Sensory Neuropathy

Etiology

Recognizing the varying causative factors directly associated with sensory neuropathy is paramount to providing prompt and effective treatment as a clinician. When generating differential diagnoses, a direct causative factor may not be readily apparent, and a diagnosis of exclusion (ie, idiopathic sensory neuropathy) must merit consideration, as this constitutes 20% to 30% of cases.[8] Clinicians should consider a comprehensive list of potential underlying etiologies, including:

• Immune-mediated conditions: sarcoidosis, Sjögren syndrome, systemic lupus erythematosus, celiac disease
• Metabolic: diabetes mellitus, hyperlipidemia
• Nutritional deficiencies: vitamin B12, copper, vitamin E, folic acid [2]
• Toxic: chemotherapy, drug-induced, alcohol
• Hereditary: hemochromatosis, Fabry disease, Ehlers-Danlos syndrome, Friedreich ataxia
• Infectious: herpes simplex, varicella-zoster virus, leprosy, HIV, hepatitis C, cryoglobulinemia
• Other: idiopathic, fibromyalgia, vasculitis [9]

Epidemiology

Studies that have assessed the incidence of sensory neuropathy in the general population report a range of 1% to 3% prevalence, with an increase of up to 7% in older adults.[8] Studies have shown that developing countries exhibit a lower prevalence, which may, in part, be due to variations in life expectancy. From a global perspective, Western countries are most commonly affected, with a slight preference towards females. In developing countries, infectious diseases like leprosy are the predominant causes of neuropathy. In contrast, in Western countries, polyneuropathy is predominantly associated with several conditions, including diabetes, alcohol overconsumption, cytostatic drugs, and cardiovascular disease.[8]

From a public health standpoint, clinicians should be aware that diabetes mellitus is the leading cause of peripheral neuropathy worldwide.[10] Up to 50% of older patients with diabetes mellitus will acquire some form of distal peripheral neuropathy, which affects their sense of pain and temperature discrimination. A pioneering orthopedic surgeon, Dr. Paul Brand, was renowned for his work on neuropathy, which was inspired after working in India, where he noticed that the loss of peripheral sensation ("gift of pain") was the reason his patients with Hansen disease suffered from severe scarring and ulceration. Similarly, in the diabetic population, distal peripheral neuropathy is a major risk factor in developing diabetic foot complications.[11][12]

Pathophysiology

The pathophysiology of sensory neuropathy varies according to the cause, including:

Diabetes: Excess glucose and lipids lead to oxidative stress, which damages mitochondria and disrupts normal cellular function. Nerve ischemia and impaired nerve fiber repair also contribute to diabetic neuropathy. These metabolic impairments lead to a vicious cycle of ROS accumulation, reduced antioxidant defense, and peripheral nerve damage.[13]

Guillain-Barré syndrome: This neuropathy is predominantly demyelinating, but axonal forms also exist, such as acute motor axonal polyneuropathy (AMAN), where the primary invasion of axons by inflammatory cells.[14]

Uremic polyneuropathy: Demyelination and axonal degeneration characterize this neuropathy. The cause is unknown, but it may be related to thiamine, zinc, biotin deficiencies, and decreased transketolase activity.[15] Other contributing factors include increases in phenols, myoinositol, beta2-microglobulin, hyperparathyroidism, and hyperkalemia. The changes are most severe distally, and longer axons are affected first.[16]

Vitamin B12 deficiency: Sensory neuropathy can be caused by this vitamin deficiency due to myelin production interference, the fatty substance that surrounds and insulates nerves. Without enough myelin, nerve signals are not transmitted efficiently, leading to the symptoms of sensory neuropathy.

Environmental: Environmental factors can significantly impact nerve health, causing disorders primarily affecting axons. For example, neuropathies resulting from prolonged exposure to cold, vibration-induced nerve damage, or hypoxemia are well-documented.[17]

Sarcoidosis: Sensory neuropathy in sarcoidosis is believed to be caused by infiltrating granulomas in peripheral nerves. The granulomas can compress or disrupt the normal function of sensory nerves, leading to sensory abnormalities (eg, tingling and numbness).[18] 

Varicella-zoster virus: The virus can enter the sensory ganglia and establish latency, leading to chronic inflammation and nerve damage. This can result in sensory neuropathy and characteristic symptoms of pain, tingling, and numbness.[19]

History and Physical

One of the most distinct symptoms of sensory neuropathy is early-onset ataxia, mainly due to the disruption of the afferent neurons, which transmit impulses from the body's extremities.[20] If these symptoms progress, resultant "writhing" movements will manifest in the hands and feet as the patient closes their eyes. Positive sensory symptoms are also common when small- and medium-sized fibers are affected. Classic clinical findings include complaints of "pins and needles" and "electricity" in the affected extremities, which follow a stocking-glove pattern.[5] Especially in people with diabetes, a clinician must be vigilant in assessing for negative neuropathic symptoms manifest in small-fiber neuropathies. Numbness, a negative neuropathic symptom, is commonly seen in the feet and is non-length dependent and multifocal.

When performing a clinical history, variability in disease progression will be significant. Subacute sensory neuropathies are commonly seen in immune-mediate and post-infectious cases, whereas idiopathic variants are more stagnant.[21] In many cases, motor weakness does not accompany sensory neuropathy. However, the motor output may be affected in those with paraneoplastic sensory neuropathies, resulting in absent stretch reflexes.

Evaluation

Neurophysiological and Dermatopathological Diagnostic Studies

Evaluation of sensory neuropathy primarily revolves around neurophysiological examination and dermatopathological studies such as skin biopsy. When diagnosing small fiber neuropathies, electromyography (EMG) results may appear normal, and the presence of sural and plantar responses does not exclude purely small fiber neuropathy. In EMG studies, sensory neuropathies mostly demonstrate a reduced or absent sensory nerve action potential.[22] For patients with diabetic peripheral sensory neuropathy, a Semmes-Weinstein 5.07 monofilament nylon test is often performed at varying locations of the foot to test for a protective threshold previously defined as 10 g of force.[23]

Demyelination is linked to a reduction in conduction velocity, which is slower than 75% of the lower limit of normal. Additionally, it can cause marked prolongation of distal latency, which is longer than 130% of the upper limit of normal. Demyelination can also result in amplitude changes due to secondary axonal loss. Demyelination can occur in Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy.[24]

Regarding autonomic sensory testing, quantitative exams assess for hot and cold sensations, transient changes in the electrical potential of the skin (eg, sweat gland activity), and noninvasive electrochemical skin conductance studies to detect sudomotor dysfunction.[25] Some of the most valuable studies for small fiber-dominant neuropathy are thermoregulatory sweat testing and the quantitative sudomotor axon reflex test. Though these studies are not readily available, recent literature shows that their clinical additions yield higher diagnostic success.[26]

The current validated gold standard for diagnosing small fiber neuropathy is a skin biopsy.[6] Depending on the research, sensitivities for skin biopsy can be as high as 90%, with specificities as high as 97%.[27] The benefits of skin biopsy include ease of use and low morbidity. Common sites of the acquisition include the distal leg, just 10 cm proximal to the lateral malleolus, and the lateral distal or proximal thigh. In general, nerve biopsy is not necessary to diagnose sensory neuropathy.

Imaging Studies

Imaging studies are also used to evaluate sensory neuropathies and are of greatest utility when assessing paraneoplastic etiologies. Magnetic resonance imaging and its analogs, inversion recovery MRI pulse sequencing, and T2-weighted spoiled gradient-echo sequencing are particularly useful in visualizing dorsal column pathology.[28]

Treatment / Management

Guidelines on specific treatment modalities for sensory neuropathies have not been defined. The majority of the data regarding treatments are based on expert opinions, along with well-constructed research. Treatments include injection of intravenous immunoglobulins, methotrexate, corticosteroids, infliximab, plasma exchange, and various oral topical medications, depending on the etiology.[7] Recent data suggest that sensory symptomatology generally plateaus after 7 to 10 months.[29] If possible, treatment protocols should be initiated within this period.

The efficacy of various oral medications, including anticonvulsants (eg, pregabalin and oxcarbazepine), serotonin-norepinephrine reuptake inhibitors (eg, duloxetine and venlafaxine), tricyclic antidepressants, opioids (eg, tramadol and tapentadol), and botulinum toxin A with and without chemodenervation have demonstrated more effectiveness than a placebo in numerous randomized controlled trials.[30][31] The American Academy of Neurology has also recommended topical agents (eg, lidocaine and capsaicin).(A1)

Future clinical avenues for research are promising for the utility of physical exercise in sensory neuropathy secondary to diabetes mellitus. Some current studies show increased nerve fiber density in patients with diabetes mellitus and measured pain response to exercise in those with established neuropathy.[32][33] Results such as these are encouraging and much warranted as the general etiologies of sensory neuropathy are considered rare compared to those cases caused by diabetes mellitus, which is far more widespread.(B3)

Sensory Neuropathy Management

The following are some management strategies for specified neuropathies. See StatPearls' companion topics on the following neuropathies for detailed management information.[34][35][36]

Diabetic neuropathy: The management involves tight glycemic control, risk factor management, and symptom control. Tight glycemic control includes maintaining blood glucose levels within a target range. Risk factor management involves addressing factors such as hypertension, hyperlipidemia, and smoking. Symptom control can be achieved using medications such as duloxetine, amitriptyline, pregabalin, and gabapentin, along with lifestyle modifications and physical therapy. Amitriptyline should be avoided in patients with benign prostatic hyperplasia as it can cause urinary retention.

Guillain-Barre syndrome: Management includes physical therapy, pain management, and assistive devices. In severe cases, intravenous immunoglobulin or plasmapheresis may reduce inflammation and improve outcomes.

Uremic polyneuropathy: The most crucial management plan is to control underlying conditions contributing to the development of uremic polyneuropathy, such as diabetes and hypertension. Medications that may be used to manage symptoms of Uremic polyneuropathy include:

• Gabapentin
• Pregabalin
• Duloxetine
• Tricyclic antidepressants (eg, amitriptyline)
• Opioids (eg, tramadol)

Vitamin B12 deficiency: This neuropathy is managed through replacement with vitamin B12 supplementation.

Chronic inflammatory demyelinating neuropathy: Corticosteroids are used to treat this neuropathy initially but can also be treated using intravenous immunoglobulin, plasma exchange, and some immunosuppressant drugs.

Differential Diagnosis

Sensory neuropathy can have various underlying causes. Differential diagnoses that should be considered include:

• Diabetic neuropathy
• Alcohol neuropathy
• Guillain-Barre syndrome
• Charcot-Marie-Tooth disease
• Autoimmune neuropathy
• HIV-associated neuropathy
• Nutritional deficiencies (eg, vitamin B12 deficiency)
• Infectious neuropathy (eg, Lyme disease or leprosy)
• Toxin-induced neuropathy (eg, arsenic or lead poisoning)

In a substantial portion of patients, the exact cause of sensory neuropathy is not readily apparent, and the disease is considered idiopathic.[37] Literature suggests that idiopathic sensory neuropathy is a diagnosis of exclusion and that there may be an autoimmune component of the pathophysiology behind the disease.[38] Other diseases that may present in a similar clinical fashion include distal acquired demyelinating symmetric neuropathy and sensory chronic inflammatory demyelinating polyradiculoneuropathy. These symptoms may also mimic other radiculopathies, myelopathies, and autoimmune diseases.

Treatment Planning

Table. Commonly Used Drugs in Sensory Neuropathy

Prognosis

Outcomes for patients who suffer from different forms of sensory neuropathy will vary. When Wallerian degeneration occurs, a series of events leads to complete structural and chemical disintegration of the nerve, resulting in a more guarded prognosis. Recovery is contingent on the regeneration of the nerve, depending largely upon how well the transected nerve endings are aligned, as well as the severity of any adjacent soft tissue injury and scarring. To achieve a noticeable clinical outcome, the affected muscles and organs must become reinnervated after adequate nerve regeneration and remyelination occurs. If the pathology causing any sensory neuropathic symptoms is purely due to segmental demyelination, the prognosis will be much more positive. This is because it entails a shorter recovery and quicker return to function. Pain and temperature are typically the first sensations to recover.

Regarding those patients with glucose dysregulation, monitoring their hemoglobin A1c lab values is vital to track the progression of the disease. Current recommendations from the American Diabetes Association underscore maintenance of a value less than 7% in conjunction with a healthy lifestyle (ie, diet and exercise) for those with established diabetes.[45]

Complications

The results can be debilitating if sensory neuropathy is not managed within an acute time frame. Patients will often suffer from varying degrees of burns and other traumatic dermal injuries due to the lack of protective sensation. This sensory loss, in turn, increases the risk of infection secondary to these traumatic events, as these injuries are usually not treated quickly and efficiently. In older populations, the risk of accidental falls increases as balance and strength diminish.

Again, in patients with diabetes mellitus who present with concomitant sensory neuropathy, the complications are significant and life-altering. As a protective threshold is lost, it is not uncommon for patients to step on a sharp object such as glass or a rusty nail and remain unaware until they notice bleeding from their socks. These injuries are prevalent in the emergency room and constitute a significant challenge for the medical team.

Severe infections leading to sepsis and gangrene of the lower extremities due to chronic neuropathic ulcerations or retention of a foreign body is a leading cause of amputation in people with diabetes. The overall risk of developing diabetic foot ulceration is around 2% per year; that statistic increases to about 7% in those with sensory neuropathy, a staggering causal finding.[12] Proper patient education with a communicative multidisciplinary healthcare team mitigates these risks.