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Review: Low-quality of Clinical Evidence Exists when Comparing Antibiotics for the Treatment of LNB

Posted: Fri 9 Dec 2016 18:13
by dlf ... 38B.f04t01

Antibiotics for the neurological complications of Lyme disease
Diego Cadavid, Paul G Auwaerter, Jeffrey Rumbaugh, Harald Gelderblom
First published: 9 December 2016
DOI: 10.1002/14651858.CD006978.pub2


Various central nervous system-penetrant antibiotics are bactericidal in vitro and in vivo against the causative agent of Lyme neuroborreliosis (LNB), Borrelia burgdorferi. These antibiotics are routinely used clinically to treat LNB, but their relative efficacy is not clear.

To assess the effects of antibiotics for the treatment of LNB.
Search methods

On 25 October 2016 we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We searched clinical trial registers on 26 October 2016. We reviewed the bibliographies of the randomized trials identified and contacted the authors and known experts in the field to identify additional published or unpublished data. There were no language restrictions when searching for studies.
Selection criteria

Randomized clinical trials of antibiotic treatment of LNB in adults and children that compared any antibiotic treatment, including combinations of treatments, versus any other treatment, placebo, or no treatment. We excluded studies of entities considered as post-Lyme syndrome.
Data collection and analysis

We used standard methodological procedures expected by Cochrane.

Main results

We identified seven randomized studies involving 450 European participants with LNB for inclusion in this systematic review. We found no trials conducted in the United States. Marked heterogeneity among these studies prevented meta-analysis. None of the studies included a placebo control on the initial antibiotic treatment, and only one was blinded. None were delayed-start studies. All were active comparator studies, and most were not adequately powered for non-inferiority comparison. The trials investigated four antibiotics: penicillin G and ceftriaxone in four studies, doxycycline in three studies, and cefotaxime in two studies. One study tested a three-month course of oral amoxicillin versus placebo following initial treatment with intravenous ceftriaxone. One study was limited to children. The trials measured efficacy using heterogeneous physician- or patient-reported outcomes, or both. In some cases cerebrospinal fluid analysis was included as an indirect biomarker of disease and outcome. None of the studies reported on our proposed primary outcome, 'Improvement in a measure of overall disability in the long term (three or more months).' None of the trials revealed any between-group differences in symptom resolution in response to active treatment. In general, treatment was tolerated well. The quality of adverse event reporting, however, was low.

Authors' conclusions

There is mostly low- to very low-quality clinical evidence from a limited number of mostly small, heterogeneous trials with diverse outcome measures, comparing the relative efficacy of central nervous system-penetrant antibiotics for the treatment of LNB. The few existing randomized studies have limited power and lack consistent and well-defined entry criteria and efficacy endpoints. It is not possible to draw firm conclusions on the relative efficacy of accepted antibiotic drug regimens for the treatment of LNB. The majority of people are reported to have good outcomes, and symptoms resolve by 12 months regardless of the antibiotic used. A minority of participants did not improve sufficiently, and some were retreated. These randomized studies provide some evidence that doxycycline, penicillin G, ceftriaxone, and cefotaxime are efficacious in the treatment of European LNB. No evidence of additional efficacy was observed when, in one study, an initial antibiotic treatment with intravenous ceftriaxone was followed by additional longer treatment with oral amoxicillin. There is a lack of evidence identified through our high-quality search strategy on the efficacy of antibiotics for treatment of LNB in the United States.
Plain language summary

Treatment for the neurological complications of Lyme disease

Review question

Are antibiotics effective for the treatment of Lyme disease affecting the nervous system?


In humans, a bacterium called Borrelia burgdorferi causes Lyme disease. People become infected when bitten by ticks carrying the bacterium. The person may experience symptoms in the joints, skin, muscles, and nervous system (peripheral nerves (nerves outside the brain and spinal cord), the brain, and the spinal cord). Without antibiotic treatment, neurological Lyme disease either may resolve or cause long-term problems. Neurological Lyme disease differs between Europe and the United States, probably because of differences in B. burgdorferi. Limited information exists about which antibiotics are better for the treatment of neurological Lyme disease.

Study characteristics

We found seven trials studying antibiotic treatments for neurological Lyme disease. All but one trial compared different antibiotics. The other trial compared the treatment effects of oral amoxicillin to placebo following initial ceftriaxone treatment. The trials included 450 Europeans. The antibiotics tested were penicillin G, doxycycline, ceftriaxone, and cefotaxime. One of the trials involved children only, while the others included mostly adults. We only selected studies in which treatment allocation was determined by chance (randomly), as such studies provide the best information for comparing the effects of different treatments. Most studies were not blinded (meaning that those taking part and the study staff knew the treatment being given). We could not find any studies of antibiotic treatments for neurological Lyme disease from the United States. No studies assessed the effects of delaying the start of treatment.

Key results and quality of the evidence

The seven studies were too different for their results to be combined, so we analyzed them individually.

None of the studies provided clear evidence that one antibiotic was better than another. One study failed to find evidence that a second and longer treatment with an oral antibiotic (amoxicillin) offered any extra benefit following initial intravenous treatment with ceftriaxone. As none of the other studies used a dummy treatment (placebo), the extra benefit offered by antibiotic treatment over recovery that occurs naturally is unknown. In general, the treatment was tolerated well, although the quality of adverse event reporting in most studies appeared to be low.

The results indicate that treatment with any of the four antibiotics produced similarly good outcomes for treatment of neurological Lyme disease in Europe. A second treatment with amoxicillin does not appear to provide added benefit to ceftriaxone. We found no trials of antibiotics for treatment of neurological Lyme disease in the United States.

Re: Review: Low-quality of Clinical Evidence Exists when Comparing Antibiotics for the Treatment of LNB

Posted: Fri 9 Dec 2016 19:35
by duncan
One would hope they could at least identify LNB in the US whenever it occurs. :?

Re: Review: Low-quality of Clinical Evidence Exists when Comparing Antibiotics for the Treatment of LNB

Posted: Wed 14 Dec 2016 15:13
by Lorima
That last paragraph is amusing. Throwing a big juicy bone to the IDSA, ALDF, and European equivalents, after detailing the scarcity and poor quality of the trials on which their policies are based. I guess that's what they have to do to stay "reputable" and "prestigious."

Re: Review: Low-quality of Clinical Evidence Exists when Comparing Antibiotics for the Treatment of LNB

Posted: Wed 14 Dec 2016 15:15
by Lorima
duncan wrote:One would hope they could at least identify LNB in the US whenever it occurs. :?
But one's hopes would be dashed, after reviewing the literature.

Re: Review: Low-quality of Clinical Evidence Exists when Comparing Antibiotics for the Treatment of LNB

Posted: Thu 15 Dec 2016 19:00
by duncan
My hopes are pretty much dashed after reading THIS literature. :D

Does "high-quality search strategy" sound right? Is it even a thing? Is it along the lines of high-quality merchandise or high-quality hooch from old gangster films?

Re: Review: Low-quality of Clinical Evidence Exists when Comparing Antibiotics for the Treatment of LNB

Posted: Fri 16 Dec 2016 5:22
by dlf
Yes, Lorima that last paragraph is truly amusing, particularly given what the authors wrote leading up to it.

From the Review Article - the Authors' conclusions:
There is a lack of evidence identified through our high-quality search strategy on the efficacy of antibiotics for treatment of LNB in the United States.
AND the last paragraph:
We found no trials of antibiotics for treatment of neurological Lyme disease in the United States.

Duncan, I think if it is even a "thing" their "high-quality search strategy" was way off the mark based on what I located...........They were either cherry picking their information to emphasize that they think that neurological manifestations of Lyme don't really occur in the U.S. or maybe they simply didn't like what they found in the information available about neurological treatment studies done in the U.S. Admittedly not much was done in terms of neurological treatment research, but that is likely mostly due to not acknowledging the neurological presentations of Lyme in North America and therefore by and large not testing patients for them. There was a time when the studies of neurological Lyme in the U.S. (although small and under-powered) were a little more honest about reporting results in the full texts.

So, here is what I found........

Practice Parameter: Treatment of nervous system Lyme disease (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology
J. J. Halperin, MD, E. D. Shapiro, MD, E. Logigian, MD, A. L. Belman, MD, L. Dotevall, MD, G. P. Wormser, MD, L. Krupp, MD, G. Gronseth, MD and C. T. Bever Jr, MD
The first treatment trial,10 published in 1983, compared outcomes in 12 US patients with Lyme meningitis treated with high dose IV penicillin to those in a group of patients evaluated previously and treated only with prednisone. Symptoms resolved far more quickly in penicillin-treated patients. No penicillin-treated patients had relapses following treatment, although several had residual symptoms. One eventually was retreated for persistent rheumatologic symptoms.

Although most studies have focused on patients with Lyme meningoradiculitis, two have assessed treatment response in patients with Lyme encephalopathy, defined as objectively demonstrable cognitive abnormalities on formal mental status testing or neuropsychological testing. In the first23 (Class III), 27 adults with Lyme encephalopathy, polyneuropathy, or both were treated with ceftriaxone, 2 g IV daily for 2 weeks. Response to therapy, as measured by clinical signs and symptoms, CSF analyses, and neuropsychologic testing, was gradual and typically was not apparent until several months following completion of treatment. Six months following treatment, 17 (63%) had improved, 6 (22%) improved but relapsed, and 4 (15%) were unchanged. Since symptoms had been prolonged and unremitting prior to treatment, this was believed to be due to the effect of treatment, even though no control group was included for direct comparison.

A second study, in which CSF abnormalities were present in 89%, demonstrated efficacy of ceftriaxone (2 g daily for 30 days) in 18 adult patients with Lyme encephalopathy (Class III).24 In this study, at 12 to 24 months follow-up, all patients were somewhat improved (2 patients; 11%), greatly improved (9 patients; 50%), or normal (7 patients; 39%).
Unfortunately, for the first study mentioned, the full text is pay-wall protected. I suspect there are a lot of details in the actual study that have been obfuscated by the conclusions they delineated in the abstract: ... t=Abstract

Ann Intern Med. 1983 Dec;99(6):767-72.
Neurologic abnormalities of Lyme disease: successful treatment with high-dose intravenous penicillin.
Steere AC, Pachner AR, Malawista SE.
Twelve patients were treated with high-dose intravenous penicillin for neurologic abnormalities of Lyme disease. Headache, stiff neck, and radicular pain usually began to subside by the second day of therapy and were often gone by 7 to 10 days. Five of the 12 patients continued to have intermittent mild headache for several more weeks, but no patient relapsed after therapy was stopped. Compared to 15 previous patients treated with prednisone alone, the duration of meningitic syndrome was significantly shorter in those given penicillin (mean duration, 1 versus 29 weeks, p less than 0.000001). However, in both groups, a mean of 7 to 8 weeks was required for complete recovery of motor deficits. Despite antibiotic therapy, 3 of the 12 patients treated with penicillin continued to have frequent arthralgias, musculoskeletal pain, and fatigue. We conclude that high-dose intravenous penicillin is effective therapy for neurologic abnormalities of Lyme disease.
Yale J Biol Med. 1984 Jul-Aug; 57(4): 481–483.
PMCID: PMC2590042
Neurological findings of Lyme disease.
A. R. Pachner and A. C. Steere
Neurologic involvement of Lyme disease typically consists of meningitis, cranial neuropathy, and radiculoneuritis, alone or in combination, lasting for months. From 1976 to 1983, we studied 38 patients with Lyme meningitis. Headache and mild neck stiffness, which fluctuated in intensity, and lymphocytic pleocytosis were the common findings. Half of the patients also had facial palsies, which were unilateral in 12 and bilateral in seven. In addition, 12 patients had motor and/or sensory radiculoneuropathies; asymmetric weakness of extremities was the most common finding. Although incomplete presentations of neurologic involvement of Lyme disease may be confused with other entities, the typical constellation of neurologic symptoms represents a unique clinical picture.
Full text: ... 0-0040.pdf

This includes a little more information about the patients but almost none of the results of treatment from the 1983 study mentioned in Practice Parameter:
The duration of neurological abnormalities
varied according to treatment. In the 24 prednisone-treated patients, the
neurological stage of their illness lasted for a mean of thirty weeks, with symptoms
fluctuating during this period. In the 14 patients treated with high-dose intravenous
penicillin most symptoms resolved within ten days
[4]. It should be stressed that
meningitis may be the first manifestation of Lyme disease. The first sign of illness in one of our early patients was meningitis which recurred three times. The diagnosis became clear only when he developed arthritis.

In addition to meningitis, 11 patients experienced mild encephalitic symptoms -
lethargy, difficulty in concentrating, fatigue, emotional lability, irritability, and
poor memory. These symptoms also varied from day to day but did not necessarily
correlate with the severity of headache and stiff neck. Although a few patients made
occasional mistakes in their mental status testing, none had a definite organic brain
syndrome, obtundation, or coma. Neither the CT scan nor the EEG was helpful in
supporting the diagnosis of encephalitis. The CT scan was normal in all eight patients
studied. Nine of the 11 patients with encephalitic symptoms had abnormal
electroencephalograms, which showed mild generalized slowing or some sharp activity.
However, four patients without such symptoms also had these EEG findings.
Although some of the initial patients were thought to have significant encephalitis
[1], we now believe that these subtle encephalitic symptoms may have been due to
subarachnoid inflammation and not to parenchymal CNS disease.

Except for one patient, other signs of parenchymal CNS disease were absent. This
patient had transient bowel and bladder dysfunction and an intermittently positive
Babinski on the right. Although these findings suggest the possibility of myelitis,
they were not documented well enough for us to be certain whether myelitis is a
feature of Lyme disease.

Lumbar puncture was performed on all patients and consistently revealed a lymphocytic
pleocytosis with a normal opening pressure. The median CSF white count
was 166 with a range of 5-700. The median protein was 79 with a range of 8-400.
The CSF glucose was usually normal.

Facial palsies were present in half of the patients; twelve had unilateral involvement
and seven, bilateral. The weakness was often preceded or accompanied by a
sensation of numbness or tingling on the weak side of the face, but a clear sensory
abnormality could not be demonstrated. The facial palsy characteristically occurred
at or very near the same time as the headache and meningismus. The weakness was
rarely a complete paralysis and usually began improving within weeks of its onset.
Residual weakness was usually minimal to none at all. It should be stressed that
unilateral or bilateral facial palsy often occurs alone in Lyme disease, without other
neurological abnormalities.

Involvement of other cranial nerves was unusual. A few patients had intermittent
diplopia without clinically evident extraocular movement palsy. However, one patient
had a VI nerve palsy along with an ipsilateral VII.

Twelve patients had radiculoneuritis. Nine patients had symptoms in their extremities,
and three had only thoracic sensory radiculopathy. Thoracic radiculopathy
appeared concurrently with other neurological symptoms and was experienced
as intense pain or pressure within the distribution of a few dermatomes, usually between
T8 and T12. On examination, hypoesthesia was present over affected areas in
two of the patients and hyperesthesia in one.

The radiculoneuritis in the extremities involved more than one extremity in six of
the nine patients. Radicular pain, dysesthesias, and weakness were the most common
symptoms. On examination, most patients had focal weakness or loss of reflexes but
lacked sensory findings. The duration of symptoms was related to the severity of
the lesion. Patients with little or no weakness recovered within days to weeks, but the
two patients with severe weakness and atrophy required months to recover. In the
two patients with mononeuritis multiplex, different sites became affected days to
weeks apart.

In Lyme disease, it seems that peripheral nerve lesions may occur at the root,
plexus, or distal nerve. Although this distinction was often difficult to make clinically,
electromyography and nerve conduction studies (EMG/NCV) sometimes
helped. Of two patients with a clinical picture of mononeuritis multiplex, one had
marked slowing of nerve conduction velocity in a number of nerves. In three other
patients with clinically diagnosed radiculitis, nerve conduction velocities were relatively
spared, but neuropathic abnormalities were noted electromyographically in
muscles innervated by one or more roots. A patient with scapular winging had
denervation changes in the infraspinatus muscle. One patient was thought to have
brachial plexitis and another radiculitis, but their EMG/NCV were normal. These
tests were not done in the final patient.
Nothing more than the abstract available to me for the following, so it is difficult to know how many of these patients were neurological versus arthritic Lyme patients. However apparently this one is cited in the Review article featured in this thread....I do wonder why. ;)

Lancet. 1988 May 28;1(8596):1191-4.

Treatment of late Lyme borreliosis--randomised comparison of ceftriaxone and penicillin.
Dattwyler RJ1, Halperin JJ, Volkman DJ, Luft BJ.

23 patients with clinically active late Lyme disease were randomly assigned to intravenous treatment with either penicillin or ceftriaxone. Of the 10 treated with penicillin, 5 were judged treatment failures; of the 13 who received ceftriaxone, only 1 did not respond. An additional 31 patients were subsequently treated with ceftriaxone 4 g/day (n = 17) or 2 g/day (n = 14); success rates in both groups were comparable to those in the cohort randomised to ceftriaxone. Patients unresponsive to ceftriaxone were more likely to have received corticosteroid treatment. ... #t=article

Chronic Neurologic Manifestations of Lyme Disease
Eric L. Logigian, M.D., Richard F. Kaplan, Ph.D., and Allen C. Steere, M.D.
N Engl J Med 1990; 323:1438-1444November 22, 1990
Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi, is associated with a wide variety of neurologic manifestations. To define further the chronic neurologic abnormalities of Lyme disease, we studied 27 patients (age range, 25 to 72 years) with previous signs of Lyme disease, current evidence of immunity to B. burgdorferi, and chronic neurologic symptoms with no other identifiable cause. Eight of the patients had been followed prospectively for 8 to 12 years after the onset of infection.

Of the 27 patients, 24 (89 percent) had a mild encephalopathy that began 1 month to 14 years after the onset of the disease and was characterized by memory loss, mood changes, or sleep disturbance. Of the 24 patients, 14 had memory impairment on neuropsychological tests, and 18 had increased cerebrospinal fluid protein levels, evidence of intrathecal production of antibody to B. burgdorferi, or both. Nineteen of the 27 patients (70 percent) had polyneuropathy with radicular pain or distal paresthesias; all but two of these patients also had encephalopathy. In 16 patients electrophysiologic testing showed an axonal polyneuropathy. One patient had leukoencephalitis with asymmetric spastic diplegia, periventricular white-matter lesions, and intrathecal production of antibody to B. burgdorferi. Among the 27 patients, associated symptoms included fatigue (74 percent), headache (48 percent), arthritis (37 percent), and hearing loss (15 percent). At the time of examination, chronic neurologic abnormalities had been present from 3 months to 14 years, usually with little progression. Six months after a two-week course of intravenous ceftriaxone (2 g daily), 17 patients (63 percent) had improvement, 6 (22 percent) had improvement but then relapsed, and 4 (15 percent) had no change in their condition.

Months to years after the initial infection with B. burgdorferi, patients with Lyme disease may have chronic encephalopathy, polyneuropathy, or less commonly, leukoencephalitis. These chronic neurologic abnormalities usually improve with antibiotic therapy. (N Engl J Med 1990; 323:1438–44.) ... f_ipsecsha

Clinical and electrophysiologic findings in chronic neuropathy of Lyme disease
Eric L. Logigian, MD and Allen C. Steere, MD

doi: http:/​/​dx.​doi.​org/​10.​1212/​WNL.​42.​2.​303
Neurology February 1992 vol. 42 no. 2 303

We evaluated 25 patients with Lyme disease and chronic peripheral neuropathy. All had immunologic evidence of exposure to Borrelia burgdorferi and no other identifiable cause of neuropathy. Neuropathic symptoms began a median of 8 months (range, 0 to 165) after erythema migrans and had been present for a median of 12 months (range, 2 to 168) prior to evaluation. Twelve patients (48%) had generally symmetric distal, nonpainful pares-thesia, and another 12 (48%) had generally asymmetric radicular pain. One patient (4%) had asymptomatic neuropathy. The most common physical finding was multimodal sensory loss, which was observed in 13 patients (52%); weakness and hyporeflexia were less common. Motor or sensory nerve conduction was slightly slow in 16 patients (64%). The paresthesia group more often had abnormalities on physical examination and on nerve conduction testing than did the radicular group. In 75% to 80% of patients from both groups, however, needle examination showed denervation in paraspinal and limb muscles. Among 20 patients who underwent lumbar puncture, only one had a slight spinal fluid pleocytosis. Six months after treatment with intravenous ceftriaxone, 19 patients (76%) were clinically improved. We conclude that Lyme disease can be associated with a reversible, mild chronic axonal sensorimotor polyradiculoneuropathy or polyradiculopathy.

I was able to access the full text pdf from the page with the abstract.
Results. Course of Lyme disease. Of the 25 study
patients, 22 (88%) had symptoms of early infection,
particularly erythema migrans (table 1). Early neurologic
involvement-facial palsy sometimes
accompanied by meningitis or radiculoneuritis developed
shortly thereafter in five (20%) of the
patients. Of these five patients, all made a complete recovery except one, who had slight residual
facial weakness and sensorineural hearing loss.
Prior to or concurrent with the onset of chronic
neurologic symptoms, 12 (48%) of the patients had
oligoarticular arthritis, usually involving the knee.
All four patients who did not have a history of erythema
migrans developed oligoarticular arthritis
prior to onset of chronic neuropathy.
Symptoms of peripheral neuropathy developed a
median of 8 mohths after the onset of infection and
had been present for a median of 12 months prior to
our evaluation. In addition to peripheral neuropathy,
CNS involvement in the form of mild encephalopathy
was found in 17 patients (68%). When the patients
were seen by us, 23 (92%) were seropositive. Of the
two seronegative patients, one (4%) had a positive
proliferative assay, and one had a positive
immunoblot. Both seronegative patients had a history
of erythema migrans, and the immunoblot-positive
patient had a history of facial palsy.
Fifteen patients (60%) had been treated previously
with a course of oral or intravenous antibiotics.
Of the 15 patients, eight were thought to
have had an adequate antibiotic regimen: five
received tetracycline for treatment of erythema
migrans, and three were treated with intravenous
ceftriaxone for arthritis.

Symptoms of peripheral neuropathy. Peripheral
neuropathy presented either as nonpainful distal
paresthesia (48%) or as a painful radiculopathy
(48%) (figure 1). One patient had asymptomatic
stocking sensory loss (4%). Distal paresthesia, described as “tingling,” “pins and needles,” or
“falling asleep,” was generally intermittent, often
symmetric, and more commonly involved the legs
than the arms, and in only one case (#3), the face.
It was sometimes associated with negative sensory
phenomena such as “numbness” or a “muffled or
“dead” feeling to touch. As with distal paresthesia,
radicular pain was often intermittent, but was
more frequently asymmetric and involved the cervical,
thoracic, or lumbosacral segments often in
combination. The pain was typically spinal with
radiation into affected limbs or trunk, but in three
patients it was described as an intermittent
paraspinal muscle “spasm.”
In only one of the 25 patients did chronic Lyme
neuropathy appear to be related to previous acute
Lyme neuropathy. This patient (#15) had had acute
radiculoneuritis, bilateral facial palsy, meningitis,
and spinal fluid pleocytosis followed 10 years later
by chronic radicular pain in the same dermatomal
locations affected previously. However, she did not
have facial palsy or CSF abnormalities during the
later illness.
Bedside examination. Physical examination was
abnormal in 64% of the patients, more commonly in
those with paresthesia than in those with radiculopathy
(p < 0.05) (table 2). The most common finding
was multimodal sensory loss to light touch, to
sharp-dull discrimination, and to vibratory sense
generally in the most distal extent of the symptomatic
cutaneous zones. Weakness, hyporeflexia,
and multiple tender points (fibromyalgia) were less
In patients with paresthesia, sensory loss was
most commonly found in the toes. Only rarely was
it found proximal to the ankles (#7) or fingers
(#12). In patient 7, symptoms of sensory loss began
in the medial aspect of the left foot, spared the toes,
and slowly expanded in the distribution of the
saphenous, superficial peroneal and ultimately the
sural nerves. Similar symptoms then developed in
the right leg.
Treatment. All 25 patients were treated with ceftriaxone,
2 g/d for 14 days. Two patients with radicular
pain (#15 and #16) had an intensification of
symptoms during the first days of therapy; no one
had a classic Jarisch-Herxheimer reaction.31 At the
6-month follow-up, 19 of the 25 patients (76%) had
improvement in symptoms or signs. However,
recovery was seldom complete and was usually
noted only weeks to months after completion of
therapy, not during the time of treatment. Three
patients, all with radicular pain and negative spinal MRIs, did not improve. Another three
patients, two with distal paresthesia, improved by
3 months, but relapsed by 6 months. There were no
clear predictors of response of the neuropathy to
antibiotic treatment. In particular, prior history of
antibiotic treatment; type, severity, or duration of
neuropathy; or seropositivity did not correlate with
the outcome of treatment. Of the two patients with
fibromyalgia, both showed no improvement in this
problem, although neuritic symptoms and signs
improved in one.

Of the 19 patients who were improved clinically,
seven (37%) had follow-up nerve conduction studies.
In these seven, the mean number of
abnormal/total nerve conduction measurements
decreased from 4.4/16 (28%) before treatment to
1.1/16 (7%) after treatment for an overall normalization
rate of 75%. Even the patient with neuropathic
symptoms of 14 years’ duration showed
improvement in nerve conduction after treatment
(figure 3). Of the six patients who did not respond
to treatment, two (33%) were retested. In these
two, the mean number of abnormal/total nerve conduction measurements remained unchanged at
5.5/20 (28%) before and after therapy.
<snip from discussion section>
Treatment. Neuropathy developed in many of
our patients despite treatment with antibiotics
months to years earlier (table 1). Nevertheless, a 2-
week course of ceftriaxone therapy resulted in
slow, often incomplete, improvement in most
patients. None of our patients had a classic
Jarisch-Herxheimer reaction, which includes high
fever and intensification of symptoms during the
first 24 hours of therapy.31 Intensification of symptoms
without fever, which occurred during the first
days of therapy in two of our patients, does not confirm
the diagnosis of Lyme neuropathy. Because a
few of our patients relapsed after 2 weeks of therapy,
we are now testing 4-week courses of ceftriaxone
for this disorder. ... f_ipsecsha

Successful Treatment of Lyme Encephalopathy with Intravenous Ceftriaxone

Eric L. Logigian1,4,a, Richard F. Kaplan1,2,a and Allen C. Steere2,3
Received 26 May 1998; revised 3 March 1999; electronically published 9
July 1999.
Presented in part: VII International Congress of Lyme Borreliosis, San
Francisco, June 1996 (p. 133)
The efficacy of intravenous ceftriaxone, 2 g per day for 30 days, was evaluated in a case series of 18 consecutive patients who met strict criteria for Lyme encephalopathy. Months to years after classic manifestations of Lyme disease, the 18 patients presented with memory difficulty, minor depression, somnolence, or headache. Sixteen (89%) had abnormal memory scores; 16 (89%) had cerebrospinal fluid (CSF) abnormalities, and all 7 patients tested had frontotemporal perfusion defects on single photon emission computed tomographic (SPECT) imaging. Six months after treatment, memory scores in the 15 patients who completed the study according to protocol were significantly improved (P < .01). In the 10 patients who had follow-up CSF analyses, total protein levels were significantly lower (P < .05). In the 7 patients who had SPECT imaging, posttreatment perfusion was significantly better (P < .01). Twelve to 24 months after treatment, all 18 patients rated themselves as back to normal or improved. We conclude that Lyme encephalopathy can be treated successfully with ceftriaxone.

There are only a few previous studies of Lyme encephalopathy. In an initial study, Halperin et al. [4] reported clinical features and neuropsychological test results in 17 patients with Lyme encephalopathy. The patients had significant improvement in the California Verbal Memeory Test (CVLT) and Wechsler memory scores after antibiotic treatment, but the diagnostic entrance criteria were not specified, the antibiotic regimen was not standardized, and the duration of follow-up was only 5–28 weeks. In a subsequent series of 65 patients with various neurological manifestations of Lyme disease, Halperin et al. reported 21 patients with symptoms of encephalopathy who had abnormalities on the bedside Mini-Mental Status Examination [6]. Almost all of the patients improved after treatment with intravenous (iv) ceftriaxone, but the parameters for measuring response were not spelled out.

Our initial report was a case series of 27 patients with chronic neuroborreliosis, 24 of whom had encephalopathy [3]. All but 1 of these patients had objective abnormalities on formal neuropsychological tests of memory or abnormal CSF analyses. As measured 6 months after treatment with iv ceftriaxone, 2 g once a day for 2 weeks, 17 patients (63%) improved, 6 (22%) had improvement but then relapsed, and 4(15%) had no change in their condition. However, this was not a formal treatment study with uniform entrance criteria, outcome measures, and prolonged follow-up.

In 1985, Dattwyler et al. began a series of studies to test ceftriaxone in the treatment of late Lyme disease. In their initial study, 23 patients with Lyme arthritis, encephalopathy, or poly-neuropathy, alone or in combination, were randomized to receive iv penicillin, 20 million U/d for 10 days, or iv ceftriaxone, 4 g per day for 14 days [10]. In the next phase of the study, 31 patients were randomized to receive ceftriaxone, 2 or 4 g per day for 2 weeks [10].

Altogether, 37 of the patients had symptoms of encephalopathy. Although most of the patients had gradual improvement after this therapy, 5 of 7 given penicillin versus only 3 of 30 who received one of the ceftriaxone regimens continued to have symptoms (P <.002). Finally, in an open-labeled, randomized multicenter study, patients with late manifestations of Lyme disease—primarily Lyme arthritis but, in some instances, chronic neuroborreliosis—were treated with iv or intramuscular ceftriaxone for 2 or 4 weeks [11]. Symptoms resolved in 76% of those treated for 2 weeks and in 70% of those who received 4 weeks of therapy (P not significant). Among patients with persistent symptoms, the most common ones were arthralgia, weakness, malaise, or fatigue. It was concluded that 2 g per day of iv ceftriaxone for 2 weeks was equivalent to higher doses and longer courses for the treatment of late Lyme disease. However, since the diagnosis of encephalopathy was based on clinical symptoms and serological results, and since end points for improvement were subjective, the objective treatment response of strictly defined Lyme encephalopathy to iv ceftriaxone of 2 or 4 weeks' duration still remains unclear.

In the present study, our goal was to evaluate the efficacy of iv ceftriaxone, 2 g once per day for 30 days, in patients who met strict criteria for Lyme encephalopathy, using 3 objective outcome measures in addition to subjective improvement in symptoms. Because documented Lyme encephalopathy is rare (we see only 2 or 3 such patients per year), the study design was an observational case series of a single antibiotic regimen. Treatment for 4 weeks was selected because previous series, including our own, suggested that relapse may sometimes occur with 2 weeks of therapy. Although some of the patients had been treated previously with antibiotics, none had received a 1-month course of iv ceftriaxone.

Prior to enrollment in our study, 15 (83%) of the 18 patients had been treated previously with antibiotics, usually oral regimens for early disease or Lyme arthritis. However, 4 patients (22%) had received iv antibiotics (table 1). Of these 4, 1 patient had been treated for early Lyme neuroborreliosis with iv penicillin for 6 weeks. Three patients had been treated with iv ceftriaxone for ⩽2 weeks, 1 for early neuroborreliosis, 1 for cardiac conduction block, and 1 as initial treatment for Lyme encephalopathy 3 years prior to study entry. Despite iv therapy, these 4 patients had progressive problems with memory; 3 had local production of antibody to B. burgdorferi in CSF, and 1 had a positive PCR test for borrelial DNA in CSF.

Eight months after treatment, 1 patient reported a relapse. At the 6-month follow-up visit, he had noted improvement in memory, his neuropsychological tests of verbal memory had increased by 1 SD compared with pretreatment values, and his perfusion defect index had improved almost to the normal range. However, 2 months later, his encephalopathic symptoms returned, and his neuropsychological test results of verbal and visual memory deteriorated again. The CSF examination, which had been normal on study entry, was repeated and was again normal. Thus, although we lacked proof that his relapse resulted from treatment failure, he was retreated with a second 1-month course of iv ceftriaxone, 2 g per day, because of this possibility. He again experienced improvement in symptoms, which was sustained for the duration of the study.

A final assessment was made of all 18 patients in the intention-to-treat group 12–24 months (average duration, 22 months) after treatment. In 12 patients, this was done in the clinic, and in 6, including the 3 patients who did not return for the 6-month follow-up assessment, it was done by telephone, All 18 patients, including the 1 patient who had relapsed, now reported that they were improved or even back to normal. Of the 15 patients who completed the study according to protocol, 5 said that they were now normal, 7 were greatly improved, and 3 were somewhat improved. Of the 3 patients in the intention-to-treat group who did not complete the study according to protocol, 2 rated themselves back to normal, and 1 was greatly improved.

Re: Review: Low-quality of Clinical Evidence Exists when Comparing Antibiotics for the Treatment of LNB

Posted: Fri 16 Dec 2016 6:17
by Lorima
Thanks for collecting and conveying this info, dlf.
There does seem to be something odd about the search strategy. There must be some indication in the full text as to why these studies were excluded. Too small? (underpowered, observational, non-RTC, "subjective," nonspecific, etc.) They still should have been springboards for hypothesis generation and further studies, but maybe the visible push to discredit US neurolyme diagnoses made that politically unfeasible.