Prognosis of Epilepsy

by Michael Wong, MD, PhD

NATURAL HISTORY OF UNTREATED EPILEPSY

Epidemiological Data

  1. In developing countries where epilepsy mostly goes untreated, if there was no spontaneous remission, prevalence rates should be higher than the prevalence in developed countries (0.5-1%) where epilepsy is treated, and should aproach the cumulative incidence rate (2-5%) (Sander 1993).
  2. Large population studies in Ecuador (Placencia et al. 1992), Nigeria (Osunotokum et al. 1987), and Ethiopia (Tekle-Haimanst et al. 1990) calculate prevalence rates for active epilepsy to be ~0.5%, despite low treatment rates, with a resulting estimate of ~50% of untreated patients in long-term remission.

Hospital and Community-Based Studies: Studies from Finland (Keranen and Riekkinen 1993) and India (Mani et al. 1993) have directly observed a remission rate of ~50% in untreated patients.

REMISSION OF TREATED EPILEPSY

Overall Remission Rate with AED Treatment

  1. Hospital-based studies:
    1. Earlier views of prognosis of epilepsy portrayed a poor outcome with remission occurring in only 20% or less of patients (Gowers 1881, Rodin 1968). These pessimistic conclusions were drawn mainly from retrospective hospital-based studies that were likely biased toward severe chronic epilepsy patients.
    2. In contrast, more recent prospective hospital-based studies of patients with newly-diagnosed epilepsy have reported ~70-80% remission rates after AED treatment (Callaghn et al. 1985, Elwes et al. 1984, Shorvan and Reynolds 1982), leaving ~20-30% of patients with chronic, intractable epilepsy.
  2. Retrospective population-based studies in Rochester, MN and the UK (Annegers et al. 1979, Goodridge and Shorvon 1983): Both estimated a terminal remission rate of ~70%.
  3. Prospective population-based studies:
    1. UK Study (Cockerell et al. 1995): Prospective study of 792 patients with at least 6 year follow-up. ~70% achieved 5 year remission by 9 years after diagnosis. Age, seizure type, and broad etiological categories had minimal effect on remission rate.
    2. Finland Study (Sillanpaa et al. 1998): Long-term prospective study of 220 patients with childhood-onset epilepsy with mean follow-up of 28 years. ~80% of patients had been in a 5-year remission at some point in the study, but ~50% of those subsequently relapsed; then 50% of those who relapsed entered remission again by the end of the study. Overall ~75% of all patients were in remission at the end of the study and ~50% were in remission off AEDs. Idiopathic epilepsy had a much better prognosis (~85% remission) than remote symptomatic epilepsy (~25% remission).

Timing of Remission

  1. The majority of patients who enter remission do so in the first 2 years post diagnosis (Annegers et al. 1979, Goodridge and Shorvon 1983).
  2. In the Rochester study (Annegers et al. 1979), the percentage of patients entering at least a 5 year remission was 42% at 1 year, 51% at 2 years, 65% at 10 years, and 70% at 15 years after initial diagnosis.

Predictors/Risk Factors for Remission

  1. Seizure type:
    1. partial seizures have lower remission rates than generalized seizures (Annegers et al. 1979, Elwes et al. 1984, Goodridge and Shorvon 1983).
    2. isolated complex partial seizures have lower remission rates (~25%) than secondarily generalized seizures (~50%) (Matteson et al. 1985).
    3. patients with multiple/mixed seizure types have lower remission rates (Goodridge and Shorvon 1983, Shorvon and Reynolds 1982).
    4. Other studies have not found a difference between partial and generalized seizures (Cockerell et al. 1995).
  2. Etiology:
    1. Some studies found lower remission rates in patients with remote symptomatic epilepsy compared to idiopathic (Annegers et al. 1979, Berg et al. 1996, Shorvon and Reynolds 1982, Sillanpaa et al. 1998).
    2. Other studies have found no difference between symptomatic and idiopathic epilepsy (Cockerell et al. 1995).
  3. Neurodevelopmental status: In some studies, patients with neurodevelopmental deficits or delay have lower remission rates (Annegers et al. 1979, Elwes et al. 1984).
  4. Frequency or number of seizures prior to AED treatment:
    1. Data from the prospective hospital-based studies of Reynolds found that patients with higher frequency or number of seizures prior to treatment had lower remission rates (Elwes et al. 1984, Reynolds 1995, Shorvan and Reynolds 1982). Reynolds interprets these findings to support the view that “seizures beget seizures” and that AEDS improve the prognosis of epilepsy.
    2. Shinnar and others (Shinnar and Berg 1996) have argued that Reynolds’ data only show that the number of partial seizures prior to AED treatment correlates with a poorer prognosis. Thus, they interpret the data to show that partial epilepsy has a poorer prognosis but seizures in general do not promote further seizures.
    3. Other studies have found no correlation between the number of pretreatment seizures and the probability of remission with AEDs, especially if the number of pretreatment seizures is less than 10 (Camfield et al. 1996).
  5. Duration, number, and type of AED treatment:
    1. Treatment for 3 years has higher remission rates (~70%) than treatment for 1 year (~50%), although this was only significant for patients with complex partial seizures (Braathen et al. 1996).
    2. If the first AED tried fails to induce remission, addition of a 2nd AED will make only ~10% of patients seizure-free (Mattson et al. 1985). The chance of subsequent AEDs succeeding becomes progressively smaller (Kwan and Brodie 2000).
    3. The “new” AEDs have succeeded in inducing remission in only a very small percentage (<2%) of patients that were refractory to the traditional AEDs (Walker and Sander 1996).
  6. Impact of AEDs on natural history of epilepsy: Whether AED treatment in itself changes the prognosis of epilepsy or simply suppresses seizures long enough to allow spontaneous remission has been debated intensely (Shinnar and Berg 1996, Reynolds 1995). A study directly comparing treated versus untreated epilepsy patients in terms of long-term prognosis has not been done. Therefore the debate has relied on indirect evidence (e.g. #3d above) which is not definitive for either position. However, while AEDs can reduce the frequency of acute symptomatic seizures, such as febrile seizures and acute posttraumatic seizures, AEDs do not appear to reduce the risk of developing subsequent epilepsy in these conditions (Foy et al. 1992, Knudsen et al. 1996, Temkin et al. 1990).

RELAPSE OF TREATED EPILEPSY WITH AED WITHDRAWAL

Overall Relapse Rate

  1. Meta-analysis (Berg and Shinnar 1994):
    1. Meta-analysis of 25 studies found an overall relapse rate after AED withdrawal to be 25% at 1 year and 29% at 2 years (range 12 to 67%).
    2. Three risk factors were identified: adolescent-onset (1.8 relative risk (RR)) or adult-onset epilepsy (1.3 RR) versus childhood-onset epilepsy, remote symptomatic epilepsy (1.5 RR versus idiopathic), and abnormal EEG (1.45 RR versus normal EEG).
  2. Prospective Randomized Multicenter Trial (MRC AED Withdrawal Study Group 1991): 1013 patients randomized to slow AED withdrawal or continued treatment. At 2 years, 41% of slow AED withdrawal group had relapsed compared to 22% of the continued treatment group.

Timing of Relapse: relapse risk is greatest during and the first few months after AED withdrawal.

  1. In the MRC study with slow AED withdrawal (6 months), ~50% of seizure relapses occurred during the AED withdrawal period and ~50% occurred after AED withdrawal (MRC AED Withdrawal Study Group 1991).
  2. With faster AED withdrawals (mean 1-2 months), the median and mean times to relapse after initiation of AED withdrawal were 4.3 and 9.5 months, respectively; ~40% relapsed within the first 3 months and ~60% relapsed within the first 6 months of initiation of AED withdrawal (Shinnar et al. 1994).

Risk Factors for Relapse

  1. EEG: Reports of the effects of abnormal EEGs prior to AED withdrawal on relapse rate are extremely variable. Different studies have reported an increased risk of relapse with:
    1. Any EEG abnormality (epileptiform or non-epileptiform) (Berg and Shinnar 1994).
    2. Non-specific EEG abnormalities (e.g. slowing), but not epileptiform abnormalities (Shinnar et al. 1994).
    3. Any epileptiform abnormality (Callaghan et al. 1988, Matricardi et al. 1989)
    4. Generalized spike-wave activity, but not other epileptiform abnormalities (Andersson et al. 1997).
    5. No effect of any EEG abnormality on relapse rate (Holowach et al. 1982, Overweg et al. 1987).
    6. Improvement of EEG during AED treatment may reduce relapse rate (Callaghan et al. 1988, Matricardi et al. 1989).
  2. Etiology/Neurological Deficits
    1. Remote symptomatic etiology and neurological deficits/mental retardation have higher relapse rate in many studies (Arts et al. 1988, Berg and Shinnar et al. 1994, Matricardi et al. 1989, Shinnar et al. 1994).
  3. Duration of seizure-free or AED treatment period:
    1. The longer period of being seizure-free before AED withdrawal reduces the risk of relapse (0.5 RR for >10 years, 0.75 RR for 3-5 years, versus
    2. Treatment for 3 years has a lower relapse rate (~30%) than treatment for 1 year (~50%) (Andersson et al. 1997).
  4. Number of AEDs:
    1. Patients on >1 AED at the time of withdrawal have a higher relapse risk (1.73 RR versus 1 AED) (MRC AED Drug Withdrawal Group).
    2. Relapse rates after AED withdrawal in patients requiring monotherapy trials of 1, 2, or 3 AEDS before remission were 29%, 40%, and 80%, respectively (Callaghan et al. 1988).
  5. Other factors that have reported to have some correlation with higher relapse rates include:
    1. later age of onset of epilepsy (Berg and Shinnar 1994, Shinnar et al. 1994).
    2. family history of epilepsy (Arts et al. 1988, Shinnar et al. 1994).
    3. history of complex febrile seizures (Shinnar et al. 1994).
    4. complex partial seizures (Callaghan et al. 1988)

PROGNOSIS OF SPECIFIC EPILEPSY SYNDROMES

Neonatal Seizures

  1. Cumulative Incidence: seizures occur in ~0.5-1% of all neonates.
  2. Prognosis is strongly related to etiology (Rust and Volpe 1993; Watanabe et al. 1982).
    1. risk for epilepsy beyond the neonatal period and poor neurodevelopmental outcome is highest (>80%) in patients with cerebral dysgenesis.
    2. hypoxic-ischemic encephalopathy, meningitis, and hemorrhage have intermediate (~30-60%) risk of subsequent epilepsy and neurological deficits.
    3. idiopathic neonatal seizures (e.g benign familial neonatal convulsions) have the lowest risk of subsequent epilepsy (~10%), and almost always have normal neurodevelopmental outcome.
  3. Other risk factors for subsequent epilepsy and neurodevelopmental deficits following neonatal seizures are prematurity/low birth weight, EEG abnormalities, and abnormal neonatal examination (Legido et al. 1991, Rose and Lombroso 1970).

Infantile Spasms/West Syndrome

  1. Prevalence: ~1-4% of childhood seizures.
  2. Prognosis: Poor prognosis in terms of both seizure control and neurodevelopmental outcome (Jeavons et al. 1973, Koo et al. 1993, Kurokawa et al. 1980, Matsumoto et al. 1981, Rantala and Putkonen 1999, Riikonen 1982, Trevathan et al. 1999).
    1. ~50% have long-term intractable epilepsy.
    2. ~80% develop mental retardation.
    3. poor prognostic factors: symptomatic etiology is most important factor; other factors associated with poor prognosis include abnormal neurodevelopment at onset, other seizure types, early age at onset, delayed ACTH treatment, and poor response to ACTH, but these may be secondarily related to symptomatic etiology.

Lennox-Gastaut Syndrome

  1. Prevalence: ~1% of patients with epilepsy; ~5% of childhood epilepsy.
  2. Prognosis: Very poor prognosis in terms of both seizure-control and neurodevelopmental outcome.
    1. 60-90% have long-term intractable epilepsy (Blume et al. 1973, Kurokawa et al. 1980, Rantala and Putkonen 1999).
    2. >90% have mental retardation (Kurokawa et al. 1980, Rantala and Putkonen 1999, Trevathan et al. 1997).

Childhood Absence Epilepsy

  1. Prevalence: ~2-8% of patients with epilepsy.
  2. Prognosis: Generally good prognosis, but highly dependent on the absence of GTC szs.
    1. ~80% of patients enter remission with valproate or ethosuximide (Dieterich et al. 1985).
    2. The majority remain in remission upon AED withdrawal (~20% relapse rate) (Shinnar et al. 1994).
    3. Meta-analysis of 23 studies showed an average long-term remission rate of 59% (range 21-89%) in all patients, 78% in patients with absence seizures only, and 35% in patients with accompanying GTC seizures. ~50% of all patients with absence seizures also have GTC seizures (Bouma et al. 1996).
    4. One study reported that ~15% of patients progress to JME (Wirrell et al. 1996).
    5. Neurocognitive outcome in absence epilepsy may not be as good as previously thought, as mild neurocognitive deficits can be detected with detailed neuropsychological testing (Pavone et al. 2001).
  3. Risk factors for poor prognosis: presence of generalized tonic-clonic seizures, mental retardation/abnormal neurological exam, onset before age 4 years, and positive family history (Sato et al. 1976).

Juvenile Myoclonic Epilepsy

  1. Prevalence: ~5-10% of patients with epilepsy
  2. Prognosis: Excellent prognosis for remission with AEDs, but high rate of relapse with AED withdrawal.
    1. ~90% of patients enter remission with valproate (Panayiotopoulos et al. 1994).
    2. Close to 100% relapse upon AED withdrawal (Shinnar et al. 1994).

Benign Rolandic Epilepsy

  1. Prevalence:
  2. Prognosis: Excellent prognosis – Majority of patients enter remission with AEDs.
    1. Close to 100% remain in remission upon AED withdrawal (Shinnar et al. 1994).
    2. Meta-analysis of 13 studies found that independent of AED treatment, 50% were in remission at age 6 years, 92% at age 12 years, and 99.8% at age 18 years (Bouma et al. 1997).
    3. However, a potentially-related syndrome, malignant rolandic-sylvian epilepsy, has been described with a poor prognosis, including
      medically-intractable seizures (Otsubo et al. 2001)

OTHER MORBIDITY AND MORTALITY OF EPILEPSY

Non-Seizure Morbidity

  1. School performance/employment status: Although the data are variable for numerous reasons, most studies show that patients with epilepsy, even idiopathic or “uncomplicated” epilepsy, have poorer outcomes in educational and employment measures compared to the general population (Mitchell et al. 1991, Seidenberg et al. 1986, Sillanpaa 1990, Sillanpaa et al. 1998).
  2. Social: Patients with epilepsy, even idiopathic epilepsy in remission without AEDs, are less likely to become married or have children compared to the general population (Sillanpaa et al. 1998).

Mortality

  1. Standardized Mortality Ratio (SMR): Patients with epilepsy have higher mortality rates than the general population (~2-4 SMR) (Cockerell et al. 1994, Hauser et al. 1980, Nilsson et al. 1997).
  2. Timing of mortality: Mortality is highest during the first year and 5-10 years after the initial diagnosis (Cockerell et al. 1994), suggesting that underlying etiology is a very significant factor in determining mortality.
  3. Risk factors for mortality:
    1. Seizure type: Patients with myoclonic seizures (SMR=4.1) and primary GTCs (SMR=2.4) have higher mortality rates. Absence and complex partial seizures are not significantly different than the general population (Hauser et al. 1980)
    2. Etiology: Symptomatic (SMR=4.3) > cryptogenic (SMR=2.4) > idiopathic (SMR=1.6). The mortality rate in idiopathic epilepsy is still significantly higher than the general population, indicating that underlying etiology is not the only determinant of mortality (Cockerell et al. 1994).
    3. Seizure Control: Post-epilepsy surgery patients with persistent seizures have a significantly higher mortality rate than seizure-free surgery patients, whose mortality rate is the same as the general population (Sperling et al. 1999).
  4. Causes of death (Nilsson et al. 1997)
    1. Most common causes of death (in decreasing frequency): cancer, ischemic heart disease, CVA, pneumonia and other respiratory illnesses.
    2. Standardized Mortality Ratio by cause of death: Patients with epilepsy are at increased risk compared to the general population (high SMR) for death by cancer (even non-brain), cardiovascular disease, respiratory disease, gastrointestinal disease, dementia/psychiatric disease, and injuries, accidents, and suicide.
    3. Status epilepticus: Status epilepticus has been estimated to account for ~1% of deaths in epilepsy patients.
    4. Sudden unexpected death: Sudden unexpected death in epilepsy (SUDEP) may account for up to 18% of deaths in epilepsy patients (Walczak et al. 2001). The incidence of SUDEP may be significantly less in children compared to adults (Donner et al. 2001).

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