Diabetic Neuropathy

Diabetic peripheral neuropathy encompasses various neurogenic disorders resulting from diabetes
mellitus type 1 and type 2. This condition can be classified into distal symmetric polyneuropathy (DSPN),
diabetic autonomic neuropathy, superimposed mononeuropathies, and though rare polyradiculopathy 1 .
The incidence of diabetic neuropathy in individuals with diabetes mellitus can reach 50–66% over their
lifetime 3 . Half of diabetic neuropathy cases are subclinical or asymptomatic until the condition becomes
severe 1 .

Recognizing diabetic neuropathy is essential to ensure timely treatment and improve quality of life.
Diabetic autonomic neuropathy, a diagnosis of exclusion, requires a thorough evaluation of the
sympathetic and parasympathetic nervous systems for timely recognition in individuals with type 1
(DM1) or type 2 diabetes mellitus (DM2). Also, distal symmetric polyneuropathy can be clinically
screened using sensation tests for pinprick, temperature, vibration, and proprioception in a ‘stocking
and glove’ distribution, as well as assessing ankle reflexes. There are clinical criteria and scoring systems
available for establishing a diagnosis of clinical DSPN. Examples include the Neurological Disability Score
and the Neurological Symptom Score (NSS). However, these tools are designed for general peripheral
neuropathy rather than specifically for DSPN and include multiple items, making them less practical for
routine use in general practice 4 . In 2010, the Toronto Expert Panel on Diabetic Neuropathy published a
consensus definition of diabetic peripheral neuropathy (DPN), which was subsequently cited in the
position statement of the American Diabetes Association 4 . According to the Toronto Consensus, a
clinician can establish a diagnosis of ‘Confirmed’ or ‘Subclinical’ DSPN only with the support of
quantitative data, such as nerve conduction studies (NCS) or validated measures of small-fiber
neuropathy 4 .

Distal symmetric polyneuropathy (DSPN) can be divided into three subtypes: small-fiber neuropathy,
large-fiber neuropathy, and mixed small- and large-fiber neuropathy. The most common form of distal
symmetric polyneuropathy (DSPN) is the mixed type. Both mixed and large-fiber neuropathies can be
objectively tested using electrodiagnostic (EDX) studies 1 . For small-fiber neuropathy, a skin punch biopsy
can be used to measure intraepidermal nerve fiber density for diagnostic purposes.

Differential diagnosis
There is a list of differential diagnoses to consider. The required tests depend on the underlying
etiology; however, obtaining a thorough history and conducting a complete examination are essential.
The differential diagnoses for diabetic peripheral neuropathy include the following 2, 3, 5 :

1. Alcoholic neuropathy
2. Uremic neuropathy
3. Genetic neuropathy
4. Neoplastic neuropathy
5. Treatment-induced neuropathy (e.g., chemotherapy, HIV treatment, radiation therapy)
6. Amyloidosis
7. Vitamin B12 deficiency
8. Monoclonal gammopathy
   The list of high-yield screening lavatory tests for DSPN include 5 :
9. Complete blood cell count
10. Serum sodium, potassium, chloride and bicarbonate
11. Serum urea and creatinine
12. Liver function tests
13. Fasting blood glucose and hemoglobin A1c
14. Serum protein electrophoresis
15. Vitamin B12 with or without methylmalonic acid

EDX of DPN
Nerve conduction studies (NCS) have been reported to identify one or more abnormalities in 60–90% of
individuals with diabetes, regardless of whether they have type 1 or type 2 diabetes or exhibit clinical
symptoms. Moreover, NCS serve as a valuable tool for monitoring disease progression, as they can
objectively demonstrate worsening abnormalities in correlation with the increasing severity of
symptoms and clinical signs over time—insights that other quantitative measures cannot provide 4 . Baba
et al. demonstrated that over 90% of individuals with diabetes exhibited one or more abnormal findings
on nerve conduction studies (NCS). These findings were based on sensory nerve conduction velocity and
sensory nerve action potential amplitude of the sural nerve, motor nerve conduction velocity and
compound muscle action potential amplitude of the tibial nerve, as well as minimal F-wave latency of
the tibial nerve and the presence of A-waves. These results highlight the excellent sensitivity of NCS in evaluating DSPN 4 . Additionally, NCS data have been shown to verify improvements in response to
interventions 4 .

Treatment and management
Patients with neuropathies of acute to subacute onset (evolving over days to up to eight weeks to reach
to plateau), as well as those with non-length-dependent patterns, require urgent referral to a
neurologist specializing in neuromuscular diseases 5 . This is due to concerns about inflammatory
neuropathies, such as Guillain-Barré syndrome, acute-onset chronic inflammatory demyelinating
polyneuropathy (CIDP), vasculitis, paraneoplastic neuropathy, or multifocal motor neuropathy 5 . A
diagnostic screening approach that considers onset, distribution patterns, and the presence of systemic
features—such as skin changes, weight loss, autonomic symptoms, fever and chills, or joint
inflammation—can effectively identify patients with inflammatory neuropathies. This approach has
been shown to have a sensitivity of 96% and a specificity of 85% in detecting inflammatory
neuropathies 7 . Nerve biopsy is a valuable diagnostic tool in cases where vasculitis, sarcoidosis, or
infiltrative disorders such as malignancy or amyloidosis are suspected 5 . When dysimmune
neuropathies, neoplastic neuropathies, and vasculitic neuropathies are excluded, the treatment
approach for general peripheral neuropathy focuses on symptomatic management, regardless of the
underlying cause 5 . The diabetic peripheral neuropathy is the most prevalent form of peripheral
neuropathy 3 .
For patients with diabetic polyneuropathy with DM1, enhancing glycemic control may help improve
neuropathic symptoms and potentially reduce the risk of diabetic complications 2 . However, in patients
with DM2, large meta-analyses have found no conclusive evidence that improving glucose control alone
leads to significant improvement in neuropathic symptoms 2 . This disparity may be attributed to the
presence of diverse metabolic factors in DM2 patients beyond hyperglycemia, including dyslipidemia,
insulin resistance, large BMI, and chronic inflammation, which are not typically observed in DM1 2 .
Recent studies have demonstrated that dietary and lifestyle interventions hold significant promise for
improving neuropathic symptoms, enhancing small-fiber nerve density, and improving large-fiber nerve
function 2, 4 .

Conclusions
As with other problems and their solutions, the classification of conditions serves as the crucial first step
in addressing issues related to diabetic neuropathy. Is the patient we are seeing experiencing
neuropathy? How severe is the condition, and can it be measured quantitatively? Depending on the
severity of the condition, alternative regimens may not always be necessary. However, in some cases,
simple yet effective treatment options identified through objective tests can significantly enhance the
quality of life for individuals with diabetic neuropathy.

Paul Bang, PT, DPT, ECS

References

1. Rodica Pop-Busui et al., (2017), Diabetic Neuropathy: A Position Statement by the American
   Diabetes Association, Diabetes Care 40:136–154 | DOI: 10.2337/dc16-2042
2. Eva L. Feldman et l., (2019), Diabetic neuropathy, nature reviews | disease primers 5:41|
   https://doi.org/10.1038/ s41572-019-0092-1
3. Myron A. Bodman et al., (2024), Diabetic Peripheral Neuropathy, StatPearls Publishing
4. Tatsuhito Himeno et al., (2020), Lumos for the long trail: Strategies for clinical diagnosis and severity
   staging for diabetic polyneuropathy and future directions, J Diabetes Investig 2020; 11: 5–16|doi:
   10.1111/jdi.13173
5. Ario Mirian et al., (2023), Diagnosis and management of patients with polyneuropathy, CMAJ 2023
   February 13;195:E227-33. doi: 10.1503/cmaj.220936
6. Silsby M, Feldman EL, Dortch RD, et al., (2023), Advances in diagnosis and management of distal
   sensory polyneuropathies, J Neurol Neurosurg Psychiatry 2023;94:1025–1039
7. Chafic Karam et al., (2016), Rapid screening for inflammatory neuropathies by standardized clinical
   criteria, Neurol Clin Pract 2016;6:384–388