Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.

BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient. CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cranial nerve Palsy following COVID-19 Vaccination Responsive to Plasma Exchange.

BACKGROUND: Globally, mass COVID-19 vaccine administration has revealed various adverse effects of the vaccine, such as various neurological symptoms, which are currently identified as a result of an excessive immune response. CASE REPORT: A 70-year-old woman presented with progressive unilateral oculomotor nerve palsy and decreased visual acuity 12 days after receiving the Moderna COVID-19 vaccine. In adults, such palsy is typically caused by microvascular disease (ischemia) or compressive tumors. Given the temporal relationship between vaccination and symptoms and the exclusion of other possible causative factors, the patient's oculomotor nerve palsy and optic nerve involvement was considered to be related to the vaccination. Cranial nerve palsy following COVID-19 vaccination was diagnosed, and after pulse steroid and plasma exchange, the patient showed steady recovery. CONCLUSION: Our patient with cranial nerve palsy following COVID-19 vaccination responded well to plasma exchange after limited improved toward steroid. This case highlights the importance of early identification and treatment of the immunological effects of COVID-19 vaccines on cranial nerves.

Anti-SRP Myopathy with Sensorimotor Polyneuropathy: A Case Report.

PURPOSE: Anti-signal recognition particle (SRP) myopathy is a subtype of immune-mediated necrotizing myopathy. It rarely presents with extramuscular features, involving the skin, lung, and heart. This paper presents a case of anti-SRP myopathy associated with sensorimotor polyneuropathy. CASE REPORT: A 33-year-old woman with no history of systemic disease presented to our hospital with weakness and numbness of the lower limbs for 1 year. Electromyography and nerve conduction study (NCS) revealed combined myopathy and axonal sensorimotor polyneuropathy. Blood examination revealed increased levels of serum muscle enzymes and anti-SRP antibodies. T1-weighted magnetic resonance imaging revealed diffuse muscular hyperintensities in the thighs, indicative of fatty replacement. She was administered methylprednisolone pulse therapy, followed by oral prednisolone and azathioprine. Muscle power increased, and serum muscle enzyme levels decreased significantly. Subsequent NCS performed 2 years later revealed persistent axonal degeneration in the lower limbs. CONCLUSION: Anti-SRP myopathy can present with sensorimotor polyneuropathy. Thus, the possibility that the same pathological process affected the skeletal muscles and peripheral nerves should be considered.

Sudden onset hearing loss as initial presentation of Susac syndrome: a rare case report and brief review.

Susac syndrome is a rare disease presenting with a classic triad of symptoms. These are sensorineural hearing loss, encephalopathy, and branch retinal artery occlusions. Initial presentation is usually headache and symptoms of encephalopathy. Hearing loss is unusual in the early stages but, when it does present, can often lead to a misdiagnosis of sudden sensorineural hearing loss. Hence, neurological and retinal examinations are essential to an accurate diagnosis. In this study, we aimed to raise awareness of Susac syndrome among physicians and facilitate recognition of its manifestation, especially in those patients presenting with hearing loss alone. Identifying Susac syndrome that presents as sudden sensorineural hearing loss can be challenging but a number of case reviews have been reported in recent years and treatment guidelines are available.

Primary Familial Brain Calcification Caused by a Novel Compound Heterozygous Mutation in the MYORG Gene.

BACKGROUND PURPOSE: To demonstrate a novel compound heterozygous mutation in MYORG-related recessive primary familial brain calcification. CASE REPORT: We report a case of primary familial brain calcification with newly-discovered compound heterozygous mutation in the MYORG gene presenting with progressive parkinsonism, cerebellar signs, and typical diffuse brain calcifications. CONCLUSION: Clinicians should consider MYORG testing in patients who have primary brain calcifications with either a negative or recessive family history.

Treatable Rapid Progressive Dementia: A First Case Report of Anti-dipeptidyl-peptidase-like Protein 6 Encephalitis in Taiwan.

PURPOSE: Anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis is a rare but treatable autoimmune disorder, characterized by gastrointestinal symptoms, cognitive dysfunction, and central nervous system hyperexcitability. CASE REPORT: Herein, we report a case of an 80-year-old male patient who presented with unexplained diarrhea, weight loss, rapidly progressive dementia, tremors, and myoclonus. His serum tested positive for anti-DPPX antibodies. He was treated with plasma exchange, oral prednisolone, and azathioprine. All his symptoms improved substantially after treatment. CONCLUSION: Early recognition of anti-DPPX encephalitis is important because it can be treated with immunotherapy. To the best of our knowledge, this is the first reported case of anti-DPPX encephalitis in Taiwan.

Identifying genetic variants for age of migraine onset in a Han Chinese population in Taiwan.

BACKGROUND: Considering the involvement of genetics in migraine pathogenesis in diverse ethnic populations, genome-wide association studies (GWAS) are being conducted to identify migraine-susceptibility genes. However, limited surveys have focused on the onset age of migraine (AoM) in Asians. Therefore, in this study, we aimed to identify the susceptibility loci of migraine considering the AoM in an Asian population. METHODS: We conducted a GWAS in 715 patients with migraine of Han Chinese ethnicity, residing in Taiwan, to identify the susceptibility genes associated with AoM. Based on our standard demographic questionnaire, the population was grouped into different subsets. Single-nucleotide polymorphism (SNP) associations were examined using PLINK in different AoM onset groups. RESULTS: We discovered eight novel susceptibility loci correlated with AoM that reached the GWAS significance level in the Han Chinese population. First, rs146094041 in ESRRG was associated with AoM [Formula: see text] 12 years. The other SNPs including rs77630941 in CUX1, rs146778855 in CDH18, rs117608715 in NOL3, rs150592309 in PRAP1, and rs181024055 in NRAP were associated with the later AoM. CONCLUSIONS: To our knowledge, this is the first GWAS to investigate the AoM in an Asian Han Chinese population. Our newly discovered susceptibility genes may have prospective associations with migraine pathogenesis.

Subjective cognitive complaints and migraine characteristics: A cross-sectional study.

OBJECTIVES: Subjective cognitive complaints by patients with migraine have been associated with memory impairment. However, whether the severity of memory impairment relates to migraine characteristics, such as attack frequency and aura, remains undetermined. We investigated the relationship between subjective cognitive complaints and migraine characteristics. MATERIALS AND METHODS: This cross-sectional study recruited 669 clinic outpatients from Taiwan. We stratified them by migraine frequency and the presence or absence of aura, and we controlled the data for confounding variables. We performed multivariable linear and logistic regressions to investigate whether different migraine frequencies are associated with subjective cognitive complaints, which were evaluated by the subjective memory complaints scale and the Ascertain Dementia 8 (AD8) questionnaire. RESULTS: Total subjective memory complaints scores tended to increase with the migraine attack frequency (P = .022) in patients with migraine with aura; similar results were obtained for AD8 scores in women with migraine with aura. Poor sleep quality was associated with a higher total subjective memory complaint (B = 0.08, 95% confidence interval [CI] = 0.03-0.14) and AD8 (B = 0.07, 95% CI = 0.02-0.11) scores. In addition, more severe depression was associated with higher total subjective memory complaints and AD8 scores (B = 0.05, 95% CI = 0.02-0.09; B = 0.08, 95% CI = 0.05-0.11, respectively). CONCLUSIONS: Subjective cognitive complaints tend to increase with the frequency of migraines with aura, and this interrelation is substantially influenced by depression severity and sleep disturbances.

Mathematical Framework of Deconvolution Algorithms for Quantification of Perfusion Parameters.

PURPOSE: MR perfusion weighted imaging (PWI) has been used as sensitive indicator of tissue at risk for infarction. Quantitative perfusion parameters such as cerebral blood flow (CBF), mean transit time (MTT) and cerebral blood volume (CBV) can be obtained from post processing of PWI data using standard singular value decomposition algorithm (SVD). Assumption regarding absence of arterial - tissue delay (ATD) used in SVD algorithm results in underestimation of perfusion parameters. To estimate accurate values for perfusion parameters it is important to understand the mathematical framework behind SVD and improved SVD algorithms (bSVD and rSVD). METHOD: This study explains the mathematical framework of SVD and improved SVD algorithms and uses computational techniques that use bSVD algorithm to obtain perfusion parameters maps of CBF, CBV and MTT for acute stroke patient. RESULT: Computational techniques based on mathematical deconvolution algorithms are used to post process CBV, CBF and MTT maps where decrease in CBF and CBV were seen in left hemisphere. CONCLUSION: The bSVD algorithm is found to be sensitive to ATD and provides more accurate estimates of perfusion parameters than the SVD algorithm, however CBF estimates from bSVD and rSVD still remain influenced by other artifacts Keywords: PWI = perfusion weighted imaging, CBF= cerebral blood flow, MTT = mean transit time, CBV= cerebral blood volume, SVD = singular value decomposition algorithm.

Increased risk of sleep apnoea among primary headache disorders: a nationwide population-based longitudinal study.

BACKGROUND: Primary headache disorders (PHDs) are associated with sleep problems. It is suggested that headache and sleep disorder share anatomical and physiological characteristics. We hypothesised that patients with PHDs were exposed to a great risk for developing sleep apnoea (SA). METHODS: In this retrospective longitudinal study, the data obtained from the Longitudinal Health Insurance Database in Taiwan were analysed. The study included 1346 patients with PHDs who were initially diagnosed and 5348 patients who were randomly selected and age/sex matched with the study group as controls. PHDs, SA, comorbidities and other confounding factors were defined based on International Classification of Diseases, Ninth Revision, Clinical Modification. Cox proportional hazards regressions were employed to examine adjusted HRs after adjusting with confounding factors. RESULTS: Our data revealed that patients with PHDs had a higher risk (HR 2.17, 95% CI 1.259 to 3.739, p<0.05) to develop SA compared with matched cohorts, whereas patients with migraine exhibited a high risk (HR 2.553, 95% CI 1.460 to 4.395, p<0.01). The results showed that patients with PHDs aged 18-44 exhibited highest risk of developing SA. In addition, males with PHDs exhibited an HR 3.159 (95% CI 1.479 to 6.749, p<0.01) for developing SA, respectively. The impact of PHDs on SA risk was progressively increased by various follow-up time intervals. CONCLUSION: Our results suggest that PHDs are linked to an increased risk for SA with sex-dependent and time-dependent characteristics.

Increased risk of non-multiple sclerosis demyelinating syndromes in patients with preexisting septicaemia: a nationwide retrospective cohort study.

BACKGROUND: Growing evidence shows links between septicaemia and non-multiple sclerosis demyelinating syndromes (NMSDS); nevertheless, epidemiological data are still very limited. This study aimed to explore the relationship between septicaemia and NMSDS in a general population. METHODS: The study included 482 781 individuals diagnosed with septicaemia and 1 892 825 age/sex-matched non-septicaemia patients for the comparison. Data were drawn from a population-based nationwide National Health Insurance Research Database Taiwan, from 1 January 2002 to 31 December 2011. The two cohorts of patients with and without septicaemia were followed up for the occurrence of NMSDS. The Cox-proportional hazard regression model was performed to estimate adjusted HR after multivariate adjustment. RESULTS: Individuals with septicaemia had a 4.17-fold (95% CI 3.21 to 5.4, p < 0.001) higher risk to develop NMSDS compared with those without septicaemia. Patients aged <65 years had a greater NMSDS risk (<45 years: HR = 6.41, 95% CI 3.65 to 11.3, p < 0.001; 45-64 years: HR = 6.66, 95% CI 3.98 to 11.2, p < 0.001). Furthermore, females with septicaemia and individuals with higher severity of septicaemia were associated with increased risks of developing NMSDS. CONCLUSIONS: Our results indicated that patients with septicaemia were likely to develop NMSDS. A possible contributing role of septicaemia in increasing the hazard of NMSDS is proposed, based on the outcome that individuals with higher severity of septicaemia carried elevated threat of encountering NMSDS.

Valproate is protective against 6-OHDA-induced dopaminergic neurodegeneration in rodent midbrain: A potential role of BDNF up-regulation.

BACKGROUND/PURPOSE: The main purpose of this study was to extend previously reported showing potent neuroprotective effect of valproic acid (VPA) in primary midbrain neuro-glial cultures to investigate whether VPA could protect dopamine (DA) neurons in vivo against 6-hydroxydopamine (6-OHDA)-induced neurodegeneration and to determine the underlying mechanism. METHODS: Male adult rats received a daily intraperitoneal injection of VPA or saline for two weeks before and after injection of 5, 10, or 15 µg of 6-OHDA into the brain. All rats were evaluated for motor function by rotarod performance. Brain samples were prepared for immunohistochemical staining and for determination of levels of dopamine, dopamine metabolites, and neurotrophic factors. RESULTS: 6-OHDA injection showed significant and dose-dependent damage of dopaminergic neurons and decrease of striatal dopamine content. Rats in the VPA-treated group were markedly protected from the loss of dopaminergic neurons and showed improvements in motor performance, compared to the control group at the moderate 6-OHDA dose (10 µg). VPA-treated rats also showed significantly increased brain-derived neurotrophic factor (BDNF) levels in the striatum and substantia nigra compared to the levels in control animals. CONCLUSION: Our studies demonstrate that VPA exerts neuroprotective effects in a rat model of 6-OHDA-induced Parkinson's disease (PD), likely in part by up-regulation BDNF.

Associations Between Depression/Anxiety and Headache Frequency in Migraineurs: A Cross-Sectional Study.

BACKGROUND: While migraines have been associated with emotional disturbances, it remains unknown whether the intensity of emotional expression is directly related to migraine frequency. OBJECTIVE: The present study investigated depression/anxiety among migraineurs. METHODS: This cross-sectional study included 588 clinical outpatients in Taiwan. Migraines were stratified by attack frequency, with and without auras, and with well-controlled confounding variables. Demographic and clinical data, including sleep characteristics, were collected. Multivariable linear regressions were employed to examine whether migraine frequency (1-4 headache days per month, 5-8 headache days per month, 9-14 headache days per month, or >14 headache days per month) was associated with depression/anxiety symptoms, as indicated by the Beck's Depression Inventory (BDI) and Hospital Anxiety and Depression Subscales (HADS). RESULTS: BDI total scores were highest in patients with chronic migraines (mean ± SD: 13.2 ± 8.5), followed by those with high frequency (12.1 ± 8.5), medium frequency (10.6 ± 8.0), low frequency (9.1 ± 7.1), and lowest in nonmigraine controls (6.6 ± 5.9), with a significant trend in frequency (P trend < .001); similar results were obtained for HADS scores. BDI and HADS scores were independently related to high-frequency episodic and chronic migraine frequency and to poor sleep quality. The relationship between BDI score and migraine frequency was present in both aura-present (P trend = .001) and aura-absent subgroups (P trend = .029). CONCLUSION: Higher migraine frequency, either with or without auras, correlated with higher symptom scores of anxiety and depression.

Homozygous ALDH2*2 Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men.

BACKGROUND AND PURPOSE: The *2 allele of the aldehyde dehydrogenase 2 gene (ALDH2) is the most common variant in Asian populations. The variant resulting in enzyme dysfunction was highly related to coronary artery disease. Recently, genome-wide association studies also discovered that the 12q24 locus near ALDH2 gene was associated with hypertension and ischemic stroke. This study intended to further investigate whether the above variant of ALDH2 increases the risk for ischemic stroke in Taiwanese. METHODS: A case-control study was conducted on 914 patients with acute ischemic stroke and 746 nonstroke controls. Polymerase chain reaction and sequencing were used to identify the ALDH2 genotype. Vascular risk factors, stroke subtypes, vascular stenosis, and stroke outcomes were analyzed. RESULTS: ALDH2 genotypes differed significantly between male controls (*1/*1 versus *1/*2 versus *2/*2=53.8% versus 39.9% versus 6.4%) and male patients with ischemic stroke (*1/*1 versus *1/*2 versus *2/*2=51.5% versus 37.3% versus 11.2%; P=0.048). No significant difference was found between groups for female patients (P=0.228). Multivariate logistic regression analysis revealed that the ALDH2*2/*2 genotype was an independent risk factor for ischemic stroke in male patients (odds ratio, 1.93 [95% confidence interval, 1.07-3.46]; P=0.028). Further analysis of men with ischemic stroke demonstrated that the polymorphism of ALDH2 was not related to vascular risk factors, severity of vascular atherosclerosis, stroke subtypes, and stroke functional outcomes. CONCLUSIONS: The study demonstrated that ALDH2*2/*2 may be an independent risk factor for ischemic stroke in Taiwanese men, but not in Taiwanese women.

Co-Cccurrence of Guillain-Barre Syndrome and Primary Sjögren Syndrome in an Elderly Woman.

PURPOSE: Co-occurrence of Guillain-Barré syndrome (GBS) and other autoimmune diseases is rare. We present the case of a patient with co-occurrence of GBS and primary Sjögren syndrome (pSS). CASE REPORT: An 82-year-old woman presented with acute ascending flaccid paralysis and acute respiratory failure. Nerve conduction studies and cerebrospinal fluid analysis confirmed the diagnosis of GBS of acute inflammatory demyelinating polyradiculoneuropathy subtype. The initial unresponsiveness to plasma exchange therapy raised the suspicion of other potential diseases. She was later proved to have underlying pSS. Her neurological deficits and respiratory failure improved dramatically with combination therapy of intravenous immunoglobulin (IVIg) and immunosuppressive agent. CONCLUSION: pSS should be considered as a possible cause of refractory GBS, particularly in elderly women. Combination therapy with IVIg and immunosuppressive agent may be beneficial.

The potential impact of primary headache disorders on stroke risk.

BACKGROUND: Headache such as migraine is associated with stroke. Studies focused on primary headache disorders (PHDs) as a risk factor for stroke are limited. The purpose of this population-based cohort study was to explore whether patients with PHDs were at a high risk for developing stroke. METHODS: A total of 1346 patients with PHDs were enrolled and compared with 5384 age-, gender- and co-morbidity-matched control cohorts. International Classification of Diseases, Clinical Modification codes were administered for the definition of PHDs, stroke, and stroke risk factors. Cox proportional-hazards regressions were performed for investigating hazard ratios (HR). RESULTS: PHDs patients exhibited a 1.49 times (95% CI :1.15-1.98, p < 0.01) higher risk for developing ischaemic stroke compared with that of control cohorts. Both migraine (HR = 1.22, 95% CI :1.13-1.97, p < 0.05) and tension-type headache (HR = 2.29, 95% CI :1.22-2.80, p < 0.01) were associated with an increased risk of ischemic stroke. Females with PHDs were at greater risk of developing ischaemic stroke (HR = 1.49, 95% CI :1.13-1.90, p < 0.01) than those without PHDs. PHDs patient aged 45 to 64 years displayed significantly higher risk to develop ischaemic stroke (HR = 1.50, 95% CI: 1.11-2.10, p < 0.05) than the matched controls. The impact of PHDs on ischaemic stroke risk became gradually apparent by different following time intervals beyond 2 years after first diagnosis. CONCLUSION: PHDs is suggestive of an incremental risk for ischaemic stroke with gender-dependent, age-specific and time-dependent characteristics.

Microglial regulation of immunological and neuroprotective functions of astroglia.

Microglia and astroglia play critical roles in the development, function, and survival of neurons in the CNS. However, under inflammatory conditions the role of astrogliosis in the inflammatory process and its effects on neurons remains unclear. Here, we used several types of cell cultures treated with the bacterial inflammogen LPS to address these questions. We found that the presence of astroglia reduced inflammation-driven neurotoxicity, suggesting that astrogliosis is principally neuroprotective. Neutralization of supernatant glial cell line-derived neurotrophic factor (GDNF) released from astroglia significantly reduced this neuroprotective effect during inflammation. To determine the immunological role of astroglia, we optimized a highly-enriched astroglial culture protocol and demonstrated that LPS failed to induce the synthesis and release of TNF-α and iNOS/NO. Instead we found significant enhancement of TNF-α and iNOS expression in highly-enriched astroglial cultures required the presence of 0.5-1% microglia, respectively. Thus suggesting that microglial-astroglial interactions are required for LPS to induce the expression of pro-inflammatory factors and GDNF from astroglia. Specifically, we found that microglia-derived TNF-α plays a pivotal role as a paracrine signal to regulate the neuroprotective functions of astrogliosis. Taken together, these findings suggest that astroglia may not possess the ability to directly recognize the innate immune stimuli LPS, but rather depend on crosstalk with microglia to elicit release of neurotrophic factors as a counterbalance to support neuronal survival from the collateral damage generated by activated microglia during neuroinflammation.

Comparison of activities of daily living impairments in Parkinson's disease patients as defined by the Pill Questionnaire and assessments by neurologists.

OBJECTIVES: To compare the clinical judgment of experienced neurologists after interviewing Parkinson's disease (PD) patients and their caregivers with the use of the Pill Questionnaire to determine the presence of impairments on activities of daily living (ADL). BACKGROUND: ADL impairment is a criterion for the diagnosis of dementia associated with PD. The Pill Questionnaire has been recommended as a screening tool to assess ADL impairment in PD patients, but its usefulness and validity have not been fully investigated. METHODS: We recruited idiopathic PD patients from 12 hospitals in Taiwan, and the patients underwent clinical assessments, a neuropsychological test battery and the Unified Parkinson Disease Rating Scale evaluation. The Pill Questionnaire was administered by study assistants. Patient and caregiver interviews were performed by experienced neurologists who were blinded to the Pill Questionnaire results. RESULTS: In total, 284 PD patients (mean age 71.8±9 years, mean education 8.7±5.3 years, mean disease duration 5.4±5.3 years) were recruited. 63 patients showed ADL impairment by the Pill Questionnaire, and 108 patients showed ADL impairment by neurologists' clinical interviews. κ Statistics showed moderate agreement between the two methods (κ=0.521, p<0.001). Of the 108 patients who were diagnosed with ADL impairment by neurologists, only 56 patients (51.9%) showed impairment according to the Pill Questionnaire. Most of the missed patients had milder cognitive impairment and lower motor disability. CONCLUSIONS: A comprehensive interview is essential to determine the presence of ADL impairment in PD patients, especially in patients with early PD.