treating nerves: a call to arms

2007 PNS PLENARY LECTURE AND REVIEW

Treating nerves: a call to arms

Richard A. C. Hughes

Department of Clinical Neuroscience, King’s College London, London, UK

Abstract The process of proving that new treatments for peripheral nerve diseaseswork has often been slow and inefficient. The lack of adequate evidence for some existingtreatments has been highlighted by Cochrane systematic reviews. This article uses fourdifferent conditions to illustrate the need for more research. Both corticosteroid injectionsand surgical decompression of the median nerve are efficacious in carpal tunnel syn-drome, but whether corticosteroid injections avoid the need for operation needs to be dis-covered. Corticosteroids are efficacious for Bell’s palsy, but the role of antiviral agentsneeds clarification, which should come from ongoing trials. Intravenous immunoglobulin(IVIg) and plasma exchange are both efficacious in Guillain-Barre syndrome, but corticoste-roids are not. More trials are needed to discover the best dose of IVIg in severe cases andwhether mild cases need treatment. In chronic inflammatory demyelinating polyradiculo-neuropathy, corticosteroids, IVIg and plasma exchange are all efficacious, at least in theshort term, but trials are needed to discover whether and which other immunosuppres-sive agents help. The Peripheral Nerve Society has formed a standing committee, theInflammatory Neuropathy Consortium (http://pns.ucsd.edu/INC.htm), to facilitate the trialsneeded to answer the remaining questions in the inflammatory neuropathies.

Key words: Bell’s palsy, carpal tunnel syndrome, chronic inflammatory demyelinatingpolyradiculoneuropathy, Guillain-Barre syndrome, peripheral nerve disease, systematicreview, treatment

IntroductionDespite major advances in the understanding of

peripheral nerve diseases, our evidence base for theirtreatment has, until recently, been surprisingly defi-cient. We have relied on case reports and cohort stud-ies, which have often been suggestive but rarelyconclusive. Not all treatments require trials becausetheir benefits are so immediate and obvious, such asthe use of parachutes to prevent death on jumpingout of aeroplanes (Smith and Pell, 2003) or the mother’skiss to blow a peanut out of an infant’s nostril (Glasziouet al., 2007). However, most of our treatments haveonly modest benefit, and most carry risks of harm.

Paradoxically, the variable natural history of manyperipheral neuropathies and remarkable ability ofthe injured peripheral nervous system to repair itselfmake it difficult to demonstrate the efficacy of treat-ments.

Many treatments have simply been introducedand become established in clinical practice despitethese difficulties without being challenged and thor-oughly tested with clinical trials. Clinical trials haveoften lacked important quality attributes and have usu-ally been too small to establish or refute the hypothe-sis that they were designed to test. The results ofsmall trials have sometimes pointed in different direc-tions. Because the number of clinical trials has grown,the effort to collect and summarize all the evidencehas become challenging. Since 1998, to meet this chal-lenge, the Cochrane Neuromuscular Disease Grouphas been applying the methods of the Cochrane

Address correspondence to: Richard A. C. Hughes, MD, Depart-ment of Clinical Neuroscience, King’s College London, London SE11UL, UK. E-mail: [email protected]

Journal of the Peripheral Nervous System 13:105–111 (2008)

ª 2008 Peripheral Nerve Society 105 Blackwell Publishing

Collaboration to produce systematic reviews of inter-ventions for peripheral nerve disorders (Annane et al.,2006). By January 2008, 29 reviews of interventionsfor peripheral nerve disorders had been published,and almost all have concluded that reliable evidencefor the treatments considered is inadequate or evenentirely absent. Despite this dearth of evidence, oursociety and other organisations have laboriously pre-pared consensus reports about the management ofsome peripheral nerve disorders (Joint Task Force ofthe EFNS and the PNS, 2005; 2006a; 2006b) andmore are in progress. These reports have frequentlyconcluded that more evidence is needed on crucial as-pects of disease management.

This article uses four important peripheral nervedisorders, carpal tunnel syndrome, Bell’s palsy, Guillain-Barre syndrome (GBS) and chronic inflammatorydemyelinating polyradiculoneuropathy (CIDP), to illus-trate how evidence has been collected from earlycase reports to clinical trials and now systematic re-views. While progress has been made in each ofthese, much of it very recent, the common conclusionis always that more evidence is needed. The Periph-eral Nerve Society should play its part in collectingthis evidence by mastering the modern academic,commercial and regulatory environment and testingexisting and new interventions.

Carpal Tunnel SyndromeIn the beautiful early description of division of the

flexor retinaculum for severe carpal tunnel syndrome,benefit was clear in all six cases (Brain et al., 1947). Intheir discussion, the authors described how extensionand flexion of the wrist increased the pressure in thecadaver carpal tunnel, providing a plausible biologicalexplanation for the procedure. So striking was thisresult that one might have considered the value ofsurgery resolved. The first randomized trial supportedthis idea. Two of 11 participants randomized to splint-ing improved compared with 10 of 11 randomized tooperation, the one who did not having declined surgery(Garland et al., 1964). However, the situation is notstraightforward. In a review of 209 studies including32,936 patients, the average success rate was only75% (Bland, 2007). In Bland’s own southeast Englandpopulation, 8% of patients considered that they wereworse after operation than before. In the only otherrandomized trial, 46 out of 89 participants allocated tosplinting (51.6%) had improved after 3 months com-pared with 62 out of 87 allocated to surgery (71%)(Gerritsen et al., 2002). In a meta-analysis of the tworandomized trials (Verdugo et al., 2003), a significant

proportion of those randomized to splinting eventuallyrequired surgery while the risk of reoperation in surgi-cally treated people was very low (relative risk 0.04,95% CI 0.01–0.17).

Despite 33 trials of alternatives to the standardopen operation, no other approach has merged asconsistently superior (Scholten et al., 2007). However,endoscopic procedures may permit an earlier returnto work. In three trials with altogether 294 partic-ipants, the weighted mean difference was a 6-day(95% CI 3–9) earlier return to work with endoscopicrather than open surgery.

In the 1950s, corticosteroid injections were in-troduced for carpal tunnel syndrome (Phalen andKendrick, 1957). There is now evidence from two trialswith altogether 141 participants that corticosteroidinjection produces clinical improvement at 1 monthmore often than placebo, relative rate 2.58 (95% CI1.72–3.87) (Marshall et al., 2007). An important butunresolved question is whether corticosteroid injec-tion may avoid the need for operation in some pa-tients. The two trials addressing this question gaveopposite results (Hui et al., 2005; Ly-Pen et al., 2005).The Cochrane review of 14 other treatments showedpossibly significant benefit from some, includingsplints and ultrasound treatment, but the risk of biasin most of the trials was high (O’Connor et al., 2003).The most urgent question for investigation is whethercorticosteroid injection, which is simple, cheap andalmost free from side effects, would avoid the needfor operation in a worthwhile proportion of patientsand reduce the number of operations performed.Because the number of operations performed ap-proaches half a million a year in the United States,even a 5% reduction could produce a major saving inhealth care costs (Palmer and Hanrahan, 1995).

Bell’s PalsyBell’s palsy usually gets better but leaves about

15% of people with serious facial disfigurement. Inthe first report of the use of corticosteroids, a womanwoke with a complete facial palsy, was given corti-sone 100 mg four times daily, and recovered in 7 days(Rothendler, 1951). The author remarked, ‘‘It is indeeddifficult, though tempting, to draw a conclusion froma single satisfactory case.’’ An early, small (only 26participants) but otherwise high-quality trial comparedcortisone with placebo and found no significant differ-ence in any outcome (Taverner, 1954). This conclu-sion was supported by the Cochrane meta-analysis ofthis and two other small trials (Salinas et al., 2004).However, a Scottish trial with 496 participants in a

Hughes Journal of the Peripheral Nervous System 13:105–111 (2008)

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general practice setting has now shown a significantbenefit from prednisolone (Sullivan et al., 2007). Thetrial had a factorial design comparing prednisolone,acyclovir and placebo. After 9 months, 94.4% of thosetreated with prednisolone had recovered comparedwith only 81.6% treated without prednisolone (p ,

0.001). It is wonderful to have an answer to this long-standing question but salutary to reflect that its reso-lution has taken 56 years and that the problem wassolved by general practitioners and not neurologists.

In addition to corticosteroids, there has beeninterest in the use of antiviral agents, based on thehypothesis that herpes simplex infection underliesmany cases of Bell’s palsy. No clear conclusionemerged from the first small trials of antiviral agents(Allen and Dunn, 2004). In the Scottish study justmentioned, there were 496 participants for assess-ment of acyclovir. Recovery occurred by 9 months in85.4% of those treated with acyclovir and 90.8% ofthose treated without (p ¼ 0.1) (Sullivan et al., 2007).This result would seem to sound the death knell forantiviral agents, were it not for a recent Japanese trialwith 221 patients in which 96.5% of those treatedwith valacyclovir recovered compared with 89.7% ofthose treated without (p , 0.05). There is some doubtabout the conclusions from this trial, which was oflower quality than the Sullivan trial. However, valacy-clovir is better absorbed than acyclovir. At present, itis difficult to decide whether to recommend antiviralagents, but, if they are recommended, valacyclovirwould be the obvious choice. The issue should beresolved by a meta-analysis including the results ofthe ongoing Scandinavian trial, which is comparingprednisolone, valacyclovir, both and prednisolone witha target of 800 patients in a factorial design (Clinical-Trials.gov NCT00510263).

Guillain-Barre¤ SyndromeIn GBS, progress in investigating corticosteroids

was not much faster than in Bell’s palsy. They weretried soon after their introduction into clinical practice.The authors of the first report sensibly concludedfrom the satisfactory outcome of their single patientthat it was ‘‘impossible to make any statement aboutthe value of steroids’’ but that it was ‘‘promisingenough to justify further investigation’’ (Stillman andGanong, 1952). The first trials of oral corticosteroidswere small and underpowered, but meta-analysis ofall of them showed that they were more likely tocause harm than benefit (Hughes et al., 2006a). Thefirst adequately powered trial was published in 1993,41 years after the first case report. It showed no

significant benefit from intravenous methylpredniso-lone (Guillain-Barre Syndrome Steroid Trial Group,1993). A second large trial in which both groupsreceived intravenous immunoglobulin (IVIg) showedthat intravenous methylprednisolone added to IVIggave no long-term benefit and no or only marginalshort-term benefit (van Doorn et al., 2004; Hugheset al., 2007).

By contrast, the time from the introduction ofplasma exchange to its proper investigation was muchshorter than that of corticosteroids. The first success-ful case report (Brettle et al., 1978) was followed bysmall and then large, randomized, but not blinded, tri-als that showed highly significant benefit in terms ofboth hastening recovery and increasing the chance offull recovery of strength (The Guillain-Barre SyndromeStudy Group, 1985; French Cooperative Group in PlasmaExchange in Guillain-Barre Syndrome, 1987; McKhannet al., 1988). A consensus statement recommendedplasma exchange for GBS in 1985 (Consensus Con-ference, 1986). The recommendation was subse-quently endorsed by meta-analyses incorporating allthe available evidence (Hughes et al., 2007; Raphaelet al., 2007).

The acceptance of plasma exchange as the goldstandard treatment complicated the introduction ofIVIg. Because of anecdotal successes with CIDP, thefirst cases of GBS were treated with IVIg (Kleyweget al., 1988) before plasma exchange had been univer-sally accepted. The promising results led immediatelyto the large Dutch multicentre trial in which IVIg wascompared with plasma exchange in patients withmoderate to severe GBS (van der Meche et al., 1992).This trial showed no significant difference in outcomefollowing treatment between plasma exchange andIVIg. An international multicentre trial showed that theoutcomes with the two treatments were so similarthat their effects could be regarded as identical(Plasma Exchange/Sandoglobulin Guillain-Barre Syn-drome Trial Group, 1997), a conclusion supported bythe Cochrane meta-analysis of these and other trials(Hughes et al., 2006b; 2007).

This is where the evidence now rests. We knowthat IVIg and plasma exchange are efficacious in mod-erate to severe GBS, especially early in the disease,but this does not resolve the problem because 10–15% of patients are left disabled by the disease andabout 5% still die. We know that the combination ofplasma exchange followed by IVIg is not significantlymore efficacious than either alone (Plasma Exchange/Sandoglobulin Guillain-Barre Syndrome Trial Group,1997), but we do not know whether repeated dosesof IVIg would be even more efficacious. A trial to dis-cover this is one of the most urgent needs and couldbe efficiently targeted on those patients who are


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predicted by a new outcome score to have a poorprognosis (van Koningsveld et al., 2007). We also donot know whether patients with mild disease, whoremain able to walk at presentation, benefit fromtreatment or have such a good prognosis withouttreatment (Green and Ropper, 2001) that the dangersoutweigh the benefits. Although mycophenolate mo-fetil did not appear promising (Garssen et al., 2007),many other treatments could be tried. These includeimmunosuppressive agents targeted at T cells or thecomplement system that have already been tried andtested or are undergoing investigation in multiplesclerosis (Meyer zu Horste et al., 2007) and neuro-protective agents that have been shown beneficial inexperimental auto-immune neuritis (Bechtold et al.,2005). Regrettably, according to the international con-trolled clinical trials meta-register (http://www.controlled-trials.com/mrct/search.html), there are no randomizedtrials of any such agents actively recruiting.

Chronic Inflammatory DemyelinatingPolyradiculoneuropathy

The accumulation of evidence for the treatmentof CIDP has been somewhat faster considering thatits prevalence is only about 4 per 100,000 (Chio et al.,2007). It only emerged as a clearly demarcated condi-tion separate from other chronic neuropathies withthe publication of large series of patients from theMayo Clinic and Sydney groups in the 1970s (Dycket al., 1975; Prineas and McLeod, 1976). Subsequentconsensus groups have published sets of diagnosticcriteria including those of the American Academy ofNeurology (AAN) and the Peripheral Nerve Society (AdHoc Subcommittee of the American Academy of Neu-rology AIDS Task Force, 1991; Joint Task Force of theEFNS and the PNS, 2005).

Very soon after the delineation of the syndrome,Dyck et al. (1982) reported significant benefit from oralprednisone in a randomized trial. Although this positiveconclusion was not fully supported by a strict intentionto treat analysis, corticosteroids have become accept-ed as a first-line treatment on the basis of clinical expe-rience and observational studies (Mehndiratta andHughes, 2002). Although further randomized trials ofcorticosteroids are probably inappropriate and unlikelyto be performed, ongoing trials of pulsed oral dexa-methasone (Molenaar et al., 1997) vs. conventionaloral prednisolone and of intravenous methylpredniso-lone vs. IVIg (I. van Schaik, 2007, pers. comm., AMC,Amsterdam) are in progress (E. Nobile-Orazio, 2007,pers. comm., IRCCS Istituto Clinico Humanitas Milan).

Case reports of benefit from plasma exchangein CIDP were published in 1979 (Levy et al., 1979;

Server et al., 1979). Randomized trials in 1986 and1996 both showed the short-term efficacy of plasmaexchange for CIDP (Dyck et al., 1986; Hahn et al.,1996). Further trials have not been reported, but themeta-analysis confirmed benefit (Mehndiratta et al.,2004). A small study at the Mayo Clinic showed nosignificant difference in the efficacy of the two treat-ments (Dyck et al., 1994). Because plasma exchangeis so inconvenient, it has been supplanted by IVIgas the alternative to corticosteroids. Following theirsuccessful use in auto-immune thrombocytopenic pur-pura, plasma and then IVIg were used with apparentbenefit in 13 of 17 patients with CIDP (Vermeulenet al., 1985). However, the first parallel group random-ized trial in treatment naıve patients did not showsignificant benefit (Vermeulen et al., 1993). This mayhave been because of the presence of unrecognizedimbalance in confounding baseline factors (van Doornet al., 1991). Subsequent trials have shown benefit,and the meta-analysis of all available trials showeda significant short-term improvement in disability andstrength (van Schaik et al., 2002). This conclusion issupported by the positive results of a study with 117participants (Hughes et al., 2008), which showedlong-term as well as short-term efficacy of IVIg.

While controversy still exists about whether IVIgor corticosteroids should be the preferred first-linetreatment and about the optimal dosing regimens ofboth, the most important question is whether addi-tional immunosuppressive treatment is beneficial.Anecdotal reports and case series of many agents,from azathioprine to natalizumab and even peripheralblood cell transplantation, have been published. Suchreports seem unlikely to resolve the question ofefficacy without being rigorously tested in randomizedtrials. A small, randomized, short-term trial did not showsignificant benefit from azathioprine (Dyck et al.,1985). Two randomized trials have failed to show sig-nificant benefit from beta-interferon 1a, despite en-couraging initial case reports and series (Haddenet al., 1999; Hughes et al., 2008). A parallel group trialof methotrexate with 60 participants is in progress inEurope and will be reported at the Inflammatory Neu-ropathy Consortium meeting in Paris in July 2008. Noother trials of immunosuppressive agents for CIDPhave been published (Hughes et al., 2004).

ConclusionsAlthough substantial progress has been made in

identifying treatments for peripheral nerve diseases,the neurological community is open to criticism fornot making faster progress in the past and for not


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having a proactive programme of trials even now toresolve the remaining questions. Questions stillremain in each of the conditions considered in thisarticle. For carpal tunnel syndrome, how can we pre-dict better who will respond to the available treat-ments? And would corticosteroid injections savesome patients from the inconvenience, discomfortand expense of operation? For Bell’s palsy, we arelikely to discover from the ongoing trial whether vala-cyclovir is beneficial despite the lack of benefit fromacyclovir. However, is the standard dose of oral pred-nisolone or prednisone the last word in treatmentor would higher doses, such as 1,000 mg of intrave-nous or oral methylprednisolone as commonly usedin the treatment of multiple sclerosis relapses, beeven better? Neurologists may not be in the best posi-tion to answer these questions because, at least inthe UK, patients with carpal tunnel syndrome arepredominantly dealt with by orthopaedic surgeonsand rheumatologists, and Bell’s palsy is usually man-aged in general practice or perhaps Ear, Nose andThroat departments. However, GBS and CIDP areclearly the responsibility of neurologists and especiallythe peripheral nerve specialist and Peripheral NerveSociety.

In response to the need for a more coordinatedapproach to clinical trials, the Peripheral Nerve Societyhas formed a standing committee, the InflammatoryNeuropathy Consortium (http://pns.ucsd.edu/INC.htm).This consortium aims to work with academia, fundingagencies, the pharmaceutical industry and patientsupport organisations to prioritize the inflammatoryneuropathy trials that need to be done and facilitatetheir conduct. It will do so through its extensive net-work of peripheral nerve centres of excellence. InGBS, these trials are likely to include testing of exist-ing treatments in mild disease, dose-ranging studiesin moderate to severe disease, repeated treatment inunresponsive disease and novel immunoregulatoryand neuroprotective agents. In CIDP, trials will includedose-ranging studies of IVIg and trials of existing andnovel immunoregulatory drugs. Similar efforts will bemade in other inflammatory neuropathies. Such a col-laborative approach should ensure answers to unre-solved questions so that patients with inflammatoryneuropathy will have access to better treatmentswithin a small number of years. As the possibilities fortreating metabolic neuropathies multiply and thegenetic revolution brings treatment of even hereditaryneuropathies into view, such collaborative effortsshould be applied to the whole of peripheral nervedisease. Finally, as the clinical trial results accumu-late, high-quality systematic reviews of the Cochranetype become even more important as the basis ofresearch, guidelines and practice.

AcknowledgementsThe author or his department received consul-

tancy fees from Biogen Idec, Genzyme, Kedrion, LFB,Novartis, Octapharma, Talecris and ZLB Behring,which make IVIg or immunomodulatory drugs thathave been considered for inflammatory neuropathy.

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