Early Recognition of Symptoms of Peripheral Neuropathy

PN symptoms, which may manifest during diabetes diagnosis or prediabetes, pose a challenge for early recognition due to their vague nature, often mistaken for aging or unrelated conditions [33]. This hindrance in timely identification is compounded by individuals’ frequent oversight of symptoms and the potential misinterpretation by primary care physicians [34]. It becomes imperative to educate healthcare professionals on diverse presentations, symmetrical symptoms, and atypical neuropathic manifestations for improved diagnosis. Often, screening and diagnosis are overlooked until patients complain of PN-related symptoms, at which point the disease would have already progressed. In addition, it is crucial to provide healthcare professionals (HCP) and nurses with comprehensive education about PN symptomatology. HCPs need to be aware of other symptoms that may not be distinctly neuropathic, such as a wide array of symptoms affecting different nerve areas, alongside non-neurological problems such as diarrhea and slowed digestion. In addition, HCPs need to be aware of patients at risk of developing PN. An increasing amount of research associates prediabetes, obesity, and metabolic syndrome with the risk of developing both DPN and chronic sensorimotor peripheral neuropathy (CSPN). The impact of DPN can be severe. About 50% of individuals with diabetes will experience a foot ulcer at some point in their lives, and diabetes is a leading cause of lower limb amputations. Additionally, neuropathic pain and reduced sensation can lead to numerous adverse outcomes, such as falls, diminished quality of life, limitations in daily activities, and depressive symptoms [4, 8]. This highlights the substantial burden of PN.

Screening for Peripheral NeuropathyScreening Methods

Screening methods such as the 10-g monofilament test are currently used to detect patients with advanced neuropathy [17]. Integration of innovative screening methods, such as continuous glucose monitoring and simplified questionnaires, should be prioritized to streamline the identification process. In resource-available settings, more sophisticated diagnostic techniques can be utilized for the earlier detection of PN.

Challenges with Subjective Questionnaires

In a review conducted by Gad et al., scoring systems for PN were evaluated, emphasizing the difficulties associated with subjective questionnaires due to their time-consuming nature. Clinical questionnaires commonly used in practice, like the DN4 (Douleur Neuropathique 4), LANSS (Leeds Assessment of Neuropathic Symptoms and Signs), and NTSS-6 (Neuropathy Total Symptom Score-6), among others, exhibit restricted diagnostic precision, demand substantial time for completion, and produce varying prevalence estimates for PN due to inconsistencies in agreement on sensitivity and specificity [34].

Simplified Questionnaires for PN Diagnosis

As a solution, a 5-item patient-led questionnaire (Fig. 1) was developed to empower individuals with prediabetes and diabetes to self-refer to their primary healthcare providers upon experiencing symptoms related to PN. Additionally, a physician-led questionnaire (Fig. 2) consisting of a 2-item sensation test was introduced to confirm PN diagnosis [35]. This approach can potentially streamline the diagnostic process, reducing the time physicians require to make accurate diagnoses.

Fig. 1

Taken from Gad H, Kalra S, Pinzon R, Gracia RAN, Yotsombut K, Coetzee A, et al. Earlier diagnosis of peripheral neuropathy in primary care: a call to action. J Peripher Nerv Syst JPNS. 2024 Jan 24; Permission to publish was obtained from the copyright holder

Patient-led questionnaire—screening for peripheral neuropathy.

Fig. 2

Taken from Gad H, Kalra S, Pinzon R, Gracia RAN, Yotsombut K, Coetzee A, et al. Earlier diagnosis of peripheral neuropathy in primary care: a call to action. J Peripher Nerv Syst JPNS. 2024 Jan 24; Permission to publish was obtained from the copyright holder

Physician-led questionnaire—confirmation of peripheral neuropathy diagnosis.

Emphasizing Mandatory Screening

Mandatory screening for PN, like retinopathy evaluation during type 2 diabetes diagnosis, should be emphasized, considering surprising statistics that reveal up to 62% of patients with idiopathic PN exhibit prediabetes [36].

Limitations of the 10-g Monofilament Test

Challenges in diagnosing PN in primary care settings are exacerbated by the unreliability of simple and inexpensive tests like the 10-g monofilament test. An observational and comparative cross-sectional study conducted by Dube et al. indicates that while the test’s sensitivity is about 70% when compared to nerve conduction studies (NCS) and autonomic function testing (AFT), its specificity and negative predictive value are extremely low—0% against AFT and 20% against NCS. The positive predictive value varies widely, ranging from 92% with AFT to 70% with NCS. These inconsistencies are due to variability in testing procedures, lack of standardization, differences in patient populations, and issues with patient cooperation. Intra-observer and inter-observer variations also affect results. Therefore, relying solely on the 10-g monofilament test is not advisable; it should be used alongside other diagnostic methods like NCS and AFT for more accurate results [21].

Addressing Underdiagnosed and Undertreated PN

A paradigm shift in healthcare strategies, coupled with robust awareness campaigns, is essential to address the global trend of underdiagnosed and undertreated PN in patient care for diabetes. Integrating a simplified questionnaire into nurses’ vital sign assessments is a practical and effective screening tool for PN, filling a gap often overlooked in discussions on macrovascular complications. This comprehensive approach, encompassing the 10-g monofilament and vibration/proprioception testing, enhances early case detection. Nurses’ education on questionnaire use and a thorough physical examination are pivotal for a holistic approach to neuropathy identification. Karahan et al. assessed the knowledge and awareness of nurses regarding neuropathic pain in a hospital in Turkey. Sixty nurses participated, and their knowledge was evaluated using a questionnaire covering the definition, symptoms, treatment, and management of neuropathic pain. Results showed a significant lack of knowledge, with 80% of nurses unfamiliar with the definition, 83.3% unaware of causes and symptoms, and 90% lacking knowledge on pain management. The study highlights the need for enhanced in-service training to improve nurses’ understanding of neuropathic pain, ultimately aiming to improve patient care [37]. In Kuwait, for example, a World Health Organization (WHO)-accredited foot screening program led by trained nurses and podiatrists with the support of doctors assesses various aspects, including fall risk, ABPI, and neuropathy screening using monofilament and vibration perception threshold testing. The multidisciplinary collaboration ensures that primary healthcare providers and nurses gain the knowledge and skills needed to screen and categorize an individual’s risk of foot ulceration. Furthermore, they provide appropriate education advocating for self-care and ulcer prevention. The pragmatic adoption of a simplified questionnaire, while recognizing the gold standard for screening complications, requires fully accredited training. Emphasizing the need for a user-friendly tool applicable to a broader population, including those with comorbidities, underscores the imperative nature of comprehensive screening protocols in patient care for diabetes.

Unified Care System Proposal

Proposing a unified care system involves combining foot examinations with retina screenings to optimize system efficiency, reduce non-attendance rates, and enhance early detection. Successfully implemented in Kuwait, where WHO-accredited training empowered primary healthcare personnel to conduct foot screenings during retinal screening appointments, this integrated approach streamlined patient visits, reducing inconvenience and potentially increasing screening uptake. Notably, retinal screening appointments demonstrated significant attendance rates, with around 80% of patients participating compared to other screenings, highlighting this integrated screening strategy’s feasibility and potential success.

Flash Testing and Glucose Level Variability

Flash testing revealing increased glucose level variability may correlate with a higher incidence of neuropathy and retinopathy. Sheng et al. studied the relationship between blood glucose indexes generated by the flash glucose monitoring system (FGMS) and diabetic vascular complications. The time in range (TIR) index was used, derived from retrospective analysis of continuous glucose monitoring or FGMS. In this study of 545 patients with type 2 diabetes, TIR showed a strong negative correlation with HbA1c, indicating its potential as both a short-term and long-term diabetes management marker. Higher TIR correlated with lower interday glycemic variability and mean glucose variability. The study suggested that lower TIR is linked to higher risks of microvascular complications, supporting TIR as a valuable marker for long-term outcomes [38]. Therefore, if flash glucose monitoring is used for screening for prediabetes, individuals with greater glucose variability may have a higher incidence of neuropathy and retinopathy due to factors such as increased oxidative stress, advanced glycation end products, and inflammatory cytokine generation. Consequently, the significance of glucose variability in the context of prediabetes should be emphasized [38]. Primary care physicians often rely on HbA1c, which is notoriously insensitive for diagnosing type 2 diabetes, rather than using flash testing or continuous glucose monitoring. However, an HbA1c level of 5.7–6.4%, which includes patients with prediabetes, should be considered as a potential indicator of neuropathy. While HbA1c remains a common tool, recognizing its potential in signaling neuropathy necessitates further evaluation and timely interventions.

Vitamin B12 and Neuropathy Screening

Routine screening for PN faces challenges with the reliance solely on normal vitamin B12 levels, given the wide population range and variations in reference values across laboratories. To address the variability in vitamin B12 levels, it is advisable to check these levels in people with diabetes, particularly among vegetarians and metformin users, before prescribing vitamin B complex. This comprehensive approach underscores the consideration of routine B vitamin measurement in populations at risk of neuropathy, striking a balance between financial feasibility and healthcare system constraints. Prioritize addressing vitamin B12 deficiency over correcting iron deficiency anemia; parenteral treatments, such as intramuscular (IM) injections, may offer superior benefits over oral pills for vitamin B12 supplementation in cases of conditions like pernicious anemia and post bariatric surgery but should be reserved for certain conditions.

Evaluating Vitamin B Levels

Assessing B vitamin levels, particularly vitamin B6, is advised in cases of entrapment neuropathy, given its potential link to carpal tunnel syndrome. Unfortunately, evaluating vitamin B levels is frequently overlooked in entrapment neuropathy cases. To enhance diagnostic precision, healthcare providers should pay attention to crucial indicators such as nocturnal pain and specific affected fingers, which are identified as crucial aspects to be evaluated for potential carpal tunnel neuropathy.

Neuropathy and COVID-19

Individuals with pre-existing neuropathy often experience worsening symptoms during COVID-19 infection, and those with long COVID exhibit severe neuropathic symptoms. This highlights the complex relationship between neuropathy and COVID-19 outcomes.

Access to Healthcare in Rural Areas

Addressing the challenge of limited access to diabetologists or primary care physicians in rural areas significantly impacts the care received by people with diabetes. Increasing awareness regarding the importance of screening and treating PN becomes crucial for nurses, primary healthcare physicians, and general practitioners. Their involvement is essential for not only alleviating PN symptoms but also preventing severe complications such as neuro-ischemic ulcers and diabetic foot complications.

Education and Awareness Campaigns

Disseminating knowledge about PN treatment and screening uniformly across urban and rural healthcare settings ensures comprehensive care for patients with diabetes. Launching targeted awareness campaigns designed to educate HCPs and patients becomes imperative for bridging gaps in awareness and promoting proactive care strategies.

Early Detection and Management

Recognizing the importance of early detection, timely diagnosis, and efficient management, PN progression significantly affects patients, influencing their quality of life, symptoms, and economic aspects. Beyond symptom relief, the profound impact of PN progression involves various economic implications and healthcare utilization patterns for all involved parties within the healthcare system.

A summary of these recommendations is listed in Table 3.

Table 3 Recommendations for rational screening for peripheral neuropathy in generalImportance of Early Detection and Annual Screening for Peripheral Neuropathy

Annual screening for PN is recommended for all patients, with increased screening advised for those with comorbid conditions such as obesity, prediabetes, non-alcoholic steatohepatitis (NASH), and macronutrient deficiencies, including individuals diagnosed with established diabetes. Early detection of PN is crucial in recognizing individuals at risk for more severe complications, such as cardiovascular autonomic neuropathy (CAN).

Early Identification and Risk Recognition

Identifying PN early is vital for recognizing individuals at risk for CAN. Studies by Ziegler et al. indicate an increased risk of DSPN and CAN in those with prediabetes, sparking debates among diabetologists and neurologists. This highlights the necessity of proactive screening and early intervention to prevent the progression of these complications [39].

Enhancing Quality of Life

Stressing the importance of early detection and management of neuropathy is critical for improving the quality of life among affected individuals. Utilizing tools like the 36-Item Short Form Survey (SF-36), which includes domains specifically linked to neuropathy, underscores the profound impact of PN on overall health and well-being. Early intervention can lead to significant improvements in patient outcomes, reducing symptom severity and slowing disease progression [40].

Special Considerations for High-Risk Groups

In individuals with comorbid conditions like obesity, prediabetes, NASH, and macronutrient deficiencies, early detection of PN is particularly important. These conditions increase the risk of developing neuropathy, making regular and thorough screening essential. For patients with prediabetes, early identification of PN can halt the progression to full-blown diabetes and its associated complications. Implementing annual screening protocols for PN, and increasing the frequency of screening for high-risk groups, ensures timely diagnosis and intervention. This approach not only prevents the progression of neuropathy but also improves the overall management of diabetes and related conditions [41].

The incidence of DPN is associated with hyperglycemia and cardiovascular risk factors such as raised cholesterol, triglycerides, hypertension, obesity, and smoking, which can be modulated by early intervention. In a large longitudinal study of 1441 people with type 1 diabetes (T1D) in the Diabetes Control and Complications trial (DCCT), intensive insulin treatment reduced the risk of developing DPN by 60%, but a multifactorial approach, including managing hypertension, obesity, and hypertriglyceridemia, is necessary for those with type 2 diabetes (T2D) because of the disease’s heterogeneous nature [41].

Nutritional Assessments and GLP-1 Receptor Agonists for Long-Term Weight Management

Incorporating nutritional assessments for patients on long-term weight management with GLP-1 receptor agonists is essential, as these therapies show promising outcomes for neuropathy by improving vascular function and lipid profiles and reducing inflammation. Before initiating treatment, physicians should consider baseline vitamin B levels to identify individuals at risk of undetected neuropathy. Screening for PN is crucial before its onset, especially among individuals with obesity seeking GLP-1 receptor agonist treatment. The growing trend of using GLP-1 receptor agonists for obesity management, particularly in the UK, underscores its cost-effectiveness for those with prediabetes and a BMI > 30 eligible for reimbursement. Maintaining mandatory assessment and ongoing neuropathy evaluations is crucial post bariatric surgery, especially for patients lacking adequate follow-up care. Neuropathy risks post surgery primarily stem from nutritional deficiencies, notably vitamin B1, B6, and B12, with 4.6% to 16% of patients experiencing neurological symptoms [42]. Regularly measuring vitamin B levels in individuals at risk of deficiencies in B1, B6, and B12, and thus at an increased risk of PN, is imperative. Groups vulnerable to these deficiencies include individuals dealing with obesity, impaired nutrient absorption, renal issues, proton pump inhibitor (PPI) users, elderly individuals with elevated Clinical Frailty Scores, women, taller individuals, and post-bariatric surgery patients, especially those lacking postoperative care [3, 43,44,45]. Additionally, advising regular measurement of B vitamin levels for patients diagnosed with obstructive sleep apnea is recommended. A summary of these recommendations is listed in Table 4.

Table 4 Recommendations for neuropathy screening in high-risk patientsExperts’ Recommendations for Early Screening and Diagnosis

We recommend an annual screening for patients at risk of PN, such as obesity, prediabetes, NASH, and macronutrient deficiency, including individuals diagnosed with established diabetes. The American Diabetes Association (ADA) already recommends an annual screening for patients with diabetes [36]. Utilizing simple and reproducible screening methods is crucial to enhance effective neuropathy assessment. Comprehensive assessment for DSPN involves evaluating small and large fiber function through temperature/pinprick sensation and 128-Hz tuning fork vibration sensation, respectively, along with 10-g monofilament testing to identify feet at risk of ulceration and amputation [46]. There is no single tool that can objectively evaluate all aspects of DPN, such as sensory, motor, and autonomic deficits. Combining multiple assessments improves the sensitivity, specificity, and accuracy of detection. Therefore, we suggest using a multiphasic screening approach to better identify these deficits, aiding in clinical decision-making [36]. This collective approach underscores the importance of systematic and timely screening for PN in individuals with diabetes. However, limited accessibility and insurance coverage for advanced diagnostic methods, such as corneal confocal microscopy (CCM) and NCS, pose challenges to their widespread use in population screening. CCM is an advanced imaging technique that provides detailed visualization of corneal nerve fibers, offering valuable insights into early DPN. NCS, on the other hand, measure the speed and strength of electrical signals in the nerves, helping to diagnose the extent and type of nerve damage in individuals with diabetes [47]. Integrating new technologies into neuropathy screening processes will allow for earlier detection in settings where resources are available [47]. We suggest the integration of CCM alongside retinal screening. This approach aims to enhance pickup rates of PN and retinopathy without significantly increasing costs by allowing patients to do two-in-one screening and reducing the burden of too many appointments. A comparative analysis of diagnostic techniques highlights the varying sensitivity and specificity in detecting DPN. CCM and Sudoscan, which offer advanced diagnostic capabilities, tend to have higher sensitivity and specificity compared to simple clinical assessments like the monofilament test. While the monofilament test is widely used owing to its simplicity and cost-effectiveness, its sensitivity and specificity are generally lower. In contrast, CCM provides detailed imaging of corneal nerve fibers, and Sudoscan assesses sweat gland function, both offering more precise early detection of neuropathy [48]. Although we advocate for the use of newer technology such as CCM and Sudoscan, there remains substantial value in simple routine clinical testing in resource-limited settings. Adopting a multifaceted approach that includes questionnaires and straightforward clinical examinations for comprehensive neuropathy screening and identification aims to address barriers to accessibility and promote efficient and cost-effective neuropathy screening in diverse healthcare settings. A summary of these recommendations is listed in Table 5.

Table 5 Experts’ recommendations for early screening and diagnosisExperts’ Recommendations for Therapeutic Landscapes

The extended use of metformin, a key player in preventing type 2 diabetes among individuals with prediabetes, has been associated with vitamin B12 deficiency, particularly concerning for specific subgroups such as those with a BMI of ≥ 35 kg/m2, individuals below the age of 60, and women with prior gestational diabetes mellitus [46]. Alharbi et al. showed that low serum vitamin B12 levels were observed in individuals taking metformin at doses over 2000 mg/day, and a prevalence of mild neuropathy reaching 22.3% in the metformin-users group compared to 15.1% in the non-metformin users group, consistent with the results of previous studies in the literature [49]. Prolonged use of metformin not only reduced vitamin B12 levels but also significantly aggravated neuropathy. To address this risk, consideration is recommended for vitamin B supplementation in patients prescribed metformin doses exceeding 1 g per day for over 1 year [49]. Periodic measurement of vitamin B12 levels for individuals undergoing metformin treatment, especially if they display symptoms like anemia or PN, is integral to this integrated approach aiming to optimize metformin’s benefits while mitigating potential risks associated with vitamin B12 deficiency, ensuring comprehensive patient care in the context of diabetes prevention and management [7, 46].

Neuropathic pain is very challenging; it leads to conditions that significantly affect the patient’s quality of life. Currently, there is no definite treatment for neuropathic pain, and many medications used to manage it have side effects that limit their use [50]. First-line therapy for neuropathic pain includes gabapentinoids, tricyclic antidepressants (TCAs), and serotonin–norepinephrine reuptake inhibitors (SNRI) and second-line medications include opioids and topical treatments such as capsaicin [51]. Our recommendation is to implement a holistic approach emphasizing a multifaced approach rather than relying solely on medication. This comprehensive strategy involves incorporating drugs, nutritional supplements, and non-medication-based methods such as health behavior interventions to address various aspects of neuropathy management. Consideration should be given to combination therapy, exploring potential synergistic effects of vitamin B supplementation alongside traditional treatments for neuropathic pain.

Considering GLP-1 receptor agonists as a preferred treatment for diabetes is recommended owing to its cardiovascular protective effects, especially in cases where neuropathy is present, in addition to optimizing glucose control. A systematic review conducted by García-Casares et al. that studied the effects of GLP-1 receptor agonists on neurological complications of diabetes (stroke, cognitive impairment, and peripheral neuropathy) showed that GLP-1 receptor agonists provide neuroprotection through anti-inflammatory, antioxidant, and antiapoptotic mechanisms. Although more studies are needed to provide a conclusive effect of GLP-1 receptor agonists on peripheral neuropathy, studies have shown that among participants with type 2 diabetes mellitus receiving exenatide treatment, a significant increase in corneal nerve branch density (p = 0.02) and vibration perception threshold was observed [52]. Positive outcomes associated with specific GLP-1 receptor agonists extend beyond glycemic management, showcasing promise in improving cognition and olfactory function and reducing the risk of major adverse cardiovascular events (MACE), particularly relevant for patients with neuropathy [53]. Therefore, we advocate for the use of GLP-1 receptor agonists as a favorable treatment for patients with diabetes because of its positive effects on glycemic control, weight reduction, cardiovascular safety profile, and neuroprotective effects.

Ensuring optimal care for patients with diabetes with neuropathic symptoms involves a stepwise approach initiated by primary care physicians. Beginning with basic pain relief, the treatment plan progresses through tricyclic antidepressants and duloxetine and culminates with gabapentin or pregabalin as necessary. In cases where patients exhibit symptoms beyond standard diabetic concerns or face medication limitations, a seamless referral system to specialists is crucial. Establishing effective referral mechanisms relies on specialized primary care physicians determining the appropriate moment to refer patients to neurologists or diabetic specialists after thorough assessments. However, challenges in accessing essential drugs like gabapentin, pregabalin, and tramadol, categorized as narcotics in certain regions like Qatar, Kuwait, and the United Arab Emirates, raise concerns about potential impacts on patient care and management, highlighting the importance of addressing medication limitations in diverse healthcare systems. A flowchart detailing an optimized pathway for referral of patients with diabetes is shown in Fig. 3.

Fig. 3

Flowchart for optimizing referral of patients with diabetes: a comprehensive flowchart for primary care physicians

A summary of these recommendations is listed in Table 6.

Table 6 Experts’ recommendations for therapeutic landscapesExperts’ Recommendations for Early Intervention with Neurotropic B Vitamins

Embracing vitamin B supplements as a cornerstone and complementary approach to PN treatment holds significant promise. Studies indicate the potential alleviation of neuropathy symptoms through B vitamins, although trials face limitations, particularly in non-diabetic cases where pre-treatment vitamin levels are examined. The nuanced roles of specific B vitamins contribute to their therapeutic impact, with vitamin B1 supporting energy metabolism and antioxidative functions crucial for neural function, vitamin B6 acting as a coenzyme in neurotransmitter synthesis, and vitamin B12 being vital for myelin synthesis and nerve repair [54]. Understanding the intracellular action mechanisms of B vitamins in nociceptive pathways sheds light on their potential to lower excitability, reduce sensitization, modulate neuroinflammation, and impact neurotransmitter systems involved in pain modulation [54]. The critical importance of neuropathy screening is emphasized for high-risk individuals, especially those with diabetes or belonging to at-risk groups, where vitamin B supplementation becomes pivotal. The utilization of a combined B complex, such as neurotropic B vitamins, emerges as a potential avenue for improved outcomes, especially for patients less responsive to B12 treatment alone. In the context of type 2 diabetes, the connection between low B1 and B6 levels and reduced homocysteine is noted, emphasizing the relevance of B-vitamin deficiencies in diabetic nerve complications. Furthermore, the impact of B1 extends to influencing conditions like fatty liver disease, underscoring the need for proactive assessment and targeted supplementation strategies. For patients experiencing sensory peripheral neuropathy associated with metabolic diseases or medications, an initial high dose of neurotropic B vitamins (B1, B6, and B12) may offer relief, followed by a transition to a lower maintenance dose upon symptom improvement [55]. Treatment is warranted for any B12 level below 400 pmol/L, considering overall well-being and potential cognitive function decline, with regular monitoring recommended for individuals at risk or diagnosed with PN. Oral vitamin B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) are generally well tolerated, with rare instances of side effects, making them considered safe for use (Fig. 4). B-vitamin deficiency is indeed more common in low-income countries. In high-resource settings, replacement of B vitamins should be based on initial laboratory tests. To determine their effectiveness definitively, adequately powered randomized controlled trials (RCTs) are needed.

Fig. 4

Flowchart guiding neuropathy screening and management for at-risk individuals with assessment of vitamin B levels. IM intramuscular. Disclaimer: vitamins B1, B6, and B12 have been shown to have good safety profiles and may be considered for patients, especially those at high risk of peripheral neuropathy

A summary of these recommendations is listed in Table 7.

Table 7 Experts’ recommendations for early intervention with neurotropic B vitamins