J R Soc Med 2003;96:432-435
doi:10.1258/jrsm.96.9.432
© 2003 Royal Society of Medicine
Treating nerves: from anecdote to systematic review
Richard A C Hughes MD FRCP
Department of Clinical Neurosciences, Guy's, KIng's and St Thomas' School
of Medicine, London SE1 1UL, UK
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INTRODUCTION
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The principle that systematic reviews are the best evidence
on which to
base clinical practice seems so obvious that it
is surprising that their
methodology is so recent. It was only
in 1979 that Archie Cochrane berated the
medical profession
for not constructing such reviews. In 1991 the UK Cochrane
Centre
was founded to respond to this
challenge.
1 In 1998
we founded
the Cochrane Neuromuscular Disease Review Group to apply the
principles
and methods of the Cochrane Collaboration to peripheral nerve
and
muscle disease. In this article, examples principally from
peripheral nerve
diseases illustrate how our knowledge of the
effectiveness of treatments has
progressed from anecdotes or
observational studies through randomized
controlled trials to
systematic reviews.
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SCURVY: AN ANECDOTE, THE FIRST CONTROLLED TRIAL AND THE VALUE OF
LARGE EFFECT SIZES
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In 1600 Admiral James Lancaster set out for the East Indies
with four
ships. They met with contrary winds and took more
than six months to reach the
west coast of South Africa. By
that time the crews of three of the ships were
so weak with
scurvy that they were unable to man their anchors. His own ship
was
not affected because the admiral had 'brought to see with him
certaine
Bottles of the Juice of Limons, which hee gave to each one,
as long
as it would last, three spoonfuls every morning
fasting'.
2 A
marginal note labels this regimen 'The best remedy for scurvy',
but
this prescient remark did not receive the attention it deserved.
In 1747 a naval surgeon, James Lind, undertook a carefully controlled trial
of oranges and lemons. He took 12 sailors with scurvy of about the same stage,
divided them into pairs and gave each pair one of the following: a quart of
cider; 75 drops of vitriol elixir (sulphuric acid); 6 spoons of vinegar; half
a pint of seawater; three nutmegs; or two oranges and a
lemon.3
'The consequence was, that the most sudden and visible effects were
perceived from the use of the oranges and lemons; one of those who had taken
them, being at the end of six days fit for duty... The other was the best
recovered of any in his condition and being now deemed pretty well was
appointed nurse to the rest.'
With such a large effect size no further trials were needed to conclude
that citrus fruits are effective for treating scurvy. The 350 000 references
to randomized trials in the Cochrane Library do not include any trials (not
even Lind's trial) or systematic reviews of treatment for scurvy. 20 of the
2500 systematic reviews mention vitamin C and one is of particular interest.
It concludes that a daily dose of 1 g or more of vitamin C does not prevent
the common cold but shortens symptoms by 12 hours (95% confidence intervals 4
to 22 hours),4
sufficient in my view to make it worthwhile.
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BELL'S PALSY: AN ANECDOTE, A RANDOMIZED TRIAL AND TWO CONFLICTING
REVIEWS
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Acute idiopathic facial palsy, named after the 19th century
physician-scientist
Sir Charles Bell, affects 20 per 100 000 of the population
each
year. Most patients make a good recovery but 15% remain concerned
by
residual disfigurement, either asymmetry due to contractures
or synkinetic
movements.
5 In the
first anecdotal report of steroid
therapy a woman woke with a complete facial
palsy, was given
cortisone 100 mg four times daily, and recovered in seven
days.
The author concluded 'It is indeed difficult, though tempting,
to
draw a conclusion from a single satisfactory
case'.
6 The
first
randomized trial was a high-quality study of 26 patients and
showed no
difference between cortisone and
placebo.
7
There have been two systematic reviews of steroid treatment for Bell's
palsy. One included low-quality trials and concluded that steroids are
probably
beneficial.8
However, the Cochrane review, confined to high-quality trials, judged that the
combined evidence does not show significant
benefit.9 In my
opinion this is the safest conclusion. It is an indictment of our profession
that we have not done adequate trials to discover whether steroids really work
in Bell's palsy. Time and again the conclusion of a systematic review is that
more research is needed. Furthermore, it has become unethical to embark on a
trial without conducting a systematic review first to discover whether a trial
is really necessary.
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CARPAL TUNNEL SYNDROME: ANECDOTES, RANDOMIZED TRIALS AND UPDATED
SYSTEMATIC REVIEWS
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Carpal tunnel syndrome affects at least 3% of women and 2% of
men at any
one time.
10 It
causes tingling and pain in the fingers
and forearm, which may wake the
patient at night and is sometimes
worsened by manual activity. The cause is
compression of the
median nerve where it passes through the carpal tunnel.
Marie
and Foix in 1913 described an advanced case with wasting and
weakness of
the thenar eminence. In 1947 Brain, Dickson Wright
and Wilkinson described
relief of symptoms following division
of the flexor
retinaculum.
11
Nocturnal tingling in the fingers
had been recognized since the late 19th
century, labelled as
'acroparaesthesiae' and attributed to
compression of the brachial
plexus at the thoracic outlet. MJ McArdle, from
Guy's and the
National Hospitals, was the first to propose, in an unpublished
paper
to the Association of British Neurologists in
1951,
12 that this
symptom
was due to median nerve compression and could be relieved by
operation.
Two randomized controlled trials have found that patients do better one
year after operative division of the flexor retinaculum than with conservative
treatment
(splinting).13,14
Figure 1 updates the Cochrane
review meta-analysis to include the second of these
trials.15 The
meta-analysis shows considerable heterogeneity, reflecting probably the higher
quality of the second and larger trial, but both trials showed benefit.
Attempts have been made to improve on the standard operation by additional
procedures such as neurolysis or by endoscopic release through smaller
incisions. A recent Cochrane systematic review concluded that these
modifications have not yielded significant extra
benefit.16
View larger version (10K):
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Figure 1. Meta-analysis of randomized trials of surgery compared with conservative
treatment for carpal tunnel syndrome: relative rate of clinical improvement
after 1 year. After Verdugo et al (Ref.
15). The reader should consult
The Cochrane Library for the latest version of a Cochrane Review. Information
on The Cochrane Library can be found at
www.update-software.com
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In 1957 Phalen reported improvement of carpal tunnel syndrome symptoms in
16 out of 20 patients after corticosteroid injections, usually repeated, into
the carpal
tunnel.17 In a
parallel-group randomized trial in 60 patients the proportion of patients
improved four weeks after injection (proximal to the carpal tunnel) was 3.4
times greater in the injected patients than in the controls (95% confidence
intervals 1.8 to
8.0).18 However,
the evidence was inadequate to decide whether the benefit from steroids lasts
longer than a
month.19 Moreover,
in another trial the benefit of local steroids was no greater than that of
antiinflammatory treatment and splinting. The systematic reviews highlight our
ignorance about the duration of benefit from steroids and how they compare
with surgical treatment.
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GUILLAIN–BARRÉ SYNDROME: ANECDOTES, RANDOMIZED TRIALS
AND SYSTEMATIC REVIEWS
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Guillain–Barré syndrome (GBS) affects about 2 per
100 000 of
the population each year. It causes progressive flaccid
areflexic tetraparesis
with sensory loss and in 25% of patients
a requirement for artificial
ventilation. It is usually due
to acute inflammatory demyelinating
polyradiculoneuropathy and
in the UK less than 10% of patients have acute
axonal neuropathy.
It is thought to be an autoimmune condition triggered by
one
of several different
infections.
20 About
5% of patients die
in the acute stage, 15% are left requiring aid to walk at
the
end of a year and as many as 80% are left with persistent
fatigue.
21
During the 1970s plasma exchange became popular for treating autoimmune
conditions and in 1978 Brettle and colleagues described its use in a patient
with GBS who recovered quickly. They drew the cautious conclusion that plasma
exchange warranted further
assessment.22 The
first randomized trial did not reveal significant benefit but it included only
29 participants and was too small to detect modest
effects.23 By
contrast the systematic review of all trials comparing plasma exchange with no
treatment concluded that plasma exchange significantly hastens recovery
(Figure
2).24
The favourable results of the trials established plasma exchange as the
standard with which other treatments had to be compared.
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Figure 2. Guillain–Barré syndrome: meta-analysis of randomized trials
comparing mean improvement on a 7-point disability grade scale 4 weeks after
randomization to IVIg or plasma exchange. After Hughes et al.
(Ref. 27)
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After intravenous immunoglobulin (IVIg) was found useful for treating
autoimmune thrombocytopenia, it was tried and seemed successful in chronic
inflammatory demyelinating polyradiculoneuropathy. Its many mechanisms include
down-regulation of antibody production, blocking of autoantibodies through
anti-idiotypes, inhibition of Fc receptors and modulation of T cells. Kleyweg
et al.25
first reported its use in GBS. 4 of 6 consecutive bedbound patients improved
after its use. The 2 who did not had severe axonal degeneration. The authors
suggested that IVIg might be comparable in efficacy to plasma exchange but
recommended that 'before clinical application these results should be
confirmed in a large trial'. They duly undertook the large trial in 150
patients and showed that the outcome after IVIg was at least as good as that
after plasma
exchange.26 This
was subsequently confirmed by further trials and the Cochrane systematic
review.27 Because
it is more convenient, IVIg has replaced plasma exchange as the preferred
treatment for GBS in most centres.
In the first report of the use of steroids for GBS, a man with GBS began to
improve within hours of starting corticotrophin (ACTH) but then worsened. He
was thought to have exhausted his adrenal reserves. When given cortisone he
improved again and recovered by 7
weeks.28 Debate
continued about whether steroids really do benefit patients with GBS. The
first randomized trial, not published until 1978, suggested that any effect
from oral prednisolone was certainly marginal and possibly
harmful.29 The
current Cochrane systematic review shows no significant benefit from
steroids.30
However, an unpublished Dutch trial reports slightly more rapid recovery in
patients treated with the combination of intravenous methylprednisolone and
IVIg than with IVIg alone. This new report will need to be included in the
Cochrane systematic review and with updating of the meta-analysis. Whether the
combined evidence including the new trial will alter the present conclusion
remains to be seen.
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CONCLUSIONS
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It is scarcely surprising that the first published reported
use of each of
these interventions suggested a favourable effect
(
Table 1).
The corollary is
that initial anecdotal reports provide
unreliable evidence although in the
past they have heavily influenced
clinical practice. Even the first randomized
controlled trial
is an unreliable indicator of where the balance of evidence
now
lies as to whether an intervention is beneficial or not. The
trial has to
be free from bias and adequately powered to prove
or disprove the efficacy of
the agent. Failure to appreciate
this point has allowed many treatments, such
as corticosteroids
for Bell's palsy, to be recommended on the basis of
evidence
that systematic reviews show to be wholly inadequate. Conversely
we
have almost certainly rejected many treatments which are
in reality
effective.
View this table:
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Table 1. Summary of the conclusions from the first anecdotes and randomized
trials and the current Cochrane systematic reviews
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It might be argued that some treatments are so obviously effective, such as
surgical decompression for severe carpal tunnel syndrome, that randomized
trials are unnecessary. However, effect sizes are rarely so large that
non-randomized studies are adequate to draw conclusions. Even when effect
sizes are large, a small randomized trial such as that of James Lind may still
be the most efficient way of showing efficacy. Single, large randomized trials
are rarely powerful enough to establish the efficacy of an intervention beyond
reasonable doubt. They leave unanswered questions about reproducibility and
about generalizability to other patient populations and treatment settings.
Well conducted up-to-date systematic reviews should be the best evidence on
which to base clinical practice—a conclusion which now seems banal but
has yet to pervade the whole of medicine.
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Acknowledgments
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I thank the authors of the Cochrane reviews on whose work I
have drawn, and
Carolyn Reid for typing the paper.
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Footnotes
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Note: I have received research grants from Novartis, and honoraria
and
travel expenses from Novartis, Bayer, LFB, and Octapharma, all
of whom
manufacture human immunoglobulin.
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- Douglas RM, Chalker EB, Treacy B. Vitamin C for preventing and
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- Rowlands S, Hooper R, Hughes RAC, Burney P. The epidemiology and
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Treating nerves: from anecdote to systematic review
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97(2):
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INTRODUCTION
SCURVY: AN ANECDOTE, THE...
