Sensory and Autonomic Small Fiber Neuropathy

Background

Small fiber neuropathy (SFN) results from damage to the small, unmyelinated nerve fibers that convey pain and temperature sensations from receptors in the skin, and that mediate autonomic functions (Stewart et al, 1992; Novak et al, 2001). Patients usually present with painful sensations and hypersensitivity, but can also exhibit a lack of sensitivity to pain, or autonomic dysregulation. The neurological examination and EMG and nerve conduction studies that measure the large fibers are usually normal (Lacomis, 2002; Herrmann et al, 2004), so that the diagnosis is frequently made by punch skin biopsy demonstrating a reduction in the Intraepidermal nerve fiber density (IENFD).

Cinical presentation and differential diagnosis

Symptoms of small fiber neuropathy include numbness, and annoying or painful sensations, called paresthesias, that vary in severity, and described as aching, tingling, stinging, stabbing, burning, freezing, itching, squeezing, or electric shock-like. . Innocuous stimuli can provoke unpleasant sensations, called dysesthesias; Clothes can feel like sandpaper against the skin, the hands may become hypersensitive to touch, or pressure from shoes or socks can causes severe pain in the feet. These sensations can occur anywhere in the body, including the feet, arms, legs, torso, scalp, face, or even the mouth (Walk et al, 2003; Lauria et al, 2005a)

Loss of small fibers may also cause an inability to feel pain, as when stepping on a sharp nail or suffering a burn from a hot stove without being aware of the injury. Autonomic symptoms include abnormal sweating or temperature regulation, lightheadedness or fainting from low blood pressure, postural hypotension or tachycardia, gastroparesis with bloating and constipation or diarrhea, incomplete bladder emptying or difficulty initiating a stream, sexual dysfunction from hypo or hypersensitivity, dryness and thinning of the skin, hair loss in the legs, and ridged or brittle nails ( Low et al, 2003; Freeman 2007; Waldinger et al, 2009).

The differential diagnosis includes various pain syndromes such as Reflex Sympathetic Dystrophy, Regional Pain Syndrome (RSD) (Oaklander et al, 2006), polymyalgia, polyarthralgia or fibromyalgia (Caro et al, 2008) , Erythromelalgia (Patricoff et al, 2007; Kumar and Davis, 2006), Raynaud syndrome (Manek et al, 2009) restless leg syndrome ( Polysdefkir et al, 2005; Gemignai et al, 2009), neuromas, fasciitis, or somatic pains resulting from anxiety or depression. Patients may also be diagnosed as having nonspecific neuropathic pain, although that requires demonstration of the lesion or disease responsible for the symptoms (Treede et al, 2008). Autonomic symptoms can be misdiagnosed as being due to cardiac arrhythmia, colitis or irritable bowel syndrome, chronic bladder infections, skin allergies, or psychological stress.

How is small fiber neuropathy diagnosed; technical performance and diagnostic accuracy

Small fiber neuropathy is most easily and reliably diagnosed by skin biopsy, with demonstration of a reduction in the intraepidermal nerve fiber density (IENFD) (Periquet et al, 1999; Ebenezer et al, 2007). Specimens are routinely obtained using a 3 mm punch biopsy at standard sites at the lateral calf and thigh, and occasionally at the dorsum of the foot. The small nerve fibers are visualized by immunocytochemistry, using an antibody to an axonal protein, PGP-9.5. The number and structural integrity of the small fibers is then evaluated by a pathologist. Patients with small fiber neuropathy exhibit a reduction is the IENFD, or structural abnormalities that are indicative of neuropathy. Procedures are done according to international standards and guidelines (Lauriae et al, 2005b). The biopsy is done under local anaesthesia, and the site is covered by a band aid. The procedure is generally well tolerated and causes little discomfort.

The sensitivity of skin biopsy in diagnosing small fiber neuropathy has been reported to be 88.4%, in comparison to 54% for the clinical examination, and 49% for quantitative sensory testing (QST). The specificity of the test is 95 to 97% (Lauria and Devigli, 2007; Devigli et al, 2008). The IENFD test is also positive in patients with both small and large fiber neuropathy but negative in patients with purely large fiber neuropathy or in patients with other nonperipheral neuropathic disorders (Hlubocky et al, 2010).

In length dependent neuropathies, such as toxic neuropathies, the IENFD is more severely reduced distally at the foot or calf, but in sensory neuronopathies or multifocal neuropathies, it may be preferentially reduced proximally at the thigh (Gorson et al, 2008). In patients with sensory radiculopathy, where the sensory nerve root is affected, the IENFD is normal in the leg. In compressive mononeuropathies there may be a reduction of the IENFD in the distribution of the compressed nerve in comparison to the normal side.

Clinical Utility; underlying causes and treatment

Determination of the IENFD is a highly sensitive and specific test for SFN. Making the diagnosis of SFN enables the physician to explain the symptoms, direct further testing for possible underlying causes, and institute appropriate treatment. Studies show that providing an explanation of their symptoms and reassuring the patients that their evaluation is complete, is as important to patients as treatment of their pain (Petrie et al, 2005; McCraken et al, 2002). Understanding the cause of their symptoms helps the patient accept their illness, cope with their symptoms, and be more receptive to their physician’s recommendations.

There are many causes of SFN, and in some cases, the neuropathy is the first manifestation of an underlying systemic disease. The most common cause is diabetes mellitus or glucose intolerance (Polydefkis and McArthur, 2005). Other causes include hypothyroidism (Devigli et al, 2008; Penza et al, 2009), Sjogren’s syndrome (Chai et al, 2005), lupus (Omdal et al, 2002; Goransson et al, 2006), scleroderma (Poncelet and Connolly, 2003), mixed connective tissue disease (Olney, 1998), sarcoid (Hoitsman et al, 2005), vasculitis (Lacomis et al, 1997; Zafrir et al, 2004; Lee et al, 2005), inflammatory bowel disease (Gondim et al, 2005), psoriasis (Narayanaswami et al, 2007), unspecified inflammatory conditions (Dabby et al, 2006), Guillain-Barre syndrome (Seneviratne and Gunasekera, 2002), nutritional deficiencies, celiac disease (Brannagan et al, 2005), Lyme disease, HIV-1 infection (polydifkis et al, 2002), Hepatitis C infection (Tembl et al 1999), Fabry disease (Dutsch et al, 2003; Torvin Moller et al, 2009), amyloid, alcohol abuse (Zambelis et al, 2005), neurotoxic drugs including statins (Lo et al, 2003), toxins (Kuo et al, 2005), or vaccinations (Souayah et al, 2009). In cases where no cause can be found, the neuropathy is called idiopathic. In some cases, progressive neuropathies that affect both the small and large nerve fibers can present as small fiber neuropathies before they can be detected by electrodiagnostic studies. A listing of the known causes of small fiber neuropathy, and the corresponding diagnostic tests, is provided in Table I.

In approximately 40% of patients, no cause for the neuropathy could be found on initial evaluation, but in a 2 year follow-up study, a potential cause was identified in 25% of these patients. Thirteen percent of patients went on to develop a large fiber neuropathy (Devigili et al, 2008). Progression of the underlying neuropathy can be evaluated by repeating the biopsy and monitoring the IENFD.

Therapy in patients with small fiber neuropathy is directed at both the underlying cause, if one can be identified, and at ameliorating the symptoms. Some acute onset, otherwise idiopathic small fiber neuropathies respond to prednisone (Dabby et al, 2006). Painful paresthesias can be treated using oral medications for neuropathic pain such as Lyrica or Cymbalta, or with topical medications such as Lidoderm.

Table I : Causes and evaluation of Small Fiber Neuropathy.

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