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Classification of progressive myoclonus epilepsies and related disorders.

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Clashcation of Progressive Myoclonus
Epilepsies and Related Disorders
Marseille Consensus Group"
The progressive myoclonus epilepsies (PMEs) are a
group of rare genetic disorders characterized by myoclonus, epileptic seizures, and progressive neurological
deterioration, particularly dementia and ataxia. Many
specific diseases can cause the PME syndrome. There
has been considerable confusion in the literature regarding classification and nomenclature of the PMEs.
This has been due to at least three factors. First, in the
past, diagnosis of specific disorders in life was often
impossible. Recent advances in clinical, biochemical,
and pathological diagnosis have rectified this [l, 21.
Second, there is considerable variation in the geographical distribution of specific disease entities. Third,
patients with different types of diseases present to neurologists with a prime interest in epilepsy, compared
with those with a principal interest in movement disorders.
Drs J. Roger, F. Andermann, and C. A. Tassinari
convened an international workshop on the PMEs in
Marseille, France, June 22-24, 1089. This was attended by representatives of most of the centers
around the world with a major interest in these disorders. Considerable clarification was achieved by exchange of data and by analysis of videotapes of the
conditions as seen in various parts of the world.
*Marseille Consensus Group (alphabetical listing) (tdenotes manuscript preparation committee; $denotes manuscript coordinator):
J. Aicardi (Paris, France), E. Andermannt (Montreal, Canada),
F. Andermannt (Montreal, Canada), D. Arnold (Montreal, Canada),
G. Avanzini (Milan, Italy), S. F. Rerkovictt (Melbourne, Australia),
M. Bureau (Marseille, France). S. Carpenter (Montreal, Canada),
T. De Barsy (Brussels, Belgium), D. C . De Vivo (New York, NY),
C . Dravet (Marseille, France), F. E. Dreifuss (Charlottesville, VA),
A. Federico (Siena, Italy), N. Fukuhara (Niigara, Japan), Y. Fukuyama (Tokyo,Japan), P. Gentont (Marseille, France), G. C . Guazzi
(Siena, Italy), A. E. Hardingt (London, England), G. Karpati
(Montreal, Canada), M. L. Koskiniemi (Helsinki, Finland), C. D.
Marsdeni (London, England), F. Maugui+re (Lyon, France), E. Merv d a (Kuopio, Finland), R. Michelucci (Bologna, Italy), H. Naito
(Niigata, Japan), R. Norio (Helsinki, Finland), U. Nousiainen
(Kuopio, Finland), J. A. Obeso (Pamplona, Spain), S. Oyanagi (Tokyo, Japan), J.-F. Pellissier (Marseille, France), J. Roger? (Marseille,
France), P. Santavuori (Helsinki, Finland), J. M. Shoffner (Atlanta,
GA), E. A. Shoubridge (Montreal, Canada), N. K. So (Cleveland,
OH) D. C. Wallace (Atlanta, GA), L. S. Wolfe (Montreal, Canada),
A. Ylinen (Kuopio, Finland).
Received Oct 12, 1989, and in revised form Jan 12, 1090. Accepted
for publication Jan 17, 1990.
Address correspondence to Dr Anderrnann, Montreal Neurological
Institute and Hospital, 3801 University, Montreal, Quebec, H3A
2B4. Canada.
This consensus statement highlights previous areas
of controversy for which international agreement has
now been reached. Descriptions of the well-established causes of PME are not given here but can be
found in recent reviews {l,2). A monograph detailing
the clinical, electrophysiological, pathological, biochemical, and genetic aspects of this group of diseases
is in preparation.
Myoclonus refers to sudden, brief, shocklike involuntary movements [ 3 , 4). In patients with moderate or
severe action myoclonus, it is difficult or impossible to
determine if cerebellar signs are present as well, unless
the myoclonus can be controlled by drug therapy.
The clinical characteristics of myoclonus in all the
specific causes of the PME sy,idrome are very similar.
Although the spectrum of severity of action myoclonus may vary in different diseases, the nature of the
myoclonus does not enable a specific diagnosis to be
reached. In addition to action myoclonus, spontaneous
myoclonus may occur, particularly in severe cases, and
is not important in the differential diagnosis of specific
Electrophysiological findings in the specific diseases
share more similarities than differences E5). Generalized spike-wave discharges, photosensitivity, focal
(especially posterior) epileptiform discharges, vertex
spikes in rapid eye movement sleep, and giant somatosensory-evoked potentials may be found in most
of the disorders that cause the PME syndrome. Slowing of background activity occurs in all forms of PME
but is usually much more prominent and early in those
diseases with diffuse neuronal damage or storage,
compared with those diseases with restricted neuronal
Specific Diseases
The specific disorders that cause PME are diagnosed
by recognition of the characteristic ages of onset of the
disorders, their associated clinical signs, and their clinical course; knowledge of the pattern of inheritance,
and of the ethnic and geographical origin of the patient; and by special investigations [I, 2).
In most parts of the world, five disease entities account for most of the cases of PME presenting to
epilepsy clinics {l, a}. These conditions are PME of
Copyright 0 1990 by the American Neurological Association 113
Unverricht-Lundborg type (defined below), Lafora disease, neuronal ceroid-lipofuscinoses, mitochondrial
disorders, and the sialidoses. A different spectrum of
diseases is seen in movement disorder clinics where a
common additional category, particularly among older
patients, is a degenerative cerebellar syndrome of unknown cause 16, 71.
The relative frequency of the five major causes of
PME varies in different parts of the world. For example, Lafora disease is relatively common in southern
Europe but is rare in Scandinavia. In Japan, another
entity known as dentatorubral-pallidoluysian atrophy
(DRPLA) is often encountered [81. This autosomal
dominant disorder seems to be extremely rare elsewhere in the world.
The clinical characteristics and methods of diagnosis of Lafora disease, neuronal ceroid-lipofuscinoses,
sialidoses, and several other very rare causes of PME
were reviewed. There was agreement with previously
published descriptions [ l , 2, 7, 91.
The PMEs without Lafora bodies or neuronal storage (“degenerative PMEs”) have been the source of
most disagreement. It is now clear that the major
specific disorders in t h s group are PME of UnverrichtLundborg type, mitochondrial disorders, degenerative
cerebellar disorders, and in Japan, DRPLA.
PME of Unverricht-Lundborg T y p e
This disorder was described by Unverricht in Estonian
patients in 1891 [lo, 111, and subsequently Lundborg
reported cases in Sweden {12). It is an autosomal recessive disorder characterized by clinical onset at the
age of 8 to 13 years (limit, 6-16 years), with spontaneous, stimulus-sensitive and action myoclonus, tonicclonic seizures, and cerebellar signs. Dementia is mild
and occurs late in the course of the disease. The rate of
progression may vary considerably between and within
families [10- 161.
Unverricht-Lundborg disease is relatively common
in Finland [13, 141. It is now clear that a phenocypically identical disorder occurs in many other regions
including the whole of Europe, North Africa, North
America, and Japan. A large group of patients described by the Marseille workers as having Ramsay
Hunt syndrome have the same clinical phenotype {2,
17, 181.
The term “Baltic myoclonus” has also been used for
this disease 115, 161. This term is now considered inappropriate because the disorder occurs worldwide;
areas of increased prevalence occur outside the Baltic
region and include North Africa and Italy. The name
PME of Unverricht-Lundborg type was adopted. It
should be noted, however, that in the early literature,
the names of Unverricht and Lundborg were often
incorrectly used for a variety of patients with PME,
including certain patients with Lafora disease.
114 Annals of Neurology
Vol 28 No 1 July 1990
The phenotypic similarity of this disorder in different parts of the world has now been established.
Molecular genetic studies are required to determine
the question of the genotypic identity of PME of Unverricht-Lundborg type in different geographical areas.
Mitochondrial Diseases
Mitochondrial diseases with the phenotype known as
myoclonus epilepsy and ragged red fibers (MERRF),
have emerged as a major cause of previously undiagnosed cases of PME [19-231. Although the clinical
presentation of M E W is more variable than that
of the other causes of PME, certain clinical features
should suggest the diagnosis. These clinical clues,
which are not always present, include deafness, optic
atrophy, myopathy, lactic acidosis, intrafamilial variation in age of onset and clinical severity, and a pattern
of inheritance compatible with maternal transmission.
The finding of ragged-red fibers in a skeletal muscle
biopsy confirms the diagnosis, but their absence does
not exclude it. Improved methods of diagnosis are required and may include biochemical analysis of muscle
and other tissues, study of mitochondrial DNA, magnetic resonance spectroscopy, and positron emission
tomography {22, 231. It is now clear that MERRF is a
biochemically heterogeneous disorder, and at present,
there is little correlation between the biochemical and
clinical features.
It was evident from discussions at the workshop that
MERRF is still underdiagnosed in many parts of the
world. A high degree of suspicion of this disorder is
required in undiagnosed cases of PME, particularly
those with late onset.
Ramsay H u n t Syndrome and Unclassified Cases
The term Ramsay Hunt syndrome [241 has caused
great confusion in the literature { 11, largely because
the term has been used inappropriately. It was universally agreed, as stated by a number of earlier authors,
that this term does not represent a specific disease
entity [7, 9, 25, 261. As noted previously, one homogeneous group of patients described as having Ramsay
Hunt syndrome has PME of Unverricht-Lundborg
type P, 17, 181.
Two points of view were expressed regarding further use of the term Ramsay Hunt syndrome. One
school believes it should not be used at all because it
may lead to diagnostic complacency and may hnder
attempts to reach a specific diagnosis [l, 271. A difficulty with this point of view is that not all patients
previously considered to have Ramsay Hunt syndrome
have seizures, so that it is not logical to include them
under the broad rubric of the PMEs. The second point
of view was to use Ramsay Hunt syndrome as a clinically convenient term referring to the broad spectrum
of patients with ataxia and myoclonus, with or without
Schematic representation of the clinicalfeatures and relatzonship
of the syndromes dprogressive myoclonic epilepsy (PMEI and of
progressive myoclonic ataxia (PMA).The bars in the upper part
of the figure give a general indication of the prominence of the
kty clinical signs in the PME and P M A syndromes (see text).
Initial recognition of either syndrome then demands an attempt
t o reach a specific diagnosis. A specifc diagnosis can now usually
be made in patients with PME, whereas a larger proportion o f
cases with P M A remain undiagnosed. Previous authors have
used the term Ramsay Hunt syndrome t o describe d;fferent groups
of patients within this spectrum.
seizures, including currently undiagnosable and atypical cases [7, 261. The problem with this approach is
that it will further confuse the literature because the
term has been used in so many different ways.
A consensus was reached to discard the term Ramsay Hunt syndrome and to divide the patients into two
broad syndromic categories, each of which demands a
speclfic approach to diagnosis. These two categories
are the PMEs and the progressive myoclonic ataxias
The syndrome of PME is defined, as before, as
myoclonus with epileptic seizures and progressive
neurological decline, particularly ataxia and dementia.
The syndrome of PMA comprises myoclonus, progressive cerebellar ataxia with infrequent or absent
epileptic seizures, and little or no cognitive dysfunction. It is emphasized that these terms represent syndromes and that they overlap (Figure). For example,
different members of one family with mitochondrial
disease may present with a PME or with a PMA syndrome. Indeed, a patient’s illness may begin with ataxia
and myoclonus and no epileptic seizures but then
evolve into the typical PME syndrome.
The major causes of the PME syndrome have been
previously outlined. It was apparent from discussions
at the workshop that the vast majority of patients with
PME can now have a spechc diagnosis made in life.
The residuum of cases without a specific diagnosis is
steadily shrinking as the diagnostic criteria for qpecific
diseases have emerged and have been accepted. Working groups have been established to clarify further as-
pects of the electrophysiology and neuropathology of
patients seen in different centers.
In contrast, specific diagnoses often cannot be
reached in life in patients with the PMA syndrome.
Known causes include spinocerebellar degenerations,
mitochondrial disease, and rarely, the early presentation of certain cases that later evolve into a typical
PME syndrome due to Unverticht-Lundborg disease,
sialidosis, or some other cause. Celiac disease has been
observed in association with PMA [28). Progression is
central to the concept of the PMAs, to distinguish
them from static myoclonic encephalopathies such as
postanoxic myoclonus (Lance-Adams syndrome).
Treatment of myoclonus in these patients may be
difficult. The deleterious effect of phenytoin was
confirmed. Valproate and the benzodiazepines are
the most effective conventional drugs at present.
Piracetam may also be useful [29). In contrast to the
general principle of monotherapy in epilepsy, polytherapy may produce additional benefit in the treatment of severe rnyoclonus, although drug toxicity
should be carefully avoided 1301. The associated ataxia
has no symptomatic therapy at present. A program of
physical therapy and of social rehabilitation is also very
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progressive, epilepsies, disorder, myoclonus, classification, related
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