Result of Skin Biopsy is Negative
 

Hi.
I received a call from the doctor yesterday informing me that the result of my skin biopsy is negative. This makes me happy knowing that I dont have PN, but at the same time more confused and anxious.

Confused and anxious because I experienced (and still is) most of the symptoms of a peripheral neuropathy. In fact, this was my official diagnosis from my previous 2 neurologist until I was referred to this 3rd neurologist who did the skin biopsy. I have very painful (both) feet, tingling, prickly skin similar to being rubbed by a sandpaper. I used to experienced severe burning but that stopped since March 15.

My doctor is no longer keen to pursue any further investigation of my condition. When I asked what would be the next course of action, he simply said "lets wait and observe". I am hoping not to just wait and observe. With the negative result, I asked if I have PN, but he could not give me a straight answer.

If my doctor is correct, what other condition/s could I have?

I am really hoping that anyone can give me some thoughts about my condition.

Thank you.

Mary

one thing that you should do is get the exact results, the full report of your skin biopsy. what percentages and description of condition of nerves may help you now if they are borderline, or may help you down the road to compare where you are at now and where you are at then. sometimes tests come back negative that are borderline positive but you dont get that information unless you get a copy of the report for yourself.

Echoes long agoYes, I will get the result soon. Hopefully, within the week. I will post when I get it.

Did I get you right - if one is in the borderline of positive, this will reflect negative? How long should be the ideal next biopsy to reflect changes, if any?



Mrs D, regardless of the result of my test, I will continue the supplements I am currently taking now. Ddo you think this is the right thing to do?

Thank you both!!!:)

Glentaj is the person to ask about the skin biopsy. There are certain high and low percentiles that are considered abnormal. He knows much more than me about it, and would also better be able to tell you when you should do it again.
I do know on tests you can be trending towards abnormal but still be in normal range for that test. For example i was usually at 115% of expected for my age and height and weight, on a pulmonary function test in July 2001. I retook the test in October of 2001 and was at 80% of expected. 79% would be failing the test. The doctor told me that the test came back normal and when i looked at the numbers i said to him yeah but i dropped 35% in 3 months and he said yes but you are still normal.

For neurological tests for peripheral neuropathy, emg/ncs can come back negative even if you have large fiber nerve damage because a certain amount of damage must have occured for it to show up on the test.
The skin biopsy you took also of course has percentages.
I just wanted to let you know about the percentages thing so that you can look for yourself and better understand where you stand at the present time and be better able to compare it to where you are in the future.

I will post my results as soon as get my report for comments hopefully of Glenntaj.

Thank you for your feedback.

Part of the problem --
 

--with the skin biopsy results is that the definitions of "normal" and "abnormal' were rather arbitrarily set by MacArthur and his colleagues at Johns Hopkins when this was first investigated as a way to detect small-fiber neuropathies (which are very difficult to detect, as there may be no other abnormal test results, including normal nerve conduction and electromyography studies).

The Hopkins researchers did skin biopsies on a range of what were assumed to be people with normal nerve fiber densities and found that there was a wide range of fiber density even in asymptomatic individuals. After playing with the statistics for a while, they designated those who had nerve fiber density levels below the fifth percentile and above the ninety-fifth percentile as being "abnormal".

I'm fairly convinced that those with nerve fiber densities in those areas have something going on, but I also think one can have neuropathies even within that "normal" middle range. The trick is that one doesn't usually know at what density levels one started at before symptoms. As Echoes implies, one can move a lot within the normal range over time, and to me that's an indication of something going on. If one was at the sixtieth percentile in young adulthood, say, and then after symptoms is in the twentieth percentile, one is still technically "normal", but that reduction implies some neuropathic process.

This is also why one needs a neurologist familiar with these protocols to interpret. They are also supposed to note the condition of the fibers, not just density--are they swollen/inflamed, is there excessive branching, are there signs of autoimmune degeneration.

My skin biopsy was done at Hopkins two years ago, and the results were as follows:
Ankle- devoid of nerve fibers
Above the knee- reduced in a patchy distribution
Thigh- normal, but segmented and breaking down
That along with a confirmation of SFN is all that appears on the lab sheet. There were no percentiles, etc. This way of expressing the results doesn't sound like anyone else's, but it was one by a Hopkins neuro at Hopkins, says Hopkins lab on the paper.
Other tests show large fiber neuropathy as well with muscle loss. I have CMT, with no sensation to above the knee. Hands and arms are also affected, with pinched nerves.

The neurologist at Hopkins asked if I wanted further genetic testing and a spinal tap. I said no, he agreed, and it was "goodbye and good luck".

I am curious if anyone else has results expressed in this way.

I have not seen my results yet. I know that my specimen was sent to John Hopkins. I will post here when I have it.
As you may have read my post, my neurologist advised me (through phone)that my skin biopsy result is negative. I am thankful about it but this makes me so confused because I have the symptoms of a PN.

I got a similar position from my doctor too when I asked him if I need to have more tests. He said "Lets just wait and observe."

The good thing is we have this forum. Reading the posts here gives me more information - more information than I get from all my doctors combined.

Hi. I got my skin biopsy result today. The result is not reflected in percentile. It reads as follows:

Distal Leg Right : The epidermal nerve fiber density and appearance are within the normal range.

Prox. Thigh Right : The epidermal nerve fiber density and appearance are within the normal range.

"Session Summary : The epidermal nerve fiber density is within the normal ranges at both sites and therefore there is no definitive evidence for a neuropathic process affecting small caliber sensory nerve fibers."

How can I get the results in percentile? Can the clinic of my doctor request it from John Hopkins? Or, is there a certain kind of skin biopsy protocol that does not yield the percentage but instead just a general impression?

How will I proceed from here in my treatment? My symptoms are still the same: very painful feet, prickly skin, deep and stabbing pins and needles. I no longer have the severe burning skin. I dont want my doctor to dismiss me like my symptoms are just "in my head".

Are there any others in this forum who have had a normal skin biopsy result but experiencing the PN symptoms?

I really want to know....
Thank you.

there should be a written record of what your nerve density was. it is part of the procedure to calculate that percentage.

http://www.ccjm.org/content/76/5/297.full

This is from the Cleveland Clinic Journal of Medicine

Skin biopsy
Skin biopsy is a minimally invasive procedure in which 3-mm-diameter punch biopsy specimens are taken from the distal leg, distal thigh, and proximal thigh of one lower limb. The procedure takes only 10 to 15 minutes.

Biopsy specimens are immunostained using an antibody against protein gene product 9.5, which is a panaxonal marker. Small nerve fibers in the epidermis are counted under a microscope, and intraepithelial nerve fiber densities are calculated and compared with established normative values. The diagnosis of small fiber neuropathy can be established if the intraepidermal nerve fiber density is lower than normal (FIGURE 1). Nerve fiber density may be normal in the early stage of small fiber neuropathy, but in this setting skin biopsy often shows abnormal morphologic changes in the small fibers, especially large swellings,24 and repeat biopsy in 6 to 12 months may be considered.

The diagnostic efficiency of skin biopsy is about 88%.21,23 For diagnosing small fiber neuropathy, it is more sensitive than quantitative sensory testing21,25 and more sensitive and less invasive than sural nerve biopsy.26 Intraepidermal nerve fiber density also correlates well with a variety of measures of severity of HIV distal sensory neuropathy and thus may be used to measure the severity and treatment response of small fiber neuropathy.27

It could be then that I am in an early stage of small fiber neuropathy? But, they should have included a notation in the report about abnormal morphologic changes, if they saw one.

I should call my doctor's clinic to request for the record of my nerve density. Is this what its called - "record of the nerve density"? I am sorry for this kind of question...I dont know what to ask for...If I say to the clinic staff "skin biopsy result", they will say I have it. I want to say the specific report I need. ( I dont even know myself how the report looks like:confused:)

Thank you and sorry for ranting....:o

Yes, you should.
 

The only way the result could have been determined is by comparison with "normal" ranges.

I've written a lot about this before--I think the normal ranges are rather arbitrarily set. There is considerable variation in nerve fiber density among asymptomatic people, which was discovered when they first started doing this at Johns Hopkins a few decades ago. So the range of normal was set at between 5% and 95% density levels of all the subjects they tested. People with density levels below 5% and above 95% are considered to be positive for small fiber neuropathy.

The problem with this is that one seldom has any idea of what level one was at BEFORE symptoms--almost no one goes in for skin biopsy until there are symptoms. Suppose one started at around the 50th percentile (though one would not know this, generally). One has a skin biopsy and the results show the density at around the 20th percentile. This would be listed as "normal", but it might well represent a significant dimunition from that person's "normal" level.

This is part of the reason why they are also supposed to report the condition of nerves--if there are swellings, excessive branchings, evidence of inflammatory infiltration. It's also why often multiple skin biopsies with numbers tracked can be informative--one looks for the trend.

When you mentioned about : "It's also why often multiple skin biopsies with numbers tracked can be informative....", does that mean that the doctor should have punched from several areas or does it mean that I should have follow up skin biopsies to establish trending?

Actually--
 

--it means BOTH.

Typical skin biopsy sites are the lower leg near the ankle, the outside of the thigh, and often right above the elbow int he fleshy part of the arm. This is done to see how "length-dependent" any neurological process may be; many neuropathies show slow progression from the nerves farthest away from the center of the body to those closer over time ("distal to proximal gradient").

Since skin biopsy is a quick, relatively non-invasive procedure, it can be repeated in the same locations over time to track progression and patterns. I've had four in nine years. They have shown my re-enervation--I went from being in the second percentile originally three months into my neuropathic syndrome to the eighteenth percentile on the last one almost two years ago (which technically makes me "normal"--though I doubt I was at the eigtheenth percentile before all this began).

The neurologist who did the skin biopsy kept on citing a new paper indicating that the new sites for punching are two: one from the thigh and one from just above the ankle. He said that one site used to be above the knee. I relied on his words because he co-wrote a paper himself (which I think you posted as one of the links).

I really want to have a copy of my report in "percentage format". I want to have a reference point for my next biopsy. Unfortunately, when I talked with the nurse, she informed me that they receive only a one-page report and she does not know about the percentile report. Would you be kind to give me a copy of your report (delete the personal information, of course!) just to have an idea of how it looks like and so I can confidently discuss with her. If I could not get this through her, I will talk to my doctor when I see him next month.

Until now, I am still very confused how come that I registered "normal" when I am feeling all these pain. Sometimes I doubt if the skin punch was from the correct leg but I am convinced that it is - because my symptoms are are symmetrical in my feet/legs and arms/hands. I have the same level of pain in both. May be I am not so familiar yet how complicated nerves are and how it can "trick" test results.

Also, this normal result gives me a little hint of pressure when asked about it. My family can understand but those who are "not-so-close' might think that it could just be in my mind. ;)

contact the lab that did the tests. for what they get paid to do it, it should be a complete report.

Basically--
 

here's what my first skin biopsy report said (without the extraneous stuff about how the sample was collected):

Epidermal nerve fibers per millimeter:

Thigh Mean 4.7
Range 3.0-7.7
Reference Values: 21.1 +/- 10.4; range 2.9--57.5
Fifth percentile value 5.2

Leg Mean 3.2
Range 1.3-4.3
Reference Values: 13.8 +/- 5.6; range 0.6--32.2
Fifth percentile value 3.8

The reference values indicate the mean in the tested reference group, which presumably included normals and people suffering from small-fiber syndromes normals (first number), then the standard deviation in that group (the +/- number), then the total range across everyone. These are known as the McArthur protocols. The fifth percentile values are then given, and as you can see, my means are both below that value, so by protocol definition, I have "abnormal intraepidermal nerve fiber density, consistent with a small fiber neuropathy". The report also states "the nerve fibers within the thigh suggest excessive branching, also consistent with a small-fiber neuropathy".

In my most recent skin biopsy, my thigh mean comes back at 9.5, and my leg mean comes back 5.8, which they tell me averages out at about the 18th percentile. This was almost two years ago--it's possible I would show even more re-enervation now, but who knows at what figures I "began".

Feeling Stigmatized?
 

This "pressure" is stigmatization. I recently came across this article from 2005 on Stigma, Liminality, and Chronic Pain,* which I believe can apply equally to PN and/or other chronic medical conditions. It may help to explain and understand this common experience/phenomenon. It looks to be interesting reading at any rate. :Clever: Disclaimer: I haven't fully digested the article yet. :Hum: :picknose:

More views and experiences - from professionals to fellow painees - can be found googling: stigma chronic pain and stigma peripheral neuropathy

Personally, I try not to care :Dunno: what "those who are 'not-so-close' might think". I have learned enough (from experience) not to share details of my own medical situation with those inclined to think such things, but that's a personal choice/decision.

* FWIW, I had to look up liminality too... :o

Doc

This problem of having an "invisible" disease is one that drives me crazy. My mom was a hypochondriac, imagining serious diseases, going for unnecessary tests and complaining constantly for her 87 years, only the last few of which were compromised at all by her health. As a result having quantifiable test results is disproportionately important to me. I did not mention the progressive loss of sensation until it had passed my ankles and I had developed a serious staph infection. I need a demonstrable problem, preferably blood and pus or at least a better than even certainty of something showing up on an MRI or other test to get me into a doctor's office. When I developed Sciatica years go from a ruptured disc I kept going until I couldn't walk.
But I am insane, and this is a bad way to think. Dr. Smith is right. Remember, we wouldn't care so much about what other people think of us if we realized how seldom they do....
But I can sincerely empathize with your desire to have lab certified proof of your disease, beyond your very real suffering and symptoms. I have been known to carry my results with me, although no one, not TSA agents when I need to bring my hiking pole, or attendants at Disney World when I need to take it with in line, have asked to see them! My husband makes fun of me for this need for documentation. He says watching me walk is more than enough proof.
The problem is almost everyone knows someone like my mother, but not everyone knows someone like us.

The article is interesting, the topic important and valid, but the writer really obscures his point with an almost bizarre quantity of jargon and pedantic words most of which have readily comprehended synonyms. Makes me want a red pencil. Heavy sledding indeed!

I don't tell people details of my problems. I walk with my walking stick, limp and that's that.

In general people make judgements, esp if you seem articulate.

I also don't complain much.

"Arthritis" is what I give back...and no details are necessary.

Last Christmas, I was on my second month of the PN symptoms and my feet were so painful - I was limping, and my skin was extremely prickly, a distant relative asked why I was limping. I said I have peripheral neuropathy and she exclaimed, "Oh, but you look healthy! You dont look sick." :mad:

I am trying to understand what the numbers mean. I will keep on re-reading them until I understand them.
I googled "McArthur protocols" but I did not find much information about the percentile. :confused:

Thank you.

People tell me that. With Chronic Fatigue Syndrome and Dysautonomia. Gets old, but it is meant to be nice.

IIRC, It's illegal for them to ask to see such. They can inspect/scan/search, and in certain specific cases (like if you have residual radiation from medical testing) they can prohibit you from boarding without producing documentation for that, but they cannot ask to see documentation/proof of any medical condition/disability.

You won't get an argument from me on that point. Scholarly articles are often written that way. That's one reason I provided criteria for searches for more 'lay-friendly' articles. ;)

[Addition:] The article is also invaluable for the compiled list of cited references/sources, which may or may not be written in academese. :wink:

Doc

I've been compiling this list for some time. My idea (previously expressed in the SCS & Pain Pumps forum) was to pare it down to something manageable and print it up on one side of a business card. The other side would bear chronic pain awareness facts & figures.

Things NOT to Say to Someone with Chronic Pain*
(*alternate: Disabling Chronic Condition)

But you don’t look sick
But you look so good
Maybe if you just got out more
If you’d get out more
If you just got out of the house
You can learn to live with it
You’ll just have to tough it out
It’s all in your head <--- This one's the biggie, right? :hissyfit:
You’re just having a bad day
This will pass
This too shall pass
Just get more exercise
If you’d get more exercise
You just need to exercise more (and lose some weight)
I used to have chronic fatigue too – I just got active & it went away
It can’t be that bad
You can’t be in that much pain
It must be neat not to have to work
It must be nice not having to go to work
You’re so lucky to stay in bed all day
I wish I had time to take a nap
If you got more sleep, you'd feel better
Stop being lazy and get a job
My friend has back problems and still manages to work
You just need to get a hobby to take your mind off the pain
Just be more positive
You just need a more positive attitude
It could be worse
At least it's not fatal
There are people worse off than you
Everybody gets tired
Your illness is caused by stress
It's probably just a touch of arthritis
You’re just getting older
We all get more aches and pains as we get older
You’re just depressed
You just want attention
No pain – no gain!
Just pray harder
I've heard Fibromyalgia is just a diagnosis they give when there's really nothing wrong
When I get migraines, a brisk walk outside always helps take it away
I heard/read about this new product....

Doc

The literature on skin biopsy--
 

--is getting more and more extensive, and the articles are certainly complex and technical, but here's one to look at to start (it's long, but well-written, adn the reference list can lead you to most of the other useful articles):

http://www.hopkinsmedicine.org/neuro...10.747-758.pdf

My pain is getting worse...

Is it possible that a Sensory Neuropathy cannot be detected when its in the early stage? Is it a disease that is "building up" before it shows in the test?

With my pain getting worse, I cannot help but think if my specimen was mixed up with someone else's.

Has there been anyone who had a negative skin biopsy but later on re-tested and was positive? In this case, how many months should be the interval before getting another test (assuming doctor and insurance will allow).

Thank you.

It is possible to go undetected in early stages. However, it would be helpful if you had the actual numbers/percentile from the skin biopsy...which I don't think you do. I didn't get the numbers from mine either so would not be able to tell if progression is occurring or not.

Being that everyone is different and the causes/progression rates vary, it would be impossible to guess at how long between testing would be appropriate.

Thank you en bloc.

Two negative sfn skin biopsy
 

Hello, I have had burning, tingling, stabbing shooting pains in hands and feet for over ten years. It has, at times, gone into remission or was mild. In 2009 had EMG, nerve conduction and skin biopsy..all normal. Symptoms came back strong this July. Rhemo, pain doctor and neuro all said symptoms of small fiber so I had another skin biopsy. Came back negative so neuro (a new one) said I don't have neuropathy and told me to go to the Mayo clinic (which denied me last go around with this). My hands and feet are getting increasining numb. neuro confirmed that my vibration was decreased. Tips of fingers and heals cannot detect hot or cold.
My question is...I'm on Cymbalta, neurontin and 150 MG prednisone 1 week for four weeks. Can the medications alter the testing results? Particulary wondering about past EMGs and nerve conduction. one said totally normal, one said radiculapathy. Was on meds during that time also.
PS offical diag. Undifferentiated Tissue Disease (last ten years) ANA only blood test to come out high. ten years ago complements also came out low..
Any input would be appreciated.

In a strange way, I feel relieved that there is also another case like mine. Like you, I feel all the very unpleasant sensations in my skin. My legs are painful. I cannot stand for too long, nor walk (but I can tolerate the walking than standing). I could not exactly describe the pain when I stand, suffice it to say that I need to sit down immediately.

As of my last neuro visit, the doctor noticed a reduction in reflex of my left leg compared to his previous examinations. He needs another EMG/NCV. This time, he will do the test himself.

I am on gabapentin at 1500 mg/day.

I dread the touch of my clothes in my legs and arms, so I am not looking forward to wearing thick clothes this coming winter. I am always on constant look out for materials that will not bother me. I noticed that pajamas with spandex materials are less prickly to me.

I would be interested for your updates.
I am sorry I could not answer your question as to your medicines altering your test results. I am sure the experts will reply to your query.

Hi glenn,
Are those reference values still valid? The reference values shown on my skin biopsy were different. (Done Oct 2012) Could they have changed the protocals? Using your reference values for my skin biopsy I would have been in the normal range. What lab did your tests? Mine were done by Therapath.
Pardon my ignorance but what do you mean by "re-enervation"? Your most recent report shows higher numbers. Doesn't that mean improvement.
As usual Thank you for your help.

Hi Bernadettmarie,
I have the same symptoms as you except for the numbness. Vibration was normal. I had an EMG/NCS twice. One year apart. Both came out normal for Large nerve N. I finally had a skin biopsy this past Fall. It showed I have small nerve neuropathy. Did you find out what is going on with you? Did the cymbalta alter your tests. I tryed cymbalta but it was horrible. How much neurotin are you taking? Im taking lyrica but thinking about changing to neurotin/gabapentin because of bad side effects . Hope your doing better!

Yes--
 

--repeat skin biopsies from the same locations at eighteen months, forty months, and seventy months have shown somewhat increased nerve fiber density each time; on the last one I am back to about the 18th percentile, which certainly corresponds with re-enervation and the improvement in symptoms.

Of course, we'll never know what was normal for me before all this started, and what percentile I would have been at then.

Can you list the reference ranges from your skin biopsy? I am not aware of any changes to the numbers, but it is possible your numbers are normed to your age and gender (I am male and was 43 at time of first skin biopsy; it is known that "normal" intraepidermal nerve fiber density does decrease with age).

With regards to the biopsy, I must caution you and others about the results. I am seeing Dr. James Berry at Mass General who specializes in SFN and he explained the difficulties of biopsy. He said at one time he did them frequently but discovered in too many cases the nerve counts were normal or near normal when there was clearly a problem. He also saw cases where the nerve counts were abnormally low and there was no associated problems. He definitely uses them when the neuropathy appears to be advancing rapidly. But in general, when the neuropathy is not advancing, it does not take him in any new diagnostic direction.

dAC122: Does it mean that there are cases when nerve counts are normal or near normal but patients are symptomatic while on the other hand, there are nerve counts that are abnormally low and yet patients are asymptomatic?

For t hose asymptomatic patients, how can they subject themselves to skin biopsy when they dont have symptoms of discomforts in the first place? I'd like to understnd what the doctor meant about his precaution of getting a skin biopsy. My skin biopsy last year showed normal result but my pain is getting worse than when it started.

I am sorry I probably stated that wrong. You are right, asymptomatic patient would not even see this doctor, much less take a skin biopsy. I think he meant patients who had milder symptoms.

My take away from discussions with Dr. Berry is that he did not see strong enough correlation between nerve counts and symptoms to take him in a different diagnostic direction for cases where symptoms did not advance. Hence he has stopped doing skin biopsies, except in cases where symptoms are rapidly advancing.

My wider point is that skin biopsies have their place but maybe not for those with stable symptoms. Following his protocol you might be a candidate for another skin biopsy.