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Peripheral neuropathy is a general term that indicates any disorder of the peripheral nervous system. It is a common neurological disorder, with variable presentation and numerous causes. The broad definition of peripheral neuropathy includes all types of diseases associated with the peripheral neurons system; hence, there is a need to subclassify this disorder, and the clinical approach has to be sequential and logical for a cost-effective management. In this review, we highlight well-founded principles of clinical diagnosis and investigations that are useful for both general physicians and specialists.
Peripheral neuropathies are hereditary or acquired diseases affecting the cell body of peripheral sensory or motor neurons, their axon, or myelin; they are clinically defined as demyelinating and axonal, or neuronopathy (when the cell body is affected), and classified into sensory, motor or autonomic. Peripheral neuropathies can be classified depending on their time course into acute, sub acute or chronic. They are also defined as polyneuropathies or mononeuropathy, which can be isolated or can spread to different sites (multiple mononeuropathy) according to the anatomical distribution of the sensory motor and autonomic loss.
Polyneuropathies are diseases affecting all peripheral nerves and typically heralding on the feet where fibres are the longest. Mononeuropathies affect peripheral nerves focally, beginning with symptoms at one site – usually a limb – and then spreading to a different site, with an asymmetrical pattern. When the disease causing mononeuropathy progresses, multiple nerves might be affected (multiple mononeuropathy) ending with a clinical picture quite akin to a polyneuropathy.
Types of Peripheral Neuropathy
Peripheral neuropathy can be into divided into
- Chronic forms
- Symmetrical polyneuropathy
- Multiple mononeuropathy
- Uremic polyneuropathy – Chronic kidney disease (CKD) affects all levels of the nervous system. In a cross-sectional study from Andhra Pradesh,[rx] out of 74 patients of CKD, 65% of the study population was suffering from peripheral nerve dysfunction. It was more prevalent in elderly (>65 years), patients with longer duration of CKD, males, and patients with creatinine clearance <15 ml/min. CKD may also be present with entrapment neuropathies, autonomic neuropathies, and cranial neuropathies
- Chronic dysimmune neuropathy – The chronic dysimmune neuropathies are a clinically heterogeneous group of polyneuropathies united by their presumed immune-mediated etiology. The subdivision is based on a combination of clinical, electrophysiological, pathological, and immunological features
- Chronic inflammatory demyelinating polyneuropathy – CIDP is a chronic PN with progressive phase beyond 8 weeks. The distinction between AIDP and CIDP may be artificial as the distribution of onset phases is unimodal not bimodal[rx] and intermediate or subacute forms occur.[rx]
- Vasculitic neuropathies – Vasculitic neuropathy usually presents with painful mononeuropathies or asymmetric polyneuropathy of acute or subacute onset. The disorder may be classified as being systemic or nonsystemic. The systemic vasculitides are divided into primary systemic disorders, for which there is no known cause, and secondary systemic disorders, for which a virus, drug, or connective-tissue disease causes inflammation of the vessel wall.[rx]
- Human immunodeficiency virus-associated neuropathy – PN is one of many neurological complications of human immunodeficiency virus (HIV). Clinically, there are at least six patterns of HIV-associated PN.[rx] Distal sensory PN, which is the most common out of all HIV-associated neuropathies,[rx] can exist as two major types: primary HIV-associated distal sensory polyneuropathy (HIV-DSP) and antiretroviral toxic neuropathy.[rx]
- Diphtheritic neuropathy – Diphtheria is caused by toxin-producing strains of Corynebacterium diphtheriae spread by human-to-human contact. Diphtheritic polyneuropathy (DP) is recognized as one of the most severe complications of diphtheria. Among 20,000 cases of diphtheria reported by the WHO during 2007–2011, 17,926 (89.6%) cases were from India alone.[rx]
- Toxin-induced Neuropathies – Toxins may be environmental, occupational, recreational, or iatrogenic. In India, Ayurveda, Homeopathy, and Arabic medicine are potential sources of toxicity. In a survey, 14 of the seventy herbal medical products available commercially were found to contain lead in 13 (median concentration 40 mg/g; range, 5–37,000), mercury in 6 (median concentration, 20,225 mg/g; range, 28–104,000), and arsenic in 6 (median concentration 430 mg/g; range, 37–8130).[rx] One should be cautious when evaluating a case of PN about possible toxic causes. In early stage, it is reversible, but in advanced stage, it becomes progressive and irreversible.
- Alcoholic neuropathy – Polyneuropathy has been reported to be present in 13%–66% of chronic alcoholics.[rx] The relative risk of polyneuropathy in chronic alcoholics is estimated at 3.9 times.[rx] The pathophysiology of alcoholic polyneuropathy combines the toxic effect of alcohol with nutritional deficiency.[rx] Both alcoholic neuropathy and thiamine-deficiency neuropathy are mainly of axonal type and are usually characterized by painful sensory disturbance and weakness in the distal lower extremities. Autonomic dysfunction often occurs. Pure alcoholic neuropathy without accompanying thiamine deficiency mainly affects small fibers, whereas thiamine-deficiency neuropathy predominantly affects large fibers polyneuropathy with predominantly motor symptoms.[rx]
- Drug-induced toxic neuropathies – There are many drugs that cause polyneuropathy as an adverse effect. An Indian study estimated the incidence of polyneuropathy from medications or toxins to be 2%–4%.[rx] However, there are no epidemiological data but mostly anecdotal reports.
- Tropical ataxic neuropathy – Tropical myeloneuropathies are classified into two clinical syndromes that can have overlapping features – tropical ataxic neuropathy (TAN) and tropical spastic paraparesis TAN are predominantly a SN seen in malnourished populations who consume large quantities of cassava. In a study of clinical and laboratory profile of forty TAN cases diagnosed in a tertiary referral center in Kerala, demographic characteristics included female preponderance, peak age at onset in the thirties, rural residence, and poor socioeconomic status. In addition to SN, 90% had decreased hearing, 50% decreased vision, and 25% had spasticity of lower extremities. Serum, urine, and sural nerve thiocyanate levels were significantly elevated in the patients and cessation of cassava intake, and better nutrition caused improvement in the neurological disability.[rx]
- Nutritional Neuropathy – Malnutrition affects both peripheral and CNS. PN may coexist with myelopathy (myeloneuropathy) can be seen with nutritional neuropathies.
- Critical Illness Polyneuropathy – Critical illness polyneuropathy is a condition occurring in critically ill patients who have been on mechanical ventilation for more than 1 week and usually identified by failure to wean the patient from ventilator. Based on clinical evaluation alone, an incidence of 25%–36% has been shown in prospective studies.[rx,rx] Electrophysiologic testing revealed that neuropathy and/or myopathy is present in 52%–57% of patients in Intensive Care Unit for 7 days or more.[rx]
- Paraneoplastic Neuropathy – In up to 50% of patients with carcinoma, PN can be due to treatment toxicity, tumorous infiltration, metabolic disturbances, or terminal cachexia.[rx] Neuropathy is defined as paraneoplastic when none of the above causes are detected or when cancer-related immunological mechanisms are involved. About 15% of patients with cancer develop a paraneoplastic sensorimotor neuropathy, which is usually mild and develops during the terminal stage of the disease.[rx]
- Hereditary Neuropathies – The inherited neuropathies can broadly be classified into two groups: Those in which neuropathy is primary (e.g. Charcot–Marie–Tooth disease, CMT) and those in which neuropathy is part of generalized neurological or multisystem disorder.
- Amyloid neuropathy – is another hereditary neuropathy due to deposition of transthyretin or less commonly other proteins, in peripheral nerves. It may be an acquired disorder secondary to B-cell dyscrasia and immunoglobulin light chain deposition. In a report from North-West India, six members of a family spanning two generations were affected with polyneuropathy, autonomic neuropathy, vitreous, and cardiac involvement.[rx]
Causes of Peripheral Neuropathy
- Genetic diseases – Friedreich’s ataxia, Fabry disease,[rx] Charcot-Marie-Tooth disease,[rx] hereditary neuropathy with liability to pressure palsy
- Hyperglycemia – induced formation of advanced glycation end products (AGEs)[rx][rx][rx]
- Metabolic and endocrine diseases – [rx] chronic kidney failure, porphyria, amyloidosis, liver failure, hypothyroidism
- Toxic causes – drugs (vincristine, metronidazole, phenytoin, nitrofurantoin, isoniazid, ethyl alcohol, statins), organic herbicides TCDD dioxin, organic metals, heavy metals, excess intake of vitamin B6 (pyridoxine). Peripheral neuropathies also may result from long term (more than 21 days) treatment with Linezolid.
- Adverse effects of fluoroquinolones – irreversible neuropathy is a serious adverse reaction of fluoroquinolone drugs
- Inflammatory diseases – Guillain–Barré syndrome,[rx] systemic lupus erythematosus, leprosy, multiple sclerosis,[rx] Sjögren’s syndrome, Babesiosis, Lyme disease,[rx]vasculitis,[rx] sarcoidosis,[rx]
- Vitamin deficiency states – Vitamin B12 (Methylcobalamin),[rx] vitamin A, vitamin E, vitamin B1 (thiamin)
- Physical trauma – compression, automobile accident, sports injury, sports pinching, cutting, projectile injuries (for example, gunshot wound), strokes including prolonged occlusion of blood flow, electric discharge, including lightning strikes
- Effect of chemotherapy – Chemotherapy-induced peripheral neuropathy[rx]
- Others – electric shock, HIV,[rx][rx] malignant disease, radiation, shingles, MGUS (Monoclonal gammopathy of undetermined significance).[rx]
- Drug – Alcohol, vincristine, phenytoin, organophosphate, statins, metronidazole, dapsone
- Infection – Leprosy, HIV, Borreliosis
- Connective tissue – Sjogren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis
- Paraneoplastic – Carcinoma of the lung and ovary.
- Inherited – CMT 2 and CMT X
- Endocrine – Hypothyroidism
- Paraproteinemia – Myxedema, Waldenstorm’s disease, Benign monoclonal gammopathy
- Entrapment neuropathy – Carpal tunnel syndrome, ulnar nerve at the elbow, common peroneal at the fibular head
- Endocrinal – diabetes mellitus, myxedema, acromegaly.
- Hereditary neuropathy susceptible to pressure palsy
- Multifocal motor neuropathy with conduction block
Causes of chronic demyelinating neuropathy
- Charcot-Marie-Tooth disease type 1
- Other forms of Charcot-Marie-Tooth disease
- Hereditary liability to pressure palsies
- Other genetic causes—for example, Refsum’s disease, metachromatic leucodystrophy
- Chronic inflammatory demyelinating polyradiculoneuropathy
- Multifocal motor neuropathy
- Paraproteinaemic demyelinating neuropathy: Associated with monoclonal gammopathy ofundetermined significanceAssociated with solitary myeloma.
Causes of multiple mononeuropathy
- Primary systemic vasculitis: Polyarteritis nodosaChurg-Strauss syndrome (vasculitis with blood eosinophilia and asthma)
- Systemic vasculitis associated with connective tissue diseases: Rheumatoid arthritisSjögren’s syndrome
- Vasculitis confined to peripheral nerves
- Associated with metabolic or toxic neuropathy
- Hereditary neuropathy with liability to pressure palsies
- Vitamin B12, B6, niacin, and thiamine deficiencies result in PN of predominantly axonal distal symmetrical sensory-motor type. However, well-designed studies on these are lacking.
CIDP – Chronic inflammatory demyelinating polyneuropathy
Urine – Bence-Jones protein
Biochemistry – Oral glucose tolerance test
Cerebrospinal fluid – Cells, protein, immunoglobulin oligoclonal bands
Immunology – Anti-HIV antibodies, antineuronal antibodies (Hu, Yo), antigliadin antibodies, serum angiotensin converting enzyme, antiganglioside antibodies, antimyelin associated glycoprotein antibodies
Tests for Sjögren’s syndrome – Salivary flow rate, Schirmer’s test, Rose Bengal test, labial gland biopsy
Search for carcinoma, lymphoma, or solitary myeloma – Skeletal survey, pelvic ultrasonography, abdominal and chest computed tomography, mammography, or positron emission tomography
Molecular genetic tests – Peripheral nerve myelin protein 22 gene duplication (the commonest cause of Charcot-Marie-Tooth disease type 1) or deletion (hereditary neuropathy with liability to pressure palsies), connexin 32 mutation (X linked Charcot-Marie-Tooth disease), PO gene mutation (another cause of Charcot-Marie-Tooth disease type 1), etc
Stage 1 and 2 investigations of peripheral neuropathy
Urine – Glucose, protein
Haematology – Full blood count, erythrocyte sedimentation rate, vitamin B-12, folate
Biochemistry – Fasting blood glucose concentration, renal function, liver function, thyroid stimulating hormone.
Neurophysiological tests – Assessment of distal and proximal nerve stimulation
Biochemistry – Serum protein electrophoresis, serum angiotensin converting enzyme
Immunology – Antinuclear factor, antiextractable nuclear antigen antibodies (anti-Ro, anti-La), antineutrophil cytoplasmic antigen antibodies
Other – Chest radiography
- For the evaluation of peripheral neuropathy – nerve conduction study of sensory and motor nerves, late responses (F response and H reflex) and needle electromyography (EMG) are performed. Conduction block refers to a decline in the compound muscle action potential exceeding 20% on proximal stimulation compared to that on distal stimulation. The slowing of nerve conduction velocity, prolongation of terminal latency, temporal dispersion and conduction block are consistent with demyelinating neuropathy. Uniform demyelination favors inherited neuropathy. On the other hand, findings with difference between nerves and segments of the same nerve are more in favor of acquired demyelination.[rx,rx]
- In axonal neuropathy – there is mild slowing of nerve conduction due to a fall out of large-diameter axons, whereas the remaining axons may have normal nerve conduction. The other evidence of axonal neuropathy is reduced CMAP amplitude and fibrillations on EMG. Sensory nerve action potentials and sensory conduction velocities are reduced in both axonal and demyelinating neuropathies.
- For the interpretation of nerve conduction studies – the age of the patient needs to be considered. Normal nerve conduction velocity is half the adult value in infant, reaches the adult range by 3–5 years of age, and may decline in the elderly. For the interpretation of results, the temperature of the limb should be taken into account. The conduction velocity changes by 2.4 m/s for each degree change in centigrade from 29 to 38 °C.[rx,rx]
- Nerve conduction and EMG – studies are uncomfortable for the patient despite the neurophysiologist’s best efforts. It takes 30–60 min of neurophysiologist’s precious time. The EDx tests do not replace or substitute clinical evaluation but supplement it and it is more difficult to obtain cooperation from patients for EDx than for clinical examination. It is easier to localize significant weakness or sensory loss than the mild ones, and the same holds true for the EDx study. EMG and nerve conduction studies are operator dependent and proper standardization of the technique and generating laboratory’ control values are essential pre-requisites for proper interpretation of the results.
- Nerve biopsy – Sensory nerve biopsy is an established diagnostic procedure, but should be performed in the center where facilities for electron microscopy, teased fiber technique and immunohistochemistry are available.[rx] Biopsy only to confirm the presence of neuropathy is not necessary. With the advent of genetic testing, the need for biopsy remains the primary method of establishing vasculitic neuropathy when histology is not available from elsewhere. Combined nerve and muscle biopsy has been recommended to improve the diagnostic yield.[rx] In a prospective study on 50 nerve biopsies in consecutive patients, the management was altered in 60% and diagnosis altered in 14%. Biopsy was considered to cause persistent pain in 33% patients.[rx]
The clinical and EDx evaluations should be followed by the first line laboratory tests as listed below.
First-line screening test for neuropathy
Blood count, ESR
Liver and renal function tests
Serum vitamin B12
Thyroid function tests
Treatment of Peripheral Neuropathy
- Painful paresthesia – especially when the pain is of lancinating type can be helped by tricyclic antidepressants and anticonvulsants such as phenytoin, carbamazepine, and gabapentin. Based on randomised controlled trials there was no superiority of any of these anticonvulsants over the others. It is however recommended that these anticonvulsants should be used in DN when the other interventions have failed.[rx]
- Tramadol – is effective in the treatment of neuropathic pain in placebo controlled trials. Depending on the quality of pain, different drugs have been recommended. For paresthesia and lancinating pain tricyclic antidepressants and fluphenazine are recommended. For superficial burning pain and allodynia capsaicin and isosorbide dinitrate spray and for focal or neuropathic pain carbamazepine or other anticonvulsants are recommended.
- Analgesics – are not of much benefit and narcotics should be avoided because of possible addiction. However, non‐steroidal anti‐inflammatory drugs (ibuprofen 400 mg four times daily) has been reported to relieve neuropathic pain.[rx] Tramadol also is useful in relieving pain but is avoided because of addiction potential. In a small study, calcitonin 100 IU daily relieved pain in 39% patients by two weeks.[rx]
- Transcutaneous nerve stimulation – magnetic field therapy, infrared light therapy, and spinal cord stimulation has been tried in small number of patients with painful DN.
- Large fibre neuropathy – The management of large fibre neuropathy is by gait and strength training, pain management as discussed above, orthopaedic devices, tendon lengthening for Achilles contracture, and immunomodulation as detailed above.
- Anticonvulsants – Pregabalin was the first anticonvulsant to receive approval from the Food and Drug Administration (FDA) for the treatment of postherpetic neuralgia, DNP[rx,rx] and neuropathic pain after spinal cord injury[rx]. Pregabalin is a GABA analogue that selectively binds to pre-synaptic voltage-gated calcium channels containing the α2δ subunit in the brain and spinal cord, causing inhibition of the release of excitatory neurotransmitters[rx,rx].
- Besides pregabalin – gabapentin is the only other anticonvulsant drug that demonstrated efficacy in the treatment of this condition[rx] with an NNT of 5.8[rx]. Gabapentin and pregabalin have a similar mechanism of action and the first is licensed for neuropathic pain in the United Kingdom, but not in the United States[rx].
- Antidepressants – Antidepressants represent the first line drugs in DNP management. Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is rated level A for efficacy and is approved in the United States for the treatment of this condition. Additionally, some clinical trials have pointed out the effectiveness of duloxetine in other chronic pain conditions, such as fibromyalgia and chronic musculoskeletal pain[rx,rx].
- Venlafaxine – is also a selective serotonin and noradrenaline reuptake inhibitor, that predominantly inhibits serotonin reuptake at low doses and noradrenaline at higher doses[rx]. Venlafaxine was also shown to be effective in reducing pain intensity in diabetic neuropathic patients[rx], with an NNT between 2.2 and 5.1 and a number needed to harm (NNH) of 9.6, to minor adverse effects, and of 16.2, for major adverse effects[rx].
- Tricyclic antidepressants – can also be an alternative to treat DNP[rx]. Amitriptyline was shown to be as effective as gabapentin in a direct meta-analysis study[rx] and as duloxetine in a randomized, double-blind, crossover trial[rx]. Likewise, nortriptyline was reported as being as effective as gabapentin in attenuating neuropathic pain in a double-blind crossover trial enrolling diabetic patients[rx].
- Capsaicin topical cream – Topical agents may be associated with fewer and less clinically significant adverse events than systemic agents[rx]. In addition, the possibilities of drug interactions are markedly reduced with the use of local treatments, which represent good options for patients with multiple medical problems[rx]. The capsaicin cream has been shown to be effective in the treatment of neuropathic conditions[rx] and is approved for topical relief of neuropathic pain[rx].
- Lidocaine patch – Lidocaine patches act as peripheral analgesics with minimal systemic absorption and are used in combination with other analgesic drugs[rx,rx]. Lidocaine blocks sodium channels and counteracts the hyperexcitability of peripheral nociceptors that contributes to neuropathic pain[rx,rx]. The blockade reduces ectopic discharges and raises the peripheral sensory neuron discharge threshold[rx]. The few DNP clinical trials that compared topical lidocaine with other relevant interventions suggested that the effects in pain reduction are comparable to other drugs, such as capsaicin, gabapentin, amitriptyline[rx] and pregabalin[rx,rx]. Adverse events include local irritation[rx], contact dermatitis and itching[rx].
- Alpha lipoic acid – The benefit provided by alpha lipoic acid (ALA) in the treatment of DNP possibly is due to its direct effects on the neuropathy, by reducing the oxidative stress, which has been defined as an important factor in the physiopatology of the diabetic neuropathy[rx]. Its antioxidant and anti-inflammatory actions may contribute to an all-round improvement of diabetic neuropathy symptoms[rx]. In some clinical trials that evaluated ALA effect in diabetic patients, pain was not a primary end point. However, they have shown a moderate benefit in terms of pain reduction[rx]. In a randomized double-blinded trial, ALA-treated patients reported a greater reduction in neuropathic pain when compared to placebo-treated subjects[rx]. Compared to several drugs currently in use for DNP treatment, ALA has fewer side effects[rx], being nausea and vomiting the most common[rx].
- Isosorbide dinitrate spray – Isosorbide dinitrate is a nitric oxide-dependent vasodilator with effects on both arteries and veins[rx]. The improvement of pain and burning sensation could be associated with the increased generation of nitric oxide, improving microvascular blood flow[rx]. In a clinical trial with diabetic patients, the isosorbide dinitrate spray reduced overall neuropathic pain and burning sensation in about 50% of the patients, which also reported improvement in their quality of life, with improvements in sleep, mobility and mood[rx,rx].
- Final considerations about DNP treatment – Besides the fact of many diabetic complications can be reduced with improved blood glucose control and other lifestyle interventions[rx,rx], such as quit smoking and reducing alcohol consumption[rx], the efficacy of these measures, as well as the pharmacological treatments on DNP are not predictable. The medications rated as level A based on their efficacy are able to reduce pain and improve some aspects of patients’ quality of life, but are not able to fully eliminate pain or prevent/revert the neuropathy.