Tissue Plasminogen Activator (tPA): Treatment for Acute Ischemic Strokes

“Someone in the United States has a stroke every 40 seconds. Every 4 minutes, someone dies of stroke ⁽⁶⁾.” The highest death rates from stroke are in the southeastern United States, thus being titled the “Stroke Belt.” Kentucky, being part of the Southeastern United States, is part of this statistic. A stroke is a vascular disease in the brain that causes a lack of oxygen to part of the brain, hindering metabolic activity in neurons ⁽⁶⁾.There are two types of strokes; ischemic and hemorrhagic. An ischemic stroke is where the blood supply to certain parts of the brain is blocked due to either narrowing of arteries due to plaque (atherosclerosis) or thrombotic (blood clot) ⁽¹⁾. A hemorrhagic stroke is due to the rupture of an artery allowing blood flow to pool out of the arteries into the skull ⁽¹⁾ .

 

Source:  Blumenthal M.D., R. S., 23 November 2016)

Out of the two types of strokes, an ischemic stroke is the most common type accounting for 88% of all strokes ⁽⁶⁾. Many things cause ischemic strokes including atrial fibrillation, cigarette smoking, alcohol abuse, obesity, carotid stenosis, diabetes and hypertension⁽⁷⁾. These factors increase the chances at which an individual will produce a blood clot. Many situations can influence the production of a blood clot; surgery, intravenous line, flying for long periods of time and a sedentary lifestyle are only a few. A thrombosis is a clot that is formed in an artery⁽⁷⁾. An embolism is a piece of a blood clot or circulatory material that has been dislodged and trapped in an artery, blocking blood flow⁽⁷⁾. People with plaque, cholesterol, in their arteries create a perfect environment for these embolisms to get stuck.

Stroke is the leading cause of disability in adults⁽⁶⁾. With this information in mind the treatment for strokes is incredibly important. The treatment for strokes depend on what type of stoke is occurring. Once an emergency doctor determines that the patient is having a stroke, they order for a CT angiogram. The CT angiogram is a type of imaging that uses contrast to determine whether or not the stroke is hemorrhagic or ischemic. A hemorrhagic stroke has much less treatment plans than an ischemic stroke. A hemorrhagic stroke is treated by either; putting in a ventricular drain directly under the skull to relieve pressure or removing part of the skull to relieve pressure⁽⁶⁾.

An ischemic stroke is due to a blockage, giving doctors the choice to perform a mechanical thrombectomy or introduce tPA ⁽⁸⁾. Many ischemic strokes are not candidates for a thrombectomy because the clot must be located in a large vessel. Tissue Plasminogen Activator (tPA) is an intravenous medication that degrades the thrombus ⁽⁴⁾. tPA is a serine protease found in endothelial cells (cells that line the blood vessels) ⁽⁴⁾. In the presence of fibrin, tPA works by cleaving the plasminogen enzyme into a protease plasmin ⁽⁹⁾. The plasmin degrades the fibrin clot into fibrinogen degradation products ⁽⁵⁾ . tPA also works by enhancing the catalytic efficiency by localizing the active site of fibrin to the clot ⁽⁹⁾. According to diapharma.com, “rt-PA is probably the most effective thrombolytic agent…”

 

Flow chart showing the fibrinolytic system, Diapharma.com

       

Although this idea of having a “clot busting” medication is great, there is a timeline involved when administering tPA. The countdown begins once the signs and symptoms of the stroke begin and physicians only have 4.5 hours to diagnose and treat the patient with tPA ⁽³⁾. Studies have shown that a broader range of 6.0 hours is still acceptable but the risk of secondary hemorrhaging greatly increases ⁽⁴⁾. Unfortunately, even with administration in a timely manner, tPA can still cause hemorrhaging as a side effect ⁽³⁾. The patient must be strictly monitored after tPA is given to evaluate any changes showing a secondary hemorrhage ⁽⁴⁾.

Tissue Plasminogen Activator is not a perfect solution for acute ischemic strokes, it has serious side effects. However, according to Paek, “IV-TPA treatment within 4.5 h was associated with an improvement of functional disability with an acceptable risk.” When administered tPA, mortality rates have reduced by 25% ⁽⁴⁾. Although tPA is a great medication to treat an acute ischemic stroke, when possible, prevention is the best treatment. Maintaining a healthy weight, eating a heart healthy diet, quitting smoking, exercise regularly and managing cholesterol levels can inhibit many ischemic strokes ⁽⁸⁾.

References

1. Blumenthal M.D., R. S.(23 November 2016). “What is a stroke?” Health After 50; University of California, Berkeley, School of Public Health. Retrieved by https://www.healthcentral.com/article. Accessed on September 20th, 2019.

2. Cerebral Angiography (n.d.). National Institute of Neurological Disorders and Stroke. Retrieved by http://www.strokecenter.org/professionals/stroke-diagnosis/guide-to-imaging-techniques-in-stroke-diagnosis/cerebral-angiography/

3. Gravanis I, Tsirka SE (February 2008). "Tissue-type plasminogen activator as a therapeutic target in stroke". Expert Opinion on Therapeutic Targets. 12 (2): 159–70. doi:10.1517/14728222.12.2.159.

4. Paek, Y. M., Lee, J. S., Park, H.-K., et. al. (1 June, 2019). Intravenous Thrombolysis with Tissue-Plasminogen Activator in Small Vessel Occlusion. Journal Of Clinical Neuroscience: Official Journal Of The Neurosurgical Society Of Australasia, 64, 134–140. https://doi-org.ezproxy.uky.edu/10.1016/j.jocn.2019.03.036

5. Parsons J. C. (1 June 2012). Fibrinolysis pathway. Retrieved from http://www.pathologyoutlines.com/topic/coagulationfibrinolysis.html. Accessed September 21st, 2019.

6. Stroke (May 13, 2019). Centers for Disease Control and Prevention. Received by  https://www.cdc.gov/stroke/index.htm. Accessed September  19^th, 2019.

7. Stroke; also called: Brain Attack, CVA. 21 August 2019. Medline Plus.  Retrieved from https://medlineplus.gov/stroke.html.

8. Stroke Treatment. (n.d). American Stroke Association. Retrieved from https://www.stroke.org/en/about-stroke/treatment.

9. Tissue Plasminogen Activator (n.d.). Diapharma. Retrieved from https://diapharma.com/tissue-plasminogen-activator-tpa/#Thrombolytic%20therapy. Accessed September 19, 2019.

By Erin Harris, Master's of Medical Science Student at the University of Kentucky

The Ketogenic Diet for Drug-Resistant Epileptic Patients

Imagine being out with friends and suddenly something comes over you. An aura, if you will. Your senses begin to perceive the world around you differently. Your fingers and legs start to twitch. You see flashes of light, and then ultimately, nothing. Your seizure begins. According to the Epilepsy Foundation, 65 million people have epilepsy worldwide, which often include episodes such as this. One-third of those 65 million have uncontrolled seizures that do not respond to traditional drug therapies.¹ An alternative treatment plan was necessary.

The first true report of using diet modification to treat epilepsy was in 1911. Such modification required prolonged periods of fasting and reported improvements in seizure episodes after only 2 to 3 days. This began the proposition that an absence of macronutrients caused a change in metabolism. Eventually, the macronutrient responsible for this metabolic shift was discovered to be carbohydrates.¹ Thus, solidifying the ketogenic diet as an acceptable treatment for pharmacoresistant epilepsy. In 1938, the ketogenic diet, also referred to as “keto”, fell from popularity due to the discovery of phenytoin. With the strict adherence of the keto diet, this new medication became the norm. However, with 30% of the epileptic population not responding to pharmaceutical intervention, it was clear the ketogenic diet needed to be reintroduced, but maybe with less-restrictive versions.²

The ketogenic diet (KD) is defined as a high fat, low-carbohydrate, and moderate-protein diet with intentions to force the body into a state of ketosis, meaning the breakdown of fat for energy (ATP), rather than glucose. A classic KD calculation is 1 g protein/kg of body weight, 10 to 15 g carbohydrates/day, and the remaining calories from fat.¹ Often a ratio of 4:1 is prescribed, as a ratio of grams of fat to grams of carbohydrates and proteins combined.³

There are several other varieties of the ketogenic diet, perhaps making it more palatable for the patients and increasing adherence to the diet. While each type has proven some level of positive effects on seizure control, the most effective is still the classic ketogenic diet. The Medium Chain Triglyceride Diet (MCT) allows for larger amounts of protein and carbohydrates, allowing for a more flexible meal plan.⁴

                                                    Source:  https://www.raps.org/regulatory-focus™/news-articles/2017/10/intractable-epilepsy-and-the-value-of-formulated-ketogenic-diet-products

The ketogenic diet has several proposed mechanisms of action often involving alterations in current body status. As previously mentioned, this diet alters energy metabolism. As less carbohydrates are consumed, the supply of glucose in the body decreases. Subsequently, this decreases glycolysis which has been found to play a role in seizure reduction. Due to adequate energy intake by way of fat, gluconeogenesis is prevented which increases beta-oxidation and ketone bodies.^1,4 These ketone bodies then become the main source of energy for the body. Alterations in neurotransmitters are another potential mechanism for how seizure activity is reduced, similar to how antiepileptic drugs work. Ketone bodies have been found to inhibit g-aminobutyric acid receptor-induced seizures by decreasing the amount of glutamate converted to aspartate. They also block neuronal uptake of glutamate.¹Furthermore, ketone bodies have been found to reduce reactive oxygen species (ROS) and inflammation that results from seizure activity, helping to mend the effects brought on by an epileptic brain.

The MCT diet has a specific fatty acid that is the most important piece in its efficacy. Medium-chain triglyceride oil is made up of two major fatty acids: N-octanoic acid and n-decanoic acid. Decanoic acid readily crosses the blood-brain barrier through diffusion and mediated-transport via a medium-chain fatty acid transporter, which coincidentally is the same transporter that mediates brain uptake of the antiseizure drug, valproic acid.⁴ Once inside the brain, decanoic acid blocks excitatory synaptic currents and causes a non-competitive inhibition of AMPA receptors, which are a basis for seizure activity.⁴

The reported rates of seizure freedom reach as high as 55% in a classic KD 4:1 diet after three months and reported rates of seizure reduction are up to 85% in exact same circumstances. Of course, there are some adverse effects within the vast amount of studies relating to the ketogenic diet. Most notably are short-term gastrointestinal-related issues and increased cholesterol.³ But given the incredible results, these unfavorable effects seem trivial. Even if the ketogenic diet is deemed outdated, it cannot be ignored how large of a stepping-stone it has been for science to curing seizure episodes and epilepsy. By following the mechanisms of action of the ketogenic diet, we better understand seizures and possibly accept the idea that food can in fact be medicine.

References

 1.      Practice Paper of the Academy of Nutrition and Dietetics: Classic and Modified Ketogenic Diets for Treatment of Epilepsy. (2017) EatrightPRO, 117(8), 1279–1292.

  2.   Chen F, He X, Luan G and Li T. Role of DNA Methylation and Adenosine in Ketogenic Diet for Pharmacoresistant Epilepsy: Focus on Epileptogenesis and Associated Comorbidities. (2019) Front. Neurol. 10(119) doi: 10.3389/fneur.2019.00119.1.      

  3.  Martin-McGill KJ, Jackson CF, Besnahan R, Levy RG, Cooper PN. Ketogenic diets for drug-resistant epilepsy. (2018) Cochrane Database of Systematic Reviews. 11. doi: 10.1002/14651858.CD001903.pub4.

  4.  Rogawski M. A fatty acid in the MCT ketogenic diet for epilepsy treatment blocks AMPA receptors. (2016) Brain. 139(2), 306–309. https://doi.org/10.1093/brain/awv369

By Alivia Larkin, A Master’s in Medical Sciences Student, University of Kentucky

	https://www.raps.org/regulatory-focus™/news-articles/2017/10/intractable-epilepsy-and-the-value-of-formulated-ketogenic-diet-products