Peripheral neuropathy overview

# Overview

# Classification
Peripheral neuropathy may be classified according to the number and distribution of nerves affected into three groups: Mononeuropathy, Mononeuritis multiplex and Polyneuropathy.It may also be classified according to the type of nerve fiber predominantly affected into three groups: Motor, sensory and Autonomic. peripheral neuropathy may also be classified according to the process affecting the nerves into three groups: Inflammatory neuritis, compression neuropathy andchemotherapy-induced peripheral neuropathy.

# Pathophysiology
The pathophysiologic processes that can adversely affect peripheral nerves is very extensive. Processes which can damage the peripheral nerves at multiple levels via many molecular pathways include: Immunologic, metabolic, genetic, infectious, toxic and traumatic processes. Any pathologic process affecting the cell body will result in downstream degeneration of the cell's axon. Primary motor neuron diseases, such as ALS or SMA, demonstrate axonal pathology peripherally when central neurons degenerate. Similarly, metabolic conditions, such as diabetes, the metabolic syndrome, nutritional deficiencies, or chronic renal failure, affect DRG cell bodies by mechanisms involving insulin resistance, oxidative stress, and apoptosis. Pathologic damage may also be considered to take place directly at the axon, independent of the cell body. Schwann cells and the myelin sheath are often selectively targeted in immune-mediated processes such as GBS, CIDP, paraproteinemias, and their variants. It is theorized that a phenomenon of molecular mimicry occurs in these diseases, wherein glycoprotein epitopes found in myelin bear structural similarity to those found in other infectious agents. Immune recognition of these pathogens then spreads to include normal epitopes on the myelin sheath. Pathologic studies reveal both humoral and cellular immune activation and lymphocytic infiltration with patchy demyelination and remyelination. A number of GBS variants which are more prevalent in Asia and Central/South America also damage axons along with myelin, and are commonly associated with Campylobacter jejuni infection. Hereditary neuropathies can also affect both axons and/or their myelin sheaths. The most common type, hereditary motor sensory neuropathy (HMSN or Charcot-Marie-Tooth disease), is classified into many clinical subtypes. Many other genetic syndromes also produce varying disruption of Schwann cell, axon and/or neuronal function. Both the Schwann cells and axons of the peripheral nerve depend upon delicate vasa nervorum for perfusion and metabolic support. Many metabolic and inflammatory processes, while directly affecting peripheral nerves and neuronal cell bodies, can also result in damage to nerve vasculature and indirectly produce ischemic damage, particularly to axons. Primary vasculitides as well as other rheumatologic disorders (systemic lupus erythematosus, Sjogren's syndrome, nonsystemic vasculitis of the peripheral nerves, etc.)

# Causes
Diabetes mellitus is the most common cause of peripheral neuropathy in developed countries. As a summary; aside from diabetes (see Diabetic neuropathy), the common causes of neuropathy are herpes zoster infection, HIV-AIDS, toxins, alcoholism, chronic trauma (such as repetitive motion disorders) or acute trauma (including surgery), various neurotoxins and autoimmune conditions such as celiac disease, which can account for approximately 16% of small fiber neuropathy cases. Neuropathic pain is common in cancer as a direct result of the cancer on peripheral nerves (e.g., compression by a tumor), as a side effect of manychemotherapy drugs, and as a result of electrical injury. In many cases the neuropathy is idiopathic, meaning no cause is found.  A form of spinal nerve entrapment called Posterior Rami Syndrome can led to neuropathic pain. Other common causes of peripheral neuropathy may include: Friedreich's ataxia, Charcot-Marie-Tooth syndrome, Chronic renal failure, Porphyria, Amyloidosis, Liver failure, Hypothyroidism, Alcoholism, Vincristine, Phenytoin, Procarbazine, Isoniazid, Altretamine, Guillain-Barre syndrome, Systemic lupus erythematosus, Leprosy, Sjogren's syndrome, Vitamin deficiency states(vitamin B12, Vitamin A, vitamin E, thiamin), malignant disease and Radiation.

# Differentiating peripheral neuropathy from Other Diseases
Peripheral neuropathy must be differentiated from other diseases that cause , sensorineural, motor, autonomic and balance problems, such as spinal cord lesions and brain lesions. Peripheral neuropathy usually causes lower motor nerve damage, while lesions in brain and spinal cord usually cause lower motor neuron damage. The difference between upper and lower motor neuron symptoms and signs may be very helpful to differentiate peripheral neuropathy from brain and spinal cord lesions. Lower motor neuron signs and symptoms in peripheral neuropathy typically present with diminished deep tendon reflexes, flaccid paralysis, severe muscle atrophy, negative babinski reflex andfasciculation whereas upper motor neuron signs and symptoms in brain and spinal cord lesions typically present with hyperactive deep tendon reflexes, spastic paralysis, no muscle atrophy, positive babinski reflex and no fasciculation.

# Epidemiology and Demographics
The prevalence of the peripheral neuropathy is approximately 2400 per 100,000 to 7000 per 100,000 individuals depending on the region. The case-fatality rate of the peripheral neuropathy is very low. Patients of all age groups may develop peripheral neuropathy. The incidence of peripheral neuropathy increases with age. Peripheral neuropathy affects men more then women. The males develop neuropathy earlier than the females.

# Risk Factors
The most potent risk factor in the development of peripheral neuropathy is diabetes mellitus . Common risk factors in the development of peripheral neuropathy may be occupational, environmental, genetic, and viral. Common risk factors in the development of peripheral neuropathy include: Alcohol abuse, vitamin deficiencies (thiamin, cobalamin), environmental Stress, infections (lyme disease, Shingles, Epstein-Barr virus, Hepatitis C, HIV), kidney disease, Liver disease, genetic diseases, Amyloidosis, Cancer, Dyslipidemia, Family history of neuropathy, repetitive motion, Thyroid disorders, immune system disorders (guillian-Barre syndrome, Chronic inflammatory demyelinating polyneuropathy, charcot-Marie Tooth, Celiac disease, Lupus, Rheumatoid arthritis) and Drugs.

# Screening
Annual screening for peripheral neuropathy is recommended every year among patients with diabetes mellitus by: Semmes-Weinstein monofilament examination, Superficial pain sensation testing, vbration testing by the on-off method and vibration testing by the timed method. The reported operating characteristics for each sensory modality can be applied to positive findings on the physical examination of individual patients to predict the likelihood of neuropathy. Semmes-Weinstein monofilament examination is an appropriate, cheap and easy to use tool for identifying patients at risk of having neuropathy in primary care setting in patients with diabetes mellitus. The 1 g monofilament and total Norfolk quality of life diabetic neuropathy are effective, low-cost tools for the early detection of diabetic peripheral neuropathy. The 128 Hz tuning fork and 10 g monofilament may assist diabetic peripheral neuropathy screening as a tandem, but not primary, early diabetic peripheral neuropathy detection screening tools.

# Natural History, Complications, and Prognosis
The symptoms of peripheral neuropathy usually start with symptoms such as numbness, prickling or tingling in feet or hands, which can spread upward into legs and arms. The symptoms of peripheral neuropathy typically develop five years after diagnosis of diabetes mellitus. Fifty percent of people with diabetes eventually develop diabetic peripheral neuropathy. Common complications of peripheral neuropathy include: Foot ulcers, Gangrene of the limbs from infected wounds, Amputation from infected wounds, Cardiovascular automatic neuropathy, Gastroparesis, Bladder control loss, Fecal incontinence and Ataxia and frequent falls. Peripheral neuropathy may worsen over time. Very few forms of peripheral neuropathy are fatal: Cardiac autonomic neuropathy is a frequent chronic complication of diabetes mellitus with potentially life-threatening outcomes.

# Diagnosis

## Diagnostic Study of Choice
There is no single diagnostic study of choice for the diagnosis of peripheral neuropathy, and peripheral neuropathy can be diagnosed based on the exact pathophysiology witch affects the peripheral nerves.

## History and Symptoms
Patients with peripheral neuropathy may have a positive history of: Metabolic disorder, long-standing illness, childhood clumsiness, unsteady gait and falls, Neurological diseases, neurological diseases, occupational inorganic lead exposure and Malignancy. The most common symptoms of peripheral neuropathy include: Gradual progressive numbness, Prickling or tingling in feet and hands, Burning pain in extremities, extreme sensitivity to touch, Ataxia, frequent falls, muscle weakness or paralysis, Constipation, diarrhea, early satiety, nausea, problems controlling bowel movements, Swallowing problems, Abdomen distention,Vomiting, impaired heart rate, resting tachycardia, exercise intolerance, abnormal blood pressure regulation, orthostatic hypotension, Heat intolerance and altered sweating, urine incontinence, pain (usually from optic neuritis), Vision loss, Visual field los, loss of color vision and flashing lights.

## Physical Examination
Testing for peripheral neuropathy may include: Gross light touch, pinprick sensation test, gait tests, a 128-Hz tuning fork placement at the base of the great toenail, semmes-Weinstein monofilament, deep tendon reflexes tests, muscle Strength Grading ( Motor testing, muscle strength grading, manual muscle testing), tinel testing (Paresthesias or pain suggests median nerve injury), cranial nerve testing, anal sphincter tone test, cardiovascular reflexes, pupillary reflexes. The 2 tests should be performed at least every year for patients with diabetic peripheral neuropathy.Patients with peripheral neuropathy usually appear normal. In vital signs examination  these findings may be seen: High-grade or low-grade fever, hypothermia or hyperthermia, tachycardia with regular pulse or irregular pulse, bradycardia with regular pulse or regularly irregular pulse, tachypnea or bradypnea, high or low blood pressure with normal pulse pressure or wide pulse pressure or narrow pulse pressure. In physical examination of the skin of patients with peripheral neuropathy these finding may be present: skin dryness, calluses, bruises, skin color changes.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of peripheral neuropathy according to the common causes of it, include: Blood glucose, HbA1c, Thyroid function tests, BUN, cr eatinine, serum calcium, K, Na, CL,CBC; serum vitamin B12, plasma vitamin B6, plasma vitamin B6,  vitamin B1, serum vitamin E, serum folate, Lead, Arsenic, Mercury, 24-hour urine heavy metals panel ,Calcium channel autoantibodies to rule out eaton lambert disease, anti acidic glycosphingolipids sialosyl paragloboside antibodies, anti sialosyl lactosaminyl paragloboside antibodies, anti sulfated glucuronyl paragloboside antibodies, ANA, dsDNA antibodies, ayclic citrullinated peptide antibody, rheumatoid factor, Anti neutrophil cytoplasmic antibody, Myeloperoxidase antibody, Cryoglobulins, Hepatitis B and C serology, Parvovirus serology, HIV-1roteinase 3 antibody, mitochondrial antibody, SS-A/Ro antibody, SS-B/La antibody, thyroid peroxidase antibody, Kappa/lambda light chains and free with ratio in serum, Nerve biopsies, Liver function tests, Renal function tests, AIP (a urine porphobilinogen), Serum drugs level and Bone marrow biopsy.

## Electrocardiogram
An ECG may be helpful in the diagnosis of peripheral neuropathy. Findings on an ECG suggestive of of peripheral neuropathy include: Prolongation or shortening of the QRS interval, increased QT and QT dispersion intervals, increased or decreased heart rate, prolongation of the PR interval, enlarged P-wave, ST-segment depression, Cardiac arrhythmia, Heart block.

## Echocardiography and Ultrasound
Echocardiography may be helpful in the diagnosis of cardiac autonomic neuropathy. Findings on an echocardiography suggestive  of cardiac autonomic neuropathy include: Reduced ejection fraction, left ventricular diastolic abnormality, mild septal bounce.

## MRI
MRI is not commonly used in diagnosis and evaluation of peripheral neuropathy but it may be helpful in the diagnosis of some kinds of peripheral neuropathy and other associated soft tissue damages. Normal nerves appear isointense to the surrounding tissue on T1- and T2-weighted (w) MRIs, but upon injury the nerves become hyperintense and thus visible on T2-w MRI. In certain instances, MRI may confer additional diagnostic advantages in peripheral neuropathy such as improved tissue characterization and imaging of deep or bone-encased structures. Interpretation of MRI of peripheral nerves requires availability of clinical differential diagnoses  and experience in performing studies. MRI may have some advantages in comparison to other non-invasive imaging methods of peripheral nerves imagings such as: Can be used to develop numerical nerve health standards for clinical applications, correlates with electrophysiology, correlates with axon count and myelination, has a high sensitivity and specificity, determines stage of nerve injury, MRI cannot examine long nerves in a single scan and cannot determine degree of nerve injury.

# Treatment

## Medical Therapy

## Interventions
Intervention which may be helpful in treatment and prevention of sign and symptoms of peripheral neuropathy include: Exercise, acupuncture, massage and foot bath. Overall, balance training appears to be the most effective exercise intervention. Studies focusing exclusively on strength, or a combination of endurance and strength, appear to have a lower impact. For metabolically-induced neuropathies, endurance training also plays an important role. Further research with high methodological quality needs to be conducted in order to establish evidence-based clinical recommendations for neuropathic patients. Aerobic and strengthening activity such as Tai Chi may promote a relatively broad range of benefits to those with peripheral neuropathy.

## Surgery
Surgically decompression of compressed lower-extremity nerves can improve sensation, decreases pain and decreases balance problems, and should be recommended for patients with peripheral neuropathy who have failed to improve with traditional medical treatment. More data are needed to elucidate the role of surgical procedures for peripheral neuropathy treatment in the future.

## Prevention
The cornerstone of pharmacologic interventions to prevent complications of diabetic peripheral neuropathy is medications and strategies that improve glucose control. Other pharmacologic interventions that address comorbid conditions in patients with diabetes are statins and antihypertensives. These agents may also contribute to preventing diabetic peripheral neuropathy complications, since co-existing peripheral vascular disease can contribute to long-term diabetic complications, such as [[foot ulcerations. Although diabetic peripheral neuropathy is not an outcome in studies addressing these comorbid conditions, they may be described as important comorbidities in studies of glucose control that report on diabetic neuropathy outcomes. Nonpharmacologic treatment options to prevent complications which include: Non-pharmacologic glucose control interventions, such as diet and exercise, interventions to prevent specific complications, Foot care for prevention of foot ulcers and Exercise and balance training for the prevention of falls. A variety of pharmacological approaches has been evaluated to reduce pain and improve health-related quality of life through a number of mechanisms. These include drugs with direct impact on neurotransmitters and inhibitory pathways or drugs that bind to opioid receptors. Several medications are Food And Drug Administration ( FDA) approved for diabetic peripheral neuropathy (e.g., pregabalin) or other types of neuropathy (e.g., gabapentin, lidocaine patches for herpes zoster), but most are approved for other indications (e.g., depression, seizure disorders) and evaluated and used off-label for painful diabetic peripheral neuropathy. For diabetic peripheral neuropathy, pain is the most commonly studied symptom in the literature, although other symptoms, such as paresthesia, that are less commonly addressed in trials are also important to patients. These interventions also focus mainly on treating pain. Although there is less evidence in this area, modalities that have been evaluated specifically for diabetic peripheral neuropathy and addressed in previous, reviews include acupuncture, physical therapy and exercise, electrical stimulation, and surgical decompression. For pharmacologic and lifestyle interventions, prior reviews have mainly addressed medications for glucose control [which have been evaluated in multiple reviews, including recent and ongoing Evidence-based Practice Center (EPC) reviews on oral diabetes medications which have generally not evaluated neuropathy as an outcome, lifestyle interventions, and a variety of quality improvement strategies (such as care management) previously included in the EPC review closing the quality gap series. For nonpharmacologic interventions, some systematic reviews have addressed specific interventions, such as exercise training or improving footwear. The International Working Group on the Diabetic Foot (IWGDF) conducted a systematic review to investigate the effectiveness of interventions (i.e., care intervention, self-management intervention, medical intervention) to prevent first and recurrent foot ulcers or amputation in persons with diabetes who are at-risk for complications. This review found moderate evidence supporting the home-monitoring of foot skin temperatures with subsequent preventative actions and the use of therapeutic footwear with a demonstrated pressure-relieving effect consistently worn by the patient. There was some evidence to suggest that prevention of a recurrent foot ulcer by integrated foot care is effective. Surgical interventions can be effective in selected patients, but the evidence is limited. A variety of pharmacological and non-pharmacological approaches have been evaluated for preventing complications of diabetic peripheral neuropathy. However, complications other than foot ulcers and amputations have not been comprehensively addressed in recent reviews or guidelines.