**4.2. Pathophysiology**

The pathophysiology of mononeuropathies in diabetes is not well understood. They are generally divided into compression-site mononeuropathies, occurring at typical compression points such as the transverse ligament in the wrist (median), cubital tunnel (ulnar nerve), across the knee (fibular nerve), the inguinal ligament (lateral femoral cutaneous nerve/meralgia paresthetica) and tarsal tunnel (tibial nerve). Cranial nerve mononeuropathies and thoracic radiculopathies, diabetic amyotrophies are thought to have an ischemic etiology, either due to microvascular disease (such as cranial nerve involvement) or inflammation (diabetic amyotrophy). Some patients (described in type 2 diabetes) have a rapid development of multiple mononeuropathies which is indistinguishable from a vasculitic mononeuritis multiplex in presentation and can be associated with inflammation on biopsy [76].

The greater prevalence of compression mononeuropathies in diabetes (20-30% of Type 1 and 2 patients) [9, 77] has been observed for decades, but the pathophysiology is not well known. Experimental compression neuropathies trigger Schwann cell proliferation, apoptosis causing local demyelination then remyelination. This occurs prior to the development of axonal degeneration [78]. The median nerve when visualized with ultrasonography is larger in patients with compression compared to healthy controls which may be due to remyelination [79]. It has been presumed that hyperglycemia injured nerves are more vulnerable to com‐ pression than normal nerves. Another possibility is lack of symptoms in the diabetic may make compression mononeuropathies worse because of delayed recognition [77]. Other possible etiologies include greater edema within the nerve and diabetic cheiroarthropathy (thickening/ fibrosis of the flexor synovium from excessive connective tissue) [80, 81].

#### **4.3. Assessment**

Identification of mononeuropathies may be based on signs and symptoms localizable to a specific nerve in a diabetic patient (e.g. ptosis, diploplia in a Cranial nerve III/oculomotor nerve palsy). This is typically the case for cranial nerve palsies, optic neuropathies, thoracic radicu‐ lopathies, or lateral femoral cutaneous nerve palsy where the distribution of deficit is patho‐ gnemonic. If the symptoms and signs are specific to one cranial nerve in a previously diagnosed diabetic patient, imaging with magnetic resonance imaging, CT or other modality is typically not needed to confirm the diagnosis. Especially in cranial nerve III palsies, there is controversy whether imaging should occur in a diabetic patient with a classical papillary-sparing presen‐ tation [82, 83].

Mononeuropathies may be identified on testing with nerve conduction studies. This is more common in carpal tunnel syndrome, ulnar mononeuropathy, and fibular mononeuropathy which are often asymptomatic. Nerve conduction studies in compression mononeuropathies distally typically demonstrate slowing of conduction velocity across the compressed segment (ulnar, fibular, tibial nerve) or increased distal latency compared to nearby nerves (median nerve). Multiple nerves are often compared, or side to side comparisons are made to exclude underlying DSP.

For carpal tunnel syndrome, nerve ultrasound has become a more common procedure, demonstrating enlarged median nerve cross sectional area in the wrist in affected individ‐ uals compared to controls [84]. Thus far, no differentiation between ultrasound appear‐ ance of diabetic vs. non-diabetic nerves have been found [85]. Another study suggested a larger cross-sectional area of the tibial nerve at the tarsal tunnel in diabetic patients [86]. Further studies are still needed on the utility of this measure for diabetic patients. Magnet‐ ic resonance imaging is also used for assessment of carpal tunnel syndrome, but data in diabetes vs. control patients is lacking and cost is significantly higher than nerve conduc‐ tion studies or ultrasound [87].

#### **4.4. Treatment**

uncommon for mononeuropathies to occur prior to the development of DSP or identification of diabetes, particularly in type 2 patients [71, 72]. This has not been described in type 1 patients.

Median mononeuropathy at the wrist, e.g. carpal tunnel syndrome is the most common mononeuropathy in diabetes and occurs three to four times as commonly in diabetics com‐ pared to healthy controls, and is more common in diabetics with DSP than without [72-74]. Median mononeuropathy has been reported as early as 11 years old [75]. Risk factors for development of carpal tunnel syndrome include obesity and lipid-lowering medications [74].

The pathophysiology of mononeuropathies in diabetes is not well understood. They are generally divided into compression-site mononeuropathies, occurring at typical compression points such as the transverse ligament in the wrist (median), cubital tunnel (ulnar nerve), across the knee (fibular nerve), the inguinal ligament (lateral femoral cutaneous nerve/meralgia paresthetica) and tarsal tunnel (tibial nerve). Cranial nerve mononeuropathies and thoracic radiculopathies, diabetic amyotrophies are thought to have an ischemic etiology, either due to microvascular disease (such as cranial nerve involvement) or inflammation (diabetic amyotrophy). Some patients (described in type 2 diabetes) have a rapid development of multiple mononeuropathies which is indistinguishable from a vasculitic mononeuritis

multiplex in presentation and can be associated with inflammation on biopsy [76].

fibrosis of the flexor synovium from excessive connective tissue) [80, 81].

The greater prevalence of compression mononeuropathies in diabetes (20-30% of Type 1 and 2 patients) [9, 77] has been observed for decades, but the pathophysiology is not well known. Experimental compression neuropathies trigger Schwann cell proliferation, apoptosis causing local demyelination then remyelination. This occurs prior to the development of axonal degeneration [78]. The median nerve when visualized with ultrasonography is larger in patients with compression compared to healthy controls which may be due to remyelination [79]. It has been presumed that hyperglycemia injured nerves are more vulnerable to com‐ pression than normal nerves. Another possibility is lack of symptoms in the diabetic may make compression mononeuropathies worse because of delayed recognition [77]. Other possible etiologies include greater edema within the nerve and diabetic cheiroarthropathy (thickening/

Identification of mononeuropathies may be based on signs and symptoms localizable to a specific nerve in a diabetic patient (e.g. ptosis, diploplia in a Cranial nerve III/oculomotor nerve palsy). This is typically the case for cranial nerve palsies, optic neuropathies, thoracic radicu‐ lopathies, or lateral femoral cutaneous nerve palsy where the distribution of deficit is patho‐ gnemonic. If the symptoms and signs are specific to one cranial nerve in a previously diagnosed diabetic patient, imaging with magnetic resonance imaging, CT or other modality is typically not needed to confirm the diagnosis. Especially in cranial nerve III palsies, there is controversy whether imaging should occur in a diabetic patient with a classical papillary-sparing presen‐

**4.2. Pathophysiology**

338 Type 1 Diabetes

**4.3. Assessment**

tation [82, 83].

Treatment of compression induced mononeuropathies is aimed at relieving the site of trauma. Bracing, avoiding extenuating activity, and changing postures are initial non-surgical ap‐ proaches. Data for surgical approach to compressive neuropathy is better known in median mononeuropathies at the wrist (carpal tunnel syndrome) because of larger reported cohort studies. However, data are conflicting in regards to outcome of carpal tunnel syndrome surgical release with some studies showing poorer outcomes and some not significantly different from non-diabetic patients [88, 89]. This may occur due to differences in patient selection. Results of surgical release of the ulnar nerve at the cubital tunnel, the second most common mononeuropathy (2.1%) are worse compared to carpal tunnel syndrome [81, 90]. It is not clear whether this is due to underlying diabetic polyneuropathy or due to patient selection bias (misdiagnosis).

Treatment of ischemic induced mononeuropathies is typically supportive. Pain management is often needed for thoracic radiculopathies, meralgia paresthetica (lateral femoral cutaneous nerve palsy). Prisms or patching can be used for diploplia in ocular motor cranial nerve palsies (cranial nerve 3, 4, and 6). Taping of the eyelid and lubrication may be needed in facial nerve palsies to prevent corneal abrasion. Little data are available for prognosis. Many patients improve over 3-6 months, but some may have permanent muscle weakness or ptosis [91, 92]. Treatment with intravenous alpha-lipoic acid has also been reported as improving outcomes but was not placebo controlled [93]. Otherwise, treatment for mononeuropathies in diabetes is not significantly different than in non-diabetics.
