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Home , Diabetic neuropathy

Why Diabetic Neuropathy?

• is the most common cause of Diabetic Neuropathy in the western countries • There are 20.8 million Americans with Bakri Elsheikh, MD diabetes mellitus The Ohio State University Medical Center • Nearly one third are undiagnosed • There are 54 million Americans who have pre-diabetes

American Diabetes Association - http://www.diabetes.org

Diabetic Neuropathy Talk Outline Why Diabetic Neuropathy? • Why diabetic neuropathy? • What is diabetic neuropathy ? • Diabetic neuropathy is a major contributory factor • How common is diabetic neuropathy in the pathogenesis of • Who gets diabetic neuropathy? foot ulceration and • How to recognize the different types? Charcot joints • How to evaluate diabetic neuropathy? • How does causes peripheral • 15% of diabetics develop neuropathy? foot during life time • How to treat it? • What is the future prospective?

1 What is Diabetic The Rochester Diabetic Neuropathy? Neuropathy Study Neuropathy type Type 1 Type 2 • A simple definition of DN for clinical Any neuropathy 66% 59% practice is Distal neuropathy 54% (15%) 45% (13%) “ The presence of symptoms and/or signs of CTS 33% (11%) 35% (6%) peripheral dysfunction in people with Autonomic 7% 5% diabetes after exclusion of other causes” Ulnar neuropathy 2% 2% Boulton AJM et al. Diabet Med 1998 LSRPN 1% 1%

• About 10%of diabetic patients had neurologic deficits attributable to non-diabetic causes Dyck PJ et al. Neurology 1993

How common is Staging Severity of diabetic neuropathy? Diabetic Neuropathy • N0: No objective evidence of DN • A prospective study of 4400 patients found • N1: Asymptomatic 8% had neuropathy at the time of N1a: No symptoms, no signs, abnormal diagnosis, and 50% after 25 years test N1b: No symptoms, abnormal signs, Pirart J. Diabetes Care 1978 abnormal test • A landmark study of 380 diabetic subjects • N2: Symptomatic neuropathy were evaluated for development and N2a: Symptoms, signs and test abnormality distribution of neuropathy N2b: N2a plus significant ankle dorsiflexor weakness Dyck PJ et al. Neurology 1993 • N3: Disabling neuropathy

2 The Rochester Diabetic Neuropathy Study Risk factors for DPN N2b 1% N2a 12% • Duration of diabetes N1 39% • The degree of hyperglycemia N2a 9% N1 32% N2b 6% • The presence of other microvascular N0 55% N0 46% complications is a marker for the presence of neuropathy rather than a risk factor per se Type 1 Type 2 Dyck PJ et al. Diabetes Care 1992; Adler AI et al. Diabetes care 1997; Van de Poll-Franse L et al. Diabet Med 2002

The Rochester Diabetic Diabetic Neuropathy Neuropathy Study Classification

Symmetric Asymmetric

N2b N2a N2b N2b Diabetic distal N2a Cranial neuropathies N2a polyneuropathy N0 N1 N0 Diabetic Mononeuropathies N0 N1 N1 Polyneuropathy with Radiculoplexus impairment neuropathies Diabetic truncal Diabetic cachectic radiculoneuropathy < 10 years >10 - <20 years > 20 years neuropathy

CIDP in diabetes Dyck PJ et al. Neurology 1993

3 Diabetic Distal Symmetric Polyneuropathy

• Symptoms begin with sensory disturbance usually in the toes Symmetric Diabetic and feet • With time, as symptoms progress to involve the calves, the hands Neuropathies may be affected • eventually may develop a “tear drop” pattern of loss over the anterior trunk • In patients with hand symptoms early in the course, entrapment neuropathy is the likely cause

Diabetic Distal Symmetric Diabetic Distal Symmetric Polyneuropathy Polyneuropathy • The most common form of diabetic Clinical examination tools: neuropathy • Pin prick test using • It is a length dependent, distal process a disposable pin • Light touch using • It is very slowly progressive a cotton wisp • It is rarely disabling • Vibration test using • Sensory symptoms predominate 128Hz tuning fork • Ankle reflex using a • Painful symptoms are present in about 10% reflex hammer of the patients • Pressure perception using • Motor symptoms are usually minimal 10 g monofilament may be used to assess the risk of ulceration

4 Diabetic Autonomic Polyneuropathy with Neuropathy Glucose Impairment • Usually accompanies mixed neuropathies • Usually correlates with severity of somatic neuropathy • The neuropathy associated with IGT is • Occasionally, occurs out of proportion to milder than the neuropathy associated with underlying neuropathy newly diagnosed diabetes mellitus • May involve cardiovascular, genitourinary, • Small fiber involvement may be the earliest gastrointestinal, and/or thermoregulatory systems detectable sign of neuropathy • Common symptoms are orthostatic dizziness, Sumner CJ et al. Neurology 2003 , , vomiting, , abdominal , constipation or , anhydrosis and . Vinik AI et al. Diabetes Care 2003

Polyneuropathy with Diabetic Neuropathic Glucose Impairment Cachexia • Rare entity • Acute painful neuropathy • Prospective study of 107 patients with • Associated with rapid, profound weight loss idiopathic neuropathy found 13 of 107 had diabetes and 36 had IGT • Occurs in the setting of poor glucose control • Hypersensitivity and painful dyesthesias over the Singleton JR et al. Diabetes Care 2001 limbs and trunk • Minimal sensory impairment • Normal to near normal strength • Prognosis is good

Ellenberg M Diabetes 1974; Jackson CE et al. J Neurol Neurosurg Psychiatry 1998

5 Chronic Inflammatory Demyelinating Diabetic Polyradiculoneuropathy (CIPD) in Diabetes Mononeuropathies • Diabetics are more susceptible to • The possibility of increased incidence in compression neuropathies diabetic patients is raised • Median neuropathy at the wrist (carpal • It is a gradually progressive disorder tunnel syndrome) • It is usually painless with proximal and • Ulnar neuropathy at the elbow distal arm and leg weakness • Common peroneal neuropathy at the fibular • Diagnosis is problematic head Cornblath DR et al. Ann Neurol 1987 • Lateral femoral cutaneous neuropathy Gordon KC et al. Muscle Nerve 2002 (Meralgia paresthetica)

Stevens JC et al. Neurology 1988; Dyck PJ et al. neurology 1993

Cranial Neuropathies • Acute in onset • Can be accompanied by severe pain Asymmetric Diabetic • Usually occurs after the age of 50 Neuropathies • CN III is the most common 9 Retroorbital pain 9 , 20 to partial ophthalmoplegia 9 sparing

Asbury AK et al. 1970; Smith BE et al. Ann Neurol 1992

6 Lumbosacral Cranial Neuropathies Radiculoplexopathy

• CN IV and VI may also be affected • Presents with: • Thought to be ischemic in nature 9 Severe pain in the back, hip, +/or thigh • Self limiting with symptoms resolving over 9 Followed by proximal > distal leg months to a year weakness 9 Weight loss 9 Minimal sensory features 9 Onset usually unilateral; may progress to other leg Asbury AK et al. Brain 1970; Smith BE et al. Ann Neurol 1992

Lumbosacral Lumbosacral Radiculoplexopathy Radiculoplexopathy

• Also known as diabetic amyotrophy, Bruns-Garland syndrome, or proximal • Clinical examination: diabetic neuropathy 9Atrophy of the thigh • It affects older patients, usually after the age of 50, with Type 2 DM 9Patellar reflex abnormal (Achilles’ reflex +/-) • Glucose control is not a clear factor o • May be the presenting sign of diabetes (1/3) 9Strength difficult to assess 2 pain

Barhon RJ et al. Arch Neurol 1991

7 Diabetic Truncal Radiculoneuropathy Red Flags

• Acute or subacute pain in one or more thoracic • Rapidly progressive symptoms dermatomes “Shingles without the rash” • Asymmetry • Pain is stabbing or burning in nature • Significant weakness • Usually asymmetric • Occurs after age 50 • Severe loss of position sense • Often diagnosed after fruitless and expensive • The presence of any of the above is an abdominal evaluation and exploratory surgeries alert to look for other etiologies • EMG useful

Stewart JD. Ann Neurol 1989

What else should we know about diabetic Diabetic Peripheral neuropathy? Neuropathies: • Peripheral nerve involvement can present Part II in a number of distinct syndromes Miriam L. Freimer, M.D. • Patient with diabetes mellitus can develop Ohio State University several types of peripheral nerve disorder at the same time Dept. of Neurology Director, Lab • Not all peripheral neuropathies occurring in patients with diabetes mellitus are due to March 2008 the diabetes

8 Diabetic Neuropathy Talk Outline Diagnostic Testing • Why diabetic neuropathy? • Nerve conduction studies and • What is diabetic neuropathy ? electromyography are used to define the characteristics of the neuropathy (e.g. axonal, • How common is diabetic neuropathy demyelinating) and the extent of neuropathy • Who gets diabetic neuropathy? (e.g. distal length dependent; • How to recognize the different types? mononeuropathy; radiculopathy) • How to evaluate diabetic neuropathy? • Autonomic testing (tilt table, R-R variation) is usually reserved for patients with symptoms • How does hyperglycemia causes peripheral referable to the ANS (e.g. or near neuropathy? syncope). Less useful for other autonomic • How to treat it? symptoms (GI, GU) • What is the future prospective?

Diagnostic Testing Diagnostic Testing • Quantitative Blood Work: sudomotor testing • Fasting plasma glucose and hemoglobin A1c - (QSART) screening tools and are useful for following glycemic control • Small fiber • Two-hour - May be more neuropathy sensitive in borderline cases • Screening labs to rule out other etiologies – BUN, • Helpful in Cr, ANA, immunoelectropheresis and documenting extent immunofixation, vitamin B-12, folate, T4 and TSH • Following progression (research tool)

9 Diagnostic Testing Skin Biopsy • Nerve Biopsies 9 May confirm the presence of neuropathy. 9 HOWEVER, there is little clinical use in the setting of DN 9 Biopsies should be reserved for cases in which the etiology is in doubt • Could this be vasculitis? • Could this be amyloid?

Diabetic Neuropathy Diagnostic Testing Talk Outline • Why diabetic neuropathy? • Skin biopsies • What is diabetic neuropathy ? • How common is diabetic neuropathy 9 Useful in evaluating small fiber neuropathy • Who gets diabetic neuropathy? 9 Research tool to evaluate potential therapies • How to recognize the different types? • How to evaluate diabetic neuropathy? • How does hyperglycemia causes peripheral neuropathy? • How to treat it? • What is the future prospective?

10 Hyperglycemia and Peripheral Neuropathy Diabetes Hyperglycemia

DAG FA metabolism PKC Glycated Oxidative Polyol activation products stress pathway

Neurotrophic factors Na+, K+ ATPase Decrease blood flow Nerve conduction velocities

Degeneration of axon structure

Vascular Pathogenesis of Diabetic Neuropathy Diabetic Neuropathy Talk Outline • Why diabetic neuropathy? • Temporal relationship of neuropathy, • What is diabetic neuropathy ? retinopathy, and nephropathy • How common is diabetic neuropathy? • Retinopathy and nephropathy are • Who gets diabetic neuropathy? associated with thickened basement • How to recognize the different types? membranes and narrowed endothelial lumens microvascular pathology • How to evaluate diabetic neuropathy? • How does hyperglycemia causes peripheral • Perhaps, hypoxia or ischemia also play a neuropathy? role in neuropathy • How to treat it? • What is the future prospective?

11 Current Treatment of Diabetic Neuropathy

• Tight glucose control • Foot care • Symptomatic relief

Diabetic Neuropathy: Diabetic Neuropathy: Therapy Therapy *****Prevention***** • Prediabetics or those with impaired glucose tolerance ***Early diagnosis and Glucose Control*** FBG >100 and <126 or • DCCT study (1993) demonstrated 69% GTT >140 and <200 reduction in risk of diabetic neuropathy in • Prelim data from U of Michigan (2006) suggests patients with DM <5 years duration that earliest signs of neuropathy may be reversible • Glucose control has less impact on 9 Lifestyle changes (diet and exercise) resulted established neuropathy in improvement in QSART and nerve fiber density (skin biopsy)

12 Treatment of Diabetic Treatment of Diabetic Neuropathy Neuropathy: Symptom Relief

Foot Care • : • Loss of sensation means that sores 9FDA approved: or injuries may go unnoticed, causing (Cymbalta), Pregabilin (Lyrica) ulcers and/or to develop 9Anticonvulsants, , • 86,000 a year related to antiarrhthymics, -like drugs diabetes. Some estimate that this # could be reduced by 50% with good care

Treatment of Diabetic Treatment of Diabetic Neuropathy Neuropathy: Symptom Relief

• To decrease the risk of osteomyelitis • /Exercise: (and ): 9Beneficial for quality of life • Inspect feet daily 9Range of motion • Keep feet clean and dry 9Maintain mobility • Wear light colored socks (to recognize blood or oozing more quickly) 9Sense of well-being • Podiatric care

13 Treatment of Diabetic Treatment of Diabetic Neuropathy: Symptom Relief Neuropathies Caution!! • Other (????) American Academy of Neurology issued a practice advisory June 2006: • Anodyne therapy • Little or no data to support this • Magnetic field therapy treatment (surgical release) • Foot vibrating massager • Standard methods of nerve evaluations not included in the few published reports available • Need randomized controlled trials to evaluate this technique

Treatment of Diabetic Diabetic Neuropathy Neuropathies Talk Outline • Why diabetic neuropathy? • Surgery: • What is diabetic neuropathy ? 9Decompression of at known • How common is diabetic neuropathy sites of narrowing or entrapment • Who gets diabetic neuropathy? 9As of Jan 2006, 240 surgeons • How to recognize the different types? trained in this procedure. 1280 • How to evaluate diabetic neuropathy? surgeries performed on 990 pts in • How does hyperglycemia causes peripheral International Neuropathy neuropathy? Decompression Registry • How to treat it? • What is the future prospective?

14 Treatment of Diabetic Diabetic Neuropathy: Neuropathy: Research Directions Future Therapies • Despite these relative failures, ongoing trials with new agents are directed at: • Goal is to develop treatments: 9 Preventing or reversing oxidative stress 9Reverse neuropathy 9 Preventing or accumulating glucose end products 9Change the rate of progression 9 Nerve growth factors • Combinations of the above • Verdict on these new approaches is not clear

Treatment of Diabetic Neuropathy: Research Directions • Most experimental approaches are aimed at one or more of the pathogenic models: 9Alpha (oxidative stress) 9Aldose reductase inhibitors (prevent accumulation of metabolic byproducts) 9Nerve growth factors

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