Small fiber neuropathy: a disabling and underrecognized syndrome.

PURPOSE OF REVIEW: To discuss cause, clinical manifestations, diagnostics, and treatment of small fiber neuropathy (SFN). The diagnosis is difficult and can be easily missed. RECENT FINDINGS: SFN causes high morbidity with disabling symptoms and impact on quality of life. Patients may benefit from being diagnosed with SFN, even if no underlying cause is identified and no specific treatment is yet available. Recently, genetic mutations as a possible cause of SFN were identified. Clinical diagnostic criteria have been proposed, but no gold standard exists, and each test has its limitations. The diagnosis requires a combination of typical symptoms, abnormal neurologic findings, and absence of large fiber involvement. Clinicians should be aware of overlapping symptoms of SFN and fibromyalgia. Treatment is often difficult, even when the underlying cause is identified and appropriately treated. Usually, only symptomatic relief of complaints is available. SUMMARY: Awareness of SFN and related symptoms is of great clinical relevance. Guidelines for appropriate diagnostic workup using a stepwise approach involving a combination of tests are warranted. Even if no treatment is available, patients may benefit from timely recognition of SFN.

Thermal threshold testing: call for a balance between the number of measurements and abnormalities in the diagnosis of sarcoidosis-associated small fiber neuropathy.

Introduction: Several recent studies of diagnosing small fiber neuropathy (SFN) have shown a lack of uniformity in thermal threshold testing (TTT) or quantitative sensory testing (QST) which makes it a challenge to compare the data. It is known that the chance of finding an abnormality increases with increasing number of measurements. Objectives: With this study, we first wanted to investigate whether TTT could benefit from a new approach focusing on the balance between the number of measurements, depending on the selection of parameters and measuring sites, and on number of abnormalities (NOAs). Second, we wanted to address the role of the method of levels (MLe) in possible desensitization during TTT measurements. Methods: One hundred seventeen participants were included (48 patients with sarcoidosis with probable SFN, 49 without SFN, and 20 healthy controls). Thermal threshold testing measurements and Small Fiber Neuropathy Screening List (SFNSL) questionnaire were used to assess SFN. Results: A combination of measuring all thermal threshold parameters at both feet except for MLe showed the best diagnostic performance. Increasing TTT NOAs correlates with the severity of SFN. Adding the SFNSL questionnaire further improves diagnostic performance. Discussion: Looking at TTT NOAs in all TTT parameters except for MLe at both feet should be considered as a new approach to improve the consistency and balance between the selection of TTT parameters, measuring sites, and definition of "abnormal QST." Moreover, the SFNSL questionnaire is a valuable tool to quantify SFN symptoms and could improve SFN diagnosis.

Fully Automatic, Semiautomatic, and Manual Corneal Nerve Fiber Analysis in Patients With Sarcoidosis.

Purpose: No guidelines are available on the preferred method for analyzing corneal confocal microscopy (CCM) data. Manual, semiautomatic, and automatic analyzes are all currently in use. The purpose of the present study was threefold. First, we aimed to investigate the different methods for CCM analysis in patients with and without small fiber neuropathy (SFN). Second, to determine the correlation of different methods for measuring corneal nerve fiber length (CNFL) and nerve fiber area (NFA). Finally, we investigated the added value of automatic NFA analysis. Methods: We included 20 healthy controls and 80 patients with sarcoidosis, 31 with established SFN and 49 without SFN. The CNFL was measured using CCMetrics, ACCMetrics, and NeuronJ. NFA was measured with NFA FIJI and ACCMetrics NFA. Results: CNFL and NFA could not distinguish sarcoidosis with and without SFN or healthy controls. CCMetrics, NeuronJ, and ACCMetrics CNFL highly correlated. Also, NFA FIJI and ACCMetrics NFA highly correlated. Reproducing a nonlinear formula between CNFL and NFA confirmed the quadratic relation between NFA FIJI and ACCMetrics CNFL. CCMetrics and NeuronJ instead showed a square root relationship and seem to be less comparable owing to differences between automatic and manual techniques. Conclusions: ACCMetrics can be used for fully automatic analysis of CCM images to optimize efficiency. However, CNFL and NFA do not seem to have a discriminatory value for SFN in sarcoidosis. Further research is needed to determine the added value and normative values of NFA in CCM analysis. Translational Relevance: Our study improves the knowledge about CCM software and pathophysiology of SFN.

Infliximab decreases inflammatory activity but has no effect on small fiber neuropathy related symptoms in Dutch patients with sarcoidosis

BACKGROUND AND AIM: Small fiber neuropathy (SFN) may present as complication in sarcoidosis.(1) SFN can potentially result into a large range of symptoms with a high impact on quality of life.(2) Although treatment of the underlying disease of SFN is paramount, little research has been performed to investigate SFN improvement as consequence of sarcoidosis treatment. This retrospective study investigates whether there is an association between the anti-inflammatory effects of infliximab and SFN-symptoms Methods: The Small Fiber Neuropathy Screening List (SFNSL) was used to measure changes in SFN symptoms during infliximab treatment. Maximal standardized uptake value (SUVmax) from Fluordeoxyglucose Positron Emission Tomography (FDG-PET) was used as a measure for inflammatory activity. RESULTS: 36 sarcoidosis patients were eligible for analysis. SFNSL-score showed a mean decrease of -1,9 points (p = 0.446). SUVmax did improve with a mean of -3.7 (p<0.001). No correlation between a decrease of SUVmax and SFNSL screening list could be found (p=0.610). CONCLUSIONS: Our data reveal no association between anti-inflammatory effect of infliximab and SFN-related symptoms in patients with sarcoidosis, which contradicts previous case-reports and case-series.(3-6) Given the major negative impact of SFN-related symptoms on the quality of life in patients with sarcoidosis, it is necessary that the possible beneficial effect of anti-inflammatory therapy will be further addressed in future prospective studies.1.

Current View of Diagnosing Small Fiber Neuropathy.

Small fiber neuropathy (SFN) is a disorder of the small myelinated Aδ-fibers and unmyelinated C-fibers [5, 6]. SFN might affect small sensory fibers, autonomic fibers or both, resulting in sensory changes, autonomic dysfunction or combined symptoms [7]. As a consequence, the symptoms are potentially numerous and have a large impact on quality of life [8]. Since diagnostic methods for SFN are numerous and its pathophysiology complex, this extensive review focusses on categorizing all aspects of SFN as disease and its diagnosis. In this review, sensitivity in combination with specificity of different diagnostic methods are described using the areas under the curve. In the end, a diagnostic work-flow is suggested based on different phenotypes of SFN.

Effect of sensory stimuli on restless legs syndrome: a randomized crossover study.

STUDY OBJECTIVE: A variety of sensory stimuli relieve restless legs syndrome symptoms. Because systematic evaluations of sensory stimulation in restless legs syndrome are largely lacking, we performed a randomized crossover study to evaluate the effect of external sensory stimulation on restless legs syndrome symptoms. METHODS: Eighteen patients underwent 3 consecutive suggestive immobilization tests with the order of the following 3 conditions randomly assigned: no electrical stimulation (condition 1), tactile and proprioceptive sensory stimulation (condition 2), and tactile sensory stimulation only (condition 3). Restless legs syndrome symptoms were quantified by visual analog scales, and periodic leg movements during wake were measured. RESULTS: Baseline visual analogue scale score was 4.5 (range 0-60) in condition 1, 10.5 (range 0-96) in condition 2, and 8.5 in condition 3 (p = 0.21). There was a tendency towards a higher maximum visual analogue scale score and visual analogue scale score at the end of the suggested immobilization test in the conditions with tactile sensory stimulation, though not significant (p = 0.74 and p = 0.29, respectively). Fifteen patients suffered from periodic leg movements during wake. Median indices were 18 (range 0-145) in condition 1, 26 (range 0-190) in condition 2, and 49 (range 0-228) in condition 3 (p = 0.76). CONCLUSIONS: We found a tendency towards less leg discomfort in the conditions in which an external sensory input was applied. This potential benefit of sensory stimuli on restless legs syndrome severity merits further investigation as this could open new ways towards a better pathophysiological understanding and non-pharmacological treatments.

Arterial stiffness is increased in Hodgkin lymphoma survivors treated with radiotherapy.

Radiotherapy has been associated with an increased risk for cardiovascular disease (CVD) in Hodgkin lymphoma survivors (HLS). Identifying subjects most likely to develop these complications is challenging. Arterial stiffness has been frequently used as an early marker of CVD, but has never previously been investigated in patients treated with radiotherapy. The carotid-femoral pulse wave velocity (PWV) and the distensibility coefficient (DC) of the common carotid artery were used as markers of arterial stiffness. Eighty-two HLS and 40 age- and gender-matched control subjects were studied. The aorta and the carotid arteries were situated within the radiation field in 50 and 39 patients. Mean PWV was not significantly different in HLS treated with radiotherapy on the mediastinum when compared to HLS treated without mediastinal radiotherapy and to controls. If HLS were 40 years or older at radiotherapy their PWV was significantly higher (8.54 m/s) than patients irradiated at a younger age (7.14 m/s, p = 0.004) and controls (6.91 m/s, p < 0.001), after adjusting for current age and other CVD risk factors. Mean DC was lower, indicative of stiffer arteries, in HLS treated with radiotherapy on the common carotid artery (2.79) than in HLS without radiotherapy (3.35, p = 0.029) and versus controls (3.60, p = 0.001). DC was lowest in HLS treated at 35 years of age or later (2.05), compared to HLS irradiated at a younger age (2.98, p = 0.046). In HLS, radiotherapy is associated with increased arterial stiffness. The effect of radiotherapy seems most evident when radiotherapy is administered at ages above 35-40 years.

Progressive muscle atrophy and weakness after treatment by mantle field radiotherapy in Hodgkin lymphoma survivors.

PURPOSE: To describe the damage to the muscles and propose a pathophysiologic mechanism for muscle atrophy and weakness after mantle field radiotherapy in Hodgkin lymphoma (HL) survivors. METHODS AND MATERIALS: We examined 12 patients treated by mantle field radiotherapy between 1969 and 1998. Besides evaluation of their symptoms, the following tests were performed: dynamometry; ultrasound of the sternocleidomastoid, biceps, and antebrachial flexor muscles; and needle electromyography of the neck, deltoid, and ultrasonographically affected arm muscles. RESULTS: Ten patients (83%) experienced neck complaints, mostly pain and muscle weakness. On clinical examination, neck flexors were more often affected than neck extensors. On ultrasound, the sternocleidomastoid was severely atrophic in 8 patients, but abnormal echo intensity was seen in only 3 patients. Electromyography of the neck muscles showed mostly myogenic changes, whereas the deltoid, biceps, and antebrachial flexor muscles seemed to have mostly neurogenic damage. CONCLUSIONS: Many patients previously treated by mantle field radiotherapy develop severe atrophy and weakness of the neck muscles. Neck muscles within the radiation field show mostly myogenic damage, and muscles outside the mantle field show mostly neurogenic damage. The discrepancy between echo intensity and atrophy suggests that muscle damage is most likely caused by an extrinsic factor such as progressive microvascular fibrosis. This is also presumed to cause damage to nerves within the radiated field, resulting in neurogenic damage of the deltoid and arm muscles.

Characterization of chronic fatigue in patients with sarcoidosis in clinical remission.

BACKGROUND: Patients with sarcoidosis frequently complain of fatigue, even when sarcoidosis has come into clinical remission. The primary aim of this study was to assess the severity of fatigue in patients with sarcoidosis in clinical remission and to characterize it according to the international criteria for chronic fatigue syndrome (CFS). Furthermore, we evaluated whether fatigue is associated with depression and anxiety, health status, and patient-reported sleep quality, and we recorded physical activity levels and muscle strength as objective assessments of fatigue. METHODS: Data on 75 patients with sarcoidosis in clinical remission were obtained by questionnaires (Checklist Individual Strength [CIS], Symptom Checklist-90, Beck Depression Inventory for primary care, Medical Outcomes Study 36-Item Short-Form Health Survey), standardized interview (CFS criteria), sleep diary, accelerometer, and muscle strength tests. RESULTS: Fatigue severity mean score in patients with sarcoidosis in clinical remission was high (CIS fatigue severity 30.5 ± 15.5), and criteria for CFS were met in 47% of fatigued participants. Median time since diagnosis was 9 years. Fatigue was associated with depression (P = .01), anxiety (P = .013), and reduced health status (P < .001). Scores on sleep quality were normal. Physical activity levels were reduced in fatigued participants. Muscle strength, particularly handgrip (P = .006) and quadriceps strength (P < .001), was significantly associated with fatigue. CONCLUSIONS: Fatigue in patients with sarcoidosis in clinical remission is a frequent symptom and can be characterized as a severe and long-lasting problem, symptomatically similar to CFS. Psychologic distress and reduced health status are associated with fatigue. Interestingly, we observed significantly reduced physical activity and muscle weakness in fatigued patients.

Screening Hodgkin lymphoma survivors for radiotherapy induced cardiovascular disease.

Long term prognosis of Hodgkin lymphoma (HL) survivors is affected by late toxicity of radiotherapy and chemotherapy. Cardiovascular complications of radiotherapy have been shown to have a great impact on the long term survival. The aim of this review is to summarize the available data on different screening modalities for cardiovascular disease and to suggest a screening program. Patients older than 45 years at HL diagnosis should be screened for coronary artery disease (CAD) starting 5 years after mediastinal radiotherapy; they are at increased risk of pre-existent atherosclerosis which can be accelerated by radiotherapy. Screening for CAD should start 10 years after radiotherapy in younger patients. The best screening modality for CAD is subject of discussion, based on the latest studies we suggest screening by Coronary artery calcium score measurements or CT-angiography. Valvular disorders should be looked for by echocardiography starting 10 years after radiotherapy. Electrocardiograms should be performed at each cardiovascular screening moment in order to detect arrhythmia's or conduction abnormalities. We suggest repeating these screening tests every 5 years or at onset of cardiovascular complaints; patients should be extensively instructed about signs and symptoms of cardiovascular disease. Furthermore traditional risk factors for cardiovascular disease should be carefully monitored and treated. We suggest determining a cardiovascular risk profile at diagnosis of HL in patients older than 45 years. In case of a high risk, treating HL without RT should be considered.

Outcome of carotid artery stenting for radiation-induced stenosis.

PURPOSE: Patients who have been irradiated at the neck have an increased risk of symptomatic stenosis of the carotid artery during follow-up. Carotid angioplasty and stenting (CAS) can be a preferable alternative treatment to carotid endarterectomy, which is associated with increased operative risks in these patients. METHODS AND MATERIALS: We performed a prospective cohort study of 24 previously irradiated patients who underwent CAS for symptomatic carotid stenosis. We assessed periprocedural and nonprocedural events including transient ischemic attack (TIA), nondisabling stroke, disabling stoke, and death. Patency rates were evaluated on duplex ultrasound scans. Restenosis was defined as a stenosis of >50% at the stent location. RESULTS: Periprocedural TIA rate was 8%, and periprocedural stroke (nondisabling) occurred in 4% of patients. After a mean follow-up of 3.3 years (range, 0.3-11.0 years), only one ipsilateral incident event (TIA) had occurred (4%). In 12% of patients, a contralateral incident event was present: one TIA (4%) and two strokes (12%, two disabling strokes). Restenosis was apparent in 17%, 33%, and 42% at 3, 12, and 24 months, respectively, although none of the patients with restenosed vessels became symptomatic. The length of the irradiation to CAS interval proved the only significant risk factor for restenosis. CONCLUSIONS: The results of CAS for radiation-induced carotid stenosis are favorable in terms of recurrence of cerebrovascular events at the CAS site.

Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial.

BACKGROUND: Pulsed high-dose dexamethasone induced long-lasting remission in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in a pilot study. The PREDICT study aimed to compare remission rates in patients with CIDP treated with high-dose dexamethasone with rates in patients treated with standard oral prednisolone. METHODS: In eight neuromuscular centres in the Netherlands and one in the UK, patients aged 18 years or older who had newly diagnosed definite or probable CIDP were randomly assigned to a treatment regimen of either pulsed high-dose dexamethasone or standard oral prednisolone. Randomisation was done with a random number generator. The primary outcome measure was remission at 12 months, defined as improvement of at least three points on the Rivermead mobility index and improvement of at least one point on the inflammatory neuropathy cause and treatment disability scale. Analysis was by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07779236. FINDINGS: Between December, 2003, and December, 2008, 40 patients were treated: 24 received dexamethasone and 16 received prednisolone. At 12 months, 16 patients were in remission: ten in the dexamethasone group and six in the prednisolone group (odds ratio [OR] 1.2, 95% CI 0.3-4.4). Most adverse events were minor and did not differ substantially between treatment groups; however, sleeplessness and Cushing's face occurred more often in the prednisolone group. INTERPRETATION: Pulsed high-dose dexamethasone treatment did not induce remission more often than prednisolone treatment. A substantial proportion of patients were in remission at 12 months in both treatment groups. High-dose dexamethasone could be considered as induction therapy in CIDP, but comparison with intravenous immunoglobulin treatment is needed. FUNDING: The Prinses Beatrix Fonds (MAR01-0213) and the Department of Neurology, Academic Medical Center.

Carotid angioplasty and stent placement: comparison of transcranial Doppler US data and clinical outcome with and without filtering cerebral protection devices in 509 patients.

PURPOSE: To prospectively evaluate emboli detected at transcranial Doppler ultrasonography (US) and outcome of carotid angioplasty and stent placement and compare these findings in patients treated with the use of filtering cerebral protection devices (CPDs) with the findings in patients treated without the use of filtering CPDs. MATERIALS AND METHODS: This study was approved by the institutional human research committee. Written informed consent was obtained for all patients. Patients were divided into three groups: 161 patients treated before filtering CPDs had become available (group 1), 151 patients treated with filtering CPDs (group 2), and 197 patients treated without CPDs after CPDs had become available (group 3). Clinical end points were cerebral ischemic events and death. Transcranial Doppler US end points included isolated microemboli, microembolic showers, macroemboli, and distal thrombus. The procedure was divided into five phases: wiring, predilation, stent deployment, postdilation, and CPD handling. Data not distributed normally were analyzed with the Mann-Whitney U statistic. For binomial data, the chi(2) test was used. P < .05 indicated statistical significance. RESULTS: For each phase, median and interquartile range (IQR) for isolated microemboli in group 2 versus group 3 were as follows: wiring, 51 (IQR, 31-69) versus 27 (IQR, 15-48); predilation, 19 (IQR, 13-33) versus 13 (IQR, 8-19); stent deployment, 64 (IQR, 46-82) versus 48.5 (IQR, 33.25-66); and postdilation, 24 (IQR, 14-39) versus 16 (IQR, 11-27.5) (P < .001 for each phase). Median and IQR for microembolic showers were as follows: wiring, 0 (IQR, 0-3) versus 0 (IQR, 0-0); predilation, 1.5 (IQR, 0-4) versus 0 (IQR, 0-2); stent deployment, 22 (IQR, 11-36) versus 11 (IQR, 6-17); postdilation, three (IQR, 0-9) versus one (IQR, 0-4); (postdilation phase, P = .001; all other phases, P < .001). Median for isolated microemboli in group 1 versus groups 2 and 3 combined were as follows: predilation, 10 (IQR, 5-22.75) versus 16 (IQR, 9-25) (P = .001); stent deployment, 32 (IQR, 15-58) versus 54 (IQR, 40.5-74) (P < .001); and postdilation, 11 (IQR, 6-19) versus 18 (IQR, 12-33) (P < .001). Median for microembolic showers during stent deployment were six (IQR, 1-14) versus 13 (IQR, 7-26) (P < .001). Five patients died, and five major strokes and 14 minor strokes occurred. Eight macroemboli occurred in unprotected procedures; six distal thrombi occurred in protected procedures. CONCLUSION: Carotid angioplasty and stent placement yielded more microemboli in patients treated with filtering CPDs than in unprotected procedures. The infrequent occurrence of cerebral sequelae did not allow comprehensive statistical comparison between groups.