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
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.
71
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.
72
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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