A comprehensive overview on progressive myoclonic epilepsies

1. Progressive Myoclonic
Epilepsies
Dr Aditya Nayan
SR Neurology
Moderator
Dr Jitupam Baishya
AP, Department of Neurology, PGIMER

2. Contents
• Introduction
• History of Progressive Myoclonic Epilepsies
• Electrophysiology in PME
• Few important PMEs
• Approach to PME
• Drugs in PME including the frontiers

3. • PMEs are rare 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 of PME
• 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. History of PMEs

6. Relationship
between
myoclonus
and epilepsy
[Prichard]
1822 1903
Cases of
Myoclonic
Epilepsies in a
Swedish
Family
[Lundborg]
Familiare’
Myoclonie
[Unvericcht]
1891

8. 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]

9. 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

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 activity may 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
Main types – 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. Few well characterised PMEs

15. Unverricht-Lundeborg Disease

16. Chromosome 21q22.3
CSTB gene
Cystatin B
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 years After 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 Year Patients 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
EEG with 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. Frontiers

21. Lafora Body Disease
• Severe autosomal recessive progressive myoclonic epilepsy
• More frequent in Mediterranean countries, North America, Middle
east

22. Genetics
• More than 200 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
• 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)

24. Myoclonus
Seizures
Cognitive
decline
Onset 10-13 years Duration 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
• 20 year 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 gland biopsy 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 replacement using AAV
• Alpha – amylase – Degradation of accumulations
• Intrathecally delivered anti-sense oligonucleotide

31. Neuronal Ceroid Lipofuscinosis

32. Group of lysosomal storage 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. Granular
osmophilic
deposits
Curvilinear
profile
Fingerprint
profile
Rectilinear
profiles

34. 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]

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 of onset 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 of onset 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 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

39. 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

40. Diagnosis
• Not specific or 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
can lead to
development of
syndrome
Breakdown of complex
macromolecules in the
lysosomes
Normomorphic
Dysmorphic
Sialidosis 1
Sialidosis 2
Sialidosis

43. Natural History
• Mean age 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
MRI of 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
mitochondrial disorders

47. • Epilepsy in mitochondrial 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 well defined 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
• 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

50. Symmetrical paramedian/ median lipomas
SR Chandra et al, JPGM, 2015

52. Other identified PMEs

53. Neuroserpinosis AD Variable onset 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 year male
• 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. Approach to PMEs

57. Patients with PME
Lafora body 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. Pharmacotherapy in PME

59. First line Second line 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 Used with caution Not documented
Phenytoin Lamotrigine Lacosamide
Carbamazepine Valproate to MERRF Felbamate
Oxcarbazepine Rufinamide
Vigabatrin Ethosuximide
Gabapentin Eslicarbazepine
Pregabalin
Tiagabine

61. Post Modern Therapeutic
approaches for PME
Single gene associated diseases – A cure may be possible !

62. Small
molecules
ASO
Protein
Replacement
CRISPR
Gene therapy

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. Thank You !