Narcolepsy is a chronic sleep disorder of autoimmune origin that affects roughly 1 in 2000 to 4000 individuals, occurring in men and women but with some variability in prevalence among racial and ethnic groups.

 It is characterized by excessive daytime sleepiness (EDS), sleep paralysis, hallucinations while falling asleep or waking, and, in some cases, sudden loss of muscle tone triggered by strong emotion (cataplexy), all symptoms that can seriously diminish quality of life.

 Comorbid neuropsychiatric manifestations in patients with 

 (eg, eating disorders, depression, anxiety, and psychosis) often impair early diagnosis due to shared common features.

 To date, there are no treatments that hinder or slow disease development, but lifestyle changes and support groups have helped patients cope with narcolepsy. Medications that suppress sleepiness can also assist with managing symptoms, but careful selection and supervision are required due to the potent adverse effects (AEs) and addiction potential of most prescribed stimulants.

Managing narcolepsy via behavioral strategies (eg, implementing good sleep hygiene and seeking counseling) to improve EDS may be challenging but has shown some added efficacy when combined with pharmacological treatment for EDS.

 Current treatments for narcolepsy symptoms include classic central nervous system (CNS) stimulants (eg, modafinil, amphetamines, sodium oxybate, and caffeine) to treat EDS and antidepressants (eg, fluoxetine, venlafaxine, or clomipramine) to treat cataplexy.

 These drug therapies may be costly and are sometimes associated with harmful AEs, including dependency; therefore, a need exists for narcolepsy treatments with improved safety and efficacy.

Narcolepsy is a chronic neurological condition affecting neurons in the hypothalamus that produce hypocretins 1 and 2 (also called orexins A and B, respectively),

 which can have severe consequences for the patient. Problems faced by patients with narcolepsy include social stigma associated with this disease, difficulties in obtaining an education and keeping a job, a reduced quality of life and socioeconomic consequences. Two subtypes of narcolepsy have been described (narcolepsy type 1 and narcolepsy type 2 Genetic analysis of individuals with narcolepsy has shown that lack of the peptide neurotransmitter hypocretin, a hallmark of this disease, is generally not caused by mutations in hypocretin-encoding genes. Instead, the approximately 70,000 hypothalamic neurons that produce hypocretin are lost in a process that is poorly understood but remarkably specific, sparing adjacent neurons that express melanin-concentrating hormone.

 This deficit in hypocretin neurons cannot be compensated for simply by administration of hypocretins because of their poor bioavailability. However, patients with narcolepsy have a documented 94% increase in the number of histaminergic neurons within the hypothalamic tuberomammillary nucleus; over time, this may compensate for the loss of hypocretin signaling.

 In fact, the brain histaminergic system controls several essential physiological functions, including arousal and maintenance of wakefulness.

 For these reasons, the histaminergic system has gained interest in narcolepsy research.

Histamine, also known as the “waking amine,”

 mediates its effects through binding to 4 known G protein—coupled receptor subtypes, H1R to H4R. H4R, which remains poorly understood, shares high homology with H3R but not with H1R and H2R.

 H1R, H2R, and H4R expression is described in immune cells, hepatocytes, and endothelial cells, where they mediate slow excitatory postsynaptic potentials.

 H3R, on the other hand, is predominantly expressed in the CNS, where it functions as a presynaptic autoreceptor to negatively regulate histamine synthesis and release,

 as well as a heteroreceptor to control the release of other neurotransmitters, such as acetylcholine, in various brain regions.

 Modulation of cortical activity and the sleep-wake cycle could therefore be achieved via H3R and its ligands.

Such histamine receptor ligands can be classified as agonists, neutral antagonists, or inverse agonists: agonists are ligands with a lower affinity for receptors in the uncoupled state, whereas the affinity of neutral antagonists is unaffected by the coupling state, and inverse agonists have a higher affinity for the uncoupled state of the receptor.

 Of significance to narcolepsy therapeutics and the treatment of brain disorders (eg, Alzheimer disease and schizophrenia) are inverse agonists of H3R; it is especially important to suppress the relatively high constitutive activity of H3R.

 Inverse agonists of H3R work by enhancing the release of histamine, which then competes with the ligand for occupancy of autoreceptors, thus inhibiting the constitutive activity of H3R and stabilizing it in the inactive state (

H3R inverse agonists have had success in therapeutic management of behavioral deficiencies associated with schizophrenia in mouse models,

 supporting the development of H3R inverse agonists to treat EDS and cataplexy. Classic H3R inverse agonists have been shown to increase wakefulness and to decrease sleep in rodent and feline models,

 although the effects are compound- and species-dependent.

 For example, the imidazole H3R inverse agonists thioperamide and ciproxifan promote cortical activation and waking, whereas the H3R agonists α-methylhistamine, imetit, and BP2-94 enhance cortical slow activity and increase slow-wave sleep.

 Based on these robust effects in animal sleep-wake control, H3R ligands were investigated for treatment of human sleep-wake disorders, with the hope that these ligands would be H3R specific, modulate only histamine neurotransmission, and promote effects on sleep-wake parameters that are comparable or even stronger than those of classic psycho-stimulants. Most chemical series currently under investigation are nonimidazole in nature, which provides advantages of being more selective for H3R versus H1R, H2R, or H4R, and increasing CNS penetration while minimizing drug-drug interactions.

Pitolisant (Wakix; Harmony Biosciences) is a potent, orally available, once-daily, first-in-class, wake-promoting selective inverse agonist of H3R with a good preclinical and clinical benefit to risk ratio for the treatment of narcolepsy.

 It was approved in the European Union in March 2016 for the treatment of narcolepsy with or without cataplexy in adults,

 and United States approval was granted in August 2019 for the treatment of EDS in adults with narcolepsy.

 Pitolisant functions by activating not only histaminergic and noradrenergic neurons but also the wake-promoting cholinergic and dopaminergic neurons.

 Results from pivotal, supportive phase 3 trials (HARMONY I, NCT01067222; HARMONY 1bis, NCT01638403) suggested that a dose of up to 40 mg per day for adults was significantly superior to placebo for enhancing wakefulness and decreasing cataplexy rate, although pitolisant was comparable to modafinil in management of EDS.

Pitolisant was demonstrated to have minimal risk of abuse in preclinical and clinical studies, and it remains the only antinarcoleptic drug not scheduled as a controlled substance in the United States.

 In the HARMONY CTP (NCT01800045) and HARMONY I (NCT01067222) trials, no patients on pitolisant experienced amphetamine-like withdrawal syndrome during the withdrawal phase, whereas this AE occurred in several patients treated with modafinil.

 Patients taking pitolisant also did not experience hypersomnia or fatigue upon treatment interruption, and Beck Depression Inventory scores improved significantly from baseline compared with placebo (P = .02).

 Blood chemistry and hematological and cardiovascular parameters were consistent with those of controls.

 Overall, pitolisant was well tolerated in clinical trials, with participants typically experiencing few AEs, primarily headache, insomnia, nausea, and anxiety, which are consistent with its mechanism of action.

 Long-term safety data for pitolisant in individuals with narcolepsy are currently limited to the HARMONY III trial in adults (NCT01399606),

 with a complementary prolonged open-label study ongoing in pediatric patients (NCT02611687).

Other H3R inverse agonists have been evaluated in clinical trials for treatment of narcolepsy. The efficacy of GSK189254 was similar to that of modafinil in terms of increased wakefulness, reduced slow-wave sleep, and decreased paradoxical sleep in mice,

 although a phase 2 clinical trial (NCT00366080) was terminated based on the interim results of a futility test.

A phase 2 study (NCT00424931) of a new formulation of modafinil, JNJ-17216498, was conducted based on promising preclinical data for a related compound, JNJ-5207852, which demonstrated increased wakefulness and a favorable pharma- cokinetic profile in mice.

 Although the clinical trial was completed in 2007, no additional information has been released since 2014. Preclinical data for SUVN-G3031 showed increased wakefulness in a rat model of narcolepsy.

 In 2 phase 1 clinical studies (NCT02342041 and NCT02881294), single doses up to 20 mg and multiple doses up to 6 mg once daily were found to be safe and well tolerated in healthy human subjects, with no effects of age, sex, or fasting status on the agent’s pharmacokinetics and safety profile.

 An ongoing phase 2 study evaluating SUVN-G3031 safety and efficacy in patients with narcolepsy began in September 2019 (NCT04072380).

In conclusion, narcolepsy is a condition of sleepiness for which life-long treatment is likely to be required. Promising advances involve using novel agents to treat targeted symptoms such as EDS, with the potential to treat more than 1 symptom of narcolepsy. However, cost, convenience, and AEs remain challenges. Furthermore, although the beneficial effects of pitolisant in EDS and cataplexy treatment are well substantiated, the use of H3R inverse agonists in cognitive disorders is promising but requires further testing.References 

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12. Berlin M, Boyce CW, Ruiz M de L. Histamine H3 receptor as a drug discovery target. J Med Chem. 2011;54(1):26-53. doi:10.1021/jm100064d 

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19. Harmony Biosciences announces FDA approval of WAKIX (pitolisant), a first-in-class medication for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. News release. Harmony Biosciences. August 15, 2019. Accessed June 5, 2020. https://www.finance.yahoo.com/news/harmony-biosciences-announces-fda-approval-120000845.html 

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22. Dauvilliers Y, Bassetti C, Lammers GJ, et al; HARMONY I Study Group. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068-1075. doi:10.1016/S1474-4422(13)70225-4 

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Articles

NeuroPathways

Managing narcolepsy via behavioral strategies to improve excessive daytime sleepiness may be challenging but has shown some added efficacy when combined with pharmacological treatment for EDS. 

Selective Inverse Agonists of the Histamine 3 Receptor as Treatment for Narcolepsy

In recent decades, the development of therapies for patients with relapsing-remitting multiple sclerosis (RRMS) has significantly progressed, with FDA approval of numerous anti-inflammatory disease-modifying therapies (DMTs). However, advances in drug development for progressive forms of MS—affecting an estimated 10% to 15% of patients with MS&mdash;have lagged considerably in comparison.

“Disease modification for progressive MS continues to be challenging,” said Kathleen Costello, MS, a board-certified adult nurse practitioner and MS nurse specialist as well as the National Multiple Sclerosis Society’s associate vice president of healthcare access. “Most current therapies that are FDA approved for relapsing forms of MS include ‘active secondary progressive MS’ in the approval, but that implies that there is ongoing inflammation as seen on MRI or presenting as a relapse,” she told 

, whereas primary-progressive MS (PPMS) is characterized by steadily worsening neurologic function with no relapses.

This treatment gap is largely attributed to the continued lack of clarity regarding the mechanisms that drive disease activity in PPMS and secondary-progressive MS. Disease progression has been cited as the main contributing factor in MS-related disability accumulation, further underscoring the need for effective treatment strategies for the disease’s progressive forms.

“I think the biggest challenge in treating progressive MS is understanding its pathophysiology,” said Robert J. Fox, MD, staff neurologist at the Mellen Center for Multiple Sclerosis and vice-chair for research at the Neurological Institute of Cleveland Clinic in Ohio. “What is truly driving the insidious decline? Is it compartmentalized inflammation? A metabolic derangement? A mitochondrial dysfunction? At this point, we really don’t know.”

While it is understood that relapses in RRMS are driven by inflammation due to infiltration of peripheral leukocytes across the blood-brain barrier into the central nervous system (CNS), the relationship between inflammation and the blood-brain barrier in progressive MS is less clear.

 Historically, MS research has focused predominantly on the relapsing phase of MS, in which relapses and inflammation can be assessed on MRI.

 In progressive MS, the lack of specific biomarkers and outcomes measures have presented barriers to the development of new therapies.

The available evidence suggests that “progressive MS is characterized by ongoing inflammation that occurs within the CNS, with an intact blood-brain barrier,” according to Costello. “There appear to be more activated microglia as well as involvement of T and B lymphocytes in progressive MS, and there is evidence of mitochondrial and axonal damage from reactive oxygen species and nitrogen species, which can lead to neurodegeneration.”

The compartmentalized inflammation associated with progressive MS may limit or preclude the effectiveness of anti-inflammatory DMTs that have shown promise in RRMS.

“Currently, where there is ongoing inflammation, we know that stopping the infiltrating inflammation with anti-inflammatory therapies can be helpful—at least, modestly helpful,” Fox told 

. Aside from this benefit, the effects of such therapies on progressive MS pathologies remain unclear. “If there is no active infiltrative inflammation, the potential benefits of anti-inflammatory therapies are modest, with risks often outweighing them.”

In research described in 2019 in the European Journal of Neurology, investigators from the MSBase cohort study conducted an analyses of pooled data (n = 1284) to examine the effects of anti-inflammatory DMTs approved for RRMS and used off-label to treat progressive MS.

  The MSBase team found that these agents had no substantial effect on the short- to medium-term disability outcomes of progressive MS patients, as indicated by a lack of significant difference between treated and untreated patients in the hazard ratios of 3&#8208;month confirmed Expanded Disability Status Scale (EDSS) progression events (HR, 1.0; 95% CI, 0.6—1.7; 

 = .87), confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6—1.6; 

 = .91), or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7—1.6; 

Ocrelizumab, currently the only FDA-approved agent to treat PPMS, is the only therapy thus far that has demonstrated efficacy in reducing the accumulation of disability in this patient population. In the results of the phase 3 ORATORIO trial of 732 patients with PPMS, published in 2017 in the 

, the primary end point of confirmed disability progression at 12 weeks was observed in 32.9% of patients taking ocrelizumab compared with 39.3% of those in the placebo arm (HR, 0.76; 95% CI, 0.59-0.98; P = .03).

In terms of secondary end points, confirmed disability progression at 24 weeks was noted in 29.6% of those taking ocrelizumab versus 35.7% with placebo (HR, 0.75; 95% CI, 0.58-0.98; 

 = .04); also, performance on the timed 25-foot walk declined by 38.9% with ocrelizumab versus by 55.1% with placebo (

 = .04). In addition, there was a 3.4% reduction in the total volume of brain hyperintense T2 lesions on MRI with ocrelizumab compared with a 7.4% increase with placebo (

 <.001), and brain volume decreased by 0.90% with ocrelizumab versus 1.09% with placebo (

Patients taking ocrelizumab experienced more frequent infusion-related reactions, upper respiratory tract infections, oral herpes infections, and neoplasms, compared with placebo. Rates of serious adverse events and serious infections did not differ significantly between groups.

“While these results are modest, they do indicate a place for ocrelizumab in the treatment of some individuals with PPMS,” Costello said.

Many researchers are trying “to better understand the true driving pathophysiology of progressive MS,” said Fox. “Once that is better understood, it should be easier to develop therapies for it.”

To effectively guide the development of new treatment strategies, Costello said that the immunopathological mechanisms involved in progressive MS, as well as mechanisms that inhibit remyelination, both need to be elucidated. “Treatments that can slow or stop progression and reduce damage to axons, and strategies that could promote remyelination, would certainly change the treatment paradigm in progressive MS” and improve disease stability, she said, allowing patients to participate in desired activities.

Potential therapies under investigation include agents to inhibit microglial activation and reduce oxidative stress.

 Additionally, researchers are currently aiming to identify the most appropriate biomarkers to use in screening progressive MS therapies. In this area, a wide range of potential measures may indicate disease progression, including plasma neurofilament light chain levels, unique volatile organic compounds in the breath, and other MRI, blood, and cerebrospinal fluid biomarkers.

“At this point, imaging biomarkers appear to hold the most promise in progressive MS,” said Fox. “Cortical atrophy and magnetization transfer ratio (MTR) imaging appear to have good reproducibility and dynamic change over time. The phase 2 SPRINT-MS trial found both of these to be particularly powerful in measuring the effect of ibudilast in progressive MS.”

The estimated rate of annual change in MTR over the 96-week study period was −0.0282 with placebo and −0.0051 with ibudilast (difference, 0.0231; 95% CI, 0.0003-0.0458). For cortical thickness, the estimated rate of annual change was −0.0105 with placebo and −0.0019 with ibudilast (difference, 0.0086; 95% CI, 0.0028-0.0144). “These markers may allow for smaller, shorter, and more efficient phase 2 trials in the future,” Fox said.

“Progressive forms of MS present increased challenges due to the accumulation of disability, which may include difficulties with mobility, cognition, balance, or other symptoms, leading to greater challenges with maintaining employment and other role responsibilities,” Costello explained. “These complex issues require a coordinated and comprehensive approach that may include rehabilitation, mental health, neuropsychology, vocational rehabilitation, and others to optimize function and ability to participate.”

Costello noted that not all practices have access to the resources listed above. To help, the National Multiple Sclerosis Society has a staff of highly trained MS Navigators available to partner with health care providers and patients to provide support, identify resources, and assist with job challenges and disability affecting individuals with progressive MS.

1. Lorscheider J, Kuhle J, Izquierdo G, et al; MSBase Study Group. Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study.&#8239;Eur J Neurol. 2019;26(2):363-370. doi:10.1111/ene.13834 

2. Hollen CW, Paz Soldán MM, Rinker JR 2nd, Spain RI. The future of progressive multiple sclerosis therapies.&#8239;Fed Pract. 2020;37(Suppl 1):S43-S49. 

3. Ruiz F, Vigne S, Pot C. Resolution of inflammation during multiple sclerosis.&#8239;Semin Immunopathol. 2019;41(6):711-726. doi:10.1007/s00281-019-00765-0 

4. Machado-Santos J, Saji E, Tröscher AR, et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells.&#8239;Brain. 2018;141(7):2066-2082. doi:10.1093/brain/awy151 

5. Montalban X, Hauser SL, Kappos L, et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis.&#8239;N Engl J Med. 2017;376(3):209-220. doi:10.1056/NEJMoa1606468 

6. Multiple Sclerosis Society (United Kingdom). Biomarkers: the road to certainty. May 29, 2020. Accessed July 2, 2020. https://www.mssociety.org.uk/research/latest-research/latest-research-news-and-blogs/biomarkers-the-road-to-certainty 

7. Fox RJ, Coffey CS, Conwit R, et al; NN102/SPRINT-MS Trial Investigators. Phase 2 trial of ibudilast in progressive multiple sclerosis.&#8239;N Engl J Med. 2018;379(9):846-855. doi:10.1056/NEJMoa1803583 

Features

New biomarkers of disease activity may help better vet investigational therapies aimed at slowing the insidious neurodegeneration seen in primary progressive multiple sclerosis.

Closing the Treatment Gap in Progressive MS

In June, Amylyx announced that it had completed enrollment and dosing in 96 of the previously planned 100 participants in the phase 2 PEGASUS trial (NCT03533257), which will assess the safety, tolerability, drug target engagement, and neurobiological effects of treatment with 

 in patients with early dementia due to Alzheimer disease (AD) or late mild cognitive impairment (MCI).

AMX0035 is a first-in-class investigational therapy designed to reduce neuronal death and dysfunction. It targets mitochondrial and endoplasmic reticulum-dependent neuronal degenera- tion pathways through a combination of sodium phenylbutyrate and tauroursodeoxycholic acid—a treatment developed using the rationale of successful tandem therapies in HIV, cancer, and heart disease.

“In sporadic Alzheimer disease, for example, dysfunction in these pathways can be both a cause and consequence of amyloid-beta and tau pathologies, driven by a host of other cellular, genetic and environmental factors,” Steven E. Arnold, MD, PEGASUS principal investigator and translational neurology head of the Interdisciplinary Brain Center at Massachusetts General Hospital and Harvard Medical School, told 

The eligibility criteria for the 24-week, randomized, double-blind, placebo-controlled study is purposefully broad, which will allow the study to “assess the biological effects of AMX0035 across the disease spectrum,” Arnold said. “Further appreciating the heterogeneity of Alzheimer disease, we allow a diverse set of supporting biomarkers to determine Alzheimer’ disease diagnostic eligibility. Our hope was that this would open our study up to patients often ineligible for other trials while providing deep phenotypic insight into patients with a combination of neuroimaging, plasma, and spinal fluid biomarkers and multisequence MR imaging.”

Those eligible for inclusion in the study are between age 55 and 89, with Montreal Cognitive Assessment (MoCA) scores between 8 to 26 and a Geriatric Depression Scale score of less than 7. Patients with any central nervous system (CNS) disease other than suspected AD are excluded from the trial (

In addition to safety and tolerability, the study will focus on several disease-relevant brain biomarkers that be will be evaluated on both a composite and individual level. “These include cognition with established neuropsychological assessment and interview measures, hippocampal structure and function with MR neuroimaging, and cerebrospinal fluid and plasma amyloid, tau, and neurodegeneration biomarkers,” Arnold said, adding that the research teams will also examine more exploratory markers of inflammation and metabolism, as well. “Understanding how the drug may be working, and if a particular subset of patients is especially responsive in the phase 2 study, will allow us to tailor the design of a phase 3 study.”

The 2-drug combination approach makes AMX0035 1 of the more distinguished drugs making its way through the Alzheimer dementia pipeline. Arnold relayed that sodium phenylbutyrate is used in urea cycle abnormalities but also crosses the blood-brain barrier and is a histone deacetylase inhibitor. One of its main functions is to suppress the unfolded protein response which is overactive in AD. Tauroursodeoxycholic acid stabilizes mitochondrial membranes, thus improving the bioenergetics of cells. It can reduce or make cells more resistant to oxidative stress, while also working as a neuroprotectant by preventing apoptosis, he said.

“We recognize that there are a lot of mechanisms that are driving neurodegeneration in Alzheimer [disease], and if you just hit 1 thing and others are left unaddressed, you may have some very modest benefit, but you may have no benefit because everything else is working against the cell,” Arnold told 

. “By combining drugs to ameliorate the damaging effects of these different mechanisms that are active, overactive, or abnormally active in Alzheimer disease, we have a better chance of rescuing sick and dying cells.”

Confidence in the combination drug has only been bolstered by results from Amylyx’s CENTAUR trial (NCT03127514), where treatment with AMX0035 has been shown to be associated with a statistically significant (

 < .05) slowing of amyotrophic lateral sclerosis disease progression based on change from baseline on the ALS Functional Rating Scale-Revised.

Results from the PEGASUS trial are expected to be released in the first quarter of 2021. “We will work to accelerate patient access to AMX0035 according to any requirements issued by the FDA,” Arnold said.

1. Amylyx Pharmaceuticals announces completion of enrollment in the PEGASUS trial of AMX0035 in Alzheimer’s disease. News release. Amylyx Pharmaceuticals. June 15, 2020. Accessed July 9, 2020. https://www.biospace.com/article/releases/amylyx-pharmaceuticals-announces-completion-of-enrollment-in-the-pegasus-trial-of-amx0035-in-alzheimer-s-disease/ 

2. Amylyx Pharmaceuticals announces first patients dosed in PEGASUS phase 2 trial of AMX0035 in Alzheimer’s disease and expansion of the trial. News release. Amylyx Pharmaceuticals. April 9, 2019. Accessed July 9, 2020. https://www.businesswire.com/news/home/20190403005471/en/Amylyx-Pharmaceuticals-Announces-Patients-Dosed-PEGASUS-Phase 

3. Amylyx Pharmaceuticals announces AMX0035 demonstrated statistically significant treatment benefit for people with ALS in the CENTAUR trial. News release. Amylyx Pharmaceuticals. December 17, 2019. Accessed July 9, 2020. https://www.businesswire.com/news/home/20191217005248/en/Amylyx-Pharmaceuticals-Announces-AMX0035-Demonstrated-Statistically-Significant 

Clinical Trial in Progress

With a positive track record in ALS, the investigational agent now sets its sights on the Alzheimer disease pipeline.

AMX0035 Takes Dual Approach to Dementia

Although there have been relatively effective treatments for seizures since 1912, beginning with phenobarbital, the focus on the symptoms of epilepsy rather than the cause means that many patients with difficult to treat epilepsy still long for effective therapies. This is especially the case for autoimmune epilepsy, a under-recognized condition that is often unmanageable with conventional antiseizure medications.

 As a result, a truly “seizure-free” life has remained out of reach for many. This may be set to change as researchers continue to uncover the causes of different types of epilepsy and the mechanisms of action of different treatment modalities.

“Autoimmune epilepsy is essentially a seizure disorder where a neural-specific antibody is present, may be pathogenic, and may cause seizures,” said Lindsay Higdon, MD, a neurologist and epilepsy specialist at Jefferson University Hospital in Philadelphia, Pennsylvania. In one study, experts found that approximately 20% of unexplained epilepsy cases had evidence of circulating neural antibodies, suggesting an autoimmune cause.

 These antibodies can target antigens present on neural surfaces or within the neural cell.

Over the past decade, several neural surface antigens and intracellular antigens have been found and documented in patients presenting with epilepsy, and in 2017, autoimmune epilepsy was officially recognized as a distinct entity by the International League Against Epilepsy.

“There are several clues,” Sarosh Irani, BMBCh MA (Oxon), DPhil, head of the Oxford Autoimmune Neurology Group and associate professor at Oxford University in the United Kingdom, told 

. “These patients often present with an explosive onset, and a higher frequency of seizures than normal.” Most of these patients also present with other features of autoimmune encephalitis, such as memory disturbances, mood changes, and changes in personality. Some patients experience faciobrachial dystonic seizures, which are essentially diagnostic of an underlying antibody.

Patients with autoimmune epilepsy can also show characteristic MRI findings that are consistent with limbic encephalitis. A retrospective cohort study found that such patients usually demonstrated parenchymal atrophy that was disproportionate to age, or T2 hyperintensities in cortical or subcortical regions.

To help clinicians make an early and accurate clinical diagnosis, Divyanshu Dubey, MBBS, and a team of investigators at Mayo Clinic have developed and validated a predictive tool.

 The APE (Antibody Prevalence in Epilepsy of unknown etiology) score takes into consideration the onset and progression of the seizure disorder, clinical signs, and MRI and cerebrospinal fluid (CSF) findings. If the APE score is greater than 4, there is a high chance that the epilepsy is of autoimmune origin.

One of the main hallmarks of autoimmune epilepsy is that it is generally resistant to antiepileptic drugs. In a systematic review of 6 studies that included 169 patients with autoimmune epilepsy, antiepileptic drugs were effective in only 10.7% of cases.

 “Antiepileptic drugs may still be effective in a few cases, but they treat the symptom of the autoimmune condition, and not the cause,” Higdon said.

Once the cause is known, it makes sense to treat autoimmune epilepsy just like other autoimmune diseases—by modulating the immune system. “Along with antiepileptic drugs, we use either steroids, intravenous immunoglobulin (IVIG), or plasma exchange,” Higdon said. “All 3 treatments decrease immune-mediated inflammation in the central nervous system by suppressing or changing the immune system or removing anti- bodies.” Indeed, one study showed that immunomodulatory therapy led to a 19-fold increase in odds of a better seizure outcome, with plasmapheresis (odds ratio [OR], 32.5) proving to be more effective than intravenous steroids (OR, 8.25).

 In another study, about 75% of patients became seizure-free in the 2 months after starting immunotherapies.

Many researchers are exploring IVIG—a concentrate of human antibodies obtained from healthy donors&mdash;as an alternative to steroids and plasmapheresis. Its administration is a simpler procedure compared with plasmapheresis and can help avoid the adverse effects of steroid therapy.

This form of treatment—flooding the body with more antibodies&mdash;may seem counterintuitive. However, IVIG is believed to stabilize and strengthen the immune system. How does this happen? “Currently, no one can answer that accurately, but there are a few hypotheses,” said Irani. “The IVIG possibly saturates the immune system, preventing key causative antibodies like leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 immunoglobulin G (CASPR-2) from functioning. IVIG antibodies could also directly interfere with these antibodies, or with their targets.”

A recent randomized controlled trial conducted at Mayo Clinic provided further evidence that IVIG was effective in reducing seizures in a cohort who met criteria for autoimmune epilepsy.

 Patients who tested positive for LGI1 antibodies and CASPR-2 were enrolled in the study. Of 8 patients enrolled in the IVIG arm, 6 showed more than 50% improvement in seizure frequency compared with none in the placebo group. After 5 weeks, 6 patients in the placebo arm of the trial who had persistent seizures were switched to IVIG; 4 of these then reported more than 50% improvement in seizure frequency. IVIG is still a relatively new treatment strategy and needs more research before it is adopted as the main modality of treatment. “We don’t know how it accesses the central nervous system, and how it affects B cells that produce target antibodies,” Irani said. “Assessing these factors could help identify groups of patients who would respond better to treatment.” Indeed, not all studies have shown favorable results with IVIG. For instance, one study showed a poor response rate in patients who tested positive for antiglutamic acid decarboxylase 65 antibodies (GAD-65); only about 32% of these patients responded to treatment with IVIG.

Higdon clarified that the kind of antibody present could influence response to immunotherapy. “While antibodies to neural surface antigens (such as LGI1 and CASPR2) may respond well to immunotherapy, antibodies to intracellular antigens (like GAD-65) are less responsive,” she said. “This is because these antibodies may not be the cause of seizures, but more an epiphenomenon—a secondary symptom that occurs simultaneously with a condition but is not directly related to it.”

In a retrospective study of 50 patients, researchers showed that those who had antibodies to a neural surface antigen, the voltage gated potassium channel complex antigen, were more likely to become seizure-free compared with patients who had GAD-65 antibodies (

 Notably, those with antibodies to intracellular antigens may benefit from the addition of cytotoxic chemotherapy.

To predict which patients are more likely to respond to immunotherapy, Dubey and his team have also introduced and validated the RITE (Response to Immunotherapy in Epilepsy) score.

 This takes into account all the factors of the APE score, whether immunotherapy was started within 6 months of seizure onset, and, in addition, whether or not a neural antibody has been detected in plasma or CSF. Patients with a RITE score greater than 7 are more likely to respond to immunotherapy.

While IVIG may potentially be more convenient and safer compared with steroids and plasmapheresis, well-designed comparative studies are currently lacking. “Based on my current clinical experience, it is likely that steroids and plasma exchange will prove to be more effective,” Irani said. This opinion is partially shared by Higdon. Often, she said, “the response is transient and there needs to be repeated infusions or more aggressive immunotherapy with cyclophosphamide or rituximab.”

Many patients with autoimmune epilepsy can be successfully managed if a proper algorithm is followed, such as the one suggested by Higdon.

 “The first step, when you deal with a patient who has epilepsy of unknown origin, is to apply the APE score. If it is greater than 4, neural antibody testing should be carried out,” Higdon said. “Immunotherapy should ideally be initiated even before the antibody test results are received, either with steroids or IVIG.” She suggested that plasmapheresis be reserved for patients who fail to respond to previous treatments, or who have severe symptoms. If the antibody tests reveal the presence of an intracellular antigen, tumor screening must additionally be considered.

Of course, this fundamental algorithm does not cover all bases. “The ideal protocol for the duration of treatment and evaluation of response still needs to be developed,” Higdon said. It is also unclear if antiepileptic drugs can be tried again, if immunotherapy fails. In a retrospective study, a small proportion of patients did respond to antiepileptic drugs after immunotherapy had failed.

 The researchers stated that certain antiepileptics, like carbamazepine, also had immunomodulatory properties, and this dual effect could have been responsible for a seizure-free response in a small subset of patients.

Most experts feel that a better understanding of the pathophysiology of autoimmune epilepsy is the way forward. “We are currently focusing on how the B cells produce antibodies, and how these antibodies interfere with target antigens,” said Irani, whose most recent research has focused on exploring the characteristics and pathogenic potential of the LGI1 antibody. Understanding these key mechanisms could pave the way to establishing innovative methods of blocking the antibody effects.

1. Dubey D, Alqallaf A, Hays R, et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol. 2017;74(4):397-402. doi:10.1001/jamaneurol.2016.5429

2. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521. doi:10.1111/epi.13709

3. Fredriksen JR, Carr CM, Koeller KK, et al. MRI findings in glutamic acid decarboxylase associated autoim- mune epilepsy. Neuroradiology. 2018;60(3):239-245. doi:10.1007/s00234-018-1976-6

4. Dubey D, Singh J, Britton JW, et al. Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia. 2017;58(7):1181-1189. doi:10.1111/epi.13797

5. Cabezudo-Garci&#769;a P, Mena-Va&#769;zquez N, Villagra&#769;n-Garci&#769;a M, Serrano-Castro PJ. Efficacy of antiepi- leptic drugs in autoimmune epilepsy: a systematic review. Seizure. 2018;59:72-76. doi:10.1016/j. seizure.2018.05.004

6. Thompson J, Bi M, Murchison AG, et al; Faciobrachial Dystonic Seizures Study Group. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain. 2018;141(2):348-356. doi:10.1093/brain/awx323

7. Dubey D, Britton J, McKeon A, et al. Randomized placebo&#8208;controlled trial of intravenous immunoglob- ulin in autoimmune LGI1/CASPR2 epilepsy. Ann Neurol. 2020;87(2):313-323. doi:10.1002/ana.25655

8. Li TR, Zhang YD, Wang Q, et al. Intravenous methylprednisolone or immunoglobulin for anti-glutamic acid decarboxylase 65 antibody autoimmune encephalitis: which is better? BMC Neurosci. 2020;21(1):13. doi:10.1186/s12868-020-00561-9

9. Feyissa AM, Lo&#769;pez Chiriboga AS, Britton JW. Antiepileptic drug therapy in patients with autoimmune epilepsy. Neurol Neuroimmunol Neuroinflamm. 2017;4(4):e353. doi:10.1212/NXI.0000000000000353

10. Higdon LM. Autoimmune epilepsy. Practical Neurology. October 2018. https://practicalneurology. com/articles/2018-oct/autoimmune-epilepsy 

Could expanding insights into the pathophysiology of autoimmune epilepsy offer seizure-free hope for patients?

Unraveling Autoimmune Epilepsy

Although 2020 has presented the medical community with many unique challenges and required adjustments to care, clinicians have sought to focus on the silver linings, instead.

The rapid transition to a telemedicine-based model of care now provides many elderly patients and their caretakers with an easier way to connect with their physicians and health care team. From the provider perspective, this window into a patient’s home life also has its advantages, as it allows for additional observations and guidance for improved care and well-being.

In an interview with NeurologyLive®, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, and clinical professor of geriatric medicine and palliative care, medicine, and neuroscience at Mount Sinai School of Medicine, discussed the impact that the coronavirus disease 2019 pandemic has had on dementia care and the long-coming updates to the care model that it has actually helped to ignite.

What advantages does telemedicine offer to the Alzheimer disease community? 

Telehealth has been percolating along for decades now, but this has really just accelerated the adoption of it in medical practice, and I think in a really good way. It’s going to change the future of how we practice medicine, and I think it’s a good thing for geriatric patients in general. I’m a geriatrician. These patients are often frail, they have multiple comorbidities, many of them are in living in poverty, and even just to get to the doctor is tough. Especially for someone with Alzheimer disease and their loved ones, their caregivers.  

Getting dressed, getting in the taxi in confusing environments, getting to the waiting room, sitting in the waiting room—all that stuff is hard for a lot of patients with Alzheimer disease. Same with getting in the car if you’re in suburbia or outside the cities, so I think that telehealth is a big advantage for patients with Alzheimer disease. I hope that, going forward, especially with new payment models for telemedicine, that this will be encouraged.

The kind of questions that patients often ask of doctors in the care of patients with Alzheimer disease are often about care and management. We do have medications that are modestly effective, but certainly most of the questions that I get are about care and management of patients and advice to caregivers. It can be very effectively delivered on a telemedicine platform—and when I say telemedicine, I include the old-time technology that we call the phone. We don’t have to have video conferencing to give advice. I have gotten phone calls from stressed out caregivers asking “What should I do? What should I do about this?” and in the extreme, sometimes, it requires medication, for agitation for example, but I definitely think that Alzheimer disease can be effectively managed with the advice of physicians through technology platforms.

Have you encountered any challenges with applying telemedicine? 

The main challenge, which I don’t see as a big challenge, is incorporating telemedicine and especially video conferencing. We all do phone calls. Doctors often say, “OK, I’ll take your phone calls from 8 AM to 9 AM, and then I have to see patients,” but with video conferencing, you really have to sit there and [go] face-to-face [with patients]. It’s managing and figuring out how to incorporate telemedicine into the workflow of the day. That’s the biggest challenge, setting aside time for video conferencing with patients and doing scheduling.

The other thing is that patients with Alzheimer disease can often be confused, and I think actually seeing the patient through a video conferencing platform can be really advantageous as opposed to just a plain phone call in many ways.

At the Alzheimer’s Drug Discovery Foundation, through our work with the Diagnostics Accelerator and Bill Gates and his organization, we’re looking at incorporating all kinds of other technologies besides video conferencing in order to better evaluate a patient with Alzheimer disease. Things like evaluating speech and language, motion detectors and looking at how people move around, and all kinds of other symptoms that we can detect with new technology. The video conferencing and the telemedicine—it’s just 1 aspect of how technology will be used in the future care of patients with Alzheimer. There will be many other platforms, including computerized cognitive testing. Testing that you can do on your phone to see how a patient’s doing and these other aspects of behavior that will help us with early diagnosis, to ramp up and improve the rigor and efficiency and cost of clinical trials, and bring new drugs to market for Alzheimer disease.

What do you forsee as the future impact of telemedicine care? 

To me, it’s amazing. Honestly, I remember when we got our first TV in 1953. That’s where I’m coming from. I was only 5 years old then, but it’s just amazing. To apply that to health care now, I really do think it’s going to change things. It’ll make health care more efficient, more effective, and it’s also from your point of view of peer to peer. In geri- atric medicine, we often have family conferences, and often, families these days are all over the country—all over the world. I’ve had family conferences already to discuss a particular issue regarding

a patient with Alzheimer disease with a video conference that included someone from California, Florida, New York, and Paris all in 1 place. That wouldn’t have happened if we had to do it physically. It could have been done on telephone, but I don’t think it has the same impact. There’s no turning back at this point. Telemedicine is going to be a vital part of geriatric care and of health care in general.

Clinical Viewpoint

Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation and clinical professor of geriatric medicine and palliative care, medicine, and neuroscience at Mount Sinai School of Medicine, detailed the role telemedicine plays in treating Alzheimer disease. 

Telemedicine, Technology, and the Future of Alzheimer and Dementia Care

Avoiding siloed thinking also applies to medical decisions. Much of the information in treatment guidelines and medical textbooks is based on varied experiences and reports, brought together to help form a collective opinion. Knowledge to be gained from the experience of others is especially meaningful in a disease where treatment optimization is a work in progress. Although many treatments exist for multiple sclerosis (MS), the decision to pursue one treatment over another can often be enhanced based on the experiences of our peers and their patients.

Differences in treatment, from drug availability to strategy, are especially apparent across inter- national borders, where usage and clinical guidelines may vary. In MS, there are clear departures in diagnostic and treatment guidelines between those set forth by various clinical governing bodies; these are exacerbated by differences in drug approval patterns by the US FDA and the European Medicines Agency (EMA), as well.

In an effort to capture these differences and learn from them in a leveled environment, 

A group of international experts in the treatment of multiple sclerosis offer their varying viewpoints on the history, identification, and management of the disease.

August 2020

Selective Inverse Agonists of the Histamine 3 Receptor as Treatment for Narcolepsy

Closing the Treatment Gap in Progressive MS

AMX0035 Takes Dual Approach to Dementia

Unraveling Autoimmune Epilepsy

Telemedicine, Technology, and the Future of Alzheimer and Dementia Care

Approaching Multiple Sclerosis With a Global Perspective

Early Intervention in SMA: How Access to Therapy Will Alter Disease Management As We Know It