Costanza Simoncini Università di Pisa

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

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. Stroke-like episodes100% • Focal or generalized seizures 85-96% • Migraine-like headaches 77-92% • Dementia 65-90% • Mitochondrial myopathy 87-89% • Short stature 55-95% • Hypertrophic cardiomyopathy 7-18% • PEO 13% • Diabetes 21% • Hearing loss 27-75% • Family history consistent 20-86% • Lactic acidosis 94-97% Thambisetty 2002 MELAS clinical features

5. WORKS FROM THE ITALIAN NETWORK

7. MELAS: stroke-like lesions toxic effect of lactic acid mitochondrial angiopathy blood-brain barrier permeability 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

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

10. MELAS: stroke-like episodes Atipical case 45 years ER: episodes of confusionand headachein last 3 weeks, two generalisedseizuresfollowed 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. CSFpresented increased proteins, glucose and lactatebut not white cells. Increased lactatewas also present in serum.

11. A one-month later brain MRI showed regression of cerebral edema and marked lactate reduction Rapid clinical improvement (GCS 13) and regression of the lactic acidosis 2 gr endovenous carnitineand 600 mgs of coenzyme Q10 AEDs, NO ARGININE!!! 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. right temporo-parietal and thalamic lesions Spectroscopy: lactate peak in the lesion and in the CSF Age 20:Migraine, cortical blindness and status epilepticus partial m.15092G>A cyt b p.G116S

15. enisa

16. A B C D

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

21. 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 hallucinationvery typical but: WHO KNOWS?? • Stroke like episode driven by SEIZURE activity -> potentially treatable??

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. 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