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Clinical Questions Neuro Test 2
test review
192
Biology
Professional
04/26/2012

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Term
Why might a lesion to the ventral pallidum be of clinical significance?
Definition
This is the major basal ganglia output of the "Limbic Channel," which is important in regulation of emotions, memory and motivation.

You might see lack of emotion or aggressive behavior, reminiscent of bhFTD

1) VTA/hippocampus/medial temporal cortex/amygdala (in)
2) NA (BG in)
3) Ventral Pallidum (BG out)
4) Mediodorsal N. of thalamus
5) Anterior cingulate/Orbitofrontal/Medial temporal CTX
Term
What is the difference between the function and anatomy of the pre-frontal and high occulomotor channels of the Basal Ganglia?
Definition
Function
1) Pre-frontal- subserve cognitive processes
2) High oculomotor- smooth pursuit and saccades

Anatomy
**both use GPi/SnPr (BG out) and MD/VA (thalamus)
1) Pre-frontal
- Posterior parietal and Pre-motor (input)
- Caudate head (BG in)
- Pre-frontal (CTX)

2) High occulomotor
- Posterior parietal (smooth pursuit) and Prefrontal (saccades) input
- Caudate body (BG in)
- FEF and Supp. EF (CTX)
Term
What is the functional anatomy of the Basal Ganglia channel which underlies hypokinetic and hyperkinetic movements?
Definition
Motor Channel affects descending motor tracts without projecting to periphery

1) S1/M1/Premotor (Input)
2) Putamen (BG-in)
3) Gpi/SNpr (BG-out)
4) VL/VA (thalamus)
5) Premotor/Supp. motor cortex (motor planning)
Term
Why might a lesion to the Ansa Lenticularis be of clinical concern?
Definition
Could disrupt any of the 4 Basal Ganglia channels, affecting affective, cognitive, ocular and/or motor processing.

Remember, the Ansa Lenticularis is one of two output pathways from GPi in the basal ganglia (along with Lenticular Fasciculus, which penetrates the internal capsule).

It runs under the internal capsule on its way to the thalamus.
Term
What is the clinical manifestation of decreased D2 input into the striatum?

What other lesions within the basal ganglia circuitry could cause this?
Definition
Hypokinetic movement (Bradykinesia, Akinesia, Rigidity)
- SNpc lesion
- Gpe lesion
- Ventral thalamus lesion
- lack of D1 signaling

Explanation
1) Decreased D2 means there is less inhibition of the striatum, and more inhibitory signal being sent to the Gpe

2) Since the Gpe is inhibited, it cannot inhibit the STN, which sends excitatory drive to the GPi/SNpr

3) More activity from GPi/SNpr means more inhibition of ventral thalamus and LESS excitation of motor cortex.
Term
A patient presents with velocity-dependent, unidirectional weakness of arm flexers and leg extensors.

What movement disorder is this?
Definition
UMN Spasticity- Hypokinetic rigidity with atrophy due to denervation

Remember, Lead-Pipe and Cog-wheeling Rigidity are velocity-independent and occur without atrophy (PD)
Term
How can differentiating between a resting and intention type tremor assist you in localizing a lesion?
Definition
1) Resting is typically seen in PD, which is SNpc
2) Intention is typically a Cerebellum + Efferent projection issue
Term
How can you distinguish between the 3 types of involuntary jerking movements?
Definition
1) Length of movement
- Chorea>Myoclonus ("burst")

2) Ability to Suppress
- Tick (good)
- Chorea (partial)
- Myoclonus (not)
Term
A patient presents with involuntary movements in their left hand and wrist that "flow from joint to joint."

What 2 other characteristics would you expect to see in this condition?

What is it called in its "violent, proximal form"?
Definition
1) This sounds like Chorea (distal distribution)
- look for motor impersistence (hold out tongue?)
- look for hypotonia

2) Violent, proximal form in hemiballismus (STN)
Term
Why do you see Chorea early in the development of Huntington's?
Definition
Early degeneration of Striatal neurons in the indirect BG tract promote these brief, low -amplitude distal movements.
Term
What does the presence of Chorea tell you about the localization of a lesion?
Definition
Could be caudate (striatum-HD) or STN (hemiballismus)

Also seen in Wilson's
Term
Which cells are vulnerable vs. resistant to degeneration in HD?
Definition
1) medium spiny, projecting neurons that use Enkephalin and Substance P are sensitive

2) large spiny, intrinsic neurons that use ACh and medium spiny, intrinsic neurons that use NO are resistant.
Term
What are the 4 primary pathological processes occurring in HD?
Definition
1) HD Protein (aggregation/intracellular inclusions that soak up t-factors for proteolysis)

2) Mitochondria (calcium handeling and apoptosis)

3) NMDA-mediated, calcium-induced Excitotoxicity

4) Transcriptional deregulation (HDAC inhibitors are used)
Term
Should you test a child of 2 parents with 38 CAG repeats of the polyglutamine tail for HD who is not exhibiting symptoms?
Definition
NO!
# of repeats is important to predict onset (>40 will get it and >60 will get juvenile), but is not relevant for selecting testable population.

You CAN test
1) Symptomatic adults and children
2) Unaffected adults at risk
3) Unborn individuals at risk
Term
How does Juvenile HD differ from Adult-onset?
Definition
10% of cases, all >60 CAG repeats

1) Less Chorea
2) More Bradykinesia (Parkinsonian)
Term
What is the course of degeneration in HD?
Definition
NA is spared!

Mostly in striatum
1) Starts in tail of caudate (ocular BG path)
2) Goes to dorsomedial head (pre-frontal BG path)
3) Spreads to ventrolateral head (pre-frontal BG)
Term
What are the primary clinical features of HD?
Definition
1) Movement-
- Early affect on slow saccades (tail of caudate)
- Chorea
- Late onset of dystonia and bradykinesia

2) Emotional
- Depression may precede chorea
- Pers/behavior changes

3) Cognitive
- Executive function (cortico-striatal-thalamic-cortical(
- Decision making and planning
Term
How would you treat a patient who presents with chorea, dystonia, depression and impaired executive function?
Definition
sounds like Huntington's, so you can only treat symptoms (Chorea and Psychosis).

1) Tetrabenazine (DA depletion)
- block chorea but causes side effects and does not improve overall motor symptoms

2) Neuroleptics (DA-R antagonists)
- Only use for Psychosis
Term
Explain the functional/anatomical organization of the PFC
Definition
Comprised of heteromodal and limbic cortices and acts as neural "buffer between stimulus and response."

1) LPFC- attention, focus and working memory (goal-directed behavior in response to environmental stimuli)

2) MPFC (anterior cingulate)- intentions to actions, reward and error monitoring (highest density of DA-R)

3) OFC- emotional and memory responses to internal/external stimuli (social decorum and inhibition)
Term
Why would a lesion to the mediodorsal thalamic nuclei be of clinical concern?

What symptoms might you observe?
Definition
Subcortical structure shared by all divisions of PFC. Also relevant for high oculomotor path of BG signaling.

- see issues in working memory, social decorum and intention/action transitions.
- see issues with saccades and smooth pursuit.
Term
What is the functional distinction between the posterior and anterior regions of heteromodal cortex?
Definition
1) Posterior PFC primarily involves sensory integration (parietotemporal)

2) Anterior PFC primarily involves reactions to integrated information.
Term
A patient appears awake and alert. However, they exhibit no spontaneous movements or vocal responses, even to noxious stimuli.

What is going on and what could be causing it?
Definition
1) Akinetic mutism- lesion to medial prefrontal cortex (anterior cingulate).

This is an issue with generating motor responses to internal and external sensory signals.

2) Causes include ACA stroke or aneurysm, tumors and degeneration
Term
A patient is impulsive, exhibiting lack of insight and numerous episodes of explosive, socially inappropriate behavior.

What could be going on?
Definition
Likely an Orbitofrontal Cortex issue, which is important for emotional and memory responses (the "internal") to the external environment.

2) Typically caused by TBI, FTD and Herpes encepthalitis
Term
A patient is complaining of an inability to "keep their train of thought." They say that they "cannot even follow a recipe to cook their favorite dish."

What neurological etiology could produce these symptoms?
Definition
Lateral PFC issue- attention, focus and working memory

- basically, regulating behavior in response to environmental stimuli (the "out there"), or "goal-directed behavior" on top-down processing.
Term
A patient is having difficulty with directing attention towards a goal, and later develops more of an issue with stimulus processing.

What is the difference, in terms of neurobiological substrates, between the two processes affected here?
Definition
1) Attention and goal-direct behavior is a "Top down" phenomenon and relies on Bilateral Frontal-Parietal processing

2) Processing incoming stimulus information and reacting to salient points relies on "Bottom-up" processing and relies on non-dominant (right) VLPFC (the "what stream")
Term
A patient is playing a game of chess with you but fails to notice that a piece has gone missing, even when it is perfectly obvious?

What could be going on?
Definition
Sounds like a failure to respond to feature saliency ("re-orientation"), but not with "top-down" attentional processing.

Probably arises from a focal lesion in the non-dominant VLPFC
Term
A patient exhibits profound difficulty with empathy and with reading other people's emotions.

What neural regions could be involved? What conditions manifest in this way?
Definition
1) This is a social cognition issue (i.e. Theory of Mind), so think Ventro-Medial and Orbito-Frontal Cortex

2) Autism, FTD and TBI can all manifest this way.
Term
What could a lesion in the VTA have to do with responding to environmental information?
Definition
The MPFC, or "Anterior Cingulate" receives the largest input contribution from the VTA (highest # of receptors), and it is involved in translating intentions into actions in response to environmental information.

lesions of the MPFC or the VTA can lead to "akinetic mutism" or related conditions.
Term
A patient presents with Bradykinesia, unilateral cog-wheeling rigidity and a resting tremor in their right wrist.

What pathological features define this condition?
Definition
This is PD

1) Degeneration of SNpc neurons (no more input to striatum, posterior Putamen>anterior Putamen)

2) Lewy bodies (alpha synuclein and ubiquitin) found in degenerating neurons

3) Inflammation (microglia activation- NSAID protective)

4) Iron deposition from oxidative stress (fenton reaction)
Term
How does Alpha-synuclein relate to the Parkin protein in PD?
Definition
Protein mis-folding and aggregation of Alpha-synuclein arising from abnormal processing due to Parkin mutations, which also leads to mitochondrial impairment.

Alpha-synuclein is seen as aggregated mess in Lewy bodies (along with proteolytic transcription factors), and it is a substrate for Parkin, which is an E3 ligase.

Mutations in Parkin and UHCL1 (both involved in proteolytic machinery) are seen in PD.
Term
What does MPTP have to due to mitochondrial abnormalities seen in Parkinson's disease
Definition
Originally taken in by IV drug use,

1) MPTP gets converted to MPP+ within astrocytes, and then gets taken up into neurons via DA-transporter

2) Acts as a COMPLEX 1 INHIBITOR in the mitochondria.

** other evidence comes from Rotenone exposure
Term
What do PINK, DJ1 and OM1 have to do with PD?
Definition
Mutated forms lead to abnormal mitochondrial processing, which causes free-radical release oxidative stress.

Oxidative stress can lead to iron accumulation and to Lewy Body formation
1) PINK (mitochondrial autophagy)
2) DJ1 (oxidative stress in mitochondria)
3) OM1
Term
Why might you try to give a patient Coenzyme Q (Ubiquinone) who has PD?
Definition
It may act as a free-radical scavenger to reduce oxidative stress arising from mitochondrial abnormalities.
Term
Why is dopamine replacement therapy centered around increasing D2-receptor signaling in the treatment of PD?
Definition
D2 receptor agonists including as Ergotamine and Non-Ergotamie agents will inhibit the striatum, which will lead to increased cortical activation via the direct and indirect pathways of BG signaling.

You want to reverse Bradykinesia and Rigidity.
Term
A patient with PD is suffering from severe resting tremors, but his rigidity and bradykinesia is manageable.

How might you treat the seizures?
Definition
1) Amantadine/Rimantadine

2) Anti-ACh
Term
Why might you choose to treat a PD patient with Non-ergotamine D2 agonists vs. Levodopa?

Why not use Ergotamine D2 agonists like Pergoilide or Bromocriptine?
Definition
1) Levodopa is better for symptomatic therapy (Bradykinesia, rigidity, tremor), but it causes dose-dependent motor fluctuations and dyskinesias.

2) D2 agonists (renal metabolism) don't cause dyskenesia, but will cause DA side-effects such as Sleep attacks, neuroyschiatric and compulsive behaviors.

- Excite D3>D2 and D4 but NOT D1/D5 or NA/5-HT
** remember, Ergotamine (hepatic metabolism) agents excite D3>D2>>D1/D4/D5, as well as NA receptors and 5-HT receptors causing many side effects**
Term
Why is Levodopa given with Carbidopa?
Definition
- L-DOPA crosses BBB and is converted to DA via AADC
- Carbidopa is an AADC inhibitor that does not cross the BBB, so that it will prevent L-DOPA from being converted to DA before getting to the brain

- Prevent hyperkinetic dyskinesia!
Term
A patient with mild PD symptoms requests therapy. What would be the best way to start?
Definition
Long-half-life DA agonist monotherapy to avoid dyskinesia if possible.

- Pulsative L-DOPA exposure disrupts post-synaptic DA-reeptor signaling, leading to motor "fluctuations"
Term
Why might you give a patient a Monoamine Oxidase B inhibitor (MAOB) such as Selegiline, or Rasagiline?

What about a COMT such as Entacapone?
Definition
PD!

1) Reduce DA catabolism at DA and NE stages
- Don't inhibit MAO-A, because it causes "cheese effect" with HTN, hyperpyrexia and seizures when eating tyramine.

2) Reduce DA catabolism at L-DOPA and Epi stages
- Prolonged Levodopa half-life
- causes orange urine and diarrhea, as well as DA side effects.
Term
Where do you use DBS in PD patients?
Definition
STN or GPi in "young," idiopathic, levodopa-unrespsive cases with a normal MRI.

Sometimes Gp and Thalamus ablation is an option as a last resort.
Term
A patient presents with a bilateral action tremor involving the upper limbs, but exhibits no other neurological abnormalities.

He explains that the tremor tends to get better when he drinks, but that it has been going on for 5 years.

What is the pathology/treatment for this condition?
Definition
This is Essential tremor, which is believed to involve the ION

- Remember, bilateral tremor without other issues that gets better with alcohol is usually ET

1) Propanolol (Beta Adrenergic blocker)
- fatigue, impotence and depression
- don't give with asthma or heart block

2) Primidone (Anti-convulsant)
- Deoxybarbiturate metabolized to phenobarbital and phenylthymalonimide.
- Somnelence is side effect

3) Surgery
- Can lesion Vental intermediate nucleus (Vin) of thalamus for contralateral tremor (DBS or Gamma Knife)
Term
Why would you give a patient Primidone and/or Propranalol?
Definition
Anti-convulscent and Beta-adrenergic blockers used to treat Essential Tremor.


**Only release amplitude, NOT frequency*
Term
A patient presents with a slow-frequency tremor that increases as when he tries to take his finger to touch yours.

What conditions manifest with this sort of tremor and how can you treat it?
Definition
Cerebellar Tremor (Intentional)
- MS, Wilson's and Cerebellar Stroke

1) Arises because cerebellar outflow tracts are lesioned. Progressive with poor treatment availability.

2) DBS Vim thalamus only works 70% and only in MS
Term
A patient presents with dystonic symptoms that have started in his foot, but have been spreading to the rest of your body.

He is also an Ashkenazi jew.

What is known about the pathology of this condition?
Definition
DYT1
-CAG mutation in Torsin A, 90% of cases occur in Ashkenazi jews and present initially in the feet.

1) AAA ATPase (molecular chaperone in protein folding, membrane fusion and vesicle trafficking).

2) Torsin A is high concentrated in SNpc
Term
What is the pathological basis of the condition that presents as generalized dystonia in early childhood with parkinsonian symptoms (Bradykinesia and Rigidity)
Definition
DYT5- Dopa-responsive dystonia (DRD)

1) AD mutation in GTP cyclohydrolase involved in THB synthesis (co-factor for TH)
** occurs rarely as AR mutation in TH

2) Improved with L-Dopa therapy!
Term
What are the major available treatments for Dystonia?
Definition
MAIN
1) Chemodenervation with Botulinum toxin (ACh inhibition)
2) High-stimulation DBS in GPi (vs. lower stimulation in Vim of Thalamus for tremor)

SECONDARY
1) Anti-ACh in high dose
2) Benzos
3) L-DOPA (if DYT5)
Term
A patient presents with a persistent, distractible tremor. What could be going on?
Definition
Psychogenic tremor

Unlike PD, where it is non-distractable
Term
What are the important differences between Childhood-onset and Adult-onset Dystonia?
Definition
1) Chidlhood starts in lower body, with generalized progression (commonly inherited).

2) Adult is focal, and may become segmental, but is NOT generalized (often sporadic vs. inherited).
Term
True or False:

Ataxia often results from lesion to the outflow tracts of the cerebellum.
Definition
False.

Cerebellar Ataxia results from lesions to Cerebellum proper or to the proprioceptive input tracts (spinocerebellar or dorsal columns)

Cerebellar intention tremors, on the other hand, result from lesions to the outflow tracts of the cerebellum (Dentate...Red nucleus...Thalamus)
Term
What can an appendicular vs. truncal ataxia tell you about lesion localization?
Definition
1) Appendicular indicates cerebellar hemisphere pathology (most likely cerebrocerebellum)

2) Truncal ataxia/gait issues indicates midline cerebellar pathology in flocculus or fastigial nucleus (vestibulocerebellum and spinocerebellum )
Term
A patient presents with bilateral/symmetrical dysmetria, dysdiadochokinesis and kinetic tremors.

What kind of pathology is probably going on? How would you focus treatment?
Definition
Ataxia caused by Metabolic or Degenerative process (i.e. Hypothyroidism or hereditary issues)

Focal lesions (stroke, tumor) would present unilaterally.

**focus treatment at UNDERLYING cause (i.e. thyroid replacement for hypothyroid condition)**
Term
A patient presents with truncal ataxia and absence of joint position sense on the left side. She also has a positive Romberg.

No dysarthria or eye movement abnormalities are present.

Whats could be going on?
Definition
Sensory Ataxia- involvement of position sense that gets worse without sensory input rules out Cerebellar ataxia

1) Large fiber neuropathies include
- Inflammatory
- Paraneoplastic
- B6 toxicity

2) Spinal Cord/Dorsal Column neuropathies
- B12 deficiency (severe combined spinal cord degeneration)
- Hereditary
- Tabes dorsales (Syphilis)
Term
A patient in liver failure presents with negative myclonus when holding out there arms in front of them.

What is this called?
Definition
Asterixis
Term
A patient with Epilepsy presents with brief, shock-like, rapid movements that are involuntary and that cannot be suppressed.

How do you treat these movements?
Definition
1) This is symptomatic Myoclonus associated with an underlying brain disease.

2) AEDs

1) Valproate
2) Clonazepam (benzo)
3) Levetiracetam (benzo)
Term
A patient with a history of liver disease presents with akinetic, rigid movements, cerebellar ataxia and facial dystonia involving a retracted upper lip.

What other things should you do to diagnose/treat this condition?
Definition
Liver Disease and Lip Dystonia makes you think Wilson's (Curable, but needs to be diagnosed early!

1) Diagnose
- Look in eye for Copper in Descemet's membrane within cornea
- Look for low serum copper and Caeruplasmin and high urinary copper

2) Treat
- Penicillamine and Trientene to raise urinary output
- Zinc salts to prevent copper absorption
Term
A 17 year old patient presents with multiple motor tics as well as unpredictable outbursts of profanity. These behaviors are inhibiting his ability to interact socially.

What treatments are available for this condition?
Definition
Multiple motor tics with >=1 vocal tic before 18 means Tourette's (primary motor tic disorder)

1) Alpha agonists (Clonidine)
2) Atypical anti-psychotics (Resperidone)
3) Neuroleptics (Da-R antagonist)
4) DA-depeletor (Tetrabenezine)
5) Benzos (Clonazepam)
Term
A patient presents with gaze-evoked nystagmus and is unable to suppress their VOR reflex when moving their head.
Definition
Cerebellar Ataxia
- Floculonodular lobe, Vermis or brainstem connections
- Can be acute, subacute or chronic
Term
A patient presents with bilateral/symmetric acute ataxia, confusion and ocular-motor issues.

The MRI doesn't show any evidence of brain disease, but the patient received a kidney transplant the previous year.

What is going on and how should you proceed?
Definition
B1 deficiency- Give B1 quick and before giving Glucose

The ataxia sounds like Wernicke's encepthalopathy.

Taken with the confusion and ocular-motor issues, as well as the recent transplant, this is probably a B1/Thiamin deficiency resulting from abnormal absorption of nutrients following transplantation.

The bilateral distribution also supports a metabolic cause, rather than a focal lesion.
Term
A patient presents with bilateral subacute ataxia.

What is the most likely cause of this and how would you treat?
Definition
Paraneoplastic Syndrome- T-cell mediated response to tumor.

REMOVE IT.
Term
Why might you give IV-IG to a patient who presents with ataxia and recently had a campylobacter jejuni infection?
Definition
Post-infectious Miller Fischer syndrome.

- Cross-reactive auto-immune response leading to neuropathy that is treated by IV-IG.
Term
A patient presents with ataxia, loss of position sense and a positive Romberg sign.

Babinski sign is present and there is evidence of paresis, but no evidence of dysarthria or eye abnormalities.

What is the pathological basis of this condition.
Definition
Subacute combined degeneration of spinal cord from B12 deficiency.

Deficiency leads to pernicious macrocytic anemia, which causes demyelination of cervical spinal cord.

-Ataxia, position sense and Romberg point to Sensory Ataxia.

-Babinski sign and Paresis are common in B12 deficiency.
Term
A young child with strep throat presents with a suppressible involuntary movement of his left hand.

What is going on and how do you treat?
Definition
Post-infectious autoimmune neuropathy (PANDAS) causing secondary tic.

Treat throat infection!
Term
What muscles are involved in hemifacial spasm and how do you treat?
Definition
1) Orbicularis oculi and Zygomaticous (compressing facial nerve by vasculature)
2) Treat with Botox
Term
A child presents with akinetic-rigid movements, cerebellar ataxia, tremor, dystonia and psychiatric signs, as well as liver disease.

What tests should you order?
Definition
Fits with Wilson's Disease (AR copper metabolism issue)

1) Physical
- Look for brown spots in eyes and dystonia of upper lip

2) Labs
-Get Urine (high copper) and Serum analysis (lower copper and Caeruplasmin).

**Treat with tientene, penicillamine and zinc salts

** Remember, pathology involves trans-golgi ATPase involved in copper metabolism**
Term
What is the difference between Guillon Barre and Miller Fischer?
Definition
Both Auto-immune neuropathies that are secondary to infection.

GB presents with Paresis while Miller Fischer shows sensory Ataxia.
Term
A patient with the HLA-DRB1 1501-DR2 complains of extreme fatiguability, bladder control issues and presents with Lhermitte's sign and double vision.

She also cannot see well at all in her left eye and complains of pain when trying to move it.

On PE you notice internuclear opthalmoplegia


What are the useful treatments for this condition?
Definition
MS (B-interferon, Glutiramer acetate, Natalizumab, Mitoxantrone)

-Genetic susceptibility matches MS and double vision and left visual loss could be arising from Optic neuritis and the Lhermitte's sign is consistent with Partial myelitis of cervical cord.

INO is consistent with demyelination of MLF

**B12 deficiency and cervical spine degeneration are also possible**
Term
A patient comes in complaining of fatigue, as well as difficulty seeing out of their right eye.

They seem depressed and you order an MRI.
You notice supratentorial, periventricular and juxtacortical lesions with finger-like projections at peri-venular regions.

What is going on, how could you confirm and how do you treat?
Definition
1) MS
- Depression is actually most worrisome finding
- Location of lesions and presence of Dawson's fingers are very consistent
- Vision issues suggest unilateral optic neuritis of right eye

2) Must see 2 CNS lesions separated by time. MRI is 90-95% sensitive, but you can LP for IgG and look at Evoked potentials for subtle lesions

3) Treat
-IFN-beta/Avonex (T-cell proliferation and activation)

- Glatiramer acetate/Copaxone (MHC presentation for Th2 suppresion)

- Natlizumab/Tysabri (VLA-4 antibody)- best option

- Mitoxantrone/Novantrone (Chemo- second line)

- Dalfampridine (K-channel blocker for weakness)
Term
What important side effects are associated with MS treatments?
Definition
1) INF-b (Avonex) can cause myalgia, miscarriage, leukopenia

2) Glatiramer acetate (Copaxone) can cause benign, frightening chest pain

3) Natalizumab (Tysabri) can cause PML (1:1000)

4) Mitoxantrone (Novantrone) can cause vacuolar cardiomyopathy, alopecia and nausea

5) Fingdimod can cause susceptibility to HSV

6) Dalfampridine can cause seizures
Term
What autonomic/sensory/brainstem functions are affected in MS?
Definition
1) Autonomic
-Bladder control
-Sexual
- Bowel

2) Sensory
- MS "hug"
- Lhermitte's
- V neuralgia
- Hemibody paresis (dorsal column>spinothalamic)

3) Dysarthria/Dysphagia/Vertigo/V neuralgia
Term
Which inherited disorders of myelin function should be on your differential when considering MS?
Definition
1) Adrenoleukodystrophy (adrenal gland or CNS dysfunction evident in young men)

2) Metachromatic leukodystrophy (AR with psychiatric dysfunction)
Term
A patient presents with a mild/moderate headache that she claims has lasted the past 4 days.

She experiences it on both sides of her head and experiences no worsening with exercise. However, it does get worse when she is under stress.

She experiences no photophobia and only rarely gets nauseous with the pain.

How do you treat this kind of headache?
Definition
Episodic Tension headache

1) 30m- 7d with nausea or photophobia (or neither) and at least 2:
-tightening
-bilateral
-no aggravation with physical exercise
-mild-moderate

2) Aspirin
Term
A patient presents with a headache that she claims has been recurring 2-4 times per day with intense, peri-orbital pain on the left side lasting 30-40 minutes.

There is evidence of lacrimation and nasal congestion on her left and she is pacing around the room restlessly.

What kind of headache is this?
Definition
Cluster headache (Inferior Posterior Hypothalamus with pain from both autonomic and trigeminal systems)

** not a migraine, because it doesn't last long enough and the pacing/restlessness doesn't fit**

1) at least 5 attacks with severe unilateral orbital/supraorbital pain lasting 15-180m.
2) Presence of potent autonomic features and pacing/restlessness
Term
A patient presents with a moderate/severe headache that she claims has lasted the past 4 days (each attack lasting approximately 5 hours).

She experiences it only on the left side of her head and it gets worse with exercise

She experiences photophobia/phonophobia, but only rarely gets nauseous with the pain.

How do you treat this kind of headache? What is the basic pathophysiology?
Definition
Migraine without Aura (13% of adults and 25-30% of women ages 40-50 get migraines, with 94% of cases presenting at offices being migraines).

1) Pathophysiology
- Enhanced sensitivity on dorsal-medial forebrain and dorso-lateral pons (RF, periaqueductal gray and LC).

2) Treatments
- NSAIDS
- reversible COX inhibition in prostaglandin synthesis pathway through hydrophobic channel blockage

- Triptans (5-HT agonists, B1= vascular, D1= neuronal)
Term
What is the pathophysiology underlying the "aura" experienced in migraine headaches?
Definition
25% of migraines have aura (13% of adults and 25-30% of women ages 40-50 get migraines, with 94% of cases presenting at offices being migraines)

1) Painless wave of electrical excitation followed by "spreading cortical depression across occipital cortex, leading to activation of trigeminal system.

2) Secondary vascular effects of hyperemia wave followed by oligemia (CGRP, Sub P and Neurokinin A release)
Term
Why do people with migraines sometimes complain of "tension" or "sinus" headaches?
Definition
Think about the pathway of pain generation.

Pain comes from Dura, Periosteum and Vessels
1) Nerve terminal (V1) releases CGRP (vasodilation), Substance P (Leakage of BBB) and Neurokinin A (Inflammation)

2) Events transmitted to spinal trigeminal nucleus, integrating with signals from extra-cranial structures served by CN V

3) Information from V2 (maxillary), superior salutatory nucleus (VII) and cervical nerve roots is integrated in spinal trigeminal nucleus and sent to S1 with all of the rest.
Term
How can blind people experience photophobia with migraines?
Definition
The retinitis pigmentosa spares the melanopsin path regulating diurnal circadian rhythms.

Convergent input from melanopsin path and spinal trigeminal pathway in the thalamus (Ventral medial) leads to photophobia despite absence of photoreceptors.
Term
What is the chronological course of a migraine headache with aura?
Definition
1) Prodrome
- Mood/fatigue/muscle pain/food cravings

2) Aura
- Reversible <1h, Vocal/vision/speech

3) Early Headache
- nasa congestion (V2)

4) Migraine
5) Post-migraine
Term
What opioid receptor do each of the following endogenous opioids act upon?

1) Enkephalon
2) Endorphin
3) Dynorphin
Definition
Calcium-mediated release with GPCR action

1) Delta in descending pathways from pons/medulla to SC and entorhinal cortex to dentate gyrus

2) Mu in medial hypothalamus, diencephalon and pons

3) Kappa in dentate-CA3 connections
Term
How do endogenous opioids inhibit pain processing?
Definition
Either through 1) direct inhibition of SG or 2) activation of descending pain modulatory pathways from periaqueductal gray, which project to medullary raphe nuclei

1) Bind pre- and post-synaptically to opioid receptors

2) Inhibit N-type calcium channel conduction pre-synaptically and inhibit AC

3) Enhance post-synaptic K conduction
Term
What are the clinical effects of opioids?
Definition
1) Analgesia (selective)
2) Cough suppression (Codeine and Dextrmethorphan)
3) Respiratory suppression
4) Constipation (Diphenoxylate & Loperamide)
5) Sedation
6) Vasodilatation (in MI)
Term
What non-opioid analgesics are available to treat pain? What side effects are associated with their use?
Definition
1) Tramadal
- dual mechanism with supra-spinal opioid-like action and spinal MAOI

2) Acetaminophen
- COX 2 and 3
- Don't give in liver failure (hepatic toxicity due to NAPQI)

3) Acetylsalicilic acid
- anti-pyretic
- anti-thrombotic (irreversible COX 1)
- Gut toxicity
- Reye's in children (microvascular steatosis and hepatic encephalopathy)

NSAIDS
- anti-pyretic (high doses)
- reversible COX inhibition in prostaglandin synthesis pathway through hydrophobic channel blockage
- Don't give with asthma or Kidney failure
Term
Why not give patients tylenol who have CYP2D6 mutations?
Definition
Cytochrome P450 issue causes slow metabolism, leading to buildup of NAPQI metabolite, which is damaging for the liver!
Term
How do Tryptans work to treat migraines?
Definition
5HT-R agonists! Don't give with vascular disease. They prevent, but do not reverse sensitization of ST N.

**pharm. less relevant than mode of administration**

1) 5HT-1B receptors on blood vessels to reverse vasodilation

2) 5HT-1D receptors on nerve terminals to inhibit Neurokinin A (inflammation), Substance P (BBB breakdown) and CGRP (vasodilation) release.
Term
What are the 2 most common types of brain tumors seen in kids?
Definition
70% are in posterior fossa

1) Pilocytic Astrocytoma (I)
- Cerebellum

2) Medulloblastoma (IV)
- Primitive Neuroectodermal Tumor (PNET)
- 70% 10 year survival if no CSF spread
Term
What are the 3 most common primary brain tumors found in Adults?
Definition
1) Meningioma (II-III)

2) Pituitary Adenoma

3) Astrocytoma (III-IV)
- Anaplastic (III)
- GBM (IV)
Term
What 3 important pathological features are associated with GBM in adults?
Definition
Often crosses corpus callosum

1) Necrosis with pseudopallisading
2) Multiple mitotic figures
3) Endothelial proliferation
Term
A patient presents with bilateral acoustic neuroma, multiple meningiomas and ependymomas in the spinal cord.

What hereditary syndrome do they have?
Definition
NF-2 (usually adult-onset)
Term
A patient presents with "cafe-au-lait spots," neurofibromas, bilateral optic nerve gliomas and plexiform neurofibromas.

What hereditary syndrome do they have?
Definition
NF-1

- Bilateral optic nerve gliomas are characteristic
- Plexiform neurofibromas of peripheral nerves may become malignant nerve sheath tumors that can kill!
Term
What molecular processes distinguish primary and secondary GBM tumors?
Definition
1) Primary
- EGFR amplification (MAPK signaling and division) and LOH at chromosome 10q
- The more EGFR amp, the more susceptible to treatment.
- No loss of P53

2) Secondary
- P53 mutation (DNA repair and synthesis shutdown from damage) and LOH at chromosomes 17p
- Progresses from II to III/IV
Term
What do each of the following terms refer to in terms of Circadian Rhythms?

1) Ultra-radian
2) Infra-radian
3) Zeitgeber
4) Internal de-synchrony
Definition
1) functions that occur more than once every 24h (cardiac and respiratory rhythms)

2) function that occur less than once every 24h (menstrual cycle)

3) External cues that can entrain circadian rhythms (light)

4) When day length is beyond range of entrainment (>26h), certain rhythms such as core temperature and melatonin will become de-synchronized with sleep-wake
Term
A patient claims to have been awake for 43 hours. What would you expect to be different about the patient's core body temperature rhythm than a patient who sleeps regularly?
Definition
Core body temperature can be "masked," where the trough will be less prominent during times of prolonged wakefulness
Term
What the major efferent/afferent pathways of the Circadian system?
Definition
1) Afferent
- Melanopsin-containing neurons in retinal ganglion cells project to SCN (light-sensitive) at the base of the 3rd ventricle, on top of the optic chiasm

2) Efferent
- Subparaventricular nuclei of hypothalamus
- Medial Pre-optic area of hythalamus
- Anterior and Lateral hypothalamus
- LGN
Term
Describe the characteristics of Wakefulness, NREM and REM sleep states on PSG
Definition
1) Wakefulness
- High frequency, low amplitude alpha waves
- Volitional eye movements
- High, variable EMG

2) N1
- EEG slower with higher Amp.
- EOG slow, rolling movements
- EMG reduced

3) N2
- Sleep spindles and K complexes

4) N3
- Delta waves
- No EOG
- EMG very low

5) REM
- EEG low amplitude, high frequency
- EMG is atonic, except brief twitches
- EOG is rapid with dreams
Term
Distinguish between "Homeostatic" and "Circadian" regulation of Sleep-Wake states.
Definition
1) Homeostatic drives initiation of sleep
- builds up with increased wakefulness

2) Circadian keeps you asleep in 2nd half of night
- highest propensity between 5-9am
Term
What is the neurobiological circuitry controlling "wakefulness"?
Definition
1) Brainstem ARAS (LC/NA, RN/5-HT, ACh/PPT & LDT
- Gets GABA input from VLPO in hypothalamus

2) Tuberomamillary Nuclei of Post. Hypthalamus
- gets direct input from SCN and VLPO

3) Hypocretin (orexin) system in Lateral Hypothalamus
- project to arousal centers like LC (Gets GABA input from VLPO)

4) Basal forebrain ACh center

5) Cerebral cortex and limbic cortex
Term
What is the neurobiological circuitry controlling "NREM"?
Definition
Brainstem and Diencephalon

1) Brainstem Solitary tract (dorsal/ventral paths like ARAS)

2) VLPO/MnPO "sleep switch" of hypothalamus

3) Thalamocortical sleep rhythms (T-type calcium channels regulated by RTN and TRN signaling)

4) Basal forebrain "sleep hemostat" builds of adenosine during wakefulness (inhibited by caffeine)
Term
What is the neurobiological circuitry controlling "REM sleep"?
Definition
Rostral Pons

1) PPT/LDT reciprocally activate themselves with ACh drive, promoting REM sleep and simultaneously activating LC and RN in brainstem

2) As LC and RN activation builds up (NA and 5-HT signaling), it inhibits the PPT/LDT and switches the person back to NREM from REM.
Term
Explain the functional neuroanatomy of a basic wake-NREM-REM-NREM cycle.
Definition
1) During wakefulness, ARAS (LC, NR and PPT/LDT), Tuberomamillary nuclei, Hypocretin system, Basal Forebrain and Limbic/Cortex are active.

2) As adenosine builds up in basal forebrain (homeostat), VLPO "switch" is activated, which uses GABA to inhibit structures in 1.

3) As NREM progresses, NA/5-HT gradually decline and REM sleep sets in with increased PPT/LDT ACh activity

4) When PPT/LDT activation of LC/RN builds up enough to inhibit PPT/LDT, NREM sleep again dominates.
Term
What are the major types of Sleep disorders according to ICSD-2?
Definition
1) Insomnia
2) Sleep-related Breathing Disordrs
3) Hypersomnia
4) Circadian Rhythm Disorders
5) Parasomnia
6) Sleep-related movement
Term
What is the most important part of diagnosing a sleep disorders?

How is Multiple Sleep Latency Testing used to diagnose sleep disorders?
Definition
1) 24h sleep HISTORY!

2) PSG and MSLT also useful
- MSLT involves 4-5 brief PSG studies during course of a day (each terminated after 20 minutes if sleep does not set in)
Term
A patient presents with excessive daytime sleepiness, cataplexy, hynogogic hallucinations at sleep-wake transitions and sleep paralysis.

What is the pathophysiology of this condition?
Definition
4 cardinal features of Narcolepsy (confirmed with >2 naps with REM sleep)

- Autoimmune destruction of hypocretin secreting system in lateral hypothalamus (project to brainstem arousal centers during wakefulness)

- CSF hypocretin is 100% specific for Narcolepsy/50% sensitive for cases with Cataplexy
- HLA DQB1 0602 is very sensitive/30% specific
Term
A patient comes into your office complaining of poor concentration, depression ad morning headaches.

Their partner reports very odd, loud snoring

What are the key symptoms/objective findings of this condition?
Definition
OSAS
1) Key symptoms
- history of loud snoring
- mental slowing from intermittent hypoxia
- breathing pauses

2) OF
- Decreased 02 saturation
- HTN and CVD and impaired glucose tolerance
- Paradoxical breathing
- Abnormal chemoresponsivity to hypoxia and Obesity common causes
Term
A patient comes into your office complaining of difficulty falling asleep and both frequent and prolonged awakenings during sleep.

They have been having difficulty concentrating and have been irritable.

What are the objective findings/treatment of this condition?
Definition
Insomnia (have opportunity to, but cannot sleep)

1) OF
- PSG not reliable
- W> M and increases with age

2) Pathophysiology
- 24-h hyper-arousal with potential role of increased cortical/limbic activation and decreased "switching off"

3) Treat
- Regularizing S/W schedule
- Benzo receptor agonists
Term
A patient complains of insomnia with persistent episodes of excessive sleepiness at different times during the day. They tend to go to bed very late and wake up very lage

What is the pathophysiology/treatment of this disorder?
Definition
Circadian Rhythm Sleep Disorder (DSPD in particular)

1) Mismatch of SCN and desired sleep-wake hours

2) Since this is DPSD, use light zeitgeber at early points in morning and melatonin in early evening.

**If APSD, give light in early evening and melatonin in early morning.
Term
A patient comes into your office complaing of an urge to move their legs and toes, accompanied by dysthesia.

They say that it comes on strongest at night and prevents them from falling asleep.

The partner reports observing dorsiflexion of the foot and flexion at the hip and knee of the patient during their sleep.

What is the pathophysiology/treatment of this condition?
Definition
Restless Legs Syndrome/Periodic Limb Movement DIsorder (if occurs during NREM sleep)
- May be familial and occurs in 5-10% of population

1) Pathophysiology
- Abnormalities in iron metabolism, which is cofactor for tyrosine hydroxylase (reduced SNpc iron and reduced ferretin in CSF).

2) Treat
- Pramipexole or Pergolide (Non-ergotamine DA agnoists)
- L-Dopa can cause rebound symptoms during daytime.
Term
What is the difference between sleep walking/terrors and REM sleep/behavior disorder?
Definition
1) Walking/Terrors occur because of incomplete phase transitions from NREM sleep

- Common in middle childhood (25%) and treat them with BzRA hypnotics and avoid sleep deprivation

2) REM sleep/behavior disorders include violent outbreaks due to brainstem lesions, which release voluntary muscles from atonia during REM sleep.

- Occurs in middle-aged patients and is associated with Lewy Body Disease (alpha synuclein)
- treat with Benzos for motor activity, Gabapentin and DA receptor agonists and imagery rehearsal.
Term
What do the "digit span +1", "paired recall and "complex figure" test tell you about memory deficits?

What neurological structures are involved?
Definition
If they are abnormal, it suggests an issue with declarative, long-term memory, which means

Consolidation
1) Medial Temporal Lobe (spatial component)
- Hippocampus
- Rhinal cortices (especially parahippocampal gyrus)

2) Medial Diencephalon
- Anterior and dorsomedial thalamic nuclei
- Mammillary bodies of hypothalamus

3) Basal forebrain
- Nucleus basalis of meynert

4) Frontal lobe (temporal component)

Storage
1) Secondary sensory cortices

Retrieval
1) Frontal lobe
Term
A patient exhibits a extreme anterograde amnesia, but no difficulties with the word-stem completion and perceptual identification tasks.

What is going on?
Definition
Probably issue with consolidation of declarative, long-term memory, but not non-declarative

Lesion to medial temporal lobe, medial diencephalon, basal forebrain or frontal lobes.
Term
A patient exhibits abnormal word-stem completion, rotary learning task and perceptual identification of complex pictures.

What kind of pathology is going on?
Definition
Non-declarative long-term memory issue.

1) Consolidation occurs in Striatum and Cerebellum
2) Storage occurs in premotor/supplementary motor cortices
Term
What type of deficit would a lesion to the DLPFC cause?
Definition
Working memory

- Abnormal digit-span test and Self-ordered task.
Term
What deficit arises from damage to the Mamillary bodies of the hypthalamus?
Definition
Korsakoff's Syndrome

- LTM declarative issue arises from B12 deficiency caused by alcoholism.
Term
What is common abut Benign Familial Neonatal Convulsion (BFNC), Genetic Epilepsy with Febrile Seizures Plus and Idiopathic Generalized Epilepsy (IGE)?

What is different about Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE)
Definition
All 3 forms of epilepsy (spontaneous generation of seizures) are caused by mutations in ion channels.

ADNFLE is a missense mutation in nAChR (ligand-gated)

1) BFNC is KCNQ potassium channel
2) GEFSP is SCNA sodium channel
3) IGE is CLCN chloride channel
Term
What is the relevance of "Paroxysmal depolarization shifts" (PDS) for diagnosing epilepsy?
Definition
PDS are large, prolonged depolarizations occuring in Epileptic Foci of neurons that lead to bursts of spike activity ("trains" of APs) that correspond to inter-ictal discharges recorded on EEG (IIEDs)

Could mean either
1) Intrinsic membrane abnormalities
2) Excessive excitatory or reduced inhibitory input.
Term
How does the locus ceruleus influence seizure termination?
Definition
Brainstem nuclei that release NA, thereby increasing extracellular adenosine and decreasing excitation.

** analogous to how adenosine buildup in basal forebrain acts as "sleep homeostat**
Term
What are 3 possible neural mechanisms underlying temporal lobe epilepsy?
Definition
These "Partial" seizures start in brain and spread variably to other regions

1) Enhanced NMDAR-mediated transmission in dentate granule cells (leading to CA3 activity)

2) Loss of hilar neurons that normally activate inhibitory basket cells

3) Synaptic reorganization of granule cell excitatory cell output and feedback to dentate.

HIPPOCAMPAL CIRCUITRY
1) Entorhinal cortex projects (+) to dentate granule cells, which projects (+) to hilar cells (CA4) and CA3 cells (which project to CA1 cells via Schaffer collaterals)

2) Mossy Hilar cells (+) basket cells, which (-) dentate granule cells
Term
What is the basic tri-synaptic hippocampal circuitry?
Definition
1) Entorhinal cortex projects (+) to dentate granule cells,

2) Granule cells project (+) to hilar cells (CA4) and to CA3 cells

3a) CA3 cells (+) project to CA1 cells via Schaffer collaterals)
3b) Mossy Hilar cells project (+) to basket cells, which (-) dentate granule cells
Term
Why are some patients with temporal lobe epilepsy resistant to medications?
Definition
Usually have a history of early brain insults that led to febrile convulsions during early childhood.

"Second insults" tend to activate these already-sensitized networks.
Term
A patient appears to be having seizures and you order an MRI. It comes back with "Mesial Temporal Sclerosis"

What pathological findings would you expect to see?
Definition
This is Temporal Lobe epilepsy

1) Gliosis in hippocampus with selective neuron loss
2) Axonal and dendritic reorganization (mossy fiber sprouting)
3) Altered NT and receptor expression
4) Dispersion of dentate granule cell layer
Term
A patient presents with generalized, non-convulsive seizures where they stare in one direction but are totally unaware of their surroundings.

How are these seizures generated?
Definition
Absence seizures are generated when there is abnormally high GABA-ergic input into TRN neurons, influencing cortical pyramidal cells via T-type calcium channel-mediated signaling.

Can be recapitulated by GABAb agonists


NETWORK
1) L4/L5 cortical pyramidal cells (glutamate) and thalamic relay neurons (glutamate) are reciprocally connected and excite GABA-ergic Reticular thalamic nuclear cells.

2) RTN cells release GABA which binds GABAa receptors on RTN neurons and GABAb receptors on TRN cells.

3) TRN cells express T-type calcium channels, which require hyper-polarization to be "de-inactivated," so they depend upon RTN GABA-ergic input to fire.
Term
How can you tell whether a Seizure is "epileptic" or "non-epiletpic"?
Definition
If it is epileptic, you will see EEG changes with 2 or more episodes of unprovoked seizures.

Epileptic seizures
1) Focal
- with or w/o syncope
- can evolve to convulsive

2) Generalized/Convulsive
- Tonic-clonic
- Tonic
- Clonic

3) Generalized/Non-convulsive
- Absence
- Myoclonic
- Atonic
Term
An adult patient presents with a seizure that has lasted 30 minutes. What do you do?
Definition
They are Status Epileptics (>5 minutes in adults)

IMMEDIATELY administer Benzo with a long-acting AED like Fosphenytoin (30-50% morbidity without treatment)
Term
What are the 5 major etiologies of seizures and epilepsy?
Definition
1) Toxic-metabolic
2) Acquired structural lesion
3) Familial
4) Genetic
5) Idiopathic (genetic)
Term
What type of epilepsy etiology dominates each of the following age groups?

1) <14
2) 15-24
3) 25-44
4) >45
Definition
Head injury, CVD, Infections and Medication withdrawal are the most common overall causes

1) Developmental
2) Brain injury
3) Brain tumor
4) Vascular
Term
A patient who is fully aware is exhibiting motor abnormalities consistent with a seizure. They spread from his right hand to his right arm and right body.

After the seizure subsides, he has weakness in the affected arm.

What happened?
Definition
Todd's Paralysis with post-ictal weakness and "Jacksonian March" spread from right hand to other muscle groups.
Term
A patient is staring at the wall, but with impaired consciousness and recall.

He is also smacking his lips and tapping on the table

All of a sudden, he appears normal, but is lethargic.

What happened?
Definition
Focal seizure of temporal lobe involving subjective psychic phenomenon (with impairment of awareness)

Lip smacking and tapping are "automatisms" and he experiences "post-ictal lethargy" afterwords.

You wouldn't see these automatisms in an Absence seizure.
Term
A patient appears to have fainted right after letting out a shrill cry. His body is stiff.

He is breathing laboriously, his back spontaneously arching, his heart is racing and his mouth is foaming.

He intermittently exhibits convulsions.

The whole event lasts several minutes.

What is going on and what should you be concerned about after the patient comes to?
Definition
Generalized tonic-clonic seizure (GTCS) (can be primary or secondary to focal seizure- important for treatment)

Agitation or depression are common following the seizure!
Term
A 5 year old suddenly falls to the ground, with noted decreased muscle tone.

What might have happened?
Definition
Atonic generalized seizure (more common in young people)
Term
What is the link between Absence and GTCS seizures?
Definition
50% of those with Absence seizures between 4-12 years old develop GTCS later in life
Term
What are the 5 major diagnostic methods utilized for seizure disorders?
Definition
1) EEG- sum of EPSP and IPSP from apical dendrites of pyramidal cells in upper cortex (modified by thalamus)

- video-EEG or long-term monitoring is GOLD STANDARD
- look for spikes and sharp-waves

2) MRI- cerebral structural status
3) PET- focally decreased metabolism
4) SPECT- IV-injected radioisotopes to look at CBF.
5) MEG- non-invasive for small brain centers (LOCALIZATION)
Term
What is the relationship between "bursting" thalamic neurons and EEG synchronization in term of states of consciousness?
Definition
1) During Sleep, EEG is synchronized
- RTNs give GABA-ergic input to TRNS, hyper-polarizing and de-inactivating T-type calcium channels that leads to "burst" firing of those neurons.

2) During arousal, EEG is de-synchronized (Transition mode)

- ARAS in rostral pons projects to RTN in thalamus and reduces their inhibitory drive onto TRN cells
- lack of GABA-ergic input from RTN to TRN neurons prevents bursting and allows TRN cells to faithfully transmit incoming sensory signals
Term
How might a focal lesion to the ARAS manifest clinically, and why?
Definition
Coma (also caused by widespread, bilateral lesions in thalamus/cortex)

ACTIVE during wakefulness
REDUCED during sleep causing lack of responsiveness

1) ARAS in rostral pons protects fibers to RTN of thalamus, inhibiting those cells and decreasing their inhibitory drive onto TRN cells.

2) When TRN cells are not hyper-polarized by RTN cells, T-type Ca channels cannot be de-inactivated, and TRN cells cannot fire "bursts," as seen in sleep. They therefore can process incoming sensory information.

3) Without burst-suppression by the ARAS, patients cannot process incoming sensory information, because their TRN fibers are "bursting" and their EEG is synchronized.
Term
A patient presents in coma. How do you proceed with a neurological workup to distinguish between possible causes (Mass lesion, toxic/metabolic/seizure condition, focal lesion of upper brainstem)?
Definition
GARPEMS M

1) Gen evaluation- Temperature/Muscle Tension
2) Alertness- Alert/Delirious/Lethargic/Stupor/Coma
3) Respirations-
4) Pupils
5) Eve movements
6) Motor responses
7) Synthesis
8) Management
Term
How do each of the following Pupil sizes help achieve lesion localization?

1) Small-reactive
2) Large-fixed
3) Pin-point
4) Mid-position fixed
5) Unilateral dilated
Definition
1) Diencephalic or Metabolic
2) Tectal issue (can't constrict)
3) Pons
4) Midbrain
5) CN III (uncal herniation)
Term
A patient presents with crescendo-decrescendo periodic respirations, frequently with an apneic pause. Pupils are small and reactive.

What is going on?
Definition
Cheyne-Stokes respirations suggets bilateral dysfunction of hemispheres or diencephalon.

The small reactive pupils could indicate diencephalic involvement.
Term
A coma patient has been hyperventilating for 2 hours and exhibits pin-point pupils.

What is going on? What other respiratory sign might you expect to see?
Definition
Central Neuronic Hyperventilation in context of coma with pin-point pupils suggests lesion involving Pons.

Could also see Apneustic respirations, which are rare but localizing
Term
If a coma patient presents with unilateral motor defects, what does that tell you about the etiology of the coma?
Definition
Supratentorial lesions present asymetrically, and usually progress rostral to caudal.

Narrows it to hemisphere infarction, hemorrhage, subdural or epidural hematoma, cerebral neoplasm or brain abscess.
Term
A patient presents to your office in a state of confusion and stupor.

They exhibit bilateral asterixis and a bilateral intention tremor, as well as a number of symmetric motor signs.

Eye movements are all intact

What could be going on?
Definition
Intact eye movements with bilateral motor signs and confusion/stupor suggests toxic/metabolic etiology

Narrows it do drug/alcohol, hypoglycemia, hepatic failure, shock, heat stroke ect.
Term
A patient presents with an uncoordinated rate and rhythm of breathing. Why should you be worried?
Definition
Ataxic respirations are suggestive of impending respiratory or ventilatory failure and indicate lower pontine or medullary level of dysfunction (brainstem).
Term
What are the 4 major treatment options for a patient with Epilepsy?
Definition
1) AED (1st line for seizures, not epilepsy)
2) Ketogenic diet
3) VNS
4) Surgery (underutilized!)
Term
What are the principle mechanisms of AED action for treating seizures in epilepsy?
Definition
1) Inactivation of VG-Na channels by stabilizing inactive state
- Phenytoin (dose-dependent kinetics) & Carbamazepine (ENZYME INDUCERS)

2) Inactivation of Ca channels (T-type)
- Ethosuximide (Enzyme inducer-not protein bound)

3) Activation of K channels

4) Increase GABA
- Phenobarbital gets both

5) Decrease excitatory transmission
Term
When should Phenytoin (PHT) and Carbamazepine (CBZ) be given to treat seizures in epilepsy and how do they work?
Definition
Enzyme inducers (older drugs)
** CBZ goes by CYP3A4 pathway and auto-induces it**
** PHT exhibits non-linear kinetics**

1) Contraindicated with
- Oral contraceptives (pregnancy)
- Warfarin (decrease warfarin concentration..DVT)
- Statin (increase statin clearance....cholesterol)
- TCA (decrease TCA conc. and increase AED)

2) Stabilize inactive state of VG-sodium channels.
Term
When should Phenobarbital be given to treat seizures in epilepsy and how do they work?
Definition
Enzyme-inducer

1) Contraindicated
- Oral contraceptives (pregnancy)
- Warfarin (decrease warfarin concentration..DVT)
- Statin (increase statin clearance....cholesterol)
- TCA (decrease TCA conc. and increase AED)

2) Action
- stabilize GAB binding to GABAa receptor
- Interfere with post-synaptic glutamate signaling
Term
How do Lacosamade and Rufinamide work to treat seizures in epilepsy?
Definition
1) Lacosamide
- enhances slow-innactivation of Na currents
- low protein-binding (interactions)
- fairly low half-life

2) Rufinamide
- Inhibits VGSC
- short half-life (6-10h), with some protein interactions
Term
What is Carbatrol and how it used?
Definition
Extended-release version of Carbamazepine (CYP34A auto-inducer and hepatic metabolism)
Term
What is the major issue with use of AEDs for epilepsy treatment?
Definition
1) COST associated with drug interactions is higher than CVD and diabetic care

- Neuro/Psychiatric effects include Dizziness/Vertigo and Diplopia/Nystagmus (RISK OF SUICIDE)

- Phenytoin, Phenobarbital and Carbamezipine induce metabolism of other drugs, and are therefore more associated with interactions.

- Valproate and Felbamate inhibit enzymes and are thought to be safer
Term
When should Felbamate be given to treat seizures in epilepsy and how does it work?
Definition
Newer AED

1) Inhibitor of metabolism of other drugs
- Avoid with Warfarin (increase concentration and bleed/stroke)

2) Exhibits 4 types of mechanisms (Na, Ca, Glut, GABA)
Term
Why are newer AEDs preferred over older AEDs in the treatment of Epilepsy?
Definition
1) Fewer drug-interactions
2) Renal excretion
3) Pharmakokinetics
4) Weight-neutral
5) Low protein-binding
Term
Which AEDs have the broadest efficacy against seizure-subtypes?
Definition
1) Lamotrigine (not with birth control/breakthrough seizures)
2) Levitiracetam
3) Valproate
4) Topiramate
5) Zonisamide
Term
What is the most common issue when giving Phenytoin or Valproate for Epilepsy treatment?
Definition
Protein-binding issues (serum albumen)
Term
What AED options should be chosen for Focal seizures without impairment of consciousness?
Definition
1) CBZ (contraceptives, warfarin, statins, TCA)
2) Gabapentin (antacids)
3) Lamotigine (oral contraception)
4) Levitiracetam
Term
What AED options should be chosen for Focal seizures with impairment of consciousness?
Definition
1) Oxycarbazepine (K channel)

2) Topiramate (4 mechanisms)
Term
How do you treat generalized absence seizures?
What would be contraindicated?
Definition
1) Ethosuximide or Valproic acid (also for Myoclonic)

2) CBZ and PHT (also for Myoclonic)
Term
What is the dilemma over how to treat a first, unprovoked seizure?
Definition
1) 50% of the time, it won't come back
2) If you treat, 2.8x risk reduction (but long-term risk is unknown)

- If it happens again, TREAT.
Term
What risks are associated with chronic AED use?
Definition
1) Bone turnover
2) Osteoporosis and bone quality
3) Cognitive consequences (POLYTHERAPY
Term
A patient presents with right hemiplegia and cortical sensory loss, right homonymous hemianopia and global aphasia

Whats going on?
Definition
Global Aphasia Syndrome (left frontal, temporal and parietal involvement with non-fluent aphasia)

- Caused by internal carotid artery or MCA occlusion
Term
A patient presents with non-fluent aphasia.

What could be going on?
Definition
Perisylvian lesion with or without involvement of actual Broca's area.
Term
What fiber tract connects the inferior frontal gyrus (Broca) and the superior temporal gyrus (Wernicke)
Definition
Arcuate Fasciculus
Term
A patient presents with effortless language production, but with paraphasia (innacuracy) and abnormal comprehension. They are unaware of the deficit.

What could be causing these symptoms?
Definition
Fluent Aphasia

Lesion in posterior temporal/inferior parietal region.
Term
A patient has intact language production and comprehension, but with abnormal repetition.

What could be causing this deficit?
Definition
Perisylvian Conduction Aphasia, usually (but not always) occurring in Arcuate Fasciculus connecting Broca's and Wernicke's areas.
Term
A patient presents with non-fluent verbal output, but intact comprehension and repetition. They appear to have a lack of "verbal initiative"

Whats going on?
Definition
Extrasylvian Motor Aphasia
- Usually Broca area and adjacent regions
- May involve the supplementary motor area
- Distinguished from Broca's aphasia, because repetition is intact.


- Comprehension rules out Wernicke's
- Repetition rules out Conduction
Term
A patient presents with impaired verbal comprehension, but is conversation fluent. Repetition intact with frequent echolalia

Whats going on?
Definition
Extrasylvian Sensory Aphasia

- Not Wernicke's, because they are conversation fluent.
- Damage in temporo-occipital and parieto-occipital regions
Term
Why might a patient present with non-fluent verbal output and difficulty with comprehension?
Definition
Mixed Extrasylvian Aphasia due to infarcts in watershed zones.
Term
A patient presents with Acalculia, Agraphia, Alexia, left - right disorientation, finger agnosia.

What is going on?
Definition
Gerstman Syndrome (lesion to Gerstman area of Left Supramarginal-Angular Gyrus at temporal-parietal-occipital junction).
Term
What is known about the molecular basis for language processing?
Definition
FOXP2 transcription factor important for development of neural language areas.
Term
A patient presents with anterograde amnesia and non-fluent aphasia and visual agnosia. She is also having difficulty holding her attention.

What is going on and what should you do?
Definition
AD-type dementia


DSM criteria
1) Memory impairment
2) 2 or more of
- Aphasia
- Apraxia
- Agnosia
- Executive function
Term
A patient presents with reduced alertness and reduced ability to focus or shift attention. They appear lethargic.

It started approximately 4 hours ago and has since come in and out.

Whats going on?
Definition
Hypoactive Delirium

**Fluctuations are key for diagnosis, as is temporal pattern**

DSM criteria for Delirium

1) Develops over hours-days and fluctuates during course of day
2) Can by hypo or hyper-active
3) Supporting lab evidence of general medical condition
Term
What are the major important differences between Dementia and Delirium?
Definition
Dementia is irreversible and involves a structural as well as metabolic etiology

Delirium is reversible and usually stems from metabolic abnormality
Term
What is the relationship between ACh signaling and Delirium?
Definition
1) PPT/LDP project ACh fibers to RTN and intralaminal thalamic nuclei maintaining Attention, Arousal, Memory and REM Sleep.

2) Basal forebrain also produces ACh important for executive function.

3) Age-related decline in ACh neurons and decreased oxidative metabolism required for ACh synthesis/degradation has been observed.

4) Delirious patients have EEG that looks like NREM and anti-ACh drugs cause delirium
Term
What is the relationship between DA signaling and Delirium?
Definition
Mesocortical (VTA to frontal cortex) and Mesolimbic (VTA/NA/VP/Amygdala) systems important- TOO much DA in delirium (vs. too little ACh)

1) Hypoxia induces DA synthesis and delirium
2) Age-related DA-R decline and dementia with lewy bodies (DLB) seen with delirium
3) Hyperactivity in delirious patients
Term
What are the major causes of Delirium?
Definition
VITAMIN D

Vascular, Infection, Trauma, ANOXIA, Medications/Metabolic, Iatrogenic, Neoplasm, Development
Term
What major pathological changes are seen in AD?
Definition
1) Brain atrophy (selective neuron loss)
2) Amyloid plaques
3) Intracellular tangles tau (correlates with cognitive impairment)
4) Nucleus basalis of Mynert (ACh)
Term
How does Neurofibrillary tangle progression (NFT) correlate with cognitive symptoms?
Definition
1) Starts with episodic memory (NFT in entorhinal cortex and hippocampus)

2) Unimodal and heteromodal spread (this is where you find A-beta) leads to Aphasia (left), Visuospatial (right parieto-frontal) and/or executive (bilateral parieto-frontal) issues.

3) Primary sensory cortices spared until later (if you see early motor changes, it is not AD!)
Term
What are demonstrated risk factors for the development of AD?
Definition
1) APOE-4 allele
2) Age
3) Family history of dementia
Term
A patient appears parkinsonian and is experiencing visual hallucinations that began 3 months after the PD symptoms began. He explains that the hallucinations occur "minute-to-minute," but are worst at sleep-wake transitions.

The patien'ts partner complains that her husband has become "angry and violent" in his sleep, and that he as been experiencing ED as well.

What is the pathology of this condition?
Definition
DLB with characteristic autonomic dysfunction and REM sleep disorder. Don't give 1st generation anti-psychotics.

-Aggregates of alpha-synuclein form Lewy bodies in brainstem and limbic cortex, as well as diffuse cortical involvement.

1) Autonomic symptoms occur first

2) Pathology then ascends from the BG (SNpc) and Basal forebrain (NBM) into limbic cortex (Medial temporal lobe and amygdala)

3) Final spread to unimodal and heteromodal associative cortex.
Term
Which tau-based neurodegenerative disorder involves breakdown of dentate gyrus (cerebellum), midbrain and basal ganglia?
Definition
Parkinson Plus Syndrome (PSP)

- Shows axial rigidity, frequent falls, bradykinesia, abnormal vertical eye movements and dysexecutive symtpoms.
Term
A patient presents with axial rigidity, frequent falls, bradykinesia, abnormal vertical eye movements and dysexecutive symptoms.

What is going on?
Definition
Parkinson Plus Syndrome (PSP)

Tau-based neurodegenerative disorder involving breakdown of dentate gyrus (cerebellum), midbrain and basal ganglia
Term
Which tau-based neurodegenerative disorder involves degeneration of both Cortical and Sub-cortical (basal ganglia) neurons and glia
Definition
CBD


1) Extrapyramidal- rigidity, tremor, bradykinesia

2) Cortical:
Motor- apraxia, myoclonus, increased reflexes , speech disorders
Cognitive- neglect, aphasia, visualspatial difficulties, late memory problems
Term
What are the 2 categories of FTD and 2 important pathological markers?
Definition
Defined by abnormal behavior, dysexecutive problems and motor symptoms
**Cognitive initially overshadowed by motor**

1) Language predominant (SD)
2) Behavioral predominant (bvFTD)

1) Tau
2) Tar-DNA binding protein (TDP-43)
Term
What are the 2 AD forms of FTD?
Definition
Chromosome 17 representing 10-20% of FTD cases. Other common cause is TBI and both are more common <65 (compared to DLB)

1) Tau
2) Progranulin
Term
A patient presents with fluent speech, but poor single-word comprehension, especially of nouns. They seem to be quite egocentric with poor insight.

Whats going on?
Definition
Sounds like semantic predominant FTD

If it was non-fluent, agrammatic speech, you should think PFNA (progressive non-fluent aphasia)
Term
When do you most commonly see FTD with motor neuron disease?
Definition
bvFTD>>>SD/PNFA
Term
Which 3 brain regions are classically involved in FTD pathology?
Definition
1) OFC (bvFTD and SD)
- early in bvFTD and late in SD

2) DMPFC/Anterior Cingulate
- Decision-making/intentions into actions with DA from VTA
- Lesions produce apathy

3) Anterior temporal lobes (SD)
- Amygdala
- Left (word/object meaning) vs. Right (social/facial-emotional)
Term
A patient presents with poor insight, disinhibited and socially inappropriate behavior, emotional blunting and OCD tendencies.

Memory is fairly normal

Whats going on?
Definition
bvFTD (Pick's Disease)- associated with ALS

1) Early behavior changes and/or language problems and executive issues.

2) Symmetric gross atrophy in frontal an temporal lobes (vs. asymmetry in SD)

3) Intraneuronal au inclusions in frontal/temporal/limbic cortex (Pick bodies) or intraneuronal TDP-43 inclusions.
Term
Other than the Caudate, what other neural structures are often damaged in Huntington's disease?
Definition
Cerebellar vermis (truncal ataxia) and Cerebral cortex.
Term
A patient presents with bilateral cog-wheeling rigidity and bradykinesia, but no tremor is present. He has impaired postural reflexes on physical exam.

He also exhibits impaired eye motion in the horizontal directions as well as vertically.

He is not affected by Levodopa/Carbidopa treatment.

What is going on (including pathological basis)?
Definition
Progressive Supranuclear Palsy

**Progressive akinetic-rigid syndrome with eye movement abnormalities, and with eventual executive involvement**

1) Lesion to Basal ganglia (putamen and SNpc)
- causes rigidity, bradykinesia and postural reflex impairment.

2) Lesion to Optic tectum
- eye movement abnormality
- subtle degeneration of superior colliculi and adjacent areas near midbrain-diencephalic junction

3) Tau-tangles and loss of D2 receptors in Striatum
Term
A 32 year old patient presents with mild, symmetrical ataxia on finger-nose-finger testing. She has a wide-gait.

What is going on?
Definition
Early stages of Spinocerebellar disease (progressive and will include pons and middle cerebellar peduncle, as well as cerebral hemispheres, eventually).

- Appendicular ataxia and gait issues suggest involvement of vermis and intermediate zone of cerebellum (i.e. spinocerebellum).
Term
What autosomal recessive cerebellar ataxias are most common?
Definition
Earlier onset than AD ataxias

1) Friedreich ataxia
2) Ataxia-teangectasia
3) CoeQ deficiency
4) Inborn errors of metabolism
Term
What type of disease is indicated by rigidity and a "flapping tremor"
Definition
BG

Cerebellar tremors do not appear "flapping" and there is no rigidity in cerebellar disease
Term
What is the metabolic defect in Wilson's Disease?
Definition
Defect in ATP7B enzyme, which is necessary for transfer of copper to ceruloplasmin (this is how copper ends up in brain and exerts toxicity).
Term
A 26 year old female presents with right side numbness, right present babinski sign and bilateral hyperreflexia. There is also mild decrease in right proprioception on foot.

What is going on?
Definition
Could potentially be MS or partial transverse myelitis (need 2 lesions separated in time and space for MS)

Need an MRI
1) Right dorsal column involvement
2) Right Babinski (UMN)
3) Bilateraal hyperreflexia
Term
A 63 year old woman began suffering from developing weakness and sensory loss in her hands at age 25.

Her PE is normal for cranial nerves and mental status, but atrophy and fasciculations of the muscles of her hands and forearms are detected, as well as absent reflexes.

Proximal arm strength is good, as is leg strength, but temp/pain are absent bilaterally in a cape-like distribution from C4 down to T1.

What could be going on?
Definition
Could be Syringomyelia, Intrinsic spinal neoplasm or inflammatory process (Sarcoid).

Unifocal location suggets worsening structural lesion

There are LMN signs, but cannot be only motor, because there are sensory symptoms.
Term
A 41 year old woman presents with abnormal gait, Lhermitte's phenomenon, a positive romberg sign and sustained clonus bilaterally.

What could be going on?
Definition
Could be B12 deficiency (subacute combined degeneration of spinal cord)

- Copper deficiency, myeloneuropathy, MS, spinocerebellar degenernations, HIV and others are all possible.
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