progressive myoclonic epilepsy

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.