Alternating Hemiplegia

1
U.O. di Neuropsichiatria Infantile Ospedale
Maggiore C.A. Pizzardi Bologna-Italy
Long term neurological outcome in AHCFunctional
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)

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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)

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Ataxia and Hypotonia

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

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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

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Research projectIntroduction

• One of the major and unresolved issue is whether
  AHC is a static encephalopathy or a progressive
  condition.
• To date, there isnt any specific study about
  chronic non paroxysmal neurological disorders in
  AHC

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Research projectAim

• We propose to study the chronic non
• paroxysmal neurological disorders by
• functional neuroimaging.

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What are we looking for?

• Several clinical observation suggest impairment
  of several cortical and subcortical structures in
  patients with Alternating Hemiplegia

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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 tr
emor
Basal ganglia
Attention Disturbances Behavioural
Problems Learning Disabilities Mental Retardation
Frontal cortex Orbitofrontal circuit
Fronto-cerebellar circuit?
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• 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
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• 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.

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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

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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).

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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 studied AHC subjects (Chugani el
  al.2002)

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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

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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.

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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
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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 theres no mention of study with
  fMRI in Patients with Alternating Hemiplegia

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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.

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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.

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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.

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

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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 patients main
  chronic disorder (dystonia? basal ganglia).

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Research project

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

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Results

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

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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