Size matters – Small fiber neuropathy in the Guillain–Barré syndrome
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Commentary Size matters – Small fiber neuropathy in the Guillain–Barré syndrome Do clinicians have to revise their impression of Guillain–Barré syndrome (GBS)? GBS has long been thought to represent an acute and subacute inflammatory polyneuropathy that consists of differ- ent pathophysiologically distinct subtypes (for review [3]). The inflammatory process primarily affects large myelinated fibers in motor nerves (for review [3]). The attack of specific antibodies against gangliosides and glycolipids leading to carbohydrate mim- icry triggers destruction of the axonal myelin. Complement activa- tion and lymphocytic infiltration lead to disruption of sodium channels, detachment of paranodal myelin terminals and axonal desintegration and loss. All these factors result in deficits in periph- eral nerve conduction, including those in autonomic efferents. However, although the common autonomic symptoms in GBS already indicate involvement of peripheral small fiber function, de- tailed data on the incidence and pathophysiological concepts about autonomic and afferent small fiber involvement in GBS are sparse. Moreover, sensory symptoms including dysesthesias and pain clearly point to additional involvement of thinly or unmyelinated nociceptive afferents [3,4,12]. In the present issue of PAIN, Martinez et al. very elegantly dem- onstrated two very important and novel findings about afferent fi- ber function in GBS patients [7]: (1) Using quantitative sensory testing (QST) they clearly docu- mented an impairment of afferent small fiber function. (2) They convincingly showed that the deficit of afferent small fiber function is positively correlated with the burning pain inten- sity that occurs in the acute phase of the disease and that the def- icit predicted the persistence of neuropathic pain in its later course. (3) Taken together these observations establish that GBS can manifest not only as an acute condition, but also in many patients as a chronic neuropathic pain syndrome. The finding of small fiber involvement in neuropathic pain syn- dromes is in line with previous reports of reduced intraepidermal nerve fiber density in skin biopsies of GBS patients [9]. It follows that the pathological inflammatory processes not only affect the functional state of these neurons but also lead to structural deficits of unmyelinated fibers. With these results in mind several ques- tions immediately arise: Why are small fibers affected in a disease in which it is believed that antibodies attack the myelin sheath of large afferent neurons and what impact might these findings have on the clinical and re- search aspects that relate to GBS? First, researchers and clinicians, notably neurologists, will have to broaden their perspective as to the pathophysiology of GBS, so as to clarify further the underlying mechanisms and the conse- quences of small fiber damage. Since most nociceptors are unmy- elinated the above-described mechanisms are not sufficient to explain the full clinical picture of GBS. Several approaches might be useful for future research. Damage to neuronal structures causes biomarkers to be released into the nearby extracellular fluid compartments. When this occurs in the region of proximal nerve roots, as occurs in GBS, then these biomarkers may diffuse into the cerebrospinal fluid (CSF). Protein biomarkers of axonal damage, i.e., neurofilament H and tau, have already been shown to be upregulated in GBS patients and high levels of these markers pre- dict a poor functional outcome [13]. Thus, a correlation of afferent impairment with various axonal biomarkers may also be helpful to unravel the mechanisms of small fiber damage. This is particular relevant as CSF samples were conserved in all of the patients in the study by Martinez et al. [6]. In non-inflammatory polyneurop- athies, serum levels of the cytokines, TNF-a and interleukin-6, have been shown to correlate with the occurrence of mechanical allo- dynia and with the severity of neuropathic symptoms [5]. Based on these data also the association of CSF cytokine content and var- ious positive and negative sensory abnormalities measured by QST might illuminate the underlying mechanisms. Recently, a detailed assessment of sensory symptom profiles in neuropathic pain patients has identified several phenotypic sub- groups [1,6]. Conceivably, these new classification schemes for neuropathic pain patients could be used to compare subgroups with the CSF content of axonal and inflammatory biomarkers. Second, since pain is a common problem in GBS, being present in up to 85% of patients in the acute stage of the disease, and be- cause pain persists in 30% of the patients, even after recovery of motor function [3,4,7,12], there is a critical need to evaluate the efficacy of symptomatic pain therapy in clinical trials. To date only a few randomized controlled trials have been conducted [8,10,11,14]. Third, strategies for the prevention of chronic pain in GBS pa- tients who are identified to have a high chronicity risk should be developed. For example, a recent study by Bauer et al. found that one mode of action of pregabalin is associated with an impaired anterograde trafficking of a(2)d-1 calcium channels, resulting in a decreased presence of the channels in presynaptic terminals and a consequent reduction of neurotransmitter release and cen- tral sensitization [2]. As central sensitization is an important con- tributor to the maintenance of neuropathic pain states, but likely also contributes to inflammatory neuropathic pain conditions, early modulation of nerve trafficking could be a potential option to prevent GBS patients from developing long-lasting neuropathic pain. In summary, patients with GBS must be recognized as patients who endure significant pain. The study of Martinez et al. identified 0304-3959/$36.00 Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2010.06.009 PAIN Ò 151 (2010) 9–10 www.elsevier.com/locate/pain
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Transcript of Size matters – Small fiber neuropathy in the Guillain–Barré syndrome
PAIN�
151 (2010) 9–10
w w w . e l s e v i e r . c o m / l o c a t e / p a i n
Commentary
Size matters – Small fiber neuropathy in the Guillain–Barré syndrome
Do clinicians have to revise their impression of Guillain–Barrésyndrome (GBS)? GBS has long been thought to represent an acuteand subacute inflammatory polyneuropathy that consists of differ-ent pathophysiologically distinct subtypes (for review [3]). Theinflammatory process primarily affects large myelinated fibers inmotor nerves (for review [3]). The attack of specific antibodiesagainst gangliosides and glycolipids leading to carbohydrate mim-icry triggers destruction of the axonal myelin. Complement activa-tion and lymphocytic infiltration lead to disruption of sodiumchannels, detachment of paranodal myelin terminals and axonaldesintegration and loss. All these factors result in deficits in periph-eral nerve conduction, including those in autonomic efferents.
However, although the common autonomic symptoms in GBSalready indicate involvement of peripheral small fiber function, de-tailed data on the incidence and pathophysiological concepts aboutautonomic and afferent small fiber involvement in GBS are sparse.Moreover, sensory symptoms including dysesthesias and painclearly point to additional involvement of thinly or unmyelinatednociceptive afferents [3,4,12].
In the present issue of PAIN, Martinez et al. very elegantly dem-onstrated two very important and novel findings about afferent fi-ber function in GBS patients [7]:
(1) Using quantitative sensory testing (QST) they clearly docu-mented an impairment of afferent small fiber function.
(2) They convincingly showed that the deficit of afferent smallfiber function is positively correlated with the burning pain inten-sity that occurs in the acute phase of the disease and that the def-icit predicted the persistence of neuropathic pain in its latercourse.
(3) Taken together these observations establish that GBS canmanifest not only as an acute condition, but also in many patientsas a chronic neuropathic pain syndrome.
The finding of small fiber involvement in neuropathic pain syn-dromes is in line with previous reports of reduced intraepidermalnerve fiber density in skin biopsies of GBS patients [9]. It followsthat the pathological inflammatory processes not only affect thefunctional state of these neurons but also lead to structural deficitsof unmyelinated fibers. With these results in mind several ques-tions immediately arise:
Why are small fibers affected in a disease in which it is believedthat antibodies attack the myelin sheath of large afferent neuronsand what impact might these findings have on the clinical and re-search aspects that relate to GBS?
First, researchers and clinicians, notably neurologists, will haveto broaden their perspective as to the pathophysiology of GBS, soas to clarify further the underlying mechanisms and the conse-
0304-3959/$36.00 � 2010 International Association for the Study of Pain. Published bydoi:10.1016/j.pain.2010.06.009
quences of small fiber damage. Since most nociceptors are unmy-elinated the above-described mechanisms are not sufficient toexplain the full clinical picture of GBS. Several approaches mightbe useful for future research. Damage to neuronal structurescauses biomarkers to be released into the nearby extracellular fluidcompartments. When this occurs in the region of proximal nerveroots, as occurs in GBS, then these biomarkers may diffuse intothe cerebrospinal fluid (CSF). Protein biomarkers of axonal damage,i.e., neurofilament H and tau, have already been shown to beupregulated in GBS patients and high levels of these markers pre-dict a poor functional outcome [13]. Thus, a correlation of afferentimpairment with various axonal biomarkers may also be helpful tounravel the mechanisms of small fiber damage. This is particularrelevant as CSF samples were conserved in all of the patients inthe study by Martinez et al. [6]. In non-inflammatory polyneurop-athies, serum levels of the cytokines, TNF-a and interleukin-6, havebeen shown to correlate with the occurrence of mechanical allo-dynia and with the severity of neuropathic symptoms [5]. Basedon these data also the association of CSF cytokine content and var-ious positive and negative sensory abnormalities measured by QSTmight illuminate the underlying mechanisms.
Recently, a detailed assessment of sensory symptom profiles inneuropathic pain patients has identified several phenotypic sub-groups [1,6]. Conceivably, these new classification schemes forneuropathic pain patients could be used to compare subgroupswith the CSF content of axonal and inflammatory biomarkers.
Second, since pain is a common problem in GBS, being presentin up to 85% of patients in the acute stage of the disease, and be-cause pain persists in 30% of the patients, even after recovery ofmotor function [3,4,7,12], there is a critical need to evaluate theefficacy of symptomatic pain therapy in clinical trials. To date onlya few randomized controlled trials have been conducted[8,10,11,14].
Third, strategies for the prevention of chronic pain in GBS pa-tients who are identified to have a high chronicity risk should bedeveloped. For example, a recent study by Bauer et al. found thatone mode of action of pregabalin is associated with an impairedanterograde trafficking of a(2)d-1 calcium channels, resulting ina decreased presence of the channels in presynaptic terminalsand a consequent reduction of neurotransmitter release and cen-tral sensitization [2]. As central sensitization is an important con-tributor to the maintenance of neuropathic pain states, but likelyalso contributes to inflammatory neuropathic pain conditions,early modulation of nerve trafficking could be a potential optionto prevent GBS patients from developing long-lasting neuropathicpain.
In summary, patients with GBS must be recognized as patientswho endure significant pain. The study of Martinez et al. identified
Elsevier B.V. All rights reserved.
10 Commentary / PAIN�
151 (2010) 9–10
many significant new features of the quality and pathogenesis ofpain in GBS and underscores the importance of continuing re-search. Future studies need to focus on the pathophysiologicalmechanisms, specific treatment options and especially approachesto prevention of pain in GBS patients. These efforts, of course, willtake time. Until then, it is essential that we provide adequate treat-ment of GBS patients, paying particular attention to their symp-toms and signs of pain.
Conflicts of interest
The authors declare no conflicts of interest.
References
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Andreas BinderRalf Baron
Sektion Neurologische Schmerzforschung und Therapie,Klinik für Neurologie,
Christian-Albrechts-Universität Kiel, GermanyCorresponding author. Address: Sektion NeurologischeSchmerzforschung und Therapie, Klinik für Neurologie,
Christian-Albrechts-Universität Kiel,Arnold-Heller-Str. 3, Haus 41, 24105 Kiel, Germany
Tel.: +49 431 597 8504; fax: +49 431 597 8530.E-mail address: [email protected]
