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The broad spectrum of first seizure and newly-diagnosed epilepsy

Open ArchivePublished:February 12, 2017DOI:https://doi.org/10.1016/j.seizure.2017.02.001
      The assessment of patients presenting with a first seizure (FS) is not trivial at all. This frequent clinical scenario [
      • Rizvi S.
      • Téllez-Zenteno J.F.
      • Hernandez-Ronquillo L.
      Epidemiology of early stages of epilepsy – risk factors and risk for seizure recurrence.
      ] deserves an extremely careful clinical exploration and a systematic diagnostic algorithm to disentangle contributing factors, analyze individual predisposing variables, arrive at a reasonable first “working diagnosis”, and to provide the best possible counseling in a situation of huge uncertainty [
      • Legg K.
      • Newton M.
      Counseling for Adults Who Experience a First Seizure.
      ,
      • Nowacki Y.
      • Jirsch J.
      Evaluation of the first seizure patient: keys points in the history and physical examination.
      ].
      There is increasing evidence that the FS leading to clinical attention and awareness may actually represent only the loudest “noise” in a biochemical and/or structural environment which is already quite significantly altered [
      • Pohlmann-Eden B.
      Conceptual relevance of new-onset epilepsy.
      ]. Psychiatric comorbidities often precede the onset of the seizure disorder, and affect the life of these patients and the course of the seizure disorder at several levels, including through reducing tolerance of pharmacotherapy with antiepileptic drugs [
      • Kanner A.M.
      Psychiatric comorbidities in new onset epilepsy: should they be always investigated?.
      ]. Cognition is often already found to be compromised at the time of the diagnosis of FS [
      • Helmstaedter C.
      Epilepsy and cognition– a bidirectional relationship?.
      ], further supporting the hypothesis that the FS may only represent the tip of the iceberg of complex subtle brain pathology and network disturbance. The definition and recognition of the stage of early “epilepsy” are critical (first seizure is different from new-onset epilepsy or long-lasting first ever newly diagnosed epilepsy) to understand the underlying dynamics and, possibly, inherent prognosis [
      • Pohlmann-Eden B.
      First seizure, new-onset epilepsy, newly diagnosed epilepsy – current definitions and implications for conceptual thinking.
      ].
      Treatment decisions can be quite challenging in this scenario and may lead to controversial perspectives [
      • Hamer H.
      The debate: treatment after the first seizure – the PRO.
      ,
      • Steinhoff B.
      The debate: treatment after the first seizure – the CONTRA.
      ], as individual preferences and requests for “overall safety” have to be considered as well as conceptual questions around the epilepsy syndrome.
      We introduce our special issue on “first seizure” with 2 illustrative cases demonstrating the diversity and spectrum of severity of the different epilepsy syndromes. The first case was a “straightforward” one, only requiring adequate diagnosis and subsequent treatment, while the second one is much more complex, emphasizing the need for the early identification of drug refractoriness and consideration of alternative interventions including possible surgical procedures.

      Case 1: a “straightforward” case requiring adequate diagnosis

      A 17-year-old, right-handed, young man presented to our clinic after he had experienced a generalized tonic-clonic seizure. This seizure occurred in the context of stress. He was attending his high school graduation ceremony and was under stress, with preceding lack of sleep the night before, when the generalized tonic-clonic seizure occurred. Initial assessment in the emergency room led to the performance of a CT scan of the head as well as basic blood tests such as full blood count, electrolyte panel, and urine toxicology screen. The studies were unremarkable. Five months later the patient experienced another generalized tonic-clonic seizure and was referred to our first-seizure clinic.
      Upon questioning, the patient described episodes of myoclonic jerks mainly on awakening for the last 3 years. And, prior to his last generalized tonic-clonic seizure, he had a cluster of myoclonic jerks.
      His past medical history was otherwise unremarkable. He was not taking any medications, vitamins or herbal products. He had no risk factors for epilepsy, such as previous central nervous system infections, head trauma, febrile seizures or perinatal problems. He had just finished high school and was planning to pursue university studies. He did not smoke cigarettes, tobacco or marijuana. He never used any recreational/illicit drugs.
      Nobody in his family had seizures or epilepsy.
      His neurological exam was unremarkable.
      He was started on divalproex and reached a dose of 500 mg twice a day without experiencing any side effects.
      Subsequent routine EEG revealed generalized polyspikes as well as 3 Hz generalized spike and wave discharges. No photosensitivity was appreciated.
      He did not have any further generalized tonic-clonic or myoclonic seizures. He was seen in follow up multiple times, and is now pursuing a career in sciences at a local University. He has been seizure free for over a year, without any side effects.
      Diagnosis and selected learning points:
      • -
        This young man could have been diagnosed with Juvenile Myoclonic Epilepsy early on based on clinical history and supporting EEG [
        • Debicki D.
        Electroencephalography after a single unprovoked seizure.
        ].
      • -
        The response to treatment with antiepileptic medications of this epilepsy syndrome is high with seizure freedom rates up to 90%. Continuation of treatment is recommended, given the high seizure recurrence rate.
      • -
        It is important to ask about the presence of myoclonic seizures. Myoclonic seizures are usually interpreted by patients as normal phenomena and may not cause them to seek medical attention.
      • -
        There is some suggestion that seizure freedom can be achieved without antiepileptic treatment in individual cases by just adjusting lifestyle.
      • -
        The EEG is highly characteristic, but not needed to make the diagnosis. The diagnosis is a clinical one. EEG is a confirmatory tool [
        • Debicki D.
        Electroencephalography after a single unprovoked seizure.
        ].
      • -
        Magnetic-resonance imaging in presence of a normal CT is optional, as structural lesions are unlikely in this syndrome which represents a functional abnormality that is largely genetically determined [
        • Pohlmann-Eden B.
        • Newton M.
        First seizure: EEG and neuroimaging following.an epileptic seizure.
        ].

      Case 2: a case with a first seizure – complex from start

      This case is a real life scenario of a patient navigating the health care system after an initial diagnosis of new-onset epileptic seizures, which highlights the need for a timely well-organized diagnostic algorithm leading to a well-differentiated diagnosis and a conceptual framework [
      • Pohlmann-Eden B.
      Conceptual relevance of new-onset epilepsy.
      ].
      A 31-year-old previously healthy woman presented to the emergency room (ER) after her family members had observed 3 stereotyped episodes of impaired awareness of sudden onset associated with abnormal movements of her lips and tongue, lasting 60–90s. The patient was amnestic afterwards and appeared confused for 30 min. All episodes occurred within 36 h, separated by 12 and 24 h. The ER physician initiated investigation with a CT head scan, EKG and extensive lab work. Neurological examination as well as all test results were reported to be normal. The patient was discharged after an observation period of 12 h with a putative diagnosis of new-onset seizures, likely dyscognitive seizures (complex partial seizures). Treatment was initiated with levetiracetam BID 500 mg. A referral to the Halifax First Seizure Clinic (HFSC) was arranged for further diagnostic work-up and treatment. The patient received a full comprehensive assessment by the HFSC team (epileptologist and nurse practitioner) within 2 weeks of the referral.
      Seizure history: Seizures were described as a sudden “rush” of an indescribable feeling starting at the top of the head, spreading to chest and abdomen, preceding loss of awareness. Witnesses reported that the patient would call out or speak, make chewing movements, smack and lick her lips and wring her hands. Episodes would last for a maximum of 90s, ending abruptly. She would be amnestic for the automatisms and exhibit mild confusion after these events, with no indication of Todd’s paresis. Seizures were classified as dyscognitive seizures likely of temporal lobe origin. There was no evidence of any other seizure type.
      The patient reported 3 identical spells in first 4 days after ER discharge. Following a dosage increase to 1000 mg twice daily she was seizure-free for 10 days but developed significant mood problems.
      Neurological exam: Normal, mild obesity.
      Past medical history: Gall bladder removal, asthma, anxiety & depression for preceding 12 months.
      Family history: Mother had febrile seizures and epilepsy in her youth, seizure-free without antiepileptic drugs since adolescence. No siblings.
      Social history: Grade 12 education, manager at a hardware shop for 13 years, financially independent, own apartment, single, no smoker, no recreational drugs, rarely alcohol, no driver’s license.
      EEG (routine and double-length sleep-deprived): Interictal epileptiform activity in the right fronto-temporal to mesiobasal area (Fig. 1).
      Fig. 1
      Fig. 1Longitudinal anterior-posterior bipolar montage EEG montage revealing sharp waves in the right fronto-temporal area.
      MRI: Showed bilateral periventricular heterotopia and changes suspicious of right hippocampal sclerosis (Fig. 2a and b).
      Fig. 2
      Fig. 2a: Biventricular heterotopia in axial and coronal T2-MRI imaging in patient with new onset epilepsy. b: Marked atrophy and subtle intrinsic signal changes in right hippocampal area (coronal T2-MRI).
      Final diagnosis: New-onset epilepsy with dyscognitive seizures & psychiatric comorbidity likely originating from mesial structures of the right temporal lobe.
      Counselling: The functional and structural findings and final diagnosis were explained to the patient in detail. Her seizure recurrence risk (SR) was considered to be very high without treatment. Several antiepileptic drugs (AE) were offered as alternatives to levetiracetam (lamotrigine, carbamazepine, eslicarbazepine). The patient was advised to avoid working at heights, being too close too heavy machinery, being exposed to open water (hot tub), swimming in the ocean, and to pay attention to regular sleep and regular medication intake. Driving restrictions were not an issue in this case because the patient had no license.
      Further course: Patient requested a withdrawal of levetiracetam because of her mood problems. She was fully aware of the increased risk for seizure recurrence. Within only 1 week of stopping levetiracetam, the patient experiences a seizure re-occurrence with up to 7 seizures within 5 days.
      She then started on lamotrigine with weekly increase of 25 mg. She initially improved and had only 1 seizure every 2 weeks, with periods of seizure-freedom for up to 3 months whilst taking a high dosage of lamotrigine (200 mg twice daily), then had a seizure relapse. Despite the subsequent addition of valproate acid and high serum levels of both antiepileptic medications, patient continued to have 2–3 dyscognitive seizures per months.
      Patient was considered pharmacoresistant (PR) and presented to epilepsy case conference with a request for presurgical evaluation.
      Further work-up included interictal PET imaging, stereotactic depth EEG recording, and neuropsychology to identify the epileptogenic zone (EZ) and risk associated with resective surgery. Surface EEG recording and seizure semiology suggested EZ in the right hippocampal area. The patient is currently awaiting admission for presurgical evaluation.

      Impression and selected learning points from this case

      This is an interesting case whose initial presentation already suggests stereotyped new-onset temporal lobe seizures. Here are selected learning points:
      • 1)
        Preceding anxiety and depression are frequent in patients with new-onset epilepsy, particularly from the temporal lobe, and markers of an already disturbed neuronal network [
        • Kanner A.M.
        Psychiatric comorbidities in new onset epilepsy: should they be always investigated?.
        ,
        • Pohlmann-Eden B.
        • Aldenkamp A.
        • Baker G.A.
        • Brandt C.
        • Cendes F.
        • Coras L.
        • Crocker C.
        • Helmstaedter C.
        • Jones-Gotman M.
        • Kanner A.M.
        • Mazarati A.
        • Mula M.
        • Smith M.L.
        • Omisade A.
        • Tellez-Centeno J.
        • Hermann B.
        The Relevance of neuropsychiatric symptoms and cognitive problems in new-onset epilepsy – current knowledge and understanding.
        ].
      • 2)
        Especially in the presence of psychiatric comorbidity (missed in the ER in this case), levetiracetam can lead to mood problems. In this patient, this drug was certainly not the best choice.
      • 3)
        Focal seizures, should immediately prompt EEG recording, if possible even in the ER [
        • Paliwal P.
        • Wakerley B.
        • Yeo L.L.
        • Ali K.M.
        • Ibrahim K.
        • Wilder-Smith E.
        • Sim T.B.
        • Pohlmann-Eden B.
        • Rathakrishnan R.
        Early electroencephalography in patients with Emergency Room diagnoses of suspected new-onset seizures: diagnostic yield and impact on clinical decision-making.
        ].
      • 4)
        MRI following epilepsy protocol is critical to reveal subtle changes. In our case a complex (dual) pathology was demonstrated early raising the question of the epileptogenic zone [
        • Crocker C.
        • Pohlmann-Eden B.
        • Schmidt M.H.
        Role of neuroimaging in First Seizure Diagnosis.
        ].
      • 5)
        The occurrence of initial frequent focal seizures in the presence of abnormal neurobiological factors (EEG and MRI) suggests intrinsic severity [
        • Rogawski M.A.
        • Johnson M.R.
        Intrinsic severity as a determinant of antiepileptic drug refractoriness.
        ] and early pharmacoresistance (PR).
      • 6)
        An organized approach such as a First Seizure Clinic is necessary to early identify pharmacoresistance (PR) and potential epilepsy surgery candidates. In our case it needed less that 8 months to recognize PR and consider epilepsy surgery.
      These are only 2 selected exemplary cases in a wide spectrum of possible presentations and individually challenging situations.
      The guest editors would like to emphasize, that systematic evaluations of FS presentations in a prospective cohort in a well organized First Seizure Clinic will allow new insights into mechanisms of epileptogenesis and an overall better understanding of the role of both seizures and epilepsy in complex brain pathologies. This kind of research will likely question traditional concepts and open up for innovative thinking [
      • Pohlmann-Eden B.
      • Burneo J.
      Future directions in recognizing and dealing with first seizure patients-Research and operational issues.
      ].

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        Conceptual relevance of new-onset epilepsy.
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