Frequently asked questions

Small fiber neuropathy (SFN) is a type of nerve dysfunction or damage that is specific to small nerve fibers.  These nerves can be found on both the skin as well as the autonomic nervous system. It can thus lead to a wide variety of sensory and autonomic symptoms. These can include numbness, pain, strange sensations such as feelings of electric shocks, and dysautonomia.

Unlike other forms of neuropathy, SFN often does not show up on conventional nerve testing and is commonly misunderstood by doctors who aren't familiar with the condition. Typically neurologists are most familiar with the "classic" pattern observed in diabetes, which includes burning pain in the hands and feet, but this is just one possible presentation.

A comprehensive article for getting started with understanding SFN can be found here: https://www.ncbi.nlm.nih.gov/books/NBK582147/

Dysautonomia is a general term for the autonomic nervous system not working as it should. It can include a number of different symptoms such as inability to sweat, inappropriately high or low heart rate, constipation, bladder problems, sexual dysfunction, vision problems, or dizziness.

Autonomic neuropathy refers to damage specific to the autonomic nervous system, which is one possible cause of dysautonomia.

PSSD is an understudied and poorly recognized medical condition where patients experience persistent symptoms such as numbness in the genitals and sexual dysfunction after SSRI exposure.

With numbness being a textbook symptom of nerve problems in general, PSSD has been openly suspected to involve SFN by some researchers like professor David Healy since 2015. In fact, after hearing about several patients having tested positive for it, Dr. Healy attempted to start a study exploring the connection in 2022, although it ended up being canceled due to logistical problems.

Besides numbness, sexual dysfunction itself is a textbook symptom of autonomic dysfunction, and although the EMA refuses to recognize other SSRI-induced symptoms as a part of PSSD, many patients do present with additional symptoms pointing to SFN or dysautonomia such as paresthesias, pain or dizziness.

Therefore we believe that there is good reason to suspect that PSSD may in fact be a novel form of small fiber neuropathy, and several patients have been formally diagnosed with it by now.

Small nerve fibers often lack myelin and are sensitive to many potential stressors. Thus SFN can have many possible causes ranging from toxic, metabolic, immune and inflammatory ones.

In order to maximize chances of healing, it is likely a good idea to take a wholistic mindset and correct anything that might be off as several factors may be at play depending on the person.

Community interest in immune-mediated neuropathies started when one patient had a severe reaction to SSRIs, and was taken to a university hospital where he was eventually diagnosed with a novel autoimmune condition affecting the central and peripheral nervous systems. He urged other patients to get tested with the same obscure antibody panel that he was positive for, and to date, only one patient has been negative to all of them (~~ACE2 in particular has a high prevalence~~).

In addition, the symptoms themselves have more in common with focal or non-length dependent neuropathies than length-dependent ones, which are also more commonly seen in immune or inflammatory types.

Then there is the matter of onset. Toxic or metabolic neuropathies typically have a slower, less certain date of onset while immune or infectious ones tend to start more suddenly, which is again typical of PSSD.

Finally, a historical SSRI, zimelidine, was banned in Sweden shortly after it turned out to trigger Guillain-Barré syndrome in some patients, which is a serious form of autoimmune neuropathy.

Of course, these are admittedly still early days for PSSD research and there are currently no formal clinical studies that have examined this connection, so it is admittedly still speculative. Still, interest in neuropathy itself is becoming more common among researchers, and more and more patients have been diagnosed with autoimmune neuropathy in clinical settings all over the world, with some responding to treatments such as IVIG. 

We therefore encourage PSSD patients to consider getting tested for autoimmune neuropathy, although finding a doctor who is knowledgeable about a rare, poorly understood disease like this can be challenging.

Confirming small fiber neuropathy can be challenging due to it evading common nerve tests such as nerve conduction studies, and currently there is no "gold standard" way to determine it. Typically diagnosis involves evaluation of symptoms combined with tests such as skin biopsies to determine nerve density in the skin, quantitative sensory testing, as well as various tests to evaluate autonomic function such as a tilt-table test. 

In addition, for suspected autoimmune cases, being positive for TS-HDS and FGFR3 autoantibodies would strongly support that conclusion. The roles of many other antibodies (such as the infamous GPCR ones) are currently less clear and may not be enough to convince most doctors or insurance companies to approve treatment

Treatment is largely dependent on addressing the underlying cause if one can be identified, and for inflammatory polyneuropathy, IVIG is a first line option. Prognosis may vary depending on the cause and extent of damage, but even if some of it cannot be corrected (or no cause can be identified, as in the case of idiopathic SFN), it may still be possible to ease symptoms with medications and lifestyle changes. In addition, new potential treatments such as WST-057 are also in the pipeline.

Yes, but a negative leg biopsy does not necessarily rule out neuropathy. The biopsies have a higher rate of false negatives than false positives, and for one, they will completely miss autonomic neuropathy because the autonomic nervous system resides inside the body. 

In addition, even when on the skin, the neuropathy may still be limited to just some areas of the body and not others, and thus may be missed by testing on conventional sample sites. 

It is also possible that the nerves start to function abnormally before actual tissue death starts to occur, which is good in terms of having a better chance of making a full recovery, but naturally makes it harder to get properly diagnosed.

Firstly, peripheral dysfunction does not rule out central dysfunction, and both the brain *and* nerves in the skin or autonomic nervous system could be affected at the same time. In fact, at least two patients have been diagnosed with autoimmune encephalitis (brain inflammation) in addition to SFN by now. In addition, inflammation in general can also contribute to mood symptoms. 

Secondly, the brain could also be affected more indirectly as abnormal sensory input and dysautonomia can themselves cause things to feel "off". This has been noted in historical cases of surgery targeting the autonomic nervous system, which resulted in emotional side effects that resemble the kind of emotional blunting seen in PSSD.

This is further supported by the common observation that many of those afflicted can feel emotions and sexuality more normally in their dreams, which is a state of consciousness where some of the sensory input occurring from the outside world is temporarily cut off.

As stated in another answer, the nerves can become dysfunctional before tissue death starts to occur. Thus variation in levels of stressors such as inflammation could theoretically allow the nerves to work better or worse.

Additionally, autoimmune cases in particular may be dealing with "functional" autoantibodies, which, in some cases, can merely block or activate different receptors rather than causing direct damage. Naturally, if their levels are suddenly lowered, function can then return quite quickly. This may explain why some have had fast, if temporary responses to treatments like corticosteroids and plasmapheresis.