Advances in diagnostics and outcome measures in peripheral neuropathies.

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ARTICLE IN PRESS Neuroscience Letters xxx (2015) xxx–xxx

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Research article

Advances in diagnostics and outcome measures in peripheral neuropathies Ingemar S.J. Merkies a,b , Catharina G. Faber b , Giuseppe Lauria c,∗ a b c

Department of Neurology, Spaarne Hospital, Hoofddorp, The Netherlands Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands 3rd Neurology Unit, IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy

h i g h l i g h t s • • • •

Pathologic and functional diagnostic tests in small fiber neuropathy. Peripheral nerve imaging: new diagnostic approaches. New genetic tests: next-generation sequencing techniques in hereditary neuropathies. Outcome measures in neuropathies: improving the quality of trials.

a r t i c l e

i n f o

Article history: Received 28 November 2014 Received in revised form 5 February 2015 Accepted 17 February 2015 Available online xxx Keywords: Neuropathy Sodium channel genes Outcome measures Skin biopsy Quantitative sensory testing Confocal corneal microscopy Evoked potential Imaging Ultrasounds Cardiac scintigraphy

a b s t r a c t Peripheral neuropathies are a group of acquired and hereditary disorders presenting with different distribution and nerve fiber class involvement. The overall prevalence is 2.4%, increasing to 8% in the elderly population. However, the frequency may vary depending on the underlying pathogenesis and association with systemic diseases. Distal symmetric polyneuropathy is the most common form, though multiple mononeuropathies, non-length dependent neuropathy and small fiber neuropathy can occur and may require specific diagnostic tools. The use of uniform outcome measures in peripheral neuropathies is important to improve the quality of randomized controlled trials, enabling comparison between studies. Recent developments in defining the optimal set of outcome measures in inflammatory neuropathies may serve as an example for other conditions. Diagnostic and outcome measure advances in peripheral neuropathies will be discussed. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Peripheral nerves can be affected as a consequence of underlying systemic illnesses (e.g., diabetes mellitus, vitamin deficiencies, infectious diseases, malignancies), neurotoxic drugs (e.g., chemotherapy), primary disorders of the immune system (e.g., Guillain–Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN)), and hereditary disorders (e.g., Charcot–Marie-Tooth

∗ Corresponding author at: 3rd Neurology Unit, IRCCS Foundation “Carlo Besta” Neurological Institute Via Celoria, 11, Milan 20133, Italy. Tel.: +39 02 2394 4018; fax: +39 02 2394 4057. E-mail address: [email protected] (G. Lauria).

disease (CMT), amyloidosis, mitochondrial diseases). Among them, primarily axonal or demyelinating neuropathies, and in some cases mixed forms, can be recognized, and different classes of nerve fibers, namely motor, large sensory conveying touch and proprioceptive sensation, and small sensory conveying thermal and nociceptive sensation and autonomic functions, can be differently involved. The large spectrum of clinical presentations can make the diagnosis challenging. Specific laboratory and neurophysiologic investigations are required to achieve the correct diagnosis and to guide adequate disease-modifying and symptomatic therapies. Finally, the use of uniform outcome measures is determinant to improve the quality of randomized controlled trials, that are of major importance to advance the evidence-based knowledge in the field.

http://dx.doi.org/10.1016/j.neulet.2015.02.038 0304-3940/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: I.S.J. Merkies, et al., Advances in diagnostics and outcome measures in peripheral neuropathies, Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.02.038


ARTICLE IN PRESS I.S.J. Merkies et al. / Neuroscience Letters xxx (2015) xxx–xxx

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The epidemiology of peripheral neuropathy varies from quite common (e.g., in diabetes) to rare (e.g., CIDP). The overall prevalence is approximately 2400 (2.4%) per 100,000 people, but in individuals older than 55 years, it rises to approximately 8000 (8%) per 100,000 [53,54]. Hereditary neuropathies have an estimated prevalence of 1 per 2500 people [170], but may be as high as 1 in 1214 persons [24]. The diagnosis of a peripheral neuropathy can be made by careful history, neurological examination and nerve conduction studies (NCS) that helps to distinguish between demyelinating and axonal neuropathies [109]. Features of demyelination are slowing of motor and/or sensory nerve conduction velocity, dispersion of compound motor action potentials (CMAP), prolongation of distal latencies, and increased latency of F-waves. Some forms are typically characterized by motor or sensorimotor conduction blocks outside the entrapment sites (e.g., MMN and Lewis–Sumner syndrome, respectively) or at the entrapment sites (e.g., hereditary neuropathy with liability to pressure palsies [HNPP]). In contrast, axonal neuropathies are characterized by reduced amplitude of compound motor action potentials (CMAP) and sensory nerve action potentials (SNAP) with relative preservation of conduction velocities, distal latencies, and F-waves [109]. NCS can only assess motor and sensory large nerve fibers. Therefore, it does not provide information on small nerve fibers (e.g., thinly myelinated A␦ and unmyelinated C fibers) that are selectively affected in small fiber neuropathies (SFN). The clinical picture of SFN includes neuropathic pain and autonomic complaints. Pathologically, it is characterized by the degeneration of the distal endings of small nerve fibers in the skin as demonstrated by reduced density of dermal and intraepidermal nerve fibers (IENF) [93,94]. In addition, various other tests may contribute to the diagnosis of SFN, including quantitative sensory testing (QST), corneal confocal microscopy (CCM) and nociceptive evoked potentials. Several tests, including cardiovascular reflex recording, Laser doppler analysis of cutaneous blood flow (e.g., single-point laserdoppler flowmetry and 2-dimensional laser doppler imaging), and quantitative sudomotor axon reflex testing (QSART) may be useful as a diagnostic tool in autonomic neuropathies. Capturing changes in peripheral neuropathies using uniform outcome measures is important to improve the quality of randomized controlled trials in neuropathies that enables comparison between studies, but also for clinical practice. Recent developments in defining and getting international consensus regarding the optimal set of outcome measures in inflammatory neuropathies may serve as an example for other conditions [200]. 2. Advances in diagnostics NCS still represent the most important tool in the diagnostic work-up of patients with clinically suspected peripheral neuropathy [130]. Recent advances include recommendations for the interpretation of the neurophysiologic findings useful for the diagnosis of the different forms of neuropathy, among which we emphasize diabetic neuropathy [186], CIDP [1,2], MMN [2], paraproteinemic neuropathies [3], and CMT [134]. 3. Skin biopsy The availability of skin biopsy with quantification of IENF has enabled the recognition of SFN as a distinct clinical entity. IENF are unmyelinated sensory endings with exclusive somatic function that arise from nerve bundles of the subpapillary dermis. They lose the Schwann cell ensheathment as they cross the dermal–epidermal junction [23,92,98] and widely express the capsaicin receptor, making them the most distal nociceptors.

Their quantification is possible by means of a 3-mm skin biopsy performed using a disposable circular punch that can include the epidermis and the dermis, allowing also the analysis of sweat glands, hair follicles, and arterovenous anastomosis [96]. A less invasive sampling method is the removal of the epidermis alone by applying a suction capsule to the skin [86,133]. The number of IENF is counted under the optical microscope and is divided by the length of the epidermal surface to obtain a linear density per millimetre (IENF/mm). Normative reference values adjusted for gender and age decade (using the bright-field method) are available [91]. The density of IENF declines with aging and differs between genders. The quantification of epidermal nerve fibers is highly reproducible. However, sensitivity is moderate to good, as in about 12% of patients with complaints of SFN IENF density was normal [45]. The diagnostic value of skin biopsy in patients with SFN neuropathy has been established [95]. The combination between IENF density and dermal nerve quantification may increase the diagnostic yield of skin biopsy in SFN [205]. The morphometric analysis of dermal nerves is more complex than that of IENF. A new method for determination of dermal nerves by measuring the overall length of the fibers was reliable in terms of diagnostic yield in patients with pure SFN [93], but the diagnostic value of this test needs to be established. New methods were recently proposed to obtain a reliable morphometry of sweat gland and pilomotor muscle innervation, which appeared to be concordant with sweating impairment in diabetic neuropathy [64,125]. Skin biopsy correlated with the loss of pinprick sensation in idiopathic SFN [207], with the number of symptoms of SFN assessed by a specific inventory questionnaire [17], and, inversely, with the pain score in patients with sarcoid neuropathy [14]. The relationship between IENF density and neuropathic pain has been investigated in several studies. Although SFN patients may have a higher probably to suffer from neuropathic pain, no correlation was found with pain features [45]. On the other hand, profound loss of IENF has been reported in several painless conditions, like hereditary sensory and autonomic neuropathy type IV with insensitivity to pain [124], Friedreich’s ataxia [126], and Ross syndrome characterized by altered sweating but no pain complaints [127]. However, regeneration of IENF has been associated with the recovery from neuropathic pain [172], as observed in hypothyroidism related neuropathy after hormonal therapy [137], steroid responsive neuropathy [123], and impaired glucose tolerance after metabolic improvement [171]. Therefore, our current understanding is that IENF loss may increase the risk to develop neuropathic pain in neuropathy patients, but likely it is not the only cause. Indeed, IENF density can be normal even in some patients harbouring mutations in genes encoding for pain-related sodium channel subunits [56,79]. In patients with Guillain–Barré syndrome, the loss of IENF was found to occur early in the course of the disease and to correlate with severity of neuropathic pain [157]. In CIDP, skin biopsy also revealed a correlation between loss of IENF and autonomic symptoms, but not with pain [33]. Specific IgM deposits have been found on skin nerves in anti-myelin-associated glycoprotein neuropathy [103,173] and a correlation between with IgM blood levels was also described [173]. Skin biopsy is not useful in the diagnosis of vasculitic neuropathy because dermal nerves bundles do not include vessels. However, mononuclear cell infiltration has been observed in unspecific vasculitic neuropathy, systemic lupus erythematosus or eosinophilia [31,192]. The quantification of inflammatory cells in skin biopsies has been proposed as an additional diagnostic tool in diagnosing non-systemic vasculitic neuropathy [194], but this finding needs further studies. Skin biopsy may deserve interest in immune-mediated and inflammatory neuropathies for research purposes, but currently it does not have a role in the diagnosis and no biomarkers have been established yet.




The ability of small nerves to regenerate in patients and the correlation with recovery of nociception were demonstrated using skin biopsy [50,51,97,123,128,137,143,169]. The rate of degeneration and regeneration of IENF, as shown in human and animal experimental models, makes sequential skin biopsies a potential method for investigation the therapeutic effects of neuroprotective drugs [50,51,69,78,143,147,169,189].

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In vivo CCM has shown a decrease in the number and density of sub-basal nerves in a variety of abnormal ocular and systemic conditions, including dry eyes either related or not to primary Sjögren’s syndrome [20,63,193]. Isolated dry eye syndrome has been suggested to represent a neuropathic phenomenon, and as a possible SFN-like condition [154]. Indeed, dry eyes are a frequent complaint of patients with SFN [75]. 5. Evoked potentials

4. Corneal confocal microscopy In vivo, corneal confocal microscopy (CCM) has evolved rapidly from a predominantly research application to a diagnostic tool with a variety of clinical applications in ocular and neurological diseases. The cornea is densely innervated by both A␦ and C-fibers of trigeminal origin [122,131]. The nerves enter the cornea in the middle third of the stroma and run forward anteriorly in a radial fashion toward the center, where they lose their myelin sheath. The larger myelinated fibers (6 ␮m) are straight nerves that respond primarily to mechanical stimuli. The unmyelinated fibers (2–4 ␮m) fibers respond to thermal and chemical stimuli [183]. CCM is a noninvasive test that enables observation of microstructures of the cornea, including the epithelial cell layer, Bowman’s membrane, sub-basal nerve plexus, stroma, and endothelium [82]. A variety of quantification algorithms, which differs by methodology and detection properties have been used, which hampers comparability of study results [183]. The majority of studies has defined the sub-basal nerve density as the total number of nerves in each image, which allows quantification of the nerve density in an area (number/mm2 ) [7,30,52,108,116,182,184]. Others have presented the data as the number of nerves per image [117] or the total length of the nerves within a frame [55,68], but have nevertheless referred to the measure as a nerve density, which can be confusing [183]. Adaptation of a global protocol to quantify corneal nerve morphology is needed, as it will enable a direct comparison of the results from different studies and allow multicenter studies. Most studies have used semi-automated image analysis to assess sub-basal nerve alterations, which is a labor-intensive, subjective, and time consuming task, but recently automated image analysis has been developed for the rapid quantification of the corneal nerve images [40,41,43,136,139,140]. Most recently, a normative reference study has been published and demonstrated an age-related decline in corneal innervation [177]. It would be helpful to confirm findings from previous studies, the majority of which has been performed in patients with diabetes mellitus and showed that CCM was able to identify small nerve fiber damage even at very early stage of neuropathy [77,140,145,209,216]. This latter finding may be surprising considering that corneal nerves are short, and diabetic neuropathy is expected to cause a length-dependent neuropathy with early degeneration of the most distal sensory axons, in keeping with the early occurrence of sensory disturbances in the feet. Reduction of the corneal nerve fiber density was also correlated with the severity of neuropathy and IENF loss at the distal leg [63,77,108,145]. A reappraisal of these findings based on the newly available age-adjusted normative data is warranted to figure out the correct percentage of patients with decreased corneal innervation at the different stages of diabetic neuropathy and the correlation with the clinical picture. CCM has been suggested as a possible surrogate endpoint of nerve fiber regeneration after improvement of glycemia, blood pressure, and lipids in diabetes patients [178], but also after pancreas transplantation [112,182]. A reduction of corneal nerve fiber density was also found in other neuropathies, like idiopathic SFN, Charcot–Marie-Tooth disease type 1A, hereditary sensory and autonomic neuropathy, Fabry disease, autoimmune neuropathy and chemotherapy-induced neuropathy [58,90,118,179–181].

Nociceptive evoked potentials have been developed to investigate the conduction properties of small nerve fibers in a fashion not dependent on patients’ cooperation and attention [99]. Both laser-evoked potentials (LEPs) and contact heat-evoked potentials (CHEPs) are based on a selective activation of A␦ and C-fibers, whereas induction of pain-related evoked potentials (PREPs) involves the preferential stimulation of A␦-fibers [84]. More recently, intraepidermal electrical stimulation (IES) was described as a potential additional tool in detecting functional changes in A␦-fibers and C-fibers in SFN [80,88]. 5.1. Laser-evoked potentials Laser stimulation selectively activates A␦- and C-nociceptors in the superficial layers of the skin. Solid-state (thulium or neodiniumbased) lasers have several advantages over CO2 laser stimulation: shorter wavelengths cause a steeper temperature rise, with shorter pulses, higher amplitudes, shortening of cortical response latency, and reduced risk of superficial burns [195]. However, due to shorter wavelength, solid-state lasers are more sensitive to skin pigmentation, which makes the distribution of cutaneous energy unpredictable. Laser skin stimulation leads to two types of sensations: a pricking sensation, related to A␦-fiber activation, and a more diffuse and burning sensation, related to C-fiber activation. The main clinically useful LEP signal is a widespread negative–positive complex (N2–P2) that ranges from 150 to 380 ms in latency and reaches maximum amplitude at the vertex [38]. This complex is generated by the anterior cingulate gyrus, and possibly contributed to by the bilateral opercular-insular regions [38]. An earlier, smaller negative wave (N1; 150–180 ms after hand stimulation) is detected by the temporal leads and inverts polarity over the midline. The N1 response has a lower sensitivity to attention as compared to the vertex complex, which is an advantage in the clinical setting [38,62]. However, the small amplitude of N1 is a disadvantage, though the use of a bipolar montage linking temporal and midline electrodes may enhance the N1, and makes it suitable for clinical use [38]. Although laser stimuli activate both A␦ and C fibers [26], the ‘ultralate’ potentials (750–1200 ms), related to C-fiber activation, can be obtained only with dedicated techniques, limiting its clinical applicability [25,39,83,142]. LEP amplitudes correlate with the reported intensity of the perceived pain [62], and negatively with age [190]. Abnormal LEP can represent conduction abnormalities at any point in the paintemperature pathway, including peripheral nerves, plexus, roots, spinal cord or brainstem [38]. The technique may be diagnostically useful in sensory neuropathy [6,60,100,191], although due to these limitations, it cannot discriminate the level of nerve damage and should be considered as a supportive tool for diagnosing SFN. 5.2. Contact heat-evoked potentials A heat-foil contact heat stimulator has an extremely rapid heat rising time (70 ◦ C/s), and very rapid elicitation of pain, which allows for detection of contact heat-evoked potentials [66]. Compared with laser stimuli, contact heat stimulators cause




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mechanical activation of the skin and stimulate a larger surface area [29]. The stimulus of contact heat stimulators can be controlled very precisely [10,66], and the technology is easy to use and has a lower risk of causing skin irritation compared to laser [11]. Late CHEPS are associated with A␦-fiber activation and ultra-late CHEPs with C-fiber activation [32,66]. Recently, normative values have been provided making CHEPS a reliable non-invasive technique to investigate the function of small nerve fibers [89]. However, CHEPS cannot be recorded in all healthy participants. Whether technical adaptations, such as baseline temperature and optimum number of stimuli might improve test performance remains uncertain [89]. 5.3. Pain-related evoked potentials Transcutaneous electrical stimulation at pain threshold can elicit PREPs [84]. The potentials are obtained through the use of a concentric planar electrode that delivers electrical stimuli, limited to the superficial layer of the dermis. Superficial nociceptive A␦-fibers are primarily depolarized, excluding the activation of deeper non-nociceptive fibers [84]. If concomitantly large and small peripheral afferents would be stimulated, the resulting cortical potentials would largely be dominated by the non-nociceptive signals [61], thereby not reflecting specifically the pain/temperature ascending volleys. In patients with HIV-related SFN, a correlation between reduced IENF density and abnormal PREPs was found [129]. Results from another study in diabetic patients suggest that measurement of PREPs may contribute to early detection of diabetic neuropathy [121]. For intraepidermal electrical stimulation, a pushpin-like electrode of 0.2 mm in length is gently pressed against the skin, inserting the needle tip adjacent to the thin nerve endings in the skin. After delivery of an electrical stimulus, the evoked potential is measured in the same way as in the other nociceptive evoked potentials [81]. This intra-epidermal technique did not produce any scalp response earlier than 100 ms, and estimated conduction velocity of the activated fibers was about 15 m/s, thus, consistent with selective A␦ stimulation. However, the A␦ selectiveness may disappear for stimulus intensities approaching nociceptive ranges [120], thus, limiting possible clinical application of the technique. 6. Quantitative sensory testing Quantitative sensory testing (QST) is a psychophysical examination of sensory nerve fiber functions based on different threshold and suprathreshold stimuli (e.g., mechanical, pressure, vibration, cold, warm, heat, cold pain, heat pain). QST can also investigate the thresholds for gain-of-function phenomena (e.g., allodynia, hyperalgesia), and repetitive suprathreshold stimuli. Consensus criteria on use and interpretation has been published under the auspices of the International Association for the Study of Pain [12]. The first automated systems to investigate different sensory modalities were developed in the 1970s [49,59]. Currently, over 15 types of devices are available and being used worldwide with a variety of methodological approaches for location, stimulus application, and sensation qualities examined, indicative of the lack of standardization of QST as a diagnostic, follow-up, and endpoint tool in patients [15,35,168]. QST may be a useful tool in the diagnosis of SFN [45,75,76]. IEN density has been reported to be inversely correlated with both cold and warm thresholds, but correlation with specific sensory modalities is unclear [45,95]. However, QST has several drawbacks. For reliable results, it requires the patient to be alert and cooperative. It is not a specific test of peripheral nerve function; as such, central nervous system dysfunction (e.g., stroke, multiple sclerosis) may

also produce QST abnormalities. This relatively poor ability to localize the site of injury in the somatosensory system has been recently emphasized by a study in a large cohort of patients [107] that showed a remarkable phenotypic heterogeneity of the QST parameters across neuropathic pain syndromes and an overlap between central and peripheral nervous system diseases [107]. Furthermore, QST is a psychophysical test, and may be influenced by malingering or other nonorganic factors [168,204,212]. A recent consensus meeting has provided recommendations for the clinical practice, [12] emphasizing the need of a standardized protocol, adequate equipment, trained staff and use of normative values. Usually, two types of testing—the method of levels and the method of limits—are used [152,211]. A preference for the method of levels has been suggested, since there is no effect of stimulus temperature change rate [138,210] and applicability is possible even in subjects with cognitive impairment and children [42,210]. Repeatability with the method of levels is comparable or better compared to the method of limits [36,85,211]. Recently, combining bilateral warm and cold assessment of feet and hands with the method of levels showed the highest acceptable sensitivity and specificity values, and substantially reduced patient burden [16]. However, QST should be used in relation to the clinical context and in conjunction with other tests, and not alone for the diagnosis of a neurological lesion [70]. 7. Microneurography Microneurography can quantify spontaneous activity in sensory fibers and measure both positive and negative phenomena [160]. The technique has contributed substantially to improving our knowledge on the physiology of nociceptors and the mechanisms underlying their sensitization [161,162,165,166]. A microelectrode is placed inside the nerve, and the cutaneous receptive field is stimulated with another set of electrodes. The signal recorded is a series of action potentials from individual peripheral axons [160]. There are different techniques to visualize these evoked action potentials, but raster plots have proved to be useful. Several parameters can be measured, such as conduction velocity of myelinated and unmyelinated fibers and changes in latency due to activity-dependent slowing of conduction velocity (a property of unmyelinated fibers). Different profiles correspond to specific subpopulations of dorsal root ganglion neurons (DRG) and sympathetic neurons [163]. Spontaneous ongoing discharges of C-nociceptors are considered pathological and pain-related findings, and have been demonstrated in a proportion of painful (small fiber) neuropathies and, most recently, fibromyalgia patients [87,164,166], leaving open interpretation about the others. 8. Peripheral nerve imaging In the last decade, magnetic resonance imaging (MRI) and ultrasound (US) techniques for the evaluation of peripheral nerves have been developed. Recent advances have increased the diagnostic performances of both MRI and US, which are now important complement to the clinical and neurophysiologic diagnosis of various neuropathies. Both MRI and US can provide information on nerve morphology, site and extent of nerve damage and evaluation of areas difficult to evaluate by electrodiagnostic testing [215]. High-resolution US is a safe, noninvasive, and painless method of imaging peripheral nerves, and is increasingly accepted for diagnosing mononeuropathies [18,28,159]. US has been used to investigate, also diffuse neuropathies and reported pathological changes were nerve enlargement, increased hypoechogenicity and increased intraneural vascularization [65,73]. In Charcot–Marie-Tooth disease type 1A, US can demonstrate the




diffuse nerve enlargement, especially of the median and ulnar nerves, both in adults [65,73,214] and children [213], and may become a screening tool to investigate the course of the disease. In CIDP, US can detect multifocal nerve enlargements or hypertrophy that may be supportive in the diagnosis [73,214]. MRI can localize nerve lesions in areas that are difficult to investigate using electrodiagnostic studies or to visualize by US [19]. Different MRI approaches have been applied to assess peripheral nerve pathology [19]. MR neurography can be used to visualize injured nerves based on changes in hyperintensity on T2-weighted images. Increased nerve fascicle T2w-signal may be a diagnostic sign to indicate lesion and spatial dispersion. In particular, the differentiation of focal from non-focal lesion patterns and the recognition of fascicular lesion types by increased nerve fascicle T2w-signal holds potential to improve recognition and classification of peripheral neuropathies [141]. Diffusion tensor imaging (DTI) is an advanced MRI technique that can give quantitative estimates of fiber integrity in the peripheral nervous system and that showed to be useful in animal models of nerve injury and regeneration [101]. Furthermore, the technique can be used to assess the integrity of proximal peripheral nerve segments not accessible to standard nerve conduction studies [111]. However, spatial resolution is limited and longitudinal coverage is restricted [141]. Novel contrast-enhanced techniques have shown the potential to assess in vivo nerve degeneration and regeneration, inflammation and blood perfusion [175]. MRI and US have both advantages and limitations for imaging nerve pathology [215]. Advantages of US include lower cost, rapidity of examination, and higher spatial resolution. MRI has diagnostic advantages such as improved tissue characterization and imaging of deep or bone-encased structures [215]. However, as US has greater sensitivity than MRI in examining mononeuropathies and brachial plexopathies [215], it is currently the first-line tool in most patients. 9. Motor nerve biopsy Biopsy of the motor branch of the obturator nerve and gracilis muscle [37] was recently proposed as a tool to differentiate motor neuropathies from lower motor neuron disease [153]. Neuropathological analysis was based on parameters reflecting nerve degeneration (e.g., fiber density, g-ratio [axonal/fiber diameter], nerve fiber demyelination/remyelination, onion bulbs, reduction of myelinated fibers, active axonal degeneration) and regeneration (number of regenerating clusters/mm2 , clusters/fiber ratio). The underlying meaning was to capture motor neuropathies through signs of regeneration, which are supposed to be absent in motor neuron pathology, comparable to the loss of sensory neurons in dorsal root ganglia in sensory neuronopathy [37,167]. In clinical setting, motor nerve biopsy may be considered as a supportive tool in the diagnostic work-up of motor axonopathies in selected patients, though long-term confirmatory studies are warranted to determine its role. 10. Tandem mass spectrometry and cardiac scintigraphy in amyloid neuropathies The assessment of amyloid myocardial infiltration is an important complement to the diagnosis of several neurological diseases complicated by dysautonomia, including peripheral neuropathies. There are two major types of amyloidosis that can cause neuropathy: amyloid light-chain (AL) and transthyretinrelated amyloidosis (ATTR). In the AL subtype, the fibril proteins are composed of immunoglobulin light chains that are produced by monoclonal plasma cells in the bone marrow.

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ATTR amyloidosis primarily affects the heart and peripheral and/or autonomic nervous system. Wild-type transthyretin (TTR) molecule causes senile systemic amyloidosis that has a cardiacdominant presentation in the very elderly population [119]. More than 100 variants of the TTR gene are associated with autosomal dominant forms of the disease, known as familial amyloidotic polyneuropathy. While these subtypes can involve the heart among other organs, they carry different prognosis and have different treatment options [119]. The diagnostic approach to subtyping is currently based on direct gene sequencing in suspected cases and identification of the amyloid-forming protein in abdominal fat using tandem mass spectrometry [104,206]. Cardiac magnetic resonance imaging (MRI) is a useful investigation to confirm the presence and potential severity of cardiac involvement in AL and ATTR, but cannot differentiate between the subtypes of amyloidosis [106]. Heart amyloid infiltration can be demonstrated using a different scintigraphic tracers, each of which binds with different specificity [8,21]. Scintigraphy with 99m Tc-DPD can detect the myocardial deposition of TTR amyloid (both mutated and wildtype) but not of AL-related amyloid [148], making this technique a useful tool for the differential diagnosis in clinical practice. A further tracer particularly useful is 123 I-MIBG that does not directly bind to the amyloid fibrils but indirectly provides functional information on the degree of myocardial dysfunction induced by amyloid deposition.

11. New approaches to genetic analysis Hereditary neuropathies are a group of disorders characterized by a marked clinical and genetic heterogeneity [13,134,135,151]. Based on clinical presentation, they can be distinguished in different groups that do not overlap the classification based on causative genes: (1) length-dependent predominantly painless neuropathies (hereditary motor sensory neuropathies also known as CMT; distal hereditary motor neuropathies [dHMN]); (2) predominantly painful neuropathies (familial amyloid polyneuropathies; Nav1.7, Nav1.8, Nav1.9 and TRPA1-related SFN; Fabry disease; Tangier disease); (3) sensory and autonomic neuropathies (hereditary sensory and autonomic neuropathies [HSAN], including Nav1.7 and Nav1.9related congenital insensitivity to pain syndromes); (4) acute and mono/multiplex neuropathies (hereditary neuropathy with liability to pressure palsies [HNPP]; hereditary neuralgic amyotrophy; porphyrias; refsum disease; Tangier disease); (5) ataxic sensory neuronopathies. A larger classification is based on causative genes and assigned loci, and shows that in CMT, the most common hereditary neuromuscular disease [48,105,146], over 70 genes have been identified so far [13,188]. Although about 80% of patients with dominantly inherited CMT1 can be diagnosed genetically by screening a few genes [158], no mutations of known genes were found in the majority of patients affected by other subtypes [46,156]. Recently, the large group of neuropathies associated with mitochondrial disorders has been systematically reviewed [135]. The development of next-generation high-throughput technologies has resulted in the description of many new causal genes [13,155]. Whole genome DNA sequencing (WGS) has become a feasible tool both in scientific research and clinical diagnostics [196]. Various approaches addressing defined regions of the genome have been developed [74]. In whole exome sequencing (WES), only the coding regions of the genome are sequenced. The exome represents less than 2% of the human genome, but contains 85% of known disease-causing variants [34,196]. Therefore, WES has introduced a highly effective development in the genetic approach to diseases. However, insufficient sequencing coverage in certain regions of the genome may cause false-negative results.




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For evaluation of a limited number of disease-related variants, a higher level of targeting can be offered by amplicon sequencing, in which selected genome regions are amplified. This approach has the advantage of better coverage of selected disease genes and a lower risk of missing relevant variants due to automated data filtering in WES pipelines [150].

12. Outcome measures Peripheral neuropathies may cause a wide range and severity of deficits at the body level (impairments, e.g., weakness and sensory deficit, autonomic complaints), which may cause functional limitations in a daily life (e.g., walking, washing) and social activities (e.g., work activities) with a reduction in the quality of life expectations [5,54,115]. These consequences have been the focus of numerous disease-modifying and symptomatic trials in peripheral neuropathies. The choice of a proper outcome measure representing the level of interest to be examined is one of the most fundamental steps that should be taken in the design of clinical studies. Choosing a proper outcome is not only dependent on the proposed research purposes, but also, and perhaps more importantly, on the fulfilment of the clinimetric needs by the scale of interest [176,197]. With an increasing demand for accuracy, all outcome measures should be rigorously examined to determine their scientific soundness before being generally used. Physicians are generally well informed on the basic clinimetric requirements of outcome measures such as being simple, communicable, valid, reliable and responsive. These requirements have been considered for years as the most important bricks to build upon a solid clinimetric foundation [57,102,176]. However, additional modern clinimetric essentials in the design and evaluation of outcome measures are equally important. Measuring the height of a patient is generally performed without any difficulty, using a ruler with a fixed unit (in Europe: centimeters; in Anglo-Saxon communities: foot/inch) and every physician understands this. However, in health care, it is often necessary to measure less tangible qualities such as pain, fatigue or disability, where there is no ruler with a fixed unit available. Such qualities are nevertheless generally assessed using constructed surrogate outcome measures that are often composed by a set of items or questions. In science, “to measure” involves numbers that can be used in calculations. Even after multiplying and dividing, the numbers should maintain their values (“known unit”). Most clinical trials performed thus far (e.g., in inflammatory neuropathies) have collected raw data from a set of items or questions that have not been measured in this way [72,187]. Whether the collected numbers can be used in calculations depends on the type of data in the scale. For example, data at the nominal level consist of numbers or labels with unknown magnitude. It is therefore not possible to determine which category is greater or less than another. Examples of these are gender, blood type, religion, etc. Data measured at the ordinal level can be ordered or ranked, but the difference between the categories is unknown or unequal (e.g., level of disability). Since the distance between the numbers assigned to the different categories is highly unlikely to be equal, sum scores cannot be used. Also, it is not possible to compare different multi-item composite scales measuring the same trait [44,67,113,174,187]. For example, the overall disability sum score (ODSS) [114] and the Rankin disability scale [199] are both disability scales, but their outcomes cannot be compared. In addition, using the Medical Research Council (MRC) grading system to examine strength at bedside assumes a fixed unit for the assessment of strength in the various muscle groups [4,202]. However, the MRC grading system is a descriptive

categorical measure, thus, the data collected are at the ordinal level with no intrinsic numerical value. Clinical outcome measures often require a mathematical model to assess a particular patient’s quality of interest. Such a model is a mathematical representation of reality and can be used to create a surrogate outcome measure in the absence of a known ruler with a fixed unit [71]. There are two modern techniques to transform the outcome measures to the interval level: the Rasch model and the item response theory (IRT), which have the same mathematical background. The IRT approach includes additional model parameters to reflect the patterns observed in the data [22,72,208]. According to the Rasch approach, the data should fit the model, before any reliable claim about the presence of a trait can be made. Therefore, misfitting responses require further examination to explore the reason for the misfit, and may be excluded from the data set if one can explain substantively why they do not address the latent trait [71,110,149,187]. When the expectations of the model are fulfilled, interval measurement can be obtained. Rasch analysis should be used when there is a need to use a set of items in order to create sum scores. In scale development, Rasch can be used to create a new unidimensional outcome measure free from item bias. Also, the scientific properties of existing scales can be examined using Rasch and item banks can be constructed [132,185]. Another major advantage of the Rasch model is that it overcomes the problem of missing data by providing calculations of these as part of the modeling [9,208]. In the Rasch model, person ability and item difficulty are estimated separately. The difference between the ability and the difficulty should not deviate significantly from the model and various checkpoints are being used to monitor this. All data should fulfill the Rasch model’s expectations like good item and person statistical fit, threshold ordering, no item bias or local dependency and demonstrating unidimensionality. Only after these, criteria are satisfied will the measurement be at the interval level on a logits scale and suitable for conventional statistics. Only then, meaningful sum scores and changes in scores can be measured properly. To overcome the shortcomings of ordinal-based outcome measures, the inflammatory-RODS (I-RODS), a Rasch-built overall disability interval scale, has been specifically developed for patients with immune-mediated neuropathies (Guillain–Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)) and monoclonal gammopathy of undetermined significance related polyneuropathy [198]. The I-RODS is a simple 24-items questionnaire with high internal/external validity, proper reliability scores for its items’ weights and patients’ ability, and high discriminatory validity [198]. Moreover, the I-RODS more often captured clinically meaningful changes over time, with a greater magnitude of change, compared to the INCAT-ONLS disability scale in patients with GBS and CIDP [47]. In an international consensus meeting, the I-RODS was choses as the primary outcome measure in immune-mediated neuropathies [200].

13. Conclusions Peripheral neuropathies are a heterogeneous group of disorders, requiring thorough clinical investigations to identify the correct diagnosis and to guide adequate treatment. Nerve conduction studies still represent the most important tool in the diagnostic work-up of patients with clinically suspected peripheral neuropathy. However, several other diagnostic tools have been developed, such as skin biopsy, in vivo corneal confocal microscopy, nociceptive evoked potentials, peripheral nerve imaging, motor nerve biopsy and advanced genetic testing, and these developments are likely to change the diagnostic approach to peripheral neuropathies. The use of uniform outcome measures in peripheral neuropathies is




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