Small Fiber Neuropathy Patients Research Articles

Unclear etiology and current hypotheses of the pathogenesis of fibromyalgia

Introduction and purpose: Fibromyalgia is a chronic condition affecting almost 2% of the general population, mostly women. The main symptoms are chronic diffuse musculoskeletal pain or stiffness, tiredness, nonrestorative sleep, anxiety, depression and cognitive dysfunction. The etiology of fibromyalgia remains unclear and has been the subject of debate and scientific investigation. The aim of this article was to collect and analyse current and new information on the etiology of fibromyalgia and present the most popular hypotheses.Brief description of the state of knowledge: Pathogenesis of fibromyalgia is multifactorial. Genetic factors, in addition to environmental factors, such as psychical stress and various types of infection, are considered to be the triggers of the disease. Central sensitization became a commonly accepted hypothesis of the fibromyalgia’s pathogenesis. However, the newest finding of small fiber neuropathy in patients with fibromyalgia supports another hypothesis, in which the disease is presented as stress-related dysautonomia with neuropathic pain features.Conclusions: Understanding the pathogenesis of fibromyalgia is essential to provide the best care to the patients with fibromyalgia. Although there are multiple evidence for central sensitization hypothesis, new findings continue to emerge and question commonly accepted paradigm. Despite numerous findings on etiology of fibromyalgia, more studies are needed.

Associations of Small Fiber Neuropathy with Geriatric Nutritional Risk Index and Arterial Stiffness in Hemodialysis.

Background Peripheral neuropathy is a common neurological complication in uremic patients, and quantitative sensory testing (QST) is effective for diagnosis of small fiber neuropathy. Malnutrition and arterial stiffness are prevalent in patients undergoing hemodialysis (HD). The associations of small fiber neuropathy with nutritional status and arterial stiffness remain uncertain in maintenance HD patients. Methods A total of 152 HD patients were included. Geriatric nutritional risk index (GNRI), an indicator of nutritional status, was calculated by serum albumin and actual and ideal body weight. Arterial stiffness was defined as brachial-ankle pulse wave velocity (baPWV) > 1400 cm/s. Small fiber neuropathy was assessed by an abnormal QST threshold of cold and warm sensation in patients' hands or feet. Multivariate forward logistic regression analysis was performed to examine the associations among abnormal QST threshold, GNRI, and arterial stiffness. Results baPWV and prevalence of abnormal QST threshold were significantly higher in diabetic patients. Multivariate logistic analyses revealed that older age (OR, 1.081; 95% CI, 1.026–1.139, p = 0.003) and male gender (OR, 4.450; 95% CI, 1.250–15.836, p = 0.021) were associated with abnormal warm threshold of hands. Furthermore, diabetes (OR, 3.966; 95% CI, 1.351–11.819, p = 0.012) and lower GNRI (per 1 unit increase, OR, 0.935, 95% CI, 0.887–0.985, p = 0.012) were associated with abnormal cold threshold of feet. Arterial stiffness (OR, 5.479, 95% CI, 1.132–22.870, p = 0.020) and higher calcium-phosphorus product (OR, 1.071, 95% CI, 1.013–1.132, p = 0.015) were associated with abnormal warm threshold of feet. Conclusions Lower GNRI and arterial stiffness were significantly associated with small fiber neuropathy in patients undergoing HD. Malnutrition risk and vascular factors might play important roles in small fiber neuropathy among patients undergoing HD.

P52 No cure, no care? Hopes and needs in 100 idiopathic small fiber neuropathy patients

P52 No cure, no care? Hopes and needs in 100 idiopathic small fiber neuropathy patients

Prevalence of denervation in the intrinsic foot muscles in patients with distal predominantly small fiber neuropathy

We aimed to evaluate the significance of electromyographic findings in the intrinsic foot muscles (IFMs) of patients with skin biopsy proven small fiber neuropathy (SFN). This was a single-center retrospective analysis of patients who underwent skin biopsy for intra-epidermal nerve fiber density (IENFD) measurement and electrodiagnostic (EDX) study for evaluation of polyneuropathy. A total of 1416 patents with normal lower extremity EDX studies proximal to the foot were included. Active denervation was seen in 16.1% of IFMs in patients with skin biopsy proven SFN and 4.1% of patients without SFN (P < .0001). Reinnervation changes without active denervation were observed in 30.4% of SFN patients and 23.8% of patients without SFN (P = .01). IENFD was lower in SFN patients with active denervation in IFMs than without (P < .0001). Evaluation of active denervation in the IFMs can reveal large fiber dysfunction in SFN patients with otherwise normal routine EDX findings.

Reduced association between dendritic cells and corneal sub-basal nerve fibers in patients with fibromyalgia syndrome.

In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age-matched female controls. After screening for dry eye disease, corneal LC were counted and sub-classified as dendritic (dLC) and non-dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17%) and SFN (28%) patients than in controls (5%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling.

Patient-derived in vitro skin models for investigation of small fiber pathology.

ObjectiveTo establish individually expandable primary fibroblast and keratinocyte cultures from 3‐mm skin punch biopsies for patient‐derived in vitro skin models to investigate of small fiber pathology.MethodsWe obtained 6‐mm skin punch biopsies from the calf of two patients with small fiber neuropathy (SFN) and two healthy controls. One half (3 mm) was used for diagnostic intraepidermal nerve fiber density (IENFD). From the second half, we isolated and cultured fibroblasts and keratinocytes. Cells were used to generate patient‐derived full‐thickness three‐dimensional (3D) skin models containing a dermal and epidermal component. Cells and skin models were characterized morphologically, immunocyto‐ and ‐histochemically (vimentin, cytokeratin (CK)‐10, CK 14, ki67, collagen1, and procollagen), and by electrical impedance.ResultsDistal IENFD was reduced in the SFN patients (2 fibers/mm each), while IENFD was normal in the controls (8 fibers/mm, 7 fibers/mm). Two‐dimensional (2D) cultured skin cells showed normal morphology, adequate viability, and proliferation, and expressed cell‐specific markers without relevant difference between SFN patient and healthy control. Using 2D cultured fibroblasts and keratinocytes, we obtained subject‐derived 3D skin models. Morphology of the 3D model was analogous to the respective skin biopsy specimens. Both, the dermal and the epidermal layer carried cell‐specific markers and showed a homogenous expression of extracellular matrix proteins.InterpretationOur protocol allows the generation of disease‐specific 2D and 3D skin models, which can be used to investigate the cross‐talk between skin cells and sensory neurons in small fiber pathology.

Nonorgan manifestations of sarcoidosis.

The current review discusses the diagnosis and management of nonorgan-related symptoms that commonly arise in the setting of systemic sarcoidosis. Fatigue, small fiber neuropathy (SFN) and neuropsychological symptoms are highlighted. The debilitating effects of chronic nonorgan-based symptoms in sarcoidosis have led to recent studies focusing on incidence rates, contributing factors and potential therapeutic strategies. In a web-based survey of over 1000 sarcoidosis patients, the most common symptom was fatigue, which was reported by over 90% of participants, whereas memory loss and concentration problems were reported in 50%. SFN was also common, and may be diagnosed with tools such as skin biopsy measurement of intraepidermal nerve fibers and corneal confocal microscopy. In a recent cohort study of SFN patients, serologic evaluation demonstrated other contributing causes such as diabetes and vitamin B12 deficiency, which warrant-specific treatment. Finally, physical inactivity in patients with sarcoidosis correlated with lower quality-of-life (QOL) scores and possibly fatigue. Multidisciplinary programs that include physical therapy, patient education and psychological support were found to improve fatigue and mood disorders. Recognition of nonorgan-related symptoms and their impact on patient QOL is essential to optimal treatment of the sarcoidosis patient.

A zebrafish model to study small-fiber neuropathy reveals a potential role for GDAP1

Mutations in genes involved in mitochondrial dynamics (fusion and fission) have been implicated in many peripheral neuropathies. We hypothesized that defects in these genes could result in a phenotype resembling features of small-fiber neuropathy (SFN). This was investigated in zebrafish by knocking down two genes involved in mitochondrial dynamics gdap1 (possibly fission and motility) and opa1 (fusion) using established morpholinos. Our read-outs were nerve density in the caudal fin and a behavioral response to temperature changes, both based on comparable hallmarks of SFN in patients. Knockdown of gdap1 resulted in zebrafish embryos with a reduced density of sensory neurites compared to control morpholino-injected embryos. Furthermore, these embryos demonstrated a decreased temperature-related activity. In contrast, a knockdown of opa1 did not affect the density of sensory neurites nor the temperature-related activity. However, only the opa1 morphants had an effect on mitochondrial network morphology. As we were not able to visualize the mitochondria in the neurons, it could well be that changes in the mitochondrial network remained undetected. Our data indicate that GDAP1 knockdown affects sensory neurite development, however, it is unclear if a problem in mitochondrial fission and network formation is the pathophysiological mechanism. Although we did not observe an effect of inhibiting mitochondrial fusion during development, we still propose that genes involved in mitochondrial dynamics should be screened for mutations in patients with SFN.

Small-fiber neuropathy: Expanding the clinical pain universe.

Small-fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ and unmyelinated C fibers. SFN is clinically dominated by neuropathic pain and autonomic complaints, leading to a significant reduction in quality of life. According to international criteria, the diagnosis is established by the assessment of intraepidermal nerve fiber density and/or quantitative sensory testing. SFN is mainly associated with autoimmune diseases, sodium channel gene variants, diabetes mellitus, and vitamin B12 deficiencies, although in more than one half of patients no etiology can be identified. Recently, gain-of-function variants in the genes encoding for the Nav 1.7, Nav 1.8 and Nav 1.9 sodium channel subunits have been discovered in SFN patients, enlarging the spectrum of underlying conditions. Sodium channel gene variants associated with SFN can lead to a diversity of phenotypes, including different pain distributions and presence or absence of autonomic symptoms. This suggests that SFN is part of a clinical continuum. New assessments might contribute to a better understanding of the cellular and molecular substrates of SFN and might provide improved diagnostic methods and trial designs in the future. Identification of the underlying mechanisms may inform the development of drugs that more effectively address neuropathic pain and autonomic symptoms of SFN.

Expression of pathogenic SCN9A mutations in the zebrafish: A model to study small-fiber neuropathy

Small-fiber neuropathy (SFN) patients experience a spectrum of sensory abnormalities, including attenuated responses to non-noxious temperatures in combination with a decreased density of the small-nerve fibers. Gain-of-function mutations in the voltage-gated sodium channels SCN9A, SCN10A and SCN11A have been identified as an underlying genetic cause in a subpopulation of patients with SFN. Based on clinical-diagnostic tests for SFN, we have set up a panel of two read-outs reflecting SFN in zebrafish, being nerve density and behavioral responses. Nerve density was studied using a transgenic line in which the sensory neurons are GFP-labelled. For the behavioral experiments, a temperature-controlled water compartment was developed. This device allowed quantification of the behavioral response to temperature changes. By using these read-outs we demonstrated that zebrafish embryos transiently overexpressing the pathogenic human SCN9A p.(I228M) or p.(G856D) mutations both have a significantly decreased density of the small-nerve fibers. Additionally, larvae overexpressing the p.(I228M) mutation displayed a significant increase in activity induced by temperature change. As these features closely resemble the clinical hallmarks of SFN, our data suggest that transient overexpression of mutant human mRNA provides a model for SFN in zebrafish. This disease model may provide a basis for testing the pathogenicity of novel genetic variants identified in SFN patients. Furthermore, this model could be used for studying SFN pathophysiology in an in vivo model and for testing therapeutic interventions.

Characterization of Neuropathic Pain in Primary Sjögren's Syndrome with Respect to Neurophysiological Evidence of Small-Fiber Neuropathy.

To determine whether clinical features of neuropathic pain differ with respect to the presence of small-fiber neuropathy (SFN) in patients with primary Sjögren's syndrome (pSS). We compared the clinical presentation of neuropathic pain between 15 patients with pSS and SFN detected by neurophysiological tests (laser-evoked potentials, cold and warm detection thresholds, sympathetic skin responses, and electrochemical skin conductance) and 15 patients with pSS but no neurophysiological evidence of SFN. The patients with SFN had more intense squeezing and pressure sensations and more frequent dynamic mechanical allodynia (pain provoked by brushing) than the patients without SFN. Restless leg syndrome was also more frequently observed in patients with SFN, who had pain aggravated at rest that improved by moving. These findings are in favor of the sensitization of relatively spared large Aβ-fibers and second-order nociceptive neurons in patients with SFN. On the other hand, burning sensations, which rather reveal sensitization of small nociceptive fibers, were observed whether SFN was present or not. Thus, some discriminating clinical features may help to suggest the presence of SFN in patients with pSS and chronic neuropathic pain.

Fibromyalgia: is it a neuropathic pain?

Fibromyalgia is a chronic pain syndrome of unclear pathophysiology. It is believed to be a dysfunction of the CNS, but no definite structural lesion has been identified so far. Despite a number of changes in the diagnostic criteria, diagnosis remains a clinical one. Since the 2011 revision of the IASP definition of neuropathic pain, fibromyalgia has been excluded from the diagnosis of neuropathic pain. More recent studies however found newer evidences of pathophysiology including small fiber neuropathy in patients with fibromyalgia. This may challenge the existing consensus and have implications on future diagnosis and management of this condition.

0668 Small Fiber Neuropathy in Patients with Refractory RLS: A Case Series

0668 Small Fiber Neuropathy in Patients with Refractory RLS: A Case Series

Associated conditions in small fiber neuropathy - a large cohort study and review of the literature.

Background and purposeSmall fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals.MethodsA total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings.ResultsNo associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients.ConclusionsBased on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral.

55. Assessing the risk of restless legs syndrome in small fiber peripheral neuropathy

The pathophysiology of restless legs syndrome (RLS) isn’t completely understood. Small Fiber Neuropathy (SFN) patients may have RLS-like sensory symptoms. The aim of this study was to assess the prevalence and clinical features of RLS in patients with SFN, compared with Large Fibres Neuropathy (LFN) patients and healthy controls. All patients underwent nerve-conduction studies and electromyography, and a skin biopsy to confirm SFN. RLS was diagnosed according to international criteria. We compared: frequency of RLS, age of onset, severity as measured by IRLS, insomnia and diabetes comorbidity. We included 39 SFN patients, 37 LFN patients and 40 matched controls. Peripheral nerve-conduction velocities were normal in SFN patients and controls. SFN patients had a 25.60% prevalence of RLS, compared to 10.80% in LFN and 7.50% in controls. Age of onset was 42.91 years, versus 62.67 in LFN and 58.50 in controls. Mean IRLS was 15.6 versus 19.5 in LFN and 18.6 in controls. The occurrence of insomnia was similar between SFN and LFN (43.58% and 43.24%), but higher than in controls (20%). Biopsy-proven SFN patients had a higher risk for an early-onset RLS. They show a less severe RLS, but it can frequently cause insomnia.

The histopathological evaluation of small fiber neuropathy in patients with vitamin B12 deficiency.

Small fiber neuropathy (SFN), due to loss of A-delta and unmyelinated C fibers, is a cause of neuropathic pain. Although the patients with vitamin B12 deficiency are included in SFN studies in the literature, there is no histopathological study investigating the small fiber loss solely in patients with vitamin B12 deficiency. In this pilot study, we aim to demonstrate the intraepidermal nerve fiber density (IENFD) in skin punch biopsy of patients with vitamin B12 deficiency. Ten patients with vitamin B12 deficiency suffering from neuropathic pain and as control group ten patients with vitamin B12 deficiency without neuropathic pain were included. Neurological examination, electrophysiological evaluation, and DN4 questionnaire were performed. Subsequently, skin punch biopsy 10cm above the lateral malleolus was done. The biopsy samples were stained with PGP9.5 antibody, and IENFD was determined. IENFD was low in two groups compared to their age normative values. The median of IENFD was 3.345 (1.12-5.32) in patients with neuropathic pain and 6. 20 (4.6-9.8) in controls (p<0.001). Our pilot study showed that vitamin B12 deficiency causes symptomatic as well as asymptomatic small fiber loss like diabetes mellitus.

Presence of Decreased Intraepidermal Nerve Fiber Density Consistent with Small Fiber Neuropathy in Patients with Central Post-Stroke Pain

Dear Editor, In the United States, approximately 800,000 strokes occur annually, with 11%-55% of stroke survivors experiencing post-stroke pain [1–5]. Central post-stroke pain (CPSP) is recognized as a neuropathic condition often defined as being of thalamic origin, although extra-thalamic stroke can also result in CPSP [3,5–7]. The reported prevalence of CPSP is between 1% and 12% following all stroke, and up to 18% when sensory deficits are present [3,6,7]. Although the pathophysiology of CPSP remains incompletely understood, as the name implies, CPSP is most often associated with “central,” not peripheral nervous system abnormalities. Here we report four consecutive patients without prior evidence of a peripheral neuropathy, who developed CPSP following a stroke and in who further evaluation led to the documentation of skin biopsy findings consistent with small fiber neuropathy (SFN). Decreased peripheral intraepidermal nerve fiber density (IENF) is observed in many painful conditions associated with SFN including complex regional pain syndrome, diabetic neuropathy, chemotherapy-induced neuropathy, and hypothyroidism [8–15]. Similar skin biopsy findings have been recently reported in some, but not all, fibromyalgia patients leading some clinicians to consider the diagnosis of SFN in certain fibromyalgia patients. Although the precise role that the loss of small caliber (presumptive nociceptor) IENF plays in clinical pain symptoms is still unclear, their normal physiologic role in acute pain mechanisms is well-defined. Since the anatomy of the nociceptive/pain pathways (matrix) approximates a closed-loop system, coupled with the recognition that …

No Fabry Disease in Patients Presenting with Isolated Small Fiber Neuropathy.

ObjectiveScreening for Fabry disease in patients with small fiber neuropathy has been suggested, especially since Fabry disease is potentially treatable. However, the diagnostic yield of testing for Fabry disease in isolated small fiber neuropathy patients has never been systematically investigated. Our aim is to determine the presence of Fabry disease in patients with small fiber neuropathy.MethodsPatients referred to our institute, who met the criteria for isolated small fiber neuropathy were tested for Fabry disease by measurement of alpha-Galactosidase A activity in blood, lysosomal globotriaosylsphingosine in urine and analysis on possible GLA gene mutations.Results725 patients diagnosed with small fiber neuropathy were screened for Fabry disease. No skin abnormalities were seen except for redness of the hands or feet in 30.9% of the patients. Alfa-Galactosidase A activity was tested in all 725 patients and showed diminished activity in eight patients. Lysosomal globotriaosylsphingosine was examined in 509 patients and was normal in all tested individuals. Screening of GLA for mutations was performed for 440 patients, including those with diminished α-Galactosidase A activity. Thirteen patients showed a GLA gene variant. One likely pathogenic variant was found in a female patient. The diagnosis Fabry disease could not be confirmed over time in this patient. Eventually none of the patients were diagnosed with Fabry disease.ConclusionsIn patients with isolated small fiber neuropathy, and no other signs compatible with Fabry disease, the diagnostic yield of testing for Fabry disease is extremely low. Testing for Fabry disease should be considered only in cases with additional characteristics, such as childhood onset, cardiovascular disease, renal failure, or typical skin lesions.

Quick, non-invasive and quantitative assessment of small fiber neuropathy in patients receiving chemotherapy.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect; however, it is poorly investigated at an early stage due to the lack of a simple assessment tool. As sweat glands are innervated by small autonomic C-fibers, sudomotor function testing has been suggested for early screening of peripheral neuropathy. This study aimed to evaluate Sudoscan, a non-invasive and quantitative method to assess sudomotor function, in the detection and follow-up of CIPN. Eighty-eight patients receiving at least two infusions of Oxaliplatin only (45.4%), Paclitaxel only (14.8%), another drug only (28.4%) or two drugs (11.4%) were enrolled in the study. At each chemotherapy infusion the accumulated dose of chemotherapy was calculated and the Total Neuropathy Score clinical version (TNSc) was carried out. Small fiber neuropathy was assessed using Sudoscan (a 3-min test). The device measures the Electrochemical Skin Conductance (ESC) of the hands and feet expressed in microSiemens (µS). For patients receiving Oxaliplatin mean hands ESC changed from 73 ± 2 to 63 ± 2 and feet ESC from 77 ± 2 to 66 ± 3 µS (p < 0.001) while TNSc changed from 2.9 ± 0.5 to 4.3 ± 0.4. Similar results were observed in patients receiving Paclitaxel or another neurotoxic chemotherapy. During the follow-up, ESC values of both hands and feet with a corresponding TNSc < 2 were 70 ± 2 and 73 ± 2 µS respectively while they were 59 ± 1.4 and 64 ± 1.5 µS with a corresponding TNSc ≥ 6 (p < 0.0001 and p = 0.0003 respectively). This preliminary study suggests that small fiber neuropathy could be screened and followed using Sudoscan in patients receiving chemotherapy.

Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy.

There are multiple neurological complications of cancer and its treatment. This study assessed the utility of the novel non-invasive ophthalmic technique of corneal confocal microscopy in identifying neuropathy in patients with upper gastrointestinal cancer before and after platinum based chemotherapy. In this study, 21 subjects with upper gastrointestinal (oesophageal or gastric) cancer and 21 healthy control subjects underwent assessment of neuropathy using the neuropathy disability score, quantitative sensory testing for vibration perception threshold, warm and cold sensation thresholds, cold and heat induced pain thresholds, nerve conduction studies and corneal confocal microscopy. Patients with gastro-oesophageal cancer had higher heat induced pain (P = 0.04) and warm sensation (P = 0.03) thresholds with a significantly reduced sural sensory (P<0.01) and peroneal motor (P<0.01) nerve conduction velocity, corneal nerve fibre density (CNFD), nerve branch density (CNBD) and nerve fibre length (CNFL) (P<0.0001). Furthermore, CNFD correlated significantly with the time from presentation with symptoms to commencing chemotherapy (r = -0.54, P = 0.02), and CNFL (r = -0.8, P<0.0001) and CNBD (r = 0.63, P = 0.003) were related to the severity of lymph node involvement. After the 3rd cycle of chemotherapy, there was no change in any measure of neuropathy, except for a significant increase in CNFL (P = 0.003). Corneal confocal microscopy detects a small fibre neuropathy in this cohort of patients with upper gastrointestinal cancer, which was related to disease severity. Furthermore, the increase in CNFL after the chemotherapy may indicate nerve regeneration.