EDITORIALS
an agricultural worker. A presurgical carotid amytal
The Cognitive Consequences
of Epilepsy
In addition to the overt physical effects of seizures and
the psychological, social and economic sequelae of a
diagnosis of epilepsy, a major complaint of those with
epilepsy is impaired memory.1 Studies have demon-
strated deficits in new learning, particularly in those
with temporal lobe epilepsy, and with impaired verbal
episodic memory in left temporal epilepsy being the
most consistent finding.2 Furthermore, recent evidence
suggests that the incidence of verbal memory impair-
ment has been underestimated because of limitations of
traditional assessment techniques.3 Verbal memory is
the prime basis of day-to-day learning and memory,
and deficits can have a devastating impact on people’s
lives.4
Memory impairment may be caused by the underly-
ing pathology, the effects of the epilepsy, and the im-
pact of recurrent seizures.5 In addition, antiepileptic
drugs may result in impairments of attention and cog-
nitive slowing,6 which can have secondary effects on
memory by reducing the efficiency of encoding and re-
trieval processes.
Anxiety and depression are associated with memory
complaints, and mood can have a profound effect on
an individual’s perception of the adequacy of their
memory, to the extent that there is often a poor cor-
relation between self-rating of memory and perfor-
mance on formal memory tests.7 There is also evidence
that low mood can have a negative impact on the con-
solidation of memories.8
Anterior temporal lobe resection renders more than
two thirds of those with refractory temporal lobe ep-
ilepsy seizure-free, with marked improvements in
quality of life.9,10 When evaluating and advising a
candidate for this surgery the potential adverse effects
need careful consideration. The stakes are high, par-
ticularly for resection of the speech dominant anterior
temporal lobe, with the possible impact on language
and verbal memory. The risk of a significant deterio-
ration in verbal memory postoperatively can be pre-
dicted from preoperative factors: essentially the better
the verbal memory at baseline, the greater the risk of
a serious deterioration.11,12 Further factors include
age at surgery,11 severity of hippocampal sclerosis,
and the functional and structural integrity of the rest
of the brain.13 The impact of a worsened verbal
memory on a person’s occupation also will need care-
ful consideration: for example, the same decrement is
likely to have more impact on a trial lawyer than on
Published by Wiley-Liss, Inc., through Wiley Subscription Services
test is useful to guard against the development of a
severe amnesic syndrome and to lateralize language
function. Research evidence that clearly demonstrates
the carotid amytal test has a role in predicting the
severity of material specific memory deficits that is
superior or additional to data from baseline neuropsy-
chological test results is much less convincing, partic-
ularly given concerns about the invasiveness, cost, and
reliability of the procedure.14
The study by Helmstaedter and colleagues in this
issue addresses the impact of temporal lobe epilepsy
and surgical treatment in large cohorts of patients.15
Despite the limitations of a nonrandomized design,
and the absence of an age-matched control group,
there were important findings: principally, that
chronic temporal lobe epilepsy was associated with a
progressive impairment of memory, and that left tem-
poral lobe resection was associated with a subsequent
significant step down in memory, particularly if the
resection was extensive. In those who became seizure-
free, memory stabilized over subsequent years, and
this is a more positive cognitive outcome than re-
cently reported by Rausch and colleagues.16 Those
who did not become seizure-free after surgery, how-
ever, were subject to a “double whammy,” with wors-
ened memory performance and continued seizures.
This reinforces the potential benefits of successful ep-
ilepsy surgery, and the need for a very careful multi-
disciplinary evaluation and advising of the patient for
reasonable expectations and the risks of both surgical
and of continued medical treatment. All too often,
epilepsy surgery is considered only after a decade or
more, whereas it is usually apparent after administra-
tion of two to three antiepileptic drugs that the con-
dition is medically refractory.17 Therefore, patients
are exposed to the morbidity and mortality of contin-
ued seizures for longer than may be necessary.
In parallel with the evidence of cognitive impair-
ment associated with refractory epilepsy, there is evi-
dence from longitudinal imaging studies that second-
ary cerebral damage may occur in association with
epilepsy. Two studies of selected patients with tem-
poral lobe epilepsy attending specialist clinics have re-
ported hippocampal volume decreases over 3.5 years
in those with recurrent seizures.18,19 A larger study of
a community-based, and hence heterogeneous, popu-
lation did not find this but did find evidence of sig-
nificant focal or diffuse neocortical volume losses in
54% of patients with refractory epilepsy and 39% of
those with newly diagnosed epilepsy, compared with a
rate of 24% in age-matched and community-based
controls.20 The inference is that secondary cerebral
damage may occur with epilepsy. What is less certain
is whether this is a simply a direct consequence of
overt seizures or may be the consequence of an un-
© 2003 American Neurological Association 421
derlying “epileptic process.” The possible roles of
neuroprotective strategies are under consideration but
remain speculative at this time.21 Currently, the best
treatment strategy for epilepsy remains to strive for
compete seizure control without adverse effects of
therapy, using expeditious medical and surgical treat-
ments as appropriate for the individual patient and
their life style.
John S. Duncan, MA, DM, FRCP, and
Pam J. Thompson, PhD, DipPsych
Department of Clinical and Experimental Epilepsy
Institute of Neurology UCL
National Society for Epilepsy
National Hospital for Neurology and Neurosurgery
Buckinghamshire, United Kingdom
References
1. Hendriks MP, Aldenkamp AP, Van der Vlugt H, et al. Mem-
ory complaints in medically refractory epilepsy: relationship to
epilepsy related factors. Epilepsy Behav 2002;3:165–172.
2. Helmstaedter C, Kurthen M. Memory and epilepsy: character-
istics, course and influence of drugs and surgery. Curr Opin
Neurol 2001;14:211–216.
3. Blake RV, Wroe S, Breen EK, McCarthy R. Accelerated for-
getting in patients with epilepsy. Brain 2000;123:472– 483.
4. Wilson BA, Clare L. Rehabilitation of memory disorders. In:
Greenwood R, Barnes M, McMillan TM, Ward C, eds. Hand-
book of neurological rehabilitation. 2nd ed. Hove, UK: Psycho-
logical Press, 2003:377–388.
5. Thompson PJ. Epilepsy and memory. In: Cull C, Goldstein L,
eds. Clinical psychologists handbook of epilepsy. London: Rou-
tledge, 1997:35–53.
6. Meador KJ. Cognitive outcomes and predictive factors in epi-
lepsy. Neurology 2002;58(suppl 5):S21–S26.
7. Vermeulen J, Aldenkamp AP, Alpherts WC. Memory com-
plaints in epilepsy: correlations with cognitive performance and
neuroticism. Epilepsy Res 1993;15:157–170.
8. Ellwart T, Rinck M, Becker ES. Selective memory and memory
deficits in depressed patients. Depress Anxiety 2003;17:
197–206.
9. Wiebe S, Blume WT, Girvin JP, Eliasziw M. Effectiveness and
efficiency of surgery for temporal lobe epilepsy study. A ran-
domized, controlled trial of surgery for temporal lobe epilepsy.
N Engl J Med 2001;14:211–216.
10. Engel J Jr, Wiebe S, French J, et al. Practice parameter: tem-
poral lobe and localized neocortical resections for epilepsy: re-
port of the Quality Standards Subcommittee of the American
Academy of Neurology, in Association with the American Ep-
ilepsy Society and the American Association of Neurological
Surgeons. Neurology 2003;60:538 –547.
11. Davies KG, Bell BD, Bush AJ, Wyler AR. Prediction of verbal
memory loss in individuals after anterior temporal lobectomy.
Epilepsia 1998;39:820 – 828.
12. Jokeit H, Ebner A, Holthausen H, et al. Individual prediction
of change in delayed recall of prose passages after left-sided an-
terior temporal lobectomy. Neurology 1997;49:481– 487.
422 © 2003 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
13. Baxendale SA, Van Paesschen W, Thompson PJ, et al. Hip-
pocampal cell loss and gliosis: relationship to pre and post-
operative memory function. Neuropsychiatry Neuropsychol Be-
hav Neurol 1998;11:12–21.
14. Baxendale SA. Carotid amytal testing and other amytal proce-
dures. In: Oxbury JM, Polkey CE, Duchowny M, eds. Intrac-
table focal epilepsy: medical and surgical treatment. London:
WB Saunders, 2000:627– 636.
15. Helmstaedter C, Kurthen M, Lux S, et al. Chronic epilepsy and
cognition: a longitudinal study in temporal lobe epilepsy. Ann
Neurol 2003;54:425– 432.
16. Rausch R, Kraemer JD, Pietras CJ, et al. Early and late cogni-
tive changes following temporal lobe surgery. Neurology 2003;
60:952–959.
17. Kwan P, Brodie MJ. Early identification of refractory epilepsy.
N Engl J Med 2000;342:314 –319.
18. Briellmann RS, Berkovic SF, Syngeniotis A, et al. Seizure-
associated hippocampal volume loss: a longitudinal magnetic
resonance study of temporal lobe epilepsy. Ann Neurol. 2002;
51:641– 644. Comment: Ann Neurol 2002;52:861; author
reply: 862.
19. Fuerst D, Shah J, Shah A, Watson C. Hippocampal sclerosis is
a progressive disorder: a longitudinal volumetric MRI study.
Ann Neurol 2003;53:413– 416.
20. Liu RSN, Lemieux L, Bell GS, et al. Progressive neocortical
damage in epilepsy. Ann Neurol 2003;53:312–324.
21. Meldrum BS. Implications for neuroprotective treatments. In:
Sutula T, Pitkanen A, eds. Progress in brain research. Vol 135.
Do seizures damage the brain? Amsterdam: Elsevier, 2002:
487– 495.
DOI: 10.1002/ana.10710
Paternal Transmission of
Mitochondrial DNA is
(Fortunately) Rare
The field of mitochondrial disorders has seen an explo-
sion of information since the first human mitochon-
drial DNA (mtDNA) mutations were discovered in
1988.1 One of the bedrock principles of mitochondrial
genetics has been the strict maternal inheritance of
mtDNA. Paternal transmission of mtDNA is well
demonstrated in lower organisms (plants, fungi), but
occurs rarely in animals (mice, Drosophila, mussels,
birds).2 Elimination of sperm-derived paternal mito-
chondria in animals appears to be an active proteolytic
process that occurs after fertilization in early embryonic
development.3 MtDNA point mutations or small
structural lesions (eg microdeletions or microinsertions)
were assumed to be strictly maternally-inherited. How-
ever a single case report in 2002 in the New England
Journal of Medicine called into question this assump-
tion. Schwartz and Vissing4 studied a singleton male
with mitochondrial myopathy and exercise intolerance
attributed to a novel 2-nucleotide deletion in the ND2
gene of mtDNA. Extensive analysis of mtDNA ex-
tracted from different tissues was performed in the in-
dex patient, his father, and his mother. The novel mi-
crodeletion was present only in the skeletal muscle of
the patient and had arisen sporadically on the paternal
mtDNA haplotype. The mtDNA from all other tissues
studied in the patient contained the maternal mtDNA
haplotype. Challenging a central dogma has been dis-
ruptive since the days of Copernicus and this report
was met with great skepticism initially. Careful consid-
eration of the report reveals that the methodology is
sound and the conclusions of the authors are well sup-
ported. This first demonstration of the paternal trans-
mission of mtDNA in humans potentially had pro-
found implications for the management of patients
with mitochondrial disease, particularly the proper ge-
netic counseling.
The seminal report by Schwartz and Vissing4 raised
a number of important questions about paternal
transmission of mtDNA and its relevance to human
evolution and disease. Does this finding only apply to
the transmission of mutant paternal mtDNA? Does
paternal transmission of mutant mtDNA only occur
in a very restricted manner to a single tissue (eg skel-
etal muscle) or can it occur more diffusely in other
tissues and organ systems? How frequently does pa-
ternal transmission of mtDNA occur? Is paternal
transmission of mtDNA a rare curiosity or do we
need to change in a substantial way the genetic coun-
seling provided to patients with mitochondrial dis-
ease?
Two reports in this issue of the Annals5,6 address
some of these issues in populations of patients with
mitochondrial disease due to known pathogenic muta-
tions. Both groups included patients demonstrating the
enigmatic phenomena of mtDNA point mutations
confined only to skeletal muscle. Taylor et al.5 studied
35 singleton patients with proven mitochondrial dis-
ease (histochemically, clinically) due to a single, large
mtDNA deletion (32/35) or sporadic point mutations
(3/35) confined to skeletal muscle. Sequence analysis of
the highly polymorphic, non-coding D-loop region of
mtDNA was used to determine if the background
mtDNA haplotype on which the mutations arose was
of maternal or paternal origin. Comparison was made
of blood (non-mutant) and muscle (mutant) mtDNA.
There was no evidence of paternal transmission of
mtDNA in these patients. Differences between the
blood and muscle mtDNA sequences were detected in
five patients and these were attributed to somatic
mtDNA mutations.7
Filosto et al6 performed a very similar study on ten
patients with mitochondrial myopathy, five with a sin-
gle, large mtDNA deletion and five with mtDNA
point mutations (four missense mutations). The data
set was smaller and less complete (paternal samples
were not available in eight patients), but these authors
also found no evidence of paternal transmission of
mtDNA. Six of the patients had single nucleotide
changes present only in muscle, but all occurred on the
maternal mtDNA haplotype. The lack of paternal
transmission of mtDNA demonstrated by Taylor and
Filosto are reassuring to physicians and genetic coun-
selors who provide management and genetic counseling
to our patients with these challenging disorders. Both
of these studies focused on a specific subset of patients
with mitochondrial disorders, namely those with
mtDNA mutations confined to skeletal muscle. The
populations studied had a disproportionate fraction of
patients with an isolated exercise-intolerance phenotype
(i.e. the same phenotype exhibited by the index patient
of Schwartz and Vissing4). Thus the implication of
these conclusions to the much broader clinical and mo-
lecular genetic spectrum of patients with mitochondrial
disease should be tempered.
Proper genetic counseling in patients with mito-
chondrial disease is still quite complex and is a field
very much still in evolution. Issues that complicate ge-
netic counseling include the dissociation of genotype
(mtDNA mutation) and the phenotype (eg Leber’s he-
reditary optic neuropathy); the same mitochondrial dis-
ease phenotype with different mtDNA mutations (e.g.,
chronic progressive external ophthalmoplegia); and dif-
ferent phenotypes associated with the same mtDNA
mutation (eg the “MELAS mutation” at nucleotide po-
sition 3243 in mtDNA). There is complex interaction
of both the nuclear and mitochondrial genomes in mi-
tochondria and mutations in either nuclear DNA or
mtDNA may cause a mitochondrial disease phenotype.
We also know that diseases caused by genetic abnor-
malities in mtDNA can be inherited via a number of
different mechanisms. For instance large-scale mtDNA
deletions can be single and sporadic; multiple and au-
tosomal dominant; multiple and autosomal recessive;
and somatic.
Potential paternal transmission of mtDNA has im-
plications in other fields of medicine. Intracytoplasmic
sperm injection (ICSI) is an innovative fertility-
enhancing technique that involves the direct injection
of the whole sperm into the middle of the oocyte. ICSI
is employed in oligozoospermic men whose sperm may
harbor mtDNA mutations. This procedure by-passes
the normal acrosomal reaction of sperm and egg and in
theory may not trigger the active destruction of the pa-
ternal mitochondria. Fortunately there has been no ev-
idence of transmission of paternal mtDNA in ICSI to
date.8
Sequence analysis of mtDNA is also used extensively
in forensic matters and is the basis of an entire branch
of population genetics. The implications of paternal
Johns: Paternal Transmission of MtDNA is Rare 423
transmission of mtDNA for those fields is also pro-
found, but awaits more extensive studies specifically fo-
cused on those issues.
Donald R. Johns, MD
Division of Neuromuscular Disease, Departments of
Neurology and Ophthalmology, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston,
MA
References
1. Johns DR. The other human genome: mitochondrial DNA and
disease. Nature Med 1996;2:1065-1068.
2. Kvist L, Martens J, Nazarenko AA, Orell M. Paternal leakage of
mitochondrial DNA in the Great Tit (Parus Major). Mol Biol
Evol 2003;20:243-247.
3. Cummins JM. Fertilization and elimination of the paternal mi-
tochondrial genome. Hum Reprod 2000;15:92-101
4. Schwartz M, Vissing J. Paternal inheritance of mitochondrial
DNA. N Engl J Med 2002;347:576-580.
5. Taylor RW, McDonnell MT, Blakely EL, et al. Genotypes from
patients indicate no paternal mitochondrial DNA contribution.
Ann Neurol 2003;54:521–524.
6. Filosto M, Mancuso M, Vives-Bauza C, et al. Lack of paternal
inheritance of muscle mitochondrial DNA in sporadic mitochon-
drial myopathies. Ann Neurol 2003;54:524 –526.
7. Howell N, Smejkal CB, Mackey DA et al. The pedigree rate of
sequence divergence in the human mitochondrial genome: there
is a difference between phylogenetic and pedigree rates. Am J
Hum Genet 2003:72:659-670.
8. Marchington DR, Scott Brown MS, Lamb VK, et al. No evi-
dence for paternal mtDNA transmission to offspring or extra-
embryonic tissues after ICSI. Mol Hum Reprod 2002;8:1046-
1049.
DOI: 10.1002/ana.10771

424 Annals of Neurology Vol 54 No 4 October 2003