Disorders of the Peripheral Nervous System: Mechanisms, Clinical Manifestations, and Therapeutic Strategies

Peripheral neuropathy represents a heterogeneous group of disorders caused by damage to the peripheral nervous system, the extensive network of nerves responsible for transmitting sensory, motor, and autonomic signals between the central nervous system and the rest of the body. These conditions are characterized by combinations of sensory loss, neuropathic pain, muscle weakness, and autonomic dysfunction, most commonly affecting the distal portions of the upper and lower limbs.

What Is Peripheral Neuropathy?

Peripheral neuropathy refers to structural or functional impairment of peripheral nerves. Depending on the fibers involved, the condition may affect sensory perception, voluntary muscle control, or autonomic regulation. In many patients, multiple fiber types are involved simultaneously, leading to complex clinical pictures.

Neuropathic involvement often follows a length-dependent pattern, meaning that the longest nerves are affected first. For this reason, symptoms typically begin in the toes or fingers and gradually progress proximally, producing the characteristic “stocking-and-glove” distribution.

Causes of Peripheral Neuropathy

Peripheral neuropathy has a broad etiological spectrum, with metabolic disorders representing the most frequent cause in clinical practice. Chronic hyperglycemia leads to structural nerve damage through oxidative stress, microvascular dysfunction, and inflammatory mechanisms.

Other important causes include traumatic nerve injury from compression, stretching, or transection, which may occur following accidents, surgical procedures, or space-occupying lesions such as tumors. Prolonged nerve compression can also develop in compartment syndromes, where increased tissue pressure compromises neural perfusion.

Certain infections are well-recognized triggers of neuropathy. Viral, bacterial, and post-infectious immune-mediated mechanisms can all lead to peripheral nerve involvement. Exposure to neurotoxic substances, chronic alcohol consumption, and nutritional deficiencies further contribute to nerve degeneration.

Inherited neuropathies are less common but clinically relevant. These conditions arise from genetic mutations affecting myelin structure or axonal transport, leading to slowly progressive, often symmetric neuropathic symptoms beginning in childhood or early adulthood.

Symptoms of Peripheral Neuropathy

Clinical manifestations depend on the number and type of nerves involved:

Mononeuropathy affects a single nerve and produces localized symptoms restricted to its anatomical territory. Patients may experience focal numbness, tingling, weakness, or pain.

Multiple mononeuropathy involves sequential or simultaneous damage to several individual nerves, often with asymmetric distribution.

Polyneuropathy is the most common pattern and typically presents as bilateral, symmetric involvement of distal extremities.

Sensory symptoms are often the earliest and most prominent features. Patients describe numbness, tingling, reduced sensitivity to touch or temperature, and neuropathic pain with burning, stabbing, or electric qualities. Pain may intensify at rest or during the night.

Motor involvement manifests as muscle weakness, reduced coordination, difficulty with fine movements, muscle cramps, and progressive muscle wasting. Gait instability and increased risk of falls are frequent in advanced stages.

Autonomic nerve involvement may lead to abnormal sweating, altered heat tolerance, blood pressure instability, gastrointestinal dysmotility, and urinary or bowel dysfunction, significantly affecting quality of life.

Diagnosis of Peripheral Neuropathy

Accurate diagnosis requires careful clinical correlation and targeted investigations. A detailed medical history and neurological examination establish the distribution and functional impact of nerve involvement.

Electrodiagnostic testing plays a central role. Nerve conduction studies and electromyography differentiate axonal from demyelinating processes, assess severity, and identify the pattern of nerve damage.

Laboratory investigations help identify underlying causes by evaluating metabolic, autoimmune, infectious, and endocrine disorders. In selected cases, imaging studies or genetic testing may be required to clarify etiology.

Treatment of Peripheral Neuropathy

Management focuses on treating the underlying cause whenever possible. Correction of metabolic abnormalities, treatment of infections, removal of compressive lesions, or immune modulation may halt or slow disease progression.

Symptomatic treatment aims to reduce neuropathic pain and improve functional capacity. Pharmacological approaches are combined with physical therapy, balance training, and neuromodulation techniques to support nerve function and prevent complications.

In chronic cases, multidisciplinary care is essential, addressing pain control, mobility preservation, fall prevention, and management of autonomic symptoms. Early intervention improves long-term outcomes and reduces irreversible nerve damage.

Scientific references

1. Martyn CN, Hughes RA. Epidemiology of peripheral neuropathy. Journal of Neurology, Neurosurgery & Psychiatry. 1997;62(4):310–318.

2. Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. The Lancet Neurology. 2012;11(6):521–534.

3. Tesfaye S, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285–2293.

4. England JD, et al. Practice parameter: evaluation of distal symmetric polyneuropathy. Neurology. 2009;72(2):177–184.

5. Feldman EL, et al. Advances in the pathogenesis and management of diabetic peripheral neuropathy. Diabetes/Metabolism Research and Reviews. 2019;35(2):e3107.