DS21150768 treatment. Our results provide a path forward for the future development of HPK1 inhibitors and fundamental insights into biomarkers of HPK1-targeted therapy.

Ultrashort Echo Time Magnetic Resonance Angiography as an Alternative Tool to Digital Subtraction Angiography in the Follow-up of Stent-Assisted Coil Embolization Outcomes.

BACKGROUND: Follow-up of aneurysms treated with stent-assisted coil embolization has been performed using digital subtraction angiography (DSA) because in time-of-flight magnetic resonance angiography, metal artifacts from the stent often affect visualization. OBJECTIVE: To confirm whether ultrashort echo time (TE) MRA may be an alternative for DSA during follow-up. METHODS: Patients with unruptured aneurysms initially treated with stent-assisted coil embolization between April 2019 and March 2021 were enrolled. After 3 months of treatment, follow-up DSA and ultrashort TE MRA were performed. All images were independently reviewed by neurosurgeons to evaluate in-stent flow and rated from 1 (not visible) to 4 (excellent). Aneurysmal embolization status was assessed as complete obliteration, residual neck, or residual aneurysm. Ultrashort TE MRA findings were classified as evaluative or nonevaluative state based on the presence of metal artifacts. We investigated the types of aneurysms that were evaluative and the agreement between ultrashort TE and DSA. RESULTS: Overall, 89 aneurysms were examined, of which 74% (n = 66) were classified as evaluative on ultrashort TE. Significant differences were observed in size and stent type. Evaluative cases had an aneurysm size of <7 mm ( P = .0007) and a higher rate of Neuroform Atlas ( P = .0006). The rate of agreement between ultrashort TE with evaluative state and DSA was 95%. CONCLUSION: Ultrashort TE MRA could evaluate an embolization status treated with stenting, and the findings are in excellent agreement with those of DSA. Aneurysms measuring <7 mm and treated with Neuroform Atlas are evaluative on ultrashort TE, and DSA might not be necessary.

Necessity of neutrophil-to-lymphocyte ratio monitoring for hypothyroidism using nivolumab in patients with cancer.

BACKGROUND: Low neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with a favorable therapeutic response to nivolumab. The activation of immunocompetent cells such as lymphocytes exhibits an antitumor effect; however, the development of excessive immune responses in autologous organs along with the breakdown of self-tolerance causes immune-related adverse events, including hypothyroidism. Therefore, the possibility that NLR is associated with immune response shows that NLR can be not only a predictive factor for good response to nivolumab but also a predictive factor for the development of hypothyroidism. AIM: To evaluate whether continuous NLR monitoring during nivolumab treatment is useful for predicting the incidence and onset period of hypothyroidism. METHODS: This retrospective study comprised patients who received nivolumab for treating all types of cancer at our hospital between January 2015 and December 2019. The NLRs of patients were measured before each administration, and the patients were followed up till the administration of 12 doses. NLR at treatment initiation was compared between patients with and without hypothyroidism. Patients who developed hypothyroidism were categorized into three groups: those with NLR < 3.5, 3.5 to < 5, and ≥ 5 according to their maximum NLR from treatment initiation to hypothyroidism development. Further, the onset periods of hypothyroidism were compared between the groups. RESULTS: Overall, 104 patients were included in the analysis. Twenty-one patients developed hypothyroidism throughout the observation period. NLR at treatment initiation was significantly lower (2.54 ± 1.21 vs 4.58 ± 4.03; P = 0.017) in patients with hypothyroidism than in those without hypothyroidism, and patients with NLR < 5 had a significantly higher incidence of hypothyroidism than those with NLR ≥ 5 (26%: 20 of 78 patients vs 4%: 1 of 26 patients; P = 0.022). Additionally, treatment continuity in patients with hypothyroidism was significantly longer than in those without hypothyroidism (median not reached vs 7 times administration, P = 0.010). Patients with maximum NLR < 3.5 until the development of hypothyroidism had a significantly earlier onset of hypothyroidism than those with maximum NLR ≥ 5 (hazard ratio for low tertile [NLR < 3.5] vs high tertile [NLR ≥ 5]: 5.33, P = 0.011). CONCLUSION: Low NLR at treatment initiation increases the incidence of treatment-induced hypothyroidism. Furthermore, its persistence may be a risk factor for the early onset of hypothyroidism.

Gadolinium-enhanced MR improved motion sensitized driven equilibrium (iMSDE) for intracranial vessel imaging in giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) generally affects extracranial large and medium-sized vessels. It rarely causes intracranial vessel stenosis, presenting as cerebral infarction (CI). Consequently, accurate diagnosis of CI induced by GCA is often challenging. Improved motion-sensitized driven-equilibrium (iMSDE) is one of the advanced high-resolution magnetic resonance (MR) vessel wall imaging techniques that enables direct visualization of the vessel wall because of a strong reduction in blood flow artifacts, leading to higher quality images. Herein, we effectively used gadolinium-enhanced MR iMSDE imaging to diagnose a patient presenting with recurrent CI due to right intracranial internal carotid artery (ICA) stenosis as GCA. CASE DESCRIPTION: A 64-year-old man with polymyalgia rheumatica for several years and who had experienced CI due to moderate intracranial ICA stenosis one year ago, presented to the emergency room with dysarthria and left hemiparesis. Diffusion-weighted MR imaging showed high signals in the right centrum ovale, and MR angiography revealed severe stenosis of the right intracranial ICA. Gadolinium-enhanced MR iMSDE imaging showed marked concentric enhancement in the vessel wall of the right stenosed ICA, which led to a definitive diagnosis of GCA via biopsy from the right superficial temporal artery. The patient's symptoms gradually improved after initiation of steroid treatment. Three months later, gadolinium-enhanced MR iMSDE imaging revealed improvement in the contrast enhancement in the vessel wall and vascular stenosis. CONCLUSION: Gadolinium-enhanced MR iMSDE imaging is useful to diagnose and evaluate GCA with intracranial vessel involvement.

[A case of recurrent cerebral embolism associated with Lambl's excrescence].

A 75-year-old female had a history of prior ischemic stroke with aphasia and right hemiplegia. Magnetic resonance angiography showed left internal carotid artery occlusion. She was successfully treated with intravenous recombinant tissue plasminogen activator (IV t-PA) and underwent endovascular thrombectomy (EVT). She was diagnosed with cardioembolic stroke due to the presence of atrial fibrillation and mitral valve stenosis, and warfarin was administered. However, she experienced large vessel occlusion twice within 2 years. Upon further analysis, transesophageal echocardiography revealed a mobile hyperechoic structure on the aortic valve, which was assumed to be an embolic source. Thus, we decided to perform mitral and aortic valve replacement. The excised aortic valve structure was suggested to be an example of Lambl's excrescence, histopathologically. After surgery, the patient had no recurrence for 3 years. Several cases of ischemic stroke associated with Lambl's excrescence have been reported, but definitive guidelines for managing patients with Lambl's excrescence do not currently exist. Surgical intervention for Lambl's excrescence with recurrent ischemic events may be important for preventing further recurrence.