Abnormal Skin Biopsy Research Articles

Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients – a randomized controlled trial. (OxaNeuro)

BackgroundOxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors’ quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN.MethodsThe OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months.The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy.DiscussionIf readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival.Trial registrationClinicalTrial.gov identifier: NCT05404230Protocol version: 1.2, April 25th. 2023

Initial validation of the Mass. General Neuropathy Exam Tool (MAGNET) for evaluation of distal small-fiber neuropathy.

Diagnosis of small-fiber neuropathy (SFN) is hampered by its subjective symptoms and signs. Confirmatory testing is insufficiently available and expensive, so predictive examinations have value. However, few support the 2020 SFN consensus-case-definition requirements or were validated for non-diabetes neuropathies. Thus we developed the Massachusetts General Hospital Neuropathy Exam Tool (MAGNET) and measured diagnostic performance in 160 symptomatic patients evaluated for length-dependent SFN from any cause and 37 healthy volunteers. We compared prevalences of abnormalities (vital signs, pupil responses, lower-limb appearance, pin, light touch, vibration and position sensitivity, great-toe strength, muscle stretch reflexes), and validated diagnostic performance against objective SFN tests: lower-leg skin-biopsy epidermal neurite densities and autonomic function testing (AFT). Sensitivity/specificity, feasibility, test-retest and inter-rater reliability, and convergence with the Utah Early Neuropathy Scale were calculated. Patients' ages averaged 48.5 ± 14.7 years and 70.6% were female. Causes of neuropathy varied, remaining unknown in 59.5%. Among the 46 with abnormal skin biopsies, the most prevalent abnormality was reduced pin sharpness at the toes (71.7%). Inter-rater reliability, test-retest reliability, and convergent validity excelled (range = 91.3-95.6%). Receiver operating characteristics comparing all symptomatic patients versus healthy controls indicated that a MAGNET threshold score of 14 maximized predictive accuracy for skin biopsies (0.74) and a 30 cut-off maximized accuracy for predicting AFT (0.60). Analyzing patients with any abnormal neuropathy-test results identified areas-under-the-curves of 0.87-0.89 for predicting a diagnostic result, accuracy = 0.80-0.89, and Youden's index = 0.62. Overall, MAGNET was 80%-85% accurate for stratifying patients with abnormal versus normal neuropathy test results. MAGNET quickly generates research-quality metrics during clinical examinations.

TS-HDS and FGFR3 antibodies in small fiber neuropathy and Dysautonomia.

The specificity of trisulfated heparin disaccharide/fibroblast growth factor receptor 3 (TS-HDS/FGFR3) antibodies in the diagnosis of autoimmune small fiber neuropathy (SFN) is unclear. This was a retrospective study of patients evaluated for SFN and dysautonomia in the Brigham and Women's Faulkner Hospital Autonomic Laboratory in 2019-2020. Associations were assessed between TS-HDS/FGFR3 antibodies and SFN markers, including epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD), and autonomic dysfunction assessed by Valsalva maneuver, deep breathing, sudomotor, and tilt testing. Of 322 patients; 28% had elevated anti-TS-HDS, 17% had elevated anti-FGFR3, 96% had autonomic dysfunction, 71% had abnormal ENFD, and 49% had abnormal SGNFD. TS-HDS/FGFR3 antibodies were present in patients with autonomic dysfunction irrespective of whether they had normal or abnormal skin biopsies unless ENFD/SGNFD were combined for anti-FGFR3 seropositivity. TS-HDS/FGFR3 antibodies are present in patients with evidence of autonomic dysfunction. Further studies are needed to document the clinical value of these antibodies in assessment of immune mediated dysautonomia.

Prediabetes, diabetes, metabolic syndrome, and small fiber neuropathy.

This study was conducted to evaluate the association between prediabetes (PD), elements of the metabolic syndrome (MetS), and small fiber neuropathy (SFN). A total of 268 patients with SFN symptoms and normal electrophysiology underwent tests to assess small fibers. SFN was diagnosed based on abnormality of at least two among intraepidermal nerve fiber density (IEFND), quantitative sensory testing, and quantitative sudomotor axon reflex testing. There was no difference in IENFD or abnormal skin biopsy frequency between PD and normoglycemia (NG). However, IENFD was lower in people with diabetes mellitus (DM) than in those with NG. An association between HbA1C and IENFD was observed only if DM patients were included. Attributes of the MetS were more common in those with an abnormal skin biopsy but not among those with autonomic dysfunction or meeting SFN criteria. DM, but not PD alone, is associated with SFN. Other MetS elements appear to preferentially impact small fiber structure over function.

65. Laser evoked potentials and skin biopsy to evaluate small nerve fiber dysfunction in myotonic dystrophy type 1(DM1): A preliminary study

Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system. We recruited 3 patients with previously diagnosed DM1 (mean age was 51 ± 8 years; height 166 ± 8 cm) who underwent leg skin biopsy and laser evoked potentials (LEP). The specific aim of this study is to ascertain the small nerve fiber involvement in DM1 by means of LEP and skin biopsy. Two patents showed abnormalities in both LEP and skin biopsy whereas one patient displayed abnormal skin biopsy but normal findings in LEP. Our data demonstrated a reasonable concordance between LEP and skin biopsy in evaluating small fiber loss in DM1. However, these are preliminary data and a larger number of patients must be recruited before to draw any definite conclusion.

Updates on hypomelanosis of Ito

Hypomelanosis of Ito is a multisystem neurocutaneous syndrome.The pathogenesis hasn′t been clear and typical cutaneous lesions are associated with variable extracutaneous abnormalities involved the central nervous system and musculoskeletal system.Its clinical manifestations include abnormal skin biopsy and chromosomal patterns and brain iconography.The treatments have to be adapted to the individual and prognosis depends on the severity of clinical manifestations and complications. Key words: Hypomelanosis; Neurocutaneous syndrome

109. Laser evoked potentials and skin biopsy to evaluate small nerve fiber dysfunction in Fabry disease: A preliminary study

Fabry’s disease (FD) is caused by an X-linked mutation, and a characteristic feature is a severe loss of small myelinated fibers (AΔ) and small unmyelinated fibers (C) shown by skin biopsy. However, the pathophysiological mechanisms underlying the disease are still largely unknown. We recruited 3 patients with previously diagnosed Fabry’ disease. The specific aim of this study is to verify a possible correlation between laser evoked potentials and skin biopsy to diagnose small nerve fibers involvement in these patients. Two patients showed abnormal skin biopsy which disclosed a somatic and autonomic small fiber neuropathy and altered LEPs with increased latencies of N2-P2 and N1 cortical responses (or absence), involving both AΔ fiber responses (hand, foot and trigeminal nerve) and C-fiber responses. The third patient showed LEPs and skin biopsy normal findings. Our data demonstrated a good concordance between LEP and skin biopsy in evaluating small nerve fiber loss in FD. However these data should be considered preliminary and a larger number of patients must be recruited before to draw any definite conclusion.

Pain Characteristics do not Distinguish Fibromyalgia Patients with Abnormal Skin Biopsy (P5.069)

Pain Characteristics do not Distinguish Fibromyalgia Patients with Abnormal Skin Biopsy (P5.069)

P627: Is precautionary neurophysiological monitoring useful for beta-thalassemia patients?

P627: Is precautionary neurophysiological monitoring useful for beta-thalassemia patients?

Non-length-dependent and length-dependent small-fiber neuropathies associated with tumor necrosis factor (TNF)-inhibitor therapy in patients with rheumatoid arthritis: Expanding the spectrum of neurological disease associated with TNF-inhibitors

ObjectiveSmall-fiber neuropathy causes severe burning pain, requires diagnostic approaches such as skin biopsy, and encompasses two subtypes based on distribution of neuropathic pain. Such biopsy-proven subtypes of small-fiber neuropathies have not been previously described as complications of tumor necrosis factor (TNF)-inhibitor therapy. MethodsWe therefore characterized clinical and skin biopsy findings in three rheumatoid arthritis (RA) patients who developed small-fiber neuropathies associated with TNF-inhibitors. We also conducted a systematic review of the literature to characterize subtypes of neuropathies previously reported in association with TNF-inhibitor therapy. ResultsTwo patients presented with a “non-length-dependent” small-fiber neuropathy, experiencing unorthodox patterns of burning pain affecting the face, torso, and proximal extremities. Abnormal skin biopsy findings were limited to the proximal thigh, which is a marker of proximal-most dorsal root ganglia degeneration. In contrast, one patient presented with a “length-dependent” small-fiber neuropathy, experiencing burning pain only in the feet. Abnormal skin biopsy findings were limited to the distal feet, which is a marker of distal-most axonal degeneration. One patient developed a small-fiber neuropathy in the context of TNF-inhibitor-induced lupus. In all patients, neuropathies occurred during TNF-inhibitor-induced remission of RA disease activity and improved on withdrawal of TNF-inhibitors. ConclusionsWe describe a spectrum of small-fiber neuropathies not previously reported in association with TNF-inhibitor therapy, with clinical and skin biopsy findings suggestive of dorsal root ganglia as well as axonal degeneration. The development of small-fiber neuropathies during inactive joint disease and improvement of neuropathic pain upon withdrawal of TNF-inhibitor suggest a causative role of TNF-inhibitors.

Usefulness of Skin Biopsies in the Evaluation and Management of Patients with Suspected Small Fiber Neuropathy

ABSTRACTObjective: To assess the usefulness of skin biopsy in the assessment of patients with suspeted small fiber neuropathy (SFN). Methods: Retrospective chart review of patients with sensory symptoms or findings restricted to small nerve fibers and normal nerve conduction studies (NCS) seen in a subspecialty neuromuscular private practice. Results: Assessments were made on 145 patients. Skin biopsy was abnormal in at least one site in 86 patients (59%). There was no significant difference between patients with normal or abnormal skin biopsies with respect to age, gender, or duration of symptoms. Compared to patients with normal skin biopsies, patients with confirmed SFN were significantly more likely to have pain and were more than twice as likely to respond to standard neuropathic pain medications. Conclusions: Skin biopsy is useful in the diagnosis and management of patients with otherwise unexplained sensory symptoms or findings.

The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology

Small fibre neuropathy (SFN), a condition dominated by neuropathic pain, is frequently encountered in clinical practise either as prevalent manifestation of more diffuse neuropathy or distinct nosologic entity. Aetiology of SFN includes pre-diabetes status and immune-mediated diseases, though it remains frequently unknown. Due to their physiologic characteristics, small nerve fibres cannot be investigated by routine electrophysiological tests, making the diagnosis particularly difficult. Quantitative sensory testing (QST) to assess the psychophysical thresholds for cold and warm sensations and skin biopsy with quantification of somatic intraepidermal nerve fibres (IENF) have been used to determine the damage to small nerve fibres. Nevertheless, the diagnostic criteria for SFN have not been defined yet and a ‘gold standard’ for clinical practise and research is not available. We screened 486 patients referred to our institutions and collected 124 patients with sensory neuropathy. Among them, we identified 67 patients with pure SFN using a new diagnostic ‘gold standard’, based on the presence of at least two abnormal results at clinical, QST and skin biopsy examination. The diagnosis of SFN was achieved by abnormal clinical and skin biopsy findings in 43.3% of patients, abnormal skin biopsy and QST findings in 37.3% of patients, abnormal clinical and QST findings in 11.9% of patients, whereas 7.5% patients had abnormal results at all the examinations. Skin biopsy showed a diagnostic efficiency of 88.4%, clinical examination of 54.6% and QST of 46.9%. Receiver operating characteristic curve analysis confirmed the significantly higher performance of skin biopsy comparing with QST. However, we found a significant inverse correlation between IENF density and both cold and warm thresholds at the leg. Clinical examination revealed pinprick and thermal hypoesthesia in about 50% patients, and signs of peripheral vascular autonomic dysfunction in about 70% of patients. Spontaneous pain dominated the clinical picture in most SFN patients. Neuropathic pain intensity was more severe in patients with SFN than in patients with large or mixed fibre neuropathy, but there was no significant correlation with IENF density. The aetiology of SFN was initially unknown in 41.8% of patients and at 2-year follow-up a potential cause could be determined in 25% of them. Over the same period, 13% of SFN patients showed the involvement of large nerve fibres, whereas in 45.6% of them the clinical picture did not change. Spontaneous remission of neuropathic pain occurred in 10.9% of SFN patients, while it worsened in 30.4% of them.

Bortezomib and Thalidomide Treatment of Newly Diagnosed Patients with Multiple Myeloma - Efficacy and Neurotoxicity.

Introduction: As single agents, Bortezomib (V) and thalidomide (T) have activity in less than 50% of newly diagnosed myeloma (MM) patients whereas combinations with dexamethasone (D) with T (TD) and V (VD) demonstrated response rates of 63% and 85%, respectively. We sought to examine the anti-myeloma activity of VT, a steroid-free regimen. Considering the neurotoxicity of both agents, we examined the baseline neuropathy and progression of neurotoxicity post-VT.Methods: Eligible patients had untreated Salmon-Durie Stage II/III MM and an ECOG performance status ≤2. V was given 1.3mg/m2 i.v. on days 1, 4, 8, 11 every 21 days. T was started at 50mg daily and increased weekly to 150mg. Patients were treated for a minimum of 4 (evaluable), but to a maximum of 8 cycles. The neurologic evaluation utilized the reduced Total Neuropathy Score (rTNS), a validated scoring system combining symptoms, signs and nerve conduction studies. The rTNS was measured at baseline and after every 2 cycles. rTNS scores range between 0 to 32.Results: 30 patients have been enrolled and 27 are evaluable for response. Median age is 59 (37–83), b2-microglobulin 3.3 (1.2–36.9), and albumin 3.6 (2.3–5.2). The mean dose of V was 1.11mg/m2 and of T 110 mg/d. A dose reduction for ≥1 agent was required in all patients. Treatment was discontinued in 5 patients due to neurotoxicity, and 1 due to disease progression. A ≥ 50% reduction in M-spikes was observed in 82% of patients with 31% achieving undetectable levels. Median time to best response was 5 cycles (range 2–8). Clinical evidence of baseline peripheral neuropathy (PN) was noted in 15%, whereas 67% had abnormal baseline skin biopsies. By cycle 5 all patients developed PN: rTNS 2–8, (grade 1) 50%; rTNS 9–16 (grade 2) 31%; rTNS 17–24 (grade 3) 15%; and rTNS 25–32 (grade 4) 4%. There was no correlation between severity of PN and the cumulative V/T doses. Neuropathic symptoms improved with T/V dose reductions. Additional common adverse events (≥ grade 2) included fatigue 57%, constipation 52%, generalized pain 44%, and leg cramps 23%. Although the incidence of thromboembolic events with steroid-containing regimens ranges between 15–20%, no deep vein thromboses occurred in this study.Conclusions: The VT combination achieved an 82% response rate in previously untreated multiple myeloma patients. No DVTs occurred with this steroid-free combination. This study established the baseline PN in newly diagnosed, untreated myeloma patients and demonstrated progression of neuropathy post-VT therapy. Future studies utilizing neuropathic preventive agents, lower doses of VT, or V in combination with other agents may yield similar disease responses with reduced neuropathic toxicities.

Autoimmune optic neuropathy with anticardiolipin antibody mimicking multiple sclerosis in a child

Purpose To demonstrate that autoimmune optic neuropathy (AON) may occur in the pediatric population. Design Interventional case report. Methods A 4-year-old developed four episodes of bilateral optic neuritis with mild concurrent weakness, ataxia, or dizziness; one episode of unilateral optic neuritis; and one episode of weakness over a period of 4 years. Results Autoimmune optic neuropathy was diagnosed because of the presence of anticardiolipin antibody and an abnormal skin biopsy with thrombin and immunoreactant deposition. She was treated with corticosteroids, aspirin, and gammaglobulin. This diminished the frequency and intensity of her attacks. Conclusion This case represents the diagnosis and treatment of AON in a child.

A Comparison of Quantitative Sensory Testing With Skin Biopsy in Small Fiber Neuropathy

Patients with a small fiber neuropathy often are difficult to diagnose. They frequently undergo various diagnostic studies including quantitative sensory testing (QST) and skin biopsy. We wanted to determine if there was a correlation between findings on a QST study to that of a skin biopsy. Twenty patients were prospectively studied. Nine had an abnormal skin biopsy. Thirteen patients had an abnormal QST. Seven of the nine patients with an abnormal skin biopsy had an abnormal QST. Assuming that skin biopsy is the gold standard for identification of small fiber neuropathies, the sensitivity of QST for detection of such neuropathies is high, provided that both cold and warm sensation thresholds are studied. However, the specificity of QST for small fiber neuropathies is low (46%).

Cutaneous nerve fibre depletion in vibration white finger.

Vibration white finger or hand-arm vibration syndrome is the episodic blanching of the fingers in response to cold occurring in those who work with hand held vibrating tools. Clinically the condition differs from primary Raynaud's phenomenon as persistent paraesthesiae and pain are common in the hands and arms and these occur independently from the 'white attacks'. Symptoms can become severe enough to warrant a change of occupation. Industrial compensation may be awarded for vibration white finger but, at present, no simple or reliable objective diagnostic test is available. Calcitonin gene-related peptide (CGRP) is a neuropeptide with powerful vasodilator properties. A deficiency of immunoreactive CGRP nerve fibres has been previously demonstrated in the digital cutaneous microvasculature of patients with primary and secondary Raynaud's phenomenon with the distribution and quantity of other types of nerve fibres not being significantly altered. To determine if the innervation of the cutaneous microvasculature in vibration white finger was also abnormal skin biopsy samples from the fingers of 15 patients with vibration white finger, six healthy age matched controls who worked with vibrating machinery and 26 healthy age matched controls who were heavy manual workers without exposure to vibrating machinery were examined by immunohistochemistry. To try to correlate any histological abnormalities with clinical neurological deficit sensory nerve conduction studies have so far been performed in six patients with vibration white finger.(ABSTRACT TRUNCATED AT 250 WORDS)

Skin biopsies in the evaluation of atypical optic neuropathies

Patients with atypical clinical presentations of common optic neuropathies such as optic neuritis (ON), anterior ischemic optic neuropathy (AION), or optic neuropathy of unknown etiology (UON) are difficult to distinguish from inflammatory autoimmune optic neuropathy (AON) which is typically associated with a poor visual prognosis, unless treated with high doses of corticosteroids and/or immunosuppressive agents. The authors retrospectively evaluated 34 patients [AON (n = 12); AION (n = 5); ON (n = 9); UON (n = 8)] with visual loss which deteriorated over weeks to months or followed an atypical course, for the presence of immunological markers suggestive of AON. These markers included serological testing for antiphospholipid (APA) and antinuclear (ANA) antibodies, and evaluation of histopathologic and immunofluorescent staining of skin biopsies. All patients underwent a skin biopsy. Four of the 12 patients with AON had urticarial cutaneous lesions which revealed leukocytoclastic and/or lymphohistiocytic vasculitis. Seven of the remaining eight AON patients had skin biopsies of non-lesional skin which revealed immunoreactant deposition. Seven of the 21 skin biopsies obtained from the non-AON patients had findings of vacuolization or mild perivascular infiltration of lymphocytes (n = 5) and immunofluorescent deposits (n = 2). Abnormal skin biopsies (92%;p = 0.0009) and circulating APA (82%; p = 0.013) were common in AON patients while ANA was not statistically increased in AON patients (p = 0.06) when compared to the remaining patients as a whole. AON patients typically demonstrate evidence of systemic autoimmune involvement, as manifested by cutaneous abnormalities such as urticarial vasculitis and/or immunoreactant deposition and circulating APA. These may serve as markers for identifying AON patients who may be treated with immunomodulatory agents.

Characterization of Two Monoclonal Antibodies to Human Epidermal Keratohyalin: Reactivity With Filaggrin and Related Proteins

Two monoclonal antibodies (AKH1 and AKH2) were elicited with partially purified human filaggrin and characterized by immunohistochemistry on normal and abnormal skin biopsies, immunoblotting techniques, and antigen purification. Both antibodies react strongly with the granular cell layer consistent with the distribution of keratohyalin and show a more diffuse reaction with the stratum corneum in normal skin biopsies. Reaction in cultured human keratinocytes is limited to immunofluorescent granules in flattened, well-differentiated cells in confluent cultures, in which we have previously demonstrated keratohyalin. On immunoblots AKH1 reacts with filaggrin (37 kD) and profilaggrin (400 kD), while AKH2 primarily stains bands of 150 and 300 kD. The AKH2 antigens were identified in the cationic protein fraction used for immunization and were purified by gel permeation and high-performance liquid chromatography. Amino acid composition of these proteins differs only slightly from filaggrin. Immunohistochemical staining patterns of the two antibodies are very similar in the genetic disorders of keratinization tested, except for ichthyosis vulgaris, and reflect the presence and distribution of keratohyalin. In ichthyosis vulgaris, AKH1 staining is weak, consistent with the morphology and with biochemical absence of profilaggrin/filaggrin; however, AKH2 staining is positive, although weaker than normal, suggesting the presence of the AKH2 antigens even when keratohyalin is absent or abnormal. Antibodies AKH1 and AKH2 may be useful as differentiation markers for keratinization in tissues and for cells in culture. Antibody AKH1 can be used specifically for detection of profilaggrin/filaggrin in tissues, cultured keratinocytes, and extracts.