Small Fibre Neuropathy and Painful Channelopathy
Small Fibre Neuropathy and Painful Channelopathy
The exact incidence and prevalence of SFN is unknown. There have been no satisfactory studies to assess the epidemiology of SFN, because until recently, there was no generally accepted definition for SFN and no standardised classification. There are a few natural history studies, and the general consensus is that in most patients the disease does not progress or progresses very slowly.
There are many potential causes of SFN (Table 1), the commonest being diabetes mellitus, responsible for approximately a third of all cases of SFN. In diabetes mellitus, a complex interplay of metabolic factors, ischaemia and impaired recovery predispose peripheral neurones, glial cells and vascular endothelial cells to damage that ultimately leads to neuronal injury and peripheral neuropathy.13–, Interestingly, in those patients with SFN whom a diagnosis is not immediately apparent, a significant number have impaired glucose tolerance both at time of presentation or at subsequent follow-up, usually after about 1 year. However, the diagnosis of impaired glucose tolerance may merely reflect the underlying high incidence of impaired glucose tolerance in the population studied rather than a causal link. HIV and the continued use of neurotoxic antiretrovirals are probably the major causes of SFN in sub-Saharan Africa. HIV causes peripheral axonal injury through immune activation that creates a toxic microenvironment for peripheral nerves. Anti-retrovirals, specifically the nucleoside reverse transcriptase inhibitors such as didanosine and stavudine, cause axonal injury through mitochondrial toxicity. SFN occurs in several autoimmune and inflammatory diseases (Table 1). The exact pathophysiological mechanisms are unknown, and the most likely candidate mechanisms include autoantibodies targeted against neuronal proteins (the identity of which is not yet known), elevated pro-inflammatory cytokines in the skin and dermal vasculitis. Amyloid neuropathy (either hereditary or acquired) can present as a pure SFN and usually progresses to involve the large neuronal fibres and major organs, such as the kidneys and heart.
SFN features in a number of rare genetic conditions (Table 1). A recent study described variants of the SCN9A gene, which encodes the Nav1.7 sodium channel in a third of patients labelled as having idiopathic SFN. This voltage-gated ion channel is selectively expressed in sensory and autonomic neurones. Nav1.7 variants associated with SFN cause enhanced excitability of sensory neurones and eventual degeneration of small fibres, which is probably mediated through increased sodium load and reversal of sodium–calcium exchange. Nav1.8 is a related voltage-gated sodium channel selectively expressed in nociceptors. Variants in the SCN10A gene, which encodes the Nav1.8 sodium channel, enhance the excitability of dorsal root ganglion cells and are also associated with SFN. The penetrance of these variants in voltage-gated sodium channels has not yet been fully elucidated and in some cases these variants may be important risk factors, rather than being fully penetrant in causing SFN. This currently makes genetic counselling complex. Idiopathic SFN has historically accounted for 23–94% of cases. In our experience, approximately 50% of cases of SFN are idiopathic. However, this is highly dependent on referral patterns, and the number of idiopathic cases will reduce as genetic causes are identified.
Aetiology, Epidemiology and Pathogenesis
The exact incidence and prevalence of SFN is unknown. There have been no satisfactory studies to assess the epidemiology of SFN, because until recently, there was no generally accepted definition for SFN and no standardised classification. There are a few natural history studies, and the general consensus is that in most patients the disease does not progress or progresses very slowly.
There are many potential causes of SFN (Table 1), the commonest being diabetes mellitus, responsible for approximately a third of all cases of SFN. In diabetes mellitus, a complex interplay of metabolic factors, ischaemia and impaired recovery predispose peripheral neurones, glial cells and vascular endothelial cells to damage that ultimately leads to neuronal injury and peripheral neuropathy.13–, Interestingly, in those patients with SFN whom a diagnosis is not immediately apparent, a significant number have impaired glucose tolerance both at time of presentation or at subsequent follow-up, usually after about 1 year. However, the diagnosis of impaired glucose tolerance may merely reflect the underlying high incidence of impaired glucose tolerance in the population studied rather than a causal link. HIV and the continued use of neurotoxic antiretrovirals are probably the major causes of SFN in sub-Saharan Africa. HIV causes peripheral axonal injury through immune activation that creates a toxic microenvironment for peripheral nerves. Anti-retrovirals, specifically the nucleoside reverse transcriptase inhibitors such as didanosine and stavudine, cause axonal injury through mitochondrial toxicity. SFN occurs in several autoimmune and inflammatory diseases (Table 1). The exact pathophysiological mechanisms are unknown, and the most likely candidate mechanisms include autoantibodies targeted against neuronal proteins (the identity of which is not yet known), elevated pro-inflammatory cytokines in the skin and dermal vasculitis. Amyloid neuropathy (either hereditary or acquired) can present as a pure SFN and usually progresses to involve the large neuronal fibres and major organs, such as the kidneys and heart.
SFN features in a number of rare genetic conditions (Table 1). A recent study described variants of the SCN9A gene, which encodes the Nav1.7 sodium channel in a third of patients labelled as having idiopathic SFN. This voltage-gated ion channel is selectively expressed in sensory and autonomic neurones. Nav1.7 variants associated with SFN cause enhanced excitability of sensory neurones and eventual degeneration of small fibres, which is probably mediated through increased sodium load and reversal of sodium–calcium exchange. Nav1.8 is a related voltage-gated sodium channel selectively expressed in nociceptors. Variants in the SCN10A gene, which encodes the Nav1.8 sodium channel, enhance the excitability of dorsal root ganglion cells and are also associated with SFN. The penetrance of these variants in voltage-gated sodium channels has not yet been fully elucidated and in some cases these variants may be important risk factors, rather than being fully penetrant in causing SFN. This currently makes genetic counselling complex. Idiopathic SFN has historically accounted for 23–94% of cases. In our experience, approximately 50% of cases of SFN are idiopathic. However, this is highly dependent on referral patterns, and the number of idiopathic cases will reduce as genetic causes are identified.
Source...