This document discusses progressive myoclonus epilepsy (PME), which consists of myoclonic seizures, tonic-clonic seizures, and progressive neurological dysfunction like ataxia and dementia. The main causes of PME include Unverricht-Lundborg disease, myoclonic epilepsy with ragged-red fiber syndrome, Lafora body disease, neuronal ceroid lipofuscinoses, and sialidoses. Each of these disorders is described in detail, outlining their characteristic symptoms, age of onset, genetic basis, diagnostic criteria, management approaches, and other relevant clinical information. Rare causes of PME like dentatorubral-pallidoluysian atrophy and non

1. Dr. Nishtha Jain
Senior Resident
Department of Neurology
GMC, Kota.

2.  The syndrome of PME consists of myoclonic seizures,
tonic–clonic seizures, and progressive neurologic
dysfunction, particularly ataxia and dementia.
 Onset - Any age (usually in late childhood or
adolescence).

3.  Progressive myoclonus epilepsy should considered in a
patient with myoclonic seizures, with or without
generalized convulsive seizures in the following settings:
-Progressive cognitive decline
-Myoclonus resulting in progressive motor impairment
-Cerebellar signs
-Background slowing on EEG (particularly if increasing
over time)
-Myoclonus that is refractory to trials of appropriate
antiseizure medication

4.  The most important causes of PME include:
 Unverricht– Lundborg disease (ULD),
 myoclonic epilepsy with ragged-red fiber (MERRF)
syndrome,
 Lafora body disease (LBD),
 neuronal ceroid lipofuscinoses (NCL),and
 sialidoses.

7. Lafora Body Disease
 The characteristics of LBD include:
 generalized tonic–clonic seizures (GTCS),
 resting and action myoclonus,
 ataxia,
 dementia,
 polyspike and wave discharges in the
electroencephalogram (EEG)
 basophilic cytoplasmic inclusion bodies in portions of
brain, liver, and skin, as well as the duct cells of the
sweat glands.

8.  Autosomal recessive inheritance
 Age of onset between 5 and 20 years
 Death usually within 10 years of onset.
 Characteristically, visual seizures are the first manifestation, followed
by generalized tonic–clonic seizures, absences, or drop attacks.
 Visual seizures present as transient blindness, simple or complex
visual hallucinations.
 Myoclonus is often fragmentary, asymmetric, arrhythmic, and
progressively disabling.

9.  Presence of optic atrophy and retinal degeneration has been
documented but normal retina is usually noted.
 Lafora disease is caused by mutations in one of two genes,
EPM2A and EPM2B- 95% patients.
 EPM2A gene codes for laforin and EPM2B codes for malin.
 The condition tends to progress more slowly in some people
with EPM2B gene mutations than in those with EPM2A gene
mutations.

10.  Imaging of brain - diffuse cortical atrophy with no
obvious parenchymal changes.
 MRS in patients with LBD with no structural MRI
abnormalities: reduction in the N-acetylaspartate
(NAA):creatine ratio and altered NAA:choline, and
choline:creatine ratios in frontal cortex, cerebellum, and
basal ganglia.

12.  Brain biopsy - neuronal intracytoplasmic basophilic,
round to oval bodies, which were periodic acid–Schiff
(PAS)-positive and diastase-resistant.
 Axillary skin biopsies - oval to round PAS-positive,
diastase-resistant Lafora body inclusions in the sweat
glands.
 Histochemically, Lafora bodies are polyglucosan due to
an error of carbohydrate metabolism.

14. Management
 Symptomatic treatment of myoclonus and epileptic
seizures - valproate and benzodiazepines, usually
clonazepam, and antimyoclonic drugs such as piracetam.
 Other drugs - lamotrigine, zonisamide, topiramate, and
levetiracetam.
 Phenytoin, carbamazepine, gabapentin, and vigabatrin
should be avoided.
 Genetic counseling

15. Neuronal Ceroid Lipofuscinosis
 autosomal recessive disease.
 characterized by progressive myoclonus with visual
failure and accumulation of an autofluorescent
lipopigment in the neurons and glial elements.

16.  There are five types of NCL that may cause PME:
 Classic late infantile NCL (type 2) or Jansky-
Bielschowsky disease;
 Juvenile NCL (type 3), Spielmeyer-Vogt-Sjogren
disease, or Batten disease;
 Adult NCL (type 4), Kuf’s disease, or Parry disease;
 Late infantile Finnish variant NCL (type 5);
 Late infantile variant NCL (type 6).

18. Classic late infantile NCL
 Onset between 2·5 and 4 years.
 Myoclonic, tonic-clonic, atonic, and atypical absence
seizures are typically the first manifestation of the
disease.
 Within a few months, ataxia and psychomotor regression
appear, whereas visual failure develops later.
 Dementia and spasticity are relentlessly progressive,
with death occurring about 5 years after onset.

19.  EEG - posterior spikes in response to low-frequency
photic stimulation studies, and the giant visual evoked
potentials with flash stimulation.
 Gene for this disease (TPP1) - chromosome 11- encodes
the protein tripeptidyl peptidase 1 (TPP1).
 Reduced or undetectable TPP1 enzyme activity in
fibroblasts or leucocytes - confirm the diagnosis.

20. Late infantile Finnish variant NCL
 A variant of late infantile NCL
 Onset is later, at around age 5 years, and includes
symptoms of clumsiness and hypotonia.
 Followed by visual impairment : 5–7 years, ataxia : 7–10
years, Myoclonic and tonic-clonic seizures : 8 years of
age.
 Progression is slower.
 EEG is similar to that in NCL type 2, but the substantial
response to photic stimulation develops later, at age 7–8
years.

21.  The gene associated with the disease, CLN5, is found
almost exclusively in Finland and has been mapped to
chromosome 13.

22. Late infantile variant NCL
 A variant of late infantile NCL, sometimes called early
juvenile NCL, Gypsy-Indian late infantile NCL, or NCL
type 6, features an intermediate onset of symptoms at
age 5–7 years and a course that leads to death in the
mid twenties.
 The associated gene, CLN6, has been mapped to
chromosome 15.

23. Juvenile NCL
 Juvenile-onset NCL, also known as Batten disease or NCL
type 3, starts at age 4–10 years with visual failure.
 Dementia and extrapyramidal features develop gradually.
 Most patients are blind by their second decade.
 The most common seizure type is generalised tonic-clonic;
myoclonus is usually subtle.
 Behavioural and psychiatric problems, including psychosis and
hallucinations are common.

24.  Fundoscopy reveals optic atrophy, macular degeneration, and
attenuated vessels.
 Death occurs 8 years after disease onset.
 EEG - slow background with generalised spike and wave.
 Epileptiform abnormalities are accentuated during sleep but
not with photic stimulation.
 The gene associated with this disease, CLN3, is located on
the short arm of chromosome 16.

25. Adult NCL
 Adult NCL (Kuf’s disease, or NCL type 4).
 Myoclonus can first occur as late as age 30 years.
 Dementia, ataxia, and extrapyramidal signs may develop first.
 No ophthalmological abnormalities or visual failure.
 EEG shows generalised fast spike-and-wave discharges with
photosensitivity.
 Genetically heterogenous.

27.  Inclusions are also present in the peripheral blood
lymphocytes and their morphology correlate with the
clinical course and genetic analysis
 (1) infantile NCL—granular bodies/GRODs,
 (2) late infantile NCL—curvilinear bodies,
 (3) juvenile NCL—finger print bodies, and
 (4) adult onset NCL with varied forms and combination of
inclusions.

30. Management
 Valproate is probably one of the most effective AEDs in
the NCLs.
 The benzodiazepines (clobazam, clonazepam) and
piracetam have been used with good effect for
myoclonus.
 Phenobarbitone has also provided some benefit for
prolonged and frequent seizure and for myoclonic status
in advanced disease.

31. Myoclonic Epilepsy with Ragged-red
Fibers
 Multisytemic mitochondrial syndrome
 Typically begins in childhood, but adult onset has been
reported
 Clinically characterized by
(1) myoclonus,
(2) generalized epilepsy,
(3) ataxia, and
(4) ragged-red fiber in the muscle biopsy

32.  Other features of MERRF include peripheral neuropathy,
dementia, deafness and optic atrophy.
 Affected individuals sometimes have short stature and
heart abnormalities, cardiomyopathy.
 Mutations in the MT-TK gene are the most common
cause of MERRF, occurring in more than 80% percent of
the cases.

33.  Blood levels of lactate at rest are commonly elevated in
MERRF patients.
 Blood leukocyte DNA should be screened for a
mitochondrial DNA point mutation.
 MRI may show brain atrophy and basal ganglia
calcifications.

34.  Muscle biopsy can be performed to confirm the
diagnosis.
 Ragged-red fibers on modified Gomori trichrome stain -
hallmark histological feature and a defining criterion.
 In addition, a mosaic pattern of cytochrome oxidase
(COX or complex IV)-deficient fibers is typically seen.

36.  Valproic acid should be avoided as it depletes body
stores of carnitine, a molecule critical for mitochondrial
importation of long-chain fatty acids.
 Aerobic exercise is helpful in MERRF and other
mitochondrial diseases.
 Coenzyme Q10 (100–200 mg three times a day) and L
carnitine(1,000 mg daily) - improve mitochondrial
function.

37. Unverricht–Lundborg Disease
 autosomal recessive neurodegenerative disorder that has
the highest incidence among the progressive myoclonus
epilepsies worldwide.
 between the ages of 6 and 15 years.
 The characteristic feature is myoclonus which increase in
frequency and severity over time and stimulus sensitive.
 GTCS is the other seizure type.

38.  Eventually these patients develop ataxia, depression,
and mild decline in intellectual functioning.
 Patients with ULD typically live into adulthood and the
life expectancy may be normal.
 Mutations in the CSTB gene cause ULD.

39.  The main mutation in CSTB is an unstable expansion of
a dodecamer repeat (CCCCGCCCCGCG) in the 5´
untranslated promoter region.
 The range of normal alleles (repeats) is two to three
copies, but expanded alleles associated with the disease
phenotype contain at least 30 copies.
 The CSTB gene provides instructions for making a
protein called cystatin B.

40.  This protein reduces the activity of enzymes called
cathepsins which help break down certain proteins in the
lysosomes.
 Levels of cystatin B in affected individuals are only 5%–
10% of normal, and cathepsin levels are significantly
increased.

41.  EEG - diffuse slow background activity and generalised
high-voltage spike and wave, and polyspike and wave
paroxysms, ranging from 2–3 Hz to 4–6 Hz, which reach
a maximum anteriorly.
 Photosensitivity is typical.
 MRI of the brain may be normal or can show reduced
bulk of the basis pontis, medulla, and cerebellar
hemispheres.

42. Management
 Pharmacologic intervention includes valproic acid (the
first drug of choice), clonazepam, high doses of
piracetam (for myoclonus), levetiracetam (for myoclonus
and generalized seizures), and topiramate and
zonisamide (as supplements).
 Loud noises and bright lights should be avoided and the
patient should remain in a quiet, peaceful space.

43. Sialidoses
 Two sialidoses are rare causes of PME.
 Sialidoses type I (cherry-red spot myoclonus syndrome) -
caused by deficiency of neuraminidase.
 Juvenile or adult onset
 produces a pure intention and action myoclonus.
 Slow progression and absence of mental deterioration or
dysmorphism are characteristic of the syndrome.
 Gradual visual failure, tonic-clonic seizures, ataxia, and a
characteristic cherry-red spot in the fundus.

44.  Sialidoses type II is caused by a deficiency of both N-
acetyl neuraminidase and -galactosialidase.
 From the neonatal period to the second decade of life.
 Clinical features include coarse facial features, corneal
clouding, hepatomegaly, skeletal dysplasia, and learning
disability in addition to the myoclonus.

45.  EEG background shows low-voltage fast activity, but
slowing can be seen in patients with dementia.
 Massive myoclonus is associated with trains of 10–20
Hz, small, vertex-positive spikes preceding the
electromyographic artefact.
 MRI findings in sialidoses range from normal in the early
stages to cerebellar, pontine, and cerebral atrophy as the
disease progresses.

46.  The cherryred spot should be sought when sialidoses is
suspected clinically.
 Diagnosis is confirmed by the detection of high urinary
sialyloligosaccharides and by confirmation of the
lysosomal enzyme deficiency in leucocytes or cultured
fibroblasts.

49. Dentatorubral-pallidoluysian atrophy
 Rare autosomal-dominant neurodegenerative disorder,
characterised by various combinations of cerebellar
ataxia, choreoathetosis, myoclonus, epilepsy, dementia,
and psychiatric symptoms.
 Three clinical forms: an ataxochoreoathetoid form, a
pseudo- Huntington form, and a PME form.
 Patients with onset before age 20 years often present
with the phenotype of PME, characterised by ataxia,
seizures, myoclonus, and progressive intellectual
deterioration.

50.  caused by unstable expansion of CAG repeats of a gene
at 12p13.31.
 MRI findings include atrophy of midsaggital structures of
the cerebellum and brain stem, particularly the pontine
tegmentum.
 There is strong inverse correlation between the age at
diagnosis by MRI and the areas of atrophy in patients
with large expanded CAG repeats.

51.  However, cerebral white-matter involvement is
associated with the duration of the illness rather than with
the size of the CAG repeats.
 Diagnosis is confirmed by identifying the abnormal CAG
repeats.

54. Rare causes of PME
 Action-myoclonus renal-failure syndrome
 Juvenile form of Huntington’s disease
 Familial encephalopathy with neuroserpin inclusion
bodies
 Non-infantile neuronopathic Gaucher’s disease,
 Atypical inclusion body disease,
 Neuraxonal dystrophy,
 Coeliac disease,
 Juvenile GM2 gangliosidosis,
 Hallervorden-Spatz disease, and
 Early onset Alzheimer’s disease

55. Non-Infantile Neuronopathic Gaucher’s
Disease
 Most common lysosomal storage disorder.
 Characterized by an autosomal recessive inherited deficiency
of the enzyme glucocerebrosidase on ch. 1.
 Classified as type II (early onset and severe) or type III (late
onset and slowly progressive).
 Type IIIA - saccadic horizontal eye movements and
supranuclear gaze palsy with strabismus, myoclonic and
generalized tonic–clonic seizures, dementia, ataxia, and
spasticity.

56.  Blood tests- pancytopenia and an elevated serum acid
phosphatase levels.
 Low leukocyte b-glucocerebrosidase activity.
 EEG - background slowing and bursts of predominantly
posterior or multifocal polyspike-waves, as well as clinical
photosensitivity with myoclonias.
 Poor brainstem auditory evoked potentials.
 Bone marrow aspirate - large cells containing abundant
PAS-positive fibrillary material in the cytoplasm.

58. Treatment
 Replacement therapy with high doses of exogenous
enzyme, may halt or even reverse neurological
progression although the outcome is not always
favorable.

59. Action Myoclonus–Renal Failure
Syndrome
 autosomal-recessive disorder
 a distinctive form of PME associated with renal
dysfunction.
 starts between 17 and 25 years of age with either
neurological or renal symptoms.
 Characterised by tremeors and severe cerebelllar
syndrome with debilitating action myoclonus and ataxia.
 Unlike most PMEs, intellect is remarkably preserved in
this disorder.

60.  caused by mutations in SCARB2/LIMP2 that encodes a
lysosomal membrane protein.
 symptomatic treatment of epilepsy and myoclonus.
 Renal transplantation improves the proteinuria and renal
failure but neurological symptoms progress unaltered
despite this measure.

62. Autosomal-Recessive Progressive
Myoclonus Epilepsy-Ataxia Syndrome
 age of onset with ataxia at 4–5 years.
 Myoclonus starts at 5–10 years with a mean at 7 years.
 Impaired up-gaze.
 The intellect is usually preserved an neuroimaging
studies are normal.
 Caused by a missense mutation in the PRICKLE-1 gene.

63. Juvenile Form of Huntington’s Disease
 Onset is in the first decade, usually after age 3 years,
with loss of acquired psychomotor skills, cerebellar
impairment, and extrapiramidal signs such as rigidity and
dystonic posturing.
 Choreic movements are not seen.
 inherit the disease by paternal transmission of the
abnormal HD gene and tend to have larger CAG
expansions than later onset patients.
 No any specific treatment.
 The prognosis is very poor; death occurring at an
average of 4–6 years after the onset.

64. Familial Encephalopathy with
Neuroserpin Inclusion Bodies
 can manifest both as a PME syndrome or as a presenile
dementia with frontal symptoms.
 onset is between ages 13 and 30.
 autosomal-dominant inheritance and is caused by
mutations in the gene coding for the serine protease
inhibitor (serpin) on chromosome 3.

68. Referrences
 Progressive myoclonic epilepsies: a review of genetic
and therapeutic aspects. S Amre,F Michael,D Norman.
Lancet Neurol 2005; 4: 239–48.
 Progressive myoclonic epilepsies:Definitive and still
undetermined causes.F Silvana et al. Neurology
2014;82:405–411.
 Progressive myoclonic epilepsy. P. Satishchandra, S.
Sinha. Neurology India 2010; Vol 58: Issue 4.
 Atlas of epilepsies. C.P.panayiotopoulos.
 Epilepsy. A comprehensive textbook. Second edition. E
jerome, A P timothy.