Patients will frequently present with the initial complaint of finding blood in their socks or on their floors as they do not perform routine pedal examinations. For the ulceration itself, the history should be thorough and include the nature of the ulceration, the location, the duration and onset, as well as the course, things that both aggravate the ulceration and alleviate the associated symptoms and any treatment used or pursued this issue.

A detailed past medical history is highly recommended. It is important to establish the background of the disorder to include the length of time the patient has been neuropathic if there is a diagnosis associated with the neuropathy, and all information pertinent to that disease. For instance, oftentimes, the patient has diabetes, and it is vital to know the length of time they have had this disease, how their diabetes is controlled via medication and diet, and how their blood sugars have been. The laboratory value hemoglobin A1C of the patient can help provide insight. The patient's listed allergies and medications are also important here and can help guide antibiotic therapy if needed. 

Past surgical history should be obtained as well to include a history of pedal ulcerations and possible surgical interventions such as amputation, any history of vascular surgery, and how the patient's body reacted to anesthesia. This can also help guide the decision on if the patient is a good surgical candidate or not.

Social history can provide insight into the patient's career and how often they are in a position to increase pressure to the area. Substance use history should be considered as nicotine can decrease blood flow to an area, and alcohol can be a causality of neuropathy. 

The history should be taken thoroughly and should include a complete review of symptoms. Oftentimes the ulcerations can present infected and are accompanied by nausea, fever, vomiting, or chills to some degree as well as the potential for shortness of breath and chest pain if the patient is in systemic sepsis. The systemic inflammatory response syndrome (SIRS) criteria can help evaluate the possibility of sepsis, however, this is nonspecific. The SIRS criteria evaluate the body’s temperature, heart rate, respiratory rate, and white blood cell count and correlate that with the clinical picture to evaluate the body’s response to infection. The SIRS criteria have been refuted recently, but it is still used in practice in most hospital system’s protocols.[11]

The physical exam should include all aspects of the ulceration but also about the patient's vascular status, neurological status, and any musculoskeletal abnormalities that could be the causality of the ulceration. A dermatologic examination should include the appearance of the wound bed and edges, if any undermining or tunneling is present, to what layer is the wound exposing, if any malodor is associated with the wound, whether or not the ulceration probes deep to the bone, and if there is any drainage, and what type of drainage is present. 

The vascular examination should include palpation of pulses in the area, ultrasound doppler with an evaluation of waveforms and blood flow, as well as capillary refilling time both peri-wound and distal to the ulceration within the digits or distal foot if the digits are not present. Adequate blood flow and tissue perfusion increases healing potential and prognosis and can be used to assess for the concomitance of peripheral arterial disease and vascular insufficiency.

The neurological evaluation should include an evaluation of all types of nerve fibers. This can be done by following multiple neurologic tests such as two-point discrimination, sharp versus dull sensation, vibratory sensation, and pinpoint monofilament testing. Multiple other types of testing are available as well for further evaluation and can include nerve conduction velocity testing, but usually, a clinical evaluation without such advanced testing can provide information as to the patient's sensorium. The evaluation should also include whether this is asymmetric or symmetric, and what type of fibers the neuropathy is affecting (sensory, motor, autonomic).[4]

The musculoskeletal evaluation of the patient is important and often missed. The anatomical structure and biomechanical function should be fully assessed to evaluate for the possibility of deformity reduction and decreasing the prominence of pressure points. If lower extremity ulcerations are the issue, this should include a gait exam, shoe gear examination, and full biomechanical evaluation of the area.

Initially, the cause of the neuropathy should be identified and diagnosed (this is often done prior to the development of ulceration in an ideal world, however oftentimes, this is not the case). The different types of neuropathy can be distinguished based on the physical exam in conjunction with electrodiagnostic testing and laboratory markers. The electrodiagnostic testing consists of electromyography (EMG) and nerve conduction studies/nerve conduction velocity (NCS/NCV). These tend to be performed at the initial presentation of symptoms, and are often only used to evaluate peripheral neuropathy sources and not neuropathic ulcerations. Additionally, epidermal nerve fiber density test can be performed to objectively measure and document small fiber peripheral neuropathy. Laboratory studies that can help evaluate sources of neuropathy include complete blood count, erythrocyte sedimentation rate, fasting blood glucose, hemoglobin A1c, thyroid studies, vitamin B12 levels, renal function studies, and any tests that can help evaluate autoimmune disorders, infectious processes, and toxic etiologies can be performed.[4]

All ulcerations should be evaluated with plain radiographs immediately. Plain radiographs help to assess multiple aspects of neuropathic ulcerations. The soft tissues can be assessed for the possibility of soft tissue emphysema or gas-forming organisms infecting the foot. The structure of the bones can be evaluated as well for any hypertrophy or deformity, causing ulceration. Lastly, the quality of the bone can be assessed for signs of osteomyelitis, which will require further workup for confirmation of a diagnosis. Different signs of osteomyelitis may be seen in the form of sequestrum as a sclerotic area with a radiolucent rim, an involucrum of thick bone surrounding a sequestrum, and cortical destruction. Plain radiographs are highly useful for ruling out many differentials.[12] 

In order to help differentiate neuropathic ulcers from ulcers of vascular origin, vascular studies should also be ordered. This helps to evaluate blood flow, arterial efficacy, and perfusion to certain tissues. This can adjunct surgical decisions and predict healing capabilities as well. The society for vascular surgery developed a risk stratification system that takes into account healing potential in patients with diminished vascular status, including the likelihood of amputation. This shows a direct correlation in vascular insufficiency with the prognosis of an ulceration and the incidence and necessity of surgical intervention in patients with poor blood flow in a limb.[13]

The initial laboratory evaluation of a neuropathic ulcer should include a complete blood count with differential, complete metabolic profile, c-reactive protein, erythrocyte sedimentation rate, and hemoglobin A1c (if recent value not known); with adjunct testing that can also be performed in certain situations. These help to evaluate markers of infection and inflammation. The white blood cell count gives further information on the body's attempt to fight infection, and the differential allows us to analyze which cells in the body are activated for this. The complete metabolic profile helps analyze the ability of the patient's body to maintain a proper electrolyte balance. The c-reactive protein, or CRP, is an enzyme released by the liver that quantifies the amount of inflammation occurring in the body. It has been shown that levels of 7.9 mg/dL associated with an erythrocyte sedimentation rate (ESR) of 60 mm/h are associated with an increased probability of osteomyelitis. ESR is a measurement of how fast the erythrocytes, or red blood cells, settle at the bottom of the test tube and is a nonspecific measurement of chronic inflammation. The ESR greater than 60mm/h has a sensitivity of 74% and a specificity of 56%, while the CRP levels of 7.9 mg/dL have a sensitivity of 49% and specificity of 80%.[14] These tests can not only help us evaluate for infection, but also for the severity of the illness that the patient has. 

At the time of initial evaluation, it is important to perform any debridement of devitalized tissue, a cleansing of the wound with a sterile solution, and obtain a culture of the wound for microbiological analysis. The culture and sensitivities that the laboratory can perform can help guide antibiotic treatment in cases of infection. The Infectious Diseases Society of America came out with clinical practice guidelines in 2012 for diabetic foot infections and have recommended criteria such as inflammation, purulent drainage, positive probe to bone test, chronic ulceration >30 days, previous amputation, a history of ulcerations and multiple other conditions to be of strong evidence for suspicion of infection; thus necessitating the need for cultures. This same paper also recommends that cultures be taken prior to the initiation of antibiotic therapy if possible and that the specimen should be taken from the deepest tissue after cleansing and debridement.[15]

Secondary evaluation should include advanced imaging if indicated. Indications include any suspicion for deep soft tissue abscess and bone infection but should be considered in most instances that any deep infection is a possibility. This can include a computed tomography (CT) scan, magnetic resonance imaging (MRI) scan, 3 phase bone scintigraphy, and ultrasound. Each of these have their pitfalls; however, they can each provide insight into certain nuances of ulcerations for workup on soft tissue abscesses and osteomyelitis. If osteomyelitis is indicated, a bone biopsy is the gold standard for evaluation. Although it has been shown that microbiological and pathological evaluation and interpretation are clinician dependent and maybe not as reliable as it was once thought for diagnosis of bone infection. The advanced imaging modality preferred is MRI and has a high sensitivity for infection diagnosis and can be used with contrast for further evaluation of both bone and soft tissue. Triple phase bone scans are a viable alternative and can be combined with different radionuclides for further sensitivity and specificity. CT scan can also be a viable alternative as it has superior bone resolution than does MRI and is much more readily available, however evaluation of the soft tissue envelope is much poorer when compared to MRI.[12]

The treatment and management of neuropathic ulcers require a two-fold approach; the underlying cause of the neuropathy must be treated, and the ulceration itself must be treated. Both treatment strategies are multifactorial. In order to treat the underlying cause of neuropathy, the testing performed, as discussed previously, can help dictate treatment guidelines depending on what the deficiency or disorder is within the patient.

Ulceration treatment includes a multimodal approach. This is because after the ulceration heals (or before it begins), the efforts must be focused on preventative medicine. Understanding the biomechanical evaluation behind the structures at risk help inform clinical practice guidelines, including orthotic prescriptions and modifications, as well as possible surgical intervention and reconstruction of underlying deformities to decrease plantar loading.[16]

The ulceration itself should be treated based on the physical exam, clinical evaluation, and laboratory findings. The ulceration should be evaluated for surgical intervention for proper irrigation and debridement. Debridement of any necrotic or hyperkeratotic peri-wound tissue, proper cultures if an infection is suspected for microbiological analysis, and possible biopsy of underlying tissue (bone) for pathological evaluation should be done even if surgical intervention is not pursued. If an underlying infection is suspected, this should include proper culture and sensitivity directed antibiotic therapy as well as proper wound care techniques. If an underlying bone infection is suspected, the gold standard approach for evaluation is bone biopsy with both pathology and microbiology analysis for osteomyelitis; however, the sensitivity and specificity of the provider evaluating these remains debated.[15]

All ulcerations should be offloaded to decrease the pressure and redistribute forces to the surrounding tissues. This has been evaluated in many studies and shown to help prevent recurrence of neuropathic ulcers, as well as promote healing in current ulcerations. Offloading treatment comes in many forms and is usually clinician dependent. It can include total contact casting, felt offloading, controlled ankle motion (CAM) boot therapy with custom orthoses, forefoot casting, etc. and is increasingly important in plantar wounds.[17][18] There continues to be strong evidence supporting non-removable devices that extend up to near the level of the knee as the primary therapy for offloading in both forefoot and midfoot ulcerations.[19] 

A recent article published in May of 2019 of the guidelines for offloading the foot in patients with neuropathic ulcers recommends nonremovable knee-high devices as first-line therapy for offloading, removable knee-high devices as second-line, removable ankle-high offloading as the third line, and felted foam or custom footwear as the fourth line for offloading ulcerations.[20] In adjunct to proper offloading, wound care therapy promotes wound healing and should be based on the size, depth, and intrawound properties present that include the moisture and drainage level, pH of the wound, and type of tissues intrawound. There are many different wound care products and grafts available on the market today with a diversity of selections that expedite the healing in wounds with different characteristics.[15]

There are multiple separate subsets of ulcerations that can and should be considered. Certain types of malignancies can present similarly as well, and further evaluation for this should be considered often. Multiple types or conditions of ulcerations are:

• Venous stasis ulceration
• Arterial ulceration
• Traumatic ulcerations
• Decubitus ulceration
• Skin cancers
• Hypertensive ulceration
• Burns
• Cutaneous infectious diseases
• Chemotoxic or drug-induced ulceration
• Side effects of treatment
• Side effects of comorbidities (i.e., Kaposi's sarcoma)

These must be evaluated for life or limb-threatening conditions such as gas gangrene and necrotizing fasciitis.

There are multiple classification systems for diabetic foot wound evaluation. The most common systems are Meggitt-Wagner (often referred to as Wagner), Texas University classification system, S(AD)SAD, PEDIS, and WIFI. There are many studies that evaluate the reliability and comparisons between the systems, and the general conclusion is that the Wagner classification system and Texas University remain reliable and simple to use for classifying diabetic foot ulcers, and WIFI provides the added ability to classify the ischemia with prognostic correlates.[21][22]

The Wagner Classification system is based on a grading system from 0-5. A grade 0 ulceration is considered a pre-ulcerative lesion with skin that remains intact, with the potential of breakdown. A grade 1 ulceration presents with the breakdown of superficial skin or subcutaneous tissue. A grade 2 ulceration has exposed tendon, bone, or capsule. A grade 3 ulceration is deep with osteomyelitis or an abscess present. A grade 4 ulceration is one with gangrene of the partial foot. A grade 5 ulceration is one with gangrene of the entirety of the foot. This system has been shown reliable; however, it does not address the blood flow or infectious properties of the ulceration and is merely a grading system for the ulcer itself.[23]

The University of Texas Diabetic Foot Ulcer Classification System takes both blood flow and infectious properties into consideration. It is a dual system that has both 4 separate grades and 4 separate stages. The four grades from 0-3 are as follows: grade 0- pre-ulcerative site or post-ulcerative site that has healed, grade 1- superficial wound not involving the tendon, capsule or bone, grade 2- wound penetrating to tendon or capsule, grade 3- wound penetrating bone or joint. Within each of these wound grades, the staging of the ulceration is achieved by establishing the blood flow and infectious qualities of the ulceration. This is divided into four stages: A- clean wounds with adequate blood flow, B- non-ischemic wounds that are infected, C- noninfected wounds that are ischemic, and D- infected and ischemic wounds. This provides a more in-depth classification system for use in medicine; however, it lacks information on how to determine ischemia and infectious qualities.[24]

The society for vascular surgery developed a risk stratification system based on wound, ischemic, and foot infection (WIFI), and detail of the WIFI classification system can provide further insight into the analysis of vascular status and infection and how these correlate to the healing potential within the staging system. This system has three separate portions. The wound portion is from grades 0-3 and is as follows: grade 0- no ulcer and no gangrene with the possibility of ischemic rest pain, grade 1- minimal tissue loss and the ulcer has no exposed bone, grade 2- the ulcer extends to the tendon, joint or bone with gangrenous changes to the digits and grade 3- the ulcer involves extensive tissue loss of the forefoot and/or midfoot with or without hindfoot involvement with extensive gangrenous changes to the forefoot and midfoot. The ischemia aspect is broken down using ankle-brachial index (ABI) measurements, transcutaneous oximetry, pulse volume recording, and skin perfusion or toe pressure. It must be taken into account whether or not the patient has calcified vessels, which can alter many of these readings. The ischemia portion is also broken down into 4 grades: grade 0- no ischemia with an ABI greater than or equal to 0.80 and toe pressure greater than or equal to 60 mmHg, grade 1- mild ischemia with an ABI between 0.6-0.79 with a toe pressure ranging from 40 to 59, grade 2- moderate ischemia with an ABI between 0.4 to 0.59 and a toe pressure between 30 to 39, and grade 3- severe ischemia with an ABI less than or equal to 0.39 and a toe pressure less than 30. The final portion of this describes the foot infection portion: grade 0- no infection present, grade 1- superficial infection with cellulitis/erythema that is localized and within 2 cm of the ulceration edge, grade 2- moderate infection with cellulitis/erythema greater than 2 cm from the wound edge with abscess present or infection extending into the bones or joints, and grade 3- severe infection with both local and systemic inflammatory response syndrome (SIRS). Upon completion of the grading system, each ulceration is then staged from 1 to 5; with stage 1 being a low amputation risk, and stage 5 being unsalvageable, with low, moderate, and high risk from stages 2 to 4.[13][21]

In a multicenter cohort prospective study, it was found that 17.4% of patients with diabetic foot ulcers die within 14 years, compared to 3.1% in patients without a pedal ulcer. In the diabetic foot ulcer group, the 5-year mortality rate was 22%, and the 10-year mortality rate was 71%. About 29% of all patients underwent some form of limb amputation. Other variables that predicted early mortality were duration of diabetes greater than 10 years, history of nephropathy, and both minor and major amputations. Overall, the presence of a diabetic foot ulcer increases the risk of amputation, complications, and long term prognosis. This shows roughly one-third of patients diagnosed with a diabetic foot ulcer require amputation, and this number appears to continue to increase with time.[10]

There are multiple complications associated with peripheral neuropathy, with the major complication being amputation. Amputations are due to ulcerations in a neuropathic foot that are associated with infection. Roughly 80% of nontraumatic amputations have been seen due to diabetes and peripheral neuropathy in the United States. With each ulceration and amputation, the morbidity and mortality rate increases, with the probability of contralateral amputation and death increases with each ulceration and surgical intervention.[5] It has been previously estimated that anywhere between 14% and 24% of patients with a pedal ulcer will require amputation of some portion or all of that limb.[25]

One study on predicting the lower extremity amputation rates in patients with diabetic foot ulcers found that roughly 35.4% of patients underwent amputation and that multiple factors such as soft tissue infection, osteomyelitis, duration of ulceration, and vascular insufficiency or peripheral arterial disease played a significant role in this prevalence.[26] This leads to the belief that prompt diagnosis and attention with proper interventions play a significant role in reducing the complications associated with peripheral neuropathy; however, the source of the neuropathy must be controlled as well.

Many complications are discussed in the previous sections.

An interprofessional approach should be used in all patients with neuropathic ulcerations. Consultations should be considered to help dictate certain types of treatment. Podiatry or general surgery should be consulted for the evaluation of surgical intervention necessity. Alongside the surgical team, multiple other specialties should be considered in a patient for inpatient and outpatient therapy. Most hospital systems also offer infectious disease specialists to help dictate antibiotic therapy and duration. Consultations for nerve conduction testing, vascular testing, and advanced imaging should be placed.

Clinical evaluation is provider and specialty-specific but operates on a generalized set of guidelines. If patients have a history of ulceration, have poor vascular status, or have a history of amputation, they should be seen by their foot and ankle specialist every few months, with regular primary care appointments. If patients have any diagnosis related to peripheral neuropathy, they should be seen at a minimum of once per year by their specialist, with primary care appointments more often for overall medical management. Patients should perform daily pedal examinations while at home. If they are unable to evaluate the plantar aspect of their feet, a mirror placed on the floor may come in handy. The best way to decrease the probability of neuropathic ulcerations is vigilance and proper treatment of the underlying causes of neuropathy.

Understanding proper pedal evaluation and which populations are at risk help to identify situations in which intervention is required. It is important for all practitioners to understand that though diabetes mellitus is the most commonly associated underlying disorder leading to plantar ulcers in neuropathic patients, increased age, obesity, improper healing of pedal injuries, and underlying neuropathic causes should all be evaluated for. Early intervention and proper offloading is the key to decreasing morbidity and mortality associated with neuropathic ulcers.[27] Proper patient and family education are vital to the long term healthcare outcomes associated with peripheral neuropathy.