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Background: Spreading depolarization describes a near-complete electrical discharge with altered local cerebral blood flow. It is described in association with acute and chronic diseases like hemorrhagic stroke or migraine. Moyamoya vasculopathy is a chronic, progressive cerebrovascular disorder leading to cerebral hypoperfusion, hemodynamically insufficient basal collateralization, and increased cortical microvascularization., Methods: In a prospective case series, we monitored for spontaneous spreading depolarization activity by using intraoperative laser speckle imaging for real-time visualization and measurement of cortical perfusion and cerebrovascular reserve capacity during cerebral revascularization in 4 consecutive patients with moyamoya., Results: Spontaneous spreading depolarization occurrence was documented in a patient with moyamoya before bypass grafting. Interestingly, this patient also exhibited a marked preoperative increase in angiographic collateral vessel formation., Conclusions: The spontaneous occurrence of SDs in moyamoya vasculopathy could potentially provide an explanation for localized cortical infarction and increased cortical microvascular density in these patients., Competing Interests: Disclosures Dr Mathys is a paid consultant for Siemens AG. Dr Witt received compensation from Stada, Fundação Bial, Deutsche Forschungsgemeinschaft, and Boston Scientific Corporation for other services not related to the current study. The other authors report no conflicts.

Objective: Characterize the neurophysiological effects of mild hypothermia on stroke and spreading depolarizations (SDs) in gyrencephalic brains., Methods: Left middle cerebral arteries (MCAs) of six hypothermic and six normothermic pigs were permanently occluded (MCAo). Hypothermia began 1 h after MCAo and continued throughout the experiment. ECoG signals from both frontoparietal cortices were recorded. Five-minute ECoG epochs were collected 5 min before, at 5 min, 4, 8, 12, and 16 h after MCAo, and before, during, and after SDs. Power spectra were decomposed into fast (alpha, beta, and gamma) and slow (delta and theta) frequency bands., Results: In the vascular insulted hemisphere under normothermia, electrodes near the ischemic core exhibited power decay across all frequency bands at 5 min and the 4th hour after MCAo. The same pattern was registered in the two furthest electrodes at the 12th and 16th hour. When mild hypothermia was applied in the vascular insulted hemispheres, the power decay was generalized and seen even in electrodes with uncompromised blood flow. During SD analysis, hypothermia maintained increased delta and beta power during the three phases of SDs in the furthest electrode from the ischemic core, followed by the second furthest and third electrode in the beta band during preSD and postSD segments. However, in hypothermic conditions, the third electrode showed lower delta, theta, and alpha power., Conclusion: Mild hypothermia attenuates all frequency bands in the vascularly compromised hemisphere, irrespective of the cortical location. During SD formation, it preserves power spectra more significantly in electrodes further from the ischemic core., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Díaz-Peregrino, Kentar, Trenado, Sánchez-Porras, Albiña-Palmarola, Ramírez-Cuapio, San-Juan, Unterberg, Woitzik and Santos.)

Aim: To describe the spatial and temporal electrocorticographic (ECoG) changes after middle cerebral artery occlusion (MCAo), including those caused by spreading depolarization (SD) in the pig brain., Methods: The left middle cerebral arteries (MCAs) were clipped in six pigs. The clipping procedure lasted between 8 and 12 min, achieving a permanent occlusion (MCAo). Five-contact ECoG stripes were placed bilaterally over the frontoparietal cortices corresponding to the irrigation territory of the MCA and anterior cerebral artery (ACA). ECoG recordings were performed around 24 h: 1 h before and 23 h after the MCAo, and SDs were quantified. Five-minute ECoG signal segments were sampled before, 5 min, and 4, 8, and 12 h after cerebral artery occlusion and before, during, and after the negative direct current shift of the SDs. The power spectrum of the signals was decomposed into delta, theta, alpha, beta, and gamma bands. Descriptive statistics, Wilcoxon matched-pairs signed-rank tests, and Friedman tests were performed., Results: Electrodes close to the MCAo showed instant decay in all frequency bands and SD onset during the first 5 h. Electrodes far from the MCAo exhibited immediate loss of fast frequencies and progressive decline of slow frequencies with an increased SD incidence between 6 and 14 h. After 8 h, the ACA electrode reported a secondary reduction of all frequency bands except gamma and high SD incidence within 12-17 h. During the SD, all electrodes showed a decline in all frequency bands. After SD passage, frequency band recovery was impaired only in MCA electrodes., Conclusion: ECoG can identify infarct progression and secondary brain injury. Severe disturbances in all the frequency bands are generated in the cortices where the SDs are passing by., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kentar, Díaz-Peregrino, Trenado, Sánchez-Porras, San-Juan, Ramírez-Cuapio, Holzwarth, Maier-Hein, Woitzik and Santos.)

Spreading depolarizations (SDs) are characterized by near-complete breakdown of the transmembrane ion gradients, cytotoxic edema, and glutamate release. SDs are associated with poor neurological outcomes in cerebrovascular diseases and brain trauma. Ketamine, a N-methyl-d-aspartate receptor antagonist, has shown to inhibit SDs in animal models and in humans. However, little is known about its SD-inhibitory effect during long-term administration. Lissencephalic animal models have shown that ketamine loses its SD-blocking effect after some minutes to hours. Physio-anatomical differences between lissencephalic and the more evolved gyrencephalic animals may affect their SDs-blocking effect. Therefore, information from the last may have more translational potential. Therefore, the aim of this study was to investigate the 18 h-effect of s-ketamine as a basis for its possible long-term clinical use for neuroprotection. For this purpose, two gyrencephalic swine brain models were used. In one, SDs were elicited through topical application of KCl; in the other model, SDs were spontaneously induced after occlusion of the middle cerebral artery. S-ketamine was administered at therapeutic human doses, 2, 4 and 5 mg/kg BW/h for up to 18 h. Our findings indicate that s-ketamine significantly reduces SD incidence and expansion without clear evidence of loss of its efficacy. Pharmacological susceptibility of SDs to s-ketamine in both the ischemic gyrencephalic brain and well-perfused brain was observed. SDs were most potently inhibited by s-ketamine doses that are above the clinically recommended (4 mg/kg BW/h and 5 mg/kg BW/h). Nonetheless, such doses are given by neurointensivists in individual cases. Our results give momentum to further investigate the feasibility of a multicenter, neuromonitoring-guided, proof-of-concept clinical trial., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: Spreading depolarizations (SD) are characterized by breakdown of transmembrane ion gradients and excitotoxicity. Experimentally, N-methyl-D-aspartate receptor (NMDAR) antagonists block a majority of SDs. In many hospitals, the NMDAR antagonist s-ketamine and the GABA A agonist midazolam represent the current second-line combination treatment to sedate patients with devastating cerebral injuries. A pressing clinical question is whether this option should become first-line in sedation-requiring individuals in whom SDs are detected, yet the s-ketamine dose necessary to adequately inhibit SDs is unknown. Moreover, use-dependent tolerance could be a problem for SD inhibition in the clinic., Methods: We performed a retrospective cohort study of 66 patients with aneurysmal subarachnoid hemorrhage (aSAH) from a prospectively collected database. Thirty-three of 66 patients received s-ketamine during electrocorticographic neuromonitoring of SDs in neurointensive care. The decision to give s-ketamine was dependent on the need for stronger sedation, so it was expected that patients receiving s-ketamine would have a worse clinical outcome., Results: S-ketamine application started 4.2 ± 3.5 days after aSAH. The mean dose was 2.8 ± 1.4 mg/kg body weight (BW)/h and thus higher than the dose recommended for sedation. First, patients were divided according to whether they received s-ketamine at any time or not. No significant difference in SD counts was found between groups (negative binomial model using the SD count per patient as outcome variable, p = 0.288). This most likely resulted from the fact that 368 SDs had already occurred in the s-ketamine group before s-ketamine was given. However, in patients receiving s-ketamine, we found a significant decrease in SD incidence when s-ketamine was started (Poisson model with a random intercept for patient, coefficient - 1.83 (95% confidence intervals - 2.17; - 1.50), p < 0.001; logistic regression model, odds ratio (OR) 0.13 (0.08; 0.19), p < 0.001). Thereafter, data was further divided into low-dose (0.1-2.0 mg/kg BW/h) and high-dose (2.1-7.0 mg/kg/h) segments. High-dose s-ketamine resulted in further significant decrease in SD incidence (Poisson model, - 1.10 (- 1.71; - 0.49), p < 0.001; logistic regression model, OR 0.33 (0.17; 0.63), p < 0.001). There was little evidence of SD tolerance to long-term s-ketamine sedation through 5 days., Conclusions: These results provide a foundation for a multicenter, neuromonitoring-guided, proof-of-concept trial of ketamine and midazolam as a first-line sedative regime.

Spreading depolarization (SD) occurs alongside brain injuries and it can lead to neuronal damage. Therefore, pharmacological modulation of SD can constitute a therapeutic approach to reduce its detrimental effects and to improve the clinical outcome of patients. The major objective of this article was to produce a systematic review of all the drugs that have been tested against SD. Of the substances that have been examined, most have been shown to modulate certain SD characteristics. Only a few have succeeded in significantly inhibiting SD. We present a variety of strategies that have been proposed to overcome the notorious harmfulness and pharmacoresistance of SD. Information on clinically used anesthetic, sedative, hypnotic agents, anti-migraine drugs, anticonvulsants and various other substances have been compiled and reviewed with respect to the efficacy against SD, in order to answer the question of whether a drug at safe doses could be of therapeutic use against SD in humans.

In the recently published article, "Heterogeneous incidence and propagation of spreading depolarizations," it is shown, in vivo and in vitro, how KCl-induced spreading depolarizations in mouse and rat brains can be highly variable, and that they are not limited, as once thought, to a concentric, isotropic, or homogenous depolarization wave in space or in time. The reported results serve as a link between the different species, and this paper contributes to changing the way in which SD expansion is viewed in the lissencephalic brain. Here, we discuss their results with our previous observations made in the gyrencephalic swine brain, in computer simulations, and in the human brain.

Spreading depolarization (SD) generates significant alterations in cerebral haemodynamics, which can have detrimental consequences on brain function and integrity. Ketamine has shown an important capacity to modulate SD; however, its impact on SD haemodynamic response is incompletely understood. We investigated the effect of two therapeutic ketamine dosages, a low-dose of 2 mg/kg/h and a high-dose of 4 mg/kg/h, on the haemodynamic response to SD in the gyrencephalic swine brain. Cerebral blood volume, pial arterial diameter and cerebral blood flow were assessed through intrinsic optical signal imaging and laser-Doppler flowmetry. Our findings indicate that frequent SDs caused a persistent increase in the baseline pial arterial diameter, which can lead to a diminished capacity to further dilate. Ketamine infused at a low-dose reduced the hyperemic/vasodilative response to SD; however, it did not alter the subsequent oligemic/vasoconstrictive response. This low-dose did not prevent the baseline diameter increase and the diminished dilative capacity. Only infusion of ketamine at a high-dose suppressed SD and the coupled haemodynamic response. Therefore, the haemodynamic response to SD can be modulated by continuous infusion of ketamine. However, its use in pathological models needs to be explored to corroborate its possible clinical benefit.

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão's historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

Study Objective: Recent experimental evidence identified GABAergic sedation as a possible cause for deprived neuroregeneration and poor outcome after acute brain injury. Patients with aneurysmal subarachnoid hemorrhage are often sedated, and GABAergic sedation, such as midazolam and propofol, is commonly used., Design: Retrospective cohort study based on a prospectively established database., Setting: Single-center neurointensive care unit., Patients: Twenty-nine patients after subarachnoid hemorrhage., Intervention: Noninterventional study., Measurements: The relationship between mean GABAergic sedative dose during the acute phase and outcome after 6 months according to the Glasgow Outcome Scale, and initial Glasgow Coma Scale was investigated., Main Results: Use of GABAergic sedatives was negatively correlated with Glasgow Outcome Scale (r 2 =0.267; P=.008). Administration of sedatives was independent of the initial Glasgow Coma Scale. GABAergic sedatives flunitrazepam, midazolam, and propofol were used differently during the first 10 days after ictus., Conclusion: Administration of GABAergic sedation was associated with an unfavorable outcome after 6 months. To avoid bias (mainly through the indication to use sedation), additional experimental and comparative clinical investigation of, for example, non-GABAergic sedation, and clinical protocols of no sedation is necessary., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Spreading depolarization (SD) is a wave of almost complete depolarization of the neuronal and glial cells. Nowadays there is sufficient evidence demonstrating its pathophysiological effect in migraine with aura, transient global amnesia, stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and traumatic brain injury. In these cases, occurrence of SD has been associated with functional neuronal damage, neuronal necrosis, neurological degeneration, and poor clinical outcome. Animal models show that SD can be modulated by drugs that interfere with its initiation and propagation. There are many pharmacological targets that may help to suppress SD occurrence, such as Na⁺, K⁺, Cl⁻, and Ca²⁺ channels; Na⁺/K⁺ -ATPase; gap junctions; and ligand-based receptors, for example, adrenergic, serotonin, sigma-1, calcitonin gene-related peptide, GABAA, and glutamate receptors. In this regard, N-methyl-d-aspartate (NMDA) receptor blockers, in particular, ketamine, have shown promising results. Therefore, theoretically pharmacologic modulation of SD could help diminish its pathological effects.

Objectives: The detection of the hemodynamic and propagation patterns of spreading depolarizations (SDs) in the gyrencephalic brain using intrinsic optical signal imaging (IOS)., Methods: The convexity of the brain surface was surgically exposed in fourteen male swine. Within the boundaries of this window, brains were immersed and preconditioned with an elevated K(+) concentration (7 mmol/l) in the standard Ringer lactate solution for 30-40 min. SDs were triggered using 3-5 μl of 1 mol/l KCl solution. Changes in tissue absorbency or reflection were registered with a CCD camera at a wavelength of 564 nm (14 nm FWHM), which was mounted 25 cm above the exposed cortex. Additional monitoring by electrocorticography and laser-Doppler was used in a subset of animals (n=7) to validate the detection of SD., Results: Of 198 SDs quantified in all of the experiments, 187 SDs appeared as radial waves that developed semi-planar fronts. The morphology was affected by the surface of the gyri, the sulci and the pial vessels. Other SD patterns such as spirals and reverberating waves, which have not been described before in gyrencephalic brains, were also observed. Diffusion gradients created in the cortex surface (i.e., KCl concentrations), sulci, vessels and SD-SD interactions make the gyrencephalic brain prone to the appearance of irregular SD waves., Conclusion: The gyrencephalic brain is capable of irregular SD propagation patterns. The irregularities of the gyrencephalic brain cortex may promote the presence of re-entrance waves, such as spirals and reverberating waves., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Leishmaniosis is an important human disease very difficult to treat. For this reason, many researchers in the world have been look- ing for anti-leishmanial chemical components present in several plant species. In Costa Rica, since no studies have been done in this field, this work aimed at the search of active chemical components in local plants that may have an activity against Leishmania sp. A total of 67 plants were selected from the Alberto Manuel Brenes Biological Reserve (REBAMB). For these collected plants, fresh or dried hidroalcoholic extracts of root, stem, mature or young leaves, flowers, and immature or mature fruits, were prepared under conventional methods. All extracts were tested for their effect against a strain of Leishmania (OCR with known characteristics). Firstly, by presumptive tests, we selected only those with some activity, and then, more specific studies were done to determine the IC50 in μg/mL; a promising plant was considered only if at least one of its parts presented an IC50 < 100 μg/mL. Under this parameter, the following active plants were obtained and their lowest and highest IC50 obtained values presented (μg/mL): Bocconia frutescens (0.6 and 66.7), Clematis dioica (27.5 and 44.4), Cordia megalantha (80.0), Eugenia austin-smithi (90.6), Guarea bullata (98.8), Guateria tonduzii (44.4 and 66.3), Mikania holwayana (45.0 and 95.6), Nectandra membranacea (44.5 and 58.6), Neurolaena lobata (25.0 and 100.0), Persea povedae (76.9), Piper auritum (60.0), Rollinia pittieri (43.1), Solanum arboreum (25.8 and 72.5), Tetrorchidiumn eurphyllum (53.8 and 95.0), Witheringia solanacea (15.9 and 98.1) and Zanthoxylum juniperinum (23.4 and 97.5). Although the parasitic effect of fresh or dried extracts were almost similar, the fresh material slightly showed better results. That anti-parasitic effect occurred in one or more than four parts of the plant. Most of the active extracts did not produce lysis and aglutination which indicates a low toxicity. Since the species studied are different from those analyzed by other authors, we discuss the importance of these new findings, in relation to the new scientific knowledge, and the possible use of these plants as a leishmaniosis treatment.

Spreading depolarization (SD) is a wave of mass neuronal and glial depolarization that propagates across the cerebral cortex and has been implicated in the pathophysiology of brain injury states and migraine with aura. Analgesics and sedatives seem to have a significant effect on SD modulation. Studies have shown that ketamine, an NMDA receptor blocker, has the capacity to influence SD occurrence. The aim of this study was to analyze the dose-dependent effect of ketamine on SD susceptibility through electrocorticography (ECoG) and intrinsic optical signal (IOS) imaging in a gyrencephalic brain. Ketamine in a low-dose infusion (2 mg/kg/h) decreases SD spread and had an effect on the amplitude of SD deflections, as well as on duration, and speed. Moreover, during ketamine infusion at this dose, there was a sustained decrease in the hyperemic response following SD. However, a high-dose infusion (4 mg/kg/h) of ketamine inhibited SD induction and expansion. Furthermore, a high-dose bolus (4 mg/kg), 1 min after stimulation, blocked SD propagation abruptly within 1-2 min, and hindered SD induction and expansion for the following 15-30 min. The results suggest that ketamine may be therapeutically beneficial in preventing SDs. Nonetheless, an adequate dosage and way of administration should be considered and established for human use., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cortical spreading depolarization is a wave of almost complete depolarization of the neuronal and glial cells that occurs in different neurological diseases such as migraine with aura, subarachnoid hemorrhage, intracerebral hemorrhage, head trauma and stroke. These depolarization waves are characterized by a change in the negative potential with an amplitude between -10 and -30mV, duration of ∼1min and changes in the ion homeostasis between the intra- and extracellular space. This results in neuronal edema and dendritic distortion. Under pathologic states of hypoperfusion, cortical spreading depolarization can produce oxidative stress, worsen hypoxia and induce neuronal death. This is due to intense arterial vasoconstriction produced by an inverse response called spreading ischemia. Only in the last years there has been an electrophysiological confirmation of cortical spreading depolarization in human brains. Occurrence of cortical spreading depolarization has been associated with worse outcome in patients. Currently, increased knowledge regarding the pathophysiologic mechanisms supports the hypothetical correlation of cortical spreading depolarization with brain damage in humans. There are diverse therapeutic alternatives that promise inhibition of cortical spreading depolarization and subsequent better outcomes., (Copyright © 2013 Elsevier España, S.L. All rights reserved.)

Background: Cerebral autoregulation and, consequently, cerebrovascular pressure reactivity, can be disturbed after traumatic brain injury (TBI). Continuous monitoring of autoregulation has shown its clinical importance as an independent predictor of neurological outcome. The cerebral pressure reactivity index (PRx) reflects that changes in seconds of cerebrovascular reactivity have prognostic significance. Using an alternative algorithm similar to PRx, we investigate whether the utilization of lower-frequency changes of the order of minutes of mean arterial blood pressure (MAP) and intracranial pressure (ICP) could have a prognostic value in TBI patients., Materials and Methods: Head-injured patients requiring continued advanced multimodal monitoring, including hemodynamic, ICP and microdialysis (MD) monitoring, were analyzed retrospectively. A low-frequency sample pressure reactivity index (L-PRx) was calculated, using 20-min averages of MAP and ICP data as a linear Pearson's correlation. The mean values per patient were correlated to outcome at 6 months after injury. Differences of monitoring parameters between non-survivors and survivors were compared., Results: A total of 29 patients (mean age 37.2 years, 26 males) suffering from TBI were monitored for a mean of 109.6 h (16-236 h, SD ± 60.4). Mean L-PRx was found to be of 0.1 (-0.2 to 0.6, SD ± 0.20), six patients presented impaired (>0.2) values. The averaged L-PRx correlated significantly with ICP (r = 0.467, p = 0.011) and 6-month outcome (r = -0.556, p = 0.002). Significant statistical differences were found in L-PRx, cerebral perfusion pressure (CPP), lactate, and lactate-pyruvate ratio when comparing patients who died (n = 5) and patients who survived., Conclusions: L-PRx correlates with the 6-month outcome in TBI patients. Very slow changes of MAP and ICP may contain important autoregulation information. L-PRx may be an alternative algorithm for the estimation of cerebral autoregulation and clinical prognosis.

Background: Cortical spreading depolarization (CSD) has been implicated in the pathophysiology of migraine with aura. Patients that suffer from this type of migraine have shown a higher risk of developing an ischaemic stroke., Case: A 42-year-old female exhibited reoccurring migraine attacks for the first time 1 month before suffering an ischaemic infarction. Imaging studies revealed an occlusion in the right middle cerebral artery. Other possible disorders were excluded. It was possible to register 20 CSDs, of which 12 coincided with high levels of glutamate and lactate/pyruvate ratio. Loss of electrocorticographic activity was observed for 89 hours after the 8th depolarization., Conclusions: Migraine with aura symptoms may be induced by CSDs triggered by hypoperfusion states. Our case supports the idea of the migraine with aura-stroke continuum.

Vitiligo is a common depigmenting disorder which may have devastating psychological and social consequences and is characterized by the presence of circumscribed white macules in the skin due to the destruction of melanocytes in the epidermis. Various hypotheses have been proposed to explain the pathomechanisms involved in this disease, and studies have shown the participation of autoimmune processes in the pathogenesis of vitiligo. Cellular and humoral immunities have been implicated in the development of vitiligo and their role continues to be investigated. Peripheral blood and skin biopsies of patients with vitiligo show that T-cells, mononuclear cells, various pro-inflammatory cytokines, and auto-antibodies can damage melanocytes. Further research is required to determine whether autoimmunity is the main mechanism of vitiligo or only a consequence., (Copyright © 2011. Published by Elsevier B.V.)