From the Guidelines
The earliest manifestations of neurotrophic disorders, such as neuropathic corneal pain, include peripheral sensitization initiated by corneal nerve injury and subsequent inflammation, which can be alleviated by therapeutic strategies targeting neuronal regeneration, such as autologous serum tears (AST) or nerve growth factor (NGF) 1.
Key Manifestations
- Decreased corneal sensitivity
- Persistent epithelial defects
- Mild corneal haze
- Irregular tear film
- Increased tear break-up time
- Punctate epithelial erosions primarily in the lower third of the cornea These manifestations occur due to impaired trigeminal nerve function, reducing protective reflexes and trophic factors necessary for corneal epithelial integrity and healing.
Pathophysiology
The corneal epithelium becomes compromised due to decreased metabolic activity and mitosis, leading to epithelial breakdown.
Other Neurotrophic Disorders
In contrast, Fabry disease, another neurotrophic disorder, presents with episodic acroparesthesias, constant burning pain and tingling, especially in the feet and hands, as early as age 2, related to small-fiber involvement in the peripheral nervous system 1.
Clinical Approach
Early intervention is critical, as neurotrophic disorders can progress to more severe stages involving stromal involvement, corneal ulceration, and even perforation if left untreated.
Treatment
Treatment at this early stage typically involves aggressive lubrication with preservative-free artificial tears, overnight lubricating ointments, and possibly punctal occlusion to maintain corneal surface moisture and promote epithelial healing. In summary, the earliest manifestations of neurotrophic disorders, such as neuropathic corneal pain, can be identified and treated with therapeutic strategies targeting neuronal regeneration, such as AST or NGF, to prevent progression to more severe stages 1.
From the Research
Earliest Manifestations of Neurotrophic Disorders
The earliest manifestations of neurotrophic (nerve growth factor) disorders can be understood by examining the role of nerve growth factor (NGF) in the pathophysiology of various neurological conditions.
- NGF is critical for the survival and maintenance of sensory neurons, and its dysregulation has been implicated in the sensitization of pain pathways 2.
- Peripheral neuropathies, which may include various subpopulations of motor, sensory, or autonomic neurons, are likely to be the first group of neurological disorders to be successfully treated with growth factors 3.
- Decreased NGF in leprosy skin may explain cutaneous hypoalgesia even with inflammation, and recombinant human NGF (rhNGF) may restore sensation 4.
- NGF is depleted in early human diabetic neuropathy skin, in correlation with dysfunction of nociceptor fibers, suggesting that rhNGF prophylaxis may prevent diabetic foot ulceration 4.
Neurotrophic Factors and Their Receptors
Neurotrophic factors, including NGF, brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF), play key roles in the pathophysiological mechanisms of human neuropathies.
- Mutations of the NGF high-affinity receptor tyrosine kinase A (TrkA) have been found in congenital insensitivity to pain and anhidrosis 4.
- NGF and BDNF are known to modulate immune cell function and thus serve as mediators in the reciprocal cross-talk between neurons and immune cells 5.
- Physiological combinations of NGF, NT-3, and GDNF may provide a novel 'homeostatic' approach to prevent the development and ameliorate intractable neuropathic pain 4.
Clinical Trials and Therapeutic Strategies
Recent clinical trials have explored the therapeutic properties of NGF in various neurological conditions.
- Therapeutic approaches employing neutralizing antibodies and molecule inhibitors have been highly effective at both preclinical and clinical levels 2.
- Clinical trials have been conducted to evaluate the efficacy of NGF in the treatment of diabetic neuropathy, with mixed results 4.
- NGF has been shown to possess important therapeutic properties, including the prevention of death of NGF-receptive cells, and has been used to treat human cutaneous pressure ulcer, corneal ulcers, and other conditions 6.