Gretchen M. Brophy, PharmD, BCPS, FCCP, FCCM, FNCS
https://www.usfq.edu.ec/eventos/neurocritico/Documents/gretchen_brophy.html
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Remission occurs before age 15 generic 150 mg pregabalin mastercard, but patients may be left cognitively impaired (6). Seizure types that may be observed include atypical absence, myoclonic, clonic, and complex partial seizures. There are not usually clear sharp waves unless the patient is having atypical absence seizures, and the findings have been referred to as "ill-defined slow-spike-and wave" (48). Rett syndrome is encountered between 6 months and 3 years of age and only in females. It is helpful to have specific neuroimaging protocols that are designed to detect neuronal migrational disorders that might further implicate a potentially surgically remediable localization remediable epilepsy (53). Metabolic and genetic evaluations without a clinical direction suspected from the history, physical, and neuroimaging is presently of low yield. Specific genetic analyses may become more commonplace as the genetic basis for different cortical malformations becomes known. Early in the course of the epilepsy when this evaluation is done, mitochondrial disorders and neuronal ceroid lipofuscinosis may present similarly, and appropriate biochemical evaluations should be considered. Additionally, molecular genetic studies have identified causative genes and loci for a number of early malignant epileptic encephalopathies creating the possibility of genetic testing (22) both for diagnosis and differential diagnosis. Further evaluation for aminoacidopathies, organic acidopathies, urea cycle defects, chromosomal abnormalities should be performed where appropriate. Lumbar puncture should be used in cases of suspected infectious and metabolic etiologies (especially mitochondrial and neurotransmitter deficiencies). Many other medications have purported benefit including levetiracetam, clonazepam, and clobazam. Clobazapam may be preferable to clonazepam given a lesser likelihood to cause sedation. Over sedation may be as damaging to development and gaining functional skills as the recurrent seizures. In particular, benzodiazepines use may evoke sedation and may provoke atypical absence and tonic status epilepticus (30,31). There was no increase in adverse effects as compared to placebo except for an increase in respiratory infections. From a practical standpoint, it is difficult to use it as an initial drug because of the slow titration. An open label extension of the same study utilizing an average of close to 10 mg/kg/day showed a greater than 50% decrease in drop attacks in 55% of the patients including 15% with elimination of drop attacks (65). Parental reports of increased alertness and improved verbal output were noted very early in its use (67). Now, it has more limited use due to the risk of liver failure in children (approximately 1 in 30,000).
However cheap pregabalin 75 mg on line, no clinical reports of an interaction between bilberry and these or other drugs appear to have been published. Constituents the berries contain anthocyanins, mainly glucosides of cyanidin, delphinidin, malvidin, petunidin and peonidin. Bilberry berries also contain flavonoids (including catechins, quercetin-3-glucuronide and hyperoside), and vitamin C. For information on the interactions of individual flavonoids found in bilberry, see under flavonoids, page 186. Use and indications Traditionally bilberry has been used to treat diarrhoea, haemorrhoids and venous insufficiency, gastrointestinal inflammation and urinary complaints. Use and indications Bistort is traditionally used as an astringent and antiinflammatory agent. For information on the pharmacokinetics of individual flavonoids found in bistort, see under flavonoids, page 186. Constituents the bistort root and rhizome contain polyphenolic compounds, mainly flavonoids. For information on the interactions of individual flavonoids found in bistort, see under flavonoids, page 186. Constituents Bitter orange contains the sympathomimetic alkaloid oxedrine (synephrine), flavonoids (hesperidin, naringenin, tangeretin and others; often referred to as citrus bioflavonoids), and natural coumarins (umbelliferone, 6,7-dimethoxycoumarin, and the furanocoumarins 6,7-dihydroxybergamottin and bergapten). Some sources standardise the flowers to flavonoid content, expressed as naringin, and the peel to essential oil content. The juice may also inhibit P-glycoprotein transport (see dextromethorphan, page 69). For information on the pharmacokinetics of individual flavonoids present in bitter orange, see flavonoids, page 186, and for the pharmacokinetics of individual furanocoumarins, see under natural coumarins, page 297. Interactions overview the juice of bitter orange has been used in some drug interaction studies (as a comparator to grapefruit juice, page 235). Information from these studies has been included here, but note that it should not be directly extrapolated to herbal medicines containing bitter orange, because some differences in interaction potential have been seen. A bitter orange decoction increased ciclosporin levels in animals, whereas the juice of bitter orange does not appear to interact clinically. The juice of bitter orange does not appear to affect the pharmacokinetics of indinavir, but it may raise dextromethorphan and felodipine levels. For a possible interaction of supplements containing bitter orange with caffeine, resulting in adverse cardiac effects, see Caffeine + Herbal medicines; Bitter orange, page 101. For specific interactions of citrus flavonoids such as naringenin, see flavonoids, page 186, and for citrus furanocoumarins such as bergapten, see natural coumarins, page 297.
Diseases
Safety of intrahippocampal depth electrodes for presurgical evaluation of patients with intractable epilepsy buy 75 mg pregabalin with amex. Insertion of subdural strip electrodes for the investigation of temporal lobe epilepsy. Intracranial electroencephalography with subdural grid electrodes: techniques, complications, and outcomes. Clinical outcome after complete or partial cortical resection for intractable epilepsy. Subdural electrodes in the evaluation for epilepsy surgery in children and adults. Intraventricular monitoring for temporal lobe epilepsy: report on technique and initial results in eight patients. Responses to single pulse electrical stimulation identify epileptogenesis in the human brain in vivo. However, any lesion should not be assumed to be the source of the seizures ("dual pathology"), as some are often incidental. Scenarios When Intracranial Localization May Be Limited Although most cases of extratemporal onset involve difficult intrahemispheric localization, lateralization is occasionally at issue. This is particularly common in seizures arising from the supplementary sensorimotor area, where symptomatology and midline epileptiform discharges indicate mesial frontal onset, but lateralization is unclear in the absence of imaging abnormalities or clinical lateralizing signs (55). When the noninvasive presurgical evaluation does not sufficiently narrow the possibilities for localization, invasive studies may be of limited benefit. Presurgical evaluation strategies in patients with localization-related epilepsy remain variable and controversial. No universal scheme is accepted by all epilepsy surgery centers, and techniques continue to evolve (56). Appreciating the brain coverage, strengths, and weaknesses of each invasive technique will help in this choice. In addition, the risk of invasive techniques varies among surgeons; as with other types of surgical procedures, experience and successful practice are important. Advancement in neuronavigation techniques allows for more accurate placement of the electrodes with less complication rate. Of course, the lowest complication rates can be expected from experienced epilepsy neurosurgeons at high-volume epilepsy surgery centers. The predictive value of intraoperative electrocorticography in resections for limbic epilepsy associated with mesial temporal sclerosis.
This editorial highlighted several other medical conditions and situations that are associated with a similar or higher relative risk of a car crash compared with epilepsy buy pregabalin 75 mg on-line, such as sleep, apnea, diabetes, dementia, and cell phone use (distraction) (29). Persons with epilepsy are reported to have lower household incomes, which are estimated to be 93% of the U. In the United States, the rate of unemployment for persons with epilepsy is reported to be between 25% and 69% (33,34). The overall nationwide rate of graduation from high school is approximately 82%; for persons with epilepsy, this rate is approximately 64% (33). Although many factors are likely to contribute to the high rate of unemployment among persons with epilepsy, poorly controlled epilepsy is associated with a high level of unemployment (34). Age of epilepsy onset also impacts employment status, with an earlier age of onset correlating with work difficulties later in life (35). In patients with adult-onset epilepsy, initial seizure control or lack of control does affect work status. Newly diagnosed, unprovoked seizures in adults do not seem to negatively impact employment rates. The same study associated the development of refractory seizures in adults with reduced income (36). Many persons with epilepsy have to deal with the reality of employment discrimination. A survey of young persons with epilepsy enrolled in a job-training program in Ireland indicated that 50% of the participants believed they were being actively discriminated against when seeking employment (37). The law was intended to help persons with epilepsy and persons with other disabilities obtain and retain employment. Furthermore, what constitutes a reasonable accommodation was left open to interpretation. The standard may be based on the actual cost of any modifications required that allow a person to keep a specific job. Administrative and court rulings have made it clear that the protection sought has not been achieved (38). The law was passed in an effort to clarify and be more inclusive on what constitutes disability under the law. Major life activities specifically covered in the law are highlighted in Table 94. The major life limitations due to epilepsy can result from seizures or the complications and side effects of medications used to treat the seizures. When making decisions about participating in any activity, a person with epilepsy must consider the consequences of a seizure that may occur at any moment during that particular activity. Certain jobs may be perfectly safe for many persons with epilepsy but other jobs may impose unacceptable risk. A person with epilepsy must carefully evaluate jobs involving dangerous machinery, or equipment heights, or situations in which there is a possibility for injury or death because of potentially dangerous conditions in the event of a seizure.
Brief muscle spikes and eye movement artifacts are time-locked to the photic flashes that cease when the stimulus is discontinued (49) 150mg pregabalin otc. These paroxysms of rhythmic sharp-wave discharges or rhythmic activity in the -, -, or -frequency ranges may occur in a focal or multifocal distribution. The interictal background activity is prognostically important in this population. Neonatal seizures associated with symptomatic neurologic disease such as anoxic encephalopathy may feature a low-voltage background abnormality or a burst-suppression pattern indicative of a poor prognosis. Due to the association of neonatal seizures with neurodevelopmental abnormalities, early and accurate detection is important (50). Depending on the expertise of the interpreting neonatologist, the sensitivity may range from 12% to 55% (50). Hypsarrhythmia Hypsarrhythmia is a chaotic mixture of high-amplitude (exceeding 300 mV), generalized, continuous, arrhythmic slow-wave activity intermixed with spike and multifocal spike discharges. Comparison of nasopharyngeal with scalp electrodes including ear and true temporal electrodes in the detection of spikes. Interictal epileptiform discharges: discriminating characteristics and clinical correlations. International Federation of Society for Electroencephalography and Clinical Neurophysiology. Periodic lateralized epileptiform discharges with transitional rhythmic discharges: association with seizures. Generalised periodic epileptiform discharges: clinical features, neuroradiological evaluation and prognosis in 37 adult patients. Nonconvulsive seizures: developing a rational approach to the diagnosis and management in the critically ill population. Electroencephalographic studies of simple partial seizures with subdural electrode recordings. Electroencephalographic spiking activity, drug levels, and seizure occurrence in epileptic patients. Clinical outcome after complete or partial resection for intractable partial epilepsy. A new type of epilepsy: benign partial epilepsy of childhood with occipital spike-waves. Generalized sharp and slow wave complexes-associated clinical features and long-term follow-up. Childhood epileptic encephalography with diffuse slow spike-waves (otherwise known as "petit mal variant") or Lennox syndrome. Photomyoclonic response of epileptic and nonepileptic subjects during wakefulness, sleep, and arousal.
Syndromes
An additive effect with antithyroid drugs such as propylthiouracil might also occur discount pregabalin 75 mg otc, and therefore similar caution would seem advisable. Since, in euthyroid animals, thyroid hormones were decreased and hepatic lipid peroxidation was increased, the authors suggest that high amounts of this plant extract should not be consumed, as hepatotoxicity as well as hypothyroidism may occur. Cardio-protective role of Terminalia arjuna bark extract is possibly mediated through alterations in thyroid hormones. Its use now focuses more on hypercholesterolaemia, hyperlipidaemia and irritable bowel syndrome, and some cardiovascular disorders such as atherosclerosis. Artichoke flowers are also used as food and artichoke extracts are used as flavouring agents. For information on the pharmacokinetics of individual flavonoids present in artichoke, see under flavonoids, page 186. Constituents Artichoke leaf is usually standardised to the caffeoylquinic acid derivative, chlorogenic acid. Other major constituents are flavonoid glycosides based on luteolin, including cynaroside and scolymoside, and sesquiterpene lactones including cynaropicrin. For information on the interactions of individual flavonoids present in artichoke, see under flavonoids, page 186. Use and indications the leaf extract has been traditionally used for liver and 38 Asafoetida Ferula asafoetida L. Asafoetida is obtained from various Ferula species, the main sources being Ferula asafoetida L. Use and indications Asafoetida is used for its carminative, antispasmodic and expectorant properties in chronic bronchitis, pertussis, and specifically for intestinal flatulent colic. Studies in rats fed with asafoetida suggest that, it did not stimulate levels of cytochrome P450, and glucuronyl transferase activity remained unaffected. The sesquiterpene dienones, fetidones A and B, samarcandin and galbanic acid are also present. Interactions overview In theory the use of asafoetida with conventional antihypertensives may be expected to produce additive hypotensive effects. Although it has been suggested that asafoetida may interact with anticoagulants, the available data do not appear to support this prediction. Influence of spices and spice principles on hepatic mixed function oxygenase system in rats. Experimental evidence In a study in rats, asafoetida gum extract significantly reduced mean arterial blood pressure. Importance and management Because of the nature of the evidence, applying these results in a clinical setting is extremely difficult and, until more is known, it would be unwise to advise anything other than general caution.
Electromagnetic source analysis adds information to the localization and organization of both generic pregabalin 150 mg with visa, epileptogenic and normal cortical areas, which turns out to be clinically relevant in at least 10% of the cases. In addition, the impact of electromagnetic source analysis in the prediction of postsurgical seizure outcome has to be further investigated. Magnetoencephalography: evidence of magnetic fields produced by alpha rhythm currents. Interictal electromagnetic source imaging in focal epilepsy: practices, results and recommendations. Modality-specific spike identification in simultaneous magnetoencephalography/electroencephalography: a methodological approach. Functional organization of the human first and second somatosensory cortices: a neuromagnetic study. Magnetoencephalography: theory, instrumentation and applications to noninvasive studies of the working human brain. Demonstration of useful differences between magnetoencephalogram and electroencephalogram. Magnetoencephalography in partial epilepsy: clinical yield and localization accuracy. Detection of epileptiform activity by human interpreters: blinded comparison between electroencephalography and magnetoencephalography. Magnetoencephalographic spikes not detected by conventional electroencephalography. Magnetoencephalography is more successful for screening and localizing frontal lobe epilepsy than electroencephalography. Feasibility and limitations of magnetoencephalographic detection of epileptic discharges: simultaneous recordings of magnetic fields and electrocorticography. Interictal and ictal magnetoencephalographic study in patients with medial frontal lobe epilepsy. Single and multiple clusters of magnetoencephalographic dipoles in neocortical epilepsy: significance in characterizing the epileptogenic zone. Magnetic source imaging versus intracranial electroencephalogram in epilepsy surgery: a prospective study. Anatomical correlates for magnetoencephalography: integration with magnetic resonance images. Source localization determined by magnetoencephalography and electroencephalography in temporal lobe epilepsy: comparison with electrocorticography: technical case report. Multiple source analysis of interictal spikes: goals, requirements and clinical value. Application of magnetoencephalography in epilepsy patients with widespread spike or slow-wave activity. Magnetoencephalographic evaluation of children and adolescents with intractable epilepsy.
Specific Populations Hepatic Impairment the pharmacokinetics of perampanel following a single 1 mg tablet dose were evaluated in 12 subjects with mild and moderate hepatic impairment (Child-Pugh A and B order pregabalin 150 mg with visa, respectively) compared with 12 demographically matched healthy subjects. Perampanel has not been studied in subjects with severe hepatic impairment [see Dosage and Administration (2. Renal Impairment A dedicated study has not been conducted to evaluate the pharmacokinetics of perampanel in patients with renal impairment. Considering the substantial overlap in the exposure between normal and mildly impaired patients, no dosage adjustment is necessary for patients with mild renal impairment. Perampanel has not been studied in patients with severe renal impairment and patients undergoing hemodialysis [see Dosage and Administration (2. Pediatrics In a population pharmacokinetic analysis of healthy subjects and pediatric and adult patients with partial onset seizures, including 123 children 4 years to less than 12 years of age, 226 adolescents 12 years to less than 18 years of age, and 1912 adults 18 years of age and older, no significant effect of age or body weight on perampanel clearance was found. Transporters In vitro studies showed that perampanel is not a substrate or significant inhibitor of the following: organic anion transporting polypeptides 1B1 and 1B3; organic anion transporters 1, 2, 3, and 4; organic cation transporters 1, 2, and 3; efflux transporters P-glycoprotein and Breast Cancer Resistance Protein. Eslicarbazepine is structurally similar to oxcarbazepine and thus may also reduce perampanel plasma concentrations when used concomitantly. A modest effect of phenobarbital and primidone on perampanel concentrations cannot be excluded. Mutagenesis Perampanel was negative in the in vitro Ames and mouse lymphoma tk assays, and in the in vivo rat micronucleus assay. Impairment of Fertility In male and female rats administered perampanel (oral doses of 1, 10, or 30 mg/kg/day) prior to and throughout mating and continuing in females to gestation day 6, there were no clear effects on fertility. Prolonged and/or irregular estrus cycles were observed at all doses but particularly at the highest dose tested. All trials had an initial 6week Baseline Period, during which patients were required to have more than five seizures in order to be randomized. The Baseline Period was followed by a 19-week Treatment Period consisting of a 6-week Titration Phase and a 13-week Maintenance Phase. Patients in these 3 trials had a mean duration of epilepsy of approximately 21 years and a median baseline seizure frequency ranging from 9 to 14 seizures per 28 days. Patients experiencing intolerable adverse reactions were permitted to have their dose reduced to the previously tolerated dose. The primary endpoint in Studies 1, 2, and 3 was the percent change in seizure frequency per 28 days during the Treatment Period as compared to the Baseline Period. A statistically significant decrease in seizure rate was observed at doses of 4 to 12 mg per day. Dose response was apparent at 4 to 8 mg with little additional reduction in frequency at 12 mg per day. Proportion of Patients Exhibiting Different Percent Reductions During the Maintenance Phase Over Baseline Across All Three Trials. The percentages of patients with a 50% or greater reduction in seizure frequency were 19%, 29%, 35%, 35% for placebo, 4, 8, and 12 mg, respectively. Patients were titrated over 4 weeks up to a dose of 8 mg per day or the highest tolerated dose and treated for an additional 13 weeks on the last dose level achieved at the end of the titration period.
The extent of the coverage is also dictated by the proximity of the abnormalities to anatomical structures that serve critical cortical functions cheap 150mg pregabalin amex, such as cognitive, speech, or motor functions. The coregistration makes it possible to study the spatial relationship of the abnormalities to each other, and also to appreciate their relationship to neuroanatomical structures. Through this method, the irritative and the ictal-onset zones are related topographically to the functional imaging abnormalities. Therefore, the coregistration technique used must be validated to determine the "worst case" degree of error. This is accomplished by pointing the tip of a probe at the spot of interest on the exposed brain. This technology makes it possible to locate the functional imaging abnormality on a normal-appearing brain surface. After this procedure, the positions of these fiduciary scalp markers are manually registered by an infrared probe into a transformational matrix. Evidence of lateralizing or localizing abnormalities must be sought from noninvasive sources and tests, specifically from the results of clinical, electrophysiologic, neuropsychologic, and functional imaging studies. Careful presurgical evaluation in both intractable temporal and extratemporal nonlesional epilepsy patients can lead to favorable postsurgical outcome similar to that in lesional patients (35). However, the limitations and drawbacks of each noninvasive or minimally invasive modality must be considered. C: During surgery, the surgeon uses a probe to point at the location in the operative field. This observation is used to guide implantation of intracranial electrodes or surgical resection or transection of the abnormal focus. Patients should understand that the outcome of nonlesional epilepsy surgery is generally not as favorable as that of lesional surgery. Standard magnetic resonance imaging is inadequate for patients with refractory focal epilepsy. Factors underlying extracranial interictal epileptiform discharges in intractable frontal lobe epilepsy. Interictal, unifocal spikes in refractory extratemporal epilepsy predict ictal origin and postsurgical outcome. Theodore W, Sato S, Kufta C, et al, Temporal lobectomy for uncontrolled seizures: the role of positron emission tomography. Identification of frontal lobe epileptic foci in children using positron emission tomography. Verbal memory impairment after right temporal lobe surgery: the role of contralateral damage as revealed by 1H magnetic resonance spectroscopy and T2 relaxometry. Surgical outcome and prognostic factors of cryptogenic neocortical epilepsy [see comment]. A 10-year experience with magnetic source imaging in the guidance of epilepsy surgery.
Electroencephalographers are used to looking for phase reversals in a bipolar montage generic pregabalin 75mg without a prescription. In this tracing there is no phase reversal; therefore, the discharge must be coming from either the beginning or the end of the chain. If the sharp wave is negative, implying that the activity is at the beginning of the chain (F7), the distribution has a much more realistic falloff. If the sharp wave is assumed to be positive, then the maximum would have to be at the end of the chain (F8) with an oddly flat distribution on the right and a rapid falloff on the left. The amplitudes of the differences between the voltages at input 1 and input 2 do not indicate the maximum of the electrical field. In this circumstance, the amplitude of the sharp wave is actually maximum at F7 and T7, but approximately equal in those two adjacent eletrodes, so the discharge is localized to both electrodes. This montage, which employs a contralateral reference chosen because it appeared to be uninvolved in the discharge, helps to clarify the location of a spike widely distibuted across the left temporal region. Since there is a phase reversal between channels 2 and 3, the reference is neither minimum nor maximum, that is, it must be "involved. If the reference electrode is the minimum of the electrical field, the maximum will be at the electrode with the largest amplitude. This situation is the easiest to analyze, because the amplitude of the deflection in each channel directly reflects the level of activity in input 1 of the channel. If the reference is maximum, the electrode at input 1 of the largest-amplitude channel is at the minimum of the electrical field. If the reference is maximum and some channels show no deflection, the electrodes connected to input 1 of those channels are also maximum. If there is a phase reversal, then the reference electrode is neither the minimum nor the maximum of the electrical field. This indicates that some electrodes connected to input 1 have a greater potential and some a lower potential than the reference. If, for instance, the polarity of the discharge is negative, those electrodes connected to input 1 that have a higher potential than the reference will point upward, whereas those less negative than the reference will point downward. The channels that show no activity (isopotential with the reference) measure a negativity at input 1 equal to that at the reference. If the recorded potential has two maxima of opposite polarity, such as seen in tangential dipole sources, then referential montages will show phase reversals even if the reference is the minimum. Choice of a Reference In a referential montage, any electrode may be the reference, but ordinarily it is the one uninvolved in the electrical field. The voltage difference between any pair of electrodes is entirely unrelated to the choice of reference (83,84); subtracting the voltage measured referentially at electrode B from that measured referentially at electrode A will produce exactly the voltage measured bipolarly from the A-B derivation, regardless of the reference chosen. The amplifiers in a reference montage perform their differential function exactly as in a bipolar montage.
Kamak, 51 years: Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Barbiturates, pentobarbital, phenobarbital and primidone are contraindicated in patients with a history of manifest or latent porphyria. Available evidence suggests that it is unlikely that infusions prepared with water, or alfalfa seeds, would pose any problem, due to the lower vitamin K1 content. Importance and management Evidence is limited to this one study, which suggests that no pharmacokinetic interaction is expected between decaffeinated green tea extract and losartan.
Benito, 47 years: The diagnosis is usually made after initiation of treatment and observation of the clinical course. Rabies is distinguished from other viruses by dysphagia, dysarthria, facial numbness, and facial muscle spasm. Overall driving performance was the poorest after taking diphenhydramine, and participants were most drowsy after taking diphenhydramine (before and after testing). Patients are taught to become aware of these unresolved experiences, which include suppressed or avoided trauma, adversity, and conflict, and to adaptively express their emotions related to these experiences.
Bandaro, 37 years: The withholding behavior, which may be mistaken for absence or tonic seizures, evolves as a way to prevent the painful passage of stool that is large and hard because of chronic constipation. The liquid from injectable solutions can be gently heated to evaporate the water, leaving a white powder (ketamine hydrochloride) which can be snorted or orally ingested. Conversely, some patients with long seizure-free intervals may require a more abrupt withdrawal schedule in order to achieve the goals of monitoring within a realistic timeframe. The first has been the recognition that superrefractory status epilepticus may be due to antibodies directed Super-refractory status epilepticus Brain 2011: 134; 28022818 2809 Hypothermia Hypothermia has been shown to exert anti-epileptic action and to be neuroprotective in experimental status epilepticus (Liu et al.
Avogadro, 36 years: Dizziness, somnolence, and ataxia were observed with a frequency similar to that after phenytoin infusion (226). For uncontrolled status epilepticus valproate maintains a 24-hour, seizure-free state better than phenobarbital with statistically fewer significant adverse events. As with high doses of fish oils (marine omega-3 fatty acids), it may be prudent to use some caution with the concurrent use of high doses of flaxseed supplements in patients also taking aspirin or anticoagulants. If these large-amplitude occipital "spikes" were epileptogenic, electrical field theory would dictate a much more gradual falloff.
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