Epilepsy specialists are faced with treating several disease variations that all present unique challenges, including a pair of rare, early-onset syndromes: Dravet and Lennox-Gastaut. In a NeurologyLiveTM Peer Exchange panel discussion, a group of epileptologists explored the spectrum of obstacles they face when treating these severe syndromes, including creating the correct cocktail of medications to control seizures and making sure that patients adhere to therapy.

Led by Anup Patel, MD, section chief of pediatric neurology at Nationwide Children’s Hospital and associate professor of neurology and clinical pediatrics at The Ohio State University College of Medicine in Columbus, the panel began by covering the current treatment landscape, including the drawbacks to some of the current pharmaceutical therapies, and the challenges that providers and caregivers have to overcome to address adherence to these treatments.

“Historical treatments for Dravet syndrome have been challenging,” Elaine Wirrell, MD, director of pediatric epilepsy and professor of neurology at Mayo Clinic in Rochester, Minnesota, said.

“It’s a difficult epilepsy, and I think our usual antiseizure medicines have really not worked very well. Traditionally, people want to use a broad-spectrum medication.”

She noted how early diagnosis is extraordinarily important in Dravet syndrome, as is avoiding medications that may worsen symptoms, which means avoiding sodium channel agents such as oxcarbazepine, carbamazepine, phenytoin, and lamotrigine. Often, physicians start with clobazam or valproate, following up with the other as an add-on if the response is poor.

“We know that our ability to actually get successful seizure control, even with that combination of medicine, is very low,” Wirrell said. “So it’s actually a very exciting time to be in Dravet syndrome and see some of the newer therapies that are coming in.” She also advocated for topiramate, which can have some effi- cacy in this population, as well as treatment with alternative thera- peutic approaches, namely the ketogenic diet.

As stiripentol was only recently approved by the FDA, although it has been used off label, the panel focused on the anticonvulsant. In European studies from the early 2000s, the therapy showed ≥50% response among roughly 70% of patients when added to a combination of valproate and clobazam, Wirrell said.

“Stiripentol must be combined with clobazam for it to work. But it seems to be very effective,” she explained. “The one thing you have to watch is if you add stiripentol to clobazam. You do need to drop your clobazam dose way down because there is an inhibition there. Otherwise you’re going to have a child who becomes toxic on their clobazam.”

Ian Miller, MD, medical director of the Comprehensive Epilepsy Clinic at Nicklaus Children’s Hospital in Miami, Florida, remarked that the biggest issue with stiripentol has been the context in which it was studied—as an add-on&mdash; that resulted in its specific indication.

“One open question is how those interact or what the relationship is, in terms of efficacy, between fenfluramine, cannabidiol, [and] stiripentol, plus all the old medications that we’ve been using for a long time because we didn’t have any other alternatives,” Miller said.

Patel and Miller dove into the process of starting a patient on stiripentol, noting that lowering doses of other medications, such as clobazam, divalproex, and valproic acid is essential, as stiripentol can be a fickle medication.

“I would say I learned to respect it the hard way by having kids have a lot of adverse effects to it if I am not paying close attention and seeing them frequently and moderating the doses of those other medications,” Miller noted.

He explained that monitoring clinical toxicity—temperature instability, somnolence, or gastrointestinal upset, among others&mdash;is paramount. Miller suggested that to handle these issues, his strategy is often to adjust the medication stiripentol is being added to.

“In any patient, if we’re adding a new medication, it’s because there’s an unmet need and uncontrolled seizures,” Elizabeth Thiele, MD, PhD, director of the Pediatric Epilepsy Program and Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital, and professor of neurology at Harvard Medical School, both in Boston, said. “So if I add a new medication, I always look at what are the coexisting medications and try to drop one of those, rather than the new medicine, to help optimize tolerability and give the new medicine a chance to see how effective it can be.”

Positing about the optimal dosing, Patel asked Wirrell to talk the panelists through her step-based approach for stiripentol. Wirrell explained that dosing is done milligram per kilogram, typically administered twice daily, although it isn’t a cookie-cutter situation. Stiripentol is available in 250- and 500-mg sachets, and the recommended dose is roughly 50 mg/kg. Wirrell said that she usually spends 3 to 4 weeks getting to that point, additionally monitoring liver enzymes and complete blood counts.

“For those older kids, probably, your target should be 25 mg/kg per day. For the younger kids, I think you can certainly go up to 50 mg/kg per day, but I would start at maybe 10 to 15 mg/kg and sort of take your time getting there,” she explained. “One of the big adverse effects that we see, as Dr Miller has already alluded to, is the sedation and bit of ataxia that is probably clobazam related. But stiripentol itself can also cause kids to not be very hungry, to have a decreased appetite, and that can be a challenge as well. So taking a little bit of time to get there makes sense.”

"If I add a new medication, I always look at what are the coexisting medications and try to drop one of those, rather than the new medicine, to help optimize tolerability and give the new medicine a chance to see how effective it can be," said Elizabeth Thiele, MD, PhD.

While working up to and settling on an optimal dose is essentially clearing 1 hurdle, getting the patient to remain adherent to that treatment presents a whole new category of challenges to both providers and caregivers.

“For a lot of patients, there are several barriers, starting with the fact that most of these kids are on more than 1 medication. If we stop and think about the number of pills we’re actually asking them to take a couple of times per day, it’s sometimes shockingly overwhelming to me that it’s quite a large number. And oftentimes, it’s a problem,” Thiele said. “Some kids can’t swallow pills, some refuse to swallow pills, and some might just have difficulty with oral motor function. So our nurses are actually very good at working with patients and trying to figure out what strategies will work, and I’m always impressed that parents can also be pretty creative.”

Sharing some of her personal patient experience, Thiele recalled a patient who takes 4 medications per day, but will only do so if the parents crush and combine the pills into 1 capsule.

“That’s a huge amount of effort for that family every day, which is I think one reason we and the pharmaceutical industry realizes that we need formulations other than pills for many of our patients,” she said.

With drug levels so important to seizure control, Patel added that these alternative ways of getting patients to take medications can introduce dosing issues. For instance, if a caregiver is mixing the medication with food and the patient doesn’t eat the whole portion, their drug levels may be off and it may leave them more vulnerable for seizure.

Turning to Jesus Eric Pina-Garza, MD, director of pediatric epilepsy at TriStar Medical Group Children’s Specialists in Nashville, Tennessee, Patel wondered what his thoughts were on new drug formulations aimed at improving administration and adherence.

“One of the delivery systems that is new and could potentially be helpful, not just for anticonvulsants but for medications in general, is the film delivery, and I have actually tested it in several patients with Lennox-Gastaut because they offer a particular challenge,” Pina-Garza said. “Just like any other kid, they don’t like to take medications, and sometimes if they’re cognitively impaired, which is often a comorbidity [in Lennox-Gastaut], they don’t understand why it’s so important. And then we talk about dysphasia, and dysphasia with liquid is worse. So liquid is just a possible option for the person that prefers liquid over tablet, which is usually a child, but not one with dysphasia. So the fact of having a film tech- nology that dissolves on your tongue and you’re not able to spit it out is incredible. That hopefully will be something that expands to other medications.”

Pina-Garza noted that there is much potential for medication given by oral film, and that although the current focus is on improving medication absorption through the gastrointestinal tract, in the future, this route of administration may be particularly helpful as a rescue medication that can be administered safely. You can be confident that the person is ingesting it and the treatment is being absorbed.

Articles

Clinical Insights

Panelists review the delicate process of introducing a new medication to a treatment regimen and the creative endeavors employed to improve adherence.

Treating Rare Epilepsies: Overcoming Issues With Tolerability and Adherence

As the chair of the Huntington Study Group, Andrew S. Feigin, MD, is at the center of some of the most groundbreaking research being conducted in Huntington disease (HD). The disease currently has no FDA-approved disease-modifying therapies, but it is experiencing a heightened degree of attention thanks to several novel therapies that have shown encouraging results.

Feigin, also a professor of neurology and the executive director of The Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders at 

 in New York, has long balanced his work in the clinic with his role as a clinical trial investigator. He sees it as an opportunity to provide his patients with not only a potential treatment, but the chance to help foster hope and medical advancements. He sat down with 

 to provide updates on some of the most promising therapies currently under investigation and to discuss barriers in HD that can pose unusual challenges for drug development.

Q: As the principal investigator for the ongoing SIGNAL trial, what are some of the distinctive characteristics of the trial and where are you now in the process? 

The focus of the SIGNAL trial is a study drug, VX15/2503. It’s a monoclonal antibody to SEMA4D, which is a signaling protein in the body and in the brain that’s involved in, [first], the process by which immune cells—such as microglia in the brain&mdash;become activated, and [second], the process by which astrocytes and oligodendrocytes extend and contract their processes in response to injury or inflammation. Even though there’s a normal physiological role for SEMA4D, it can actually have a destructive role in certain situations. Evidence from preclinical transgenic animal models shows that blocking it can ameliorate some of the effects of the huntingtin gene.

The SIGNAL trial is interesting in that it started about 3 or 4 years ago and was designed from the start to have an adaptive design; it wasn’t known how big an effect the drug would have, if any. The study was designed to start with cohort A, which included 36 patients: Roughly half were early symptomatic and diagnosed with Huntington disease, and roughly half [had] prodromal [or premanifest] HD, meaning they have subtle signs but have not reached the level of being diagnosed with HD. That trial was double-blind, randomized, and placebo-controlled. It ran for 6 months, then the people who were on placebo were switched over to the study drug and everybody was followed to the end of the year. We used a series of clinical and biomarker outcome measures to look at those data to get a sense of whether there’s any suggestion that the drug is doing anything, then we used that information to create a sample size power calculation for cohort B. In the end, cohort B [was supposed to have] 240 patients, but we ended up overshooting, so by the end of the recruiting period in 2018, 265 patients had actually [been enrolled] into cohort B. Notably, in light of the interim analysis, we ended up enrolling more patients who were early symptomatic than premanifest. [This occurred] partly because it’s easier to detect clinical changes in people who have symptoms, as you might imagine, and [detection of such changes] is required for approval of the drug, at least as things stand now. People who are prodromal may have subtle signs and symptoms, but it is much harder to detect the effect of a drug on them.

The interim analysis didn’t really prove anything; we weren’t certain whether the drug was working or not. But some encouraging indications [allowed] us to say, “Let’s continue doing this, let’s expand cohort B.” Because of the nature of the way people came into the trial, the majority of people will be in the trial for 18 months. So participants will be randomized, they will get monthly infusions of this monoclonal antibody for 17 months, and then follow up at 18 months. Actually, more than 40 patients who came into the trial very early have agreed to continue out to 36 months in the double-blind portion. Vaccinex is hoping that with a good result, they’ll be able to use this as a pivotal trial.

Q: The study outcomes for SIGNAL mainly focus on imaging. Why are imaging biomarkers so important in Huntington disease, especially in terms of clinical trial design and measuring efficacy?

A couple of very large observational studies have used imaging and other kinds of biomarkers, as well as clinical outcome measures, in people who are symptomatic and in people who are prodromal to get a sense for which of these measures are sensitive to change over time. And the results showed that MRI [magnetic resonance imaging] volume metrics, for example, can measure the loss of volume in a wide range of brain structures involved in HD. Originally, we thought of HD as a disease that causes atrophy in the striatum, mainly the caudate and also the putamen, but we’ve recognized over the last 20 years or so that volume loss is really widespread and seems to have a lot of clinical significance and can measure disease progression. So if you see increasing volume loss, that [often] goes along with clinical decline. Certainly for a premanifest or prodromal population in whom it’s really difficult to measure changes in clinical measures, measuring loss of brain volume and regional brain volume can be very valuable and give you a clue as to whether a therapy is having an effect or not.

In terms of disease modification, we also use an outcome measure in SIGNAL which looks at brain metabolism with 

F-fludeoxyglucose positron emission tomography]. A lot of evidence in the literature suggests that regional brain metabolism can be quite sensitive to disease progression over time, and it gives you slightly different information from brain volume because FDG brain metabolism can be acutely changed, at least theoretically,

by therapy. So we are using both of those outcome measures in the SIGNAL trial in both cohorts, and in cohort A, results from both the MRI volumetric scan and the FDG PET signaled that the drug might have a positive effect. While the results didn’t conclusively prove anything, it looked like things were moving in the direction favorable to the study drug, for sure.

Q: What are your thoughts on some of the other therapeutic agents in development for HD? 

Roche, Ionis, and Genentech are working together on an antisense oligonucleotide, HTT

 [now known as RG6042], which basically decreases the translation of the huntingtin protein from the RNA and diminishes its production. That is a non—allele-specific approach; they’re just knocking down the production of normal huntingtin protein and the mutant huntingtin protein. [The agent is] delivered intrathecally; originally, they thought they would have to administer it once per month, but the trial is going to actually involve doing it every 2 months and every 4 months to see if there’s any difference in efficacy. It’s going to involve 660 patients over 2 years, and everybody’s very excited about it. There are still a lot of unknowns and a lot of uncertainty about whether it’s going to work, but that’s why we do these trials.

There are questions: “Does it matter that it’s not allele-specific? And could there be problems related to knocking down normal huntingtin?” But if you talk to people who know about this field, I think most would say we just don’t know, or, actually, it’s one of the things we’re going to find out from this trial.

On the other hand, you have Wave Life Sciences, which has a couple of SNPs [single nucleotide polymorphisms] that are associated with the abnormal gene mutation that is involved in their therapy, so they’re only knocking down the abnormal mutant huntingtin and leaving the normal huntingtin alone. Whether that’s important or not, we don’t really know, but it is a different approach. And then other types of therapies, which I think are more traditional gene therapies, are being developed by Uniqure and Voyager Therapeutics. These are delivered via adeno-associated viral vector through a surgical procedure into regions of the brain that they’re interested in. This kind of RNA interference approach has the advantage of being a 1-time procedure: People come in, they get the thing infused surgically, and then they’re done. There’s no coming back every 2 months for a lumbar puncture, and so again, it’s a very rational approach that makes a lot of sense. Just like with the ASOs [antisense oligonucleotides], a lot of questions arise in terms of what brain regions need to be targeted. If you target the striatum, which is essentially what Uniqure is doing, will that really translate into a brain-wide effect? Some data suggest it might, but we don’t have a clear answer yet.

Q: Do you feel that we’re disproportionately focusing on symptomatic patients versus those who are at risk but haven’t begun to show symptoms? 

About 90% of people who are at risk for HD don’t get genetically tested. I think that’ll change a lot if a therapy [is developed]. The current trials mainly focus on symptomatic and early symptomatic subjects, but if the results look promising, I think there will be no shortage of people to do a trial in premanifest or prodromal HD. The issue is whether it will be necessary, or will the FDA say, “Well, you have approval, and it probably will work in prodromal”? I’ve heard a lot of discussions at meetings about this, and I think that if Roche is successful in their trial, the FDA may require them to do a trial in premanifest, and I think they would gladly take on that trial. It will be doable at that point because people will see that something out there will actually be helpful to them.

As of right now, it can be a challenge to do a trial in premanifest subjects because not too many of them know their genetic status, and you don’t want to link participation in a trial with getting genetic testing, as that would be considered unethical. But as soon as a therapy that looks promising emerges, I think a lot more people will start to get tested for sure. 

Q: As a clinician and a researcher, are you hopeful for the future?

I think we have the most promising therapies in development ever. [The field has] really come a long way. Whether the therapies work is far from proven, and we have to be cautious and do these trials in a careful way, but I think that it’s really a promising time. Other types of small molecules may be effective for reducing mutant huntingtin, and a lot of other symptomatic therapies exist for various aspects of the disease as well. It just seems to be a time when HD has a lot of interest, so we just have to make sure that we have the capacity to do all the trials that people want to do and hopefully, quickly get answers.

That is where the Huntington Study Group can be really instrumental: We are more of a professional, caregiver-facing organization and we’re very involved with patients. Many pharmaceutical companies could benefit from working with the Study Group to do multicenter clinical trials, because we have very good, close relationships with our centers—about 120 HD clinical research sites&mdash;and with the investigators and coordinators at those sites. So I think we bring a lot to the table to potential sponsors who want to do clinical trials in HD.

Clinical Viewpoint

In an interview with NeurologyLive, Andrew S. Feigin, MD, details ongoing trials that aim to treat Huntington disease, including the notable SIGNAL trial. 

Treating Huntington Disease: New Trials Aim to Explore Uncharted Territory

One of the greatest and most persistant challenges in the prevention and treatment of Alzheimer disease (AD) is difficulty in understanding its pathology

 and establishing consensus between researchers and clinicians on the topic. It has become increasingly clear that AD is multifactorial and that pursuing a singular pathology may be misguided. “There may be numerous insults that all lead to AD pathology,” George Perry, PhD, Semmes Foundation Distinguished University Chair in Neurobiology at the University of Texas at San Antonio, said in an interview with 

. “The field has been chasing a common patho- genesis when what we observe is a common response. We would not expect inflammation to have a single cause, so why would we expect the same for AD pathology?”

Among the changes associated with AD that occur in the brain, 2 have sparked particular interest among researchers: the accumulation of amyloid-β, whose plaques impair communication between neurons at synapses and contribute to neuronal damage, and the build up of twisted strands of tau proteins within neurons, restricting the transport of nutrients and other molecules. Referred to as the amyloid hypothesis or amyloid cascade hypothesis,

 the toxicity of these amyloid plaques and tau tangles is thought to trigger an inflammatory response, resulting in cell death, brain atrophy, and functional degeneration.

Endorsed by the Alzheimer’s Association

 and the National Institute on Aging (NIA),

 the amyloid hypothesis has been the primary target of numerous drug development pipelines, but with little success.

 Efforts to stop or reduce the production of amyloid beta or remove it from the brain have been attempted by using monoclonal antibodies (mABs) and gamma secretase inhibitors (GSIs),

 but no investigational therapy has hit its end point.

“Targeting amyloid is appealing as a therapeutic target, as it is extra-neuronal and is associated with toxicity to the milieu,” wrote Marwan Sabbagh, MD, and colleagues in a 2017 review.

 “However, amyloid does not correlate with cognitive decline in the symptomatic phase of the dementia, which could explain why the mABs have not succeeded to date.”

Perry added that “amyloid is an antioxidant response to oxidative stress, so removal, especially during normal aging, could be detrimental. To advance AD research, we need to be more open to the biology of the brain.”

Although the amyloid hypothesis has held sway for quite some time, alternative theories are being advocated for by AD researchers across the globe—some of whom support the amyloid hypothesis, some that oppose it in parts, and others that are independent of it.

One theory of AD pathology, that the condition is caused by infectious microbes such as viruses, bacteria, and fungi, has faced significant criticism in the past. However, recent research has generated fresh interest in this theory.

Although the role of microbes in AD has been tossed around since the 1950s,

 the idea had little impact until it was resurrected by Ruth Itzhaki, PhD, MSc, MA, and her team at the University of Manchester. This first occurred in 1991 when they discovered herpes simplex virus type 1 (HSV1) DNA in the brains of elderly people, including patients with AD.

 The second instance was in 1997 when they proposed that carriers of the epsilon 4 allele of apolipoprotein E (APOE ε4) who have HSV1 present in their brains were at a significantly high risk of AD, whereas either of these features alone presented a much more insignificant risk.

“We showed that although HSV1 was probably in a latent state, usually in the brain, it could be reactivated, leading to an active infection—although presumably one of limited extent,” Itzhaki told NeurologyLiveTM. “We suggested that this occurred intermittently, with damage accumulating and leading eventually to development of the disease. We discovered that HSV1 infection of cell cultures caused the accumulation of β-amyloid and AD-like tau and infection of mice led to deposits of beta amyloid in their brains. In AD brains, most of the viral DNA is localized within amyloid plaques. Treatment of HSV1-infected cells with antiviral agents greatly reduced the accumulation of beta amyloid and AD-like tau.”

Rather than spark wide interest and encourage further research, Itzhaki’s hypothesis generated significant criticism and hostility from the AD research world. Although not in complete disagreement with the amyloid hypothesis, Itzhaki implicates HSV1 as leading to the formation of amyloid plaques and tau tangles

 and APOE ε4 as responsible for the negative effects of the virus. “How the 2 [HSV1 and APOE ε4] interact is unknown,” she said, “but there are many cases where a genetic factor determines whether an individual is seriously or mildly infected and affected by an infectious agent or whether the person is infected but not affected.”

Taking Itzhaki’s work a step further, Rudolph Tanzi, PhD, the Joseph P. and Rose F. Kennedy Professor of Neurology, Harvard Medical School, vice chair of neurology, and director, Genetics and Aging Research Unit at Massachusetts General Hospital, along with colleague Robert Moir, PhD, assistant professor of neurology at Harvard Medical School and Mass General, found that particular bacteria or viruses that get into the brain through a compromised blood-brain barrier, or that get activated in the brain, trigger the deposition of amyloid beta protein as a defense mechanism.

 The amyloid beta adheres to and traps the microbes by forming plaques around them to protect the brain from damage from the bacteria or viruses, they said.

“Although the amyloid-β protein starts with the intention of protecting the brain from the damage of viruses, the plaques it forms cause tau tangles within the neurons that eventually cause inflammation and neuronal cell death,” Tanzi and Moir said. Even the tau tangles that form within neurons try to block the spread of the herpes virus, they noted, which typically travels along the axon of a neuron and crosses the synapse onto another neuron.

The HSV1 pathogen is not the only microbe implicated in the pathology of AD. There is also a case to be made for human herpesvirus 6 and human herpesvirus 7, which have been found in higher concentrations in the brains of people with

AD who died compared with levels found in controls.

 With several microbes inhabiting the brain, Tanzi and colleagues have set out to uncover the bacteria, fungi, or viruses that interact with amyloid beta as part of the Brain Microbiome Project.

Other researchers have expanded beyond the brain, linking microbiota found in the gut to AD

 as well as noting a rela- tionship between periodontitis and AD.

 These pathologies and risk factors could be taken as evidence that AD pathology is multifactorial, as Perry suggested, or that we don’t yet know as much as we think we do about the disease.

“One reason why the amyloid hypothesis is being challenged is that in the brains of many elderly people there is a lot of amyloid presence, yet they’re cognitively normal. So, obviously, if amyloid beta causes AD, if you have a person whose brain is filled with amyloid beta, you would assume that this person should have a cognitive impairment,” said Miroslaw Mackiewicz, PhD, program director for the Integrative Neurobiology, Sleep & Biorhythms section in the

Neurobiology of Aging Branch of the Division of Neuroscience at the NIA. “However, we have plenty of examples where we can find amyloid beta in the brain using imaging technologies, and these people are cognitively normal. This is an important discrepancy to consider.”

“If we look at how the presence of tau tangles correlates with cognitive performance, their presence correlates better than amyloid beta. However, it is not a perfect correlation,” he added. “Again, we should keep in mind that we originally thought amyloid-β was important, then we added tau tangles and decided both amyloid and tau tangles are important. Perhaps tau tangles are even more important than amyloid?” he suggested, noting that there are several other proteins in the brain that also form aggregates. For this reason, he said, the mixed-pathology theory is preferred over the amyloid hypothesis.

The proposed poor correlation between amyloid beta protein and cognitive performance brings the premise of the amyloid hypothesis into question. Indeed, the role amyloid beta plays in cognitive performance needs to be examined further. Postmortem examination of the brains of cognitively normal people who lived to be 90 and older have showed amyloid plaques and tau tangles characteristic of AD.

 Referred to as superagers, the amount of neurons found in these patients’ brains compared with the brains of those who died of AD indicates they were protected from the assumed toxicity of the amyloid plaques and destructive nature of the tau tangles.

Despite our growing understanding of AD pathology, finding effective treatments continues to be a major challenge. Whereas some researchers are optimistic that recent discoveries in infectious pathologies may lead to the development of preventive solutions, others opine that the findings still require extensive investigation before any reasonable prediction of a solution can be made. Speaking on AD prevention, A. David Smith, DPhil, MA, FMedSci, professor emeritus of pharmacology at the University of Oxford, told 

 that “infections should not be allowed to become chronic, particularly herpes and gingivitis. My view is that infection is a rather neglected area of research in AD, like nutrition was a few years ago. The increase in research on nutritional risk factors is leading to methods of preven- tion. I think the infection field is at an early stage and should be supported more strongly in the hope that preventive measures

Itzhaki added, “We don’t yet know if antiviral treatment would slow or even stop disease progression or if, more speculatively, prior antiviral treatment would delay onset of the disease, but it seems possible. Either consequence would be of enormous benefit to patients and to their caregivers.” In terms of a potential AD vaccine, “If an anti-HSV1 vaccine could be produced, vaccination would stop HSV1 infection or possibly stop the virus from entering the brain,” she said.

For Tanzi, addressing disease prevention means getting ahead of symptoms by nearly a decade. “We’re creating drugs that reduce the amyloid deposition, and we now know they need to be used at least 5 to 10 years before symptoms because it’s too late to treat amyloid in somebody who already has the symptoms. However, we can also catalogue the microbes that are most common in AD brains and see which viruses and bacteria are most commonly trapped by the plaque. In the future, we might consider a primary prevention by trying to actually fight against those microbes or developing drugs to stop these microbes from getting into the brain so that you don’t need to make amyloid,” he said.

Tanzi and colleagues have been focusing their efforts on γ-secre- tase modulators (GSMs),

 small molecules that modulate rather than inhibit gamma-secretase processivity, shifting the profile of the secreted amyloid-β peptides produced from the longer type, which are more prone to plaque formation, to a shorter type.16 Previous iterations of GSIs, such as semagacestat, were discontinued due to adverse effects caused by other gamma-secretase substrates, such as Notch, which are essential for cellular development, as well as the build up of the amyloid precursor protein carboxyl-terminal fragments, toxic fragments that likely cause loss of neuronal function.

 Phase 1 trials of a new class of GSMs, soluble 2-aminothiazole GSMs,

should be starting later this year, Tanzi said.

Without question, there is still a lot of work to be done to understand the pathology of AD and how to prevent and treat it. The research community is no longer afraid to step outside of traditional theories in their efforts to identify the root cause, or causes, of the disease.

1. DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. 2019;14(1):32. doi: 10.1186/s13024-019-0333-5.

2. Beta-amyloid and the amyloid hypothesis. Alzheimer’s Association website. alz.org/national/docu- ments/topicsheet_betaamyloid.pdf. Updated March 2017. Accessed September 2, 2019.

3. What happens to the brain in Alzheimer’s disease?. National Institute on Aging website. nia.nih.gov/ health/what-happens-brain-alzheimers-disease. Accessed September 2, 2019.

4. Mehta D, Jackson R, Paul G, Shi J, Sabbagh M. Why do trials for Alzheimer’s disease drugs keep failing? a discontinued drug perspective for 2010-2015. Expert Opin Investig Drugs. 2017;26(6):735- 739. doi: 10.1080/13543784.2017.1323868.

5. Readhead B, Haure-Mirande J, Funk CC, et al. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron. 2018;99(1):64-82. doi: 10.1016/j.neuron.2018.05.023.

6. Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF. Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. Med Virol. 1991; 33(4):224-227.

7. Itzhaki RF, Lin W, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet. 1997;349(9047):241-244.

8. Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J Pathol. 2009; 217(1):131-138. doi: 10.1002/path.2449.

9. Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, et al. Alzheimer’s disease-associated β-am- yloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron. 2018;99(1):56-63. e3. doi: 10.1016/j.neuron.2018.06.030.

10. Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and Alzheimer’s disease. J Alzheimers Dis. 2017;58(1):1-15. doi: 10.3233/JAD-161141.

11. Kowalski K, Mulak A. Brain-gut-microbiota axis in Alzheimer’s disease. J Neurogastroenterol Motil. 2019;25(1):48-60. doi: 10.5056/jnm18087.

12. Ide M, Harris M, Stevens A, et al. Periodontitis and cognitive decline in Alzheimer’s disease. PLoS One. 2016;11(3):e0151081. doi: 10.1371/journal.pone.0151081.

13. Dominy SS, Lynch C, Ermini F, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;5(1):eaau3333. doi: 10.1126/sciadv.aau3333.

14. Gefen T, Peterson M, Papastefan ST, et al. Morphometric and histologic substrates of cingulate integrity in elders with exceptional memory capacity. J Neurosci. 2015;35(4):1781-1791. doi: 10.1523/JNEUROSCI.2998-14.2015. 15. Raven F, Ward JF, Zoltowska KM, et al. Soluble gamma-secretase modulators attenuate Alzheimer’s

β-amyloid pathology and induce conformational changes in Presenilin 1. EBioMedicine. 2017;24:93-

16. Golde TE, Koo EH, Felsenstein KM, Osborne BA, Miele L. γ-secretase inhibitors and modulators.

Biochim Biophys Acta. 2013;1828(12):2898-2907. doi: 10.1016/j.bbamem.2013.06.005.

17. Semagacestat. Alzforum website. alzforum.org/therapeutics/semagacestat. Accessed September 4, 2019. 

Cover Story

Bogged down by a decades-long chase for a common pathology, investigators exploring alternative and complimentary theories are pushing to extend their time in the spotlight.

Seeking the True Pathogenesis of Alzheimer Disease

Neuropsychiatric manifestations represent a core feature of Parkinson disease (PD), from the prediagnostic phase to end-stage disease. Parkinson disease psychosis (PDP) is thought to be a result of an increase in the numbers of 5-HT2A receptors and dopaminergic hyperactivity. However, dopamine agonist (DA) medications like levodopa (L-dopa) that help reduce muscle rigidity and tremors can also trigger psychosis, marked by hallucinations and delusions. The clinical approach for treating PDP traditionally relies on initially reducing the dopaminergic agent and considering an add-on therapy for psychiatric symptom management.

Co-occurring psychiatric conditions in PD are common, and despite having considerable impact on patient quality of life (QOL), they remain underrecognized. Multiple scales have been developed in the clinical and research settings to help physicians assess symptoms like hallucinations, delirium, and psychosis. There is increasing evidence for pharmacological and nonpharmacological treatment options for depression, but the evidence for treatment of other neuropsychiatric features is much less robust.

 PDP has been reported to affect up to 60% of patients over their lifetime, and this risk increases with age and larger doses of DA medications.

 PDP also is associated with poor prognosis and usually entails greater caretaker burden, mortality, and increasing rates of nursing home placement.

Definition and formal criteria for PDP as a distinct disease entity have been established. PDP symptoms are believed to progress and can include hallucinations involving all 5 senses (most commonly, sight), illusions, and delusions. The progression is such that symptoms that are merely bothersome at an early stage will likely become more severe, varied, and troublesome as the disease progresses. PDP and impulse control disorders are reported to be associated with DA intake

 and are included in the behavioral spectrum of nonmotor symptoms of PD.

“Once a patient starts having psychosis symptoms, they will progress,” said Rajesh Pahwa, MD, Laverne & Joyce Rider Professor of Neurology at the University of Kansas Medical Center. “Clinicians should closely monitor patients and treat as the symptoms start causing problems for the patient or caregiver.”

Onset of chronic PDP or transition from an acute to chronic state of PDP should prompt an evaluation of current therapies and a systematic reduction of those therapies in the following order: anticholinergic agents, selegiline, amantadine, DAs, catechol-O-methyltransferase inhibitors, and levodopa.

 If this strategy does not improve psychosis symptoms, physicians should consider use of cholinesterase inhibitors (eg, rivastigmine 6-12 mg/2-3 days, donepezil 5-10 mg daily, or galantamine 4-32 mg/2-3 days) or antipsychotic medication (clozapine 12.5-62.5 mg daily or quetiapine 12.5-75 mg daily).

The use of atypical antipsychotics in PD has been associated with a statistically significant risk of mortality.

 As an atypical antipsychotic, clozapine is slightly stronger than quetiapine but is associated with an increased risk for agranulocytosis, with an estimated prevalence of 1% to 2%.

 Quetiapine, a dibenzothiazepine derivative structurally related to clozapine, is the weakest atypical antipsychotic and thus has a lower risk of mortality. In a study comparing the efficacy of clozapine and quetiapine, Merims and colleagues

 found an overall trend for clozapine over quetiapine in controlling hallucinations and reducing delusions, but the high incidence of agranulocytosis with clozapine suggests a limitation in its use.

Other atypical antipsychotics have shown unreliable efficacy or unacceptable reductions in motor function. There is no evidence of efficacy for olanzapine in treating PDP, and it is associated with motor function deterioration.

 Risperidone has also been shown to worsen motor function and thus is not recommended for PDP.

 Melperone, an atypical antipsychotic of the butyrophenone chemical class, showed no benefit compared with placebo in a trial by Friedman.

The only medication currently approved by the FDA for the treatment of PDP is pimavanserin (Nuplazid; Acadia), a potent and highly selective 5-HT2A inverse agonist without dopaminergic, adrenergic, histaminergic, or muscarinic affinity.

 These attributes make it unlikely to block postsynaptic DA and other off-target receptors. Pimavanserin’s mechanism of action is thought to decrease the excessive neurotransmission permitted by the 5-HT2A receptors, thereby reducing visual hallucinations in PDP.

Approved by the FDA in April 2016, pimavanserin is recommended as a daily 34-mg dosage and is indicated for the treatment of delusions and hallucinations in patients with PDP. In its phase 3 ACP-103-020 trial with an enrollment of 199 participants, pimavanserin was shown to decrease delusions by 41% and hallucinations by 34% compared with 21% and 18%, respectively, in the placebo group.

 Improvement in hallucinations and delusions was statistically significant on the Scale for the Assessment of Positive Symptoms global ratings. Researchers also found that treatment with pimavanserin did not worsen motor symptoms.

Pimavanserin is not approved for the treatment of patients with dementia-related psychosis that is unrelated to the hallucinations and delusions associated with PDP, thereby creating a challenge when treating older patients with PD, who are more likely to have dementia. However, the results of a recent efficacy analysis of the phase 3 HARMONY study revealed that pimavanserin statistically significantly reduced the risk for relapse of dementia-related psychosis.

The drug should be avoided in patients with a history of cardiac arrhythmias, symptomatic bradycardia, hypokalemia, hypomagnesemia, and QT prolongation or in combination with other medica- tions known to prolong the QT interval, including Class 1A or Class 3 antiarrhythmics. In clinical trials, pimavanserin has been shown to be well tolerated; its adverse effect profile includes urinary tract infections (UTIs), peripheral edema, hallucinations, confusion, nausea, and headaches.

“As the symptoms often begin gradually, and if a patient is seen in clinic and has hallucinations occasionally and the patient has insight about them that they are not real, my approach is to monitor the patients,” said Pahwa, who is also chief of the Parkinson and Movement Disorder Division and director of the Parkinson Foundation Center of Excellence at the University of Kansas Medical Center. “If the patient calls before their next appointment and says their hallucinations are worse or bothersome, I check to make sure no new medications, such as narcotic pain medications, were added and check routine labs and [urinalysis] to make sure they don’t have a UTI or dehydration. If the patient [does have disease-related] delusions, we start pimavanserin.”

Compared with atypical antipsychotics to manage PDP that may cause adverse events such as worsened motor symptoms and orthostatic hypotension, pimavanserin is the preferred option for most patients based on its demonstrated clinical efficacy and safety.

“If possible, I might reduce medications with anticholinergic properties [if they are taking them], reduce or eliminate amantadine, and reduce dopamine agonists,” Pahwa said. “If reducing medication does not reduce hallucination, I add pimavanserin.”

Recent findings presented at the American Academy of Neurology Annual Meeting held May 4-10, 2019, in Philadelphia, Pennsylvania, demonstrated that among individuals with PDP or Lewy body dementia, there were no significant differences in efficacy with pimavanserin or quetiapine in time to medication discontinuation, mortality, or psychosis improvement.

“Pimavanserin is the only approved medication for PDP. Since it was approved based on [results from] 1 study, clinicians often feel that there are not enough data available for its efficacy,” Pahwa said.

Enhancement of serotonergic neurotransmission and mesocorticolimbic pathway activation via electroconvulsive therapy (ECT) may have an antipsychotic and antidepressant effect in PD.

 Beneficial effects of ECT have been reported, with Caldero&#769;n-Fajardo and colleagues noting an improvement in measures of motor and nonmotor function on different scales with use of ECT in 29 drug-refractory PD patients with psychiatric symptoms, including 12 patients with psychosis and depression.

 Issues related to safety and tolerability of ECT have not been reported; it’s important to note that studies to date have only been performed in small sample sizes and have not been blinded, begging the need for larger, sham-controlled studies.

The potential of deep brain stimulation (DBS) to treat psychiatric disorders has shown promise in conditions such as obsessive compulsive disorder and major depressive disorder; however, evidence of the effect of DBS in PDP is lacking.

Studies have identified a variable positive and negative impact on psychiatric symptoms following DBS in PD, with some reporting worsening of or the emergence of new symptoms and others reporting improvements, namely in mood-related conditions.

 These findings, while inconclusive for patients with PDP, stress the importance of patient selection for DBS, as prior history of neuropsychiatric disorders appears to have an impact on outcomes.

Results from preclinical and preliminary studies also suggest that cannabidiol (CBD) has therapeutic potential for nonmotor symp- toms of PD.

 The multifaceted mechanism of action as an agonist of 5-HT1A, partial agonist of CB1 and CB2 receptors, and antagonist of the G-protein—coupled receptor GPR55 reverses the iron-induced epigenetic modification of mitochondrial DNA and the reduction of succinate dehydrogenase activity and decreases the levels of the pro-inflammatory cytokines IL-1β, TNF-α, IFN-β, IFN-γ, IL-17, and IL-6—all of which decrease pro-inflammatory mediators resulting in neuroprotective, anxiolytic, and antipsychotic effects.

“Several in vitro experiments have demonstrated promising neuro- protective effects of CBD in PD models. In one of these models, using PC12 and SH-SY5Y cells treated with MPP+ [1-methyl-4-phenylpyridinium], CBD increased cell viability, differentiation, and the expression of axonal [GAP-43] and synaptic [synaptophysin and synapsin I] proteins,” Ferreria-Junior and colleagues wrote,

 while acknowledging the paucity of studies that have addressed the biological bases for the purported effects of CBD on PD. “Double-blind, placebo-controlled, randomized trials with larger samples of patients with PD are needed to elucidate the possible effectiveness and mechanisms involved in the therapeutic potential of CBD in this movement disorder. This will also include the putative effects of CBD in preventing L-dopa—induced severe [adverse] effects and preventing PD progression.”

The endocannabinoid system serves as an important filter of excitatory, inhibitory, and modulatory inputs that act at the midbrain and terminal regions to orchestrate DA neurotransmission by controlling DA cell body firing patterns, terminal release, and effects on postsynaptic sites in the striatum.

 Beneficial effects of CBD administration have been observed prior to or immediately after induction of PD-like symptoms in animal studies, which may suggest a preventive role rather than a therapeutic one.

 In an early open-label pilot study to evaluate the efficacy of CBD on nonmotor symptoms of PD in 6 patients with PDP, psychotic symptoms significantly decreased under CBD treatment, as evaluated by the brief psychiatric rating scale and the Parkinson psychosis questionnaire.

With PD and psychosis residing on what may be considered opposite ends of the DA spectrum, the complex interaction between the two presents physicians, patients, and caregivers with the difficult task of striking a balance between physical and emotional stability.

Despite estimates that the prevalence of PD will more than double by 2060, training in PD-specific mental health care is not standard in most programs, and the need for subspecialty-trained mental health care providers will only increase over time with the aging population. With limits on the extension of mental health care into existing models of integrated or multidisciplinary care, specialty mental health care is not routinely available, accessible, or integrated in most neurology practices.

Psychiatric comorbidities prevalent in the majority of patients with PD are associated with more disease severity, impaired QOL, and increased use of health care resources, with longer hospital stays and rehospitalizations adding to the total cost burden. A multidisciplinary approach to managing PDP is crucial to improving the overall outcome and the health-related QOL of these patients and their caregivers.

 Future research should utilize clinical data and employ longitudinal designs to evaluate outcomes among patients with PDP and comorbid depression and other neuropsychiatric conditions.

1. Nagy A, Schrag A. Neuropsychiatric aspects of Parkinson’s disease. 

. 2019;126(7):889-896. doi: 10.1007/s00702-019-02019-7.

2. Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson disease. 

. 2010;67(8):996-1001. doi: 10.1001/archneurol.2010.166.

3. Weintraub D, David AS, Evans AH, Grant JE, Stacy M. Clinical spectrum of impulse control disorders in Parkinson's disease. 

. 2015;30(2):121-127. doi: 10.1002/mds.26016.

4. Taddei RN, Cankaya S, Dhaliwal S, Chaudhuri KR. Management of psychosis in Parkinson's disease: emphasizing clinical subtypes and pathophysiological mechanisms of the condition. 

2017;2017:3256542. doi: 10.1155/2017/3256542.

5. Merims D, Balas M, Peretz C, Shabtai H, Giladi N. Rater-blinded, prospective comparison: quetiapine versus clozapine for Parkinson's disease psychosis. 

. 2006;29(6):331-337. doi 10.1097/01.WNF.0000236769.31279.19.

6. Friedman JH. Melperone is ineffective in treating Parkinson's disease psychosis. 

. 2012;27(6):803-804. doi: 10.1002/mds.24942.

7. Meadowcraft LM, Tsurutis V, Morrisette T. Pimavanserin for treatment of hallucinations and delusions associated with Parkinson disease psychosis. 

8. A Study of the Safety and Efficacy of Pimavanserin in Patients With Parkinson's Disease Psychosis. clinicaltrials.gov/ct2/show/NCT01174004. Updated March 26, 2014. Accessed August 26, 2019.

9. Acadia Pharmaceuticals announces pivotal phase 3 HARMONY trial stopped early for positive efficacy as pimavanserin meets the primary endpoint in patients with dementia-related psychosis [news release]. San Diego, CA: Acadia Pharmaceuticals Inc; September 9, 201 biospace.com/article/releases/acadia-pharmaceuticals-announces-pivotal-phase-3-harmony-trial-stopped-early-for-positive-efficacy-as-pimavanserin-meets-the-primary-endpoint-in-patients-with-dementia-related-psychosis/. Accessed September 10, 2019.

10. Lyons KE, Pahwa R, Hermanowicz N, Davis T, Pagan F, Isaacson S. Changing the treatment paradigm for Parkinson’s disease psychosis with pimavanserin. 

. 2019;12(7):681-691. doi: 1080/17512433.2019.1623669.

11. Horn S, Dahodwala N. Pimavanserin versus quetiapine for the treatment of psychosis in Parkinson’s disease and dementia with Lewy bodies. Presented at: 2019 American Academy of Neurology Annual Meeting; May 4-10, 2019. Philadelphia, Pennsylvania. n.neurology.org/content/92/15_Supplement/P2.8-037.

12. Calderón-Fajardo H, Cervantes-Arriaga A, Llorens-Arenas R, Ramírez-Bermudez J, Ruiz-Chow Á, Rodríguez-Violante M. Electroconvulsive therapy in Parkinson's disease. 

. 2015;73(10):856-860. doi: 10.1590/0004-282X20150131.

13. Accolla EA, Pollo C. Mood effects after deep brain stimulation for Parkinson's disease: an update. 

2019;10:617. doi: 10.3389/fneur.2019.00617.

14. Peres FF, Lima AC, Hallak JEC, Crippa JA, Silva RH, Abílio VC. Cannabidiol as a promising strategy to treat and prevent movement disorders? 

 2018;9:482. doi: 10.3389/fphar.2018.00482.

15. Ferreira-Junior NC, Campos AC, Guimarães FS, et al. Biological bases for a possible effect of cannabidiol in Parkinson’s disease [published online July 15, 2019]. 

16. Covey DP, Mateo Y, Sulzer D, Cheer JF, Lovinger DM. Endocannabinoid modulation of dopamine neurotransmission. 

. 2017;124(15):52-61. doi: 10.1016/j.neuropharm.2017.04.033.

17. Zuardi AW, Crippa J, Hallak JEC, et al. Cannabidiol for the treatment of psychosis in Parkinson’s disease.

. 2009;23(8):979-983. doi: 10.1177/0269881108096519.

18. Pontone GM, Dissanayaka N, Dobkin RD, et al. Integration and extension of specialty mental healthcare services to community practice in Parkinson Disease. 

. 2019;27(7):712-719. doi: 10.1016/j.jagp.2019.03.005.

19. Imran S, Patel RS, Onyeaka HK, et al. Comorbid depression and psychosis in Parkinson's disease: A report of 62,783 hospitalizations in the United States. 

. 2019;11(7):e5227. doi: 10.7759/cureus.5227.

Features

Although the indication of pimavanserin has provided some relief, more work remains to improve how physicians diagnose, treat, and manage psychosis symptoms.

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