Efficacy and Safety of Deep Cervical Lymph Node-vein Bypass Surgery in ALS Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the simultaneous involvement of upper and lower motor neurons, leading to progressive muscle atrophy and weakness in patients. Advanced stages of the disease manifest as symptoms such as swallowing difficulties and respiratory problems. Currently, effective treatments for ALS are lacking, and most patients succumb to the disease within 3 to 5 years of onset. Therefore, there is an urgent need to explore new therapeutic approaches. Although the exact pathogenesis of ALS remains unclear, various mechanisms including oxidative stress, glutamate toxicity, mitochondrial dysfunction, endoplasmic reticulum stress, and protein misfolding are thought to contribute to its development. Pathological findings indicate the presence of abnormal protein deposits, including phosphorylated TDP-43 (Transactive response DNA-binding protein 43 kDa), superoxide dismutase 1 (SOD1), and dysfunctional ribosomal proteins, in the brains and spinal cords of ALS patients. Additionally, elevated levels of neurotoxic factors in the cerebrospinal fluid, such as inflammatory cytokines and reactive oxygen species, have been implicated in the pathogenesis of ALS. Therefore, clearance of abnormal proteins and neurotoxic factors from the brain and spinal cord may have potential therapeutic implications for delaying or preventing neurodegeneration and associated clinical disabilities in ALS patients.

Recently, the discovery of the brain "glymphatic-lymphatic" system has updated our understanding of cerebrospinal fluid circulation. Similar to the peripheral lymphatic circulation, there exists an interstitial fluid circulation system in the brain parenchyma. Studies have revealed that cerebrospinal fluid in the brain parenchyma enters the perivascular spaces surrounding arteries through aquaporin-4 channels on astrocytes and then flows directionally into the perivascular spaces surrounding veins, facilitating waste clearance and nutrient transport in the brain. This phenomenon is known as the glymphatic system. Furthermore, abundant lymphatic vessels have been found adjacent to the dural venous sinuses, participating in cerebrospinal fluid drainage and ultimately draining into the cervical lymph nodes. In animal models of Alzheimer's disease (AD) and Parkinson's disease (PD), impairment of the glymphatic-lymphatic drainage function has been associated with the accumulation of disease-related proteins such as amyloid beta (Aβ), Tau, and alpha-synuclein, and ligating the cervical lymph nodes has been shown to exacerbate disease progression. Clinical studies using magnetic resonance imaging have confirmed the decline in glymphatic-lymphatic system function in patients with AD and PD. Although research on the role and mechanism of the glymphatic-lymphatic drainage system in the occurrence and development of ALS is lacking, magnetic resonance imaging has revealed a significant reduction in glymphatic system function in ALS patients compared to healthy individuals, suggesting an important role of the glymphatic-lymphatic drainage system in the pathogenesis of ALS.

As the final destination of glymphatic-lymphatic cerebrospinal fluid drainage, the cervical lymph nodes play a crucial role in the entire cerebrospinal fluid circulation. With aging, infection, and chronic inflammation, the function of the cervical lymph nodes gradually declines, leading to increased cerebrospinal fluid circulation reflux pressure. Furthermore, the production of large amounts of neurotoxic substances during the progression of AD, PD, and ALS further impairs the function of the cervical lymph nodes, resulting in abnormal accumulation of toxic substances in the brain and disease progression. We speculate that establishing drainage connections between the cervical lymphatic vessels and veins will reduce cerebrospinal fluid circulation pressure in brain tissues, accelerate interstitial fluid reflux, and alleviate the accumulation of metabolic waste, thereby slowing the progression of neurodegenerative diseases.

• Baseline of slow vital capacity (SVC) [Time frame: Pre-surgery and post-surgery 1month, 3 months, 6 months and 1 year]
• Evaluation of glymphatic and meningeal lymphatic drainage [Time frame: Pre-surgery and post-surgery 3 months, 6 months and 1 year]
• Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) [Time frame: Pre-surgery and post-surgery 3 months, 6 months and 1 year]