Sensory neuropathies encompass a wide spectrum of conditions characterized by sensory loss throughout the body. These neuropathies are broadly categorized into small fiber pain-dominant and large fiber ataxia-predominant types. Accurate classification, based on nerve fiber size and myelination, is crucial for effective treatment and management. Small fiber neuropathies particularly involve the somatic Aδ and unmyelinated C fibers, responsible for transmitting pain and temperature signals, and regulating autonomic functions. Dysfunction of these fibers often manifests as burning, shooting pain, and paresthesia.
Patients commonly describe symptoms as “pins and needles” and “electricity” in the extremities, typically in a stocking-glove distribution. Diagnosis of sensory neuropathy relies heavily on neurophysiological examinations and dermatopathological studies, with skin biopsy currently considered the gold standard for small fiber neuropathy diagnosis. This article aims to enhance healthcare professionals’ proficiency in selecting appropriate diagnostic tests, managing sensory neuropathies, and promoting effective interprofessional collaboration to optimize patient outcomes, with a specific focus on the Axonal Sensorimotor Polyneuropathy Differential Diagnosis.
Objectives:
- Identify the diverse etiologies of sensory neuropathy, with a focus on axonal and sensorimotor types.
- Interpret common physical exam findings associated with sensory neuropathy, differentiating between axonal and other forms.
- Implement evidence-based management options for sensory neuropathy, tailored to the underlying cause and neuropathy type.
- Enhance interprofessional team collaboration in the care of patients with sensory neuropathy to improve patient outcomes.
Introduction
Sensory neuropathies are a diverse group of disorders leading to sensory impairment across the body, arising from a multitude of underlying conditions. These can be broadly divided into pain-predominant small fiber neuropathies and ataxia-predominant large fiber neuropathies. The classification of sensory neuropathy, determined by nerve fiber size and myelination status, guides appropriate treatment and management strategies. Small somatic Aδ and unmyelinated C fibers are particularly relevant in small fiber neuropathies. These fibers are responsible for transmitting noxious and thermal stimuli, and they regulate preganglionic sympathetic and parasympathetic functions (Aδ fibers) and postganglionic autonomic functions (C fibers). [1] Disruption of these fibers’ normal function commonly results in burning and shooting pain accompanied by paresthesia.
Large fiber neuropathies, conversely, result from dysfunction of Aβ fibers, which mediate proprioception, vibration, and touch sensations. Sensory ataxia in these patients often indicates damage to the dorsal columns of the spinal cord and dorsal root ganglia. [2] While ataxia is a hallmark of large-fiber sensory neuropathy, smaller fibers can also be affected subsequently. Consequently, some conditions, such as diabetes mellitus, can lead to mixed etiology polyneuropathies involving both small and large fibers. These mixed neuropathies represent a significant public health concern in modern medicine. [3, 4]
Classic clinical presentations include patient complaints of “pins and needles” sensations and “electricity” in the extremities, following a stocking-glove pattern. [5] The diagnostic evaluation of sensory neuropathy primarily involves neurophysiological examination and dermatopathological assessments, such as skin biopsy, which is the current gold standard for diagnosing small fiber neuropathy. [6] While specific treatment guidelines for sensory neuropathies are not fully established, current management strategies are largely based on expert consensus and well-designed research. Treatment approaches vary based on the underlying etiology and may include intravenous immunoglobulins, methotrexate, corticosteroids, infliximab, plasma exchange, and various oral and topical medications. [7] This article provides a comprehensive review of the evaluation and management of sensory neuropathies, with a particular emphasis on the axonal sensorimotor polyneuropathy differential diagnosis, a crucial aspect for accurate diagnosis and tailored treatment.
Etiology
Identifying the underlying causes of sensory neuropathy is critical for clinicians to deliver timely and effective treatment. When formulating differential diagnoses, the causative factor may not always be immediately apparent. In such cases, idiopathic sensory neuropathy, a diagnosis of exclusion, should be considered, accounting for 20% to 30% of cases. [8] Clinicians should consider a broad spectrum of potential underlying etiologies, including:
- Immune-mediated conditions: Sarcoidosis, Sjögren syndrome, systemic lupus erythematosus, celiac disease
- Metabolic disorders: Diabetes mellitus, hyperlipidemia
- Nutritional deficiencies: Vitamin B12, copper, vitamin E, folic acid [2]
- Toxic exposures: Chemotherapy, drug-induced neuropathy, alcohol
- Hereditary conditions: Hemochromatosis, Fabry disease, Ehlers-Danlos syndrome, Friedreich ataxia
- Infectious agents: Herpes simplex virus, varicella-zoster virus, leprosy, HIV, hepatitis C, cryoglobulinemia
- Other causes: Idiopathic neuropathy, fibromyalgia, vasculitis [9]
Epidemiology
Epidemiological studies estimate the prevalence of sensory neuropathy in the general population to be between 1% and 3%, increasing to approximately 7% in older adults. [8] Lower prevalence rates have been reported in developing countries, potentially due to differences in life expectancy. Globally, Western countries are more frequently affected, with a slight predilection for females. In developing nations, infectious diseases like leprosy are major contributors to neuropathy. Conversely, in Western countries, polyneuropathy is predominantly linked to conditions such as diabetes, excessive alcohol consumption, cytostatic drug use, and cardiovascular disease. [8]
From a public health perspective, diabetes mellitus stands out as the leading global cause of peripheral neuropathy. [10] Up to half of older adults with diabetes mellitus will develop some form of distal peripheral neuropathy, impairing their pain and temperature sensation. Dr. Paul Brand, a pioneering orthopedic surgeon, significantly contributed to the understanding of neuropathy. His work in India highlighted that the loss of peripheral sensation, which he termed the “gift of pain,” was a primary factor in severe scarring and ulceration among patients with Hansen’s disease. Similarly, in the diabetic population, distal peripheral neuropathy is a major risk factor for developing diabetic foot complications. [11, 12]
Pathophysiology
The pathophysiology of sensory neuropathy is diverse, reflecting the wide range of underlying causes:
Diabetes: Hyperglycemia and hyperlipidemia induce oxidative stress, leading to mitochondrial damage and impaired cellular function. Nerve ischemia and compromised nerve fiber repair also contribute to diabetic neuropathy. This cascade of metabolic disturbances creates a cycle of reactive oxygen species (ROS) accumulation, diminished antioxidant defenses, and peripheral nerve damage. [13]
Guillain-Barré syndrome (GBS): While predominantly demyelinating, axonal forms of GBS exist, such as acute motor axonal neuropathy (AMAN). In AMAN, inflammatory cells directly invade axons. [14]
Uremic polyneuropathy: This neuropathy is characterized by both demyelination and axonal degeneration. The precise etiology is not fully understood but may involve deficiencies in thiamine, zinc, and biotin, as well as reduced transketolase activity. [15] Other contributing factors include elevated levels of phenols, myoinositol, beta2-microglobulin, hyperparathyroidism, and hyperkalemia. The distal portions of longer axons are typically affected most severely and earliest. [16]
Vitamin B12 deficiency: This deficiency can cause sensory neuropathy by disrupting myelin production, the fatty sheath that insulates nerves. Insufficient myelin impairs nerve signal transmission, leading to sensory neuropathy symptoms.
Environmental factors: Environmental exposures can significantly impact nerve health, primarily affecting axons. Neuropathies resulting from prolonged cold exposure, vibration-induced nerve damage, or hypoxemia are well-documented. [17]
Sarcoidosis: In sarcoidosis, sensory neuropathy is thought to result from granulomas infiltrating peripheral nerves. These granulomas can compress or disrupt sensory nerve function, causing sensory abnormalities like tingling and numbness. [18]
Varicella-zoster virus (VZV): VZV can enter sensory ganglia and establish latency, leading to chronic inflammation and nerve damage. This can result in sensory neuropathy with pain, tingling, and numbness. [19]
History and Physical Examination
A prominent early symptom of sensory neuropathy is ataxia, primarily due to disruption of afferent neurons that transmit sensory information from the extremities. [20] As symptoms progress, patients may exhibit “writhing” movements in the hands and feet when their eyes are closed. Positive sensory symptoms are also common when small and medium-sized fibers are involved. Classic clinical findings include complaints of “pins and needles” and “electricity” in the extremities, following a stocking-glove pattern. [5] Clinicians, especially when evaluating patients with diabetes, must be vigilant in assessing for negative neuropathic symptoms associated with small-fiber neuropathies, such as numbness, commonly reported in the feet, which can be non-length-dependent and multifocal.
When taking a patient’s history, the variability in disease progression is important to note. Subacute sensory neuropathies are often seen in immune-mediated and post-infectious cases, whereas idiopathic variants tend to be more stable. [21] Motor weakness is often absent in sensory neuropathy. However, paraneoplastic sensory neuropathies may affect motor output, leading to diminished or absent stretch reflexes.
Evaluation
Neurophysiological and Dermatopathological Diagnostic Studies
The evaluation of sensory neuropathy primarily relies on neurophysiological examination and dermatopathological studies like skin biopsy. In small fiber neuropathies, electromyography (EMG) findings may be normal, and the presence of sural and plantar responses does not rule out a purely small fiber neuropathy. In EMG studies, sensory neuropathies typically show reduced or absent sensory nerve action potentials. [22] For patients with diabetic peripheral sensory neuropathy, the Semmes-Weinstein 5.07 monofilament nylon test is frequently used at various foot locations to assess for loss of protective sensation, defined as the inability to perceive 10 g of force. [23]
Demyelination is associated with reduced nerve conduction velocity (slower than 75% of the lower limit of normal) and prolonged distal latency (longer than 130% of the upper limit of normal). It can also cause amplitude changes due to secondary axonal loss. Demyelination is observed in conditions like Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). [24]
Autonomic sensory testing includes quantitative assessments of hot and cold sensation, transient changes in skin electrical potential (e.g., sweat gland activity), and noninvasive electrochemical skin conductance studies to detect sudomotor dysfunction. [25] Thermoregulatory sweat testing and quantitative sudomotor axon reflex testing (QSART) are particularly valuable for small fiber-dominant neuropathy. Although not universally available, recent studies indicate that these tests significantly improve diagnostic accuracy. [26]
Skin biopsy is currently the validated gold standard for diagnosing small fiber neuropathy. [6] Skin biopsy sensitivity can be as high as 90%, with specificity up to 97%, depending on the study. [27] Skin biopsy is advantageous due to its ease of use and low morbidity. Common biopsy sites include the distal leg (10 cm proximal to the lateral malleolus) and the lateral distal or proximal thigh. Nerve biopsy is generally not required for diagnosing sensory neuropathy.
Imaging Studies
Imaging studies also play a role in evaluating sensory neuropathies, particularly in assessing paraneoplastic etiologies. Magnetic resonance imaging (MRI) and specialized sequences like inversion recovery MRI pulse sequencing and T2-weighted spoiled gradient-echo sequencing are particularly useful for visualizing dorsal column pathology. [28]
Treatment / Management
Specific guidelines for sensory neuropathy treatment are not fully defined. Most treatment recommendations are based on expert opinions and well-designed research. Treatments include intravenous immunoglobulins, methotrexate, corticosteroids, infliximab, plasma exchange, and various oral and topical medications, depending on the underlying cause. [7] Recent data suggests that sensory symptoms typically stabilize after 7 to 10 months. [29] Treatment protocols should ideally be initiated within this timeframe if possible.
Several oral medications have demonstrated efficacy compared to placebo in randomized controlled trials for symptomatic relief, including anticonvulsants (e.g., pregabalin and oxcarbazepine), serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., duloxetine and venlafaxine), tricyclic antidepressants, opioids (e.g., tramadol and tapentadol), and botulinum toxin A (with and without chemodenervation). [30, 31] The American Academy of Neurology also recommends topical agents (e.g., lidocaine and capsaicin).
Emerging research is exploring the potential of physical exercise in managing sensory neuropathy secondary to diabetes mellitus. Some studies show increased nerve fiber density in diabetic patients and improved pain response to exercise in those with established neuropathy. [32, 33] These findings are encouraging, especially given the prevalence of diabetic neuropathy compared to rarer etiologies of sensory neuropathy.
Sensory Neuropathy Management Strategies
Specific management strategies for various neuropathies are outlined below. For detailed management information, refer to StatPearls’ companion topics on these neuropathies. [34, 35, 36]
Diabetic neuropathy: Management involves strict glycemic control, risk factor management, and symptom control. Glycemic control aims to maintain blood glucose levels within a target range. Risk factor management addresses hypertension, hyperlipidemia, and smoking cessation. Symptom control can be achieved with medications like duloxetine, amitriptyline, pregabalin, and gabapentin, along with lifestyle modifications and physical therapy. Amitriptyline should be used cautiously in patients with benign prostatic hyperplasia due to the risk of urinary retention.
Guillain-Barré syndrome (GBS): Management includes physical therapy, pain management, and assistive devices. In severe cases, intravenous immunoglobulin or plasmapheresis may be used to reduce inflammation and improve outcomes.
Uremic polyneuropathy: The primary management strategy is to address underlying conditions contributing to uremic polyneuropathy, such as diabetes and hypertension. Medications for symptom management include:
- Gabapentin
- Pregabalin
- Duloxetine
- Tricyclic antidepressants (e.g., amitriptyline)
- Opioids (e.g., tramadol)
Vitamin B12 deficiency neuropathy: Management involves vitamin B12 supplementation.
Chronic inflammatory demyelinating polyneuropathy (CIDP): Initial treatment often involves corticosteroids, followed by intravenous immunoglobulin, plasma exchange, and immunosuppressant drugs.
Differential Diagnosis
Sensory neuropathy has a broad differential diagnosis due to its diverse etiologies. Conditions to consider in the axonal sensorimotor polyneuropathy differential diagnosis include:
- Diabetic neuropathy: The most common cause of peripheral neuropathy, often presenting with distal sensorimotor involvement.
- Alcohol neuropathy: Typically a chronic, length-dependent sensorimotor neuropathy.
- Guillain-Barré syndrome (GBS): An acute inflammatory polyneuropathy, which can have axonal variants, requiring differentiation from other acute neuropathies.
- Charcot-Marie-Tooth disease (CMT): A group of inherited neuropathies, often presenting with sensorimotor features and axonal degeneration.
- Autoimmune neuropathy: Including CIDP and vasculitic neuropathy, which can present with sensory and motor deficits.
- HIV-associated neuropathy: Can manifest as distal sensory neuropathy or sensorimotor polyneuropathy.
- Nutritional deficiencies (e.g., vitamin B12 deficiency): Can cause sensory or sensorimotor neuropathy, needing to be ruled out through lab testing.
- Infectious neuropathy (e.g., Lyme disease or leprosy): Specific infections can lead to both sensory and sensorimotor neuropathies.
- Toxin-induced neuropathy (e.g., arsenic or lead poisoning): Exposure to toxins can result in various types of neuropathy, including sensorimotor axonal forms.
- Distal acquired demyelinating symmetric neuropathy (DADS) and sensory chronic inflammatory demyelinating polyradiculoneuropathy (sensory CIDP): These demyelinating neuropathies need to be differentiated from axonal sensorimotor neuropathies.
In a significant proportion of patients, the cause of sensory neuropathy remains undetermined, classified as idiopathic. [37] Idiopathic sensory neuropathy is a diagnosis of exclusion, and an autoimmune component is suspected in its pathophysiology. [38] It’s also important to differentiate sensory neuropathy from other neurological conditions such as radiculopathies, myelopathies, and other autoimmune diseases that may present with similar symptoms. A thorough neurological examination, electrodiagnostic studies (EMG/NCS), and relevant laboratory investigations are crucial to narrow down the axonal sensorimotor polyneuropathy differential diagnosis and arrive at an accurate diagnosis.
Treatment Planning
Table
Table. Commonly Used Drugs in Sensory Neuropathy.
Prognosis
The prognosis for sensory neuropathy varies significantly depending on the underlying cause and the type of nerve damage. Wallerian degeneration, a process involving complete nerve fiber disintegration, carries a more guarded prognosis. Recovery in such cases depends on nerve regeneration, which is influenced by factors such as the alignment of transected nerve endings and the extent of surrounding tissue injury and scarring. Clinically meaningful recovery requires successful reinnervation of affected muscles and organs following nerve regeneration and remyelination. In contrast, sensory neuropathy caused purely by segmental demyelination generally has a more favorable prognosis, with quicker recovery and functional return. Pain and temperature sensations are typically the first to recover.
For patients with glucose dysregulation and diabetic neuropathy, monitoring hemoglobin A1c levels is crucial for tracking disease progression. Current recommendations from the American Diabetes Association emphasize maintaining HbA1c below 7% in conjunction with a healthy lifestyle (diet and exercise) for individuals with established diabetes. [45]
Complications
Untreated or poorly managed sensory neuropathy can lead to debilitating complications. Patients may experience burns and other traumatic skin injuries due to impaired protective sensation. This sensory loss elevates the risk of infections secondary to these injuries, as they may go unnoticed and untreated promptly. In older adults, the risk of falls increases due to diminished balance and strength.
In patients with diabetes mellitus and concomitant sensory neuropathy, complications are particularly severe and life-altering. Loss of protective sensation can result in patients unknowingly stepping on sharp objects, leading to injuries that may not be detected until bleeding is noticed. These injuries are common in emergency departments and present significant medical challenges.
Severe infections, potentially leading to sepsis and gangrene of the lower extremities due to chronic neuropathic ulcers or retained foreign bodies, are major causes of amputation in people with diabetes. The annual risk of developing diabetic foot ulceration is approximately 2%, but it increases to about 7% in those with sensory neuropathy, highlighting the significant causal link. [12] Effective patient education and a communicative multidisciplinary healthcare team are essential to mitigate these risks.
Deterrence and Patient Education
To effectively deter the progression of sensory neuropathy, clinicians must educate patients about potential signs and symptoms. Lifestyle modifications are crucial upon symptom onset. Patients with established sensory neuropathy should limit exposure to temperature extremes and monitor for changes in gait patterns to minimize repetitive micro-trauma to the feet. Shoe modifications may also be necessary.
For diabetic patients, a daily foot self-examination protocol is essential for early detection of lesions. Regular visits to a podiatric physician every 2 to 3 months for formal evaluation and care are recommended as part of a comprehensive management approach. Primary care physicians and endocrinologists also play vital roles in overall diabetes management and mitigating sensory neuropathy symptoms.
Enhancing Healthcare Team Outcomes
Sensory neuropathy involves peripheral nerve dysfunction, resulting in abnormal sensations or sensory loss. Clinicians must recognize the diverse etiologies, including diabetes, infections, and autoimmune disorders, crucial for effective axonal sensorimotor polyneuropathy differential diagnosis. Diagnosis involves patient history, physical examination, and nerve conduction studies if indicated. Management focuses on treating the underlying cause, providing symptomatic relief, and recommending lifestyle modifications. Regular monitoring for complications and patient education on self-care are essential components of care. A holistic approach, considering both physical and emotional aspects, is crucial for optimal patient outcomes in sensory neuropathy, a condition that significantly impacts sensory perception and daily life.
Access to healthcare is not universally equitable, emphasizing the need for evidence-based treatment delivered through an interprofessional team approach. Patient education is paramount in preventing sensory neuropathy-related morbidities. Neurologists, vascular surgeons, physical and occupational therapists, infectious disease specialists, endocrinologists, and podiatric physicians each contribute essential expertise and tools to combat this condition and its symptoms.
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References
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