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Showing posts with label epilepsy. Show all posts
Showing posts with label epilepsy. Show all posts

Saturday, November 20, 2010

Epilepsy, Ketogenic Diet & The Mind

In this informative essay entitled "Epilepsy's Big, Fat Miracle" published online in The New York Times Nov. 17, 2010, Fred Vogelstein tells us how a ketogenic diet helped drastically diminish petit-mal seizures in his eight-year old son Sam who suffers from epilepsy. Medication is still needed. But Sam had suffered up to 130 seizures a day, producing short, at times frightening, pauses of consciousness. Since he has been on the diet, their frequency dropped by 75 percent. Experience with patients like Sam tells that he may not need it anymore at some point in the future. Why the diet provides this effect has remained little understand.

A ketogenic diet consists almost entirely of fatty foods and very low sugar. When we deprive our body of sugar for an extended period of time, we begin to metabolize fat. The liver converts fat into ketone bodies that all cells can use instead of glucose to produce the energy they need to function. Nerve cells in the brain do not only utilize the ketone bodies as sources of energy, but also may produce the neurotransmitter glutamate, as a derivative of the intermediate  α-ketoglutarate in the same metabolic energy pathway in the mitochondria that consumes the ketone bodies as well as glucose derivative pyruvate, known as Krebs cycle.

Krebs Cycle (courtesy: Narayanese, WikiUserPedia, YassineMrabet, TotoBaggins)
Glutamate constitutes the most prevalent excitatory neurotransmitter in the brain. Neurotransmitters pass information across the contacts between nerve cells known as synapses.  Glutamate receptors, notably the N-methyl D-aspartate receptor, play a crucial role in the shaping of nerve cell connections. The kainate receptor is known to be excitatory when located postsynaptically and modulate inhibition when located presynaptically. Kainic acid triggers epileptic seizures. During a seizure nerve cells release glutamate in unusually large amounts causing waves of excitation that the nerve cells otherwise do not experience. Under normal conditions, nerve cells manage to adapt their responses to increasing stimulation, keeping the released amounts of glutamate low (read my post with title "Good News for Brain Energy Use" dated Sep. 12, 2009).

However, when we are on a ketogenic diet, the glutamate that can be derived from ketone bodies is at best half of that derived from glucose. The diminished availability of glutamate may make the difference (but also see Morris, 2005).

Addendum
  • A wise biochemist made me aware of the possibility that ketogenic diets may take advantage of yet another metabolic mechanism. By far not all α-ketoglutarate in the Krebs cycle is converted into glutamate. Rather, the larger fraction is turned into succinate in a reaction that also produces guanosine triphosphate (GTP) from guanosine diphosphate (GDP). Neurotransmitter receptors can be divided into two fundamentally two different types: ionotropic and metabotropic. The first type of receptor is coupled to channel proteins in the nerve cell membrane that control ion fluxes instrumental for the generation and propagation of the electrical impulses encoding the information processed in the brain. The afore-mentioned NMDA and kainate receptors are ionotropic. The second type of receptor is coupled to G-proteins that effect molecular signals regulating ionotropic receptor function, gene expression and energy metabolism.  Eight metabotropic glutamate receptors have been identified. The activation of G-proteins depends on GTP. In addition to curtailing the availability of glutamate per se, a ketogenic diet may therefore diminish glutamate's action indirectly, diminishing metabotropic glutamate receptor activity (12/07/10).
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Tuesday, April 28, 2009

Hemispherectomies, Brain Plasticity & The Mind

Hemispherectomy strikes us as a radical procedure. It chillingly reminds us of the lobectomies performed in the 1940s and 1950s. Lobectomies impacted the patients' personality so profoundly that they were quickly abandoned.

The case of Henry Gustav Molaison is one example. He underwent this procedure at the age of sixteen to subdue deleteriously frequent bouts of epilepsy. Epileptic seizures are produced by bursts of electrical signals from nerve cells clustered in small discrete brain regions known as epileptic foci. The bursts send waves of hyper-excitation through the cerebral cortex that lead to loss of consciousness and uncontrollable limb movements. Henry Molaison's surgeon, William Scoville, found reasons to believe that Henry had such foci on each cerebral hemisphere and, therefore, removed parts of the medial temporal lobe on both sides.

Indeed, the surgery freed Henry from his violent seizures. He suffered very few mild attacks in his later years. However, he could not remember anymore who he was. Known only by the initials H.M. until his death last year, he volunteered for numerous psychological studies, offering crucial insights into the workings of memory. I have written about him in my post dated Feb. 20, 2009. Scoville would never use the technique again.

After such discouraging results, lobectomies were replaced with surgical procedures that aimed to block seizures more discretely. Already in the 1940s, the neurosurgeon William Van Wagenen had pioneered a procedure that consisted of the transection of the nerve cell connections between the cerebral hemispheres. He cut the structure containing the nerve cell fibers of these connections, called corpus callosum, at the midline between the hemispheres, leaving the latter unharmed. If the epileptic foci were located in only one hemisphere, the transection of the interhemispheric connections would prevent the waves of excitation from crossing to the other hemisphere devoid of foci. The procedure was successful in eliminating seizures and became known as callosotomy (Mathews and others, 2008).

The Nobel Prize-laureate Roger Sperry had spent years of research on the transfer of information from one cerebral hemisphere to the other and had the opportunity of studying some of Van Wagenen's patients.  Based on this experience, Sperry and his colleagues at the California Institute of Technology, began to perform callosotomies in the early 1960s. The neurophysiologist and neurosurgeon Joseph Bogen pioneered and refined the procedure. The callosotomies, while successfully suppressing seizures, produced utterly subtle mental changes. The team began a long series of elaborate psychological tests to examine the patients' differences in behavior. The studies became widely known as the split brain experiments and provided fundamental insights into differences in function of the cortical hemispheres and their interactions.

In very severe cases of epilepsy like Rasmussen syndrome, however, callosotomies alone have proven ineffective, and hemispherectomies have shown superior results. Complete hemispherectomies were performed only early in the 20th century. They affected the patients' mental capabilities gravely, and the method was abandoned.  In the 1960s, however, the procedure was revived in a more refined and restricted fashion. The pediatric neurosurgeon Benjamin Carson at the Johns Hopkins University School of Medicine became a pioneer in this field. He achieved the effective suppression of seizures of the severest nature with hemidecortications and  functional hemispherectomies (Carson and others, 1996).

Hemidecortications comprise the temporal, frontal, parietal and occipital lobes of the cerebral hemisphere with the epileptic foci. The cortical gray matter is removed, while leaving the underlying white matter in tact as much as possible. Functional hemispherectomies, on the other hand, entail the removal of the temporal lobe and the complete transection of the corpus callosum. In both types of surgery, brain structures under the cerebral cortex are left intact.

The surgeries are preferably performed in young children. Depending on their age, the resulting long-term disabilities can be small. Except the limited use of the arm on the opposite side of a hemidecortication, behavioral differences may be difficult to notice (ScienceDaily reports in a post dated Oct. 16, 2003).

Roughly the same cortical functions are mapped symmetrically on both cerebral hemispheres. Differences develop during the first years of life. One major difference is that language is processed on the left hemisphere in all right-handed and most left-handed adults. Early in life, however, nerve cell connections are still forming in exuberance. That is, cortical nerve cells grow transitory endings into several regions of cortex on the same hemisphere and on the other hemisphere, into subcortical brain structures and into the spinal cord. Used connections stabilize; unused ones are pruned. Similar exuberance and elimination has been observed in the pathways that provide sensory input to cerebral cortex.

If cortical tissue is removed on one hemisphere in this sensitive period, nerve cells that would have innervated the removed tissue may stabilize connections with the other hemisphere, and the latter may compensate the loss of function (Holloway and others, 2000). The extraordinary extent of the compensation is evident in the young man featured in the second installment of the Public Broadcasting Service series "The Secret Life of the Brain" which premiered in 2002. Another child is portrayed in the report by WBFF Channel 45 Fox News from 1997 below:


Pulsifer and others (2004) examined the cognitive abilities of 71 children before and after the surgery. Most parents were satisfied with the outcome and most children were able to attend mainstream schools at the time of the study, though more than half needed support. If we were asked to select these children's brain scans among the scans of their classmates in school, we would pick the correct ones without hesitation. If we were to pick out the children mingling with their peers during recess, we were likely to fail.

Addendum
  • I have written extensively about differences in brain plasticity between the developing and the mature brain in my post with the title "Brain Plasticity & The Mind" published Jan. 7, 2011. During development nerve cell connections undergo a period of exuberance followed by elimination. That is, underutilized connections are pruned and used connections strengthen. In the adult brain, ascending sensory pathways to the cerebral cortex and the descending motor pathways are crossed. The degree of decussation varies. While half of the optic nerve fibers cross at the optic chiasm in the visual system, in the motor system 80-85 percent decussate. However, transitory uncrossed nerve cell projections have been observed in equal proportion with the crossed projections during early brain development. Tolbert and others (1984) provide an example. Possibly, such connections are stabilized after an early hemispherectomy and may account for the observed recovery of motor functions (03/ 03/11).
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