Patients improve after levodopa wear off: paradoxical "on"
 

Hi,

I ran across this article and found it interesting. Even if only four people...means others are experiencing it too. The "it" is a prolonged period of "on" time or time where patient feels near normal long after a medical dosage has worn off. This is like an hour after wear off meaning this entire experience is highly unusual. I am wondering if this isn't further indication that all of our cells are on an inevitable path of self-destruction; that in fact, many of our cells are merely impaired or "stuck" somehow? Has anyone experienced anything like this? This also serves to highlight how hard it is to study advanced PD when medication masks everything

Novel pattern of levodopa-related motor fluctuations: ‘Paradoxical’ on

-Laura

Stories
 

We were discussing this recently,a bunch of PWP,one of whom had acquired a lathe to turn wood ,he could immerse himself for hours as soon as he stopped he couldnt function .Others responded with similar stories

Hi Laura,
I have had a number of occasions when I suddenly switch on whilst unmedicated. I have posted about it before, but have not found anyone else who experience it. It happens either on getting up from bed or when my meds have worn off. As I mentiomned in another thread, the phantom "on" seems to be initiated (but not always by eating. The longest on time I have seen is 90 minutes.
Very pleased to see your post, I was starting to think it did not happen to anyone else.
Ron

I experience a similar thing almost routinely at night. Typically, I take the last meds at 6:00 PM and am OFF and in bed by 10:00. If I awaken at midnight I find that I am again ON and can get up and remain so for as much as 30 minutes or so.

I agree with this because I also own a wood lathe and can turn for hours without medication. As soon as I stop I am in trouble. It is as if....... how to explain...... As if I am in another body that does not have PD. All of my focus is on what I am doing not on what my body is doing. Once I stop and become aware of reality I can't walk, the tremor returns, and postural instability returns. I think that is why I keep turning. It has become an escape for me.

GregD

clue may be in the details
 

I would think that a daily log of what time of day this extra "ON" is occuring, last meds/dosage and most importantly, WHAT activity were you engaged in prior to the extended ON time would be helpful so that you might be able to replicate it. Exercise does it for me.

TG

everything is relative
 

Hi Laura,

After two years taking sinemet (1 tab 10/00 3 X per day), I have been experiencing a systemic improvement as well as acute improvement with the med... using both an hourly trajectory vs overall well being . altho I am at my best in morning and afternoons. the boundary between "on" and off was in the beginning very fuzzy and only recently is more acutely apparent tho more like switching a light off and on with a dimmer switch and the light is steadily getting brighter.

I notice I always tend to improve in the Spring. Also a while back Janice W-Hadlock mentioned t hat she observes a 23 day cycle of in PWP.

kind regards
md (pd sx since 94)

Wondering if ...
 

Interesting that many people experience this. This "on" in the article is not to be confused with that good half hour we sometimes have in the morning due to sleep benefit or dopa reserves. In fact, it's odd, the people involved would actually feel worse upon dosing then do well, hit wear off, then bam feel great like an hour after their dose wore off. This was so marked that some people would skip a dosage. I think this is a combo of us tapping into our natural dopa reserve and our bodies reaction to med withdrawal abating.
I really think the harsh on-off effect is due to drug dependency and our heightened symptoms are like a withdrawal effect. I underwent a 12 hour drug washout last October and surprisingly despite a prominent tremor did okay; I noticed that I only felt brain foggy upon taking a dose of Sinemet in the doc's office; it went away after drug kicked in.

How many of you feel brain fog when in these "on" states? Again, based on my experiences, I think the brain fog is a withdrawal symptom. I feel it when meds starting to kick in or not at all.

Any other thoughts?

MD, what do you mean by "23 day cycle"?

Laura

to everything turn turn turn
 

[QUOTE=Conductor71;71386

Any other thoughts?

MD, what do you mean by "23 day cycle"?

Laura[/QUOTE]

JWH observed that her patients as a group experienced fluctuations of well being to symptoms worsening together that cycled every 23 days. I take comfort in knowing that when I'm low that in "time" this will be followed by bettter days ahead and that has certainly been true for me. thats just natures way.

maybe we all vibrate to some planet out there ? (not kidding ) -what a complex and manificent world (universe) we live iin!:grouphug:

love your intuitive thinking Laura !
md

brain fog
 

As a PWP virgin not on meds, I have been trying various vitamins and supplements over the last few months, some such as CQ10 and Riboflavin having no discernible effect

Others -induced your aptly named 'brain fog' - (difficulty thinking logically, transposing numbers on spreadsheets in my job, and wrong use of words when talking)

Iradapine - Blood Pressure Calcium Blocker - undergoing trials to see if it slows PD - I stopped taking after 3 weeks
Coconut Oil - Stopped after 3 days - muzzy head
Evening Primrose Oil - induced a 24 hour headache each time

I was uncertain if the 'brain fog ' was leading to positive or negative effects, so chose to stop taking them.
In the light of your post, it appears that they act to some degree like meds ?
Not having taken meds, I'm not sure if a degree of 'brain fog' is expected ?

I have been off meds since December 2009 trying to control my symptoms with diet and exercise. the exercise I took up was jogging. While I jog, my symptoms seem to disappear, except for a slight limp on my right I am smooth sailing. When I wasn't eating any carbs, my symptoms while still present were not as bothersome. it's pretty exhilirating.

Ive had sort of on periods after midnight many nights..My meds wear off at about 7:00 pm..I at least can walk without shuffling

Another thing..When my meds wear off I shuffle around the house, but if I go outside for a walk, I dont shuffle at all

When Im out fishing, especially when Im catching good, it amazes me what I can do..But when Im done fishing, and heading back to the dock, the symptoms start rearing their ugly heads

Many of these observations seem related to either activities that we lose ourselves in and the endorphins that come with them or to time of day fluctuations in hormones or, possibly, electrolytes.

The mention of carbohydrates adds in the influence of insulin as well. Insulin causes the ebb and flow of potassium levels at least which, in turn, affects muscles and nerves.

Near normal during the night unmedicated
 

My last dose is usually around 5pm, about a 1/2 hour before supper. I'm usually a bit overmedicated by this time. I often have difficulty talking and I'm a bit antsy. It's a fine balance between taking to much or to little. I'm in my 10 year of having PD. It's becoming more of a roller coaster ride now.
But starting around 7pm, my body will go through a transition from being overmedicated to being unmedicated.This can takes up 3 hours. My symptoms varies during transition: (tremors, difficulty walking, sweating, body ache and I'm very weak). Then by 10pm, my body is settled down and most of my symptoms fades away, even my strength improves. Tremors are gone, sweating stopped, walking returns back to almost normal and my speech is fine. I usually go out in the hallway (I live in a condo) for mid-night walks. I'm far from being normal, but overall I can manage quite well unmedicated 'till my next dose at 7am.
I still need to take meds during the day so I can function normally. I'm not able to produce enough dopamine on my own right now. When my meds are working, I can appear quite normal, my strength is back, balance is fine, etc. But as the day wears on, my On-Off times worsens. My doctor suggested I start taking Bromocriptine to help smooth things out. I'm currently taking 1/2 200/50 Sinemet CR and 1/2 tsp of mucus every 2 nows. A total of 3 200/50 tablets a day.
I mentioned this to my doctor that my symptoms are greatly reduced unmedicated, just overall weakness and my balance is a bit off. He was a bit surprised but didn't give an explanation. Who knows, maybe I'm cured, but just dependent on pd drugs and suffer from the side effects.
I know these drugs are doing me more harm than good, but my body isn't healed enough to manage on its own right now. I injured my back a year ago when I went Bungee Jumping (You only live once. I never regret what I've done only what I haven't done.) I'm scheduled for a spinal fusion, but I keep postponing it, giving my back a chance to heal on its own. So far it's recovering, but it's a slow process. Taking my pd drugs/helps strengthens my body so I can move without much backspin.

One day at a time..
EnJOY life always.
Max

correction
 

I'm currently taking 1/2 200/50 Sinemet CR and 1/2 tsp of mucus every 2 nows.

I meant to say "Mucuna" not mucus.

Silly me.

no tremor during exersize!
 

I experience no tremor during exersize! They tell me this is typical in PD. We have resting tremor instead. (Typically also: they don't know why!)
Imad

Rick: can you elaborat/explain your statement above on the role of carbohyderates.
thanks
Imad

Imad-
I was referring to a phenomenon that I was forced to learn about earlier this year and which I'm not at all sure has no bearing on PD. When we eat carbs our bodies secrete insulin. This serves as a signal for the muscles to absorb the glucose that the carbs form in the bloodstream. A certain amount of potassium moves with it. In normal people, things quickly balance out but a number of us have a genetic problem that delays this. Our muscles go weak and we can't move until things slowly balance out.

The reason that I have doubts about this is that while of the 20 or so forms of this disorder almost all are hereditary with the exception of one. It can develop as a result of thyroid problems caused by stress. Combine that with sinemet messing with insulin systems and there were real questions in my mind. I seem to have gotten over the "attacks" but I still wonder if it ties in to our stress response. You can read about it here.

carbohydrates/sinemet
 

Breathing
 

Imad,

I don't have much to add but wanted to say that you are not alone in this. I have noted that since starting drugs I have more shallow breathing and feel quite winded after the least amount of exertion. I just attributed it to med side effects but also wonder if it just a PD symptom that does not respond to "the gold standard". I do hope your neuro can help with finding a med that works for you. I can't recall...have you tried a beta blocker to help your tremor?

Laura

I had a mysterious on period tonight

Took last stalevo at 3:00

Went into a hard off at 6:30

Completely rebounded for an hour and a half at 8:30

Whats up with that?

Wonder whether the paradoxical 'offs' are in someway related to the l-dopa cycle in the brain/body, and the half life thing. By this I mean we take our dose, experience wearing on, which can be as bad as the PD or worse, and accompanied by things like excessive sleepiness, brain fog, dystonias etc., then we come on and feel great for a while, and when the initial half life of what we have taken has worn off we go bump, get the wearing off signs, take another dose, and go through the whole cycle again. But there is still residual dopa left floating around in our systems, as well as what we are still making for ourselves. And we need less at nighttime anyway because that is when the body demands less, as per the whole circadian rhythm thing. So our last dose gives us the nasty bump, and then we slowly come out of that into a clear patch where we are dopa balanced. Night times are good for me too, but only if I keep on taking the sinemet in the day.....

And the doing something absorbing is a different thing, I am sure there is another circuit that gets activated by our being absorbed by particular activities - I wish someone would really look at this, you know, observe what is happening when we are like that - because the other paradoxical thing is that when we are disturbed or shaken out of that state we go off almost immediately........

Maybe that is why quite a lot of us become creative in some way, because that is where we can be ourselves again....... Laura, I am sure I have read about scientific observation relating to creativity..... just don't remember where:confused:


Lindy

only thing.....
 

off the top of my head is a flood of amino acids in the bloodstream after a high protein intake.

paradoxical "on"
 

Jazz trumpeter Tom Harrell makes the schizophrenia voices go away by playing.

It was strange, because I went off a 6:30, and didnt eat super untill a little after 9:00, for a couple of reasons..One reason was because my girlfriend went Xmas shopping after work, and I would be at an AA meeing untiil 8:30, and I was in no shape to cook anything, so all I had inbetween 6:30 and 9:00 was a cup of coffee..At around 8:15 I started getting dyskinetic which never has happened after my meds have supposedly worn off for the day..I get short periods of dyskenisia when my meds are either kicking in, or wearing off..Anyway, by the time I got home at about 8:45, I was on again, and after I finally ate super a little after 9:00, I felt even better untill about 10:00, when I went off for the night

Is there an explanation as to why the meds lay dormant in our system for hours sometimes, cuz the other thing that happened yesterday was it took an hour and a half for my morning meds to kick in, but in this case, not untill I was eating breakfast?

Steven53,
I get very similar unmedicated "ons" as yourself. See my thread
http://neurotalk.psychcentral.com/sh...ight=Ronhutton
and my earlier post in this thread. it is strange, since L-dopa has a short half life, about 2.5 hours I think. So it should have dropped below the on threshold yet we are seeing an on situation long after then.

I did a search and found the following abstract on storage of dopamine.

http://www.neurology-apd.com/article...fused-duodenum

Dopamine Storage Mechanisms
In the normal brain or the brain in early stages of PD, there are still residual dopaminergic neurons. Thus, when the neurotransmitter is synthesised from its precursor dopa it can be stored in specialised vesicles and released relatively steadily into the synaptic cleft. In advanced PD, dopamine is still synthesised in the same manner; however, owing to the degeneration, this appears to take place in non-dopaminergic cells that lack the ability to store and release dopamine. Therefore, striatal post-synaptic cells are stimulated in a pulsatile manner every time a bolus of levodopa is presented to the brain. This hypothesis was developed more than two decades ago and evidence for it is still mounting. A recent study used positron emission tomography scans in patients with PD before and after an oral dose of levodopa. The amount of dopamine released in the synapse was indirectly easured by recording the amount of raclopride binding, which has an inverse relationship with dopamine levels. The data showed evidence of increased dopamine release in the putamen in patients with advanced PD compared with those with early or mild disease. Additionally, dopamine release correlated positively with the incidence and severity of dyskinesias.4 Greater dopamine release following administration of levodopa suggests impairment of pre-synaptic storage. Other hypotheses include impairment of the mechanisms that govern the release or re-uptake of dopamine

Ron

Levodopa daily withdrawal
 

4 hours after my last dose of the day of Levodopa 25/100 (I can't tolerate more than 400 mg a day, 2 to 2.5 hours apart (either dyskenesia with feet curled up so I can't walk, or falling down risk) I am at maximum freeze-up of the day, when I don't dare lay down, because I get stuck and can't move or turn over and it's too freaky. By 6 hours after last dose of the day I can move again. So I have to time my last dose of the day 6 hours or more before I will want to go to bed. This makes meal time akward to say the least, and as for doing anything in the evening, forget it.

This maximum freeze-up at 4 hours following last dose is consistant, happens every day. If I go to bed before the 4 hour withdrawal maximum has passed, I have a tremendously uncomfortable freeze-up crisis, and have to call for help to turn over (and get up to pee for the first few of the half a dozen times in the night).

Haven't seen this phenomenon described anywhere --- surely I'm not the only one this happens to! Have been on Levodopa/carbidopa for almost 9 years; can't tolerate agonists. Am noticing that if I eat a lot of chicken for supper I risk not recovering my mobility after the 4 hour withdrawal maximum, and have to get help to turn all night, suffer painful distonia, and after a scary episode when for the first time ever I couldn't dress myself in the morning, I am sticking to a vegetarian diet! Anyone else have this going on?

Atme
 

Hi Atme,
A lot of what you say rings true for how I used to be.
Chicken for me too for some reason I've never been able to work out but it was one of the worst offenders for prolonged offs.
Dystonia also was excruciatingly painful and the akinesia which made not being able to turn in bed close to impossible but also get up and go to the loo!
Dyskinesia I can tick that box too.
The only answer I can give to you is that it's a bloody awful way to live and perhaps it's time to think about DBS? Just a thought.

My latest weird idea
 

Hi kids. Haven't been here in a while. Dad's been having tons of problems with dyskinesia. Anyhow, this just suddenly occurred to me- you guys may have more than one infection. With opposite effects.

Despite the fact that my father has a Parkinson's diagnosis, I have just realized that in the past months he has been very clearly exhibiting all the symptoms of Sydenham's Chorea. Although many of his symptoms could be attributed to levodopa therapy, his involuntary movements had a sudden onset and have been getting progressively worse despite numerous changes in medication. He also has other documented symptoms of streptococcal infection: periodontal disease, chronic tearing from the eyes, and obsessive-compulsive behaviors. He has also been craving and bingeing on sugar. I cannot think of a reason why Parkinson's would preclude him from also having a strep infection.

My guess is an atypical streptococcal species. For instance- I am currently being treated for a chronic bacterial infection of my parotid gland, his brother has recently been diagnosed with a benign tumor and pathology in his submandibular glands, and my grandfather had esophageal cancer. Streptococcus anginosus is strongly implicated in all of these disorders, as well as skin cancer, a diagnosis that is common in PWP and which my father has already been given several times.

As I posted a long time ago, I believe the neurons in the substantia nigra are destroyed by an autoimmune-viral interaction. The strep antibodies in Sydenham's bind to the D2 and D3 receptors. If comorbid, these two disorders would create more complex presentations and drug (and food) interactions than ordinarily assumed.

Dad hates this idea for some reason. Totally uncooperative. I must somehow convince his doctor to test him...

Anyhow, I'm glad to see all you smart people are still here working on this. Hope this helps.

Heidi

You have just described more or less my daily routine, plus or minus a few particulars

This is something Ive been experimenting with to deal with those deadful 6 hours every night, in the following thread......

http://neurotalk.psychcentral.com/thread146026.html

I too have paradoxical on, almost exactly as Ron describes. And occasionally when extremely absorbed in something. Creative people of all kinds without PD experience what is sometimes called being 'in the zone', as do athletes. I wonder if these are related. If you are in the zone you are able to work at a higher intensity, concentrate more, and become unaware of the passage of time. Perhaps there are different circuits of motor control, and we are simply using the other one, the one they are not describing yet...... I think there may also be an enjoyment circuit too, laughing and really enjoying oneself also can bring a paradoxical on........

Which ever way though it comes with a price, if you do not take your meds at the same time as normal, when you do go off, it can be harder to get back on again. It is also paradoxical because you are never sure when it is going to happen, because it is not consistent.

Lindy

Sorry, probably posted something similar in earlier thread

yep
 

i want to share a similiar experience. i underwent dbs in nov 2010. it was a success as far as eliminating most of my left hand tremor & neck dystonia. however, i have been unable to get a definite schedule as far as meds. as prior to dbs, there have been days when i have "better" coverage, & days when i can barely walk & cannot get to the bathroom in time. i changed my diet, little protein, no gluten, no food till dinner... i changed time intervals, doses, etc. but this past weekend i finally think ive got it! i had one of the most stressful two days i have had, & my symptoms went wild, for the weekend and monday after i could not walk, & had awful painful muscle spasms & jerking in my left arm. the thing is i could not focus on anything else. the more i thought about it the more upset since i couldnt figure it out. i was mad, i was anxious, i was worried. i could not focus outside me, which was really contributing to the horrible symptoms. i spent my life as a nurse, and think i took really good care of other people. i liked helping & making a difference. i am vowing to apply that care to me. oh yeah, i can walk & even wait 5-7 hours between doses this week, as long as i do not get too anxious, and start thinking too much. i forgot that if i think i can i can, and you know the rest. so profoundly simple, thanx FG :)

A couple things-

Strep anginosus is much more prevalent in alcoholics. I do not know if this is due to a genetic predisposition, loss of orexin function, or effect of the alcohol. Alcohol changes the permeability of the oral membranes. Anyhow, my face now swells up when I have a drink.

When my parotid flared up I had incredible anxiety, anger and obsessive thoughts. I called them rage attacks. And since I've been on penicillin it has abated completely. My mind has never been so quiet.

Seriously guys, I think there's a combination of things causing your symptoms. At least some of you. And they are further confouded by the effects of your drugs.

So, did you have the DBS done?

Yes I did
 

7 yrs ago.

How's your life now? would you recommend the DBS? Do you still have to take medication?

How is your life now? Do you still have to take medication? would you recommend DBS?

Somewhere there is a paper on my desk which says that levodopa taken orally causes a dramatic drop in cortisol levels and the more advanced the disease the more drop.

What does it do to your day if you get up as your cortisol rises to greet the dawn only to be knocked back? And it is repeated every few hours? And what about in the evenings when production is down and you drive it even lower?

1. Clin Neuropharmacol. 2007 Mar-Apr;30(2):101-6.

Acute levodopa intake and associated cortisol decrease in patients with Parkinson
disease.

Müller T, Muhlack S.

Department of Neurology, St Josef Hospital, Ruhr University Bochum, Germany.
thomas.mueller@ruhr-uni-bochum.de

Levodopa application improves motor symptoms in patients with Parkinson disease
(PD). Levodopa induces lower cortisol plasma levels and decreases serotonergic
activity in certain brain areas of fish. The objectives of this study were to
perform repeat cortisol concentration measurements before and after the
administration of soluble levodopa/benserazide (dose, 200 mg) in 32 patients with
PD during an interval of 150 minutes. The cortisol concentrations significantly
decreased after levodopa intake, particularly in the patients with more advanced
stage of PD, but not in the less affected patients. There were significantly
lower cortisol levels in the patients at the advanced stage of PD compared with
those of the earlier patients with PD, particularly at -30, 0, and 90 minutes
before/after levodopa application. Significant inverse relations were found
between the cortisol levels and the Unified Parkinson Disease Rating Scale total
score, particularly at 60 and 90 minutes after levodopa intake. Neurodegeneration
occurs in striatal regions and in the brain stem of patients with PD. The
5-HT-containing neuronal terminals of the brain stem hypothetically mediate the
cortisol level decrease after levodopa intake because these cells contain an
important fraction of amino acid decarboxylase. Therefore, this compartment may
be the site of enzymatic conversion of superfluous, exogenous levodopa to
dopamine. Consequently, short-term levodopa administration also leads to levodopa
uptake in these 5-HT-metabolizing neurons, which interferes with the 5-HT
synthesis and may cause a decrease of 5-HT levels. These lower 5-HT levels reduce
the hypothalamic function and, via the corticotropin axis, the subsequent
peripheral cortisol release. Thus, levodopa-induced cortisol decrease may be
related to PD progression.


PMID: 17414942 [PubMed - indexed for MEDLINE]