Download Dear Dr Neurologist - Fluoroquinolone Toxicity of the Thyroid

Dear Dr. (Neurologist),
Thank you for looking into this for me, and considering additional testing for my neurological symptoms.
The Fluoroquinolone antibiotics have a long history of either causing, or possibly “unmasking” CNS, PNS, and MGrelated (Myasthenia Gravis/ACh) symptoms as part of their adverse profile.
As you may be aware, the FDA required an update on all drug labels and Medication Guides as of 8/15/13 to warn
of the risk for permanent Peripheral Neuropathy:
http://www.fda.gov/Drugs/DrugSafety/ucm365050.htm FDA Drug Safety Communication: FDA requires label
changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by
mouth or by injection (8/15/13 update). “The U.S. Food and Drug Administration (FDA) has required the drug
labels and Medication Guides for all fluoroquinolone antibacterial drugs be updated to better describe the serious
side effect of peripheral neuropathy. This serious nerve damage potentially caused by fluoroquinolones (see Table
for a list) may occur soon after these drugs are taken and may be permanent.”
Additionally, the FDA required an updated similar warning regarding Myasthenia Gravis in February 2011:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm247115.htm Risk of fluoroquinolone-associated
Myasthenia Gravis Exacerbation February 2011 Label Changes for Fluoroquinolones. New safety information
should be included in the labeling for fluoroquinolone products. “Fluoroquinolones have neuromuscular blocking
activity and may exacerbate muscle weakness in persons with myasthenia gravis.”
These Fluoroquinolone-Induced adverse reactions can appear to be very autoimmune in nature. Indeed,
previously healthy Fluoroquinolone Toxicity patients have been diagnosed with known autoimmune neurological,
neuromuscular, and rheumatological conditions post antibiotic. However, these diagnoses may be underrepresented, as too often, patients are not appropriately tested based on initial screening criteria such as a
negative ANA. As you are probably aware, ANA values are somewhat fluid and can fluctuate in both symptomatic
and asymptomatic patients over time. As such, it is not a reliable “gateway screening” criterion in patients with
negative ANA’s and obvious symptomatology representative of a variety of known neurological, neuromuscular,
and rheumatological conditions. Based on current knowledge, FDA warnings, and published research about the
CNS and PNS Fluoroquinolone-Induced Symptoms, there are a number of simple blood tests that can be run to
help provide a possible diagnosis, and rule in or out an autoimmune component.
I’m providing an extensive listing of peer reviewed published references at the end of this letter for information on
some of this blood testing, along with information on the association of the fluoroquinolones with CNS /
Encephalopathy-related and ACh/ MG-related cases and symptoms. Because tendinopathies are a unique but
characteristic adverse effect and a hallmark of Fluoroquinolone Toxicity Syndrome for most patients in addition to
the CNS, PNS, and ANS symptoms, I’m also including some references implicating both glutamate/NMDA and ACh
in tendinopathies in general. I don’t expect you to read all of them; however, I’m hoping you’ll at least skim
through the titles of the entire list to get a feel as to why these tests are being suggested.
Based on the fact that fluoroquinolones are known to have neuromuscular blocking activity, as well as their known
association with Myasthenia Gravis, I’m hoping you’ll consider running clinically available tests which may indicate
damage associated with the normal production, storage, transmission, and metabolism of ACh, either directly or
via autoimmunity. Examples of such testing would include the following:
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Anti - ACh-R Binding, Blocking, and Modulating Ab’s, anti-SM Ab, anti-MuSK , and anti-striated (Titin/RyR)
Ab to cover Generalized, Ocular, and MuSK -related MG
anti-VGCC for LEMS (Lambert-Eaton Myasthenic Syndrome)
anti-Ganglionic AChR for AAG (Autoimmune Autonomic Ganglionopathy/Neuropathy)
Serum/Plasma (for acute) and/or RBC Cholinesterase (chronic/permanent) test for cholinesterase toxicity
Based on the fact that fluoroquinolones are known to cause acute and chronic CNS and Encephalopathy-type
symptoms, and that much of the published research is implicating damage to Glutamate/GABA receptors and/or
metabolism in these symptoms, I’m hoping that you’ll consider running the following clinically available tests:
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NMDA-R: Anti-Glutamate Receptor antibody
GAD65: Glutamic Acid Decarboxylase antibody
anti-VGKC: Anti-Voltage Gated Potassium Channel antibodies cause hyper-excitability of the peripheral
nerve and central nervous system
Anti-GABA-B (available at Mayo Clinic Medical Labs and recommended as a serological evaluation of
patients who present with a subacute neurological disorder of undetermined etiology, as part of a
paraneoplastic profile, or differentiating autoimmune neuropathies from neurotoxic effects of
chemotherapy)
Anti-TPO: Anti-Thyroid Peroxidase for Hashimoto’s Encephalopathy
Others: (These may not be available clinically yet, and serum testing is not as reliable as the more invasive
CSF testing): NMDA-NR1, NMDA-NR2[A/B] subtypes, anti-AMPA-GluR3B, anti-mGluR1 , anti-mGluR5 for
additional Glutamate receptor antibodies
Based on the case report of Levofloxacin “unmasking” a case of hereditary subclinical (asymptomatic) CharcotMarie-Tooth (CMT) Disease (see references), and that CMT is the most common inherited disorder involving the
peripheral nerves, with a prevalence of 1 in 2,500 people, I’m also hoping you’ll consider running a genetic blood
test to help rule in or out the common chromosomal defects causing CMT as a potential cause of my symptoms.
I understand these tests are beyond the traditional basic screening tests, but I’m hoping you’ll consider them
anyway. For those of us affected by FQ Toxicity, we desperately need more thorough diagnostics beyond basic
screening, in the hopes of finding an actual verifiable diagnosis as well as a biomarker of some sort for this toxicity.
Without such testing , we’re never going to find it. There are FQ victims who have been diagnosed with MG, LEMS,
and other neurological disorders post antibiotic by physicians willing to test for these. So I think they are a
possibility in my case as well. If there are additional blood tests you feel are warranted, please feel free to run
those you see fit.
Attached is also a separate page with the results of testing I’ve had so far.
Again, thank you for your time and consideration,
Sincerely,
FQ-Induced CNS/Encephalopathy symptoms implicating NMDA-R and GABA-R:
http://www.ncbi.nlm.nih.gov/pubmed/12052667 Clinical toxicological aspects of fluoroquinolones. “Pathogenesis
of the neurotoxic effects of fluoroquinolones could be related to the activation of the NMDA receptor.”
http://www.ncbi.nlm.nih.gov/pubmed/10456380 Potential interactions of the extended-spectrum
fluoroquinolones with the CNS. “Inhibition of brain gamma-aminobutyric acid (GABA) receptor binding appears to
be a strong indicator of CNS activity, though N-methyl-D-aspartate receptor binding has also been implicated.”
http://www.ncbi.nlm.nih.gov/pubmed/9132619 Psychopathological syndromes in treatment with gyrase
inhibitors. “Psychopathological and neurological adverse drug reactions (ADR) have been repeatedly reported
during treatment with gyrase inhibitors (fluorquinolones).”
http://www.ncbi.nlm.nih.gov/pubmed/7902066 Involvement of inhibitory and excitatory neurotransmitters in
levofloxacin- and ciprofloxacin-induced convulsions in mice. “ . . . convulsions induced by these quinolones alone
and by these quinolones administered with BPAA may be mediated largely through glutamate and GABA(B) rather
than GABA(A) receptors in mice.”
http://www.ncbi.nlm.nih.gov/pubmed/17478598 A case of ciprofloxacin-induced acute polymorphic psychosis
with a distinct deficit in executive functions. “Comparing the psychopharmacological features of ketamine and
ciprofloxacine we hypothesize that ciprofloxacine leads to psychosis similar to a ketamine induced psychosis . . . we
were the first in obtaining a detailed neuropsychological testing . . . from a more psychopharmacological point we
hypothesize that the ciprofloxacine-induced psychosis shares aspects with an NMDA-antagonist induced psychosis .
. . ciprofloxacine shows inhibiting properties at the GABAa-receptor and leads to an up regulation of glutamatergic
neurotransmission. Other drugs, which act via up regulation of glutamatergic neurotransmission, are NMDAantagonists like ketamine or phenycyclidine, which cause a so-called model-psychosis . . . Second, a recent fMRI
study in healthy probands showed that ketamine induces a distinct deficit of the prefrontal cortex (Honey et al.
1203-14) , a deficit with parallels to the one seen in our patient. As a consequence of this, we hypothesize that
ciprofloxacine induced a deficit in prefrontal mediated executive functions via enhanced glutamate
neurotransmission. Our case is a clinical hint for the hypothesis that ciprofloxacine gains its psychosis-inducing
properties via a glutamate-induced disruption of frontal executive functions. From a clinical point of view it
highlights the need of a better understanding of the central nervous side effects ofcommon used antibiotics.”
http://www.ncbi.nlm.nih.gov/pubmed/1504404 Ciprofloxacin-induced psychosis.
http://www.ncbi.nlm.nih.gov/pubmed/23616064 Levofloxacin-induced seizures in a patient without predisposing
risk factors: the impact of pharmacogenetics.
http://www.ncbi.nlm.nih.gov/pubmed/1647389 The effects of quinolones and NSAIDs upon GABA-evoked
currents recorded from rat dorsal root ganglion neurones.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC105691/ Determination of the Excitatory Potencies of
Fluoroquinolones in the Central Nervous System by an In Vitro Model “Fluoroquinolones have been reported to
induce central nervous system side effects, including seizures and psychiatric events . . . These investigations
pointed to the N-methyl-D-aspartate receptor as the probable target of the fluoroquinolone effects”.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202555/ The Effect of Ciprofloxacin Injection on Genetically
Absence Prone (Wag/Rij) Rat's Electroencephalogram Characteristics. “These results may be due to involvement of
GABA antagonistic effects of FQs and/or Mg2+ linked blockade of NMDA receptors.”
http://www.ncbi.nlm.nih.gov/pubmed/17046250 Microwave prompted multigram synthesis, structural
determination, and photo-antiproliferative activity of fluorinated 4-hydroxyquinolinones. “3-Unsubstituted 4hydroxyquinolin-2(1H)-one containing F and CF(3) substituent in ring is important pharmacological and synthetic
target and basic synthones for a number of antibacterial fluoroquinolones and is promising potent and selective
glycine site NMDA receptors.”
http://www.ncbi.nlm.nih.gov/pubmed/9347323 Role of nitric oxide in the convulsive seizures induced by
fluoroquinolones coadministered with 4-biphenyl acetic acid. “These findings suggest that FQs + BPAA exert
convulsions by activating NOS partly through the mediation of the NMDA receptor in the brain cells.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC172741/ Structure-Epileptogenicity Relationship of Quinolones
with Special Reference to Their Interaction with -y-Aminobutyric Acid Receptor Sites. “These results indicate that
the epileptogenic activity of quinolones possibly relates to the GABA-like structures of substituents at their 7
positions, which act as antagonists of GABA receptors.”
http://www.ncbi.nlm.nih.gov/pubmed/9266796 Inhibitory effect of new quinolones on GABA(A) receptormediated response and its potentiation with felbinac in Xenopus oocytes injected with mouse-brain mRNA:
correlation with convulsive potency in vivo. “These findings suggested that the blockade of GABA-ersic
neurotransmission in CNS is a dominant mechanism of convulsion induced by NQs and that the convulsant-adverse
reaction of NQs in vivo may be predicted from the inhibitory effect on the GABA(A) receptor in vitro using the
Xenopus oocytes translation system of exogenous mRNA”
http://www.ncbi.nlm.nih.gov/pubmed/9021202 Effects of some excitatory amino acid antagonists and drugs
enhancing gamma-aminobutyric acid neurotransmission on pefloxacin-induced seizures in DBA/2 mice.
http://www.ncbi.nlm.nih.gov/pubmed/8788959 A patch clamp study of the effects of ciprofloxacin and biphenyl
acetic acid on rat hippocampal neurone GABAA and ionotropic glutamate receptors.
http://www.ncbi.nlm.nih.gov/pubmed/24259701 SIADH associated with ciprofloxacin. “The likely mechanism of
this reaction is ciprofloxacin crossing the blood-brain barrier and stimulating the γ-aminobutyric acid and N-methylD-aspartate receptors, which leads to the synthesis and release of antidiuretic hormone.”
http://www.ncbi.nlm.nih.gov/pubmed/24259611 Orofacial dyskinesia associated with the use of levofloxacin.
“They are most commonly associated with ciprofloxacin and are thought to be related to inhibition of γaminobutyric acid receptors and activation of N-methyl-d-aspartate receptors. Orofacial dyskinesia has previously
been reported primarily with second-generation fluoroquinolones, with only a single case report implicating a thirdgeneration fluoroquinolone.”
http://www.ncbi.nlm.nih.gov/pubmed/19430173 Quantitative comparison of the convulsive activity of
combinations of twelve fluoroquinolones with five nonsteroidal antiinflammatory agents. “Concomitant
administration of certain fluoroquinolone antimicrobials and nonsteroidal antiinflammatory agents (NSAIDs)
induces serious convulsion in humans.”
http://www.ncbi.nlm.nih.gov/pubmed/2771865 Neurochemical studies on quinolone antibiotics: effects on
glutamate, GABA and adenosine systems in mammalian CNS.
http://www.ncbi.nlm.nih.gov/pubmed/12367622 Characterization of the interaction between a novel convulsant
agent, norbiphen, and GABA(A) and other ligand-gated ion channels. “A hybrid molecule composed of the
antimicrobial, norfloxacin, linked to the non-steroidal anti-inflammatory drug (NSAID), biphenylacetic acid, which
we have termed norbiphen, is a lethal convulsant in vivo and an antagonist of rodent GABA(A) receptors in vitro.”
http://www.ncbi.nlm.nih.gov/pubmed/11796360 Convulsant and subconvulsant doses of norfloxacin in the
presence and absence of biphenylacetic acid alter extracellular hippocampal glutamate but not gammaaminobutyric acid levels in conscious rats.
http://www.ncbi.nlm.nih.gov/pubmed/11529690 Biphenylacetic acid enhances the antagonistic action of
fluoroquinolones on the GABA(A)-mediated responses of the isolated guinea-pig ileum. “This suggests that
combined administration of fluoroquinolones and biphenylacetic acid synergistically inhibits GABA(A)-receptors at
the intestinal level.”
http://www.ncbi.nlm.nih.gov/pubmed/10078039 Encephalopathy induced by fleroxacin in a patient with
Machado-Joseph disease.
http://www.ncbi.nlm.nih.gov/pubmed/9351519 Selective antagonism of the GABA(A) receptor by ciprofloxacin
and biphenylacetic acid.
http://www.ncbi.nlm.nih.gov/pubmed/9142563 Interaction of ciprofloxacin with diclofenac and paracetamol in
relation to it's epileptogenic effect.
FQ-Induced Peripheral Neuropathy
http://www.ncbi.nlm.nih.gov/pubmed/11793615 Peripheral neuropathy associated with fluoroquinolones.
“These cases suggest a possible association between fluoroquinolone antibiotics and severe, long-term adverse
effects involving the PNS as well as other organ systems.”
http://www.neurology.org/content/early/2014/08/22/WNL.0000000000000846.short Oral fluoroquinolone use
and risk of peripheral neuropathy
http://jac.oxfordjournals.org/content/37/4/831.full.pdf Peripheral sensory disturbances related to treatment with
fluoroquinolones
http://hic.sagepub.com/content/2/3/2324709614545225.full.pdf Permanent Peripheral Neuropathy: A Case
Report on a Rare but Serious Debilitating Side-Effect of Fluoroquinolone Administration. “The health risks and side
effects of fluoroquinolone use include the risk of tendon rupture and myasthenia gravis exacerbation, and on
August 15, 2013, the Food and Drug Administration updated its warning to include the risk of permanent peripheral
neuropathy. We present a case of fluoroquinolone-induced peripheral neuropathy in a patient treated for clinically
diagnosed urinary tract infection with ciprofloxacin antibiotic.”
http://aop.sagepub.com/content/45/10/1312.extract Hereditary Neuropathy Unmasked by Levofloxacin. “The
molecular genetic analysis revealed the existence of the most common type of hereditary motor and sensory
neuropathy or Charcot-Marie-Tooth disease” in this previously asymptomatic patient, although the patient’s father
and only brother revealed mild subclinical (asymptomatic) symptoms upon testing.
http://www.ncbi.nlm.nih.gov/pubmed/15133830 Propriospinal myoclonus after treatment with ciprofloxacin.
http://www.ncbi.nlm.nih.gov/pubmed/11172695 Adverse reactions to fluoroquinolones. an overview on
mechanistic aspects.
http://www.ncbi.nlm.nih.gov/pubmed/8835045 Association of a Tourette-like syndrome with ofloxacin.
http://www.ncbi.nlm.nih.gov/pubmed/17357133 Ciprofloxacin Induced Palatal Tremor Palatal tremor
http://www.ncbi.nlm.nih.gov/pubmed/21585220 Quinolones: Review of Psychiatric and Neurological Adverse
Reactions.
http://www.ncbi.nlm.nih.gov/pubmed/10832955 Trovafloxacin-induced weakness due to a demyelinating
polyneuropathy.
http://www.medicine.virginia.edu/education/more/cme/slides/old
slides/racm2012/racmthurs/Thur0925InfectionsCox.pdf Antimicrobials & drug-related adverse effects: focus on
fluoroquinolones
FQ-Induced Myasthenia Gravis
http://www.ncbi.nlm.nih.gov/pubmed/9521283 Fluoroquinolone antibiotics block neuromuscular transmission.
http://www.ncbi.nlm.nih.gov/pubmed/21879778 Fluoroquinolone-associated myasthenia gravis exacerbation:
evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review.
http://www.ncbi.nlm.nih.gov/pubmed/23218195 Levofloxacin-induced myasthenic crisis.
http://www.ncbi.nlm.nih.gov/pubmed/24029473 Fluoroquinolone associated myasthenia gravis exacerbation:
clinical analysis of 9 cases.
http://www.ncbi.nlm.nih.gov/pubmed/19232642 Prulifloxacin as a trigger of myasthenia gravis.
http://www.ncbi.nlm.nih.gov/pubmed/16858118 Levofloxacin induced myasthenia crisis.
http://www.ncbi.nlm.nih.gov/pubmed/15259168 Fluoroquinolones should be avoided in myasthenia gravis.
http://www.ncbi.nlm.nih.gov/pubmed/2309517 Exacerbation of myasthenia gravis by norfloxacin.
http://www.ncbi.nlm.nih.gov/pubmed/9017031 Myasthenia gravis and ciprofloxacin.
http://www.ncbi.nlm.nih.gov/pubmed/7481384 Exacerbation of myasthenia gravis by pefloxacin.
http://www.ncbi.nlm.nih.gov/pubmed/8263560 Probable exacerbation of myasthenia gravis by ofloxacin.
http://www.ncbi.nlm.nih.gov/pubmed/2895386 Possible exacerbation of myasthenia gravis by ciprofloxacin.
http://www.ncbi.nlm.nih.gov/pubmed/9932991 Ofloxacin in the Lambert-Eaton myasthenic syndrome.
Glutamate/NMDA and ACh implicated in Tendinopathies
http://www.ncbi.nlm.nih.gov/pubmed/22354721 Glutamate receptors in tendinopathic patients. “Tendinopathic
biopsies exhibited increased occurrence of NMDAR1, phospho-NMDAR1, SP, and mGluR5, while mGluR6-7 were not
increased and mGluR1 was not found.”
http://www.ncbi.nlm.nih.gov/pubmed/18050306 VGluT2 expression in painful Achilles and patellar tendinosis:
evidence of local glutamate release by tenocytes.
http://www.ncbi.nlm.nih.gov/pubmed/19422642 Coexistence of up-regulated NMDA receptor 1 and glutamate
on nerves, vessels and transformed tenocytes in tendinopathy. “ Elevated levels of the neurotransmitter
glutamate and the presence of its receptor, N-methyl-d-aspartate receptor type 1 (NMDAR1), have been
established in patients with tendinopathy, i.e. chronic tendon pain and degeneration.”
http://www.ncbi.nlm.nih.gov/pubmed/11562137 In vivo microdialysis and immunohistochemical analyses of
tendon tissue demonstrated high amounts of free glutamate and glutamate NMDAR1 receptors, but no signs of
inflammation, in Jumper's knee.
http://www.ncbi.nlm.nih.gov/pubmed/11899264 Chronic tendon pain: no signs of chemical inflammation but high
concentrations of the neurotransmitter glutamate. Implications for treatment?
http://www.ncbi.nlm.nih.gov/pubmed/11354854 Glutamate NMDAR1 receptors localised to nerves in human
Achilles tendons. Implications for treatment? “The NMDAR1 immunoreaction was usually confined to
acetylcholinesterase-positive structures, implying that the reaction is present in nerves.”
http://www.ncbi.nlm.nih.gov/pubmed/11186404 In vivo investigation of ECRB tendons with microdialysis
technique--no signs of inflammation but high amounts of glutamate in tennis elbow.
http://www.ncbi.nlm.nih.gov/pubmed/19139865 Glutamate and capsaicin-induced pain, hyperalgesia and
modulatory interactions in human tendon tissue.
http://www.ncbi.nlm.nih.gov/pubmed/16888051 Microarray analysis of the tendinopathic rat supraspinatus
tendon: glutamate signaling and its potential role in tendon degeneration.
http://www.ncbi.nlm.nih.gov/pubmed/16514666 Microarray analysis of healing rat Achilles tendon: evidence for
glutamate signaling mechanisms and embryonic gene expression in healing tendon tissue. “Interestingly, there
was also evidence of central nervous system-like glutamate-based signaling machinery present in tendon cells, as
has recently been shown in bone. This type of signaling mechanism has not previously been shown to exist in
tendon.”
http://www.ncbi.nlm.nih.gov/pubmed/15998342 The chronic painful Achilles and patellar tendon: research on
basic biology and treatment. “The neurotransmitter glutamate (a potent modulator of pain in the central nervous
system) was, for the first time, found in human tendons. Microdialysis showed significantly higher glutamate levels
in chronic painful tendinosis (Achilles and patellar) tendons, compared with pain-free normal control tendons.”
http://www.ncbi.nlm.nih.gov/pubmed/12712235 Intratendinous glutamate levels and eccentric training in chronic
Achilles tendinosis: a prospective study using microdialysis technique.
http://www.ncbi.nlm.nih.gov/pubmed/10639657 In situ microdialysis in tendon tissue: high levels of glutamate,
but not prostaglandin E2 in chronic Achilles tendon pain.
http://www.ncbi.nlm.nih.gov/pubmed/24872365 Up-regulation of Glutamate in Painful Human Supraspinatus
Tendon Tears. “A significant increase in the expression of glutamate was seen in tendon tears. There were
differences in the expression of metabotropic and ionotropic glutamate receptors. Expression changes were also
observed for markers of the sensory and autonomic systems.”
http://www.ncbi.nlm.nih.gov/pubmed/23738276 From muscle research to clinical applications: Do glutamate
antagonists aid muscle recovery? “In addition, blocking of NMDA receptors by various substances rescues
motoneurons and increases the number of motor units surviving into adulthood. In this way, glutamate receptor
blockers may represent a promising therapeutic approach to retain nerve and muscle function during
neurodegenerative events.”
http://www.ncbi.nlm.nih.gov/pubmed/24677026 Glucocorticoids induce specific ion-channel-mediated toxicity in
human rotator cuff tendon: a mechanism underpinning the ultimately deleterious effect of steroid injection in
tendinopathy? “The increase in the glutamate receptor NMDAR1 after GCI raises concerns about the potential
excitotoxic tendon damage that may result from this common treatment.”
http://www.ncbi.nlm.nih.gov/pubmed/23212463 Human tenocytes are stimulated to proliferate by acetylcholine
through an EGFR signalling pathway. “Studies of human patellar and Achilles tendons have shown that primary
tendon fibroblasts (tenocytes) not only have the capacity to produce acetylcholine (ACh) but also express
muscarinic ACh receptors (mAChRs) through which ACh can exert its effects.”
http://www.ncbi.nlm.nih.gov/pubmed/21808665 Novel information on the non-neuronal cholinergic system in
orthopedics provides new possible treatment strategies for inflammatory and degenerative diseases. “It is now
known that not only is there a neuronal cholinergic system but also a non-neuronal cholinergic system in various
parts of the body. Therefore, interference with the effects of acetylcholine (ACh) brought about by the local
production and release of ACh should also be considered . . . The conditions discussed are painful and degenerative
tendon disease (tendinopathy/tendinosis), rheumatoid arthritis, and osteoarthritis.”
http://www.ncbi.nlm.nih.gov/pubmed/19409915 New insight into the non-neuronal cholinergic system via
studies on chronically painful tendons and inflammatory situations. “There is evidence of both acetylcholine (ACh)
production and a marked existence of muscarinic (M2) ACh receptors in these situations . . . The new information
obtained suggests that this system plays an important functional role in chronically painful tendons and in
inflammatory conditions. The findings of such a system in various parts of the body, when taken together, show
that not only should the classical neuronal cholinergic system be considered in discussion of the cholinergic
influences in the body. Additionally, the production of ACh in local cells in the tissues represents an important extra
supply of the transmitter. ACh effects can be obtained whether or not there is a cholinergic innervation in the
tissue.”
http://www.ncbi.nlm.nih.gov/pubmed/18621096 Unexpected finding of a marked non-neuronal cholinergic
system in human knee joint synovial tissue. “The cholinergic anti-inflammatory pathway is a newly discovered
pathway. Another recent concept is the existence of a non-neuronal cholinergic system that has, so far, been
defined for human tendons, intestine, airways and urinary bladder.”
http://www.ncbi.nlm.nih.gov/pubmed/23378267 The plantaris tendon in association with mid-portion Achilles
tendinosis: tendinosis-like morphological features and presence of a non-neuronal cholinergic system. “The
tendon cells showed a distinct immunoreaction for the acetylcholine (ACh) -producing enzyme choline
acetyltransferase (ChAT). Frequent fibroblasts were found in the loose connective tissue and these cells also showed
a marked ChAT immunoreactions.”
http://www.ncbi.nlm.nih.gov/pubmed/17999088 Presence of a non-neuronal cholinergic system and occurrence
of up- and down-regulation in expression of M2 muscarinic acetylcholine receptors: new aspects of importance
regarding Achilles tendon tendinosis (tendinopathy). “We have studied pain-free normal Achilles tendons and
chronically painful Achilles tendinosis tendons with regard to immunohistochemical expression patterns of the M(2)
muscarinic acetylcholine receptor (M(2)R), choline acetyltransferase (ChAT), and vesicular acetylcholine transporter
(VAChT).”
http://www.ncbi.nlm.nih.gov/pubmed/17289083 Extensive expression of markers for acetylcholine synthesis and
of M2 receptors in tenocytes in therapy-resistant chronic painful patellar tendon tendinosis - a pilot study. “Thus,
the results of this pilot study suggest that non-neuronal ACh is highly involved in the pathology of therapy-resistant
patellar tendinosis.”
http://www.ncbi.nlm.nih.gov/pubmed/16830327 Immunohistochemical and histochemical findings favoring the
occurrence of autocrine/paracrine as well as nerve-related cholinergic effects in chronic painful patellar tendon
tendinosis. “ It was found that immunoreactions for the M(2) receptor could be detected intracellularly in both
blood vessel cells and tenocytes, especially in tendinosis specimens. Furthermore, in the tendinosis specimens, some
tenocytes were seen to exhibit immunoreaction for ChAT and VAChT.”
References on Blood/Serum Testing for CNS/Encephalopathy, PNS, and AChrelated Disorders
http://www.eaneurology.org/fileadmin/user_upload/guidline_papers/EFNS_guideline_2011_Use_of_antibody_tes
ting_in_nervous_system_disorders.pdf Use of antibody testing in nervous system disorders
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706412/pdf/jcn-5-53.pdf Muscle-Specific Receptor Tyrosine
Kinase Antibody Positive Myasthenia Gravis Current Status “This antibody to muscle-specific receptor tyrosine
kinase (MuSK-Ab) was reported in 70% of patients with generalized seronegative MG”
http://www.ncbi.nlm.nih.gov/pubmed/25557356 Maintenance plasma exchange treatment for muscle specific
kinase antibody positive myasthenia gravis patients.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671239/pdf/nihms102467.pdf Other Autonomic Neuropathies
Associated with Ganglionic Antibody
http://www.mayomedicallaboratories.com/media/articles/algorithms/Encephalopathy-Serum.pdf Mayo Clinic
Autoimmune Encephalopathy Serum Evaluation Algorithm
http://link.springer.com/article/10.1007%2Fs00702-014-1193-3 Glutamate receptor antibodies in neurological
diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1
antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis,
cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome,
schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few
brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced
signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce
behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in
some patients by immunotherapy . . . Such tests are especially recommended in ‘mysterious’ cases when the
etiology of the neurological problems is unknown, when the symptoms are confusing, when the diagnosis is
unclear, when the response to ‘classical therapy’ is poor, and when the patient is suffering for a prolonged period of
time and loses hope. “
http://www.cmtausa.org/index.php?option=com_content&view=article&id=741&catid=10&Itemid=37 Genetic
testing information for CMT
http://www.mayomedicallaboratories.com/test-catalog/Overview/83380 Mayo Clinic Medical Laboratories for
NMDA, GABA, and other clinically available antibody tests.
Patients may want to include information about their
particular symptoms as an attachment:
As a reminder, my neuromuscular and neurological symptoms include the following:
(List your CNS, ANS, and PNS symptoms here,):
I’ve already had the following tests to help rule out Endocrine, Metabolic, Nutritional, Heavy Metal,
Rheumatological, Paraneoplastic, Infections, and Inflammatory conditions as potential causes of my neurological
symptoms :
(List the tests, with results and normal values here; a table form is nice for ease of reading. Make sure you include
normal ranges. Or, provide direct copies to the physician of test results or printouts if you don’t want to put them
in a table form). Here is a nice summary from Quest Diagnostics which show some of the basic testing that should
be done to rule out neuro symptoms:
http://www.questdiagnostics.com/testcenter/testguide.action?dc=WP_LabDiagnosis_PeripheralNeurop
Example table:
Test
B12
Glucose, fasting
Copper
Etc., etc.
Date of Test
1/5/13
6/4/13
Test myself 2-3 X/ week
1/5/13
My Result
700 pg/mL
692 pg/mL
84 – 86 mg /dL
1.02 mcg/mL
Normal Ranges
200 – 900 pg/mL
< 100 mg/dL
0.75 – 1.45 mcg/mL