Diabetes Distal Peripheral Neuropathy: Subtypes and Diagnostic and Screening Technologies

Diabetes distal symmetrical peripheral neuropathy (DSPN) is the most prevalent form of neuropathy in industrialized countries, substantially increasing risk for morbidity and pre-mature mortality. DSPN may manifest with small-fiber disease, large-fiber disease, or a combination of both. This review summarizes: (1) DSPN subtypes (small- and large-fiber disease) with attention to clinical signs and patient symptoms; and (2) technological diagnosis and screening for large- and small-fiber disease with inclusion of a comprehensive literature review of published studies from 2015-present ( N = 66). Review findings, informed by the most up-to-date research, advance critical understanding of DSPN large- and small-fiber screening technologies, including those designed for point-of-care use in primary care and endocrinology practices.

In Vivo Reflectance Microscopy of Meissner Corpuscles and Bedside Measures of Large Fiber Sensory Function: A Normative Data Cohort

Background and Objectives:To establish age-, gender- and body dimension-adjusted normal cut-off values for Meissner’s corpuscle (MC) densities via in-vivo reflectance confocal microscopy (RCM), timed vibration sensory thresholds using a 128Hz tuning fork, and touch-pressure sensory thresholds using standardized monofilaments, for clinical and research application.Methods:77 prospectively recruited individuals without signs or symptoms of peripheral neuropathy or a condition or neurotoxin exposure that can alter sensory function underwent cross-sectional evaluation of MC densities via in-vivo RCM, monofilament touch-pressure sensory thresholds, and timed vibration sensory thresholds in non-dominant upper and lower extremities. Age-, gender-, and body dimension- (e.g., height) adjusted normal values were developed. The 5th percentile for MC densities and timed vibration thresholds and 95th percentile for MF touch-pressure thresholds were selected as normal cut-off points.Results:Subjects were aged 9 to 89 years old. Age and gender were uniformly distributed. Timed vibration and touch-pressure thresholds were less sensitive with increasing age and were more sensitive in the hand than in the leg or foot within individuals. Timed vibration thresholds did not differ by gender or body dimensions. Touch-pressure thresholds were lower (more sensitive) at the thenar eminence and digit V in the hand in women compared to men but otherwise did not differ by gender at other measurement locations. Body dimensions did not affect touch-pressure thresholds. There were no apparent age-related floor effects for the 5th and 95th percentile normal cutoff values for timed vibration or touch-pressure thresholds, respectively. MC densities also declined with age and were highest at digit V and lowest at the arch within individuals. MC densities were affected by gender or body dimensions at all imaging sites, with lower densities seen in males or larger individuals. MC densities were quantifiable in the hand of all participants and were associated with touch-pressure thresholds at all locations.Discussion:This study establishes age-, gender- and body dimension-adjusted normal cut-off values for two easily applied measures of large fiber sensory function and RCM assessment of MC densities for multiple limb locations. These results will aid in the detection and monitoring of peripheral sensory nerve disorders.

Difficult-to-Treat Polyradiculoneuropathy

A 51-year-old healthy man sought care for a 6-month history of progressive, distal, lower extremity weakness, imbalance, and numbness in the feet. Neurologic examination showed a steppage gait, upper and lower extremity weakness, distal greater than proximal, absent tendon reflexes, and large fiber–predominant sensation loss in the feet. Nerve conduction studies showed marked temporal dispersion and slowed conductions. Cerebrospinal fluid analysis showed an increased protein concentration, 1 white blood cell/µL, and normal glucose level. Lumbar spine magnetic resonance imaging showed enlargement and enhancement of the nerve roots in the cauda equina, along with hypointensity in lumbar vertebral bodies. He underwent right sural nerve biopsy that showed an inflammatory demyelinating process. The patient was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy and started on intravenous immunoglobulin. He was markedly worse at 12-week follow-up, with severe proximal and distal weakness and requiring the use of a walker. The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy was revisited. Lumbar spine magnetic resonance imaging again showed enhancement of the nerve roots. Because of concern for neurolymphomatosis, a proximal fascicular nerve biopsy of the right sciatic nerve was performed. It showed the hallmark pathologic features of chronic inflammatory demyelinating polyradiculoneuropathy: endoneurial inflammation and signs of long-standing demyelination and remyelination with stacks on Schwann cell processes. The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy was confirmed. Intravenous immunoglobulin was stopped, and the patient was started on an aggressive plasma exchange regimen. He had modest improvement. Azathioprine was also started. The patient continued to improve. He remained on this regimen for 2 years. Over the next year, the intravenous methylprednisolone dose was reduced. He was weaned off plasma exchange and intravenous methylprednisolone. At the last follow-up the disease was still in remission. Chronic inflammatory demyelinating polyradiculoneuropathy was described and named in 1975. It is a fairly symmetric peripheral neuropathy that usually presents with proximal and distal weakness, imbalance, and large fiber sensory dysfunction. Cerebrospinal fluid analysis shows albuminocytologic dissociation in 80% to 95% of those with typical chronic inflammatory demyelinating polyradiculoneuropathy.

Small Fiber Neuropathy Incidence, Prevalence, Longitudinal Impairments, and Disability

Background and Objectives:There is limited population-based data on small fiber neuropathy (SFN). We wished to determine SFN incidence, prevalence, comorbidities, longitudinal impairments, and disabilities.Methods:Test-confirmed patients with SFN in Olmsted, Minnesota and adjacent counties were compared 3:1 to matched controls (January 1st, 1998-December 31st, 2017).Results:Ninety-four patients with SFN were identified, incidence 1.3/100,000/year increasing over the study period, prevalence 13.3/100,000. Average follow-up was 6.1 years (0.7-43 years), mean onset age 54 years (range 14–83). Female (67%), obesity (BMI mean 30.4 versus 28.5), insomnia (86% versus 54%), analgesic-opioid prescriptions (72% versus 46%), hypertriglyceridemia (180 mg/dl mean versus 147 mg/dl) and diabetes mellitus (DM) (51% versus 22%, p<0.001) were more common (OR 3.8-9.0, all p<0.03). Patients with SFN did not self-identify as disabled with median mRS of 1.0 (range 0-6) versus controls 0.0 (0-6), p=0.04. Higher Charlson comorbidities (median 6, range 3-9) occurred versus controls (median 3, range 1-9) p<0.001. Myocardial infarctions occurred in 46% versus 27% of controls (p<0.0001). Classifications included: idiopathic (70%); DM (15%); Sjögrens (2%); AL-amyloid (1%); transthyretin-amyloid (1%); Fabry (1%); lupus (1%); post viral (1%); Lewy body (1%) and multifactorial (5%). Foot ulcers occurred in 17, with 71% having DM. Large fiber neuropathy developed in 36%, on average 5.3 years (range 0.2-14.3 years) from SFN onset. Median onset Composite Autonomic Severity Score (CASS) was 3, change/year 0.08 (range 0-2.0). Median Neuropathy Impairment Score (NIS) was 2 at onset (range 0 to 8), change/year +1.0 (range -7.9 to +23.3). NIS and CASS change >+1 point/year occurred in only AL-amyloid, hereditary transthyretin-amyloid, Fabry, uncontrolled DM, and Lewy body. Death from symptom onset was higher in patients with SFN 19% versus controls 12%, p<0.001, 50% secondary to DM complications.Discussion:Isolated SFN is uncommon but increasing in incidence. Most patients do not develop major neurological impairments and disability but have multiple comorbidities, including cardiovascular ischemic events, and increased mortality from SFN onsets. Development of large fiber involvements and DM are common over time. Targeted testing facilitates interventional therapies for DM but also rheumatologic and rare genetic forms.

Larger muscle fibers and fiber bundles manifest smaller elastic modulus in paraspinal muscles of rats and humans

The passive elastic modulus of muscle fiber appears to be size-dependent. The objectives of this study were to determine whether this size effect was evident in the mechanical testing of muscle fiber bundles and to examine whether the muscle fiber bundle cross-section is circular. Muscle fibers and fiber bundles were extracted from lumbar spine multifidus and longissimus of three cohorts: group one (G1) and two (G2) included 13 (330 ± 14 g) and 6 (452 ± 28 g) rats, while Group 3 (G3) comprised 9 degenerative spine patients. A minimum of six muscle fibers and six muscle fiber bundles from each muscle underwent cumulative stretches, each of 10% strain followed by 4 minutes relaxation. For all specimens, top and side diameters were measured. Elastic modulus was calculated as tangent at 30% strain from the stress–strain curve. Linear correlations between the sample cross sectional area (CSA) and elastic moduli in each group were performed. The correlations showed that increasing specimen CSA resulted in lower elastic modulus for both rats and humans, muscle fibers and fiber bundles. The median ratio of major to minor axis exceeded 1.0 for all groups, ranging between 1.15–1.29 for fibers and 1.27–1.44 for bundles. The lower elastic moduli with increasing size can be explained by relatively less collagenous extracellular matrix in the large fiber bundles. Future studies of passive property measurement should aim for consistent bundle sizes and measuring diameters of two orthogonal axes of the muscle specimens.

A novel algorithm for significantly increasing the fiber volume fraction in the reconstruction model with large fiber aspect ratio

Geometric reconstruction is an important precondition for the computational micromechanics analysis of chopped fiber reinforced composites. When fiber aspect ratio increases, the maximum fiber volume fraction in reconstruction model reduces rapidly because of jamming limit, which greatly limits the application of reconstruction methods. A novel algorithm is proposed to significantly increase the fiber volume fraction in the reconstruction model of the chopped fiber reinforced composites with large fiber aspect ratio. The algorithm is made up of two stages. At the first stage, fibers are packed into the sublayers of initial filling space to preliminarily design fiber orientation distribution. The unidirectional arrangement of fibers is adopted to achieve high fiber volume fraction. At the second stage, a new multi-step fiber shaking strategy is used to introduce randomness into reconstruction model. The high fiber volume fraction over 30% is achieved within the wide range of fiber aspect ratio from 50 to 200 while the results of the existing methods are not more than 10%, showing the remarkable increase of the fiber volume fraction under large fiber aspect ratio. The proposed algorithm is verified by the statistical results of the four representative microstructural characteristics from reconstruction model and realistic material.

POS0015 PREVALENCE OF NEUROPATHIES IN RHEUMATIC AND MUSCULOSKELETAL DISEASES

Background:In rheumatic and musculoskeletal diseases (RMDs), peripheral neurons can be affected, which can result in sensory symptoms like pain, burning, tingling, numbness and motor symptoms like muscle-atrophy or even paresis. More detailed knowledge about the prevalence and the cause of neuropathy (NP) in RMD are urgently needed, especially as RMD patients may develop different subtypes of NP.Objectives:The aim of this project was to assess the prevalence and the individual types of NP in rheumatoid arthritis (RA), spondyloarthritis (SpA) and systemic sclerosis (SSc) patients, and to elucidate the clinical, neurophysiological and neuropathologic features of associated NP.Methods:Baseline questionnaires and neurological and physical examination were used to elucidate the presence of neuropathic pain and autonomic dysfunction. Laboratory tests were performed to exclude other causes for NP. Electrophysiological tests were performed to differentiate demyelinating from axonal large fiber (LF)NPs. Additionally, skin biopsies were used to detect an involvement of small fibres (SF).Results:A total of 31 patients (median age 64 years (range 43-75)) were included. The majority of patients were female (90%). The mean disease duration was 10 years (1-41 years). More than 50% of the patients were diagnosed with RA, 7 with SpA and 6 with SSc. Of 31 patients, 48% (15/31) had clinical signs of NP and of those, neurophysiological examination showed 14 axonal 2, demyelinating and 4 mixed types. A combined LFNP and SFNP was present in 35% (11/31) of the patients. In 4 patients, only a SFNP was detectable, and in only two patients, no NP was detectable.Conclusion:NP was detectable in 94% (29/31) of the RMD patients, with LFNP predominating. This high proportion of NP in RMD suggests a surprisingly high coincidence of both diseases.Table 1.Subtypes of NP in RMDNumber of patientsAxonal NP14/31 (45%)Demyelinating NP2/31 (6%)Mixed axonal and demyelinating NP4/31 (12%)Sensory NP9/31 (26%)Sensorimotor NP5/31 (10%)Motor NP1/31 (3%)Disclosure of Interests:None declared.

CISP-Plus: Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy (CISP)

Objectives:Sensory loss with normal nerve conduction studies (NCS) from focal sensory root inflammatory demyelination is characteristic of chronic immune sensory polyradiculopathy (CISP). However, non-pure cases involving motor and distal sensory nerves exist (CISP-plus). We hypothesize that CISP-plus and CISP are fundamentally part of the same syndrome through comparison of clinical, neurophysiological and pathological features.Methods:CISP-plus (primary dorsal root with lesser motor and sensory nerve involvement) and CISP cases were retrospectively analyzed (1986-2019).Results:We identified 44 CISP-plus and 28 CISP cases (n=72) with 86% (38/44) of CISP-plus and 79% (22/28) of CISP patients experiencing imbalance. On examination, large fiber sensory loss was present in 98% (43/44) of CISP-plus and 96% (27/28) of CISP. Gait ataxia was evident in 93% (41/44) of CISP-plus and 79% (22/28) of CISP. Mild distal weakness was common in CISP-plus (75%, 33/44). NCS showed mild abnormalities in all CISP-plus and were normal (by definition) in all CISP. Elevated cerebral spinal fluid (CSF) protein, slowing of somatosensory evoked potentials and MRI root enhancement occurred in most CISP-plus and CISP cases. Eleven CISP-plus nerve biopsies showed loss of large myelinated fibers and onion-bulb formation most prominent in rootlet biopsies. Immunotherapy resulted in marked improvement of gait ataxia in 84% (27/32) of CISP-plus and 93% (14/15) of CISP cases with return to normal neurological examination in half (25/46).Conclusion:The recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure-CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.