General neurology: Current challenges and future implications.

BACKGROUND AND PURPOSE: In the coming decades, the world will face an increasing burden of neurological disorders (ND) and an urgent need to promote brain health. These challenges contrast with an insufficient neurological workforce in most countries, as well as decreasing numbers of general neurologists and neurologists attracted to work in general neurology (GN). This white paper aims to review the current situation of GN and reflect on its future. METHODS: The European Academy of Neurology (EAN) task force (TF) met nine times between November 2021 and June 2023. During the 2023 EAN annual meeting, attendees were asked to answer five questions concerning the future of GN. The document was sent for suggestions and eventually approval to the board and the presidents of the 47 national societies of the EAN. RESULTS: The TF first identified four relevant current and future challenges related to GN: (i) definition, (ii) practice, (iii) education, and (iv) research. The TF then identified seven initiatives to further develop GN at both the academic and community level. Finally, the TF formulated 16 recommendations to promote GN in the future. CONCLUSIONS: GN will remain essential in the coming decades to provide rapid, accessible, and comprehensive management of patients with ND that is affordable and cost-effective. There is also a need for research, education, and other initiatives aiming to facilitate improved working conditions, recognition, and prestige for those pursuing a career in GN.

Establishing a hyperacute stroke service during the COVID-19 pandemic: our institution's one year experience.

BACKGROUND AND AIMS: The corononavirus 2019 (COVID-19) pandemic resulted in modifications in the workflow and redistribution of human resources, causing challenges in setting up of an acute stroke service. We would like to share our preliminary outcome amid this pandemic, to determine if the implementation of COVID-19 standard operating procedures (SOPs) affected the delivery of our hyperacute stroke service. METHODS: We retrospectively analyzed one-year data from our stroke registry that began with the establishment of our hyperacute stroke service at Universiti Putra Malaysia Teaching Hospital from April 2020 until May 2021. RESULTS: Setting up acute stroke services during the pandemic with constrained manpower and implementation of COVID-19 SOPs, was challenging. There was a significant dip of stroke admission from April to June 2020 due to the Movement Control Order (MCO) implemented by the government to curb the spread of COVID-19. However, the numbers of stroke admission steadily rose approaching 2021, after the implementation of recovery MCO. We managed to treat 75 patients with hyperacute stroke interventions i.e. intravenous thrombolysis (IVT), mechanical thrombectomy (MT) or both. Despite implementing COVID-19 SOPs and using magnetic resonance imaging (MRI) as our first line acute stroke imaging modality, clinical outcomes in our cohort were encouraging; almost 40% of patients who underwent hyperacute stroke treatment had early neurological recovery (ENR), and only 33% of patients had early neurological stability (ENS). In addition, we were able to maintain our door-to-imaging (DTI) and door-to-needle (DTN) time in line with international recommendations. CONCLUSIONS: Our data reflects that COVID-19 SOPs did not deter successful delivery of hyperacute stroke services in our center. However, bigger and multi center studies are required to support our findings.

Immune-mediated necrotizing myopathy (NAM) related to SARS-Cov-2 infection: a case report.

BACKGROUND: There is a growing body of evidence that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or COVID-19 infection is associated with the development of autoimmune diseases. A recent systematic review reported that the new-onset autoimmune disorders during or after COVID-19 infection included inflammatory myopathies such as immune-mediated necrotizing myopathies. CASE PRESENTATION: We described a 60-year-old man diagnosed with COVID-19 infection and later presented with a two-week history of myalgia, progressive limb weakness, and dysphagia. He had a Creatinine Kinase (CK) level of more than 10,000 U/L, was strongly positive for anti-signal recognition particle (SRP) and anti-Ro52 antibody, and a muscle biopsy revealed a paucity-inflammation necrotizing myopathy with randomly distributed necrotic fibers, which was consistent with necrotizing autoimmune myositis (NAM). He responded well clinically and biochemically to intravenous immunoglobulin, steroids and immunosuppressant and he was able to resume to his baseline. CONCLUSION: SARS-CoV-2 may be associated with late-onset necrotizing myositis, mimicking autoimmune inflammatory myositis.

High-frequency repetitive transcranial magnetic stimulation at dorsolateral prefrontal cortex for migraine prevention: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of high-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex as a migraine prevention by conducting a systematic review and meta-analysis. BACKGROUND: The efficacy of high-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex as preventive migraine treatment remains debatable. METHODS: PubMed, Scopus, CINAHL, CENTRAL, and BioMed Central databases were searched from their inception until December 2020. Randomised trials comparing high-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex with sham for migraine prevention were included. The risk of bias was assessed using the Cochrane guidelines. Headache days, pain intensity, acute medication intake, and disability were extracted as study outcomes and the mean difference with a random-effects model was used to determine the effect size. RESULTS: Meta-analysis revealed that high-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex significantly reduced acute medication intake (Mean Difference = 9.78, p = 0.02, 95%CI: 1.60, 17.96, p = 0.02) and functional disability (Mean Difference = 8.00, p < 0.05, 95%CI: 4.21, 11.79). However, no differences were found in headache days and pain intensity reduction, although there was a slight trend favouring high-frequency repetitive transcranial magnetic stimulation. CONCLUSION: High-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex may be effective in reducing acute medication intake and disability. However, more studies are needed to strengthen this preliminary evidence.

Longitudinal extensive transverse myelitis following ChAdOx1 nCOV-19 vaccine: a case report.

BACKGROUND: Transverse myelitis (TM) is a relatively uncommon condition, and vaccine-associated myelitis is even rarer. Concern regarding neurological complications following vaccination escalated following the report of TM during the safety and efficacy trials of the COVID-19 vaccine. CASE PRESENTATION: We report the first case of Longitudinal Extensive Transverse Myelitis (LETM) in Malaysia following administration of the chimpanzee adenovirus-vectored (ChAdOx1 nCoV-19) vaccine. A 25-year-old female presented with bilateral lower limb weakness and inability to walk with a sensory level up to T8 with absent visual symptoms. Urgent gadolinium-enhanced magnetic resonance imaging (MRI) of the spine showed long segment TM over the thoracic region. Cerebrospinal fluid autoantibodies for anti-aquaporin-4 and anti-myelin-oligodendrocyte were negative. A diagnosis of LETM following vaccination was made, and the patient was started on a high dose of intravenous methylprednisolone. The patient eventually made a recovery following treatment. CONCLUSION: LETM is a rare but serious adverse reaction following vaccination. Previously reported cases showed an onset of symptoms between 10 to 14 days post-vaccination, suggesting a delayed immunogenic reaction. However, the incidence of myelitis in COVID-19 is much more common, far greater than the risk associated with vaccination.

Transcranial direct current stimulation with multiple oral re-reading therapy for pure alexia without agraphia: a case report.

Pure alexia without agraphia is characterized by impaired reading due to damage to the occipitotemporal cortex with preserved writing skills. In this case report, we investigate the effect of multiple oral re-reading (MOR) therapy adjunct with transcranial direct current stimulation (tDCS) in improving reading recovery of a 64-year-old patient with pure alexia without agraphia following a stroke. His MRI revealed an area of infarct with microhemorrhages at the left occipitotemporal region. The patient was blinded to each therapy and underwent seven consecutive sessions of sham tDCS followed by seven consecutive sessions of real tDCS, coupled with 1-hour MOR therapy during each session. Western Aphasia Battery (WAB) was performed at baseline, before sham and real-tDCS, and 6 weeks after completing tDCS therapy. The patient showed improvement using both sham and real-tDCS with better reading comprehension, average reading time, and word per minute after real-tDCS. This study suggests that MOR, coupled with tDCS therapy may accelerate the reading recovery in patients with pure alexia.

Stroke Care Trends During COVID-19 Pandemic in Zanjan Province, Iran. From the CASCADE Initiative: Statistical Analysis Plan and Preliminary Results.

BACKGROUND: The emergence of the COVID-19 pandemic has significantly impacted global healthcare systems and this may affect stroke care and outcomes. This study examines the changes in stroke epidemiology and care during the COVID-19 pandemic in Zanjan Province, Iran. METHODS: This study is part of the CASCADE international initiative. From February 18, 2019, to July 18, 2020, we followed ischemic and hemorrhagic stroke hospitalization rates and outcomes in Valiasr Hospital, Zanjan, Iran. We used a Bayesian hierarchical model and an interrupted time series analysis (ITS) to identify changes in stroke hospitalization rate, baseline stroke severity [measured by the National Institutes of Health Stroke Scale (NIHSS)], disability [measured by the modified Rankin Scale (mRS)], presentation time (last seen normal to hospital presentation), thrombolytic therapy rate, median door-to-needle time, length of hospital stay, and in-hospital mortality. We compared in-hospital mortality between study periods using Cox-regression model. RESULTS: During the study period, 1,026 stroke patients were hospitalized. Stroke hospitalization rates per 100,000 population decreased from 68.09 before the pandemic to 44.50 during the pandemic, with a significant decline in both Bayesian [Beta: -1.034; Standard Error (SE): 0.22, 95% CrI: -1.48, -0.59] and ITS analysis (estimate: -1.03, SE = 0.24, p < 0.0001). Furthermore, we observed lower admission rates for patients with mild (NIHSS < 5) ischemic stroke (p < 0.0001). Although, the presentation time and door-to-needle time did not change during the pandemic, a lower proportion of patients received thrombolysis (-10.1%; p = 0.004). We did not see significant changes in admission rate to the stroke unit and in-hospital mortality rate; however, disability at discharge increased (p < 0.0001). CONCLUSION: In Zanjan, Iran, the COVID-19 pandemic has significantly impacted stroke outcomes and altered the delivery of stroke care. Observed lower admission rates for milder stroke may possibly be due to fear of exposure related to COVID-19. The decrease in patients treated with thrombolysis and the increased disability at discharge may indicate changes in the delivery of stroke care and increased pressure on existing stroke acute and subacute services. The results of this research will contribute to a similar analysis of the larger CASCADE dataset in order to confirm findings at a global scale and improve measures to ensure the best quality of care for stroke patients during the COVID-19 pandemic.

Call to Action: SARS-CoV-2 and CerebrovAscular DisordErs (CASCADE).

BACKGROUND AND PURPOSE: The novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), now named coronavirus disease 2019 (COVID-19), may change the risk of stroke through an enhanced systemic inflammatory response, hypercoagulable state, and endothelial damage in the cerebrovascular system. Moreover, due to the current pandemic, some countries have prioritized health resources towards COVID-19 management, making it more challenging to appropriately care for other potentially disabling and fatal diseases such as stroke. The aim of this study is to identify and describe changes in stroke epidemiological trends before, during, and after the COVID-19 pandemic. METHODS: This is an international, multicenter, hospital-based study on stroke incidence and outcomes during the COVID-19 pandemic. We will describe patterns in stroke management, stroke hospitalization rate, and stroke severity, subtype (ischemic/hemorrhagic), and outcomes (including in-hospital mortality) in 2020 during COVID-19 pandemic, comparing them with the corresponding data from 2018 and 2019, and subsequently 2021. We will also use an interrupted time series (ITS) analysis to assess the change in stroke hospitalization rates before, during, and after COVID-19, in each participating center. CONCLUSION: The proposed study will potentially enable us to better understand the changes in stroke care protocols, differential hospitalization rate, and severity of stroke, as it pertains to the COVID-19 pandemic. Ultimately, this will help guide clinical-based policies surrounding COVID-19 and other similar global pandemics to ensure that management of cerebrovascular comorbidity is appropriately prioritized during the global crisis. It will also guide public health guidelines for at-risk populations to reduce risks of complications from such comorbidities.

Anti-Wolbachia therapy for onchocerciasis & lymphatic filariasis: Current perspectives.

Onchocerciasis and lymphatic filariasis (LF) are human filarial diseases belonging to the group of neglected tropical diseases, leading to permanent and long-term disability in infected individuals in the endemic countries such as Africa and India. Microfilaricidal drugs such as ivermectin and albendazole have been used as the standard therapy in filariasis, although their efficacy in eliminating the diseases is not fully established. Anti-Wolbachia therapy employs antibiotics and is a promising approach showing potent macrofilaricidal activity and also prevents embryogenesis. This has translated to clinical benefits resulting in successful eradication of microfilarial burden, thus averting the risk of adverse events from target species as well as those due to co-infection with loiasis. Doxycycline shows potential as an anti-Wolbachia treatment, leading to the death of adult parasitic worms. It is readily available, cheap and safe to use in adult non-pregnant patients. Besides doxycycline, several other potential antibiotics are also being investigated for the treatment of LF and onchocerciasis. This review aims to discuss and summarise recent developments in the use of anti-Wolbachia drugs to treat onchocerciasis and LF.

Acute Stroke Registry Malaysia, 2010-2014: Results from the National Neurology Registry.

BACKGROUND: Stroke remains a major health burden worldwide. The incidence and prevalence rates of stroke are decreasing in developed countries, an opposite trend is taking place in the Asia Pacific, where an increasing number of patients are being diagnosed with acute stroke. The results of the present study on acute stroke in multi-ethnic Malaysia will significantly contribute to the global stroke epidemiological data. We aimed to present epidemiological data of stroke including incidence and prevalence rates as well as associated risk factors from a prospective nationwide hospital-based registry from 2010 to 2014. METHODS: Patients diagnosed with stroke upon admission at the hospital were prospectively enrolled into the registry from January 1, 2010, to December 31, 2014. Descriptive analyses were performed. RESULTS: A total of 7668 patients were available for analysis. On average, patients were aged 62.7 years (standard deviation of 12.5). Ischemic stroke accounts for 79.4% of the cohort with a slightly higher proportion of male patients (55%). Ischemic stroke incidence is estimated to increase annually by 29.5% and hemorrhagic stroke by 18.7%. Hypertension is a major risk factor for both ischemic and hemorrhagic strokes regardless of stroke event with an excess of 8.4% hypertensive female compare to male patients (P ≤ .001). Majority of patients with ischemic and hemorrhagic strokes experienced mild and moderate stroke with 11.7% and 21.1%, respectively, documented as severe (P ≤ .001). CONCLUSIONS: The incidence and prevalence of stroke in Malaysia increased dramatically in the 5-year study period. Therefore, implementation of risk factor control strategies is important to prevent further increase of stroke burden in the country.

A case report of an unusual complication from bee sting: acute brachial plexopathy.

Brachial plexopathy is usually related to trauma like direct injury to the nerve and stretching injuries. Neurological complications following bee sting are uncommon. Here, we describe a rare case of acute brachial plexopathy as a neurological complication following bee sting. A23-year-old maleinitially presented with angioedema and anaphylactic shock one hour after a bee stung at his neck. Twenty four hours after the incidence, he presented with sudden onset of left upper limb weakness. Nerve conduction study and electromyography had shown evidence of left brachial plexopathy.

Video head impulse test in stroke: a review of published studies.

Accurate and timely diagnosis of posterior circulation stroke in patients with acute dizziness is a challenge that can lead to misdiagnosis and significant harm. The present review sought to identify and describe published research on the clinical application of vHIT in posterior circulation stroke. vHIT, a portable device, has gained prominence in evaluating peripheral vestibular disorders and offers potential applications in diagnosing neurological disorders, particularly posterior circulation stroke. Several studies have shown that vHIT can differentiate between stroke and vestibular neuritis based on VOR gain values, with high sensitivity and specificity. The manuscript also discusses vHIT's performance in differentiating between types of posterior circulation stroke, such as PICA, AICA, and SCA strokes. While vHIT has demonstrated promise, the review emphasizes the need for further research to validate its use as a tool to rule out stroke in acute dizziness patients in the emergency department. In conclusion, the manuscript underscores the potential of vHIT as a valuable addition to the diagnostic arsenal for acute dizziness, particularly in the context of posterior circulation stroke. It calls for further research and wider adoption of vHIT in clinical settings to improve patient care and reduce unnecessary costs associated with misdiagnoses.

Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention.

Ischemic heart disease and stroke are the two leading causes of death worldwide. Antiplatelet therapy plays the most significant role in the management of these cardiovascular and cerebrovascular occlusive events to prevent recurrent ischemic attack. Clopidogrel, an antiplatelet drug, is widely prescribed either alone or in combination with aspirin as dual antiplatelet therapy for the prevention of vascular occlusive events. The antiplatelet response to clopidogrel varies widely. Hyporesponders and nonresponders are likely to have adverse cardiovascular events during follow-up. Some drugs, such as proton pump inhibitors (omeprazole), calcium channel blockers, selective serotonin reuptake inhibitors (nefazadone), coumarin derivatives (phenprocoumon), benzodiazepines, sulfonylurea, erythromycin, and itraconazole, decrease the antiplatelet effect of clopidogrel when administered concomitantly. Decreased response to clopidogrel is common among Asians due to genetic polymorphisms associated with clopidogrel resistance, and it is nearly 70% in some of the Asian communities. It is necessary to study Asian populations, because there are a large number of Asians throughout the world due to increased migration. Current guidelines do not make genetic testing or platelet response testing mandatory prior to clopidogrel prescription. Therefore, it is important for clinicians treating Asian patients to keep in mind the interindividual variability in response to clopidogrel when prescribing the drug.

Phase behaviour and formation of fatty acid esters nanoemulsions containing piroxicam.

Fatty acid esters are long-chain esters, produced from the reaction of fatty acids and alcohols. They possess potential applications in cosmetic and pharmaceutical formulations due to their excellent wetting behaviour at interfaces and a non-greasy feeling when applied on the skin surfaces. This preliminary work was carried out to construct pseudo-ternary phase diagrams for oleyl laurate, oleyl stearate and oleyl oleate with surfactants and piroxicam. Then, the preparation and optimization study via 'One-At-A-Time Approach' were carried out to determine the optimum amount of oil, surfactants and stabilizer using low-energy emulsification method. The results revealed that multi-phase region dominated the three pseudo-ternary phase diagrams. A composition was chosen from each multi-phase region for preparing the nanoemulsions systems containing piroxicam by incorporating a hydrocolloid stabilizer. The results showed that the optimum amount (w/w) of oil for oleyl laurate nanoemulsions was 30 and 20 g (w/w) for oleyl stearate nanoemulsions and oleyl oleate nanoemulsions. For each nanoemulsions system, the amount of mixed surfactants and stabilizer needed for the emulsification to take place was found to be 10 and 0.5 g (w/w), respectively. The emulsification process via high-energy emulsification method successfully produced nano-sized range particles. The nanoemulsions systems passed the centrifugation test and freeze-thaw cycle with no phase failures, and stable for 3 months at various storage temperatures (3°C, 25°C and 45°C). The results proved that the prepared nanoemulsions system cannot be formed spontaneously, and thus, energy input was required to produce nano-sized range particles.

Encephalitis followed by optic neuritis: a case report and review of literature.

Encephalitis has been included in the causes of optic neuritis, but post encephalitic optic neuritis has been rarely reported. Majority of the cases of optic neuritis are either idiopathic or associated with multiple sclerosis, especially in western countries. This is very important in the Asian population where the incidence and prevalence of multiple sclerosis is not as high as in the Western countries. Although post infectious optic neuritis is more common in children, it can also be found in adults and is usually seen one to three weeks after a symptomatic infective prodrome. Here, we present a case of a 48 year-old-male who developed optic neuritis following viral encephalitis. His first presentation was with severe headache of two weeks duration. Viral encephalitis was diagnosed and treated. The patient presented again three weeks later with right eye pain and other features typical of optic neuritis. Corticosteroid therapy facilitated prompt recovery. Optic neuritis is an uncommon manifestation of encephalitis. It is important that both doctors and patients remain aware of post infectious cause of optic neuritis, which would enable a timely diagnosis and treatment of this reversible cause of vision loss.

Relationship of sleep quality, chronotype, and obstructive sleep apnea with migraine in the elderly population.

PURPOSE: Disturbances of sleep have frequently been reported in individuals with migraine. On top of this, an elderly patient with migraine also suffers from sleep disturbances due to changes in physiologic and mental health associated with aging. This study aimed to compare several sleep factors, namely sleep quality, chronotype, and obstructive sleep apnea (OSA) risk, between elderly people with and without migraine. METHODS: This was a multicenter cross-sectional study conducted in 10 neurologic clinics located in Tehran, Iran, over 2 years. The sample size was calculated as 189, including 63 migraine and 126 non-migraine patients. RESULTS: A significant difference was observed in the mean score of the global Pittsburgh Sleep Quality Index (PSQI) between migraine and non-migraine groups (p-value = 0.002), and in the individual components of the PSQI. However, there were no significant differences in the frequency of different types of chronotype (p-value = 0.125, T = 1.541) or OSA risk between the two groups (p-value = 0.568, T = -0.573). The binary logistic regression model showed that the relationship between global PSQI and migraine was significant (p = 0.002). CONCLUSION: Sleep quality is a problem for elderly migraine sufferers. Meanwhile, certain factors such as chronotype and OSA have no significant relationship with migraine among community-dwelling seniors. Further studies are required to enhance our understanding of this observation.

In Vitro Blood-Brain Barrier Models for Neuroinfectious Diseases: A Narrative Review.

The blood-brain barrier (BBB) is a complex, dynamic, and adaptable barrier between the peripheral blood system and the central nervous system. While this barrier protects the brain and spinal cord from inflammation and infection, it prevents most drugs from reaching the brain tissue. With the expanding interest in the pathophysiology of BBB, the development of in vitro BBB models has dramatically evolved. However, due to the lack of a standard model, a range of experimental protocols, BBB-phenotype markers, and permeability flux markers was utilized to construct in vitro BBB models. Several neuroinfectious diseases are associated with BBB dysfunction. To conduct neuroinfectious disease research effectively, there stems a need to design representative in vitro human BBB models that mimic the BBB's functional and molecular properties. The highest necessity is for an in vitro standardised BBB model that accurately represents all the complexities of an intact brain barrier. Thus, this in-depth review aims to describe the optimization and validation parameters for building BBB models and to discuss previous research on neuroinfectious diseases that have utilized in vitro BBB models. The findings in this review may serve as a basis for more efficient optimisation, validation, and maintenance of a structurally- and functionally intact BBB model, particularly for future studies on neuroinfectious diseases.

Spontaneous Bilateral Basal Ganglia Haemorrhage Secondary to Methanol Poisoning.

Methanol toxicity remains as major problem in the medical field.[1],[2],[3] With its active metabolite, formic acid often leads to severe metabolic acidosis and to some extend brain damaged.[4],[5],[6] We are reporting a case of brain hemorrhage at the right external capsule and left basal ganglia with mass effect and obstructive hydrocephalus in a methanol poisoning patient. A confused 29-year-old gentleman was brought into hospital. Initial investigation showed severe metabolic acidosis with raised anion gap. Initial brain CT scan was normal. Subsequently, serum methanol was reported to be high (112 mg/dL). Intravenous (IV) ethanol 10% was given without any delayed. As there was no improvement in his consciousness level, a repeat brain CT was performed and it showed multiple cerebral hemorrhage with obstructive hydrocephalus. Hence, clinicians should have high index of suspicion for cerebral hemorrhage in a patient with methanol toxicity, who presented with altered mental status and severe metabolic acidosis.

Formulation optimization of a palm-based nanoemulsion system containing levodopa.

Response surface methodology (RSM) was utilized to investigate the influence of the main emulsion composition; mixture of palm and medium-chain triglyceride (MCT) oil (6%-12% w/w), lecithin (1%-3% w/w), and Cremophor EL (0.5%-1.5% w/w) as well as the preparation method; addition rate (2-20 mL/min), on the physicochemical properties of palm-based nanoemulsions. The response variables were the three main emulsion properties; particle size, zeta potential and polydispersity index. Optimization of the four independent variables was carried out to obtain an optimum level palm-based nanoemulsion with desirable characteristics. The response surface analysis showed that the variation in the three responses could be depicted as a quadratic function of the main composition of the emulsion and the preparation method. The experimental data could be fitted sufficiently well into a second-order polynomial model. The optimized formulation was stable for six months at 4 °C.

Repetitive Transcranial Magnetic Stimulation of the Primary Motor Cortex beyond Motor Rehabilitation: A Review of the Current Evidence.

Transcranial magnetic stimulation (TMS) has emerged as a novel technique to stimulate the human brain through the scalp. Over the years, identifying the optimal brain region and stimulation parameters has been a subject of debate in the literature on therapeutic uses of repetitive TMS (rTMS). Nevertheless, the primary motor cortex (M1) has been a conventional target for rTMS to treat motor symptoms, such as hemiplegia and spasticity, as it controls the voluntary movement of the body. However, with an expanding knowledge base of the M1 cortical and subcortical connections, M1-rTMS has shown a therapeutic efficacy that goes beyond the conventional motor rehabilitation to involve pain, headache, fatigue, dysphagia, speech and voice impairments, sleep disorders, cognitive dysfunction, disorders of consciousness, anxiety, depression, and bladder dysfunction. In this review, we summarize the latest evidence on using M1-rTMS to treat non-motor symptoms of diverse etiologies and discuss the potential mechanistic rationale behind the management of each of these symptoms.