1. MELAS COME PARADIGMA DELLO STROKE-LIKE
Costanza Simoncini
Università di Pisa

2. Monogenic diseases and juvenile ischemic stroke
Dichgans 2007
Terni et al, BBA 2015 2

3. MELAS
MITOCHONDRIAL ENCEPHALOMYOPATHY, LACTIC ACIDOSIS, AND STROKE-LIKE EPISODES
Acute episodes can present at any age with neurological and/or psychiatric symptoms typically associated with cortical/subcortical MRI changes and EEG abnormalities.
Stroke-like: metabolic stroke!
Recurrent stroke-like episodes: mostly posterior lesions
Mutation A3243G tRNA Leu gene but also other tRNA mutations and POLG

4. MELAS clinical features
Stroke-like episodes %
Focal or generalized seizures %
Migraine-like headaches %
Dementia %
Mitochondrial myopathy %
Short stature %
Hypertrophic cardiomyopathy %
PEO %
Diabetes %
Hearing loss %
Family history consistent %
Lactic acidosis %
Thambisetty 2002 4

5. WORKS FROM THE ITALIAN NETWORK

7. MELAS: stroke-like lesions
mitochondrial angiopathy
blood-brain barrier
permeability
toxic effect
of lactic acid pH
vasogenic edema
focal neuronal dysfunction
inability to respond to high
energy demand
seizures

8. MELAS neuroradiological features
right temporo-parietal and thalamic lesions
Spectroscopy: lactate peak in the lesion and in the CSF
DWI
MRI
Migrant injuries: spread slowly (weeks - months from the onset of symptoms) from the temporal cortex to the parietal and occipital cortex
During the episodes:
- Vasodilatation for lactic acidosis (not ischemia!)
- Vasogenic edema 8

9. Selection of take home messages from m.3243 MELAS cases

10. Medical history: hearing loss
MELAS: stroke-like episodes
Atipical case
45 years
ER: episodes of confusion and headache in last 3 weeks, two generalised seizures followed by coma (GCS 5).
family history: negative for neuromuscular or neurodegenerative disorders
Medical history: hearing loss
Brain MRI showed temporal lobes T2 hyperintensity with diffusion restriction and contrast uptake and bilateral temporal lobes T1 hyperintensity. Proton spectroscopy showed a lactate peak with reduction of N-Acetyl-Aspartate.
CSF presented increased proteins, glucose and lactate but not white cells. Increased lactate was also present in serum.

11. Genetic testing showed the 3243A> G mtDNA mutation in urine
2 gr endovenous carnitine and 600 mgs of coenzyme Q10
AEDs, NO ARGININE!!!
Rapid clinical improvement (GCS 13) and regression of the lactic acidosis
A one-month later brain MRI showed regression of cerebral edema and marked lactate reduction
Genetic testing showed the 3243A> G mtDNA mutation in urine

12. Case I take home messages
Poor knowledge in no mito expert setting (not only stroke, but also encephalitys mimic)
Full recovery with carnitene, AEDs and coq, NO ARGININE

13. Case II
Age 20: Migraine, cortical blindness and status epilepticus partial
No family history

14. Age 20: Migraine, cortical blindness and status epilepticus partial
right temporo-parietal and thalamic lesions
Spectroscopy: lactate peak in the lesion and in the CSF
m.15092G>A cyt b p.G116S

15. enisa

16. A C D B

17. Case II take home message
Chraniotomy in selected cases

18. Case III
A 41-year-old woman –teacher- complained of subacute afasia, followed by one focal motor seizure
Clinical and family history both negative

20. Case III Four months after.. m.3243 in urine
Tp: l-arg, coq10, carnitene, riboflavine
and delorazepam, aloperidol, cbz
Four months after..

21. Acute negative symptoms
Acute negative symptoms. Loss of interest in ADL, hypersonnia, negative symptoms, such as depressed mood, loss of interest in activities, psychomotor retardation, refuse of food and liquid, bedridden
Diagnosis: catatonia
Tp: aloperidol, BDZ (lorazepam, delorazepam, diazepam,), promazine
Almost 20 days at the hospital!

23. Case III take home message
Catatonia & psichosis
An alert for psychiatrists

24. Case IV 48-yrs Acute aphasia and partial motor seizures
Mild eyelid ptosis
Previous medical history negative

25. m.3243 in urine
Tp: l-arg, coq10, LEV, cbz
One year after…..

26. Acute visual hallucination
ER-> ophtalmologist (sic) -> discharged at home
Few days after also confusion……

27. Larg ev. LEV, CBZ

28. Case IV take home message
Visual hallucination very typical but: WHO KNOWS??
Stroke like episode driven by SEIZURE activity -> potentially treatable??

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30. MANAGEMENT
There is no specific consensus approach for treating individuals with MELAS syndrome.
All patients suspected to be suffering a stroke-like episode due to underlying mitochondrial disease
should be discussed or referred to a mitochondrial disease specialist in the acute setting.
Monitoring for the development of arrhythmia
Gastroparesis and small bowel intestinal pseudo-obstruction

31. BEYOND NEUROLOGY -cardiopathy -liver imp. -diabetes -lactic acidosis
SNC: stroke like episodes and…
-seizures & myoclonus
-ataxia
-cognitive imp.
-mov. disorders
-optic atrophy
-NSHL
-psycomotor imp. And hallucinations
NEUROMUSCULAR
-PEO
-Exercise intolerance
-Weakness, fatigue, ex.int.
-wasting
-dysphagia
-numbness
-paresthesia
BEYOND NEUROLOGY
-cardiopathy
-liver imp.
-diabetes
-lactic acidosis
As a general hint, the apparently unrelated involvement of two or more tissues should suggest the possibility of mitochondrial disease, including the cases where the family history is unremarkable

32. MANAGEMENT L-Arginine 0.5 g/kg AEDs (no valproic acid) CoQ10
Riboflavin
Creatine
No antiplatelet therapy of fibrinolisis!

33. Thank you