This document discusses progressive myoclonic epilepsy (PME), a group of rare genetic neurological disorders characterized by myoclonus and epileptic seizures with progressive neurological decline. It describes several specific forms of PME, including neuronal ceroid lipofuscinoses (NCLs), Lafora body disease, Unverricht-Lundborg disease, and myoclonic epilepsy with ragged-red fibers. For each, it covers clinical features, genetics, investigations such as EEG and MRI findings, pathology, treatment approaches, and prognosis. The document provides a detailed review and comparison of these progressive myoclonic epilepsy syndromes.

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