KCNJ3 is a novel candidate gene for autosomal dominant pure hereditary spastic paraplegia identified using whole genome sequencing.

Hereditary spastic paraplegia (HSP) is a group of familial diseases characterized by progressive corticospinal tract degeneration. Clinically, patients present with lower-limb spasticity and weakness. To date, more than 80 genetic HSP types have been identified. Despite advances in molecular genetics, novel HSP gene discoveries are ongoing, with a low genetic diagnostic yield. In this study, we aimed to determine pathogenic variants in a family with HSP, which was not diagnosed through conventional genetic testing. We clinically characterized a large family and conducted whole genome sequencing (WGS) analysis of four affected and three unaffected individuals in the family to identify the genetic cause of HSP. This family had autosomal dominant pure (uncomplicated) late childhood-onset HSP. The patients' symptoms accelerated between the ages of 20 and 30. Brain magnetic resonance images typically showed white matter changes, a thin corpus callosum, and cerebellar atrophy. We identified a heterozygous missense variant, KCNJ3 c.1297T>G (p.Leu433Val), through WGS and family genetic analysis, confirmed by Sanger sequencing. We suggest that the identification of KCNJ3 c.1297T>G (p.Leu433Val) constitutes the discovery of a potential novel gene responsible for HSP in this family. This is the first study to report the possible role of a KCNJ3 variant in HSP pathogenesis. Our findings further expand the phenotypic and genotypic spectrum of HSP.

Determinants of Functional Independence or Its Loss following Subthalamic Nucleus Stimulation in Parkinson's Disease.

OBJECTIVE: This study aimed to describe the change in functional status following bilateral subthalamic nucleus stimulation (STN-DBS) in Parkinson's disease (PD) and to identify predictors of postoperative functional dependence. METHODS: We included PD patients with bilateral STN-DBS who had complete Schwab & England Activities of Daily Living (S&E ADL) Scale data at baseline and 6 months after surgery from our prospective registry. Functional dependence was defined as an S&E ADL score of less than 80%. All data were collected from the on-medication state and on-stimulation state (after surgery). Logistic regression analyses were performed to determine the factors predictive of functional dependence after surgery. RESULTS: A total of 196 patients were included. At baseline, 41 patients were functionally dependent and the other 155 were functionally independent. Among the patients with preoperative dependence, 32 (78%) became functionally independent after surgery, and this conversion was associated with a lower baseline axial score (p = 0.012). Among the patients with preoperative independence, 21 (14%) developed postoperative dependence, and this conversion was associated with a higher baseline axial score (p = 0.013) and its smaller improvement (p < 0.001). Female sex (odds ratio [OR] 3.214; 95% confidence interval [CI] 1.210-8.542; p = 0.019) and a higher baseline axial score (OR 1.184; 95% CI 1.056-1.327; p = 0.004) significantly predicted the risk of postoperative functional dependence. CONCLUSIONS: We found that functional status following bilateral STN-DBS is closely related to preoperative axial symptoms. When loss of independence is a potential target for STN-DBS, clinicians should take into consideration the severity of axial impairment before surgery.

Expanding the Spectrum of Dopa-Responsive Dystonia (DRD) and Proposal for New Definition: DRD, DRD-plus, and DRD Look-alike.

Previously, we defined DRD as a syndrome of selective nigrostriatal dopamine deficiency caused by genetic defects in the dopamine synthetic pathway without nigral cell loss. DRD-plus also has the same etiologic background with DRD, but DRD-plus patients have more severe features that are not seen in DRD because of the severity of the genetic defect. However, there have been many reports of dystonia responsive to dopaminergic drugs that do not fit into DRD or DRD-plus (genetic defects in the dopamine synthetic pathway without nigral cell loss). We reframed the concept of DRD/DRD-plus and proposed the concept of DRD look-alike to include the additional cases described above. Examples of dystonia that is responsive to dopaminergic drugs include the following: transportopathies (dopamine transporter deficiency; vesicular monoamine transporter 2 deficiency); SOX6 mutation resulting in a developmentally decreased number of nigral cells; degenerative disorders with progressive loss of nigral cells (juvenile Parkinson's disease; pallidopyramidal syndrome; spinocerebellar ataxia type 3), and disorders that are not known to affect the nigrostriatal dopaminergic system (DYT1; GLUT1 deficiency; myoclonus-dystonia; ataxia telangiectasia). This classification will help with an etiologic diagnosis as well as planning the work up and guiding the therapy.

Characteristics of Early Oropharyngeal Dysphagia in Patients with Multiple System Atrophy.

BACKGROUND/AIMS: Dysphagia, a symptom of multiple system atrophy (MSA), is a major clinical concern. In this study, we investigate the characteristics of early oropharyngeal dysphagia (OD) in patients with MSA, and the differences between MSA subtypes. METHODS: Patients enrolled in the study had previously been diagnosed with MSA at the clinic of the Department of Neurology, and had been referred for a videofluoroscopic swallowing study (VFSS), between 2005 and 2014, to check for dysphagia. The clinical characteristics and VFSS findings were analyzed and compared between the MSA subtypes. RESULTS: This study enrolled 59 patients with MSA (24 men; 31 with MSA-P, 21 with MSA-C, and 7 with MSA-PC). Dysphagia symptoms were mostly limited to aspiration symptoms (90.48%) in patients with MSA-C, while difficulty in swallowing, increased mealtime, and drooling were frequent in those with MSA-P. The most common VFSS finding amongst patients was vallecular residue (n = 53, 89.8%), followed by penetration/aspiration (n = 40, 67.8%), and coating of the pharyngeal wall (n = 39, 66.1%). Comparison analysis between subtypes showed that apraxia and vallecular residue were more frequent and severe in MSA-P than in MSA-C (p = 0.033 and p = 0.010, respectively). CONCLUSION: Understanding early OD characteristics in patients with MSA and the differences between MSA subtypes could be helpful in managing dysphagia in patients with MSA. Several dysphagia symptoms similar to those of Parkinson disease were frequently observed in MSA-P, but not in MSA-C. A follow-up study is needed to elucidate the natural course of OD in MSA patients and the difference between MSA subtypes.

Validation of Freezing-of-Gait Monitoring Using Smartphone.

BACKGROUND: Freezing of gait (FOG) is a commonly observed motor symptom for patients with Parkinson's disease (PD). The symptoms of FOG include reduced step lengths or motor blocks, even with an evident intention of walking. FOG should be monitored carefully because it not only lowers the patient's quality of life, but also significantly increases the risk of injury. INTRODUCTION: In previous studies, patients had to wear several sensors on the body and another computing device was needed to run the FOG detection algorithm. Moreover, the features used in the algorithm were based on low-level and hand-crafted features. In this study, we propose a FOG detection system based on a smartphone, which can be placed in the patient's daily wear, with a novel convolutional neural network (CNN). METHODS: The walking data of 32 PD patients were collected from the accelerometer and gyroscope embedded in the smartphone, located in the trouser pocket. The motion signals measured by the sensors were converted into the frequency domain and stacked into a 2D image for the CNN input. A specialized CNN model for FOG detection was determined through a validation process. RESULTS: We compared our performances with the results acquired by the previously reported settings. The proposed architecture discriminated the freezing events from the normal activities with an average sensitivity of 93.8% and a specificity of 90.1%. CONCLUSIONS: Using our methodology, the precise and continuous monitoring of freezing events with unconstrained sensing can assist patients in managing their chronic disease in daily life effectively.

Correlation of electrode position and clinical outcomes in globus pallidus stimulation for dystonia.

BACKGROUND: The correlation between the electrode location and the clinical outcome for internal globus pallidus (GPi) deep brain stimulation (DBS) has not been fully elucidated. OBJECTIVE: The aim of this study was to determine the discrepancies between the theoretical target planned by magnetic resonance imaging (MRI) and the actual electrode location in postoperative MRI, as well as to find the correlation between the final electrode locations and the clinical outcome after GPi DBS. METHODS: Thirty-six patients who underwent GPi DBS for dystonia were included in this retrospective study. The X coordinate was defined as the lateral distance from the midline, the Y coordinate as the anterior distance from the midcommissural point, and the Z coordinate as the inferior distance from the intercommissural line. RESULTS: All coordinates showed a significant difference between theoretical and actual values for all electrode locations (p < 0.05). In particular, greater differences were exhibited for Y than for the X and Z coordinates. There was no significant difference in the accuracy of the localization of the left-side versus the right-side electrode for any coordinates. The patients whose electrodes were located within or near the posteroventral GPi showed better clinical outcomes. CONCLUSIONS: The actual electrode location was slightly more posterior to the theoretically planned target. Electrodes concentrated near the posteroventral GPi tended to yield favorable outcomes.

Visual Hallucination and Pattern of Brain Degeneration in Parkinson's Disease.

BACKGROUND AND OBJECTIVES: The incidence of visual hallucination (VH) increases with Parkinson's disease (PD) progression, and its development is thought to be related to a specific neurodegenerative process in PD. This study aimed to reveal brain degeneration related to VH in PD by analyzing neuroimaging data obtained from patients in their different stages of PD. METHODS: Data from 48 PD patients - 21 nondemented without VH (PNV group), 10 nondemented with VH (PV group), and 17 demented with VH (PVD group) - and 30 age-matched healthy controls (HC group) were analyzed. Voxel-based morphometry and tract-based spatial statistics were conducted. Previous magnetic resonance volumetric studies on VH in PD were collectively reviewed. RESULTS: The PV group showed gray matter atrophy in the right inferior parietal lobule and supramarginal gyrus compared with the HC and PNV groups. The PVD group showed a wider range of gray matter atrophies in the temporo-parieto-occipital regions than those in the PV group. White matter changes seemed to be an earlier event than gray matter changes. Fractional anisotropy values diffusely decreased in all three PD subgroups compared with the HC group without significant differences between the PD subgroups. Mean diffusivity was not different between the PNV and HC groups but increased in the parieto-temporal region in the PV group and increased diffusely in the PVD group, additionally including the fronto-occipital regions. A review of previous studies supported our observations. CONCLUSIONS: Gray matter degenerations from the parieto-temporal junction to the parieto-occipital and temporo-occipital regions may be responsible for VH on the typical timeline of PD progression.

Lateral geniculate atrophy in Parkinson's with visual hallucination: A trans-synaptic degeneration?

INTRODUCTION: Defective visual information processing contributes to visual hallucination in PD, for which "top-down" and "bottom-up" impairment are suggested mechanisms. This study was aimed to investigate macro- and microstructural neural changes in afferent visual pathways in relation to visual hallucination in nondemented PD patients. METHODS: This study included 24 nondemented, nondepressed PD patients (10 hallucinating and 14 nonhallucinating) and 15 age-matched healthy controls. We analyzed volumetric and diffusion tensor MRI data by applying region of interest analyses on the visual pathways, including the optic chiasm, bilateral optic nerves, lateral geniculate bodies, optic radiations, and primary visual cortex. RESULTS: Patients' demographic characteristics, daily medication doses, as well as duration and motor severity of PD were similar in the two PD groups. Compared to PD patients without hallucination, those with hallucination had fractional anisotropy decrease in the left optic nerve and showed atrophy of lateral geniculate bodies, especially in the left side. In addition, the PD with hallucination group had diffusivity increase in the left optic radiation compared to that in the PD without hallucination and healthy control groups. There were no differences in the primary visual cortex volume among the study groups. CONCLUSIONS: We found microstructural alterations in visual pathways in nondemented PD patients with hallucination, mainly in first-order neurons and atrophy in the lateral geniculate body where the retinal ganglion cells synapse to second-order neurons. Afferent visual pathway degeneration may occur in a trans-synaptic way in PD. Further studies warrant to be conducted.

Clinical spectrum of dopa-responsive dystonia and related disorders.

Dopa-responsive dystonia (DRD) has a classic presentation of childhood or adolescent-onset dystonia, mild parkinsonism, marked diurnal fluctuations, improvement with sleep or rest, and a dramatic and sustained response to low doses of L-dopa without motor fluctuations or dyskinesias. However, there have been many papers on patients with a wide range of features, which report them as DRD mainly because they had dystonic syndromes with L-dopa responsiveness. Many mutations in the dopaminergic system have been found as molecular genetic defects. Therefore, the clinical and genetic spectra of DRD are unclear, which lead to difficulties in diagnostic work-ups and planning treatments. We propose the concept of DRD and DRD-plus to clarify the confusion in this area and to help understand the pathophysiology and clinical features, which will help in guiding diagnostic investigations and planning treatments. We critically reviewed the literature on atypical cases and discussed the limitations of the gene study.

Influence of propofol and fentanyl on deep brain stimulation of the subthalamic nucleus.

We investigated the effect of propofol and fentanyl on microelectrode recording (MER) and its clinical applicability during subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. We analyzed 8 patients with Parkinson's disease, underwent bilateral STN DBS with MER. Their left sides were done under awake and then their right sides were done with a continuous infusion of propofol and fentanyl under local anesthesia. The electrode position was evaluated by preoperative MRI and postoperative CT. The clinical outcomes were assessed at six months after surgery. We isolated single unit activities from the left and the right side MERs. There was no significant difference in the mean firing rate between the left side MERs (38.7 ± 16.8 spikes/sec, n=78) and the right side MERs (35.5 ± 17.2 spikes/sec, n=66). The bursting pattern of spikes was more frequently observed in the right STN than in the left STN. All the electrode positions were within the STNs on both sides and the off-time Unified Parkinson's Disease Rating Scale part III scores at six months after surgery decreased by 67% of the preoperative level. In this study, a continuous infusion of propofol and fentanyl did not significantly interfere with the MER signals from the STN. The results of this study suggest that propofol and fentanyl can be used for STN DBS in patients with advanced Parkinson's disease improving the overall experience of the patients.

Herpes simplex encephalitis initially presenting without fever or cerebrospinal fluid pleocytosis and with typical neuroimaging findings: a case report.

Herpes simplex encephalitis (HSE) is a common viral encephalitis that can be fatal if not adequately treated. Fever, cerebrospinal fluid (CSF) pleocytosis, and typical neuroimaging findings are commonly observed in HSE cases. We encountered a patient with HSE who did not exhibit these classic clinical features. A 63-year-old male presented with his first-ever seizure. Fever did not develop until the fourth day of admission, and neither neuroimaging nor CSF analysis revealed abnormalities. Under suspicion of autoimmune encephalitis, methylprednisolone was administered. Subsequently, when the patient developed fever, a follow-up neuroimaging study was performed and revealed abnormalities consistent with HSE. The patient was promptly treated with acyclovir, which led to a full recovery. Diagnosing HSE in patients who present without fever or CSF pleocytosis and with typical neuroimaging findings poses a challenge. Therefore, prior to initiating immunosuppressive treatment, it is crucial to closely observe patients and to conduct follow-up tests, including neuroimaging and CSF analysis.

A Survey of Perspectives on Telemedicine for Patients With Parkinson's Disease.

OBJECTIVE: Parkinson's disease (PD) patients often find it difficult to visit hospitals because of motor symptoms, distance to the hospital, or the absence of caregivers. Telemedicine is one way to solve this problem. METHODS: We surveyed 554 PD patients from eight university hospitals in Korea. The questionnaire consisted of the clinical characteristics of the participants, possible teleconferencing. METHODS: , and preferences for telemedicine. RESULTS: A total of 385 patients (70%) expressed interest in receiving telemedicine. Among them, 174 preferred telemedicine whereas 211 preferred in-person visits. The longer the duration of disease, and the longer the time required to visit the hospital, the more patients were interested in receiving telemedicine. CONCLUSION: This is the first study on PD patients' preferences regarding telemedicine in Korea. Although the majority of patients with PD have a positive view of telemedicine, their interest in receiving telemedicine depends on their different circumstances.

Clinical and diagnostic characteristics of Hashimoto's encephalopathy: a single-center, retrospective study.

BACKGROUND AND PURPOSE: Diagnosing Hashimoto's encephalopathy (HE) is challenging. In contrast to other types of autoimmune encephalitis, HE shows an excellent response to steroid treatment. We aimed to investigate the rates of antithyroid antibodies (ATAs) and probable HE in patients with unexplained mental dysfunction and compare the clinical characteristics between the good- and poor-outcome groups. METHODS: We retrospectively reviewed the medical records and electroencephalography (EEG) and neuroimaging findings of patients admitted to the Department of Neurology of our hospital from March 1, 2006, to February 28, 2023. Using our proposed diagnostic criteria for probable HE, we compared the clinical characteristics between the good- and poor-outcome groups. We also investigated the rates of ATA positivity and probable HE. RESULTS: In total, 198 patients exhibited altered mentation, rapidly progressive cognitive decline, or myoclonus. ATA tests were performed on 86 patients, and the detection rates of ATAs and probable HE were 29.1% and 25.6%, respectively. Of the 22 patients enrolled, the good- and poor-outcome groups comprised 19 and 3 patients, respectively. Clinical seizures occurred in seven patients. Nonconvulsive status epilepticus on EEG was observed in six patients, all of whom were intractable to antiepileptic drugs. Nineteen of 21 patients (90.5%) treated with immunosuppressants showed good outcomes. CONCLUSIONS: HE is a rare clinical disorder, but not as rare as previously thought. When HE is suspected, steroids should be considered the first-line treatment. Early diagnosis and adequate treatment are critical to achieve good outcomes in HE.

Long Short-Term Memory-Based Deep Learning Models for Screening Parkinson's Disease Using Sequential Diagnostic Codes.

BACKGROUND AND PURPOSE: It is challenging to detect Parkinson's disease (PD) in its early stages, which has prompted researchers to develop techniques based on machine learning methods for detecting PD. However, previous studies did not fully incorporate the slow progression of PD over a long period of time nor consider that its symptoms occur in a time-sequential manner. Contributing to the literature on PD, which has relied heavily on cross-sectional data, this study aimed to develop a method for detecting PD early that can process time-series information using the long short-term memory (LSTM) algorithm. METHODS: We sampled 926 patients with PD and 9,260 subjects without PD using medical-claims data. The LSTM algorithm was tested using diagnostic histories, which contained the diagnostic codes and their respective time information. We compared the prediction power of the 12-month diagnostic codes under two different settings over the 4 years prior to the first PD diagnosis. RESULTS: The model that was trained using the most-recent 12-month diagnostic codes had the best performance, with an accuracy of 94.25%, a sensitivity of 82.91%, and a specificity of 95.26%. The other three models (12-month codes from 2, 3, and 4 years prior) were found to have comparable performances, with accuracies of 92.27%, 91.86%, and 91.81%, respectively. The areas under the curve from our data settings ranged from 0.839 to 0.923. CONCLUSIONS: We explored the possibility that PD specialists could benefit from our proposed machine learning method as an early detection method for PD.

A Role of ß2-Adrenoreceptor Agonists Related to the Development of Parkinson's Disease.

Background: Several studies have suggested the potential protective role of ß2-adrenoreceptor agonist (ß2AR-agonist) on the development of Parkinson's disease (PD). However, those could not reflect a different epidemiologic background in eastern countries. We explored ß2AR-agonist's effect on PD development by controlling for smoking. Materials and Methods: We used the Korean national sample cohort data (from 2002 to 2013) containing 1,025,340 participants (2.2% of the whole population). The subjects over 60 years were included. PD was defined based on the ICD-10 code, which should be diagnosed by neurologists. Atypical Parkinsonisms or ataxic disorders were excluded. We made Set 1 (from 2003 to 2007) and Set 2 (from 2003 to 2008) based on the exposure period for the sensitivity analysis. We observed whether PD had developed during the follow-up periods in each subset. Results: The PD (Set 1, n = 742; Set 2, n = 699) and non-PD group (Set 1, n = 57,645; Set 2, n = 66,586) were collected. Old age, Medicaid, and asthma were risk factors, whereas smoking was a significant protective factor for PD development. The proportion of ß2AR-agonist use was significantly higher in the PD group than in the non-PD group (Set 1, 3.6% vs. 2.4%; Set 2, 4.1% vs. 2.6%). ß2AR-agonist use still was a risk factor in developing PD from the multiple logistic regression analysis. Conclusions: ß2-AR-agonist looked like a risk factor rather than a protective factor for PD development. Well-controlled studies reflecting various epidemiologic backgrounds are required to confirm the role of ß2AR-agonist.

Characteristic MR Imaging Features and Serial Changes in Adult-Onset Alexander Disease: A Case Report.

Adult-onset Alexander Disease (AOAD) is a rare genetically determined leukoencephalopathy that presents with ataxia, spastic paraparesis, or brain stem signs including speech abnormalities, swallowing difficulties, and frequent vomiting. The diagnosis of AOAD is frequently proposed based on the findings on MRI. We demonstrate two cases (37-year-old female and 61-year-old female) with characteristic imaging findings and changes in follow-up MRI in patients with AOAD, which were confirmed via glial fibrillary acidic protein (GFAP) mutation analysis. On MRI, the typical tadpole-like brainstem atrophy and periventricular white matter abnormalities were noted. The presumptive diagnoses were made based on the typical MRI appearances and, subsequently, confirmed via GFAP mutation analysis. Follow-up MRI demonstrated the progression of atrophy in the medulla and upper cervical spinal cord. Our report could help raise awareness of characteristic MRI findings of AOAD, thus helping clinicians use GFAP analysis for AOAD diagnosis confirmation.

Diffusion tensor tractography of the corticobulbar tract in a dysphagic patient with progressive supranuclear palsy: A case report.

RATIONALE: This paper reports the changes over time in the corticobulbar tract (CBT) analyzed using diffusion tensor tractography (DTT) in a dysphagic patient with progressive supranuclear palsy (PSP). PATIENT CONCERNS: A 53-year-old man initially presented with dysarthria, gait disturbance, and bradykinesia, and approximately 1-year later, downward gaze paralysis appeared. Initially, there was no dysphagia; however, approximately 2 years after visiting the hospital, symptoms of dysphagia, including difficulty swallowing pills, aspiration, and oral movement impairments appeared. The symptoms gradually progressed, and finally, mouth opening was severely damaged to the extent that it was difficult to orally feed. INTERVENTIONS: We performed diffusion tensor imaging 3 times; at 3-month, 20-month, and 41-month from onset. OUTCOMES: On 3-month DTT, the left CBT was well reconstructed, whereas the right CBT showed partial tearing. In the 20-month DTT, both CBTs became thinner compared to the 3-month DTT. On 41-month DTT, both CBTs became much thinner than after 3-month and 20-month DTT. LESSONS: We observed the degree of CBT injury over time in a dysphagic patient with PSP. These results suggest that the analysis of CBT using DTT is helpful in predicting the degree of dysphagia and prognosis in patients with PSP.

Patient with Epilepsy Showing Psychiatric Symptoms after Remission of Seizures and Normalization of Electroencephalography: The Phenomenon of Forced Normalization?

Psychiatric disorders are commonly observed in patients with epilepsy. Among them, the phenomenon known as forced normalization is scarce. Herein, we report the case of a 41-year-old patient who showed long-term first-onset psychiatric symptoms after seizure remission and normalization of electroencephalography. After changing the antiepileptic drug regimen and psychiatric treatment, the patient's symptoms regressed. However, the exact pathological mechanisms remain to be elucidated. Changing the regimen of antiepileptic drugs and long-term psychiatric treatment may help control this phenomenon.

Aphasic Status Epilepticus Associated with Alzheimer's Disease: Clinical and Electrographic Characteristics.

In aphasic status epilepticus (ASE), aphasia is the sole manifestation of seizure in patients with this disorder. Alzheimer's disease (AD) is one of neurological disorders causing ASE. Herein, we report two cases of ASE associated with AD, and discuss their clinical characteristics. Patient 1 presented Broca's aphasia, and patient 2 presented global aphasia during the ictal period. Both patients exhibited atypical ictal electroencephalographic (EEG) patterns, which improved after antiepileptic drug administration. ASE was the presenting symptom of AD in patient 1. ASE can develop at any stage of AD. Alterations in clinical symptoms and EEG patterns after treatment with antiepileptic drug are the key to diagnosis. Prompt diagnosis and treatment are critical for preventing further consciousness dysfunction.

Phenotypic differences in Dyt1 between ethnic groups.

A DYT1 mutation is the most common genetic cause of early-onset primary torsion dystonia. Herein we present the phenotypes of 25 Korean dystonia patients with DYT1 mutations. We further compare the clinical features of the Asian patients with those of the Western DYT 1 mutation patients. In Korean patients, upper extremity was the most common site of symptom onset while there were a few patients with axial-onset dystonia. Generalized dystonia was the most common subtype followed by segmental dystonia. A few patients from the same families had their symptoms at the same age. The clinical features of Korean patients were similar to those of other Asian patients. The Asian patients were differentiated from Western patients by more frequent axial onset, no cranial involvement at onset, and more common segmental dystonia. The variable clinical manifestation in different ethnic groups may suggest that ethnicity is a significant modifier of DYT1 dystonia.