Can we skip all this and go straight to intrathecal injection? Rich, Freddd?

[Rockt]

Ok, the title is a bit facetious, but after reading Freddd's reference to the Japanese study of intrathecal B12 injection for treatment of peripheral neuropathy in diabetics, I typed "B12 intrathecal" into Google and this came up:


Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy.

Ide H, Fujiya S, Asanuma Y, Tsuji M, Sakai H, Agishi Y.
Abstract

Seven men and four women with symptomatic diabetic neuropathy were treated with methylcobalamin (2,500 micrograms in 10 ml of saline) injected intrathecally. Treatment was begun when patients had good metabolic control, as determined by measurements of plasma glucose and hemoglobin, and was repeated several times with a one-month interval between injections. Three patients were re-treated one year after the last intrathecal injection. Symptoms in the legs, such as paresthesia, burning pains, and heaviness, dramatically improved. The effect appeared within a few hours to one week and lasted from several months to four years. The mean peroneal motor-nerve conduction velocity did not change significantly. The mean (+/- SD) concentration of methylcobalamin in spinal fluid was 114 +/- 32 pg/ml before intrathecal injection (n = 5) and 4,752 +/- 2,504 pg/ml one month after intrathecal methylcobalamin treatment (n = 11). Methylcobalamin caused no side effects with respect to subjective symptoms or characteristics of spinal fluid. These findings suggest that a high concentration of methylcobalamin in spinal fluid is highly effective and safe for treating the symptoms of diabetic neuropathy.


I know it's a small study, but results were very positive with no side effects. Goes right along with what Freddd has been saying about CNS repair, doesn't it? And I heard they're now thinking that diabetes is the result of mitochondrial dysfunction - don't more than a few of us have mito. problems?

So my question is, why aren't PWC's trying this? I don't have peripheral neuropathy but I have mondo brain fog and bad mental PEM. Maybe this would help.

We should get Cheney going on this - he'd charge $11,000 per injection, but if it works and other docs do it, the price should drop to a couple hundred bucks, (sorry coudln't resist a bit of sarcasm - no offence meant to anyone )

Thoughts?

PS Something that's intrigued me since I started reading Fredd's comments about CNS/CSF penetration is my experience with osteopathy. I went to 2 separates DO's and they both told me they couldn't detect the flow or rhythm of cerebral spinal fluid in me, (osteopaths claim to be able to feel or detect this flow and improve it if necessary with gentle manipulation - sounds a bit out there, but some sports concussion sufferers swear it has helped them). I wonder if this could be effecting me and again, if intrathecal injection of B12 could help?

 

[Mark]

Hi Rockt.

I find your question quite thought-provoking. Have you spent much time on the mammoth "B12: The Hidden Story" thread? There's a huge amount of discussion there on B12 and intravenous B12 in particular.

http://forums.aboutmecfs.org/showthread.php?188-B-12-The-Hidden-Story

One of the problems here is that it seems to be very difficult for us to find a physician who is prepared to provide this sort of treatment. The case of Dr Myhill in the UK is eye-opening in this respect. Her prescription of B12 injections was a large part of the General Medical Council (GMC) case against her, and she's currently only able to practice medicine on some strict conditions that demand she doesn't prescribe outside of the official 'NICE' guidelines.

This effectively means that Dr Myhill is currently only able to practice medicine provided she stops providing the most effective treatments available to people with ME/CFS: as I understand it, she is not able to provide B12 injections for people with ME/CFS at the present time - even though such treatments are available through the normal channels for other conditions. I've already spoken to one friend with long-term depression and other long-term medical problems who told me she has received intravenous B12, and she was shocked that the treatment would be denied to anyone; it's known to be safe and effective and a standard treatment, as far as she was concerned.

I don't actually think the mechanisms at play here are a deliberate plan to deny all effective tests and treatments to people with ME/CFS, but that's the way it works out in practice so that's how it comes across to many patients.

I don't think B12 injections are likely to be a complete solution for many people, and treatments like this need to be administered as part of a larger programme of treatment advised by a well-informed and competent physician. But finding a well-informed and competent physician, who hasn't been struck off the medical register for treating people with ME/CFS....that's the hard part...

 

[Rockt]

Thanks Mark.

Yeah, I've looked through, "B12: The Hidden Story" Awesome stuff. It just seems like maybe this intrathecal injection could take things farther, but who knows until we try it. How do we get to try it, is a good question. You're right about the conservative medical establishment in Britain and Canada, but I bet someone like Dr. Cheney in the U.S. could do it. If there's even probable cause to try it - I don't know - I'm really just wondering/speculating.... hoping. That's why I'm hoping Rich and Freddd will weigh in.

 

[SpecialK82]

Thanks for posting, I have neuropathy and would love to see something like this work for us.

We should get Cheney going on this - he'd charge $11,000 per injection, but if it works and other docs do it, the price should drop to a couple hundred bucks, (sorry coudln't resist a bit of sarcasm - no offence meant to anyone )

Tee hee hee - thanks for making me laugh today!

 

[Freddd]

Ok, the title is a bit facetious, but after reading Freddd's reference to the Japanese study of intrathecal B12 injection for treatment of peripheral neuropathy in diabetics, I typed "B12 intrathecal" into Google and this came up:


Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy.

Ide H, Fujiya S, Asanuma Y, Tsuji M, Sakai H, Agishi Y.
Abstract

Seven men and four women with symptomatic diabetic neuropathy were treated with methylcobalamin (2,500 micrograms in 10 ml of saline) injected intrathecally. Treatment was begun when patients had good metabolic control, as determined by measurements of plasma glucose and hemoglobin, and was repeated several times with a one-month interval between injections. Three patients were re-treated one year after the last intrathecal injection. Symptoms in the legs, such as paresthesia, burning pains, and heaviness, dramatically improved. The effect appeared within a few hours to one week and lasted from several months to four years. The mean peroneal motor-nerve conduction velocity did not change significantly. The mean (+/- SD) concentration of methylcobalamin in spinal fluid was 114 +/- 32 pg/ml before intrathecal injection (n = 5) and 4,752 +/- 2,504 pg/ml one month after intrathecal methylcobalamin treatment (n = 11). Methylcobalamin caused no side effects with respect to subjective symptoms or characteristics of spinal fluid. These findings suggest that a high concentration of methylcobalamin in spinal fluid is highly effective and safe for treating the symptoms of diabetic neuropathy.


I know it's a small study, but results were very positive with no side effects. Goes right along with what Freddd has been saying about CNS repair, doesn't it? And I heard they're now thinking that diabetes is the result of mitochondrial dysfunction - don't more than a few of us have mito. problems?

So my question is, why aren't PWC's trying this? I don't have peripheral neuropathy but I have mondo brain fog and bad mental PEM. Maybe this would help.

We should get Cheney going on this - he'd charge $11,000 per injection, but if it works and other docs do it, the price should drop to a couple hundred bucks, (sorry coudln't resist a bit of sarcasm - no offence meant to anyone )

Thoughts?

PS Something that's intrigued me since I started reading Fredd's comments about CNS/CSF penetration is my experience with osteopathy. I went to 2 separates DO's and they both told me they couldn't detect the flow or rhythm of cerebral spinal fluid in me, (osteopaths claim to be able to feel or detect this flow and improve it if necessary with gentle manipulation - sounds a bit out there, but some sports concussion sufferers swear it has helped them). I wonder if this could be effecting me and again, if intrathecal injection of B12 could help?

Hi Rockt,

First of all 99% of what we do have is NOT even at issue in this including brainfog. Secondly, the nature of the procedure is such that only an anesthesiologist is going to do it. Third, I would need at least half a gram of the proposed mb12 crystal in injectable solution to test out whether it even suitable qualitatively. Forth, I would propose trying it ONLY after a suitable large dose trial (the purpose of the half gram solution) to makle sure it works both response wise and with qualitatively suitable mb12. How much is charged for a spinal anesthesia? That might be the minimum cost we might expect. I'll talk about the possibility again with my anesthesiologist pain doc next week. So far he has not been willing to try such an experimental procedure.

One other thing I would like to mention, is that cutting back on frequency of folic acid doses has succeeded in kicking up the CNS considerably with what I am doing just in the past week.

 

[Rockt]

Thanks Fred. I was hoping you would comment.

I know there would be huge resistance to something like this from the medical establishment - there always is. But if it could help, they should be challenged about it. Sounds like it's safe and would be relativley cost effective, (don't know what the anesthesiologists make, probably a LOT!, but B12 is relatively cheap). If you've inquired about it and are going to do so again, you must think it has potential?

SpecialK82, you should ask your doc about it too.

 

[Freddd]

Thanks Fred. I was hoping you would comment.

I know there would be huge resistance to something like this from the medical establishment - there always is. But if it could help, they should be challenged about it. Sounds like it's safe and would be relativley cost effective, (don't know what the anesthesiologists make, probably a LOT!, but B12 is relatively cheap). If you've inquired about it and are going to do so again, you must think it has potential?

SpecialK82, you should ask your doc about it too.

Hi Rockt,

I have inquired because I have been struggling with healing subacute combined degeneration that I have had going on for 20 years and is presumed permanent by the medical establishment after 2 weeks of symptoms. If I had to spend $1000 each 3 months to maintain it I wouldn't call that cheap. It is an experimental procedure and insurance wouldn't cover it if I even was able to buy insurance which I haven't been able to do since 02/09/1972 at 10:30 am. Any injection into the spinal area has very definite risks.

I inject 30mg a day to force mb12, via diffusion, into the CSF/CNS. Now that I have that working again after all the glutathione and folic acid setbacks. As each injection only lasts about 8-10 hours it suggests I loose cobalamin rapidly from the CSF. According to one doc working with neurological healing with mb12 it takes 5 years of continuous healing to make neurological healing "permanent". My experience is that iot takes about 9 months for each cycle of healing. Until now, in 8 years I haven't been able to keep healing going longer than 2-3 months without setbacks. The glutathione was a 2+ year setback and caused me much addtional damage. I have had lots of setbacks quite regularly and now they appear to be folic acid caused. So we shall see. I have worked long and hard "debugging" the active b12/folate protocol. Now for the first time I think that I might be able to put 9 months together back to back. This healing of the cord appears to be very sensitive to the presence or absence of Metafolin.

And most docs won't do something, espcially something with risk unless they can have a high expectation of sucess. That is why a person needs to work up through the titrations and find out if they have a problem getting the cobalamin into the spinal cord, brain via CSF. There is a completely worked out sequence that will demonstrate if it will work so why would you want to try something risky and expensive until you know if it will work?

 

[Rockt]

Great points Fred - as always, thanks for your input and all you do.

I guess I was jumping the gun, trying to find the magic bullet. I have to admit that I have some trouble understanding the protolcol and the experimentation required, (especially with your new folic acid discovery), so the idea of an injection that might help greatly is appealing. But we're not there yet, so, with your help and the help of others out here, we'll soldier on with what we have available now.

Thanks again.

 

[Freddd]

Great points Fred - as always, thanks for your input and all you do.

I guess I was jumping the gun, trying to find the magic bullet. I have to admit that I have some trouble understanding the protolcol and the experimentation required, (especially with your new folic acid discovery), so the idea of an injection that might help greatly is appealing. But we're not there yet, so, with your help and the help of others out here, we'll soldier on with what we have available now.

Thanks again.

Hi Rockt,

Look at it this way. First you need to find all the cofactors needed to actually allow the mb12/adb12 to heal. Until these are found with the sublinguals anything more is wasted anyway. Then consider that the sublinguals are probably all that most people need, with cofactors, and in that case, injections or intrathecal injections are a waste of time and money and won't do any more. That whole range of Japanese studies were on people with very damaged nervous systems which unfortunately I have. What reasons do you have to think that you are that damaged? Are you having symptoms of subacute combined degeneration?

 

[Rockt]

"What reasons do you have to think that you are that damaged? Are you having symptoms of subacute combined degeneration? "


Well, not sure what this means, but I have had several concussions and since a lot of my CFS troubles started afterwards, I always think there might be neurological damage. The funny thing is though, I had neuro-psych testing done a few years after the last concussion and it showed that my processing speed was mildly lower than average. Had the test re-done a year ago and my processing speed is WAY down, which isn't normal for a post-concussion syndrome-type situation, (it should get slightly better with time as the brain compensates and heals a bit). I tend to think my current symptoms, while possibly triggered or worsened by the concussion, are more CFS in nature. My MRI shows mild scarring, typical of a male who's participated in sports, (or really just lived a normal childhood full of bumps and bruises), but is otherwise quite normal. Brain fog and mental PEM are bad, though.

 

[Freddd]

"What reasons do you have to think that you are that damaged? Are you having symptoms of subacute combined degeneration? "


Well, not sure what this means, but I have had several concussions and since a lot of my CFS troubles started afterwards, I always think there might be neurological damage. The funny thing is though, I had neuro-psych testing done a few years after the last concussion and it showed that my processing speed was mildly lower than average. Had the test re-done a year ago and my processing speed is WAY down, which isn't normal for a post-concussion syndrome-type situation, (it should get slightly better with time as the brain compensates and heals a bit). I tend to think my current symptoms, while possibly triggered or worsened by the concussion, are more CFS in nature. My MRI shows mild scarring, typical of a male who's participated in sports, (or really just lived a normal childhood full of bumps and bruises), but is otherwise quite normal. Brain fog and mental PEM are bad, though.

Hi Rockt,

I have had several concussions as well; football, rocks thrown, a bad parachute landing and a heavy duty head plant on white asphalt while skiing. However, the subacute combined degeneration comes about from demyelination within the brain and cord. It takes away feeling, muscular control, position awareness of limbs, vibration sense, balance, absent reflexes or brisk reflexes or different reflexes (Babinsky sign), incontinence, extreme psychosis, mood changes, personality changes, paralysis of the diaphram and death. Some of these overlap functional changes that reverse quickly with normal amounts of mb12/adb12/Metafolin.

 

[Rockt]

Hi Rockt,

I have had several concussions as well; football, rocks thrown, a bad parachute landing and a heavy duty head plant on white asphalt while skiing. However, the subacute combined degeneration comes about from demyelination within the brain and cord. It takes away feeling, muscular control, position awareness of limbs, vibration sense, balance, absent reflexes or brisk reflexes or different reflexes (Babinsky sign), incontinence, extreme psychosis, mood changes, personality changes, paralysis of the diaphram and death. Some of these overlap functional changes that reverse quickly with normal amounts of mb12/adb12/Metafolin.

That's amazing. Why doesn't the medical establishment know this? Sorry if I answer my own question cynically, but probably because Big Pharma funds most of the studies and there's not a ton 'o dough in B12.

Fortunately, I don't have any of those symptoms.

Hey, do you think any of your other issues are related to the concussions?

 

[Freddd]

That's amazing. Why doesn't the medical establishment know this? Sorry if I answer my own question cynically, but probably because Big Pharma funds most of the studies and there's not a ton 'o dough in B12.

Fortunately, I don't have any of those symptoms.

Hey, do you think any of your other issues are related to the concussions?

Hi Rockt,

Why doesn't the medical establishment know this? Sorry if I answer my own question cynically, but probably because Big Pharma funds most of the studies and there's not a ton 'o dough in B12.

But they do know all about subacute combined degeneration. It is well documented in the literature and diagnostics manuals. Based on research on cyanocbl and hydroxycbl it is said to be incurable 2 weeks after symptoms start. I've had better than 90% recovery of the symptoms I had of 10-20 years standing. Daily oral doses of cyanocbl and folic acid never prevented it from occurring once I became a vegetarian. My neurology continued to deteriorate through sublingual mb12/adb12 doses and injected SC mb12 doses through 6mg each. At 7.5mg somethiong wonderful occurred. Progression stopped. At 4x7.5mg or 3x10mg daily progression has been reversed. Glutathione set me back 2 years or more in this. Folic acid keeps stopping progress. It can reverse a month of progress in 3-5 days of fallback. I just found this out 2 weeks ago now.

It isn't so much a lack of research on the matter, it is asking the wrong questions in research and using statistical methods. This part of it I have investigated thoroughly. The research builds on previous research kicked off by a lab mistake naming cyanocbl as "B12" officially. Now there is a substantil body of research protecting the idea of inactive cobalamins - cycbl/hycbl. The therapies developed with them work, even in me, and are effective against macrocytic anemia. The problem is that monthly doses of a few micrograms of active cobalamin, which can be gained from the inactive cobalamins sort of as a starvation mechanism, can mature red blood cells of normal size while doing almost nothing at all for functional neurological problems and even less for neurological damage. Then there are those with CFS/FMS and many other neurological disorders that have depressed CSF cobalamin levels regardless of serum levels. This is just being researched now and it is increasing. Maybe in 50 years they will get around to a therapy that would have saved my life if it had been 70 years sooner. Right now they are trying their therapies with cycbl/hycbl and folic acid. That is a really dirty joke and kills people like me and some percentage of people here.

There have been hundreds of "combination" therapies with methylb12 that have had patents filed so somebody will own the rights to any therpies discovered by somebody else. That too is a really dirty joke and discourages big pharma from even looking.

 

[Freddd]

Hi Rockt,

I talked with my doc today. He wants to see what research there is on intrathecal mb12 usage and might possibly consider it.

 

[Rockt]

Hey isn't that cool! Thanks for looking into it.

I just think it's worth looking at. If it worked well for diabetic neuropathy, why not for other neurological conditions?

Please keep us posted.

 

[mtnbibliophile]

Rockt, in response to your post "I have had several concussions and since a lot of my CFS troubles started afterwards, I always think there might be neurological damage. The funny thing is though, I had neuro-psych testing done a few years after the last concussion and it showed that my processing speed was mildly lower than average. Had the test re-done a year ago and my processing speed is WAY down, which isn't normal for a post-concussion syndrome-type situation, (it should get slightly better with time as the brain compensates and heals a bit)..."
I too believe I have neurological damage in addition to my CFS, based on seeing my cognitive abilities plummet. I have been wondering about a possible connection between CFS and neurological damage, since (1) we know there is a greater risk of CFS among people abused as kids and (2) many abused kids were repeatedly punched in the head (where bruises don't show), putting them, like football players, at greater risk of post-concussive syndrome (PCS) or chronic traumatic encephalopathy (CTE). (Rockt, if you have CTE and not PCS, you would get the progressive degeneration that your neuro tests show.).
At least two thirds of the symptoms of PCS are also symptoms of CFS; several of the symptoms of CTE also overlap CFS.
Any thoughts? Is anyone aware of any research into these possible connections?

 

[ahmo]

Rockt, in response to your post "I have had several concussions and since a lot of my CFS troubles started afterwards, I always think there might be neurological damage. The funny thing is though, I had neuro-psych testing done a few years after the last concussion and it showed that my processing speed was mildly lower than average. Had the test re-done a year ago and my processing speed is WAY down, which isn't normal for a post-concussion syndrome-type situation, (it should get slightly better with time as the brain compensates and heals a bit)..."
I too believe I have neurological damage in addition to my CFS, based on seeing my cognitive abilities plummet. I have been wondering about a possible connection between CFS and neurological damage, since (1) we know there is a greater risk of CFS among people abused as kids and (2) many abused kids were repeatedly punched in the head (where bruises don't show), putting them, like football players, at greater risk of post-concussive syndrome (PCS) or chronic traumatic encephalopathy (CTE). (Rockt, if you have CTE and not PCS, you would get the progressive degeneration that your neuro tests show.).
At least two thirds of the symptoms of PCS are also symptoms of CFS; several of the symptoms of CTE also overlap CFS.
Any thoughts? Is anyone aware of any research into these possible connections?

My ME/CFS began after a heat stroke event. I had increasing neurological symptoms, until 9 years later, 2011, I felt as if my whole existence was reduced to a white hot neuron. There were no answers, no respite. I even arranged for an MRI, which showed only small "stress spots". Fortuitously I discovered the GAPS diet, Gut and Psychology syndrome. 3 days into the diet my nervous system calmed. The improvements to my nervous system have continued during this year on the diet. I didn't add methylfolate and methylB12 until about 8 months on the diet. The neurological healing began much sooner. Neurologist Natasha Campbell McBride devised the diet to help her autistic son. (revised SCD) Animal fat is a core healing agent for the brain. I could feel the benefits increasing over time. Less brain fog, greater cognition, an end to the tremulousness and over-reactivity.

 

[Freddd]

There were several high dose Japanese studies which established the range in which I found the CNS threshold effect. After and equilibrium in body with MeCbl, AdoCbl and the other necessary items, and startup is dealth with and no more effect from increasing the dose, then single dose trials of 50mg of each AdoCbl and MeCbl sublinguals on different occasions, MeCbl FIRST, then the single dose trial can tell you if there is a separate CNS threshold for you or not.

I had several concussions myself, all of known causes like bad parachute landings, beaned with a rock, doing a head plant skiing and maybe a couple more. The Mecbl and AdoCbl can cause a speed increase in the nerves. Also with the right cofactors, including omega3 oils, myelin can be healed to an extent. I went through a difficult year of neurological healing with all the mood volitility, changing from irritable and basically Mr Hyde to the kindly Dr Jeckyl as my senses returned, the multisensory hallucinations (noise) went away, life long depression went away and my memory and cognition returned to normal from very impaired. My blurry unfocuisng eyes were easlily focused within hours of body level doses. MeCbl does appear to prevent cascading neuron death accpording to some studies.

The reason I haven't tried the intrathecal injections is that I have not been able to locate suitable 5 star MeCbl. Further my docs, are nervous about things like that since the mold contaminated spinal injections from that one pharmacy

The other high dose studies were done oin various ways on people with ALS and MS. They had significant restoration of funtion for the duration of the stury. The intrathecal injections were done in people that were not known to have CSF cobalamin problems and show the tremendous variability of retention time. In people like us, an intrathecal injection might only last a few days. That is one thing we don't know.

 

[Lotus97]

There were several high dose Japanese studies which established the range in which I found the CNS threshold effect. After and equilibrium in body with MeCbl, AdoCbl and the other necessary items, and startup is dealth with and no more effect from increasing the dose, then single dose trials of 50mg of each AdoCbl and MeCbl sublinguals on different occasions, MeCbl FIRST, then the single dose trial can tell you if there is a separate CNS threshold for you or not.

I had several concussions myself, all of known causes like bad parachute landings, beaned with a rock, doing a head plant skiing and maybe a couple more. The Mecbl and AdoCbl can cause a speed increase in the nerves. Also with the right cofactors, including omega3 oils, myelin can be healed to an extent. I went through a difficult year of neurological healing with all the mood volitility, changing from irritable and basically Mr Hyde to the kindly Dr Jeckyl as my senses returned, the multisensory hallucinations (noise) went away, life long depression went away and my memory and cognition returned to normal from very impaired. My blurry unfocuisng eyes were easlily focused within hours of body level doses. MeCbl does appear to prevent cascading neuron death accpording to some studies.

The reason I haven't tried the intrathecal injections is that I have not been able to locate suitable 5 star MeCbl. Further my docs, are nervous about things like that since the mold contaminated spinal injections from that one pharmacy

The other high dose studies were done oin various ways on people with ALS and MS. They had significant restoration of funtion for the duration of the stury. The intrathecal injections were done in people that were not known to have CSF cobalamin problems and show the tremendous variability of retention time. In people like us, an intrathecal injection might only last a few days. That is one thing we don't know.

Wow. The dosages in those studies seem extremely high. I hope you're not suggesting that any of the people here take that kind of dosage because someone new to methylation reading that could cause serious damage to themselves by even taking a fraction of that dose.

 

[Freddd]

Wow. The dosages in those studies seem extremely high. I hope you're not suggesting that any of the people here take that kind of dosage because someone new to methylation reading that could cause serious damage to themselves by even taking a fraction of that dose.

Hi Lotus,

In the Japanese studies they just jumped right into it. Last I heard they were doing pump type deal that feeds something like 4mg/hour into the body to maintain that high diffusion gradiant to get the b12 into the spinal system without having to do intrathecal injections with their inherent dangers. In order to derive the most information possible it has to be done differently. First comes the body titration, balancing all cofactors and getting everything working. Also, alll essentials have to be in place so we know what we are seeing After the startup effects have simmered down and additional titration makes no detectable difference, ie 15mg sublingual makes no difference over 5 or 10mg, and there has been plenty of time for the cobalamins to work their way into the CSF/CNS then I might suggest the single 50mg dose. If done properly it won't be noticable in the body. That is essential, because the CNS only effect are usually much more subtle and is completely obscured by a big body reaction. What we are trying to detect here is if the person has that problem of getting and/or retaining cobalamins in the CSF/CNS. Then if there is a reaction to MeCbl, and that one is repeatable, how often indicates how fast the person looses MeCbl from the CSF/CNS. The response to AdoCbl might not be repeatable more than once each 6 months. If there is no response to either then the larger doses by injection or sublingually or combination serve no purpose.