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The broad and challenging – but promising – landscape of peripheral neuropathy
Peripheral neuropathy is becoming an increasing focal point for clinicians when treating patients because of the plethora of causes to which the disorder has been attributed. Characterized by damage to the peripheral nervous system, peripheral neuropathy causes sharp, burning pain; numbness of the extremities that can travel proximally; muscle weakness; and an overall diminished quality of life. Rather than being a self-developing disease, peripheral neuropathy has mostly been identified as a symptom of causative disorders and therapeutic agents – making prevention and treatment extremely important for patients and providers.
The etiology of peripheral neuropathy has been studied thoroughly over the past 2 decades. In this review, we summarize the landscape of peripheral neuropathy, including the more common causative entities; diagnostic tools that can potentially be employed to identify the disorder; and treatments that are in use or being tested to prevent, slow, or reverse the effects of peripheral neuropathy.
DIABETIC PERIPHERAL NEUROPATHY
The most common cause of peripheral neuropathy is diabetes mellitus. Diabetic peripheral neuropathy (DPN) is a symmetrical, length-dependent neuropathy that affects more than 50% of type I and type II diabetes patients.1 Not only is DPN an initiating factor of foot ulcers and nontraumatic lower-limb amputation, but it also leads to a severely lower quality of life, financial burden, and increased risk of death after major surgical procedures.2
Once DPN has progressed significantly, its effects are irreversible; there are no agents capable of reversing or halting DPN past initial stages of disease.3 It is important to detect and treat DPN early on, as it has a favorable prognosis and most DPN-related amputations are preventable.
Diagnosis
Nerve-conduction studies are the preferred diagnostic tool for DPN; however, these studies are costly and difficult to conduct in a clinical setting.2 Currently, such diagnostic tools as the 10-g monofilament and tuning fork are more commonly utilized to detect loss of protective foot sensation to decrease the risk of foot ulceration.2 In addition, other common aspects of diagnosing DPN include assessment of symptoms in the patient’s hands or feet and patient-reported symptoms.
Several diagnostic devices are in experimental stages and have shown potential for utilization in clinical settings.
DPNCheck is a handheld device, with a turnaround time of 3 minutes, that measures sural nerve conduction velocity, which can identify DPN early in asymptomatic cases; and amplitude of sensory-nerve action potentials, which decrease with the degeneration of axons, a clinical characteristic of DPN. In a study of patients with diabetes (n = 162 [type 1, n = 80; type 2, n = 82]) and healthy controls (n = 80), a comparative analysis of DPNCheck and reference techniques showed a strong linear relationship between between clinical neuropathy scores and LDIFLARE (r = 0.64-0.84; P < 0.03), which suggests that the device might be viable in clinical settings.4 LDIFLARE is a method developed to assess axon reflex to detect neuropathy in type 2 diabetes.4
Neuropad, a 10-minute test, measures foot plantar-surface sweat production, indicated by a cobalt compound color change on the device. The test is advantageous because it is highly sensitive – 73% more sensitive than DPNCheck – and does not rely on patient response or require operator training.5 A study of Neuropad showed that a drier foot and, therefore, increased risk of foot ulceration correlated with greater abnormal readings on the device, which might indicate onset of more severe DPN in the future.6
Sudoscan measures sudomotor function in 3 minutes through an electrochemical reaction between stimulated sweat glands and electrodes.2 A study performed in China in patients with type 2 diabetes (n = 394) showed that electrical conductance in the feet is associated with increasing risk and severity of symptoms of DPN in asymptomatic patients (r = 0.98 [95% confidence interval, 0.962-0.993]; P < .01) and might serve as a biomarker of DPN.7
Although these three techniques present favorable data, each is a nerve conduction study that can access only small-fiber nerves. Additional testing is required for larger-fiber nerves that are also affected by DPN.2 Also, some of the studies of these devices have high heterogeneity and a small sample size. Further research utilizing these three methods should include larger sample sizes to appropriately assess any clinically significant patient outcomes.
Corneal confocal microscopy (CCM), another potential technique for DPN screening, is a noninvasive ophthalmic device for assessing corneal small-fiber nerves. A study of patients with diabetes or obesity or both (n = 35) showed high reproducibility of corneal-nerve pathology identification using CCM.8 A larger-scale study showed that CCM can detect a reduction in corneal-nerve parameters in DPN patients, as well as in patients who have yet to develop DPN – thus demonstrating the technique’s ability to detect both early subclinical and established DPN.9 Once CCM is approved as a point-of-care device, it might provide a reliable, sensitive screening method for DPN as an early-intervention tool.
Therapeutic options
The three principal types of treatment for DPN are tricyclic antidepressants, anticonvulsants, and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs). Only three medications are Food and Drug Administration (FDA) approved for the treatment of DPN: pregabalin, duloxetine, and the recently approved capsaicin patch. Some opioid analgesics, including extended-release tapentadol, are FDA approved for DPN-associated neuropathic pain; however, evidence of their efficacy is questionable, and they present a risk of addiction.10 Here, we focus on potential treatments for DPN and DPN-associated neuropathic pain.
Cinacalcet. Several potential treatments have been studied for alleviating DPN symptoms after progression. Cinacalcet is a calcimimetic agent that activates the adenosine monophosphate-activated protein kinase–endothelial nitric oxide synthase pathway, which mediates DPN development. The drug has shown evidence of improving sensorimotor function and restoring nerve function in human Schwann cells expressed in diabetes-induced mice.11 In these animal models, cinacalcet improved tactile response when interventional mice were compared with a control group (P < .01).11 Further research is necessary to determine similar efficacy in human subjects.
Traditional Chinese medicine. Recent studies have focused on traditional Chinese medicine and practice, such as acupuncture and moxibustion, for DPN.
Moxibustion is the technique of burning moxa floss (a plant also known as mugwort) on different points on the body, which is thought to alleviate disease. In a study performed on rats, moxibustion increased nerve velocity (P < .05) and preserved sciatic-nerve ultrastructure.12 Research on the use of moxibustion is preliminary. A meta-analysis of available data found that all clinical studies took place in China, and results were therefore subject to high heterogeneity and small sample size.13 Previously, a lack of high-quality data prevented moxibustion from being considered a potential treatment.3 The technique has demonstrated potential benefit, but larger-scale and more rigorous studies must be utilized to verify its clinical efficacy.
Quercetin. This common dietary flavonoid is in development. In rat models with induced DPN, treatment produced significant neuroprotective effects, such as rescued mechanical withdrawal threshold, lowered nerve densities (P = .0378), and rescued lowered levels of reactive O2 species (P < .0001), which contribute to neurotoxicity in many peripheral neuropathies.14 Another study of the anti-inflammatory effects of quercetin in rat models found significant lowering of inflammatory factors, including proteins encoded by toll-like receptor 4 and MyD88, and protein transcription factor nuclear factor kappa B (P < .001), which can be beneficial in the treatment of DPN.15 Future testing in human subjects might reveal similarly positive effects.
Vitamin B. A systematic review examined the therapeutic effects of vitamin B supplementation on DPN. Through a meta-analysis on 14 studies (N = 997), it was revealed that statistically significant improvements in pain and electrophysiological sensory outcomes were observed after vitamin B supplementation. However, the majority of the studies included in the analysis utilized combination therapies with different vitamins (such as vitamin D) and other vitamin B types. Furthermore, deficiencies in B vitamins – especially folic acid and vitamin B12 – have been observed in diabetic patients, and may be the potential cause of DPN in them. The validity of the studies and their findings are weakened by this observation. Therefore, the clinical efficacy of individual B vitamin supplements must be evaluated in long-term, larger scale future studies that exclude those with B vitamin deficiency and DPN to minimize potential error.71
CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY
Another cause of peripheral neuropathy has been directly linked to particular chemotherapeutic agents. Platinum-based agents have been widely accepted as an ideal solution for slowing tumor progression; however, it has been established that platinum adducts within DNA are the cause of neuronal degeneration – specifically in dorsal-root ganglion neurons of the peripheral nervous system. In a 2010 meta-analysis in the United States, the prevalence of chemotherapy-induced peripheral neuropathy (CIPN) was observed to range from 65% to 75%, depending on the platinum-based agent.16 This problem is often dose-limiting and can lead to cessation of treatment, causing patients physical and financial harm. CIPN can be acute or chronic, and symptoms affect motor, sensory, and autonomic function, which can lead to reduced quality of life.17
Diagnostic tools and strategies
A variety of avenues can be taken to assess whether a patient has CIPN. Because peripheral neuropathy is often subjective, it has been recommended that clinicians use patient-reported outcome measures in this setting, in the form of a questionnaire.
Common toxicity criteria. The most conventional measure of CIPN is the National Cancer Institute’s Common Toxicity Criteria, which grades severity of adverse effects on a scale of 1 to 5 and has been found to be statistically valid.18 This questionnaire assesses a patient’s neuropathic pain score and sensory deficits, and can detect other potential adverse findings, such as neutropenia.
Total neuropathy score. This commonly used questionnaire measures subjective autonomic, sensory, and motor symptoms on a scale of 0 to 4 for each item, with the individual item scores then summed. A score > 5 indicates CIPN.19 The tested validity of this measure shows that it has an inter-rater reliability of 0.966 and an intra-rater reliability of 0.986.19
Other questionnaires. The Neuropathy Screening Questionnaire, Treatment-Induced Neuropathy Assessment Scale, and Chemotherapy-Induced Peripheral Neuropathy Assessment Tool have been identified as means of understanding what a patient experiences following neurotoxic chemotherapy.18
Pain caused by CIPN can also be assessed with one of several general scales, such as the Neuropathic Pain Scale for Chemotherapy-Induced Neuropathy (NPS-CIN), which identifies a patient’s level of pain on a scale from 0 to 4 on six items: intensity, unpleasantness, sharpness, depth, numbness, and tingling. This scale has been found to be reliable.18
Other scales that can be used are the Neuropathic Pain Symptom Inventory, Patient-Reported Outcomes Measurement Information System: Pain Quality Neuro, and Leeds Assessment of Neuropathic Symptoms and Signs.18
Other diagnostic tests. Tests to determine a chemotherapy patient’s functional ability regarding their extremities include postural stability tests, the Timed Up and Go (TUG) test, the Fullerton Advance Balance (FAB) Scale, the 6-minute walk test, and the grooved pegboard test.
Nerve conduction studies have been identified as useful tools to assess the physiologic function of fibers, but are costly and used most often in research settings.18 Quantitative sensory testing and the Bumps test are used to assess threshold capacities for varying sensations. Nerve-imaging tools, such as high-resolution ultrasonography, magnetic resonance neurography, and positron emission and computed tomography, have been found to be successful in identifying nerve damage.18
Additionally, the accumulation of mitochondrial DNA (mtDNA) in the blood has been identified as a potential biomarker for CIPN following animal trials on rats.69 Researchers conducted a double-blind trial where healthy rats were given doses of paclitaxel, oxaliplatin, and bortezomib and compared to vehicle-treated rats. Researchers found that there was a correlation between the onset of CIPN and levels of mtDNA, with 1-2-fold increases of mtDNA found in paclitaxel and oxaliplatin treated patients (P < 0.01).69 Dysfunctional mitochondria can cause an increase in the activity of reactive oxygen species which results in damage to mtDNA; and abnormal bioenergetics, which may lead to irregular ATP production and result in cellular damage.
Navitoclax. The antineoplastic agent cisplatin is used to treat a variety of cancers, including ovarian, lung, head and neck, testicular, and bladder.20 Using single-cell RNA sequencing of dorsal-root ganglion cells in mouse models that have been given human equivalent doses of cisplatin to induce peripheral neuropathy, a study identified that the drug was upregulating the cyclin-dependent kinase inhibitor 1A gene (CDKN1A) and leading to overproduction of its product, the p21 protein.21 This is due to a cellular response to DNA damage that causes the dorsal-root ganglion sensory neuron to change into a senescence-like state to survive. Subsequently, accumulation of senescent sensory neurons correlates with induction of neuropathic pain and peripheral neuropathy. It has been established, in mouse models, that removing senescent cells has the potential to reduce or reverse peripheral neuropathy associated with cisplatin treatment.21
A study induced irreversible CIPN using cisplatin on mice that were subsequently treated with antineoplastic agent navitoclax (n = 5) or vehicle (n = 10). Using navitoclax, a broad-spectrum senolytic agent, the study examined the dorsal-root ganglia of the mice and found that CIPN was reversed following clearance of senescent cells, with baseline mechanical thresholds able to be reestablished without difference, compared with the control group (P = .7734).22 The investigators found that clearance of senescent cells using navitoclax proved a promising avenue toward mitigating CIPN. More studies should be completed to validate this treatment as an effective preventive.
NGF Monoclonal Antibody (Tanezumab). Tanezumab has been identified as a potential analgesic for CIPN having observed success during animal trials. This monoclonal antibody targets the NGF-TrkA pathway in a dose-dependent manner which results in a reduction of neuronal sensitivity and subsequently neuropathic pain (P < 0.05).70 NGF is a peripheral pain mediator that has functional properties relating to inflammation and neuropathy. Therefore, by targeting this protein and inhibiting its activation, patients could potentially see a dramatic improvement in their quality of life following a CIPN diagnosis. This potential analgesic was observed to be successful for a variety of chemotherapeutic agents including cisplatin, vincristine, and paclitaxel.70
SASP inhibitors. A second possible approach to neutralizing senescent cells would be by inhibiting the senescence-associated secretory phenotype (SASP). This could be accomplished through the use of nuclear factor kappa B inhibitors, mammalian target of rapamycin (mTOR) inhibitors, bromodomain and extra-terminal (BET) inhibitors, and inhibitors of secretory factors, such as interleukin (IL)-6 and tumor necrosis factor (TNF) alpha.23 Rapamycin, an mTOR inhibitor that is already used in clinical settings, has been found to reduce the inflammatory effects of senescent cells, expanding the lifespan of mice.24 JQ1, OTX015, and ARV825 are BET inhibitors that have been found to block bromodomain-containing protein 4, thus inducing senescent cell death.25 IL-6 inhibitors (for example, tocilizumab) and TNF alpha inhibitors (for example, adalimumab) are already used clinically and can mitigate the effects of SASP.23,26 However, further studies are needed to examine potential adverse effects of this type of therapy.
Mitigation of oxaliplatin adverse effects. This platinum-based chemotherapeutic agent associated with peripheral neuropathy is primarily used to treat colorectal cancer and digestive-tract malignancies.27 Oxaliplatin-induced peripheral neuropathy (OIPN) can be acute or chronic, and causes neuropathic pain, autonomic nerve dysfunction, and hypersensitivity to cold, which lead to abnormal nervous system effects, such as peripheral paresthesia.
These symptoms derive from oxaliplatin’s effects on a variety of cellular mechanisms, and differ in chronic and acute OIPN. Acute OIPN includes abnormal changes to sodium, potassium, calcium, and transient receptor potential channels, which lead to dysregulation and dysfunction in peripheral neurons; glia activation associated with dysregulation of pain modulation, by reducing thresholds; and upregulation of the octamer-binding transcription factor (OCT) protein.
Chronic OIPN has been associated with damage to nuclear DNA by platinum adducts, mitochondrial dysfunction (due to oxidative stress), and neuroinflammation caused by glia activation and gut microbiota.28
With increased understanding regarding cellular mechanisms affected in OIPN, treatment options are being established to prevent or reduce its effects. A treatment being tested for the treatment of OIPN is the serotonin and norepinephrine reuptake inhibitor (SSNRI) antidepressant duloxetine.29 In a clinical trial of 40 patients with gastrointestinal cancer, duloxetine was found to reduce cold sensitivity (P = .001), tingling or discomfort of hands (P < .002) and feet (P = .017), and peripheral neuropathic pain (P = .001), and was found to prevent paresthesia (P = .025).29 The SNRI antidepressant venlafaxine has also shown that it can alleviate neuropathic pain and motor neuropathy in clinical trials.30
Antioxidant agents, such as amifostine and calmangafodipir, have also been identified as possible preventive measures against OIPN. Amifostine prevents neuronal hyperactivation and nitrosative stress, while calmangafodipir modulates reactive O2 species, regulates ion channels, and protects axons and the myelin sheath.31,32
Treatments such as riluzole, lidocaine, and pregabalin have all shown promise in reducing the effects of OIPN by their action on potassium, sodium, and calcium channels, respectively.28 A study conducted on mice (n = 565) with OIPN found that riluzole effectively mitigated motor and sensory deficits associated with the use of oxaliplatin.33
TREK-1 and TRAAK, potassium channels that are important for thermal and motor sensitivity, and that act as silencing mechanisms to excitatory stimuli, were shown to degenerate following oxaliplatin treatment, leading to hypersensitivity. Riluzole performs its therapeutic function by activating TREK-1 and TRAAK channels and blocking excessive accumulation of glutamate. Following riluzole treatment, mice were observed to show a significant reduction in sensorimotor deficits. Interestingly, riluzole also aided in reducing depression associated with oxaliplatin (P < .01).33 However, more studies are necessary to ensure the safety and efficacy of riluzole in humans.
Pyridoxine, pyridostigmine for vincristine-induced peripheral neuropathy. Vinca alkaloids have also been identified as chemotherapeutic agents that induce peripheral neuropathy. One such agent, vincristine, which is used primarily to treat leukemia and brain cancer, has been observed to cause peripheral neuropathy, including motor, autonomic, and sensory symptoms, such as abnormal gait, mechanical allodynia, paresthesia, ptosis, and obstipation, and altered perception of stimuli.34,35 These symptoms are caused primarily by the ability of vincristine to activate neuroinflammatory mechanisms in dorsal-root ganglia. This is caused by activation of nucleotide-binding oligomerization domain 3 (NLRP3)-dependent release of IL-1b and subsequent cleavage of gasdermin D and caspase-1 in macrophages (observed in mouse models). Vincristine activates the NLRP3 signaling cascade that results in production of proinflammatory cytokines, thus inducing symptoms of peripheral neuropathy.36
Pyridoxine and pyridostigmine have been introduced as potential treatments for vincristine-induced peripheral neuropathy. Following a clinical trial of pediatric acute lymphoblastic leukemia patients, a study of 23 patients with vincristine-induced peripheral neuropathy found statistical validity for using pyridoxine and pyridostigmine because the drugs improved the neuropathy score (P < .001).37 However, more research is needed before implementing their use in point-of-care settings.
AUTOIMMUNE PERIPHERAL NEUROPATHY
Autoimmune peripheral neuropathies (APNs) occur when the immune system targets peripheral nervous system and its various cells. Although there is a wide range of conditions in this category of peripheral neuropathy, the two most common types – Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) – have been targeted for clinical research.
Guillain-Barré syndrome: Diagnostic tools and strategies
Guillain-Barré syndrome encompasses a variety of acute inflammatory polyneuropathies, including axonal motor, sensory, and autonomic neuropathies and Miller Fisher syndrome (MFS).38 In particular, the anti-GQ1b ganglioside antibody is considered archetypical in APNs because it is detected in MFS patients and not found in normal and disease-control samples, which makes it a good clinical marker.39
It is difficult to distinguish GBS from CIDP because the time frame of onset of maximum deficit of neuropathy – 4 weeks – can overlap with subacute CIDP symptoms.40 Current diagnosis is based on elevated levels of cerebrospinal fluid (CSF) proteins, which can increase fourfold 6 weeks into the early phase of disease, and nerve conduction studies.40 However, electrodiagnostic readings and CSF protein levels are normal in 30% to 50% of patients in the first week after onset of disease and must be repeated in weeks that follow.41 A major disadvantage in the workup of suspected GBS is that the syndrome can be confirmed only several weeks after onset of symptoms.
Ultrasonography. A potential new diagnostic tool is serial peripheral nerve ultrasonographic (US) imaging. A pilot study of GBS patients (n = 16) showed that US can detect enlarged nerve cross-sections in median, ulnar, and sural nerves in the first 3 weeks of disease. Imaging performance was consistent with that of nerve conduction studies, and was advantageous because US is easier to perform and for patients to undergo.42
Spinal inflammation. Another study hints at the importance of spinal-root inflammation as an early indicator of disease, especially when nerve conduction study readings are normal.43 Further research is needed to demonstrate the clinical efficacy of this diagnostic method in larger population groups.
Guillain-Barré syndrome: Therapeutic options
The standard of care for GBS in the United States is intravenous immunoglobulin (IVIG) therapy and plasmapheresis, but there is no FDA-approved treatment.44 Although the two treatments have been shown to be equally effective in early stages of disease, early relapses can occur with both. One study found that 20% of patients who underwent plasmapheresis relapsed.40 Because nearly 50% of GBS patients do not respond to IVIG or plasmapheresis, the need is urgent for new therapies to decrease the risk of permanent disability.45
Antibody therapy. Recent developments include the use of monoclonal antibodies against GBS. ANX005 is an immunoglobulin G4 recombinant antibody that inhibits complement component 1q (C1q). Activation of this protein triggers the classical complement cascade, a natural part of the innate immune system that is nonetheless inappropriately activated in some autoimmune diseases, leading to neurodegeneration as a consequence of tissue damage.
ANX005 was found to have high-binding affinity to C1q in human, rat, cynomolgus monkey, and dog sera in nonclinical trials, and demonstrated low cross-reactivity despite being a plasma protein present throughout human tissue. Furthermore, studies show that ANX005 can deplete C1q completely in the CSF of monkeys.46 Phase 1b clinical trials in Bangladesh with GBS patients (n = 23) 18 to 58 years of age against a placebo group (n = 8) indicate that treatment is well tolerated. Drug-related serious adverse events were lacking and subjects’ GBS-Disability Score improved compared with placebo controls at week 1 (r2 = 0.48; P < .0001) and week 8, when an improvement of three or more in the score was observed.40
ANX005 is entering phase 2 trials, which are expected to be completed in 2023.47
Eculizumab. This promising treatment is a monoclonal antibody against C5 convertase, an enzyme that catalyzes formation of C5b-9, a membrane attack complex in nerve membranes. Studies in mouse models showed that treatment could significantly improve symptoms of terminal motor neuropathy and completely block formation of membrane attack complexes.48 Rats in this study were paralyzed by anti-GQ1b antibodies to emulate GBS pathogenesis.
A double-blind, placebo-controlled phase 2 clinical trial in Japan enrolled 34 patients (23 assigned to receive eculizumab; 11, to placebo); all were 18 years old or older and could not walk independently (3-5 on the GBS functional grading scale). Results showed that:
- Sixteen percent more patients receiving eculizumab treatment (n = 14; 42-78 years) than in the placebo group (n = 5; 20-73 years) could walk independently after 4 weeks.
- Fifty-six percent more patients in the functional group (n = 17; 52-90 years) than in the placebo group (n = 2; 20-52 years) could run after 6 months.49 While it is noted that the first portion of the trial failed to meet the predefined significance level, its long-term effects are observed to have therapeutic potential.
Eculizumab is in phase 3 clinical trials with primary data to be released in October 2022.50
Alemtuzumab, which inhibits the CD52 gene, was found to alleviate symptoms and restore strength in a rapidly deteriorating patient with MFS and chronic lymphocytic leukemia. By week 4 of treatment, anti-GQ1B antibodies were eliminated. However, the cause of this patient’s MFS is unclear; recovery might have been the result of multiple factors.51
IgG inhibition. Additional ongoing studies include therapies geared toward the neonatal Fc receptor as a potential clinical target for IgG inhibition.52
Chronic inflammatory demyelinating polyneuropathy (CIDP): Diagnostic tools and strategies
CIDP is the most common chronic APN and shares many similarities with GBS but differs in its responsiveness to corticosteroids, prognosis, and more. Lack of consensus on diagnostic criteria for CIDP has led to reliance on nerve conduction studies and clinical findings for making the diagnosis.53
Guidelines. European Federation of Neurological Societies/Peripheral Nerve Society guidelines have high sensitivity (81%) and specificity (96%) and are utilized as diagnostic criteria for CIDP; however, a survey found that these criteria may be underutilized in clinical practice – which might contribute to a high misdiagnosis rate.54 Furthermore, although current diagnostic methods are dependent on CSF proteins, this disease is lacking a diagnostic biomarker, leading to easy overdiagnosis and unnecessary immunotherapy.55
Electrodiagnostic testing, which is often used, is limited because it cannot evaluate small-fiber nerves, cannot access the CNS adequately, and does not provide a specific diagnosis.56
Sphingomyelin in CSF. Recently, a study in Italy explored the potential of CSF sphingomyelin as a biomarker for CIDP and for GBS. Findings reveal that sphingomyelin levels can be used to diagnose more than 80% of APN cases in the clinical setting. Different levels were identified in GBS, acute inflammatory demyelinating polyneuropathy, and typical and atypical CIDP patients. Additionally, sphingomyelin showed potential to diagnose the correct stage of disease. An increase in sphingomyelin in relapsing CIDP patients was noted, compared with what was seen in controls and stable CIDP patients.57 Larger-scale studies are needed to further test the efficacy of this method.
Chronic inflammatory demyelinating polyneuropathy: Therapeutic options
First-line therapy for CIDP comprises prednisone, 60-100 mg/d, plasmapheresis, and IVIG, all of which have proved effective. Some patients respond better to one treatment than to others40; some have subpar response to all these treatments and are categorized as having refractory CIDP.45
Although there are no newly approved treatments for CIDP, several show promise in ongoing clinical trials.
Rituximab is an anti-CD20 monoclonal antibody being studied in two phase 2 clinical trials of efficacy for refractory CIDP with IgG4 autoantibodies, after showing potential efficacy.58,59
Efgartigimod is an Fc fragment that blocks the neonatal Fc receptor, prevents lysosome degradation of IgGs, and thus allows them to be “recycled.”60 These autoantibodies are crucial in disease pathology because lowering their concentration provides effective therapy.61 Phase 1 trials showed that repeated doses of efgartigimod reduced IgG levels in healthy volunteers by 50%. Repeated dosing lowered IgG levels, on average by 75% in serum, which was an effect that was sustained for an 8-week period.62 Phase 2 trials are recruiting, with a projected primary completion in 2023.
INFECTION-INDUCED PERIPHERAL NEUROPATHY
Infections have been identified as a primary cause of peripheral neuropathy. Infection-induced peripheral neuropathy has been associated with Lyme disease, Epstein-Barr and human immunodeficiency virus (HIV) infection, shingles, hepatitis B and C, diphtheria, leprosy, and rabies.63 Extensive research on peripheral neuropathy has not been completed for most of the diseases, highlighting an unmet need for patients who experience this sequela of infection.
HIV is a well-documented viral cause of peripheral neuropathy. The most common symptom is distal sensory polyneuropathy, which affects more than 50% of patients with HIV.64 The incidence of distal sensory polyneuropathy in HIV has been correlated with the use of antiretroviral therapy – specifically, tenofovir disoproxil fumarate – and with certain proteins secreted by the virus.65 Symptoms include loss of sensory properties, neuropathic pain, and allodynia.66
Diagnostic tools and strategies
Nerve conduction studies have primarily been used to diagnose HIV-induced peripheral neuropathy, as well as electrophysiological testing and noninvasive CCM. These assays can detect changes or abnormalities in large- and small-fiber nerves in HIV infection patients.66
Therapeutic options
Studies in mouse models have illustrated how the Tat protein correlates with induction of motor and sensory distal symmetric polyneuropathy. Expression of Tat can lead to mitochondrial disruption, resulting in degeneration of sensory dorsal root ganglia and subsequent neuropathic pain.67
Pirenzepine. Studies on mice have identified a potential treatment for HIV infection-induced peripheral neuropathy with pirenzepine, targeting the muscarinic subtype-1 receptor. Pirenzepine activates a molecular pathway that promotes neurite growth and mitochondrial function. Researchers found that, following treatment with pirenzepine (n = 6), there was marked reduction in mitochondrial degeneration and HIV-induced distal sensory neuropathy.66 This outcome was due to the ability of pirenzepine to block the effects of Tat protein expression, leading to reversal of its neurodegenerative effects.
Exercise combined with analgesics has also been identified as a potential treatment for alleviating distal sensory polyneuropathy in HIV infection–induced peripheral neuropathy. In a 12-week study, researchers instructed subjects who were receiving a combination of HIV treatments, including tenofovir, lamivudine, and efavirenz, to perform aerobic and resistance exercises. This regimen was intended to improve peripheral nerve-conduction velocity and increase the density of nerve fibers and neurogenic branching.
The study identified baseline pain scores and divided participants into three groups: aerobic exercise (n = 45), resistance exercise (n = 44), and controls (n = 47), for whom the average level of pain was 2 on an ascending scale of 1 to 10. There was significant reduction in pain score in the experimental groups by the end of the study, as well as an increased sensory profile.64 This study has elucidated a pain management therapy for HIV-induced peripheral neuropathy that can prove beneficial for patients.
CRYPTOGENIC SENSORY POLYNEUROPATHY
Also known as idiopathic neuropathy or small-fiber sensory peripheral neuropathy, cryptogenic sensory polyneuropathy (CSPN) affects one-third of patients with peripheral neuropathy, in whom (despite extensive testing) no known cause of their condition is revealed.
Diagnostic tools and strategies
Applicable clinical and laboratory tests of any potential known underlying causes of neuropathy, including diabetes, hereditary disorders, and autoimmune disease, must be performed to rule out those causes and suggest an idiopathic cause.68
Therapeutic options
There are no FDA-approved treatments for CSPN, as most treatments are geared toward neuropathic pain management, rehabilitation, and supportive care.68 Due to a lack of research and data regarding these types of peripheral neuropathies, various studies suggest different first-line therapies. For example, anticonvulsants (pregabalin, gabapentin), antidepressants (duloxetine), and opioid-like compounds (tramadol) are all threapy options to treat DPN.3
Adequate data are lacking to support the efficacy of immunosuppressive therapy in CSPN.
Summing up
The combination of an understanding of a widening range of underlying diseases, advancements in cancer therapies, and the rising prevalence of diabetes have all led to an increasing incidence of peripheral neuropathy. Coupled with the fact that one-third of patients with peripheral neuropathy experience idiopathic neuropathy, this indicates that extensive studies must be undertaken to identify mitigation and prevention strategies for peripheral neuropathy. To summarize the landscape of treatment for peripheral neuropathy:
Diabetic peripheral neuropathy. Treatment for DPN comprises three FDA-approved products: pregabalin, duloxetine, and a higher (8%)-strength capsaicin patch.3 Pain-management therapies also exist to reduce diabetes-induced neuropathic pain, including gabapentin, amitriptyline, and extended-release tapentadol.10
Chemotherapy-induced peripheral neuropathy has yet to be effectively treated in humans; however, many trials are being completed in animals with promising results. Treatment for CIPN has been identified using senolytic agents, such as navitoclax,22 and through inhibition of SASP by a variety of agents, including ARV825, tocilizumab, and adalimumab.23-26
Oxaliplatin-induced peripheral neuropathy. Research has identified a potential preventive agent in duloxetine, with human trials already showing efficacy and safety.29 Animal models have shown progress studying antioxidant agents, such as amifostine31 and calmangafodipir,32 which target ion channels. In a similar mechanism of action, riluzole has been observed to reduce motor and sensory deficits and depression resulting from treatment with oxaliplatin.
Vincristine-induced peripheral neuropathy. Progress has been seen in treating vincristine-induced peripheral neuropathy with pyridoxine and pyridostigmine, which have improved neuropathy scores in trial subjects;37 more studies must be completed before these agents can be established as effective therapy.
Autoimmune PN. There are no FDA-approved drugs to mitigate the peripheral neuropathy induced by GBS and CIDP; however, studies are being conducted to resolve this impediment. Potential treatments, such as ANX005, a recombinant antibody, and eculizumab, a monoclonal antibody, have both shown efficacy in human trials and provide a potential path toward treatment against peripheral neuropathy caused by GBS.47,50 CIDP is currently treated using prednisone, plasmapheresis, and IVIG.40 Clinical trials are studying the efficacy of rituximab and efgartigimod for CIDP.58-60
Infection-induced peripheral neuropathy. Although many infections can induce peripheral neuropathy, HIV is most well documented and therefore was singled out for discussion in this article. Pirenzepine has been shown to promote neurite growth and reduce mitochondrial degeneration – both of which factors are associated with reduction of neuropathic pain.66 Exercise and analgesics have also been found to mitigate the effects of HIV-induced distal sensory neuropathy, with pain scores being reduced.61
Cryptogenic sensory polyneuropathy. Research has yet to identify a causative agent of, or subsequent potential therapy for, CSPN. Increased knowledge about this neuropathy will, it is hoped, bring patients closer to a cure – beyond current pain mitigation strategies with anticonvulsants, antidepressants, and opioid-like compounds.3
Ms. Lee is a first-year master of science candidate in applied life sciences, with an emphasis on infectious diseases, and Mr. Kosacki is a first-year master of science candidate in applied life sciences, with an emphasis on translational research, both at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif. Dr. Bhandari is professor of clinical sciences and Dr. Tran is professor of clinical sciences, Keck Graduate Institute School of Pharmacy and Health Sciences.
References
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33. Poupon L et al. Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin. Neuropharmacology. 2018 Sep 15;140:43-61. doi: 10.1016/j.neuropharm.2018.07.026.
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36. Starobova H et al. Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1-beta release. J Exp Med. 2021;218(5):e20201452. doi: 10.1084/jem.20201452.
37. Aydin Köker S et al. Effect of pyridoxine plus pyridostigmine treatment on vincristine-induced peripheral neuropathy in pediatric patients with acute lymphoblastic leukemia: A single-center experience. Neurol Sci. 2021 Sep;42(9):3681-6. doi: 10.1007/s10072-020-04970-w.
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41. Leonhard SE et al. Diagnosis and management of Guillain-Barré syndrome in ten steps. Nat Rev Neurol. 2019;15(11):671-83. doi: 10.1038/s41582-019-0250-9.
42. Razali SNO et al. Serial peripheral nerve ultrasound in Guillain–Barré syndrome. Clin Neurophysiol. 2016 Nov;127(2):1652-6. doi: 10.1016/j.clinph.2015.06.030.
43. Gallardo E et al. Spinal nerve involvement in early Guillain-Barré syndrome: A clinico-electrophysiological, ultrasonographic and pathological study. Clin Neurophysiol. 2015 Apr;126(4):810-9. doi: 10.1016/j.clinph.2014.06.051.
44. Islam Z et al. Inhibition of C1q, initiator of the classical complement cascade, by ANX005 for the treatment of Guillain–Barré syndrome: Results from a phase 1b study (763). Neurology. 2020 Apr;94(15 Suppl):763.
45. Hughes R et al.; . Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): A double-blind, multicentre, randomised controlled trial. Lancet Neurol. 2018 Aug;17(8):689-98. doi: 10.1016/S1474-4422(18)30202-3.
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48. Halstead SK et al. Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model. Brain. 2008 May;131(Pt 5):1197-1208. doi: 10.1093/brain/awm316.
49. Misawa S et al. Safety and efficacy of eculizumab in Guillain-Barré syndrome: A multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018 Jun;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.
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Peripheral neuropathy is becoming an increasing focal point for clinicians when treating patients because of the plethora of causes to which the disorder has been attributed. Characterized by damage to the peripheral nervous system, peripheral neuropathy causes sharp, burning pain; numbness of the extremities that can travel proximally; muscle weakness; and an overall diminished quality of life. Rather than being a self-developing disease, peripheral neuropathy has mostly been identified as a symptom of causative disorders and therapeutic agents – making prevention and treatment extremely important for patients and providers.
The etiology of peripheral neuropathy has been studied thoroughly over the past 2 decades. In this review, we summarize the landscape of peripheral neuropathy, including the more common causative entities; diagnostic tools that can potentially be employed to identify the disorder; and treatments that are in use or being tested to prevent, slow, or reverse the effects of peripheral neuropathy.
DIABETIC PERIPHERAL NEUROPATHY
The most common cause of peripheral neuropathy is diabetes mellitus. Diabetic peripheral neuropathy (DPN) is a symmetrical, length-dependent neuropathy that affects more than 50% of type I and type II diabetes patients.1 Not only is DPN an initiating factor of foot ulcers and nontraumatic lower-limb amputation, but it also leads to a severely lower quality of life, financial burden, and increased risk of death after major surgical procedures.2
Once DPN has progressed significantly, its effects are irreversible; there are no agents capable of reversing or halting DPN past initial stages of disease.3 It is important to detect and treat DPN early on, as it has a favorable prognosis and most DPN-related amputations are preventable.
Diagnosis
Nerve-conduction studies are the preferred diagnostic tool for DPN; however, these studies are costly and difficult to conduct in a clinical setting.2 Currently, such diagnostic tools as the 10-g monofilament and tuning fork are more commonly utilized to detect loss of protective foot sensation to decrease the risk of foot ulceration.2 In addition, other common aspects of diagnosing DPN include assessment of symptoms in the patient’s hands or feet and patient-reported symptoms.
Several diagnostic devices are in experimental stages and have shown potential for utilization in clinical settings.
DPNCheck is a handheld device, with a turnaround time of 3 minutes, that measures sural nerve conduction velocity, which can identify DPN early in asymptomatic cases; and amplitude of sensory-nerve action potentials, which decrease with the degeneration of axons, a clinical characteristic of DPN. In a study of patients with diabetes (n = 162 [type 1, n = 80; type 2, n = 82]) and healthy controls (n = 80), a comparative analysis of DPNCheck and reference techniques showed a strong linear relationship between between clinical neuropathy scores and LDIFLARE (r = 0.64-0.84; P < 0.03), which suggests that the device might be viable in clinical settings.4 LDIFLARE is a method developed to assess axon reflex to detect neuropathy in type 2 diabetes.4
Neuropad, a 10-minute test, measures foot plantar-surface sweat production, indicated by a cobalt compound color change on the device. The test is advantageous because it is highly sensitive – 73% more sensitive than DPNCheck – and does not rely on patient response or require operator training.5 A study of Neuropad showed that a drier foot and, therefore, increased risk of foot ulceration correlated with greater abnormal readings on the device, which might indicate onset of more severe DPN in the future.6
Sudoscan measures sudomotor function in 3 minutes through an electrochemical reaction between stimulated sweat glands and electrodes.2 A study performed in China in patients with type 2 diabetes (n = 394) showed that electrical conductance in the feet is associated with increasing risk and severity of symptoms of DPN in asymptomatic patients (r = 0.98 [95% confidence interval, 0.962-0.993]; P < .01) and might serve as a biomarker of DPN.7
Although these three techniques present favorable data, each is a nerve conduction study that can access only small-fiber nerves. Additional testing is required for larger-fiber nerves that are also affected by DPN.2 Also, some of the studies of these devices have high heterogeneity and a small sample size. Further research utilizing these three methods should include larger sample sizes to appropriately assess any clinically significant patient outcomes.
Corneal confocal microscopy (CCM), another potential technique for DPN screening, is a noninvasive ophthalmic device for assessing corneal small-fiber nerves. A study of patients with diabetes or obesity or both (n = 35) showed high reproducibility of corneal-nerve pathology identification using CCM.8 A larger-scale study showed that CCM can detect a reduction in corneal-nerve parameters in DPN patients, as well as in patients who have yet to develop DPN – thus demonstrating the technique’s ability to detect both early subclinical and established DPN.9 Once CCM is approved as a point-of-care device, it might provide a reliable, sensitive screening method for DPN as an early-intervention tool.
Therapeutic options
The three principal types of treatment for DPN are tricyclic antidepressants, anticonvulsants, and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs). Only three medications are Food and Drug Administration (FDA) approved for the treatment of DPN: pregabalin, duloxetine, and the recently approved capsaicin patch. Some opioid analgesics, including extended-release tapentadol, are FDA approved for DPN-associated neuropathic pain; however, evidence of their efficacy is questionable, and they present a risk of addiction.10 Here, we focus on potential treatments for DPN and DPN-associated neuropathic pain.
Cinacalcet. Several potential treatments have been studied for alleviating DPN symptoms after progression. Cinacalcet is a calcimimetic agent that activates the adenosine monophosphate-activated protein kinase–endothelial nitric oxide synthase pathway, which mediates DPN development. The drug has shown evidence of improving sensorimotor function and restoring nerve function in human Schwann cells expressed in diabetes-induced mice.11 In these animal models, cinacalcet improved tactile response when interventional mice were compared with a control group (P < .01).11 Further research is necessary to determine similar efficacy in human subjects.
Traditional Chinese medicine. Recent studies have focused on traditional Chinese medicine and practice, such as acupuncture and moxibustion, for DPN.
Moxibustion is the technique of burning moxa floss (a plant also known as mugwort) on different points on the body, which is thought to alleviate disease. In a study performed on rats, moxibustion increased nerve velocity (P < .05) and preserved sciatic-nerve ultrastructure.12 Research on the use of moxibustion is preliminary. A meta-analysis of available data found that all clinical studies took place in China, and results were therefore subject to high heterogeneity and small sample size.13 Previously, a lack of high-quality data prevented moxibustion from being considered a potential treatment.3 The technique has demonstrated potential benefit, but larger-scale and more rigorous studies must be utilized to verify its clinical efficacy.
Quercetin. This common dietary flavonoid is in development. In rat models with induced DPN, treatment produced significant neuroprotective effects, such as rescued mechanical withdrawal threshold, lowered nerve densities (P = .0378), and rescued lowered levels of reactive O2 species (P < .0001), which contribute to neurotoxicity in many peripheral neuropathies.14 Another study of the anti-inflammatory effects of quercetin in rat models found significant lowering of inflammatory factors, including proteins encoded by toll-like receptor 4 and MyD88, and protein transcription factor nuclear factor kappa B (P < .001), which can be beneficial in the treatment of DPN.15 Future testing in human subjects might reveal similarly positive effects.
Vitamin B. A systematic review examined the therapeutic effects of vitamin B supplementation on DPN. Through a meta-analysis on 14 studies (N = 997), it was revealed that statistically significant improvements in pain and electrophysiological sensory outcomes were observed after vitamin B supplementation. However, the majority of the studies included in the analysis utilized combination therapies with different vitamins (such as vitamin D) and other vitamin B types. Furthermore, deficiencies in B vitamins – especially folic acid and vitamin B12 – have been observed in diabetic patients, and may be the potential cause of DPN in them. The validity of the studies and their findings are weakened by this observation. Therefore, the clinical efficacy of individual B vitamin supplements must be evaluated in long-term, larger scale future studies that exclude those with B vitamin deficiency and DPN to minimize potential error.71
CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY
Another cause of peripheral neuropathy has been directly linked to particular chemotherapeutic agents. Platinum-based agents have been widely accepted as an ideal solution for slowing tumor progression; however, it has been established that platinum adducts within DNA are the cause of neuronal degeneration – specifically in dorsal-root ganglion neurons of the peripheral nervous system. In a 2010 meta-analysis in the United States, the prevalence of chemotherapy-induced peripheral neuropathy (CIPN) was observed to range from 65% to 75%, depending on the platinum-based agent.16 This problem is often dose-limiting and can lead to cessation of treatment, causing patients physical and financial harm. CIPN can be acute or chronic, and symptoms affect motor, sensory, and autonomic function, which can lead to reduced quality of life.17
Diagnostic tools and strategies
A variety of avenues can be taken to assess whether a patient has CIPN. Because peripheral neuropathy is often subjective, it has been recommended that clinicians use patient-reported outcome measures in this setting, in the form of a questionnaire.
Common toxicity criteria. The most conventional measure of CIPN is the National Cancer Institute’s Common Toxicity Criteria, which grades severity of adverse effects on a scale of 1 to 5 and has been found to be statistically valid.18 This questionnaire assesses a patient’s neuropathic pain score and sensory deficits, and can detect other potential adverse findings, such as neutropenia.
Total neuropathy score. This commonly used questionnaire measures subjective autonomic, sensory, and motor symptoms on a scale of 0 to 4 for each item, with the individual item scores then summed. A score > 5 indicates CIPN.19 The tested validity of this measure shows that it has an inter-rater reliability of 0.966 and an intra-rater reliability of 0.986.19
Other questionnaires. The Neuropathy Screening Questionnaire, Treatment-Induced Neuropathy Assessment Scale, and Chemotherapy-Induced Peripheral Neuropathy Assessment Tool have been identified as means of understanding what a patient experiences following neurotoxic chemotherapy.18
Pain caused by CIPN can also be assessed with one of several general scales, such as the Neuropathic Pain Scale for Chemotherapy-Induced Neuropathy (NPS-CIN), which identifies a patient’s level of pain on a scale from 0 to 4 on six items: intensity, unpleasantness, sharpness, depth, numbness, and tingling. This scale has been found to be reliable.18
Other scales that can be used are the Neuropathic Pain Symptom Inventory, Patient-Reported Outcomes Measurement Information System: Pain Quality Neuro, and Leeds Assessment of Neuropathic Symptoms and Signs.18
Other diagnostic tests. Tests to determine a chemotherapy patient’s functional ability regarding their extremities include postural stability tests, the Timed Up and Go (TUG) test, the Fullerton Advance Balance (FAB) Scale, the 6-minute walk test, and the grooved pegboard test.
Nerve conduction studies have been identified as useful tools to assess the physiologic function of fibers, but are costly and used most often in research settings.18 Quantitative sensory testing and the Bumps test are used to assess threshold capacities for varying sensations. Nerve-imaging tools, such as high-resolution ultrasonography, magnetic resonance neurography, and positron emission and computed tomography, have been found to be successful in identifying nerve damage.18
Additionally, the accumulation of mitochondrial DNA (mtDNA) in the blood has been identified as a potential biomarker for CIPN following animal trials on rats.69 Researchers conducted a double-blind trial where healthy rats were given doses of paclitaxel, oxaliplatin, and bortezomib and compared to vehicle-treated rats. Researchers found that there was a correlation between the onset of CIPN and levels of mtDNA, with 1-2-fold increases of mtDNA found in paclitaxel and oxaliplatin treated patients (P < 0.01).69 Dysfunctional mitochondria can cause an increase in the activity of reactive oxygen species which results in damage to mtDNA; and abnormal bioenergetics, which may lead to irregular ATP production and result in cellular damage.
Navitoclax. The antineoplastic agent cisplatin is used to treat a variety of cancers, including ovarian, lung, head and neck, testicular, and bladder.20 Using single-cell RNA sequencing of dorsal-root ganglion cells in mouse models that have been given human equivalent doses of cisplatin to induce peripheral neuropathy, a study identified that the drug was upregulating the cyclin-dependent kinase inhibitor 1A gene (CDKN1A) and leading to overproduction of its product, the p21 protein.21 This is due to a cellular response to DNA damage that causes the dorsal-root ganglion sensory neuron to change into a senescence-like state to survive. Subsequently, accumulation of senescent sensory neurons correlates with induction of neuropathic pain and peripheral neuropathy. It has been established, in mouse models, that removing senescent cells has the potential to reduce or reverse peripheral neuropathy associated with cisplatin treatment.21
A study induced irreversible CIPN using cisplatin on mice that were subsequently treated with antineoplastic agent navitoclax (n = 5) or vehicle (n = 10). Using navitoclax, a broad-spectrum senolytic agent, the study examined the dorsal-root ganglia of the mice and found that CIPN was reversed following clearance of senescent cells, with baseline mechanical thresholds able to be reestablished without difference, compared with the control group (P = .7734).22 The investigators found that clearance of senescent cells using navitoclax proved a promising avenue toward mitigating CIPN. More studies should be completed to validate this treatment as an effective preventive.
NGF Monoclonal Antibody (Tanezumab). Tanezumab has been identified as a potential analgesic for CIPN having observed success during animal trials. This monoclonal antibody targets the NGF-TrkA pathway in a dose-dependent manner which results in a reduction of neuronal sensitivity and subsequently neuropathic pain (P < 0.05).70 NGF is a peripheral pain mediator that has functional properties relating to inflammation and neuropathy. Therefore, by targeting this protein and inhibiting its activation, patients could potentially see a dramatic improvement in their quality of life following a CIPN diagnosis. This potential analgesic was observed to be successful for a variety of chemotherapeutic agents including cisplatin, vincristine, and paclitaxel.70
SASP inhibitors. A second possible approach to neutralizing senescent cells would be by inhibiting the senescence-associated secretory phenotype (SASP). This could be accomplished through the use of nuclear factor kappa B inhibitors, mammalian target of rapamycin (mTOR) inhibitors, bromodomain and extra-terminal (BET) inhibitors, and inhibitors of secretory factors, such as interleukin (IL)-6 and tumor necrosis factor (TNF) alpha.23 Rapamycin, an mTOR inhibitor that is already used in clinical settings, has been found to reduce the inflammatory effects of senescent cells, expanding the lifespan of mice.24 JQ1, OTX015, and ARV825 are BET inhibitors that have been found to block bromodomain-containing protein 4, thus inducing senescent cell death.25 IL-6 inhibitors (for example, tocilizumab) and TNF alpha inhibitors (for example, adalimumab) are already used clinically and can mitigate the effects of SASP.23,26 However, further studies are needed to examine potential adverse effects of this type of therapy.
Mitigation of oxaliplatin adverse effects. This platinum-based chemotherapeutic agent associated with peripheral neuropathy is primarily used to treat colorectal cancer and digestive-tract malignancies.27 Oxaliplatin-induced peripheral neuropathy (OIPN) can be acute or chronic, and causes neuropathic pain, autonomic nerve dysfunction, and hypersensitivity to cold, which lead to abnormal nervous system effects, such as peripheral paresthesia.
These symptoms derive from oxaliplatin’s effects on a variety of cellular mechanisms, and differ in chronic and acute OIPN. Acute OIPN includes abnormal changes to sodium, potassium, calcium, and transient receptor potential channels, which lead to dysregulation and dysfunction in peripheral neurons; glia activation associated with dysregulation of pain modulation, by reducing thresholds; and upregulation of the octamer-binding transcription factor (OCT) protein.
Chronic OIPN has been associated with damage to nuclear DNA by platinum adducts, mitochondrial dysfunction (due to oxidative stress), and neuroinflammation caused by glia activation and gut microbiota.28
With increased understanding regarding cellular mechanisms affected in OIPN, treatment options are being established to prevent or reduce its effects. A treatment being tested for the treatment of OIPN is the serotonin and norepinephrine reuptake inhibitor (SSNRI) antidepressant duloxetine.29 In a clinical trial of 40 patients with gastrointestinal cancer, duloxetine was found to reduce cold sensitivity (P = .001), tingling or discomfort of hands (P < .002) and feet (P = .017), and peripheral neuropathic pain (P = .001), and was found to prevent paresthesia (P = .025).29 The SNRI antidepressant venlafaxine has also shown that it can alleviate neuropathic pain and motor neuropathy in clinical trials.30
Antioxidant agents, such as amifostine and calmangafodipir, have also been identified as possible preventive measures against OIPN. Amifostine prevents neuronal hyperactivation and nitrosative stress, while calmangafodipir modulates reactive O2 species, regulates ion channels, and protects axons and the myelin sheath.31,32
Treatments such as riluzole, lidocaine, and pregabalin have all shown promise in reducing the effects of OIPN by their action on potassium, sodium, and calcium channels, respectively.28 A study conducted on mice (n = 565) with OIPN found that riluzole effectively mitigated motor and sensory deficits associated with the use of oxaliplatin.33
TREK-1 and TRAAK, potassium channels that are important for thermal and motor sensitivity, and that act as silencing mechanisms to excitatory stimuli, were shown to degenerate following oxaliplatin treatment, leading to hypersensitivity. Riluzole performs its therapeutic function by activating TREK-1 and TRAAK channels and blocking excessive accumulation of glutamate. Following riluzole treatment, mice were observed to show a significant reduction in sensorimotor deficits. Interestingly, riluzole also aided in reducing depression associated with oxaliplatin (P < .01).33 However, more studies are necessary to ensure the safety and efficacy of riluzole in humans.
Pyridoxine, pyridostigmine for vincristine-induced peripheral neuropathy. Vinca alkaloids have also been identified as chemotherapeutic agents that induce peripheral neuropathy. One such agent, vincristine, which is used primarily to treat leukemia and brain cancer, has been observed to cause peripheral neuropathy, including motor, autonomic, and sensory symptoms, such as abnormal gait, mechanical allodynia, paresthesia, ptosis, and obstipation, and altered perception of stimuli.34,35 These symptoms are caused primarily by the ability of vincristine to activate neuroinflammatory mechanisms in dorsal-root ganglia. This is caused by activation of nucleotide-binding oligomerization domain 3 (NLRP3)-dependent release of IL-1b and subsequent cleavage of gasdermin D and caspase-1 in macrophages (observed in mouse models). Vincristine activates the NLRP3 signaling cascade that results in production of proinflammatory cytokines, thus inducing symptoms of peripheral neuropathy.36
Pyridoxine and pyridostigmine have been introduced as potential treatments for vincristine-induced peripheral neuropathy. Following a clinical trial of pediatric acute lymphoblastic leukemia patients, a study of 23 patients with vincristine-induced peripheral neuropathy found statistical validity for using pyridoxine and pyridostigmine because the drugs improved the neuropathy score (P < .001).37 However, more research is needed before implementing their use in point-of-care settings.
AUTOIMMUNE PERIPHERAL NEUROPATHY
Autoimmune peripheral neuropathies (APNs) occur when the immune system targets peripheral nervous system and its various cells. Although there is a wide range of conditions in this category of peripheral neuropathy, the two most common types – Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) – have been targeted for clinical research.
Guillain-Barré syndrome: Diagnostic tools and strategies
Guillain-Barré syndrome encompasses a variety of acute inflammatory polyneuropathies, including axonal motor, sensory, and autonomic neuropathies and Miller Fisher syndrome (MFS).38 In particular, the anti-GQ1b ganglioside antibody is considered archetypical in APNs because it is detected in MFS patients and not found in normal and disease-control samples, which makes it a good clinical marker.39
It is difficult to distinguish GBS from CIDP because the time frame of onset of maximum deficit of neuropathy – 4 weeks – can overlap with subacute CIDP symptoms.40 Current diagnosis is based on elevated levels of cerebrospinal fluid (CSF) proteins, which can increase fourfold 6 weeks into the early phase of disease, and nerve conduction studies.40 However, electrodiagnostic readings and CSF protein levels are normal in 30% to 50% of patients in the first week after onset of disease and must be repeated in weeks that follow.41 A major disadvantage in the workup of suspected GBS is that the syndrome can be confirmed only several weeks after onset of symptoms.
Ultrasonography. A potential new diagnostic tool is serial peripheral nerve ultrasonographic (US) imaging. A pilot study of GBS patients (n = 16) showed that US can detect enlarged nerve cross-sections in median, ulnar, and sural nerves in the first 3 weeks of disease. Imaging performance was consistent with that of nerve conduction studies, and was advantageous because US is easier to perform and for patients to undergo.42
Spinal inflammation. Another study hints at the importance of spinal-root inflammation as an early indicator of disease, especially when nerve conduction study readings are normal.43 Further research is needed to demonstrate the clinical efficacy of this diagnostic method in larger population groups.
Guillain-Barré syndrome: Therapeutic options
The standard of care for GBS in the United States is intravenous immunoglobulin (IVIG) therapy and plasmapheresis, but there is no FDA-approved treatment.44 Although the two treatments have been shown to be equally effective in early stages of disease, early relapses can occur with both. One study found that 20% of patients who underwent plasmapheresis relapsed.40 Because nearly 50% of GBS patients do not respond to IVIG or plasmapheresis, the need is urgent for new therapies to decrease the risk of permanent disability.45
Antibody therapy. Recent developments include the use of monoclonal antibodies against GBS. ANX005 is an immunoglobulin G4 recombinant antibody that inhibits complement component 1q (C1q). Activation of this protein triggers the classical complement cascade, a natural part of the innate immune system that is nonetheless inappropriately activated in some autoimmune diseases, leading to neurodegeneration as a consequence of tissue damage.
ANX005 was found to have high-binding affinity to C1q in human, rat, cynomolgus monkey, and dog sera in nonclinical trials, and demonstrated low cross-reactivity despite being a plasma protein present throughout human tissue. Furthermore, studies show that ANX005 can deplete C1q completely in the CSF of monkeys.46 Phase 1b clinical trials in Bangladesh with GBS patients (n = 23) 18 to 58 years of age against a placebo group (n = 8) indicate that treatment is well tolerated. Drug-related serious adverse events were lacking and subjects’ GBS-Disability Score improved compared with placebo controls at week 1 (r2 = 0.48; P < .0001) and week 8, when an improvement of three or more in the score was observed.40
ANX005 is entering phase 2 trials, which are expected to be completed in 2023.47
Eculizumab. This promising treatment is a monoclonal antibody against C5 convertase, an enzyme that catalyzes formation of C5b-9, a membrane attack complex in nerve membranes. Studies in mouse models showed that treatment could significantly improve symptoms of terminal motor neuropathy and completely block formation of membrane attack complexes.48 Rats in this study were paralyzed by anti-GQ1b antibodies to emulate GBS pathogenesis.
A double-blind, placebo-controlled phase 2 clinical trial in Japan enrolled 34 patients (23 assigned to receive eculizumab; 11, to placebo); all were 18 years old or older and could not walk independently (3-5 on the GBS functional grading scale). Results showed that:
- Sixteen percent more patients receiving eculizumab treatment (n = 14; 42-78 years) than in the placebo group (n = 5; 20-73 years) could walk independently after 4 weeks.
- Fifty-six percent more patients in the functional group (n = 17; 52-90 years) than in the placebo group (n = 2; 20-52 years) could run after 6 months.49 While it is noted that the first portion of the trial failed to meet the predefined significance level, its long-term effects are observed to have therapeutic potential.
Eculizumab is in phase 3 clinical trials with primary data to be released in October 2022.50
Alemtuzumab, which inhibits the CD52 gene, was found to alleviate symptoms and restore strength in a rapidly deteriorating patient with MFS and chronic lymphocytic leukemia. By week 4 of treatment, anti-GQ1B antibodies were eliminated. However, the cause of this patient’s MFS is unclear; recovery might have been the result of multiple factors.51
IgG inhibition. Additional ongoing studies include therapies geared toward the neonatal Fc receptor as a potential clinical target for IgG inhibition.52
Chronic inflammatory demyelinating polyneuropathy (CIDP): Diagnostic tools and strategies
CIDP is the most common chronic APN and shares many similarities with GBS but differs in its responsiveness to corticosteroids, prognosis, and more. Lack of consensus on diagnostic criteria for CIDP has led to reliance on nerve conduction studies and clinical findings for making the diagnosis.53
Guidelines. European Federation of Neurological Societies/Peripheral Nerve Society guidelines have high sensitivity (81%) and specificity (96%) and are utilized as diagnostic criteria for CIDP; however, a survey found that these criteria may be underutilized in clinical practice – which might contribute to a high misdiagnosis rate.54 Furthermore, although current diagnostic methods are dependent on CSF proteins, this disease is lacking a diagnostic biomarker, leading to easy overdiagnosis and unnecessary immunotherapy.55
Electrodiagnostic testing, which is often used, is limited because it cannot evaluate small-fiber nerves, cannot access the CNS adequately, and does not provide a specific diagnosis.56
Sphingomyelin in CSF. Recently, a study in Italy explored the potential of CSF sphingomyelin as a biomarker for CIDP and for GBS. Findings reveal that sphingomyelin levels can be used to diagnose more than 80% of APN cases in the clinical setting. Different levels were identified in GBS, acute inflammatory demyelinating polyneuropathy, and typical and atypical CIDP patients. Additionally, sphingomyelin showed potential to diagnose the correct stage of disease. An increase in sphingomyelin in relapsing CIDP patients was noted, compared with what was seen in controls and stable CIDP patients.57 Larger-scale studies are needed to further test the efficacy of this method.
Chronic inflammatory demyelinating polyneuropathy: Therapeutic options
First-line therapy for CIDP comprises prednisone, 60-100 mg/d, plasmapheresis, and IVIG, all of which have proved effective. Some patients respond better to one treatment than to others40; some have subpar response to all these treatments and are categorized as having refractory CIDP.45
Although there are no newly approved treatments for CIDP, several show promise in ongoing clinical trials.
Rituximab is an anti-CD20 monoclonal antibody being studied in two phase 2 clinical trials of efficacy for refractory CIDP with IgG4 autoantibodies, after showing potential efficacy.58,59
Efgartigimod is an Fc fragment that blocks the neonatal Fc receptor, prevents lysosome degradation of IgGs, and thus allows them to be “recycled.”60 These autoantibodies are crucial in disease pathology because lowering their concentration provides effective therapy.61 Phase 1 trials showed that repeated doses of efgartigimod reduced IgG levels in healthy volunteers by 50%. Repeated dosing lowered IgG levels, on average by 75% in serum, which was an effect that was sustained for an 8-week period.62 Phase 2 trials are recruiting, with a projected primary completion in 2023.
INFECTION-INDUCED PERIPHERAL NEUROPATHY
Infections have been identified as a primary cause of peripheral neuropathy. Infection-induced peripheral neuropathy has been associated with Lyme disease, Epstein-Barr and human immunodeficiency virus (HIV) infection, shingles, hepatitis B and C, diphtheria, leprosy, and rabies.63 Extensive research on peripheral neuropathy has not been completed for most of the diseases, highlighting an unmet need for patients who experience this sequela of infection.
HIV is a well-documented viral cause of peripheral neuropathy. The most common symptom is distal sensory polyneuropathy, which affects more than 50% of patients with HIV.64 The incidence of distal sensory polyneuropathy in HIV has been correlated with the use of antiretroviral therapy – specifically, tenofovir disoproxil fumarate – and with certain proteins secreted by the virus.65 Symptoms include loss of sensory properties, neuropathic pain, and allodynia.66
Diagnostic tools and strategies
Nerve conduction studies have primarily been used to diagnose HIV-induced peripheral neuropathy, as well as electrophysiological testing and noninvasive CCM. These assays can detect changes or abnormalities in large- and small-fiber nerves in HIV infection patients.66
Therapeutic options
Studies in mouse models have illustrated how the Tat protein correlates with induction of motor and sensory distal symmetric polyneuropathy. Expression of Tat can lead to mitochondrial disruption, resulting in degeneration of sensory dorsal root ganglia and subsequent neuropathic pain.67
Pirenzepine. Studies on mice have identified a potential treatment for HIV infection-induced peripheral neuropathy with pirenzepine, targeting the muscarinic subtype-1 receptor. Pirenzepine activates a molecular pathway that promotes neurite growth and mitochondrial function. Researchers found that, following treatment with pirenzepine (n = 6), there was marked reduction in mitochondrial degeneration and HIV-induced distal sensory neuropathy.66 This outcome was due to the ability of pirenzepine to block the effects of Tat protein expression, leading to reversal of its neurodegenerative effects.
Exercise combined with analgesics has also been identified as a potential treatment for alleviating distal sensory polyneuropathy in HIV infection–induced peripheral neuropathy. In a 12-week study, researchers instructed subjects who were receiving a combination of HIV treatments, including tenofovir, lamivudine, and efavirenz, to perform aerobic and resistance exercises. This regimen was intended to improve peripheral nerve-conduction velocity and increase the density of nerve fibers and neurogenic branching.
The study identified baseline pain scores and divided participants into three groups: aerobic exercise (n = 45), resistance exercise (n = 44), and controls (n = 47), for whom the average level of pain was 2 on an ascending scale of 1 to 10. There was significant reduction in pain score in the experimental groups by the end of the study, as well as an increased sensory profile.64 This study has elucidated a pain management therapy for HIV-induced peripheral neuropathy that can prove beneficial for patients.
CRYPTOGENIC SENSORY POLYNEUROPATHY
Also known as idiopathic neuropathy or small-fiber sensory peripheral neuropathy, cryptogenic sensory polyneuropathy (CSPN) affects one-third of patients with peripheral neuropathy, in whom (despite extensive testing) no known cause of their condition is revealed.
Diagnostic tools and strategies
Applicable clinical and laboratory tests of any potential known underlying causes of neuropathy, including diabetes, hereditary disorders, and autoimmune disease, must be performed to rule out those causes and suggest an idiopathic cause.68
Therapeutic options
There are no FDA-approved treatments for CSPN, as most treatments are geared toward neuropathic pain management, rehabilitation, and supportive care.68 Due to a lack of research and data regarding these types of peripheral neuropathies, various studies suggest different first-line therapies. For example, anticonvulsants (pregabalin, gabapentin), antidepressants (duloxetine), and opioid-like compounds (tramadol) are all threapy options to treat DPN.3
Adequate data are lacking to support the efficacy of immunosuppressive therapy in CSPN.
Summing up
The combination of an understanding of a widening range of underlying diseases, advancements in cancer therapies, and the rising prevalence of diabetes have all led to an increasing incidence of peripheral neuropathy. Coupled with the fact that one-third of patients with peripheral neuropathy experience idiopathic neuropathy, this indicates that extensive studies must be undertaken to identify mitigation and prevention strategies for peripheral neuropathy. To summarize the landscape of treatment for peripheral neuropathy:
Diabetic peripheral neuropathy. Treatment for DPN comprises three FDA-approved products: pregabalin, duloxetine, and a higher (8%)-strength capsaicin patch.3 Pain-management therapies also exist to reduce diabetes-induced neuropathic pain, including gabapentin, amitriptyline, and extended-release tapentadol.10
Chemotherapy-induced peripheral neuropathy has yet to be effectively treated in humans; however, many trials are being completed in animals with promising results. Treatment for CIPN has been identified using senolytic agents, such as navitoclax,22 and through inhibition of SASP by a variety of agents, including ARV825, tocilizumab, and adalimumab.23-26
Oxaliplatin-induced peripheral neuropathy. Research has identified a potential preventive agent in duloxetine, with human trials already showing efficacy and safety.29 Animal models have shown progress studying antioxidant agents, such as amifostine31 and calmangafodipir,32 which target ion channels. In a similar mechanism of action, riluzole has been observed to reduce motor and sensory deficits and depression resulting from treatment with oxaliplatin.
Vincristine-induced peripheral neuropathy. Progress has been seen in treating vincristine-induced peripheral neuropathy with pyridoxine and pyridostigmine, which have improved neuropathy scores in trial subjects;37 more studies must be completed before these agents can be established as effective therapy.
Autoimmune PN. There are no FDA-approved drugs to mitigate the peripheral neuropathy induced by GBS and CIDP; however, studies are being conducted to resolve this impediment. Potential treatments, such as ANX005, a recombinant antibody, and eculizumab, a monoclonal antibody, have both shown efficacy in human trials and provide a potential path toward treatment against peripheral neuropathy caused by GBS.47,50 CIDP is currently treated using prednisone, plasmapheresis, and IVIG.40 Clinical trials are studying the efficacy of rituximab and efgartigimod for CIDP.58-60
Infection-induced peripheral neuropathy. Although many infections can induce peripheral neuropathy, HIV is most well documented and therefore was singled out for discussion in this article. Pirenzepine has been shown to promote neurite growth and reduce mitochondrial degeneration – both of which factors are associated with reduction of neuropathic pain.66 Exercise and analgesics have also been found to mitigate the effects of HIV-induced distal sensory neuropathy, with pain scores being reduced.61
Cryptogenic sensory polyneuropathy. Research has yet to identify a causative agent of, or subsequent potential therapy for, CSPN. Increased knowledge about this neuropathy will, it is hoped, bring patients closer to a cure – beyond current pain mitigation strategies with anticonvulsants, antidepressants, and opioid-like compounds.3
Ms. Lee is a first-year master of science candidate in applied life sciences, with an emphasis on infectious diseases, and Mr. Kosacki is a first-year master of science candidate in applied life sciences, with an emphasis on translational research, both at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif. Dr. Bhandari is professor of clinical sciences and Dr. Tran is professor of clinical sciences, Keck Graduate Institute School of Pharmacy and Health Sciences.
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56. Ginsberg MR et al. Using and interpreting electrodiagnostic tests. Cleve Clin J Med. 2020 Nov 2;87(11):671-82. doi: 10.3949/ccjm.87a.19154.
57. Capodivento G et al. CSF sphingomyelin: A new biomarker of demyelination in the diagnosis and management of CIDP and GBS. J Neurol Neurosurg Psychiatry. 2021;92(3):303-10. doi: 10.1136/jnnp-2020-324445.
58. Shimizu S et al. Efficacy and safety of rituximab in refractory CIDP with or without IgG4 autoantibodies (RECIPE): Protocol for a double-blind, randomized, placebo-controlled clinical trial. JMIR Res Protoc. 2020 Jan 4;9(4):e17117. doi: 10.2196/17117.
59. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet. 1997;349(9047):225-30.
60. Zuercher AW et al. Next-generation Fc receptor–targeting biologics for autoimmune diseases. Autoimmun Rev. 2019 Oct;18(10):102366. doi: 10.1016/j.autrev.2019.102366.
61. Sesarman A et al. The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases. Cell Mol Life Sci. 2010 Aug;67(15):2533-50. doi: 10.1007/s00018-010-0318-6.
62. Ulrichts P et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest. 2018 Oct;128(10):4372-86. doi: 10.1172/JCI97911.
63. Peripheral neuropathy [symptoms and causes]. Mayo Clinic [Internet]. Accessed Feb 23, 2022. http://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/symptoms-causes/syc-20352061.
64. Maharaj SS, Yakasai AM. Does a rehabilitation program of aerobic and progressive resisted exercises influence HIV-induced distal neuropathic pain? Am J Phys Med Rehabil. 2018 May;97(5):364-9. doi: 10.1097/PHM.0000000000000866.
65. Fields JA et al. Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice. Sci Rep. 2019 Nov 20;9(1):17158. doi: 10.1038/s41598-019-53466-x.
66. Han MM et al. Prevention of HIV-1 TAT protein-induced peripheral neuropathy and mitochondrial disruption by the antimuscarinic pirenzepine. Front Neurol. 2021 Jun 15;12:663373. doi: 10.3389/fneur.2021.663373.
67. Rozzi SJ et al. Human immunodeficiency virus Tat impairs mitochondrial fission in neurons. Cell Death Discov. 2018;4:8. doi: 10.1038/s41420-017-0013-6.
68. Pasnoor M et al. Cryptogenic sensory polyneuropathy. Neurol Clin. 2013 May;31(2):463-76. doi: 10.1016/j.ncl.2013.01.008.
Peripheral neuropathy is becoming an increasing focal point for clinicians when treating patients because of the plethora of causes to which the disorder has been attributed. Characterized by damage to the peripheral nervous system, peripheral neuropathy causes sharp, burning pain; numbness of the extremities that can travel proximally; muscle weakness; and an overall diminished quality of life. Rather than being a self-developing disease, peripheral neuropathy has mostly been identified as a symptom of causative disorders and therapeutic agents – making prevention and treatment extremely important for patients and providers.
The etiology of peripheral neuropathy has been studied thoroughly over the past 2 decades. In this review, we summarize the landscape of peripheral neuropathy, including the more common causative entities; diagnostic tools that can potentially be employed to identify the disorder; and treatments that are in use or being tested to prevent, slow, or reverse the effects of peripheral neuropathy.
DIABETIC PERIPHERAL NEUROPATHY
The most common cause of peripheral neuropathy is diabetes mellitus. Diabetic peripheral neuropathy (DPN) is a symmetrical, length-dependent neuropathy that affects more than 50% of type I and type II diabetes patients.1 Not only is DPN an initiating factor of foot ulcers and nontraumatic lower-limb amputation, but it also leads to a severely lower quality of life, financial burden, and increased risk of death after major surgical procedures.2
Once DPN has progressed significantly, its effects are irreversible; there are no agents capable of reversing or halting DPN past initial stages of disease.3 It is important to detect and treat DPN early on, as it has a favorable prognosis and most DPN-related amputations are preventable.
Diagnosis
Nerve-conduction studies are the preferred diagnostic tool for DPN; however, these studies are costly and difficult to conduct in a clinical setting.2 Currently, such diagnostic tools as the 10-g monofilament and tuning fork are more commonly utilized to detect loss of protective foot sensation to decrease the risk of foot ulceration.2 In addition, other common aspects of diagnosing DPN include assessment of symptoms in the patient’s hands or feet and patient-reported symptoms.
Several diagnostic devices are in experimental stages and have shown potential for utilization in clinical settings.
DPNCheck is a handheld device, with a turnaround time of 3 minutes, that measures sural nerve conduction velocity, which can identify DPN early in asymptomatic cases; and amplitude of sensory-nerve action potentials, which decrease with the degeneration of axons, a clinical characteristic of DPN. In a study of patients with diabetes (n = 162 [type 1, n = 80; type 2, n = 82]) and healthy controls (n = 80), a comparative analysis of DPNCheck and reference techniques showed a strong linear relationship between between clinical neuropathy scores and LDIFLARE (r = 0.64-0.84; P < 0.03), which suggests that the device might be viable in clinical settings.4 LDIFLARE is a method developed to assess axon reflex to detect neuropathy in type 2 diabetes.4
Neuropad, a 10-minute test, measures foot plantar-surface sweat production, indicated by a cobalt compound color change on the device. The test is advantageous because it is highly sensitive – 73% more sensitive than DPNCheck – and does not rely on patient response or require operator training.5 A study of Neuropad showed that a drier foot and, therefore, increased risk of foot ulceration correlated with greater abnormal readings on the device, which might indicate onset of more severe DPN in the future.6
Sudoscan measures sudomotor function in 3 minutes through an electrochemical reaction between stimulated sweat glands and electrodes.2 A study performed in China in patients with type 2 diabetes (n = 394) showed that electrical conductance in the feet is associated with increasing risk and severity of symptoms of DPN in asymptomatic patients (r = 0.98 [95% confidence interval, 0.962-0.993]; P < .01) and might serve as a biomarker of DPN.7
Although these three techniques present favorable data, each is a nerve conduction study that can access only small-fiber nerves. Additional testing is required for larger-fiber nerves that are also affected by DPN.2 Also, some of the studies of these devices have high heterogeneity and a small sample size. Further research utilizing these three methods should include larger sample sizes to appropriately assess any clinically significant patient outcomes.
Corneal confocal microscopy (CCM), another potential technique for DPN screening, is a noninvasive ophthalmic device for assessing corneal small-fiber nerves. A study of patients with diabetes or obesity or both (n = 35) showed high reproducibility of corneal-nerve pathology identification using CCM.8 A larger-scale study showed that CCM can detect a reduction in corneal-nerve parameters in DPN patients, as well as in patients who have yet to develop DPN – thus demonstrating the technique’s ability to detect both early subclinical and established DPN.9 Once CCM is approved as a point-of-care device, it might provide a reliable, sensitive screening method for DPN as an early-intervention tool.
Therapeutic options
The three principal types of treatment for DPN are tricyclic antidepressants, anticonvulsants, and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs). Only three medications are Food and Drug Administration (FDA) approved for the treatment of DPN: pregabalin, duloxetine, and the recently approved capsaicin patch. Some opioid analgesics, including extended-release tapentadol, are FDA approved for DPN-associated neuropathic pain; however, evidence of their efficacy is questionable, and they present a risk of addiction.10 Here, we focus on potential treatments for DPN and DPN-associated neuropathic pain.
Cinacalcet. Several potential treatments have been studied for alleviating DPN symptoms after progression. Cinacalcet is a calcimimetic agent that activates the adenosine monophosphate-activated protein kinase–endothelial nitric oxide synthase pathway, which mediates DPN development. The drug has shown evidence of improving sensorimotor function and restoring nerve function in human Schwann cells expressed in diabetes-induced mice.11 In these animal models, cinacalcet improved tactile response when interventional mice were compared with a control group (P < .01).11 Further research is necessary to determine similar efficacy in human subjects.
Traditional Chinese medicine. Recent studies have focused on traditional Chinese medicine and practice, such as acupuncture and moxibustion, for DPN.
Moxibustion is the technique of burning moxa floss (a plant also known as mugwort) on different points on the body, which is thought to alleviate disease. In a study performed on rats, moxibustion increased nerve velocity (P < .05) and preserved sciatic-nerve ultrastructure.12 Research on the use of moxibustion is preliminary. A meta-analysis of available data found that all clinical studies took place in China, and results were therefore subject to high heterogeneity and small sample size.13 Previously, a lack of high-quality data prevented moxibustion from being considered a potential treatment.3 The technique has demonstrated potential benefit, but larger-scale and more rigorous studies must be utilized to verify its clinical efficacy.
Quercetin. This common dietary flavonoid is in development. In rat models with induced DPN, treatment produced significant neuroprotective effects, such as rescued mechanical withdrawal threshold, lowered nerve densities (P = .0378), and rescued lowered levels of reactive O2 species (P < .0001), which contribute to neurotoxicity in many peripheral neuropathies.14 Another study of the anti-inflammatory effects of quercetin in rat models found significant lowering of inflammatory factors, including proteins encoded by toll-like receptor 4 and MyD88, and protein transcription factor nuclear factor kappa B (P < .001), which can be beneficial in the treatment of DPN.15 Future testing in human subjects might reveal similarly positive effects.
Vitamin B. A systematic review examined the therapeutic effects of vitamin B supplementation on DPN. Through a meta-analysis on 14 studies (N = 997), it was revealed that statistically significant improvements in pain and electrophysiological sensory outcomes were observed after vitamin B supplementation. However, the majority of the studies included in the analysis utilized combination therapies with different vitamins (such as vitamin D) and other vitamin B types. Furthermore, deficiencies in B vitamins – especially folic acid and vitamin B12 – have been observed in diabetic patients, and may be the potential cause of DPN in them. The validity of the studies and their findings are weakened by this observation. Therefore, the clinical efficacy of individual B vitamin supplements must be evaluated in long-term, larger scale future studies that exclude those with B vitamin deficiency and DPN to minimize potential error.71
CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY
Another cause of peripheral neuropathy has been directly linked to particular chemotherapeutic agents. Platinum-based agents have been widely accepted as an ideal solution for slowing tumor progression; however, it has been established that platinum adducts within DNA are the cause of neuronal degeneration – specifically in dorsal-root ganglion neurons of the peripheral nervous system. In a 2010 meta-analysis in the United States, the prevalence of chemotherapy-induced peripheral neuropathy (CIPN) was observed to range from 65% to 75%, depending on the platinum-based agent.16 This problem is often dose-limiting and can lead to cessation of treatment, causing patients physical and financial harm. CIPN can be acute or chronic, and symptoms affect motor, sensory, and autonomic function, which can lead to reduced quality of life.17
Diagnostic tools and strategies
A variety of avenues can be taken to assess whether a patient has CIPN. Because peripheral neuropathy is often subjective, it has been recommended that clinicians use patient-reported outcome measures in this setting, in the form of a questionnaire.
Common toxicity criteria. The most conventional measure of CIPN is the National Cancer Institute’s Common Toxicity Criteria, which grades severity of adverse effects on a scale of 1 to 5 and has been found to be statistically valid.18 This questionnaire assesses a patient’s neuropathic pain score and sensory deficits, and can detect other potential adverse findings, such as neutropenia.
Total neuropathy score. This commonly used questionnaire measures subjective autonomic, sensory, and motor symptoms on a scale of 0 to 4 for each item, with the individual item scores then summed. A score > 5 indicates CIPN.19 The tested validity of this measure shows that it has an inter-rater reliability of 0.966 and an intra-rater reliability of 0.986.19
Other questionnaires. The Neuropathy Screening Questionnaire, Treatment-Induced Neuropathy Assessment Scale, and Chemotherapy-Induced Peripheral Neuropathy Assessment Tool have been identified as means of understanding what a patient experiences following neurotoxic chemotherapy.18
Pain caused by CIPN can also be assessed with one of several general scales, such as the Neuropathic Pain Scale for Chemotherapy-Induced Neuropathy (NPS-CIN), which identifies a patient’s level of pain on a scale from 0 to 4 on six items: intensity, unpleasantness, sharpness, depth, numbness, and tingling. This scale has been found to be reliable.18
Other scales that can be used are the Neuropathic Pain Symptom Inventory, Patient-Reported Outcomes Measurement Information System: Pain Quality Neuro, and Leeds Assessment of Neuropathic Symptoms and Signs.18
Other diagnostic tests. Tests to determine a chemotherapy patient’s functional ability regarding their extremities include postural stability tests, the Timed Up and Go (TUG) test, the Fullerton Advance Balance (FAB) Scale, the 6-minute walk test, and the grooved pegboard test.
Nerve conduction studies have been identified as useful tools to assess the physiologic function of fibers, but are costly and used most often in research settings.18 Quantitative sensory testing and the Bumps test are used to assess threshold capacities for varying sensations. Nerve-imaging tools, such as high-resolution ultrasonography, magnetic resonance neurography, and positron emission and computed tomography, have been found to be successful in identifying nerve damage.18
Additionally, the accumulation of mitochondrial DNA (mtDNA) in the blood has been identified as a potential biomarker for CIPN following animal trials on rats.69 Researchers conducted a double-blind trial where healthy rats were given doses of paclitaxel, oxaliplatin, and bortezomib and compared to vehicle-treated rats. Researchers found that there was a correlation between the onset of CIPN and levels of mtDNA, with 1-2-fold increases of mtDNA found in paclitaxel and oxaliplatin treated patients (P < 0.01).69 Dysfunctional mitochondria can cause an increase in the activity of reactive oxygen species which results in damage to mtDNA; and abnormal bioenergetics, which may lead to irregular ATP production and result in cellular damage.
Navitoclax. The antineoplastic agent cisplatin is used to treat a variety of cancers, including ovarian, lung, head and neck, testicular, and bladder.20 Using single-cell RNA sequencing of dorsal-root ganglion cells in mouse models that have been given human equivalent doses of cisplatin to induce peripheral neuropathy, a study identified that the drug was upregulating the cyclin-dependent kinase inhibitor 1A gene (CDKN1A) and leading to overproduction of its product, the p21 protein.21 This is due to a cellular response to DNA damage that causes the dorsal-root ganglion sensory neuron to change into a senescence-like state to survive. Subsequently, accumulation of senescent sensory neurons correlates with induction of neuropathic pain and peripheral neuropathy. It has been established, in mouse models, that removing senescent cells has the potential to reduce or reverse peripheral neuropathy associated with cisplatin treatment.21
A study induced irreversible CIPN using cisplatin on mice that were subsequently treated with antineoplastic agent navitoclax (n = 5) or vehicle (n = 10). Using navitoclax, a broad-spectrum senolytic agent, the study examined the dorsal-root ganglia of the mice and found that CIPN was reversed following clearance of senescent cells, with baseline mechanical thresholds able to be reestablished without difference, compared with the control group (P = .7734).22 The investigators found that clearance of senescent cells using navitoclax proved a promising avenue toward mitigating CIPN. More studies should be completed to validate this treatment as an effective preventive.
NGF Monoclonal Antibody (Tanezumab). Tanezumab has been identified as a potential analgesic for CIPN having observed success during animal trials. This monoclonal antibody targets the NGF-TrkA pathway in a dose-dependent manner which results in a reduction of neuronal sensitivity and subsequently neuropathic pain (P < 0.05).70 NGF is a peripheral pain mediator that has functional properties relating to inflammation and neuropathy. Therefore, by targeting this protein and inhibiting its activation, patients could potentially see a dramatic improvement in their quality of life following a CIPN diagnosis. This potential analgesic was observed to be successful for a variety of chemotherapeutic agents including cisplatin, vincristine, and paclitaxel.70
SASP inhibitors. A second possible approach to neutralizing senescent cells would be by inhibiting the senescence-associated secretory phenotype (SASP). This could be accomplished through the use of nuclear factor kappa B inhibitors, mammalian target of rapamycin (mTOR) inhibitors, bromodomain and extra-terminal (BET) inhibitors, and inhibitors of secretory factors, such as interleukin (IL)-6 and tumor necrosis factor (TNF) alpha.23 Rapamycin, an mTOR inhibitor that is already used in clinical settings, has been found to reduce the inflammatory effects of senescent cells, expanding the lifespan of mice.24 JQ1, OTX015, and ARV825 are BET inhibitors that have been found to block bromodomain-containing protein 4, thus inducing senescent cell death.25 IL-6 inhibitors (for example, tocilizumab) and TNF alpha inhibitors (for example, adalimumab) are already used clinically and can mitigate the effects of SASP.23,26 However, further studies are needed to examine potential adverse effects of this type of therapy.
Mitigation of oxaliplatin adverse effects. This platinum-based chemotherapeutic agent associated with peripheral neuropathy is primarily used to treat colorectal cancer and digestive-tract malignancies.27 Oxaliplatin-induced peripheral neuropathy (OIPN) can be acute or chronic, and causes neuropathic pain, autonomic nerve dysfunction, and hypersensitivity to cold, which lead to abnormal nervous system effects, such as peripheral paresthesia.
These symptoms derive from oxaliplatin’s effects on a variety of cellular mechanisms, and differ in chronic and acute OIPN. Acute OIPN includes abnormal changes to sodium, potassium, calcium, and transient receptor potential channels, which lead to dysregulation and dysfunction in peripheral neurons; glia activation associated with dysregulation of pain modulation, by reducing thresholds; and upregulation of the octamer-binding transcription factor (OCT) protein.
Chronic OIPN has been associated with damage to nuclear DNA by platinum adducts, mitochondrial dysfunction (due to oxidative stress), and neuroinflammation caused by glia activation and gut microbiota.28
With increased understanding regarding cellular mechanisms affected in OIPN, treatment options are being established to prevent or reduce its effects. A treatment being tested for the treatment of OIPN is the serotonin and norepinephrine reuptake inhibitor (SSNRI) antidepressant duloxetine.29 In a clinical trial of 40 patients with gastrointestinal cancer, duloxetine was found to reduce cold sensitivity (P = .001), tingling or discomfort of hands (P < .002) and feet (P = .017), and peripheral neuropathic pain (P = .001), and was found to prevent paresthesia (P = .025).29 The SNRI antidepressant venlafaxine has also shown that it can alleviate neuropathic pain and motor neuropathy in clinical trials.30
Antioxidant agents, such as amifostine and calmangafodipir, have also been identified as possible preventive measures against OIPN. Amifostine prevents neuronal hyperactivation and nitrosative stress, while calmangafodipir modulates reactive O2 species, regulates ion channels, and protects axons and the myelin sheath.31,32
Treatments such as riluzole, lidocaine, and pregabalin have all shown promise in reducing the effects of OIPN by their action on potassium, sodium, and calcium channels, respectively.28 A study conducted on mice (n = 565) with OIPN found that riluzole effectively mitigated motor and sensory deficits associated with the use of oxaliplatin.33
TREK-1 and TRAAK, potassium channels that are important for thermal and motor sensitivity, and that act as silencing mechanisms to excitatory stimuli, were shown to degenerate following oxaliplatin treatment, leading to hypersensitivity. Riluzole performs its therapeutic function by activating TREK-1 and TRAAK channels and blocking excessive accumulation of glutamate. Following riluzole treatment, mice were observed to show a significant reduction in sensorimotor deficits. Interestingly, riluzole also aided in reducing depression associated with oxaliplatin (P < .01).33 However, more studies are necessary to ensure the safety and efficacy of riluzole in humans.
Pyridoxine, pyridostigmine for vincristine-induced peripheral neuropathy. Vinca alkaloids have also been identified as chemotherapeutic agents that induce peripheral neuropathy. One such agent, vincristine, which is used primarily to treat leukemia and brain cancer, has been observed to cause peripheral neuropathy, including motor, autonomic, and sensory symptoms, such as abnormal gait, mechanical allodynia, paresthesia, ptosis, and obstipation, and altered perception of stimuli.34,35 These symptoms are caused primarily by the ability of vincristine to activate neuroinflammatory mechanisms in dorsal-root ganglia. This is caused by activation of nucleotide-binding oligomerization domain 3 (NLRP3)-dependent release of IL-1b and subsequent cleavage of gasdermin D and caspase-1 in macrophages (observed in mouse models). Vincristine activates the NLRP3 signaling cascade that results in production of proinflammatory cytokines, thus inducing symptoms of peripheral neuropathy.36
Pyridoxine and pyridostigmine have been introduced as potential treatments for vincristine-induced peripheral neuropathy. Following a clinical trial of pediatric acute lymphoblastic leukemia patients, a study of 23 patients with vincristine-induced peripheral neuropathy found statistical validity for using pyridoxine and pyridostigmine because the drugs improved the neuropathy score (P < .001).37 However, more research is needed before implementing their use in point-of-care settings.
AUTOIMMUNE PERIPHERAL NEUROPATHY
Autoimmune peripheral neuropathies (APNs) occur when the immune system targets peripheral nervous system and its various cells. Although there is a wide range of conditions in this category of peripheral neuropathy, the two most common types – Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) – have been targeted for clinical research.
Guillain-Barré syndrome: Diagnostic tools and strategies
Guillain-Barré syndrome encompasses a variety of acute inflammatory polyneuropathies, including axonal motor, sensory, and autonomic neuropathies and Miller Fisher syndrome (MFS).38 In particular, the anti-GQ1b ganglioside antibody is considered archetypical in APNs because it is detected in MFS patients and not found in normal and disease-control samples, which makes it a good clinical marker.39
It is difficult to distinguish GBS from CIDP because the time frame of onset of maximum deficit of neuropathy – 4 weeks – can overlap with subacute CIDP symptoms.40 Current diagnosis is based on elevated levels of cerebrospinal fluid (CSF) proteins, which can increase fourfold 6 weeks into the early phase of disease, and nerve conduction studies.40 However, electrodiagnostic readings and CSF protein levels are normal in 30% to 50% of patients in the first week after onset of disease and must be repeated in weeks that follow.41 A major disadvantage in the workup of suspected GBS is that the syndrome can be confirmed only several weeks after onset of symptoms.
Ultrasonography. A potential new diagnostic tool is serial peripheral nerve ultrasonographic (US) imaging. A pilot study of GBS patients (n = 16) showed that US can detect enlarged nerve cross-sections in median, ulnar, and sural nerves in the first 3 weeks of disease. Imaging performance was consistent with that of nerve conduction studies, and was advantageous because US is easier to perform and for patients to undergo.42
Spinal inflammation. Another study hints at the importance of spinal-root inflammation as an early indicator of disease, especially when nerve conduction study readings are normal.43 Further research is needed to demonstrate the clinical efficacy of this diagnostic method in larger population groups.
Guillain-Barré syndrome: Therapeutic options
The standard of care for GBS in the United States is intravenous immunoglobulin (IVIG) therapy and plasmapheresis, but there is no FDA-approved treatment.44 Although the two treatments have been shown to be equally effective in early stages of disease, early relapses can occur with both. One study found that 20% of patients who underwent plasmapheresis relapsed.40 Because nearly 50% of GBS patients do not respond to IVIG or plasmapheresis, the need is urgent for new therapies to decrease the risk of permanent disability.45
Antibody therapy. Recent developments include the use of monoclonal antibodies against GBS. ANX005 is an immunoglobulin G4 recombinant antibody that inhibits complement component 1q (C1q). Activation of this protein triggers the classical complement cascade, a natural part of the innate immune system that is nonetheless inappropriately activated in some autoimmune diseases, leading to neurodegeneration as a consequence of tissue damage.
ANX005 was found to have high-binding affinity to C1q in human, rat, cynomolgus monkey, and dog sera in nonclinical trials, and demonstrated low cross-reactivity despite being a plasma protein present throughout human tissue. Furthermore, studies show that ANX005 can deplete C1q completely in the CSF of monkeys.46 Phase 1b clinical trials in Bangladesh with GBS patients (n = 23) 18 to 58 years of age against a placebo group (n = 8) indicate that treatment is well tolerated. Drug-related serious adverse events were lacking and subjects’ GBS-Disability Score improved compared with placebo controls at week 1 (r2 = 0.48; P < .0001) and week 8, when an improvement of three or more in the score was observed.40
ANX005 is entering phase 2 trials, which are expected to be completed in 2023.47
Eculizumab. This promising treatment is a monoclonal antibody against C5 convertase, an enzyme that catalyzes formation of C5b-9, a membrane attack complex in nerve membranes. Studies in mouse models showed that treatment could significantly improve symptoms of terminal motor neuropathy and completely block formation of membrane attack complexes.48 Rats in this study were paralyzed by anti-GQ1b antibodies to emulate GBS pathogenesis.
A double-blind, placebo-controlled phase 2 clinical trial in Japan enrolled 34 patients (23 assigned to receive eculizumab; 11, to placebo); all were 18 years old or older and could not walk independently (3-5 on the GBS functional grading scale). Results showed that:
- Sixteen percent more patients receiving eculizumab treatment (n = 14; 42-78 years) than in the placebo group (n = 5; 20-73 years) could walk independently after 4 weeks.
- Fifty-six percent more patients in the functional group (n = 17; 52-90 years) than in the placebo group (n = 2; 20-52 years) could run after 6 months.49 While it is noted that the first portion of the trial failed to meet the predefined significance level, its long-term effects are observed to have therapeutic potential.
Eculizumab is in phase 3 clinical trials with primary data to be released in October 2022.50
Alemtuzumab, which inhibits the CD52 gene, was found to alleviate symptoms and restore strength in a rapidly deteriorating patient with MFS and chronic lymphocytic leukemia. By week 4 of treatment, anti-GQ1B antibodies were eliminated. However, the cause of this patient’s MFS is unclear; recovery might have been the result of multiple factors.51
IgG inhibition. Additional ongoing studies include therapies geared toward the neonatal Fc receptor as a potential clinical target for IgG inhibition.52
Chronic inflammatory demyelinating polyneuropathy (CIDP): Diagnostic tools and strategies
CIDP is the most common chronic APN and shares many similarities with GBS but differs in its responsiveness to corticosteroids, prognosis, and more. Lack of consensus on diagnostic criteria for CIDP has led to reliance on nerve conduction studies and clinical findings for making the diagnosis.53
Guidelines. European Federation of Neurological Societies/Peripheral Nerve Society guidelines have high sensitivity (81%) and specificity (96%) and are utilized as diagnostic criteria for CIDP; however, a survey found that these criteria may be underutilized in clinical practice – which might contribute to a high misdiagnosis rate.54 Furthermore, although current diagnostic methods are dependent on CSF proteins, this disease is lacking a diagnostic biomarker, leading to easy overdiagnosis and unnecessary immunotherapy.55
Electrodiagnostic testing, which is often used, is limited because it cannot evaluate small-fiber nerves, cannot access the CNS adequately, and does not provide a specific diagnosis.56
Sphingomyelin in CSF. Recently, a study in Italy explored the potential of CSF sphingomyelin as a biomarker for CIDP and for GBS. Findings reveal that sphingomyelin levels can be used to diagnose more than 80% of APN cases in the clinical setting. Different levels were identified in GBS, acute inflammatory demyelinating polyneuropathy, and typical and atypical CIDP patients. Additionally, sphingomyelin showed potential to diagnose the correct stage of disease. An increase in sphingomyelin in relapsing CIDP patients was noted, compared with what was seen in controls and stable CIDP patients.57 Larger-scale studies are needed to further test the efficacy of this method.
Chronic inflammatory demyelinating polyneuropathy: Therapeutic options
First-line therapy for CIDP comprises prednisone, 60-100 mg/d, plasmapheresis, and IVIG, all of which have proved effective. Some patients respond better to one treatment than to others40; some have subpar response to all these treatments and are categorized as having refractory CIDP.45
Although there are no newly approved treatments for CIDP, several show promise in ongoing clinical trials.
Rituximab is an anti-CD20 monoclonal antibody being studied in two phase 2 clinical trials of efficacy for refractory CIDP with IgG4 autoantibodies, after showing potential efficacy.58,59
Efgartigimod is an Fc fragment that blocks the neonatal Fc receptor, prevents lysosome degradation of IgGs, and thus allows them to be “recycled.”60 These autoantibodies are crucial in disease pathology because lowering their concentration provides effective therapy.61 Phase 1 trials showed that repeated doses of efgartigimod reduced IgG levels in healthy volunteers by 50%. Repeated dosing lowered IgG levels, on average by 75% in serum, which was an effect that was sustained for an 8-week period.62 Phase 2 trials are recruiting, with a projected primary completion in 2023.
INFECTION-INDUCED PERIPHERAL NEUROPATHY
Infections have been identified as a primary cause of peripheral neuropathy. Infection-induced peripheral neuropathy has been associated with Lyme disease, Epstein-Barr and human immunodeficiency virus (HIV) infection, shingles, hepatitis B and C, diphtheria, leprosy, and rabies.63 Extensive research on peripheral neuropathy has not been completed for most of the diseases, highlighting an unmet need for patients who experience this sequela of infection.
HIV is a well-documented viral cause of peripheral neuropathy. The most common symptom is distal sensory polyneuropathy, which affects more than 50% of patients with HIV.64 The incidence of distal sensory polyneuropathy in HIV has been correlated with the use of antiretroviral therapy – specifically, tenofovir disoproxil fumarate – and with certain proteins secreted by the virus.65 Symptoms include loss of sensory properties, neuropathic pain, and allodynia.66
Diagnostic tools and strategies
Nerve conduction studies have primarily been used to diagnose HIV-induced peripheral neuropathy, as well as electrophysiological testing and noninvasive CCM. These assays can detect changes or abnormalities in large- and small-fiber nerves in HIV infection patients.66
Therapeutic options
Studies in mouse models have illustrated how the Tat protein correlates with induction of motor and sensory distal symmetric polyneuropathy. Expression of Tat can lead to mitochondrial disruption, resulting in degeneration of sensory dorsal root ganglia and subsequent neuropathic pain.67
Pirenzepine. Studies on mice have identified a potential treatment for HIV infection-induced peripheral neuropathy with pirenzepine, targeting the muscarinic subtype-1 receptor. Pirenzepine activates a molecular pathway that promotes neurite growth and mitochondrial function. Researchers found that, following treatment with pirenzepine (n = 6), there was marked reduction in mitochondrial degeneration and HIV-induced distal sensory neuropathy.66 This outcome was due to the ability of pirenzepine to block the effects of Tat protein expression, leading to reversal of its neurodegenerative effects.
Exercise combined with analgesics has also been identified as a potential treatment for alleviating distal sensory polyneuropathy in HIV infection–induced peripheral neuropathy. In a 12-week study, researchers instructed subjects who were receiving a combination of HIV treatments, including tenofovir, lamivudine, and efavirenz, to perform aerobic and resistance exercises. This regimen was intended to improve peripheral nerve-conduction velocity and increase the density of nerve fibers and neurogenic branching.
The study identified baseline pain scores and divided participants into three groups: aerobic exercise (n = 45), resistance exercise (n = 44), and controls (n = 47), for whom the average level of pain was 2 on an ascending scale of 1 to 10. There was significant reduction in pain score in the experimental groups by the end of the study, as well as an increased sensory profile.64 This study has elucidated a pain management therapy for HIV-induced peripheral neuropathy that can prove beneficial for patients.
CRYPTOGENIC SENSORY POLYNEUROPATHY
Also known as idiopathic neuropathy or small-fiber sensory peripheral neuropathy, cryptogenic sensory polyneuropathy (CSPN) affects one-third of patients with peripheral neuropathy, in whom (despite extensive testing) no known cause of their condition is revealed.
Diagnostic tools and strategies
Applicable clinical and laboratory tests of any potential known underlying causes of neuropathy, including diabetes, hereditary disorders, and autoimmune disease, must be performed to rule out those causes and suggest an idiopathic cause.68
Therapeutic options
There are no FDA-approved treatments for CSPN, as most treatments are geared toward neuropathic pain management, rehabilitation, and supportive care.68 Due to a lack of research and data regarding these types of peripheral neuropathies, various studies suggest different first-line therapies. For example, anticonvulsants (pregabalin, gabapentin), antidepressants (duloxetine), and opioid-like compounds (tramadol) are all threapy options to treat DPN.3
Adequate data are lacking to support the efficacy of immunosuppressive therapy in CSPN.
Summing up
The combination of an understanding of a widening range of underlying diseases, advancements in cancer therapies, and the rising prevalence of diabetes have all led to an increasing incidence of peripheral neuropathy. Coupled with the fact that one-third of patients with peripheral neuropathy experience idiopathic neuropathy, this indicates that extensive studies must be undertaken to identify mitigation and prevention strategies for peripheral neuropathy. To summarize the landscape of treatment for peripheral neuropathy:
Diabetic peripheral neuropathy. Treatment for DPN comprises three FDA-approved products: pregabalin, duloxetine, and a higher (8%)-strength capsaicin patch.3 Pain-management therapies also exist to reduce diabetes-induced neuropathic pain, including gabapentin, amitriptyline, and extended-release tapentadol.10
Chemotherapy-induced peripheral neuropathy has yet to be effectively treated in humans; however, many trials are being completed in animals with promising results. Treatment for CIPN has been identified using senolytic agents, such as navitoclax,22 and through inhibition of SASP by a variety of agents, including ARV825, tocilizumab, and adalimumab.23-26
Oxaliplatin-induced peripheral neuropathy. Research has identified a potential preventive agent in duloxetine, with human trials already showing efficacy and safety.29 Animal models have shown progress studying antioxidant agents, such as amifostine31 and calmangafodipir,32 which target ion channels. In a similar mechanism of action, riluzole has been observed to reduce motor and sensory deficits and depression resulting from treatment with oxaliplatin.
Vincristine-induced peripheral neuropathy. Progress has been seen in treating vincristine-induced peripheral neuropathy with pyridoxine and pyridostigmine, which have improved neuropathy scores in trial subjects;37 more studies must be completed before these agents can be established as effective therapy.
Autoimmune PN. There are no FDA-approved drugs to mitigate the peripheral neuropathy induced by GBS and CIDP; however, studies are being conducted to resolve this impediment. Potential treatments, such as ANX005, a recombinant antibody, and eculizumab, a monoclonal antibody, have both shown efficacy in human trials and provide a potential path toward treatment against peripheral neuropathy caused by GBS.47,50 CIDP is currently treated using prednisone, plasmapheresis, and IVIG.40 Clinical trials are studying the efficacy of rituximab and efgartigimod for CIDP.58-60
Infection-induced peripheral neuropathy. Although many infections can induce peripheral neuropathy, HIV is most well documented and therefore was singled out for discussion in this article. Pirenzepine has been shown to promote neurite growth and reduce mitochondrial degeneration – both of which factors are associated with reduction of neuropathic pain.66 Exercise and analgesics have also been found to mitigate the effects of HIV-induced distal sensory neuropathy, with pain scores being reduced.61
Cryptogenic sensory polyneuropathy. Research has yet to identify a causative agent of, or subsequent potential therapy for, CSPN. Increased knowledge about this neuropathy will, it is hoped, bring patients closer to a cure – beyond current pain mitigation strategies with anticonvulsants, antidepressants, and opioid-like compounds.3
Ms. Lee is a first-year master of science candidate in applied life sciences, with an emphasis on infectious diseases, and Mr. Kosacki is a first-year master of science candidate in applied life sciences, with an emphasis on translational research, both at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif. Dr. Bhandari is professor of clinical sciences and Dr. Tran is professor of clinical sciences, Keck Graduate Institute School of Pharmacy and Health Sciences.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Peripheral neuropathy is becoming an increasing focal point for clinicians when treating patients because of the plethora of causes to which the disorder has be</metaDescription> <articlePDF/> <teaserImage>289760</teaserImage> <teaser>This review of peripheral neuropathy summarizes the more common causative entities, diagnostic tools, and treatments to prevent, slow, or reverse its effects.</teaser> <title>The broad and challenging – but promising – landscape of peripheral neuropathy</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>nr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Neurology Reviews</journalTitle> <journalFullTitle>Neurology Reviews</journalFullTitle> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> <publicationData> <publicationCode>endo</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>fp</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">22</term> <term>34</term> <term>21</term> <term>15</term> <term>31</term> </publications> <sections> <term canonical="true">73052</term> <term>27980</term> </sections> <topics> <term canonical="true">285</term> <term>258</term> <term>270</term> </topics> <links> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24011354.jpg</altRep> <description role="drol:caption">Yun Seo Lee</description> <description role="drol:credit"/> </link> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24011355.jpg</altRep> <description role="drol:caption">Jonathan Kosacki</description> <description role="drol:credit"/> </link> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24011356.jpg</altRep> <description role="drol:caption">Dr. Kanika Bhandari</description> <description role="drol:credit"/> </link> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24011357.jpg</altRep> <description role="drol:caption">Dr. Amanda Tran</description> <description role="drol:credit"/> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>The broad and challenging – but promising – landscape of peripheral neuropathy</title> <deck/> </itemMeta> <itemContent> <p>Peripheral neuropathy is becoming an increasing focal point for clinicians when treating patients because of the plethora of causes to which the disorder has been attributed. Characterized by damage to the peripheral nervous system, peripheral neuropathy causes sharp, burning pain; numbness of the extremities that can travel proximally; muscle weakness; and an overall diminished quality of life. Rather than being a self-developing disease, peripheral neuropathy has mostly been identified as a symptom of causative disorders and therapeutic agents – making prevention and treatment extremely important for patients and providers. </p> <p>[[{"fid":"289760","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Yun Seo Lee is a first-year master's of science candidate in applied life sciences, with an emphasis on infectious diseases at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Yun Seo Lee"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]<br/><br/>The etiology of peripheral neuropathy has been studied thoroughly over the past 2 decades. In this review, we summarize the landscape of peripheral neuropathy, including the more common causative entities; diagnostic tools that can potentially be employed to identify the disorder; and treatments that are in use or being tested to prevent, slow, or reverse the effects of peripheral neuropathy. </p> <h2>DIABETIC PERIPHERAL NEUROPATHY</h2> <p>The most common cause of peripheral neuropathy is diabetes mellitus. Diabetic peripheral neuropathy (DPN) is a symmetrical, length-dependent neuropathy that affects more than 50% of type I and type II diabetes patients.<sup>1</sup> Not only is DPN an initiating factor of foot ulcers and nontraumatic lower-limb amputation, but it also leads to a severely lower quality of life, financial burden, and increased risk of death after major surgical procedures.<sup>2</sup> </p> <p>[[{"fid":"289761","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Jonathan Kosacki is a first-year master's of science candidate in applied life sciences, with an emphasis on translational research at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Jonathan Kosacki"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]<br/><br/>Once DPN has progressed significantly, its effects are irreversible; there are no agents capable of reversing or halting DPN past initial stages of disease.<sup>3</sup> It is important to detect and treat DPN early on, as it has a favorable prognosis and most DPN-related amputations are preventable.<br/><br/></p> <h2>Diagnosis</h2> <p>Nerve-conduction studies are the preferred diagnostic tool for DPN; however, these studies are costly and difficult to conduct in a clinical setting.<sup>2</sup> Currently, such diagnostic tools as the 10-g monofilament and tuning fork are more commonly utilized to detect loss of protective foot sensation to decrease the risk of foot ulceration.<sup>2</sup> In addition, other common aspects of diagnosing DPN include assessment of symptoms in the patient’s hands or feet and patient-reported symptoms.</p> <p>[[{"fid":"289762","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Kanika Bhandari, PharmD, is a is professor of clinical sciences at Keck Graduate Institute School of Pharmacy and Health Sciences, Claremont, Calif.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Kanika Bhandari"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]<br/><br/>Several diagnostic devices are in experimental stages and have shown potential for utilization in clinical settings.<br/><br/><strong>DPNCheck</strong> is a handheld device, with a turnaround time of 3 minutes, that measures sural nerve conduction velocity, which can identify DPN early in asymptomatic cases; and amplitude of sensory-nerve action potentials, which decrease with the degeneration of axons, a clinical characteristic of DPN. In a study of patients with diabetes (n = 162 [type 1, n = 80; type 2, n = 82]) and healthy controls (n = 80), a comparative analysis of DPNCheck and reference techniques showed a strong linear relationship between between clinical neuropathy scores and LDI<sub>FLARE</sub> (r = 0.64-0.84; P < 0.03), which suggests that the device might be viable in clinical settings.<sup>4 </sup>LDI<sub>FLARE</sub> is a method developed to assess axon reflex to detect neuropathy in type 2 diabetes.<sup>4<br/><br/>[[{"fid":"289763","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Amanda Tran, PharmD, is a professor of clinical sciences, Keck Graduate Institute School of Pharmacy and Health Sciences, Claremont, Calif.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Amanda Tran"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]</sup><strong>Neuropad,</strong> a 10-minute test, measures foot plantar-surface sweat production, indicated by a cobalt compound color change on the device. The test is advantageous because it is highly sensitive – 73% more sensitive than DPNCheck – and does not rely on patient response or require operator training.<sup>5</sup> A study of Neuropad showed that a drier foot and, therefore, increased risk of foot ulceration correlated with greater abnormal readings on the device, which might indicate onset of more severe DPN in the future.<sup>6</sup> <br/><br/><strong>Sudoscan</strong> measures sudomotor function in 3 minutes through an electrochemical reaction between stimulated sweat glands and electrodes.<sup>2</sup> A study performed in China in patients with type 2 diabetes (n = 394) showed that electrical conductance in the feet is associated with increasing risk and severity of symptoms of DPN in asymptomatic patients (r = 0.98 [95% confidence interval, 0.962-0.993]; <em>P</em> < .01) and might serve as a biomarker of DPN.<sup>7</sup> <br/><br/>Although these three techniques present favorable data, each is a nerve conduction study that can access only small-fiber nerves. Additional testing is required for larger-fiber nerves that are also affected by DPN.<sup>2</sup> Also, some of the studies of these devices have high heterogeneity and a small sample size. Further research utilizing these three methods should include larger sample sizes to appropriately assess any clinically significant patient outcomes.<br/><br/><strong>Corneal confocal microscopy (CCM),</strong> another potential technique for DPN screening, is a noninvasive ophthalmic device for assessing corneal small-fiber nerves. A study of patients with diabetes or obesity or both (n = 35) showed high reproducibility of corneal-nerve pathology identification using CCM.<sup>8</sup> A larger-scale study showed that CCM can detect a reduction in corneal-nerve parameters in DPN patients, as well as in patients who have yet to develop DPN – thus demonstrating the technique’s ability to detect both early subclinical and established DPN.<sup>9</sup> Once CCM is approved as a point-of-care device, it might provide a reliable, sensitive screening method for DPN as an early-intervention tool.<br/><br/></p> <h2>Therapeutic options</h2> <p>The three principal types of treatment for DPN are tricyclic antidepressants, anticonvulsants, and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs). Only three medications are Food and Drug Administration (FDA) approved for the treatment of DPN: pregabalin, duloxetine, and the recently approved capsaicin patch. Some opioid analgesics, including extended-release tapentadol, are FDA approved for DPN-associated neuropathic pain; however, evidence of their efficacy is questionable, and they present a risk of addiction.<sup>10</sup> Here, we focus on potential treatments for DPN and DPN-associated neuropathic pain.</p> <p><strong>Cinacalcet.</strong> Several potential treatments have been studied for alleviating DPN symptoms after progression. Cinacalcet is a calcimimetic agent that activates the adenosine monophosphate-activated protein kinase–endothelial nitric oxide synthase pathway, which mediates DPN development. The drug has shown evidence of improving sensorimotor function and restoring nerve function in human Schwann cells expressed in diabetes-induced mice.<sup>11</sup> In these animal models, cinacalcet improved tactile response when interventional mice were compared with a control group (<em>P</em> < .01).<sup>11</sup> Further research is necessary to determine similar efficacy in human subjects.<br/><br/><strong>Traditional Chinese medicine.</strong> Recent studies have focused on traditional Chinese medicine and practice, such as acupuncture and moxibustion, for DPN. <br/><br/>Moxibustion is the technique of burning moxa floss (a plant also known as mugwort) on different points on the body, which is thought to alleviate disease. In a study performed on rats, moxibustion increased nerve velocity (<em>P</em> < .05) and preserved sciatic-nerve ultrastructure.<sup>12</sup> Research on the use of moxibustion is preliminary. A meta-analysis of available data found that all clinical studies took place in China, and results were therefore subject to high heterogeneity and small sample size.<sup>13</sup> Previously, a lack of high-quality data prevented moxibustion from being considered a potential treatment.<sup>3</sup> The technique has demonstrated potential benefit, but larger-scale and more rigorous studies must be utilized to verify its clinical efficacy.<br/><br/><strong>Quercetin.</strong> This common dietary flavonoid is in development. In rat models with induced DPN, treatment produced significant neuroprotective effects, such as rescued mechanical withdrawal threshold, lowered nerve densities (<em>P</em> = .0378), and rescued lowered levels of reactive O<sub>2</sub> species (<em>P</em> < .0001), which contribute to neurotoxicity in many peripheral neuropathies.<sup>14</sup> Another study of the anti-inflammatory effects of quercetin in rat models found significant lowering of inflammatory factors, including proteins encoded by toll-like receptor 4 and MyD88, and protein transcription factor nuclear factor kappa B (<em>P</em> < .001), which can be beneficial in the treatment of DPN.<sup>15</sup> Future testing in human subjects might reveal similarly positive effects.<br/><br/><strong>Vitamin B.</strong> A systematic review examined the therapeutic effects of vitamin B supplementation on DPN. Through a meta-analysis on 14 studies (N = 997), it was revealed that statistically significant improvements in pain and electrophysiological sensory outcomes were observed after vitamin B supplementation. However, the majority of the studies included in the analysis utilized combination therapies with different vitamins (such as vitamin D) and other vitamin B types. Furthermore, deficiencies in B vitamins – especially folic acid and vitamin B<sub>12</sub> – have been observed in diabetic patients, and may be the potential cause of DPN in them. The validity of the studies and their findings are weakened by this observation. Therefore, the clinical efficacy of individual B vitamin supplements must be evaluated in long-term, larger scale future studies that exclude those with B vitamin deficiency and DPN to minimize potential error.<sup>71</sup></p> <h2>CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY</h2> <p>Another cause of peripheral neuropathy has been directly linked to particular chemotherapeutic agents. Platinum-based agents have been widely accepted as an ideal solution for slowing tumor progression; however, it has been established that platinum adducts within DNA are the cause of neuronal degeneration – specifically in dorsal-root ganglion neurons of the peripheral nervous system. In a 2010 meta-analysis in the United States, the prevalence of chemotherapy-induced peripheral neuropathy (CIPN) was observed to range from 65% to 75%, depending on the platinum-based agent.<sup>16</sup> This problem is often dose-limiting and can lead to cessation of treatment, causing patients physical and financial harm. CIPN can be acute or chronic, and symptoms affect motor, sensory, and autonomic function, which can lead to reduced quality of life.<sup>17</sup></p> <h2>Diagnostic tools and strategies</h2> <p>A variety of avenues can be taken to assess whether a patient has CIPN. Because peripheral neuropathy is often subjective, it has been recommended that clinicians use patient-reported outcome measures in this setting, in the form of a questionnaire. <br/><br/><strong>Common toxicity criteria.</strong> The most conventional measure of CIPN is the National Cancer Institute’s Common Toxicity Criteria, which grades severity of adverse effects on a scale of 1 to 5 and has been found to be statistically valid.<sup>18</sup> This questionnaire assesses a patient’s neuropathic pain score and sensory deficits, and can detect other potential adverse findings, such as neutropenia. <br/><br/><strong>Total neuropathy score.</strong> This commonly used questionnaire measures subjective autonomic, sensory, and motor symptoms on a scale of 0 to 4 for each item, with the individual item scores then summed. A score > 5 indicates CIPN.<sup>19</sup> The tested validity of this measure shows that it has an inter-rater reliability of 0.966 and an intra-rater reliability of 0.986.<sup>19</sup><strong>Other questionnaires.</strong> The Neuropathy Screening Questionnaire, Treatment-Induced Neuropathy Assessment Scale, and Chemotherapy-Induced Peripheral Neuropathy Assessment Tool have been identified as means of understanding what a patient experiences following neurotoxic chemotherapy.<sup>18</sup><br/><br/>Pain caused by CIPN can also be assessed with one of several general scales, such as the Neuropathic Pain Scale for Chemotherapy-Induced Neuropathy (NPS-CIN), which identifies a patient’s level of pain on a scale from 0 to 4 on six items: intensity, unpleasantness, sharpness, depth, numbness, and tingling. This scale has been found to be reliable.<sup>18</sup> <br/><br/>Other scales that can be used are the Neuropathic Pain Symptom Inventory, Patient-Reported Outcomes Measurement Information System: Pain Quality Neuro, and Leeds Assessment of Neuropathic Symptoms and Signs.<sup>18</sup> <br/><br/><strong>Other diagnostic tests.</strong> Tests to determine a chemotherapy patient’s functional ability regarding their extremities include postural stability tests, the Timed Up and Go (TUG) test, the Fullerton Advance Balance (FAB) Scale, the 6-minute walk test, and the grooved pegboard test. <br/><br/>Nerve conduction studies have been identified as useful tools to assess the physiologic function of fibers, but are costly and used most often in research settings.<sup>18</sup> Quantitative sensory testing and the Bumps test are used to assess threshold capacities for varying sensations. Nerve-imaging tools, such as high-resolution ultrasonography, magnetic resonance neurography, and positron emission and computed tomography, have been found to be successful in identifying nerve damage.<sup>18</sup><br/><br/>Additionally, the accumulation of mitochondrial DNA (mtDNA) in the blood has been identified as a potential biomarker for CIPN following animal trials on rats.<sup>69</sup> Researchers conducted a double-blind trial where healthy rats were given doses of paclitaxel, oxaliplatin, and bortezomib and compared to vehicle-treated rats. Researchers found that there was a correlation between the onset of CIPN and levels of mtDNA, with 1-2-fold increases of mtDNA found in paclitaxel and oxaliplatin treated patients (<em>P</em> < 0.01).<sup>69</sup> Dysfunctional mitochondria can cause an increase in the activity of reactive oxygen species which results in damage to mtDNA; and abnormal bioenergetics, which may lead to irregular ATP production and result in cellular damage.</p> <p><strong>Navitoclax.</strong> The antineoplastic agent cisplatin is used to treat a variety of cancers, including ovarian, lung, head and neck, testicular, and bladder.<sup>20</sup> Using single-cell RNA sequencing of dorsal-root ganglion cells in mouse models that have been given human equivalent doses of cisplatin to induce peripheral neuropathy, a study identified that the drug was upregulating the cyclin-dependent kinase inhibitor 1A gene (CDKN1A) and leading to overproduction of its product, the p21 protein.<sup>21</sup> This is due to a cellular response to DNA damage that causes the dorsal-root ganglion sensory neuron to change into a senescence-like state to survive. Subsequently, accumulation of senescent sensory neurons correlates with induction of neuropathic pain and peripheral neuropathy. It has been established, in mouse models, that removing senescent cells has the potential to reduce or reverse peripheral neuropathy associated with cisplatin treatment.<sup>21</sup><br/><br/>A study induced irreversible CIPN using cisplatin on mice that were subsequently treated with antineoplastic agent navitoclax (n = 5) or vehicle (n = 10). Using navitoclax, a broad-spectrum senolytic agent, the study examined the dorsal-root ganglia of the mice and found that CIPN was reversed following clearance of senescent cells, with baseline mechanical thresholds able to be reestablished without difference, compared with the control group (<em>P</em> = .7734).<sup>22</sup> The investigators found that clearance of senescent cells using navitoclax proved a promising avenue toward mitigating CIPN. More studies should be completed to validate this treatment as an effective preventive.</p> <p><strong>NGF Monoclonal Antibody (Tanezumab).</strong> Tanezumab has been identified as a potential analgesic for CIPN having observed success during animal trials. This monoclonal antibody targets the NGF-TrkA pathway in a dose-dependent manner which results in a reduction of neuronal sensitivity and subsequently neuropathic pain (<em>P</em> < 0.05).<sup>70</sup> NGF is a peripheral pain mediator that has functional properties relating to inflammation and neuropathy. Therefore, by targeting this protein and inhibiting its activation, patients could potentially see a dramatic improvement in their quality of life following a CIPN diagnosis. This potential analgesic was observed to be successful for a variety of chemotherapeutic agents including cisplatin, vincristine, and paclitaxel.<sup>70</sup><strong>SASP inhibitors.</strong> A second possible approach to neutralizing senescent cells would be by inhibiting the senescence-associated secretory phenotype (SASP). This could be accomplished through the use of nuclear factor kappa B inhibitors, mammalian target of rapamycin (mTOR) inhibitors, bromodomain and extra-terminal (BET) inhibitors, and inhibitors of secretory factors, such as interleukin (IL)-6 and tumor necrosis factor (TNF) alpha.<sup>23</sup> Rapamycin, an mTOR inhibitor that is already used in clinical settings, has been found to reduce the inflammatory effects of senescent cells, expanding the lifespan of mice.<sup>24</sup> JQ1, OTX015, and ARV825 are BET inhibitors that have been found to block bromodomain-containing protein 4, thus inducing senescent cell death.<sup>25</sup> IL-6 inhibitors (for example, tocilizumab) and TNF alpha inhibitors (for example, adalimumab) are already used clinically and can mitigate the effects of SASP.<sup>23,26</sup> However, further studies are needed to examine potential adverse effects of this type of therapy.<br/><br/><strong>Mitigation of oxaliplatin adverse effects.</strong> This platinum-based chemotherapeutic agent associated with peripheral neuropathy is primarily used to treat colorectal cancer and digestive-tract malignancies.<sup>27</sup> Oxaliplatin-induced peripheral neuropathy (OIPN) can be acute or chronic, and causes neuropathic pain, autonomic nerve dysfunction, and hypersensitivity to cold, which lead to abnormal nervous system effects, such as peripheral paresthesia.<br/><br/>These symptoms derive from oxaliplatin’s effects on a variety of cellular mechanisms, and differ in chronic and acute OIPN. Acute OIPN includes abnormal changes to sodium, potassium, calcium, and transient receptor potential channels, which lead to dysregulation and dysfunction in peripheral neurons; glia activation associated with dysregulation of pain modulation, by reducing thresholds; and upregulation of the octamer-binding transcription factor (OCT) protein.<br/><br/>Chronic OIPN has been associated with damage to nuclear DNA by platinum adducts, mitochondrial dysfunction (due to oxidative stress), and neuroinflammation caused by glia activation and gut microbiota.<sup>28</sup><br/><br/>With increased understanding regarding cellular mechanisms affected in OIPN, treatment options are being established to prevent or reduce its effects. A treatment being tested for the treatment of OIPN is the serotonin and norepinephrine reuptake inhibitor (SSNRI)<span class="hgkelc"> antidepressant</span> duloxetine.<sup>29</sup> In a clinical trial of 40 patients with gastrointestinal cancer, duloxetine was found to reduce cold sensitivity (<em>P</em> = .001), tingling or discomfort of hands (<em>P</em> < .002) and feet (<em>P</em> = .017), and peripheral neuropathic pain (<em>P</em> = .001), and was found to prevent paresthesia (<em>P</em> = .025).<sup>29</sup> The SNRI antidepressant venlafaxine has also shown that it can alleviate neuropathic pain and motor neuropathy in clinical trials.<sup>30</sup><br/><br/>Antioxidant agents, such as amifostine and calmangafodipir, have also been identified as possible preventive measures against OIPN. Amifostine prevents neuronal hyperactivation and nitrosative stress, while calmangafodipir modulates reactive O<sub>2</sub> species, regulates ion channels, and protects axons and the myelin sheath.<sup>31,32</sup> <br/><br/>Treatments such as riluzole, lidocaine, and pregabalin have all shown promise in reducing the effects of OIPN by their action on potassium, sodium, and calcium channels, respectively.<sup>28</sup> A study conducted on mice (n = 565) with OIPN found that riluzole effectively mitigated motor and sensory deficits associated with the use of oxaliplatin.<sup>33</sup> <br/><br/>TREK-1 and TRAAK, potassium channels that are important for thermal and motor sensitivity, and that act as silencing mechanisms to excitatory stimuli, were shown to degenerate following oxaliplatin treatment, leading to hypersensitivity. Riluzole performs its therapeutic function by activating TREK-1 and TRAAK channels and blocking excessive accumulation of glutamate. Following riluzole treatment, mice were observed to show a significant reduction in sensorimotor deficits. Interestingly, riluzole also aided in reducing depression associated with oxaliplatin (<em>P</em> < .01).<sup>33</sup> However, more studies are necessary to ensure the safety and efficacy of riluzole in humans. <br/><br/><strong>Pyridoxine, pyridostigmine for vincristine-induced peripheral neuropathy.</strong> Vinca alkaloids have also been identified as chemotherapeutic agents that induce peripheral neuropathy. One such agent, vincristine, which is used primarily to treat leukemia and brain cancer, has been observed to cause peripheral neuropathy, including motor, autonomic, and sensory symptoms, such as abnormal gait, mechanical allodynia, paresthesia, ptosis, and obstipation, and altered perception of stimuli.<sup>34,35</sup> These symptoms are caused primarily by the ability of vincristine to activate neuroinflammatory mechanisms in dorsal-root ganglia. This is caused by activation of nucleotide-binding oligomerization domain 3 (NLRP3)-dependent release of IL-1b and subsequent cleavage of gasdermin D and caspase-1 in macrophages (observed in mouse models). Vincristine activates the NLRP3 signaling cascade that results in production of proinflammatory cytokines, thus inducing symptoms of peripheral neuropathy.<sup>36</sup><br/><br/>Pyridoxine and pyridostigmine have been introduced as potential treatments for vincristine-induced peripheral neuropathy. Following a clinical trial of pediatric acute lymphoblastic leukemia patients, a study of 23 patients with vincristine-induced peripheral neuropathy found statistical validity for using pyridoxine and pyridostigmine because the drugs improved the neuropathy score (<em>P</em> < .001).<sup>37</sup> However, more research is needed before implementing their use in point-of-care settings.<br/><br/></p> <h2>AUTOIMMUNE PERIPHERAL NEUROPATHY</h2> <p>Autoimmune peripheral neuropathies (APNs) occur when the immune system targets peripheral nervous system and its various cells. Although there is a wide range of conditions in this category of peripheral neuropathy, the two most common types – Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) – have been targeted for clinical research.</p> <h2>Guillain-Barré syndrome: Diagnostic tools and strategies</h2> <p>Guillain-Barré syndrome encompasses a variety of acute inflammatory polyneuropathies, including axonal motor, sensory, and autonomic neuropathies and Miller Fisher syndrome (MFS).<sup>38</sup> In particular, the anti-GQ1b ganglioside antibody is considered archetypical in APNs because it is detected in MFS patients and not found in normal and disease-control samples, which makes it a good clinical marker.<sup>39</sup> </p> <p>It is difficult to distinguish GBS from CIDP because the time frame of onset of maximum deficit of neuropathy – 4 weeks – can overlap with subacute CIDP symptoms.40 Current diagnosis is based on elevated levels of cerebrospinal fluid (CSF) proteins, which can increase fourfold 6 weeks into the early phase of disease, and nerve conduction studies.<sup>40</sup> However, electrodiagnostic readings and CSF protein levels are normal in 30% to 50% of patients in the first week after onset of disease and must be repeated in weeks that follow.<sup>41</sup> A major disadvantage in the workup of suspected GBS is that the syndrome can be confirmed only several weeks after onset of symptoms.<br/><br/><strong>Ultrasonography.</strong> A potential new diagnostic tool is serial peripheral nerve ultrasonographic (US) imaging. A pilot study of GBS patients (n = 16) showed that US can detect enlarged nerve cross-sections in median, ulnar, and sural nerves in the first 3 weeks of disease. Imaging performance was consistent with that of nerve conduction studies, and was advantageous because US is easier to perform and for patients to undergo.<sup>42</sup> <br/><br/><strong>Spinal inflammation.</strong> Another study hints at the importance of spinal-root inflammation as an early indicator of disease, especially when nerve conduction study readings are normal.<sup>43</sup> Further research is needed to demonstrate the clinical efficacy of this diagnostic method in larger population groups.<br/><br/></p> <h2>Guillain-Barré syndrome: Therapeutic options</h2> <p>The standard of care for GBS in the United States is intravenous immunoglobulin (IVIG) therapy and plasmapheresis, but there is no FDA-approved treatment.<sup>44</sup> Although the two treatments have been shown to be equally effective in early stages of disease, early relapses can occur with both. One study found that 20% of patients who underwent plasmapheresis relapsed.<sup>40</sup> Because nearly 50% of GBS patients do not respond to IVIG or plasmapheresis, the need is urgent for new therapies to decrease the risk of permanent disability.<sup>45</sup></p> <p><strong>Antibody therapy.</strong> Recent developments include the use of monoclonal antibodies against GBS. ANX005 is an immunoglobulin G4 recombinant antibody that inhibits complement component 1q (C1q). Activation of this protein triggers the classical complement cascade, a natural part of the innate immune system that is nonetheless inappropriately activated in some autoimmune diseases, leading to neurodegeneration as a consequence of tissue damage. <br/><br/>ANX005 was found to have high-binding affinity to C1q in human, rat, cynomolgus monkey, and dog sera in nonclinical trials, and demonstrated low cross-reactivity despite being a plasma protein present throughout human tissue. Furthermore, studies show that ANX005 can deplete C1q completely in the CSF of monkeys.<sup>46</sup> Phase 1b clinical trials in Bangladesh with GBS patients (n = 23) 18 to 58 years of age against a placebo group (n = 8) indicate that treatment is well tolerated. Drug-related serious adverse events were lacking and subjects’ GBS-Disability Score improved compared with placebo controls at week 1 (r<sup>2</sup> = 0.48; <em>P</em> < .0001) and week 8, when an improvement of three or more in the score was observed.<sup>40</sup> <br/><br/>ANX005 is entering phase 2 trials, which are expected to be completed in 2023.<sup>47</sup><strong>Eculizumab.</strong> This promising treatment is a monoclonal antibody against C5 convertase, an enzyme that catalyzes formation of C5b-9, a membrane attack complex in nerve membranes. Studies in mouse models showed that treatment could significantly improve symptoms of terminal motor neuropathy and completely block formation of membrane attack complexes.<sup>48</sup> Rats in this study were paralyzed by anti-GQ1b antibodies to emulate GBS pathogenesis. <br/><br/>A double-blind, placebo-controlled phase 2 clinical trial in Japan enrolled 34 patients (23 assigned to receive eculizumab; 11, to placebo); all were 18 years old or older and could not walk independently (3-5 on the GBS functional grading scale). Results showed that:</p> <ul class="body"> <li>Sixteen percent more patients receiving eculizumab treatment (n = 14; 42-78 years) than in the placebo group (n = 5; 20-73 years) could walk independently after 4 weeks.</li> <li>Fifty-six percent more patients in the functional group (n = 17; 52-90 years) than in the placebo group (n = 2; 20-52 years) could run after 6 months.49 While it is noted that the first portion of the trial failed to meet the predefined significance level, its long-term effects are observed to have therapeutic potential.</li> </ul> <p>Eculizumab is in phase 3 clinical trials with primary data to be released in October 2022.<sup>50</sup> <br/><br/><strong>Alemtuzumab,</strong> which inhibits the CD52 gene, was found to alleviate symptoms and restore strength in a rapidly deteriorating patient with MFS and chronic lymphocytic leukemia. By week 4 of treatment, anti-GQ1B antibodies were eliminated. However, the cause of this patient’s MFS is unclear; recovery might have been the result of multiple factors.<sup>51</sup> <br/><br/><strong>IgG inhibition.</strong> Additional ongoing studies include therapies geared toward the neonatal Fc receptor as a potential clinical target for IgG inhibition.<sup>52</sup></p> <h2>Chronic inflammatory demyelinating polyneuropathy (CIDP): Diagnostic tools and strategies</h2> <p>CIDP is the most common chronic APN and shares many similarities with GBS but differs in its responsiveness to corticosteroids, prognosis, and more. Lack of consensus on diagnostic criteria for CIDP has led to reliance on nerve conduction studies and clinical findings for making the diagnosis.<sup>53</sup></p> <p><strong>Guidelines.</strong> European Federation of Neurological Societies/Peripheral Nerve Society guidelines have high sensitivity (81%) and specificity (96%) and are utilized as diagnostic criteria for CIDP; however, a survey found that these criteria may be underutilized in clinical practice – which might contribute to a high misdiagnosis rate.<sup>54</sup> Furthermore, although current diagnostic methods are dependent on CSF proteins, this disease is lacking a diagnostic biomarker, leading to easy overdiagnosis and unnecessary immunotherapy.<sup>55</sup> <br/><br/><strong>Electrodiagnostic testing,</strong> which is often used, is limited because it cannot evaluate small-fiber nerves, cannot access the CNS adequately, and does not provide a specific diagnosis.<sup>56</sup><strong>Sphingomyelin in CSF.</strong> Recently, a study in Italy explored the potential of CSF sphingomyelin as a biomarker for CIDP and for GBS. Findings reveal that sphingomyelin levels can be used to diagnose more than 80% of APN cases in the clinical setting. Different levels were identified in GBS, acute inflammatory demyelinating polyneuropathy, and typical and atypical CIDP patients. Additionally, sphingomyelin showed potential to diagnose the correct stage of disease. An increase in sphingomyelin in relapsing CIDP patients was noted, compared with what was seen in controls and stable CIDP patients.<sup>57</sup> Larger-scale studies are needed to further test the efficacy of this method.<br/><br/></p> <h2>Chronic inflammatory demyelinating polyneuropathy: Therapeutic options</h2> <p>First-line therapy for CIDP comprises prednisone, 60-100 mg/d, plasmapheresis, and IVIG, all of which have proved effective. Some patients respond better to one treatment than to others40; some have subpar response to all these treatments and are categorized as having refractory CIDP.<sup>45</sup></p> <p>Although there are no newly approved treatments for CIDP, several show promise in ongoing clinical trials. <br/><br/><strong>Rituximab</strong> is an anti-CD20 monoclonal antibody being studied in two phase 2 clinical trials of efficacy for refractory CIDP with IgG4 autoantibodies, after showing potential efficacy.<sup>58,59</sup><strong>Efgartigimod</strong> is an Fc fragment that blocks the neonatal Fc receptor, prevents lysosome degradation of IgGs, and thus allows them to be “recycled.”<sup>60</sup> These autoantibodies are crucial in disease pathology because lowering their concentration provides effective therapy.<sup>61</sup> Phase 1 trials showed that repeated doses of efgartigimod reduced IgG levels in healthy volunteers by 50%. Repeated dosing lowered IgG levels, on average by 75% in serum, which was an effect that was sustained for an 8-week period.<sup>62</sup> Phase 2 trials are recruiting, with a projected primary completion in 2023.<br/><br/></p> <h2>INFECTION-INDUCED PERIPHERAL NEUROPATHY</h2> <p>Infections have been identified as a primary cause of peripheral neuropathy. Infection-induced peripheral neuropathy has been associated with Lyme disease, Epstein-Barr and human immunodeficiency virus (HIV) infection, shingles, hepatitis B and C, diphtheria, leprosy, and rabies.<sup>63</sup> Extensive research on peripheral neuropathy has not been completed for most of the diseases, highlighting an unmet need for patients who experience this sequela of infection.</p> <p>HIV is a well-documented viral cause of peripheral neuropathy. The most common symptom is distal sensory polyneuropathy, which affects more than 50% of patients with HIV.<sup>64</sup> The incidence of distal sensory polyneuropathy in HIV has been correlated with the use of antiretroviral therapy – specifically, tenofovir disoproxil fumarate – and with certain proteins secreted by the virus.<sup>65</sup> Symptoms include loss of sensory properties, neuropathic pain, and allodynia.<sup>66</sup></p> <h2>Diagnostic tools and strategies</h2> <p>Nerve conduction studies have primarily been used to diagnose HIV-induced peripheral neuropathy, as well as electrophysiological testing and noninvasive CCM. These assays can detect changes or abnormalities in large- and small-fiber nerves in HIV infection patients.<sup>66</sup> </p> <h2>Therapeutic options</h2> <p>Studies in mouse models have illustrated how the Tat protein correlates with induction of motor and sensory distal symmetric polyneuropathy. Expression of Tat can lead to mitochondrial disruption, resulting in degeneration of sensory dorsal root ganglia and subsequent neuropathic pain.<sup>67</sup> </p> <p><strong>Pirenzepine.</strong> Studies on mice have identified a potential treatment for HIV infection-induced peripheral neuropathy with pirenzepine, targeting the muscarinic subtype-1 receptor. Pirenzepine activates a molecular pathway that promotes neurite growth and mitochondrial function. Researchers found that, following treatment with pirenzepine (n = 6), there was marked reduction in mitochondrial degeneration and HIV-induced distal sensory neuropathy.<sup>66</sup> This outcome was due to the ability of pirenzepine to block the effects of Tat protein expression, leading to reversal of its neurodegenerative effects.<br/><br/><strong>Exercise combined with analgesics</strong> has also been identified as a potential treatment for alleviating distal sensory polyneuropathy in HIV infection–induced peripheral neuropathy. In a 12-week study, researchers instructed subjects who were receiving a combination of HIV treatments, including tenofovir, lamivudine, and efavirenz, to perform aerobic and resistance exercises. This regimen was intended to improve peripheral nerve-conduction velocity and increase the density of nerve fibers and neurogenic branching. <br/><br/>The study identified baseline pain scores and divided participants into three groups: aerobic exercise (n = 45), resistance exercise (n = 44), and controls (n = 47), for whom the average level of pain was 2 on an ascending scale of 1 to 10. There was significant reduction in pain score in the experimental groups by the end of the study, as well as an increased sensory profile.<sup>64</sup> This study has elucidated a pain management therapy for HIV-induced peripheral neuropathy that can prove beneficial for patients.<br/><br/></p> <h2>CRYPTOGENIC SENSORY POLYNEUROPATHY </h2> <p>Also known as idiopathic neuropathy or small-fiber sensory peripheral neuropathy, cryptogenic sensory polyneuropathy (CSPN) affects one-third of patients with peripheral neuropathy, in whom (despite extensive testing) no known cause of their condition is revealed. </p> <h2>Diagnostic tools and strategies</h2> <p>Applicable clinical and laboratory tests of any potential known underlying causes of neuropathy, including diabetes, hereditary disorders, and autoimmune disease, must be performed to rule out those causes and suggest an idiopathic cause.<sup>68</sup> </p> <h2>Therapeutic options</h2> <p>There are no FDA-approved treatments for CSPN, as most treatments are geared toward neuropathic pain management, rehabilitation, and supportive care.<sup>68</sup> Due to a lack of research and data regarding these types of peripheral neuropathies, various studies suggest different first-line therapies. For example, anticonvulsants (pregabalin, gabapentin), antidepressants (duloxetine), and opioid-like compounds (tramadol) are all threapy options to treat DPN.<sup>3</sup> </p> <p>Adequate data are lacking to support the efficacy of immunosuppressive therapy in CSPN.<br/><br/></p> <h2>Summing up</h2> <p>The combination of an understanding of a widening range of underlying diseases, advancements in cancer therapies, and the rising prevalence of diabetes have all led to an increasing incidence of peripheral neuropathy. Coupled with the fact that one-third of patients with peripheral neuropathy experience idiopathic neuropathy, this indicates that extensive studies must be undertaken to identify mitigation and prevention strategies for peripheral neuropathy. To summarize the landscape of treatment for peripheral neuropathy:</p> <p><strong>Diabetic peripheral neuropathy.</strong> Treatment for DPN comprises three FDA-approved products: pregabalin, duloxetine, and a higher (8%)-strength capsaicin patch.<sup>3</sup> Pain-management therapies also exist to reduce diabetes-induced neuropathic pain, including gabapentin, amitriptyline, and extended-release tapentadol.<sup>10</sup><strong>Chemotherapy-induced peripheral neuropathy</strong> has yet to be effectively treated in humans; however, many trials are being completed in animals with promising results. Treatment for CIPN has been identified using senolytic agents, such as navitoclax,<sup>22</sup> and through inhibition of SASP by a variety of agents, including ARV825, tocilizumab, and adalimumab.<sup>23-26</sup> <br/><br/><strong>Oxaliplatin-induced peripheral neuropathy.</strong> Research has identified a potential preventive agent in duloxetine, with human trials already showing efficacy and safety.<sup>29</sup> Animal models have shown progress studying antioxidant agents, such as amifostine<sup>31</sup> and calmangafodipir,<sup>32</sup> which target ion channels. In a similar mechanism of action, riluzole has been observed to reduce motor and sensory deficits and depression resulting from treatment with oxaliplatin.<br/><br/><strong>Vincristine-induced peripheral neuropathy.</strong> Progress has been seen in treating vincristine-induced peripheral neuropathy with pyridoxine and pyridostigmine, which have improved neuropathy scores in trial subjects;<sup>37</sup> more studies must be completed before these agents can be established as effective therapy. <br/><br/><strong>Autoimmune PN.</strong> There are no FDA-approved drugs to mitigate the peripheral neuropathy induced by GBS and CIDP; however, studies are being conducted to resolve this impediment. Potential treatments, such as ANX005, a recombinant antibody, and eculizumab, a monoclonal antibody, have both shown efficacy in human trials and provide a potential path toward treatment against peripheral neuropathy caused by GBS.<sup>47,50</sup> CIDP is currently treated using prednisone, plasmapheresis, and IVIG.<sup>40</sup> Clinical trials are studying the efficacy of rituximab and efgartigimod for CIDP.<sup>58-60</sup> <br/><br/><strong>Infection-induced peripheral neuropathy.</strong> Although many infections can induce peripheral neuropathy, HIV is most well documented and therefore was singled out for discussion in this article. Pirenzepine has been shown to promote neurite growth and reduce mitochondrial degeneration – both of which factors are associated with reduction of neuropathic pain.<sup>66</sup> Exercise and analgesics have also been found to mitigate the effects of HIV-induced distal sensory neuropathy, with pain scores being reduced.<sup>61</sup> <br/><br/><strong>Cryptogenic sensory polyneuropathy.</strong> Research has yet to identify a causative agent of, or subsequent potential therapy for, CSPN. 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