Neurological disease

Insomnia refers to a sleep disorder marked by persistent difficulty initiating or maintaining sleep, or experiencing non-restorative sleep, despite adequate opportunity for sleep. It can be categorized as episodic, lasting up to three months, or persistent, lasting more than three months.

Several neurotransmitters play essential roles in regulating the sleep-wake cycle. The neuronal systems in which neurotransmitters and neuropeptides act to control the sleep–wake cycle lie in the brainstem, hypothalamus, and basal forebrain, with connections in the thalamus and cortex.

Noradrenergic, histaminergic, and acetylcholine-containing neurons, the neuropeptides, orexin A and orexin B, excitatory amino acids, such as glutamate, and stimulating neuropeptides (e.g., substance P, thyrotropin-releasing factor, corticotropin-releasing factor) all promote wakefulness.

Sleep takes over as the wakefulness-maintaining neuronal systems weaken and sleep-promoting neurons become active. Serotonin-containing neurons, opiate peptides (e.g., enkephalin, endorphin), the inhibitory neurotransmitter, GABA, adenosine, and melatonin, (a hormone released by the pineal gland in response to darkness) all promote sleep.

The drugs used in treating insomnia modulate the effects of the neuropeptides and neurotransmitters involved in sleep-wake cycle.

Management of Insomnia

Non-pharmacologic approaches are considered the first-line treatment for insomnia. These interventions aim to improve sleep hygiene, promote relaxation, and establish healthy sleep patterns. Non-pharmacologic management strategies include sleep hygiene education, cognitive behavioral therapy for insomnia (considered standard of care) and optimizing the sleep environment.

If nondrug interventions fail or cannot be implemented or when insomnia is severe and significantly impacting an individual's quality of life, then pharmacotherapy is indicated. The drugs used are classified as sedatives, hypnotics, or both. A sedative drug decreases activity, moderates excitement, and calms the recipient. A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep and from which the recipient can be aroused easily.

Commonly prescribed pharmacological options include:

Benzodiazepine receptor agonists: These sedative-hypnotic benzodiazepines including triazolam, temazepam and flurazepam, enhance the effect of GABA in the brain, promoting sedation and relaxation. Zolpidem, zaleplon and eszopiclone are unrelated to benzodiazepines but they interact with the benzodiazepine GABA receptor complex. Thus, they similarly enhance the effect of GABA in the brain but they have less potential for dependence than the benzodiazepines.

Melatonin receptor agonists: These medications, including ramelteon, target melatonin receptors (MT₁ and MT₂) to promote sleepiness and adjust circadian rhythms.

Orexin receptor antagonists: These drugs, which include suvorexant, promote sleep by blocking the binding of the wake-promoting neuropeptides orexin A and orexin B to their receptors (OX₁R and OX₂R).

Doxepin, a tricyclic antidepressant, promotes sleep maintenance through its affinity for H₁-histamine receptors which is considered to be responsible for its sedating effect. It is used in much lower doses that those used for treating depression. It is used for sleep maintenance.

Hypnotics with a rapid onset of action are preferable when the problem is falling asleep. If the problem is staying asleep, a hypnotic with a slower rate of elimination may be more appropriate. The table below summarizes the onset and duration of action, and recommended uses of the hypnotics.

It is important for health professionals to consider the underlying causes of insomnia, and its severity and duration of symptoms in tailoring a management approach. Combining non-pharmacologic strategies with pharmacologic interventions can provide comprehensive and effective treatment for insomnia.

Acute ischemic stroke is caused by thrombotic or embolic occlusion of a cerebral artery, which leads to a sudden loss of blood circulation to a focal area of the brain. This results in a corresponding loss of neurologic function. The text that follows has been summarized and adapted from a transcript written by Amanda Dippold as part of her clinical pharmacology training.

Worldwide ischemic stroke is more common than hemorrhagic stroke. In Western societies, ischemic pathology accounts for about 80% of strokes. The burden of hemorrhagic strokes may be more significant in African and Eastern societies. Still, ischemic strokes remain the predominant phenotype. The remaining 20% are hemorrhage-induced. Advances in management mean that acute ischemic stroke is now a ‘treatable medical emergency’.

Much of the discussion of the pathophysiology and treatment of acute ischemic stroke deals with a concept referred to as the ‘ischemic penumbra’ which refers to the potentially viable area of brain tissue that surrounds the arterial occlusion, and which is the area targeted for acute stroke management and treatment, in a bid to establish timely reperfusion and prevent infarction.

Presentation

One of the issues of upmost importance in dealing with acute ischemic stroke is the time to diagnosis and treatment.  While the diagnosis of acute stroke is often obvious, the onset of neurological deficits may be stepwise or more gradual, and may present in severity from mild to severe. So, diagnosis may occasionally be less than straightforward.

Initial evaluation

The three main goals cited as most important for the initial phase of acute ischemic stroke management include 

1. ensuring medical stability (check that airway, breathing, and circulation are intact, recording vital signs, performing a neurological exam, determining when the stroke occurred)
2. deciding whether or not the patient at hand can receive thrombolytic therapy, and
3. starting down the pathway of determining the pathophysiologic cause of the stroke.

Workup

Aside from obtaining a detailed history and physical assessment, a good workup for acute ischemic stroke should include laboratory testing, imaging, and a continued search for the underlying pathophysiologic cause.

Urgent studies for acute stroke evaluation should include noncontrast brain CT or brain MRI, blood glucose (finger stick), and oxygen saturation. Other immediate tests in the initial workup phase should include a complete blood count, a prothrombin time and and international normalized ratio (INR), activated partial thromboplastin time, and a blood glucose measurement to search for an underlying cause such as infection, coagulation issues, or hypoglycemia, as well as to evaluate candidacy for thrombolytics.  Cardiac monitoring including an electrocardiogram and possibly an echocardiogram should be completed to determine if a cardiac source of emboli is present.  This monitoring should be continued via telemetry for at least 24 hours as stroke may be complicated by arrhythmias or cardiac ischemia.  Cardiac enzymes should also be considered.

If it is suspected or known that a patient is taking a direct thrombin inhibitor or direct factor Xa inhibitor, and they are otherwise eligible for intravenous thrombolytic therapy, then an ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assay should be performed. This is necessary to accurately determine the level of anticoagulation and assess the risk of bleeding complications before administering thrombolytic therapy.

Imaging should not be delayed as it can provide evidence as to the presence or absence of hemorrhage, the infarct size, the existence of arterial occlusions, and nonvascular causes.  A non-contrast computed tomography (CT) is generally the imaging modality performed initially due to its availability and relatively low cost.  While it may show signs of early ischemia, it is currently unclear as to whether or not visualizing the ischemic infarct early on has an effect on treatment or outcome.  In general, therefore, CT is more often used for its utility in detecting the presence or absence of hemorrhage, as ischemic and hemorrhagic stroke cannot be easily distinguished with history and physical alone.  Studies such as computed tomography angiography (CTA), magnetic resonance angiography (MRA), multimodal CT, magnetic resonance imaging (MRI), and transcranial Doppler ultrasonography may be more useful in showing areas of ischemia, delineating the ischemic penumbra, and demonstrating vessel patency.  However, they are often less readily available and awaiting such tests should not delay treatment.

Treatment Options

Thrombolytics:

Recombinantly produced versions of tissue plasminogen activator (rT-PA) such as alteplase, reteplase, and tenecteplase are thrombolytic agents that catalyze the conversion of plasminogen to plasmin (the major enzyme responsible for clot breakdown). These can be used provided the clinician has evaluated the indications and contraindications for their appropriate use. Alteplase is one of the most commonly used thrombolytics for the treatment of acute ischemic stroke. The current dosing is 0.9mg/kg (up to a maximum of 90mg).  This is administered with a 10% intravenous bolus over one minute, with the remainder infused intravenously over one hour. Alteplase should ideally be administered within 3 hours of symptom onset, although extension to 4.5 hours post-onset is also considered appropriate (provided the patient is under 80 years old, does not have both a prior ischemic stroke history and diabetes mellitus, and has not recently used any anticoagulant agent).  Intra-arterial direct catheter thrombolysis may be considered for certain patients, including those with large vessel occlusions, those with intravenous rT-PA contraindications, and those who fail intravenous therapy.

To reduce the risk of intracerebral hemorrhage, it is essential to ensure adequate blood pressure control before administering and during the first 24 hours after thrombolytic therapy. The recommended blood pressure target for patients eligible to start thrombolysis is less than or equal to 185/110 mmHg. Once thrombolytic therapy has been administered, blood pressure must be maintained below 180/105 mmHg throughout the first 24 hours. Intravenous antihypertensive agents (such as intravenous labetalol, nicardipine, or clevidipine) are typically used to control blood pressure.

Mechanical Clot Retrieval:

Mechanical thrombectomy is indicated for ischemic stroke patients with large artery occlusion in the anterior circulation and within 24 hours of their time last known well. Intravenous thrombolysis does not contraindicate mechanical thrombectomy for the same ischemic stroke event. Even if mechanical thrombectomy is being considered, eligible patients should receive intravenous thrombolysis without delay.

Several devices, including second-generation stent retrievers and catheter aspiration devices, can be used for mechanical thrombectomy. The choice of device depends mainly upon local expertise and availability. These devices offer a potential solution to stroke patients not eligible for other treatments including intravenous thrombolytics with the caveat that the success of these devices is operator dependent and only available at certain healthcare centers.

Antiplatelet agents:

The initiation of aspirin therapy within 48 hours of acute ischemic stroke prevents the risk of early recurrent stroke as well as improved long-term outcome without a major increase in the risk of hemorrhage. In addition to treatment in the acute phase, aspirin therapy has become a mainstay of prevention for acute ischemic stroke. Note that aspirin therapy should be withheld for at least 24 hours in patients receiving thrombolytics. 

Aside from aspirin, there is some controversy surrounding the use of the thienopyridine derivatives, mainly clopidogrel, in the management of acute ischemic stroke, especially because these drugs have been shown efficacious in cardiovascular disease and coronary intervention procedures.  The thienopyridine derivatives include clopidogrel, ticlopidine, ticagrelor, and prasugrel, and work by inhibiting ADP-induced platelet aggregation.  Several trials have been conducted to date on the use of these agents.  On review of these studies, it seems that aspirin, clopidogrel, and combination aspirin-extended-release dipyridamole have all been shown to be acceptable antiplatelet options for the management of acute ischemic stroke.  If a patient cannot tolerate aspirin or clopidogrel, then ticagrelor, ticlopidine, or cilostazol (a phosphodiesterase-3 inhibitor) may be an appropriate alternative for monotherapy.

For selected patients with minor ischemic stroke or stroke due to intracranial large artery atherosclerosis, short-term dual antiplatelet therapy (DAPT) with aspirin and clopidogrel may be appropriate to reduce the risk of recurrent ischemic stroke. However, for most ischemic stroke patients, long-term DAPT does not offer better stroke prevention than aspirin or clopidogrel alone but substantially increases the risk of bleeding complications.

Anticoagulants:

Currently, early (i.e., within the first 48 hours of acute ischemic stroke) anticoagulation with heparin, heparinoids, or low molecular weight heparin is not recommended for the acute treatment of ischemic stroke. The risk of symptomatic intracranial hemorrhage far outweighs any benefits early anticoagulation may offer. 

Preventative pharmacology

Aspirin therapy has become a mainstay of secondary stroke prevention.

Anticoagulants such as warfarin can also be used for secondary stroke prevention. Anticoagulation with warfarin must be monitored and adjusted based on the International Normalized Ratio (INR) which is a standardized measure of the prothrombin time.  Warfarin's effects can be reversed in the setting of over anticoagulation with numerous agents including fresh frozen plasma, prothrombin complex concentrate, recombinant factor VIIa, or vitamin K.  The choice of which agent to use depends on the INR of the patient as well as their clinical status, mainly whether or not they are currently bleeding.

Four oral anti-thrombotic drugs are now commonly used as alternatives to warfarin: dabigatran etexilate, rivaroxaban, edoxaban and apixaban.  Since the antithrombotic effects of these drugs are more predictable than those of warfarin regular blood testing to monitor clotting level is not required.

Dabigatran etexilate is a prodrug and is a direct thrombin inhibitor that can prevent thrombus development. It inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation.

Rivaroxaban, edoxaban and apixaban are factor Xa inhibitors that inhibit platelet activation by selectively and reversibly blocking the active site of factor Xa.

All four of these drugs are indicated to reduce the risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation.

In recent years reversal agents for dabigatran etexilate, rivaroxaban and apixaban have become available. These are used to rapidly neutralize the anticoagulant effects of the drugs in patients that need emergency surgery or urgent procedures, or those suffering from life-threatening or uncontrolled bleeding.  Idarucizumab is a monoclonal antibody that reverses the effects of dabigatran and andexanet alfa is a peptide designed to bind and neutralise the factor Xa inhibitors rivaroxaban and apixaban. 

Attention-deficit/-hyperactivity disorder (ADHD) is a neurobehavioural and neurodevelopmental syndrome, that is characterised by the onset of persistent hyperactivity, impulsivity, and inattention in children, persisting into adulthood in some cases. The core symptoms are pervasive and become detrimental to home life, psychological, social, and/or educational progress. ADHD might be diagnosed later in life, particularly if hyperactivity is not present. Other mental health conditions may occur along with ADHD, or develop as a result of its effects on quality of life.

Once diagnosed, patients with significant functional impairments due to ADHD will be offered both non-pharmacological interventions and therapies determined by a specialist team. Lifestyle (nutrition, exercise, sleep), environmental and psychological/psychoterapeutic interventions can all contribute to improving the patient’s quality of life, and may be sufficient if impairment is moderate.

First-line drug treatment is with stimulants, such as lisdexamfetamine (a slowly activated amphetamine prodrug) or methylphenidate. Although unlicensed in the UK, dexamfetamine (dextroamphetamine) can be offered as a shorter-acting alternative to lisdexamfetamine. Adderall is the trade name of a widely prescribed (in the US) racemic amphetamine formulation that delivers both dexamfetamine and levoamphetamine.

The non-stimulant atomoxetine can be considered for patients who are unresponsive to/can not tolerate stimulant therapies.

There is limited evidence of the efficacy of additional drug classes in the management of ADHD, but they may provide benefit in exceptional cases, especially in the case of psychiatric comorbidity. Options include the antidepressant bupropion hydrochloride, tricyclic antidepressants, and venlafaxine (a SNRI antidepressant). Use of these drugs for ADHD is unlicensed in the UK.

Dementia is a term that describes a group of symptoms affecting memory, thinking and social abilities. Dementia isn't a specific disease; several diseases can cause dementia. Dementia is amongst the leading causes of death and disability in the global elderly population.

Vascular dementia is caused by damage to blood vessels in the brain. Blood vessel problems can cause strokes or damage white matter fibers in the brain.

Lewy body dementia is associated with deposits of balloon-like clumps of proteins (i.e, Lewy bodies) in the brains of people with Lewy body dementia, Alzheimer's disease and Parkinson's disease. This is one of the more common types of progressive dementia. Common signs and symptoms include acting out dreams during sleep, visual hallucinations, and problems with focus and attention. Other signs include uncoordinated or slow movement, tremors, and rigidity (parkinsonism).

Alzheimer's disease is the most common cause of progressive dementia in older adults. Alzheimer’s disease is characterized by progressive loss of memory and cognitive function. The disease can be sporadic or may be familial. Prevalence increases with age, with as many as 20% of individuals over 85 years of age being affected. Early onset Alzheimer’s disease is associated with specific gene deficits.

Pathologic changes in the brains of those with Alzheimer’s disease include deposits of beta-amyloid peptide in the cerebral cortex which form extracellular plaques and lesions as well as intraneuronal fibrillary tangles of the tau protein. With these changes, there is progressive loss of cholinergic neurons. Some evidence also indicates glutamate excitation may contribute to neuronal cell death.

Most treatment methods have relied upon cholinomimetic drugs to increase acetylcholine. Specifically, drugs acting as cholinesterase inhibitors, e.g., donepezil, rivastigmine and galantamine are commonly used. Of course, these drugs also cause typical cholinergic-related adverse effects (e.g, bronchoconstriction, diarrhea, etc.).

The excitotoxic effects of glutamate transmission is the target of the drug memantine, which is a noncompetitive blocker of NMDA receptors. 

Aducanumab and lecanemab are newly approved monoclonal antibodies that target beta-amyloid. Aducanumab targets beta-amyloid and removes it from the brain.  Lecanemab targets a different structure of beta-amyloid and blocks formation of amyloid plaques. Both drugs decrease beta-amyloid plaques in the brain. They are administered intravenously. In clinical trials, 41% of patients experienced brain swelling or bleeding with aducanumab; lecanemab was associated with brain edema in 13% of patients. Regular MRIs are needed (e.g., every 6 months). These drugs are expensive and have been the source of controversy since they were approved based upon surrogate endpoints (e.g., fewer beta-amyloid deposits) rather than clinical outcomes. After its approval, lecanemab was been found to slow progression of the disease slightly. 

Educational Activity for the classroom:

You are the Chief Medical Officer for a healthcare provider (e.g., Blue Cross/Blue Shield Medical Advantage program). You’ve convened a team of experts (your classroom work group} to decide which, if any, of the drugs approved to treat Alzheimers disease will be covered for subscribers to your health plan.

The 4 drugs for you to consider are:  donepezil, memantine, aducanumab and lecanemab. Complete the table below, to help inform your decision.

Kelly Karpa

Migraine is a complex condition, but it is characterised as a moderate to severe, pulsating headache that is typically unilateral, and is often accompanied by nausea and disturbed vision (aura). Migraines can last from two hours to several days. Associated symptoms can include nausea and vomiting, as well as sensitivities to light, sound or smell.

Medical intervention is indicated when the migraines become frequent and/or are severe.

Treatments for acute migraine

Simple analgesics including aspirin, paracetamol and NSAIDs may provide symptomatic relief. Concomitant anti-emetic treatment (e.g. metoclopramide or domperidone, or phenothiazine and antihistamine antiemetics) may be beneficial.

If analgesics are ineffective, acute attacks can be treated with 5HT₁-receptor agonists (triptans). The triptans available to treat acute migraine include almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan. 5HT₁-receptor agonists can be co-administered with a NSAID such as naproxen in patients with prolonged and recurrent attacks.

Historically ergot alkaloids such as ergotamine were used to treat migraine, but since efficacy is limited (by difficulties in absorption and adverse side-effects) their use is best avoided.

Migraine prophylaxis

For patients experiencing frequent attacks, identifying and reducing potential provoking factors (such as stress, lack of sleep, or chemical triggers including alcohol and nitrates) can be beneficial.

Preventative treatments should be considered for patients who:

• experience >2 attacks per month
• experience increasing attack frequency
• experience significant resistance to prescribed treatments
• are intolerant to suitable anti-migraine treatments
• suffer from rare migraine subtypes or are at risk of migrainous infarction.

In these patients groups beta-blockers (propranolol, atenolol, metoprolol, nadolol, and timolol) can be effective. Tricyclic antidepressants, topiramate, valproic acid, and gabapentin show some efficacy, but use of these drugs as migraine prophylactics is unlicensed. Botulinum toxin type A is licensed for the prophylaxis of headaches in adults with chronic migraine.

Novel mechanistic approach to migraine prophylaxis

A recent advance in migraine prophylaxis saw the FDA approval (in May 2018) of the first-in-class biologic drug erenumab (Aimovig).  Erenumab acts as a functional calcitonin receptor-like receptor (CGRPR) antagonist, by selectively blocking binding of endogenous calcitonin-related polypeptide (CGRP) to its receptor complex and arresting downstream signalling. CGRP is a neuropeptide that is involved in migraine pathophysiology (Hansen et al., 2010), and the receptor-ligand pathway has been validated as a novel mechanistic target for drug discovery as a migraine prevention strategy by erenumab's clinical approval (Edvinsson et al., 2018; Edvinsson, 2018). As a result of the long serum half-life of monoclonal antibodies, erenumab need only be administered once-monthly. See Dodick et al. (2018) for detailed results from the Phase 3 ARISE clinical trial.