Praca naukowa Fallona juz w druku

[artur737]

Jak wczesniej pisalismy sama praca nie stanowi jakiegos przelomu w leczeniu
boreliozy oraz nie wnosi nowych informacji do leczenia.
Stanowi jednak bardzo wazny przyczynek dla swiatowego ruchu chorych poniewaz w
bardzo rygorystycznych badaniach (podwojnie slepa proba kliniczna)
potwierdzono statystycznie korzysc z wielomiesiecznego leczenia abx w boreliozie.
Tym samym pozycja ILADS osiaga znaczace uwiarygodnienie swojego podejscia do
diagnostyki i leczenia boreliozy.

Praca stanowi swietne antidotum na ostatnie ataki ze strony IDSA i grupy
Wormsera.
Od tego momentu wskazowki IDSA staja sie przestarzale.

Praca nosi tytul “A Randomized, Placebo-Controlled Trial of Repeated IV
Antibiotic Therapy for Lyme Encephalopathy,” i jest opublikowana on-line przez
prestizowy the Journal Neurology numer z 10-tego pazdziernika 2007.
Praca wywodzi sie z fundowanego czesciowo przez pacjntow Columbia University
Medical Center

Super!!! Może coś się ruszy,

[domin46]

zresztą wg mnie to kwestia czasu, ale na czasie najbardziej zależy nam - chorym.

Pozdrawiam!

[484848a]

No to może z czasem nasi lekarze będą otrzymywali inne odgórne
protokoły leczenia i nawet jak się nie będą za bardzo znali, to
przynajmniej nie będą z nas robili hipochondryków albo idiotów.
Dobre wieści

[artur737]

Juz w lutym zlozyl do druku, ale czasopismo musialo stwarzac jakies utrudnienia.
Zapewne krytycy (niewatpliwie z IDSA bo czasopisma staraja sie dawac artykuly do
krytyki naukowcom o przeciwleglych pogladach, maksymalnie wykorzystali ilosc
czasu, ktora jest dozwolona zanim wydali swoja opinie)

Published online before print October 10, 2007
(Neurology 2007, doi:10.1212/01.WNL.0000284604.61160.2d)

Received February 12, 2006
Accepted June 26, 2007
A randomized, placebo-controlled trial of repeated IV antibiotic therapy for
Lyme encephalopathy
B. A. Fallon MD*, J. G. Keilp PhD, K. M. Corbera MD, E. Petkova PhD, C. B.
Britton MD, E. Dwyer MD, I. Slavov PhD, J. Cheng MD, PhD, J. Dobkin MD, D. R.
Nelson PhD, and H. A Sackeim PhD

From the Department of Psychiatry (B.A.F., J.G.K., K.M.C., E.P., I.S., J.C.,
H.A.S.), Department of Biostatistics (E.P.), Department of Neurology (C.B.B.),
Department of Medicine (E.D., J.D.), and New York State Psychiatric Institute
(B.A.F., J.G.K., K.M.C., E.P., I.S., J.C., H.A.S.), Columbia University, New
York; and Department of Cell and Molecular Biology, University of Rhode Island,
Kingston (D.R.N.).

* To whom correspondence should be addressed. E-mail: [e-mail].

Background: Optimal treatment remains uncertain for patients with cognitive
impairment that persists or returns after standard IV antibiotic therapy for
Lyme disease.

Methods: Patients had well-documented Lyme disease, with at least 3 weeks of
prior IV antibiotics, current positive IgG Western blot, and objective memory
impairment. Healthy individuals served as controls for practice effects.
Patients were randomly assigned to 10 weeks of double-masked treatment with IV
ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome
was neurocognitive performance at week 12—specifically, memory. Durability of
benefit was evaluated at week 24. Group differences were estimated according to
longitudinal mixed-effects models.

Results: After screening 3368 patients and 305 volunteers, 37 patients and 20
healthy individuals enrolled. Enrolled patients had mild to moderate cognitive
impairment and marked levels of fatigue, pain, and impaired physical
functioning. Across six cognitive domains, a significant treatment-by-time
interaction favored the antibiotic-treated group at week 12. The improvement was
generalized (not specific to domain) and moderate in magnitude, but it was not
sustained to week 24. On secondary outcome, patients with more severe fatigue,
pain, and impaired physical functioning who received antibiotics were improved
at week 12, and this was sustained to week 24 for pain and physical functioning.
Adverse events from either the study medication or the PICC line were noted
among 6 of 23 (26.1%) patients given IV ceftriaxone and among 1 of 14 (7.1%)
patients given IV placebo; these resolved without permanent injury.

Conclusion: IV ceftriaxone therapy results in short-term cognitive improvement
for patients with posttreatment Lyme encephalopathy, but relapse in cognition
occurs after the antibiotic is discontinued. Treatment strategies that result in
sustained cognitive improvement are needed.

[artur737]

Prasa swiatowa juz to zaczyna podchwytywac:
www.dentalplans.com/articles/26353/
www.sciencedaily.com/releases/2007/10/071010164755.htm
Cognitive Impairment Due To Chronic Lyme Disease Can Be Treated

Science Daily — Findings from the first placebo-controlled study of chronic
cognitive impairment after treated Lyme disease (also known as chronic Lyme
encephalopathy) demonstrate that patients report moderate cognitive impairment,
physical dysfunction comparable to patients with congestive heart failure, and
fatigue comparable to patients with multiple sclerosis. In the study, repeated
intravenous (IV) antibiotic therapy was shown to be effective in treating
cognitive dysfunction and the debilitating pain, fatigue and physical
dysfunction associated with this disease.

The study was led by Principal Investigator Brian Fallon, M.D., M.P.H., director
of the recently established Lyme and Tick-borne Disease Research Center at
Columbia University Medical Center. The research was conducted jointly at the
Columbia University Medical Center and New York State Psychiatric Institute and
was funded by the National Institute of Neurological Disorders and Stroke (NINDS).

"These findings replicate results from a prior placebo-controlled trial of
post-Lyme fatigue, which found positive treatment results from repeated
antibiotic therapy. They also replicate the degree of physical impairment
results demonstrated in another prior study of chronic Lyme disease," said Dr.
Fallon (*see citations below). "The door should be left open for physicians to
prescribe medications as warranted, after a careful discussion with the patient
of the potential risks and benefits."

Dr. Fallon and his research team identified patients with cognitive problems
that developed after being diagnosed with Lyme disease and which persisted or
relapsed despite prior treatment, in order to determine whether patients who
have already received the "standard" course of antibiotic treatment (three weeks
of IV antibiotic therapy), would benefit from an additional 10 weeks of
antibiotic therapy. They also set out to determine whether patients relapse when
taken off antibiotics or whether the alleviation of symptoms is sustained or
enhanced with time.

cd

[artur737]

Study participants (57 subjects: 37 patients with a history of Lyme disease and
20 controls) were divided into three subject groups: patients with a history of
treated Lyme disease who were randomized to IV treatment with an antibiotic
called ceftriaxone for 10 weeks; patients with a history of treated Lyme disease
who were randomized to IV placebo for 10 weeks; and, healthy controls who were
tested at the same time points as the patients to help to control for the
practice effect on neuropsychological testing. All patients had to meet criteria
for memory impairment at the start of the study and they were also required to
have a positive IgG Western blot for Lyme disease at study entry.

Key findings from the Neurology paper are as follows:

Cognition

* There was significantly greater improvement in cognition in the antibiotic
treated sample at the primary end point for efficacy (week 12).
* When patients were retested three months after antibiotic treatment, the
initial gains in cognition for the ceftriaxone-randomized sample were no longer
present.
* Patients lose their cognitive improvement when IV antibiotic therapy is
stopped.

Pain, Fatigue and Physical Dysfunction

* Among patients with greater severity at the start of the study, those
randomized to ceftriaxone had more significant symptom relief of pain, fatigue,
and physical dysfunction at week 12, as compared to those patients who did not
receive ceftriaxone.
* Patients initially randomized to IV ceftriaxone who had greater severity
of symptoms at baseline continued to show reduced pain and improved physical
functioning at week 24. Improvement in fatigue continued, but was no longer
statistically different from placebo at week 24.
* Repeated IV antibiotic therapy is effective in improving cognition, and
among the more impaired, in improving pain, fatigue, and physical dysfunction.

Safety

* 18.9 percent of the 37 patients had serious adverse effects associated
with either the IV line or a reaction to the antibiotic itself. Although all
fully recovered, IV antibiotic therapy has the potential for serious risks, such
as systemic infection, thrombus formation, or allergic reactions.

Clinical Recommendations

* Repeated IV antibiotic therapy should be considered a valuable option with
long-term benefit for managing the disabling symptoms associated with chronic
Lyme disease.
* Given the risks and benefits associated with IV antibiotic therapy,
physicians and patients need to have a thoughtful discussion prior to initiating
treatment.


Reference for this research: The study, titled "A Randomized, Placebo-Controlled
Trial of Repeated IV Antibiotic Therapy for Lyme Encephalopathy," will be
published on-line by the journal Neurology on Oct. 10, 2007.

*Citations of other articles mentioned: The percentage of patients with
meaningful improvement in fatigue noted at six months in this Neurology study
(66.7 percent for patients treated with ceftriaxone vs. 25 percent for placebo)
was comparable to the improvement in fatigue noted after repeated IV ceftriaxone
therapy in a prior placebo controlled study (64 percent for drug vs. 18.5
percent for placebo) (Krupp et al., Neurology, 2003).

The degree of physical impairment (comparable to congestive heart failure) was
comparable to the impairment noted in another chronic Lyme study (Klempner et
al., NEJM, 2001).

"Future research needs to focus on identifying a treatment approach that either
allows not only for acute efficacy, but also long-term cognitive improvement;
or, a treatment that could be given after the IV antibiotic therapy that would
allow for sustained or enhanced cognitive improvement over time. Our Lyme and
Tick-borne Disease Research Center continues to work towards finding these
solutions," said Dr. Fallon. "The most important lesson of this study is that
physicians and patients need to collaborate openly to design an individual
treatment plan to manage the long-term and complex suffering from symptoms of
chronic Lyme disease."

[artur737]

Teraz juz jest ta sama mniej wiecej tresc i tutaj
www.newswise.com/articles/view/534159/?sc=rsmn
W tym tempie bedzie bardzo szybko kilkadziesiat publikacji, moze nawet kilkaset.

Inna tresc

[artur737]

www.wtnh.com/global/story.asp?s=7195719
Debate continues over chronic Lyme disease

by Health Team 8's Jocelyn Maminta
Posted Oct. 10, 2007
4:15 PM

(WTNH) _ New information released today could have an impact in the fiery debate
over Lyme disease.

Researchers at Columbia University released a study today that shows extended
antibiotic therapy can provide relief to patients with long-term symptoms.
Treatment is at the heart of a heated discussion that has patients and doctors
here in Connecticut at odds with one another.

Diane Blanchard was diagnosed with Lyme disease 20 years ago and says,
"Literally I was treated off and on for eight years."

She says extended antibiotic therapy gave her back her health. Last week the New
England Journal of Medicine published a study that says there is no scientific
evidence to support the existence of chronic Lyme disease and that the risks of
antibiotic treatment outweighed the benefits.

Diane Blanchard is also the co-founder of the non-profit group, Time for Lyme,
and was among those outraged by the study.

"I must say when people say there is no such thing as chronic Lyme disease, I
scratch my head and wonder, what was it that I had," said Blanchard.

Dr. Henry Feder is an infectious disease specialist at Connecticut Children's
Medical and UConn Health Centers. He contributed to the review of all the data
available on Lyme disease.

"What we do know is when people get Lyme disease and get treated for the
standard two to four weeks, 95-percent are fine, but 5-percent will be
complaining of recurrent symptoms.

Blanchard says the implications of the study can be problematic for chronic
sufferers.

"This has the capacity to completely shutdown down treatment for countless
patients who rely on this right now to give them some quality of life just as I
did during that time period," she said.

Dr. Feder says that physicians and patients can still agree on the treatment
regimen.

"Someone who receives months of therapy for chronic Lyme disease should just be
informed that this is a judgement call on the physicians doing it and not based
on data or science," Dr. Feder said.

Blanchard thinks more research needs to be done the disease saying, "The single
most important thing this article has done I believe, is that it has pointed to
the fact that we clearly need more research, more money, more resources in order
to better understand what is happening."

Routers

[artur737]

Researchers seek help for advanced Lyme disease

By Will Dunham

WASHINGTON (Reuters) - Intravenous antibiotics can help people with symptoms of
advanced Lyme disease, but some of these improvements end once the drug is
stopped, U.S. researchers said on Wednesday.


There has been controversy over how to treat people with the tick-borne
bacterial disease, in particular whether extended antibiotic treatment fights
symptoms that remain after standard initial antibiotics.

The Lyme disease bacterium is spread to people by the bite of infected ticks.
Symptoms can include fever, headache, fatigue and a round red skin rash. If left
untreated, the infection can spread to joints, the heart and brain.

The disease also can cause cognitive problems like memory loss, problems in
concentrating, and changes in mood and sleeping habits, as well as temporary
facial paralysis.

The new research, published in the journal Neurology, provided a mixed picture
of extended intravenous treatment with antibiotics.

The researchers screened 3,368 Lyme disease patients to select 37 with moderate
cognitive impairment and significant levels of fatigue, pain and impaired
physical functioning. All previously had taken antibiotics.

Some of the patients were given another 10 weeks of intravenous treatment with
the antibiotic ceftriaxone. The others were given a placebo.

Those getting the antibiotic had improvements in their symptoms compared to the
placebo group, the study found, but the improvement in cognitive symptoms
dissipated after the treatment ended.

A boost in physical functioning and reduced pain were seen particularly among
patients given ceftriaxone who had entered the study with the most severe
symptoms, and these benefits endured after the drug treatment stopped.

This suggests that ceftriaxone may provide short-term and long-term benefits for
these symptoms, the researchers said, adding that future studies should examine
how to make the overall improvements more enduring.

Most people who develop Lyme disease can be treated successfully with a few
weeks of antibiotics.

"Unfortunately, for those patients who have cognitive problems, their options
aren't that many in terms of what treatments might be helpful for them," Dr.
Brian Fallon, director of the Lyme and Tick-borne Disease Research Center at
Columbia University Medical Center in New York who led the study, said in a
telephone interview.

The researchers said about a quarter of the patients given the intravenous
antibiotic experienced serious side effects, illustrating that such treatment
has risks.

[michal056]

Czy te badania i On sam sa na tyle wiarygodne ze nie bedzie to podwazane przez przeciwników.

[franiolek1]

Bedzie podwazane, ale do podawzenia potrzebne beda argumenty, a tych
IDSA nie znajdzie latwo.
To naprawde bardzo wazna wiadomosc dla nas. Teraz jeszcze dobrze by
bylo, by ktos w Europie to podchwycil.

Ide do lekarza dopiero pod koniec listopada, wtedy z nim
porozmawiam.
Wiem, ze jest on promotorem pracy doktoranckiej lekarki z oddzialu.
Mam wiec wielka nadzieje, ze ta pracacos wniesie na skale
europejska. Trzeba jednak poczekac, bo dopiero zostala zlozona.

[artur737]

Za duzo aby podawac dokladnie, ale dzisiaj jest juz 15 artykulow w roznej prasie
na temat tej nowej pracy Fallona. Wszystkie mowia mniej wiecej to samo, co te
przytoczone nizej.

Do tego dochodzi blizej nieokreslona ilosc raportow radiowych i telewizyjnych.

[artur737]

Ciezko bedzie podwazyc bo jest to ponoc bardzo dobra jakosciowo praca.

[likorek]

moja znajomość angielskiego w wydaniu medycznym jest bardzo kiepska
ale czy dobrze zrozumiałam, że podczas tych badań podawano tylko
ceftriaxone?

[artur737]

Chyba tak, ale pracy jeszcze nikt nie czytal. Wiec co wiemy, to tylko to co z
przeciekow oraz z informacji prasowych.
Obecnie jest juz w prasie swiatowej 20 artykulow na temat tego doniesienia.
Czyli media to bardzo dobrze podchwycily. Ilosc artykulow bedzie jeszcze rosla
przez kilka nastepnych dni.

Jak praca zrobi sie dostepna to prawdopodobnie dodamy do materialow dla lekarzy.

W kazdym razie autorzy wyraznie w niej pisza, ze oprocz cech encefalopatii,
pacjenci wykazuja uposledzenie fizyczne podobnego rzedu co pacjenci z
niewydolnoscia krazenia a objawy zmeczenia maja na podobnym poziomie co pacjenci
ze stwardnieniem rozsianym.

"Findings from the first placebo-controlled study of chronic cognitive
impairment after treated Lyme disease (also known as chronic Lyme
encephalopathy) demonstrate that patients report moderate cognitive impairment,
physical dysfunction comparable to patients with congestive heart failure, and
fatigue comparable to patients with multiple sclerosis."

[artur737]

Tzn ja nie czytalem. Bedzie dostepna dla mnie w ciagu kilku tygodni.

Z dziennikarskich doniesien wynika, ze w oparciu o artykul to miec borelioze to
tak samo jak miec niewydolnosc krazenie i stwardnienie rozsiane na raz.

Cytat

[artur737]

Cytat z jednego z artykulow:
Pacjenci z borelioza zatrwozyli sie tydzien temu, kiedy poczytny dziennik
lekarski NEJM oglosil, ze borelioza nie istnieje.
Poprzez publikacje swoich badan Fallon (zapewne z przyjemnoscia) zdementowal ten
raport. "Publikacja NEMJ jest juz nieaktualna, chociac zostala wydana zaledwie
tydzien temu.

The study heartened those who think chronic Lyme disease exists. They were
dismayed last week when the New England Journal of Medicine published a review
article declaring chronic Lyme disease a "misnomer''

[fikemola]

Praca Fallona jest już dostępna na stronie Stowarzyszenia:
www.borelioza.org/artykuly.htm

Fallon w mat. dla lekarzy

[fikemola]

ups, praca Fallona jest dostępna w materiałach dla lekarzy na
stronie Stowarzyszenia a nie w artykułach
www.borelioza.org/ostrzezenie.htm
pozdrawiam

[artur737]

Niech sie wszyscy upewnia, ze ich lekarz ma kopie pracy Fallona.
Jest to bardzo powazny dowod naukowy (podwojna slepa proba kliniczna
kontrolowana przez placebo), ze dlugoterminowe leczenie antybiotykami ma sens.

Nalezy ja sciagnac ze strony Stowarzyszenia (haslo: lyme).

Najlepiej samemu wydrukowac i zaniesc swojemu lekarzowi lub wyslac emailem.

[nataszkam]

Wykorzystam to dokładnie za miesiąc- na wizycie "kontrolno-
uzdrawiającej"
A swojej rodzinnej to z przyjemnością ją wręczę

[tosho]

A randomized, placebo-controlled trial of repeated IV antibiotic therapy for
Lyme encephalopathy

B.A. Fallon, MD
J.G. Keilp, PhD
K.M. Corbera, MD
E. Petkova, PhD
C.B. Britton, MD
E. Dwyer, MD
I. Slavov, PhD
J. Cheng, MD, PhD
J. Dobkin, MD
D.R. Nelson, PhD
H.A Sackeim, PhD

ABSTRACT

Background: Optimal treatment remains uncertain for patients with cognitive
impairment that persists or returns after standard IV antibiotic therapy for
Lyme disease.

Methods: Patients had well-documented Lyme disease, with at least 3 weeks of
prior IV antibiotics, current positive IgG Western blot, and objective memory
impairment. Healthy individuals served as controls for practice effects.
Patients were randomly assigned to 10 weeks of doublemasked treatment with IV
ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome
was neurocognitive performance at week 12—specifically, memory. Durability of
benefit was evaluated at week 24. Group differences were estimated according to
longitudinal mixedeffects models.

Results: After screening 3368 patients and 305 volunteers, 37 patients and 20
healthy individuals enrolled. Enrolled patients had mild to moderate cognitive
impairment and marked levels of fatigue, pain, and impaired physical
functioning. Across six cognitive domains, a significant treatment-by-time
interaction favored the antibiotic-treated group at week 12. The improvement was
generalized (not specific to domain) and moderate in magnitude, but it was not
sustained to week 24.
On secondary outcome, patients with more severe fatigue, pain, and impaired
physical functioning who received antibiotics were improved at week 12, and this
was sustained to week 24 for pain and physical functioning. Adverse events from
either the study medication or the PICC line were noted among 6 of 23 (26.1%)
patients given IV ceftriaxone and among 1 of 14 (7.1%) patients given IV
placebo; these resolved without permanent injury.

Conclusion: IV ceftriaxone therapy results in short-term cognitive improvement
for patients with posttreatment Lyme encephalopathy, but relapse in cognition
occurs after the antibiotic is discontinued. Treatment strategies that result in
sustained cognitive improvement are needed. Neurology® • • •
GLOSSARY

CDC _ Centers for Disease Control and Prevention; LMM _ longitudinal
mixed-effects models; NAART-R _ North American Adult Reading Test-Revised; PCS _
Physical Component Scale; ITT _ intent-to-treat; VAS _ visual analog scale;
WMS-III _ Wechsler Memory Scale.

Lyme disease, a tick-borne bacterial illness caused by Borrelia burgdorferi, can
induce cognitive deficits when it affects the CNS.1 These deficits, often mild
to moderate in severity, extend across multiple domains of cognitive function,
including memory, working memory, verbal fluency, and psychomotor
performance.2,3 Although treatment with 4 weeks of IV ceftriaxone usually
results in marked improvement, in a subgroup this treatment results in only
partial or nonsustained benefit.4,5

Posttreatment cognitive deficits may reflect residual effects of past infection,
continuing effects of current low-grade B burgdorferi infection, the presence of
an unrecognized coinfection, or incorrect diagnosis. Consequently, clinicians
are uncertain about optimal treatment strategies. For patients in whom no other
cause of symptoms can be found, community practice varies widely, ranging from
no treatment to palliative treatment to use of repeated or longterm antibiotic
courses.

To evaluate the benefit of additional IV antibiotic therapy, we conducted a
trial comparing clinical improvement from 10 weeks of IV ceftriaxone vs IV
placebo in patients with previously treated Lyme disease who had objective
memory impairment and a currently positive IgG Western blot.


METHODS

Study participants. Between January 2000 and April 2004, healthy volunteers
(controls) and individuals with a history of Lyme disease (patients) between the
ages of 18 and 65 years were recruited; follow-up evaluations were completed by
April 2005. The institutional review boards at Columbia University and the New
York State Psychiatric Institute approved the study, and all participants
provided written informed consent. Evaluations were conducted at the New York
State Psychiatric Institute and Columbia University Medical Center.

Treatments were conducted at each patient’s home. Patients met the following
criteria: (1) history of physician-documented erythema migrans or U.S. Centers
for Disease Control and Prevention (CDC)-defined manifestation of Lyme disease,
and a positive or equivocal ELISA confirmed by positive Western blot
serology6,7; (2) current positive IgG Western blot using CDC surveillance
criteria, assessed using a single reference laboratory (University Hospital of
Stony Brook); (3) treatment for Lyme disease with at least 3 weeks of IV
ceftriaxone, completed at least 4 months before study entry; (4) subjective
memory impairment that, by participant report, started after the onset of Lyme
disease; and (5) objective evidence of memory impairment as documented by the
Wechsler Memory Scale–III8 compared with age-, sex-, and education-adjusted
population norms.

These study criteria were conservative and narrow to enhance diagnostic
confidence. Prior IV antibiotic therapy was required to ensure that all patients
had received treatment considered adequate for neurologic Lyme disease by
published guidelines.9,10

The control sample of healthy volunteers had (1) negative history of Lyme
disease, fibromyalgia, or chronic fatigue; (2) negative IgM and IgG Western blot
for Lyme disease; and (3) no evidence of memory impairment on neuropsychological
testing.

Patients and controls were excluded if their history revealed a prior learning
disability or medical condition that could confound neuropsychological
assessment. Patients with cephalosporin allergy or a history of major
psychiatric disorder before the onset of Lyme disease were also excluded. The
control and patient samples were matched on the mean, variance, and shapes of
the distributions of age and education, and the distribution of gender.

Study design.
Treatment. The controlled phase of this study consisted of 10 weeks of
randomized treatment with either IV ceftriaxone (2 g/d) or IV placebo (0.9%
normal saline), and then 14 weeks off all antibiotics. Ceftriaxone was chosen
because it is the recommended treatment for neurologic Lyme disease and has
excellent penetration of the blood–brain barrier.9 A 10-week duration was chosen
because of reports of persistent or relapsing symptoms after 3 weeks of IV
ceftriaxone, and because of case series suggesting that longer courses of
antibiotic therapy may be more effective.4,11

After week 24, treatment assignment was revealed by a research staff member not
involved in data collection, and no further constraints were placed on
subsequent care. Participants underwent one follow-up assessment at week 48.
This report concerns only the controlled phases of the study, from baseline to
week 24.

Randomization. Patients were assigned in a 2:1 ratio to IV ceftriaxone or IV
placebo, using permuted blocks of size 20 based on a computer-based
randomization list. A 2:1 randomization schedule was used to encourage enrollment.

Masking. An unmasked off-site pharmacist, who had no contact with patients,
ensured that patients were sent the assigned treatment; this pharmacist was the
only unmasked individual during the 24 weeks of each patient’s masked treatment.
The neuropsychological technicians were not privy to information about adverse
events. To assess success of masking, patients were asked to guess treatment
assignment at both the week 12 and 24 evaluations.

Compliance with treatment. Compliance and safety were monitored by home infu

[tosho]

Compliance with treatment. Compliance and safety were monitored by home infusion
nurses who visited twice weekly. Patients had weekly telephone contact with a
research physician and monthly in-person evaluations with the patient’s private
physician. Study medication was packaged in pressured infusion devices, numbered
from 1 to 70. Both the visiting nurse and the research physician recorded the
number of completed infusions. Patients who missed a day’s dose were instructed
to continue in consecutive sequence until all 70 doses were infused.

Sample size. The target sample size of 45 Lyme patients (30 randomized to active
treatment and 15 randomized to placebo) provided at least 80% power to detect an
effect size of 1.1 with a two-sided test with __0.05. Power calculations were
based on the results of an uncontrolled pilot study,4 with the outcome measure
of memory assessed with the Buschke Selective Reminding Test total verbal memory
score.

Although cognitive improvement was expected in both visual and verbal memory, as
well as in multiple other cognitive domains, verbal memory was selected for the
power analysis, given the lack of pilot data for other aspects of cognition.

Assessments.
Screening. Subjects were screened for memory impairment with the Wechsler Memory
Scale (WMSIII), 8 which measures immediate, delayed, and working memory in
auditory and visual domains. Demographically adjusted t scores were computed for
all indices, correcting for the influence of sex, ethnicity, and education level.
Memory impairment was defined as a t score of one or more SD below population
norms on at least one of the six primary WMS-III indices. Premorbid IQ was
estimated using the Barona demographic formula12 and the North American Adult
Reading Test–Revised (NAART-R).13

Outcome measures. The primary clinical outcome measure assessed neurocognitive
performance, and the primary biologic outcomes assessed brain structure and
function. Relative to the placebo and control groups, IV antibiotic therapy was
hypothesized to lead to superior outcome in the memory domain scores, as well as
across cognitive domains.

The cognitive assessments sampled six domains: motor function (finger tapping,
simple reaction time, choice reaction time), psychomotor function (Trail Making
A&B; Digit Symbol), attention (Continuous Performance Test, Stroop task), memory
(Buschke Selective Reminding Test [verbal memory]; Benton Visual Retention Test
[visual memory]), working memory (A, Not B Logical Reasoning Test; N-Back Test),
and verbal fluency (Controlled Oral Word Association
Test and Category Fluency Test).

Descriptions of these measures may be found elsewhere.14,15 Scores on these
tests were z transformed relative to either published norms or a reference
sample of healthy controls and were adjusted for the effects of age, gender, and
education. Domain scores represent the average of the z scores for the primary
tests within each cognitive domain. To characterize overall performance, the six
domain scores were averaged to produce a cognitive “index” score; this index was
not used in the primary mixedmodel analyses.

Brain imaging measures included MRI and PET scans; these imaging results will be
reported elsewhere. Assessments of physical outcome included the
rheumatologist’s exam (trigger points, total number of joints in pain at rest or
on movement) and self-report measures of fatigue (Fatigue Severity Scale–1116),
pain (McGill Pain Questionnaire–Short Form17), and physical functioning (Short
Form–36 Physical Component Scale [PCS]18,19). Psychopathology was assessed with
respect to depression (Beck Depression Inventory20), anxiety (Zung Anxiety
Scale21), mental functioning (SF-36 MCS18,19), and global symptoms (SCL-90
Global Symptom Index22).

Time of assessment. Major assessments occurred at baseline, week 12, and week
24. The primary end point for efficacy analyses was week 12. The week 24
assessments evaluated durability of benefit. Controls were assessed at the same
time points to allow correction for the impact of practice effects on the
repeated neurocognitive measures. The secondary outcome self-report scales were
collected at 4-week intervals (baseline and weeks 4, 8, 12, 16, 20, and 24).

The rheumatologist exam was conducted at baseline, week 12, and week 24. The
lumbar puncture (for patients) and neurology exam (for all participants) were
done only at baseline. The neurologic exam assessed five areas: cranial nerves,
reflexes, sensory, motor, and associated motor (cerebellar and basal ganglia)
functions. For the standardized neurology exam, a summary score (0 –5) indicated
the number of areas with at least one minor or major abnormal finding. An
objective neurologic abnormality was considered major if it was associated with
either a significant deficit or impairment in the person’s functioning.

[tosho]

Laboratory assessments. Screening serum was sent for Lyme IgM and IgG Western
blot testing. Enrolled patients had serum examined by IFA for signs of
coinfection with Anaplasma phagocytophila (human granulocytic erhlichiosis) and
Babesia microti (Babesiosis). Samples of whole blood and CSF were tested by PCR
assay for B burgdorferi DNA, using the plasmid ospA primer.

CSF was sent for cell count, protein, glucose, total gammaglobulin, Lyme ELISA,
and oligoclonal bands. Serum and CSF were sent for determination of Bbspecific
intrathecal Ab production to University Hospital of Stony Brook using the
whole-cell sonicate ELISA (positive cutoff _ 1.1). To determine whether viable B
burgdorferi cells were present, spinal fluid was cultured in BSKII containing
kanamycin (5 _g/mL) at 33°C and was checked weekly for up to 12 weeks.

Statistical analysis. Efficacy analyses were performed using all randomized
participants, the intent-to-treat (ITT) sample. Lyme patient and healthy
controls were compared with respect to demographic and baseline clinical
characteristics, using t tests for continuous measures and _2 tests for
categorical measures.

Tests and estimates of differences between groups (IV antibiotic, IV placebo,
and healthy controls) with respect to the multivariate measure of cognition (six
domains: motor, psychomotor, working memory, attention, verbal fluency, and
memory) over time (baseline, week 12, and week 24) were based on longitudinal
mixed-effects models (LMM),23 which account for the correlation between the
domains and between the repeated observations over time.24 The LMM included main
effects and all interaction terms. Time was modeled as a nominal factor rather
than a continuous variable.

Including all two- and three-way interactions, the model for the covariance
structure was selected based on maximizing Bayesian information criteria.25,26
Keeping the model for the covariance as selected, stepwise backward elimination
was used to select the “best” model for the mean structure. Inference regarding
the comparison between the groups was based on the best model. Significant
omnibus tests for ITT differences among the three groups over time (two-sided __
0.05) were followed by pairwise comparisons; the p values for these post hoc
tests are reported unadjusted.

Secondary outcome measures were analyzed with LMMs, using a similar strategy.
Healthy controls were not included because practice effects were not of concern.
For the outcome number of joints with pain, a Poisson variable, an appropriate
generalized LMM23 was employed, using log link. As initially planned, the LMMs
included the baseline value of the outcome as a continuous covariate to account
for heterogeneity in clinical characteristics and to remedy potential floor effects.

The significance of the interaction terms was judged at a two-sided __ 0.15, to
avoid the erroneous omission of potentially important effects for which the
study was not powered; the significance of a main effect for drug vs placebo was
still judged at __ 0.05. To illustrate the impact on outcome of different
baseline severity scores, an estimate of the mean response based on the best
model for each outcome was computed at weeks 4, 12, and 24 for drug and placebo
for hypothetical subjects with baseline symptom severity equal to the lowest
(first) or highest (third) quartile of the observed baseline severities.

The reporting of outcomes for “low” and “high” baseline severity is for
illustration purposes only: the actual analysis based on LMMs included all
patients and used baseline severity as a continuous covariate without
dichotomizing it into low and high values. All analyses were performed using SAS
software version 925; the LMMs were fit using PROC MIXED and PROC GLIMMIX.

To explore whether particular patient subgroups had preferential benefit from
active treatment, ANCOVAs tested for associations between selected demographic,
clinical, and laboratory variables and the primary and secondary outcomes at
week 12 and week 24 that had shown a treatment effect in the LMM analyses.
Treatment group, baseline severity of the outcome measure, and (dichotomous or
continuous) potential predictor were examined as fully factorial,
between-subject factors.

[tosho]

RESULTS
Study population.

Healthy controls. Of 305 individuals contacted by telephone, 58 were invited for
on-site screening, and 20 were enrolled. Reasons for exclusion included
laboratory abnormalities, memory deficits on testing, or other exclusions. Of
the 20 enrolled, two participants had impaired scores on baseline
neuropsychological testing and were excluded.

Patients. Of 3368 initial clinic contacts, 1439 were excluded because of
insufficient prior IV treatment, and 1316 were excluded because the patient had
not met the CDC criteria for Lyme disease (figure). Among the remaining 613
patients, 512 were excluded because their serum was not IgG Western blot
positive, and 20 were excluded for other reasons.

Of the 81 patients invited to Columbia for neuropsychological screening, 31 did
not have sufficient memory impairment, 12 were not able to provide adequate
documentation of their clinical history, and one patient who had been deemed
eligible for the study withdrew for private treatment before randomization.

Thirty-seven patients were randomized to interventions, representing 1% of all
patients screened for the study. Of these 37 patients, five withdrew from the
study during the first 12 weeks: three within the first 3 weeks of therapy (two
because of thrombus and one because of hemolytic anemia; all three on
antibiotic), one after 8 weeks because of a systemic infection (on placebo), and
one after 10 weeks (on placebo) because of intolerable joint pain that required
narcotic medications for relief.

Three additional patients had adverse events that required early termination of
study medication (one at week 6 and two at week 8), but each of these patients
continued in a masked fashion through to the week 12 and 24 evaluations. No
patients withdrew from the study between weeks 12 and 24.

Laboratory results for enrolled patients.

Blood. All samples were IgG WB positive, and 18 of 37 were IgM WB positive. No
patient samples were PCR positive using the OspA primer assay. None of the serum
samples were IgM positive on either of the two coinfection tests, whereas low
positive IgG results were noted on 4 of 37 (10.8%) samples for Anaplasma
phagocytophila and on 10 of 37 (27.0%) samples for Babesia microti.

Cerebrospinal fluid. Baseline lumbar puncture, conducted in 33 of the 37
patients, revealed few abnormalities: mildly elevated WBC (two samples), mildly
elevated protein (four samples), and elevated gammaglobulin (one sample).
Positive results were noted for 22 on Lyme ELISA, 28 on IgG WB, and none on IgM
WB. For intrathecal Ab production, samples tested positive for 4 of 31 (12.9%)
patients; each positive intrathecal sample was also seropositive. No patient had
a positive CSF PCR. When cultured, one sample was positive for growth and
revealed spirochetes by both phase contrast and dark-field microscopy. To
exclude contamination as an explanation, the cells’s DNA was extracted and was
used as a template for PCR amplification of the spoT gene.

Examination of the PCR amplicon by agarose gel electrophoresis revealed an
approximately 3-kbp band, whereas a PCR amplicon from wild-type strains was
approximately 2 kbp. Additionally, the B burgdorferi isolated from the CSF
culture was able to grow when transferred into BSKII containing kanamycin (5
_g/mL) plus streptomycin (100 _g/mL). These results strongly suggest that the B
burgdorferi strain found in the CSF culture was the result of contamination by a
spoT mutant strain (WC07) of B burgdorferi containing a deletion of part of the
spoT gene plus the insertion of a streptomycin resistance gene; spoT mutant
strains were under investigation in the lab at the time of the culture.

[tosho]

Demographics and pretreatment clinical characterization of patients and
controls. The patients and healthy controls did not differ in the matching
variables of age, gender, or education (table 1). The patients’ clinical
histories indicated that all had rheumatologic symptoms, and most had neurologic
symptoms associated with cognitive complaints.

Nearly half (49%) had had a prior lumbar puncture; only three of these patients
had had elevated B burgdorferi–specific intrathecal Ab production.

The total amount of prior antibiotic therapy for Lyme disease was extensive,
with 57% of the patients in each treatment group having had more than 1 month of
prior IV antibiotic therapy. Patients reported having been symptomatic with Lyme
disease for a mean of 1.7 (SD 3.5) years before diagnosis, and they reported
having been ill for a total of 9.0 (SD 6.8) years.

Patients and controls on the screening measures. The groups did not differ in
estimated premorbid IQ according to the Barona method (111.5 [SD 6.2] for
patients vs 113.7 [SD 5.5] for controls), although healthy controls had superior
IQ as estimated by the NAART (108.9 [SD 8.1] for patients vs 115.9 [SD 6.0] for
controls, p _ 0.01). There were pronounced differences between the groups in
WMS-III scores for immediate memory (93.1 [SD 12.4] for patients and 119.7 [SD
11.4] for controls, p _ 0.01) and delayed (general) memory (94.7 [SD 10.2] for
patients and 122.1 [11.5] for controls, p _ 0.01). The magnitude of these
differences in memory substantially exceeded the difference between the groups
in estimated IQ.

Table 1 Demographic and clinical characteristics of all participants by study
group (omitted)

Patients and controls on postscreening measures. Participants were entered into
the study based on a predetermined level of impairment (patients) or lack of
impairment (controls), using the WMS-III. Because Lyme disease typically affects
multiple aspects of cognition,2,27 patients and controls were expected to differ
at baseline on other cognitive domains as well. It was also expected, based on
prior studies of posttreatment Lyme disease, 5,28,29 that the two groups might
differ on several of the secondary clinical outcome measures.

Patients and controls differed significantly on all clinical outcome measures,
both primary and secondary. Mean difference of at least one SD (moderate
impairment) occurred in the psychomotor, memory, working memory, and verbal
fluency domains. In the secondary measures, the impairment was severe in the
physical measures (fatigue, current pain, physical functioning, joint pain on
exam) and was mild in the psychopathology measures (depression, anxiety, general
symptom index, mental component scale).

Compared with published samples, reports of pain were similar to those of
postsurgery patients,17 fatigue was similar to that of patients with multiple
sclerosis16, and limitations in physical functioning were comparable with those
of patients with congestive heart failure.19 Individual subject scores on
secondary measures ranged from mild to severe, reflecting our enrollment
criteria, which did not preselect patients based on a level of impairment in
these areas.

Patients, compared with controls, had significantly more trigger points, joints
with pain, and joint swelling on rheumatologic exam (table 1). Patients averaged
1.8 (SD _ 3.00) trigger points, with only one subject meeting the criteria for
fibromyalgia with more than 10 trigger points. Joint pain was common, elicited
on exam in 35 patients, with pain on motion (34/37) being more common than
tenderness (13/37, McNemar _2 _ 17.39, df _ 1, p _ 0.01) or swelling (10/37,
McNemar _2 _ 22.04, df _ 1, p _ 0.01).

The number of abnormal areas on neurologic exam was greater in patients (mean
1.8 _ 1.2, median 2) than in controls (0.67 _ 1.1, median 0; t _ 3.3, df _ 53, p
_ 0.01). Major neurologic abnormalities were infrequent in the patients and
absent in the controls (3/37 vs 0/18, p _ NS). However, minor abnormalities on
neurologic exam were found in 73% of the patients vs 27.8% of the controls
(Fisher p _ 0.01); most frequent was a mild sensory abnormality among the patients.

Completeness of follow-up. Eighty-seven percent (32/37) of patients and 100%
(18/18) of controls completed the week 12 acute-phase efficacy evaluation and
week 24 follow-up durability evaluation, representing 20 patients in the
ceftriaxone group, 12 in the placebo group, and all healthy controls.

Primary outcome:

Treatment effects on neuropsychological tests. Arithmetic means and standard
deviations are given in table 2. The inference regarding ITT comparisons between
the groups over time is based on the best-fitting LMM that contained the main
effects for group, time, and domain, and the two-way interactions of group by
time and group by domain (table 3).

The primary omnibus LMM analysis revealed a group-by-time interaction effect (p
_ 0.04), indicating that with respect to cognition, the groups (drug, placebo,
and healthy controls) differed in change over time (week 0 to week 12; week 12
to week 24) across all domains. The lack of a threeway interaction among group,
domain, and time indicates that differential improvement over time between the
domains was not demonstrated as had been hypothesized for memory and that the
joint effect of time and group can be described without reference to a cognitive
domain. Because the primary omnibus p value was significant, we
then conducted model-based estimation of the effect of time within groups and
pairwise comparisons of the effect of time between the groups.

These comparisons demonstrated within-group cognitive improvement (as measured
by the six cognitive domains) during the acute course of treatment (from week 0
to week 12) for the patients given ceftriaxone (p _ 0.01) but not for the
patients given placebo (p _ 0.15) or the healthy controls (p _ 0.51). The
cognitive improvement between baseline and week 12 in the drug-treated patients
was better than in the healthy controls (p _ 0.01) and better than in the
placebo-treated patients (p _ 0.053).

During the antibiotic-free interval to week 24, the patients initially on
ceftriaxone lost the preferential cognitive gains seen at week 12, whereas the
two control groups (placebo and healthy volunteers) continued to show the same
mild cognitive improvement as they had demonstrated in the acute phase. At week
24, the within-group improvement from baseline continued to be significant for
the drug-treated group, but it was also now seen in the placebo-treated group.

At week 24, the between-group treatment effects were no longer seen. In summary,
the inability of the drugtreated group to sustain the distinguishing acutephase
improvement in cognition during the subsequent antibiotic-free interval resulted
in a loss of the differential treatment effect among the three groups at week 24.

[tosho]

Secondary outcomes. Arithmetic means are presented in table E-1 on the
Neurology® Web site (www.neurology.org), and the best-fitting models for each
secondary outcome measure are presented in table E-2. Table E-2 also provides
model-based estimates of the means over time for subjects’ baseline severity
scores corresponding to the lowest or highest quartile of the distribution of
baseline scores of all 37 patients. These means are obtained from the respective
LMMs (given in the right-hand side of table E-2) by substituting the selected
baselines in the models. When the LMM contained an interaction involving group,
post hoc comparisons between groups were performed within baseline severity level.

Table 2 Neuropsychological test results (raw scores) by domain, treatment group,
and time (omitted)

The majority of the physical self-report measures (fatigue, current pain,
physical functioning) indicate interaction effects at week 12 favoring drug over
placebo as a function of baseline severity, with the drug effect increasing with
higher baseline impairment. Improvement continued to week 24, but only for
current pain and physical functioning. For example, for physical functioning as
measured by PCS, table E-2 indicates a two-way interaction (p _ 0.06) for
baseline severity and treatment, such that the beneficial effect of drug over
placebo increased as baseline severity increased; model-based comparisons reveal
the main effects of drug vs placebo (p _ 0.05) at high levels of baseline severity.

As an illustration of the LMM results, figure E-1 shows that among hypothetical
subjects starting with a higher current pain severity (visual analog scale [VAS]
_ 8.1), there is a greater improvement in pain for the drug group compared with
placebo (p _ 0.05) that is sustained to week 24, whereas among those starting
with a lower pain severity (VAS _ 2.1), there is little difference between
treatment groups.

In a post hoc analysis with time as a continuous variable, we examined whether
there would be a treatment effect for the secondary outcome measures of current
pain, fatigue, and physical functioning during the 24 weeks if baseline severity
were not included as a covariate in the LMM analysis. No significant
interactions (group and week) or main group effects were noted, except on one
outcome measure (physical functioning, measured by PCS), for which there was a
weak interaction between group and week (p _ 0.15), such that improvement in
physical functioning was greater across time for the ceftriaxone group compared
with the placebo group, with the magnitude of improvement increasing to week 24.

On the rheumatologist assessment of joint pain (at rest and with movement), the
treatment effect was not dependent on baseline severity, but there was a
group-by-time interaction. There was no difference between drug and placebo at
week 12 or at week 24 in improvement compared with baseline, whereas between
weeks 12 and 24 the placebo-treated patients improved more than the drug group
(p _ 0.052).

On measures of psychopathology and its effects (depression, anxiety, global
symptoms, mental functioning), there were no differences between drug and
placebo at weeks 12 or 24, although there was a transient treatment difference
on the global psychopathology index at week 4 when patients with low baseline
symptoms who had received the drug had less improvement than did patients with
low baseline symptoms who had received the placebo.

Table 3 Summary of the model for the six domains of neurocognitive performance
(omitted)

Variables associated with outcome measures. Selected baseline variables were
examined for interaction effects with treatment group on the cognitive and
self-report physical outcomes. Likelihood of improvement with ceftriaxone vs
placebo was not related to demographic variables, CSF values, or clinical
history (amount of prior oral or IV antibiotic therapy; the interval since last
antibiotic course). Interaction effects between baseline physical exam and
treatment on outcome were noted.

On joint exam, patients with more joints in pain at baseline had a preferential
improvement with ceftriaxone on the measures of cognitive index at week 12 (p _
0.06) and at week 24 (p _ 0.04), and on the self-report measures of fatigue (p _
0.11) and pain (p _ 0.07) at week 24. On neurologic exam, patients with more
areas of abnormality at baseline had a preferential improvement with ceftriaxone
on the measure of memory at week 24 (p _ 0.11) and on the selfreport measures of
fatigue at week 12 (p _ 0.06) and week 24 (p _ 0.01) and physical functioning as
measured by PCS (p _ 0.09) at week 24.

Adverse events. Five patients withdrew from the study because of adverse events:
two because of thrombus (both on drug), one because of staphylococcal infection
(on placebo), one because of an allergic reaction (on drug), and one because of
worsening joint pain (on placebo) that required narcotic pain medication. Four
patients remained in the study despite adverse events that required either early
termination of study medication (three on drug; two with allergic reactions, and
one with abdominal pain) or hospitalization (one on drug; cholecystectomy at
week 16); for these patients, ratings at weeks 12 and 24 continued to be
conducted without revealing treatment randomization.

The adverse reactions of seven of these nine patients were thought likely to
have been directly related to the study treatment (presence of a PICC line or
medication), for a rate of treatment-related adverse events of 6 of 23 (26.1%)
among patients given IV ceftriaxone and 1 of 14 (7.1%) among patients given IV
placebo; all patients recovered fully.

Masking. Patients assigned to ceftriaxone did not differ from those assigned to
placebo in their rate of guessing whether they had received active medication
either at week 12 (68.4% vs 53.8%; p _ 0.40) or at week 24 (75.0% vs 58.3%, p _
0.32). Analyses of covariance found no relationship to outcome of a patient’s
guess of medication vs placebo and the actual treatment assignment at week 12.

At week 24, there were trends for patients who believed that they had received
active medication to report less fatigue (p _ 0.08) and less impairment in
physical function (p _ 0.05), but this main effect was independent of actual
treatment assignment. Finally, patients who had severe side effects were not
more likely to report a beneficial effect from ceftriaxone; indeed, there was a
trend for patients with severe side effects to report worsened physical
functioning at week 12.

Compliance. Compliance was excellent. Weekly notes indicate that patients
completed all 70 doses, except for those who terminated early. Of 37 patients
who began treatment, 30 completed the full 10-week course (17 on ceftriaxone; 13
on placebo). Among the seven who did not complete the full course, one person on
placebo completed 58 doses, and among the six antibiotic noncompleters, the
total numbers of completed doses were 5, 11, 19, 35, 54, and 58; patients with
the latter three totals returned for week 12 assessments.

[tosho]

DISCUSSION

This placebo-controlled, doublemasked trial tested the efficacy and safety of
repeated IV antibiotic treatment in a sample of patients with posttreatment Lyme
encephalopathy. Conservative inclusion criteria were used to attain high
diagnostic confidence. More than half of the patients had prior courses of IV
antibiotic therapy that exceeded the standard recommendations for neurologic
Lyme disease.

Although enrollment required objective memory deficits, the patients had
generalized, mild to moderate cognitive deficits. They also had more sensory and
joint abnormalities on physical exam and selfreports of marked pain, fatigue,
and impaired physical functioning, replicating earlier findings.4,28

The primary result was that the three groups (ceftriaxone, placebo, health
control) differed in cognitive improvement over time (p _ 0.04), favoring
ceftriaxone at week 12 but not at week 24. At week 12, the end point for
efficacy selected a priori, patients given 10 weeks of IV ceftriaxone had better
within-group and between-group improvement in cognition compared with the
placebo group or healthy controls.

This improvement was manifested broadly across several cognitive domains—not
specific to the domain of memory. Benefits from ceftriaxone exceeded the
benefits expected from retesting, both in the healthy controls and the placebo
group.

For the drug vs placebo comparison, the borderline p value of 0.053 reflects
both the modest magnitude of cognitive improvement and the small sample size,
and it indicates that this finding has a slightly elevated risk of having
occurred by chance: 5.3% vs 5%. On self-report measures, a benefit of
ceftriaxone relative to placebo was observed at week 12 for physical
functioning, current pain, and fatigue for those patients with greater severity
of symptoms at baseline.

Durability of benefit was assessed at week 24 after patients had been off of all
treatment for 14 weeks. At this time point, there was no difference among the
three groups in cognitive improvement from baseline. Sustained improvement,
however, was noted in physical functioning and current pain among patients with
greater baseline impairment, suggesting that ceftriaxone may have both short-
and long-term benefits for these symptoms.

A post hoc analysis suggested that the ceftriaxone group’s sustained improvement
in physical functioning to week 24 could also be seen when baseline severity of
impairment was not included as abcovariate.

Ceftriaxone has both infection-independent neuroprotective and
infection-dependent antimicrobial effects that could account for improvement in
both primary and secondary measures. Ceftriaxone upregulates the expression of
glutamate transporters on the astroglia of rat brains with neuroprotective
effects30—presumably because of reduced extracellular glutamate, a potentially
neurotoxic neurotransmitter.

This could explain short-duration improvement in that continued exposure to
ceftriaxone would be required for sustained upregulation of the glutamate
transporter. Another explanation for the observed relapse is that the course of
ceftriaxone may have killed some borrelia, but it exerted little effect on other
organisms in sequestered sites.31,32 There is one North American report of
persistent B burgdorferi by culture after antibiotic therapy,33 and there are
several such European cases.34-38

However, in our study, the baseline CSF specimens were PCR- and culture negative
for B burgdorferi. Few variables at baseline showed consistent associations with
the primary or secondary outcome measures, perhaps because of inadequate sample
size, which limits the power to detect interaction effects. However, the
analysis suggests that the physical exam may be an important predictor variable
of short- and long-term response, because patients with more painful joints or
more areas of neurologic abnormality at baseline were more likely to benefit
from ceftriaxone than placebo on various outcome measures.

We did not find evidence that unmasking contributed significantly to the
positive results in this study, because patients in each treatment group did not
differ in the rate of guessing assignment to ceftriaxone. Further, patients’
guesses had no relation with treatment response at the primary outcome time
point of week 12. At week 24, although patients’ guesses of ceftriaxone were
associated with greater improvement in physical functioning, this was true for
both the drug and
placebo groups; when only those who guessed ceftriaxone were included in the
analysis, a nonsignificant pattern continued to be evident of greater
improvement in the drug group compared with the placebo group, supporting a drug
effect
independent of guess. Third, the presence of severe side effects was not
associated with a more favorable outcome on the primary or secondary
measures at either week 12 or 24.

How do these findings compare with those of other placebo-controlled studies of
posttreatment Lyme disease? In two trials,28 3 months of antibiotics conferred
no greater benefit than did placebo on the primary SF-36 functional measure or
the secondary outcome measure of cognition. Inability to detect a treatment
effect may reflect a true failure of repeated antibiotic therapy or limitations
of the study design (e.g., lack of severity standard for study enrollment).28,39
In contrast, in a study of posttreatment Lyme disease for patients with at least
moderate fatigue, improvement at 6 months on the Fatigue Severity Scale was
noted among 64% of patients who received 1 month of IV ceftriaxone vs 18.5% who
received IV placebo (p _ 0.001).29

Improvements in cognitionbor spinal fluid levels of OspA protein were not
detected, but patients were not required to manifest impairment on either of
these measures at study entry.29 For post hoc comparison, we reanalyzed our data
using the post-Lyme fatigue’sbstudy enrollment criteria, and we applied the same
definition for response (change _ 0.7 on FSS). Our results were compatible: at 6
months, 66.7% of ceftriaxone-treated patients vs 25% of placebo-treated patients
were responders (Fisher exact test, p _ 0.05).

The strengths of this study were recruitment of a rigorously diagnosed patient
sample, use of quantitative measures of cognition with multiple alternative
forms, use of self-report instruments employed in other trials to facilitate
comparison, inclusion of a healthy control group to account for practice
effects, and the randomized, placebocontrolled design that included a
discontinuation phase to test durability.

Noteworthy is that the pattern of change and degree of cognitive improvement
during the 24 weeks were nearly identical for the healthy volunteers and
placebotreated patients; the healthy control group,btherefore, served to
increase the precision of the estimates of the treatment effect and to provide
enhanced power for the overall analysis to detect treatment effects in the
active drug group, thus reducing the risk of a type II error. The primary
limitations of this study were its restrictive inclusion criteria (only 1% of
screened patients were enrolled), the relatively small sample size, and theblack
of posttreatment lumbar puncture or neurologic exam. Therefore, generalizability
is uncertain to posttreatment Lyme patients without cognitive impairment or to
seronegative patients with persistent symptoms.

Conclusions from this study are mixed. At the primary efficacy end point of week
12, IV ceftriaxone treatment resulted in greater improvement in cognition and,
among the more impaired, in physical functioning, pain, and fatigue. Clinical
significance, however, depends on long-term effects. Notable were the long-term
benefits for the ceftriaxone group on physical functioning and pain among the
more severely affected patients at baseli

[tosho]

among the more severely affected patients at baseline, because these are among
the most troubling aspects of posttreatment Lyme disease.28

However, our primary interest in this study was on cognition, for which the
improvement was not sustained to week 24. Further, adverse effects attributed to
IV ceftriaxone occurred in 26% of patients. Therefore, considering both the
limited duration of cognitive improvement and the risks, 10 weeks of IV
ceftriaxone and then 14 weeks of no antibiotic is not an effective strategy for
sustained cognitive improvement.

Although certain subgroups (patients with more joint or neurologic
abnormalities) may experience long-term benefitbfrom ceftriaxone, the predictor
analyses were exploratory rather than hypothesis driven, and they require
independent confirmation. Pending such confirmation, treatment strategies that
are safer and more durable are needed.

[tosho]

ACKNOWLEDGMENT
National Institutes of Neurological Disorders and Stroke (Al Kerza-Kwiatecki,
PhD, Michael Nunn, PhD), National Institute of Neurological Disorders and Stroke
DSMB (Justin McArthur, MBBS, Andrew Pachner, MD, Thomas Marcotte, PhD, Jorge
Benach, PhD, Roland Martin, MD, Bruce Barton, PhD), Columbia University research
team (Megan Romano, Dexterie Clemente, MA, Tani Viera, Marcia Kimmeldorf, PhD),
Irving Center for Clinical Research at Columbia University (Karen Marder, MD,
Yakov Stern, PhD, Michael J. Taylor, PhD, Robert Heaton, PhD, Wendy Coy, PhD),
Home Care Services, Roche Pharmaceuticals, participating private physicians
(especially Emilia Eiras, MD, Andrea Gaito, MD, Kornelia Keszler, MD, and
Kenneth Liegner, MD), community leaders who helped arrange screening clinics,
Patricia Smith, Lyme Disease Association, Inc, Time for Lyme, Inc, National
Research Fund for Tick-Borne Diseases, Phyllis Mervine, MEd, The Lyme Times,
Medical Diagnostic Laboratories, University Hospital of Stony Brook, Mel Evans,
Richard Tilton, PhD, Steven Schutzer, MD, Allen Steere, MD, and Mark Klempner, MD.
Received February 12, 2006. Accepted in final form June 26, 2007.

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34. Schmidli J, Hunziker T, Moesli P, Schaad UB. Cultivation of Borrelia
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37. Haupl T, Hahn G, Rittig M, et al. Persistence of Borrelia burgdorferi in
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39. Kaplan RF, Trevino RP, Johnson GM, et al. Cognitive function in
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[tosho]

Pub ahead of print at www.neurology.org.
From the Department of Psychiatry (B.A.F., J.G.K., K.M.C., E.P., I.S., J.C.,
H.A.S.), Department of Biostatistics (E.P.), Department of
Neurology (C.B.B.), Department of Medicine (E.D., J.D.), and New York State
Psychiatric Institute (B.A.F., J.G.K., K.M.C., E.P., I.S., J.C.,
H.A.S.), Columbia University, New York; and Department of Cell and Molecular
Biology, University of Rhode Island, Kingston (D.R.N.).

Primary location of research: Columbia University Medical Center, New York.
This study was funded by a grant from NINDS to Dr. Fallon (R01- NS38636).

Disclosure: Roche Pharmaceuticals supplied ceftriaxone free of charge for this
study but were not involved in any other aspect of the study.

Dr. Fallon has given expert testimony at hearings related to Lyme disease and
its treatment. The other authors report no conflicts of interest.

[artur737]

Dzieje sie cos dziwnego. Praca Fallona zostala opublikowana w wersji
elektronicznej juz wiele miesiecy temu w czasopismie Neurologia. Jest to tzw
wersja ahead of print dostepna tylko na Internecie.
Normalnie kilka tygodni pozniej takie prace sa normalnie drukowane w wersji
papierowej tego czasopisma. Wtedy praca otrzymuje parametry wystarczajace do
tego aby ja cytowac w kolejnych pracach.

A praca Fallona zostala pominieta i nigdy nie pojawila sie w wersji drukowanej.
Czyli ciagle nie zostala wciagnieta formalnie w naukowa wiedze medyczna.

Zaniepokojony wyslalem list do redakcji z prosba o wyjasnienie.

Od kilku tygodni mniej wiecej raz na tydzien otrzymuje informacje, ze pracuja
nad tym i badaja sprawe. Moj list zostal przeslany do kogos wazniejszego
poniewaz edytor nie chcial odpowiedziec z jakis powodow na moje dociekania. Nie
wiadomo, kto jest to nastepna instancja i czy kiedykolwiek otrzymam odpowiedz.

A moze po prostu zapomnieli wydrukowac?

A moze nigdy nie wydrukuja.

Fiola mozna dostac!

[artur737]

Pomimo, ze Tosho zapostowal tu badania Fallona to sugeruje by jednak sciagac je
ze strony Stowarzyszenia jako, ze wtedy bedzie to cala praca w tym rysunki,
tabele i bibliografia.

[tosho]

Tak, pomyslalem, zeby to jednak zapostowac.
Czasem sie moze zdarzyc, ze haslo, czy serwer nie zadziala, a praca moze akurat
byc w danym momencie potrzebna.

Artur a moze umiescic link do pracy w opisie forum? Np. zaraz pod linkiem do
stowarzyszenia.
A jak nie w opisie to w watku podczepionym?
Tak zeby bylo widoczne, bez balaganu.

[artur737]

Kombinujemy wlasnie jak ta prace zrobic bardziej widzialna.

[tosho]

Moze zrezygnujcie z dostepu z haslem. (?)

[artur737]

Tak sie niestety nie stanie.

nadal pracuja!

[franiolek1]

Study now recruiting chronic Lyme patients at Columbia University in
NYC: “SPECT Imaging of Chronic Lyme Disease vs. Other Disorders”
ImmuneSupport. com
12-28-2007

The following description of this study, to be led by Lyme expert
Brian A. Fallon, MD, is taken from the Columbia Lyme Research
website: www.columbia -lyme.org/ flatp/resstud. html

[Note: You can read about Dr. Fallon’s most recent study, reported
in October 2007 – “Columbia University Medical Center Researchers
Lead Placebo-Controlled Study of Cognitive Impairment Among Patients
With Previously Treated Lyme Disease” at www.immunesu
pport.com/ library/showarti cle.cfm?id= 8445 ]



* * * *
Participants: People with chronic Lyme Disease ages 18-60


Goals:
1) To examine differences between SPECT images of Lyme disease vs
psychiatric disorders.
2) To determine how consistently brain imaging experts can
distinguish the SPECT scans of patients with Lyme Disease from the
SPECT scans of patients with depression and patients with anxiety
disorders.


Status of study: Currently recruiting


Principal Investigator: Brian A. Fallon, MD


Design: This study is supported by funds from the Lyme Disease
Association and from the Wilton Lyme Disease Task Force. Patients
with a history of erythema migrans positive or seropositive Lyme
Disease and typical manifestations of Lyme Disease who have
persistent cognitive problems despite prior treatment will be
recruited. The brain SPECT scans of the Lyme patients will be
compared to age- and sex-matched controls.. Controls will consist of
patients with depression and patients with an anxiety disorder.


Frequently asked question: Why is this study needed?


One of the more difficult diagnostic areas is to determine whether a
patient is suffering from a primary psychiatric disorder or a
secondary neuropsychiatric disorder as a result of a primary
neurologic condition.


Because patients with central nervous system involvement of Lyme
Disease may develop irritability, mood swings, sleep disorder,
cognitive problems, marked fatigue, low sexual interest, pain, and
anhedonia, these patients may easily be misdiagnosed as having
primary depression.


As one tool to assist in the differential diagnosis, a SPECT scan is
often ordered. The assumption is that if the brain SPECT reveals a
pattern of global decreased perfusion in a heterogeneous pattern
then the patient is more likely to have had CNS involvement as a
result of Lyme disease..


The pattern in depression would be more likely one of decreased
perfusion only in the frontal lobes. The pattern in OCD would be
increased perfusion in the orbitofrontal cortex or basal ganglia.


The questions we wish to ask are:
a) Are these assumptions accurate using the technology of HMPAO
SPECT?;
b) Are the nuclear medicine physicians capable of differentiating
(blind to diagnosis) whether a scan comes from a patient with Lyme
Disease or from a patient with a primary psychiatric disorder alone?
<


Contact for further info: If you wish further info about the study,
send an e-mail to [e-mail]


Screening Questionnaire to Fax to Us: Not active yet

Fallon pracuje

[franiolek1]

jeszcze link
www.immunesupport.com/library/showarticle.cfm/ID/8602

[borelka46]

Artur czy to pismo jest organem potwierdzającym prawdziwość tej pracy? czy też
musiała być przez jakąś instytucje organ medyczny zweryfikowana. W jakim sensie
może stracić swą wartość i nie być nową metodą terapii dla ludzi na całym świecie ?

[artur737]

Przed chwila przyszedl kolejny list, ze jeszcze nie maja dla mnie odpowiedzi.

Neurologia to powazne czasopismo. Ale trudno traktowac powaznie prace, ktora
nigdy nie ukazala sie drukiem, bo taka elektroniczna publikacja na stronie
internetowej czasopisma jest malo powazna.

[artur737]

Fallonowi pewnie niezrecznie sie bylo dopytywac co sie dzieje, bo nie chcial
sobie psuc stosunkow z wydawnictwem aby go nie wsadzili na czarna liste.
Ostatecznie jeszcze moze chciec aby mu opublikowali kiedys cos jeszcze.

Mysle, ze przyszedlem mu w sukurs.

[artur737]

A teraz dostalem email, ze artykul ukaze sie w druku 25 Marca br.

Czyli co? Chyba naprawde zapomnieli wydrukowac.

[borelka46]

no to hurra!

[fionka21]

Zapomnieli Trudno uwierzyć w takie zapiminalstwo. Znam to ze środowiska naukowego u nas, gdzie wiele rzeczy rozgrywa się "pod kołderką". A chodzi wyłącznie o idee. Natomiast tu w grę wchodzą duuuuże pieniądze. I w tm momencie chorzy są nieistotni.
Pozdrawiam, Anka