Expert opinion on screening, diagnosis and management of diabetic peripheral neuropathy: a multidisciplinary approach.

The proposed expert opinion aimed to address the current knowledge on conceptual, clinical, and therapeutic aspects of diabetic peripheral neuropathy (DPN) and to provide a guidance document to assist clinicians for the best practice in DPN care. The participating experts consider the suspicion of the disease by clinicians as a key factor in early recognition and diagnosis, emphasizing an improved awareness of the disease by the first-admission or referring physicians. The proposed "screening and diagnostic" algorithm involves the consideration of DPN in a patient with prediabetes or diabetes who presents with neuropathic symptoms and/or signs of neuropathy in the presence of DPN risk factors, with careful consideration of laboratory testing to rule out other causes of distal symmetric peripheral neuropathy and referral for a detailed neurological work-up for a confirmative test of either small or large nerve fiber dysfunction in atypical cases. Although, the first-line interventions for DPN are currently represented by optimized glycemic control (mainly for type 1 diabetes) and multifactorial intervention (mainly for type 2 diabetes), there is a need for individualized pathogenesis-directed treatment approaches for DPN. Alpha-lipoic acid (ALA) seems to be an important first-line pathogenesis-directed agent, given that it is a direct and indirect antioxidant that works with a strategy targeted directly against reactive oxygen species and indirectly in favor of endogenous antioxidant capacity for improving DPN conditions. There is still a gap in existing research in the field, necessitating well-designed, robust, multicenter clinical trials with sensitive endpoints and standardized protocols to facilitate the diagnosis of DPN via a simple and effective algorithm and to track progression of disease and treatment response. Identification of biomarkers/predictors that would allow an individualized approach from a potentially disease-modifying perspective may provide opportunities for novel treatments that would be efficacious in early stages of DPN, and may modify the natural course of the disease. This expert opinion document is expected to increase awareness among physicians about conceptual, clinical, and therapeutic aspects of DPN and to assist them in timely recognition of DPN and translating this information into their clinical practice for best practice in the management of patients with DPN.

Effects of Computer-based Balance Exercises on Balance, Pain, Clinical Presentation and Nerve Function in Patients With Diabetic Peripheral Neuropathy: A Randomized Controlled Study.

OBJECTIVE: To evaluate the use of a computer-based biodex balance exercise system (BBS) on balance, neuropathic pain, clinical presentation and nerve function in patients with diabetic peripheral neuropathy (DPN). METHODS: A total of 32 participants with DPN were randomly assigned in a 1:1 ratio to an intervention group (IG) or control group (CG). The IG performed exercises using the BBS twice weekly for 8 weeks, while CG were informed regarding diabetes self-management. At baseline and after study completion, participants underwent balance (postural stability and fall risk) and neuropathic pain assessment (DN4 questionnaire) and were screened using the Michigan Neuropathy Screening Instrument and nerve conduction test. RESULTS: Among the baseline participants, 14 in the IG and 13 in the CG completed the study. Balance training improved postural stability (overall, p<0.001), fall risk (p<0.001), neuropathic pain (p=0.01) and symptoms (p<0.001), and clinical presentation (p=0.02), but not nerve function, within the IG. At follow-up, IG displayed significantly improved stability (p<0.001) and fall risk (p=0.02) and decreased neuropathic symptoms (p=0.01) compared to the CG. CONCLUSION: Computer-based balance exercises improve balance, pain, and clinical presentation of DPN, but not nerve function, in patients with DPN. CLINICALTRIALS: gov ID: NCT05255497.

Expert opinion on the diagnostic odyssey and management of late-onset Pompe disease: a neurologist's perspective.

This consensus statement by a panel of neurology experts aimed to provide a practical and implementable guidance document to assist clinicians with the best clinical practice in terms of diagnosis, treatment, and monitoring of late-onset Pompe disease (LOPD). The participating experts consider the clinical suspicion of LOPD by the physician to be of utmost importance in the prevention of diagnostic and therapeutic delay in LOPD patients. A diagnostic algorithm is proposed to facilitate the diagnosis of LOPD in patients presenting with unexplained proximal/axial weakness (with or without respiratory symptoms) or restrictive respiratory insufficiency with hyperCKemia and/or exercise intolerance as the red flag symptoms/signs that raise the index of suspicion for LOPD diagnosis. The diagnosis is based on the subsequent use of dried blood spot (DBS) assay, and the DBS assay can be confirmed by acid alpha-glucosidase (GAA) tissue analysis in leukocytes, fibroblasts, or muscle fibers and/or genetic mutation analysis. Accordingly, experts consider increased awareness among physicians about potential presenting characteristics with a high index of suspicion for LOPD to be crucial to suspect and consider LOPD in the differential diagnosis, while strongly suggesting the use of a diagnostic algorithm combined with DBS assay and confirmatory tests in the timely diagnosis of LOPD and implementation of best practice patterns.

Therapeutic plasma exchange in neurological diseases: Eleven years experience at a tertiary care center in Turkey.

Therapeutic plasma exchange (TPE) is an apheresis procedure in which plasma is separated from the blood cellular components ex vivo, allocated, and replaced with another plasma or a plasma-replacing fluid. This study aimed to define the rate of complications and determine TPE distribution in various neurological diseases. Our study is a retrospective analysis of neurologic diseases requiring TPE between 2008 and 2019 that were selected using the medical records of neurology departments and apheresis units database. We performed 1459 TPE procedures on 207 patients between 2008 and 2019. TPE Procedure is most frequently applied in patients with Myasthenia-Gravis syndrome (34.7%). The complication ratio was 1.6% from a total of 1459 TPE procedures. The most commonly specified adverse event was allergic reactions 11 (5.3%), followed by hypotension 6 (2.9%). TPE was safe and tolerable, with manageable complications in experienced hands.

Neuropathic Pain Frequency in Neurology Outpatients: A Multicenter Study.

INTRODUCTION: Neuropathic pain is common, but the frequency of misdiagnosis and irrational treatment is high. The aim of this study is to evaluate the rate of neuropathic pain in neurology outpatient clinics by using valid and reliable scales and review the treatments of patients. METHODS: The study was conducted for 3 months in eleven tertiary health care facilities. All outpatients were asked about neuropathic pain symptoms. Patients with previous neuropathic pain diagnosis or who have neuropathic pain symptoms were included and asked to fill painDETECT and douleur neuropathic en 4 questions (DN4) questionnaire. Patients whose DN4 score is higher than 3 and/or painDETECT score higher than 13 and/or who are on drugs for neuropathic pain were considered patients with neuropathic pain. The frequency of neuropathic pain was calculated and the treatments of patients with neuropathic pain were recorded. RESULTS: Neuropathic pain frequency was 2.7% (95% CI: 1.5-4.9). The most common cause was diabetic neuropathy. According to painDETECT, the mean overall pain intensity was 5.7±2.4, being lower among patients receiving treatment. Pharmacological neuropathic pain treatment was used by 72.8% of patients and the most common drug was pregabalin. However, 70% of those receiving gabapentinoids were using ineffective doses. Besides, 4.6% of the patients were on medications which are not listed in neuropathic pain treatment guidelines. CONCLUSION: In our cohort, the neuropathic pain severity was moderate and the frequency was lower than the literature. Although there are many guidelines, high proportion of patients were being treated by ineffective dosages or irrational treatments.

Selective Bilateral Vestibular Neuropathy in a Turkish CMT1B Family With a Novel MPZ Mutation.

PURPOSE OF REVIEW: To report the findings in 12 members over 3 generations of a family with dominantly inherited Charcot-Marie-Tooth disease (CMT1B) due to a novel MPZ mutation, who all had moderately severe selective impairment of vestibular function with normal hearing. Methods used were video head impulse testing of the function of all 6 semicircular canals, Romberg test on foam, nerve conduction studies, and whole exome and Sanger sequencing. RECENT FINDINGS: All affected patients had a demyelinating neuropathy and a novel MPZ mutation: c.362A>G (chr1: 161276584, p.D121G). All also had normal hearing for age but a moderately severe impairment of semicircular canal function and a positive Romberg test on foam. SUMMARY: Some CMT mutations can impair vestibular function, presumably because of a vestibular nerve involvement but spare hearing. In such patients, impairment of vestibular function and impairment of proprioception contribute to imbalance.

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

BACKGROUND: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. OBJECTIVE: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. METHODS: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. RESULTS: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. CONCLUSION: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.

Vestibular impairment in Charcot-Marie-Tooth disease.

OBJECTIVE: To find out if Charcot-Marie-Tooth (CMT) patients, who have peripheral vestibular as well as peripheral somatosensory impairment, have worse postural balance than those who do not. METHODS: We studied 32 patients with various CMT phenotypes and genotypes. Vestibular function was measured with the video head impulse test (vHIT) which tests vestibulo-ocular reflex (VOR) gain from each of the six semicircular canals in response to rapid head rotations. Postural balance was evaluated with a battery of four postural tests with emphasis on the modified clinical test of sensory integration in balance (mCTSIB). RESULTS: Half of the 32 patients had some impairment of vestibular function ranging from mild, affecting only 1-2 semicircular canals, to almost total affecting all 6 semicircular canals. Their mCTSIB scores correlated with VOR gain from the vertical rather than from the lateral semicircular canals. The worse the vertical VOR gain the worse the mCTSIB score. CONCLUSION: We propose that any CMT patient could have clinically inapparent vestibular impairment that can be easily measured with the vHIT. This vestibular impairment could be contributing to their imbalance and could respond to a focused vestibular rehabilitation program.

A database for screening and registering late onset Pompe disease in Turkey.

The aim of this study was to search for the frequency of late onset Pompe disease (LOPD) among patients who had a myopathy with unknown diagnosis registered in the pre-diagnostic part of a novel registry for LOPD within a collaborative study of neurologists working throughout Turkey. Included in the study were 350 patients older than 18 years who have a myopathic syndrome without a proven diagnosis by serum creatine kinase (CK) levels, electrodiagnostic studies, and/or muscle pathology, and/or genetic tests for myopathies other than LOPD. Acid alpha glucosidase (GAA) in dried blood spot was measured in each patient at two different university laboratories. LOPD was confirmed by mutation analysis in patients with decreased GAA levels from either both or one of the laboratories. Pre-diagnostic data, recorded by 45 investigators from 32 centers on 350 patients revealed low GAA levels in a total of 21 patients; from both laboratories in 6 and from either one of the laboratories in 15. Among them, genetic testing proved LOPD in 3 of 6 patients and 1 of 15 patients with decreased GAA levels from both or one of the laboratories respectively. Registry was transferred to Turkish Neurological Association after completion of the study for possible future use and development. Our collaborative study enabled collection of a considerable amount of data on the registry in a short time. GAA levels by dried blood spot even from two different laboratories in the same patient may not prove LOPD. LOPD seemed to be rarer in Turkey than in Europe.

Vestibular impairment in chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a common, treatable, autoimmune peripheral neuropathy considered to produce imbalance by weakness and proprioceptive impairment rather than vestibular impairment. We measured semicircular canal vestibular function in 21 CIDP patients (15M/6F) by the video head impulse test and postural stability with a battery comprising the modified Clinical Test of Sensory Integration and Balance, the Berg Balance Scale, the Dynamic Gait Index, the Fall Efficiency Scale, and the International Cooperative Ataxia Rating Scale. Of the 21 patients, 16 had vestibular impairment, ranging from mild-affecting just a single semicircular canal, to severe-affecting all 6 canals. Although the severity of the vestibular impairment did not correlate either with the severity of the postural imbalance or of the peripheral neuropathy, our data show that vestibular impairment is an additional challenge to balance that some CIDP patients will face.

Preoperative parameters and their prognostic value in amyotrophic lateral sclerosis patients undergoing implantation of a diaphragm pacing stimulation system.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease with devastating and fatal respiratory complications. Diaphragm pacing stimulation (DPS) is a treatment option in diaphragm insufficient ALS patients. Ventilatory insufficiency depending on diaphragmatic failure is treated by the present study aimed to investigate prognostic value of preoperative clinical and functional characteristics of ALS patients undergoing implantation of a DPS system and to determine appropriate indications for the DPS system. METHODS: The study included 34 ALS patients implanted with DPS system. All patients underwent multidisciplinary and laboratory evaluations before the surgery. The laboratory examinations included pulmonary function tests and arterial blood gas analysis. Survival rates were recorded in a 2-year follow-up after the surgery. RESULTS: Twenty-eight of 34 patients with ALS survived after a 2-year follow-up. These patients were younger than those who died and had the disease for a longer time; however, the differences were not significant. Both right and left hemidiaghragms were thicker in the survived patients (P < 0.0001 for each). Pulmonary function tests revealed no significant differences between the patients who survived. Arterial blood gas analysis demonstrated lower partial pressure of carbon dioxide in the survived patients (P = 0.025). CONCLUSIONS: DPS implantation was more efficacious in ALS patients with mild respiratory failure and thicker diaphragm. Predictors of long-term effectiveness of DPS system are needed to be addressed by large-scale studies.

Importance of diaphragm thickness in amyotrophic lateral sclerosis patients with diaphragm pacing system implantation.

INTRODUCTION: Severe respiratory failure develops as a result of the involvement of the respiratory muscles in patients with amyotrophic lateral sclerosis (ALS). Implantation of diaphragm pacing system (DPS) has been carried out on ALS patients since 2005 to avoid these situations, but the importance of diaphragm thickness has not yet been established clearly. MATERIAL AND METHOD: We retrospectively evaluated 34 ALS patients who had previously implanted DPS to detect the importance of diaphragm thickness. We investigated the effect of diaphragm thickness, which was measured by preoperative thorax computerized tomography on preoperative respiratory function tests (RFT), arterial blood gas (ABG) analysis, postoperative 3- and 6-month oxygen saturations and mortality. RESULTS: The right diaphragm thickness was calculated as 4.60 (2.95-6.00) mm, while the left diaphragm thickness was 4.10 (2.77-6.00) mm. Six patients died during the follow-up period. We did not detect a significant relationship between ABG parameters, RFT and diaphragm thickness. However, according to our observations, the diaphragm thickness was significantly related to mortality. The right diaphragm was significantly thinner in cases that required preoperative respiratory support and had percutaneous endoscopic gastrostomy. When the cut-off values for the diaphragm thickness were accepted as 3.50 mm, significantly higher mortality among patients below this was observed. CONCLUSION: Diaphragm thickness is an important criterion in cases for which DPS implantation is planned. We consider that avoidance of DPS implantation is more suitable for cases with a diaphragm thickness below 3.50 mm because of mortality.

Serum anti-Fas antibody levels in amyotrophic lateral sclerosis.

In this study, the levels of anti-Fas antibodies were evaluated in patients with amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Sera from 25% of patients with sporadic ALS (sALS) and 22% of patients with familial ALS (fALS) contained abnormal levels of anti-Fas antibodies compared with normal controls. Half of patients with Parkinson's disease (PD), but no patients with Alzheimer's disease (AD), had abnormal levels of anti-Fas antibodies. There was no correlation between the antibody levels of patients with ALS and the length or stage of their disease. These data demonstrate that the peripheral immune system is activated as reflected by anti-Fas antibodies in ALS, but this activation is not specific to ALS.

PARP expression is increased in astrocytes but decreased in motor neurons in the spinal cord of sporadic ALS patients.

The evidence for increased oxidative stress and DNA damage in amyotrophic lateral sclerosis (ALS) prompted studies to determine if the expression of poly(ADP-ribose) polymerase (PARP) is increased in ALS. Using Western analyses of postmortem tissue, we demonstrated that PARP-immunoreactivity (PARP-IR) was increased 3-fold in spinal cord tissues of sporadic ALS (sALS) patients compared with non-neurological disease controls. Despite the increased PARP-IR, PARP mRNA expression was not increased significantly. Immunohistochemical analyses revealed PARP-IR was increased in both white and gray matter of sALS spinal cord. While PARP-IR was predominantly seen in astrocytes, large motor neurons displayed reduced staining compared with controls. This result contrasts sharply to the staining of Alzheimer and MPTP-induced Parkinson diseased tissue, where poly(ADP-ribose) (PAR)-IR was seen mostly in neurons, with little astrocytic staining. PARP-IR was increased in the pellet fraction of sALS homogenates compared with control homogenates, representing potential PARP binding to chromatin or membranes and suggesting a possible mechanism of PARP stabilization. The present results demonstrate glial alterations in sALS spinal cord tissue and support the role of glial alterations in sALS pathogenesis. Additionally, these results demonstrate differences in sALS spinal motor neurons and astrocytes compared to brain neurons and astrocytes in Alzheimer disease and MPTP-induced Parkinson disease despite the presence of markers for oxidative stress in all 3 diseases.

Multiple sclerosis and parkinsonism: a case report.

Multiple sclerosis (MS) is a well-known disease characterized by the distribution of plaques in the periventricular and subcortical white matter. Although plaques can also be found in the striatum, pallidum and thalamus, extrapyramidal symptoms are very rare in MS. However, the association of MS and parkinsonism is still a controversial topic as it has not been established whether these two conditions occur coincidentally or causally. In the literature, eleven cases of parkinsonism associated with MS have been described. Here, we report a patient with clinically definite MS and signs of parkinsonism. Our patient had slow progressive bradykinesia, static tremor and bradymimia that were not associated with exacerbation or progression of the MS. This rare and interesting association of multiple sclerosis with parkinsonism is discussed in the light of literature reports.