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Alzheimer's & Epilepsy: A Case for Off-Label Use

Updated: Nov 1, 2018


 

One off-label use leading to a drug being repurposed for Alzheimer’s disease, include a phase 2 study of an FDA approved antiepileptic drug called Keppra for Alzheimer's disease-associated network hyperexcitability. Another example is a multi-center phase 3 clinical trial of the same drug to treat amnestic mild cognitive impairment due to Alzheimer's disease[1]. When one of the drugs used in combination therapy is already FDA-approved, overall costs of combination therapy research is reduced. This increases cost efficiency of therapy, thereby benefiting the medically underserved[2]. The wide spectrum of symptoms that are unique to certain sub-populations of people under the umbrella of Alzheimer’s disease illustrates the need to approach research in a much more inclusive manner. Treating each subpopulation with a unique combination of drugs that are exclusive to the co-morbidities interacting with or occurring because of Alzheimer’s disease, may not only be preferable, but necessary. As we have learned from other medical conditions; hypertension and diabetes, recognizing pre-symptomatic and subclinical forms of disease is imperative, to protect against future organ damage. We need to utilize combination therapies today, with the hope of serving each subpopulation as best as we can, with the drugs that are available to them to protect against future brain damage. [1] Dr. Keith A Vossel MD, Maria C Tartaglia MD, Haakon B Nygaard MD, Adam Z Zeman FRCP, Bruce L Miller MD; The Lancet Neurology. https://doi.org/10.1016/S1474-4422(17)30044-3

[2] https://www.ncbi.nlm.nih.gov/pubmed/28410237


 

1. Seizures and Epileptiform Activity in the Early Stages of Alzheimer Disease

a. Conclusions and Relevance: Common clinical features of patients with aMCI- or AD-associated epilepsy at our center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.

b. Citation: Vossel KA, Beagle AJ, Rabinovici GD, Shu H, Lee SE, Naasan G, Hegde M, Cornes SB, Henry ML, Nelson AB, Seeley WW, Geschwind MD, Gorno-Tempini ML, Shih T, Kirsch HE, Garcia PA, Miller BL, Mucke L. Seizures and Epileptiform Activity in the Early Stages of Alzheimer Disease. JAMA Neurol. 2013;70(9):1158–1166. doi:10.1001/jamaneurol.2013.136


 

2. Epileptic activity in Alzheimer's disease: causes and clinical relevance

a. Conclusions and Relevance: Patients with mild cognitive impairment or Alzheimer's disease are prone to seizures and clinically silent forms of aberrant network activity, which can be associated with cognitive decline. Evidence for detrimental network hyperexcitability in the early stages of Alzheimer's disease raises new therapeutic opportunities for antiepileptic strategies that might complement or enhance existing approaches, and potentially modify disease progression. No guidelines are available for treating clinically silent forms of aberrant network activity in Alzheimer's disease. As we have learned from other medical conditions, such as hypertension and diabetes, recognizing pre-symptomatic and subclinical forms of disease seems imperative for protecting against future organ damage. Several trials are ongoing or soon to be initiated (table 4). A phase 2 study of levetiracetam for Alzheimer's disease-associated network hyperexcitability (LEV-AD; NCT02002819) is underway, and a multi-center phase 3 clinical trial of levetiracetam to treat amnestic mild cognitive impairment due to Alzheimer's disease is scheduled to begin in 2017.

b. Citation: Dr. Keith AVosselMDaMaria CTartagliaMDbHaakon BNygaardMDcAdam ZZemanFRCPdBruce LMillerMDa. The Lancet Neurology https://doi.org/10.1016/S1474-4422(17)30044-3


 

3. Epilepsy in neuropathologically verified Alzheimer’s disease

a. Conclusions and Relevance: The strength of this study is a thorough neuropathological examination of all study subjects. Our findings support the previous literature regarding the prevalence of epilepsy in subjects with AD. We have shown that the subjects with AD and epilepsy differ significantly from the subjects without epilepsy. Frequent seizures may possibly lead to faster deterioration of the already fragile neuronal networks of the AD subjects. This may lead to a vicious circle accelerating the underlying neurodegenerative process. Thus, the patients require adequate antiepileptic treatment. In this study, we reported that 17% of elderly subjects with neuropathologically verified AD had a history of epilepsy. We have shown that the patients with both AD and epilepsy differ significantly from the subjects with neuropathology restricted to AD and possible concomitant disease processes.

b.Citation:TuomasRauramaaabAnnaSaxlincKaisaLohvansuudIrinaAlafuzoffeAslaPitkänenfHilkka oinineng https://doi.org/10.1016/j.seizure.2018.03.014 Seizure Volume 58, May 2018, Pages 9-12


 

4. Do we know how to diagnose epilepsy early in Alzheimer's disease?

a. Conclusions and Relevance: Epilepsy in AD patients is frequently pharmacosensitive, and a good response can be obtained with standard doses of antiepileptic drugs. For all these reasons and based on our review of the literature, it appears that, at present, the diagnosis of epilepsy in AD is not only possible at any stage of the disease, but also to be recommended to improve the patient's prognosis. Diagnosing epilepsy in AD may be difficult for several reasons. As a consequence, it is our opinion that, if a test medication (a low dose of a well-tolerated AED) leads to a reduction in the frequency of transients, it may be regarded as a feature supportive of a diagnosis of epilepsy. It is also worth noting that a good response to AEDs is very likely in AD patients.

b. Citation:B.CretinabcdN.PhilippiabcdO.BousigesbgL.DibitontoabcdF.SellalbefC.Martin-HunyadibF.Blancabcd https://doi.org/10.1016/j.neurol.2017.03.028 Revue Neurologique Volume 173, Issue 6, June 2017, Pages 374-380


 

5. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model

a. Conclusion and Relevance: Levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.

b. Citation: Sanchez, P.E.ab, Zhu, L.ab, Verret, L.ab, Vossel, K.A.ab, Orr, A.G.ab, Cirrito, J.R.c, Devidze, N.a, Ho, K.a, Yu, G.-Q.a, Palop, J.J.ab, Mucke, L.abGladstone Institute of Neurological Disease, San Francisco, CA 94158, United States, Department of Neurology, University of California, San Francisco, CA 94158, United States, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States, Proceedings of the National Academy of Sciences of the United States of America, Volume 109, Issue 42, 16 October 2012, Pages E2895-E2903

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