Dr. Nishtha Jain
Department of Neurology
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
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
-Background slowing on EEG (particularly if increasing
-Myoclonus that is refractory to trials of appropriate
The most important causes of PME include:
Unverricht– Lundborg disease (ULD),
myoclonic epilepsy with ragged-red fiber (MERRF)
Lafora body disease (LBD),
neuronal ceroid lipofuscinoses (NCL),and
Lafora Body Disease
The characteristics of LBD include:
generalized tonic–clonic seizures (GTCS),
resting and action myoclonus,
polyspike and wave discharges in the
basophilic cytoplasmic inclusion bodies in portions of
brain, liver, and skin, as well as the duct cells of the
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
Myoclonus is often fragmentary, asymmetric, arrhythmic, and
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
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
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
Histochemically, Lafora bodies are polyglucosan due to
an error of carbohydrate metabolism.
Symptomatic treatment of myoclonus and epileptic
seizures - valproate and benzodiazepines, usually
clonazepam, and antimyoclonic drugs such as piracetam.
Other drugs - lamotrigine, zonisamide, topiramate, and
Phenytoin, carbamazepine, gabapentin, and vigabatrin
should be avoided.
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.
There are five types of NCL that may cause PME:
Classic late infantile NCL (type 2) or Jansky-
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).
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
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.
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.
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
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
The gene associated with the disease, CLN5, is found
almost exclusively in Finland and has been mapped to
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
The associated gene, CLN6, has been mapped to
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.
Fundoscopy reveals optic atrophy, macular degeneration, and
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.
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
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
Valproate is probably one of the most effective AEDs in
The benzodiazepines (clobazam, clonazepam) and
piracetam have been used with good effect for
Phenobarbitone has also provided some benefit for
prolonged and frequent seizure and for myoclonic status
in advanced disease.
Myoclonic Epilepsy with Ragged-red
Multisytemic mitochondrial syndrome
Typically begins in childhood, but adult onset has been
Clinically characterized by
(2) generalized epilepsy,
(3) ataxia, and
(4) ragged-red fiber in the muscle biopsy
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
Blood levels of lactate at rest are commonly elevated in
Blood leukocyte DNA should be screened for a
mitochondrial DNA point mutation.
MRI may show brain atrophy and basal ganglia
Muscle biopsy can be performed to confirm the
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.
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
Coenzyme Q10 (100–200 mg three times a day) and L
carnitine(1,000 mg daily) - improve mitochondrial
autosomal recessive neurodegenerative disorder that has
the highest incidence among the progressive myoclonus
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.
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.
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.
This protein reduces the activity of enzymes called
cathepsins which help break down certain proteins in the
Levels of cystatin B in affected individuals are only 5%–
10% of normal, and cathepsin levels are significantly
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
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.
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.
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.
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
MRI findings in sialidoses range from normal in the early
stages to cerebellar, pontine, and cerebral atrophy as the
The cherryred spot should be sought when sialidoses is
Diagnosis is confirmed by the detection of high urinary
sialyloligosaccharides and by confirmation of the
lysosomal enzyme deficiency in leucocytes or cultured
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
caused by unstable expansion of CAG repeats of a gene
MRI findings include atrophy of midsaggital structures of
the cerebellum and brain stem, particularly the pontine
There is strong inverse correlation between the age at
diagnosis by MRI and the areas of atrophy in patients
with large expanded CAG repeats.
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
Rare causes of PME
Action-myoclonus renal-failure syndrome
Juvenile form of Huntington’s disease
Familial encephalopathy with neuroserpin inclusion
Non-infantile neuronopathic Gaucher’s disease,
Atypical inclusion body disease,
Juvenile GM2 gangliosidosis,
Hallervorden-Spatz disease, and
Early onset Alzheimer’s disease
Non-Infantile Neuronopathic Gaucher’s
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
Blood tests- pancytopenia and an elevated serum acid
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.
Replacement therapy with high doses of exogenous
enzyme, may halt or even reverse neurological
progression although the outcome is not always
Action Myoclonus–Renal Failure
a distinctive form of PME associated with renal
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
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.
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.
The intellect is usually preserved an neuroimaging
studies are normal.
Caused by a missense mutation in the PRICKLE-1 gene.
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
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.
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.
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