U.O. di Neuropsichiatria Infantile Ospedale Maggiore “ C.A. Pizzardi” Bologna-Italy

1. U.O. di Neuropsichiatria Infantile Ospedale Maggiore “ C.A. Pizzardi” Bologna-Italy Long term neurological outcome in AHC:Functional MRI (Arterial spin labeling-perfusion imaging-ASL-PI) study

2. AHC The Course of the illness • PHASE1: Abnormal ocular movements and dystonic attacks • PHASE 2: Hemiplegic attacks and psychomotor delay/regression. • PHASE 3: persistent/chronic psychomotor delay and chronic non paroxysmal neurological deficits.(Mikati et al 2000)

3. Chronic Neurological Disturbances • Postural Dystonia, Choreoathetosis, Tremor • Ataxia, Hypotonia • Spasticity • Epilepsy • Cognitive impairment • Learning Disabilities • Behavioural Disorder • Psychomotor Delay

4. Postural Dystonia and Choreoathetosis • Frequent • Onset after 2-5 yrs • Variable intensity • Prevented fine hand movements (writing) and gait • Progressive course with successive stabilization (after 2-3 yrs or after 20 yrs of age)

5. Ataxia and Hypotonia • Marked hypotonia more frequent at onset Ataxia • Early or late onset • Mild or moderate degree • Quite significant functional impairment (walking)

6. Spasticity • Rare • Progressive onset • At times replaced marked hypotonia that may be present at onset • Acquired mild hemiparesis on the side most frequently involved by the paroxysmal attack

7. Research projectIntroduction • One of the major and unresolved issue is whether AHC is a static encephalopathy or a progressive condition. • To date, there isn’t any specific study about chronic non paroxysmal neurological disorders in AHC

8. Research projectAim We propose to study the chronic non paroxysmal neurological disorders by functional neuroimaging.

9. What are we looking for? Several clinical observation suggest impairment of several cortical and subcortical structures in patients with Alternating Hemiplegia

10. Alternating Hemiplegia Paroxysmal Oculomotor features (nystagmus and ophtalmoplegia) Autonomic features Sleep EEG pattern (slow waves) Hypothalamus and brainstem nuclei Ataxia and hypotonia cerebellum Paroxysmal and chronic Dystonia Choreoathetosis tremor Basal ganglia Attention Disturbances Behavioural Problems Learning Disabilities Mental Retardation Frontal cortex Orbitofrontal circuit Fronto-cerebellar circuit?

11. Wong et al 1993 suggested that Hemiplegic Attacks could be an intermittent paroxysmal disorder of vascular origin: FRONTAL, PARIETAL, TEMPORAL LOBE: PLEGIA APHASIA DECREASED BLOOD SUPPLY TO THE MIDDLE CEREBRAL ARTERY DECREASED BLOOD SUPPLY TO THE POSTERIOR CEREBRAL ARTERY BASAL GANGLIA: EXTRAPYRAMIDAL SIGNS

12. Since Magnetic Resonance Imaging scans of patients with AHC are normal or not informative/significative, at least at the current resolution level of this technology, further attempts at functional neuroimaging have been made with: • Single-Photonemission Computed Tomography (SPECT); • Positron Emission Tomography (PET); • Magnetic Resonance Spettroscopy.

13. SPECT Conflicting set of data: • Blood flow changes are not always present, while present may be there hyper or hypoperfusion • Different reports of regional or hemispheric blood flow changes anatomically linked or not to the side of hemiplegia. SPECT images were conducted at different stages of hemiplegic attacks and thus cannot be directly compared, so that it is difficult to understand: • Where changes in cerebral blood flow initially occur; • How it evolves both in space and time

14. PET PET offers greater resolution and the potential for measuring local and regional biochemical changes. 2-Deoxy-2[ 18 F]-fluoro-D-glucose (FDG):single or multiple areas of relative hypometabolism suggestive of local or regional damage. Older children were more likely to show discrete areas of hypometabolism as compared to young children (Da Silva, Chugani 1996).

15. PET 11-C-flumazenil (measures BDZ receptor binding): In one patient there was increasing in flumazenil binding in the controlateral hemisphere. (Chugani et al. unpublished data 1997) 11-C--methyltryptophan PET allows regional serotonin synthesis to be estimated (Chaturvedi et al unpublished data 1997). Patients with AHC studied in the ictal or postictal state showed increased serotonin synthesis capacity in the frontoparietal cortex, lateral and medial temporal structures, striatum, and thalamus when compared to controls and interictally studiedAHCsubjects (Chugani el al.2002)

16. MAGNETIC RESONANCE SPETTROSCOPY Magnetic Resonance Spettroscopy has demonstrated consistent metabolic abnormalities indicative of neural damage or dysfunction: • Decreased levels of N-acetyl-aspartate • Abnormally high-level of inorganic phosphate • Decreased phosphocreatine • Low cytosolic phosphorilation • Relatively increased in glutammate and decreased N-acetyl-asportate levels in cerebellum

17. Functional MRI(Blood oxygenation level dependent-BOLD) • The functional MRI locates neural activity by examining regional blood flow in the brain. • In a region of neural activity the supply of oxygenated is greater than its consumption, leading to a higher than normal ratio to deoxygenated blood. • Because the two forms of haemoglobin have different effects on the dephasing of protons they produce different magnetic resonance signals.

18. Functional MRI UNSTIMULATED CONDITION Minimal visual/motor information Little neuron activation Blood flow is not increased Large proportion of deoxyhemoglobin STIMULATED CONDITION Increased visual/motor information Neurons activation Blood flow is increased Decrease of deoxyhaemoglobin WEAK MAGNETIC SIGNAL STRONGER MAGNETIC SIGNAL

19. Why Functional MRI in AHC? • fMRI, like PET scanning, is sensitive to the increased blood flow, which is associated with neural activity • This tecnique has several advantages over PET scanning: - greater spatial and temporal resolution - no injection of foreign material into the bloodstream (fMRI uses endogenous hemoglobin for a marker) • In literature there’s no mention of study with fMRI in Patients with Alternating Hemiplegia

20. Functional MRI • fMRI is an emerging non-invasive methodology which provides various approaches to visualizing regional brain activity. • Although the exact mechanism underlying the coupling between neural function and fMRI signal changes remain unclear, fMRI studies have been successful in confirming task-specific activation in a variety of brain regions, providing converging evidence for functional localization.

21. Functional MRI • In particular, fMRI methods based on Blood Oxygenation Level Dependent (BOLD) contrast and arterial spin labeling (ASL) have enabled imaging of changes in blood oxygenation and cerebral blood flow.

22. Functional MRI While BOLD contrast has been widely used as the surrogate marker of neural activation and can provide reliable information on the neuroanatomy underlying transient sensorimotor and cognitive functions, recent evidence suggests perfusion contrast (ASL-PI) is suitable for studying relatively long term effects on CBF both at rest or during activation.

23. Potential anatomical site or sites of brain dysfunction underlying chronic neurological symptoms in AHC may be identified with these tecniques.

24. Research projectMethods Phase 1 Clinical and data-base evaluation of patient with chronic neurological signs Phase 2 Review of all patients’ structural neuroimaging (MRI); New MRI investigation aimed to a specific cerebral region, depending on patient’s main chronic disorder (dystonia basal ganglia).

25. Research project Phase 3 Study in depth with: perfusion maps (CBF maps) spettroscopy MRI (Hydrogen or Phosphorus). Phase 4 Possible ictal study.

26. Results Phase 1and 2 results are expected in 6 months. Further investigation (depending on phase 1 results) will be developed later.

27. Budget Travelling Meetings Workshop 5.000 US ds Equipment (ASL-PI & MRS) Workstation Silicon Graphic for post processing of Mapping perfusion Max 10.000 US ds TOTAL Max 15.000 US ds