Epilepsy in Inherited Metabolic and Mitochondrial Disorders

Douglas R. Nordli, Jr., MD Epilepsy Center, Children’s Memorial

Hospital Chicago, Illinois, USA

Metabolic Diseases

More than 11,000 characterized inherited disorders in man

200 associated with seizures and epilepsy 50 present in infancy

Metabolic Disorders

Prompt treatment Prognosis Genetic implications for family Reduce unnecessary testing Peace of mind Increase our understanding of physiology

How to Organize Material

Seizure type Myoclonic seizures, tonic seizures, spasms

General category of disease Peroxisomal, lysosomal, mitochondrial, etc.

Pathophysiological mechanisms

Pathophysiology: Energy Failure

Staring and Unresponsive

GLUT-1 DS: De Vivo’s Disease

Focal seizures in infancy Generalized seizures later Gen 2.5-3 Hz spike-wave discharges Ann Neurol 2003: PET study Thalamic involvement is hallmark (Generalized spike-waves also seen in

hyperammonemia / hypoglycemia)

Energy Failure Syndrome

Patient with Energy Failure Disorder

MELAS

With stroke-like episodes EEG shows focal features, including focal slowing,

attenuation, and spikes

Sabbagh et al. Epilepsia 2010 Respirtory Chain Disorders

Status Epilepticus in neonates with multiorgan failure (2) Neonatal myoclonic encephalopathy (3) Infantile Spasms (8) Recurrent status epilepticus (21) Epilepsia partialis continua (4) Myoclonic epilepsy (18)

In one third of patients abnl were only detected in the liver

Excitatory / Inhibitory Transmission

Note discontinuity; multifocal IEDs After Treatment

Excessive Excitation

Increased glutamate / GABA Glutamate GABA Requires B6 EEGs are discontinuous, multifocal IEDs

Accumulation of Toxic Substances After protein meal Baseline

Note attenuation of background, peculiar monorhythmic theta Multifocal spikes

OTC

Ornithine transcarbamylase deficiency Worsened by protein load Accumulation of ammonia EEG shows a low-voltage pattern, with diffuse slowing

and multifocal epileptiform discharges Two patients studied by Verma et al. in 1984

demonstrated episodes of sustained monorhythmic theta activity

Destructive Lesions

H E A D C I R C U M F E R E N C E

AGE (MONTHS)

Infant with Progressive Microcephaly

Background Attenuation Periodic

Brush-like pattern

Destructive Lesions

Erode complexity Some have peculiar EEG features Alpers- brush-like pattern NCL- vanishing EEG

Pathophysiology

Process Example EEG

Malformations PDH/PC, Zellweger Chaotic: B/S, hypsarhythmia

Destructive lesions NCL Reduced voltage (vanishing)

Toxins Urea Cycle Slowing, multiple IEDs, some unique patterns

Insufficient fuel GLUT-1 DS Gen S/W

Imbalance AA Pyridoxine Dep Chaotic: B/S

Metabolic Defect

Energy Failure

Disturbance of excitation / inhibition

Accumulation of toxic substances

Structural Damage

Seizure Types Associated with Metabolic Diseases in Infancy

Myoclonic seizures Infantile spasms Mixed seizures-combination of focal and

generalized elements Some tonic seizures

Problems Using Seizure Type to Identify Metabolic Disease

Limited repertoire in infants Seizures are etiologically non-specific

Organizing by Epilepsy Syndrome

Advantages Typical method of practice Incorporates more clinical information Some are caused by metabolic defects

Disadvantage Still not etiologically specific

Likely and Not-Likely Metabolic Disorders Likely Not-Likely

Early Myoclonic Encephalopathy (Aicardi) Benign Myoclonic Epilepsy

West Severe Myoclonic Epilepsy (Dravet)

Early Infantile Epileptogenic Encephalopathy (Ohtahara)

Benign Non-epileptic Infantile Spasms (Lombroso)

Neonatal Seizures Localization-related epilepsies with spasms

Multifocal epilepsies with focal seizures

Benign Infantile Partial Seizures (Watanabe)

Multifocal epilepsies with “generalized” seizures Localization-related epilepsies

Severe-Migrating Partial Seizures (Coppola et al.)

Age of Presentation Correlates with Epilepsy Syndrome

Age EEG Epilepsy

Neonatal Burst-suppression EME, EIEE

Early infantile Hypsarhythmia West

Late infantile Multifocal spikes/ more specific

Generalized myoclonic

Childhood Gen S/W, EPC, others (more specific) PME, EPC, others

Approach to Metabolic Disorders Presenting with Seizures

By epilepsy syndrome By age

Five Epilepsy Patterns

1. FAMILIAL EPILEPSIES

2. GENETIC GENERALIZED

EPILEPSIES

NORMAL

4a. EPILEPTOGENIC ENCEPHALOPATHIES

4b. SEVERE EPILEPTIC ENCEPHALOPATHIES

5. FOCAL STRUCTURAL

NAME

Normal

NORMAL

3. SELF-LIMITED EPILEPSY WITH FOCAL STEREOTYPED SPIKES

SLOWED

SLOWED, DISORGANIZED, AND

DISCONTINUOUS

FOCAL SLOWING/ATTENUATIO

N

EEG BACKGROUND

NONE

GENERALIZED AND STEREOTYPED

FOCAL OR MULTIFOACL AND STEROTYPED

MULTIFOCAL AND PLEOMOPRHIC

MULTIFOCAL AND PLEOMOPRHIC

FOCAL PLEOMORPHIC

SPIKES

Autosomal Dominant

SPIKES ARE STRONGLY GENETIC; EPILEPSY

ABOUT 30%

SPIKES ARE OFTEN AD; EPILEPSY LESS THAN

5%

MIXED

USUALLY DE NOVO, RARELY RECESSIVE

NONE

GENETICS

+/-

NO

NO

YES

YES

NO

GENETIC TESTING CLINICALLY

USEFUL

Mostly Favorable

VERY FAVORABLE, THOUGH SOME

REQUIRE LONG RX

VERY FAVORABLE

UNFAVORABLE

SEVERE

MIXED

OUTCOME

Electroclinical Syndromes

Nonsyndromic Epilepsies

- EME (Aicardi) - EIEE (Ohtahara)

- Benign familial neonatal epilepsy

-West syndrome -Late Infantile Epileptic Encephlopathy

-Benign familial infantile epilepsies

- Dravet; EFMR - Migrating focal seizures - Non-Progressive

Myoclonic Status

- **Febrile Seizures**

-Autosomal dominant nocturnal frontal lobe epilepsy

-Panayiotopoulos syndrome -Roladic Epilepsy -Late onset occipital (Gastaut)

-Lennox-Gastaut Syndrome

- No recognized syndromes

-With frontal foci

-Progressive Myoclonus Epilepsies

-AD with auditory features -AD familial temporal lobe

- No recognized syndromes

-Myoclonic infancy -**Febrile Seizures**

- Myoclonic atonic epilepsy -Childhood absence epilepsy -Epilepsy with myoclonic absence -Jeavons

- Juvenile absence -Juvenile myoclonic -Epilepsy with GTCs

- No recognized syndromes

1. Normal

2. Generalized stereotyped spikes; normal background

3. Focal/Multifocal Stereotyped Spikes; Normal Background

4a. Multifocal Spikes;

Background Slowing

4b. Multifocal spikes, discontinuity,

background slowing

-Epilepsies due to focal structural lesions -Can have homotopic EEG foci

5. Focal pleomorphic spikes; focal

slowing/attenuation

NEONATAL INFANCY

CHILDHOOD ADOLESCENCE

EEG FEAUTURES

Age EEG Features Screening Tests Disorders

Neonatal Burst-Suppression or Multifocal Spikes B6 Administration B6 Responsive Disorders

“ CSF Amino Acids Nonketotic Hypeglycinemia

“ Urinary Sulfite Dipstick/Serum Uric Acid

Molybdenum Cofactor Deficiency/Sulfite Oxidase Deficiency

“ Very Long Chain Fatty Acids (VLCFA) Peroxisomal Disorders

“ Lactate/Pyruvate Pyruvate Dehydrogenase Deficiency, Pyruvate Carboxylase Deficiency, Leigh syndrome

“ Serum Ammonia Early-Onset Multiple Carboxylase Deficiency

“ “ Urea Cycle Defects-neonatal citrullinemia

Low Amplitude Slowing “ Urea Cycle Defects- carbamoyl phosphate synthetase, ornithine transcarbamoylase, argininosuccinate synthetase

Comblike rhythm Serum Amino Acids/Urine Organic Acids Maple Syrup Urine Disease

Dysmature features during sleep Isovaleric Acidemia

Background slowing “ Proprionic Acidemia

Multifocal spikes, background slowing and depression “ Methylmalonic Acidemia

Early Infancy Burst-Suppression/ Multifocal spikes/slowed background

Serum Amino Acids Methylenetetrahydrofolate Reductase Deficiency

Hyposarhythmia Serum copper/ceruloplasmin Menke’s Disease

“ NONE PEHO Syndrome

“ Serum AminoAcids/Urine Organic Acids

Phenylketonuria and hyperphenylalaninemia, tyrosinemia type III, Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

“ “ Variety of organic acidurias including 3-mehtylglutaconic aciduria, 3-hyroxy- 3-mehtylglutaric aciduria, e-ydroxybutyric aciduria, 4-Hydroxybutyric aciduria

“ Lysosomal Hydrolases Tay-Sachs (hexosaminidase A)

“ “ Krabbe’s Disease (galactosylceramidase)

Multifocal spikes a-N-acetylgalactosaminidase (Schindler’s Disease)

Declining amplitude, very fast central spikes

Biotin Treatment/Biotinidase Screen

Biotinidase Deficiency

Background slowing, rhythmic temporal theta in type II (juvenile form)

Urinary oligosaccharides GM1 Gangliosidosis (Beta-Galactosidase)

Slowing/Posterior Spikes, Later 3 Hz spike-wave discharges

CSF glucose GLUT-1 Deficiency Syndrome

Late Infancy

Hypsarhythmia Serum electropheresis for CDG

Carbohydrate-deficient glycoprotein syndrome, CDG Type III

High Voltage, multifocal spikes

Lysosomal Hydrolases Metachromatic Leukodystrophy

low-amplitude fast activity (12 to 15 Hz) alternating with generalized slowing

Urine mucopolysaccharides Sanfilippo’s syndrome

Vanishing EEG in 1 Pseudoperiodic d/c in 2

Skin Biopsy with EM Infantile NCL; Late infantile NCL

continuous anterior high-voltage 1 to 3/s spike-wave-like activity

NONE Alper’s

LINCL Veneselli et al. 2001

Childhood and Adolescence

Background slowing, focal spikes Urine OA, Serum AA homocystinuria

Rhythmic trains of spike or sharp waves at 6 to 10/s

Gaucher cells in Bone Marrow Gaucher Type III

* Epilepsia Partialis Continua (EPC) Blood glucose Diabetes Mellitus with nonketotic hyperosmolar coma

* Focal slowing and spikes, 14- and 6-Hz positive bursts

Lactate MELAS

* EPC and Posterior attenuation/slowing

VLCFA Adrenoleukodsytrophy

Positive vertex spikes Urine oligosaccharides Sialidosis type I

4-6 Hz spike-wave discharges “ Sialidosis type II

Generalized 3-5 Hz SW, frontal predominance

DNA testing (no screen tests) Baltic Myoclonus

Generalized atypical spike-wave discharges

Lactate/Pyruvate MERRF

Generalized spike-wave and photoparoxysmal response

Triplet Repeats (no screening test available)

Dentatorubral-pallidoluysian atrophy

Generalized S/W, occipital spikes, with PPR

Skin Biopsy Lafora Disease

Multifocal spikes “ NCL type III

High-amplitude fast activity (16 to 24 Hz), unaltered by eye opening

Nerve Biopsy Neuroaxonal dystrophy

General Screening Tests

CBC with differential SMAC-20 Serum AA Urine OA Serum lactate / pyruvate Very long chain fatty acids Serum ammonia

Neonatal Seizures

Urea cycle defects Organic acidurias Biotin metabolism (multiple carboxylase,

holocarboxylase synthetase) Peroxisomal (Zellweger) Other: molybdenum cofactor / sulfite oxidase,

fructose, pyridoxine

Additional Neonatal Screening Tests

B6 administration CSF amino acids

Additional Infant Screening Tests

Lysosomal hydrolases Urine oligosaccharides / mucopolysaccharides Biotin treatment CSF glucose Serum copper / ceruloplasmin Lysosomal hydrolases Serum electropheresis for CDG Selective: skin biopsy

Additional Childhood Screening Tests

Urine oligosaccharides Selective

Bone marrow for Gaucher Nerve biopsy for neuroaxonal dystrophy Skin biopsy for NCL, Lafora Muscle biopsy for MELAS, MERRF DNA testing for MELAS, MERRF, DRPLA,

Baltic Myoclonus

Selected EEG Patterns and their Disorders

EEG pattern Disorder

Comb-like rhythm Maple Syrup Urine Propionic Acidemia

Fast central spikes Tay-Sachs Disease

Rhythmic vertex positive spikes

Sialidosis type I

Vanishing EEG Infantile NCL (type I)

High-amplitude 16-24 hertz activity

Infantile neuroaxonal dystrophy

Diminished spikes during sleep, giant SSEPS

PME

Marked photosensitivity PME and NCL, particularly type II

Conclusions

Rational approach is possible Several clues

Seizure types: myoclonic, spasms, tonic, mixed Epilepsies: NS, EME, West, Pleomorphic Clinical: unexplained encephalopathy

Organization by epilepsy syndrome / age EEG can be very useful Selective Diagnostic Testing