Neuropathy Knowledge What Is An Axon

Today's post from sciencedaily.com (see link below) is the seventh part of a series from the same source providing readers with explanations and information about many of the medical terms they hear when researching neuropathy, or sitting in the doctor's surgery and talking about it. Today it explains the word 'axon' and gives related definitions of other words associated with its workings in the nervous system. Worth following the links if you have the time.

Axon
Science Daily via Wikipedia

An axon, or nerve fiber, is a long slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma.

Axons are in effect the primary transmission lines of the nervous system, and as bundles they help make up nerves.

Individual axons are microscopic in diameter - typically about one micrometre across - but may extend to macroscopic lengths.

The longest axons in the human body, for example, are those of the sciatic nerve, which run from the base of the spine to the big toe of each foot.

These single-cell fibers may extend a meter or even longer. In vertebrates, the axons of many neurons are sheathed in myelin, which is formed by either of two types of glial cells: Schwann cells ensheathing peripheral neurons and oligodendrocytes insulating those of the central nervous system.

For more information about the topic Axon, read the full article at Wikipedia.org, or see the following related articles:


Myelin — Myelin is an electrically insulating phospholipid layer that surrounds the axons of many neurons. It is an outgrowth of glial cells: Schwann cells ...  read more


Neural development — The study of neural development draws on both neuroscience and developmental biology to describe the cellular and molecular mechanisms by which ...read more


Pupillary reflex — In medicine, the pupillary reflex or pupillary light reflex, is the reduction of pupil size in response to light. It is a normal response and ...  read more


Sensory neuron — Sensory neurons are nerve cells within the nervous system responsible for converting external stimuli from the organism's environment into internal ... read more


Neuron — Neurons (also known as neurones, nerve cells and nerve fibers) are electrically excitable cells in the nervous system that function to process and ...  read more


Sympathetic nervous system — The sympathetic nervous system (SNS) is part of the autonomic nervous system (ANS), which also includes the parasympathetic nervous system (PNS). The ...  read more


Neurobiology — Neurobiology is the study of cells of the nervous system and the organization of these cells into functional circuits that process information and ...  read more


Nociceptor — A nociceptor is a sensory receptor that sends signals that cause the perception of pain in response to potentially damaging stimulus. Nociceptors are ...  read more


Chemical synapse — Chemical synapses are specialized junctions through which cells of the nervous system signal to one another and to non-neuronal cells such as muscles ...  read more


Nervous system — The nervous system of an animal coordinates the activity of the muscles, monitors the organs, constructs and also stops input from the senses, and ...  read more

http://www.sciencedaily.com/articles/a/axon.htm

Chronic Inflammatory Neuropathy Is That What You Have

Today's post from nlm.nih.gov (see link below) may confuse some readers; partly because there are just way too many names for neuropathic conditions but also because they're not sure if their symptoms are 'bad' enough to qualify as having chronic inflammatory neuropathy. This article describes what it is, what the symptoms are and why it happens, as well as showing some tests and assessments. The main difference lies in the cause - the immune system attacks the nervous system and gradually degrades nerves and their linings but after that, the reasons why can be (as you know) many and varied.

Chronic inflammatory polyneuropathy
 US National Library of medicine 2014
 
Chronic inflammatory polyneuropathy involves nerve swelling and irritation (inflammation) that leads to a loss of strength or sensation.

Causes

Chronic inflammatory polyneuropathy is one cause of damage to nerves outside the brain or spinal cord (peripheral neuropathy). Polyneuropathy means several nerves are involved. It usually affects both sides of the body equally.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic neuropathy caused by an abnormal immune response. CIDP occurs when the immune system attacks the myelin cover of the nerves.

The cause of chronic inflammatory polyneuropathy is an abnormal immune response. The specific triggers vary. In many cases, the cause cannot be identified.

It may occur with other conditions, such as:
Autoimmune disorders
Chronic hepatitis
Diabetes
HIV
Inflammatory bowel disease
Systemic lupus erythematosus
Lymphoma
Paraneoplastic syndrome
Thyrotoxicosis
Side effects of medicines to treat cancer or HIV

Symptoms

Difficulty walking due to weakness or trouble feeling your feet
Difficulty using the arms and hands or legs and feet due to weakness
Sensation changes, such as numbness or decreased sensation, pain, burning, tingling, or other abnormal sensations (usually affects the feet first, then the arms and hands)
Weakness, usually in the arms and hands or legs and feet

Other symptoms that can occur with this disease:
Abnormal movement
Breathing difficulty
Fatigue
Hoarseness or changing voice
Loss of function or feeling in the muscles
Muscle atrophy
Muscle contractions
Speech impairment
Swallowing difficulty
Uncoordinated movement

Exams and Tests

The doctor will examine you and ask questions about your medical history. The physical exam shows:
Loss of muscle mass
No reflexes
Muscle weakness or paralysis
Sensation problems on both sides of the body

Tests may include:
Electromyography (EMG)
Nerve conduction tests
Nerve biopsy
Spinal tap
Blood tests may be done to look for specific proteins that are causing the immune attack on the nerves

Which other tests are done depends on the suspected cause of the condition. Tests may include x-rays, imaging scans, and blood tests.

Treatment

The goal of treatment is to reverse the attack on the nerves. In some cases, nerves can heal and their function can be restored. In other cases, nerves are badly damaged and cannot heal, so treatment is aimed at preventing the disease from getting worse.

Which treatment is given depends on how severe the symptoms are, among other things. The most aggressive treatment is usually only given if you have difficulty walking or if symptoms interfere with your ability to care for yourself or perform work functions.

Treatments may include:
Corticosteroids to help reduce inflammation and relieve symptoms
Other medications that suppress the immune system (for some severe cases)
Plasmapheresis or plasma exchange to remove antibodies from the blood
Intravenous immune globulin (IVIg), which involves adding large numbers of antibodies to the blood plasma to reduce the effect of the antibodies that are causing the problem

Outlook (Prognosis)

The outcome varies. The disorder may continue long term, or you may have repeated episodes of symptoms. Complete recovery is possible, but permanent loss of nerve function is not uncommon.

Possible Complications

Pain
Permanent decrease or loss of sensation in areas of the body
Permanent weakness or paralysis in areas of the body
Repeated or unnoticed injury to an area of the body
Side effects of medications used to treat the disorder

When to Contact a Medical Professional

Call your health care provider if you have a loss of movement or sensation in any area of the body, especially if your symptoms get worse.

Alternative Names

Polyneuropathy - chronic inflammatory; CIDP; Chronic inflammatory demyelinating polyneuropathyPolyneuropathy - chronic inflammatory; CIDP; Chronic inflammatory demyelinating polyneuropathy

References

Katirji B, Koontz D. Disorders of peripheral nerves. In: Daroff RB, Fenichel GM, Jankovic J, Mazziotta JC, eds.Katirji B, Koontz D. Disorders of peripheral nerves. In: Daroff RB, Fenichel GM, Jankovic J, Mazziotta JC, eds. Bradley's Neurology in Clinical Practice. 6th ed. Philadelphia, PA: Elsevier Saunders; 2012:chap 76.

Shy ME. Peripheral neuropathies. In: Goldman L, Schafer AI, eds.Shy ME. Peripheral neuropathies. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine. 24th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 428.

Update Date 7/27/2014

Updated by: Joseph V. Campellone, MD, Department of Neurology, Cooper University Hospital, Camden, NJ. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the A.D.A.M. Editorial team.

https://www.nlm.nih.gov/medlineplus/ency/article/000777.htm

What Actually Causes Neuropathy

Irrespective of whether you are HIV positive or not, there are many causes of neuropathy (peripheral or otherwise). People frequently ask why they've contracted neuropathy and it's such a complex subject that the answer can't usually be compressed enough to fit in a blog post. This article from the National Institute of Neurological Disorders and Stroke (see link below)gives a general idea of the main causes of the disease. It doesn't really explain why an HIV-positive person may have neuropathy but then again, your neuropathy may not necessarily stem from your HIV status.

What causes peripheral neuropathy?
Last updated August 10, 2011

Peripheral neuropathy may be either inherited or acquired. Causes of acquired peripheral neuropathy include physical injury (trauma) to a nerve, tumors, toxins, autoimmune responses, nutritional deficiencies, alcoholism, and vascular and metabolic disorders. Acquired peripheral neuropathies are grouped into three broad categories: those caused by systemic disease, those caused by trauma from external agents, and those caused by infections or autoimmune disorders affecting nerve tissue. One example of an acquired peripheral neuropathy is trigeminal neuralgia (also known as tic douloureux), in which damage to the trigeminal nerve (the large nerve of the head and face) causes episodic attacks of excruciating, lightning-like pain on one side of the face. In some cases, the cause is an earlier viral infection, pressure on the nerve from a tumor or swollen blood vessel, or, infrequently, multiple sclerosis. In many cases, however, a specific cause cannot be identified. Doctors usually refer to neuropathies with no known cause as idiopathic neuropathies.

Physical injury (trauma) is the most common cause of injury to a nerve. Injury or sudden trauma, such as from automobile accidents, falls, and sports-related activities, can cause nerves to be partially or completely severed, crushed, compressed, or stretched, sometimes so forcefully that they are partially or completely detached from the spinal cord. Less dramatic traumas also can cause serious nerve damage. Broken or dislocated bones can exert damaging pressure on neighboring nerves, and slipped disks between vertebrae can compress nerve fibers where they emerge from the spinal cord.

Systemic diseases — disorders that affect the entire body —often cause peripheral neuropathy. These disorders may include: Metabolic and endocrine disorders. Nerve tissues are highly vulnerable to damage from diseases that impair the body's ability to transform nutrients into energy, process waste products, or manufacture the substances that make up living tissue. Diabetes mellitus, characterized by chronically high blood glucose levels, is a leading cause of peripheral neuropathy in the United States. About 60 percent to 70 percent of people with diabetes have mild to severe forms of nervous system damage.

Kidney disorders can lead to abnormally high amounts of toxic substances in the blood that can severely damage nerve tissue. A majority of patients who require dialysis because of kidney failure develop polyneuropathy. Some liver diseases also lead to neuropathies as a result of chemical imbalances.

Hormonal imbalances can disturb normal metabolic processes and cause neuropathies. For example, an underproduction of thyroid hormones slows metabolism, leading to fluid retention and swollen tissues that can exert pressure on peripheral nerves. Overproduction of growth hormone can lead to acromegaly, a condition characterized by the abnormal enlargement of many parts of the skeleton, including the joints. Nerves running through these affected joints often become entrapped.

Vitamin deficiencies and alcoholism can cause widespread damage to nerve tissue. Vitamins E, B1, B6, B12, and niacin are essential to healthy nerve function. Thiamine deficiency, in particular, is common among people with alcoholism because they often also have poor dietary habits. Thiamine deficiency can cause a painful neuropathy of the extremities. Some researchers believe that excessive alcohol consumption may, in itself, contribute directly to nerve damage, a condition referred to as alcoholic neuropathy.

Vascular damage and blood diseases can decrease oxygen supply to the peripheral nerves and quickly lead to serious damage to or death of nerve tissues, much as a sudden lack of oxygen to the brain can cause a stroke. Diabetes frequently leads to blood vessel constriction. Various forms of vasculitis (blood vessel inflammation) frequently cause vessel walls to harden, thicken, and develop scar tissue, decreasing their diameter and impeding blood flow. This category of nerve damage, in which isolated nerves in different areas are damaged, is called mononeuropathy multiplex or multifocal mononeuropathy.

Connective tissue disorders and chronic inflammation can cause direct and indirect nerve damage. When the multiple layers of protective tissue surrounding nerves become inflamed, the inflammation can spread directly into nerve fibers. Chronic inflammation also leads to the progressive destruction of connective tissue, making nerve fibers more vulnerable to compression injuries and infections. Joints can become inflamed and swollen and entrap nerves, causing pain.

Cancers and benign tumors can infiltrate or exert damaging pressure on nerve fibers. Tumors also can arise directly from nerve tissue cells. Widespread polyneuropathy is often associated with the neurofibromatoses, genetic diseases in which multiple benign tumors grow on nerve tissue. Neuromas, benign masses of overgrown nerve tissue that can develop after any penetrating injury that severs nerve fibers, generate very intense pain signals and sometimes engulf neighboring nerves, leading to further damage and even greater pain. Neuroma formation can be one element of a more widespread neuropathic pain condition called complex regional pain syndrome or reflex sympathetic dystrophy syndrome, which can be caused by traumatic injuries or surgical trauma. Paraneoplastic syndromes, a group of rare degenerative disorders that are triggered by a person's immune system response to a cancerous tumor, also can indirectly cause widespread nerve damage.

Repetitive stress frequently leads to entrapment neuropathies, a special category of compression injury. Cumulative damage can result from repetitive, forceful, awkward activities that require flexing of any group of joints for prolonged periods. The resulting irritation may cause ligaments, tendons, and muscles to become inflamed and swollen, constricting the narrow passageways through which some nerves pass. These injuries become more frequent during pregnancy, probably because weight gain and fluid retention also constrict nerve passageways.

Toxins can also cause peripheral nerve damage. People who are exposed to heavy metals (arsenic, lead, mercury, thallium), industrial drugs, or environmental toxins frequently develop neuropathy. Certain anticancer drugs, anticonvulsants, antiviral agents, and antibiotics have side effects that can include peripheral nerve damage, thus limiting their long-term use.

Infections and autoimmune disorders can cause peripheral neuropathy. Viruses and bacteria that can attack nerve tissues include herpes varicella-zoster (shingles), Epstein-Barr virus, cytomegalovirus, and herpes simplex-members of the large family of human herpes viruses. These viruses severely damage sensory nerves, causing attacks of sharp, lightning-like pain. Postherpetic neuralgia often occurs after an attack of shingles and can be particularly painful.

The human immunodeficiency virus (HIV), which causes AIDS, also causes extensive damage to the central and peripheral nervous systems. The virus can cause several different forms of neuropathy, each strongly associated with a specific stage of active immunodeficiency disease. A rapidly progressive, painful polyneuropathy affecting the feet and hands is often the first clinically apparent sign of HIV infection.

Lyme disease, diphtheria, and leprosy are bacterial diseases characterized by extensive peripheral nerve damage. Diphtheria and leprosy are now rare in the United States, but Lyme disease is on the rise. It can cause a wide range of neuropathic disorders, including a rapidly developing, painful polyneuropathy, often within a few weeks after initial infection by a tick bite.

Viral and bacterial infections can also cause indirect nerve damage by provoking conditions referred to as autoimmune disorders, in which specialized cells and antibodies of the immune system attack the body's own tissues. These attacks typically cause destruction of the nerve's myelin sheath or axon (the long fiber that extends out from the main nerve cell body).

Some neuropathies are caused by inflammation resulting from immune system activities rather than from direct damage by infectious organisms. Inflammatory neuropathies can develop quickly or slowly, and chronic forms can exhibit a pattern of alternating remission and relapse. Acute inflammatory demyelinating neuropathy, better known as Guillain-Barré syndrome, can damage motor, sensory, and autonomic nerve fibers. Most people recover from this syndrome although severe cases can be life threatening. Chronic inflammatory demyelinating polyneuropathy (CIDP), generally less dangerous, usually damages sensory and motor nerves, leaving autonomic nerves intact. Multifocal motor neuropathy is a form of inflammatory neuropathy that affects motor nerves exclusively; it may be chronic or acute.

Inherited forms of peripheral neuropathy are caused by inborn mistakes in the genetic code or by new genetic mutations. Some genetic errors lead to mild neuropathies with symptoms that begin in early adulthood and result in little, if any, significant impairment. More severe hereditary neuropathies often appear in infancy or childhood.

The most common inherited neuropathies are a group of disorders collectively referred to as Charcot-Marie-Tooth disease. These neuropathies result from flaws in genes responsible for manufacturing neurons or the myelin sheath. Hallmarks of typical Charcot-Marie-Tooth disease include extreme weakening and wasting of muscles in the lower legs and feet, gait abnormalities, loss of tendon reflexes, and numbness in the lower limbs.

http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm#183593208

What Does Neuropathic Pain Feel Like

Today's post from pain.about.com (see link below) is a short but useful description of the nature of nerve pain. There's nothing here that the experienced neuropathy patient won't know but sometimes putting your symptoms into words for others is very difficult - they just don't seem to understand - and why should they - nerve pain is pretty much unique and unless they can feel it themsleves, they won't really get what you're going through. This article will help put it into words for them - it's a, 'pass on to your friends and family' article and will help them get an idea of how you're feeling.
 

What Does Nerve Pain Feel Like?
Neuropathic Pain and its Unique Symptoms
By Erica Jacques Chronic Pain Expert Updated July 16, 2014.

Written or reviewed by a board-certified physician. See About.com's Medical Review Board.

Neuropathic pain, also called nerve pain, is one of the many classes of chronic pain. Nerve pain can be caused by nerve damage, irritation or destruction.
How Nerve Pain Feels Most people describe their chronic nerve pain with a similar set of words. Regardless of the cause, nerve pain can feel like any of the following:

Burning
Tingling
Shooting
Sharp
Stabbing
Prickling

Nerve pain may vary in intensity. For some, it can feel like mildly bothersome pins and needles. For others, the pain may be severe and nearly unbearable. Nerve pain may be localized (felt at or near the area of nerve damage) or referred (felt somewhere else in the body).

Nerve Pain Terminology

Because nerve pain is unique, it has some medical buzzwords associated with it. Nerve pain sensations may be described with these buzzwords, which include:

Allodynia: When a person experiences pain after a stimulus that shouldn’t cause pain under ordinary circumstances, it is called allodynia.
Hyperalgesia: If a person has hyperalgesia, mildly painful stimuli may be felt with greater intensity.
Dysesthesia: Dysesthesia describes some sort of impairment in sensation. It can describe pain that is felt when there is no stimulus present at all, also called spontaneous pain.

Other Symptoms Associated With Nerve Pain

Like other types of chronic pain, neuropathic conditions often cause other symptoms in addition to pain. If you have any of the following in addition to the pain described above, you may have nerve damage:

Partial or complete loss of feeling
Muscle weakness
Partial or complete paralysis
Changes in skin appearance and texture
Muscle disuse atrophy
Depression and/or anxiety
More Nerve Pain Information
Definition of Neuropathic Pain
Common Nerve Pain Conditions
What Causes Nerve Pain?

Sources:

National Pain Foundation. Neuropathic Pain: Symptoms. Accessed 2/2/10. http://www.nationalpainfoundation.org/articles/353/symptoms?PHPSESSID=9c14904e64a8ad966628202be1ce5892

The Merck Manuals Online Medical Library. Neuropathic Pain. Accessed 2/2/10. http://www.merck.com/mmpe/sec16/ch209/ch209c.html#sec16-ch209-ch209c-278

http://pain.about.com/od/typesofchronicpain/a/neuropathic_pain_symptoms.htm

What explains HIV induced pain syndrome

Today's article comes from a scientific blog called 'Rule of 6ix' (see link below) and is written by Connor Bamford, currently studying for his PhD. It is somewhat complex and if interested, you may need to do some further dictionary work to find the meanings of some terms but it explains the science behind the growing incidence of pain amongst HIV-patients and is worth reading and trying to absorb (at neuron level in the nervous system, the science is inevitably complex!)
He refers to a video (TED talk) which will be posted tomorrow, otherwise there is just too much to take in in one go.

What explains HIV -induced pain syndrome?
By Connor on Sunday, September 04, 2011

Does HIV-1 Tat protein induce pain in HIV/AIDS sufferers? Notice a Tat induced increase in activity when compared to control or inactivated protein. (Taken from: Chi, et al, 2011)

Pain is an extremely complicated symptom - just see the TED talk below (tomorrow's post:Ed) on chronic pain, yet of the 33.4 million people currently living with HIV/AIDS worldwide, 90% will experience peripheral neuropathy - otherwise known as pain. This a general unrecognised and under-diagnosed (and under-treated) outcome of HIV infection, yet the reasons how and why the viral infection induces this are unknown, but probably are pretty complex.

Is it because of the inflammatory response? The antivirals being taken? Or, the direct effects of virus replication? While the importance of pain as a symptom of HIV/AIDS will only become more evident as this disease is further transformed into a chronic - yet manageable - illness.

HIV-1 genome organisation - one of these genes may be responsible for HIV/AIDS-associated pain. Notice Tat, expressed via splicing. (Wikipedia)


But HIV itself is not known to infect neurons (the major players in pain) during a natural infection, so how could it mess with their activity? One explanation for this is that the virus itself induces pain through interactions with the peripheral nervous system via the infection of a small number of cells associated with neurons (perivascular macrophages, microglia and astrocytes). And, maybe from this site, some effect of virus replication could damage the nearby neuronal cells, especially seeing as a number of HIV-encoded proteins have been shown to have a toxic effect on neurons. The role that these play in pain has not yet been explored.

A paper published this week in PLoS ONE, explores the role of HIV-1 Tat protein - a protein released by infected cells and found in patients blood - on the activity of rat dorsal root ganglia neurons, which is a widely used model system for peripheral neurons and pain.

A rat dorsal root ganglion neuron - a model system for mammalian peripheral nervous system and pain. (Rick Stahl, NikonSmallWorld)

This group determined that addition of a recombinant form of tat specifically induced hyper-excitability in a dose dependent manor (independent of viral infection and other HIV proteins). It is believed that hyper-excitability or persistent firing of neurons may be experienced as pain in the sufferer. This effect was traced to a down-regulation of mRNA levels of cdk5 (a regulator of neuron activity) and its activator, p53 while knock-down of cdk5 appeared to induce the same kind of hyper-activity in these neurons. Tat may also induce greater levels of cell-death upon treatment.

The model put forward from this investigation appears to be that following HIV acquisition, the virus infects resident non-neuronal cells among the peripheral nervous system (lying close by to neurons). From here, tat is released into the space surrounding the cells and binds to - and interacts with - the neurons causing excitability and associated pain, and possibly cell death.

To further test if this hypothesis is correct, work will have to be completed with actual HIV and not just addition of tat protein. Cells could be pre-infected with the virus and then added alongside the neurons to see whether secreted, HIV tat functioned the same. Or an in vivo model of tat/neuron interaction could be used. This also gives us some clues as to a possible anti-pain treatment through blocking of Tat activity.

Chi, X., Amet, T., Byrd, D., Chang, K., Shah, K., Hu, N., Grantham, A., Hu, S., Duan, J., Tao, F., Nicol, G., & Yu, Q. (2011). Direct Effects of HIV-1 Tat on Excitability and Survival of Primary Dorsal Root Ganglion Neurons: Possible Contribution to HIV-1-Associated Pain PLoS ONE, 6 (9) DOI: 10.1371/journal.pone.0024412

http://ruleof6ix.fieldofscience.com/2011/09/what-explains-hiv-induced-pain-syndrome.html

What Is Sensory Neuropathy

Today's post from Singapore is from sg.news.yahoo.com (see link below) and shows how neuropathy is a world wide problem (of course it is but many people tend to think only in terms of how it affects the USA and the Western countries - it's a human condition). Many people with neuropathy, wherever in the world, will receive a diagnosis of 'sensory neuropathy', which as with yesterday's post, is yet another description of the same thing in the end. You may also be told that it is idiopathic, or autonomic, or just peripheral but the symptoms pretty much apply to most sorts of neuropathy. Sensory neuropathy, as the name suggests, describes how the nerve damage affects the feeling in your feet, legs or arms, with all the variations of unpleasant feelings that you're already aware of.

Sensory peripheral neuropathy: A disease in the news

By Health Xchange | Fit to Post Health – Fri, Nov 25, 2011
Most people take the ability to walk for granted. But if you are afflicted with sensory peripheral neuropathy — one of the commonest nerve disorders, you will soon realise how difficult the simple act of walking can be.

Sensory peripheral neuropathy impedes your ability to feel or "sense" your feet, making it difficult to keep a steady gait. You may lose your balance and become more prone to falls.

National Neuroscience Institute (NNI) sees more than 100 cases of sensory peripheral neuropathy every year. As only the more severe or symptomatic cases are referred to NNI specialists, the number of cases in the whole of Singapore is presumably much higher.

The condition drew much attention recently, after it was revealed that former Minister Mentor Lee Kuan Yew suffers from it.

Sensory peripheral neuropathy tends to affect people aged over 60. "It is not life-threatening, but it can progressively lead to leg numbness or loss of sensation on the skin of the legs," says Dr Josiah Chai, senior consultant, Department of Neurology at National Neuroscience Institute.

What is the peripheral nervous system?

The body's nervous system has two parts: the central nervous system (comprising the brain and spinal cord) and the peripheral nervous system (rest of the nerves).

Damage to the peripheral nervous system can affect the sensory nerves, motor nerves or autonomic nerves.

When the peripheral sensory nerves are damaged, they fail to send sensory messages of pain, touch, heat or cold, vibration and position sense from your hands or feet to the brain, hence the loss of sensations and unsteady gait.

Symptoms of sensory peripheral neuropathy

The following symptoms may be present:

Gradual numbness and tingling in the hands or feet (may spread to arms and legs)
Burning pain
Impaired ability to sense the position of one's limbs
Loss of balance and coordination
Extreme sensitivity to touch

What causes sensory peripheral neuropathy?

About a third of peripheral neuropathy cases have no known causes. Another third is caused by diabetes. Physical injuries or trauma to the nerves, such as carpel tunnel syndrome, can also lead to nerve disorders.

Other causes may include infections, toxins (e.g. alcohol), metabolic or hormonal imbalance like hypothyroidism, autoimmune disorders, tumours pressing on the nerves, vitamin B-12 deficiency, and hereditary conditions like Charcot-Marie-Tooth disease.

How is sensory peripheral neuropathy diagnosed?

The doctor will first conduct a physical and neurological exam to test your body's reflexes, coordination, and ability to experience the different types of sensations.

A nerve conduction test, alongside an electromyography, may be carried out to evaluate how well electrical signals travel along the peripheral nerves. This helps to confirm the presence of a peripheral neuropathy, its severity and the type of nerve damage (e.g. demyelinating versus axonal). Any alternation of signals could indicate a nerve disorder.

Blood tests screening for diabetes, low thyroid hormone and vitamin B-12 deficiency may be carried out as well.

Treatment for sensory peripheral neuropathy

Doctors will first treat the underlying cause of sensory peripheral neuropathy.

Pain relief medications can be prescribed to relieve nerve pain. Physical therapy and exercise are recommended to restore strength and coordination to limbs.

"Patients with sensory peripheral neuropathy suffer from sensory loss in their feet. To prevent falls, they should walk on even grounds and avoid dimly lit areas," says Dr Chai. "Damaged peripheral nerves may regenerate with proper care, but symptoms will return unless the root cause is removed," he adds.

One last word of advice from the specialist: Don't walk bare-footed, especially if you suffer from diabetes.

http://sg.news.yahoo.com/blogs/fit-to-post-health/sensory-peripheral-neuropathy-disease-news-044348079.html

What You Need To Know About Alpha Lipoic Acid

Todays' post from tlc.howstuffworks.com (see link below) is another long one but sometimes it's more important to give as much information as possible than just a summary - it's about our health after all. It talks about Alpha Lipoic Acid which is now widely used to help combat the effects of neuropathy, often in combination with another co enzyme Acetyl L-Carnitine. You may not know how or why they work (if indeed they do in your case) but you will be paying quite a lot for them and they're rarely covered by insurance policies. Unfortunately like  everything else concerned with treating neuropathy, there are absolutely no guarantees but the sort of information shown here will help both you and your doctor make calculated choices.

Alpha Lipoic Acid: What You Need to Know

by Richard Winter

­Free radicals. It sounds like something they give away at protest rallies. But in your body, they are cells with unpaired electrons that attack other molecules to achieve stability, damaging the DNA of those molecules and spreading disease.
Enter the antioxidant -- compounds the body uses as its defense system to fight free radicals and keep them from setting off chain reactions of cell mutation that can lead to a host of chronic diseases like cancer, heart disease, Alzheimer's and Parkinson's [source: Davis]. 

One antioxidant getting a lot of attention on the free radical fighting scene is Alpha Lipoic Acid (ALA). Also known as thioctic acid, ALA is naturally produced in the body, as well as absorbed from certain foods we eat, such as red meat, spinach, potatoes, broccoli, yams, carrots, beets and yeast [source: American Cancer Society].

For 20 years, ALA supplements have been used to treat HIV, sciatica, cancer, liver problems, hepatitis, strokes, vascular disease, diabetes, cataracts, glaucoma, multiple sclerosis, burning mouth syndrome and Alzheimer's. Some doctors believe ALA can even help slow the aging process [source: National Toxicology Program].

But because they are not drugs, ALA supplements are not subject to regulation by the Food and Drug Administration. Respected medical journals haven't jumped on the antioxidant bandwagon and more studies are needed to test its effectiveness in humans.

In the following sections, you'll learn about some of the research surrounding ALA and how this antioxidant works in the body, along with its benefits, side effects, and impact on weight loss and peripheral neuropathy -- numbness in the hands and feet.

Alpha Lipoic Acid and Peripheral Neuropathy

­Peripheral neuropathy is a condition characterized by pain and numbness in the hands and feet that occurs in patients with diabetes, nerve pressure (from abnormal bone growth or a tumor), vitamin deficiency, kidney or liver disease and alcoholism. Cancer treatment chemicals can also cause it and HIV patients are prone to it [source: Mayo Clinic].
More than 20 percent of diabetic patients develop peripheral neuropathy -- the leading cause of lower limb amputation. Oral and intravenous ALA is approved for use in Germany for treatment of diabetic neuropathy and in the U.S., research has shown that ALA may be helpful in treating nerve damage in diabetics and in cancer patients [source: American Cancer Society].
In a clinical trial, diabetic patients suffering from peripheral neuropathy who were given 200 mg of ALA intravenously for 21 days reported a reduction in pain. A larger study of diabetics with peripheral neuropathy who were injected with 600 mg of ALA a day for three weeks, followed by 12 weeks of oral supplements, also experienced relief [source: Larsen].
A small study in Austria found that more than half of the cancer patients who took ALA after getting the chemotherapy drug oxaliplatin reported an improvement in neuropathy symptoms [source: American Cancer Society]. The National Cancer Institute is currently conducting a phase-3 study on ALA's use in preventing peripheral neuropathy in cancer patients undergoing chemotherapy treatment [source: Higdon, American Cancer Society].

Alpha Lipoic Acid at Work in Your Body

­AL­A is a fatty acid both produced by the body and absorbed from the foods you eat. When it binds to certain proteins, ALA plays an important role in our metabolism -- namely the Krebs cycle, the body's main process for converting carbohydrates into energy. And unlike other antioxidants, ALA is both water and fat soluble, enabling it to work throughout the body. That's why it's found in varying concentrations in all your muscles and internal organs [source: Larsen].
Your body typically produces enough ALA for its role in creating energy. But when there's an excess in your system, ALA does not bind to protein and acts as an antioxidant. When in this "free" state, ALA deactivates a wide variety of free radicals, such as heavy metals, circulating through your body. It may also help regenerate other antioxidants like Vitamin C and Vitamin E to fight more free radicals [source: Berkeley Wellness Letter].
Because we produce less ALA as we age, some researchers believe that taking a supplement may help slow the aging process. ALA, combined with acetyl-L-carnitine, has been touted as an anti-aging and vitality supplement [source: National Toxicology Program].

Alpha Lipoic Acid Benefits

­Many of the health benefits attributed to ALA supplements are based on lab testing on animals, primarily rats. Whether humans would experience similar results from ALA's antioxidant powers has not been studied enough to produce definite answers.
Early animal studies suggest that ALA may help in treating Alzheimer's and other diseases that affect the nervous system [source: Larsen]. Additional studies have shown that a combination of antioxidants (including ALA) has helped cancer patients regain their appetite and weight. While early lab experiments suggest that ALA might cause cancer cells to self-destruct, it is unknown if the same effect can be replicated in animals or humans. Researchers are studying ALA as a possible therapy for reducing the side effects of radiation and chemotherapy. Research is also underway to determine if ALA can help prevent nerve damage that may result from some chemotherapy drugs [source: American Cancer Society].
Another potential benefit of ALA is the treatment of diabetes. Although some studies have found that ALA has a positive effect on insulin sensitivity, glucose metabolism and diabetic neuropathy, more research is needed to determine whether ALA supplements provide substantial benefits for type 2 diabetes and its complications [source: National Center for Complimentary and Alternative Medicine].
ALA supplements may also decrease the buildup of plaque within the arteries. One study found that ALA reduced heart damage caused by chemotherapy drugs. Another found it beneficial in treating cardiovascular autonomic neuropathy -- a condition characterized by an irregular heartbeat that's common in diabetics [source: Higdon, American Cancer Society].
There are also reports that ALA may have health benefits in relation to cataracts, seizures, kidney damage and liver disease, but additional studies are necessary before any definite conclusion is drawn. In addition, ALA, like just about any other medication or supplement, is not without its side effects.

Alpha Lipoic Acid Side Effects

Research has shown that patients can take 300 to 600 milligrams of ALA a day with relatively few side effects, such as skin rashes, stomachaches, nausea, diarrhea and vomiting. However, the jury is still out on the long-term effects of taking ALA supplements. Anyone with pre-existing medical conditions should exercise caution. Children are not advised to take ALA. Pregnant and nursing women should consult their doctors before taking it.
Diabetics who take ALA must monitor their blood sugar levels carefully, because the supplements may lower blood glucose levels [source: National Center for Complimentary and Alternative Medicine].
ALA may also lower levels of thyroid hormone and thyroid-regulating medications (Levothyroxine). Hormone levels should be monitored closely for those taking thyroid hormones and ALA supplements [source: University of Maryland Medical Center]. There is also concern that ALA might interfere with radiation therapy or chemotherapy by making the treatments less effective [source: American Cancer Society].
Unlike prescription drugs, supplements like ALA capsules don't have to be approved by the FDA before they are released on the market. Nor are they tested for their adverse affects when taken with other medication. In 2005, supplements accounted for almost 24,000 calls to U.S. poison control centers [source: American Cancer Society]. That's why it's always best to check with your doctor before taking any herbal remedy.

Alpha Lipoic Acid and Weight Loss

­If you have a rat with a weight problem, ALA supplements might help get rid of some of that cheese you feed him. But if you're a human looking to slim down for bikini season, you should probably stick with your diet and exercise plan. At this point, ALA hasn't proven its effects on the human body.
Recent studies have shown ALAs can regulate metabolism and inhibit the metabolism of fat in the liver. Unfortunately, those findings are based on lab experiments involving cultured rat liver cells and skeletal muscles -- not bathing beauties [source: Treadwell]. So, there's no indication the same results would occur in humans.
One study conducted at the University of Ulsan College of Medicine in Seoul, Korea, found that ALA decreases the activity of fuel sensors in rats, causing the rodents to eat less and expend more energy, resulting in "profound" weight loss [source: National Center for Biotechnology Information]. But until the same effect is observed in humans, there's probably no point in popping an ALA supplement to achieve weight loss.
The bottom line is further research is necessary concerning ALA's effects on humans in regard to its use for weight loss. In general, it's always best to use extreme caution when taking supplements. And if you do decide to incorporate ALA or any other supplement into your diet, be sure to share that information with your physician.

http://tlc.howstuffworks.com/family/alpha-lipoic-acid.htm

What Have Sodium Channels To Do With Neuropathy

Today's post from neurologyadvisor.com (see link below) talks about something you may well have heard of during your journey with neuropathy treatments. Many of the pain-killing treatments for neuropathy, work by influencing 'sodium channels' which normally control, or fail to control, the 'excitability' of nerve signals, leading to the symptoms we're all aware of. Certain drugs can block these channels and that reduces the feeling of chaos in our nervous system that characterises neuropathy. It's finding the right drugs to block sodium channel signals in the right way, that is the key to solving neuropathic problems. It's a technical topic and not easy to follow but worth reading about because it increases our understanding of what's happening to us and what certain drugs can do to influence that.

The Role of Sodium Channels in Painful Neuropathies Chris Illiades, MD October 29, 2014 

The peripheral nervous system is a vast network of nerves carrying messages between the brain and spinal cord and every part of the body. Peripheral nerves are highly specialized and can cause a wide range of sensory, motor, and autonomic symptoms, making peripheral neuropathies hard to diagnose and hard to treat.1

There are more than 100 known types of peripheral neuropathy. Common acquired causes include diabetes, injury, autoimmune disease, and nutritional deficiency. However, peripheral neuropathies can also be inherited or caused by genetic mutations.1 Some genetic neuropathies cause pain due to hyperexcitability of pain-sensing nociceptors. Research into these conditions teaches us a lot about the pathophysiology of neurogenic pain.2
Sodium Channels and Painful Neuropathies

It has been known for a long time that voltage-gated sodium channels (VGSCs) control the flow of sodium ions that can trigger excitability of pain-sensing nociceptors in the peripheral nervous system. In humans, nine VGSCs have now been identified, and some have been linked to genes that alter their function.2,3

“We know that sodium channels play an important role in painful neuropathy. Genetic mutations that cause extreme pain have been linked to several disorders, and we may find that genetic polymorphisms play a role in more common peripheral neuropathies as well,” said Christina Ulane, MD, PhD, assistant professor of neurology at Columbia University Medical Center in New York City.

Gene mutations have now been linked to sodium channels Nav1.7, Nav1.8, and Nav1.9. Gain of function mutation in the gene SCN9A has been linked to Nav1.7 and a disorder called inherited erythromelalgia (IEM).2 IEM is also called “Man on Fire Syndrome,” because it causes excruciating burning pain in response to mild warmth.4

The gene SCN10A has been linked to Nav1.8 and small fiber neuropathy, a condition that causes severe pain attacks in the hands or feet..2. It may also cause autonomic pain symptoms such as palpitations, bowel problems, and abnormal sweating.2,5

Genetic mutations can also cause less excitability by reducing sodium flow through a VGSC. The gene SCN11A causes hyperpolarization of Nav1.9, which may cause loss of pain sensation.2 Nav1.9 has also been linked to mutation that causes painful neuropathy.3
Nav1.7 and Diabetes

A 2014 article published in the journal Trends in Molecular Medicine suggests that as we learn more about VGSCs and the genes that affect them, we could find that they play a much larger role in acquired peripheral neuropathy—and maybe even in some common diseases. The article notes that painful diabetic peripheral neuropathy (DPN) occurs in up to 25% of people with diabetes.

It has traditionally been believed that painful DPN is a direct result of hyperglycemia. Painful DPN may actually occur very early in diabetes and some people with long-standing diabetes never get DPN, the study authors noted. They proposed that painful DPN is not a complication of diabetes but rather the result of mutations at Nav1.7 that have been found in nerve cells and in pancreatic beta cells. Could these mutations increase both the risk for diabetes and painful DPN?6

“It may be that the diabetic pain we associated with metabolic changes may also be linked to genetic susceptibility. The pain medications we use for diabetic neuropathy now are mostly pregabalin (Lyrica, Pfizer) and duloxetine (Cymbalta, Lilly). Neither one is a sodium channel blocker, and they are only about 50% effective,” said Ulane. 

Could Sodium Channels Offer Better Treatments for Neuropathic Pain?

“We already have sodium channel blockers, but they are not very effective and are limited by side effects. If we can find more targeted sodium channel blockers, we might be able to improve treatment of neuropathic pain,” Ulane said.

The problem with the sodium channel blockers now available is that they block all sodium channels. This includes VGSCs like Nav1.3 in the central nervous system and Nav1.5 in skeletal muscle. It also means these drugs can cause lots of unwanted adverse effects.7 For example, those associated with the sodium channel blocker lamotrigine include dizziness, joint pain, blurred vision, and uncontrollable shaking.8

This emphasizes the importance of the research on Nav1.7, Nav1.8, and most recently Nav1.9. These channels seem to be the ones that are specific to nerve pain. Pharmaceutical companies are actively working on drugs for Nav1.7 and Nav1.8 and will probably begin to include Nav1.9, now that it has also been linked to human pain. Finding drugs that selectively block just these channels could be the holy grail of neuropathic pain treatment.3,7

Chris Iliades, MD, is a full-time freelance writer based in Cape Cod, Massachusetts.

This article was medically reviewed by Pat F. Bass III, MD, MPH

References
National Institute of Neurological Disorders and Stroke. Peripheral Neuropathy Fact Sheet.http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm. Updated September 26, 2014. Accessed October 28, 2014.
Brouwer BA, Merkies ISJ, Gerrits MM, Waxman SG, Hoeijmakers JGJ, Faber CG. Painful neuropathies: the emerging role of sodium channelopathies. J Peripher Nerv Syst. 2014;19(2)53-65.
Sutherland S. Third sodium channel implicated in painful small-fiber neuropathy. Pain Research Forum.http://www.painresearchforum.org/news/40751-third-sodium-channel-implicated-painful-small-fiber-neuropathy. Accessed October 28, 2014.
Boyle AM. Sodium channels offer path to personalized pain management, U.S. Medicine Web site.http://www.usmedicine.com/agencies/department-of-veterans-affairs/sodium-channels-offer-path-to-personalized-pain-management/. Accessed October 28, 2014.
Genetics Home Reference. Small Fiber Neuropathy. http://ghr.nlm.nih.gov/condition/small-fiber-neuropathy. Reviewed November 2012. Accessed October 28, 2014.
Hoeijmakers JG, Faber CG, Merkies IS, Waxman SG. Channelopathies, painful neuropathy, and diabetes: which way does the causal arrow point? Trends Mol Med. 2014;20(10):544-550.
Theile JW, Cummins TR. Recent developments regarding voltage-gated sodium blockers for the treatment of inherited and acquired neuropathic pain syndromes. Front Pharmacol. 2011;2:54.
Lamotrigine. MedlinePlus Website.http://www.nlm.nih.gov/medlineplus/druginfo/meds/a695007.html. Accessed October 28, 2014.

http://www.neurologyadvisor.com/targeting-sodium-channels-for-neuropathic-pain-treatment/article/380020/

What Is Neuropathy Keep It Simple

Today's post from livescience.com (see link below) is a new and very easy to follow summary of what neuropathy is. Useful for people new to the disease, or for friends and family who want to know more but it's only a start. From this point on, depending on the cause, severity and proposed treatment of the symptoms, people may feel the need to look further into this mysterious and complex condition. This blog has over 1000 posts (see alphabetical list to the right) but Googling neuropathy will result in all the information you may need and probably lots that you don't! Starting with this short article is a good first step.

What Is Neuropathy? 
By Joseph Castro, Live Science Contributor | March 27, 2014

Peripheral neuropathy (often referred to simply as "neuropathy") refers to any condition that damages or disrupts nerves in the peripheral nervous system.

The peripheral nervous system is the network of nerves that connects the central nervous system, which consists of the brain and spinal cord, to the rest of the body.

There are three types of nerves in the peripheral nervous system: motor nerves, which regulate the movements of muscles under your conscious control; autonomous nerves, which regulate bodily functions outside your control; and sensory nerves, which carry messages from the sensory organs to the brain.

Experts have identified more than 100 types of peripheral neuropathies, according to the National Institute for Neurological Disorders and Stroke. The exact symptoms of the different neuropathies depend on the nerves affected.

People with a neuropathy affecting motor nerves usually experience muscle pain. They may also suffer from cramps, muscle twitching, muscle and bone loss, and changes in the skin, hair and nails.

Symptoms associated with autonomic neuropathy are diverse, and depend on the organs or glands affected. For example, if the nerves of the sweat glands are damaged, a person may lose the ability to sweat normally. Damage to other autonomic nerves can result in diarrhea, constipation, loss of bladder control, abnormal blood pressure and heart rate, and dizziness or fainting when rising to a standing position.

Sensory-nerve neuropathies can result in various complex symptoms, such as general numbness, loss of coordination and reflexes, burning sensations, heightened pain sensations or the inability to feel pain.

There are many ways that neuropathies develop. Certain neuropathies are inherited, such as those associated with Charcot-Marie-Tooth disease, a type of hereditary neurological disorder.

More often, however, neuropathies are acquired from physical trauma, toxins, cancer medications, alcoholism, vitamin deficiencies, autoimmune disorders and metabolic disorders, including diabetes.

Although there are no treatments for inherited neuropathies, acquired neuropathies may sometimes be treated by addressing the underlying cause — for instance, by correcting nutritional deficiencies, undergoing physical therapy or giving up alcohol.

Follow Joseph Castro on Twitter. Follow us @livescience, Facebook & Google+.

http://www.livescience.com/44441-what-is-neuropathy.html

Small Fibre Neuropathy Is That What Youve Got

Today's post from ccjm.org (see link below) is one of those posts that, while long, is definitely worth reading for neuropathy sufferers. The reason being that it is so thorough and informative. So much well-explained and clear information in one article is a rare find, so it's worth promoting. Remember, although the title refers to small-fibre neuropathy, don't let this put you off if your neuropathy been given another label - the information here applies to most neuropathies and there will be many things of value for most neuropathy patients.

Small fiber neuropathy: A burning problem
JINNY TAVEE, MD
Neuromuscular Disease Center, Neurological Institute, Cleveland Clinic
LAN ZHOU, MD, PhD
Director, Cleveland Clinic Cutaneous Nerve Laboratory, Neuromuscular Disease Center, Neurological Institute, Cleveland Clinic ADDRESS: Lan Zhou, MD, PhD, Neuromuscular Disease Center, Neurological Institute, S90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail zhoul2@ccf.org.

Abstract

Small fiber neuropathy is increasingly being recognized as a major cause of painful burning sensations in the feet, especially in the elderly. Although strength remains preserved throughout the course of the disease, the pain and paresthesias are often disabling. Diabetes mellitus is the most common identifiable cause of small fiber neuropathy, and impaired oral glucose tolerance and individual components of the metabolic syndrome are often associated with it. Some cases, however, are idiopathic. Skin biopsy (with an evaluation of the density of intraepidermal nerve fibers) and tests of autonomic nerve function are useful for the diagnosis. Management involves controlling pain and identifying and aggressively treating the underlying cause.
CCJM 2009 5;76(5):297-305.

Key Points
Symptoms of small fiber neuropathy typically start with burning feet and numb toes.
Causes and associated conditions can be found in over 50% of cases. These include glucose dysmetabolism, connective tissue diseases, sarcoidosis, dysthyroidism, vitamin B12 deficiency, paraproteinemia, human immunodeficiency virus infection, celiac disease, neurotoxic drug exposure, and paraneoplastic syndrome.
Findings on routine nerve conduction studies and electromyography are typically normal in this disease.
Management includes aggressively identifying and treating the underlying cause, advising lifestyle modifications, and alleviating pain.

An estimated 15 to 20 million people in the United States over age 40 have some type of peripheral neuropathy.1 In many, the impairment is purely or predominantly in small nerve fibers, and the clinical presentation consists of pain, burning, tingling, and numbness in a length-dependent or stocking-glove distribution. (“Length” refers to distance from the trunk; distal fibers are affected first.) Symptoms typically begin in the feet and slowly ascend to the distal legs, at which point the hands may also be affected (FIGURE 1).

In many of these patients, the findings on neurologic examination, nerve conduction studies, and electromyography are normal, although some may show signs of mild distal sensory loss on physical examination. The lack of objective findings on routine nerve conduction studies and electromyography may lead many physicians to attribute the symptoms to other disorders such as plantar fasciitis, vascular insufficiency, or degenerative lumbosacral spine disease.

The past 2 decades have seen the development of specialized tests that have greatly facilitated the diagnosis of small fiber neuropathy; these include skin biopsy to evaluate the density of nerve fibers in the epidermis and studies of autonomic nerve function. Common etiologies have been identified for small fiber neuropathy and can be specifically treated, which is critical for controlling progression of the disease. Pain management is becoming easier with more available options but is still quite challenging.

WHAT IS SMALL FIBER NEUROPATHY?

Small fiber neuropathy is a disorder of the peripheral nerves that primarily or exclusively affects small somatic fibers, autonomic fibers, or both, resulting in sensory changes and autonomic dysfunction when both types are involved (FIGURE 2).2


FIGURE 1. Symptoms are pain, burning, numbness, and autonomic dysfunction (lack of sweating) in the hands and feet in a stocking-glove distribution. Strength is not affected. Tendon reflexes are normal, as are nerve conduction studies.

Peripheral nerve fibers can be classified according to size, which correlates with the degree of myelination.
Large nerve fibers are heavily myelinated and include A-alpha fibers, which mediate motor strength, and A-beta fibers, which mediate vibratory and touch sensation.
Medium-sized fibers, known as A-gamma fibers, are also myelinated and carry information to muscle spindles.
Small fibers include myelinated A-delta fibers and unmyelinated C fibers, which innervate skin (somatic fibers) and involuntary muscles, including cardiac and smooth muscles (autonomic fibers). Together, they mediate pain, thermal sensation, and autonomic function.

Small fiber neuropathy results from selective impairment of small myelinated A-delta and unmyelinated C fibers.

Sensory symptoms: Pain, burning, tingling, numbness

Damage to or loss of small somatic nerve fibers results in pain, burning, tingling, or numbness that typically affects the limbs in a distal-toproximal gradient. In rare cases, small fiber neuropathy follows a non-length-dependent distribution in which symptoms may be manifested predominantly in the arms, face, or trunk.

Symptoms may be mild initially, with some patients complaining of vague discomfort in one or both feet similar to the sensation of a sock gathering at the end of a shoe. Others report a wooden quality in their feet, numbness in their toes, or a feeling as if they are walking on pebbles, sand, or golf balls. The most bothersome and fairly typical symptom is burning pain in the feet that extends proximally in a stocking-glove distribution and is often accompanied by stabbing or aching pains, electric shock-like or pins-and-needles sensations, or cramping of the feet and calves.

Symptoms are usually worse at night and often affect sleep. Some patients say that their feet have become so exquisitely tender that they cannot bear having the bed sheets touch them, and so they sleep with their feet uncovered. A small number of patients do not have pain but report a feeling of tightness and swelling in their feet (even though the feet appear normal).

Examination often reveals allodynia (perception of nonpainful stimuli as being painful), hyperalgesia (perception of painful stimuli as being more painful than expected), or reduced pinprick and thermal sensation in the affected area. Vibratory sensation can be mildly reduced at the toes. Motor strength, tendon reflexes, and proprioception, however, are preserved because they are functions of large nerve fibers.

Autonomic symptoms

When autonomic fibers are affected, patients may experience dry eyes, dry mouth, orthostatic dizziness, constipation, bladder incontinence, sexual dysfunction, trouble sweating, or red or white skin discoloration.2 Examination may show orthostatic hypotension and skin changes. The skin over the affected area may appear atrophic, dry, shiny, discolored, or mildly edematous as the result of sudomotor and vasomotor abnormalities.


FIGURE 2

WHAT CAUSES SMALL FIBER NEUROPATHY?

Small fiber neuropathy has been associated with many medical conditions, including glucose dysmetabolism,3 connective tissue disease,4,5 dysthyroidism,6 vitamin B12 deficiency, paraproteinemia, human immunodeficiency virus (HIV) infection,7 hepatitis C virus infection, celiac disease,8 restless legs syndrome,9 neurotoxic drug exposure, hereditary diseases, and paraneoplastic syndrome. While most of these conditions cause a length-dependent small fiber neuropathy, others (Sjögren disease, celiac disease, and paraneoplastic syndrome) can cause a form of small fiber neuropathy that is not length-dependent.4,8,10

Diabetes and prediabetes

Glucose dysmetabolism, including diabetes and prediabetes with impaired oral glucose tolerance (a glucose level 140–199 mg/dL 2 hours after a 75-g oral dextrose load), is the most common identifiable associated condition, present in about one-third of patients with painful sensory neuropathy11 and in nearly half of those with otherwise idiopathic small fiber neuropathy.12–14

Research findings strongly suggest that even prediabetes is a risk factor for small fiber neuropathy, and that so-called “impaired glucose tolerance neuropathy” may represent the earliest stage of diabetic neuropathy. Several recent studies have found a high prevalence of impaired glucose tolerance in patients with sensory peripheral neuropathy,12–14 with a rate of up to 42% in cases initially thought to be idiopathic14 compared with 14% in the general population.15 Also, a dose-response relationship between the severity of hyperglycemia and the degree of neuropathy was demonstrated in one study, in which patients with impaired glucose tolerance more often had small fiber neuropathy, whereas those with diabetes more often had polyneuropathy involving both small and large fibers.14 And studies in animals and cell cultures have shown that intermittent hyperglycemia, which can be seen in patients with impaired glucose tolerance, caused sensory neuron and nerve fiber damage and increased spontaneous C-fiber firing, resulting in neuropathic pain.8,16,17

Metabolic syndrome

Insulin resistance with prediabetes and diabetes is a part of the metabolic syndrome, which also consists of hypertension, hyperlipidemia, and obesity. The individual components of the metabolic syndrome have been implicated as risk factors not only for cardiovascular and cerebrovascular disease but also for small fiber neuropathy.

One study in 548 patients with type 2 diabetes showed that those with the metabolic syndrome were twice as likely to have neuropathy as those without.18 Another study showed that in 1,200 patients with type 1 diabetes without neuropathy at baseline, hypertension, hyperlipidemia, and increased body mass index were each independently associated with a higher risk of developing neuropathy.19

A recent study of 219 patients with idiopathic distal symmetrical peripheral neuropathy and 175 diabetic patients without neuropathy found a higher prevalence of metabolic syndrome in patients with neuropathy than in normal populations. The prevalence of dyslipidemia (high levels of total and low-density lipoprotein cholesterol and triglycerides and low levels of high-density lipoprotein cholesterol), but not hypertension or obesity, was higher in patients with neuropathy than in patients with diabetes but no neuropathy.20 The findings linked dyslipidemia to neuropathy and showed the need for further studies of the potential pathogenic role of dyslipidemia in neuropathy.

Hereditary causes

Hereditary causes of small fiber neuropathy are rare and include Fabry disease, Tangier disease, hereditary sensory autonomic neuropathy, and hereditary amyloidosis.

HOW DO YOU EVALUATE PATIENTS WITH SUSPECTED SMALL FIBER NEUROPATHY?

A thorough history should be taken to obtain details regarding onset and features of neuropathy symptoms, exacerbating factors, and progression. It is also important to ascertain whether the patient has any associated conditions as mentioned above, a family history of neuropathy, risk factors for HIV or hepatitis C virus infection, or a history of neurotoxic drug exposure.

Clinical suspicion of small fiber neuropathy should be high if a patient presents with predominant small fiber symptoms and signs with preserved large fiber functions.

Nerve conduction studies and electromyography

For diagnostic testing, routine nerve conduction studies and electromyography assess the function of large nerve fibers only and are thus normal in small fiber neuropathy. These tests should still be ordered to rule out subclinical involvement of large fibers, which may affect the diagnostic evaluation, prognosis, and treatment plan. However, if the results of these tests are normal, specialized studies are needed to evaluate small fibers.

Although several tests are available to evaluate somatic and autonomic small fibers, the two that have the highest diagnostic efficiency for small fiber neuropathy and that are used most often are skin biopsy, to evaluate intraepidermal nerve fiber density, and quantitative sudomotor axon reflex testing (QSART), to assess sudomotor autonomic function.21–23

Skin biopsy

Skin biopsy is a minimally invasive procedure in which 3-mm-diameter punch biopsy specimens are taken from the distal leg, distal thigh, and proximal thigh of one lower limb. The procedure takes only 10 to 15 minutes.

Biopsy specimens are immunostained using an antibody against protein gene product 9.5, which is a panaxonal marker. Small nerve fibers in the epidermis are counted under a microscope, and intraepithelial nerve fiber densities are calculated and compared with established normative values. The diagnosis of small fiber neuropathy can be established if the intraepidermal nerve fiber density is lower than normal (FIGURE 1). Nerve fiber density may be normal in the early stage of small fiber neuropathy, but in this setting skin biopsy often shows abnormal morphologic changes in the small fibers, especially large swellings,24 and repeat biopsy in 6 to 12 months may be considered.

The diagnostic efficiency of skin biopsy is about 88%.21,23 For diagnosing small fiber neuropathy, it is more sensitive than quantitative sensory testing21,25 and more sensitive and less invasive than sural nerve biopsy.26 Intraepidermal nerve fiber density also correlates well with a variety of measures of severity of HIV distal sensory neuropathy and thus may be used to measure the severity and treatment response of small fiber neuropathy.27

Quantitative sudomotor axon reflex testing

QSART is an autonomic study that measures sweat output in response to acetylcholine, which reflects the function of postganglionic sympathetic unmyelinated sudomotor nerve fibers. Electrodes are placed on the arms and legs to record the volume of sweat produced by acetylcholine iontophoresis, in which a mild electrical stimulation on the skin allows acetylcholine to stimulate the sweat glands. The output is compared with normative values.

One prospective study showed that 67 (72.8%) of 92 patients with painful feet had abnormal results on QSART, ie, low sweat output.28 A retrospective study found that 77 (62%) of 125 patients with clinical features of distal small fiber neuropathy had a length-dependent pattern of QSART abnormalities.22 QSART abnormalities were detected in some patients without autonomic symptoms.

If these tests are not available

Skin biopsy and QSART are objective, reproducible, sensitive, and complementary in diagnosing small fiber neuropathy. One or both can be ordered, depending on whether the patient has somatic symptoms, autonomic symptoms, or both. However, these two tests are not widely available. Only a few laboratories in the country can process skin biopsy specimens to evaluate intraepidermal nerve fiber density. Nevertheless, it is easy to learn the skin punch biopsy procedure, and primary care physicians and neurologists can perform it after appropriate training. (A concern is avoiding damage to the epidermis.) They can then send specimens to one of the cutaneous nerve laboratories (but not to a routine reference laboratory).

TABLE 1 Drugs for pain control in small fiber neuropathy


DRUG

DOSAGE (PER DAY)

COMMON SIDE EFFECTS

Antidepressants


Sedation, weight gain, anticholinergic effects, sexual dysfunction, arrhythmia (side effects most prominent with amitriptyline)


Amitriptyline (Elavil)

20–150 mg


Nortriptyline (Aventyl)

20–150 mg


Desipramine (Norpramin)

20–200 mg


Duloxetine (Cymbalta)

60–120 mg


Anticonvulsants


Gabapentin (Neurontin)

600–3,600 mg

Sedation, dizziness, peripheral edema, weight gain


Pregabalin (Lyrica)

150–600 mg

Similar to gabapentin


Topiramate (Topamax)

25–400 mg

Weight loss, sedation, cognitive slowing, renal stones, paresthesias


Lamotrigine (Lamictal)

25–400 mg

Stevens-Johnson syndrome, rash, dizziness, nausea, sedation


Carbamazepine (Tegretol)

200–1,200 mg

Dizziness, sedation, ataxia, aplastic anemia, liver enzyme elevation


Oxcarbazepine (Trileptal)

600–2,400 mg

Dizziness, nausea, fatigue, leukopenia


Topical anesthetics


5% Lidocaine patch (Lidoderm)

Every 12 hours

Local edema, burning, erythema


0.075% Capsaicin patch

Three or four times a day

Burning


Opioids, opioid agonists


Tramadol (Ultram)

100–400 mg

Sedation, dizziness, seizures, nausea, constipation


Oxycodone (Oxycontin)

10–100 mg

Sedation, constipation, nausea; potential for addiction and abuse


A special technique, including unique fixative and cryoprotectant, is used to fix and process the biopsy specimens, because routine techniques for processing dermatologic punch biopsy specimens often result in lower intraepidermal nerve fiber densities. Therefore, it is very important to contact the laboratory regarding fixative and processing before performing a biopsy.

Key Points
Symptoms of small fiber neuropathy typically start with burning feet and numb toes.
Causes and associated conditions can be found in over 50% of cases. These include glucose dysmetabolism, connective tissue diseases, sarcoidosis, dysthyroidism, vitamin B12 deficiency, paraproteinemia, human immunodeficiency virus infection, celiac disease, neurotoxic drug exposure, and paraneoplastic syndrome.
Findings on routine nerve conduction studies and electromyography are typically normal in this disease.
Management includes aggressively identifying and treating the underlying cause, advising lifestyle modifications, and alleviating pain.
 
QSART requires specialized equipment and must be performed on site. In addition, the test is very sensitive to drugs that can affect sweating, such as antihistamines and antidepressants, and such drugs must be discontinued 48 hours before the study.

Basic laboratory tests to find the cause

Once the diagnosis of small fiber neuropathy is established, the next important step is to order a battery of laboratory tests to search for an underlying cause. The tests should include the following:
Complete blood cell count
Comprehensive metabolic panel
Lipid panel
Erythrocyte sedimentation rate
Thyroid-stimulating hormone level
Free thyroxine (T4) level
Antinuclear antibody
Extractable nuclear antigens
Angiotensin-converting enzyme (ACE) level
Serum and urine immunofixation tests
Vitamin B12 level
2-hour oral glucose tolerance test.

Oral glucose tolerance testing is much more sensitive than measuring the hemoglobin A1c and fasting glucose levels in detecting diabetes and prediabetes. These two conditions were detected by oral glucose tolerance testing in more than 50% of patients with otherwise idiopathic sensory-predominant peripheral neuropathy and normal hemoglobin A1c and fasting glucose levels.13,14 Therefore, every patient with small fiber neuropathy without a known history of diabetes or prediabetes should have an oral glucose tolerance test.

Special laboratory tests in special cases
If there is a history of gastrointestinal symptoms or herpetiform-like rash, then testing for gliadin antibody and tissue transglutaminase antibodies as well as small-bowel biopsy may be pursued to evaluate for celiac sprue.
Serologic tests for HIV or hepatitis C should be ordered if the patient has risk factors.
If there is a significant family history, further genetic testing should be considered.
Lip biopsy or bone marrow biopsy should be considered if clinical suspicion is high for Sjögren disease, seronegative sicca syndrome, or amyloidosis.
The serum ACE level has a low sensitivity and specificity; therefore, if sarcoid is suspected clinically, additional confirmatory testing, such as computed tomography of the chest, should be ordered despite a normal ACE value.

HOW DO YOU TREAT SMALL FIBER NEUROPATHY?

Treatment of small fiber neuropathy should target the underlying cause and neuropathic pain. Cause-specific treatment is a key in preventing small fiber neuropathy or slowing its progression.

Glucose control, weight control, and regular exercise

As glucose dysmetabolism is the condition most often associated with small fiber neuropathy (and since individual components of the metabolic syndrome are potential risk factors for it), tight glycemic control and lifestyle modification with diet control, weight control, and regular exercise are of paramount importance in patients with these conditions.

The Diabetic Prevention Program,29 a study in 3,234 people with prediabetes, found that diet and exercise were more effective than metformin (Glucophage) in preventing full-blown diabetes. At an average of 2.8 years of follow-up, the incidence of diabetes was 11.0 cases per 100 patient-years in a group assigned to receive placebo, compared with 7.8 in those assigned to receive metformin (31% lower), and 4.8 (58% lower) in those who were assigned to undergo a lifestyle intervention that included at least 150 minutes of physical activity per week with a weight-loss goal of 7%. Put another way, to prevent one case of diabetes over 3 years, 6.9 patients would have to undergo the lifestyle intervention program, or 13.9 would have to receive metformin. Since impaired glucose tolerance neuropathy may represent the earliest stage of diabetic neuropathy, the neuropathy at this stage may be reversible with lifestyle intervention and improvement of impaired glucose tolerance.

This concept is supported by a 3-year study in 31 people, which showed that lifestyle intervention significantly improved impaired glucose tolerance, reduced the body mass index, and lowered total serum cholesterol levels.30 Changes in these metabolic variables were accompanied by significant improvement of neuropathy as evidenced by significantly increased intraepidermal nerve fiber density, increased foot sweat volume, and decreased neuropathic pain.30

Treatment of other diseases

It has also been reported that treatment of sarcoidosis, autoimmune diseases, and celiac disease improved the symptoms of small fiber neuropathy resulting from these conditions.8,31 Therefore, it is important to identify the cause and treat it to prevent and slow the progression of small fiber neuropathy, and doing so may improve the disease in some mild cases.

Pain management

Pain management is crucial in the treatment of small fiber neuropathy, as neuropathic pain can be debilitating and can cause depression. Pain management often requires a multidisciplinary team, including a primary care physician, a neurologist, a pain specialist, and a psychiatrist. Medications include antidepressants, anticonvulsants, and topical anesthetics (TABLE 1) as well as narcotic and non-narcotic analgesics and antiarrhythmics. Nonpharmacologic management includes transcutaneous electrical nerve stimulation (TENS), heat, ice, and massage of painful areas (reviewed by Chen et al32 and Galluzzi33).

First-line choices of pain medications are the anticonvulsants gabapentin (Neurontin) and pregabalin (Lyrica), the tricyclic antidepressants amitriptyline (Elavil) and nortriptyline (Aventyl), a 5% lidocaine patch (Lidoderm), and the semisynthetic opioid analgesic tramadol (Ultram). These can be used alone or in combination.

Gabapentin is relatively well tolerated, but drowsiness can occur, especially with high starting doses. We usually start with 300 mg daily and increase it by 300 mg every week up to 1,200 mg three times a day as tolerated. Most patients need 600 to 900 mg three times a day.

Pregabalin is a newer antiepileptic drug, similar to gabapentin but less sedating. It can be started at 75 mg twice a day and gradually increased to 300 mg twice a day as needed. Weight gain and, rarely, swelling of the lower extremities may limit the use of both of these drugs.

Tricyclic antidepressants, such as amitriptyline, nortriptyline, and desipramine (Norpramin), are proven effective in controlling neuropathic pain, although no response with amitriptyline was seen in patients with painful HIV distal sensory neuropathy.34

Lidocaine patch is preferred if the painful area is small. Patients should be instructed to use the patch to cover the painful area 12 hours on and 12 hours off. If it does not provide relief within 1 week, it should be discontinued.

Tramadol is also helpful in treating neuropathic pain. It can be started at 50 mg two to four times a day as needed.

Nonsteroidal anti-inflammatory drugs and selective serotonin reuptake inhibitors are typically less effective than the other drugs mentioned.

Opioids should be reserved for refractory cases, given the potential for addiction, but they are sometimes necessary in patients with disabling pain that does not respond to other drugs.

TENS may be of benefit. The patient controls a pocket-size device that sends electrical signals to leads placed on affected areas.

Alternative therapies for small fiber neuropathy, such as meditation, yoga, and acupuncture, have yet to be studied.

It is also important to explain to patients that the typical course of small fiber neuropathy is relatively benign, as many patients worry about developing weakness and eventually not being able to walk. These concerns and fears can aggravate pain and depression, which can make treatment difficult.

WHAT IS THE PROGNOSIS OF SMALL FIBER NEUROPATHY?

Most patients with small fiber neuropathy experience a slowly progressive course, with symptoms and signs spreading proximally over time.

In one study, only 13% of 124 patients with small fiber neuropathy showed evidence of large-fiber involvement over a 2-year period. 21 None went on to develop Charcot joints, foot ulcers, weakness, or sensory ataxia, as is often seen in patients with long-standing or severe large fiber neuropathy. Neuropathic pain worsened in 30% and resolved spontaneously in 11%.21

Most patients with small fiber neuropathy require chronic pain management. Again, treatment of the underlying cause is important and can improve the prognosis.

We believe that the overall progression of small fiber neuropathy is slow. A longitudinal study with a follow-up longer than 2 years would be useful to confirm this.

TAKE-HOME POINTS

As the population continues to age and as more patients develop diabetes and the metabolic syndrome, the prevalence of small fiber neuropathy will rise. Patients who present to their primary care physicians with painful, burning feet require a thorough diagnostic evaluation, which may include referral for specialized neurodiagnostic testing. Aggressive cause-specific treatment, lifestyle modification, and pain control are key elements of a team approach to managing small fiber neuropathy.

http://www.ccjm.org/index.php?id=107953&tx_ttnews[tt_news]=362009&cHash=2e6a5924d840eef79f213dd53bb68ccf

SIGNATURE OF AGING IN BRAIN SCIENTISTS SUGGEST THAT THE BRAINS IMMUNOLOGICAL AGE IS WHAT COUNTS

How the brain ages is still largely an open question -- in part because this organ is mostly insulated from direct contact with other systems in the body, including the blood and immune systems. In research that was recently published in Science, Weizmann Institute researchers Prof. Michal Schwartz of the Neurobiology Department and Dr. Ido Amit of Immunology Department found evidence of a unique "signature" that may be the "missing link" between cognitive decline and aging. The scientists believe that this discovery may lead, in the future, to treatments that can slow or reverse cognitive decline in older people

Until a decade ago, scientific dogma held that the blood-brain barrier prevents the blood-borne immune cells from attacking and destroying brain tissue. Yet in a long series of studies, Schwartz's group had shown that the immune system actually plays an important role both in healing the brain after injury and in maintaining the brain's normal functioning. They have found that this brain-immune interaction occurs across a barrier that is actually a unique interface within the brain's territory.

This interface, known as the choroid plexus, is found in each of the brain's four ventricles, and it separates the blood from the cerebrospinal fluid. Schwartz: "The choroid plexus acts as a 'remote control' for the immune system to affect brain activity. Biochemical 'danger' signals released from the brain are sensed through this interface; in turn, blood-borne immune cells assist by communicating with the choroid plexus.This cross-talk is important for preserving cognitive abilities and promoting the generation of new brain cells."

This finding led Schwartz and her group to suggest that cognitive decline over the years may be connected not only to one's "chronological age" but also to one's "immunological age," that is, changes in immune function over time might contribute to changes in brain function -- not necessarily in step with the count of one's years.

To test this theory, Schwartz and research students Kuti Baruch and Aleksandra Deczkowska teamed up with Amit and his research group in the Immunology Department. The researchers used next-generation sequencing technology to map changes in gene expression in 11 different organs, including the choroid plexus, in both young and aged mice, to identify and compare pathways involved in the aging process.

That is how they identified a strikingly unique "signature of aging" that exists solely in the choroid plexus -- not in the other organs. They discovered that one of the main elements of this signature was interferon beta -- a protein that the body normally produces to fight viral infection. This protein appears to have a negative effect on the brain: When the researchers injected an antibody that blocks interferon beta activity into the cerebrospinal fluid of the older mice, their cognitive abilities were restored, as was their ability to form new brain cells. The scientists were also able to identify this unique signature in elderly human brains. The scientists hope that this finding may, in the future, help prevent or reverse cognitive decline in old age, by finding ways to rejuvenate the "immunological age" of the brain.