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Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia

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Om fibromyalgi og at 41% av pasientene har tynnfibernevropati. 3% av kontrollgruppen har det. Tynnfibernevropati-type smerter er en del av mange sykdommer og flere studier viser at det er underdiagnostisert.

http://www.painjournalonline.com/article/S0304-3959(13)00294-7/abstract

No specific objective abnormalities have been identified, which precludes definitive testing, disease-modifying treatments, and identification of causes.

We found that 41% of skin biopsies from subjects with fibromyalgia vs 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects (all P⩽0.001).

Abnormal AFTs (autonomic function test) were equally prevalent, suggesting that fibromyalgia-associated SFPN is primarily somatic.

These findings suggest that some patients with chronic pain labeled as fibromyalgia have unrecognized SFPN, a distinct disease that can be tested for objectively and sometimes treated definitively.

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Deconstructing the Placebo Effect and Finding the Meaning Response

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Om placeboeffekten og at «mening» er bedre å bruke enn en placeborespons når vi snakker om behandling. Placebo-sukkerpillen har ingen effekt i kroppen, men meningen vi legger i den har det. Vi får en «meningsrespons». Selv medisiner eller operasjoner får bedre effekt når det er en «mening» bak det.

http://annals.org/article.aspx?articleid=715182

http://www.homeopathy.org/wp-content/uploads/downloads/2012/05/Mossman.pdf

We provide a new perspective with which to understand what for a half century has been known as the “placebo effect.” We argue that, as currently used, the concept includes much that has noth- ing to do with placebos, confusing the most interesting and im- portant aspects of the phenomenon. We propose a new way to understand those aspects of medical care, plus a broad range of additional human experiences, by focusing on the idea of “mean- ing,” to which people, when they are sick, often respond.

We review several of the many areas in medicine in which meaning affects illness or healing and introduce the idea of the “meaning response.” We suggest that use of this formulation, rather than the fixation on inert placebos, will probably lead to far greater insight into how treatment works and perhaps to real improvements in human well-being.

If we replace the word “placebo” in the second sentence with its definition from the first, we get: “The placebo effect is the therapeutic effect produced by [things] objectively without specific activity for the condition being treated.” This makes no sense whatsoever. Indeed, it flies in the face of the obvious. The one thing of which we can be absolutely certain is that placebos do not cause placebo effects. Placebos are inert and don’t cause anything.

Moreover, people frequently expand the concept of the placebo effect very broadly to include just about every conceivable sort of beneficial biological, social, or human interaction that doesn’t involve some drug well- known to the pharmacopoeia.

The concept of the placebo effect has been expanded much more broadly than this. Some attribute the effects of various alternative medical systems, such as homeopathy (33) or chiropractic (34), to the placebo effect. Others have described studies that show the positive effects of enhanced communication, such as Egbert’s (35), as “the placebo re- sponse without the placebo” (7). No wonder things are confusing.

Instead, they can be ex- plained by the “meanings” in the experiment: 1) Red means “up,” “hot,” “danger,” while blue means “down,” “cool,” “quiet” and 2) two means more than one. These effects of color (37– 40) and number (41, 42) have been widely replicated.

In this study, branded aspirin worked better than unbranded aspirin, which worked better than branded placebo, which worked better than unbranded placebo.

Aspirin relieves headaches, but so does the knowledge that the pills you are taking are “good” ones.

n a study of the benefits of aerobic exercise, two groups participated in a 10-week exercise program. One group was told that the exercise would enhance their aerobic capacity, while the other group was told that the exercise would enhance aerobic capacity and psychological well-being. Both groups improved their aerobic capacity, but only the second group improved in psychological well-being (actually “self-esteem”). The re- searchers called this “strong evidence . . . that exercise may enhance psychological well-being via a strong placebo effect” (44).

It seems reasonable to label all these effects (except, of course, of the aspirin and the exercise) as “mean- ing responses,” a term that seeks, among other things, to recall Dr. Herbert Benson’s “relaxation response” (45). Ironically, although placebos clearly cannot do anything themselves, their meaning can.

We define the meaning response as the physiologic or psychological effects of meaning in the origins or treatment of illness; meaning responses elicited after the use of inert or sham treatment can be called the “placebo effect” when they are desirable and the “nocebo effect” (46) when they are undesirable.

Insofar as medicine is meaningful, it can affect pa- tients, and it can affect the outcome of treatment (47– 49). Most elements of medicine are meaningful, even if practitioners do not intend them to be so. The physi- cian’s costume (the white coat with stethoscope hanging out of the pocket) (50), manner (enthusiastic or not), style (therapeutic or experimental), and language (51) are all meaningful and can be shown to affect the out- come; indeed, we argue that both diagnosis (52) and prognosis (53) can be important forms of treatment.

Likewise, acupuncture analgesia can be reversed with naloxone in animals (61) and people (62). To say that a treatment such as acupuncture “isn’t better than placebo” does not mean that it does nothing.

Surgery is particularly meaningful: Surgeons are among the elite of medical practitioners; the shedding of blood is inevitably meaningful in and of itself.

The intensity of the effect was shown to be correlated with “the strength of commitment to traditional Chinese culture.” These differences in longevity (up to 6% or 7% difference in length of life!) are not due to having Chinese genes but to having Chinese ideas, to knowing the world in Chinese ways. The effects of meaning on health and disease are not restricted to placebos or brand names but permeate life.

Practitioners can benefit clinically by conceptualizing this issue in terms of the meaning response rather than the placebo effect. Placebos are inert. You can’t do anything about them. For human beings, meaning is everything that placebos are not, richly alive and powerful.

One reason we are so ignorant is that, by focusing on placebos, we constantly have to address the moral and ethical issues of prescribing inert treatments (73, 74), of lying (75), and the like. It seems possible to evade the entire issue by simply avoiding placebos. One cannot, however, avoid meaning while engaging human beings. Even the most distant objects—the planet Venus, the stars in the constellation Orion—are meaningful to us, as well as to others (76).

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Neural tissue management provides immediate clinically relevant benefits without harmful effects for patients with nerve-related neck and arm pain: a randomised trial

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Om hvordan manipulering av vevet rundt nerver gir en umiddelbar bedring av nakkesmerter med utstårling ut armen.

http://ajp.physiotherapy.asn.au/AJP/vol_58/1/Nee.pdf

These results enable physiotherapists to inform patients that neural tissue management provides immediate clinically relevant benefits beyond advice to remain active with no evidence of harmful effects.

One month prevalence rates for activity-limiting neck pain range from 7.5% to 14.5% in the general population (Hogg-Johnson et al 2008, Webb et al 2003). Neck pain spreading down the arm is more common than neck pain alone and is associated with higher levels of self-reported disability (Daffner et al 2003). One mechanism for neck pain spreading down the arm is the sensitisation of neural tissues (Bogduk 2009).

Neural tissue management was based on principles proposed by Elvey (1986) and Butler (2000). Along with advice to continue their usual activities, participants assigned to the experimental group received an educational component, manual therapy techniques, and a home program of nerve gliding exercises. The educational component attempted to reduce unnecessary apprehension participants may have had about neural tissue management (Butler 2000). The manual therapy techniques and nerve gliding exercises have been advocated for reducing nerve mechanosensitivity (Butler 2000, Coppieters and Butler 2008, Elvey 1986).

The educational component emphasised two points. First, examination findings suggested that participants’ symptoms were at least partly related to nerves in the neck and arm that had become overly sensitive to movement. Second, neural tissue management techniques would move the nerves in a gentle and pain-free manner, aiming to reduce this sensitivity. The manual therapy techniques included a contralateral cervical lateral glide and a shoulder girdle oscillation combined with active craniocervical flexion to elongate the posterior cervical spine (Elvey 1986). The home program of nerve gliding exercises involved a ‘sliding’ and a ‘tensioning’ technique for the median nerve and cervical nerve roots (Coppieters and Butler 2008).

There was no evidence to suggest that neural tissue management was harmful. ‘Worst case’ intention-to- treat and ‘complete case’ analyses showed no difference in the prevalence of worsening between groups (Table 2).

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A novel protocol to develop a prediction model that identifies patients with nerve-related neck and arm pain who benefit from the early introduction of neural tissue management

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Om hvordan mobilisering av vevet rundt nervetrådene gir solid bedring på nakkesmerter med utstrålinger ut i armen. Studien har detaljert beskrivelse av teknikkene. Kan det være at den fikk så stor bedring ved at kriteriene ble satt på subjektiv opplevelse av «moderat bedring» av klientene?

http://www.sciencedirect.com/science/article/pii/S1551714411001455

We describe a novel protocol to develop a prediction model that identifies patients with nerve-related neck and arm pain who are likely to benefit from the early introduction of neural tissue management (NTM).

Patients rating themselves at least ‘moderately better’ on a Global Rating of Change scale will be considered ‘improved’.

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Tynnfibernevropati

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Alt om small fiber neuropathy, tynnfibernevropati, på norsk. Nevner at det er en underdiagnostisert tilstand, og vanskelig å diagnostisere siden alle nevrologiske tester er normale. Nevner også medikamenter, men at disse heller ikke gir særlig god effekt. De skriver at man kan behandle den underliggende sykdommen, men vi kan vel forvente at de mener medikamentell behandling da også, uten noen forhold til ernæring, trening eller manuell behandling.

http://tidsskriftet.no/article/2961926/

På grunn av manglende kunnskap om tilstanden blant mange leger samt begrensede diagnostiske metoder, er denne typen nevropati sannsynligvis underdiagnostisert. Tynnfibernevropati kan ha mange årsaker, men symptomene er ofte relativt like.

Tynnfibernevropati gir en karakteristisk distribusjon av symptomer, spesielt smerte, og er assosiert med flere vanlige sykdomstilstander. Spesifikke tynnfibertester som hudbiopsi og termotest kan brukes for å stille diagnosen. Behandlingen er symptomatisk, men det er ofte vanskelig å oppnå fullstendig smertelindring.

Den kliniske nevrologiske undersøkelsen vil i liten grad kunne påvise tynnfibernevropati, men først og fremst bidra til å utelukke en mer generell polynevropati. Ofte er det nødvendig med supplerende undersøkelser for å stille endelig diagnose.

Tynnfibernevropati affiserer enten selektivt eller i overveiende grad de tynne nervefibrene, dvs. de umyeliniserte C-fibrene og de tynne, myeliniserte A-deltafibrene.

Tynnfiberskaden er størst hos de pasientene som også har en tykkfibernevropati (1). Forekomst av tynnfibernevropati er ikke kjent (2). Dette skyldes hovedsakelig at diagnosen baseres på metoder som er innført de senere årene og som fortsatt ikke er rutine. Men tynnfibernevropati forekommer ved mange forholdsvis vanlige tilstander.

Symptomene ved tynnfibernevropati gjenspeiler ikke årsaken til nevropatien, men hvilke fibre som er affisert. Den vanligste grunnen til at en pasient søker lege, er etter vår erfaring smerter distalt i ekstremitetene, slik det også ofte er gjengitt i den aktuelle litteraturen. Dette skyldes en affeksjon av de tynne afferente A-delta-fibrene og C-fibrene.

Efferente, tynne autonome sudomotoriske og/eller vasomotoriske fibre kan være skadet, og noen pasienter opplever da et endret svettemønster (som regel manglende svette) og/eller kalde ekstremiteter.

Det er viktig å presisere at en smertetilstand som omfatter hele kroppen som regel ikke vil være uttrykk for en perifer tynnfibernevropati.

Pasienter beskriver smerten ved tynnfibernevropati på mange ulike måter, slik det også er ved nevropatisk smerte generelt. Smerten kan være dyp og/eller overflatisk og ha mange kvaliteter; brennende, verkende, klemmende, skjærende, sviende, stikkende osv. Smerten kan være konstant eller intermitterende. Det mest typiske er at smerten forverres under, og spesielt etter, fysisk aktivitet, om kvelden når pasienten setter seg ned og om natten (2, 3). Pasienter med tynnfibernevropati kan i tillegg ha både spontan paroksysmal og provosert smerte (3). Den paroksysmale smerten innebærer støt- eller sjokkliknende smerte innenfor det smertefulle området, ofte med noe utstråling og med svært varierende frekvens. Den provoserte smerten er smerte utløst ved stimulering av det smertefulle området, som regel ved berøring, trykk, men av og til ved kulde og (noe sjeldnere) varmestimuli. Typisk vil mange pasienter beskrive smerter når de tar på seg sokker og sko, føle ubehag ved trykk fra dynen om natten og at det er smertefullt å gå barbeint. Provosert smerte kan inndeles i allodyni, dvs. smerte ved et normalt ikke-smertefullt stimulus og hyperalgesi, dvs. en unormal sterk smerte ved et normalt smertefullt stimulus (4).

Årsaken til at den nevnte smerten oppstår, er sannsynligvis ulike former for hypereksitabilitet i tynne umyeliniserte C-fibre. Det kan dreie seg om unormal spontan fyring eller doble og tredoble impulser (5). Mengden av spontan fyring synes å stå i forhold til intensiteten av den opplevde smerten (6). Fenomenene mekanisk allodyni og hyperalgesi skyldes i all hovedsak sentralnervøs sensitisering, altså endringer i det sentrale nervesystemet som inntreffer både i ryggmargen og høyere opp i sentralnervesystemet (7).

Tilstander som er assosiert med eller kan gi tynnfibernevropati

Metabolske

Diabetes mellitus type 1 og 2

Nedsatt glukosetoleranse (omdiskutert)

Hypotyreose

Hyperlipidemi

Leversvikt

Nyresvikt

Arvelige

Fabrys sykdom

Familiær amyloidose

Hereditær sensorisk og autonom nevropati

Toksiske

Alkoholmisbruk

B6-intoksikasjon

Cytostatika

Andre

Antifosfolipidsyndrom

Bindevevssykdommer

Cøliaki

Hemokromatose

Hiv

Kryoglobulinemi

Monoklonal gammopati

Paraneoplasi

Sarkoidose

Sjögrens syndrom

Den langt vanligste årsaken er antakelig diabetes mellitus (14). I flere studier har man også funnet at det er økt forekomst av forstadier til diabetes og nedsatt glukosetoleranse hos pasienter med tynnfibernevropati (15, 16) og pekt på at det er en mulig årsakssammenheng.

Det viktigste kriteriet for å mistenke tynnfibernevropati er manglende funn forenlig med generell tykkfibernevropati, dvs. at det er intakt sensibilitet for lett berøring, vibrasjon og leddsans, normal motorikk og normale reflekser. Pasientene vil ofte ha nærmest normal nevrologisk status, men kan ha nedsatt sensibilitet for stikk og temperatur, eventuelt også allodyni eller hyperalgesi, oftest i sokkeformet mønster. Allodyni undersøkes ved bruk av lett berøring med bomull eller en børste og hyperalgesi ved stikk med sikkerhetsnål eller liknende, for eksempel en spiss tannstikker.

Den viktigste delen av den kliniske undersøkelsen er anamneseopptaket, med spesielt fokus på eventuelle smerter, endret svettemønster og plager med kalde ekstremiteter.

Hudbiopsi. Hudbiopsi tas som en 3 mm eller 4 mm stansebiopsi i lokalanestesi, normalt fra nedre del av leggen

Termotest. Dette er en test av afferente temperaturmedierende A-delta-fibre og C-fibre. En termode festes på pasientens hud. Temperaturen i termoden kan være 10 – 50 °C. Pasienten signaliserer ved å trykke på en knapp når han eller hun kjenner den minste antydning til kulde (en test av A-delta-fibre), den minste antydning til varme (en test av C-fibre) og også ved terskel til kuldesmerte (en test av både A-delta-fibre og C-fibre) og varmesmerte (en test av C-fibre) (illustrasjon).

QSART (Quantitative sudomotor axon reflex test). Dette er en spesifikk og objektiv test av de efferente autonome sudomotorfibrene. Testen måler volum av svette på huden etter iontoforese av acetylkolin.

Andre tester på tynnfiberfunksjon. Det finnes en rekke andre tester på tynnfibre. Noen undersøker primært efferente fibre ved aksonreflekstest og svettetester. Det finnes også mer sofistikerte hudbiopsimetoder som kan avdekke tidlige forandringer i tynnfibre.

Hvis man kjenner årsaken til pasientens tynnfibernevropati, kan det i noen tilfeller være mulig å redusere symptomene ved behandling eller forebygging av grunnlidelsen. Foruten en alvorlig autonom nevropati som kan kreve overvåking og behandling i en intensivenhet, vil ofte smerte være det enkeltsymptomet som gjør at en pasient oppsøker lege.

Førstehåndspreparater ved behandling av smertefull tynnfibernevropati er trisykliske antidepressiver (amitriptylin, nortriptylin), serotonin-noradrenalinreopptakshemmere (duloksetin) eller anitiepileptika (gabapentin eller pregabalin) (34, 35). Antidepressiver og antiepileptika brukes alene eller i kombinasjon, og ved manglende eller partiell effekt kan det være aktuelt å prøve ut depotopioider til noen pasienter som tilleggsmedikasjon eller som monoterapi (28, 35).

Tynnfibernevropati forekommer ved mange vanlige lidelser, men det er grunn til å anta at det er en underdiagnostisert tilstand. Ved klinisk mistanke og normale funn ved EMG/nevrografi bør pasienten henvises til spesifikke tynnfibertester.

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Cramps and small-fiber neuropathy.

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Om at kramper kan ha grunnlag i small fiber neuropathy. Nevropatien øker betennelsesutskillelsen fra nervecellene som dermed øker muskelsammentreningssignalene.

http://www.ncbi.nlm.nih.gov/m/pubmed/23813593/

Introduction: Muscle cramps are a common complaint and are thought to arise from spontaneous discharges of the motor nerve terminal.

Conclusions: Our data show that 60% of patients with muscle cramps who lack neuropathic complaints have SFN, as documented by decreased IENFD. Cramps may originate as local mediators of inflammation released by damaged small nerve that excite intramuscular nerves.

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Epidermal nerve fiber length density estimation using global spatial sampling in healthy subjects and neuropathy patients.

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Om hvordan small fiber neuropathy (prikking, stikking, brenning, nummenhet, osv) kommer av redusert antall c-fibere i huden, og dermed ferre signaler opp til hjernen. Kan hjernen reagerer på lavt antall c-fibere med å sende smerte ut?

http://www.ncbi.nlm.nih.gov/m/pubmed/23399897

Assessment of intraepidermal nerve fiber density (IENFD) has become a useful tool for the investigation of patients with suspected small-fiber neuropathy (SFN).

Mean IENFD in SFN patients was 2.22 ± 1.63 mm versus 7.51 ± 2.17 mm in controls; mean length density was 112 ± 82.6 mm in SFN patients versus 565 ± 240 mm in controls (p < 0.001 for both).

There were significant differences in axonal swelling ratios between healthy subjects and patients, that is, per IENFD and per nerve fiber length

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Stretching before sleep reduces the frequency and severity of nocturnal leg cramps in older adults: a randomised trial.

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Om at enkel stretching før leggetid gjør at nattlige kramper blir markant mindre.

http://www.ncbi.nlm.nih.gov/m/pubmed/22341378/
Hele studien her: http://ajp.physiotherapy.asn.au/AJP/vol_58/1/Hallegraeff.pdf

t six weeks, the frequency of nocturnal leg cramps decreased significantly more in the experimental group, mean difference 1.2 cramps per night (95% CI 0.6 to 1.8). The severity of the nocturnal leg cramps had also decreased significantly more in the experimental group than in the control group, mean difference 1.3 cm (95% CI 0.9 to 1.7) on the 10-cm visual analogue scale.

CONCLUSION: Nightly stretching before going to sleep reduces the frequency and severity of nocturnal leg cramps in older adults.

http://origin-ars.els-cdn.com/content/image/1-s2.0-S1836955312700681-gr1.jpg

What is already known on this topic: Nocturnal leg cramps are common among the elderly, causing pain and sleep disturbance. The medications used to prevent nocturnal leg cramps have variable efficacy and may have substantial side effects.
What this study adds: Nightly stretching of the calves and hamstrings reduces the frequency of nocturnal leg cramps in older adults. Nightly stretching also lessens the pain associated with any cramps that continue to occur.

The cause of nocturnal leg cramps is unknown. However, several possible causes and precipitating factors have been hypothesised. Abnormal excitability of motor nerves, perhaps due to electrolyte imbalance, may be a contributing mechanism (Monderer et al 2010). Diuretics, steroids, morphine, and lithium are also reported to cause nocturnal cramps, as can repetitive movements during sport (Butler et al 2002, Kanaan and Sawaya 2001, Monderer et al 2010). Conversely, physical inactivity has been proposed as a cause, with inadequate stretching leading to reduced muscle and tendon length (Monderer et al 2010, Sontag and Wanner 1988).

Quinine and hydroquinine are moderately effective in reducing the frequency and severity of nocturnal leg cramps (El-Tawil et al 2010, van Kan et al 2000), perhaps by decreasing the excitability of the motor end plate and thereby increasing the refractory period of a muscle (Vetrugno et al 2007). However, quinine can have important side effects, especially for women, such as: thrombocytopenia, hepatitis, high blood pressure, tinnitus, severe skin rash, and haemolytic uremic syndrome (Aronson 2006, Inan-Arslan et al 2006).

Although other medications have been used to treat nocturnal leg cramps such as magnesium, Vitamin B Complex Forte, calcium, and vitamin E, none of these appears to be effective (Anonymous 2007, Daniell 1979).

Moreover, stretching techniques can foster a resilient attitude toward recovery in patients with nocturnal leg cramps by promoting a ‘bounce back and move on’ behavioural strategy (Norris et al 2008), because they give patients a strategy to seek immediate relief.

Each stretch was performed a total of three times, with 10 seconds of relaxation between each stretch. Stretching of both legs was done within three minutes.

Our results showed that six weeks of nightly stretching of the calf and hamstring muscles significantly reduced the frequency and severity of nocturnal leg cramps in older people. The best estimate of the average effect of stretching on the frequency of cramps was a reduction of about one cramp per night.

The stretches reduced the severity of the pain that occurred with the nocturnal leg cramps by 1.3 cm on a 10-cm visual analogue scale.
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The effect of glucose concentration on peripheral nerve and its response to anoxia.

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Denne nevner at både for høyt og for lavt blodsukker er sakdelig for nervesystemet. Hele studien er ikke publisert enda, men når den kommer blir det interessant å se hvor høyt blodsukkeret er før det begynner å påvirke nervesystemet. Den nevner at alt mellom 2,8 – 5,6 nmol/L er ok.

http://www.ncbi.nlm.nih.gov/pubmed/23733393

The effects of glucose on the nerve action potential (NAP) were investigated for concentrations between 0 mmol/l and 55.5 mmol/l in an in vitro system using rat sciatic nerve.

Results: Hypoglycemia produces immediate reductions in NAP amplitude and velocity, while hyperglycemia has the opposite effect in the short term.

Over a 12-hour experiment, the amplitude of the NAP remained stable for glucose concentrations in the range 2.8-5.6 mmol/l, but when the glucose concentration was <2.8 mmol/l or >27.8 mmol/l, the amplitude of the NAP declined.

This study confirms the importance of glucose concentration for nerve function especially during anoxia.

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nytt perspektiv på placebo

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Veldig interessant om placebo! Når placebo virker så bra, hvorfor blir ikke alle friske bare ved å tenke seg friske?
…fordi de tilstandene vi prøver å blir friske fra, smerte, feber, kvalme, osv, ikke er sykdommer eller trussler i seg selv, de er forsvarsmekanismer. Og forsvarsmekanismer må vi ikke fjerne eller undergrave. Det placebo helbreder oss fra er ideen, bevisst eller ubevisst, om at det er en trussel i kroppen vår.