Epilepsy Aspects and EEG Patterns in Neuro-Metabolic Diseases

doi:10.4236/jbbs.2011.12009

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Journal of Behavioral and Brain Science, 2011, 1, 69-74

doi:10.4236/jbbs.2011.12009 Published Online May 2011 (http://www.SciRP.org/journal/jbbs)

Epilepsy Aspects and EEG Patterns in

Neuro-Metabolic Diseases

Ilhem Ben Youssef-Turki, Ichraf Kraoua, Sourour Smirani, Kchaou Mariem,

Hanene BenRhouma, Aida Rouissi, Neziha Gouider-Khouja

Department of Chi l d an d Ad ol escent Neurology , National Institute of Neu rology, Tunis, Tunisia

E-mail: [email protected], [email protected]

Received January 18, 2011; revised April 2, 2011; accepted April 4, 2011

Abstract

Neurometabolic diseases (NMD) are a frequent cause of epilepsy in children. Epilepsy is more frequently

part of a complex clinical picture than a predominant symptom and may be of different types and various

EEG patterns. The primary goal of this article is, departing from a large personal series, to describe the sei-

zure type, EEG patterns and response to antiepileptic drugs in NMD and to discuss clinical value of epilepsy

type in the setting of specific NMD. We found epilepsy was associated to NMD in 43.1%. Disorders of en-

ergy metabolism were the most frequent cause of epilepsy (61.3%). We observed generalized epilepsy in

75% of the patients with partial epilepsy in 25%. EEG was abnormal in only 71% of cases with variable pat-

terns. Resistance to antiepileptic drugs was observed in 75% of cases. Valproate acid was incriminated in

seizure worsening in 22.7% of the patients, all of them affected by mitochondriopathies.

Keywords: Neurometabolic Diseases, Epilepsy, EEG

1. Introduction

Inborn errors of metabolism (IEM) are a group of genetic

disorders characterized by dysfunction of an enzyme or

other protein involved in cellular metabolism [1]. Most

IEMs involve the nervous system (neuro-metabolic dis-

eases or NMD). NMD often present with a complex

clinical picture: psychomotor retardation and/or regres-

sion, pyramidal signs, ataxia, hypotonia, movement dis-

orders and epilepsy [1]. Epilepsy is more frequently part

of this complex picture than a predominant symptom and

presents with various clinical and EEG features. The

primary goal of this article is, departing from a large

personal series, to describe the seizure types, EEG pat-

terns and response to antiepileptic drugs in NMD.

2. Patients and Methods

We included in our prospective study 102 subsequent

patients with confirmed or highly suspected NMD fol-

lowed at the Department of Child and Adolescent Neu-

rology at the National Institute of Neurology of Tunis

over 5 years (2005 - 2010). We found 44 patients out of

these 102 (43.1%) had epilepsy.

In addition, we performed a web search by using the

NIH pubmed database with the following keywords

“epilepsy and neurometabolic diseases”, “epilepsy and

inborn errors of metabolism”. We found epilepsy in

NMD is mostly reported disease by disease; few studies

reported on epilepsy in NMD as a group of disorders

[2-11].

3. Results

Mean age of our 44 patients (25 girls, 19 boys) was 7.8

years (range: 3 months - 20 years). The median age at

onset of seizures was 4 years (range: Birth - 16 years), 2

patients had neonatal convulsions. Disorders of energy

metabolism (such as mitochondriopathies, pyruvate de-

hydrogenase (PDH) deficiency and creatine metabolism

deficiency) which accounted for 60% of all our NMD

patients, accounted for the almost similar proportion of

NMD patients with epilepsy (61.3%, 27/44). 25% (11/44)

of the patients with NMD and epilepsy had a disorder of

complex molecules (such as ceroide lipofuscinosis,

metachromatic leukodystrophy, GM2 gangliosidosis,

Gaucher disease type III, Niemann Pick type C and San-

filippo disease), accounting for 25% of all our NMD

patients. Five patients (11.4%) with NMD and epilepsy

had a disorder giving rise to intoxication (phenylketonu-

70 I. B. YOUSSEF-TURKI ET AL.

ria, biotinidase deficiency and porphyria) accounted for

the remaining 5/44 and one patient had Aicardi Goutières

syndrome) (Table 1).

The main cause of energy metabolism disorder was

mitochondriopathy, which was found in 19 (70 %) out of

the 27 patients with this group of disorders.

As for patients with complex molecules disorders and

epilepsy, this study shows that the most frequent type of

epilepsy is progressive myoclonic epilepsy (PME), with

GM2 gangliosidosis, Austin leukodystrophy and San-

philipo disease observed each in 2 patients. Ceroide-

lipofuscinosis, Gaucher disease type III, Niemann Pick

type C disease, and metachromatic leukodystrophy were

observed each in one patient.

The relative frequency of different epilepsy types is

shown on Table 2. We observed generalized epilepsy in

33/44 (75%) of the patients, with specific epileptic syn-

dromes being rare (only 3 cases of West syndrome). Par-

tial epilepsy was observed in 11/44 (25%) of the patients.

In 50% of the cases, epilepsy was the initial symptom

of the metabolic disorder. It was in some cases ob-

served in the setting of a metabolic “crisis” or decom-

pensation of the causative disorder (porphyric crisis in

porphyria, acute episode of a mitochondrial encephalo-

pathy with lactatic acidosis and stroke like episodes

(MELAS), hypoglycaemia in hyperinsulinism and ionic

disorder in adrenoleukodystrophy). Status epilepticus

(generalized or partial) was observed in 7 patients

(15.9%) especially in the group of energy metabolism

disorders.

EEG was abnormal in 71% of cases with variable EEG

patterns: slow background, generalized discharges of

spikes-waves, with pseudo-rythmic aspects, fast EEG

rhythms, continuous spikes-waves during sleep (CSWS),

fragmental hypsarythmia during sleep and photo-parox-

ysmal responses during photic intermittent stimulation.

No suppression bursts were observed.

With regard to antiepileptic drug effect on epilepsy in

NMD, resistance was observed in 75% of cases. Val-

proate acid was directly incriminated in seizure worsen-

ing in 10 cases of mitochondriopathies.

4. Discussion

We report on a prospective series of 44 patients with

neurometabolic disease (NMD) and epilepsy and we de-

scribe the etiologies and the characteristics of epilepsy in

these disorders.

Epilepsy in NMD is more frequently part of complex

clinical picture than a predominant symptom and pre-

sents with various clinical and EEG features. According

to our study, nearly half of the patients with NMD may

have epilepsy (43%).

When managing a patient with epilepsy especially in-

augural, NMD should be suspected if: (1) the medical

history shows consanguinity, family history of similar

cases, onset at the neonatal period or psychomotor re-

gression; (2) presence of myoclonus, spasms, focal and

Table 1. Neurometabolic diseases with Epilepsy.

NMD groups Neurometabolic diseases Numbe r of patients

Mitochondriopathies 19

Lafora disease 4

Creatine deficiency 2

PDH deficiency 1

Energy metabolism

(27/44)

Hyperinsulinism 1

Phenylketonuria 3

Biotinidase deficiency 1

Intoxication

(5/44)

Phorphyria 1

Leukodystrophies 4

Gangliosidosis GM2 2

Ceroide lipofuscinosis 1

Niemann pick type C disease 1

Sanphilipo disease 2

Gaucher disease type III 1

Molecule complexe

(11/44)

Aicardi goutière syndrome 1

Total 44

I. B. YOUSSEF-TURKI ET AL.

Table 2. Frequency and type of epileptic seizures in 44 patients with NMD.

Generalized seizures Partial seizures Particular

syndrome

NMD

groups

Neurometabolic

disease Number

of patient Tonico-

clonic AbsenceClonicTonicAtonicMyoclonus Partial

simple Partial

complexe West

syndrome

Mitochondriopathies19 ++ ++ ++ ++ ++ ++ + + +

PDH deficiency 1 + − − + + + − − −

Creatine deficiency 2 + − + − − − − − −

Hyperinsulinism 1 ++ − − − + − − − −

Energy

metabolism

Lafora disease 4 ++ ++ ++ − − ++ ++ + −

Phenylketonuria 3 ++ − + + + − − − +

Biotinidase

deficiency 1 ++ + − + − + − − −

Intoxication

Porphyria 1 ++ − − − − − − − −

Gangliosidosis GM22 ++ − − + − ++ − + −

Ceroide

lipofuscinosis 1 ++ ++ + − − ++ − − −

Niemann pick type C

disease 1 − − − + + − + − −

Complexe

molecule

Gaucher disease type

III 1 − − − − − − − − −

Others Aicardi Goutieres

syndrome 1 + − − − − − − + −

and tonic seizures, unexplained status epilepticus or sei-

zures related to eating times; (3) association with a neu-

rological deterioration or systemic signs; (4) presence of

early or progressive myoclonic epilepsy; (5) seizures

worsen under certain anti-epileptic drugs such as val-

proate; (6) EEG patterns shows suppression burst, high

voltage and rhythmic delta-slow waves associated with

myoclonus and paroxysmal responses during photic in-

termittent stimulation at low frequencies [2-11].

Various NMD causing epilepsy may be suspected ac-

cording to age at onset and the presence or absence of

specific epileptic syndromes (Figure 1). In the neonatal

period, early myoclonic encephalopathy (EME) with

suppression burst EEG pattern is often due to an inborn

error of metabolism, particularly non ketotic hypergly-

cinemia [12]. If seizures are unexplained and refractory,

vitamin-responsive epilepsies should be always consi-

dered and therapeutic trial using successively pyridoxine,

pyridoxal phosphate, folinic acid and biotin should be

started [13-17]. In our series no cases of early myoclonic

encephalopathy were found probably because epileptic

patients in the neonatal period are referred to neonatolo-

gists rather than neurologists.

In early infancy, many treatable conditions should be

considered: serine deficiency, GLUT1 deficiency, bioti-

nidase deficiency, aminoacidopathies and urea cycle de-

fects [16-19]. Other less readily treatable diseases (mi-

tochondriopathies, sulfite oxidase deficiency, adenylo-

succinate lyase deficiency, succinic semialdehyde dehy-

drogenase, peroxysomal disorders and CDG syndromes)

could be also searched for [20-25]. In our study, mito-

chondriopathies were the most frequent disease, ac-

counting for 70% of cases. We found one case with a

possibly treatable NMD (biotinidase deficiency).

In childhood (as it is the case in adulthood), diagnosis

approach is based on the presence or absence of progres-

sive myoclonic epilepsy (PME). The causes of PME are

dominated by lysosomal disorders, like in our study,

(ceroide-lipofuscinosis, sialidosis, GM2 gangliosidosis,

Gaucher disease type III, Niemann Pick type C), Lafora

disease and mitochondriopathies [26-32]. In the absence

of PME, treatable diseases (such as GLUT1 deficiency,

creatine deficiency, porphyria and urea cycle disorders)

should be considered [33-35]. Finally, other non treatable

diseases (mainly mitochondriopathies) should be evoked.

In our study, PME was the most prevalent epileptic syn-

drome in childhood.

Epilepsy may be symptomatic of a metabolic” crisis”

or decompensation, as it was the case in 4 out 44 of our

patients, and these cases were diagnosed as, porphyria,

mitochondrial encephalopathy with lactic acidosis and

stroke like episodes (MELAS), hyperinsulinism and

adrenoleukodystrophy [2].

EEG findings in epilepsy related to NMD are non spe-

cific; however some EEG patterns are suggestive of

some NMD groups: suppression burst is highly sugges-

I. B. YOUSSEF-TURKI ET AL.

Figure 1. Diagnosis orientation in NMD according to the age at onset and epileptic syndromes. Abreviation: NKHG: Non

ketotic hyperglycinemia; B6: pyridoxine-dependent epilepsy; PNPO: pyridoxal phosphate deficiency; GLUT1: glucose

transporter deficiency; MTHFR: methyltetrahydrofolate deficiency; SO: sulfite oxidase deficiency; ADSL: adenylosuccinate

lyase deficiency; SSADH: succ inic semialdhehyde dehydr ogenase; CDG SD: carbohydrate deficiency syndrome; MSUD: ma-

ple syrup urine disease; UCD: urea cycle disorders; PKU: phenylketonuria; HCY: homocystinuria; MERRF: myoclonic epi-

lepsy with ragged red fibers; CLF: ceroid lipofuscinosis; NPC: Niemann Pick disease; G III: Gaucher disease type III; IAP:

intermittent acute porphyria.

tive of non ketotic hyperglycinemia and high voltage and

rhythmic delta-slow waves associated with myoclonus

and paroxysmal responses during photic intermittent

stimulation is highly suggestive of PME [11]. In our

study we observed no suppression bursts.

Epilepsy in NMD is usually pharmacoresistant. An-

tiepileptic drugs (AEDs) provide a moderate benefit as

compared to more specific metabolism-directed therapies

(eg special diet or vitamins). Some AEDs, (such as val-

proate) may worsen the clinical condition as they inter-

fere with the abnormal metabolic pathway, especially in

mitochondriopathies, urea cycle deficiency and non ke-

totic hyperglycinemia [7]. In our series valproate was

incriminated in seizure worsening in 10 patients with

mitochondriopathy.

5. Conclusions

Nearly half or the patients with NMD would present an

epilepsy of various types (the most life-threatening being

status epilepticus) that may be inaugural (50% of cases)

of the disease or symptomatic of a metabolic decompen-

sation. The most frequent provider of epilepsy is the

group of energy metabolism, most probably because it is

the most frequent group of NMD but may be also be-

cause it is a group of disorders in which the neuronal

metabolism is more fragile and susceptible of suffering

from any situation of fever or hypercatabolism. Diagno-

sis approach to a patient with epilepsy and a suspected

underlying NMD depends on age, presence or absence of

a specific epileptic syndrome and/or a specific EEG pat-

tern. A thorough diagnosis evaluation of patients with

epilepsy and NMD allows efficient management of the

underlying NMD but also of epilepsy itself, in case the

NMD is a treatable one. It also allows (with the adequate

measures) avoiding harmful AEDs, preventing meta-

bolic “crisis” and epilepsy worsening.

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