Small fiber peripheral neuropathy is a type of

peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

that occurs from damage to the small

unmyelinated Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to Insulator (electricity), insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The my ...

and myelinated peripheral nerve fibers. These fibers, categorized as

C fibers Group C nerve fibers are one of three classes of nerve fiber in the central nervous system (CNS) and peripheral nervous system (PNS). The Group C fibers are unmyelinated and have a small diameter and low conduction velocity, whereas Groups A a ...

and small Aδ fibers, are present in

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

peripheral nerves The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain a ...

, and organs.Overview of Small Fiber Neuropathy
Therapath Neuropathology. The role of these nerves is to innervate some skin sensations (''somatic afferents'') and help control autonomic function (''autonomic fibers''). It is estimated that 15–20 million people in the United States have some form of peripheral neuropathy.

Signs and symptoms

Small fiber neuropathy is a condition characterized by severe

pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...

. Symptoms typically begin in the feet or hands but can start in other parts of the body. Some people initially experience a more generalized, whole-body pain. The pain is often described as stabbing or burning, or abnormal skin sensations such as tingling or

itchiness An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

. In some individuals, the pain is more severe during times of rest or at night. The signs and symptoms of small fiber neuropathy can occur at any point in life depending on the underlying cause. Individuals with small fiber neuropathy often cannot feel pain that is concentrated in a very small area, such as the prick of a pin. However, they have an increased sensitivity to pain in general (

hyperalgesia Hyperalgesia ( or ; ''hyper'' from Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and ...

) and experience pain from stimulation that typically does not cause pain (

allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, sunburn can cause temporary allodynia, so that usually painless stimuli, such as wearing clothing or running cold or warm water over ...

). People affected with this condition may also have a reduced ability to differentiate between hot and cold.

Sudomotor Sudomotor function refers to the autonomic nervous system control of sweat gland activity in response to various environmental and individual factors. Sweat production is a vital thermoregulatory mechanism used by the body to prevent heat-related ...

dysfunction is one of the most common and earliest

neurophysiological Neurophysiology is a branch of physiology and neuroscience concerned with the functions of the nervous system and their mechanisms. The term ''neurophysiology'' originates from the Greek word ''νεῦρον'' ("nerve") and ''physiology'' (whic ...

manifestations of small fiber neuropathies. In some instances, the small fibers of the

autonomic nervous system The autonomic nervous system (ANS), sometimes called the visceral nervous system and formerly the vegetative nervous system, is a division of the nervous system that operates viscera, internal organs, smooth muscle and glands. The autonomic nervo ...

can be affected, leading to urinary or bowel problems, episodes of rapid heartbeat (

palpitations Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...

dry eye Dry eye syndrome, also known as keratoconjunctivitis sicca, is the condition of having dry eyes. Symptoms include dryness in the eye, irritation, redness, discharge, blurred vision, and easily fatigued eyes. Symptoms range from mild and occas ...

s or

mouth A mouth also referred to as the oral is the body orifice through which many animals ingest food and animal communication#Auditory, vocalize. The body cavity immediately behind the mouth opening, known as the oral cavity (or in Latin), is also t ...

, or

abnormal sweating Hyperhidrosis is a medical condition in which a person exhibits excessive sweating, more than is required for the regulation of body temperature. Although it is primarily a physical burden, hyperhidrosis can deteriorate the quality of life of the ...

. They can also experience a sharp drop in

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

upon standing (

orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...

), which can cause

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

blurred vision Blurred vision is an ocular symptom where vision becomes less precise and there is added difficulty to resolve fine details. Temporary blurred vision may involve dry eyes, eye infections, alcohol poisoning, hypoglycemia, or low blood pressur ...

, or

fainting Syncope , commonly known as fainting or passing out, is a loss of consciousness and muscle strength characterized by a fast onset, short duration, and spontaneous recovery. It is caused by a decrease in blood flow to the brain, typically from ...

. Small fiber neuropathy is considered a form of peripheral neuropathy because it affects the

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...

, which connects the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

to muscles and to cells that detect sensations such as touch, smell, and pain. Insensitivity to pain can be particularly problematic. One may be bleeding or have a skin injury without even knowing it.

Topographic pattern

Like many polyneuropathies, the symptoms are typically length-dependent, starting in the longer nerves and progressively attacking shorter nerves. This means that symptoms often start in the hands and feet before progressing upwards, and that symptoms are usually more severe in the extremities. Some patients have a widespread, non-length dependent, or "patchy", presentation which is sporadic and can affect many nerves. Patients with

Fabry disease Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, brain, and skin. Fabry disease is one of a group of conditions known as lysosomal storage dis ...

have isolated small fiber engagement, and can have a more widespread small fiber disruption.

Causes

Mutations in the SCN9A or SCN10A gene can cause small fiber neuropathy. These genes provide instructions for making pieces (the alpha subunits) of sodium channels. The SCN9A gene instructs the production of the alpha subunit for the NaV1.7 sodium channel and the SCN10A gene instructs the production of the alpha subunit for the NaV1.8 sodium channel. Sodium channels transport positively charged sodium atoms (sodium ions) into cells and play a key role in a cell's ability to generate and transmit electrical signals. The NaV1.7 and NaV1.8 sodium channels are found in nerve cells called nociceptors, that transmit pain signals to the spinal cord and brain. The SCN9A gene mutations which cause small fiber neuropathy result in NaV1.7 sodium channels that do not close completely when the channel is turned off. Many SCN10A gene mutations result in NaV1.8 sodium channels that open more easily than usual. The altered channels allow sodium ions to flow abnormally into nociceptors. This increase in sodium ions enhances transmission of pain signals, causing individuals to be more sensitive to stimulation which might otherwise not cause pain (

Allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, sunburn can cause temporary allodynia, so that usually painless stimuli, such as wearing clothing or running cold or warm water over ...

). In this condition, the small fibers that extend from the nociceptors through which pain signals are transmitted (axons) degenerate over time. The cause of this degeneration is unknown, but likely accounts for some of the signs and symptoms of the disorder, such as the loss of temperature differentiation and pin-prick sensation. The combination of increased pain signaling, and degeneration of pain-transmitting fibers, leads to a variable condition with signs and symptoms that can both vary and change over time. SCN9A gene mutations have been found in approximately 30 percent of individuals with small fiber neuropathy; SCN10A gene mutations are responsible for about 5 percent of cases. In some instances, other health conditions cause this disorder. Diabetes mellitus and impaired glucose tolerance are the most common diseases that lead to this disorder, with 6 to 50 percent of diabetics or pre-diabetics developing small fiber neuropathy. Other causes of this condition include a metabolic disorder called Fabry disease, immune disorders such as celiac disease or Sjogren syndrome, an inflammatory condition called sarcoidosis, and human immunodeficiency virus (HIV) infection. In diabetics who rapidly reduce their HbA1c value by over 3 percentage points within a short time frame (3-6 months), a temporary form of SFN often results. Recently several studies have suggested an association between autonomic small fiber neuropathy and

postural orthostatic tachycardia syndrome Postural orthostatic tachycardia syndrome (POTS) is a condition characterized by an abnormally large increase in heart rate upon sitting up or standing. POTS is a disorder of the autonomic nervous system that can lead to a variety of symptoms, ...

.Other notable studies have shown a link between

erythromelalgia Erythromelalgia, or Mitchell's disease (after Silas Weir Mitchell (physician), Silas Weir Mitchell), is a rare vascular peripheral pain disorder in which blood vessels, usually in the Human leg, lower extremities or hands, are episodically blocke ...

fibromyalgia Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...

Ehlers–Danlos Syndrome Ehlers–Danlos syndromes (EDS) is a group of 14 genetic connective-tissue disorders. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Co ...

and

long covid Long may refer to: Measurement * Long, characteristic of something of great duration * Long, characteristic of something of great length * Longitude (abbreviation: long.), a geographic coordinate * Longa (music), note value in early music mens ...

Diagnosis

The diagnosis of small fiber neuropathy often requires ancillary testing.

Nerve conduction studies A nerve is an enclosed, cable-like bundle of nerve fibers (called axons). Nerves have historically been considered the basic units of the peripheral nervous system. A nerve provides a common pathway for the electrochemical nerve impulses called ...

and

electromyography Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph to produce a record called an electromyogram. An electromyo ...

are commonly used to evaluate large myelinated sensory and motor nerve fibers, but are ineffective in diagnosing small fiber neuropathies.

Quantitative sensory testing Quantitative sensory testing (QST) is a panel of diagnostic tests used to assess somatosensory function, in the context of research and as a supplemental tool in the diagnosis of somatosensory disorders, including pain insensitivity, painless and ...

(QST) assesses small fiber function by measuring temperature and vibratory sensation. Abnormal QST results can be attributed to dysfunction in the central nervous system. Furthermore, QST is limited by a patient's subjective experience of pain sensation.

Electrochemical skin conductance Electrochemical skin conductance (ESC) is an objective, non-invasive and quantitative electrophysiological measure of skin conductance through the application of a pulsating direct current on the skin. It is based on reverse iontophoresis and ...

and quantitative

sudomotor Sudomotor function refers to the autonomic nervous system control of sweat gland activity in response to various environmental and individual factors. Sweat production is a vital thermoregulatory mechanism used by the body to prevent heat-related ...

axon reflex testing (QSART) measures sweating response at local body sites to evaluate the small nerve fibers that innervate

sweat gland Sweat glands, also known as sudoriferous or sudoriparous glands, , are small tubular structures of the skin that produce sweat. Sweat glands are a type of exocrine gland, which are glands that produce and secrete substances onto an epithelial s ...

has been evaluated for both early diagnosis of small fiber neuropathy and follow-up of treatment efficacy.

Skin biopsy

A skin biopsy for the measurement of epidermal nerve fiber density is an increasingly common technique for the diagnosis of small fiber peripheral neuropathy. Physicians can biopsy the skin with a 3-mm circular punch tool and immediately fix the specimen in 2% paraformaldehyde lysine-periodate or Zamboni's fixative. Specimens are sent to a specialized laboratory for processing and analysis where the small nerve fibers are quantified by a

neuropathologist Neuropathology is the study of disease of nervous system tissue, usually in the form of either small surgical biopsies or whole-body autopsies. Neuropathologists usually work in a department of anatomic pathology, but work closely with the cli ...

to obtain a diagnostic result. This skin punch biopsy measurement technique is called intraepidermal nerve fiber density (IENFD). The following table describes the IENFD values in males and females of a 3 mm biopsy 10 cm above the lateral malleolus (above ankle outer side of leg). Any value measured below the 0.05 Quantile IENFD values per age span, is considered a reliable positive diagnosis for small fiber peripheral neuropathy.

Treatment

Treatment is based on the underlying cause, if any. Where the likely underlying condition is known, treatment of this condition is indicated to reduce progression of the disease and symptoms. For cases without those conditions, there is only symptomatic treatment.

Epidemiology

The estimated prevalence of small fiber neuropathy is 52.95 per 100,000. The incidence it thought to be 11.73 per 100,000. This represents an estimated minimum incidence and prevalence as small fiber neuropathies are generally under diagnosed.

Comorbidities

A 2018 study (n=921) found no associated condition in 53% of the patients. In the remaining patients conditions more prevalent than reported literature findings were

autoimmune diseases An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that ...

, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies.

References

External links

Peripheral Neuropathy Fact Sheet – NINDS

{{DEFAULTSORT:Small Fiber Peripheral Neuropathy Peripheral nervous system disorders