Today's post from prohealth.com (see link below) asks the question whether both small fibre and large fibre neuropathy are present in Fibromyalgia. Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues and many patients have also reported the sort of widespread neuropathic symptoms readers of this blog are familiar with. However, experts have long tried to keep the two conditions apart, having found no proof that they can be concurrent. Then it was concluded that small fibre neuropathy may well be a symptom of fibromyalgia and now, they've added large fibre neuropathy to the mix as well. The consistent aching associated with fibromyalgia is thought to be caused by the way the brain handles pain but that is very close to the root cause of neuropathic symptoms too. Fibromyalgia patients also typically suffer symptoms above the waist and neuropathy sufferers below the waist but when the patient has both sets of symptoms, the root cause must be pretty much the same and the consequences for the patient are miserable to say the least. At least they are now thinking that both conditions are neurological and therefore symptomatic of nerve damage somewhere in the nervous system. Equally importantly it has now been found that both show demyelinating damage (damage to the protective lining of the nerves) leading to undeniable connections between both diseases.
Are Both Small AND Large Fiber Neuropathy Present in Fibromyalgia? By Cort Johnson • www.ProHealth.com • June 11, 2014 Reprinted with the kind permission of Cort Johnson and Health Rising.
We report here a surprisingly high prevalence of clinical and electrodiagnostic (EDX) abnormalities implying a demyelinating polyneuropathy, suggestive of chronic inflammatory demyelinating polyneuropathy (CIDP), in FMS. Caro et. al 2008
With three studies finding evidence of small fiber neuropathy in significant numbers of people with Fibromyalgia, the skin has become of increasing interest. (Small fiber neuropathy refers to damage to the small nerve fibers in the skin. Skin biopsies are used to determine if SFN is present).
Caro was the latest researcher to find evidence of nerve problems in FM and it turns out, he was the first as well.
From Immune Problems in the Skin
Science often moves slowly and it has in this case as well. Thirty years ago in 1984 Caro found evidence of an autoimmune process – IgG antibodies in the dermal-epidermal junction – in the skin of people with FM. Two years later he validated his findings in a blinded study. That same year Dineman found increased prevalence of Raynaud’s phenomenom, dry mouth, low complement, ANA and IgG antibodies in the skin as well. Something unusual appeared to be occurring in the skin of people with FM but progress defining it was slow. To the Nerves….
In 1988, Sim’s study “Symptoms mimicking neurological disorders in Fibromyalgia” put a focus on the nerves. Caro reported on nerve conduction tests in FM in 2005 and then in 2008 provided the first evidence of peripheral neuropathy.
Small fiber neuropathy is kind of the rage in FM right now, but Caro’s 2008 study suggested that larger nerve neuropathy (demyelination) was also present. In this article, we take a look at that 2008 study containing 58 Fibromyalgia patients. The Study
X. J. Caro, E. F. Winter and A. J. Dumas. A subset of fibromyalgia patients have findings suggestive of chronic inflammatory demyelinating polyneuropathy and appear to respond to IVIg. Rheumatology 2008; 47;208–211
A ‘demyelinating polyneuropathy’ was reported present when EMG and nerve conduction studies revealed nerve conduction speeds two (and often three) standard deviations below normal in two or more nerves. (Nerve signals travel more slowly in demyelinated nerves.). Caro, et. al followed standards proposed by the Inflammatory Neuropathy Cause and Treatment (INCAT) group for demyelinating polyneuropathy. The Findings
With 76% of patients reporting paresthesias (tingling), 88% percent reporting hypaesthesia (loss of sensation – with increased loss in the lower extremities) and 90% reporting weakness, the symptom presentation in FM suggested nerve damage was present. (The ‘stocking distribution’ of nerve symptoms which involves worsening symptoms the further down the limbs one goes is highly emblematic of peripheral nerve disorders.)
Greatly increased rates of nerve symptoms as well as muscle weakness in people with FM (90%) compared to people with rheumatoid arthritis (13%) suggested FM was a far different type of disease than it’s rheumatological counterpart. (Martinez-Lavin found that 95% of FM patients as opposed to 30% of RA patients reported sensory symptoms as well).
Nerve conduction studies revealed a polyneuropathy was present in almost 50% of their FM patients. Seventy percent of the FM patients with polyneuropathy had evidence of demyelination. (Note that demyelination refers to large nerve fibers; small nerve fibers are not myelinated.) Sural nerve biopsies suggested myelin injury (segmental de and re-myelination and/or myelinated nerve fiber dropout) had occurred in the majority of those tested. (They revealed no vasculitis or amyloidosis and provided little evidence of what was causing the demyelination.) Chronic Inflammatory Demyelinating Polyneuropathy
Comparing FM to chronic inflammatory demyelinating polyneuropathy (CIDP), Caro put FM squarely in the realm of an immune mediated neurological disorder.
CIDP is an inflammatory disorder affecting the peripheral (as opposed to the central) nervous system. Considered a chronic form of Guillain-Barre disease, CIDP is characterized by the loss of the myelin sheath in the larger nerves in the body.
The symptom presentation is quite heterogeneous and includes weakness, fatigue, numbness, tingling, pain, difficulty in walking, burning pain in the extremities, and sudden onset back or neck pain radiating down to the arms and /or legs. Loss of deep tendon reflexes (rarely increased or normal), loss of muscle mass and fasciculations (twitching) may be present. Autonomic dysfunction can cause problems standing (orthostatic intolerance, bladder, bowel and/or cardiac problems).
Left untreated about 30% of CIPD patients will end up in a wheelchair.
FM patients were determined to have a CIDP-like illness when they exhibited lower extremity stocking hypaesthesia (loss of sensation), muscle weakness in at least two extremities, and evidence of a demyelinating polyneuropathy.
Following Latov’s proposal that “most acquired demyelinating neuropathies of otherwise unknown etiology are considered to be a form of CIDP’, Caro and Winter proposed that a significant subset of FM patients have a form of CIDP.
CIDP is another disorder with decided overlaps with ME/CFS and FM. As with ME/CFS, the lack of agreed upon clinical criteria have thwarted clinical trials. It’s widely acknowledged that the criteria often used to diagnose CIDP misses many leaving many untreated (including ME/CFS and FM patients????) Treatment Treatments include steroids, IVIG and immunosuppressive drugs such as Rituximab. Suspecting that an immune mediated nervous system disorder similar to CIPD was present Caro started IVIG treatment in 15 patients. A ‘large percentage’ reported significant improvements in pain, tender points and strength. Update
Since Caro’s 2008 report indicating reduced nerve conduction and possibly demyelination of the large nerves in the body, Nacir, et. al found widespread evidence of decreased nerve conduction velocity in the upper bodies of FM patients. Conclusion
This study and others suggest that some people with FM could have both small and large fiber neuropathies. If you have symptoms similar to those described above, nerve conduction tests (for the large fiber neuropathy) and skin biopsies (for the small) may be warranted.
Caro and others propose that the neuropathies in Fibromyalgia are probably immune mediated and propose immune therapies for them.
About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising. http://www.prohealth.com/library/showarticle.cfm?libid=18996
One of the most confusing aspects of neuropathy for the patient, is the number of names and titles which are given to its different forms. If you're researching information, you will often come across the term, 'small fibre neuropathy' or 'small fibre sensory neuropathy'. If you are diagnosed with SFN you may also hear the description 'Idiopathic neuropathy' which basically means, they can't find the physical evidence they need to back up your symptoms but idiopathic neuropathy is generally, essentially, also small fibre neuropathy and to make the waters even more muddy, you may also and in the same breath, be told you have symptoms of autonomic neuropathy (there are posts about autonomic neuropathy elsewhere in the blog - see list to the right).
The important thing is not to panic - each one of these titles may describe the same thing and apply to your form of neuropathy but the doctor may not have the time to explain the subtle differences in the course of a consultation. Time to do your own research then and therefore today's post tackles Small Fibre Neuropathy and comes from the always reliable Johns Hopkins Medicine site (see link below). Just to be clear, the letters SSFN they use, refer to the title, Small Fibre Sensory Neuropathy.
Small Fiber Sensory Neuropathy
Small fiber sensory neuropathy (SFSN) is a disorder in which only the small sensory cutaneous nerves are affected. The majority of patients experience sensory disturbances that start in the feet and progress upwards. These patients have what is called a length-dependent SFSN. This type of SFSN is often due to diabetes or impaired glucose metabolism (i.e. early or pre-diabetic state) and may progress to typical diabetic polyneuropathy. However, in a significant percentage of patients, no underlying etiology is found and the patients have idiopathic SFSN. A small percentage of patients with SFSN experience sub-acute onset sensory disturbances diffusely over the whole body, including the trunk and sometimes even the face. These patients have non-length-dependent SFSN and almost all cases are idiopathic.
Symptoms
The symptoms of small fiber sensory neuropathy are primarily sensory in nature and include unusual sensations such as pins-and-needles, pricks, tingling and numbness. Some patients may experience burning pain or coldness and electric shock-like brief painful sensations. Since SFSN usually does not involve large sensory fibers that convey balance information to the brain or the motor nerve fibers that control muscles, these patients do not have balance problems or muscle weakness. In most patients, these symptoms start in the feet and progress upwards. In advanced cases, it may involve the hands.
Diagnosis
Diagnosis of SFSN is based on history, clinical examination and supporting laboratory investigations. Electromyography and nerve conduction studies are done to eliminate involvement of motor and large sensory nerve fibers. Skin biopsies are used to confirm loss of cutaneous nerve innervation. Nerve and muscle biopsies are rarely needed.
Treatment
Treatment of SFSN depends on the underlying etiology. If it is due to diabetes or pre-diabetic state, then optimum diabetic control and exercise and weight loss to reduce insulin resistance are needed. Painful sensory paresthesias can be treated with anti-seizure medications such as gabapentin (Neurontin), pregabalin (Lyrica) and topiramate (Topamax), antidepressants such as amitriptyline (Elavil) and duloxetine (Cymbalta), or analgesics including opiate drugs. In severe painful conditions patients may be referred to the Blaustein Chronic Pain Clinic for a multidisciplinary approach to pain management.
While watching today's video (see link below) you may want to switch the sound off (depending on your musical tastes) but it's the message and visuals that count and I'm sure if you're having an off-day and feeling like you're the only one with nerve problems, this video will help. It's 8 minutes of protest against a largely uncaring world, when the power of positive thinking just doesn't seem to be working for you. Small Fiber Neuropathy SFN From A Patient's View Terra Tufts Published on 16 Jan 2015
SFN has many affects on our lives and the lives of our families and friends. For the first time Our Voices are heard through this powerful and video from SFN Warriors on Facebook who courageously volunteered their thoughts and pictures, without them this video could not have been made...I love you all Some Memes and the songs DO NOT belong to me but to the talents of those who sing them and write them
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
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.
