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1. PROGRESSIVE MYOCLONIC EPILEPSY
Dr. Sachin Adukia

2. PROGRESSIVE MYOCLONIC EPILEPSY
“group of familial neurodegenerative disorders c/b myoclonus with
epileptic seizures and progressive neurologic decline”

4.  Neurodegenerative, Lysosomal storage disorders
 AR
 Characterized by progressive intellectual and motor deterioration, seizures, and
early death
 Visual loss is a feature of most forms
NEURONAL CEROID-LIPOFUSCINOSES (NCLs)

5.  Types:
 Infantile
 Late-infantile
 Juvenile
 Adult
 Northern epilepsy (or progressive epilepsy with mental retardation)
The most prevalent NCLs are
 CLN3 disease, classic juvenile
 CLN2 disease, classic late infantile

6. CLN3 disease, classic juvenile
 Onset is usually between ages four and ten years.
 Rapidly progressing visual loss resulting in severe visual impairment within
one to two years is often the first clinical sign.
 Epilepsy – GTCS and/or CPS- around age ten years.
 Life expectancy ranges from the late teens to the 30s.

7. CLN2 disease, classic late infantile:
 Age 2-4 years
 Usually starting with epilepsy f/b regression of developmental milestones,
myoclonic ataxia, and pyramidal signs.
 Visual impairment at age four to six years and rapidly progresses to light
/dark awareness only.
 Life expectancy ranges from age six years to early teenage.

8. Adult NCL (ANCL)
 Onset: around age 30 years,
 Death occurs about ten years later.
 Ophthalmologic studies are normal.

9. Histopathology and Ultrastructural Studies
Light microscopy:
PAS and Luxol Fast Blue positive, auto fluorescent intracellular ceroid material, neurons and astrocytes
in the grey matter
Electron Microscopy (skin)
(1) Infantile NCL—granular bodies/GRODs
(2) Late infantile NCL—curvilinear bodies (CV)
(3) Juvenile NCL—finger print bodies (FP)
(4) Adult onset NCL -- varied forms and combination of inclusions
Electron microscopy (Brain)
 Curvilinear , lamellar and electron dense inclusions in neurons, astrocytes and vascular endothelial
cells

10. MRI findings
 Presence of cerebellar/cerebral atrophy, leucoencphalopathy and thalamic
T2W-hypointensity
 I-NCL: leucoencphalopathy and thalamic hypointensity (T2W)
 LI-NCL: periventricular and parieto-occipital hyperintensities
 J-NCL: cerebellar atrophy

12. Treatment
• Lamotrigine (LTG), valproic acid (VPA), clonazepam (CZP)
• Lamotrigine may exacerbate Sz and myoclonus especially in CLN2 disease.
• Benzodiazepines -- benefit for seizures, anxiety, spasticity, and sleep disorders.
• Carbamazepine (CZP) and phenytoin -- may increase seizure activity and
myoclonus

13. LAFORA BODY DISEASE
• Autosomal recessive; stimulus-sensitive PME
• Two genes: Laforin (EPM2A) and Malin (NHLRC1)
• Onset in the late childhood or adolescence
• C/F
• Focal visual occipital seizure
• Myoclonus
• Visual deterioration
• Psychoses
• Rapid intellectual decline with the development of dementia
• Imaging
• Diffuse cortical atrophy without any parenchymal changes

14. Electrophysiology
• EEG background slows, alpha-rhythm and sleep features are lost with
progression, and photosensitivity with fast frequency (>30 Hz)
stimulation
• replete with paroxysms of generalized irregular spike-wave
discharges with occipital predominance and focal, especially
occipital abnormalities
• Giant SSEP, VEP: Enhanced cortical excitability

15. Pathology
• Lafora body inclusions
• Oval to round shaped PAS positive, diastase resistant
• Positive for Lugol’s Iodine and ubiquitin immune-staining
• Inclusions (Lafora bodies) are seen in the cerebral and cerebellar cortex and
in brain stem nuclei
• Inclusions are also seen in other organs including liver, muscle, and skin

16. Treatment
 Valproic acid : controls both GTCS and myoclonic jerks
 Clonazepam - adjunctive
 Zonisamide - both seizures and myoclonus
 piracetam and levetiracetam - add-on treatment

17. UNVERRICHT LUNDBERG DISEASE
(BALTIC MYOCLONIC EPILEPSY)
 neurodegenerative disorder
 Unverricht (1891) & Lundborg (1903)
 AR
 Age of onset: 6-15 yrs
 Most common and Least severe type of progressive myoclonus epilepsy
 Life expectancy may not be affected
 Disability is mainly due to myoclonus, GTCS and ataxia

18. Clinical features
 Action induced and stimulus-sensitive myoclonus
 First in 50% and essential symptom
 Focal or multifocal
 Affect predominantly the proximal muscles of the extremities
 Tonic-clonic epileptic seizures
 Ataxia, in co-ordination, intentional tremor and dysarthria
 No optic atrophy, and there are no long-tract signs

19. Electrophysiology
 background activity varies from normal to mildly slowed
 Marked photosensitive, generalized SW and polyspike-and-wave
paroxysms

21. Pathophysiology
 Defective function of cystatin B, a cysteine protease inhibitor, as a
consequence of mutations in CSTB
 The causative gene, EPM1, localized to chromosome 21q22.3

22. Treatment
• Symptomatic rehabilitative management are the mainstay
• Valproic acid: Drug of choice -- Diminishes myoclonus and freq of generalized
seizures
• Clonazepam: Only drug approved by FDA for myoclonic seizures --add-on
• Levetiracetam : -- effective for both myoclonus and generalized seizures
• Topiramate & zonisamide: Add-on
• High-dose piracetam -- useful in the treatment of myoclonus only

23. • Sodium channel blockers : should be avoided
• (carbamazepine, oxcarbazepine, phenytoin)
• GABA ergic drugs (tiagabine, vigabatrin)
• gabapentin and pregabalin
• May aggravate myoclonus and myoclonic seizures.

24. MYOCLONIC EPILEPSY WITH RAGGED-RED
FIBERS (MERRF)
 Mitochondrial cytopathy
 Mean age at onset 14.6 ± 5.8 years
 Maternal inheritance
 Mutations in the MT-TK gene are the most common cause of MERRF,
occurring in more than 80%

25. Clinical features
 Myoclonus, myopathy and spasticity
 Seizures, ataxia, peripheral neuropathy and dementia
 Deafness and optic atrophy
 Short stature and heart abnormalities, cardiomyopathy
 Lipomas

26. Electrophysiology and Imaging
Electrophysiology
 EEG:
 Slowing of background activity
 Generalized epileptiform discharges
 ENMG:
 Neuropathy and myopathy
 SSEP
 Giant potentials
 Imaging
 Diffuse atrophy of cerebrum, brainstem, and cerebellum
 Basal ganglia calcification

27. Dentato rubral-pallidoluysian atrophy
 AD
 Triplet repeat expansion
 Adoloscent or childhood onset
 Ataxia, choreoathetosis, dementia
 Neuronal loss and gliosis in dentatorubral and pallidoluysian systems

28. Differential diagnosis to PME
 IGE syndrome patients treated with inappropriate AED
 LGS/Symptomatic generalised epilepsy
 Progressive encephalopathies with seizures
(Myoclonus is not the clinical core)
 GM2 gangliosidosis
 Non-ketotic hyperglycinemia
 Niemen pick type C
 Juvenile Huntington’s disease
 Alzheimer's disease

29.  Post anoxic myoclonus- No progression
 Progressive myoclonic ataxia- No evidence of dementia
 Overlaps with spinocerebellar ataxia, celiac disease, whipple disease
 Benign myoclonic epilepsy of childhood and adult hood.
 Benign familial myoclonus

30. PME – Neuro-ophthalmology
PME syndrome
Retinal degeneration/optic atrophy – MERRF
NCL
LBD
Cherry red spot – Neurosialidosis
NCL
With visual symptoms Without visual symptoms
ULD

31. Cherry red spot
Retinitispigmentosa
Optic atrophy

32. PME – Electrophysiology
PME syndrome
ULD
NCL
LBD
Giant SSEP Photosensitivity
LBD (Seizuresat high frequency)
NCL(Seizuresat high frequency)
Neuropathy
MERRF

33. PME – Neuroimaging
PME syndrome
NCL
LBD
Diffuse
atrophy
Bilateral
thalamic
involvement
NCL (T2
hypointensity)
Tay Sach’s
disease(B/L
thalamic
calcification)
Brainstem
atrophy
ULD
DRPLA
WM signal
changes
NCL
Tay Sach’s
disease

34. Flow chart for evaluation of PME

37. Prognosis
 The prognosis of all the PMEs is poor.
 worst prognosis -- the storage disorders (NCL and Lafora), where there is
associated dementia
 somewhat better -- Unverricht-Lundborg disease, can remain ambulant for
many years .
 The prognosis of MERRF -- highly variable; cases with an earlier onset
generally have a more rapid course.

38. References
1. CP Panayiotopoulos. A Clinical Guide to Epileptic Syndrome and their
Treatment. Diseases frequently associated with epileptic seizures. Revised 2nd
edition. London. Springer Healthcare Ltd, 2010; 233-254.
2. Malek N, et al. The progressive myoclonic epilepsies. Pract Neurol
2015;15:164–171.
3. P. Satishchandra, S. Sinha. Progressive myoclonic epilepsy. Neurology India
2010.
4. Franceschetti S,Michelucci R,et al.Progressive myoclonic epilepsies: Definitive
and still undetermined causes. Neurology 2014;82;405-411
5. Shahwan A, Farrell M, Delanty N. Progressive myoclonic epilepsies: a review
of genetic and therapeutic aspects. Lancet Neurol 2005; 4: 239–48

39. THANK YOU