To evaluate whether Glucagon-like peptide-1 receptor agonist (GLP-1 RA) use at immune checkpoint inhibitor (ICI) start is associated with mortality, healthcare use, and immune-related adverse events in adults with type 2 diabetes (T2D). A target-trial emulation was conducted in the TriNetX US Collaborative Network among adults with cancer and T2D starting an ICI, with or without overlapping GLP-1 RA at ICI start. A new-user 1:1 propensity-score-matched, intention-to-treat design yielded 2,903 per group and 36-month follow-up. Primary endpoint was all-cause mortality; key secondaries were hospitalization, and composite immune-related adverse events (irAEs). Prespecified per-protocol, 90-day landmark, and semaglutide-only analyses assessed robustness. GLP-1 RA co-exposure was associated with lower mortality (hazard ratio [HR] 0.55, 95 % CI 0.51-0.61; 36-month absolute risk difference [ARD] - 16.41 %; number needed to treat [NNT] 5). Hospitalization (HR 0.76; ARD - 7.06 %; NNT 11), and composite irAEs (43.93 % vs 51.51 %; ARD - 7.58 %; NNT 11) were also lower. Diabetic-retinopathy progression (HR 1.75; ARD + 2.71 %) and non-arteritic anterior ischemic optic neuropathy (HR 1.51) were higher; hypoglycaemia, acute kidney injury, and dehydration/orthostatic hypotension were lower. GLP-1 RA use during ICI therapy correlated with lower mortality, reduced acute care, fewer irAEs; ophthalmic signals warrant monitoring. Parkinson disease (PD), also known as Idiopathic or primary parkinsonism, hypokinetic rigid syndrome, or paralysis agitans, is the second most common progressive neurodegenerative disorder, affecting 2% to 3% of people older than 65. The degeneration of dopaminergic neurons in the substantia nigra, accompanied by the intracellular accumulation of alpha-synuclein (α-synuclein) (Lewy body), represents the neuropathological hallmark of the disease. PD usually presents in later life with the cardinal clinical motor features of bradykinesia, resting tremor, and rigidity, often in various combinations. Postural instability emerges later in the disease course as another defining feature (see Image. An Illustration of Parkinson Disease). The motor symptoms of PD are typically asymmetric, which helps differentiate it from other Parkinsonian syndromes. By the time a clinical diagnosis is made, more than 50% and up to 80% of the dopaminergic neurons have degenerated. Recognition is growing that the pathology of PD begins a decade or more before clinical diagnosis, with α-synuclein deposition in other neurons, including those of the gastrointestinal tract, olfactory structures, hypothalamus, and autonomic nervous system. These early changes contribute to premotor and nonmotor symptoms such as anosmia or hyposmia, constipation, and sleep dysfunction, especially rapid eye movement sleep behavior disorder. Additional nonmotor features include depression, orthostatic hypotension, dementia, and psychosis. Current estimates suggest that PD affects at least 1% of individuals over the age of 60, and the disorder is the fastest-growing neurodegenerative condition worldwide. Most cases are idiopathic, though approximately 10% have a genetic cause, with 3% to 5% of patients carrying inherited pathogenic variants in known PD genes. Onset is generally insidious, but progression is inevitable (see Image. Progression of Symptoms in Parkinson Disease). Tremor is often the first clinical sign and may later be accompanied by bradykinesia and rigidity. Postural instability typically develops in the later stages, significantly impairing quality of life. Dopamine transporter single-photon emission computed tomography scans can aid in uncertain cases or help exclude other neurological disorders. Management focuses on dopaminergic therapies to address motor symptoms, while nonmotor manifestations often require additional targeted treatments. No disease-modifying therapy has yet been proven. However, stereotactic neurosurgical interventions, such as deep-brain stimulation, offer effective options for patients with advanced motor complications.

Multiple system atrophy (MSA) is a progressive disease with Parkinsonism, dysautonomia, and cerebellar symptoms wherein patients can present with a broad range of confusing and overlapping findings attributable to various neuroanatomical substrates. Although possible, weakness is an unusual primary complaint, warranting further work-up for another neurodegenerative disease. The involvement of the more central structures, such as the locus coeruleus, pontine micturition center, and the cerebellum, can explain the wide range of symptoms. While Onuf's nucleus contributes to the urinary symptoms, anterior horn cells can implicate a motor neuron disease. Taking the varied neuroanatomical substrates into consideration, patients can present with a plethora of dysregulated motor symptoms. The authors share the course of a patient with clinically established MSA-cerebellar type and lower motor neuron disease findings at par with progressive muscular atrophy (PMA), but tested positive for an ERBB4 gene mutation, which is linked to an amyotrophic lateral sclerosis (ALS) variant. A 65-year-old Chinese female manifested with bilateral leg weakness and urinary incontinence. Over the next five years, she developed recurrent pre-syncopal attacks, asymmetric limb tremors, memory lapses, laughing fits, and a staccato-like voice. Medical management with anti-Parkinsonism drugs did not help her condition. Repeated annual non-contrast enhanced cranial magnetic resonance imaging (MRI) revealed gradual cerebellar atrophy, and an eventual prominent "hot-cross bun" sign. Because of episodes of orthostatic hypotension, with a systolic blood pressure as low as 50 mmHg, she gradually became bedridden with progressive arm weakness and sleep issues. These prompted her admission. Saccadic dysmetria and ataxic dysarthria aided in the diagnosis of MSA-cerebellar type, while motor neuron disease findings included tongue fasciculation, asymmetric leg atrophy, and polyminimyoclonus, suggestive of PMA. Neurophysiological studies confirmed this, while whole genome sequencing yielded an ERBB4 gene ALS variant of uncertain significance. She remained compliant with physical therapy during her admission. Although she was prescribed fludrocortisone for symptomatic relief and a two-week course of edaravone, she was discharged with minimal improvement and wheelchair-bound. However, the patient eventually expired two years afterward due to systemic complications. Although suspicion for a certain movement disorder can be initially made with physical examination, diagnostics can shed further light on the patient's pathology, exemplifying the uniqueness of this case report and how varying neurodegenerative movement disorders can coexist in a single patient.

Neurological disorders encompass a complex and heterogeneous spectrum of diseases affecting the brain, spinal cord, and peripheral nervous system, each presenting unique challenges that extend well beyond primary neurological symptoms. These disorders profoundly impact cardiovascular health, prompting an intensified exploration into the intricate interconnections between the neurological and cardiovascular systems. This review synthesizes current insights and research on cardiovascular comorbidities associated with major neurological conditions, including stroke, epilepsy, Parkinson's disease, multiple sclerosis, and Alzheimer's disease. The cardiovascular sequelae of these neurological disorders are multifactorial. For instance, strokes not only predispose individuals to arrhythmia and heart failure but also exacerbate preexisting cardiovascular risk factors. Similarly, epilepsy is associated with autonomic dysregulation and an elevated risk of sudden cardiac death, underscoring the necessity for vigilant cardiac monitoring in affected individuals. Parkinson's disease manifests with orthostatic hypotension and cardiac sympathetic denervation, significantly contributing to morbidity. Additionally, multiple sclerosis and Alzheimer's disease exhibit cardiovascular autonomic dysfunction and heightened cardiovascular risk, underscoring the need for proactive management strategies. Mechanistically, these conditions disrupt autonomic nervous system regulation, induce chronic inflammation, and may share genetic susceptibilities, each contributing to cardiovascular pathology. Effective management of these complexities requires an integrative approach that includes risk factor modification, pharmacotherapy, lifestyle interventions, and comprehensive patient education. Future research directions include identifying novel therapeutic targets, conducting large-scale clinical trials, and investigating genetic biomarkers to individualize treatment strategies. By addressing the multifaceted interactions between neurological disorders and cardiovascular health, healthcare providers can optimize patient care, reducing cardiovascular morbidity and mortality in this vulnerable population.

Spontaneous intracranial hypotension (SIH) is an uncommon and frequently misdiagnosed condition characterized by a lower-than-normal volume of cerebrospinal fluid (CSF) caused by leakage of CSF through the dural membrane. The primary manifestation of SIH is an orthostatic headache, which is frequently accompanied by nausea and vomiting. Patients with connective tissue disorders are at increased risk for spontaneous CSF leaks due to the structural weakness of their dural membranes. An 18-year-old woman with no reported past medical history presented to the emergency department with 10 days of a bifrontal headache that was orthostatic in nature with associated nausea and vomiting. She was noted to have several marfanoid features on physical examination. Spontaneous intracranial hypotension was ultimately diagnosed and treated successfully with an epidural blood patch. Subsequent genetic testing revealed a diagnosis of Marfan syndrome. Spontaneous intracranial hypotension is an uncommon cause of headache. Individuals with connective tissue disorders such as Marfan syndrome are at increased risk for SIH. Knowledge of the relationship between these two conditions allows for a more rapid diagnosis of SIH.

Autonomic dysfunction is a distinctive but undervalued feature of hereditary transthyretin amyloidosis (ATTRv). It may predate the onset of polyneuropathy and cardiomyopathy, thereby providing crucial prognostic and therapeutic information. The objective of this study was to assess autonomic function by means of the standardized cardiovascular autonomic reflex tests (CRTs) in a cohort of subjects with genetically proven ATTRv from non-endemic areas who were in the symptomatic and pre-symptomatic stages. All subjects enrolled in this cross-sectional study had genetically proven ATTRv. They underwent the head-up tilt test, Valsalva manoeuvre, deep breathing test, cold face test and handgrip test while under continuous blood pressure and heart rate monitoring. Based on the results of the nerve conduction study, the subjects were divided into two groups: those with polyneuropathy (ATTRv-wPN) and those without polyneuropathy (ATTRv-woPN). Age- and sex-matched healthy controls (HC) were used for comparison. Thirty-seven ATTRv subjects (19 with ATTRv-wPN, 18 with ATTRv-woPN) and 41 HC performed the CRTs. Of these 37 subjects with ATTRv, four (11%) presented neurogenic orthostatic hypotension the during head-up tilt test. Based on the results of the CRTs, autonomic dysfunction characterized by either sympathetic or parasympathetic impairment was detected in 37% and 63% of ATTRv-wPN subjects, respectively. Subjects with ATTRv-woPN presented a significant impairment of autonomic responses to the Valsalva manoeuvre compared to the HC (overshoot p = 0.004; Valsalva ratio p = 0.001). Autonomic dysfunctions are frequent in subjects with ATTRv when investigated by means of standardized CRTs, and are also relevant in the pre-symptomatic stage. Cardiovagal functions are the primary functions affected, among others. This may be crucial in defining the proper diagnostic workout for early diagnosis and improving the likelihood of providing the patient with prompt administration of disease-modifying treatments.