Peripheral neuropathies associated with systemic disease refers to any disorder of the peripheral nervous system that is a sequela of a systemic disease process. Peripheral neuropathies have a wide-range of causes including toxic-metabolic, inflammatory or autoimmune, infectious, endocrine, and parainfectious. More specifically, systemic causes of peripheral neuropathies include hepatic disorders, endocrinopathies including diabetes and thyroid disorders, critical illness neuropathy, sarcoidosis, amyloidosis, celiac disease, autoimmune disease, vasculitis, infections such as HIV, inherited disorders such as CMT, tumors or paraneoplastic syndromes, kidney disease, alcohol use, medication side effects, toxins, vitamin deficiencies, and environmental factors. Different peripheral neuropathies can be distinguished by how the disease progresses and whether it is axonal or demyelinating. Peripheral nerves are vulnerable to several toxic-metabolic, inflammatory, infectious, or hereditary factors that can impair nerve fiber repair mechanisms as is discussed below.1-4
Patients with peripheral neuropathy associated with systemic diseases often present with distal paresthesia in the hands and feet in the early stages with progression in a classic stocking glove distribution. Longer axons are affected first, and sensory symptoms usually precede motor symptoms. Subsequently, mild weakness of the distal upper and lower extremities may occur. Hand involvement usually begins once sensory loss progresses to the mid-calf or knee. Autonomic symptoms can also occur, which include the following: gastroparesis, erectile dysfunction, and orthostatic hypotension.2,3
An Overview of the Etiology, Epidemiology, and Disease Progression of Common Peripheral Neuropathies Associated with Systemic Disease
Diabetic peripheral neuropathy:
- Etiology: There is a complex interplay between inflammatory, metabolic, and ischemic effects affecting distal peripheral nerves that has predominantly axonal features on electrophysiology studies, resulting in sensory, motor, and autonomic neuropathic features. The exact mechanism is unknown although high blood glucose levels have been shown to damage small blood vessels to the nervous system. Downstream effects include oxidative stress, advanced glycosylation end products, and neurovascular impairment with endothelial dysfunction.
- Epidemiology: Diabetes mellitus is the most common etiology of peripheral neuropathy. At the time of diagnosis of diabetes mellitus, about 10-20% of patients are concomitantly diagnosed with peripheral neuropathy.
- Disease Progression: After five years with diabetes mellitus, 26% of patients develop peripheral neuropathy. After 10 years, 41% of patients develop peripheral neuropathy. Furthermore, 50-66% of patients with diabetes mellitus will eventually develop peripheral neuropathy during their lifetime. If not recognized, patients are at increased risk for peripheral injury due to abnormal distal sensation.5-7
Hepatic peripheral neuropathy:
- Etiology: In cases of hepatitis B and C, immune complex deposition activates monocytes to release proinflammatory cytokines that attracts free radicals that ultimately cause nerve damage. The pathogenesis of peripheral neuropathy in noninfectious liver disease causes is unknown.
- Epidemiology: Peripheral neuropathy is a common complication of chronic liver disease. Studies have cited a prevalence ranging between 19 and 80%. Hepatic neuropathy is either axonal (53.7%) or mixed axonal/demyelinating (46.3%). The incidence of peripheral neuropathy in Hepatitis C is around 5%-10%.
- Disease Progression: Hepatic neuropathy has been recognized as a strong prognostic indicator for patient disability and mortality. Hepatic neuropathy is predominantly subclinical with distal symmetric pattern (sensory > motor, large fiber axonal peripheral neuropathy).8,9
Thyroid disease peripheral neuropathy:
- Etiology: The etiology of hypothyroidism associated peripheral neuropathy is not completely understood. Possible explanations for thyroid neuropathy include increased compartmental pressure from mucinous infiltration of the perineurium and endoneurium leading to focal demyelination and compression, disruption of microtubule assembly causing axonal degeneration, and secondary demyelination.
- Epidemiology: Hypothyroidism has highly variable incidence of peripheral neuropathy but reported to be around 50%. About 25% of severe thyrotoxicosis patients develop peripheral neuropathy.
- Disease Progression: Hypothyroid-associated PN presents similarly to diabetic polyneuropathy as a distal symmetric, large fiber sensory polyneuropathy. It is often asymptomatic. Woltman sign is a delayed relaxation phase on muscle stretch reflexes (MSRs) seen with clinically overt hypothyroidism and has a 72% positive predictive value. Most PN in hypothyroidism is subclinical with electromyographic findings only.10,11
Toxic peripheral neuropathy:
- Etiology: Many toxic neuropathies such as in alcohol, chemotherapy, and heavy metals such as lead can cause axonal peripheral neuropathies that present acutely vs chronically. Several medications have been implicated in causing peripheral neuropathies including antimicrobials (dapsone, fluoroquinolones, metronidazole, and nitrofurantoin), antiretrovirals (stavudine), amiodarone, colchicine, phenytoin, infliximab, and pyridoxine.
- Epidemiology: The prevalence varies depending on the cause of toxic-induced peripheral neuropathy. In developed countries, the most common cause of toxic neuropathy is adverse reactions to medications such as chemotherapy with prevalence rates reported to be around 68% within first month of chemotherapy.
- Disease Progression: Clinical signs can persist for weeks to months after exposure to the toxin has been removed. The most common presentation of toxic neuropathy involves the largest diameter axons associated with numbness in a stocking glove pattern.12
Environmental causes of peripheral neuropathy:
- Etiology: Neuropathies caused by mechanical vibration, cold exposure, or hypoxemia are mainly axonal. The mechanism of pathogenesis is broad. For example, a cold injury can cause vascular and neurological changes to induce pain, but the precise mechanism is not fully understood.
- Epidemiology: The prevalence varies depending on the cause of the peripheral neuropathy. Some studies have shown an increased incidence of acute neuropathy during winter months compared to summer months.
- Disease Progression: Clinical signs can vary depending on the etiology. Patients who are exposed to cold temperatures can experience tissue cooling with persistent sensory abnormalities of the distal upper and lower extremities with chronic pain.13
Critical illness neuropathy:
- Etiology: Critical illness peripheral neuropathy is not well understood but studies suggest involvement of multiple pathways (metabolic, inflammatory, bioenergetic alterations). Possible mechanisms include the following: microvascular changes in peripheral nervous system, increased E-selectin expression, altered lipid serum profile, damage or inhibition of complex I of the respiratory chain causing muscle adenosine triphosphate depletion, and bioenergetic failure.
- Epidemiology: 70% of patients in intensive care unit for ≤2 weeks can present with some form of critical illness neuropathy. It is commonly seen with severe inflammatory response syndrome (SIRS), sepsis, multi-organ failure; associated with increased mortality and length of weaning from the ventilator.
- Disease Progression: Critical illness neuropathy is seen in patients with protracted ICU hospitalizations or in those with major surgeries. Suspicion should be raised in a patient with limb weakness or inability to weaning ventilation. Cranial nerve involvement suggests Guillain-Barre Syndrome, motor neuron disease, or critical illness myopathy. Difficulty evaluating sensation is common due to encephalopathy or sedation.14,15
Amyloid peripheral neuropathy:
- Etiology: Amyloid peripheral neuropathy is caused by insoluble beta-fibrillar protein deposition in nerve sheaths, perineuronal tissues, and neural vasculature. Ischemic, infiltrative, inflammatory, and toxic metabolic factors are also implicated causing axon and neural capillary compression leading to loss of myelin fibers and axonal degeneration. Loss of unmyelinated fibers is also seen. Hereditary amyloidosis consists of syndromes with slightly varying characteristics from primary amyloidosis,
- Epidemiology: About 15-30% of patients with amyloidosis experience peripheral neuropathy. It is the presenting feature in 10-20% of cases. Symptoms usually present one year prior to diagnosis.
- Disease Progression: The presentation of primary amyloidosis can be variable: slowly progressive; distal symmetric mixed-fiber; sensorimotor peripheral neuropathy with or without autonomic involvement (orthostatic hypotension, diarrhea, bladder dysfunction, impotence). Constitutional symptoms (weight loss, organ involvement) should raise suspicion of primary amyloidosis. Systemic symptoms at presentation is a poor prognosticator. Median survival if congestive heart failure is seen at presentation is four months. Carpal tunnel syndrome is present in 25% of patients with amyloidosis.16,17
Sarcoidosis-induced peripheral neuropathy:
- Etiology: Peripheral neuropathy caused by sarcoidosis is due to a cell-mediated immune response with nerve granulomas and multinucleated giant cell (MNGC) formation. Memory T-cells recruit and activate macrophages, which fuse into MNGCs and gain secretory capabilities and release proteolytic enzymes damaging neighboring cells. Epineurium-located granulomas cause little to no damage. Serious damage occurs with granuloma-related necrotizing vasculitis, when endoneurium inflammation causes ischemic nerve lesions and axonal degeneration.
- Epidemiology: About five percent of patients with sarcoidosis have both peripheral and central nervous system involvement.
- Disease Progression: Sarcoidosis predominantly involves the cranial nerves. There can be multiple fluctuating and remitting cranial nerve palsies lasting weeks to months. Up to 50% of patients have facial nerve palsy. Ocular involvement is about 25%. Hearing loss, vertigo, and tinnitus have also been reported. Peripheral neuropathy with granulomas is extremely uncommon.18,19
Celiac Disease Peripheral Neuropathy:
- Etiology: The pathogenesis is unclear (malabsorption vs other immunologic mechanisms). Malabsorption includes vitamins B12, B6, and E and metals, especially copper. Furthermore, peripheral neuropathies in celiac patients may be a manifestation of other autoimmune diseases. Similarity between antigens targeted by the immune system and proteins expressed in the PNS (molecular mimicry) is a possibility.
- Epidemiology: The incidence of celiac disease peripheral neuropathy is low.
- Disease Progression: Progressive course correlates with disease severity and duration. Can present as a non-length-dependent neuropathy (ganglionopathy) or exclusively small-fiber neuropathy.20
Essentials of Assessment:
Weakness, burning sensations, or symmetrical distal sensory loss are typical characteristics of polyneuropathy. A thorough sensory examination of the lower extremities may occasionally reveal patients with extremely mild or asymptomatic polyneuropathy. In contrast, a patient may undergo electrodiagnostic testing for an unrelated issue and be found to have modest abnormalities that are suggestive of polyneuropathy.
Depending on the underlying etiology, patients with peripheral neuropathies appear in a variety of ways. To distinguish between polyneuropathy and mononeuropathy multiplex, the history is crucial. Sometimes peripheral neuropathy patients will experience symptoms that start in one foot earlier than the other or are more severe in one foot but later progress symmetrically. In its acute form, mononeuropathy multiplex typically manifests as a number of mononeuropathies involving completely unrelated nerves. Chronic axonal polyneuropathies are the most common of the polyneuropathies. Longer axons are typically impacted first, which causes symptoms to start in the lower limbs. In most cases, sensory symptoms appear before motor ones. Patients often exhibit sensory loss that slowly worsens, dysesthesias like numbness, burning, and pain in the foot, as well as moderate gait irregularities. The typical “stocking and glove” distribution of sensory loss occurs as the disease worsens, along with minor indications of lower-limb weakness and hand symptoms. Acute demyelinating polyneuropathies present often quite differently. Since they mostly damage motor nerve fibers, weakness rather than sensory loss is frequently one of the disease’s first symptoms.21,22
Physical examination abnormalities are also influenced by the type of polyneuropathy and the classes of nerve fibers implicated: axonal vs. demyelinating and motor vs. sensory.
- Motor testing may show atrophy of the intrinsic muscles in the foot or lower leg in axonal polyneuropathy. It is also possible to experience distal loss of sensation for pinprick, mild touch, vibration, cold, and proprioception. Distally, typically starting at the ankles, reflexes become hypoactive or absent.
- Patients with demyelination typically have generalized weakness. Large myelinated axons suffer the most damage, which causes anomalies in vibratory testing and proprioception. Sensation is also diminished. Reflexes are frequently missing and diffusely decreased.21,22
Assessing for the patient’s functional status at home and the community remains important. Because of the loss of sensorimotor and proprioceptive function at night, particular attention should be made to mobility and fall prevention. Fall risk can be decreased with home improvements. Ankle-foot orthoses and other assistive tools can be used as necessary to accommodate impairments.
Laboratory evaluation of peripheral neuropathy should begin with the following:
- Comprehensive metabolic profile
- Serum glucose and glycohemoglobin
- Serum vitamin B12 level
- SPEP and UPEP with immunofixation
- Thyroid function tests (TFT)
- Serum antinuclear antibodies (ANA)
- Erythrocyte sedimentation rate (ESR)21,22
Clinical characteristics requiring a thorough evaluation
These atypical features include:
- Motor dominance
- Acute onset
- Autonomic involvement
- Rapid progression
- Non-length dependance
- Sensory ataxia
Supplemental assessment tools
Electrodiagnostic studies are the initial diagnostic procedure of choice and are necessary for atypical presentations as listed above. Electrodiagnostic tests can help determine whether the patient’s symptoms are a result of polyneuropathy or another condition affecting the peripheral nerves. Chronic inflammatory demyelinating peripheral neuropathy must also be in the differential because improvement may occur with proper treatment.23
Despite their potential value in the diagnosis of suspected vasculitis, amyloidosis, and autoimmune demyelinating disorders, nerve biopsies are not frequently recommended due to their invasive nature. Generally, patients with subacute or chronic distal symmetric polyneuropathies should avoid nerve biopsy due to its low yield. The preferred location for cutaneous nerve biopsy is at the sural nerve at the distal calf.
- No firm guidelines on when to biopsy in CIP, but it may be warranted in patients with atypical presentations, previous immunosuppression (cytomegalovirus, myositis, polymyositis, direct muscle infections, other conditions mimicking CIP), or when additional prognostic information may help plan the future level of care.
- Nerve biopsies in primary biliary cirrhosis are unique, with lipid laden cells found within the nerve fascicles.24
Magnetic Resonance Neurography
Peripheral nerve damage can be examined directly and non-invasively using magnetic resonance neurography (MRN). The use of MRN to identify peripheral neuropathies associated with systemic disease has received little research, but it has been used to identify early nerve lesions in asymptomatic TTR gene carriers who have transthyretin familial amyloid polyneuropathy in patients. This might enable the disease to be diagnosed earlier.25
Rehabilitation Management and Treatments
Available or current treatment guidelines
Peripheral neuropathies associated with systemic disease typically improve upon treatment of the underlying condition. Reducing exposure to agents that cause peripheral neuropathy such as in axonal polyneuropathy secondary to alcohol of medications is effective. Control of blood glucose in diabetes and of thyroid hormone in hypothyroidism or hyperthyroidism may also help maintain nerve function. Treatment of demyelinating processes typically include intravenous immune globulin, glucocorticoids, and plasma exchange. However, some disorders respond better than others.
For symptomatic relief, medications such as Gabapentin, Pregabalin have been shown to be effective, especially in neuropathic type pain or numbness. Tricyclic antidepressants have also been effective. Medications including duloxetine, carbamazepine, phenytoin, topiramate, baclofen, dextromethorphan, mexiletine have been less efficacious in studies but generally have been used by providers as alternative treatments. Treatment with tramadol, nonsteroidal anti-inflammatory drugs, or opioids may be needed in intractable pain cases. Physical therapy is also important for helping patients with weakness caused by peripheral neuropathy. Prompt use of orthoses, splints, and assistive devices can also help patients from a functional standpoint.
There is no specific treatment for liver disease-associated neuropathy. Post-transplant effects on neuropathy have not been studied. Corticosteroids, cytotoxic immune suppression, and plasmapheresis have been reported in case studies and have some effect on hepatitis C neuropathy. Two randomized clinical trials showed rituximab was superior to placebo and conventional treatments including steroids, plasmapheresis and cyclophosphamide in treating hepatitis C neuropathy. However, a 2014 Cochrane Review found there was insufficient evidence to guide HCV neuropathy treatment decisions with the use of rituximab, antiviral treatment, or interferon alfa.
Treatment of critical illness neuropathy may improve if sepsis or multi-organ failure resolves. Supportive therapy to treat the complications associated with SIRS is crucial. Strict insulin control (80-100 mg/dL) reduces incidence of critical illness neuropathy by 44% and overall mortality. Insulin is a neurotrophic factor, hypothesized to be neural protective during SIRS, and facilitates regeneration.
In primary amyloidosis, despite treatment of the overall condition and prolonged survival, symptoms of peripheral neuropathy do not improve. In familial amyloid peripheral neuropathy with transthyretin mutation, liver transplantation has been effective. Jonsen et al showed 10 of 12 patients reported an improved quality of life following transplant. Adams et al showed that motor nerve involvement stabilized in 7 of 11 patients with mild sensory motor neuropathy and in 2 of 8 with severe sensory motor neuropathy. Tafamadis may delay progression of peripheral neuropathy impairments in patients with familial amyloid PN.
Prednisone, initially at 1 mg/kg/d, is used to treat neurosarcoidosis. In resistant cases, immunosuppressive treatment with methotrexate, cyclosporine, and azathioprine has been used. Peripheral neuropathy improves with treatment in most cases. Small fiber neuropathy symptoms may improve with intravenous immune globulin or anti-tumor necrosis factor α.
In celiac disease, a gluten-free diet should be initiated to treat the peripheral neuropathy associated with the disease. In 2006, Hadjivassiliou et al performed a systematic, controlled study of the effect of a gluten-free diet on 35 patients with celiac disease-associated neuropathy, with close serologic monitoring of adherence to the gluten-free diet. They found significant improvement in the treated group compared with the control group after one year on the gluten-free diet. Vitamin and mineral supplementation may have some benefit. The use of immunomodulatory treatments, immunoglobulin infusions, or immunosuppressant medications for celiac disease-associated neuropathy remains controversial.2,22,26-28
Coordination of care
Coordinating care between the physiatrist, primary care physician, neurologist, endocrinologists, internists, rheumatologists, gastroenterologists, pulmonary subspecialists, physical therapist, occupational therapist, dietician, podiatrist, and orthotist is imperative.
Patient & family education
Education on careful skin care of feet is important. Fall prevention strategies should be reviewed. Education to treat the underlying problem is important and may include diet and exercise education. The effects of PN can drastically alter a person’s quality of life; the worst case situations involve limb amputations and functional limitations.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Treatment for neuropathies associated with systemic diseases is usually treatment of the underlying disease.
Immunomodulators are effective in most acquired demyelinating peripheral neuropathies.
Medications such as Gabapentin and tricyclic antidepressants have been effective for treating pain associated with peripheral neuropathy.
Cutting Edge/ Emerging and Unique Concepts and Practice
Magnetic resonance neurography as a diagnostic tool shows promise, especially in its accessibility, cost, and utility.
Gaps in the Evidence-Based Knowledge
The mechanism of pathogenesis for multiple systemic disease causes of peripheral neuropathy requires further investigation to aid in proper diagnosis and treatment. Differentiating between axonal and demyelinating types has potential implications in prompt treatment of the underlying disease process. Imaging protocols and findings for MRN should be further evaluated.
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Original Version of the Topic
Christopher T. Plastaras, MD, Jerry Fang, MD, William Gleason, MD. Peripheral Neuropathies Associated with Systemic Disease. 9/20/2014.
Previous Revision(s) of the Topic
Sarah E Clevenger, MD and Stephen Kishner, MD. Peripheral Neuropathies Associated with Systemic Disease. 6/28/2018.
Richard Lau, MD
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