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