There are several possible conditions associated with small fiber sensory peripheral neuropathy, and mechanisms of disease are often incompletely understood. The disorder is localized to the somatic small nerve fibers (Aδ and C fibers), with or without clinical autonomic involvement. The mechanism of small fiber dysfunction probably varies depending on etiology. Vasomotor and sudomotor signs and symptoms can be attributed to neurogenic dysregulation of small blood vessel caliber and sweat gland function mediated by the autonomic system.
In diabetic neuropathy, arguably the most common cause of small fiber sensory peripheral neuropathy, the main hypotheses for neuropathic dysfunction are the polyol pathway, glycation, reactive oxygen species, and altered protein kinase C activity. Causes for diabetic small fiber sensory peripheral neuropathy pain are incompletely understood (Harati 2007). The relationship between impaired glucose tolerance/prediabetes and small fiber sensory peripheral neuropathy is less firmly defined and remains somewhat controversial, although the association is established (Smith and Singleton 2008).
Toxic small fiber sensory peripheral neuropathy is a group of disorders that historically include alcohol as an important etiologic factor. The role of alcohol has been questioned, and it is debatable whether it is frequently the primary cause of small fiber sensory peripheral neuropathy, or whether nutritional deficiencies (especially vitamins B1, B6, or B12) are more important contributing factors in alcoholics. Alcohol small fiber sensory peripheral neuropathy may be differentiated from thiamine deficiency large fiber peripheral neuropathy (Koike et al 2003). A rat model suggests that alcohol consumption may enhance HIV/ HAART-induced neuropathic pain via possible mitochondrial dysfunction (Ferrari and Levine 2010).
Certain chemotherapeutic agents can cause iatrogenic toxic neuropathies with sensory involvement, including vinca alkaloids (vincristine), paclitaxel and docetaxel, cisplatin, carboplatin, and oxaliplatin. Although thalidomide and bortezomib cause small fiber neuropathy, overt mixed or large fiber peripheral neuropathy is more common. Antibiotics associated with toxic small fiber sensory peripheral neuropathy include metronidazole and linezolid. There is controversy regarding the importance of statin neuropathy. Many of these issues are explored in other clinical summaries in MedLink Neurology. Experimental evidence shows that pyridoxine (vitamin B6) toxicity may cause small fiber sensory peripheral neuropathy before large fiber peripheral neuropathy in a dose-dependent fashion, although there is also evidence for this toxicity to cause sensory ganglionopathy, axonopathy, or a combination of both.
Amyloid protein deposits in multiple body tissues are features of acquired primary light-chain amyloidosis and unrelated hereditary familial amyloid polyneuropathy. Amyloidosis can cause severe small fiber sensory peripheral neuropathy and autonomic involvement. Some of the medications for the treatment of acquired primary light-chain amyloidosis may also cause or worsen small fiber sensory peripheral neuropathy due to their toxic effects. Most patients with familial amyloid polyneuropathy have transthyretin gene mutations, and possible neuropathic mechanisms include ischemia, compression, and metabolic derangement.
Sarcoidosis is an inflammatory multiorgan disease that commonly causes lung disease and hilar adenopathy. The pathognomonic noncaseating granulomas can affect the peripheral nervous system and cause small fiber sensory peripheral neuropathy with or without autonomic involvement (Bakkers et al 2009). Small fiber sensory peripheral neuropathy in systemic lupus erythematosus can show reduced intraepidermal nerve fiber density (Goransson et al 2006).
Isolated small fiber sensory peripheral neuropathy without large fiber peripheral neuropathy is common in Sjogren syndrome (Lopate et al 2006). Patients with dryness of the mouth or eyes for greater than 3 months, especially women, should be evaluated for this syndrome, although abnormal lip biopsies suggestive of Sjogren syndrome have been described even in the absence of sicca symptoms (Gorson and Ropper 2003). There is debate on whether Sjogren syndrome causes a sensory ganglionopathy rather than small fiber sensory peripheral neuropathy, although it is possible that both could be in the spectrum of the same disorder.
Small fiber sensory peripheral neuropathy can be associated with ulcerative colitis and Crohn disease. A retrospective analysis showed a frequency of small fiber sensory peripheral neuropathy in 18% of patients (Gondim et al 2005), and a consecutive series of 102 patients showed a frequency of approximately 9%. Subclinical autonomic dysfunction may occur early in patients with Crohn disease.
Celiac disease may cause small fiber sensory peripheral neuropathy or sensory ganglionopathy, as evidenced by reduced intraepidermal nerve fiber density with frequent facial involvement and, at times, non-length-dependent patterns (Brannagan et al 2005). There is some debate on whether the association is due to autoimmune phenomena or due to nutritional deficiency from gastrointestinal malabsorption. Responsiveness to IVIG therapy favors an immune pathogenesis (Souayah et al 2008; Parambil et al 2011).
Morbid obesity may be associated with small fiber sensory peripheral neuropathy, although its relation to diabetes and related disorders, such as hyperlipidemia, is not well defined. In a study in which 58 asymptomatic, morbidly obese individuals were evaluated for small fiber sensory peripheral neuropathy, obesity was claimed to be associated with small fiber sensory peripheral neuropathy independently of diabetes or prediabetes, but remarkably, 70% of the obese subjects had hyperglycemia (Herman et al 2007).
Small fiber sensory peripheral neuropathy has been described after vaccination and after viral infections, but certainty of a causal relationship is elusive.
There may be an association between monoclonal gammopathy of undetermined significance (MGUS) and small fiber sensory peripheral neuropathy, but whether it is the cause of small fiber sensory peripheral neuropathy via a primary immune mechanism in an individual, an epiphenomenon of autoimmunity, or just a casual association is uncertain, especially in IgA and IgG forms. Although not typical, anti-MAG antibodies have been reported to cause a predominantly sensory painful small fiber neuropathy (Luigetti et al 2010).
Other conditions that may be associated with small fiber sensory peripheral neuropathy with less well-defined pathophysiology include hypothyroidism and nutritional deficiencies.
Hereditary small fiber sensory peripheral neuropathy is less common than acquired small fiber sensory peripheral neuropathy. Some hereditary disorders have frequent small fiber sensory peripheral neuropathy. Fabry disease, an X-linked lysosomal storage disease with frequent kidney, cardiac, and dermatological involvement due to the accumulation of glycolipids, has frequent small fiber sensory peripheral neuropathy in affected males and in some female carriers. Mechanisms for small fiber sensory peripheral neuropathy are not fully understood in the rare congenital insensitivity to pain with anhidrosis and mental retardation (HSAN4) and congenital insensitivity to pain with mild or minimal anhidrosis and without mental retardation (HSAN5). Most other HSAN types have prominent large nerve fiber involvement characterized by reduced or absent muscle stretch reflexes. A comprehensive review of HSAN and other genetic neuropathies is available (Reilly and Shy 2009), and they are also briefly reviewed in other clinical summaries in MedLink Neurology. In patients with autosomal recessive primary erythromelalgia from heterozygous SCN9A gene mutations, sodium channel dysfunction may mediate extreme neuropathic pain. Homozygous patients may have congenital indifference to pain.
In secondary erythromelalgia from essential thrombocythemia, platelet-derived activation and thrombosis may play an important role (Michiels et al 2003).