**3.3. Epidemiology**

**3. Diabetic distal symmetric polyneuropathy in type 1 diabetes mellitus**

**Generalized Neuropathy Focal Neuropathies Autonomic Neuropathies**

Insulin Neuritis/Treatment Neuropathy Ulnar -cubital tunnel Genitourinary autonomic neuropathy

Lateral femoral cutaneous -inguinal ligament

Thoracic radiculopathies Cranial nerve palsy (III, VI, VII)

Inflammatory Neuropathy Fibular -fibular head Hypoglycemia unawareness and

polyneuropathy (DSP) *Compression:* Cardiovascular autonomic neuropathy

Gastrointestinal autonomic neuropathy

associated autonomic failure

Tibial -tarsal tunnel Sudomotor autonomic neuropathy

Distal Symmetric Polyneuropathy (DSP) is the most common type of neuropathy affecting patients with type 1 diabetes. Polyneuropathy is the greatest risk factor for non-traumatic amputations and confers a higher mortality risk [3, 4]. The incidence of DSP increases with duration of diabetes and with degree of hyperglycemia [5]. In type 1 diabetes, typically the incidence of DSP is linked to other microvascular complications of nephropathy and retinop‐ athy [6]. Unlike type 2 diabetes, polyneuropathy is rarely if ever present in the first five years of diagnosis. Metabolic memory in which improved metabolic control, even for a finite period, confers improved outcomes in the future is a phenomenon which was discovered with the Diabetes Complications and Control Treatment Trial, and may be an important factor to

The case definition of typical DSP or diabetic sensorimotor polyneuropathy from the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic

consider in the treatment of type 1 diabetic patients [7].

**3.1. Overview**

*Typical:* Distal symmetric

332 Type 1 Diabetes

Chronic inflammatory demyelinating polyneuropathy

Mononeuritis multiplex

Dyck et al. 2011 [1] and Vinik et al 2003 [2]

**Table 1.** Classification of Diabetic Neuropathy

*Atypical Neuropathy:* Median -carpal tunnel

Diabetic amyotrophy *Ischemic:*

**3.2. Diagnostic criteria**

The prevalence of DSP in type 1 diabetes mellitus has been postulated to be over 50% by 25 years of diagnosis [9, 10]. These data depend on measures used for quantification. Nerve conduction studies are typically more sensitive than monofilament tests and often show decreased conduction velocity in sensory and motor nerves prior to the development of signs or symptoms of sensory loss with monofilament and vibration testing [11]. More tests used, and more sensitive measures will increase prevalence statistics.

Risk factors for DSP incidence and severity in addition to duration of diabetes and age are hyperglycemia, systolic blood pressure, smoking, cholesterol, and height. The Diabetes Control and Complications Trial confirmed hyperglycemia as a significant risk factor for DSP in type 1 diabetes1 . Interestingly, hyperglycemia alone has not been proven in prospective cohort studies of type 2 diabetes to delay progression in this population [12] which raises the question of whether hyperglycemia is the sole cause of DSP in type 2 diabetes.

Typical progression of DSP in type 1 is very slow, with incremental sensory loss over years and decades. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study data show minimal changes in conduction velocity and amplitudes over 5 year periods, which can reassure patients [13, 14]. Progression typically affects both large, myelinated fibers conveying tactile sensitivity, vibration and joint position sense, and small, unmyelinated fibers conveying temperature and pain sensation. Motor involvement is typically subclinical until later in the disease course. While slowed conduction velocities, particularly in the fibular nerve, are common early signs of DSP, weakness typically occurs later, first affecting the toes and then more proximal muscles.

Inflammatory neuropathies such as mononeuritis multiplex and diabetic amyotrophy affecting the plexus are less common in type 1 diabetes than type 2 [15]. Chronic inflammatory demyelinating polyneuropathy is also more common in type 2, but has not been shown to

<sup>1 \*</sup>The DCCT was a groundbreaking study of patients with type 1 diabetes in the United States; a large, multicenter study designed to test whether improved glycemic control delayed the onset or progression of diabetic complications. The follow up epidemiologic study, EDIC (Epidemiology of Diabetes Interventions and Complications) continued to follow the same patients enrolled in DCCT, which is still ongoing.

affect diabetic patients at an increased rate than the general population [16]. Acute painful neuropathy associated with weight loss and abrupt improvement in glycemic control occurs in both type 1 and type 2 patients. This type of neuropathy, formerly known as "insulin neuritis" typically has significant resolution within a year of onset [17].

conduction studies measuring sensory and motor nerve action potential amplitude, latency, and conduction velocity are typically used for most studies [14]. The most common nerves assessed are sural sensory and fibular motor nerves. These were shown by Dyck et al to be involved earliest [39]. The earliest finding is conduction velocity slowing in the fibular and

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Additional measures used include quantitative sensory testing, which can be performed with multiple devices to measure vibration and thermal thresholds [40, 41]. This can be more sensitive than nerve conduction studies but is subjective and not well suited for diagnostic purposes [42]. Quantitative sensory testing is highly reproducible and has been used in several clinical neuropathy studies [43, 44]. Sural nerve biopsy is rarely per‐ formed for diagnosis due to its invasiveness (and cannot be repeated) and is usually used to evaluate for other forms of neuropathy such as chronic inflammatory demyelinating polyneuropathy, vasculitis, or inherited neuropathies. Skin biopsy with measurement of intraepidermal nerve fiber density has become more common, especially when combined with chemical axotomy with capsaicin to measure nerve regeneration [36]. Newer noninva‐ sive methods used include confocal microscopy of corneal C fibers [45] or of Meissner

Management of DSP is largely supportive. The main therapeutic aim is to achieve normogly‐ cemia or HgA1c less than 7 [13]. This can be accomplished with frequent self-monitoring and using insulin pumps for continuous subcutaneous insulin infusion or multiple daily injections. Both the EURODIAB and the Diabetes Control and Complications Trial confirmed therapeutic efficacy in delaying progression of DSP with lower glycemic levels [5, 13]. For treatment of insulin neuritis, management is largely supportive and usually requires relaxing hyperglyce‐ mia control somewhat. Inflammatory neuropathies may respond to pulsed IV steroids and intravenous immunoglobulins but class A evidence is still lacking [48, 49]. Diabetic chronic inflammatory demyelinating polyneuropathy is managed similarly to idiopathic chronic

Foot care is critical once DSP occurs. Patients should be instructed to inspect their feet every night for new ulcerations, blisters or cuts. Wearing shoes at all times will also decrease the chance of potential injury. Feeling bathwater with hands or more proximal leg is also helpful to avoid burns from insensate feet. As neuropathy occurs, the foot structure will change due to muscle atrophy and due to fractures from insensate feet (Charcot foot). Orthotic inserts may

Falls are an important complication in DSP and need to be screened for at clinic visits. Evaluation by a physical therapist can be helpful in identifying whether a cane, four-point canes, walkers, wheelchairs should be singular. Home evaluations to improve lighting, minimize obstructions and irregular floors like loose rugs are also important. Adding grab

be helpful in preventing further ulceration and stabilizing the feet [51].

bars in bath areas and minimizing steps can be helpful changes to homes.

corpuscles (mechanoreceptors) in the finger [46, 47].

inflammatory demyelinating polyneuropathy [50].

sural nerves.

**3.6. Management**

Sensory symptoms include numbness, or alteration of sensation often described by patients as "wearing multiple socks" or "walking on wood". Neuropathic pain when present can vary between sharp shooting pains, stabbing, or dull and aching. Muscle cramps in feet and legs are common complaints. Hand symptoms can occur when DSP progresses to include the hands in a length dependent process, but more commonly occur because of coexisting compression neuropathies in the hands [18, 19].

Coexisting polyneuropathy from other causes also occurs in type 1 diabetes patients and can account for as many as 10% of DSP cases [9]. The most common include alcoholic neuropathy, B12 deficiency and monoclonal gammopathies. Atypical presentations such as severe distal or proximal weakness, spasticity, faster progression over weeks to months should be signals that a coexistent polyneuropathy may be present and needs evaluation.

### **3.4. Pathophysiology**

The polyol pathway was put forth as a possible cause of diabetic neuropathy over 30 years ago when aldose reductase inhibitors were first studied [20]. Since then, the pathophysiol‐ ogy of DSP in type 1 diabetes is still not completely known but several major pathways have been the focus of most studies. 1) increased flux through the polyol pathway; 2) advanced glycation end-products affecting proteins and lipids [21, 22]; 3) increased oxidative stress with impaired mitochondrial function [23, 24], 4) protein kinase C inhibi‐ tion [25, 26] and 5) loss of nerve growth factors [27, 28]. Additional mechanisms that have been raised include inflammation, loss of nitric oxide, and hypoxia from microvascular damage [29]. Additional metabolic factors such as hypertriglyceridemia may be more pertinent to type 2 diabetes, although this also occurs in type 1 patients [30, 31]. Loss of ATP and AMP production through mitochondrial dysfunction may be a "final common pathway" for these mechanisms to cause neuronal injury [32].

The role of Schwann cells in DSP is still not completely understood. Schwann cells, not neurons produce aldose reductase [33] and are also the source of nerve growth factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor [34, 35]. Schwann cells in culture tend to be more resistant to hyperglycemia than neurons. However, the most recent evidence suggests unmyelinated fibers to be more sensitive to hyperglycemia than myelinated fibers [36]. These may have important implications for biomarkers in treatment studies.

#### **3.5. Assessment**

The assessment of DSP in type 1 diabetes significantly affects the sensitivity and specificity cited. The simplest assessments used are loss of ankle deep tendon reflexes and detection of pressure from a 10g monofilament. Monofilament sensitivity alone ranges from 20% to 64% [37, 38] and likely improves if multiple sites on the foot are tested (8 sites recommended). Nerve conduction studies measuring sensory and motor nerve action potential amplitude, latency, and conduction velocity are typically used for most studies [14]. The most common nerves assessed are sural sensory and fibular motor nerves. These were shown by Dyck et al to be involved earliest [39]. The earliest finding is conduction velocity slowing in the fibular and sural nerves.

Additional measures used include quantitative sensory testing, which can be performed with multiple devices to measure vibration and thermal thresholds [40, 41]. This can be more sensitive than nerve conduction studies but is subjective and not well suited for diagnostic purposes [42]. Quantitative sensory testing is highly reproducible and has been used in several clinical neuropathy studies [43, 44]. Sural nerve biopsy is rarely per‐ formed for diagnosis due to its invasiveness (and cannot be repeated) and is usually used to evaluate for other forms of neuropathy such as chronic inflammatory demyelinating polyneuropathy, vasculitis, or inherited neuropathies. Skin biopsy with measurement of intraepidermal nerve fiber density has become more common, especially when combined with chemical axotomy with capsaicin to measure nerve regeneration [36]. Newer noninva‐ sive methods used include confocal microscopy of corneal C fibers [45] or of Meissner corpuscles (mechanoreceptors) in the finger [46, 47].

#### **3.6. Management**

affect diabetic patients at an increased rate than the general population [16]. Acute painful neuropathy associated with weight loss and abrupt improvement in glycemic control occurs in both type 1 and type 2 patients. This type of neuropathy, formerly known as "insulin

Sensory symptoms include numbness, or alteration of sensation often described by patients as "wearing multiple socks" or "walking on wood". Neuropathic pain when present can vary between sharp shooting pains, stabbing, or dull and aching. Muscle cramps in feet and legs are common complaints. Hand symptoms can occur when DSP progresses to include the hands in a length dependent process, but more commonly occur because of coexisting compression

Coexisting polyneuropathy from other causes also occurs in type 1 diabetes patients and can account for as many as 10% of DSP cases [9]. The most common include alcoholic neuropathy, B12 deficiency and monoclonal gammopathies. Atypical presentations such as severe distal or proximal weakness, spasticity, faster progression over weeks to months should be signals that

The polyol pathway was put forth as a possible cause of diabetic neuropathy over 30 years ago when aldose reductase inhibitors were first studied [20]. Since then, the pathophysiol‐ ogy of DSP in type 1 diabetes is still not completely known but several major pathways have been the focus of most studies. 1) increased flux through the polyol pathway; 2) advanced glycation end-products affecting proteins and lipids [21, 22]; 3) increased oxidative stress with impaired mitochondrial function [23, 24], 4) protein kinase C inhibi‐ tion [25, 26] and 5) loss of nerve growth factors [27, 28]. Additional mechanisms that have been raised include inflammation, loss of nitric oxide, and hypoxia from microvascular damage [29]. Additional metabolic factors such as hypertriglyceridemia may be more pertinent to type 2 diabetes, although this also occurs in type 1 patients [30, 31]. Loss of ATP and AMP production through mitochondrial dysfunction may be a "final common

The role of Schwann cells in DSP is still not completely understood. Schwann cells, not neurons produce aldose reductase [33] and are also the source of nerve growth factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor [34, 35]. Schwann cells in culture tend to be more resistant to hyperglycemia than neurons. However, the most recent evidence suggests unmyelinated fibers to be more sensitive to hyperglycemia than myelinated fibers

The assessment of DSP in type 1 diabetes significantly affects the sensitivity and specificity cited. The simplest assessments used are loss of ankle deep tendon reflexes and detection of pressure from a 10g monofilament. Monofilament sensitivity alone ranges from 20% to 64% [37, 38] and likely improves if multiple sites on the foot are tested (8 sites recommended). Nerve

[36]. These may have important implications for biomarkers in treatment studies.

neuritis" typically has significant resolution within a year of onset [17].

a coexistent polyneuropathy may be present and needs evaluation.

pathway" for these mechanisms to cause neuronal injury [32].

neuropathies in the hands [18, 19].

**3.4. Pathophysiology**

334 Type 1 Diabetes

**3.5. Assessment**

Management of DSP is largely supportive. The main therapeutic aim is to achieve normogly‐ cemia or HgA1c less than 7 [13]. This can be accomplished with frequent self-monitoring and using insulin pumps for continuous subcutaneous insulin infusion or multiple daily injections. Both the EURODIAB and the Diabetes Control and Complications Trial confirmed therapeutic efficacy in delaying progression of DSP with lower glycemic levels [5, 13]. For treatment of insulin neuritis, management is largely supportive and usually requires relaxing hyperglyce‐ mia control somewhat. Inflammatory neuropathies may respond to pulsed IV steroids and intravenous immunoglobulins but class A evidence is still lacking [48, 49]. Diabetic chronic inflammatory demyelinating polyneuropathy is managed similarly to idiopathic chronic inflammatory demyelinating polyneuropathy [50].

Foot care is critical once DSP occurs. Patients should be instructed to inspect their feet every night for new ulcerations, blisters or cuts. Wearing shoes at all times will also decrease the chance of potential injury. Feeling bathwater with hands or more proximal leg is also helpful to avoid burns from insensate feet. As neuropathy occurs, the foot structure will change due to muscle atrophy and due to fractures from insensate feet (Charcot foot). Orthotic inserts may be helpful in preventing further ulceration and stabilizing the feet [51].

Falls are an important complication in DSP and need to be screened for at clinic visits. Evaluation by a physical therapist can be helpful in identifying whether a cane, four-point canes, walkers, wheelchairs should be singular. Home evaluations to improve lighting, minimize obstructions and irregular floors like loose rugs are also important. Adding grab bars in bath areas and minimizing steps can be helpful changes to homes.

### **3.7. Treatment of neuropathic pain**

A significant number of patients with DSP (16-60%) have symptoms of neuropathic pain [52, 53]. One UK study suggested that painful symptoms were more prevalent in type 2 than type 1 diabetes [53]. Typical pain symptoms are delayed compared to signs of neuropathy in type 1 diabetes [54, 55]. The etiology of neuropathic pain in DSP has been thought to be due to abnormalities in C-fiber nerve endings causing aberrant signaling through protein kinase C [26], increased transient receptor potential vanilloid 1 expression [56], dysregulation of ion channels [57], abnormal nerve growth factor levels [58] and possibly dysregulation of de‐ scending pain pathways [59].

as 20 -30 mg and slow titration up to 60 mg. Effectiveness of 120 mg was not statistically different from 60 mg in clinical studies, although some patients report improved benefit at higher doses [65]. Tricyclic antidepressants also have a benefit in patients reporting difficulty initiating sleep due to pain due to their sedating effects. Dosages of 25-100 mg amitriptyline 2 hours before bedtime are typically used. At higher doses and in elderly patients, an ECG should be obtained because of possible effects of tricyclics on QT prolongation and heart block. Side effects include drowsiness, urinary hesitancy, constipation, orthostatic hypotension and

Topical creams are not typically efficacious for painful DSP. Capsaicin cream/patch has shown efficacy [67], but is typically not well tolerated due to the significant initial pain with applica‐ tion. Gloves need to be worn and avoidance of the eyes is necessary. Occasionally 1% lidocaine patches can be helpful in patients with focal mononeuropathies such as meralgia paresthetica (compression of the lateral femoral cutaneous nerve). Topical compounded creams containing gabapentin, amitriptyline, and ketamine have been used but there are no published reports on

**Anti-Epileptic Medications Anti-Depressants Other**

Pregabalin\* Duloxetine\* Tramadol Carbamazepine Mexiletine

Other types of neuropathy which can occur include mononeuropathies, typically at compres‐ sion points such as median mononeuropathy at the wrist, e.g. carpal tunnel syndrome, ulnar neuropathy at the elbow, and peroneal neuropathy at the knee. In the Rochester Diabetes Trial, these occurred at about the same frequency or higher in type 1 vs. type 2 patients [9]. Cranial neuropathies and truncal radiculopathy occur at an increased rate in diabetic patients, but prevalence data for type 1 and type 2 patients is not available. Pain is a common presenting symptom in ischemic ocular motor palsies and thoracic radiculopathies in diabetes [68, 69]. The Veterans Affairs study of type II patients showed decreased prevalence of cranial mono‐ neuropathies with stricter glucose control but data is lacking for type 1 patients [70]. It is not

Lamotrigine Capsaicin Cream/Patch

nortriptyline, imipramine) Opiates

Alpha lipoic acid

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Gabapentin Tricyclic antidepressants (amitriptyline,

erectile dysfunction.

efficacy in placebo controlled studies.

\*FDA approved indication for diabetic neuropathic pain.

**Table 2.** Pharmacologic Treatments of Neuropathic Pain

**4. Focal neuropathies**

**4.1. Overview and epidemiology**

Typical pain symptoms described include "burning", "stabbing", "needle-like", "shooting", "electric" etc. Patients often complain of allodynia, e.g. normal sensations become painful such as the touch of bedcovers to the feet, as well as hyperalgesia (painful sensations such as pinprick are unbearably painful). Pain is typically worse at night, and with activities such as walking and standing. Mononeuropathies such as carpal tunnel syndrome can also cause nocturnal paresthesias. Pain symptoms are typically not completely relieved with medications. Pain can be moderate to severe with an average of 5.8/10 on a pain scale [60].

Medications used for neuropathic pain include traditional pain medications such as opioids and tramadol, antiepileptic agents and antidepressants (Table 2) [61]. Typically patients require large doses of opiates for pain relief, and long acting opiates are preferred to provide sustained relief. Sedation, constipation, pharmacologic tolerance and addiction issues are significant barriers and usually prohibit opiates as first line pain treatment in neuropathic pain. Mexiletine, a sodium channel blocker and anti-arrhythmic agent has also been shown to have some analgesic effects [62].

Alpha2-delta inhibitors gabapentin and pregabalin are the most commonly used anti-epileptic medications. These medications act at the dorsal horn of the spinal cord to inhibit voltage gated calcium channels [63, 64]. The advantage of gabapentin and pregabalin is their renal excretion and lack of interaction with other medications. Main side effects include drowsiness, dizziness, peripheral edema, weight gain, and myoclonic jerks at higher doses. Gabapentin is typically initiated at 300 mg up to three times a day and can be escalated up to 4800 mg in divided doses. Its short half-life requires three to four times a day dosing for optimal pain relief. Pregabalin has a longer half-life and is typically dosed twice a day although some patients benefit from dosing three times a day. Pregabalin is usually started at 75 mg twice a day and titrated up to 300 mg twice a day. Consultation with a nephrologist in dialysis dependent patients is needed due to renal excretion, but does not preclude use in these patients. Typically nephrologists will administer one dose after dialysis. Other anticonvulsants used for neuropathic pain include carbamazepine, oxcarbazepine, valproic acid, lamotrigine, lacosamide, and phenytoin.

Antidepressants acting on norepinephrine such as tricyclic antidepressants and the selective serotonin and norepinephrine reuptake inhibitor duloxetine are also helpful in treating neuropathic pain [65, 66]. Duloxetine is well tolerated, with few side effects. Caution should be used in patients with renal insufficiency as elevations of systolic blood pressure have been observed. Nausea can occur initially, but can be avoided with initiation at lower doses such as 20 -30 mg and slow titration up to 60 mg. Effectiveness of 120 mg was not statistically different from 60 mg in clinical studies, although some patients report improved benefit at higher doses [65]. Tricyclic antidepressants also have a benefit in patients reporting difficulty initiating sleep due to pain due to their sedating effects. Dosages of 25-100 mg amitriptyline 2 hours before bedtime are typically used. At higher doses and in elderly patients, an ECG should be obtained because of possible effects of tricyclics on QT prolongation and heart block. Side effects include drowsiness, urinary hesitancy, constipation, orthostatic hypotension and erectile dysfunction.

Topical creams are not typically efficacious for painful DSP. Capsaicin cream/patch has shown efficacy [67], but is typically not well tolerated due to the significant initial pain with applica‐ tion. Gloves need to be worn and avoidance of the eyes is necessary. Occasionally 1% lidocaine patches can be helpful in patients with focal mononeuropathies such as meralgia paresthetica (compression of the lateral femoral cutaneous nerve). Topical compounded creams containing gabapentin, amitriptyline, and ketamine have been used but there are no published reports on efficacy in placebo controlled studies.


**Table 2.** Pharmacologic Treatments of Neuropathic Pain
