Evaluation of distal symmetric polyneuropathy: The role of laboratory and genetic testing (an evidence‐based review)

Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence‐based guidelines regarding the role of laboratory and genetic tests for the assessment of DSP. A literature review using MEDLINE, EMBASE, Science Citation Index, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four‐tiered level of evidence scheme and recommendations were based on the level of evidence. (1) Screening laboratory tests may be considered for all patients with polyneuropathy (Level C). Those tests that provide the highest yield of abnormality are blood glucose, serum B₁₂ with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis (Level C). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (Level C). (2) Genetic testing is established as useful for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C). Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic (EDX) features and should focus on the most common abnormalities, which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening. There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype (Level U). Muscle Nerve 39: 116–125, 2009     

Immunotherapy‐responsive allodynia due to distal acquired demyelinating symmetric (DADS) neuropathy

Introduction: Distal acquired demyelinating symmetric (DADS) neuropathy is a distal variant of chronic inflammatory demyelinating polyradiculoneuropathy. It is characterized by chronic distal symmetric sensory or sensorimotor deficits. Sensory ataxia is a common clinical presentation. Nerve conduction studies typically show markedly prolonged distal motor latencies. Methods: We report 2 patients with chronic progressive generalized pain and fatigue, with normal neurological examinations except for allodynia. Results: Nerve conduction studies were typical of DADS neuropathy. Monoclonal protein studies were negative. Cerebrospinal fluid protein levels were elevated. Sural nerve biopsies revealed segmental demyelination and remyelination. One biopsy had marked endoneurial and epineurial lymphocytic infiltration. Immunomodulatory therapy alleviated the pain and fatigue and markedly improved distal motor latencies in both patients. Conclusions: DADS neuropathy can present with pain and a normal neurological examination apart from allodynia. Nerve conduction studies are necessary for diagnosis. These patients respond to immunotherapy better than typical DADS neuropathy patients with sensory ataxia. Muscle Nerve 54 : 973–977, 2016     

The role of blink reflex R1 latency as an electrophysiological marker in diabetic distal symmetrical polyneuropathy

ObjectiveStudies showed a relatively prolonged blink R1 latency in patients with diabetic distal symmetrical polyneuropathy (DSPN) compared to that without DSPN. We tested the hypothesis that blink R1 latency would provide a diagnostic alternative to nerve conduction studies (NCS) in DSPN and act as a marker of the severity of NCS abnormalities in DSPN.MethodA total of 109 patients with type 2 diabetes underwent blink reflex studies and NCS. We used the composite amplitude scores of nerve conductions (CAS), which consisted of motor (tibial, peroneal and ulnar) and sensory (sural and ulnar) amplitudes for estimating the severity of NCS.ResultsPatients with DSPN had longer blink R1, R2, and contralateral R2 latencies (P < 0.0001, P = 0.001, and P = 0.031, respectively) and higher CAS (P < 0.0001). Area under curve on receiver operating characteristic curve analysis in diagnosing occurrence of DSPN in blink R1 latency was 0.772 (P < 0.0001). Multiple linear regression analysis showed that blink R1 latency was independently associated with CAS.ConclusionBlink R1 latency may be valuable in auxiliary diagnosis and in determining the severity of NCS abnormalities in DSPN.SignificanceBlink R1 latency can be added as a supplemental marker of severity of NCS in DSPN, especially if the patient’s sural amplitudes has a floor effect.     

Electrophysiological testing in chronic inflammatory demyelinating polyneuropathy patients treated with subcutaneous immunoglobulin: The Polyneuropathy And Treatment with Hizentra (PATH) study

ObjectiveTo assess electrophysiology parameters that can reflect patients' clinical status and show changes in nerve function with treatment, in a study of subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy.MethodsNerve conduction studies (latency, conduction velocity, conduction block and compound muscle action potential [CMAP] on upper limb median, ulnar, and lower limb peroneal motor nerves) were conducted in the placebo-controlled PATH (Polyneuropathy And Treatment with Hizentra) study of two doses of maintenance subcutaneous immunoglobulin (SCIG) IgPro20 in CIDP.ResultsAveraged proximal latency substantially increased with placebo (+1.1 ms) indicating electrophysiologic deterioration but remained stable with IgPro20 (0.2 g/kg bodyweight [bw]: +0.1 ms; 0.4 g/kg bw: −0.1 ms). Distal latencies were also more prolonged with placebo versus IgPro20. Averaged motor nerve conduction velocity substantially decreased with placebo (−1.6 m/s) versus increasing in both IgPro20 groups (+0.2 m/s and +1.0 m/s, respectively). Conduction block and CMAP amplitudes did not change substantially.ConclusionThese findings support the effectiveness of maintenance IgPro20, as nerve function changed in the direction of increasing nerve dysfunction with placebo but remained stable with ongoing IgPro20 therapy.SignificanceElectrophysiology testing can support assessment of clinical status in CIDP to determine treatment efficacy.     

The value of skin biopsy with recording of intraepidermal nerve fiber density and quantitative sensory testing in the assessment of small fiber involvement in patients with different causes of polyneuropathy

The primary aim of our study was to demonstrate how the diagnostic characteristics of skin biopsy used to evaluate small fiber involvement in patients with different causes of polyneuropathy are intrinsically related to the method used to establish the reference values (cut-off values). We also investigated intraepidermal nerve fiber (IENF) density and abnormalities in quantitative sensory testing (QST) in patients with different causes of polyneuropathy and signs of small fiber involvement. A total of 210 patients with symptoms and signs of polyneuropathy were entered into the study. All patients underwent neurological examination, nerve conduction studies, QST on the thigh and distal part of the calf with detection of warm and cold perception thresholds, and skin biopsy with assessment of IENF density. Cut-off values for IENF density were established from our reference material using Z-scores (calculated from multiple regression analysis), fifth percentile, and receiver operating characteristic (ROC) analysis. Of the patients participating in the study, 65 had an established diagnosis of diabetes mellitus, 70 were classified with idiopathic polyneuropathy, and 75 had other possible causes of polyneuropathy. Forty-five patients met the criteria for small fiber polyneuropathy (SFN), and the remaining 165 had also involvement of large nerve fibers. Of the total patient cohort, 84 (40%) had reduced IENF density based on the Z-score, and 106 patients (50%) had at least one abnormality based on QST. In the SFN group, skin biopsy showed a sensitivity of 31% and a specificity of 98% when reference values were presented with Z-scores. When the fifth percentile was used as the cut-off value (6.7 fibers/mm), sensitivity was 35% and specificity 95%. Applying the ROC analysis with a chosen sensitivity of 78% and specificity of 64%, we had a cut-off point of 10.3 fibers/mm. We conclude that skin biopsy with assessment of IENF is a useful method for investigating patients with SFN. The diagnostic value of the test, however, depends upon on the approach used to estimate the reference values. An erratum to this article can be found at     

The role of nutrition as risk factor for polyneuropathy: a case‐control study

The aim of this case–control study is to investigate the role of nutrition as risk factor for polyneuropathy. Three hundred eighteen patients with chronic idiopathic axonal polyneuropathy and 636 matched controls completed a validated food frequency questionnaire that covered nutrient intake and alcohol consumption. As risk estimates, we calculated adjusted odds ratios for the intake of energy and nutrients. Energy and nutrient intake did not differ between patients and controls, regardless of moderate alcohol consumption. Nutrition is not a risk factor for chronic idiopathic axonal polyneuropathy.     

Construction and validation of the chronic acquired polyneuropathy patient‐reported index (CAP‐PRI): A disease‐specific,health‐related quality‐of‐life instrument

Introduction: Generic health‐related quality‐of‐life (HRQOL) patient‐reported outcome measures have been used in patients with chronic immune‐mediated polyneuropathies. We have created a disease‐specific HRQOL instrument. Methods: The chronic acquired polyneuropathy patient‐reported index (CAP‐PRI) was developed and validated in multiple steps. Items were initially generated through patient and specialist input. The performance of the preliminary 20 items was analyzed via a prospective, 5‐center study involving chronic immune‐mediated polyneuropathy patients. Results: Data analysis suggested modification to a 15‐item scale with 3 response categories rather than 5. The final CAP‐PRI was validated in another prospective, 5‐center study. The CAP‐PRI appeared to be a unidimensional outcome measure that fit the Rasch model in our multicenter cohort. It correlated appropriately with outcome measures commonly used in this patient population. Conclusions: The CAP‐PRI is a simple disease‐specific HRQOL measure that appears to be useful for clinical care and possibly also for clinical trials. Muscle Nerve 54 : 9–17, 2016     

The effects of oral‐motor exercises on swallowing in children: an evidence‐based systematic review

Aim The aim of this unregistered evidence‐based systematic review was to determine the state and quality of evidence on the effects of oral motor exercises (OME) on swallowing physiology, pulmonary health, functional swallowing outcomes, and drooling management in children with swallowing disorders. Method A systematic search of 20 electronic databases was completed to identify relevant peer‐reviewed literature published in English between 1960 and 2007. Experimental or quasi‐experimental design studies examining OME as a treatment for children with swallowing disorders were appraised for methodological quality by two assessors and reviewed by a third. Results Sixteen studies of varying methodological quality were included. No study examining the effects of OME on pulmonary health in children was identified. The included studies incorporated a wide variety of OME, and mixed findings were noted across all of the outcomes targeted in this review. Interpretation Based on the results of this evidence‐based systematic review, there is insufficient evidence to determine the effects of OME on children with oral sensorimotor deficits and swallowing problems. Well‐designed studies are needed to provide clinicians with evidence that can be incorporated into the preferences of the client and the clinicians’ knowledge of anatomy, physiology, and neurodevelopment in the management of this group of children.     

Utility of electrodiagnostic testing in evaluating patients with lumbosacral radiculopathy: An evidence‐based review

Diffuse infiltrative lymphocytosis syndrome (DILS) is a hyperimmune reaction against HIV. It leads to MHC‐restricted clonal expansion of CD8 T cells characterized by circulating CD8 hyperlymphocytosis and CD8 T‐cell infiltration in organs. Our patient presented with painful lumbosacral radiculoplexus neuropathy and tested positive for HIV. Nerve biopsy showed large collections of CD8 lymphocytes suspicious for lymphoma. Symptoms, signs, and repeat biopsy improved with antiretroviral treatment. The presentation and treatment response suggest that this case is localized DILS. Muscle Nerve, 2010     

Transthyretin familial amyloid polyneuropathy (TTR‐FAP) in Mallorca: a comparison between late‐ and early‐onset disease

The age of onset (AO) of hereditary ATTR amyloidosis (hATTR) is known to vary between populations, with differing characteristics reported according to AO in endemic/non‐endemic foci. This was a retrospective study of patients with early AO (<50 years) and late AO (≥50 years) hATTR at our center in Mallorca. Data were collected on patient demographics, clinical disease manifestation, and physical symptoms. A total of 95 patients were analyzed, with mean follow‐up of 9 years from diagnosis. The early AO group included 53 patients (33 male) and the late AO group included 42 patients (21 male). Neurologic involvement was the most common initial symptom, although it was significantly more frequent in the late AO vs. early AO group (p = 0.015). Autonomic involvement was observed in 26% of patients in the early AO group, but was rarely observed in the late AO group (5%). During follow up, cardiologic symptoms, renal involvement, and ophthalmologic symptoms were significantly more common in the late AO group (p < 0.05). This retrospective study demonstrates the variation in disease presentation and progression according to AO of hATTR at our Mallorcan center.     

Efficacy and safety of Privigen® in patients with chronic inflammatory demyelinating polyneuropathy: results of a prospective,single‐arm,open‐label Phase III study (the PRIMA study)

This prospective, multicenter, single‐arm, open‐label Phase III study aimed to evaluate the efficacy and safety of Privigen^® (10% liquid human intravenous immunoglobulin [IVIG], stabilized with l ‐proline) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients received one induction dose of Privigen (2 g/kg body weight [bw]) and up to seven maintenance doses (1 g/kg bw) at 3‐week intervals. The primary efficacy endpoint was the responder rate at completion, defined as improvement of ≥1 point on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The preset success criterion was the responder rate being ≥35%. Of the 31 screened patients, 28 patients were enrolled including 13 (46.4%) IVIG‐pretreated patients. The overall responder rate at completion was 60.7% (95% confidence interval [CI]: 42.41%–76.43%). IVIG‐pretreated patients demonstrated a higher responder rate than IVIG‐naïve patients (76.9% vs. 46.7%). The median (25%–75% quantile) INCAT score improved from 3.5 (3.0–4.5) points at baseline to 2.5 (1.0–3.0) points at completion, as did the mean (standard deviation [SD]) maximum grip strength (66.7 [37.24] kPa vs. 80.9 [31.06] kPa) and the median Medical Research Council sum score (67.0 [61.5–72.0] points vs. 75.5 [71.5–79.5] points). Of 108 adverse events (AEs; 0.417 AEs per infusion), 95 AEs (88.0%) were mild or moderate in intensity and resolved by the end of study. Two serious AEs of hemolysis were reported that resolved after discontinuation of treatment. Thus, Privigen provided efficacious and well‐tolerated induction and maintenance treatment in patients with CIDP.     

Somatic neuropathy is an independent predictor of all‐ and diabetes‐related mortality in type 2 diabetic patients: a population‐based 5‐year follow‐up study (KCIS No. 29)

Background and purpose: To investigate the relationships of diabetic neuropathy to all‐cause and diabetes‐related mortality in patients with type 2 diabetes after controlling for significant correlates. Methods: We examined 326 patients diagnosed as diabetic polyneuropathy by nerve conduction study in Keelung city, Taiwan, in 2002 and followed them up to ascertain the cause and date of death until the end of 2006. The cause and date of death were recorded for the deceased patients. Information on significant correlates in association with diabetic polyneuropathy and all‐cause and diabetes‐related mortality was also collected. Results: With median follow‐up time of 62.28 months, 44 patients with type 2 diabetes died. The cause of death related to diabetes accounted for 59% (n = 26) of the deceased. Univariate analysis shows that the presence of diabetic neuropathy confers higher risk for all‐cause mortality (hazard ratio [HR] = 4.88) and mortality from diabetes (HR = 6.58). The significant finding still persisted after adjustment for age, gender, blood pressure, smoking, history of cardiovascular/cerebrovascular disease, duration of diabetes, waist circumference, fasting plasma glucose, total cholesterol, hemoglobin, and creatinine (adjusted HR = 4.44 for all‐cause death and adjusted HR = 11.82 for diabetes‐related mortality, respectively). Conclusions: Diabetic polyneuropathy was an independent predictor for all‐cause and diabetes‐related mortality. The presence of neuropathy together with other significant prognostic factors is informative to predict all‐cause death and death from diabetes‐related disease for patients diagnosed as type 2 diabetes.     

The Swedish Longitudinal Gambling Study (Swelogs): design and methods of the epidemiological (EP‐) track

Swelogs (Swedish Longitudinal Gambling Study) epidemiological (EP‐) track is a prospective study with four waves of data‐collection among Swedish citizens aged 16–84 years at baseline. The major objectives of this track are to provide general population estimates of the prevalence and incidence of problem and at‐risk gambling and enable comparisons with the first Swedish national study on gambling and problem gambling (Swegs) conducted in 1997/1998. The overall study (Swelogs) comprises three tracks of data collection; one epidemiological, one in‐depth and one follow‐up. It is expected to provide information that will inform the development of evidence‐based methods and strategies to prevent the development of gambling problems. This paper gives an overview of the design of the epidemiological track, especially of its two first waves. The baseline wave, performed between October 2008 and August 2009, included 8165 subjects, of whom 6021 were re‐assessed one year later. A stratified random sampling procedure was applied. Computer‐supported telephone interviews were used as the primary method. Postal questionnaires were used to follow‐up those not reached by telephone. The response rate was 55% in the first wave and 74% in the second. The interview and questionnaire data are supplemented by register data. © 2014 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.     

Treatment of restless legs syndrome: An evidence‐based review and implications for clinical practice

Only in the last three decades, the restless legs syndrome (RLS) has been examined in randomized controlled trials. The Movement Disorder Society (MDS) commissioned a task force to perform an evidence‐based review of the medical literature on treatment modalities used to manage patients with RLS. The task force performed a search of the published literature using electronic databases. The therapeutic efficacy of each drug was classified as being either efficacious, likely efficacious, investigational, nonefficacious, or lacking sufficient evidence to classify. Implications for clinical practice were generated based on the levels of evidence and particular features of each modality, such as adverse events. All studies were classed according to three levels of evidence. All Level‐I trials were included in the efficacy tables; if no Level‐I trials were available then Level‐II trials were included or, in the absence of Level‐II trials, Level‐III studies or case series were included. Only studies published in print or online before December 31, 2006 were included. All studies published after 1996, which attempted to assess RLS augmentation, were reviewed in a separate section. The following drugs are considered efficacious for the treatment of RLS: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Drugs considered likely efficacious are rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, and clonidine. Drugs that are considered investigational are dihydroergocriptine, lisuride, methadone, tramadol, clonazepam, zolpidem, amantadine, and topiramate. Magnesium, folic acid, and exercise are also considered to be investigational. Sumanirole is nonefficacious. Intravenous iron dextran is likely efficacious for the treatment of RLS secondary to end‐stage renal disease and investigational in RLS subjects with normal renal function. The efficacy of oral iron is considered investigational; however, its efficacy appears to depend on the iron status of subjects. Cabergoline and pergolide (and possibly lisuride) require special monitoring due to fibrotic complications including cardiac valvulopathy. Special monitoring is required for several other medications based on clinical concerns: opioids (including, but not limited to, oxycodone, methadone and tramadol), due to possible addiction and respiratory depression, and some anticonvulsants (particularly, carbamazepine and valproic acid), due to systemic toxicities. © 2008 Movement Disorder Society     

The prevalence of primary dystonia: A systematic review and meta‐analysis

Dystonia is a hyperkinetic movement disorder characterized by sustained muscle contractions that produce repetitive movements and abnormal postures. Specific information on the prevalence of dystonia has been difficult to establish because the existing epidemiological studies of the condition have adopted different methodologies for case ascertainment, resulting in widely differing reported prevalence. Medline and Embase databases were searched using terms specific to dystonia for studies of incidence, prevalence, and epidemiology. All population‐based studies reporting an incidence and/or prevalence of primary dystonia were included. Sixteen original studies were included in our systematic review. Fifteen studies reported the prevalence of dystonia, including 12 service‐based and three population‐based studies. We performed a meta‐analysis on the results of the service‐based studies, and were able to combine data on the prevalence of several dystonia subtypes. From these studies, we calculated an overall prevalence of primary dystonia of 16.43 per 100,000 (95% confidence interval [CI]: 12.09–22.32). The prevalence of dystonia reported in the three population‐based studies appears higher than that reported in the service‐based studies. Only 1 of the 16 studies reported an incidence of cervical dystonia. This corresponded to a corrected incidence estimate of 1.07 per 100,000 person‐years (95% CI: 0.86–1.32). Despite numerous studies on the epidemiology of dystonia, attempting to determine an accurate prevalence of the condition for health services planning remains a significant challenge. Given the methodological limitations of the existing studies, our own prevalence estimate of primary dystonia likely underestimates the true prevalence of the condition. © 2012 Movement Disorder Society     

The Netherlands Mental Health Survey and Incidence Study‐2 (NEMESIS‐2): design and methods

The psychiatric epidemiological population study NEMESIS‐2 (Netherlands Mental Health Survey and Incidence Study‐2) replicates and expands the first Netherlands Mental Health Survey and Incidence Study (NEMESIS‐1) conducted from 1996 to 1999. The main objectives of the new study are to provide up‐to‐date figures on the prevalence, incidence, course and consequences of mental disorders, and to study trends in mental disorders and service use, with the use of a new sample. New topics not included in NEMESIS‐1 were added, e.g. impulse‐control disorders, and genetic correlates of mental disorders through gathering DNA from saliva samples. This paper gives an overview of the design of NEMESIS‐2, especially of its recently completed first wave. NEMESIS‐2 is a prospective study among Dutch‐speaking subjects aged 18–64 years from the general Dutch population. Its baseline wave included 6646 subjects. Three waves are planned with three year‐intervals between the waves. A multistage, stratified random sampling procedure was applied. The baseline wave of NEMESIS‐2 was performed between November 2007 and July 2009. Face‐to‐face interviews were administered with the Composite International Diagnostic Interview (CIDI) 3.0. The response rate was 65.1%, and 76.4% of the respondents donated saliva. The sample was reasonably nationally representative, but younger subjects were somewhat underrepresented. In conclusion, we were able to build a comprehensive dataset of good quality, permitting several topics to be studied in the future. Copyright © 2010 John Wiley & Sons, Ltd.