Predicting the occurrence of thrombocytopenia from free valproate levels: A prospective study.

PURPOSE: The likelihood of valproate (VPA) induced thrombocytopenia increases with higher VPA levels. In critically ill patients, the biological active free VPA level cannot be predicted from the total serum level. In this study, we evaluated the relationship between trough free VPA serum levels and concomitant platelet counts and assessed risk factors for the development of thrombocytopenia with the aim of generating a formula specifying the probabilities of developing thrombocytopenia based on trough free serum VPA levels. METHODS: Trough free VPA levels and concomitant platelet counts were collected from a large cohort of patients who participated in a prospective VPA monotherapy trial. Significant variables associated with thrombocytopenia in a univariate analysis were evaluated in a multivariate model. A receiver operator curve was performed to compute the trough free VPA levels with the greatest discriminating power in predicting thrombocytopenia. RESULTS: 844 trough free VPA levels and concomitant platelet counts obtained from 264 patients were analyzed. In a multivariate analysis, trough free VPA levels, gender, and baseline platelet counts were significantly associated with thrombocytopenia. Using stepwise regression and multivariate logistic regression analyses, we generated gender-specific formulas for predicting platelet counts and probabilities of developing thrombocytopenia. The trough free VPA with the greatest discriminating power to predict platelet values ≤ 100,000/µL was 16.65 µg/mL. CONCLUSIONS: The generated model was based on trough free VPA levels and achieved high sensitivity and specificity. Our results are therefore generalizable and can be applied to estimate the probability of developing thrombocytopenia in critically ill patients.

Coma With Absent Brainstem Reflexes and a Burst Suppression on EEG Secondary to Baclofen Toxicity.

Baclofen, a muscle relaxant prescribed for the alleviation of symptoms of spasticity acts primarily at the spinal level but with high doses, it penetrates the blood-brain barrier and can result in prominent central nervous depression. Baclofen toxicity has been associated with a variety of symptoms ranging from dizziness to deep coma. We report the clinical course, management, and outcome of a case of baclofen overdose who presented in deep coma with loss of brainstem reflexes and a burst suppression (BS) pattern on his electroencephalogram (EEG). In addition, we reviewed the presentation and outcomes of all reported cases of baclofen toxicity with a BS pattern on EEG to evaluate if those cases share a common clinical presentation and for the presence of signs and symptoms that would help the clinician to consider this diagnosis. There appears to be a common clinical picture associated with severe baclofen toxicity consisting of deep coma associated with loss of all brainstem reflexes including pupillary reactivity, frequent association with seizures/myoclonic jerks, and a BS pattern on EEG. The outcome is generally good, and serial EEGs are recommended to document a reversal of the abnormal electrographic features.

Brainstem injection of lidocaine releases the descending pain-inhibitory mechanisms in a rat model of mononeuropathy.

Lidocaine injections in the rostral ventromedial medulla (RVM) have been shown to produce significant reduction of neuropathic manifestations in rats. This effect has been attributed to selective block of a pain descending facilitatory system, responsible for chronic pain. However, recent observations from our laboratory did not provide confirmation to this hypothesis. We aimed, therefore, to investigate the spinal synaptic mechanisms activated by lidocaine injections in the RVM. Rats were subjected, under deep anesthesia, to the induction of mononeuropathy on one hindpaw, and to the stereotaxic implantation of chronic cannulae in the RVM for the injection of lidocaine or GABA antagonists. Implanted intrathecal catheter in the lumbosacral space was used for the injection of specific antagonists to GABA, 5HT, glycine, noreadrenaline and dopamine, prior to lidocaine. Tactile and cold hyperreactivity and heat hyperalgesia were assessed using von Frey hair filaments, acetone drop test and heat-induced paw withdrawal, respectively. Lidocaine injections produced significant inhibition of all neuropathic manifestations. Intrathecal injection of antagonists to GABA (bicucullin, picrotoxin and saclofen), serotonin 5HT(1-2) (ketanserin and methysergide) and α- (phentoalmine, yohimbine) and ß- (propranolol) adrenergic receptors, suppressed the lidocaine inhibitory effects; while partial or no attenuation were observed following pretreatment with glycine and dopamine D(2/3) antagonists. Comparable effects were observed with RVM injection of GABA antagonists. Lidocaine injection in the RVM results in a release of the descending pain-inhibitory systems from a tonic gabaergic inhibition. This descending system involves the activation of gabaergic, serotonergic and adrenergic mechanisms at the level of the spinal dorsal horn.

Toxocara canis myelitis: clinical features, magnetic resonance imaging (MRI) findings, and treatment outcome in 17 patients.

Toxocara myelitis is a rare disease. Few cases have been reported in the literature. Patients present with myelopathy, occasional eosinophilia in blood and cerebrospinal fluid (CSF), with abnormal signals on magnetic resonance imaging (MRI). In the current study we report 17 cases of isolated Toxocara myelitis from a single tertiary referral center in Lebanon, with description of the clinical presentation, laboratory data, MRI findings, and response to antihelminthic treatment. Clinical and laboratory data were collected for 17 patients who presented with evidence of spinal cord disease. The clinical presentation included sensory, motor, and autonomic dysfunction, predominantly in the lower extremities. Patients exhibited a subacute or chronic course; this was either slowly progressive or remitting-relapsing with mild to moderate disability. The patients underwent extensive blood and CSF workup as well as MRI of the spinal cord and brain. Only 2 patients had a high eosinophil count in the CSF, although blood eosinophilia was seen in 6 patients. All patients tested positive for Toxocara canis antibodies in the blood and CSF. MRI of the spinal cord revealed a single characteristic lesion in the spinal cord with fusiform enlargement that was isointense on T1-weighted images and hyperintense on T2-weighted images. Nodular enhancement was seen after gadolinium injection. Treatment with albendazole, with or without steroids, resulted in marked neurologic improvement and normalization of the MRI in all patients.The finding of a single inflammatory MRI lesion in the spinal cord with positive Toxocara canis serology in the blood and CSF in cases of subacute or chronic myelitis suggests the diagnosis of Toxocara myelitis, irrespective of the presence of eosinophilia. Antihelminthic treatment is associated with a good outcome.

Alteration of GABAergic and glycinergic mechanisms by lidocaine injection in the rostral ventromedial medulla of neuropathic rats.

Attenuation of neuropathic manifestations in experimental animals, by lidocaine injection in the rostral ventro-medial medulla (RVM), has been traditionally attributed to selective block of a descending pain facilitatory system. However, the presence of descending fibers carrying this effect and the selective action of lidocaine on the facilitatory neurons, have not been supported by convincing experimental evidence. The present study aimed to investigate the mechanisms underlying the hypoalgesic action of lidocaine injection in the brainstem. Several groups of rats were subjected to mononeuropathy on their left hind paws, according to the model of spared nerve injury, and were subsequently implanted with guide cannulae in the RVM. After recovery, rats received injections of lidocaine, GABA and glycine agonists or antagonists and their effects were assessed on behavioral tests of allodynia and hyperalgesia. Injections of lidocaine at doses ranging between 0.05% and 2% produced attenuation at high doses and no effects or increasing hyperalgesia at low doses. GABA and glycine agonists increased neuropathic manifestations while their antagonists elicited the opposite effects. A combined injection of GABA agonist or glycine with lidocaine (0.5%) prevented the inhibitory effects of lidocaine injection alone. Our results are in line with the abundant documentation on the alteration of the function of inhibitory neurons by lidocaine and reveal a possible action of the injected high doses on the GABAergic and glycinergic neurons in the RVM. The resulting block of the inhibitory tone exerted by these neurons can lead to a release of the descending pain inhibitory systems.

Disseminated varicella presenting as acute abdominal pain nine days before the appearance of the rash.

We report a patient presenting with severe epigastric pain and diffuse abdominal tenderness, with negative imaging and endoscopic evaluation. During hospitalization, the patient developed confusion, seizures, pneumonia, anemia and thrombocytopenia. A hemorrhagic rash appeared on day nine of admission, with serology and skin biopsy confirming a diagnosis of hemorrhagic varicella.

Spinal pathways involved in supraspinal modulation of neuropathic manifestations in rats.

Controversial results have been recently reported on the role of supraspinal centers in the modulation of nociceptive behavior in animal models of mononeuropathy. Our aim was to investigate the role of the various spinal pathways in the modulation of the neuropathic manifestations. Several groups of rats were subjected to selective spinal-tract lesions, either 2-3 weeks before or 2-3 weeks after the induction of mononeuropathy following the chronic constriction injury (CCI) or the spared nerve injury (SNI) models. Tactile and cold allodynias were assessed by Von Frey filaments and the acetone drops test, respectively. Thermal hyperalgesia was assessed by the paw withdrawal and the hot plate tests. The effects of unilateral and bilateral lesions of the dorso-lateral funiculus (DLF), the anterolateral column (ALC) or hemisection were tested over a period of 4-8 weeks. All spinal tract lesions produced reversible, but significant decrease of allodynia and hyperalgesia over a period of 1-3 weeks. The most pronounced effects were observed with bilateral lesions. The stronger attenuation was observed on thermal hyperalgesia, assessed by the paw withdrawal test, while cold allodynia was the least affected. Spinal lesions performed before the induction of neuropathy did not produce significant alterations in the temporal development of neuropathic manifestations. The present results allow the conclusion that all spinal tracts can be involved in the rostral transmission and the descending modulation of neuropathic manifestations. The recovery of symptoms following spinal lesions provides illustration on the plasticity of the neural network involved in the processing of the neuropathic syndromes.

Moyamoya syndrome with intraventricular hemorrhage in an adult with factor V Leiden mutation.

OBJECTIVE: To report a case of proximal occlusion of 2 major cerebral vessels associated with moyamoya network circulation that manifested by spontaneous intraventricular hemorrhage. DESIGN: Case report. PATIENT AND RESULTS: A 36-year-old Syrian man presented with symptoms of sudden-onset headache, neck stiffness, and confusion. The computed tomography scan of his brain showed intraventricular bleeding, and the subsequent 4 vessel angiographies revealed occlusion of the left middle and anterior cerebral arteries with moyamoya appearance in the terminal branches. The coagulation profile showed the presence of heterozygous factor V Leiden mutation. The patient was treated conservatively until resolution of his blood clot, and later he was started on oral anticoagulation. CONCLUSION: Factor V Leiden mutation may cause large cerebral vessel occlusion with moyamoya syndrome in adults.

Effects of ventral hippocampal lesion on thermal and mechanical nociception in neonates and adult rats.

The proper maturation of the hippocampus is essential for the development of different behaviours, including memory, pain responses and avoidance. The mechanisms involved in the neurodevelopment of nociception have also been implicated in several neuropsychiatric disorders. The neonatal lesion of the ventral hippocampus (VH) in rats, an animal model of schizophrenia, can be utilized to study the developmental neurobiology of animal behaviour. We examined the nociceptive responses in this animal model at different stages of development. Rat pups were lesioned at postnatal day 7 by injecting ibotenic acid into the VH bilaterally, and then tested for thermal and mechanical nociception at the age of 35, 65 and 180 days. The nociceptive tests used were the hot plate (HP), paw pressure (PP) and tail flick (TF) tests. Another group of adult rats had the same lesion in the VH and then underwent the same tests at 28, 56 and 168 days post-lesions. When compared with sham controls, the rats with neonatal VH lesion showed decreased latency for the HP and PP tests only after puberty. The TF test showed significant increase in latency for both groups at age 65 and 180 days. The adult rats with VH lesion showed no major changes over all periods of testing. These results suggest that early lesion of VH can alter the development of the neural mechanisms involved in the processing of thermal and mechanical nociception.

Continuous perfusion with morphine of the orbitofrontal cortex reduces allodynia and hyperalgesia in a rat model for mononeuropathy.

Recent imaging reports demonstrate the activation of the orbitofrontal cortical (OFC) area during acute and chronic pain. The aim of this study was to compare the effects of chronic perfusion of this area with morphine on nociception in control rats and in rats subjected to mononeuropathy. Chronic perfusion of morphine, using miniosmotic pumps, produced significant and naloxone-reversible depression of tactile and cold allodynias and thermal hyperalgesia, observed in neuropathic rats, while it produced significant elevation and naloxone insensitive increase of acute nociceptive thresholds in control rats. The observed results support the idea that this area is a component of a flexible cerebral network involved in pain processing and perception.

Chronic thalamotomy increases pain-related behavior in rats.

The thalamus has been traditionally considered as the 'chief organ' by which pain is perceived (Head H, Holmes G. Sensory disturbances from cerebral lesions. Brain 1911;34:102-254). However, several clinical and experimental observations led to a challenge of this traditional view. In this report, we demonstrate that chronic thalamic lesions, instead of producing hypoalgesia, increased pain reactivity in rats. Different groups of rats were subjected to either subtotal, lateral or medial thalamic lesions. Their reactions to nociceptive stimuli were then assessed for a period of 1-2 months. Rats in the different groups showed an increased reactivity to acute mechanical and thermal nociceptive stimuli and an increase in the pain scores of the formalin test. These results suggest an important role of the thalamus in pain modulation in addition to that of nociceptive transmission.