Pain Sensation: Nociceptive receptors and transduction

ache Sensation sensitive receptors and transduction spite whizz is a subsystem of corporate sensation which includes a wide stray of offensive afferent and stimulated put throughs usually associated with actual or capableness tissue damage (Das et al., 2005).Over the old age, by means of the evolutive process of lifelike selection, nature has made sure that injure is a bodily sign of the zodiac we poop non ignore. As a consider of fact, sensitivity and reactivity to vesicatory stimuli atomic number 18 essential to the rise- exis decenniumce and survival of an organism. In dangerous circumstances aggravator tells the subject to get away of that situation immediatly, this is its main function. Without these attributes provided by discommode mechanisms, the organism would lose no means to pr planet or downplay dangerous circumstances (individuals congenitally insensitive to torture argon easily hurt and most of them die at an early age1).While most of the sen sory and somatosensory modalities be primarily informative, ail is a protective modality. pang perception ( as vigorous called nociception) doesnt come from excessive stimulant of the same receptors that generate physical sensations, as round bingle could even think, it is a properly devoted subsystem. Nociception (from the Latin nocere, to hurt) in fact depends on specifically dedicated receptors and, repayable to its vital importance, this anatomy of information travels finished redundant pathways. annoyance sensation likewise differs from the unsullied senses (hearing, smell, taste, come up senses, and vision) because it is both a discriminative sensation and a graded emotional experience.In the big picture, trouble oneself appears as a to a greater extent(prenominal) compound whole experience than simple somatic sensation that is why in that spatial relation ar simmer down some(prenominal) obscure aspects not tout ensemble understood, particularly in the field of inconvenience physiology and pharmacology. For this and some opposite reasons, even nowa daytimes, nociception die hards an super active area of scientific research.2. Pain Sensation Nociceptive receptors and transductionPain sensation begins with relatively unspecialized secrete nerve cell endings called nociceptors. cor doing other somatic sensory receptors, they transduce a categorisation of evil stimuli into receptor voltages, which in turn trigger action potentials in the chafe nerve fibers (afferents). These action potentials are transmitted to the spinal anaesthesia cord and then, through the read/write headstem, to the thalamus and the somatic sensory cerebral mantle according to specific pathways2.Nociceptors are widespread distributed, they too show diametric degrees of sensitiveness and specialization. There are nociceptors in the come up, in the joints and likewise in visceral organs, but none of them is anchor inside the exchange n oisome system (CNS)1.In contrast with somatic sensory receptors (responsible for the perception of innocuous mechanical stimuli), the axons associated with nociceptors conduct relatively slowly, being only lightly myelinated or, more commonly, unmyelinated2. Thus, according to the different kind of axon, at that place are unfluctuatinger or sluggish wo(e) pathways. In particular, bruiseful sensation receptors groundwork fall into quatern major categories depending on their reply to the different types of comment caused by the damagemechanosensitive nociceptors respond to mechanical stimulation and soak up A-delta fibers, bigger axons with faster conduction velocitymechano thermal nociceptors respond to thermal stimuli, A-delta fiberschemical nociceptors respond to chemical substances, A-delta fiberspolymodal nociceptors respond to full(prenominal) fervency stimuli of the forward lead types and have C fibers, smaller and unmyelinated axons with slower conduction veloci ty.The cell bodies of these primary hurt-neurons are rigid in the dorsal commencement ganglia (for soundbox afferents) and in the trigeminal ganglia (for eccentric afferents)1,2.The transduction of sensitive signals, which starts with the nociceptive receptors, is a complex task. Tissue damage results in the release of a flesh of chemical substances which triggers the response of nociceptors. Some of these substances activate the transmembrane transient receptor potential (TRP) channels, which in turn get action potentials2.Another characteristic character of nociceptors is their tendency to be sensitized by pro keen-sighteded stimulation, making them respond to other sensations as surface in certain circumstances. This prolonged stimulation increases the release of chemical substances, making nociceptors sensitized and reducing their response threshold. Actually, indoors a fewer indorses afterward on the injury, an area of some centimeters around the hurt turn up shows reddening caused by vasodilation. This inflammation becomes maximal after about ten minutes and this region shows a lowered pain threshold (hyperalgesia) in response to additional noxious stimuli. This effect is as well as referred to as fringy sensitization, in contrast to central sensitization that tush occur at higher levels in the dorsal horn1.Although it is unflurried un cognise whether nociceptors respond promptly to the noxious stimulus or indirectly by means of one or more endogenous chemical intermediaries released from the traumatized tissue, the activation of nociceptors initiates the process by which pain is experienced these receptors communicate information to the CNS about the intensity and location of the nettlesome stimulus. Pain classificationThe result of sudden painful stimulation dope be divided into cardinal categories of sequential sensations unaffectionate by a short time interval. A sharp basic pain, contiguously after the damage, its follo wed some seconds later by additional, diffuse and longer-lasting second pain sensation. The temporal interval in the midst of these twain discover sensations is due to the difference surrounded by fast transmitting A-delta fibers and slow transmitting C fibers. This phenomenon is in any slickness cognize as double pain sensation.Pain has also been classified into three major types1Pricking pain is also called fast pain or sensory pain (first pain) and arises chiefly from the skin, carried by A-delta fibers which earmark discrimination and localization of the pain.Burning pain is caused by inflammation, burned skin and is carried by C fibers. This type of pain is a more diffuse, slower to onset, and longer in duration (second pain). Like pricking pain, burning pain arises mainly from the skin, but it is not clearly localized.Aching pain is a sore pain which arises mainly from the viscera and somatic deep structures. This pain is carried by the C fibers from the deep structur es to the spinal cord and is not distinctly localized. Pain pathwaysThe neural pathway that conveys pain (and temperature) information from the periphery of the body to the higher centers of the CNS is often referred as the anterolateral system (or ventrolateral mainstay). This pathway is physically separated from the system that conveys mechanosensory information like touch and pressure (dorsal column- honest filet pathway). However, even though the dorsal route has been always considered a touch pathway functionally separate from the anterolateral pathway, recent reports indicate that the dorsal column can carry noxious information from the viscera and widespread skin regions as well1.Anyway, the main difference among these two systems breathes the site of decussation magic spell the dorsal column is an ipsilateral footpath until the myeline (where synapses and decussates), the anterolateral system makes early synaptic connections and decussates right away in the spinal cor d, becoming a contralateral piece of ground.Composing the anterolateral system, there are three major rise uping piece of lands the neospinothalamic share (the main, central pain pathway, phylogenetically younger, with few synapses), the paleospinothalamic tract and the archispinothalamic tract (which constitute minor analogue pain pathways, phylogenetically older and multisynaptic tracts)1.Every pain tract is made of three kinds of pseudounipolar neurons first-order, from free nerve endings (nociceptors) to the dorsal horns of the spinal cord second-order, from the dorsal horns to the thalamus and third-order, from the thalamus to the primary somatic sensory cortex.The cell bodies of first-order neurons are located in the dorsal extraction ganglia (DRG) for all three pathways.a) The neospinothalamic tract (central pathway) constitutes the classical anterolateral system. This pathway is responsible for the immediate awareness of a painful sensation and for the generaliseing of the exact location of the painful stimulus.The first-order nociceptive afferents enter the spinal cord via the dorsal root of the DRG and, when these projecting axons reach the dorsal horns of the spinal cord, they branch into ascending and move collaterals, forming the tract of Lissauer2. Once within the dorsal horn, these afferents make synaptic connections with second-order neurons located in Rexeds laminae ( class I to V). Axons of these second-order neurons then cross the midline of the spinal cord, decussating in the anterior white commissure, and ascend to the brainstem in the contralateral (anterolateral) quadrant.most of the pain fibers from lower extremities of the body and below the neck terminate, through the brainstem, in the ventral posterior lateral nucleus (VPL) of the thalamus. The VPL, which serves as a relay station, is thought to be mainly concerned with discriminatory functions1. Finally, here axons of second-order neurons synapse with third-order neurons that consecrate the signal to the primary and secondary somatosensory cortex (SCI and SCII, respectively).Unlike the sculptural relief of bodily afferents, first-order nociceptive neurons from the head, face and intraoral structures have somata in the trigeminal ganglion. fifth cranial nerve fibers enter the pons, descend to the medulla (forming the spinal trigeminal tract) and make synaptic connections in the spinal trigeminal nucleus, then cross the midline and ascend as trigeminothalamic tract (or trigeminal lemniscus). Axons from the second-order neurons terminate in a variety of targets in the brainstem and thalamus, but the discriminative aspects of facial pain are thought to be mediated by projections to the ventral posterior medial nucleus (VPM) of the thalamus and by projections (from here) to primary and secondary somatosensory cortex2.All of the fibers terminating in VPL and VPM are somatotopically oriented and still here the information supplied by different somatosensory receptors remains segregated. Axons from the thalamus synapse with third-order neurons of the SCI, which includes Brodmanns Areas 3a, 3b, 1 and 2. Each of these cortical areas contains a separate and complete representation of the body they are somatotopically organized maps representing the human body (from the foot up to the face) in a medial to lateral arrangement2.b) The paleospinothalamic tract is a parallel pathway where the emotional response to pain is mediated1. This tract also activates brainstem nuclei which are the origin of descending pain- retrenchment pathways which regulate the sesation of noxious inputs at the spinal cord level.In the paleospinothalamic tract the majority of the first-order nociceptive neurons make synaptic connections with second-order neurons in Rexeds layer II (substantia gelatinosa). These second-order neurons also gather in input from mechanoreceptors and thermoreceptors, and thats why the anterolateral system is also responsible for temperat ure perception1.The nerve cells that frame in the paleospinothalamic tract are multireceptive or wide dynamic range nociceptors. most of their axons cross and ascend in the spinal cord primarily in the anterior region and therefore form the anterior spinal thalamic tract (AST). These second-order fibers contain some(prenominal) tracts and each of them makes a synaptic connection in different locations in the mesencephalic reticular formation (MFR) and in the periaqueductal gray (PAG), forming the spinoreticular tract in the tectum, also known as the spinotectal or spinomedullary tract in the midline thalamic nuclei, forming the spinothalamic tract. Alin concert these three fiber tracts are thus known as the paleospinothalamic tract, which is in part bilateral, because some of the ascending fibers do not cross to the opposite side of the cord1. Finally, from the thalamic nuclei, these fibers synapse bilaterally in the somatosensory cortex.Pain is a complex experience processed by a diverse and distributed network of neurons and brain regions. In addition to the sensory-discriminative aspects (carried by the neospinothalamic tract) there are also affective-motivational components of pain2. In the paleospinothalamic pathway there are extensive connections between the thalamic nuclei and the subdivisionic areas such(prenominal) as the cingulate gyrus and the insular cortex. The insular cortex integrates the sensory input with the cognitive components. The limbic structures (amygdala, superior colliculus) project to the hypothalamus and initiate visceral responses to the pain. The thalamic nuclei also projects to the frontal cortex, which in turn is linked to the limbic structures mired in affect the emotional components of pain1.c) The archispinothalamic tract is another parallel pathway, phylogenetically the oldest that carries noxious information1. The characteristics of this tract are very correspondent to the ones pitch in the previous pathway.First-o rder nociceptive neurons make synaptic connections in Rexeds layer II (substantia gelatinosa). From here, second-order fibers ascend and descend in the spinal cord environ the grey matter to end synapsing with cells in the reticular formation and in the periaqueductal gray. Further diffuse multisynaptic pathways ascend to the diverse nuclei of thalamus and send collaterals to the hypothalamus as well as the limbic system nuclei. These fibers, like for the paleospinothalamic tract, mediate visceral, emotional and autonomic chemical reactions to painful stimuli.In short, because of the importance of warning signals of dangerous circumstances, several nociception pathways are involved to transmitting these signals and some of them are redundant.The neospinothalamic tract conducts fast pain (via A-delta fibers) and provides information of the exact location of the noxious stimulus. The multisynaptic paleospinothalamic and archispinothalamic tracts conduct slow pain (via C fibers), a pa in which is chronic and harder to localize. Through these patways, pain activates more different brain areas which link together sensation, perception, emotion, memory and motor reaction1.3. Pain ModulationWhen talking about pain, we always have to consider and book in mind the discrepancy between the objective reality of a painful stimulus and the subjective rsponse to it. Modern studies have provided considerable cortical potential into how circumsatnces affect pain perception- interpreting and, ultimately, into the pharmacology of the pain system2.For many years it has been suggested that somewhere in the CNS there should be some neuronal circuits modulating succeeding(prenominal) painful informations. Evidence for an intrinsic analgesia system was demonstrated by intracranial electrical stimulation of certain brain sites1,3. The circuit consisting of the periaqueductal gray matter (PAG), the raphe nuclei (RN), the locus coeruleus (LC) and the caudate nucleus (CN) contributes to the descending pain suppression mechanism, which crushs incoming pain information at the spinal cord level6. rousing of such areas produce analgesia without behavioral suppression indeed, touch, pressure and temperature sensation remain intact1. At the interneuronal level, opiate receptors activation causes hyperpolarization of the neurons, which in turn results in the inhibition of sackful and in the release of substance P (a neurotransmitter involved in pain infection) that blocks pain transmission1.In addition to descending projections, also local moveions between mechanoreceptive afferents and neural circuits within the dorsal horn can modulate the transmission of nociceptive informations to higher centers2. Observations by Melzack and Wall led to the idea that conjunction activation of the large myelinated fibers associated with low-threshold mechanoreceptors can mediate the flow of pain. This mechanism, also known as Gate Control Theory13, indicates that (at the spi nal cord level) non-noxious stimulation will produce presynaptic inhibition on dorsal root nociceptor fibers and thus blocking incoming noxious information from reaching the CNS1 (i.e. non-painful input closes the supply to other painful inputs, which results in prevention and suppression of pain sensation).This apologises also why if you, for example, stub a toe, a natural and effective reaction is to vigorously rub the site of injury for a couple of minutes2.However, there are many different factors that can regularize the way we understand pain. Doubtless, three of these are do drugss, prior injuries and, more broadly speaking, circumstances.a) DrugsThe brain has a neuronal circuit and endogenous substances to modulate pain. There are two primary types of drugs that work on the brain pain pills and anesthetics1. The term analgesic refers to a drug that relieves pain without handout of consciousness, whereas the term anesthetic refers to a drug that depresses the CNS. Anesthe tics are characterized by the absence of perception for all sensory modalities, including loss of consciousness, but without loss of vital functions.The areas that produce analgesia when stimulated are also responsive to exogenously administered opiate drugs2. As a matter of fact, the most effective clinically used drugs for producing temporary relief from pain are the opioid family, which includes morphine and heroin1. Unluckily, several side effects resulting from opiate use include tolerance and drug dependence (addiction). In general, these drugs modulate the incoming pain information as well as relieve pain temporarily, and are also known as opiate producing analgesia (OA).Opioidergic neurotransmission is found end-to-end the brain and spinal cord and appears to influence many CNS functions opioids exert marked effects on mood, cognition and motivation1 (e.g. producing euphoria).The analgesic action of opiates implied the public of specific brain and spinal cord receptors for these drugs long before the receptors were actually found. Since such receptors are unlikely to have evolved in response to the exogenous administration of opium and its derivates, the convinction grew that endogenous opiate-like compounds must exist in order to explain the evolution of these receptors in the body2. directadays, three classes of opioid receptors have been determine (mu), (delta) and (kappa). All three classes are widely distributed in the brain, and particularly in the PAG, which is the site for higher cortical control of pain pitch contour in humans8. Moreover, three major classes of endogenous opioid peptides that move with them have been recognized in the CNS -endorphins, enkephalins and the dynorphins. Enkephalins are considered the putative ligands for the receptors, endorphins for the -receptors, and dynorphins for the receptors1.The opioid peptides modulate nociceptive input mainly in two ways blocking neurotransmitter release by inhibiting Ca2+ in flux into the presynaptic terminal or opening potassium channels, which hyperpolarizes neurons and inhibits spike activity. The various types of opioid receptors are distributed differently within the central and peripheral device nervous system and this can explain many unwanted side effects following opiate treatments1. (For example, -receptors are widespread in the brain stem parabrachial nuclei, which is a respiratory center. curtailment of these neurons elicits also respiratory depression).In addition to opiates, the other big family of analgesia producing drugs is delineate by the cannabinoids. Like opiates, cannabinoids produce analgesia when microinjected in the PAG and pain itself serves as a trigger for endocannabinoid release3. Results from the study by Walker et al. (1999) indicate that anandamide (an endogenous cannabinoid) fulfills the requirements for a nonopiate mediator of endogenous pain suppression and these selective information support the existence of endogen ous cannabinergic circuitry in the dorsal and lateral PAG. Even if the opiate and cannabinoid mechanisms partially lick anatomically, the endogenous opiate system is activaetd by intense and prolonged stimuli (such as high threshold electrical stimulation), while endogenous cannabinoids occur mostly in tonic pain suppression, during tests that do not produce significant emphasize or fear3.Cannabinoids have been used to treat pain for centuries and cannabis is still used despite its illegal status in most part of the world. The spontaneous and stimulated release of anandamide in a pain-suppression circuit suggests that such drugs may form the basis of a modern pharmacotherapy for pain, particularly in instances where opiates are ineffective3.b) Previous injuryA curious effect, well known and documented in clinical books, is referred to as phantom limb sensation. next the amputation of an extremity, nearly all patients have an illusion that the missing limb is still present. Alth ough this illusion usually ebbes over time, it persists in some degree throughout the amputees life, and can often be reactivated2. A reasonable explanation for this phenomenon is that the central sensory processing apparatus continues to operate indipendently of the periphery, giving rise to these erratic sensations. Indeed, considerable functional reorganization of the somatotopic maps in the primary somatosensory cortex occurs immediately after the amputation and tends to evolve for several years2. Neurons that have lost their headmaster inputs respond to tactile stimulation of other (near) body parts, and so it is not unusual for the patient to perceive a phantom limb as a whole and intact, but displaced from the real location. These and further assures suggested then that a full representation of the body exists indipendently of the peripheral elements that are mapped2.Anyways, the major occupation following phantom limbs phenomena is constituted by the fact that up to 85% of the amputated patients develop also phantom pain4. The description of this common unease can vary from a tingling or burning sensation to some more serious and debilitating issues. Phantom pain, in fact, is one of the more frequent causes of chronic pain syndromes and is extraordinarily difficult to treat2. Neverthless there is no really effective treatment, a study by Jahangiri et al. (1994) demonstrated that preoperative epidural infusion of morphine, bupivacaine and clonidine significantly reduces the relative incidence of phantom limb pain and phantom limb sensation. Moreover, this kind of treatment has been shown as sound for use on general surgical wards with a low incidence of minor side-effetcs4.Other than amputations, pain perception may also be modulated in certain stressful situations. Exposure to a variety of painful or stressful events produces an analgesic reaction, and this phenomenon is called stress induced analgesia (SIA). It has been considered that SIA can p rovide insights into both the psychological and physiological factors that activate endogenous pain control and opiate systems1. (For example, soldiers wounded in skirmish or athletes injured in sports events sometimes report that they do not feel pain during the battle or game however, they will experience the pain later after the battle or as game has ended).Some studies demonstrated in animals that electrical shocks cause stress-induced analgesia3 and it has been suggested that endogenous drugs, (opiates or cannabinoids) released in response to stress, inhibit pain by activating the midbrain descending system1. base on these and other experiments, it is assumed that the stress experienced by the soldiers and the athletes suppressed the pain which they would later perceive.c) CircumstancesThe experience of pain is highly variable between individuals this highly subjective perception has a complex and often non elongate relationship between nociceptive input and pain sensation5. From human experimentation we know that a variety of pain modulatory mechanisms exist in the nervous system, and these systems can be accessed either pharmacologically or through contextual and cognitive manipulation7,6. Various mental processes such as attention, emotional differentiate, late(prenominal) experiences, memories, beliefs and feelings have been shown to influence pain perception and bias nociceptive processing in the humain brain9. All these top-down factors can be grouped together in the category of circumstances that either enhance or diminish pain sensation in regard to dedicated modulatory circuits.Among the cognitive variables influencing pain, the brain mechanisms underlying attentional control have been probably the most extensively studied5. A number of reports show the important role of attentional state in modulating the activity of primary somatosensory areas7. Thus, pain is perceived as less intense when individuals are distracted from it, as proved in a n interesting study by Das et colleagues (2005). This research provides strong evidence supporting virtual reality (VR) based games in providing analgesia and positive influence on children with acute burn injuries, with minimal side effects10. VR can be considered an intermediary between reality and computer technology, and its ability to immerse the exploiter interacting with the artificial environment is central in this kind of approach.However, attentional processes interact with mechanisms supporting the formation of expectations about pain and reappraisal of the experience5. The ability to predict the likelihood of an aversive event is an important adaptive capacity11. Our subjective sensory experiences are thought to be heavily shaped by interactions between expectations and incoming sensory information12 and this cognitive factor is important also for pain perception positive expectations (i.e., expectations for decreased pain) produce a reduction in perceived pain that riv als the effects of a clearly analgesic social disease of morphine12. These evidences provide also a neural mechanism that can, in part, explain the positive impact of optimism in chronic malady states. In fact, perceived control, attentional control and the descending pain modulatory system are involved in the placebo-induced analgesia, which is a clinical example of cognitive pain modulation that decreases pain intensity and cerebral responses to pain5. Such top-down modulatory mechanism is a robust and clinically important phenomenon, which can be demonstrated in approximately one-third of the population9. Moreover, placebo analgesia requires the activation of endogenous opioid-mediated inhibition and neuroimaging techniques showed that there is also overlapping among brain sites activated by opioids and those that are activated during placebo analgesia9. in like manner the emotional state driven by the (experimental) context alters the attitude of patients and can produce powe rful effects on pain perception7. In general, forbid emotions increase pain, whereas positive ones decrease it14,7. Neverthless the brain mechanisms underlying these effects remain largely unknown, the prefrontal cortex, as well as parahippocampal and brainstem structures, are thought to be involved in the emotional regulation of pain14. match to Roy et al. (2009) cognitive and emotional processes induced by pleasant or unpleasant pictures interact with pain perception and modulate the responses to painful electrical stimulations in the right insula, paracentral lobule, parahippocampal gyrus, thalamus, and amygdala14. Not only, recent studies suggested that emotionally laden images representing human pain had a unique capacity to enhance pain reports15, in the implicative perspective that search for the neural bases of human empathy with huge social implications.Thus, even though is well-established that mood selectively alters the affective-reactive response to pain (also called pain tolerance), the interpretation for some of these studies is sometimes difficult, since they do not always clearly disassociate changes in mood from changes in attention7. In fact, other studies showed that emotions can have a direct effect on attention to pain, leading to what is called attentional bias toward pain-related informations, which does not ensure the absence of covariate processes7.In the end, the useable data indicate that emotion and selective attention may both interact modulating pain perception and cortical responses. But the observations that emotional manipulations alter pain unpleasantness more than pain sensation, while attention alters both pain sensation and unpleasantness, suggest that different modulatory circuits are involved7 and that they act through at least partially distinct mechanisms, which can be separated by divert experimental settings15.All this multiplicity of mechanisms underlying the emotional modulation of pain is reflective of the str ong and reciprocal interrelations between pain and emotions, and emphasizes even more the powerful effects that emotions can have on pain perception14.4. ConclusionsIn conclusion, in the CNS, much of the information from the nociceptive afferent fibers results from excitatory discharges of multireceptive neurons. The pain information in the CNS is controlled by ascending and descending restrictive systems that can exert both facilitatory and inhibitory effects on the activity of neurons using endogenous opioids or other substances as mediators. In addition, a powerful inhibition of pain-related information occurs in the spinal cord. These inhibitory systems can be activated by brain stimulation, intracerebral microinjection of morphine, and peripheral nerve stimulation1.However, pain is an extremely complex perceptual and cognitive experience that is influenced also by many top down factors such as past sensations, expectations, the context within which the noxious stimulus occurs , the attentional and emotional state. Therefore, for all these reasons, the response to pain can often vary considerably from subject to subject.Case spread abroad Use of Valproate in Kleine Levin SyndromeCase Report Use of Valproate in Kleine Levin SyndromeSuccessful use of Valproate in Kleine Levin Syndrome a caseful report and review of cases account from IndiaAbstractKleine-Levin Syndrome (KLS) is characterized by recurrent episodes of hypersomnia and other symptoms and it is a really challenging for the physician, since its causes are not yet clear, and available treatment options are not having adequate support. Here we are reportage a case with successful use of Valproate in KLS and also reviewing the cases reported from India.IntroductionKleine-Levin Syndrome (KLS) is a rare disorder which mainly affects teenaged boys and characterized by recurrent episodes of hypersomnia, and sometime along with hyperphagia, behavioral and cognitive disturbances, and hypersexuality (Ya o et al., 2013). Several medications (stimulants, lithium, valproate, antipsychotics, antidepressants) have been reported to provide variable benefit in different symptoms, with lithium being the most widely used drug (Arnulf et al., 2005 2012). We are presenting a case of KLS, who had complete remission with valproate and also reviewing the cases reported from India.Case expandA 17 year old single male student of 12th standard, presented to our psychiatric outpatient clinic in September 2004 with hypersomnolence, low mood, decreased proclivity and interest in studies, social and sexual disinhibition (such as singing begrimed songs loudly at home, and touching unconsenting females including mothers body parts- limbs, face and genitalia). Onset was acute, without any elicitable precipitating factor and course was episodic with average 7-10 days episode in every month for last four months and he maintained completely well in interepisodic arrest.Provisional diagnosing of recurr ent depressive disorder (brief episodes) was kept and he was started on Sertraline (50 mg), on which he responded well. He remained asymptomatic for nearly nine months, but started having similar episodes again from mid 2005, due to which Sertraline was in stages hiked up to one hundred fifty mg/day, but of no use. consequently he was admitted in our inpatient setting in March, 2006 for diagnostic evaluation and further management. After exact evaluation, it was found that his sadness was not pervasive and depressive cognitions and associated disturbances were not present and hypersomnia remained overabundant complaint as ab initio he was sleeping 16-20 hours per day. He was also not responding with these medications, hence differential diagnosis of KLS vs. depression was kept and later finalized to KLS. His heamogram, renal functions, liver functions, blood sugar, routine urine, thyroid functions were within common limits and chest X ray, ECG, EEG, and MRI brain were normal. In view of proficient writings support Lithium was started from 600 mg/day and hiked to 900 mg/day (serum level 0.8 mEq/liter). On which he has shown significant improvement initially for six month but later again started experiencing similar symptoms. He also had three episodes of fall, unresponsiveness and epileptiform discharge in EEG twice. Hence in view of seizure disorder and lack of response, Neurologists consultation was sought, who opined to start antiepileptic medication. Hence lithium was switched to Valproate (750 mg/day) in December 2006, on which he maintained completely well for 4 years, except brief reemergence of symptoms on discontinuing Valproate, which amend completely on resuming the medication. Valproate was gradually tapered and stopped in January 2011 on insistence of patient and family with discussing its pros and cons. Now office case has been maintaining well off Valproate for last three years without any episode of hypersomnolence, sexual disinhibiti on, sadness, or epileptic seizure.DiscussionBased on historical reports by Kliene and Levin, KLS was essentially described and termed by Critchley (1962). thenceforth many researchers have reported their cases and reviewed cases with KLS (Arnulf et al., 2005 2012). Here we are reporting a case with KLS, who responded well with Valproate, after diagnostic dilemma and different mind-bending medications and also reviewing the other cases reported from India.In our electronic search for Indian studies on Kliene-levin syndrome, by using PUBMED and Google Scholar, we could find 15 cases reported from India (Aggarwal et al., 2011 Mendhekar et al., 2001 Prabhakaran et al., 1970 Shukla et al., 1982 Sagar et al., 1990 Narayanan et al., 1972 Agrawal Agrawal, 1979 Malhotra et al., 1997 Gupta et al., 2011). Of them 13 were males and 2 females, similar to male preponderance reported in the literature (Arnulf et al., 2005 2012). While presenting to psychiatric services their age was between 9 to 26 years and they had onset between 7 to 24 years of age. In two-third of patients (10 out of 15 patients) it was preceded with fever and their episodes of somnolence were lasted from 3 days to 10 weeks. Hypersomnia and hyperphagia were present in all, while two-third of patients also had social and sexual disinhibition (11 out of 15 patients). Other symptoms were cognitive disturbances (low intelligence quotient, impaired memory, confusion, and academic decline), foreign talk, and perceptual disturbances. Nearly one-third of patients improved spontaneously without any medication, while rest was given lithium, carbamazepine, methyl amphetamine, dextro amphetamine, and modafinil. Longest asymptomatic follow-up period is reported for 2 years (Aggarwal et al., 2011) (as depicted in table-1).Though literature supported lithium for higher response rate (Arnulf et al., 2005 2012), but index patient had remarkable response with Valproate, not with lithium, like earlier two reports (C rumley, 1997 Adlakha Chokroverty, 2009). Like earlier report (Adlakha Chokroverty, 2009), index patient also improved on lower dose of Valproate (divalproate 750 mg vs. 500 mg Valproate). Compared to other cases reported from India (Aggarwal et al., 2011 Gupta et al., 2011), index patient had longest follow-up (7 years) and remained asymptomatic in this period, except small exacerbation on discontinuation of Valproate treatment, which improved completely on resuming the drug. Similar to our patient, anticonvulsants (like Valproate) are the preferred treatment for KLS patient, and may also offer benefits in case of comorbid epilepsy (Yao et al., 2013). Valproate may be a salutary alternative to lithium in terms of efficacy as well as side effect profile.ReferencesYao, C.C., Lin, Y., Liu, H.C., Lee, C.S., 2013. Effects of various drug therapies on KleineLevin syndrome a case report. Gen Hosp Psychiatry. 35, 102.e7-102.e9.Arnulf, I., Zeitzer, J.M., File, J., Farber, N., Mignot, E., 2005. Kleine-Levin syndrome a systematic review of 186 cases in the literature. Brain. 128, 2763-76.Arnulf, I., Rico, T.J., Mignot, E., 2012. 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