Unskilled and unaware of it

I’ve just re-read the classic study “Unskilled and unaware of it” which established that when we’re incompetent at something we’re often so incompetent that we don’t realise that we’re incompetent. I had forgotten that it starts with a wonderful story about an inept bank robber.

In 1995, McArthur Wheeler walked into two Pittsburgh banks and robbed them in broad daylight, with no visible attempt at disguise. He was arrested later that night, less than an hour after videotapes of him taken from surveillance cameras were broadcast on the 11 o’clock news. When police later showed him the surveillance tapes, Mr. Wheeler stared in incredulity. “But I wore the juice” he mumbled. Apparently, Mr. Wheeler was under the impression that rubbing one’s face with lemon juice rendered it invisible to videotape cameras.

We bring up the unfortunate affairs of Mr. Wheeler to make three points. The first two are noncontroversial. First, in many domains in life, success and satisfaction depend on knowledge, wisdom, or savvy in knowing which rules to follow and which strategies to pursue. This is true not only for committing crimes, but also for many tasks in the social and intellectual domains, such as promoting effective leadership, raising children, constructing a solid logical argument, or designing a rigorous psychological study. Second, people differ widely in the knowledge and strategies they apply in these domains, with varying levels of success. Some of the knowledge and theories that people apply to their actions are sound and meet with favorable results. Others, like the lemon juice hypothesis of McArthur Wheeler, are imperfect at best and wrong-headed, incompetent, or dysfunctional at worst.

Perhaps more controversial is the third point, the one that is the focus of this article. We argue that when people are incompetent in the strategies they adopt to achieve success and satisfaction, they suffer a dual burden: Not only do they reach erroneous conclusions and make unfortunate choices, but their incompetence robs them of the ability to realize it. Instead, like Mr. Wheeler, they are left with the mistaken impression that they are doing just fine. As perceptively observed in the quote that opens this article [It is one of the essential features of incompetence that the person so afflicted is incapable of knowing that he is incompetent.  To have such knowledge would already be to remedy a good portion of the offense.] and as Charles Darwin sagely noted over a century ago, “ignorance more frequently begets confidence than does knowledge”.

This effect has since been named the Dunning-Kruger effect after the authors of the study.

https://mindhacks.com/2010/02/11/the-burglar-with-the-lemon-juice-disguise/

Kruger J, Dunning D. Unskilled and unaware of it: how difficulties in

recognizing one's own incompetence lead to inflated self-assessments. J Pers Soc

Psychol. 1999 Dec;77(6):1121-34.

Abstract

People tend to hold overly favorable views of their abilities in many social and intellectual domains. The authors suggest that this overestimation occurs, in part, because people who are unskilled in these domains suffer a dual burden: Not only do these people reach erroneous conclusions and make unfortunate choices, but their incompetence robs them of the metacognitive ability to realize it. Across 4 studies, the authors found that participants scoring in the bottom quartile on tests of humor, grammar, and logic grossly overestimated their test performance and ability. Although their test scores put them in the 12th percentile, they estimated themselves to be in the 62nd. Several analyses linked this miscalibration to deficits in metacognitive skill, or the capacity to distinguish accuracy from error. Paradoxically, improving the skills of participants, and thus increasing their metacognitive competence, helped them recognize the limitations of their abilities.

Courtesy of a colleague

http://awesci.com/the-astonishingly-funny-story-of-mr-mcarthur-wheeler/

Generic vs brand-name epilepsy drugs

Dr. Ting:  I'm speaking for the first study that was completed in this endeavor, which was the Bioequivalence in Epilepsy Patients (BEEP) study.[1] As you know, many people are familiar with generic substitutions for their prescription medicines. Many people do very well with them and they appreciate the cost savings. Yet, some patients and doctors, especially in the field of epilepsy, are concerned that their generic substitutions are not quite the same as the brand, that a failure for them might mean a breakthrough seizure, which is very great concern. For this reason, we embarked with the US Food and Drug Administration (FDA) to test the current standards that allow generic drugs to be approved in the United States. These standards rely heavily on what we call bioequivalence testing, which means that healthy volunteers will take a dose of a medication and have levels drawn, including the rate and extent of absorption of these medicines. They have to be the same. They have to match when these healthy volunteers take the brand name.

Patients and doctors are concerned that, for patients with epilepsy, they are not like healthy volunteers. They may be more at risk from minor differences that are allowed by current standards. This is why, at our center at the University of Maryland, we conducted the study on patients who had epilepsy and were considered "generic-brittle"—folks who might have more problems or reported problems with generic substitution of their brand-name seizure medications. These folks took their medicine for 2 weeks, after which we would switch them either from brand to generic or generic to brand and see how they did. What was the bioequivalence? How were their levels, the rate, and extent of absorption compared with when they were on the other medicine? And did they have any problems with it? Did they have more seizures when they switched between the two?

It was very interesting. We did complete the trial. It was very feasible and the patients did quite well. We found that, on average, whether they were on the brand or generic, the medication levels were almost identical, and these are patients who had other medical conditions. They were on other medicines, which is very different from the healthy volunteers that the FDA typically requires for bioequivalence testing. We really pushed the limits of the standards that the FDA holds for generic medication approval and showed that they are relevant even for patients with epilepsy and patients with other medical conditions...

We were concerned that these patients, having possibly had a history of problems with generic substitutions, would have too much of what we call a nocebo effect or expectations that would affect how they did in the trial or whether they would be adherent to the medications. So, we did blind them. We overencapsulated both the generic and the brand—we picked lamotrigine as the test case—so they wouldn't know whether they were being switched from one to the other. That really holds up the science behind this prospective study.

Dr Wilner: So the bottom line is that, at least for generic lamotrigine, the patients couldn't tell the difference, the lab tests had no difference, and there was no apparent difference in seizure frequency. Is that right?

Dr Ting: That is true for the vast majority of our patients, which was about 35 patients. All of them tolerated it very well and the levels were exactly the same between the generic and the brand, except for a few patients. Very interestingly, we had one man who seemed to have a lot more seizures whenever he was on the generic product. They were focal and brief and didn't endanger him, but it made us wonder whether there is a population of people out there who may be more at risk than the general vast majority of patients. That is something that we'd like to study further.

If nothing else, this study gives everyone reassurance that the standards that the FDA sets for generic approvals are sound, they're good, and they apply to most patients. You can really rely on the medicines. But what we want to know is whether there's a small population that may be more at risk, so we are going ahead with the next study. We call it the BEEP2 study, and we're trying to identify whether there is a medical condition that might give certain epilepsy patients a slight predisposition to have trouble with very small differences between medications that might be allowed with the current approval standards. Is there a genetic inclination for how some patients handle and process medicines? Maybe they metabolize them more quickly and that brings out minor differences between products. We are also interested in whether it is their state of mind. It's patient expectation. This negative placebo effect, which we call the nocebo effect, is having a hearty effect on patients when they know that they're getting a generic substitution of what they're used to. Maybe that gives them a predisposition or inclination to not do as well or have a harder outcome than if they believed that they were on the brand-name drug.

http://www.medscape.com/viewarticle/859098?src=wnl_tp10f_160421_mscpedit&uac=60196BR&impID=1069637#vp_1

Ting TY, Jiang W, Lionberger R, Wong J, Jones JW, Kane MA, Krumholz A, Temple 

R, Polli JE. Generic lamotrigine versus brand-name Lamictal bioequivalence in   

patients with epilepsy: A field test of the FDA bioequivalence standard. Epilepsia. 2015 Sep;56(9):1415-24.

Abstract 

OBJECTIVE: 

To test the current U.S. Food and Drug Administration (FDA)

bioequivalence standard in a comparison of generic and brand-name drug

pharmacokinetic (PK) performance in "generic-brittle" patients with

epilepsy under clinical use conditions. 

METHODS:

This randomized, double-blind, multiple-dose, steady-state,

fully replicated bioequivalence study compared generic lamotrigine to

brand-name Lamictal in "generic-brittle" patients with epilepsy (n =

34) who were already taking lamotrigine. Patients were repeatedly switched

between masked Lamictal and generic lamotrigine. Intensive PK blood sampling at

the end of each 2-week treatment period yielded two 12-h PK profiles for

brand-name and generic forms for each patient. Steady-state area under the

curve (AUC), peak plasma concentration (Cmax ), and minimum plasma

concentration (Cmin ) data were subjected to conventional average

bioequivalence (ABE) analysis, reference-scaled ABE analysis, and

within-subject variability (WSV) comparisons. In addition, generic-versus-brand

comparisons in individual patients were performed. Secondary clinical outcomes

included seizure frequency and adverse events. 

RESULTS: 

Generic demonstrated bioequivalence to brand. The 90%

confidence intervals of the mean for steady-state AUC, Cmax , and Cmin for

generic-versus-brand were 97.2-101.6%, 98.8-104.5%, and 93.4-101.0%,

respectively. The WSV of generic and brand were also similar. Individual

patient PK ratios for generic-versus-brand were similar but not identical, in

part because brand-versus-brand profiles were not identical, even though

subjects were rechallenged with the same product. Few subjects had seizure

exacerbations or tolerability issues with product switching. One subject,

however, reported 267 focal motor seizures, primarily on generic, although his

brand and generic PK profiles were practically identical. 

SIGNIFICANCE: 

Some neurologists question whether bioequivalence in healthy

volunteers ensures therapeutic equivalence of brand and generic antiepileptic

drugs in patients with epilepsy, who may be at increased risk for problems with

brand-to-generic switching. Bioequivalence results in

"generic-brittle" patients with epilepsy under clinical conditions

support the soundness of the FDA bioequivalence standards. Adverse events on generic

were not related to the small, allowable PK differences between generic and

brand. 

Everolimus data for seizures in tuberous sclerosis

Results of a randomized, placebo-controlled, phase 3 trial showed that everolimus (Afinitor, Novartis) — an oral agent developed as a cancer drug — significantly reduced seizure frequency in patients with treatment-resistant tuberous sclerosis complex (TSC).

A rare genetic disorder caused by overactivation of the mammalian target of rapamycin (mTOR) pathway that promotes cell growth, TSC leads to seizures, cortical malformations, and neuronal hyperexcitability. A common feature is subependymal giant cell astrocytomas (SEGAs).

The results, though, may have much broader implications for the treatment of epilepsy.

"I have to emphasize to you what a big leap this is," Jacqueline French, MD, professor, neurology and co-director, epilepsy research and epilepsy clinical trials, NYU Comprehensive Epilepsy Center, New York, told Medscape Medical News.

"Up until now, we have not treated anybody for their epilepsy; we have only treated them for their seizures. We have given them drugs that suppress their seizures, but we have not fundamentally changed the mechanism underlying that, which caused the epilepsy."

Everolimus is proving to be successful in TSC, but it might also be useful for some cortical dysplasias and other types of epilepsy, she said.

"This might be a first step," said Dr French, who was the global principal investigator for EXIST-3 (EXamining everolimus In a Study of TSC).

She presented the results here during the American Academy of Neurology (AAN) 2016 Annual Meeting. EXIST-3 was sponsored by Novartis Pharmaceuticals.

The study included 366 patients with TSC with a median age of 10 years (range, 2 - 65 years). They had to have had at least 16 treatment-resistant seizures and were receiving 1 to 3 antiepileptic drugs (AEDs) at stable doses. In about half of the patients, 6 or more AEDs had failed before enrollment.

Many patients had also tried other treatment approaches, including the high-fat, low-carbohydrate ketogenic diet and vagus nerve stimulation.

The overall median baseline seizure frequency per 28 days was 37.5. The study didn't restrict the type of seizures, so patients had tonic-clinic, atonic, clonic, myoclonic, and several other seizure types.

After an 8-week baseline phase, patients were randomly assigned to receive, in addition to their AEDs, placebo, lower-dose everolimus (3 - 7 ng/mL), or higher-dose everolimus (9 - 15 ng/mL)...

The study showed that 15.1% of the placebo group, 28.2% of the low-dose everolimus (P = .008 vs placebo), and 40% of the high dose everolimus group (P < .001 vs placebo) attained the primary endpoint of a 50% responder rate.

The treatment also came out on top for the other primary endpoint, percentage reduction in seizure frequency: 14.9% for placebo, 29.3% for low dose (P = .003 vs placebo) and 39.6% for the high dose (P < .001 vs placebo).

"Whether looking at one or the other primary outcome, the results were statistically significant, and there was a dose-response relationship," said Dr French...

"It was very unlikely that placebo would render patients seizure-free," commented Dr French. Total seizure freedom was achieved by 0.8% of the placebo, compared with 5.1% for the low-dose and 3.8% for the high-dose treatment groups.

When asked whether the higher seizure freedom rate in the lower dose was important, Dr French said she didn't think it was "a real difference" and might change during the later extension phase.

The three study groups had a similar safety profile. Adverse events (AEs) were consistent with known risks associated with the drug. The most common ones were stomatitis, diarrhea, mouth ulceration, nasopharyngitis, and upper respiratory tract infection.

"This is not a new drug; it's been around a long time and these are the expected AEs," commented Dr French.

Perhaps the "most problematic" side effects were the ulcers in the mucus membrane of mouth, said Dr French. "But there are ways to treat those and they come and go, so it's not like you have one forever."

And the fact that there were so few dropouts "suggests that they were manageable and tolerable."

Hematologic and biochemical AEs included neutropenia, hypercholesterolemia, elevated alanine aminotransferase levels, and hypertriglyceridemia.

"These are things you don't usually see with AEDs," noted Dr French. "We have to be looking out for these when we use everolimus for this indication."...

Although this is still to be analyzed and verified, Dr French said "there is a hint" that the earlier that patients start the drug, the more benefits they get. It's possible, she said, that earlier initiation may help ward off sometimes severe developmental delays.

"The ideal would be to treat as early as possible, before you had the burden of cognitive dysfunction," said Dr French. "But again, it's very early days. The first thing we had to do was say that it works."

And the fact that this new study shows that it does work is "very exciting," said Dr French.

"In the epilepsy world, it's a big deal because it's where we want to go with epilepsy therapy in general — you don't want to be masking or suppressing the seizures; you want to be treating the epilepsy, and it's something we never have been able to do."

It's possible that other types of epilepsy are related to abnormalities of the mTOR pathway, including some focal cortical dysplasias.

http://www.medscape.com/viewarticle/862306?nlid=104129_3404&src=WNL_mdplsnews_160422_mscpedit_neur&uac=60196BR&spon=26&impID=1070464&faf=1

John Cleese explains the brain

You've met them, I'm sure. People who are so learned, so scholarly, so deeply invested in what they're doing, that you can't understand a word they're saying — well, maybe you catch a familiar word or two, but the gist? No. They seem to be speaking a language near yours, like the Sims in "SimCity." The sounds are right, but the words are beyond you. In this video John Cleese gives us a short introduction to the anatomy of the brain. It's complete nonsense. There is only one complete sentence. It comes at the very, very end.

Pity The Poor Closed Caption Robot ...

If you think you're having a stroke — or maybe hearing problems — you're not. He's just THAT good. But for a real giggle, as you listen, click on Closed Caption button at the bottom of the YouTube window. That poor translator bot is like a drowning man in very rough seas; all it can do is fling up words that sound like Cleese's, but its guesses make no sense, have no grammar, and sometimes it just ... freezes. It gives up and goes blank.

In a way, this the real lesson here: John Cleese's brain is so agile (coming up with words and cadences that sound convincingly English, but aren't) and artificial intelligence is so un-agile (not aware it's being duped), that you should be proud, proud, proud to be an intelligent mammal. It will take silicon chips another thousand years to do what Cleese does. So we're safe. For a little while.

Thank you, "Professor."

http://www.npr.org/sections/krulwich/2013/04/04/176258637/monty-pythons-john-cleese-almost-explains-our-brains?utm_source=NPR&utm_medium=facebook&utm_campaign=20130405

Video at link above.
Also:  https://www.youtube.com/watch?v=FQjgsQ5G8ug

Cannabidiol in patients with treatment-resistant epilepsy

Researchers from the Comprehensive Epilepsy Center at New York University have published an open-label trial assessing the safety, tolerability, and efficacy of cannabidiol (CBD), a compound of marijuana devoid of psychoactive properties in children and adults with severe, highly treatment-resistant epilepsy.

Between January 2014 and January 2015, they enrolled 214 patients from 11 epilepsy centers across the United States. Participants ranged in age from 1 to 30 years, and all had intractable epilepsy. Of the original participants, 162 had at least 12 weeks of follow-up after the first dose of CBD and were included in the safety and tolerability analysis, and 137 were included in the efficacy analysis. The dose of oral CBD ranged from 2 to 5 mg/kg/day, with dose titration to tolerance, or a maximum dose of 25 or 50 mg/kg/day, depending on the trial site. Seizures were recorded by parents or caregivers in diaries and reviewed by study teams at each visit.

The median reduction in total seizures was 34.6%, with the greatest reduction occurring in patients with focal and atonic seizures, followed by tonic and tonic-clonic seizures. Two patients were completely seizure free over the entire 12 weeks. Adverse events included drowsiness, decreased appetite, diarrhea, fatigue, and convulsions. Most adverse events were mild to moderate and transient, though 20 patients had serious adverse events, most commonly status epilepticus.

On the basis of these results, the researchers have progressed to a randomized controlled trial of CBD for intractable epilepsy.

http://www.medscape.com/medline/abstract/26724101

___________________________________________________________________________

Devinsky O; Marsh E; Friedman D; Thiele E; Laux L; Sullivan J; Miller I; Flamini R; Wilfong A; Filloux F; Wong M; Tilton N; Bruno P; Bluvstein J; Hedlund J; Kamens R; Maclean J; Nangia S; Singhal NS; Wilson CA; Patel A; Cilio MR.  Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol.  2016; 15(3):270-8 (ISSN: 1474-4465)

BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy.

METHODS: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test.

RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0-96·0) at baseline and 15·8 (5·6-57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0-64·7). 

INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.

The gift is life

“He's in serious trouble—someone better talk to the mother about it,” said the nurse, as I approached the patient's room. As the attending physician, I was the designated “someone” who had to tell a mother that she would be taking her teenage son home to die.

I paused in the hallway to review the patient's chart. The boy had a neuro-metabolic degenerative disease. He had gradually lost physical strength and coordination to the point of requiring assistance with simple daily activities. He had been admitted many times in the past year for dehydration, pneumonia, and seizures. He was the youngest child of a poor, small, frail woman who had tried to care for him at home despite her recent surgery. While attempting to reposition him in bed, her surgical sutures had split open and she was forced to bring him to the hospital. The boy had a severe infection that caused multiorgan failure. His health deteriorated rapidly despite modern medical treatment. From this point on, there would be more caring than curing...

“He cannot tolerate feeds, and his body is too weak to fight off infections. We may lose him if he does not come around in the next couple of days. Even if he does, the next setback would be more than he can handle.” She nodded as I spoke, indicating that her worst fears were being confirmed. After a pause that was bursting with a lifetime of memories and emotions, she voiced her acceptance of the inevitable.

“We'll be OK. I've been through this before.” She was referring to her daughter, who had been my patient for years. Her voice cracked on the last phrase. Her eyes were moist with unshed tears. I sensed that she needed both privacy and a companion.

“I know you have, and just like the last time, I'll be here if you need my help.” We talked for a few minutes. I promised to stop by later that day. She acknowledged my support and expressed her gratitude with a hug. As I was leaving the room, my mind raced back to the time I had been unsuccessful in mediating a conflict between the mother and her teenage daughter.

“Dr. D, please talk to her. She wants to go have a baby. You know she can't take care of herself. What will she do if she gets pregnant?” I agreed with the mother's viewpoint, primarily from a medical perspective. The teenager was the index case of the familial degenerative disease. The inexorable progression of the disease had taken its toll over time. The stress of pregnancy could lead to severe and possibly irreversible consequences. I asked the mother to wait in an adjoining room and interviewed the daughter separately. 

As I closed the exam room door, the daughter sat up in her chair. She looked weaker than on the last visit. Her eyes, however, flashed defiance, and she had her jaw set. As far as she was concerned, her mother was being unreasonable in sharing their private life with the doctor. I sat down and told her that I wanted to hear her side of the story. In no time at all, she let down her guard. I saw a frightened girl who surprised me by the scope of her life planning.

“I know I'll get sicker when I get older. I just want someone to love and care for, someone who will take care of me and my mother when I cannot do it.” In her own way, the daughter was trying to leave a legacy and ease the mother's burden at the same time. I was touched by her innocence. When I explained how difficult it would be for her to go through a pregnancy, she did not hesitate to inform me that it would not get any easier if she waited. She was right about that, and I struggled to come up with an alternative that would give her an affectionate companion without compromising her health.

“How about starting with a puppy instead? No diapers, no sleepless nights, and you can get all the snuggles you want.” She gave me an amused smile, and I pressed on. “Besides, you won't have to come to the hospital to get one, and I know you like to stay away from hospitals.” She promised to think about it. I thought I had done a good job of crisis intervention when both mother and daughter thanked me as they left the clinic together. A few months later, I found out that my mediation had not been as successful as I had hoped.

The daughter wasted no time in getting pregnant. She delivered prematurely at home and the baby was admitted to the neonatal ICU for several weeks. Meanwhile, the daughter took a turn for the worse, had a series of strokes, and could not feed or care for herself, let alone her new baby. During that time, I talked to the mother many times each month, trying to help one of her wards get started in life and keep the other from losing it. Within 6 months of delivering the baby, the daughter succumbed to complications of a large stroke. The usually stoic mother had gone through a difficult time coming to terms with her daughter's premature demise. Now the mother was going through the grieving process a second time. 

The boy went home the next day. About a week later he died quietly at home. After talking with the hospice staff, I called the mother. Her strained, hoarse voice had a flat tone. I knew she had shed many tears since our last conversation. I asked if the boy had been comfortable in his final days. She said he was, and added that she was glad he had died at home with his family rather than at the hospital. We talked about shared memories of small victories and big losses. When I asked about the baby, her voice brightened noticeably.

“Oh, he's tearing up the place. He's something else.” She recounted his progress and how well he was doing. “You should see him. He's just like his mother.” She was able to see her daughter in the baby's smile, and remembered how her son had adored his little nephew. She recalled how they had played and laughed together. She knew the baby would keep her busy for a long time, and expressed hope that he would do well in the long run. Her grandson was becoming the new focus of her life. In his own way, the baby was showing her a way of connecting a difficult past with a promising future. The baby would keep the family engaged and involved in life in ways a puppy never could have.

I realized then that by not following my well-meaning advice, the daughter helped her mother live through the loss of a child with the gift of a child. The disease took her life, but her spirit brought forth new life. And in so doing, she taught me that the most precious gift in life is the gift of life.

D'Cruz OF. Reflections: neurology and the humanities. The gift is life. Neurology. 2008 Feb 26;70(9):732-3.

Absence potpourri

11 yo male with a 2 years history of staring and unresponsiveness episodes noted several  times daily. These are now somewhat more frequent than they had been in the past.  A student.  EEG shows a typical absence seizure, provoked by hyperventilation. The remainder of the EEG is unremarkable. I am confident that I can eliminate the seizures and, probably, normalize the EEG with medication. What benefit will accrue to this patient from my doing so?

Correspondent A:  Medication intervention may very possibly promote vigilance along with increased attention, focusing and concentration especially at school where cognitive stress can provoke episodes. Headaches can be a difficult comorbidity. Given gender and age this is likely Juvenile Absence. No paroxysms during flash stimulation ? (best seen following sleep-deprivation). Would also be on alert for early presenting JME (Any AM jerks,e.g.?)

Correspondent B:  I am generally in agreement with Correspondent A’s answer. However, if the EEG is classic 3Hz without any polyspike features, this young man could certainly be classic childhood absence. The age criteria developed by Panayiotopoulos and others suit this child (cutoff for onset 10yo) and a long line of other excellent and meticulous electroencephalographers (Gibberd, Sato, Louiseau, etc.) have confirmed onset of the classic "childhood" pattern of absence rather than juvenile absence at even later ages, with the tendency to greater risk for prolonged persistence and for the occurrence of generalized consulsive seizures, hence some of the risks seen in juvenile absence may of course be present. Apropos of that one must weigh treatment against the risks of absence not only on vigilance in school, but in using a bicycle, later an automobile, playing sports, swimming and bathing, etc.

My response:  The EEG does seem to be that of childhood absence. The only EEG abnormalities, 3HZ S&W, are present during hyperventilation. Although the patient is 11 at presentation, the onset of his epilepsy seems to have been 2 years earlier. For 2 years, by the history given, he has gotten along just fine, albeit his observed seizures may be somewhat more frequent at the present. Would increased attention, focusing and concentration make him an A+ student, instead of an A student? His classmates have wondered why he might inexplicably halt during a dodge ball game. Perhaps his dodge ball performance could be improved. He has probably been riding a bicycle without mishaps, although who knows what might occur tomorrow. By the way, does anyone have additional information on the incidence of accidents in children with absence epilepsy specifically?

Correspondent C:  Any studies on

1. The Iikelihood of development of grand mal seizures without treatment?

2. The Iikelihood of outgrowing seizures treated v. non treated?

Correspondent A:  If "TA" w/ onset age 5-early childhood, female, the risk is very low for subsequent GTC. Later age onset absence is associated with much greater likelihood for GTC and lifelong therapy.

In JA the hv-induced SW tends to be longer than 3 Hz (3.5-4) and as Rob stated any clear multispike form presence is not "absence". While EEG is helpful and supportive of "absence" the clinical picture rules. Excellent history taking is a must. As we all know, epilepsy is a clinical diagnosis.

Me again:  A 2 yrs 4 mos girl was evaluated for staring episodes. An EEG showed 3HZ S&W associated with behavioral change. She was treated with ethosuximide.

An EEG on therapy 4 1/2 years later was normal. The last observed absence seizures had been 14 mos earlier. Ethosuximide therapy was tapered and discontinued. An EEG subsequent to ethosuximide discontinuation showed re-emergence of 3 Hz S&W with clinical change. The parents reported observing only one episode; none had been seen by her teachers. At 7 yrs of age she was doing superlative work in school and generally seemed brighter off pharmacotherapy. Medication was not restarted. On one occasion subsequently, she was observed to have 5 absence episodes at a time when she was tired. The parents preferred to try to keep her from getting unduly tired. She continues off pharmacotherapy at present and she was last reported as doing well.

Correspondent D:  i think you discontinued the drug early.

In absence seizure not only the clinical seizure must be controlled ,but the EEC must be normal And after the clinical seizure control led ,the patient must be evaluate in every visit with

hyperventilation test and every 3 mo with EEG.

after the drug discontinued, the patient must be followed with EEG and if the EEG was abnormal the AED must be restarted ,even if the patient is clinically seizure free.

My response:  My usual protocol for childhood absence which has been consistently successful (one instance of relapse requiring reinstitution of medication; the patient described above did not follow this protocol) has been to start an appropriate medication and then, when medication is at a reasonable dosage and no seizures are being observed, to obtain a repeat EEG, which generally is entirely normal. Presuming so, and presuming no one is observing seizures, the patient is maintained on medication for a minimum of 2 years. When a decision is made to taper and discontinue medication, presuming no observation of seizures, an EEG is repeated when the patient is medication free, which is generally normal.

The patient is then discharged from ongoing pediatric neurology care.

I would certainly be interested in others' thoughts, but the protocol described by Correspondent D  seems to me quite excessive. In general, childhood absence has seemed to be a disorder which is easy to treat. I still struggle, in certain instance, with what I am accomplishing by the treatment.

Correspondent E:  I use roughly the same protocol as you, but generally if things are going really well don't bother with the EEG when seizures aren’t being seen.

Correspondent E:  I am sure that most of us are aware of the fairly recent paper by Glauser et al in the New England Journal of Medicine (NEJM, 362(9), 03/04/2010, Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy). The result of this large double blinded case controlled study showed that VPA and ethosuximide were as efficacious (about 50%) but ethosuximide was better tolerated, while lamotrigine had — 70% failure rate. One of the criteria for failure rate was the presence of a clinical electrographic seizure, defined as a spike and wave burst lasting more than 3 seconds.

Me again:  A girl with childhood absence was started on pharmacotherapy. Although pharmacotherapy was effective in eliminating observed seizures, she seemed to have noteworthy difficulties with medication toleration. She was then seen by an esteemed general pediatrician at a renowned medical institution. He obtained an EEG on the patient, while she was on therapy, which was normal. This being done, he contemptuously asserted that the diagnosis of absence epilepsy was erroneous from the start, and discontinued the patient's medication.

Correspondent C:  What happened?

My response:  The mother was extremely upset at the pediatric neurologist (me)who had "erroneously" diagnosed her daughter and subjected her to the noxious medications. No further follow-up information is available.

Correspondent F:  Wow! That story leaves me sputtering with disbelief and rage.

My response:  My letter to the mother in response to her irate phone call (this was better than 22 years ago) indicated: "The normalization of the EEG in a patient with absence epilepsy is deemed by many authorities a criterion of adequate treatment. Therefore, the normalcy of an EEG obtained on therapy is expected, not unusual. Whether your daughter continues to have a paroxysmal EEG will only be known when her EEG is repeated after discontinuation of her medication. It is possible that her generalized paroxysmal discharges are no longer present. However, it is likely that this is not the case."

Correspondent G:  This is an excellent example of what motivates non- compliance. Patients and families have reasons to be afraid or concerned or annoyed by taking pills regularly, growing pimples, spending so much money or whatnot. They may feel useless to try to get a hearing having tried before. Or they know their objections are unreasonable, or will be treated as such. It is a shady world of emotions hard to describe or sometimes to take seriously but a key to non- compliance despite rational choice and appropriate explanations on that choice.

My update regarding the 2yrs 4 mos girl described above: Parents continue to report patient as doing very well. They have no concerns. Off ethosuximide for 5 months.

Correspondent H:  With reference to absence seizures the worry is this. Is the child having more seizures than what we are observing? I have had "day dreamers" who were in absence status whose performance improved after treatment. It is of course an informed choice.

Me again:  This is one that I've heard more than once. I was speaking to the mother of a young boy seen in another state by another practitioner. Following the diagnosis of absence epilepsy brand-name Zarontin was started with excellent results. Insurance then dictated use of generic ethosuximide.

There was a rapid reemergence of absence, despite blood levels, dosage adjustment, etc. Resuming brand-name Zarontin did not resolve the problem. Valproate was then utilized, evidently without excellent results and complicated by a remarkable increase in appetite and weight gain.

Currently, levetiracetam is being utilized, not surprisingly, with lack of effect and, possibly, emerging behavioral issues. When I inquired regarding academic performance, I was told that he is a superlative student, as he always has been.

My most recent update regarding the 2 yrs 4 mos girl,  22 months after the prior update:

The patient's mother called to indicate that she was seeing seizures once again. I then recommended that ethosuximide be restarted and that arrangements be made for a follow-up evaluation. Later, the patient's mother reported that she was not really sure that she had observed seizures and, in any event, no further episodes of concern were observed, leading to neither ethosuximide nor follow-up evaluation. Yet later, the patient's mother observed two unambiguous seizures, with a protracted interval of confusion accompanying these. The patient was brought to an emergency department, at which time she was behaving normally. Once again, there was a recommendation that ethosuximide be restarted with arrangements for follow up. Before departing the emergency department, she had another evident seizure, again followed by protracted confusion. The patient was then given a loading dose of intravenous valproate and started on valproate maintenance. Despite the prolonged interval of non-treatment, the patient continues to be described as doing very well academically.