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A guideline for discontinuing antiepileptic drugs in seizure-free patients – Summary Statement
 

A guideline for discontinuing antiepileptic drugs in seizure-free patients – Summary Statement

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Aula apresentada por Dr. Rafael Higashi, médico neurologista sobre quando retirar droga antiepilética. A guideline for discontinuing antiepileptic drugs in seizure-free patients – Summary ...

Aula apresentada por Dr. Rafael Higashi, médico neurologista sobre quando retirar droga antiepilética. A guideline for discontinuing antiepileptic drugs in seizure-free patients – Summary Statement

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    A guideline for discontinuing antiepileptic drugs in seizure-free patients – Summary Statement A guideline for discontinuing antiepileptic drugs in seizure-free patients – Summary Statement Presentation Transcript

    • Practice Parameter : A guideline for discontinuing antiepileptic drugs in seizure-free patients – Summary Statement Neurology 1996;47:600-602 Dr. Rafael Higashi (neurologist) Institute of Neurology Deolindo Couto UFRJ- Epilepsy Outpatient Unit
    • The Quality Standarts Subcommittee of The American Academy of neurology (AAN) Develops practice parameters for neurologists pertaining to diagnostic procedures, treatment modalities, and clinical desorders.
    • Definition of the problem :
      • When a patient with a history of epileptic has remained seizures- free for a period of years, the question arises whether to continue or reduce AEDs ?
    • Description of the process
      • they conducted a MEDLINE search for the years 1967 to 1991 using the key words : “discontinuance of antiepileptic drugs”, “prognosis of epilepsy”, “relapse and recorrence” and “remission”.
      • they identified 53 studies.
      • 53 studies, 52 were class II studies and 1 was class I study.
      • The nine factors or clinical characteristics they identified were sex, age of onset, seizure type, etiology, neurologic examination/IQ, duration of seizure freedom on AEDs, treatment regimen, age at relapse, and normalization of the EEG.
      • Only 17 studies discussed all nine factors.
      • The relapse rate were weighted according to the number of cases in that study.
    • Conclusions :
      • Seizure-free 2 to 5 years on AEDs ( mean 3.5 years);
      • Single type of partial or generalized seizure;
      • Normal neurologic examination and normal IQ;
      • EEG normalized with treatment.
    • Recommendations:
      • The data in studies demonstrate that children meeting the above profile can be expected to have at least a 69% chance and adults a 61% chance for successful withdrawal.
      • The 31.2% relapse rate in children and 39 % in adults refers to all patients studied.
      • Drug withdrawal should be offered to patients who meet this profile and who have complied with treatment.
      • The adult patient, a child’s family, and the physician should make the decision together, taking into account not only the medical factors, but also the social, emotional, or other consequences should relapse occur.
    • Recommendations for future research
      • Multicenter randomized double-blind controlled prospective trials ar needed to better define risk of relapse for individual patients.
      • The effects of a number of AEDS used, duration of treatment producing freedon from seizure, and measurement of serum levels in patients considered candidates for withdrawal.
    • Epilepsy: Discontinuing Therapy Thomas R. B., MD and Gregory L. Holmes, MD THE NEW ENGLAND JOURNAL OF MEDICINE vol. 344,No. 15, april ,2001 .
      • If after two years of therapy the patient remains free of seizures, withdrawal of the antiepileptic drug should be considered.
      • Factors associated a high risk of recurrent : structural lesion, electroencephalographic abnormalities, the onset of the disorder during adolescence , neurologic abnormalities and severe epilepsy(history the frequent seizures or seizures difficult to control requiring more than one drug).
      • Factors associated with a low risk of recurrent seizures include idiopathic seizures, normal findings on EEG, the onset of disorder in childhood, absence of neurologic abnormalities,and seizures that have been easily to controlled with one drug.
    • Epilepsy : Discontinuing Therapy Thomas R. B., MD and Gregory L. Holmes, MD THE NEW ENGLAND JOURNAL OF MEDICINE vol. 344,No. 15, april ,2001 .
      • The risk of recurrent seizures is 25 percent among patients without risk factors and more than 50 percent among risk factors.
      • Approximately 80 percent of recurrences occur with in four months after a regimen of tapered doses has been initiated , and 90 percent occur within the first year . Driving and other potentially dangerous activities should be prohibited for at least four months after the start of drug withdrawal.
      • One approach is to reduce the daily dose by 25% every two to four weeks.
      • The disadvantages of continuing treatment include the risks of side effects, drug interactions, teratogenicity as well the cost of the therapy.
    • Management of epilepsy in adolescents and adults. Martin J Brodie, Jacqueline A French THE LANCET - Vol 356 - July 22 - 2000
      • In teenagers and adults a flexible 5 years is a prudent time to wait.
      • Some forms of idiopathic generalized seizures, such as absence or tonic-clonic are less likely to recur, whereas juvenile myoclonic epilepsy conveys a high probability to relapse . Even complex partial seizures can disappear after a long period of perfect control.
      • If the patient is taking more than one AED, one should be slowly withdrawn before the second.
      • The EEG is not helpful in predicting seizure recurrence.
    • REVIEW ARTICLE : MECHANISMS OF DISEASE :EPILEPSY Bernard S. Chang, MD and Daniel H. Lowenstein, MD. THE NEW ENGLAND JOURNAL OF MEDICINE 2003;349:1257-66
      • Clinically , there is often a “ silent interval ” in many acquired and genetically determined epilepsy.
      • “ Ideally, we whould like to have a drug that prevents the development of epilepsy , rather than one that merely suppress seizures ”.
      • It is likely that generalized epilepsy originate fom alterations in eitheir neuronal net works ,as in absence seizures, or intrinsic neuronal function, as in channelopathies . Partial epilepsy syndromes presumably stem from a focal lesion .
    • .
      • Intensive studies of hippocampal sclerosis , have demonstraded many local changes , but their causative role,if any, in epileptogenesis is still unknown.
      • Newer avenues of study( such as cortical malformations) and newer conceptual mechanisms( such as the role of glial cells and the neuronal microenvironment ) are likely to yield future insights into this complicated field.
      REVIEW ARTICLE : MECHANISMS OF DISEASE :EPILEPSY Bernard S. Chang, MD and Daniel H. Lowenstein, MD. THE NEW ENGLAND JOURNAL OF MEDICINE 2003;349:1257-66.
    • The Other Half of the Brain Fields RD Sci Am. 2004;290(4):54-61
      • The glial cells of the brain have been overlooked in the medical research for nearly 50 years.
      • Sensitive imaging tests have shown that neurons and glia engage in twoway dialogue from embryonic development through old age, and that glia also communicate among themselves in a separate but parallel network to the neural network.
      • Glia have the power to alter signals at the synaptic gaps betwwen neurons and may even influence where synapses are formed.
    • The Other Half of the Brain Fields RD Sci Am. 2004;290(4):54-61
      • It has been determined that the glia have their own unique messenger system like nitric oxide(NO). NO are neuromodulators that act like cytokines/chemokines , the messenger molecules produced by the immune system.
      • The glial cells are derived embryologically from the same progenitor cells as the Kupffer cells in the liver, the lymphocytes, and the mucosal-associated lymphoid tissue(MALT) found in our gut.
      • When undergoing a rapid immunological upregulation the neuronal NO synthase is activated producing NO consequentely producing superoxide that chemically reacts to produce a caustic chemical called peroxynitrite . Peroxynitrite, in turn, can degrade into nitrosating substance that can injure proteins-nucleic acids .
    • The Other Half of the Brain Fields RD Sci Am. 2004;290(4):54-61
      • Over time, this accelerates the loss of post-mitotic tissues, increasing the loss of cellular reserve , and ultimately decreasing the function of portion of the brain, leading to decline to it’s own apoptotic death by neuronal oxidative stress.
    • LOSS OF GLUTAMINE SYNTHETASE IN THE HUMAN EPILEPTOGENIC HIPPOCAMPUS : A POSSIBLE MECHANISM FOR RAISED EXTRACELLULAR GLUTAMATE IN MESIAL TEMPORAL LOBE EPILEPSY. Eid T, Thomas M J, Spencer DD, et al. Lancet. 2004;363:28-37.
      • Studys investigated wether a deficiency in Glutamine synthetase (GS), could explain the perturbed Glutamate homeostasis in MTLE.
      • In western blot assays, the expression of GS in the hippocampus was 40 percent lower in MTLE than control
      • Interpratation of the findings is that a deficiency in glutamine synthetase in astrocytes is a possible molecular basis for extracellular glutamate accumulation and seizure generation in MTLE.
      • This study suggests that glutamate accumulation and epileptic could be coupled to a highly enzyme defect .
      • If a causal relationship is determined, it might create a novel principle for reducing seizures in MTLE.
    • Aggressive confusional state as a clinical manifestation of status epilepticus in MELAS B. Fedderson, MD; A. Bender, MD; S. Arnold, MD; Clinical/Scientific Notes ;AAN 2003; University of Munich,German.
      • Patient 1. A 43-years old man had bilateral sensorineural hearing loss since adolescence and focal epilepsy since 42 years. Before admission he had had transient left arm paresthesias and confusion and aggressive behavior. He had mild left arm paresis, aggressiveness and confused. CT showed hypodensity in the right parietal region.MRI revealed cortical and subcortical hyperintensities in T2 and perfusion/diffusion-weighted images in the right parietal region. EEG epileptiform discharges on right parietal. After a loading dose of phenytoin(PHT) 750mg followed by the administration of PTH 400mg/bid, the patient’s clinical condition improved . EEG 7 days later was free of epileptiform discharges. Muscle biopsy showed 5 % ragged red fibers. PCR analysis from muscle DNA revealed mutation at bp3243 of the mtDNA.
    • Aggressive confusional state as a clinical manifestation of status epilepticus in MELAS B. Fedderson, MD; A. Bender, MD; S. Arnold, MD; Clinical/Scientific Notes ;AAN 2003; University of Munich,German.
      • Patient 2. A 57-years-old woman had migraine-like headache, aphasia, and confusion. He had bilateral sensorineural deafness. Neurologic examination revealed bilateral gaze-induced horizontal nystagmus, apraxia, aphasia, and confusion. The EEG showed epileptiform discharges in the left occiptal region. SPECT during the status epilepticus revealed a left occiptal to occipto-parietal hyperperfusion, CSF elevated levels of lactate. Status epilepticus ceased after the patient was started on PTH(750mg loading dose followed by 100mg/bid) and clonazepan(2mg/bid) treatment. A muscle biopsy showed 7% ragged red fibers and mutation at position 3243 of the mtDNA. One month later she was readmitted because of recurrence of confusion and aggressive behavior. She recovered after additional doses of lorazepan and PTH.
    • Aggressive confusional state as a clinical manifestation of status epilepticus in MELAS B. Fedderson, MD; A. Bender, MD; S. Arnold, MD; Clinical/Scientific Notes ;AAN 2003; University of Munich,German.
      • Discussion:
      • Valproate seems to be inappropriate , because it causes reduction of serum carnitine,inhibition of beta-oxidation and oxidative phosphorylation,and ultrastuctural abnormalities of mitochondria with lipid deposition.
      • Moreover, mitochondrial diseases may be considered a risk factor for valproate-induced liver failure .
      • During status epilepticus the cerebral metabolism is increased. This has and even greater impact in patients with mitochondrial disease because ATP availability and function are diminished .
      • Thus, rapid antiepileptic treatment of patients with MELAS with non-convulsive status epilepticus is important.
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    • Thanks for every body ! Dr. Rafael Higashi neurology - INDC UFRJ [email_address]