- New cases: 1.5 million Americans diagnosed with diabetes mellitus (DM) every year.
- Prevalence: In 2015, over 30 million Americans had diabetes.
- Prevalence in seniors: 25% of people over 65 have diabetes; 12 million Americans.
- In people with type 2 diabetes (DM2): 45% lifetime incidence of polyneuropathy (PN).
- In people with type 1 diabetes (DM1): up to 60% lifetime incidence of PN.
Diabetes Causes Eight Well-Characterized Peripheral Nerve Syndromes
- Distal symmetric polyneuropathy in diabetes.
- Small-fiber diabetic neuropathy.
- Autonomic neuropathy in diabetes.
- Metabolic syndrome and neuropathy.
- Diabetic radiculoplexus neuropathy (diabetic amyotrophy).
- Insulin neuritis/treatment induced neuropathy.
- Thoracoabdominal radiculopathy.
- Diabetic oculomotor palsy.
Distal Symmetric Polyneuropathy in Diabetes
- Most common type of diabetic neuropathy.
- Slowly progressive, sensory predominant.
- Typical stocking-glove pattern sensory loss.
- Generally considered a late complication of diabetes due to dying back of nerve endings in feet and hands.
- Associated with other complications such as damage to kidneys and retinas.
- Majority of patients have some discomfort, but may be painless.
- Positive symptoms: aching, stabbing, prickling, burning, pins and needles, electrical sensations, feet feel cold or tight.
- Negative symptoms: sensory loss, numb feet – painless but dangerous; feet can be cut or develop painless ulcers.
- May present as poor balance problem or change in gait from loss of proprioception (sense of position of body parts).
- Presenting symptom can be carpal tunnel syndrome.
- Decreased large sensory fiber function: loss of vibration and position sense.
- Decreased small-fiber sensory function: loss of cold and pinprick.
- Reflexes: loss of ankle reflexes.
- Motor exam: atrophy of foot muscles.
- Gait: loss of tandem walk.
Evaluation of suspected diabetic neuropathy:
- Lab testing to rule out other causes, including vitamin B12 deficiency and serum protein electrophoresis for blood cancer.
- Electromyogram/Nerve Conduction Study (EMG/NCS):
- To confirm the diagnosis and establish severity and exclude other causes (chronic inflammatory demyelinating polyneuropathy (CIDP), lumbar spine disease).
- If EMG/NCS is normal, consider mimics such as disease of the spinal cord in the neck; consider skin biopsy for small-fiber neuropathy.
- If EMG/NCS is severely abnormal in patient with mild symptoms: Consider repeating test at a specialized center.
Small-Fiber Sensory Polyneuropathy
- Involves small unmyelinated (without insulation, called myelin, around the nerve fibers) and thinly myelinated fibers.
- Pain, temperature, and autonomic fibers.
- Associated with painful burning and itching sensations.
- Exam may show loss of cold perception and decreased pinprick.
- Usually small-fiber neuropathy is initially quite painful.
- Occurs in diabetes, prediabetes, and in patients with metabolic syndrome without diabetes.
- Pure small-fiber neuropathy does NOT affect balance or strength.
Testing for small-fiber neuropathy:
- Electromyography (EMG) and nerve conduction studies (NCS) are normal in pure small-fiber neuropathy.
- Best test for small-fiber neuropathy is skin biopsy. This compares patient epidermal nerve fiber density samples to control values matched for biopsy location and age.
- Sudomotor testing options: Sweat gland density in skin biopsies, QSART/QSWEAT testing to evaluate sweating function.
Autonomic Neuropathy in Diabetes
- The autonomic nervous system (ANS) includes the nerves that control involuntary function of the inner organs, blood vessels and sweat glands, among others. Damage to these nerves, called autonomic neuropathy, can cause changes to gut function (may include nausea/vomiting, constipation or diarrhea), urination difficulties, sexual dysfunction, heart rate or rhythm disturbances, abnormal blood pressure drop when standing suddenly, decreased sweating and other issues.
- Autonomic neuropathy in diabetes correlates with severity and duration of elevated blood sugar.
- Usually autonomic neuropathy starts after having diabetes for about a decade, but rarely it is the presenting symptom.
- Autonomic dysfunction in DM increases with: age, high blood pressure, high cholesterol and triglycerides, poor control of blood sugar, duration of diabetes.
- Erectile dysfunction is often the presenting symptom of autonomic dysfunction in men.
Cardiac autonomic neuropathy:
- Cardiac autonomic neuropathy in diabetics may first be detectable while patient has no other symptoms.
- The presence of cardiac autonomic neuropathy increases mortality.
- Heart rate variability test can detect early cardiac autonomic dysfunction.
- In diabetic autonomic neuropathy, there is a loss of heart rate modulation. This leads to a relatively fixed heart rate which can lead to exercise intolerance and prevents adaptation to physiologic demands.
- Heart rate variability can be tested by most EMG machines.
- Resting tachycardia (fast heart rate) is another early sign of autonomic neuropathy due to loss of vagal innervation.
- Parasympathetic functions deteriorate more severely than sympathetic functions.
- Decreased lower extremity sweating.
- Increased torso and upper body sweating.
- Control of sweating has three tests: QSART/QSWEAT (quantitative sudomotor axon reflex test), SSR (sympathetic skin responses), skin biopsies for sweat gland density.
- Assess the volume of sweat produced in the limbs.
- Most accurate in younger patients.
- May be the first abnormality detectable in small-fiber neuropathy.
- Acetylcholine is transported into skin by a small electric current (iontophoresis).
- Peripheral nerve is stimulated and causes sweating.
- Small plastic chamber collects sweat and analyses volume.
- SSR: change in electrical potential in skin due to activated eccrine sweat glands, absent=abnormal, but absent in hands of 25% of adults over 60.
Gastrointestinal autonomic neuropathy:
- More severe diabetic autonomic neuropathy can cause gastrointestinal motility changes: delayed stomach emptying, nausea, early satiety, bloating, gastroparesis, in which the stomach’s contractions are impaired, slowing passage of food, alternating diarrhea and constipation.
- Loss of sympathetic vasomotor innervation causes blood to pool in peripheral blood vessels. It occurs in 6% to 30% of diabetics, and it can cause dizziness or fainting upon sitting up or standing suddenly.
Metabolic Syndrome and Neuropathy
Metabolic syndrome includes at least three of the following:
- Increased fasting glucose (100 to 125).
- High blood triglycerides (≥150 mg/dL).
- Decreased HDL (High Density Lipoprotein <40 men, <50 women).
- Central obesity (WHO: BMI over 30).
- Hypertension (> 130/85).
- Metabolic syndrome is a risk factor for polyneuropathy even in patients without diabetes.
- High blood sugar may cause sensory neuropathic pain.
- Experiments with humans and lab animals show that transient high blood sugar increases spontaneous discharges from small diameter type C fibers (the fibers associated with neuropathic pain).
- Elevated blood sugar can directly cause nerve toxicity by disrupting axonal transport and mitochondrial metabolism.
- Neuropathic pain associated with metabolic syndrome may be reversible.
- Impaired glucose tolerance is a risk factor for coronary artery disease, heart attack, stroke and death from all causes.
- Obesity is an independent risk factor for polyneuropathy: Non-diabetic obese patients have lower amplitude motor and sensory nerve conduction velocity compared to age-matched controls.
- High blood triglyceride level is common in patients with idiopathic painful neuropathy.
- Non-diabetic mice fed a high-fat diet develop increased levels of oxidized low density lipoproteins (“bad” cholesterol) as well as increased overall and nerve oxidative stress. These mice develop sensory loss and nerve conduction velocity changes before impaired glucose tolerance.
Treating metabolic syndrome:
- National Institutes of Health-funded study of over 3,000 patients.
- Non-diabetic patients with elevated fasting glucose: three groups.
- Placebo, metformin 850 mg twice daily, lifestyle modification (150 min. activity per week and 7% weight loss).
- Lifestyle changes and treatment with metformin both reduced incidence of diabetes after almost three years.
- Lifestyle modifications were more effective than metformin (drop of diabetes incidence of 58% vs. 31%).
- Impaired glucose tolerance: insulin resistance may be fluctuating and reversible.
- If you catch it early, when patient has only impaired glucose tolerance, may be able to avoid development of neuropathy or slow progression of neuropathy.
- Important to make lifestyle changes when a patient can still exercise and before disability begins.
- Onset of neuropathic pain can be a warning and can inspire a patient to make meaningful lifestyle changes for long term health.
Diabetic Radiculoplexus Neuropathy (Diabetic Amyotrophy)
- Typical case: 55-year-old man with well-controlled type 2 diabetes develops acute onset of severe pain in one hip and thigh followed by upper leg weakness in the same leg.
- Exam shows abnormalities in one leg; wasting of quadriceps, absent reflexes, foot drop, and sensory loss.
- Most likely injury to the nerves because of decreased blood supply due to microvasculitis, which is inflammation of the small blood vessels.
- Often starts in a well-controlled diabetic who decides to lose weight, increase exercise, or improve their control of blood sugar levels.
- Often starts in distribution of femoral nerve, but really is a multifocal process that involves nerve roots, plexus, and peripheral nerves.
- EMG/NCS can distinguish this from lumbosacral root lesion.
- Weakness and sensory loss can progress for up to a year.
- Followed by slow and sometimes incomplete recovery.
- Can spread to other leg or neck and shoulder region.
- Not associated with duration or severity of diabetes.
- No benefit from IVIG or other immunomodulatory therapy.
- Often shows elevated spinal fluid protein.
- An MRI of the nerve plexus may show nerve root enhancement.
- Treatment-induced small-fiber neuropathy can be set off by rapid control of blood sugar in setting of chronic high blood sugar – severely painful distal neuropathy.
- Occurs with abrupt blood glucose control, usually two to six weeks later.
- Associated with quick drop in HgbA1c over a few months.
- Can occur in type 1 or type 2 diabetes.
- Abrupt glycemic control can be due to insulin, oral medications or sudden diet change. Can come on after sudden increase in glucose control during a hospitalization.
Insulin Neuritis: Treatment-Induced Polyneuropathy
- Example: 22-year-old woman with long history of poorly controlled diabetes presents with HgbA1c 12.
- She is hospitalized for complications of elevated blood sugar, starts aggressive insulin regimen.
- A few weeks later, she develops an acute severe, unbearable burning pain in hands and lower extremities below the knees requiring narcotics.
- Routine office exam does not seem to find a clear explanation for her complaints of severe pain.
- Mainly affects small fibers including both somatic and autonomic.
- May present as an acute autonomic neuropathy.
- May be reversible, unlike chronic autonomic neuropathy.
- Sometimes also associated with significant weight loss.
- Treatment is aggressive pain control.
- Pain can be severe and refractory.
- Pain slowly resolves over 12 to 18 months.
- Presents with acute radiating pain in one side of thorax.
- Pain similar to shingles or Lyme disease, but no rash (lack of rash does not rule out shingles as cause of pain).
- Focal radiculopathy due to low blood supply to tissues, caused by inflammation of blood vessels.
- Spinal MRI to rule out structural cause, other tests as appropriate.
- Treatment: supportive treatment with meds for neuropathic pain.
- Self-limited, resolves spontaneously over time.
Diabetic Oculomotor Palsies
- Diabetes is the most common cause of an isolated palsy (abnormal movements) of the main nerves to the eye muscles.
- Cause of “pupil-sparing” third nerve palsy, although pupil is NOT always completely spared.
- Usually presents with pain behind the eye.
- Treatment is watchful waiting, consider eye-patch.
- Usually resolves in six to eight weeks.
Treatment of Diabetic Neuropathy
- Weight loss and exercise, lifestyle modification.
- Metformin, glucose control.
- Pain control if needed with gabapentin (Neurontin), pregabalin (Lyrica), duloxetine (Cymbalta).
- Type 1 diabetics – intense glucose control may decrease the incidence of neuropathy.
- Alpha lipoic acid 600 mg daily.
- Pancreas transplant in type 1 diabetics – serves to stabilize neuropathy but not reverse it.
- If you catch neuropathy early, lifestyle changes and exercise can delay the onset or slow progression of neuropathy.