Peripheral neuropathy

Over 5% of individuals older than 55 years of age and over 30% of those older than 80 have probable or definite neuropathy.

There are 200 or more causes of peripheral neuropathy exist, with symptoms ranging its severity from mild toe  numbness to debilitating symptoms.

In patients with newly diagnosed diabetes is evident in 8% of cases and increases with disease duration to 30-60%, depending upon the definition by clinical or electrophysiological criteria.

Neuropathy is a significant cause of morbidity and reduce quality of life due to pain, gait disturbance, foot ulceration, and amputation, particularly among diabetic patients.

Gait is normal in patients with mild sensory, predominant peripheral neuropathy, but those with more severe neuropathy may have unsteady, wide base gait due to large fiber proprioceptive sensory loss.

Patients with Charcot – Marie – Tooth disease typically present with distal foot and ankle weakness, absence of positive neuropathic sensory symptoms, and presence of pes cavus and hammer toes.

Up to 50% of patients with neuropathy have diabetes, and about 25-40% have idiopathic neuropathy.

Other causes of neuropathy include hereditary causes, such as Charcot – Marie-Tooth disease, toxic neuropathy from medications (chemotherapies cisplatinum, paclitaxel, vincristine), amiodarone, HIV nucleotide reverse transcriptase inhibitors, vitamin deficiency, such as vitamin B12, and monogammopathy.

Approximately 1/3 to 1/2 of all idiopathic neuropathies are likely inherited, most commonly Charcot-Marie-tooth disease.

Infectious disease diseases can cause peripheral neuropathy include leprosy and HIV.

Length dependent peripheral neuropathy (LDPN)  typically begins in the toes and may progress approximately toward the knees and hands.

LDPN typically manifest primarily as sensory signs and symptoms, such as numbness and parathesias indicative of damage to the large fiber sensory axons involved in appropriate perception and vibration sensation and

/or small fiber sensory axons responsible for temperature and pain sensations.

The sensory predominance of LDPN may be partly due to the presence of fenestrated capillaries in the dorsal root ganglion, which reduces the blood neuron barrier and increases susceptibility to systemic factors such as hyperglycemia or exposure to neurotoxic medications.

Typically, LDPN initially affects the sensory function of a peripheral nerve and progresses over weeks to months in a symmetric fashion.

Symptoms of LDPN are typically sensory loss and parathesias beginning in the toes and feet.

Neuropathic pain – burning, stabbing, electrical shocks, allodynia, may be present.

As the neuropathy progresses, symptoms extend proximally up the lower legs.

Patients with symptoms up to the knees often report symptoms in the fingertips because the length of the nerves to the fingertips is similar to the distance to the of the nerves to the knees.

Motor weakness may begin in the toes with weakness of flexion and extension, and is typically mild.

Patients with LDPN may have autonomic symptoms, such as lack of sweating in the feet, and those with diabetes or amyloidosis may experience postural, lightheadedness, dry eyes/dry mouth, postprandial, nausea, vomiting, diarrhea, constipation, and erectile dysfunction.

Axons innovating the toes can be up to 3 feet long and require a high metabolic support for axonal transport, explaining why LDPN first affects the toes and later the lower legs and hands.

Risk factors for idiopathic neuropathy include pre-diabetes and metabolic syndrome.

Obesity, even in the absence of diabetes or prediabetes is a significant risk factor for neuropathy.

Diabetes and obesity are the most common metabolic factors associated with neuropathy.

Normoglycemic obese patients have a high prevalence of neuropathy, indicating that obesity alone is sufficient to cause neuropathy.

Weight circumference, but not general obesity is significantly associated with neuropathy.

Central obesity is associated with neuropathy.

Occurs in more than 6% of the population older than age 60 years.

Loss of Achilles tendon reflex and vibratory sensation are the earliest symptoms of diabetic neuropathy.

The most important neurologic finding is the loss of protective sensation.

Distal symmetric polyneuropathy in the primary care setting is the most common systemic complication of diabetes mellitus.

Patients usually present with sensory signs or symptoms before motor or autonomic symptoms prevail.

Schwann cells, which myelinate large axons or envelop small unmyelinated fibers, maintain axonal health through growth factors – nerve growth factor, brain derived neurotrophic factor, vascular endothelial, growth factor, and by regulating axonal iron and lactate metabolism.

Schwann cells damage slow conduction and may contribute to axonal degeneration.

Neuropathy develops when neurons die, axons degenerate, neuronal excitability is altered, or support from Schwann cells fail.

If neuronal survival is preserved after injury, axonal regeneration can occur at a rate of 1 to 3 mm per day.

Sensory symptoms of numbness, tingling, weakness, autonomic symptoms of early satiety, impotence, orthostatic hypotension, sweating abnormalities, burning, stabbing, electrical discomfort suggest the presence of a peripheral neuropathy.

Sensory fibers include large diameter fibers mediating vibratory sensation and proprioception and small diameter fibers mediating pain and temperature sensation.

Most neuropathies affect both large and small fibers, and symptoms vary on the basis of the relative involvement of each group.

Skin biopsy can help identify a distal, small fiber neuropathy, which is a length dependent neuropathy, limited to pain and small fiber dysfunction.

Skin punch biopsies obtained approximately 10 cm above the lateral malleolus and some instances at a second site such as the distal thigh has limited utility in determining the cause of small fiber neuropathy.

Epidermal nerve fiber density values less than the 5th percentile compared with age and six matched controls are considered abnormal.

Skin biopsy has a sensitivity 80% and specialty of 90% for diagnosis of small fiber neuropathy.

When motor deficits are equal to or greater than sensory deficits, demyelinating disorders such as chronic inflammatory demyelinating polyneuropathy and hereditary neuropathies are considered.

The sensory examination should test both large and small fibers-large fibers relate to vibratory and proprioception and small fibers pain and temperature.

Proprioception abnormalities manifest as sensory ataxia, mimicking cerebellar dysfunction.

The Romberg sign is an effective screening tool for sensory ataxia.

Deep tendon reflexes may be diminished in a links dependent pattern with unobtainable ankle reflexes.

Diffuse arreflexia should indicate the presence of chronic inflammatory demyelinating polyneuropathy or hereditary neuropathy.

Asymmetrical reflexes may suggest mononeuropathy or a radiculopathy.

Accentuated deep tendon reflexes suggest a superimposed CNS involvement, such as cervical spinal stenosis or vitamin B 12 deficiency.

Neuropathic pain occurs in 1/3 of patients with peripheral neuropathy.

Some patients experience hyperesthesia, an accentuated sensation of tactile stimulation, or allodynia, the perception of normally non-painful stimuli as painful.

Autonomic symptoms are often underrecognized, but have a great impact on quality of life.

Orthostatic intolerance, gastroparesis, constipation, diarrhea, neurogenic bladder, erectile dysfunction, pupillomotor and vasomotor symptoms, leading to dry eyes, mouth, skin was burning and flushing are relatively common.

On rare occasions autonomic symptoms may be the most prominent or only symptoms indicating neuropathy.

Most common in patients with diabetes mellitus, HIV, dysproteinic disorders and in patients receiving chemotherapy.

When symptoms of neuropathy develop acutely, differential diagnosis is narrowed significantly: Guillain-Barre syndrome, vasculitis, critical illness polyneuropathy, porphyria, and toxic exposure.

Differential diagnosis-diabetes, amyloidosis, paraproteinemia, autoimmune disorders lupus, Behcet’s disease, antiphospholipid syndrome, ating polyneuropathies, Guillain-Barre syndrome, hereditary sensory and autonomic neuropathy, Charcot-Marie Tooth disease, Friedreich’s ataxia, HIV medications, hypothyroidism, acromegaly, hepatitis B, hepatitis C, HIV, Lyme disease, leprosy, vasculitis, chronic inflammatory ating polyradiculopathy, sarcoidosis, primary biliary cirrhosis, paraneoplastic syndromes, lymphoma, Hodgkin’s disease, multiple myeloma, amiodarone, colchicines, isoniazid, metronidazole, nitrofurantoin, hydralazine, phenytoin, statins, fibrates, vitamin B12 deficiency, folic acid deficiency, vitamin B1 deficiency, deficiency of copper, supratherapeutic doses of pyridoxine, exposure to cold, exposure to hypoxia, renal insufficiency, toxic exposure to alcohol, arsenic, lead, mercury or organophosphorous agents.

Symptoms such as burning feet have poor diagnostic accuracy for neuropathy.

Neurologic examination findings such as sensory loss or absent ankle jerks are more sensitive and specific.

The presence of two or three suggestive symptoms, abnormal temperature sensation, or diminished reflexes are 87% sensitive and 91% specific for neuropathy.

Neuroimaging is not routinely indicated in patients with neuropathy, but is considered when examination suggest a concurrent myelopathy or when the diagnosis of neuropathy is not firmly established and lumbosacral radiculopathy remains in differential diagnosis.

The most reliable diagnosis for neuropathy rests on the combination of symptoms, neurologic findings on examination, and confirmatory testing on nerve conduction studies and electromyography.

Diagnostic testing:

While diagnosis is based on clinical symptoms and signs, laboratory test can identify a specific etiologies associated with peripheral neuropathy, such as diabetes, vitamin B 12 deficiency, or monoclonal gammopathy.

Lab tests include blood glucose, vitamin B 12 with metabolites (methyl melanic acid with or without homocysteine), and serum protein electrophoresis.

A study of Medicare patients demonstrated that only 20% of patients underwent electrodiagnostic examinations within six months of their initial diagnosis of neuropathy.

Electrodiagnostic studies, consisting of nerve conduction studies (NCS) can assess large fiber,nerves and electromyography (EMG) can help diagnose peripheral neuropathy.

Findings on NCS suggesting LDPN include sensory nerves affected earlier and more severely than motor fibers, lower limb NCS affected earlier and more severely than upper limbs, and symmetric NCS abnormalities in nerves of similar length.

NCS can identify underlying pathophysiology – axonal or demyelinating.

Axonal features include reduced motor and sensory amplitude on NCS and neurogenic motor unit potential on EMG.

NCS finding suggesting demyelination includes slowed conductionvelocities, prolonged distal latencies, conduction block, and temporary dispersion.

Most length dependent neuropathies are axonal, including diabetes, vitamin B12 deficiency, chemotherapy induced peripheral neuropathy, and axonall subtype of Charcot-Marie-Tooth.

Annual screening for PN is recommended for diabetics.

Screening recommendations for PN include my touch perception to a 10 gm Semmes-Weinstein monofilament, vibration testing with 120 Hz tuning fork, superficial pain with pinprick for perception, or testing of ankle deep tendon reflexes.

Monofilament light touch vibration testing are more sensitive and specific than pinprick pain or ankle reflex testing.

Single testing with one modality may miss 25-50% of patients with diabetic neuropathy because peripheral neuropathirs may affect different types of nerve fibers to varying degrees.

A combination test of vibration plus monofilament testing provides the best and efficient testing for diabetic peripheral neuropathy has it is 90% sensitive and 85 to 89% specific for diabetic neuropathy and correlates with the development of diabetic foot ulcers.

Vibration sensation declines with age and almost one fourth of individuals older than 65 years and one third older than 75 years have absent vibration sensation on examination.

The most common type of clinical peripheral neuropathy is length-dependent peripheral neuropathy.

Length-dependent peripheral neuropathy is symmetrical and begins in the longest nerves at their terminals, meaning the distal foot.

Distal symmetric polyneuropathy is length dependent: there is diffuse involvement of multiple nerves with symptoms and signs that affect the most distal segment first.

Symptoms or signs in the legs usually reach the knees or just above before symptoms or signs occur in the fingers.

A non-length-dependent pattern or asymmetry may indicate a secondary process through which is the differential diagnosis is different.

The etiology of 20-25% of these neuropathies remains uncertain and the natural history of the idiopathic neuropathies progress slowly and are unlikely to cause severe physical disabilities.

Negative sensory symptoms such as lack of feeling and positive sensory symptoms such as prickling, tingling, burning usually precede motor weakness.

Symptoms in length-dependent neuropathy ascend up the leg, with symptoms often becoming evident when leg symptoms approached the knee.

Neuropathies may be sensory predominate, motor manifestations are usually more evident than in length dependent neuropathies.

Rarely patients present with multifocal clinical symptoms such as wrist drop followed by foot drop.

Polyradiculoneuropathies and multifocal neuropathies have differential diagnostic patterns than length dependent neuropathies.

Polyradiculopathies and multifocal neuropathies etiology include sarcoidosis, amyloidosis, neoplastic, vasculitic, infectious, and inflammatory immune mediated causes.

Autonomic testing is typically reserved for patients with PN who have prominent automatic symptoms, such as postural lightheadedness, postprandial, nausea, and vomiting, and diarrhea and constipation.

Quantitative sudomotor axon reflex test measures sweating at four sites, using a non-invasive device with an electric current to deliver acetylcholine into the skin which activates the axon terminal.

The release of acetylcholine in the skin stimulates muscarinic receptors on the eccrine sweat glands in the volume of sweat collected and quantified, providing sensitive testing of distal, small fiber neuropathy.

Cardiovagal testing evaluates the heart rate response to deep breathing, and it is nearly as sensitive as nerve conduction studies for detecting, polyneuropathy.

The presence of autonomic neuropathy is more common in diabetes, amyloidosis, toxic causes such as vincristine and less common etiologies such as Sjogren syndrome or paraneoplastic causes.

Upper limb involvement with length-dependent peripheral neuropathy may never occur, and development of symptoms in the hands and feet at the same time is atypical for diabetic length-dependent neuropathy and may indicate coexistence of carpal tunnel syndrome or some other cause such as a toxic etiology.

In length-dependent PN proprioception is spared relative to the sensory findings in mild to moderate disease and only becomes affected as the neuropathy severity progresses.

With proprioceptive deficits with gait disorder or imbalance with eyes closed, evaluation requires work up for posterior column disease or for sensory cell body dysfunction as seen in the Sjogren’s syndrome or a paraneoplastic disorder.

Majority of PNs are length-dependent, sensory predominant, mild to moderate in severity, and without major functional limitations.

Neuropathy that is sensory and motor symptomatic and is more diffuse, length-independent involving proximal and distal limbs suggest a polyradiculoneuropathy.

In length-independent neuropathy sensory abnormalities may predominate but motor manifestations are usually more evident than in length-dependent neuropathies.

The differential diagnoses differ in length-dependent neuropathies from polyradiculoneuropathies and multifocal neuropathies: etiologies of the latter include sarcoidosis, amyloidosis, neoplastic, paraneoplastic, vasculitic, infectious, and inflammatory immune mediated.

The evaluation of length-dependent neuropathy a diagnosis with a combination of history, examination, laboratory testing, and serologic evaluation can be made in approximately 74-82% of the time.

Laboratory evaluation includes blood glucose for diabetics, serum B12 level with metabolites of methylmelonic acid with without homocysteine, serum protein electrophoresis with immunofixation for monoclonal gammopathy.

PN is typically length dependent, meaning that symptoms appear in the longest nerve axons (toes) and progress proximally overtime.

PN is typically symmetrical and affects sensory axons more than motor axons.

Diabetic neuropathy, which is often associated with both sensory symptoms, such as pain, tingling or numbness, mild weakness, and autonomic symptoms, such as autonomic hypotension, and accounts for  more than 50% of peripheral neuropathy in western populations.

In 20-25% of cases the etiology of length-dependent peripheral neuropathy remains undiagnosed, but the natural history is that these processes progress slowly and are unlikely to cause severe physical disability.

Evaluation for chronic, length-dependent peripheral neuropathy includes: CBC, renal testing, liver function testing, sedimentation rate, hemoglobin A-1 C, thyroid stimulating hormone, serum protein electrophoresis, vitamin B12 level with methylmalonic acid, infectious evaluation for Lyme disease, HIV, and family history of peripheral neuropathy, hammertoes or pes cavus.

Mononeuropathy including carpal tunnel syndrome with median nerve neuropathy at the wrist, radiculopathy, in the cervical and lumbosacral spine with signs and symptoms are restricted to the distribution of a single nerve, myotome, or dermatome.

Multiple concurrent mononeuropathies-mononeuropathy multiplex may suggest a vasculitic etiology.

Diabetes is the most common cause of peripheral neuropathy in Western countries, with a prevalence of up to 30-66% of diabetics.

Despite the high prevalence of neuropathy, only 10-15% of patients with diabetic neuropathy are symptomatic from motor, sensory or autonomic dysfunction but 11-26% have associated neuropathic pain.

Many patients with examination evidence of diabetic neuropathy are asymptomatic but at risk for injury to insensate feet.

All patients with diabetic neuropathy should be screened for diabetes with fasting blood sugar and hemoglobin A-1 C measurements.

Risk of diabetic neuropathy can be reduced with tight glycemic control.

Impaired glucose tolerance has been noted to be more prevalent in patients with idiopathic neuropathy than in controls.

25-50% of idiopathic neuropathies may be explained by impaired glucose tolerance.

B12 is integral in the development and maintenance of myelin and its deficiency can cause subacute combined degeneration or an isolated peripheral neuropathy without CNS involvement.

Among patients with a low-normal B12 level 5 to 10% will have elevated serum methylmalonic acid concentrations indicating cellular B12 deficiency.

By adding a methylmalonic acid level to a screen of patients with length-dependent peripheral neuropathy the finding of a cellular B12 deficiency as the cause of neuropathy will occur 2 to 8% of cases.

10% of peripheral neuropathies are associated with dysproteinemia.

Dysproteinemias associated with a sixfold increase over the general population in the incidence of peripheral neuropathy.

The majority of peripheral neuropathies associated with dysproteinemias are due to monoclonal gammopathy of undetermined significance.

The finding of a monoclonal gammopathy and peripheral neuropathy requires the exclusion of the diagnoses of amyloidosis, multiple myeloma, POEMS, lymphoma, Waldenstrom’s macroglobulinemia, or cryoglobulinemia.

The peripheral neuropathy associated with POEMS syndrome is typically a mixed ating and axonal length-independent polyradiculoneuropathy.

Atrophy can be seen in chronic neuropathy distal atrophy, hammertoes and his cave pectus characteristic of long-standing neuropathy.