Safety, tolerability, and pharmacokinetics of weight-based IV loading dose of lacosamide in the ICU.

Among the newer antiseizure medications, lacosamide (LCM) has been increasingly used for acute seizures and status epilepticus in intensive care unit (ICU). We reviewed retrospectively weight-based dosing of IV LCM in patients admitted to ICU with acute seizures and status epilepticus. We have analyzed 354/382 patient treated with IV LCM in ICU during the years 2013-2016. Data collected were age, total body weight, body mass index (BMI), loading dose, post-IV infusion LCM blood level, duration of infusion, blood pressure, heart rate, oxygen saturation, mean arterial pressures, and documented initiation of pressor agents during or within in 30 min of infusion. Larger doses >8 mg/kg of IV LCM that can be safely administered in ICU patients produce effective plasma levels of 15-20 µg/ml with relatively constant volume of distribution.

Secondary hypothermia in patients with super-refractory status epilepticus managed with propofol and ketamine.

BACKGROUND: Therapeutic hypothermia as a potent nonpharmacologic antiseizure therapy has been investigated experimentally in animal models and humans. Although induced hypothermia has been shown to be neuroprotective in acute convulsive status epilepticus, whether its use will translate into improved outcomes for patients with super-refractory nonconvulsive status epilepticus (SRNCSE) has been debated. No clinical data are available on the occurrence and prognostic impact of secondary hypothermia (s-HT) in patients with SRNCSE. With the possibility of core to periphery redistribution of heat with propofol and a centrally mediated dose-dependent fall in body temperature with ketamine, we aimed to investigate the incidence of s-HT events in patients with SRNCSE managed with propofol and ketamine and their impact on clinical outcomes. METHODS: We performed a retrospective observational analysis of consecutive patients with SRNCSE managed with propofol and/or ketamine in a single-center neurological intensive care unit between December 1, 2012 and December 31, 2015. Patients were divided according to the occurrence of hypothermia (temperature < 35.0 °C) into an s-HT group and a nonhypothermia (n-HT) group. Patients who received targeted temperature management therapy were excluded. We compared the demographics, comorbidities, treatment characteristics, and outcomes between groups. RESULTS: Ninety-nine consecutive patients with SRNCSE managed with propofol and/or ketamine were identified during the study period. Twenty patients who received targeted temperature management were excluded, leaving a total of 79 patients for analysis. Hypothermia was observed in 52% (41/79) of the study population. Ketamine was used in 63/79 patients (80%). Ketamine infusion rates were higher and of longer duration among patients who developed s-HT compared with those who did not (mean dosage: 57.35 ±â€¯26.6 mcg/kg/min vs 37.17 ±â€¯15 mcg/kg/min, P = 0.001; duration: 116.36 ±â€¯81.9 h vs 88 ±â€¯89.7 h, P = 0.048). Propofol was used in 78/79 patients (99%), with no significant differences in characteristics between groups (mean dosage: 46.44 ±â€¯20.2 mcg/kg/min vs 36.9 ±â€¯12.9 mcg/kg/min, P = 0.058; duration: 125.43 ±â€¯96.4 h vs 102.3 ±â€¯87.1 h, P = 0.215). No significant differences in demographics, comorbidities, status epilepticus duration and resolution rates, and outcomes were observed between groups. CONCLUSION: In this single-center retrospective analysis of patients whose SRNCSE is being treated, higher doses and longer durations of ketamine were associated with the occurrence of s-HT. Further investigation is warranted to clarify the thermogenic effects of ketamine and its effect on status epilepticus outcomes.

Neurosarcoidosis: clinical features, diagnosis, and management.

Sarcoidosis is a multisystemic granulomatous disease, which uncommonly affects nervous system. However, when present, it may affect both central and peripheral nervous systems and potentially mimics other chronic diseases of the nervous system. Pathogenesis of neurosarcoidosis remains largely unknown, and its diagnosis and management pose serious challenges to clinicians. Early diagnosis and aggressive treatment of neurosarcoidosis are necessary to produce satisfactory clinical outcomes. This review discusses clinical manifestations, current diagnostic studies, and currently available modalities for management of neurosarcoidosis.

Clinically presenting acute/subacute ischemic stroke: differential diagnosis of the non-enhanced CT hypodensity by advanced neuroimaging.

OBJECTIVES: Patients presenting to the emergency room with an acute or subacute onset of focal neurological deficits are evaluated initially by non-contrast computed tomogram (CT) of the brain. This is primarily carried out to differentiate an ischemic from hemorrhagic stroke. However, other neurological conditions may have a similar clinical presentation as well as only hypodensities on CT scan, thus mimicking ischemic stroke. This review focuses on the advanced neuroimaging modalities that help differentiate these other conditions from a cerebral infarction. METHODS: The literature was reviewed in order to ascertain what conditions would clinically and by CT mimic an acute/subacute ischemic infarction, and what advanced neuroimaging techniques would be most useful in differentiating these conditions. RESULTS: Several infectious, inflammatory, metabolic and vascular diseases were found with clinical presentations identical to subacute/acute ischemic cerebral infarction, which also could demonstrate only hypodensities on a non-enhanced CT scan. However, advanced neuroimaging techniques could readily differentiate these conditions from ischemic infarction. CONCLUSIONS: As presented in this review, although several diseases initially present a diagnostic dilemma upon presentation because of their clinical and non-enhanced CT similarities to cerebral infarction, advanced diagnostic neuroimaging readily establishes their unique pathologies.

Subcortical ischemic cerebrovascular dementia.

It has become increasingly apparent, especially with the advent of MRI brain scanning, that a large number of patients develop signal intensity changes in the subcortical white matter and periventricular region as they age. This appears to be accelerated by risk factors for small vessel cerebrovascular disease such as hypertension, smoking, diabetes mellitus and hyperlipidemia. The major question becomes when such changes become clinically significant. It is obvious that subcortical lacunar-type infarction can be identified by the clinical presentation. For example, typical examples of so-called "lacunar syndrome" include pure motor hemiparesis, pure sensory stroke, sensorimotor stroke, clumsy hand-dysarthria, and hemiataxia-hemiparesis. The issue becomes a measure of impact on functional ability. This is influenced by several factors. Baseline IQ and educational level, as well as expectations of age, certainly play a role. A person who develops cognitive impairment and long tract signs in their 50s or 60s is certainly going to be recognized as more impaired than an 80 year old individual who is retired and primarily is engaged in recreational activity. It would be expected that a person born with limited intellectual capacity and/or limited educational opportunity would be less likely to be identified as impaired than a person who has achieved substantial economic achievement through their innate talents. The concept of tissue loss or lesion load becomes important when determining how pronounced the ischemic cerebrovascular changes translate into functional impairment. Correlative pathology may include cortical atrophy and ventricular dilatation. Loss of either cortical or subcortical tissue function is expected to be related to functional compromise. In addition, there are potential features such as the coexistence of small vessel cerebrovascular disease and Alzheimer's disease. Small vessel cerebrovascular disease might also play a contributing factor in patients susceptible to Dementia with Lewy Bodies or patients susceptible to fronto-temporal dementia or any other dementing process. Thus, the concept of tissue loss or lesion burden of disease becomes increasingly important as we recognize the potential for multifactorial issues, including genetic factors, to contribute to the phenotypic expression. The relationships between cognitive impairment, dementia and subcortical vascular lesions are poorly understood. There have been several papers on the different aspects of cerebral insults and their impact on cognition, the various kinds of dementia and different methods of analyzing the impact of the various insults to the brain. This chapter is an attempt to review all pertinent information currently available on the poorly understood condition of "subcortical ischemic cerebrovascular dementia."

Perioperative stroke.

It is increasingly recognized that one can identify a higher risk patient for perioperative stroke. The risk of stroke around the time of operative procedures is fairly substantial and it is recognized that patients initially at risk for vascular events are those most likely to have this risk heightened by invasive procedures. Higher risk patients include those of advanced age and there is a cumulative risk, over time, of coexistent hypertension, atherosclerosis, diabetes mellitus, cardiac disease and clotting disorders. There are a number of possible mechanisms associated with the procedure (e.g., preoperative hypercoagulability, holding of antithrombic therapy at the time of the procedure and cardiac arrhythmia) that can promote a thrombo-embolic event. Examples of these include: direct mechanical trauma to extracranial vessels related to operations on the head and neck; and vascular injury as a consequence of vascular and innovative endovascular procedures affecting the cerebral circulation (e.g., carotid endarterectomy, extracranial or intracranial angioplasty with stenting, and use of the MERCI clot retrieval device), as well as various endovascular methods that have been developed to obliterate cerebral aneurysms and arteriovenous malformations as an alternative to surgical clipping and surgical resection, respectively.

Multiple sclerosis as a painful disease.

Pain is a common problem of patients with multiple sclerosis (MS) and may be due to central/neuropathic or peripheral/somatic pathology. Rarely MS may present with pain, or pain may herald an MS exacerbation, such as in painful tonic spasms or Lhermitte's sign. In other patients, pain may become chronic as a long-term sequela of damage to nerve root entry zones (trigeminal neuralgia) or structures in central sensory pathways. Migraine headache may develop as a consequence of MS, and headache can also be a side effect of interferon treatment. The pathophysiology of pain in MS may be linked to certain plaque locations which disrupt the spinothalamic and quintothalamic pathways, abnormal impulses through motor axons, development of an acquired channelopathy in affected nerves, or involve glial cell inflammatory immune mechanisms. At this time, the treatment of pain in MS employs the use of antiepileptic drugs, muscle relaxers/antispasmodic agents, anti-inflammatory drugs, and nonpharmacological measures. Research concerning cannabis-based treatments shows promising results, and substances which block microglial or astrocytic involvement in pain processing are also under investigation.

The role of quantitative neuroimaging indices in the differentiation of ischemia from demyelination: an analytical study with case presentation.

BACKGROUND AND PURPOSE: Differentiation of acute and subacute ischemic stroke lesions from acute demyelinating lesions of multiple sclerosis (MS) may not be possible on conventional magnetic resonance imaging (MRI). Both lesion types enhance on T1 with gadolinium (Gd) contrast and both are hyperintense on diffusion-weighted imaging (DWI). This study is an analysis of two quantitative MR indices: (1) calculated apparent diffusion coefficients (ADCs) and (2) T2 relaxation times (T2R) as means toward differentiating acute ischemic lesions from acute demyelinating lesions. Chronic ischemic and demyelinating lesions were evaluated for comparison as well. METHODS: The MRI of nine patients with both acute and chronic ischemic lesions and six patients with both acute and chronic demyelinating lesions were analyzed for ADC and T2Rs. The indices were measured by manually placing regions of interest (ROIs) at the anatomic center of the acute lesion. Acute ischemic lesions were chosen by their hyperintensity on DWI and hypointensity on ADC mapping. Acute demyelinating lesions were selected by peripheral contrast enhancement after the administration of Gd. Computation of the ADC involved the diffusion coefficient on a region by region basis as follows: D = -(b(0)/b(1000))ln(S(b1000)/S(b0)), where S(b1000) is the signal intensity on DWI and S(b0) is the signal intensity on T2 with diffusion sensitivities of b(0) and b(1000), respectively. Computation of the T2R was made as follows: T2R = (TE(T2)--TE(PD))/(ln SI(PD)--ln SI(T2)), where TE is the echo time of the different pulse sequences, SI is signal intensity on the different echo sequences, and PD represents proton density sequence. RESULTS: Twenty-nine acute ischemia, 27 acute demyelination, 28 chronic ischemia, and 43 chronic demyelination image sets were analyzed. The differences between ADC(acute infarct) (0.760) versus ADC(acute plaque) (1.106) were significant (p < 0.02). The differences between T2R(acute infarct) (235.5) versus T2R(acute plaque) (170.5) were also significant (p < 0.02). CONCLUSIONS: ADC in combination with T2R is a useful tool to differentiate acute ischemic from acute demyelinating lesions. The use of these neuroimaging indices along with magnetic resonance spectroscopy metabolite ratios is then demonstrated in elucidating the pathophysiological mechanism for a case of delayed posttraumatic bilateral internuclear ophthalmoplegia.

Evolving therapies for multiple sclerosis.

The introduction of immunomodulatory and immunosuppressive agents for treatment of multiple sclerosis (MS) has forever altered the natural course of this incurable and disabling neurodegenerative disorder. Despite early diagnosis of relapsing-remitting MS and early initiation of therapy, patients still experience breakthrough relapses and progression of their underlying MS pathology. The imperfect effectiveness, side effects, and toxicity of these agents, emphasize the necessity for development of more effective medications with less adverse events. This chapter presents readers with the most current information on the nature, mechanism(s) of action, and side effects of the most promising experimental agents currently under clinical trials. Some of the agents now at different stages of clinical trial have emerged as both safe and promising. The understanding of MS etiology will lead to the development of increasingly specific, safer, and effective treatments for MS by neuroscientists and neurologists.