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Integration Lecture
Neurology Week 4 Unit Week 8
What we have learned…
Recall: Embryology of the Nervous
System
1.
2.
3.
4.
5.
6.
7.
Neural plate
Neural tube
Flexures (eg:
cephalic)
Forebrain, midbrain,
hindbrain vesicles
Forebrain
“outgrowths”
laterally into
hemispheres
C-shaped cortex
Folding (gyri & sulci)
Dorsal Induction
(Neural Tube
Defects)
Ventral Induction
Cell Migration
Dr. Heather MacLean
Disorders of Neural Tube
Formation
Spina Bifida +/- Chiari Malformation
Anencephaly
Spina Bifida
Disorders of Cell Migration
Lissencephaly
Heterotopic Gray Matter
The Motor System Puzzle Finally Has
All its Pieces!…
Piecing Together Motor system puzzle
Cerebellar clinical
Ipsilateral ataxia
hypotonia
Upper Motor Neurons
Cerebellar circuits
(direct : Corticospinal
and indirect: reticulo-, rubro- ,
tecto- , vestibulo-)
UMN clinical syndrome
Spastic paresis (pattern)
Hypereflexia, Babinski
Basal ganglia
LMN clinical syndrome
Lower Motor Neurons
Basal Ganglia Clinical
1. Hypokinetic:
parkinsonian
2. Hyperkinetic: chorea,
tic, dystonia, etc
Brainstem motor nuclei
Spinal Anterior Horn cells
Atrophy, hypotonic paresis
Hyporeflexia, fasciculations
Mostly similar to LMN
NMJ , muscle
Important specific features
e.g: no fasciculations
MG:Fatigue, oculo-bulbar
Muscular Dystrophy: patterns
Overview of the motor system
Direct Path
Indirect Path
Cerebellar
Circuit
BG Circuit
Upper and Lower Motor neurons
UMN Syndrome vs. LMN Syndrome
UMN Syndome
weakness
muscle bulk
fasciculations
muscle tone
stretch reflexes
clonus
plantar reflex
yes
normal
none
LMN Syndrome
yes
wasting
Increased/
spasticity
yes
decreased
hyperactive
hypoactive
present
upgoing (Babinski)
absent
downgoing
Spasticity

One part of the Upper Motor Neuron Syndrome

Velocity dependant increase to passive stretch (tone) of
muscle

Often clasp knife phenomenom

Often unidirectional, ie extensors OR flexors

Associated with increased stretch reflexes, muscle spasms,
increased cutaneous reflexes
Can you pick out the UMN and the LMN
disorders ?
ALS
Parkinson’s
not directly an UMN disorder
!
Ant spinal infarct
MCA stroke
Spinal muscular atrophy
Occipital stroke
Diabetic
Sensorimotor polyneurop.
Epidural hematoma
We learned to localize basal ganglia
Caudate
Putamen
G. Pallidus
(Thalamus)
Parkinson’s Disease : TRAP + …
Tremor
Rigidity
Akinesia / bradyk
Post. Instab.
Depression
Psychiatric
Dysautonomia
Cognitive / dementia
Sleep Disorders
Rigidity


An “extra-pyramidal” sign
Increased tone to passive movement that is NOT
velocity-dependent



All directions of movement
Often association with tremor


Lead-pipe
Hence a cogwheeling component to the rigidity
And often associated with bradykinesia and
postural instability
We “marveled” at the complex circuitry:
BG modulate motor system
Cortical
Dopamine +
Striato
Thalamo
Pallido
Substantia Nigra comp
We met the key neurotransmitter relevant to
Parkinson’s Disease: Dopamine
LDopa  Dopamine
Nigro-striatal pathway
Both inhibitory and excitatory (it depends … net
effect is a boost for movement !)
Complicated loops: serial inhibitions … net
output from basal ganglia is inhibition of
thalamus !
Sinemet
Boosting Dopamine stimulation
A pharmacologist’s dream !
Ldopa-Cdopa
Carbi Dopa – doesn’t enter CNS
Dopamine
L Dopa
periphery
Blood brain barrier
CNS
Decarboxylase
L Dopa
Picked up by SN
neurons
Dopamine
Destroyed
by COMT
Dopamine receptors
on striatal neurons
Destroyed
by MAO
Dopamine agonists:
Pramipexole, ropirinole
COMT inhibitor
entacapone
MAO inhibitor
rasagiline
Other Neurotransmitters of Basal Ganglia
• Lots of NT’s in the BG circuits
• (Glutamate, serotonin, GABA, Substance p, somatostatin, enkephalin, cholecystokinin)
• Dopamine vs acetylcholine balance is critical
DOP
ACH
Role of Anti-Cholinergic
Medications to amplify
Dopamine activity
Short term
memory test 
What designer Medication would help a patient with Parkinson’s
1.
2.
3.
4.
COMT enzyme enhancer
Medication Blocking passage of LDopa across Blood Brain Barrier
Medication Blocking Dopa Decarboxylase inside Substantia Nigra Neurons
Medication stimulating striatal neuron dopamine receptors
Clinical case # 1
You are asked to see a 22 year old man who has a 2 year history of rigidity and tremor of
the upper limbs, as well as balance problems. He has become slow getting dressed, eating
and walking.
He and his girlfriend have done some research on Emedicine and they are now convinced
this must be Parkinson’s disease. There is no family history of tremor or any extrapyramidal
disease.
For the past 2 years, he has been followed by a psychiatrist for anxiety and depression.
O/E
• Masked facies, sitting immobile in chair during history
• Asymmetric leadpipe rigidity in arms and legs (L>R)
• Tremor of outstretched hands, rapid and of wide amplitude, disappearing when the hands
are resting on his lap or when he walks
• Normal muscle power, reflexes, sensation
Clinical case #1 questions
1. Do you agree there are features of a Parkinsonian syndrome ?
Yes: Rigidity, akinesia, tremor
2. Is the tremor typical of Parkinson’s Disease ?
No: resting is most typical, though some PD patients also get
a postural tremor
3. Parkinson’s Disease is most unlikely because …
• Age (22 years)
• Asymmetric presentation (left sided rigidity)
• Lack of family history of Parkinson’s
4. “Seeing a psychiatrist for the past 2 years” – What should we
be asking about immediately ?
Medications that could cause a parkinsonian syndrome
e.g. dopamine antagonists, “neuroleptics”
More info …



You find out that he has a sister
with unexplained liver failure !
This leads you to look more
carefully at his eyes and you see
Brown rim in periphery of cornea
this
A proud day in your medical
Recessive Disorder of Copper metabolism
career: you diagnose … Autosomal
• Young onset extrapyramidal disorder (parkinsonian,
flapping tremor) often with psychologic disorders
Wilson’s Disease
• Liver disease
• Kayser-Fleicher rings (copper deposition, cornea)
• Treatable !
• reducing copper intake (zinc)
• chelation (to wash out copper load)
• liver transplantation
Parkinsonism =
Hypokinetic disorder with features of TRAP
Parkinson’s Disease
Outside Parkinson’s Disease, what can cause a parkinsonian
syndrome ?
• Medications (dopamine antagonists)
•
•
•
•
Progressive Supranuclear palsy
Wilson’s disease
Other degenerative diseases: “Multi-system atrophy”, advanced Alzheimer’s
Rare: toxic, vascular, etc
Can you match the descriptions ?
Brief sudden jerk of
the legs when falling asleep
Painful twisting of the head
towards the left shoulder,
occurring several times a
minute; not suppressible
1. Cerebellar ataxia
2. Dystonia
3. Myoclonus
4. Tic (Tourette’s)
Rapid movements of the arms
and fingers, constantly changing,
as well as dancing gait pattern
5. Tardive dyskinesia
Grimacing movements of the face
and tongue in an elderly woman
with history of bad depression
7. Essential tremor
6. Chorea
8. Unit III – anxiety disorder
Mao
???
ALS
Lou Gehrig’s
David Niven
S Hawking?
Sue Rodriguez
Remember the SLM ?
ALS
• Sporadic (90%)
• Asymmetric progressive
• Combined UMN –LMN
• Survival 2-3 yr average
SMA
•
•
•
•
Genetic
Symmetric
Pure LMN
Survival variable
1. Infantile – 1yr
2. Juvenile
3. Adult
Can you figure out the relevant
pathology ?
SMA ALS
Hand intrinsic muscle
Diaphragm :recent denervation
Normal
Condition
Neither: Huntington’s !
NMJ – Can you rapidly localize
1. Ca++ Channels 2.Na+ Channels 3.Acetyl Cholinesterase
Voltage-gated Ca
Channels:
triggers release
of vesicles
Na channels linked to
Ach receptors: depolarize
muscle endplate
Acetyl Cholinesterase
In the folds of synaptic cleft
Myasthenia Gravis
• Fatiguable weakness
• Extraocular, facial, pharyngeal and
proximal muscles, also diaphragm
• Temporary improvement with
acetylcholinesterase inhibitor meds
• Definitive treatment
- steroids, immunosuppressants
- limited role for thymectomy
- all cases of thymoma
- some others: recent onset,
young, generalized / disabling
Can you recognize these muscle diseases ?
Inflammatory myopathy:
Polymyositis, Dermatomyositis
Proximal progressive painless
weakness, high CK
Duchenne Muscular Dystrophy
Childhood onset, X-linked (boys), progressive
Loss of motor milestones, calf hypertrophy
Myotonic Dystrophy
Most common adult onset, AD
Facial, ptosis and Distal limb m
Percussion myotonia, systemic disease:
Cataracts, cognitive, digestive, cardiac conduction !
Clinical case challenge

60 year old man presents with frequent tripping due to progressive
right foot drop. Gradual onset over the past month.
He does have a history of low back pain and “sciatica”
Frequent tingling paresthesia over top of right foot.

O/E (positive findings)






Normal muscle tone, mild atrophy right pretibial muscles
Marked weakness of Right ankle DF, inversion, hip abductors.
Slight relative  pain perception over dorsum of right foot
Normal/symmetrical knee and ankle reflexes, downgoing plantar
responses
Questions
1.
Why are you certain this is not a Left mesial frontal lesion
LMN picture overall: atrophy,  tone, no  reflexes or Babinski
sign
2.
Why are you certain this is not muscle disease
Asymmetric/ distal, presence of sensory symptoms & signs
3.
What is your favored PNS localization
Right L5 radiculopathy
4.
What is your most important diagnostic next step
Imaging (MRI or CT)
Spinal roots, numbering
8 Cervical roots (7 cervical vertebra)
12 Thoracic roots
5 Lumbar roots
5 Sacral
1 Coccygeal
Common radiculopathies:
C5
C6
C7
C8
L4
L5
S1
Cervical spine
straightforward anatomy
C5 root leaves horizontally between C4-5, gets
compressed by C4-5 disk
Note: numbering changes at T1 because there
Are only 7 cervical vertebra but 8 cervical roots !
Lumbar spine
Cauda equina (down-slopping roots)
L5 root leaves under pedicle of L5 (between L5-S1)
Most often compressed by lateral disk at L4-5
With Degenerative Disc Disease, usually disc “A-B”
Affects nerve root “B”, no matter if it is cervical or
lumbosacral with the exception of C7/T1 which
compresses C8