Progressive Myoclonic Epilepsy

Progressive Myoclonic EpilepsyDr. Nishtha JainSenior ResidentDepartment of NeurologyGMC, Kota.

The syndrome of PME consists of myoclonic seizures, tonicclonic seizures, and progressive neurologic dysfunction, particularly ataxia and dementia.

Onset - Any age (usually in late childhood or adolescence).

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

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.

Lafora Body DiseaseThe characteristics of LBD include:

generalized tonicclonic 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.

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 tonicclonic 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.

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.

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.

Brain biopsy - neuronal intracytoplasmic basophilic, round to oval bodies, which were periodic acidSchiff (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.

ManagementSymptomatic 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

Neuronal Ceroid Lipofuscinosisautosomal 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-Bielschowsky disease; Juvenile NCL (type 3), Spielmeyer-Vogt-Sjogren disease, or Batten disease; Adult NCL (type 4), Kufs disease, or Parry disease; Late infantile Finnish variant NCL (type 5);Late infantile variant NCL (type 6).

Classic late infantile NCLOnset between 25 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.

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 NCLA variant of late infantile NCLOnset is later, at around age 5 years, and includes symptoms of clumsiness and hypotonia. Followed by visual impairment : 57 years, ataxia : 710 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 78 years.

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

Late infantile variant NCLA 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 57 years and a course that leads to death in the mid twenties.

The associated gene, CLN6, has been mapped to chromosome 15.

Juvenile NCLJuvenile-onset NCL, also known as Batten disease or NCL type 3, starts at age 410 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 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.

Adult NCLAdult NCL (Kufs 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.

Inclusions are also present in the peripheral blood lymphocytes and their morphology correlate with the clinical course and genetic analysis

(1) infantile NCLgranular bodies/GRODs, (2) late infantile NCLcurvilinear bodies, (3) juvenile NCLfinger print bodies, and(4) adult onset NCL with varied forms and combination of inclusions.

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.

Myoclonic Epilepsy with Ragged-red FibersMultisytemic 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

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.

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.

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.

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 (100200 mg three times a day) and L carnitine(1,000 mg daily) - improve mitochondrial function.

UnverrichtLundborg Diseaseautosomal 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.

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 lysosomes.

Levels of cystatin B in affected individuals are only 5%10% of normal, and cathepsin levels are significantly increased.

EEG - diffuse slow background activity and generalised high-voltage spike and wave, and polyspike and wave paroxysms, ranging from 23 Hz to 46 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.

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.

SialidosesTwo 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 1020 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.

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.

Dentatorubral-pallidoluysian atrophyRare 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.

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.

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.

Rare causes of PMEAction-myoclonus renal-failure syndromeJuvenile form of Huntingtons diseaseFamilial encephalopathy with neuroserpin inclusion bodiesNon-infantile neuronopathic Gauchers disease,Atypical inclusion body disease,Neuraxonal dystrophy,Coeliac disease,Juvenile GM2 gangliosidosis,Hallervorden-Spatz disease, andEarly onset Alzheimers disease

Non-Infantile Neuronopathic GauchersDiseaseMost 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 tonicclonic seizures, dementia, ataxia, and spasticity.

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.

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

Action MyoclonusRenal FailureSyndromeautosomal-recessive disordera 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.

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.

Autosomal-Recessive ProgressiveMyoclonus Epilepsy-Ataxia Syndromeage of onset with ataxia at 45 years.

Myoclonus starts at 510 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.

Juvenile Form of Huntingtons DiseaseOnset 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 46 years after the onset.

Familial Encephalopathy withNeuroserpin Inclusion Bodiescan 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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