At the Annual Meeting of the American Academy of Neurology (AAN) in Vancouver, the results of the EXIST-3 study were presented, which demonstrated the efficacy of everolimus in seizures associated with the rare hereditary disease tuberous sclerosis. In addition, neurological late effects of Ebola infection and the relationship between poor sleep quality and lower brain volume were discussed.
Autosomal dominant inherited, rare tuberous sclerosis may be associated with the formation of non-malignant tumors in organs such as the brain, kidney, heart, lungs, and skin on the one hand, and epilepsy (in nearly 85% at some point during the course of the disease), cognitive impairment, behavioral/psychological problems, and autism on the other. The disease manifests itself very differently and symptoms may take years to develop. Often, tuberous sclerosis is first diagnosed when seizures, skin lesions, or developmental abnormalities occur – which is usually very early, sometimes in infancy. In total, about one million people worldwide are estimated to be affected. Diagnostic guidelines [1] recommend that physicians familiar with this condition should attend to patients and monitor them for tumor growth and new symptoms at regular intervals throughout their lives. The biggest (and also most common) neurological problem associated with this disease is epileptic seizures. However, more than 60% of patients do not achieve adequate seizure control with available antiepileptic drugs [2].
EXIST-3: Glimmer of hope for therapy-resistant seizures
A phase III trial called EXIST-3, presented at the congress, has now shown for the first time the promising potential of adding everolimus to patients with tuberous sclerosis and therapy-resistant seizures (i.e., occurring despite at least two antiepileptic drugs). No specific seizure type was specified for study inclusion. Many patients had also tried other approaches such as a ketogenic diet or vagus nerve stimulation – but without success. In all comparison arms, participants received one to three antiepileptic drugs in addition to everolimus, which they had already been taking at a stable dose for at least four weeks. A two-month evaluation/baseline phase was conducted before randomization. Everolimus was then compared against placebo in three arms: Once titrated to a low concentration (3-7 ng/mL), once to a high concentration (9-15 ng/mL). A total of 366 patients with a median age of ten years participated.
At both low and high concentrations (results hereafter always mentioned in this order), everolimus was significantly superior to placebo in terms of percent reduction in seizures since baseline, i.e., in the primary endpoint: 29.3/39.%/39,6% vs. 14.9% (p=0.003 and p<0.001).
A response (≥50-percent reduction in seizure frequency), also a primary endpoint, was achieved by 28.%/40% vs. 15.1%. The differences were significant in each case (p=0.008 and p<0.001).
The most common adverse events on everolimus (vs. placebo) included stomatitis (28.2/30%/30,8% vs. 3.4%), mouth ulceration (23.9/21%/21,5% vs. 4.2%), diarrhea (17.%/21,5% vs. 5.0%), aphthae (4.3/14.%/14,6% vs. 1.7%), fever (19.7/13.%/13,8% vs. 5.0%) cough (11.1/10.%/10,0% vs. 3.4%), and rash (6.0/10.%/10,0% vs. 2.5%). Serious adverse events occurred in 13.7/13%/13,8% vs. 2.5%.
The results were very positively received at the congress. For the first time, there are reliable data from a clinical trial for patients with therapy-resistant seizures associated with tuberous sclerosis and thus a valid glimmer of hope, he said. Until now, the seizures have always been suppressed and the underlying mechanisms of epilepsy have not been treated. With everolimus, this could now change, making it a potentially disease-modifying therapy. Perhaps, therefore, it will find future application in other forms of epilepsy that may be associated with the mTOR pathway.
Overall, dropout rates with everolimus were relatively low compared with other trials of antiepileptic drugs, the authors said (7/8 vs. 5 people), suggesting controllable side effects. These were also within the expected range – after all, the drug is not new, but has been tested and researched for a long time (in other indications also in tuberous sclerosis). A dose-response relationship was observed: If they are tolerated, higher doses are also correspondingly more effective. The non-blinded extension of the study will show whether the benefits can be sustained. In general, it is still unclear whether lifelong use of the drug is an option. It is now necessary to wait and see how the therapy develops over time, the presenters said.
Everolimus is currently the only nonsurgical option indicated in certain patients with tuberous sclerosis and nonmalignant tumors of the kidney and brain.
What is the mechanism of action?
Everolimus is an inhibitor of the protein mTOR, which regulates numerous cellular functions. In turn, tuberous sclerosis is triggered by mutations in TSC1 or 2 genes and consecutive overactivation of the mTOR pathway, which in turn can lead to cell growth and proliferation, cortical malformations, altered network function, neuronal hyperexcitability, and impaired synaptic plasticity. Hyperactivity of the mTOR pathway is thought to play a role in epileptogenesis [3].
Neurological late effects of Ebola
A smaller study from the USA was devoted to a completely different topic. It wasn’t long ago that Ebola was on everyone’s lips. In the meantime, it has become quieter around the dangerous viral disease, and the epidemic in West Africa is considered to be largely contained. At the congress, a study of 87 Ebola survivors with an average age of 35 from Liberia met with great response, as it dealt with the insufficiently researched neurological complications of this infection. A team of neurologists examined and interviewed affected individuals six months after active disease using a standardized assessment of the neurological impairments experienced during that time.
Four individuals had to be excluded because they had already suffered head trauma with loss of consciousness prior to infection – the same was true for one individual with schizophrenia. 69.5% had been treated in a so-called Ebola Treatment Unit (ETU) for at least 14 days, and half of the participants were female. In the area of new-onset neurological symptoms during or after treatment, patients most frequently recalled headache, low mood, fatigue, myalgia, and memory loss. Severe manifestations were found in half of the patients and included hallucinations, meningitis, and coma. The rest reported moderate manifestations. Fatigue, headache, dejection, memory loss, and myalgia were also cited as the most common symptoms that continued. In some cases, these symptoms prevented them from returning to their original jobs. Two patients were currently suicidal and one had hallucinations. Clinical neurological examination revealed saccades and abnormalities of eye movement (nearly two-thirds of subjects) and tremor, impaired reflexes and sensory function (one-third), among other findings. Almost all had neurologic impairment according to the Modified Rankin Scale. The affected individuals had not developed these problems until they became infected, and the researchers were surprised that so many of the complications were still present after the actual disease.
Ebola virus disease may appear to be associated with disruptions in subcortical structures, cerebellar pathways, and sensory peripheral nerves, the study investigators concluded. Such abnormalities were found in almost all survivors. The results are to be understood as preliminary. Non-infected contacts of the affected persons should now also be included in the study as controls. The inclusion of controls from West Africa in particular is of great importance, as there are many health problem areas in this area and thus many other possible causes of neurological disorders. It must be determined which of these results are actually Ebola-specific. A connection is certainly conceivable: Ebola triggers a veritable storm of cytokines that can lead to inflammation in the brain. The Ebola virus is also known to be present in the central nervous system.
Of course, the statement is limited by the fact that the affected persons had only been examined at a certain point in time. So whether the symptoms will still resolve or persist is unclear. There are also still many open points with regard to risk factors: Is, for example, the earliest possible treatment or the disease severity resp. the viral load of importance? All these questions are now to be answered by the so-called Prevail III study, which aims to follow up a total of about 7500 people over five years (1500 survivors and 6000 controls). The results presented are part of this larger project.
Sleep and brain mass – is there a connection?
In a large, ethnically mixed cohort of 501 participants (71% women, >65 years old, average 11 years of education), researchers used imaging to examine the relationship between reduced brain volume and adequate sleep. Signs of dysfunctional sleep included restlessness, snoring, shortness of breath, headaches at night, excessive sleep duration, and daytime sleepiness. The survey was conducted by self-report interview. Brain volume was measured by T-weighted MRI. The following correlations were significant:
- Reduced left entorhinal volume was associated with longer sleep duration
- reduced cortical volume and reduced gray matter volume were associated with increased daytime sleepiness. This association became stronger after excluding the 62 patients with dementia.
In principle, this finding is not new. Previous studies had already found a correlation between poor sleep quality and smaller brain volume, but mainly for the frontal lobe. For the first time, an association with the entorhinal cortex, an area that plays a central role in Alzheimer’s disease, has now been found in a larger sample. So is poor sleep quality possibly a risk factor for Alzheimer’s disease? Gray matter reduction is likely to be less relevant in this context, as it is more nonspecific and partially associated with normal aging.
Both longer sleep duration and daytime sleepiness are also possible signs of sleep apnea – which in turn is associated with earlier cognitive decline [4].
However, all these theses fail to answer the question of cause and effect. Does poor sleep actually precede brain atrophy or is it rather the consequence of it? Further research is needed to answer this question.
Source: American Academy of Neurology (AAN) 2016 Annual Meeting, April 15-21, 2016, Vancouver.
Literature:
- Northrup, H, et al: Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatric Neurology 2013; 49: 243-254.
- Chu-Shore CJ, et al: The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010; 51(7): 1236-1241.
- Ostendorf A, Wong M: mTOR inhibition in epilepsy: rationale and clinical perspectives. CNS Drugs 2015: 29(2): 91-99.
- Osorio R, et al: Sleep-disordered breathing advances cognitive decline in the elderly. Neurology 2015; 84(19): 1964-1971.
InFo NEUROLOGY & PSYCHIATRY 2016; 14(4): 37-39.
