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-Migraines are one of the oldest documented illness being described as early as 1200 BCE by the Egyptians. Arataeus of Cappadocia is however the one credited with the discovery of migraines after having extensively described unilateral headaches with aura. Migraines have plagued humans throughout our history with little progress made in the area of treatment and cures. Several treatments have been tried with no avail, including hot irons, bloodletting, inserting garlic into incisions made in the temple and applying opium and vinegar solutions directly to the skull. Some have even gone as far as to perform surgeries such as lobotomies on migraine sufferers. Trepanation involves making a hole in the skull to let out evil spirits that presumably were causing the migraine. It is possibly the oldest surgery in history and may date as far back as 6500 BCE.
+Jean- Marie Charcot (1825-1893) noted the first reports of the characteristics of ALS in 1874, and named the fatal syndrome based on what he found.  He was a noted French neurologist who explained how the central nervous system works and who has been called “the Father of Neurology”. (Rowland, 2001)
-The first known use of medication that has shown some success is use of ergotamine in the 1930s. Ergotamine constricts blood vessels in the brain and has been shown to provide pain relief in some individuals. Many drugs have been researched and experimented with since with little success. The first and currently only class of drugs developed and used solely for the treatment of migraines are Triptans, which were developed in the early 1990s (American Migraine Foundation, 2016).
+</style>
+<style float-left>
+{{:stephen_hawking_2.jpg|Figure 1: Famous physicist Stephen Hawking}}
+   Figure 1: Famous physicist Stephen Hawking
 </style>
+<style justify>
+Drs. Scarmeas, Shih, Stern, Ottoman, and Rowland recently published a scientific article, concluding that subjects with motor neuron diseases were more likely to be slim, or had once been serious athletes. Many famous people in US history have had ALS (Scarmeas, N. et al., 2002). For example:
+  * Lou Gehrig was a very famous Yankee baseball player
+  * Ezzard Charles was a heavyweight-boxing champion
+  * Catfish Hunter- baseball player
+  * Senator Jacob Javits was an avid tennis player
+  * David Niven was a competitive sailor.
+  * Stephen Hawking, the famous physicist
+  * Even some in the musical field were subjected to ALS; Dimitri Shostakovitch and Charles Mingus both vigorously practiced musical instruments
+</style>
+\\
+\\
+\\
+\\
 ====== Epidemiology ======
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-Migraines are more common in males before puberty and in females after puberty with 19% of adult women and 11% of adult males being affected (Vos, 2010). Migraines commonly begin between the ages of 15 and 24 and have an increased incidence in adults aged 35 to 45 (Bartleson, 2010). The incidence of migraines are slightly lower in Asian and African countries, but this may be partially due to lack of diagnostic resources in these areas (Wang, 2003). In the United States, 18% of men and 43% of women will experience migraines at some point in their lives with about 6% of men and 18% of women experiencing migraines in a given year. Europeans have a lifetime risk of migraine between 12 and 28%. Chronic migraines occur in about 1.4 to 2.2% of the population. Worldwide, migraines affect about 15% of the population (Vos, 2010).
+ALS strikes about six to eight people per 100,000 (ALS Society of Canada, 2012).In any given year, about two new cases of ALS per 100,000 people will be diagnosed (ALS Society of Canada, 2012). In the US, approximately 5,000 people are diagnosed yearly with ALS (Kiernan, MC. et al., 2011).. With an estimated Canadian population of 34 million, approximately 2,000 - 3,000 people in Canada currently have ALS (ALS Society of Canada, 2012). The incidence (new cases) of ALS increases with age. Most are between the ages of 40-70, but it can also occur in older and younger adults, and rarely in teenagers.  Presently in the United States, about 30,000 people are victims of ALS; most will die within 3-5 years of contracting the fatal syndrome.  Ten percent of all known cases are hereditary.  Although males are more prone to ALS, the condition has no racial, ethnic or socioeconomic boundaries (Kiernan, MC. et al., 2011).
 </style>
-{{:stats_about_migraines_2.gif| Figure 1: Prevalence of migraines in Canada by age group and sex. The above graph illustrates that females are  significantly more likely to experience migraines compared to males after the age of 12. Individuals between the ages of 30 to 49 have the highest incidence rate for migraine attacks and act as the reference group to establish statistical significance between other age groups. http://www.statcan.gc.ca/pub/82-003-x/2014006/article/14033/c-g/fig1-eng.htm}}
+{{:prevalence_of_als.gif|Figure 2:The figure shows prevalence rates per 100,000 population for cases of amyotrophic lateral sclerosis in the United States, by age group, on the basis of data from the National ALS Registry for October 19, 2010-December 31, 2011. Prevalence rates were highest for persons aged 70-79 years and lowest for those aged 18-39 years.}}
-   Figure 1: Prevalence of migraines in Canada by age group and sex
+   Figure 2: The figure shows prevalence rates per 100,000 population for cases of amyotrophic lateral sclerosis in the United States, by age group, on the basis of data
+   from the National ALS Registry for October 19, 2010-December 31, 2011. Prevalence rates were highest for persons aged 70-79 years and lowest for those aged 18-39 years. Available at:
+   http://www.cdc.gov/als.
-====== Risk Factors ======
-<style justify>
-There are several factors that make one more prone to getting migraines.
-**Family History:** Upto 90% of people who suffer from migraines have family members who have had the same condition. If one or both of your parents have migraines, then there is a good chance that you would suffer from migraine attacks (Mayo Clinic, 2013).
-**Age:** One can develop migraines at any age, but most people who suffer from migraine attacks get their first attack during adolescence. By age 40, most people who suffer from migraines would got their first migraine attack (Mayo Clinic, 2013).
-**Sex:** Women are 3 times more likely to suffer from migraine attacks than men. Boys tend to get more headaches than girls during childhood, but during and after puberty, girls suffer from migraines overwhelmingly more than boys (Mayo Clinic, 2013).
-**Hormonal changes:** Women are more susceptible to migraines during the onset or immediately after menstruation (Mayo Clinic, 2013).
-**Genetics:** mutations in a number of difference genes have been implicated in migraines. These genetic changes tend to lead to channelopathies that make the neurovascular system hyperexcitable (Mayo Clinic, 2013).
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 **Late Stages:**
 Almost all patients with ALS end up with a respiratory failure that leads to their death within two to five years after diagnosis. However, there are some patients, around 4%, that lived with ALS for ten years or longer. (Turner, M. R. et al., 2003)
+ALS does not affect the five senses of sight, hearing, taste, smell and touch, nor does it normally affect the eye muscles, heart, bladder, bowel, or sexual muscles.
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 ====== Pathophysiology ======
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 <style float-centre>
-{{:als_pathophysiology.jpg|}}
+{{:als_pathophysiology.jpg|Figure 3: The pathophysiology of ALS}}
-   Figure 3: The Pathophysiology of ALS
+   Figure 3: The Pathophysiology of ALS (Vucic et al, 2014)
 </style>
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-Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. It is characterized by the loss of motor neurons in both the brain and spinal cord (Majoor-krakauer et. al, 2011) There is no single cause of ALS, as the disease is currently characterized by its major symptom: the death of motor neurons. For this reason, it is classified as a Complex Genetic Disorder, with no single genetic or environmental factor causing onset, and a combination of factors uniquely contributing to each case (Gordon, 2011). Due to the variety of underlying causes and mechanisms that result in ALS, there are two accepted “forms” of the disease that result in similar pathophysiology.  In approximately 10% of cases, ALS is a mostly genetic disease and is inherited, this is known as Familial ALS, or FALS. The other 90% is thought to be caused by a unknown mix of environmental factors as well as genetic predisposition, and is known as sporadic ALS or SALS (Kato, 2008). Both forms are poorly understood, and the major differentiator between the two is observable family history.
+Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. It is characterized by the loss of motor neurons in both the brain and spinal cord (Majoor-krakauer et. al, 2011) There is no single cause of ALS, as the disease is currently characterized by its major symptom: the death of both upper and lower motor neurons. For this reason, it is classified as a Complex Genetic Disorder, with no single genetic or environmental factor causing onset, and a combination of factors uniquely contributing to each case (Gordon, 2011). Due to the variety of underlying causes and mechanisms that result in ALS, there are two accepted “forms” of the disease that result in similar pathophysiology.  In approximately 10% of cases, ALS is a mostly genetic disease and is inherited, this is known as Familial ALS, or FALS. The other 90% is thought to be caused by a unknown mix of environmental factors as well as genetic predisposition, and is known as sporadic ALS or SALS (Kato, 2008). Both forms are poorly understood, and the major differentiator between the two is observable family history.
+</style>
 **Genetic abnormality**
+<style justify>
 Although a consistent genetic marker has yet to be observed in FALS patients, approximately 20% of families with a history of ALS have a mutation on chromosome 21 for a gene known as SOD1, thought to code for the enzyme superoxide dismutase (Saccon et. al, 2013). The mutation on SOD1 is thought to be autosomal dominant, meaning it only has to inherited from one parent to trigger expression in the phenotype. Due, to this mutation is present in only 20% of FALS cases, it currently has no diagnostic use.
+</style>
 {{:images_of_als_vs._control_2.png|Figure 4: Lateral sclerosis is shown in the thoracic spinal cord in SALS (A) and compared with control (B). Inserts show loss of myelin in the white matter tracts under higher power (20X). Loss of motor neurons is shown in the lumbar spinal cord in SALS (C) and compared with control (D).}}
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 **Bunina Bodies**
+<style justify>
 One of the hallmarks of ALS diagnosis is the presence of Bunina Bodies, or round to oval eosinophilic intracellular inclusions in the motor neurons of the spinal cord and brain stem of both patients with sporadic ALS (SALS) and patients with familial ALS (FALS). Although Bunina bodies are present in 85-90% of ALS cases (Saberi et. al, 2015), their relationship to the underlying cause of ALS is unknown, as they test negative for a variety of biomarkers associated with neuro-degeneration. Interestingly, the only cases where Bunina bodies are absent are FALS cases that include the SOD1 mutation (Kato, 2008). Bunina bodies are shown below (denoted by black arrows) (Saberi et. al, 2015).
+</style>
 {{:bunina_bodies.png|Figure 5: Black arrows indicate the presence of bunina bodies}}
    Figure 5: Black arrows indicate the presence of bunina bodies
 **Proteinopathy- TDP43**
+<style justify>
 A third observation of ALS proposes that the disease is a due to the presence of prions or misfolded proteins, as seen in many other neurological diseases, has been proposed. Large protein inclusions were commonly seen in the neurons of ALS patients, and in 2006, TDP-43 was identified as the major component of these inclusions. TDP-43 is a heterogeneous nuclear ribonucleoprotein and has many different cellular functions, including the stability, transport, and modification of mRNA. Mutations in the gene for TDP-43, TARDBP, have been implicated in facilitating the neurotoxic conditions of ALS, particularly in the glycine rich area of the gene (Guo et. al, 2011). This has led to the inference that variation in the mRNA metabolism is an area for further research. Similarly, to Bunina bodies, this pathology has been almost exclusively seen in ALS patients without the SOD1 mutation, suggesting that ALS can have multiple mechanisms that result in the same symptoms.
+</style>
+**Proposed Mechanism:**
-**Proposed Mechanism**
+<style justify>
-In healthy individuals, glutamate is released from the presynaptic neuron and activates receptors on the postsynaptic membrane (Foran & Trotti, 2009). This causes ion-gated calcium and sodium channels to open up and initiate an action potential. Glutamate transporters, located in adjacent astroglia cells, remove excess glutamate left in the synapse in order to prevent any further activation (Foran & Trotti, 2009). In patients with ALS, there is overactivation of these glutamate receptors, which can be caused by excessive glutamate release or a malfunctioning of the reuptake system on the presynaptic membrane (Foran & Trotti, 2009). This increased activation results in higher intracellular calcium concentrations that exceed the buffering capacity of the mitochondria and endoplasmic reticulum and ultimately lead to neuronal excitotoxicity and neuron death (Foran & Trotti, 2009). This abnormal increase in glutamate concentration can be linked to the presence of mutations in associated molecular factors.
+In healthy individuals, glutamate is released from the presynaptic neuron and activates receptors on the postsynaptic membrane (Foran & Trotti, 2009). This causes ion-gated calcium and sodium channels to open up and initiate an action potential. Glutamate transporters, located in adjacent astroglia cells, remove excess glutamate left in the synapse in order to prevent any further activation (Foran & Trotti, 2009). In patients with ALS, there is overactivation of these glutamate receptors, which can be caused by excessive glutamate release or a malfunctioning of the reuptake system on the presynaptic membrane (Figure 3) (Foran & Trotti, 2009). This increased activation results in higher intracellular calcium concentrations that exceed the buffering capacity of the mitochondria and endoplasmic reticulum and ultimately lead to neuronal excitotoxicity and neuron death (Figure 3) (Foran & Trotti, 2009). This abnormal increase in glutamate concentration can be linked to the presence of mutations in associated molecular factors.
 Astrocytes, which absorb and recycle neurotransmitters, containing a superoxide dismutase 1 mutation (SOD1) are thought to be implicated in this hyperexcitability phenotype observed in individuals with ALS. To demonstrate the involvement of the SOD1 mutation, researchers cultured induced pluripotent stem cell-derived motor neurons with the SOD1 mutation and compared the spontaneous firing of these neurons to controls (Wainger et.al, 2014). They were able to show that SOD1 mutant neurons fired significantly more than neurons lacking this mutation supporting the idea that astrocytes are not executing their normal function (Wainger et al, 2014). When researchers corrected the mutant SOD1 gene to a wild-type, this overactivation was no longer observed (Wainger et al, 2014). Overall, the toxicity effects of this mutation are seen primarily in familial cases of ALS although astrocytes in general, play a role in both familial and sporadic forms (Wainger et al, 2014).
 </style>
 ====== Treatment ======
-To date, there is no actual cure for migraine sufferers. Ideally, acute treatment of migraine should work rapidly, with few side effects, be cost effective and get the patient functional as soon as possible. Drug therapeutics that do exist are primarily targeted around symptom relief during and after the migraine attack. Acute treatment can be divided into migraine specific and nonspecific therapy.
+<style justify>
+To date, there is no actual cure for individuals diagnosed with ALS. Much of the treatment available is targeted around managing the symptoms and attempting to slow down the progression of the disease. There has only been one FDA approved drug therapy available with many clinical trials taking place to test more options. Overall, management of patients with ALS requires a multidisciplinary approach, with the expertise of many different health care professionals to provide the best care and least amount of suffering for these individuals.
+</style>
-**Ergotamines:**
+**Pharmacologic treatment: Riluzole**
-<style float-left>
-{{:ergotamine_structure_5.png|}}
-   Figure 4: Chemical structure of ergotamine
+<style float-right>
+{{:riluzole_chemical_structure_.png|Figure 6: chemical structure of the drug riluzole}}
+   Figure 6: Chemical structure of the drug Riluzole
 </style>
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-It was first isolated by Arthur Stole in 1918 and first used as a treatment option for migraines in 1925 (Kalra & Elliott, 2007). Its chemical structure is similar to that of amines, serotonin, norepinephrine and dopamine. The mode of action of ergotamine in migraine may be by means of selective arterial vasoconstriction on certain cranial vessel beds or, alternatively, by depression of central serotonergic neurons mediating pain transmission or circulatory regulation (Kalra & Elliott, 2007). They have a complex mode of action that involves interaction with a variety of receptors which include 5-HT, dopamine and noradrenaline.
+The only FDA approved treatment available to date is the drug Riluzole, which is thought to extend life expectancy by 2-3 months (Dall'Igna et. al, 2013). It belongs to the class of drugs known as antiglutamates and whose chemical formula is C8H5F3N2OS (Figure 6). It functions to prevent the overactivation of neurons by regulating neurotransmitter activity and inhibiting neuronal firing (Dall’Igna et al, 2013). Dall’Igna et. al (2013) studied the influence of riluzole on glutamate uptake at doses that did not induce damage on the studied cells within a 1 h time frame (0.1–100 M). One hour pre-incubation of riluzole significantly enhanced glutamate uptake in C6 astroglial cell cultures (Figure 8a). In further studies, the researchers chose the lowest effective dose of riluzole to alter glutamate uptake (10 M). Because EAAC1 is the main glutamate transporter in C6 astroglial cells, they analyzed the effect of riluzole on EAAC1 expression (Figure 7). Treatment with 10 M riluzole for 1 h induced an 18% increase in the expression of EAAC1 transporter as detected by Western blotting, indicating a possible mechanism for the increase in glutamate uptake (Figure 7). The increase in glutamate uptake was demonstrated to be dependent on PKC, PI3K and ERK intracellular pathways; riluzole had the opposite effect on glutamate uptake when it was added simultaneously with inhibitors of these enzymes (Figure 8b). Co-incubation of riluzole with the inhibitors of PKC (bisindolylmaleimide II), PI3K (wortmannin) or FGFR (PD173074) not only blocked the stimulatory effect of riluzole on glutamate uptake, but the riluzole plus inhibitor combination also decreased glutamate uptake levels to below the basal controls (Figure 8b). Such effects occurred in doses of bisindolylmaleimide II, wortmannin and PD173074 that alone had no significant effect on basal glutamate uptake (Dall'Igna, 2013).
+</style>
+{{:screen_shot_2016-03-25_at_11.20.43_pm.png|Figure 7a:EAAC1 expression, measured by Western blotting with specific antibody, in C6 astroglial cells in the presence or absence of riluzole. Cells were pretreated with riluzole for 1 h in DMEM without serum. }}     {{:screen_shot_2016-03-25_at_11.21.14_pm.png|Figure 7b: EAAC1 expression, measured by Western blotting with specific antibody, in C6 astroglial cells in the presence or absence of riluzole. Cells were pretreated with riluzole for 1 h in DMEM without serum. }}
+   Figure 7: EAAC1 expression, measured by Western blotting with specific antibody, in C6 astroglial cells in the presence or absence of riluzole.
+   Cells were pretreated with riluzole for 1 h in DMEM without serum.
-modes of action related to migraine:
+{{:screen_shot_2016-03-26_at_10.23.14_pm.png|Figure 8 (a): Glutamate uptake in C6 astroglial cells in the presence or absence of riluzole.}}
+{{:screen_shot_2016-03-26_at_10.21.10_pm.png|Figure 8 (b): Glutamate uptake in C6 astroglial cells in the presence or absence of riluzole and/or of the inhibitor of protein kinase C (PKC) bisindolylmaleimide II (Bis II), the inhibitor of phosphatidylinositol 3-kinase (PI3K) wortimannin or the inhibitor of extracellular-signal regulated kinase (ERK) PD173074. }}
-.Activation of  5-HT1B receptors located on intracranial blood vessels, leads to vasoconstriction of blood vessels (Kalra & Elliott, 2007).
+   Figure 8: (a) Glutamate uptake in C6 astroglial cells in the presence or absence of riluzole. (b)Glutamate uptake in C6 astroglial cells in the presence or
+   absence of riluzole and/or of the inhibitor of protein kinase C (PKC) bisindolylmaleimide II (Bis II), the inhibitor of phosphatidylinositol 3-kinase (PI3K)
+   wortimannin or the inhibitor of extracellular-signal regulated kinase (ERK) PD173074.
+**Management strategies**
-.Activation of 5-HT1D receptors on sensory nerve endings of trigeminal system, inhibits pro-inflammatory neuropeptide release (Kalra & Elliott, 2007).
+Managing ALS is a continually changing challenge. Although ALS is a degenerative disease, the rate at which neurons and muscles degenerate is unpredictable and varies greatly from one individual to another. In some cases the disease seems to have reached a plateau, while in others it reaches a standstill for varying lengths of time. Also, ALS can progress steadily at a rapid or slow rate. Whatever the rate of muscle degeneration, individuals should remain as active as possible, without causing fatigue in affected muscles. Many health care professionals are involved including: the family doctor, neurologist, palliative care doctor, nurse clinicians, occupational therapist, physiotherapist, psychiatrist, dietician, respiratory therapist, speech-language pathologist and social worker (ALS Society of Canada, 2012). This speaks to the diverse nature of the symptoms and the multitude and magnitude of expertise required.
+Management options focus on aiding the individual with:
+  * changes in mobility
+  * swallowing problems and maintaining good nutrition (i.e. tube feeding)
+  * changes in speech and maintaining communication
+  * changes in breathing and maintaining lung function
-Oral absorption of ergotamine is about 60-70% and the concurrent administration of caffeine improves both the rate and extent of absorption (Tfelt-hansen et al, 2000). Due to high first-pass metabolism, ergotamine has a very low bioavailability from oral administration (Tfelt-hansen et al, 2000). Ergotamine and ergotamine-caffeine combination pills still play a role in the acute treatment of migraine in those patients who do not respond adequately to triptan therapy. Ergotamine has more side effects (nausea, vomiting, peripheral and coronary vasoconstriction) due to its relatively nonselective adherence to serotonin, dopamine and adrenergic receptors (Tfelt-hansen et al, 2000).
-</style>
+**Future directives: stem cell therapy**
-<style float-right>
+{{:screen_shot_2016-03-27_at_12.33.30_am.png|}}
-{{:experiment_ergo_edit_.png|Figure 5: Placebo controlled clinical trial with ergotamine}}
-   Figure 5: Placebo controlled clinical trial with ergotamine
+{{:screen_shot_2016-03-27_at_12.34.42_am.png|}}
-</style>
+Another potential, but preclinical therapeutic option is the use of human induced pluripotent stem cells (hIPSCs) that can differentiate to become healthy astrocytes (Kondo et al, 2014). Researchers transplanted hIPSCs into the spine of mSOD1 mice subjects after disease onset and observed differentiation of these cells into astrocytes and an overall prolonged lifespan (Kondo et al, 2014). The ability to generate functional astrocytes, to compensate for mutated ones, can be advantageous in rescuing motor neurons as it will allow for glutamate to be properly removed from the synapse, which will prevent hyperexcitability of the postsynaptic membrane.
-<style justify> \\
+====== Conclusion ======
-The study conducted by Dahlof, 1993 looked at the effect of ergotamines on headache relief in people presenting with symptoms of migraines. In comparison to the placebo treatment, ergotamines were found to be more effective in the relief of headache in 5 out of the 6 trials. In three of the trials, there was a statistically significant difference. The combination of ergotamine and caffeine was used in three of the studies (12,13,15). Caffeine was included to improve absorption and efficacy. In the other trial, ergotamine was given together with caffeine, belladonna alkaloids and a barbiturate (11).This combination of drugs is significantly more effective than ergotamine alone in relieving migraine headache and other symptoms (12).
+Overall, ALS is a rapidly, progressing disease that greatly impacts the everyday functioning of the individual who has it. ALS destroys motor neurons which are an important link in the nervous system. It is through motor neurons that the brain sends messages to the voluntary muscles throughout the body which leads to the individual losing the ability to walk, talk and breath. ALS is now recognized to have multiple interacting causes, all sharing a common pathway leading to the destruction of the motor neurons. Glutamate excitotoxicity in ALS patients can be linked to mutant astrocytes that malfunction and this can be the target of potential therapies. Drug therapy has shown promising temporary effects and although more research needs to be done, there is the potential to use innovative stem cell therapeutics to introduce healthy astrocytes into neuronal regions for longer-term effects.
-Nausea and vomiting: All ergotamine trials evaluated had some analysis of nausea and/or vomiting. In the four trials where efficacy assessments were made, nausea and/or vomiting either increased in severity after treatment with ergotamine, and more patients were affected than was observed with placebo or there was little difference between the two treatments (10, 12, 14, 15). In all trials where the symptoms were assessed as side effects, more patients were affected following ergotamine than following placebo (9, 10, 12, 13) (Dahlof, 1993).
+====== References ======
+Als society of canada. (2012). A Manual for People Living with ALS. (7th ed.). Retrieved 27 March, 2016, from https://www.als.ca/sites/default/files/files/ALS%20Manual/2012%20Manual%20People%20Living%20With%20ALS%20-%20ENGLISH%20Final.pdf
-Global evaluation of medication: Five of the ergotamine trials evaluated presented results for patients’ preference for ergotamine or placebo. In four trials, significantly more patients preferred ergotamine to placebo (10, 12, 13, 15). In the fifth trial, similar numbers of patients clinically diagnosed as having migraine preferred placebo to ergotamine as preferred ergotamine to placebo (13) (Dahlof, 1993).
+Cifra, A., Nani, F., & Nistri, A. (2011). Riluzole is a potent drug to protect neonatal rat hypoglossal motoneurons in vitro from excitotoxicity due to glutamate uptake block. European Journal of Neuroscience, 33, 899-913.
-Side effects : The side effect profile of ergotamine and placebo was reported in five of the six trials evaluated (9, 10, 12, 13, 15). In all these trials more patients reported side effects with ergotamine than with placebo. Side effects associated with ergotamine included nausea/ vomiting, dizziness/vertigo, drowsiness/tiredness, numbness, nervousness, trembling, dyspnoea and dry mouth (Dahlof, 1993).
-</style>
+Dall'Igna, O., Bobermin, L., Souza, D., & Santos, A. (2013). Riluzole increases glutamate uptake by cultured C6 astroglial cells. International Journal of Developmental Neuroscience, 31, 482-486.
-**Triptans**
-<style justify>
-Triptans like Sumatriptan were developed to treat migraines in the early 1990s. They effectively relieve pain and nausea in approximately 75% of people. Triptans are often reserved for use in those with moderate to severe pain and for those who do not respond to analgesics (Johnston, 2010). They are administered as oral tablets, injections, nasal sprays and pills. Side effects include tingling, pain and tightness in the chest or throat, vomiting, dry mouth, flushing, dizziness and fatigue. In rare cases they can lead to cardiac ischemia (Gilmore, 2011). Triptans act in a similar manner as the ergotamines but are more selective and therefore have less side effects. Triptans are selective 5-hydroxytryptamine (5-HT) receptor agonists with high affinity for 5-HT1B and 5-HT1D receptors. These receptors when activated, constrict blood vessels in the brain to provide relief (Bartleson, 2010). Triptans are often avoided in patients who have cardiovascular disease, a history of stroke or have migraines accompanied by neurological problems. Patients should be evaluated for their risk of developing vascular disease before prescription for triptans is given. Triptans are not addictive but when used frequently, such as 10 or more days per month, medication overuse headaches can result.
-</style>
+Gijn, J. (2011). Charles Bell (1774–1842). Journal of Neurology J Neurol 258, 1189–1190.
-**Cardiovascular medications in the treatment of migraine**
-Researchers do not yet understand how exactly beta blockers prevent migraines. They are traditionally used for cardiology patients to prevent the stimulation of adrenergic receptors responsible for increased cardiac action. For treating migraines it is thought that they act through beta1 adrenoreceptor inhibition of the activation of third order trigeminovascular nociceptive neurons. The beta blockers propranolol (Inderal La, Innopran XL, others), metoprolol tartrate (Lopressor) and timolol (Betimol) have proved effective for preventing migraines. You may not notice improvement in symptoms for several weeks after taking these medications. However, the usage of beta blockers are not advised if you are over 60, have heart or blood vessel conditions or use tobacco.
+Gordon PH. Amyotrophic lateral sclerosis: pathophysiology, diagnosis and management. CNS Drugs. 2011;25(1):1-15.
+Guo W, Chen Y, Zhou X, et al. An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat Struct Mol Biol. 2011;18(7):822-30.
-Another class of cardiovascular medications (calcium channel blockers) used to treat high blood pressure and keep blood vessels from becoming narrow or wide, also may be helpful in preventing migraines and relieving symptoms of an attack. The use of calcium channel blockers comes from the idea that migraine may be due to a mutation in calcium channels that make them hyperexcitable and as such this medication can help to counteract this effect. Verapamil (Calan, Verelan, others) is a calcium channel blocker that may help you.
-**Analgesics**
+Foran, E., & Trotti, D. (2009). Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxidants & Redox Signaling, 11(7)
-<style justify>
-Most first line treatments for migraines are analgesics. Generally, these treatments are used as a primary option in severe cases, and are used when the symptoms of a migraine have just manifested themselves, as to prevent further progression. Analgesics are classified as a non-specific treatment when used in the treatment of migraines, as they are used in the treatment of other conditions as well (Pfaffenrath, 1995). As such, they are often used in combination with migraine specific therapies. Common analgesics for migraines are usually a class of drug known as Non-steroidal Anti-inflammatory Drugs (NSAIDS) such as Aspirin and Aleve. NSAIDS are generally used for moderate to severe migraines and are the final non specific treatment for migraines, as they treat the symptoms of migraines, rather than the underlying cause (Pfaffenrath, 1995).
-</style>
-<style float-left>
-{{:nsaid_pathway_edit_.png| Figure 6: Mechanism of action of NSAIDs- Normally, arachidonic acid is converted to prostaglandins by COX-2 enzymatic activity. This results in vasodilation, inflammation and increased sensitivity to pain. NSAIDs inhibit COX-2 function and thus prevent these biological responses from occurring. Limiting these activities helps alleviate pain experienced from migraine.}}
-   Figure 6: Mechanism of action of NSAIDs
+Hillel, A. D., Miller, R. M., Yorkston, K., McDonald, E., Norris, F. H., & Konikow, N. (1989). Amyotrophic lateral sclerosis severity scale. Neuroepidemiology, 8(3), 142-150.
-</style>
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-NSAIDs work by inhibiting the production of prostaglandins, which are the chemical messengers that initiate the pain and inflammation response (Whalen, K., 2012). Tissue in the human body produces prostaglandins in response to damage, and prostaglandins increase sensitivity in the nerves that send the pain response to the brain, thus establishing the pain threshold (Whalen, K., 2012). The mechanism by which NSAIDs prevent prostaglandin synthesis is by the inhibition of the cyclooxygenase (COX) enzymes that are found in their metabolic pathway [Figure 6] (European Neurological Review, 2011). There are two classes of COX enzymes, and most traditional NSAIDs that are used to treat migraines inhibit both COX-1 and COX-2.  COX-1 is constitutive, while COX-2 is induced by injury (European Neurological Review, 2011). The reduction of prostaglandins inhibits pain signaling to the brain, ergo aiding in migraine management.
-</style>
-{{:side_effects_nsaid_.png|}}
+Kato S. Amyotrophic lateral sclerosis models and human neuropathology: similarities and differences. Acta Neuropathol. 2008;115(1):97-114.
-<style float-right>
-{{:effectiveness_nsaid.png| Figure 7: Effectiveness of NSAIDs in treatment of symptoms- Severity and duration of symptoms were taken as measures of efficacy for treatment. Naproxen, a NSAID, was shown to provide statistically significant relief.}}
-   Figure 7: Effectiveness of NSAIDs in treatment of symptoms (Johnson et. al, 1985)
-</style>
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+Kiernan, MC; Vucic, S; Cheah, BC; Turner, MR; Eisen, A; Hardiman, O; Burrell, JR; Zoing, MC (12 March 2011). "Amyotrophic lateral sclerosis.". Lancet 377 (9769): 942–55. doi:10.1016/s0140-
-Effectiveness of NSAIDs in the treatment of symptoms:
+(10)61156-7. PMID 21296405.
-Seventy patients with classical or common migraine were treated during their attacks with either naproxen sodium or placebo in a randomised, double-blind parallel group study (Johnson et. al, 1985). The initial dose of naproxen sodium was 825 mg followed one hour later by a further 550 mg, if symptoms were the same or had improved (Johnson et. al, 1985). Patients were seen at admission and then at monthly intervals until a total of ten attacks had been studied. During each attack the patient graded the severity of headache, visual disturbance, nausea and other important symptoms (specific to the patient) as none, mild, moderate or severe. In Figure 7, Naproxen sodium produced statistically significantly superior relief of headache in comparison with placebo (p= 0.004) and the duration of headache was significantly shorter in this group than in the placebo group (p= 0.019) (Johnson et. al, 1985). Patients in the naproxen sodium group also had a significant reduction in the severity of visual disturbances when compared with those in the placebo group (= 0.049). The differences detected between the groups with respect to the severity of nausea and vomiting and the duration of the visual disturbances, nausea and vomiting were not significant, but the score for the naproxen sodium group was numerically lower for the severity of nausea and for the duration of both visual disturbances and nausea (Johnson et. al, 1985). Scores for the severity and duration of vomiting were the same for both groups. In summary, naproxen sodium has proved to be a drug effective in relieving symptoms associated with common migraine when taken at the onset of an attack.
-</style>
-**Calcitonin gene related peptide antagonists**
+Kondo, T. et al. (2014). Focal transplantation of human iPSC-derived glial-rich neural progenitors improves lifespan of ALS mice. Stem Cell Reports, 3(2), 242-249.
-Currently CGRP1 antagonists hold promise as new anti-migraine drugs. Two recently introduced are: BIBN4096BS and Compound 1 (Kalra & Elliott, 2007). BIBN4096BS was tested in the trigeminal ganglion and found to inhibit vasodilatation (Kalra & Elliott, 2007). Other experiments support its possible role as an anti-nociceptor mediator in migraine. Compound 1 has similar properties but is less potent than BIBN4096BS in human tissues (Kalra & Elliott, 2007). A third smaller CGRP antagonistic molecule is SB-273779. It has similar properties as the other two but may have greater value for the study of migraine and CGRP activity in animal models (Kalra & Elliott, 2007). The efficacy of BIBN4096BS has been tested in humans in two studies published in 2004. In the first, the safety, tolerability and pharmacokinetics of BIBN4096BS were tested in healthy volunteers. After a single IV administration of gradually increasing dose, most of the adverse events occurred at the highest administered dose (10 mg) and were relatively mild and transient (Iovino et al 2004). In another controlled study, moderate or severe headache was treated with 2.5 mg of BIBN4096BS IV vs. placebo. The end-point of pain reduction within 2 hours to mild or no pain was achieved in 66% of BIBN4096BS treated patients vs. 27% of the placebo group (Doggrell 2004). In clinical practice, its potential use will be limited to settings appropriate for IV administration.
+Mackenzie IR, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 2010;9(10):995-1007.
-**Surgery and Devices **
-__Surgery__
+Majoor-krakauer D, Willems PJ, Hofman A. Genetic epidemiology of amyotrophic lateral sclerosis. Clin Genet. 2003;63(2):83-101.
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-Recently Plastic surgeons have advertised nerve decompression surgery as an innovative new treatment of migraine headaches. In the 1990s, the use of the muscle relaxant Botulinum toxin became popular in the treatment of chronic migraine. Its effect was thought to occur through paralysis of muscles surrounding nerves in areas of pain. This operation involves the removal of a muscle in an area of the forehead where patients experience migraine pain. The idea for surgery began with patients reporting that their headaches were disappearing after forehead rejuvenation plastic surgery (Migraine surgery Centre London, 2016).
-Combined, these observations led to a theory that migraine headache pain can be triggered by compression of superficial nerves by surrounding tissues, such as muscle, fascia, and bone.
-During nerve-decompression migraine surgery, nerves at one or multiple common migraine headache trigger sites are released from surrounding structures such as bone, muscle, fascia, and vessels (Migraine surgery Centre London, 2016). The Surgical Migraine Procedure is the removal of the corrugator muscles (small muscles associated with the eyebrows) (Migraine surgery Centre London, 2016). However, the efficacy of this method beyond placebo has been debated in the medical community.
-</style>
-__Devices__
+Mioshi, E., Hsieh, S., Caga, J., Ramsey, E., Chen, K., Lillo, P., ... & Kiernan, M. C. (2014). A novel tool to detect behavioural symptoms in ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 15(3-4), 298-304.
-<style float-left>
-{{:cefaly_.jpg|}}
-</style>
-<style justify>
+Rowland LP (March 2001). "How amyotrophic lateral sclerosis got its name: the clinical-pathologic genius of Jean-Martin Charcot". Arch. Neurol. 58 (3): 512–5. doi:10.1001/archneur.58.3.512. PMID 11255459
-Neurostimulation is the practice of applying gentle stimulation to nerves that have been identified as sending strong, frequent pain signals.
-The Cefaly is a headband designed to deliver electrical impulses to nerves that transmit migraine pain and thereby theoretically suppress this trigger mechanism. To reduce the frequency of headaches, it is to be worn for 20 minutes every day (Didier et. al, 2015). The device consists of a battery-operated electrical pulse generator and a self-adhesive electrode (Didier et. al, 2015). The patient applies the electrode to the middle of the forehead and lowers a headband containing the electrical pulse generator over the forehead to engage a pin located on the electrode. Pressing a button on the band generates a pulsed electric current that stimulates the upper branches of the trigeminal nerve, producing a tingling or massaging sensation (Didier et. al, 2015). During the treatment, which has a fixed duration of 20 minutes, the intensity of the electric current gradually increases.
-</style>
-[[http://www.cefaly.ca/#howitworks]]
-[[https://www.youtube.com/watch?v=S_p0WlJd_dw]]
-\\
+Saberi S, Stauffer JE, Schulte DJ, Ravits J. Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants. Neurol Clin. 2015;33(4):855-76.
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+Saccon RA, Bunton-stasyshyn RK, Fisher EM, Fratta P. Is SOD1 loss of function involved in amyotrophic lateral sclerosis?. Brain. 2013;136(Pt 8):2342-58.
+Scarmeas, N., Shih, T., Stern, Y., Ottman, R., & Rowland, L. P. (2002). Premorbid weight, body mass, and varsity athletics in ALS. Neurology, 59(5), 773-775.
+Turner, M. R., Parton, M. J., Shaw, C. E., Leigh, P. N., & Al-Chalabi, A. (2003). Prolonged survival in motor neuron disease: a descriptive study of the King’s database 1990–2002. Journal of Neurology, Neurosurgery & Psychiatry, 74(7), 995-997
-====== Conclusion ======
-Overall, migraines are a heterogenous, burdensome disorder that are debilitating for the individuals experiencing them. There appears to be a strong link between genetics and environment in making individuals susceptible to migraine attacks. Symptoms can vary from one individual to the next and exacerbating factors can have different effects on different individuals. Our proposed course of treatment is to use non-steroidal anti-inflammatory drugs with caffeine administration to alleviate pain in migraine sufferers. Studies have shown that NSAIDs are significantly more effective at relieving symptoms of headache compared to other proposed therapeutics. NSAIDs, like Naproxen, are much more cost-effective, have a longer lasting effect, have a reduced likelihood of producing rebound headaches, show low reports of adverse affects and are non-addictive. It has been shown that co-administration with caffeine promote more effective intestinal absorption and a higher likelihood of a positive treatment response. Great progress has been made in understand migraine pathophysiology as well as defining new specific therapies. In recognition of the large market of migraine sufferers, the pharmaceutical and bioengineering industries are working towards newer and better approaches for affective interventions.
+Wijesekera, L., & Leigh, P. (2009). Amyotrophic lateral sclerosis. Orphanet Journal of Rare Diseases, 4(3)

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