Mechanisms behind diffuse idiopathic peripheral neuropathy in humans – a systematic review

Figures & data

Figure 1. Flow chart over the identification and review process.

Table 1. Well-known entities of peripheral neuropathy which are not considered in this review.

Central causes of neuropathy
Guillain-Barre Syndrome
Well-characterized hereditary neuropathy, e.g., Amyloidosis, Charcot-Marie-Tooth disease
Local neuropathy
Malnutrition
Pain syndromes
Secondary to damage of the central nervous system
Well-characterized toxic neuropathy, e.g., chemotherapy

Table 2. Studies included in the systematic review.

Study	Country	Study design	Target group	Sample size	Mechanism
Ahlawat et al. 2014 [67]	India	Review	Neuropathic pain		Isoforms of nitric oxide synthase in neuropathic pain
Alecu et al. 2017 [28]	Switzerland/ Germany/Belgium	In vitro experiment	Diabetic neuropathy		Atypical sphingolipids in mitochondrial dysfunction
Anand 2004 [32]	UK	Review	Sensory neuropathies		The role of neurotrophic factors in sensory neuropathies
Asahchop et al. 2018 [47]	Canada/ (Australia)	Experimental, human and cell-based	HIV-associated neuropathy		Micro-RNA in HIV-associated neuropathy
Bjornsdottir et al. 2019 [64]	Iceland	GWAS + clinical follow-up	Peripheral neuropathy		Genetic variant of a protein involved in the axonal cytoskeleton that associates with reduced neural conduction amplitude and clinical phenotype
Blesneac et al. 2018 [56]	UK/South Africa	Original article	Sodium channel NaV1.7 in painful diabetic neuropathy	189	Sodium channels
Calcutt 2020 [21]		Review	Diabetic neuropathy		Pathogenic mechanisms
Chandrasekaran et al. 2019 [22]	India/USA	Review	Diabetic neuropathy		Mitochondrial pathways
Chen et al. 2021 [63]	USA	In vitro experiment	Multipotent stem cells		SARM1 TIR
Cheng et al. 2020 [52]	USA/South Korea	Review	Sodium channels in peripheral nerve disease		Sodium channels
Cortese et al. 2019 [37]	Multicenter	Cross-sectional, in vitro experiment	Chronic inflammatory demyelinating polyradiculoneuropathy	342	Anti-nodal antibodies
Elzinga et al. 2019 [35]	USA	Cross-sectional, clinical	Diabetic neuropathy		TLR
Faber et al. 2011 [57]	Netherlands/Italy/USA	Original article	NaV1.7 mutations in SFN	28	Sodium channels
Faivre-Sarralih and Devaux 2013 [40]	France	Review	Diseases affecting the nodes of Ranvier, peripheral nerve hyperexcitability syndrome		Acquired or genetic dysfunction of voltage-gated potassium channel complexes and various adhesion molecules
Fernyhough et al. 2014 [23]	Canada	Review/book chapter	Diabetic neuropathy		Mitochondrial dysfunction
Fujita et al. 2017 [29]	Japan	Review	Diabetic neuropathy		Biomarkers
Gonçalves et al. 2017 [18]	Denmark	Review	Diabetic neuropathy		Schwann cells
Han et al. 2016 [58]	USA	Review	Sodium channel NaV1.8		Sodium channels
Harboe et al. 2005 [49]	Norway/ Ethiopia	Review	Leprous neuropathy		Schwann cells, immune system interactions
Hoeijmakers et al. 2012 [53]	Netherlands/USA	Review	Genetic aspects of sodium channelopathy in SFN		Sodium channels
Jack and Wright 2012 [25]	USA	Review	Diabetic peripheral sensory neuropathy		Advanced glycation end products
Kharatmal et al. 2015 [59]	India	Review	Sodium channels in painful diabetic therapy		Sodium channels
Klatt-Schreiner et al. 2020 [69]	Israel/Germany	Cross-sectional patients and controls	Sensory neuropathy in Parkinson’s disease		Alterations in lipid metabolism, accumulation of plasma glucosylceramides.
Kobayashi et al. 2018 [30]	Japan/Canada	Review	Diabetic neuropathy		Specific changes in the dorsal root ganglion sensory neurons
Koike and Katsuno 2020 [38]	Japan	Review	Chronic inflammatory demyelinating polyneuropathy		Phagocytosis by macrophages
Küçükali et al. 2015 [60]	Turkey	Review	Peripheral nerve hyperexcitability syndromes		VGKC antibodies
Kumar et al. 2014 [50]	India	Cross-sectional	Leprous neuropathy		High resolution structural changes of Schwann cell and endothelial cells in peripheral nerves in leprosy
Körei et al. 2016 [36]	Greece, Hungary	Review	SNF		Microcirculation
Landerholm et al. 2011 [66]	Sweden	Cross-sectional, in vivo experimental	Patients with dynamic mechanical allodynia (DMA): Peripheral neuropathic pain due to traumatic nerve injury or central post-stroke-pain.	25	DMA is mediated mainly via type A-beta fibers.
Landowski et al. 2016 [31]	Australia/ USA	Review	Diabetic neuropathy		Mechanisms of axonopathy
Latremoliere and Costigan 2011 [68]	USA	Review	(Neuropathic) pain		BH4 levels and pain
Lehmann et al. 2007 [46]	Germany	Cross-sectional, human subjects and animal study	Inflammatory neuropathies		The role of NO in inflammatory neuropathies
Martinez et al. 2012 [51]	Brazil	Review	Primary Sjögren’s syndrome		Proinflammatory cytokines
Meldgaard et al. 2019 [17]	Denmark	Review	Diabetes		Hyperglycemia
Moore et al. 1983 [6]	USA	Review	Vasculitis		Ischemia
Nazıroğluet al. 2012 [24]	Turkey	Review	Diabetes type 1 and 2		Oxidative stress
Papanas et al. 2011	Germany, USA	Review	Prediabetes		Metabolic syndrome
Perzyńska-Mazan et al. 2018 [7]	Poland	Review	Primary Sjögren’s syndrome		Inflammation of vessels supplying the nerves
Pardo et al. 2001 [45]	USA	Review	HIV-associated neuropathies		Inflammatory axonal or demyelinating infiltrates
Rahman et al. 2016 [19]	Korea	Review	Diabetic neuropathy		Malfunctioning glia cells
Sántha et al. 2020 [43]	Hungary	Review	Ganglioside function		Anti-ganglioside antibodies
Skundric and Lisak 2003 [34]	USA	Review	Diabetic neuropathy		Cytokines
Sopacua 2019 [55]	Netherlands/Italy/USA	Review	SFN		Sodium channels
Teasell and Arnold 2004 [70]	Canada/UK	Review	Pain		Sympathetic nervous system, alpha-receptors
Themistocleous et al. 2014 [9]	UK/Spain	Review	SFN and channelopathy		Sodium channels
Tibbs et al. 2016 [54]	USA	Review	Sodium channels and potential therapies for neuropathic pain		Sodium channels
Tomlinson and Gardiner 2008 [16]	UK	Review	Diabetic neuropathies		Oxidative stress
Tsuda et al. 2017 [65]	Japan/Canada/China	Review	Neuropathic pain		Neuronal and microglial mechanisms for neuropathic pain
Uncini 2012 [44]	Italy	Review	Anti-ganglioside antibody-mediated neuropathies		Anti-ganglioside antibodies
Verkhratsky et al. 2007 [27]	UK/Canada	Review	Diabetic neuropathy		Mitochondrial malfunction and Ca^2+ dyshomeostasis
Vernino 2020 [39]	USA	Review	Autoimmune Autonomic Disorders		Autoantibodies
Ziegler et al. 2015 [26]	Germany	Prospective study	Diabetes type 1 and 2		Oxidative stress

BH4: tetrahydrobiopterin; HIV: human immunodeficiency virus; NO: niric oxide; SARM1: Sterile alpha and toll-like interleukin 1 receptor (TIR) motif containing 1; SFN: small fiber neuropathy; TLR: toll-like receptor; UK: United Kingdom; VGKC: voltage-gated kalium channels.

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