Vascular endothelial growth factor and POEMS.
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Hematopoietic Stem Cell Transplantation↗
Biomedical subjects
Peter J Dyck
Publications and source records attributed to Peter J Dyck.
Anesthesia and patients with congenital hyposensitivity to pain.
BACKGROUND: Congenital hyposensitivity to pain or hereditary sensory and autonomic neuropathy represents a variety of disorders characterized by decreased perception of nociception, loss of other modalities of sensation, and variable expression of autonomic dysfunction. Sensory loss, especially that of pain, is associated with self-mutilations that may require frequent operations. Little is known about the safety of anesthesia for these patients. METHODS: The authors performed a computerized search of the Mayo Clinic medical records database between January 1996 and November 2005 for patients with congenital hyposensitivity to pain and related disorders who underwent general anesthesia. Medical records were reviewed for demographics, anesthetic techniques and agents, use of opioids, and perioperative complications. In addition, the authors conducted a comprehensive review of the literature to summarize the current knowledge regarding anesthesia for patients with congenital hyposensitivity to pain, and compared it with the patients with hyposensitivity to pain identified at the Mayo Clinic. RESULTS: The authors identified seven patients with hereditary sensory and autonomic neuropathy II, IV, or V and undefined variants of congenital pain hyposensitivity who generated 17 anesthesia records: 12 for orthopedic operations, 3 for sural nerve biopsies, and 2 for ophthalmologic procedures. In all patients, standard doses of volatile agents were used during anesthesia. Small amounts of opioids were used during the course of eight operations. Most patients experienced mild hypothermia (lowest temperature 34.7 degrees C), and none experienced hyperthermia. All patients were hemodynamically stable during otherwise uneventful anesthesia. During recovery from anesthesia, opioids were given to only one patient, a single dose of 1 mg morphine. Even after major orthopedic operations, the patient did not require additional analgesia. CONCLUSIONS: The patients with profound congenital hyposensitivity to pain underwent anesthesia without any adverse events. The authors found that despite reduced pain perception, the requirements for volatile anesthetics were within the expected range for population with normal pain perception, but they did not require opioids postoperatively. Intraoperative mild hypothermia was easily managed by adjustment of environmental temperature.
Adolescent↗
Modeling chronic glycemic exposure variables as correlates and predictors of microvascular complications of diabetes.
OBJECTIVE: The degree to which chronic glycemic exposure (CGE) (fasting plasma glucose [FPG], HbA1c [A1C], duration of diabetes, age at onset of diabetes, or combinations of these) is associated with or predicts the severity of microvessel complications is unsettled. Specifically, we test whether combinations of components correlate and predict complications better than individual components. RESEARCH DESIGN AND METHODS: Correlations and predictions of CGE and complications were assessed in the Rochester Diabetic Neuropathy Study, a population-based, cross-sectional, and longitudinal epidemiologic survey of 504 patients with diabetes followed for up to 20 years. RESULTS: In multivariate analysis, A1C and duration of diabetes (and to a lesser degree age at onset of diabetes but not FPG) were the main significant CGE risk covariates for complications. A derived glycemic exposure index (GE(i)) correlated with and predicted complications better than did individual components. Composite or staged measures of polyneuropathy provided higher correlations and better predictions than did dichotomous measures of whether polyneuropathy was present or not. Generally, the mean GE(i) was significantly higher with increasing stages of severity of complications. CONCLUSIONS: A combination of A1C, duration of diabetes, and age at onset of diabetes (a mathematical index, GE(i)) correlates significantly with complications and predicts later complications better than single components of CGE. Serial measures of A1C improved the correlations and predictions. For polyneuropathy, continuous or staged measurements performed better than dichotomous judgments. Even with intensive assessment of CGE and complications over long times, only about one-third of the variability of the severity of complications is explained, emphasizing the role of other putative risk covariates.
Adolescent↗
Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.
OBJECTIVE: The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients' global assessment of efficacy. RESULTS: Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (>/=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients' global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. CONCLUSIONS: Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.
Administration, Oral↗
History of standard scoring, notation, and summation of neuromuscular signs. A current survey and recommendation.
In this article, we trace the history of scoring, notation, and summation of the neuromuscular signs of muscle weakness and decrease of tendon reflexes and sensation. We recommend a standard system to promote consistency in the effort introduced by Mitchell and Lewis to "represent systems and force by their signs." The scoring of neuromuscular signs began with Mitchell and Lewis in the 19th century who used pluses, minuses, and N (for normal) to express the activity of muscle stretch reflexes. Henry Plummer introduced an ordinal scoring approach for muscle weakness, reflex decrease and increase, and sensation loss. In 1919, he and Walter Sheldon and Henry Woltman introduced standard pre-printed examination forms with written instructions for notation and scoring. Robert Lovett, a Boston orthopedist, scored weak muscles of poliomyelitis patients from 2 (mild weakness) to 6 (paralyzed), 1 being normal. Lovett's approach was used, after reversing the order of the grades and decreasing each grade by 1, by a Committee of the Medical Research Council for evaluating return of muscle weakness after nerve injury. Despite dissimilarity to existing reflex and sensation scores and uneven width of grades, this approach was widely adopted for use in neurologic practice. We introduced the Neuropathy Impairment Score using a combination of the Mitchell, Plummer, and Lovett approaches, summing all individual scores of a standard set of neuromuscular examinations. In a non-representative survey of 19 neuromuscular physicians from different countries, we find that there is a considerable variability in the approaches used for grading. Assuming that scoring is useful, we herein suggest (a) impairments should be scored separately from hyperfunction and (b) for the scoring of impairments (muscle weakness, reflex decrease, and sensation loss), the same ordinal scoring approach should be used with 0 as normal and 1, 2, ... representing increasing impairment based on the judgment of percentage abnormality with corrections made for age, sex, physical fitness, and physical characteristics.
Data Collection↗
Genetic testing in inherited peripheral neuropathies.
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Algorithms↗
Monotonicity of nerve tests in diabetes: subclinical nerve dysfunction precedes diagnosis of polyneuropathy.
OBJECTIVE: The objective of this study was to test whether monotone worsening of nerve function, attributable to diabetes, can be demonstrated before criteria for diabetic sensorimotor polyneuropathy (DSPN) have been met. Which nerve tests are best? RESEARCH DESIGN AND METHODS: From a prevalence cohort of 504 individuals in the Rochester Diabetic Neuropathy study (RDNS), we identified 238 individuals (group 1) who at first examination were without polyneuropathy (DSPN) by a sum score of the normal deviates (from percentiles) of five attributes of nerve conduction of the legs (i.e., their five nerve conduction normal deviate values were <97.5th percentile) and were followed longitudinally two or more times. Of these 238, 90 (group 2) were followed six or more times at yearly or bi-yearly intervals. We compared different nerve tests for the ones most sensitive and reliable in showing latent nerve dysfunction and monotone (the extent to which a variable measured repeatedly over time reveals a significant trend of worsening or improvement). RESULTS: In group 1 patients, the mean sum score of five attributes of nerve conduction (sigma 5 NC nds) at baseline was 1.08 and at the last examination (only patients with Sigma 5 NC nds <97.5th percentile) was 3.63, markedly higher than that in healthy subjects (only of individuals with Sigma 5 NC nds <97.5th percentile) (-0.12), indicating a subtle latent shift of nerve conduction tests toward abnormality. Serial evaluations of many individual and especially sum scores of nerve conduction tests in group 2 patients showed statistically significant worsening with time, even when nerve conduction tests were still well within normal limits. Neurologic signs also worsened but barely to significant levels; however, symptoms and quantitative sensation tests did not. Considering the composite score sigma 5 NC nds, 42 (of 90 group 2 patients) showed significant worsening, 22 were still without DSPN by nerve conduction test criteria, and some were even below the 50th percentile at the last evaluation. CONCLUSIONS: Subtle and latent functional worsening of nerve conduction can be demonstrated even before nerve conduction test criteria for DSPN have been met. For demonstrating monotone worsening, the order (from best to worst) of tests was: some composite scores of nerve conduction and individual attributes of nerve conduction. We did not show monotone worsening of symptoms or of quantitative sensation test results. In multivariate analysis of risk factors and their association with worsening sigma 5 NC nds, 24-h microalbuminuria (a marker of microvessel disease) was found to be a significant covariate, an indication that the asymptomatic alterations of nerve conduction are meaningful.
Adult↗
Celiac disease in type 1 diabetes mellitus in a North American community: prevalence, serologic screening, and clinical features.
OBJECTIVES: To estimate the prevalence of cellac disease (CD) in pediatric and adult type 1 diabetes melitus in a defined population and to describe clinical features and HLA class II genotypes predictive of CD in screened patients with type 1 diabetes. PATIENTS AND METHODS: All residents of Olmsted County, Minnesota, with type 1 diabetes mellitus on the prevalence date January 1, 2001, were identified with the use of an established medical records linkage system (Rochester Epidemiology Project) and defined clinical criteria. Consenting patients underwent serologic screening with endomyslal antibody and tissue transglutaminase antibody testing and Intestinal biopsies to confirm the diagnosis of CD. A subset of screened patients also underwent HLA class II genotyping. Quality-of-life screening (Medical Outcomes Study 36-Item Short-Form Health Survey) was completed in a subset of patients at the time of serologic screening. RESULTS: Overall, 392 Olmsted County residents with type 1 diabetes on January 1, 2001, were Identified. A total of 158 patients with type 1 diabetes were tested, representing 40% (158/392) of the enumerated diabetic population, and 11 had biopsy-proven CD for an estimated point prevalence of 7.0% (95% confidence Interval, 3.5%-12.1%). Most CD-positive diabetic patients were asymptomatic and expressed an at-risk CD haplotype with at least one of but not both HLA DQ2 or DQ8. CONCLUSIONS: Celiac disease Is not rare In North American patients with type 1 diabetes, and most CD-positive diabetic patients are asymptomatic Irrespective of age at screening.
Adolescent↗
Identification of transthyretin variants by sequential proteomic and genomic analysis.
BACKGROUND: Transthyretin-associated hereditary amyloidosis (ATTR) is an inherited disease in which variants in the primary structure of transthyretin (TTR; prealbumin) lead to the extracellular polymerization of insoluble protein fibrils, causing organ failure and ultimately death when major organs are involved. We have developed an integrated approach to molecular diagnosis with initial analysis of intact plasma TTR by electrospray ionization mass spectrometry (MS) and referral of positive samples for DNA sequence analysis and real-time PCR to confirm the common Gly6Ser polymorphism. METHODS: Samples from 6 patients previously diagnosed with ATTR and from 25 controls with (n = 15) or without (n = 10) polyneuropathy were analyzed in a blinded fashion for the presence of variant TTR. TTR protein was extracted with an immunoaffinity resin from 20 microL of archived plasma samples. The purified TTR was reduced with tris(2-carboxyethyl)phosphine and analyzed by MS. The appearance of two peaks (or a single peak shifted in mass indicative of a homozygous variant), including the wild-type mass of 13,761 Da, was indicative of the presence of a variant, and the individual was referred for DNA sequence analysis. RESULTS: MS analysis of intact reduced TTR correctly identified each of six samples known to contain variant TTR. These results were corroborated by subsequent DNA sequence analysis. Additionally, all Gly6Ser polymorphisms were correctly called based on the +30 mass shift and an equal relative abundance of the +30 polymorphism relative to wild-type TTR. No false-positive results were seen. CONCLUSIONS: This referral method eliminates the necessity of sequencing most samples and allows screening for the familial forms of amyloidosis in a broad patient population in a timely fashion. This method correctly identified all previously known variants and also identified a novel variant, Val94Ala.
Amyloidosis, Familial↗
Adult polyglucosan body disease: case description of an expanding genetic and clinical syndrome.
A non-Jewish patient is described who had adult polyglucosan body disease (APBD) and glycogen branching enzyme (GBE) deficiency without GBE mutation. A heterozygous polymorphism (Val160Ile) was found, and also discovered in 1 of 50 normal individuals. Magnetic resonance imaging demonstrated increased T2 signal in the midbrain, medullary olives, dentate nuclei, cerebellar peduncles, and internal and external capsules, with vermian atrophy. Both muscle and nerve biopsy revealed perivascular inflammatory infiltrates. These findings expand the clinical and genetic spectrum of APBD. Factors other than mutation of the expressed GBE gene may cause enzyme deficiency and varied expression and development of APBD.
Glucans↗
A 46-year-old man with numbness and shock-like sensations in hands, feet, and jaw.
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Biopsy↗
Multifocal motor neuropathy: pathologic alterations at the site of conduction block.
The pathologic changes of nerves in multifocal motor neuropathy (MMN), a rare neuropathy with selective focal conduction block of motor fibers in mixed nerves, remain essentially unstudied. Fascicular nerve biopsy of 8 forearm or arm nerves in 7 patients with typical MMN was undertaken for diagnostic reasons at the site of the conduction block. Abnormalities were seen in 7 of 8 nerves, including a varying degree of multifocal fiber degeneration and loss, an altered fiber size distribution with fewer large fibers, an increased frequency of remyelinated fiber profiles, and frequent and prominent regenerating fiber clusters. Small epineurial perivascular inflammatory infiltrates were observed in 2 nerves. We did not observe overt segmental demyelination or onion bulb formation. We hypothesize that an antibody-mediated attack directed against components of axolemma at nodes of Ranvier could cause conduction block, transitory paranodal demyelination and remyelination, and axonal degeneration and regeneration. Alternatively, the antibody attack could be directed at components of paranodal myelin. We favor the first hypothesis because in nerves studied by us, axonal pathological alteration predominated over myelin pathology. Irrespective of which mechanism is involved, we conclude that the unequivocal multifocal fiber degeneration and loss and regenerative clusters at sites of conduction block explains the observed clinical muscle weakness and atrophy and alterations of motor unit potentials. The occurrence of conduction block and multifocal fiber degeneration and regeneration at the same sites suggests that the processes of conduction block and fiber degeneration and regeneration are linked. Finding discrete multifocal fiber degeneration may also provide an explanation for why the functional abnormalities remain unchanged over long periods of time at discrete proximal to distal levels of nerve and may emphasize a need for early intervention (assuming that efficacious treatment is available).
Adult↗
Autonomic symptoms and diabetic neuropathy: a population-based study.
OBJECTIVE: The prevalence of autonomic symptoms and deficits in certain systems is known, but a comprehensive autonomic symptom profile in diabetes is not available. We aimed to estimate this using a laboratory evaluation of autonomic function and a validated self-report measure of autonomic symptoms in patients and matched control subjects from the population-based Rochester Diabetic Neuropathy Study. RESEARCH DESIGN AND METHODS: Participants included 231 patients with diabetes (type 1, n=83; type 2, n=148) and 245 healthy age-matched control subjects. We assessed symptoms using a validated self-report instrument (Autonomic Symptom Profile) and evaluated the severity and distribution of autonomic deficits (cardiovagal, sudomotor, adrenergic) with the objective, laboratory-based Composite Autonomic Severity Score (CASS). RESULTS: Autonomic symptoms were present more commonly in type 1 than in type 2 diabetes, with symptoms of orthostatic intolerance, secretomotor, urinary control, diarrhea, and sleep disturbance and pupillomotor, vasomotor, and erectile dysfunction significantly increased over healthy control subjects in type 2 diabetic patients. The prevalence of autonomic impairment was 54% in type 1 and 73% in type 2 diabetic patients. Severity of autonomic failure was mild overall (mean CASS 2.3; maximum 10), with orthostatic hypotension occurring in 8.4 and 7.4% of type 1 and 2 diabetic patients, respectively. Fourteen percent of patients had a CASS > or =5, indicating moderate to severe generalized autonomic failure. The correlation of symptoms with autonomic deficits (CASS) was better in type 1 than type 2 diabetic subjects and was weak overall. CONCLUSIONS: These findings indicate that autonomic symptoms and deficits are common in diabetes, but mild in severity, and that the correlation between symptom scores and deficits is overall weak in mild diabetic neuropathy, emphasizing the need to separately evaluate autonomic symptoms.
Autonomic Nervous System Diseases↗
Indifference rather than insensitivity to pain.
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Hereditary Sensory and Autonomic Neuropathies↗
Individual attributes versus composite scores of nerve conduction abnormality: sensitivity, reproducibility, and concordance with impairment.
Composite scores may be more sensitive and reproducible than single attributes of nerve conduction for detection of peripheral neuropathy, but this requires validation in large patient cohorts. Also, the concordance of individual attributes versus composite scores with clinical measures of severity has not been tested. Here, we study these issues in prospectively studied cohorts: diabetic patients from Rochester, Minnesota (RDNS; n = 396); chronic inflammatory demyelinating polyneuropathy (CIDP) patients (n = 55); and multifocal motor neuropathy (MMN) patients (n = 18). With specificity fixed at the 97.5 percentile, we found that, in generalized polyneuropathies (diabetic and CIDP), composite scores (especially ones including conduction velocity, distal latencies, and F-waves) of individual or multiple nerves tended to be more sensitive than individual attributes. By contrast, for multiple mononeuropathies, some individual attributes or composite scores of individual nerves were more sensitive than composite scores. In diabetic polyneuropathy, composite scores tended to be more reproducible than individual attributes of nerve conduction. Highly significant correlations were found between individual attributes or composite scores and neurologic impairment in diabetic polyneuropathy and in CIDP; in general, correlation coefficients were higher for composite scores. These correlations were higher for amplitudes than for conduction velocities or distal latencies. We conclude that, with the availability of microprocessors and normative databases, electromyographers may increasingly seek to express nerve conduction abnormality also as composite scores of individual or several nerves.
Diabetic Neuropathies↗
Microfluidic chip-based method for genotyping microsatellites, VNTRs and insertion/deletion polymorphisms.
We have developed a method to genotype variable number of tandem repeats (VNTRs) and insertion/deletion polymorphisms using an integrated microfluidic chip-based system. We used this method to analyze a) a highly polymorphic pentanucleotide repeat (CCTTT)(n) locus within the 5'-putative promoter region of the human inducible nitric oxide synthase gene (iNOS5) which is associated with diabetic complications and infectious diseases; b) a bi-allelic 27 bp VNTR region within intron 4 of endothelial nitric oxide gene (eNOS27) which is associated with hypertension in type 2 diabetes patients with coronary heart disease and excess risk of advanced diabetic nephropathy in type 1 diabetes patients and c) an insertion/deletion polymorphism within the gene encoding angiotensin-converting enzyme (ACE/ID) which is associated with cardiovascular pathology and nitric oxide activity, and is in strong linkage disequilibrium with functional variants. Following amplifications, samples were mixed with gel-dye and markers and loaded into commercially available microfluidic chips designed for DNA sizing applications. In the study (N = 230), 95 (41%) of the DNA samples were homozygous and 135 (59%) were heterozygous for the iNOS5 repeats. For eNOS27, 173 (75%) of the genotyped DNA samples were homozygous for the larger 4b allele and the remaining 57 samples (25%) were heterozygous (4b/4a). No DNA samples were homozygous for the shorter 4a allele with four 27 bp repeats. In case of ACE/ID, 47 (20%) of the DNA samples were homozygous for the insertion, 65 (28%) were homozygous for the deletion and the remaining 118 (51%) were heterozygous. The results obtained were verified by analyzing random amplicons using bi-directional sequencing and GeneScan 3.0 analyses with 100% concordance being observed. Using the microfluidic chip-based method, separation and DNA sizing and genotyping are rapidly accomplished. The DNA fragments are resolved clearly and the system allows quantitation. Finally, the microfluidic chip-based method may be used for both large- and small-scale genotyping studies.
Alleles↗
The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial.
OBJECTIVE: Because alpha-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(+) K(+) ATPase activity in experimental diabetes and in humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms. RESEARCH DESIGN AND METHODS: Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n = 60) or placebo (n = 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Secondary end points were sum scores of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction, quantitative sensation tests (QSTs), and an autonomic test. RESULTS: At randomization, the groups were not significantly different by the criteria of metabolic control or neuropathic end points. After 14 treatments, the TSS of the ALA group had improved from baseline by an average of 5.7 points and the placebo group by an average of 1.8 points (P < 0.001). Statistically significant improvement from baseline of the ALA, as compared with the placebo group, was also found for each item of the TSS (lancinating and burning pain, asleep numbness and prickling), NIS, one attribute of nerve conduction, and global assessment of efficacy. CONCLUSIONS: Intravenous racemic ALA, a potent antioxidant, rapidly and to a significant and meaningful degree, improved such positive neuropathic sensory symptoms as pain and several other neuropathic end points. This improvement of symptoms was attributed to improved nerve pathophysiology, not to increased nerve fiber degeneration. Because of its safety profile and its effect on positive neuropathic sensory symptoms and other neuropathic end points, this drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy.
Aged↗
Rapidly progressive amyloid polyneuropathy associated with a novel variant transthyretin serine 25.
We report a 52-year-old woman with a novel transthyretin (TTR) variant serine replacing alanine at residue 25 [Ala25Ser (Serine 25)], who showed a unique clinical picture with a relatively acute onset neuropathy within a few days of an influenza vaccination, progressing to a severe degree within 2 years. Sural nerve biopsy revealed amyloid deposition in the endoneurium. Sequencing of the proband's DNA revealed a G to T transversion at the first position of codon 25 of TTR gene. DNA analysis of this family showed the same mutation in her older sister and a niece, but her parents did not have the mutation. Haplotype analysis revealed the mutation to be clearly linked to haplotype III allele inherited from the proband's father. These results indicate this novel Serine 25 mutation originated in the paternal germline mosaicism. It is possible that the vaccination had an influence on the unique clinical picture, but this remains uncertain.
Amino Acid Sequence↗