Tips and Tricks in EEG Diagnosis

1. Biallelic mutations in SZT2 associated with epilepsy and developmental delay

Case presentation

• A four year old girl was admitted to the hospital with developmental delay at the age of two.
• She is the second of two children of healthy parents. No family members, including her elder brother, have neurological diseases including macrocephaly.
• She was born by caesarean section at a gestational age of 29 weeks due to maternal induced hypertension.
• At birth her weight was 1060 g (_1.4 SD), length was 39 cm (+0.1 SD) and head circumference was 28 cm (+0.6 SD).
• She delayed in sitting at two years, and walking unassisted at three years and not able to speak meaningful words at four years.
• Seizures, followed by tonic-clonic generalization, began at two years and ten months.
• At three years and four months of age, seizures increased to at most five times per month.

Investigations

• Initial EEG at the time of presentation showed background slowing, but no apparent epileptic discharge.
• Brain MRI revealed a characteristic shape of short and thick corpus callosum.
• Second EEG performed at four years showed focal epileptic discharges which rarely occurred predominantly in the left parietal region.

Diagnosis

Thick and short corpus callosum and mutations in SZT2 indicating epilepsy and developmental delay.

Discussion

This present case revealed that deficiency results in constitutive mTORC1 signaling. A lack of macrocephaly in patient may be explained by secondary neuronal loss due to recurrent seizures. Macrocephaly associated with non-intractable epilepsy may be a hallmark of SZT2-related epilepsy. Although clinical features of SZT2-related disorders such as various degrees of epilepsy, developmental delay, and macrocephaly are non-specific, the dysmorphic corpus callosum observed in this case with epilepsy. The thick and short shape of the corpus callosum, together with epilepsy, developmental delay and macrocephaly, may be a diagnostic feature of a discernible disorder that results from mutations in SZT2.

EEG TIP

EEG recording helped in focal epileptic discharges which rarely occurred predominantly in the left parietal region.

Nakamura Y, Togawa Y, Okuno Y,et al.Biallelic mutations in SZT2 cause a discernible clinical entity with epilepsy, developmental delay,macrocephaly and a dysmorphic corpus callosum. Brain Dev. 2018 Feb;40(2):134-139.

2. Granular Osmiophilic Elements and mutation in presenilin1 in Early-Onset Alzheimer’s Disease

Case presentation

• A 38 year right handed woman presented with mood disturbances and memory dysfunctions.
• She did not have a past medical history for mood depression, substance abuse or other forms of psychiatric or neurological illnesses.
• Proposita presented an unremarkable neurological examination, though myoclonic jerks were sporadically observed in the upper limbs
• Her 41-year-old sister had experienced similar clinical complaints at 39 years of age and had received a diagnosis of presenile dementia.
• The mother died at the age of 46 following a 5-year history of cognitive decline and a clinical diagnosis of dementia.

Investigations

• She showed severe cognitive decline (Mini-Mental State Examination =8/30), associated with behavioral disturbances characterized by psychomotor agitation, wandering and visual hallucinations.
• A brain CT scan showed severe cortical and subcortical atrophy.
• An EEG showed low amplitude pseudoperiodic sequences in the occipital derivations.
• Ultra structural examination of a skin biopsy visualized granular osmiophilic deposits (GRODs).

Diagnosis

Diagnosed as early-onset Alzheimer’s disease (EOAD), characterized by rapid cognitive decline associated with myoclonus and seizures.

Discussion

The present case report describes a patient suffering from an early onset of dementia, and bearing a mutation in PSEN 1. The pattern of behavioral disturbances, the adverse response to cholinesterase inhibitors and the benefit from the administration of antiepileptic agents that abolished myoclonic jerks led us to speculate that a similar phenotype and out-come might be attributable to the position of the 2 pathogenic variants in a similar domain of presenilin 1, the gene product. Epilepsy is known to be part of autosomal dominant Alzheimer’s disease phenotype. The cholinergic loss is an early marker of memory deficits in Alzheimer’s disease, and PS1 mutant knock- show impairment of cholinergic modulation in hippocampal plasticity, providing evidence of cholinesterase inhibitor therapy in dementia.

The present case and the patient reported earlier did not harbor variants in CLN1 , it is tempting to speculate that the 2 diseases shared similar pathomechanisms eventually related to a dysfunction of the lysosomal compartment.

EEG TIP

An EEG showed low amplitude pseudoperiodic sequences with spikes and slow waves in the occipital derivations.

Alberici A, Borroni B, Bonato C,et al.. EEG and granular osmiophilic elements in early-onset Alzheimer's disease. Neurodegener Dis. 2011;8(4):259-61.

3. Focal epilepsy with 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency

Case presentation

• A 17 year-old boy experienced presented with two generalized tonic–clonic seizures and he experienced mild walking difficulties at 16 years of age.
• The patient was born at term of consanguineous parents,and had normal psychomotor development.
• His younger brother had also experienced his first convulsive seizure at one year of age.
• Electroencephalography (EEG) and brain magnetic resonance imaging (MRI) were interpreted as normal.
• Six months later,he presented with an episode of loss of awareness consistent with a complex partial seizure.
• Neurological signs comprised absence of ankle tendon reflexes, vibration loss in the lower limbs and pyramidal syndrome.

Investigations

• Neuropsychological testing showed attention deficits, but with preserved memory and instrumental functions.
• EEG showed anterior bilateral sharp theta elements and rare sharp slow waves during wakefulness.
• Brain MRI displayed posterior white-matter abnormalities.
• Electromyography confirmed a sensory-motor axonal polyneuropathy.
• Metabolic analyses revealed hyperhomocysteinemia (220 mmol/L), a plasma methionine level at the lower limit, absence of methylmalonic aciduria and macrocytic anemia, and normal renal function.
• Molecular analyses identified a homozygous c.1603C T mutation in the > MTHFR gene.

Diagnosis

Diagnosed as MTHFR deficiency in the presence of epileptic manifestations, including progressive myoclonic or focal epilepsy.

Discussion

Plasma homocysteine is a key biomarker of the disease. Plasma methionine (low to normal) and urine methylmalonic acid (normal) can then further point to the diagnosis of MTHFR deficiency, which can then be confirmed by molecular and/or enzymatic testing.

The present case report underscores the importance of diagnosing MTHFR deficiency in young adults in the presence of epileptic manifestations, including progressive myoclonic or focal epilepsy, especially when associated with central (spasticity, dysexecutive syndrome) and/or peripheral neurological signs (polyneuropathy). The correct diagnosis can lead to specific therapeutic management and the prevention of complications related to hyperhomocysteinemia, and to family screening.

EEG TIP

EEG helps in displaying anterior bilateral sharp theta elements and rare sharp slow waves during wakefulness.

Mezouar N, Mochel F, An-Gourfinkel I,et al. Focal epilepsy as the revealing symptom of 5,10-methylenetetrahydrofolate reductase deficiency in a young adult. Rev Neurol (Paris). 2018 Mar;174(3):173-175.

4. Peri-oral myoclonia with absences with multiple facial and upper body myoclonia: Overlap epilepsy syndrome

Case presentation

• A 17-year old developmentally-normal girl presented with 8 years of paroxysmal daily, multiple, brief episodes of peri-oral twitching lasting up to 6 s with occasional head nodding during the day.
• There was also a history of daydreaming and inattention at school during this period.
• Over the next three years, she had five more generalized tonic-clonic seizures lasting for less than 5 min.
• She started taking anti-epileptic drug and she developed more frequent episodes of brief behavioral arrest followed by brief right sided facial twitching.
• Her history was negative for early morning jerks/clumsiness and recurrent falls.
• There was no history of other seizure types and the family history was non-contributory.

Investigations

• First Electroencephalogram (EEG) showed a single paroxysm of bifrontal polyspike-wave activity.
• A repeat EEG showed infrequent left frontal spike and wave discharges.
• She had normal neurological examination and magnetic resonance imaging of the brain.
• During the video-EEG, multiple episodes of absence seizures with myoclonic manifestations which included peri-oral eyelid, neck and shoulder myoclonia were captured.Eye-closure sensitivity was prominent.

Diagnosis

Peri-oral myoclonia with absence epilepsy was made (POMA) in view of pre dominant myoclonia in the peri-oral region.

Discussion

Perioral myoclonia with absences (POMA) was first described in 1994 by Panayiotopoulos. It is characterized by onset between 2 and 13 years of age, absences with myoclonia of the peri-oral muscles, co-existing generalized tonic-clonic seizures, propensity to absence status and poor response to anti-epileptic drugs. Asymmetric facial twitching and focal EEG abnormalities led to a misdiagnosis of a focal epilepsy in this case. The exact epilepsy syndrome classification may be difficult in this case. Given the predominant peri-oral myoclonia, frequent generalized tonic-clonic seizures, poor response to anti-epileptic drugs, eye closure sensitivity and presence of other myoclonia, a diagnosis of POMA overlapping with EMA was considered.

EEG TIP

EEG revealed s high amplitude generalized 3.5 Hz spike wave discharges lasting for 3.5 s. which was associated with brief absence with peri-oral myoclonia.

Gulati P, Jain P, Qashqari H,et al. Peri-oral myoclonia with absences with multiple facial and upper body myoclonia: Overlap epilepsy syndrome. J Clin Neurosci. 2018 Aug;54:135-137.