Immune Checkpoint Inhibitors and Glioblastoma: A Review on Current State and Future Directions.

Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. The prognosis of GBM is grim, with a median overall survival of 14.6 months and only 6.9% of patients surviving 5 years after the initial diagnosis. Despite poor outcomes, standard therapy of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields has remained largely unchanged. The introduction of immune checkpoint inhibitors (ICI) has been a paradigm shift in oncology, with efficacy across a broad spectrum of cancer types. Nonetheless, investigations of ICIs in both newly diagnosed and recurrent GBM have thus far been disappointing. This lack of clinical benefit has been largely attributed to the highly immunosuppressive nature of GBM. However, immunotherapy still holds promise for the treatment of GBM, with combinatorial strategies offering hope for potentially overcoming these current limitations. In this review, we discuss the outcomes of clinical trials employing ICIs in patients with GBM. Afterward, we review ICI combination strategies and how these combinations may overcome the immunosuppressive microenvironment of GBM in the context of preclinical/clinical evidence and ongoing clinical trials.

Increased prevalence of mild myopathic changes in the post-COVID-19 duration.

OBJECTIVE: There are reports of peripheral nerve and muscle involvement during or after coronavirus disease 2019 (COVID-19), even following a mild infection. Here, we aimed to analyze the objective findings regarding peripheral nerve, neuromuscular junction, and muscle function using electrophysiology in patients with a previous COVID-19 infection. METHODS: All consecutive patients with a history of COVID-19 were questioned for post-COVID-19 duration-related neurological complaints via Composite Autonomic Symptom Score-31 (COMPASS-31), modified Toronto Neuropathy score (mTORONTO), and Fatigue Severity Scale (FSS). Patients were dichotomized into two groups based on their scores in the questionnaire. Group 1 (patients with high scores in any area of the questionnaire) and Group 2 (patients with normal scores in all sections of the questionnaire). In the second step, Group 1 was invited to a preplanned hospital visit for electrophysiological analysis, including nerve conduction studies, repetitive nerve stimulation, needle electromyography (EMG), quantitative motor unit potential analysis (qMUP), and single fiber EMG. We included 106 patients in the study. According to the questionnaire, 38 patients constituted Group 1, and 68 formed Group 2. RESULTS: Of the 38 patients, 14 accepted and underwent preplanned electrophysiological examinations. Needle EMG revealed small, short, polyphasic MUPs with early recruitment, and qMUP analysis demonstrated an increased percentage of polyphasic potentials in three patients. The examinations in other patients were unremarkable. CONCLUSIONS: The high prevalence of complaints and objective myopathic findings in our cohort implicated the role of muscle involvement in the post-COVID-19 duration. Considering the socioeconomic and psychological burden of the post-COVID-19 duration among individuals and societies, a better understanding of the symptoms and myopathy is warranted.

Impulse control disorders in Parkinson's disease: a retrospective analysis of 1824 patients in a 12-year period.

OBJECTIVE: This study aims to clinically evaluate the impulse control disorders (ICDs) encountered in treating Parkinson's disease. METHOD: This is a retrospective analysis between 2010 and 2022. We retrieved the medical records of all patients diagnosed with idiopathic Parkinson's disease. The demographic and clinical findings were recorded. ICDs constituted a specific item in the examination, and each one (compulsive shopping, compulsive eating, pathological gambling, hypersexuality, punding, dopamine dysregulation syndrome, and hobbyism) was noted separately. RESULTS: In the study period, we identified 1824 patients (56.2% men, n = 1025). The mean age was 70.5 ± 11.9 years. In the cohort, 128 (7%) patients with Parkinson's disease had one or more ICDs. The ICDs were compulsive shopping, punding/hobbyism, compulsive eating, hypersexuality, pathological gambling, and dopamine dysregulation syndrome. When we compared patients with and without ICDs, patients with ICDs were younger (p ≤ 0.001), and the men/women ratio was higher in this group with ICDs. Although the mean daily pramipexole dose was higher in patients with ICDs, mean daily long-acting pramipexole dose was only 1.4 ± 0.92 mg/day. CONCLUSION: The significant findings in this study were (i) the lower frequency of ICDs (7%); (ii) the common occurrence of compulsive shopping, punding/hobbyism, and compulsive eating; and (iii) the development of ICDs under relatively lower doses of pramipexole. We suggest that ICDs in Parkinson's disease should be associated with a personal trait with dopamine agonists, and potential electrophysiological or genetic markers of this trait warrant further analysis to avoid treatment in these patients.

Nociceptive flexion reflex in small fibers neuropathy and pain assessments†.

BACKGROUND: The nociceptive flexion reflex (NFR) is a polysynaptic and multisegmental spinal reflex that develops in response to a noxious stimulus and is characterized by the withdrawal of the affected body part. The NFR possesses two excitatory components: early RII and late RIII. Late RIII is derived from high-threshold cutaneous afferent A-delta fibers, which are prone to injury early in the course of diabetes mellitus (DM) and may lead to neuropathic pain. We investigated NFR in patients with DM with different types of polyneuropathies to analyze the role of NFR in small fiber neuropathy (SFN). METHODS: We included 37 patients with DM and 20 healthy participants of similar age and sex. We performed the Composite Autonomic Neuropathy Scale-31, modified Toronto Neuropathy Scale, and routine nerve conduction studies. We grouped the patients into large fiber neuropathy (LFN), SFN, and no overt neurological symptom/sign groups. In all participants, NFR was recorded on anterior tibial (AT) and biceps femoris (BF) muscles after train stimuli on the sole of the foot, and NFR-RIII findings were compared. RESULTS: We identified 11 patients with LFN, 15 with SFN, and 11 with no overt neurological symptoms or signs. The RIII response on the AT was absent in 22 (60%) patients with DM and 8 (40%) healthy participants. The RIII response on the BF was absent in 31 (73.8%) patients and 7 (35%) healthy participants (P = .001). In DM, the latency of RIII was prolonged, and the magnitude was reduced. Abnormal findings were seen in all subgroups; however, they were more prominent in patients with LFN compared to other groups. CONCLUSIONS: The NFR-RIII was abnormal in patients with DM even before the emergence of the neuropathic symptoms. The pattern of involvement before neuropathic symptoms was possibly related to an earlier loss of A-delta fibers.

Auto brewery syndrome from the perspective of the neurologist.

BACKGROUND AND PURPOSE: Auto-brewery syndrome (ABS) is a rare condition that causes the digestive system to produce intoxicating amounts of alcohol due to abnormal growth of the gut microbiota. Medicolegal inferences of ABS have two distinct edges. First, malingering in drunk-driving and abusing the syndrome as a factitious disorder may occur. Second, patients suffering from the syndrome may face medicolegal and social problems. Moreover, chronic exposure to alcohol due to undiagnosed ABS might result in cognitive and behavioral disturbances. Here, we present a patient with recurrent encephalopathy episodes and chronic cognitive disturbances, who was diagnosed with the auto-brewery syndrome, to emphasize the neurocognitive consequences of the syndrome. CASE PRESENTATION: A 58 years old female presented with mild cognitive impairment, behavioral disturbances, and recurrent encephalopathy episodes. The history of hemicolectomy, an odd smell on her breath, and cravings for high carbohydrate meals during the paroxysmal episodes raised the suspicion of ABS. Her blood ethanol concentration reached 315 mg/dL following an oral glucose tolerance test (OGTT), and stool analysis revealed increased colonization with C. krusei and C. parapsilosis. She was free of the acute episodes, cognitive and behavioral disturbances improved, and C. krusei and C. parapsilosis were eliminated from the intestinal flora with dietary recommendations and nystatin treatment. CONCLUSION: The auto brewery syndrome is a rare disorder of dysbiosis leading to a disturbed gut-brain axis. Being a treatable and relatively benign diagnosis, presentation of the ABS with neurocognitive disturbances necessitates highlighting.

Neutrophil­to­lymphocyte ratio as a marker of inflammation in restless legs syndrome during pregnancy.

PURPOSE: The pregnancy is accepted as an independent risk factor for restless legs syndrome/Willis-Ekbom disease (RLS/WED). The neutrophil-to-lymphocyte ratio (NLR) was recently reported in the pathophysiology of RLS/WED. In this report, we investigated the relationship between the presence of RLS/WED and the levels of NLR in pregnancy. METHODS: We included 268 pregnant women attending routine prenatal visits; 148 women had RLS/WED, and 120 women without RLS/WED were the control group. A pre-formed questionnaire was administered to all participants regarding demographic characteristics, habitual behaviors, detailed medical history and questions about RLS/WED including disease duration, severity, and family history. Laboratory investigations were performed in all participants regarding the complete blood count, NLR, fasting blood glucose, blood urea nitrogen, creatinine, ferritin, and total iron binding capacity. RESULTS: NLR was significantly higher in pregnant women with RLS/WED as compared to those without it (3.9±0.9 versus 3.5±1.1, p=0.039). Smoking was also significantly more common in pregnant women with RLS/WED (p=0.022). NLR significantly increased as the gestational period progressed, even after the adjustments for age, BMI, and smoking (p=0.035). Higher NLR in pregnant women with RLS/WED was especially prominent in the 3rd trimester, although the difference was not significant. CONCLUSION: These results may suggest that an increased inflammation demonstrated by the increased NLR, may, in part, play a role in higher prevalence of RLS/WED in pregnancy, especially in late gestational weeks (Tab. 2, Fig. 1, Ref. 34). Text in PDF www.elis.sk Keywords: neutrophil-to-lymphocyte ratio, restless legs syndrome/Willis-Ekbom disease, pregnancy, inflammation.

Longitudinally extensive transverse myelitis preceding primary central nervous system lymphoma: Spinal sentinel neuroinflammation.

Case Description: 65-year-old female diagnosed with longitudinally extensive transverse myelitis. She had excellent response to immunotherapy despite her atypical features, and her spinal lesion was fully recovered in the second month of the treatment.Findings: Nine months after, she was diagnosed with primary cerebral central nervous system lymphoma while there was no recurrence of the spinal cord lesion as her most recent follow-up visit being 2 years after the LETM.Clinical Relevance: Spinal sentinel neuroinflammation preceding primary central nervous system lymphoma might represent a valuable etiology in the differentials of LETM, as illustrated here.

Seizure treatment with olfactory training: a preliminary trial.

OBJECTIVE: Epilepsy is a chronic condition characterized by recurrent seizures. Despite miscellaneous antiseizure medications, resistance to treatment is still approximately 30%. This resistance brings forward the multidisciplinary approach and complementary treatments. In this study, we aimed to investigate the effect of olfactory training on epileptic seizures with special aromas having antiseizure effects in patients diagnosed with drug-resistant epilepsy. METHODS: A total of 24 patients (14 pediatric and 10 adults) with drug-resistant epilepsy were recruited for the study. Participants were asked to inhale the standardized bottle filled with lavender aroma (Lavandula Angustifolia) twice a day (morning and evening) for 30-45 s (2 cm in front of nose; 10-15 s to right and left nostril and 10-15 s to both nostrils) for 3 months. The type, frequency, duration of seizures, the quality of life (SF-36 and PedsQL 4.0), and olfactory functions (Sniffin' Sticks Test and Pediatric Smell Wheel) were re-assessed. RESULTS: Statistical analysis showed that olfactory training decreased the seizure frequency (p < 0.001) and the seizure duration (p = 0.02). A global 50% seizure reduction was seen among patients. Moreover, olfactory training increased the quality of life (p = 0.003) and improved the olfactory function in both the pediatric and adult groups (p = 0.017, p = 0.05, respectively). There was no adverse reaction and no increase in seizure frequency. SIGNIFICANCE: The observations of the present investigation suggest that olfactory training is a successful complementary therapy with no adverse reaction in patients with drug-resistant epilepsy. Large cohort studies and longer follow-up periods are needed for providing olfactory training as a therapy modality in patients with epilepsy.

Autonomic and neuropathic complaints of long-COVID objectified: an investigation from electrophysiological perspective.

PURPOSE: Here , we aimed to assess the frequency and phenomenology of autonomic and neuropathic complaints of long-COVID and to evaluate them by means of electrophysiology. METHODS: Step 1. Patients with prior COVID-19 infection were screened by COMPASS-31 and mTORONTO to create the target population for further evaluation. Step 2. Patients with high scores were invited for a detailed history of their complaints and electrophysiological analysis, which included nerve conduction studies, cutaneous silent period (CSP), and sympathetic skin response (SSR). We also constituted a control group composed of healthy subjects of similar age and sex for electrophysiological analysis. RESULTS: There were 106 patients, who matched the study criteria. Among them, thirty-eight patients (%35.8) had neuropathic or autonomic complaints or both. Fatigue and headache were significantly more frequent in patients with autonomic and neuropathic complaints. Detailed examination and electrophysiological evaluation were performed in 14 of 38 patients. Neuropathic complaints were patchy and proximally located in the majority. The entire CSP suppression index was higher in the patients (p = 0.002). There was no difference in palmar and plantar SSR between patients and healthy subjects. mTORONTO scores were negatively correlated with palmar and plantar SSR amplitudes, and the correlation was moderate. CONCLUSION: Neuropathic or autonomic complaints were seen in more than one-third of patients with long-COVID. Neuropathic complaints were generally patchy, proximally predominant, asymmetric, or diffuse. The CSP suppression index was abnormal whereas SSRs were normal.

Analysis of neurology consultations in hospitalized patients with COVID-19.

OBJECTIVE: The aim of this study was to evaluate patients who were hospitalized with a diagnosis of COVID-19 and were consulted by neurology during their hospital stay. METHODS: All files of patients with COVID-19 who were admitted to Cerrahpasa Medical Faculty Hospital between March 11th and December 31st, 2020 were retrospectively reviewed, and files of patients who consulted by neurology during their stay were included. Demographic and clinical characteristics, neurologic diagnosis, outcome and related laboratory data were extracted from electronic medical records and analyzed. Patients were categorized into the first wave and second wave according to the date of hospitalization. RESULTS: A total of 2257 patients were hospitalized for COVID-19; among them, 127 were consulted by a neurologist during their hospital stay. Fifteen patients received a consultation for possible drug interactions. Among the remaining 112 patients, the reason for neurology consultation was i. exacerbation of a neurological comorbidity vs ii. new-onset neurological manifestations. The median age was 68.5 ± 14.2 years, and 60.7% were men. Dementia and stroke were the leading neurological comorbidities. COVID-19 disease was more severe in the patients with the new-onset neurological comorbidity than in patients with exacerbation of a neurological comorbidity (p = 0.07). Serum creatinine kinase levels were higher in the new-onset patient group (p < 0.05). Exacerbation of previous neurological disease or new neurological impairment were jointly and severely related to high mortality (overall 35/112 vs 275/2145, p < 0.001; exacerbation 12/45 vs 275/2145 p < 0.01; new-onset 23/67 vs 275/2145, p < 0.001). CONCLUSION: Serious neurological involvement is relatively uncommon in hospitalized patients with COVID-19 and is associated with increased mortality.

Progression of myoclonus subtypes in subacute sclerosing panencephalitis.

OBJECTIVES: Diagnostic criteria of subacute sclerosing panencephalitis (SSPE) include myoclonus, a well-recognized clinical feature. Here, we studied the electrophysiological features of myoclonus with regards to disease staging in SSPE patients. METHODS: We included 10 patients diagnosed with SSPE between 2010 and 2018, along with 21 healthy subjects. All participants had detailed electrophysiological evaluation including polymyographic analysis, blink reflex after trigeminal stimulation, auditory startle response, startle response after somatosensory stimuli, F-waves, and long-loop reflexes. Clinical findings were retrieved from the medical records. RESULTS: Patients were categorized into Gascon stage 2B (n = 5, 50%), 2A (n = 2, 20%), 3B (n = 2, 20%) and 4A (n = 1, 10%) at the time of electrophysiological evaluation. Two patients had cortical myoclonus, four had possible cortico-subcortical myoclonus, and four had brainstem myoclonus. Patients were categorized into Gascon stages 2a and 2b had possible cortico-subcortical myoclonus (85.7%). However, none of the patients with stage 3b or 4a had possible cortico-subcortical subtype but all had the brainstem subtype. CONCLUSION: Association was seen between subtypes of myoclonus and clinical staging in SSPE. This suggests that myoclonus in SSPE may primarily involve the cortex and cortico-subcortical structures such as the thalamus at earlier stages of disease, and then involve more caudal structures as the disease progresses.