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![Relationship
between
myoclonus
and epilepsy
[Prichard]
1822 1903
Cases of
Myoclonic
Epilepsies in a
Swedish
Family
[Lundborg]
Familiare’
Myoclonie
[Unvericcht]
1891](https://image.slidesharecdn.com/progressivemyoclonicepilepsies-231113095254-6b0659b9/85/Progressive-Myoclonic-Epilepsies-pptx-6-320.jpg)
![Relationship
between
myoclonus
and epilepsy
[Prichard]
1822 1903
Cases of
Myoclonic
Epilepsies in a
Swedish
Family
[Lundborg]
Familiare’
Myoclonie
[Unvericcht]
1891 1911
Myoclonic
corpuscles
[Lafora]
1921
Ramsay Hunt
Syndrome
[Hunt]
Impulsive
Petit Mal
[Janz]
1957 1990
First
classification
[Marsielle
Group]](https://image.slidesharecdn.com/progressivemyoclonicepilepsies-231113095254-6b0659b9/85/Progressive-Myoclonic-Epilepsies-pptx-8-320.jpg)
![Siladosis
[NEU1]
1989
Infantile NCL
[CLN1]
1995
ULD
[CYSTATINB1]
1996
Lafora Disease
[EPM2A]
1998
Action
myoclonus
renal failure
2008
MERRF
1990
Genes related to PME in the order of their discovery](https://image.slidesharecdn.com/progressivemyoclonicepilepsies-231113095254-6b0659b9/85/Progressive-Myoclonic-Epilepsies-pptx-9-320.jpg)
![Natural history
• Mean disease onset 13.4 years (4-30)
• Onset – Seizures (60%), Myoclonus/ cerebellar signs (25%),
Cognitive (14%)
• Visual symptoms (20%) [at any stage]
• Mean age of loss of autonomy 19.4 years (10-42)
• Mean age at death 21.6 years (14-59)
• Mean disease duration -8.2 years (2-40)
• Indian Study – Consanguinity in 73 % (Satishchandra et al, 2010)
Systematic review and meta-analysis of 298
patients, Pondrelli et al, Orphanet J Rare Dis (2021)](https://image.slidesharecdn.com/progressivemyoclonicepilepsies-231113095254-6b0659b9/85/Progressive-Myoclonic-Epilepsies-pptx-23-320.jpg)
![Modern Definition
‘a progressive degenerative disease of the brain and, in most
cases, the retina, in association with intracellular storage of
material that is morphologically characterized as ceroid lipofuscin
or similar’ [William et al, NCL, Oxford Univ Press, p20 2011]](https://image.slidesharecdn.com/progressivemyoclonicepilepsies-231113095254-6b0659b9/85/Progressive-Myoclonic-Epilepsies-pptx-34-320.jpg)
![Adult forms of NCL
Clinical Presentation
CLN4 [Manifest – 30 years (23-40)] Kuf Type A : Marked myoclonus,
progressive epilepsy, dementia and
ataxia
Kuf Type B: Behavioral changes,
dementia, Facial dyskinesia
Vision not impaired
CLN11 [Mean onset 22 years] Rapidly progressive vision loss,
seizures, cerebellar ataxia and
cerebellar atrophy on imaging
CLN13 [Mean onset 20 years] Kuf type B like presentation
Extrapyramidal and bulbar
involvement can be there](https://image.slidesharecdn.com/progressivemyoclonicepilepsies-231113095254-6b0659b9/85/Progressive-Myoclonic-Epilepsies-pptx-38-320.jpg)
![When to suspect NCL
Developmental regression affecting infants and children
Refractory epilepsy plus neurologic symptoms at any age
Vision loss (especially retinopathy) plus neurologic symptoms at any age
[Adult forms – Vision not affected]
Progressive ataxia with cerebellar atrophy at any age](https://image.slidesharecdn.com/progressivemyoclonicepilepsies-231113095254-6b0659b9/85/Progressive-Myoclonic-Epilepsies-pptx-39-320.jpg)
![Natural history
• Onset is usually childhood/ late childhood
• Adult onset is also known (as late as 67 years) [Hirano et al, Adv in Neurol, 2012]
• Age of onset may be different among family members
• 50% family history +
• Myoclonus and epilepsy – onset 100%
• Ataxia – 83 %
• Hearing loss, peripheral neuropathy, cognitive decay, short stature
>50%
• <50 %- Cardiomyopathy, pigmentary retinopathy, ophthalmoparesis](https://image.slidesharecdn.com/progressivemyoclonicepilepsies-231113095254-6b0659b9/85/Progressive-Myoclonic-Epilepsies-pptx-49-320.jpg)
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Progressive Myoclonic Epilepsies.pptx
- 1. Progressive Myoclonic Epilepsies Dr AdityaNayan SR Neurology Moderator Dr Jitupam Baishya AP, Department of Neurology, PGIMER
- 2. Contents • Introduction • Historyof Progressive Myoclonic Epilepsies • Electrophysiology in PME • Few important PMEs • Approach to PME • Drugs in PME including the frontiers
- 3. • PMEs arerare and comprised of heterogenous group of underlying genetic etiologies recognized in the presence of 1. Myoclonus 2. Progressive motor and cognitive impairment 3. Sensory and cerebellar signs 4. Abnormal background EEG slowing 5. May appear in individuals with prior normal development and cognition Riney K et al, ILAE 2022
- 4. The spectrum ofPME • Unverricht Lundborg Disease • Lafora body disease • MERRF • NCL • Sialidosis Type 1 • Action myoclonus renal failure syndrome • PRICKLE1 related PME • ‘North sea’ PME • DRPLA • Tay Sach’s disease • Gaucher’s disease • Neuroserpinosis • GOSR2 related PME • KCDT7 related PME • SMA-PME • KCNC1 mutation • AD cortical tremor, myoclonus and epilepsy • And the list is growing…
- 5.
- 6. Relationship between myoclonus and epilepsy [Prichard] 1822 1903 Casesof Myoclonic Epilepsies in a Swedish Family [Lundborg] Familiare’ Myoclonie [Unvericcht] 1891
- 8. Relationship between myoclonus and epilepsy [Prichard] 1822 1903 Casesof Myoclonic Epilepsies in a Swedish Family [Lundborg] Familiare’ Myoclonie [Unvericcht] 1891 1911 Myoclonic corpuscles [Lafora] 1921 Ramsay Hunt Syndrome [Hunt] Impulsive Petit Mal [Janz] 1957 1990 First classification [Marsielle Group]
- 9. Siladosis [NEU1] 1989 Infantile NCL [CLN1] 1995 ULD [CYSTATINB1] 1996 Lafora Disease [EPM2A] 1998 Action myoclonus renalfailure 2008 MERRF 1990 Genes related to PME in the order of their discovery
- 10. Myoclonus in PME •Brief (20-50) ms contraction/ sudden cessation of tonic muscle activity • Myoclonus – Usually Cortical > Subcortical in origin • In PME – Both negative and positive myoclonus may be seen • Epileptic myoclonus – Due to descending neuronal firing of action potentials
- 11. Electrophysiology • EEG activitymay precede 10-40 ms the EMG activity • Techniques – Scalp EEG (Least sensitive) Jerk- locked time back Averaging Somato-sensory evoked potential
- 12. Seizures in PMEs Maintypes – Absence, GTCS, Tonic, Atonic, head drops (seen in Lafora Body disease) Excitatory/Inhibitory circuitry mismatch between the pyramidal cells and Thalamo- cortical relay cells Epileptic disord, Vol. 18, 2016
- 13. EEG in PMEs •Polyspikes, polyspikes and waves, spike and wave, multifocal spike and wave • Slow background with evolving disease • Photosensitivity at low frequency (except LBD- may show high frequency)
- 14.
- 15.
- 16. Chromosome 21q22.3 CSTB gene CystatinB Protease/ Cathepsin Unstable dodecamer expansion repeat Missense Nonsense Frame-shift Splice-site Normal 2-3 Full penetrance - >30 repeats
- 17. Myoclonus Seizures Cognitive decline Onset 10-13 yearsAfter 5-10 years Increase by months to a year, Violent, ‘Cascade seizures’, Reflex, Periodicity Major type – GTCS, abate by later adulthood Male = Female Very mild cognitive decline Highest incidence in Finland, Arab and Mediterranean countries India - Sporadic
- 18. Literature Review Study YearPatients Major Findings Finnish study (Hypponen et al) 2015 66 Age of onset and disease duration correlated with myoclonus severity; Higher number of dodecamer repeats – younger age of onset Finnish study (Sipila et al) 2020 135 Mean age to lose ability to walk was 34 (12-64)years, wheel chair bound – 35 (12-67) years, mean age of death 53 (23-63) Indian study (Sinha et al) 2010 9 (not genetically confirmed) Mean age of onset -13 years, mean duration of illness 4.1 years, neuroimaging – diffuse cortical, cerebellar and brainstem atrophy
- 19. Suspicion Diagnosis Confirmation EEGwith EMG Diffuse background slowing with spike, polyspikes and waves Photosensitivity + - abate by years Progressive impairment of sleep EEG EMG may not correlated with EEG Any patient with adolescent onset ‘drug refractory’ myoclonus with near normal cognition Demonstration of both alleles of pathogenic EPM1 gene
- 20.
- 21. Lafora Body Disease •Severe autosomal recessive progressive myoclonic epilepsy • More frequent in Mediterranean countries, North America, Middle east
- 22. Genetics • More than200 causative mutations involving EPM2A (Ch624) and EPM2B(6p22.3) EPM2A EPM2B Laforin Malin Glycogen Metabolism Accumulation of polyglucan in Brain, Liver, Skin, Muscle
- 23. Natural history • Meandisease onset 13.4 years (4-30) • Onset – Seizures (60%), Myoclonus/ cerebellar signs (25%), Cognitive (14%) • Visual symptoms (20%) [at any stage] • Mean age of loss of autonomy 19.4 years (10-42) • Mean age at death 21.6 years (14-59) • Mean disease duration -8.2 years (2-40) • Indian Study – Consanguinity in 73 % (Satishchandra et al, 2010) Systematic review and meta-analysis of 298 patients, Pondrelli et al, Orphanet J Rare Dis (2021)
- 24. Myoclonus Seizures Cognitive decline Onset 10-13 yearsDuration 20-23 years Myoclonus – Fragmentary and assymetric at rest, violent and shaking at action and reflex Seizures – GTCS, Visually evoked seizures, Tonic, Head Drop + Male = Female Prominent cognitive decline
- 25. Case Vignette • 20year girl with no family history • Onset of myoclonic jerks since 15 years age • Imbalance while walking since 16 years age • 1 GTCS – at 17 years age • Scholastic decline past 3 years • Currently bed ridden with frequent myoclonus and severe ataxia • EEG – Slowing of background with intermittent polyspikes
- 26. Axillary sweat glandbiopsy showing PAS positive diastase resistant intracytoplasmic inclusion bodies which are round to oval shaped (S-26258/2019) Courtsey- Dr Debajyoti Chatterjee, AP, Histopathology, PGIMER
- 27. Skin Biopsy –Axillary sweat gland • PAS Positive intracytoplasmic inclusion bodies • Also present in • Normal Aging • Type IV Glycogen Storage disorder • Arylsulfatase A deficiency • Amyotrophic Lateral Sclerosis
- 29. Treatment Mainstay Valproate Others Topiramate,Ethosuximide, Phenobarbital, Zonisamide Recent Perampanel Case studies of 10 patients (2016) Non pharmacological VNS Termination of GTCS in 2 studies Ketogenic diet Ineffective Orphan Designation Metformin European Commission 2016 Sodium selenate Animal data Gentamicin Animal Data
- 30. Frontiers • Gene replacementusing AAV • Alpha – amylase – Degradation of accumulations • Intrathecally delivered anti-sense oligonucleotide
- 31.
- 32. Group of lysosomalstorage disorders characterised by progressive neurodegeneration and intracellular accumulation of auto fluorescent lipopigament Infantile NCL Late infantile LCL Juvenile NCL Adult NCL Haltia Sanaturi Disease Jansky Bielschowsky disease Batten’s disease Kuf’s disease Granular osmophilic deposits Curvilinear profiles Fingerprint bodies Rectilinear profiles
- 33.
- 34. Modern Definition ‘a progressivedegenerative disease of the brain and, in most cases, the retina, in association with intracellular storage of material that is morphologically characterized as ceroid lipofuscin or similar’ [William et al, NCL, Oxford Univ Press, p20 2011]
- 35. New Classification Scheme •Axis 1 – Affected gene (using CLN gene symbol) • Axis 2 – Mutation diagnosis • Axis 3 – Biochemical Phenotype • Axis 4 – Clinical Phenotype • Axis 5 – Ultrastructural features • Axis 6 – Functionality • Axis 7 – Other remarks Williams et al, New Nomenclature and Classification Scheme for the NCL, Neurology 2012
- 36. Phenotype Age ofonset Gene Chromosome Protein Ultrastructure CLN1 INFANTILE PPT1 1p32 PPT1 GRODS CLN2 LATE INFANTILE TPP1 11p15 TPP1 Curvilinear profile CLN3 LATE INFANTILE CLN3 16p12 Lysosomal transmembrane protein Fingerprint bodies CLN4 Adult DNAJC5 20q13.33 Cysteine string protein Rectillinear profiles CLN5 Late infantile CLN5 15q21 ER transmembrane protein R, C, F CLN7 Late infantile MFSD8 4q28 Lysosomal membrane protein Fingerprint profile CLN8 Late infantile CLN8 8q23 Transmembrane ER Cuvillinear CLN9 Not confirmed CLN10 Congenital CTSD 11p15 CathepsinD GRODS
- 37. Phenotype Age ofonset Gene Chromosome Protein Ultrastructure CLN11 Adult GRN 17q21 Progranulin Fingerprint bodies CLN12 Juvenille ATP13A2 1p36 Kufor Rakeb Syndrome Whorled lamellar inclusions CLN13 Adult (Kuf type B) CTSF 11q13 Cathepsin F Fingerprint profiles CLN14 Infantile KCTD7 7q11 Potassium Channel Variable
- 38. Adult forms ofNCL Clinical Presentation CLN4 [Manifest – 30 years (23-40)] Kuf Type A : Marked myoclonus, progressive epilepsy, dementia and ataxia Kuf Type B: Behavioral changes, dementia, Facial dyskinesia Vision not impaired CLN11 [Mean onset 22 years] Rapidly progressive vision loss, seizures, cerebellar ataxia and cerebellar atrophy on imaging CLN13 [Mean onset 20 years] Kuf type B like presentation Extrapyramidal and bulbar involvement can be there
- 39. When to suspectNCL Developmental regression affecting infants and children Refractory epilepsy plus neurologic symptoms at any age Vision loss (especially retinopathy) plus neurologic symptoms at any age [Adult forms – Vision not affected] Progressive ataxia with cerebellar atrophy at any age
- 40. Diagnosis • Not specificor sensitive, but for monitoring • DTI – Disorganisation of white matter tracts • Diffuse cortical atrophy, periventricular gliosis • Thalamic T2 hypo intensity (in few adult forms) • Generalised slowing of background EEG • Slow frequency photic stimulation- evoked response • Giant SSEP Konrad et al, IJMS, 2022 • Demonstration of inclusion bodies by electron microscope in tissues – Brain, Skin, Muscle. Peripheral nerves IMAGING ELECTROPHYSIOLOGY HISTOPATHOLOGICAL EXAMINATION
- 41. TREATMENT of CLN2 •Human recombinant proenzyme of TPP1 • Approved in 2017 • Intraventricular biweekly infusion • 150 mg – 55-6k INR
- 42. Chromosome 6p21.3 (NEU1) Neuraminidase Point mutations canlead to development of syndrome Breakdown of complex macromolecules in the lysosomes Normomorphic Dysmorphic Sialidosis 1 Sialidosis 2 Sialidosis
- 43. Natural History • Meanage of onset – 16 ± 6.7 years • Most common symptom – Myoclonic seizures (95%) • Second most common symptom – Ataxia (93%) • Diminishment of vision – 63% • Other features – Dysarthria, dysphagia, hearing loss, GTCS • Very slowly progressive • Mild cognitive impairment Analysis of 77 patients, Ann Clin Trans Med, 2020
- 44. • Pathophysiology –Loss of transparency (opacification) of inner retina – absent at the macula Cherry Red Spot seen in 48-50 % patients only
- 45. Investigations Imaging Electrophysiology Confirmation MRIof brain may show cerebellar hemispheric, vermian and peduncular atrophy SEP- Demonstration of cortical myoclonus EEG Increased urinary excretion of bound sialic acid residues Neuraminidase deficiency in cultured fibroblasts Demonstration of genetic defects
- 46. Myoclonic epilepsy in mitochondrialdisorders
- 47. • Epilepsy inmitochondrial diseases – exact prevalence not known • 50-60% refractory epilepsy patients – mitochondrial biochemical abnormality (Parikh et al, Cleveland Clinic, 2008) • 80% - Other manifestations before onset of seizure (El Sabbagh et al, Epilepsia 2010) MERRF (Myoclonic epilepsy with red ragged fibres) AHC (Alpers- Huttenlocher syndrome)
- 48. MERRF • First welldefined disease in which maternal inheritance was demonstrated (Rosing et al, 1985) • Most frequent mutation – mt tRNA m.8344A>G mutation Folbergrová J, Kunz WS. Mitochondrial dysfunction in epilepsy Mitochondrion. 2012;12(1):35-40
- 49. Natural history • Onsetis usually childhood/ late childhood • Adult onset is also known (as late as 67 years) [Hirano et al, Adv in Neurol, 2012] • Age of onset may be different among family members • 50% family history + • Myoclonus and epilepsy – onset 100% • Ataxia – 83 % • Hearing loss, peripheral neuropathy, cognitive decay, short stature >50% • <50 %- Cardiomyopathy, pigmentary retinopathy, ophthalmoparesis
- 50. Symmetrical paramedian/ medianlipomas SR Chandra et al, JPGM, 2015
- 52.
- 53. Neuroserpinosis AD Variableonset PME with frontal predominant cognitive decline GOSR2 AD 1 year Ataxia at onset, seizures late, cognition preserved, pes cavus and scoliosis KCDT7 AR 5 months – 3 years Normal development f/b mental and motor regression f/b stabilisation SMA-PME AD 2.5-6 years LMN quadriparesis with PME Action myoclonus – renal failure syndrome AR Late teens/ early 20 Simultaneous onset of myoclonus and renal failure
- 54. • 32 yearmale • GTCS since 12 years age • Gait imbalance and cerebellar speech since 25 years age • Multifocal myoclonic jerks – 30 years age • Fronto- temporal cognitive decline R Singh, MK Goyal, BMJ Case Rep 2017
- 55. • EEG –Normal background with intermittent polyspikes • Mild cerebellar atrophy in MRI Brain • Bone marrow biopsy – • Gaucher’s disease
- 56.
- 57. Patients with PME Laforabody disease NCL ULD MERRF TSD Early Dementia Visual failure Occipital Seizures Early second decade Severe Dementia Retinal degeneration Optic atrophy 1st Decade Ataxia Myoclonus Normal cognition 1st/2nd decade Myoclonus Deafness Neuropathy Retinitis Pigmentosa Startle Myoclonus Cherry Red Spot 1st two year Giant SSEP Photosensitive (HF) Giant SSEP Photosensitive (LF) Giant SSEP Neuorpathy Absent VEP Pathological Biochemical Skin LBD NCL (EM) Liver LBD TSD Muscle MERRF LBD NCL Brain LBD NCL TSD Step 1: Clinical Step 2: Electrophysiology Step 3: Final Diagnosis Genetic analysis Adapted from protocol followed in NIMHANS, Published in Neurology India, 2010
- 58.
- 59. First line Secondline Third Line Emergency treatment Valproate Zonisamide 5 hydroxy L tryptophan Benzodiazepines Clonazepam Levetiracetam Lamotrigine Levetiracetam Topiramate NAC Valproate Piracetam VNS/DBS Phenytoin Phenobarbital Brivacetam Perampanel Experimental Drugs Also used- Vit E, Baclofen, Ropinirole, Ethosuximide, Alcohol
- 60. Potentially aggravating Usedwith caution Not documented Phenytoin Lamotrigine Lacosamide Carbamazepine Valproate to MERRF Felbamate Oxcarbazepine Rufinamide Vigabatrin Ethosuximide Gabapentin Eslicarbazepine Pregabalin Tiagabine
- 61. Post Modern Therapeutic approachesfor PME Single gene associated diseases – A cure may be possible !
- 62.
- 63. Take home message •Identify myoclonus and myoclonic epilepsy • Look for cognitive decline and ataxia in the patients • Family history – Important ! • Don’t forget the fundus • Remembers the drugs which exacerbate the seizures • If Valproate deteriorates clinical picture – think mitochondrial !
- 64.
Editor's Notes
- #7 Heinriccht Unvericht – 2 families in Estonia
- #9 Ramsay described - independently
- #11 Cortical myoclonus – affects distal extremities and face – largest representation in the cortex Sub-cortical myoclonus – Segmental (palatal)/ Non segmental – brainstem – startle response and reticular reflex
- #12 Bereitschaftspotentials
- #13 Schematic diagram of neuronal substrates involved in generalized seizures [22]. The key neuronal ensembles consist of the pyramidal cells (PC) and interneurons (IN) in the cortex and the thalamocortical relay cells (TC) and nucleus retularis thalami cells (NRT) in the thalamus. The model involves two dependent inhibitory neural populations IN1 and IN2 which are mediated by the fast and slow time scales of the inhibitory receptors GABA(A) and GABA(B), respectively. Excitatory synaptic connections are shown in red lines with arrows. Inhibitory synaptic connections are shown in green lines with arrows as well as closed circles, where solid and dashed ones represent the fast and slow synaptic function mediated by the GABA(A) and GABA(B), respectively.
- #14 PPR 1 – Occipital 2- Parieto occipital 3- Spreading to frontal 4- Generalised 73 % PME 22 % jme 3-4 % IGE
- #28 Substances with nearby glycol groups or their amino or alkylamino derivatives are oxidized by periodic acid to form dialdehydes, which combine with Schiff reagent to form an insoluble magenta compound
- #30 Progression of electroencephalographic (EEG) changes in a patient with Lafora disease. (A) At the time of disease onset (age 17 years), normal to slightly slowed background activity. (B) Two years later (age 19 years) EEG demonstrates asymmetric generalized spikes and polyspikes, maximum over the anterior regions on a slowed background. (C) At age 20 years, the occurrence of fast (4–6 cycles per second) spike-waves was concomitant with head drops. During the final stages of the disease, EEG recordings show long bursts of diffuse spike-waves and fast polyspikes associated with major volleys or massive myoclonic jerks (D), dramatically enhanced by photic stimulation at low frequency (E).
- #51 Focal seizures in MELAS
- #53 (a)Gomorri'strichrome staining showing ragged red fibers. (b) SDH-COX staining showing COX- deficient fibers. (c) SDH staining - showing ragged blue fibers
- #57 imiglucerase and velaglucerase alfa miglustat and eliglustat Glucocerebrocidase Bone marrow showing histiocytosis with abundant tissue paper-like wrinkled cytoplasm suggestive of Gaucher cells
- #61 Vpa 15 to 60 mg/kg, uld, mitochondrial complex iv Cln – 3-16 mg/day for adults, 6 monthly tolerance Phb – 30-120 mg/day – gtcs, vpa decreases phb elimination – increased somnolence, primidone also used Pirac- double blind placebo controlled trial in 20 uld patients – jerks, 24 g/day- gi intolerance Lev- open label 23 patients uld with myoclonus and jerks Zon- case reports – dramatic improvement upto 6 mg/kg /day laM – vpa increase plasma levels –may increase jerks in uld – not a sensible Brv – failed to reach primary end point with dose 50-150 mg/kg but ai 12 weeks quality of live increased Per – Lafora add on Lhtp – serotonergic hypofunction. Dose upto 2 g/day – transient in 3-7 weeks Nac – uld case report DBS – stn, snpr, vim b/l 50 % reduction
- #64 Small molecules – stabilizes chaperones and the tertiary structures, Tay Sachs ASO – ULD Protein replacement – Amylase in Lafora body