Identification of the Hepatic Metabolites of Flumazenil and their Kinetic Application in Neuroimaging.

Studies of the neurobiological causes of anxiety disorders have suggested that the γ-aminobutyric acid (GABA) system increases synaptic concentrations and enhances the affinity of GABAA (type A) receptors for benzodiazepine ligands. Flumazenil antagonizes the benzodiazepine-binding site of the GABA/benzodiazepine receptor (BZR) complex in the central nervous system (CNS). The investigation of flumazenil metabolites using liquid chromatography (LC)-tandem mass spectrometry will provide a complete understanding of the in vivo metabolism of flumazenil and accelerate radiopharmaceutical inspection and registration. The main goal of this study was to investigate the use of reversed-phase high performance liquid chromatography (PR-HPLC), coupled with electrospray ionization triple-quadrupole tandem mass spectrometry (ESI-QqQ MS), to identify flumazenil and its metabolites in the hepatic matrix. Carrier-free nucleophilic fluorination with an automatic synthesizer for [18F]flumazenil, combined with nano-positron emission tomography (NanoPET)/computed tomography (CT) imaging, was used to predict the biodistribution in normal rats. The study showed that 50% of the flumazenil was biotransformed by the rat liver homogenate in 60 min, whereas one metabolite (M1) was a methyl transesterification product of flumazenil. In the rat liver microsomal system, two metabolites were identified (M2 and M3), as their carboxylic acid and hydroxylated ethyl ester forms between 10 and 120 min, respectively. A total of 10-30 min post-injection of [18F]flumazenil showed an immediate decreased in the distribution ratio observed in the plasma. Nevertheless, a higher ratio of the complete [18F]flumazenil compound could be used for subsequent animal studies. [18F] According to in vivo nanoPET/CT imaging and ex vivo biodistribution assays, flumazenil also showed significant effects on GABAA receptor availability in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, indicating the formation of metabolites. We reported the completion of the biotransformation of flumazenil by the hepatic system, as well as [18F]flumazenil's potential as an ideal ligand and PET agent for the determination of the GABAA/BZR complex for multiplex neurological syndromes at the clinical stage.

Clocking tinnitus: An audiology symptom of migraine.

OBJECTIVES: In contrast to previous concept that tinnitus is confined to an otologic disorder, current evidence supports it as a phantom sensory phenomenon of vestibulocochlear damage with cortical reorganization. It is a common problem worldwide, but the treatment response is always unsatisfactory. PATIENTS AND METHODS: In this study, we report 10 patients who described their staccato tinnitus as simulating the ticking sound of a pendulum or quartz clock (or termed clocking tinnitus). The tinnitus characteristics, laboratory tests, and treatment response were recorded. RESULTS: Clocking tinnitus was unilateral in three patients, bilateral in one patient, and at midline in another six patients. It usually subsided within 15 min. Neither patient experienced vertigo, hemifacial spasm, focal neurological deficit or otic disorder in association with tinnitus. Pre-existing migraine was present in seven patients. During tinnitus attack, a few migraine symptoms concurrently occurred in six patients. Pure-tone audiometry showed symmetric sloping pattern of hearing impairment in half patients whereas brainstem auditory evoked potentials revealed a prolonged wave I-III latency in 30% of patients. The p300 and electroencephalogram were normal in all of them. Neuroimaging study did not disclose structural change. All patients responded poorly to conventional treatments but favorably to flunarizine or topiramate. CONCLUSION: Clocking tinnitus may be an audiology manifestation of migraine in some individuals. Antimigraine treatment can be considered in this specific group of staccato tinnitus. Audiogenic classification of tinnitus may provide diagnostic and treatment clues in tinnitus patients.

Drug-Associated Spontaneous Orgasm: A Case Report and Systematic Review of Literature.

OBJECTIVES: Spontaneous orgasm is characterized by a spontaneous onset of orgasm without any preceding sexual or nonsexual trigger. It sheds insight on the mechanisms underlying orgasms and the sexual response cycle in humans. METHODS: We report a male patient of repetitive spontaneous orgasm under trazodone treatment and systematically review the literature on drug-associated spontaneous orgasm (DASO). RESULTS: A total of 25 patients (18 women and 7 men), including our reported case, experienced 27 DASO events. Over half of them were under 50 years of age during the DASO event. Depression was the leading morbidity for these patients, and a limited list of antidepressants and antipsychotics were involved in 92.5% of all DASO events. Although offending drugs possess variable pharmacological properties, their common effect is an augmentation of serotonin-1A (5HT1A) neurotransmission. Offending drugs seemingly increase personal susceptibility to DASO. Over half of the patients, especially men, did not concurrently experience sexual arousal or desire during the DASO event. In the remaining patients, the orgasm was accompanied by or ensued with arousal or desire. A reduction of dose or discontinuation of the offending drug usually abolished DASO. CONCLUSIONS: It appears that 5HT1A has a key role in generating orgasm. Orgasms may be activated through arousal-independent or arousal-dependent pathways, and both orgasms and sexual arousal are bidirectionally activated. This double-bidirectional model of sexual response cycle may promote the success of sexual procreation and recreation, and further research on this pathway could offer an innovative method to manage anorgasmia in the future.

Pornography headache.

The headache associated with intercourse or masturbatory activity is a well-recognized clinical entity but pornography headache is barely mentioned. We report a young man who suffered preorgasmic headache pertaining only to pornography of specific erotic contents but not to other sexual or nonsexual act. An antecedent activation of sexual arousal and vasoconstriction during pain were found. Finally, oral indomethacin favorably prevented the pain. Therefore, pornography headache is a distinguished headache disorder distinct from other sexual-related headache disorders. Sexual arousal-mediated cerebrovascular dysregulation consequence to visuoneural uncoupling in response to erotic stimulus is proposed. Pornography headache may be underestimated in population as pain-killer overuse may mask the actual incidence in real world.

Cheiro-pedal syndrome: A revisit of etiology, localization and outcome.

OBJECTIVE: Cheiro-pedal syndrome (CPS) is an incomplete sensory disorder confined to hand and foot and is generally considered a benign entity. However, knowledge comes from case report or case series only. The aim of this study is to clarify the etiology, localization and outcome of CPS. PATIENT AND METHOD: A total of 21 CPS patients from our database and another 9 patients from literature were reviewed. CPS was classified into 4 types, namely unilateral and ipsilateral (Type I), bilateral (Type II), incomplete bilateral (Type III), and crossed (Type IV). RESULTS: They were 20 men and 10 women; including 20 Type I patients, 9 Type II patients, 1 Type III patients, and 0 Type IV patient. Vascular disorders, non-vascular cervical disorder and polyneuropathy were the responsible causes in 18 patients, 7 patients, and 2 patients, respectively. Etiology was unknown in another 3 patients. Lesions were located at brain parenchyma in 16 patients, and cervical cord above C5 level in 9 patients. Disable motoroparesis occurred between 4days to 2 months in two-third of deteriorated patients. In three patients, their lesions were detected only on recurrence or exacerbation of CPS 4 months to 2 years later. Recovery, residual deficit and deterioration ensued in 44%, 28% and 28% patients, respectively. A 33.3% of brain involvement patients and 100.0% of spinal involvement patients terminated to residual deficit or deterioration. The sensitivity and specificity of prediction for deterioration was 77.8% and 100%, respectively, by type II or III CPS. CONCLUSION: CPS is actually not a benign neurological disorder but a sensory alarm sign. A thorough examination of brain parenchyma and cervical spinal cord is urgent for identifying any treatable or preventable pathological lesions to reduce harmful consequence, especially in case of type II or III CPS.

Crossed cheiro-oral syndrome: A warning sign for medullary involvement and neurological deterioration.

Crossed cheiro-oral syndrome (CCOS) is characterized by crossed sensory disturbance confined to the unilateral perioral area and contralateral hand/finger(s). Although a few classical crossed sensory syndromes accurately predict brainstem or spinal involvement, the clinical significance of CCOS remains unclear. In this study, we analyzed the etiology, localization and outcome of CCOS patients. The results showed that ischemic stroke is the exclusive cause of CCOS. The location of responsible stroke is pertinent to the middle or upper level of the lateral medulla oblongata medial to the lateral sulcus. The vascular supply is from the vertebral artery or the posterior inferior cerebellar artery. Half of the CCOS patients progressed to Wallenberg's syndrome and complicated with disabled daily living. However, no patient died during the follow-up period. A larger size and dorsal extension of the infarction correlated with neurological deterioration. Therefore, CCOS is an independent clinical sign of medullary involvement. It strongly predicts involvement at the lateral medulla oblongata, especially the ischemic stroke, and neurological deterioration. A rapid evaluation of the infarction location and vascular status is suggested in cases of CCOS.

Clinical significance of circulating vascular cell adhesion molecule-1 to white matter disintegrity in Alzheimer's dementia.

Endothelial dysfunction leads to worse cognitive performance in Alzheimer's dementia (AD). While both cerebrovascular risk factors and endothelial dysfunction lead to activation of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin, it is not known whether these biomarkers extend the diagnostic repertoire in reflecting intracerebral structural damage or cognitive performance. A total of 110 AD patients and 50 age-matched controls were enrolled. Plasma levels of VCAM-1, ICAM-1 and E-selectin were measured and correlated with the cognitive performance, white matter macro-structural changes, and major tract-specific fractional anisotropy quantification. The AD patients were further stratified by clinical dementia rating score (mild dementia, n=60; moderate-to-severe dementia, n=50). Compared with the controls, plasma levels of VCAM-1 (p< 0.001), ICAM-1 (p=0.028) and E-selectin (p=0.016) were significantly higher in the patients, but only VCAM-1 levels significantly reflected the severity of dementia (p< 0.001). In addition, only VCAM-1 levels showed an association with macro- and micro- white matter changes especially in the superior longitudinal fasciculus (p< 0.001), posterior thalamic radiation (p=0.002), stria terminalis (p=0.002) and corpus callosum (p=0.009), and were independent of, age and cortical volume. These tracts show significant association with MMSE, short term memory and visuospatial function. Meanwhile, while VCAM-1 level correlated significantly with short-term memory (p=0.026) and drawing (p=0.025) scores in the AD patients after adjusting for age and education, the significance disappeared after adjusting for global FA. Endothelial activation, especially VCAM-1, was of clinical significance in AD that reflects macro- and micro-structural changes and poor short term memory and visuospatial function.

Antiphospholipid antibodies and cerebellar ataxia: a clinical analysis and literature review.

BACKGROUND: Although it has been established that antiphospholipid antibodies (APAbs) bind to and modulate the signaling of cerebellar neurons in vitro, the clinical correlation between increased APAbs and cerebellar ataxia has rarely been investigated. METHODS: We reviewed 10 patients presenting with cerebellar ataxia with increased blood APAbs from our database along with 3 APAb-associated cerebellar ataxia patients in the literature. RESULTS: Of these 10 patients, 4 exhibited a subacute onset of progressive ataxia, and there were no significant structural changes in their brains that appeared to be responsible for the symptoms. Another 6 showed a chronic course of ataxia, and shared similar morphological changes that included symmetrical lesions in bilateral hemispheres, periventricular lucency and central and temporal atrophy of varying severity; the cerebellum was spared. The predominant APAbs for subacute and chronic ataxia were the anti-beta2-glycoprotein I antibody and anticardiolipin antibody, respectively. Cancer was found in 1 patient with subacute ataxia and in 4 with chronic ataxia. The removal of the cancer, the plasmapheresis and immunosuppressive therapy successfully abolished the ataxia and increased APAb levels in all 5 patients. CONCLUSIONS: The relation between APAbs and nonvascular neurological disorders, such as cerebellar ataxia, should be further studied. APAbs may mediate neurological deficits via different mechanisms such as structural damage or functional neurotoxicity. Clinically, the examination of blood APAb levels is recommended for patients with cerebellar ataxia without a determined cause, and the further survey of systemic cancers in the case of APAb positivity is also recommended. Finally, plasmapheresis is a reasonable and effective treatment for APAb-associated cerebellar ataxia.

Periodic drop thumb, hypokalemia and adrenal adenoma.

OBJECTIVE: To report an unusual involvement of focal distal muscles but not proximal muscles in a patient with hypokalemic periodic paralysis (hypoPP). CLINICAL PRESENTATION AND INTERVENTION: A middle-aged woman presented with episodic weakness of the bilateral thumbs lasting for 2 years. Hypokalemia and a left adrenal mass were subsequently found. Her weakness subsided after surgical removal of the adrenal mass, which was pathologically proven to be an adrenal adenoma. CONCLUSION: The findings for this patient should alert physicians to consider focal distal motor paresis due to hypoPP. A preexisting occult trauma may predispose to paralysis at an atypical location in secondary hypoPP.

High performance liquid chromatography-tandem mass spectrometry method for ex vivo metabolic studies of a rhenium-labeled radiopharmaceutical for liver cancer.

The radio-isotope rhenium-labeled N-[2-(triphenylmethyl)thioethyl]-3-aza-19-ethyloxycarbonyl-3-[2-(triphenylmethyl)thioethyl] octadecanoate) ligand (188Re-MN-16ET) is a novel therapeutic agent under preclinical evaluation for hepatoma. A reversed-phase high performance liquid chromatography coupled with a tandem mass spectrometric analysis method and diode array detector (DAD) involving a T type splitter was developed to characterize this pharmaceutical in rat liver tissue solution and determine its biotransformation rate. The separation was accomplished on a C18 column (chromolith silica, 4.6 mm x 100 mm) using an acetonitrile-ammonium acetate buffer gradient as the mobile phase. The detection was achieved by DAD set at 250nm and tandem mass spectrometry using electrospray ionization in the positive ion mode. Re-MN-16ET displayed a retention time of 23.2 min and a transition ion pair corresponding to m/z677 --> 631 for multiple reaction monitoring. Its biotransformation reaction in rat liver homogenate proceeded for 90 min in a 37°C water bath. The characterization was conducted using aliquots that were extracted and concentrated from the reaction mixture for various incubation times. Re-MN-16ET exhibited a biotransformation half-life (t1/2) of 8-9 min in liver tissue solution and was almost completely exhausted after 90 min. Two of its metabolites, consisting of the Re-labeled carboxylic acid derivative, predominately, and its corresponding demetallized disulfide ligand were found in the liver homogenate, providing a metabolism pathway for the radio-pharmaceutical.

Nummular headache and pituitary lesion: A case report and literature review.

Nummular headache (NH) is a newly categorized headache disorder characterized by a consistent clinicographics in each attack. Currently, it is considered as a primary headache disorder due to epicranial neuralgia but the pathomechanism is still unknown. We report a woman, whose recurrent NH subsided after trans-sphenoidal surgery for her pituitary oncocytoma. The recovery of NH in this patient encourages the central mechanism for NH occurrence. After a review of literature concerning, NH and intracranial secondaries we propose that central NH is a referral pain from pain-sensitive structures, such as meninges, superimposing by pre-existing lower pain threshold or pain modulation.

Combining structure-based pharmacophore and in silico approaches to discover novel selective serotonin reuptake inhibitors.

Inhibition of human serotonin transporter (hSERT) has been reported to be a potent strategy for the treatment for depression. To discover novel selective serotonin reuptake inhibitors (SSRIs), a structure-based pharmacophore model (SBPM) was developed using the docked conformations of six highly active SSRIs. The best SBPM, consisting of four chemical features: two ring aromatics (RAs), one hydrophobic (HY), and one positive ionizable (PI), was further validated using Gunner-Henry (GH) scoring and receiver operating characteristic (ROC) curve methods. This well-validated SBPM was then used as a 3D-query in virtual screening to identify potential hits from National Cancer Institute (NCI) database. These hits were subsequently filtered by absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction and molecular docking, and their binding stabilities were validated by 20-ns MD simulations. Finally, only two compounds (NSC175176 and NSC705841) were identified as potential leads, which exhibited higher binding affinities in comparison with the paroxetine. Our results also suggest that cation-π interaction plays a crucial role in stabilizing the hSERT-inhibitor complex. To our knowledge, the present work is the first structure-based virtual screening study for new SSRI discovery, which should be a useful guide for the rapid identification of novel therapeutic agents from chemical database.

Association between MIF gene polymorphisms and carotid artery atherosclerosis.

Atherosclerosis is a chronic inflammatory disorder. Macrophage migration inhibitory factor (MIF) is a potent cytokine that plays an important role in the regulation of immune responses. Polymorphisms including five- to eight-repeat CATT variants ((CATT)(5-8)) and G-173C in the promoter region of the MIF gene are associated with altered levels of MIF gene transcription. The purpose of the study is to investigate the relationship between promoter polymorphisms of the MIF gene and the severity of carotid artery atherosclerosis (CAA). The severity of CAA was assessed in 593 individuals with a history of ischemic stroke by using sonographic examination, and the MIF promoter polymorphisms of these individuals were genotyped. The carriage of (CATT)7 (compared to genotypes composed of (CATT)5, (CATT)6, or both), carriage of C allele (compared to GG), and carriage of the haplotype (CATT)7-C (compared to genotypes composed of (CATT)5-G, (CATT)6-G, or both) were significantly associated with an increase in the severity of CAA. We conclude that polymorphisms in the MIF gene promoter are associated with CAA severity in ischemic stroke patients. These genetic variants may serve as markers for individual susceptibility to CAA.

Zoster sine herpete, vertebral artery stenosis, and ischemic stroke.

Although a previous or recent history of varicella-zoster virus (VZV) infection is known to increase the risk of stroke in both children and adults, the influence of zoster sine herpetic remains unclear. We report an immunocompetent man with common cold symptoms and conjunctivitis, followed by an acute onset of bulbar weakness and hemihypesthesia without preceding skin rash. Acute medullary infarction and left vertebral artery stenosis were detected. VZV infection was finally identified. Zoster sine herpetic interferes with accurate diagnosis of infectious stroke, and vertebral artery involvement is unusual in ischemic stroke in this situation. An unexplained course of ischemic stroke event should be suspected in patients with VZV cerebrovasculopathy, especially in those without conventional stroke risk factors and those exhibiting concomitant infectious complications.

Molecular modeling to investigate the binding of Congo red toward GNNQQNY protofibril and in silico virtual screening for the identification of new aggregation inhibitors.

Understanding the nature of the recognition between amyloid protofibrils and dye molecules at the molecular level is essential to improving instructive guides for designing novel molecular probes or new inhibitors. However, the atomic details of the binding between dyes and amyloid fibrils are still not fully understood. In this study, molecular docking, consensus scoring, molecular dynamics (MD), and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analyses were integrated to investigate the binding between Congo red (CR) and the GNNQQNY protofibril from yeast prion protein Sup35 and to further evaluate their binding stabilities and affinities. Our results reveal that there are four CR binding sites located on GNNQQNY protofibril surface. These four CR binding sites adopt dual binding modes by which CR binding with its long axis parallel and perpendicular to the long axis of the protofibril. In addition, CR was also found to bind to the edge of the protofibril via hydrophobic/aromatic and hydrogen-bonding interactions, which is inferred as the possible inhibition mechanism to prevent the elongation of the protofibril from the addition of incoming peptides. Virtual screening from National Cancer Institute (NCI) database obtained three hit compounds with higher binding affinity than CR to the edge of the protofibril due to the fact that the central parts of these compounds are able to form additional hydrogen bonds with the protofibril. The results of the study could be useful for the development of new molecular probes or inhibitors for clinical applications.

Peroxidase mimicking DNA-gold nanoparticles for fluorescence detection of the lead ions in blood.

Oligonucleotide (T30695) modified gold nanoparticles (T30695-Au NPs) have been prepared and employed for quantification of lead ions (Pb(2+)) in blood. The detection of Pb(2+) ions is through the formation of Au-Pb alloys and oligonucleotide-Pb(2+) complexes that catalyze the H(2)O(2)-mediated oxidation of non-fluorescent Amplex UltraRed (AUR) to form a highly fluorescent oxidized AUR product. Surface-assisted laser desorption/ionization time-of-flight mass spectrometry (SALDI-TOF MS) and inductively coupled plasma mass spectrometry (ICP-MS) revealed the formation of Au-Pb alloys on the surfaces of the 40T30695-Au NPs (i.e., the system featuring 40 molecules of T30695 per Au NP) in the presence of Pb(2+) ions, leading to increased catalytic activity for the H(2)O(2)-mediated oxidation of AUR. The fluorescence intensity (excitation/emission maxima: ca. 540/584 nm) of the oxidized AUR product is proportional to the concentration of Pb(2+) ions over the range 0.1-100 nM, with a linear correlation (R(2) = 0.99). The 40T30695-Au NP/AUR probe is highly selective toward Pb(2+) ions (by at least 200-fold over other tested metal ions). The 40T30695-Au NPs/AUR probe provided limits of detection (LOD, at a signal-to-noise ratio 3) for Pb(2+) ions of 0.05 and 0.1 nM, in Tris-acetate solution (5 mM, pH 8.0) without and with salt (150 mM NaCl, 5 mM KCl, 1 mM MgCl(2), and 1 mM CaCl(2)), respectively. Without conducting tedious sample pretreatment, the approach allows detection of Pb(2+) ions in blood samples, showing the potential of the 40T30695-Au NPs/AUR assay for on-site and real-time detection of Pb(2+) ions in biological samples.

Varicella-zoster virus infection and nummular headache: a possible association with epicranial neuralgia.

A nummular headache (NH) is a type of primary headache that results from cranial neuralgia without a known cause. We herein report the case of a woman who suffered two episodes of focal headache in the left parietal area with identical characteristics that were compatible with NH. During the recovery phase of the second NH episode, the pain resurged with shingles coinciding with the painful area. The patient's NH subsided in parallel with resolution of the shingles. These findings support a diagnosis of peripheral neuralgia with NH. Latent virus infections, such as Varicella-zoster virus, that frequently cause distal nerve damage in patients with zoster sine herpete may be associated with epicranial neuralgia and NH.

The antemortem neurobehavior in fatal paramethoxymethamphetamine usage.

Paramethoxymethamphetamine (PMMA) is an emerging and prevalent psychoactive drug with a structure analogous to amphetamine and related psychostimulants. However, the neurobehavioral effect is only studied in experimental animals and is barely mentioned in human. The authors report the antemortem neurobehavioral manifestations in 8 patients with PMMA use. There were 2 different antemortem presentations. The first group of patients showed delirium, hypertalkativity, and incoherence speech and then turned into convulsion and death. They did not exhibit the typical hyperdopaminergic movement disorder. The second group of patients gradually fell asleep and then suffered respiratory or cardiovascular collapse. The heart blood PMMA level was higher in the second group than in the first group of patients. Forensic autopsy showed variable findings, ranging from no remarkable change to significant pathological damage similar to serotonin syndrome in both groups of patients. PMMA seems to enhance serotoninergism than dopaminergism, and exerts a concentration-related dual effect on human.

A high prevalence of autoimmune indices and disorders in primary nummular headache.

BACKGROUNDS: Nummular headache (NH) is currently considered a form of peripheral neuralgia originating from the terminal branch in epicranial tissue but its etiopathogenesis is still unknown. Since autoimmune disorders often involve the trigeminosensory nerve to provoke craniofacial pain, we hypothesize that autoimmunity aberration may play a role with regard to NH. METHODS: We examined the antibodies to antinuclear factor, ds-DNA, extracted nuclear antigens, rheumatoid factor, as well as antiphospholipid antibodies, in 23 primary NH patients. RESULTS: Among them were 16 patients (69.6%) found as having at least one abnormal autoimmune index, namely, antibodies to antinuclear factor in 8 patients, SSA/La in 6 patients, rheumatoid factor in 4 patients, SSB/Ro in 2 patients, and ds-DNA in 1 patient. An abnormal increase of blood anti-beta2-glycoprotein I antibody was noted in 4 patients and lupus anticoagulant in 1 patient, whereas HLA-B27 seropositivity was detected in 1 patient. Except for 2 patients positive for antinuclear factor without other associated features, 15 patients (65%) were finally diagnosed as having Sjogren/sicca syndrome, rheumatoid arthritis or antiphospholipid antibody syndrome. CONCLUSIONS: A high prevalence of abnormal autoimmune indices and disorders is present in primary NH patients, suggesting a probable relationship between autoimmunity aberration and epicranial neuralgia in NH.

Clinical analysis of cheiro-pedal syndrome.

Cheiro-pedal syndrome (CPS) is an incomplete pure sensory disorder confined strictly to simultaneous hand/finger and ipsilateral foot/toe symptoms. However, its clinical significance and pathogenesis are unclear. We present nine patients with typical CPS, and review another seven previously reported patients. Ischemic stroke is the leading cause of CPS in these 16 patients. In 13 patients, the lesions responsible were distributed widely in the brain from the corona radiata to the medulla oblongata whereas in three patients the lesions were found in the cervical spinal cord or peripheral nerves. All patients had a favorable outcome. The close proximity of the cheiral and pedal sensory fibers in the pons, thalamus, internal capsule and the caudal thalamocortical projection increases the vulnerability for CPS. Therefore, the underlying cause of CPS should be investigated rapidly despite it causing only minor symptoms. The pathogenesis of CPS may consist of several interacting factors including preconditioned neuronal damage and proximity of the acral sensory fibers.