Transcranial focused ultrasound for the treatment of tremor: A preliminary case series.

BACKGROUND: Essential tremor (ET) can be debilitating. Treatments for ET include beta-blockers and surgical interventions. Low-intensity focused ultrasound (LIFU) may offer an office-based non-invasive alternative. OBJECTIVE: This pilot open label clinical trial explores safety, feasibility, and potential efficacy of LIFU in treatment of ET. METHODS: We report outcomes from the first 10 participants in this IRB-approved trial of LIFU for treatment of ET. The ventral intermediate nucleus of the thalamus (Vim) was targeted using structural and functional MRI. Participants underwent eight 10-min sessions of LIFU targeting the contralateral (Vim) to the most affected hand. Safety was closely monitored; Global Rating of Change (GRC) and The Essential Tremor Rating Scale (TETRAS) scores were collected. RESULTS: No adverse effects were reported. Eight participants reported a GRC ≥2. TETRAS performance subscale demonstrated clinically significant improvement in all participants. CONCLUSION: Preliminary findings support LIFU's safety and feasibility. The potential efficacy encourages additional sham-controlled studies.

TC-5619: an alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia.

A growing body of evidence suggests that the alpha7 neuronal nicotinic receptor (NNR) subtype is an important target for the development of novel therapies to treat schizophrenia, offering the possibility to address not only the positive but also the cognitive and negative symptoms associated with the disease. In order to probe the relationship of alpha7 function to relevant behavioral correlates we employed TC-5619, a novel selective agonist for the alpha7 NNR subtype. TC-5619 binds with very high affinity to the alpha7 subtype and is a potent full agonist. TC-5619 has little or no activity at other nicotinic receptors, including the alpha4beta2, ganglionic (alpha3beta4) and muscle subtypes. The transgenic th(tk-)/th(tk-) mouse model that reflects many of the developmental, anatomical, and multi-transmitter biochemical aspects of schizophrenia was used to assess the antipsychotic effects of TC-5619. In these mice TC-5619 acted both alone and synergistically with the antipsychotic clozapine to correct impaired pre-pulse inhibition (PPI) and social behavior which model positive and negative symptoms, respectively. Antipsychotic and cognitive effects of TC-5619 were also assessed in rats. Similar to the results in the transgenic mice, TC-5619 significantly reversed apomorphine-induced PPI deficits. In a novel object recognition paradigm in rats TC-5619 demonstrated long-lasting enhancement of memory over a wide dose range. These results suggest that alpha7-selective agonists such as TC-5619, either alone or in combination with antipsychotics, could offer a new approach to treating the constellation of symptoms associated with schizophrenia, including cognitive dysfunction.

Making the transition: the role of helical CT in the evaluation of potentially acute thoracic aortic injuries.

OBJECTIVE: The purpose of this study was to show that helical CT could be used at our center in lieu of routine aortography to examine patients who have had serious blunt chest trauma. We also wanted to assess the potential savings of using CT to avoid unnecessary aortography. MATERIALS AND METHODS: The institutional review board approved the parallel imaging-CT immediately followed by aortography-of patients presenting with blunt chest trauma between August 1997 and August 1998. To screen patients for potential aortic injuries, we performed parallel imaging on 142 patients, and these patients comprised our patient population. CT examinations of the patients were reviewed for signs of injury by radiologists who were unaware of each other's interpretations and the aortographic results. Findings of CT examinations were classified as negative, positive, or inconclusive for injury. Aortography was performed immediately after CT. The technical and professional fees for both transcatheter aortography and helical CT were also compared. RESULTS: Our combined kappa value for all CT interpretations was 0.714. The aortographic sensitivity and negative predictive value were both 100%. Likewise, the sensitivity and negative predictive value of CT were 100%. The total costs of performing aortography were estimated at approximately $402,900, whereas those for performing helical CT were estimated at $202,800. CONCLUSION: Helical CT has a sensitivity and negative predictive value equivalent to that of aortography. Using CT to eliminate the possibility of mediastinal hematoma and to evaluate the cause of an abnormal aortic contour in a trauma patient allows us to use aortography more selectively. Avoiding the performance of unnecessary aortography will expedite patient care and reduce costs. We report the results of our experience with CT and how our center successfully made this transition in the initial examination of patients with serious thoracic trauma.

Nonconvulsive status epilepticus in acute brain injury.

Whether or not nonconvulsive status epilepticus produces permanent brain damage is a source of controversy. Contributing to the controversy is the lack of clarity for classifying the clinical and electrographic phenomena that constitute nonconvulsive status epilepticus. Nonconvulsive status epilepticus commonly occurs in the context of an acute brain injury. For example, it commonly persists in generalized convulsive status epilepticus after convulsive activity has stopped, and it is not uncommonly associated with acute cerebral ischemia. Its clinical characteristics are ambiguous, subtle, and nonspecific making the diagnosis difficult. In the absence of EEG testing, it is likely to be missed or delayed. When acute brain injury and nonconvulsive status epilepticus occur concurrently, the severity of acute brain injury has traditionally been accepted as determining patient outcome. However, increasing evidence suggests that the two conditions are synergistically detrimental and increase brain injury. Guidelines remain to be established for the intensity and duration of anticonvulsant therapy in these patients. Evidence suggests that, in the absence of extreme and irreversible acute brain injury, early intensive intervention is necessary to improve the otherwise poor outcome of these patients.

Continuous EEG monitoring in the neuroscience intensive care unit and emergency department.

This article reviews established, emergent, and potential applications of continuous EEG (CEEG) monitoring in the Neuroscience Intensive Care Unit (NICU) and Emergency Department. In each application, its goal as a neurophysiologic monitor is to extend our powers of observation to detect abnormalities at a reversible stage and to guide timely and physiologically sound interventions. Since this subject was reviewed 5 years ago, the use of CEEG monitoring has become more widespread. In a modern NICU, it is no longer novel to have CEEG data contributing to management decisions. A well-trained CEEG monitoring team is important for its optimal implementation. In the diagnosis and management of convulsive and nonconvulsive status epilepticus, its value appears established. It is finding benefit in the early diagnosis and management of precarious cerebral ischemia, including severe acute cerebral infarctions and post-SAH vasospasms. In comatose patients, it can provide diagnostic and prognostic information which is otherwise unobtainable. More recently, it has been found advantageous for targeting management of acute severe head trauma patients. Networking technology has facilitated the implementation and oversight of CEEG monitoring and promises to expand its availability, credibility, and effectiveness. The maturing of CEEG use is reflected in preliminary efforts to assess its cost benefit, cost effectiveness, and impact on patient outcomes.

Surgically treated pneumothorax. Radiologic and pathologic findings.

OBJECTIVE: To compare the identifiable pulmonary abnormalities on preoperative chest radiographs and CT scans with the histologic findings in patients requiring surgical intervention for recurrent or persistent pneumothoraces. MATERIALS AND METHODS: Chest radiographs were reviewed retrospectively in 116 consecutive patients (aged 16 to 81 years) who had undergone thoracotomy for recurrent or persistent pneumothorax. CT scans were performed in 21 patients. Chest radiographs and CT scans were reviewed by two observers without knowledge of the histologic findings. All specimens were reviewed by a surgical pathologist. RESULTS: Seventy-nine (68%) patients had parenchymal abnormalities and five (4%) had pleural thickening evident on the radiograph. The most common radiographic abnormalities included apical bullae (n = 51), apical scarring (n = 17), and diffuse emphysema (n = 9). Twenty of 21 (95%) CT scans demonstrated either a parenchymal or a pleural abnormality. CT demonstrated emphysema in four patients with normal radiographs, as well as additional findings in six patients with abnormal radiographs. Histologically, 74 patients had focal irregular emphysema, 26 had distal acinar emphysema, six had mixed emphysema, four had isolated bullae or blebs, two had mesothelioma, and one each had the following: metastatic angiosarcoma, subpleural fibrosis, congenital cystic adenomatoid malformation, and tuberculous pleuritis with inactive interstitial fibrosis and honeycombing. CONCLUSION: Most patients with surgically treated pneumothorax have emphysema or an isolated bulla. Although these findings may not be apparent on the radiograph and seen on CT, this probably does not affect patient management. In most cases of pneumothorax related to other causes, findings consistent with the diagnosis can be seen on the radiograph.

An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality.

Of 49 patients with nonconvulsive seizures studied with continuous EEG monitoring, the overall mortality was 33% (16/49). Of the 23 patients with nonconvulsive status epilepticus (NCSE), 13 died (mortality 57%). Individual variables significantly associated with mortality were age, presence of NCSE, seizure duration, hospital and NICU length of stay, and delay to diagnosis and etiology (acute illness versus remote symptomatic). With multivariate logistic regression, only seizure duration (p = 0.0057, OR = 1.131/hour) and delay to diagnosis (p = 0.0351, OR = 1.039/hour) were associated with increased mortality. Acute symptomatic cases could not be adequately classified as either absence, simple, or complex partial status epilepticus when the impairment of consciousness arose form the initial illness. Current classifications of status epilepticus are inadequate for such cases.

Neurophysiologic monitoring in the neuroscience intensive care unit.

Neurologically critically ill patients, more often than others, are unable to communicate and, for a crucial period of time, have the vital functions of their brains hidden in the "black box" of the cranial vault behind a curtain of ambiguity and immobility. Customarily--and naively--we have relied upon beside clinical observations to pierce these barriers. Recent insights lead us to conclude that these "neurochecks" no longer suffice. This article has surveyed four major monitoring systems relied upon by neurointensivists to evaluate the pathophysiology of their patients. Of these, ICPM has the longest clinical track record. It provides a quantitative measure of the brain's capacity to withstand ICP and helps us monitor interventions to reduce it. To utilize this information intelligently requires an understanding of the principles of ICC, CPP, ICP wave morphology, and the hardware available. NICU-CEEG is a more recent introduction but, in principle, it transfers from the laboratory and operating suite to the ICU bedside, established correlations among electrophysiology, CBF, and CM. Digital EEG has allowed us to overcome significant logistical barriers and made NICU-CEEG a practical ICU tool. Early but impressive data suggest that NICU-CEEG has a significant clinical impact in patients with ACI, uncontrolled seizures, or coma. It also has revealed that NICU patients have a surprisingly high incidence of NCS, which may adversely affect their outcome. TCD has contributed greatly to diagnosis and management of SAH vasospasm. It also can be applied with benefit to patients with increased ICP, and has promising value in patients with ACI. It may prove beneficial in monitoring unstable cerebral embolization. Several bedside methods for monitoring CBF are available, but they require refinement to become true monitoring systems. These methods have revealed clinically important insights in patients with head trauma, SAH vasospasm, and ACI. Methods for directly monitoring CM and CMRo2 are improving our understanding of the brain's responses to injury, and becoming increasingly relevant to bedside management. SjvO2 can detect cerebral ischemia caused by overzealous hyperventilation and accelerated ICP. ICO holds promise as a noninvasive transcranial method for assessing Scvo2. We soon may see a scalp array of such detectors, similar to an EEG "montage," that allows us to assess multiregional Scvo2. To be useful, a clinical method should raise questions for further investigation. If the neurophysiologic monitoring systems described here provide us with some answers and lead us to ask useful new questions, they will prove their benefit to our patients.

Status epilepticus. A perspective from the neuroscience intensive care unit.

Patients with GCSE and NCSE are common and may present to the emergency department or the NICU. In the NICU, NCSE is a more common presentation than GCSE. In the emergency department, GCSE commonly evolves to NCSE, either as a late sequela of prolonged SE or due to partial treatment with antiepileptic medication or neuromuscular blocking agents. In the emergency department, acute cerebral injuries are commonly found in patients presenting with SE, regardless of whether they have preexisting epilepsy. In the NICU, almost by definition, SE occurs in patients with acute cerebral injuries. Status epilepticus has been found to evolve sequentially through several stages, the end-point of which is a condition of refractory SE leading to neuronal necrosis and permanent cerebral injury. The responsiveness of SE to treatment is time-dependent. This makes early diagnosis and initiation of treatment essential. Most published treatment algorithms stress a 60-minute time window from the diagnosis of SE to its successful control. Unfortunately, the practical problem of patients with SE accessing such treatment protocols has been overlooked. Our preliminary (unpublished) data suggest that this access problem must be solved for treatment algorithms to improve the outcome of SE. In the NICU, access is less of a problem, and the determining factor is early diagnosis by NICU personnel. Because these patients usually sustain NCSE, which can be difficult to diagnose, a high index of suspicion and, optimally, continuous EEG monitoring are necessary for early diagnosis. NICU patients may be more susceptible to the ravages of SE because of their preexisting cerebral injuries. Expedited treatment may therefore be more important in this patient group. Clinical management of SE requires meticulous attention to ventilation and oxygenation, maintenance of adequate blood pressure, prevention of hyperthermia, and close monitoring for cardiac abnormalities. No specific medication is ideal for controlling SE. The knowledgeable and prompt use of intravenous lorazepam, a diazepam-phenytoin combination, or phenobarbital is acceptable as first-line treatment and as part of a systematic treatment algorithm. Refractory SE has been treated conventionally with high-dose intravenous barbiturate coma. Recent evidence suggests that high-dose intravenous midazolam may provide a useful alternative.

Detection of hypervascular brown tumors on three-phase bone scan.

A patient with hyperparathyroidism secondary to chronic renal failure had multiple bony lesions with increased activity on both immediate static as well as delayed scintiphotos. One lesion in the distal femur was also exceptionally hot on the flow phase. Plain radiographs demonstrated lytic lesions with sclerotic margins and a narrow zone of transition. Open biopsy revealed histology consistent with brown tumor (osteoclastoma).

Continuous EEG and evoked potential monitoring in the neuroscience intensive care unit.

As with other methods long used in intensive care units (ICU) and operating rooms (OR), the goal of neuroscience ICU continuous EEG (NICU-CEEG) and evoked potential (NICU-EP) monitoring is to extend our powers of observation to detect abnormalities at a reversible stage. EEG is an appropriate monitoring tool because it is linked to cerebral metabolism, is sensitive to ischemia and hypoxemia, correlates with cerebral topography, detects neuronal dysfunction at a reversible stage, and is the best method for detecting seizure activity. When applied systematically, it can impact medical decision-making in 81% of monitored patients. It is useful in monitoring precarious cerebral perfusion at the bedside, and it has revealed that nonconvulsive seizures, undetectable otherwise, occur in 34% of NICU patients. In convulsive status epilepticus, NICU-CEEG can help avoid undertreatment and overtreatment. In comatose patients, it can provide useful prognostic information as well as detect potentially treatable causes. Traditional impediments to its application are yielding to technological advances and educational efforts. Real-time digitized EEG in particular has been a major advance. Within limits, somatosensory evoked potential monitoring (ICU-SEP) is useful in the prognosis of coma, but it is less helpful in monitoring focal cerebral ischemia. Brainstem auditory evoked potential monitoring has a relatively restricted role in the NICU but is helpful in distinguishing structural from nonstructural causes of coma and can supplement ICU-SEP in predicting outcome.

Hyperventilation-induced cerebral ischemia in patients with acute brain lesions: demonstration by xenon-enhanced CT.

PURPOSE: To examine the possibility that hyperventilation, commonly used to prevent or treat increased intracranial pressure in patients with acute brain lesions, may induce significant cerebral ischemia. METHODS: Local cerebral blood flow and vascular reactivity were measured before and after hyperventilation using xenon-enhanced CT in 12 patients with acute brain lesions. RESULTS: Five patients showed "paradoxical" reactivity (increased cerebral blood flow during hyperventilation) within the lesions. In five patients, hyperventilation induced ischemia in apparently normal regions of brain. In three patients, areas of luxury perfusion became ischemic during hyperventilation, while in three patients, lesions with moderate ischemia became more ischemic. Most patients showed more than one type of reactivity. CONCLUSIONS: These findings document hyperventilation-induced ischemia in acute brain lesions, and demonstrate that this phenomenon affects both injured and apparently intact areas of the brain. Further studies are required to determine the clinical significance of these pathophysiologic changes.

Structure-activity relationships for inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone lung tumorigenesis by arylalkyl isothiocyanates in A/J mice.

Phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), 4-phenylbutyl isothiocyanate (PBITC), and the newly synthesized 5-phenylpentyl isothiocyanate (PPeITC), 6-phenylhexyl isothiocyanate (PHITC), and 4-(3-pyridyl)butyl isothiocyanate (PyBITC) were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the lungs of A/J mice. Mice were administered isothiocyanates by gavage for 4 consecutive days at doses of 5, 1, or 0.2 mumol/day prior to administration of 10 mumol of NNK by i.p. injection. Mice were sacrificed 16 weeks after NNK administration and pulmonary adenomas were quantitated, PEITC effectively inhibited NNK-induced lung tumors at a dose of 5 mumol/day but was not inhibitory at doses of 1 or 0.2 mumol/day. PPITC, PBITC, PPeITC, and PHITC were all considerably more potent inhibitors of NNK lung tumorigenesis than PEITC. While virtually no differences in inhibitory activity could be ascertained for PPITC, PBITC, and PPeITC, PHITC appeared to be the most potent tumor inhibitor of all of the compounds. At a dose of 0.2 mumol/day, PHITC pretreatment reduced tumor multiplicity by 85%. PyBITC, an analogue of both NNK and PBITC, was ineffective as an inhibitor. Using the same protocol, the compounds were found to have qualitatively similar inhibitory effects on NNK-induced DNA methylation when administered at 1 mumol/day. These results extend our previous findings that increased alkyl chain length enhances the inhibitory activity of an arylalkyl isothiocyanate toward NNK lung tumorigenesis and demonstrate the exceptional chemopreventive potentials of two new isothiocyanates, PPeITC and PHITC.

Effects of deuterium substitution on the tumorigenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in A/J mice.

Bioassays and DNA-binding studies of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its analogs with deuterium substitution at the positions alpha to the nitrosamino group ([4,4-D2]NNK and [CD3]NNK) were carried out in A/J mice in order to assess the potential importance of DNA methylation or pyridyloxobutylation in lung tumor induction. The tumorigenic activities of the major NNK metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its analog with deuterium at the carbinol carbon ([1-D]NNAL) were also determined. Groups of A/J mice were given single i.p. injections of either 10 or 5 mumol of NNK, [4,4-D2]NNK, [CD3]NNK, NNAL and [1-D]NNAL, and were killed 16 weeks later. Lung tumor multiplicities were as follows in mice treated with 10 mumol: NNK, 7.3 +/- 3.5; [4,4-D2]NNK, 1.4 +/- 1.6; [CD3]NNK, 11.7 +/- 5.4; NNAL, 3.2 +/- 2.0; [1-D]NNAL, 3.2 +/- 2.0. Similar relative tumorigenic activities were observed in mice treated with 5 mumol of these compounds. These results demonstrated that [4,4-D2]NNK was less tumorigenic than NNK and [CD3]NNK was more tumorigenic than NNK. NNAL was less tumorigenic than NNK; substitution of deuterium at the carbinol carbon did not affect its activity. Levels of O6-methylguanine (O6-mG) were measured in pulmonary DNA of A/J mice treated with 10 mumol of NNK, [4,4-D2]NNK or [CD3]NNK, and killed 2 or 24 h later. O6-mG levels were lower in mice treated with [4,4-D2]NNK than in those treated with NNK; no difference in O6-mG levels was observed between those treated with NNK and [CD3]NNK. The results of this study support the hypothesis that O6-mG formation in pulmonary DNA is the key step in lung tumor induction by NNK in A/J mice.

Effects of catechol on the induction of tumors in mouse skin by 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrenes.

Catechol (1,2-dihydroxybenzene) is a major phenolic compound present in the co-carcinogenic fraction of cigarette tar. It has been shown to be a potent co-carcinogen with benzo[a]pyrene (BaP) in mouse skin. In this study we have examined the co-carcinogenic and co-initiating activities of catechol with racemic and enantiomeric 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrenes (BaP-7,8-diols) in mouse skin. Similar to enhancement of BaP carcinogenesis, repeated concurrent applications of catechol and (+/-)-BaP-7,8-diol to mouse skin strongly enhanced (+/-)-BaP-7,8-diol tumor multiplicity and tumor incidence, and decreased latency. Co-application of catechol with the racemic or either of the enantiomers of BaP-7,8-diol in a two-stage initiation--promotion protocol increased the tumor initiating activity of racemic BaP-7,8-diol, similar to that of BaP, by approximately 50%, but had no statistically significant effect on the tumor initiating activity of the (+)- or (-)-enantiomers in mouse skin. Thus, catechol is as potent a co-carcinogen with (+/-)-BaP-7,8-diol as it is with BaP. However, as tested here catechol is a weak co-initiator when applied with (+/-)-BaP-7,8-diol or BaP.

Rapid single-dose model for lung tumor induction in A/J mice by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and the effect of diet.

This paper describes the development of a relatively rapid single-dose model for induction of lung adenomas in female A/J mice by the tobacco-specific nitrosamine 4-(methylnitros-amino)-1-(3-pyridyl)-1-butanone (NNK). Mice maintained on AIN-76A semi-synthetic diet were given a single i.p. dose of 2.5, 5 or 10 mumol NNK in saline and killed 3-7 months later. Maximum lung tumor induction, measured by lung tumors per mouse (tumor multiplicity), occurred in 3.5 months. There was no significant increase in tumor multiplicity between 3.5 and 7 months. Four months after treatment, numbers of lung tumors per mouse were 11.9 +/- 1.0 (10 mumol NNK), 3.6 +/- 0.4 (5 mumol), 0.9 +/- 0.4 (2.5 mumol) and 0.07 +/- 0.1 (saline). Lung tumor multiplicity in mice treated with a single dose of 10 mumol NNK and maintained on AIN-76A diet was significantly higher (8.3 +/- 0.5) than in mice treated with NNK and maintained on NIH-07 diet (2.5 +/- 0.3). The results of this study establish a useful bioassay for identification of compounds that can modify NNK-induced lung tumorigenesis.