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Progressive myoclonic epilepsy

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progressive myoclonic epilepsy

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Progressive myoclonic epilepsy

  1. 1. Dr. Nishtha Jain Senior Resident Department of Neurology GMC, Kota.
  2. 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. 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. 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.
  5. 5. 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.
  6. 6.  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.
  7. 7.  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.
  8. 8.  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.
  9. 9.  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.
  10. 10. 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
  11. 11. 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.
  12. 12.  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).
  13. 13. 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.
  14. 14.  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.
  15. 15. 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.
  16. 16.  The gene associated with the disease, CLN5, is found almost exclusively in Finland and has been mapped to chromosome 13.
  17. 17. 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.
  18. 18. 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.
  19. 19.  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.
  20. 20. 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.
  21. 21.  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.
  22. 22. 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.
  23. 23. 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
  24. 24.  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.
  25. 25.  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.
  26. 26.  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.
  27. 27.  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.
  28. 28. 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.
  29. 29.  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.
  30. 30.  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.
  31. 31.  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.
  32. 32.  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.
  33. 33. 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.
  34. 34. 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.
  35. 35.  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.
  36. 36.  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.
  37. 37.  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.
  38. 38. 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.
  39. 39.  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.
  40. 40.  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.
  41. 41. 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
  42. 42. 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.
  43. 43.  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.
  44. 44. Treatment  Replacement therapy with high doses of exogenous enzyme, may halt or even reverse neurological progression although the outcome is not always favorable.
  45. 45. 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.
  46. 46.  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.
  47. 47. 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.
  48. 48. 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.
  49. 49. 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.
  50. 50. 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.

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