Sacral Tarlov perineurial cysts: a systematic review of treatment options.

Tarlov perineurial spinal cysts (TCs) are an underrecognized cause of spinal neuropathic symptoms. TCs form within the sensory nerve root sleeves, where CSF extends distally and can accumulate pathologically. Typically, they develop at the sacral dermatomes where the nerve roots are under the highest hydrostatic pressure and lack enclosing vertebral foramina. In total, 90% of patients are women, and genetic disorders that weaken connective tissues, e.g., Ehlers-Danlos syndrome, convey considerable risk. Most small TCs are asymptomatic and do not require treatment, but even incidental visualizations should be documented in case symptoms develop later. Symptomatic TCs most commonly cause sacropelvic dermatomal neuropathic pain, as well as bladder, bowel, and sexual dysfunction. Large cysts routinely cause muscle atrophy and weakness by compressing the ventral motor roots, and multiple cysts or multiroot compression by one large cyst can cause even greater cauda equina syndromes. Rarely, giant cysts erode the sacrum or extend as intrapelvic masses. Disabling TCs require consideration for surgical intervention. The authors' systematic review of treatment analyzed 31 case series of interventional percutaneous procedures and open surgical procedures. The surgical series were smaller and reported somewhat better outcomes with longer term follow-up but slightly higher risks. When data were lacking, authorial expertise and case reports informed details of the specific interventional and surgical techniques, as well as medical, physical, and psychological management. Cyst-wrapping surgery appeared to offer the best long-term outcomes by permanently reducing cyst size and reconstructing the nerve root sleeves. This curtails ongoing injury to the axons and neuronal death, and may also promote axonal regeneration to improve somatic and autonomic sacral nerve function.

Initial validation of the Mass. General Neuropathy Exam Tool (MAGNET) for evaluation of distal small-fiber neuropathy.

INTRODUCTION/AIMS: Diagnosis of small-fiber neuropathy (SFN) is hampered by its subjective symptoms and signs. Confirmatory testing is insufficiently available and expensive, so predictive examinations have value. However, few support the 2020 SFN consensus-case-definition requirements or were validated for non-diabetes neuropathies. Thus we developed the Massachusetts General Hospital Neuropathy Exam Tool (MAGNET) and measured diagnostic performance in 160 symptomatic patients evaluated for length-dependent SFN from any cause and 37 healthy volunteers. METHODS: We compared prevalences of abnormalities (vital signs, pupil responses, lower-limb appearance, pin, light touch, vibration and position sensitivity, great-toe strength, muscle stretch reflexes), and validated diagnostic performance against objective SFN tests: lower-leg skin-biopsy epidermal neurite densities and autonomic function testing (AFT). Sensitivity/specificity, feasibility, test-retest and inter-rater reliability, and convergence with the Utah Early Neuropathy Scale were calculated. RESULTS: Patients' ages averaged 48.5 ± 14.7 years and 70.6% were female. Causes of neuropathy varied, remaining unknown in 59.5%. Among the 46 with abnormal skin biopsies, the most prevalent abnormality was reduced pin sharpness at the toes (71.7%). Inter-rater reliability, test-retest reliability, and convergent validity excelled (range = 91.3-95.6%). Receiver operating characteristics comparing all symptomatic patients versus healthy controls indicated that a MAGNET threshold score of 14 maximized predictive accuracy for skin biopsies (0.74) and a 30 cut-off maximized accuracy for predicting AFT (0.60). Analyzing patients with any abnormal neuropathy-test results identified areas-under-the-curves of 0.87-0.89 for predicting a diagnostic result, accuracy = 0.80-0.89, and Youden's index = 0.62. Overall, MAGNET was 80%-85% accurate for stratifying patients with abnormal versus normal neuropathy test results. DISCUSSION: MAGNET quickly generates research-quality metrics during clinical examinations.

Characterization of mononeuropathy of the lateral cutaneous nerve of the calf.

INTRODUCTION/AIMS: Isolated injuries to the lateral cutaneous nerve of the calf (LCNC) branch of the common peroneal nerve can cause obscure chronic posterolateral knee and upper calf pain and sensory symptoms. Routine examination and electrodiagnostic testing do not detect them because the LCNC has no motor distribution and it is not interrogated by the typical peroneal nerve conduction study. There are only about 10 prior cases, thus scant physician awareness, so most LCNC injuries remain misdiagnosed or undiagnosed, hindering care. METHODS: We extracted pertinent records from seven patients with unexplained posterolateral knee/calf pain, six labeled as complex regional pain syndrome, to investigate for mononeuropathies. Patients were asked to outline their skin area with abnormal responses to pin self-examination independently. Three underwent an LCNC-specific electrodiagnostic study, and two had skin-biopsy epidermal innervation measured. Cadaver dissection of the posterior knee nerves helped identify potential entrapment sites. RESULTS: Initiating events included knee surgery (three), bracing (one), extensive kneeling (one), and other knee trauma. All pin-outlines included the published LCNC neurotome. One oftwo LCNC-specific electrodiagnostic studies revealed unilaterally absent potentials. Longitudinal, controlled skin biopsies documented profound LCNC-neurotome denervation then re-innervation contemporaneous with symptom recovery. Cadaver dissection identified the LCNC traversing through the dense fascia of the proximolateral gastrocnemius muscle insertion. DISCUSSION: Isolated LCNC mononeuropathy can cause unexplained posterolateral knee/calf pain syndromes. This series characterizes presentations and supports patient pin-mappings as a sensitive, globally available, low-cost diagnostic aid. Improved recognition may facilitate more rapid, accurate diagnosis and, thus, optimize management and improve outcomes.

Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations.

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in approximately 50% of POTS and fibromyalgia patients. RESEARCH QUESTION: Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN? STUDY DESIGN AND METHODS: We analyzed 1,516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mm Hg, results from 160 patients meeting ME/CFS criteria who had skin biopsy test results were compared with 36 control subjects. Rest-to-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO2 tertiles. RESULTS: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 ± 2 vs 8.3 ± 1.5; P < .0001) and peak VO2 (80% ± 21% vs 101.4% ± 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% ± 19% vs 99.5% ± 23.8% vs 99.9% ± 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low- and normal-flow participants (0.74% ± 0.1% vs 0.88 ± 0.11 vs 0.86 ± 0.1; P < .0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% were consistent with SFN (epidermal innervation ≤5.0% of predicted; P < .0001). Denervation severity did not correlate with exertional measures. INTERPRETATION: These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance-depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.

Epidermal Neurite Density in Skin Biopsies From Patients With Juvenile Fibromyalgia.

OBJECTIVE: Fibromyalgia (FM) is defined by idiopathic, chronic, widespread musculoskeletal pain. In adults with FM, a metaanalysis of lower-leg skin biopsy demonstrated 45% pooled prevalence of abnormally low epidermal neurite density (END). END < 5th centile of the normal distribution is the consensus diagnostic threshold for small-fiber neuropathy. However, the clinical significance of END findings in FM is unknown. Here, we examine the prevalence of small-fiber pathology in juvenile FM, which has not been studied previously. METHODS: We screened 21 patients aged 13-20 years with FM diagnosed by pediatric rheumatologists. Fifteen meeting the American College of Rheumatology criteria (modified for juvenile FM) underwent lower-leg measurements of END and completed validated questionnaires assessing pain, functional disability, and dysautonomia symptoms. The primary outcome was proportion of FM patients with END < 5th centile of age/sex/race-based laboratory norms. Cases were systematically matched by ethnicity, race, sex, and age to a group of previously biopsied healthy adolescents with selection blinded to biopsy results. All 23 controls matching demographic criteria were included. RESULTS: Among biopsied juvenile FM patients, 53% (8/15) had END < 5th centile vs 4% (1/23) of healthy controls (P < 0.001). Mean patient END was 273/mm2 skin surface (95% CI 198-389) vs 413/mm2 (95% CI 359-467, P < 0.001). As expected, patients with FM reported more functional disability, dysautonomia, and pain than healthy controls. CONCLUSION: Abnormal END reduction is common in adolescents with FM, with similar prevalence in adults with FM. More studies are needed to fully characterize the significance of low END in FM and to elucidate the clinical implications of these findings.

Acute monophasic erythromelalgia pain in five children diagnosed as small-fiber neuropathy.

The small-fiber polyneuropathies (SFN) are a class of diseases in which the small thin myelinated (Aδ) and/or unmyelinated (C) fibers within peripheral nerves malfunction and can degenerate. SFN usually begins in the farthest, most-vulnerable axons, so distal neuropathic pain and symptoms from microvascular dysregulation are common. It is well known in adults, e.g. from diabetes, human immunodeficiency virus, or neurotoxins, but considered extremely rare in children, linked mostly with pathogenic genetic variants in voltage-gated sodium channels. However, increasing evidence suggests that pediatric SFN is not rare, and that dysimmunity is the most common cause. Because most pediatric neurologists are unfamiliar with SFN, we report the diagnosis and management of 5 Swiss children, aged 6-11y, who presented with severe paroxysmal burning pain in the hands and feet temporarily relieved by cooling-the erythromelalgia presentation. Medical evaluations revealed autoimmune diseases in 3 families and 3/5 had preceding or concomitant infections. The standard diagnostic test (PGP9.5-immunolabeled lower-leg skin biopsy) confirmed SFN diagnoses in 3/4, and autonomic function testing (AFT) was abnormal in 2/3. Blood testing for etiology was unrevealing, including genetic testing in 3. Paracetamol and ibuprofen were ineffective. Two children responded to gabapentin plus mexiletine, one to carbamazepine, two to mexiletine plus immunotherapy (methylprednisolone/IVIg). All recovered within 6 months, remaining well for years. These monophasic tempos and therapeutic responses are most consistent with acute post-infectious immune-mediated causality akin to Guillain-Barré large-fiber polyneuropathy. Skin biopsy and AFT for SFN, neuropathic-pain medications and immunotherapy should be considered for acute sporadic pediatric erythromelalgia.

Association of small-fiber polyneuropathy with three previously unassociated rare missense SCN9A variants.

BACKGROUND: Small fiber polyneuropathy (SFN) involves ectopic firing and degeneration of small-diameter, somatic/autonomic peripheral axons. Causes include diabetes, inflammation and rare pathogenic mutations, including in SCN9-11 genes that encode small fiber sodium channels. AIMS: The aim of this study is to associate a new phenotype-immunotherapy-responsive SFN-with rare amino acid-substituting SCN9A variants and present potential explanations. METHODS: A retrospective chart review of two Caucasians with skin biopsy confirmed SFN and rare SCN9A single nucleotide polymorphisms not previously reported in neuropathy. RESULTS: A 47-year-old with 4 years of disabling widespread neuropathic pain and exertional intolerance had nerve- and skin biopsy-confirmed SFN, with blood tests revealing only high-titer antinuclear antibodies and low complement C4 consistent with B cell dysimmunity. Six years of intravenous immunoglobulin (IVIg) therapy markedly improved sensory and autonomic symptoms and normalized his neurite density. After whole exome sequencing revealed a potentially pathogenic SCN9A-A3734G variant, sodium channel blockers were tried. Herpes zoster left a 32-year-old with disabling exertional intolerance ("chronic fatigue syndrome"), postural syncope and tachycardia, arm and leg paresthesias, reduced sweating, and distal hairloss. Screening revealed antinuclear and potassium channel autoantibodies, so prednisone and then IVIg were prescribed with great benefit. During 4 years of immunotherapy, his symptoms and function improved, and all abnormal biomarkers (autonomic testing and skin biopsies) normalized. Whole exome sequencing then revealed two nearby compound heterozygous SCN9A variants that were computer-predicted to be deleterious. CONCLUSIONS: These cases newly associate three novel amino acid-substituting SCN9A variants with immunotherapy-responsive neuropathy. Only larger studies can determine whether these are contributory or coincidental, but they associate new variants with moderate or high likelihood of pathogenicity with a new highly related phenotype.

CONTEXTE: La polyneuropathie des petites fibres implique le déclenchement d'activité ectopique et la dégénérescence des axones périphériques somatiques et autonomes de petit diamètre. Ses causes comprennent le diabète, l'inflammation et de rares mutations pathogènes, notamment dans les gènes SCN9­11 qui codent les canaux sodiques des petites fibres. OBJECTIFS: Associer un nouveau phénotype de polyneuropathie des petites fibres répondant à l'immunothérapie à des variantes rares de SCN9A substituant des acides aminés et présenter des explications possibles. MÉTHODES: Examen rétrospectif des dossiers de deux personnes de race blanche ayant subi une biopsie cutanée et présentant des polymorphismes mononucléotidiques de SCN9A rares qui n'avaient pas été signalés auparavant dans le cadre d'une neuropathie. RÉSULTATS: Une homme de 47 ans souffrant depuis quatre ans de douleurs neuropathiques généralisées invalidantes et d'intolérance à l'effort a subi une biopsie des nerfs et de la peau qui a confirmé la polyneuropathie des petits fibres, les analyses sanguines ne révélant que des anticorps antinucléaires de haut niveau et un faible complément C4 correspondant à la dysimmunité des lymphocytes B. Six ans de traitement par immunoglobulines intraveineuses ont permis d'améliorer sensiblement les symptômes sensoriels et autonomes et de normaliser la densité de ses neurites. Après que le séquençage de l'exome entier ait révélé une variante de SCN9A-A3734G potentiellement pathogène, des inhibiteurs des canaux sodiques ont été essayee. Le zona a entrainé chez un homme de 32 ans une intolérance à l'effort invalidante (« syndrome de fatigue chronique ¼), une syncope posturale et une tachycardie, une paresthésie des bras et des jambes, une réduction de la transpiration et une perte de cheveux aux jambes. Le dépistage a révélé la présence d'auto-anticorps antinucléaires et de canaux potassiques, de sorte que la prednisone puis des immunoglobulines intraveineuses ont été prescrites, avec d'excellents résultats. Pendant quatre ans d'immunothérapie, ses symptômes et son fonctionnement se sont améliorés et tous les biomarqueurs anormaux (tests autonomes et biopsies cutanées) se sont normalisés. Le séquençage de l'exome entier a ensuite révélé deux variantes hétérozygotes de SCN9A composées à proximité et prédites par ordinateur comme étant délétères. CONCLUSIONS: Ces cas associent trois nouvelles variantes de SCN9A substituant des acides aminés à une neuropathie répondant à l'immunothérapie. Seules des études de plus grande envergure peuvent déterminer s'il s'agit de facteurs contributifs ou de coïncidences, mais ces cas associent de nouvelles variantes ayant une probabilité modérée ou élevée de pathogénicité à un nouveau phénotype étroitement apparenté.

Persistent genital arousal disorder: a special sense neuropathy.

INTRODUCTION: Persistent genital arousal (PGAD) is a syndrome of unprovoked sexual arousal/orgasm of uncertain cause primarily reported in female patients. Most patients are referred for mental-health treatment, but as research suggests associations with neurological symptoms and conditions, there is need to analyze cases comprehensively evaluated by neurologists. METHODS: The IRB waived consent requirements for this retrospective university-hospital study. We extracted and analyzed neurological symptoms, test, and treatment results from all qualifying participants' records and recontacted some for details. RESULTS: All 10 participants were female; their PGAD symptoms began between ages 11 to 70 years. Two patterns emerged: 80% reported daily out-of-context sexual arousal episodes (≤30/day) that usually included orgasm and 40% reported lesser, often longer-lasting, nonorgasmic arousals. Most also had symptoms consistent with sacral neuropathy-70% had urologic complaints and 60% had neuropathic perineal or buttock pain. In 90% of patients, diagnostic testing identified anatomically appropriate and plausibly causal neurological lesions. Sacral dorsal-root Tarlov cysts were most common (in 4), then sensory polyneuropathy (2). One had spina bifida occulta and another drug-withdrawal effect as apparently causal; lumbosacral disc herniation was suspected in another. Neurological treatments cured or significantly improved PGAD symptoms in 4/5 patients, including 2 cures. CONCLUSIONS: Although limited by small size and referral bias to neurologists, this series strengthens associations with Tarlov cysts and sensory polyneuropathy and suggests new ones. We hypothesize that many cases of PGAD are caused by unprovoked firing of C-fibers in the regional special sensory neurons that subserve sexual arousal. Some PGAD symptoms may share pathophysiologic mechanisms with neuropathic pain and itch.

Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy: A Review.

IMPORTANCE: Small-fiber polyneuropathy involves preferential damage to the thinly myelinated A-delta fibers, unmyelinated C sensory fibers, or autonomic or trophic fibers. Although this condition is common, most patients still remain undiagnosed and untreated because of lagging medical and public awareness of research advances. Chronic bilateral neuropathic pain, fatigue, and nausea are cardinal symptoms that can cause disability and dependence, including pain medication dependence. OBSERVATIONS: Biomarker confirmation is recommended, given the nonspecificity of symptoms. The standard test involves measuring epidermal neurite density within a 3-mm protein gene product 9.5 (PGP9.5)-immunolabeled lower-leg skin biopsy. Biopsies and autonomic function testing confirm that small-fiber neuropathy not uncommonly affects otherwise healthy children and young adults, in whom it is often associated with inflammation or dysimmunity. A recent meta-analysis concluded that small-fiber neuropathy underlies 49% of illnesses labeled as fibromyalgia. Initially, patients with idiopathic small-fiber disorders should be screened by medical history and blood tests for potentially treatable causes, which are identifiable in one-third to one-half of patients. Then, secondary genetic testing is particularly important for familial and childhood cases. Treatable genetic causes include Fabry disease, transthyretin and primary systemic amyloidosis, hereditary sensory autonomic neuropathy-1, and ion-channel mutations. Immunohistopathologic evidence suggests that small-fiber dysfunction and denervation, especially of blood vessels, contributes to diverse symptoms, including postexertional malaise, postural orthostatic tachycardia, and functional gastrointestinal distress. Preliminary evidence implicates acute or chronic autoreactivity in some cases, particularly in female patients and otherwise healthy children and young adults. Different temporal patterns akin to Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy have been described; here, corticosteroids and immunoglobulins, which are often efficacious for inflammatory neuropathic conditions, are increasingly considered. CONCLUSIONS AND RELEVANCE: Because small fibers normally grow throughout life, improving contributory conditions may permit regrowth, slow progression, and prevent permanent damage. The prognosis is often hopeful for improving quality of life and sometimes for abatement or resolution, particularly in the young and otherwise healthy individuals. Examples include diabetic, infectious, toxic, genetic, and inflammatory causes. The current standard of care requires prompt diagnosis and treatment, particularly in children and young adults, to restore life trajectory. Consensus diagnostic and tracking metrics should be established to facilitate treatment trials.

Ion channels and neuropathic pain.

Pain behaviors in a Fabry mouse model are associated with the accumulation of a fat molecule that disrupts sodium ion channels in small fiber neurons.

Specific symptoms may discriminate between fibromyalgia patients with vs without objective test evidence of small-fiber polyneuropathy.

INTRODUCTION: Multiple studies now confirm that ∼40% of patients with fibromyalgia syndrome meet diagnostic criteria for small-fiber polyneuropathy (SFPN) and have objective pathologic or physiologic evidence of SFPN, whereas 60% do not. Given possibilities that tens or hundreds of millions globally could have SFPN, developing screening tools becomes important. OBJECTIVES: This analysis explored whether specific symptoms might help distinguish these fibromyalgia endophenotypes. METHODS: With institutional review board approval, all adults tested for SFPN by distal-leg skin biopsy or autonomic function testing at Massachusetts General Hospital in 2014 to 2015 were queried about symptoms. Inclusion required a physician's fibromyalgia syndrome diagnosis plus meeting the American College of Rheumatology 2010 Fibromyalgia Criteria. The primary outcome was the validated Small-fiber Symptom Survey, which captures severity of all known SFPN-associated symptoms. The Composite Autonomic Symptom Score-31, Short-Form Health Survey-36, and Short-Form McGill Pain Questionnaires provided secondary outcomes. RESULTS: Among the 39 participants, 14 had test-confirmed SFPN (SFPN+) and 25 did not (SFPN-). Their pain severity did not differ. Paresthesias ("tingling") were different (worse) in the SFPN+ group (3.14 ± 0.9 vs 2.28 ± 1.1; P = 0.16). Their component subscore for dysautonomia symptoms was also worse (10.42 ± 4.0 vs 7.16 ± 4.0; P = 0.019). Receiver operating characteristic analyses revealed that each item had fair diagnostic utility in predicting SFPN, with areas under the curve of 0.729. No secondary questionnaires discriminated significantly. CONCLUSION: Among patients with fibromyalgia, most symptoms overlap between those with or without confirmed SFPN. Symptoms of dysautonomia and paresthesias may help predict underlying SFPN. The reason to screen for SFPN is because-unlike fibromyalgia-its medical causes can sometimes be identified and definitively treated or cured.

Initial Development and Validation of a Patient-Reported Symptom Survey for Small-Fiber Polyneuropathy.

Small-fiber polyneuropathy (SFPN) affects unmyelinated and thinly myelinated peripheral axons. Several questionnaires have been developed to assess polyneuropathy from diabetes or chemotherapy, but none for SFPN from other or unknown causes. A comprehensive survey could help clinicians diagnose and assess treatment responses, define prevalence natural history and cures, and identify research subjects. Thus, we developed the 1-page Small-Fiber Symptom Survey, using input from patients and 21 medical/scientific experts. Participants comprised consenting consecutive patients evaluated for SFPN at the Massachusetts General Hospital plus normal control subjects. Participants SFPN status was stratified on the basis of the results of their objective diagnostic tests (distal leg skin biopsy and autonomic function testing). We measured internal consistency, test retest reliability, convergent validity, and performed a receiver operating curve analysis. The 179 participants averaged 46.6 ± 15.6 years old; they were 73.2% female and 92.2% Caucasian. Eighty-five had confirmed SFPN, mostly idiopathic. Principal component analysis revealed 5 symptom clusters. The questionnaire had good internal consistency (Cronbach α = .893), excellent test retest reliability (r = .927, P < .001) and good to fair convergent validity. Participants with confirmed SFPN had more severe symptoms than others (P = .009). The Small-Fiber Symptom Survey has satisfactory psychometric properties, indicating potential future utility for surveying patient-reported symptoms of SFPN regardless of its cause. PERSPECTIVE: This article reports the initial development and early psychometric validation of a new patient-reported outcome measure intended to capture the wide range of multisystem symptoms of SFPN. When further developed, it could potentially help clinicians diagnose and monitor patients, and help advance research.

Diagnostic value of blood tests for occult causes of initially idiopathic small-fiber polyneuropathy.

Small-fiber polyneuropathy (SFPN) causes non-specific symptoms including chronic pain, cardiovascular, gastrointestinal, and sweating complaints. Diagnosis is made from history and exam in patients with known risk factors such as diabetes, but objective test confirmation is recommended for patients without known risks. If tests confirm SFPN, and it is "initially idiopathic" (iiSFPN), screening for occult causes is indicated. This study's aim was to evaluate the 21 widely available, recommended blood tests to identify the most cost-effective ones and to learn about occult causes of iiSFPN. Records were reviewed from all 213 patients with SFPN confirmed by distal-leg skin biopsy, nerve biopsy, or autonomic-function testing in our academic center during 2013. We determined the prevalence of each abnormal blood-test result (ABTR) in the iiSFPN cohort, compared this to population averages, and measured the costs of screening subjects to obtain one ABTR. Participants were 70 % female and aged 43.0 ± 18.6 years. High erythrocyte sedimentation rate (ESR) and antinuclear antibody (ANA; ≥1:160 titer) were most common, each present in 28 % of subjects. The ABTR ≥3 × more prevalent in iiSFPN than in the total population were high ESR, high ANA, low C3, and Sjögren's and celiac autoantibodies. Together, these suggest the possibility of a specific association between iiSFPN and dysimmunity. ABTR identifying diabetes, prediabetes, and hypertriglyceridemia were less common in iiSFPN than in the population and thus were not associated with iiSFPN here. The six most cost-effective iiSFPN-associated blood tests-ESR, ANA, C3, autoantibodies for Sjögren's and celiac, plus thyroid-stimulating hormone-had estimated cost of $99.57/person and 45.6 % probability of obtaining one abnormal result. Angiotensin-converting enzyme was elevated in 45 %, but no patients had sarcoidosis, so this test was futile here.

The complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is the current consensus-derived name for a syndrome usually triggered by limb trauma. Required elements include prolonged, disproportionate distal-limb pain and microvascular dysregulation (e.g., edema or color changes) or altered sweating. CRPS-II (formerly "causalgia") describes patients with identified nerve injuries. CRPS-I (formerly "reflex sympathetic dystrophy") describes most patients who lack evidence of specific nerve injuries. Diagnosis is clinical and the pathophysiology involves combinations of small-fiber axonopathy, microvasculopathy, inflammation, and brain plasticity/sensitization. Females have much higher risk and workplace accidents are a well-recognized cause. Inflammation and dysimmunity, perhaps facilitated by injury to the blood-nerve barrier, may contribute. Most patients, particularly the young, recover gradually, but treatment can speed healing. Evidence of efficacy is strongest for rehabilitation therapies (e.g., graded-motor imagery), neuropathic pain medications, and electric stimulation of the spinal cord, injured nerve, or motor cortex. Investigational treatments include ketamine, botulinum toxin, immunoglobulins, and transcranial neuromodulation. Nonrecovering patients should be re-evaluated for neurosurgically treatable causal lesions (nerve entrapment, impingement, infections, or tumors) and treatable potentiating medical conditions, including polyneuropathy and circulatory insufficiency. Earlier impressions that CRPS represents malingering or psychosomatic illness have been replaced by evidence that CRPS is a rare complication of limb injury in biologically susceptible individuals.

Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations.

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

A Man with Paraneoplastic Retinopathy plus Small Fiber Polyneuropathy Associated with Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma): Insights into Mechanisms.

PURPOSE: To report a well-characterized Waldenström's macroglobulinemia (WM) case that provides insight into the mechanisms of two paraneoplastic complications -- cancer-associated retinopathy (CAR) and small fiber polyneuropathy (SFPN). METHODS: Retrospective medical chart review. RESULTS: A 58-year old man with WM developed vision loss and bilateral lower extremity pain. CAR was diagnosed by history, a depressed electroretinogram (ERG) and positive anti-retinal antibodies. SFPN diagnosis was based on abnormal autonomic nerve function testing and a distal-leg skin biopsy that demonstrated absent epidermal small-fiber innervation, IgM and complement deposition and microvasculopathy. Plasma exchange (PLEX) led to dramatic pain relief and subjective improvement in eye symptoms along with improvement of some ERG parameters. Repeat skin biopsy after treatment showed less microvascular abnormalities and decreased complement deposition. CONCLUSIONS: The concurrence of CAR and SFPN in this patient suggest that both were complications of WM and their common response to PLEX suggests co-mediation by humoral factors that accessed target antigens through IgM-triggered, complement-mediated vascular damage.