Quantitative sensory testing and structural assessment of sensory nerve fibres in amyotrophic lateral sclerosis

İşak, Barış; Pugdahl, Kirsten; Karlsson, Páll; Tankisi, Hatice; Finnerup, Nanna Brix; Furtula, Jasna; Johnsen, Birger; Sunde, Niels; Jakobsen, Johannes; Fuglsang-Frederiksen, Anders

doi:10.1016/j.jns.2017.01.005

Cited by 30 publications

(26 citation statements)

References 38 publications

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“…Numbness, tingling and pain are the most common symptoms reported. Decreased vibration sense and abnormal pain and temperature thresholds are rarely observed during standard examination, however quantitative sensory testing shows abnormal findings in about 10% of patients, rising to almost half of the cases in advanced stages of the disease (Truini et al, 2015; Isak et al, 2017).…”

Section: The Pns As a Converging Point In Alsmentioning

confidence: 98%

“…Clustering of mitochondria, dilation of small vesicles and accumulation of neurofilaments (NF) have also been reported (Dyck et al, 1975; Di Trapani et al, 1987; Heads et al, 1991). Skin biopsy shows in about 80% of ALS patients a reduction of intraepidermal nerve fiber density (Weis et al, 2011; Truini et al, 2015; Dalla Bella et al, 2016; Nolano et al, 2017) and focal axonal swellings, suggesting axonal degeneration (Isak et al, 2017). Interestingly, small nerve fibers in the cornea are also reduced in ALS patients, correlating with bulbar disability scores (Ferrari et al, 2014).…”

Section: The Pns As a Converging Point In Alsmentioning

confidence: 99%

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The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research

et al. 2019

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Although amyotrophic lateral sclerosis (ALS) has been considered as a disorder of the motor neuron (MN) cell body, recent evidences show the non-cell-autonomous pathogenic nature of the disease. Axonal degeneration, loss of peripheral axons and destruction of nerve terminals are early events in the disease pathogenic cascade, anticipating MN degeneration, and the onset of clinical symptoms. Therefore, although ALS and peripheral axonal neuropathies should be differentiated in clinical practice, they also share damage to common molecular pathways, including axonal transport, RNA metabolism and proteostasis. Thus, an extensive evaluation of the molecular events occurring in the peripheral nervous system (PNS) could be fundamental to understand the pathogenic mechanisms of ALS, favoring the discovery of potential disease biomarkers, and new therapeutic targets.

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Section: The Pns As a Converging Point In Alsmentioning

confidence: 98%

Section: The Pns As a Converging Point In Alsmentioning

confidence: 99%

The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research

et al. 2019

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“…Axonal swellings are present in skin biopsies from HC participants, but are clearly higher in patients with polyneuropathies [5,14,20]. Axonal swellings are described in patients with AIDS/HIV [11,12], pure small fibre neuropathy [21], distal symmetric polyneuropathy of various aetiologies [20], idiopathic neuropathic pain [11][12][13][14]20], bortezomib-induced neuropathy [25] and amyotrophic lateral sclerosis (ALS) [26,27], and in myelinated nerve fibres of patients with Charcot-Marie-Tooth disease [28]. Axonal swellings may be associated with dysfunctional axonal transport and future nerve fibre loss, or may even be a potential biomarker of axonal regeneration [5,12].…”

Section: Discussionmentioning

confidence: 99%

Axonal swellings are related to type 2 diabetes, but not to distal diabetic sensorimotor polyneuropathy

et al. 2021

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Aims/hypothesis Distal diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes with many patients showing a reduction of intraepidermal nerve fibre density (IENFD) from skin biopsy, a validated and sensitive diagnostic tool for the assessment of DSP. Axonal swelling ratio is a morphological quantification altered in DSP. It is, however, unclear if axonal swellings are related to diabetes or DSP. The aim of this study was to investigate how axonal swellings in cutaneous nerve fibres are related to type 2 diabetes mellitus, DSP and neuropathic pain in a well-defined cohort of patients diagnosed with type 2 diabetes. Methods A total of 249 participants, from the Pain in Neuropathy Study (UK) and the International Diabetic Neuropathy Consortium (Denmark), underwent a structured neurological examination, nerve conduction studies, quantitative sensory testing and skin biopsy. The study included four groups: healthy control study participants without diabetes (n = 45); participants with type 2 diabetes without DSP (DSP−; n = 31); and participants with evidence of DSP (DSP+; n = 173); the last were further separated into painless DSP+ (n = 74) and painful DSP+ (n = 99). Axonal swellings were defined as enlargements on epidermal-penetrating fibres exceeding 1.5 μm in diameter. Axonal swelling ratio is calculated by dividing the number of axonal swellings by the number of intraepidermal nerve fibres. Results Median (IQR) IENFD (fibres/mm) was: 6.7 (5.2–9.2) for healthy control participants; 6.2 (4.4–7.3) for DSP−; 1.3 (0.5–2.2) for painless DSP+; and 0.84 (0.4–1.6) for painful DSP+. Swelling ratios were calculated for all participants and those with IENFD > 1.0 fibre/mm. When only those participants with IENFD > 1.0 fibre/mm were included, the axonal swelling ratio was higher in participants with type 2 diabetes when compared with healthy control participants (p < 0.001); however, there was no difference between DSP− and painless DSP+ participants, or between painless DSP+ and painful DSP+ participants. The axonal swelling ratio correlated weakly with HbA1c (r = 0.16, p = 0.04), but did not correlate with the Toronto Clinical Scoring System (surrogate measure of DSP severity), BMI or type 2 diabetes duration. Conclusions/interpretation In individuals with type 2 diabetes where IENFD is >1.0 fibre/mm, axonal swelling ratio is related to type 2 diabetes but is not related to DSP or painful DSP. Axonal swellings may be an early marker of sensory nerve injury in type 2 diabetes. Graphical abstract

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“…An increasing body of evidence has demonstrated a significant loss of intra‐epidermal nerve fibres in both experimental models and in patients with amyotrophic lateral sclerosis. To date there is one study which has demonstrated a loss of corneal nerves and related it to the bulbar function disability score …”

Section: Corneal Confocal Microscope In Central Neurodegenerationmentioning

confidence: 99%

Corneal confocal microscopy: ready for prime time

Petropoulos

Ponirakis

Khan

et al. 2020

Clinical and Experimental Optometry

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Corneal confocal microscopy is a non-invasive ophthalmic imaging modality, which was initially used for the diagnosis and management of corneal diseases. However, over the last 20 years it has come to the forefront as a rapid, non-invasive, reiterative, cost-effective imaging biomarker for neurodegeneration. The human cornea is endowed with the densest network of sensory unmyelinated axons, anywhere in the body. A robust body of evidence shows that corneal confocal microscopy is a reliable and reproducible method to quantify corneal nerve morphology. Changes in corneal nerve morphology precede or relate to clinical manifestations of peripheral and central neurodegenerative conditions. Moreover, in clinical intervention trials, corneal nerve regeneration occurs early and predicts functional gains in trials of neuroprotection. In view of these findings, it is timely to summarise the knowledge in this area of research and to explain why the case for corneal confocal microscopy is sufficiently compelling to argue for its inclusion as a Food and Drug Administration endpoint in clinical trials of peripheral and central neurodegenerative conditions.

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Quantitative sensory testing and structural assessment of sensory nerve fibres in amyotrophic lateral sclerosis

Cited by 30 publications

References 38 publications

The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research

The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research

Axonal swellings are related to type 2 diabetes, but not to distal diabetic sensorimotor polyneuropathy

Corneal confocal microscopy: ready for prime time

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