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Length-dependent Small Fiber Polyneuropathy Caused by Coxsackie and Influenza Virus CoInfection

pattismith

Senior Member
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3,932
@Hip

Case Report: Length-dependent Small Fiber Polyneuropathy Caused by Coxsackie and Influenza Virus CoInfection

Case Report Open Access https://doi.org/10.17756/jnen.2019-061

Nina Tsakadze1 , Jelena Catania2 , Michael Hoffmann1 , Lourdes Benes-Lima1 , Alvaro G Estevez3 , Maria Clara Franco3 and Fabian Rossi1

1 Orlando VA Medical Center, Orlando, FL, USA
2 Department of Infectious Disease, Orlando Veterans Administration Medical Center, Orlando, FL, USA
3 Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA * Correspondence to: Dr. Fabian H. Rossi, MD Director Clinical Neurophysiology Laboratory Orlando Veterans Administration Medical Center, 13800 Veterans Way Orlando, FL, 32827,

Published: December 17, 2019

Abstract


We describe a 34-year-old woman with an acute length-dependent small fiber polyneuropathy (SFP) caused by Coxsackie B3 and B5 and Influenza A, H3N2 viruses.

She presented with an acute onset of burning pain and distal sensory deficit in both legs shortly after the acute viral encephalopathy.

This is the first report of the serologically confirmed length dependent SFP caused by Coxsackie and Influenza viruses.

Introduction

Small fiber polyneuropathy (SFP) selectively affects small myelinated or unmyelinated nerve fibers involved in pain and temperature sensation and autonomic function.

SFP commonly presents with a variety of sensory complaints (paresthesias, brief electrical shocks, burning pain, etc.) in a length-dependent distribution, affecting predominantly the feet, and to a lesser degree - the hands.

Rarely, SFP presents in a non-length dependent pattern, affecting focal areas of the body.

SFP may also cause the autonomic dysfunction, affecting different organs. SFP has diverse range of etiologies, including several infectious agents, but remains idiopathic in up to 50% of cases.

We report a rare case of length dependent SFP caused by Coxsackie and Influenza virus co-infection.

Case Report

34-year-old black female was hospitalized with fever of 102.4°F and acute encephalopathy.
She developed an upper respiratory infection 5 days prior to admission, progressively became more lethargic and then unresponsive.
Soon after her mental status cleared, she developed constant incapacitating burning pain in her hands and feet and was unable to bear weight on her feet.
She denied symptoms of autonomic dysfunction.

She had a history of well-controlled diabetes (last HgBA1C was 5.7) and rheumatoid arthritis but denied any sensory symptoms or any limb discomfort prior to this hospitalization.
No history of HIV, unhealthy consumption of alcohol, illicit drug use, chemical exposure, kidney or liver disease.
Family history was negative for peripheral neuropathy.

Physical examination on admission showed altered mental status, confluent rash on chest and abdomen, but no organomegaly and temperature sensation or enlarged tonsils.

Serology was positive for Coxsackie virus B3 and B5 with titers ≥ 1:640 and 1:80 [normal < 1:10], respectively and Influenza A, H3N2. Convalescent sera were available for comparison of titers to be able to differentiate between current and past infection with these viruses.

Nasopharyngeal respiratory PCR was positive for influenza A, H3N2.

Other relevant labs included elevated ALT 77 and AST 351 [normal ALT 4-51; AST 5-46], respectively, low sodium 127, elevated CPK (8265, on discharge - 476) [normal 24-200] and elevated ANA at 1:1280 with a speckled pattern. Porphyria, celiac and thyroid panel, as well as vitamins B12, B1, B6 and ACE levels were all normal.

Blood serology was negative for HIV, Lyme, hepatitis, West Nile virus. EBV serology was consistent with prior infection.

Serum PCR was negative for Adenovirus HHV6, and Parvovirus B19. Lumbar puncture showed elevated opening pressure of 27 cm of water. CSF analysis revealed WBC 61 (52 % neutrophils), RBC 12, glucose 56, protein 325. CSF cultures and Cryptococcal Ag were negative.

CSF PCR was also negative for HSV-1 and 2. CT head and MRI brain were unremarkable.

EEG showed generalized slowing without epileptiform activity.

Pain remained chronic and incapacitating after the discharge, and was partially relieved by imipramine, but failed to respond to pregabalin, gabapentin, nortriptyline, and opioids.

Nerve conduction study was done six weeks after the onset of her encephalopathy, it showed reduced amplitude of the right sural nerve sensory action potential (2µV), while left was unrecordable.

Motor nerve action potentials in upper and lower extremities were unremarkable. General physical examination after discharge was unremarkable. Neurologic examination showed normal mental status, cranial nerves, coordination, motor strength and reflexes.

Pain and temperature sensation were decreased in both feet in stocking distribution; vibration and proprioception were normal.

Skin biopsy from the right thigh and right calf skin showed significant reduction in the epidermal nerve small fibers density and confirmed the diagnosis of SFP (Figures 1 and 2) and showed no evidence of vasculitis or amyloidosis.

Discussion

SFP selectively affects peripheral afferent thinly myelinated Aδ and unmyelinated C-fibers which convey pain and temperature sensation and are also involved in autonomic function (sudomotor, thermoregulatory, cardiovascular, gastrointestinal, urogenital) [1, 2].

Clinically, SFN presents with two clinical patterns: length-dependent SFN (predominantly affects the feet) and non-length dependent SFN (impairment of one or multiple nerves with a sensory patchy distribution on the face, upper limbs, or trunk).

Clinical presentation involves mainly sensory (both positive and negative) and autonomic symptoms.

Individuals present with pain, burning or electrical shock-like, allodynia, and hyperesthesia. Cramps, restless leg and foot movements may also occur.

Autonomic symptoms may include abnormal sweating, postural lightheadedness, syncope, dry eyes and dry mouth, alternating diarrhea/ constipation, early satiety, urinary frequency, and impotence.

Examination is usually normal, except for signs of small fiber loss (decreased or absent temperature and pinprick sensation) and occasionally erythromelalgia (red skin).

Sensory and motor nerve conduction studies are unremarkable, however large nerve fibers may also be co-affected, like in this case.

Gold standard for diagnosis is skin biopsy displaying a reduction in intraepidermal small nerve fiber density (as shown in the pictures).

Etiological factors are diverse and include toxic, metabolic, infectious, autoimmune, paraneoplastic, and genetic causes. In up to 50 % of cases etiology remains elusive.

Among the infectious etiologies, HIV, hepatitis C and B, Chagas disease, leprosy, Lyme, influenza, Coxsackie, herpes and varicella viruses have been reported, but are exceedingly rare.

Coxsackie B virus has been reported only once in association with autonomic neuropathy [3].

Likewise, there is only single report of the autonomic neuropathy caused by influenza. H1N1 [4],

Although the reported patient had history of diabetes, it is well controlled and there were no clinical symptoms suggestive of polyneuropathy prior to her acute illness.

However, her nerve conduction studies revealed an underlying asymptomatic length-dependent sensory predominant axonal-loss polyneuropathy.

Authors suspect that this axonal-loss polyneuropathy was already present before the acute illness and might have been a risk factor to develop the painful small-fiber polyneuropathy.

Thought, authors cannot rule out that big myelinated fibers were also damaged or partially damaged from the original viral infection.

Therefore, although we cannot entirely rule out the potential confounding role of diabetes in this case, we believe that acute presentation in the context of infection points more to the infectious etiology as the leading etiological factor.

Of note, she had a transitory elevation in her CPK most likely triggered by Coxsackie B and influenza virus induced-viral myositis, as previously reported [5].

The current is the first report of Coxsackie and/or Influenza viruses causing length dependent SFP, separately or in combination.

Treatment of the SFP includes symptomatic management of neuropathic pain (pregabalin, gabapentin, duloxetine, tricyclics, topical lidocaine, opioids [6] and disease-modifying therapies, such as IVIG and steroids [1, 2].

In summary, this is the first case report of a length dependent acute SFP caused by a combination of the Coxsackie and Influenza viruses.

http://jneuroscience.com/jnen/articles/v5n2/jnen-061-nina-tsakadze.pdf
 

pattismith

Senior Member
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3,932
I had chronic pins and needles for about 10 years after I caught coxsackievirus B4.
Do you think you have SFP?
Did you notice you had any improvement with antiviral drugs?

I found it strange that this lady didn't get any antiviral drug, even though the doc was convinced her SFP was virus induced.
 

pattismith

Senior Member
Messages
3,932
I don't have the other symptoms of SFP.
There's not much in the way of antiviral drugs for enterovirus.

I found benfotiamine 300 mg daily quite effective for the pins and needles.

I read pins and needles is more a large fibers neuropathy sign, did you get tested for That ?

Didn't you try immunovir?
 

wigglethemouse

Senior Member
Messages
776
I only tried inosine, never Imunovir (too expensive), and not many reports of success with it. But I am now just starting the home-made Imunovir of DMAE and inosine.
A couple of blogs here about inosine use in a family with ME/CFS. I think they pulse five days on, 2 days off, to maintain effectiveness (hope I remembered right).
https://livewithcfs.blogspot.com/search?q=inosine
 

pattismith

Senior Member
Messages
3,932
I only tried inosine, never Imunovir (too expensive), and not many reports of success with it. But I am now just starting the home-made Imunovir of DMAE and inosine.

just tried Inosine + DMAE two days ago but got quickly headache/nausea/gastric pain so I don't think I can tolerate this association.
(I have many difficulties with most drug/supplements so that doesn't mean others won't do well. )
 

Hip

Senior Member
Messages
17,824
just tried Inosine + DMAE two days ago but got quickly headache/nausea/gastric pain so I don't think I can tolerate this association.

Interesting. Last week I did a trial of inosine 1000 mg plus DMAE 350 mg daily, and for the first 5 days, I felt no side effects, and in fact noticed a slight improvement in mood (which I have had before with inosine taken alone).

But the by day 7, I started to feel noticeably much more tired (tired enough so that I struggled to find the energy and brain power to engage in daily household conversation, which normally is not a problem for me). And I also started to feel a bit depressed, as well as pretty tired.

So I stopped the inosine + DMAE after day 7, but it continued to feel the same tiredness and depression for 3 days after stopping. So it took me a few days to recover.

I never had these side effects with inosine alone, which does suggest that inosine + DMAE does something different, and suggests these two supplements do bind together in the body to make what is in effect Imunovir.

If you search the forums for Imunovir (often misspelt as Immunovir), you will see that people reported feeling worse for two months before getting better. There are also reports of people getting permanently worse.



In my case, since I felt no side effects for the first 5 days, I am now going to try pulsing Imunovir, taking it for 4 days in a row, then having a break for 3 days. And then repeating this each week. I felt good on the first 5 days of Imunovir, so I am hoping if I stop before the 5 day point, and have a break, then I will not experience the tiredness side effect.
 

sometexan84

Senior Member
Messages
1,229
Do you think you have SFP?
I don't have the other symptoms of SFP.
I've learned that there are many different symptoms and types of SFN and peripheral neuropathies in general. And that symptoms can be quite different from person to person.

Seems to come down to which part(s) of the peripheral nervous system is being effected. And that could trigger different symptoms.

• Motor – weakness, movement, cramps
• Sensory – numbness, pain, tingling like the pins and needles thing, or "burning"
• Autonomic - sweating, blood pressure, heart rate, orthostatic hypotension type symptoms, GI issues, pupils, bladder

Seems like oftentimes, there some sort of mix of that w/ people. And I think they're having a difficult time classifying the different symptom combos into neuropathies.

Examples...
• Acute Autonomic and Sensory Neuropathy (AASN)
• Autoimmune-Associated Small-Fiber Polyneuropathy (aaSFPN)
• Diabetic autonomic neuropathy aka Small-fiber diabetic neuropathy?
• Small-Fiber Sensory Polyneuropathy
• Autonomic Neuropathy aka Autonomic Small Fiber Neuropathy?
• Sensory-motor neuropathy
• Acute Motor Sensory Axonal Neuropathy (AMSAN)

It's ridiculous

1611605970033.png
 
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pattismith

Senior Member
Messages
3,932
I've learned that there are many different symptoms and types of SFN and peripheral neuropathies in general. And that symptoms can be quite different from person to person.

Seems to come down to which part(s) of the peripheral nervous system is being effected. And that could trigger different symptoms.

• Motor – weakness, movement, cramps
• Sensory – numbness, pain, tingling like the pins and needles thing, or "burning"
• Autonomic - sweating, blood pressure, heart rate, orthostatic hypotension type symptoms, GI issues, pupils, bladder

Seems like oftentimes, there some sort of mix of that w/ people. And I think they're having a difficult time classifying the different symptom combos into neuropathies.

Examples...
• Acute Autonomic and Sensory Neuropathy (AASN)
• Autoimmune-Associated Small-Fiber Polyneuropathy (aaSFPN)
• Diabetic autonomic neuropathy aka Small-fiber diabetic neuropathy?
• Small-Fiber Sensory Polyneuropathy
• Autonomic Neuropathy aka Autonomic Small Fiber Neuropathy?
• Sensory-motor neuropathy
• Acute Motor Sensory Axonal Neuropathy (AMSAN)

It's ridiculous

I agree Small Fiber Neuropathy is still not fully understood, but to my knowledge small fibers are either sensory or autonomic... never motor. Do you have a source?
 

Hip

Senior Member
Messages
17,824
I've learned that there are many different symptoms and types of SFN and peripheral neuropathies in general. And that symptoms can be quite different from person to person.

That's interesting. I've never really looked into SFN, so don't know much about it. I don't match the SFN symptoms detailed in the SFN Wikipedia article, which involve severe pain. I don't have any pain.

My main symptoms which might relate to SFN are:

• The chronic pins and needles I had for about 10 years after catching coxsackievirus B in 2003.

• A slight skin numbing and slight loss of tactile sensitivity on the skin (so for example if my T-shirt collar is inside out, I may not notice it until I look in the mirror, because of the blunted tactile sensitivity on the skin of my chest and neck). This loss of tactile sensitivity is still present even now, and first manifested when I caught coxsackievirus B.

• A hard-to-describe sponginess or laxity in my legs and pelvic girdle. It feels like my muscles are made from a soft material like Blu Tack. It's not EDS, because generally my joints are pretty inflexible, and my ligaments are taut. This also appeared after catching coxsackievirus B.

• Tendency to sweat a lot when I do mild exercise like going for a 30 minute walk.

• POTS

• IBS-D



Autonomic small-fiber neuropathy looks interesting, as this could explain a number of symptoms:
Symptoms of autonomic small-fiber neuropathy are less likely to be recognized, notes Dr. Oaklander, so they are often chalked up to other conditions.

"For example," she says, "neuropathy of the autonomic nerves to the heart or blood vessels can cause low blood pressure, perceived as chronic fatigue and faintness or dizziness.

Damage to nerve fibers serving the gastrointestinal tract may cause bloating, nausea, digestion problems, constipation, or diarrhea; these are often labeled as irritable bowel syndrome.
Ref: here.
 

sometexan84

Senior Member
Messages
1,229
I agree Small Fiber Neuropathy is still not fully understood, but to my knowledge small fibers are either sensory or autonomic... never motor. Do you have a source?
Sorry, I'm not entirely sure on that one. I just look at them as peripheral neuropathies (with focus on autonomic neuropathies or autoimmune neuropathies in my case).
 

sometexan84

Senior Member
Messages
1,229
That's interesting. I've never really looked into SFN, so don't know much about it. I don't match the SFN symptoms detailed in the SFN Wikipedia article, which involve severe pain. I don't have any pain.
I'm new to me as well.

I don't have any pain. But I have the TS-HDS antibodies, which for now seems to be mostly associated w/ "Small Fiber Neuropathy" (the term). The others w/ TS-HDS seem to have pain and burning, but not all. And their symptoms even vary, despite all having TS-HDS antibodies.

I see the symptoms you just described constantly in my neuropathy research. And the people in my TS-HDS Ab group in FB mention all that stuff.

Some of my TS-HDS research...

Nerve Fiber Loss
  • Loss of peripheral autonomic nerve fibers, usually unmyelinated (without insulation, called myelin, around the nerve fibers)
  • Small fiber loss with IgM deposits around the outside of medium- & larger-sized capillaries with C5b-9 complement deposits
TS-HDS in Neuropathies
  • More than 1/3 of SFN patients have TS-HDS autoantibodies, and that 92 percent of people with acute-onset SFN have these antibodies
  • 85% in Axonal Neuropathy
Monoclonal gammopathy
  • TS-HDS IgM has been found in patients w/ neuropathy and IgM Monoclonal gammopathy
    • They mostly had painful, sensory axonal neuropathy affecting unmyelinated axons w/ IgM deposits around perineurial vein
Membrane attack complex (MAC, C5b-9)
Diabetes
  • Small Fiber Neuropathy and Autoimmune Neuropathy are often linked to Diabetes, prediabetes, impaired glucose metabolism, or metabolic syndrome
  • Diabetic autonomic neuropathy
    • Can lead to exercise intolerance
    • Can cause gastrointestinal motility changes
    • Phospholipid antibodies
 
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sometexan84

Senior Member
Messages
1,229
I've got the sweating too. I'd always wondered why I was sweating more than others at the gym. I think that's when the axons are effected, autonomic.

A lot of people talk about that muscle thing you describe too. And a lot of them have POTS and fibro.

One thing I never would have made the connection to was the GI symptoms. Apparently that is linked to autonomic nerve damage.

This is a nice, quick watch I recommend...
 

sometexan84

Senior Member
Messages
1,229
This is what I've found I fit the most, so far...

Acute Autonomic and Sensory Neuropathy (AASN) - rare variant of immune-mediated acute peripheral neuropathy or ganglionopathy
  • Matching symptoms: diarrhea, hypohidrosis, dry mouth/eyes, non-reactive mid-sized pupils, orthostatic hypotension, low HRV, autonomic dysfunction, sleep apnea, cardiovascular dysfunction, urinary dysfunction, GI dysfunction
  • Antibodies: Sulfatide
  • Upper respiratory tract or gastrointestinal tract infection in two-thirds
  • Autonomic failure in all patients
  • Sensory ataxia (reduced coordination when the eyes are shut) increases over time
  • Small neuronal cells in the autonomic and sensory (dorsal root) ganglia are effected early on, then later the large neuronal cells
  • Infections: Herpes Simplex, EBV, Parvovirus B19, Coxsackie B, Influenza, CMV, Mycoplasma infection
Also, tie-in to the original topic... those w/ the TS-HDS SFN have mentioned they had the following at onset:
  • Parvovirus B19
  • EBV
  • Influenza A
  • COVID
  • VZV
Also, many had corticosteroid treatment when symptoms began. Some of them may have Coxsackie, but they don't know what that is.
 
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Hip

Senior Member
Messages
17,824
Because my possible small fiber neuropathy symptoms are mild and don't themselves concern me much, I have not taken much interest in this area.

However, it occurs to me that if there is some small fiber neuropathy going on which affects autonomic function, one can speculate this might cause a deleterious effect on the immune system, which in turn might prevent viral clearance from the body, thus perpetuating ME/CFS.

There is new research showing the autonomic nervous system (ANS) plays a role in immunity. So perhaps ANS dysfunction may indirectly cause viral issues, such as being unable to clear intracellular viral infections.

So you might get a vicious circle going on, where a viral infection you catch causes damage to the ANS (either by infecting and destroying cells, and/or by an autoimmune process destroying cells), which then hampers the immune response, and prevents the immune system from fully clearing the virus from the body, which then continues to damage the ANS.


I've also wondered if the same autonomic damage might explain why some ME/CFS patients with CCI have improved or gone into remission after corrective surgery for CCI. In this case, the CCI may cause ANS function by a mechanical pressure on the nerves in the neck.

The research of Dr David Systrom has led him to suspect that ME/CFS may be underpinned and maintained by autonomic nervous system dysfunction or imbalance. See this video interview of Dr Systrom at 25:50.

Systrom points out that up to 50% of ME/CFS patients have SFN.
 
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sometexan84

Senior Member
Messages
1,229
However, it occurs to me that if there is some small fiber neuropathy going on which affects autonomic function, one can speculate this might cause a deleterious effect on the immune system, which in turn might prevent viral clearance from the body, thus perpetuating ME/CFS
I don't think I use deleterious enough. I'm going to make a point to start using it more. You are deleterious, hehe

Furthermore, yes precisely. For instance, the parasympathetic nervous system and quality sleep is needed for healing. All healing. According to my nocturnal HRV readings, my parasympathetic activity is non-existent.