First Pass Miss Flashcards
1
Q
What germ layer gives rise to the meninges? Include the two special terms for meninges.
A
Leptomeninges - pia / arachnoid mater - neural crest
Pachymeninges - dura mater - mesoderm
2
Q
What is metabolic astrocytosis?
A
Proliferation of gray matter astrocytes in response to metabolic injury -> i.e. hepatic or renal failure
3
Q
How does CSF compare to blood with regards to protein, chloride, glucose, and WBCs? Is it constant along the spinal cord?
A
Protein - increases towards lumbar cord (non-constant). Normal is <50 mg/dL
Chloride - Higher than blood
Glucose - comparable but slightly lower than blood
WBCs - very few 0-5 cells / mL, elevations suggest meningitis
Produced at a rate of 0.5 L/day
Normal pressure 50-200 mmHg
4
Q
What is communicating hydrocephalus and what causes it? What will happen to ICP?
A
Impaired flow or resorption of CSF outside the ventricular system
- > i.e. scarring of arachnoid granulations post-meningitis
- > will increase ICP
5
Q
What is vasogenic edema? Where does it especially affect?
A
“White matter edema” - Most pronounced in white matter. Increased interstitial fluid due to blood brain barrier breakdown secondary to inflammation, tumor, etc
Associated with increased protein in the interstitium
6
Q
What is interstitial edema? Where does it especially affect?
A
Increased resistance to CSF outflow leads to increased intracranial pressure (obstructive or communicating hydrocephalus) and breakage of blood-CSF barrier, but will NOT cause a protein increase in the interstitium
Basically, edema caused by excess CSF
-> Affects predominantly the periventricular white matter (around where the CSF is)
7
Q
What are the characteristic signs of increased ICP?
A
Headache
Papilledema
Vomiting
Cushing’s triad: Bradycardia, high blood pressure, Cheyne-Stokes breathing
Focal neurological signs and dilated / blown out pupils
Abnormal posturing / altered mental status
8
Q
What is a cingulate herniation also called and what issue can it cause?
A
Subfalcine - displacement of cingulate gyrus under the falx cerebri
-> can cause compression of anterior cerebral artery, leading to infarction
9
Q
What are the two types of transtentorial herniations? What might cause them?
A
These involve displacement of brain structures through tentorium cerebelli opening (incisure)
- Central - bilateral and symmetric, leading to caudal displacement and compression of entire brainstem -> i.e. due to diffuse brain swelling
- > causes fatal Duret hemorrhages (paramedian basilar pontine) - Uncal - unilateral, with herniation of medial temporal lobe into midbrain
- > i.e. due to supratentorial hemorrhage
- > can compress ipsilateral CN3, ipsilateral PCA, and contralateral crus cerebri (false localization sign via Kernohan notch)
10
Q
What is a tonsillar herniation and what is the usual clinical result?
A
Herniation of cerebellar tonsils into foramen magnum
Compression of brain stem (medulla) leads to cardiopulmonary arrest
11
Q
What are the clinical symptoms of most brain tumors?
A
Increased ICP -> headache, papilledema, due to mass effect
Local damage to structures -> focal neural deficits
Damage to cerebral cortex -> seizures
12
Q
What molecular abnormalities characterize oligodendroglioma and what is its clinical presentation? What area of the brain is usually involved?
A
Codeletion of 1q and 19p chromosomes, and isocitrate DH
Clinical presentation - slow-growing tumor in young adults which may contain calcifications. Most often in frontal lobe, causing seizures
Fried egg appearance of oligodendrocytes
13
Q
What is the most common CNS tumor in children and where does it tend to arise in adults and children? Include the disease association.
A
Pilocytic astrocytoma - low-grade astrocytoma which does not progress like diffuse gliomas
Children - cerebellum
Adults - cerebral cortex, spinal cord, or associated with optic nerve (optic glioma of NF-1!!!)
14
Q
How does pilocytic astrocytoma appear grossly and microscopically?
A
Grossly - cystic lesion with nodular mass which grows adjacently on its wall.
Microscopically - Rosenthal fibers -> thick, eosinophilic aggregates of alpha-B-crystalline which accomulates in processes of astrocytes
15
Q
What tumor is characterized by perivascular pseudorosettes? Why does it form this pattern, and who tends to get it?
A
Ependymoma - tumor of ependymal cells which form rosettes around vasculature -> similar to choroid-plexus type shape, which is made of specialized ependymal cells
Tends to be in children
-> causes obstructive hydrocephalus by blocking 4th ventricle
16
Q
Who tends to get choroid plexus tumors and what is the major presenting symptom?
A
Tends to occur in children, even infants -> symptom is often congenital hydrocephalus (if in infants) -> overproduction of CSF, or blockade of outflow
papilloma vs carcinoma, only true primary brain tumor which is benign vs malignant
17
Q
What is “drop metastasis”?
A
Metastasis to cauda equina -> lower spinal cord
- > spread of medulloblastoma thru CSF
- > medullablastoma can also cause obstructive hydrocephalus by compressing 4th ventricle
- > homer-wright rosettes around pink neuritic cell process (neuropil), grows in cerebellum
18
Q
What is the most common benign CNS tumor in adults and who tends to get it? What is the cell of origin?
A
Meningiomas - more commonly seen in women because it expresses the estrogen receptor
Cell of origin - arachnoid cells (neural crest derived)
- > associated with chromosome 22 deletions (think meningiomas in NF-2)
- > form calcified psammoma bodies
19
Q
How is a Schwannoma different from a neurofibroma, and what genetic disease is associated with each?
A
Schwannoma - generally grow as solid masses - often associated with NF-2 (bilateral acoustic Schwannoma)
Neurofibromas - infiltrative growth pattern in nerve - associated with NF-1 - unable to resect without nerve damage
20
Q
What is Leptomeningeal carcinomatosis? What does it mimic?
A
Spread of tumor cells into subarachnoid space and through CSF
-> mimics acute or chronic leptomeningitis due to high CSF protein, hydrocephalus, and involvement of multiple cranial and spinal nerve roots
21
Q
What are Brudzinski’s and Kernig’s signs and what are they indicative of?
A
Indicative of acute meningeal irritation
Brudzinski - “B”ringing the neck forward in flexion -> observe for any flexing of hips and knees
Kernig sign - Starting from flexed hip / knee - extension of knee is resisted
22
Q
How does the clinical syndrome of aseptic meningitis differ from acute purulent meningitis?
A
Systemic signs of fever / headache are still there, but it is generally milder and does not cause significant alteration in levels of consciousness. Mild and self-limiting.
-> usually caused by enteroviruses, but may be caused by carcinomatous meningitis, or chemicals / drugs
-> acute purulent often causes focal CNS signs, seizures, and alteration of consciousness
23
Q
What is chronic meningitis and what is it caused by?
A
Chronic inflammatory process of leptomeninges
- > relatively persistent or indolent agents
- > TB, sarcoidosis, meningovascular syphilis, etc
24
Q
How is chronic meningitis diagnosed? CSF characteristics?
A
Non-specific findings of slowly evolving headache, low-grade fevers, rarely seizures / cognitive dysfunction. Difficult to diagnose.
CSF - increased pressure due to blockage of CSF flow
Increased protein
Decreased glucose, but not as much as acute
Leukocytosis - predominantly lymphocytes and monocytes (forming granulomas)
25
What cells does Rabies affect?
Pyramidal cells of the hippocampus (think of pyramid in boat with seahorse) + Purkinje cells of cerebellum (think of bungee cords from tree (folia of cerebellum)
Cytoplasmic inclusions = Negri bodies
26
How does virus usually spread to the brain, and how is encephalitis diagnosed?
Sometimes by axonal transport, but usually hematogenous spread
- > Diagnosed via index of suspicion especially following aseptic CSF findings
- > can do PCR assay for virus (HSV1 most common)
27
What are a few examples of agents causing chronic "slow" viral hepatitis?
HIV - AIDS dementia
JC virus - PML
Measles - SSPE
HTLV-1 - tropical spastic paraparesis
28
What is the pathogenesis of meningitis in HIV?
Acute - can cause acute aseptic meningitis during primary infection
Chronic HIV encephalitis - progressive dementia and infected monocytes / T cells cross BBB and infect microglia / damage white matter -> progressive demyelination like PML
29
What are the Tauopathies?
Disorders of tau protein accumulation
Alzheimer's, Pick disease, progressive supranuclear palsy
30
What are three other common changes seen in elderly patients with or without diagnosis of Alzheimer's disease?
1. Hirano bodies - crystalloid, rod-like structures made of actin alongside hippocampal neurons
2. Granulovacuolar degeneration - intracytoplasmic vesicles with tau core
3. Amyloid angiopathy - deposition of beta-amyloid in walls of leptomeningeal and intracortical blood vessels
31
How is A-beta amyloid formed? How is it usually cleared?
APP is normally cut by alpha-secretases
If APP is cut by beta-secretases -> this is further processed by gamma secretase and forms I-40 and I-42 beta-amyloid.
It is neurotoxic and usually degraded and cleared by proteosomes of astrocytes
32
What is Pick disease? What are the symptoms?
Frontotemporal dementia
Frontal lobe effects - behavioral symptoms, especially disinhibition
Temporal lobe - aphasia (language effects)
-> associated with 3R tau accumulation
Microscopic - "Pick bodies" - round aggregates of tau protein in neurons of the cortex
33
What drives amyloid formation in sporadic vs familial forms of Alzheimer's?
Sporadic - environmental factors such as metal ions, free radicals, and oxidative stress
-> antioxidants may be of some benefit
Familial - mutations induce misfolding of amyloid
34
What are the characteristic physical exam findings and EEG findings of CJD? CSF?
Physical exam - rapidly progressive dementia with startle myoclonus
-> MRI enhances in basal ganglia
EEG findings - periodic sharp waves
CSF - elevated levels of 14-3-3 protein
35
What does the pathology of CJD look like?
1. Spongiform degeneration -
Represents intracellular vacuoles filled with abnormal PrPsc protein -> tends to be in gray matter areas where there its lots of neuropil (vacuolated cytoplasmic processes)
2. Gliosis - extensive astrocyte hyperplasia and activation of microglial cells (beyond what would be normally expecting)
3. Neuronal loss - apoptosis with activation of microglial cells, but minimal inflammation and minimal atrophy (since so rapid)
4. Amyloid plaques - in various places depending on exact type of CJD
Susceptibility determined by codon 129 on chromosome 20
36
Define anomia, anosognosia, neglect
Anomia - difficulty finding words - (without name)
Anosognosia - difficulty to recognize illness / lack of awareness of one's disability
(without-disease-knowledge, nosos = disease)
Neglect - Inattention to stimuli from one side of the visuospatial environment
37
How do transcortical motor / transcortical sensory aphasia differ from other aphasias?
Transcortical motor - affects frontal lobe around Broca's area. Similar symptoms except repetition is intact (Broca's area not affected)
Transcortical sensory - affects temporal lobe around Wernicke's area. Similar symptoms except repetition is intact (Wernicke's area not affected)
Transcortical mixed aphasia = echolalia
38
What does a dominant parietal lobe lesion cause?
Gerstmann's syndrome
- think of someone trying to count their fingers
Tetrad:
-Finger agnosia - cannot identify finger named by examiner or recognize which finger has been touched / moved
-Left-right disorientation
-Acalculia
-Agraphia - writing impairment
39
What will lesion of the nondominant parietal lobule cause?
Contralateral neglect, often with anosognosia of the issue.
If it affects more superior portion can cause constructional apraxia (difficulty drawing objects like clockface) or dressing apraxia (poor processing of spatial information so cannot put clothing on well)
40
What is Balint's syndrome? What is notably preserved?
Triad:
1. Oculomotor apraxia - cannot gaze effectively via saccadic eye movements
2. Optic ataxia - can't reach out to a visual target accurately (i.e. finger to nose on someone else, but could do on themselves easily since proprioception is intact)
3. Simultanagnosia - visual inattention, can'tt ell whole from the parts. Often associated with prosopagnosia.
Basically similar in reasoning to Anton syndrome, and Anton may recover thru Balint's.
Color vision is notably preserved. -> loss would occur in achromatopsia due to inferior occipital lobe lesions
41
What is visual agnosia?
Ability to see and describe an object's features without being able to recognize / name it, as well as associate it with its function
Patient does not have anomia - i.e. they can tell you what a glove is
They can even draw the object and match it to a drawing or picture
i.e. man who took his wife for a hat
42
What are the portions of the brain responsible for each type of memory?
Working memory / attention span - frontal cortex
Short-term memory and longterm memory - hippocampus and neocortex
Motor skills / conditioned reflexes - cerebellum / neocortex
43
What are the symptoms of amnestic syndrome?
Mixture of anterograde and retrograde amnesia which will improve as the lesion resolves
-> patient will be left with a memory gap
44
What is transient global amnesia?
An acute onset transient anterograde amnesia which is usually benign, but leaves a permanent memory gap during that period
There will be a full recovery of anterograde memory
45
What are the symptoms of dissociative amnesia?
Inability to recall DISTANT memories -> personal information, with intact recent memory for recent events (how it is differentiated from other amnesias, violates Ribot's law)
- > usually occurs secondary to longterm trauma or stress
- > may be accompanied by dissociative fugue (wandering)
46
What scale helps distinguish vascular dementia from other kinds of dementia? How does it work / what is it looking for?
Modified Hachinski Ischemic Score. Score >7 = vascular dementia
-> Asks about abruptness of onset, stepwise deterioriation, presence of risk factors for CVAs, and focal neurologic signs which would not be present in other causes of dementia
47
What are the clinical features of Lewy body dementia? What precipitates symptoms?
Changes in attention and alertness that fluctuate greatly
Frequent visual hallucinations
Parkinsonism within 1 year of dementia onset
Symptoms precipitated by antipsychotics and antinausea drugs (metoclopramide) which are D2 receptor antagonists -> worsen parkinsonism
48
What are a few routine tests which should be done to rule out other causes of dementias?
Serum B12, LFTs (hepatic encephalopathy), thyroid function tests, depression screenings (pseudodementia), BUN/creatinine (metabolic encephalopathy), etc
49
What is mild neurocognitive disorder define? "pre-dementia"
```
Modest cognitive decline in one or more cognitive domains:
Complex attention
Executive function
Learning and memory
Language
Perceptual-motor
Social cognition
```
Range of 1-2 standard deviations below normal, but do not interfere with function and are not due to another mental disorder or delirium
50
How does vasogenic vs cytotoxic edema appear differently via imaging?
Vasogenic - extracellular edema due to BBB breakdown, follows white matter tracts in FINGER-LIKE projections - "white matter edema"
Cytotoxic - intracellular edema from disruption of Na/K pump - involves both gray and white matter (seen in acute stroke from ischemia) - no finger-like projections, involves large areas, MOSTLY gray matter involvement
51
What contrast type is used for CT and for MRI? What are the risks for each?
CT - iodine-based -> may cause nephropathy
MRI - gadolinium-based -> may cause nephrogenic systemic fibrosis, a scleroderma-like syndrome. Happens less now that we do MRIs less.
52
What are normal X-rays / radiographs still important for in spine evaluation? Where have they been supplanted?
Important in LIGAMENTOUS instability with flexion / extension films
-> very cheap and easy to use. Can see bony fractures, deformities, and osteophytes
Also okay for evaluation of radiculopathy (spinal nerve root impingement)
Have been supplanted in evaluation of trauma -> CT shows improved fracture detection.
-> Fractures are only thing which CT is better than MRI for
53
What is the only thing which CT has no efficacy in at all and cannot be done for?
Cord signal abnormalities -> cannot detect demyelinating diseases of the cord via CT
54
What is the best way to workup arthritis / degenerative disc disease in imaging?
Best: MRI if patient able
| Best alternative: CT / CT myelography if patient is not MRI compatible
55
How is epilepsy defined? Three definitions.
1. At least two unprovoked seizures occurring more than 24 hours apart (could be 60 years).
2. One unprovoked seizure and a probability of further seizures (i.e. tumor was due to a tumor, trauma, or stroke and will likely recur)
3. Diagnosis of an epilepsy syndrome
56
When does Todd's paralysis occur and what is it?
When there is a seizure of the premotor cortex
- > post-ictal paresis contralateral to seizure side
- > occurs due to depletion of glutamate during seizure
57
Where do partial vs generalized seizures generally start?
Partial - Medial temporal lobes
| Generalized - Thalamus
58
What else is on the differential diagnosis of seizures?
1. Movement disorders
2. REM sleep behavior disorder (may be mistaken for frontal lobe epilepsy)
3. Migraines with auras (vs simple partial seizures)
4. Limb-shaking transient ischemic attacks
5. Syncope
6. Hyperventilation syndrome
7. Psychogenic non-epileptic spells
59
What type of syncope mimics seizures? How is it told apart?
Convulsive syncope where patient can have myoclonus, hallucinations, automatisms, etc
Syncope is precipitated by postural changes, has a long prodrome, is precipitated by emotion, pain, heat, is not associated with post-ictal confusion, and is commonly associated with cardiovascular signs
60
What is the most common epilepsy syndrome and what is the most common neuropathologic finding in patients when it is medically refractive?
Temporal lobe epilepsy
- > commonly caused by hippocampal sclerosis / mesial temporal sclerosis
- > neuronal loss and gliosis in CA1/3 of ammon's horn, dentate gyrus, subiculum, and entorhinal cortex
61
What is Benign Epilepsy with CentroTemporal Spikes (BECTS) and what is the prognosis?
Focal epilepsy syndrome characterized by epileptiform spikes on EEG
Occurs in children age 3-13 years, can have hemifacial motor seizures and facial twitching which usually occurs at night -> may progress to bilateral tonic clonic
No treatment is generally required because there will be remission by mid-teens
62
What seizures characterize juvenile myoclonic epilepsy (JME)? What precipitates them?
1. Myoclonic jerks of arms (usually early morning)
2. Generalized tonic-clonic
3. Behavioral arrest / staring spells
Precipitated by sleep deprivation, alcohol use, and stress
4-6 Hz spike and wave, seizures controlled by meds for life
63
What is the diagnostic triad of Lennox Gastaut syndrome? Prognosis?
1. Multiple seizure types (atonic, absence, tonic, generalized tonic-clonic)
2. Developmental delay
3. Slow 1-2.5 spike and wave on EEG as a baseline (not just during seizures)
-> patient will have static encephalopathy with poor prognosis
64
What is EEG actually recording? And what is the gold standard for seizure diagnosis?
Summation of excitatory or inhibitory post synaptic potentials -> NOT action potentials (dendritic processes of outer cortex have EPSP and IPSP)
Gold standard: Epilepsy monitoring unit -> video recording of seizure with EEG
65
What are the non-pharmacologic treatment options for focal seizures? Generalized?
1. Resective surgery
2. Vagus nerve stimulator
3. Responsive neurostimulator device (i.e. deep brain stimulation) -> implanted near brain foci to terminate seizure
Generalized - vagus nerve stimulator and corpus callosectomy
66
What are the side effects of concern when adding phenytoin or fosphenytoin?
Hypotension and CNS depression
May cause purple glove syndrome rarely: a thrombophlebitis which could require amputation (more common with phenytoin)
67
What two drugs should never be given together in status epilepticus?
Diazepam followed by phenobarbital -> may cause hypotension / severe respiratory depression
68
What are the two general types of absence seizures and what is the treatment?
Childhood absence - usually between 4-8 years and spontaneously remits
Juvenile absence - starting closer to puberty, may progress to a worse seizure disorder
Treatment is ethosuximide
69
What are two important considerations in the dosing of phenytoin?
1. Highly protein bound to albumin >90%
| 2. Undergoes zero-order (capacity-limited) metabolism when at therapeutic concentrations
70
Other than phenytoin, what other AED is highly protein bound to albumin and what difference does this make?
Valproic acid
- plasma free drug concentration will be increased in conditions of albumin wasting:
1. Nephrotic syndrome
2. Liver disease
3. Acute illness
71
Why are bone disorders are problem in patients being treated with AEDs?
Increased risk of fractures when falling during seizures
They are really common because of enzyme induction of carbamazepine, phenytoin, and phenobarbital -> leads to vitamin D wasting.
May need to give calcium supplements and bisphosphonates, check bone mineral density every 5 years
72
How does degeneration of striatum in Parkinson's and Huntington's differ and thus relate to symptoms?
Parkinson's - preferential loss of putamen over caudate -> loss of motor function first
Huntington's - preferential loss of caudate - cognitive and eye movement abnormalities. Impulsive behavior (loss of Nucleus accumbens) occurs often before choreiform movements
73
What are the matriosomes and what do they more contribute to?
Neuronal areas which makes up both the direct and indirect pathway - Receive cortical inputs from layer V mostly sensorimotor and association cortex. Most high concentrations of D2 receptors, but also have some D1 for the direct pathway.
74
What do D1-expressing medium spiney neurons do?
They are primary striosomal, integrating sensory information, but there are also some D1-expressing medium spiney neurons which form the majority of the direct pathway.
D1 receptors are excitatory (increase cAMP)
75
Other than atherosclerosis, what are some other vascular disorders which can cause damage to the brain?
Arteriolosclerosis - i.e. hyaline, due to chronic HTN or diabetes
Aneurysms - saccular, mycotic (infectious)
Cerebral amyloid angiopathy - Abeta amyloid
Vasculitidies
Clotting disorders
Nonthrombotic emboli
76
What is the timeline of histological changes which occur in ischemic stroke?
12 hours: Red dead neurons - eosinophilic cytoplasm with pyknosis
24-72 hours: Necrosis + neutrophilic acute inflammation
3-5 days: Microglial infiltration + liquefaction, inflammatory edema peaks
1-2 weeks: Gliosis with increased astrocytes / progressive liquefaction and removal of necrotic debris
Weeks later: Fluid-filled cystic cavitation surrounded by gliosis
77
What neurons in the brain are most susceptible to ischemic infarct during diffuse ischemic injury?
1. Pyramidal neurons of cortex in layers 3, 5, and 6
2. Pyramidal neurons of hippocampus in Sommer's sector (CA1)
3. Cerebellar Purkinje cells
4. Watershed zones
78
What is a lacunar stroke and why do they generally occur?
A small infarct (<1cm) which occurs due to small vessel occlusion.
Commonly due to hyaline arteriolosclerosis secondary to chronic hypertension
-> occurs in lenticulostriate arteries most commonly
79
What are the causes of diffuse hypoxic / ischemic injury in the brain (global stroke)?
1. Global ischemia -> failure of systemic circulation (i.e. cardiogenic shock, atherosclerosis)
2. Systemic hypoxia -> anemia, CO poisoning, or respiratory issue
3. Hypoglycemia -> systemic, i.e. due to insulinoma (brain needs glucose)
80
What are the two types of intraparenchymal hemorrhage? Where do they each occur?
1. Ganglionic - "deep" - occurs in basal ganglia (lenticulostriate arteries), thalamus, pons, or deep cerebral hemisphere
- > typically secondary to charcot-bouchard aneurysms and chronic hypertension
2. Lobar - superficial in cerebral lobes, not as severe
- sometimes HTN, but usually secondary to amyloid angiopathy, vasculitidies, coagulopathies, and vascular malformations
81
What are the acute and chronic complications of subarachnoid hemorrhage and what drug can be used to reduce this?
Acute - arterial vasospasm leading to ischemia / infarction of structures supplied by vessels (secondary ischemic stroke)
-> prevented by nimodipine
Chronic - Breakdown of hematoma with scarring which may cause a communicating hydrocephalus (damage to granulations)
82
Other that Charcot-Bouchard aneurysms and lacunar infarcts, what is one important brain pathology finding that chronic hypertension can cause?
Etat crible - loss of tissue density around small arteries without any infarction
"perivascular vacuolization"
- frequently occurs in basal ganglia or white matter
83
What does malignant hypertension cause in the brain and clinically?
Acute hypertensive encephalopathy
Increased ICP, confusion, headache, brain edema, petechial hemorrhages, and fibrinoid necrosis of arterioles
84
What conditions predispose to berry aneurysms and where do they often occur? How do they predispose?
1. Autosomal dominant polycystic kidney disease
2. Marfan syndrome
3. Ehlers-Danlos
Often occur at branch points in the circle of willis:
1. Anterior communicating/ACA junction
2. Posterior communicating / MCA junction
3. MCA/lenticulostriate junction
Hypertension is the #1 risk factor for their progression
85
What are the modifiable risk factors for stroke?
Atherosclerosis risk factors, same risk factors as Alzheimer's disease:
1. Hypertension
2. Diabetes
3. Dyslipidemia
4. Smoking
5. Elevated homocysteine
6. Alcohol
7. Obesity
8. Sedentary lifestyle
86
What are the absolute contraindications to tPA?
1. Head trauma / stroke in past 3 months
2. Previous history of hemorrhage
3. BP > 185 systolic or 110 diastolic
- > achieve goals with labetalol, clevidipine or nicardipine
- > hydralazine could worsen cerebral edema
4. Elevated aPTT or PT, current anticoagulation
5. Low blood glucose
6. CT suggests multilobar infarction
7. Tumor or intracranial / intraspinal surgery in last 3 months
87
What drugs should be started for secondary prevention following a stroke?
1. Antihypertensive agents - ACE inhibitor / diuretic
2. Statin therapy - regardless of LDL
3. Antiplatelet agents - aspirin, clopidogrel, or aspirin / dipyridamole (phosphodiesterase inhibitor) -> annotate this
88
Give four examples of dysimmune chorea.
1. Sydenham's chorea -post-strept
2. anti-NMDA receptor encephalitis - usually presents with chorea
3. Chorea gravidarum - occurring in pregnancy
4. Lupus - due to anticardiolipin Abs
89
Give three examples of toxic dystonia. Genetic?
1. Acute dystonia to neuroleptics
2. Tardive dyskinesia - chronic D2 blockade
3. Tetanus - loss of GABA and glycine from Renshaw cells in spinal cord
Also caused genetically by Wilson's disease
90
Where are the three characterizing features of a tremor?
1. Rhythm - fast vs slow (they are always regular)
2. Morphology - flexion vs extension, pillrolling, etc
3. Circumstance when tremor is greatest - resting, postural, or action
91
What type of tremor is essential tremor, and what is the frequency? Is it unilateral or bilateral?
High-frequency tremor (8-12 Hz), postural tremor (worsens with sustained posture)
Onset is BILATERAL, although it may be asymmetric
92
Where do myoclonus jerks originate from and what are they frequently seen in?
Originate from any part of CNS (cortex, brainstem, spinal cord)
Frequently seen in metabolic abnormalities -> renal or liver failure
93
What are some other autosomal recessive / nutritionally related ataxia other than Friedreich's?
1. Ataxia-telangectasia (DNA repair problem)
2. Ataxia with vitamin E deficiency - spinocerebellar degeneration
3. Abetalipoproteinemia - Vitamin E deficiency
4. Refsum disease - accumulation of branched fatty acids from lack of peroxisome genesis
94
What are the autosomal dominant ataxias of concern?
Mostly spinocerebellar ataxias (SCAs) for which you should do a gene panel for
95
What are the features of postural instability in Parkinsonism?
1. Flexed posture - shoulders bent over
2. Festination - shuffling gait, walking forward quickly to catch weight
3. Retropulsion - difficulty balancing oneself when pulled backward, need to take a few steps back (walking backward)
96
Other than the motor features, what are some other broad functional deficits which occur in Parkinson's? When do these occur in relation to motor symptoms?
1. Cognitive disturbances - depression and dementia
2. Autonomic dysfunction -> especially constipation
3. Altered senses -> especially anosmia
4. Sleep disorders -> especially REM sleep behavior disorder and insomnia
These can occur (except dementia) before motor symptoms
97
What is the pattern of spread of neuronal loss in Parkinson's? What symptoms does this explain?
"Braak Stages" - Starts in medulla and moves its way up to eventually involve the cortex (final stage is dementia).
Parkinson's development exists on a spectrum, and at least 50% of dopaminergic neurons need to be lost in order to have disease
Explains early symptoms
- > anosmia - anterior olfactory nucleus involved early
- > constipation - dorsal motor nucleus of X affected early in medulla
98
What was the first discovered cause of Familial Parkinson's disease? What is the function of the malfunctioning protein?
Autosomal dominant mutations in synuclein on chromosome 4
- synucleins are abundant in neurons at presynaptic terminals
- bind lipid vesicles and integrate signalling and membrane trafficking
- important in dopamine vesicle organization, and plays are role in other neurodegenerative diseases
Synucleins can spread like prion proteins when they misfold
99
What gene is mutated in autosomal recessive Parkinson's inheritance and what is the clinical picture? Most common gene?
Parkin gene - functions as an E3 ubiquitin ligase and proteasome regulator
- Early Parkinson's (20s) but slow progression
- Patients do NOT have Lewy bodies
LRRK-2 mutations most common, low penetrance, viewable as a "super risk factor", presents like idiopathic Parkinson's
100
What Parkinson plus syndrome is characterized by more severe autonomic dysfunction and what is this dysfunction? What are its subclassifications?
Severe orthostatic hypotension and urinary incontinence, preceding movement disorder
1. Multiple System Atrophy with predominant parkinsonian features (MSA-P)
- > no resting tremor, hyperreflexia and dystonia
2. Multiple System Atrophy with predominant cerebellar features (MSA-C)
- > predominant gait disorder w/ limb ataxia
Features of both can cross over, it's a spectrum
May not respond to L-dopa.
101
What are the hallmark features of progressive supranuclear palsy (PSP)?
1. Parkinsonism -> early FALLS and axial rigidity, + symmetric! (Parkinson's usually asymmetric)
2. Impaired eye movements - "supranuclear" because cortical OKR reflex (tracking the train as it goes by) is lost, but VOR is preserved
3. Cervical dystonia with bulbar dysfunction
4. Frontal dementia
102
What is the toxicity associated with amantadine?
Ataxia, livedo reticularis
103
What can cause delayed onset of response with levodopa / carbidopa?
Delayed gastric emptying -> due to eating with large meal or taking anticholinergics (i.e. benztropine)
Too much dietary protein -> inhibits dopamine uptake
Ferrous sulfate -> chelates the drug and leads to decreased absorption
104
What are the hallucinations which can happen with dopaminergic treatment and how can they be treated?
Usually visual hallucinations, though they may become distressing
Treat with clozapine or quetiapine -> atypical antipsychotics less likely to block D2 and worsen symptoms
105
What is a triad vs a dyad and where do they exist in muscle?
Triad - T-tubule + 2 terminal cisternae (extensions of sarcoplasmic reticulum), exist at A/I junction in SKELETAL muscle, 2 per sarcomere
Dyad - T-tubule + 1 terminal cisternae, exist at Z line in CARDIAC muscle, 1 per sarcomere
106
What are the clinical features of myopathies, including type of weakness and lab values?
Symmetrical weakness, affecting proximal > distal muscles
Fatiguability
Features of myonecrosis: myoglobinuria, elevated CK, hyperkalemia
107
What are the mechanisms of polymyositis vs dermatomyositis?
Polymyositis - autoinvasive CD8+ T cells with endomysial inflammation due to direct attack of muscles
Dermatomyositis - Antibody or immune-complex mediated microangiopathy (affects blood vessels) with secondary muscle damage -> perimysial innervation (blood vessels in perimysium)
108
What are some causes of steroid myopathy and how does it occur?
1. Iatrogenic steroid
2. Endocrinopathies i.e. Cushing's disease
Steroids impair muscle protein / carbohydrate metabolism due to insulin resistance and protein catabolism -> selective atrophy of Type 2 fibers
109
What are the consequences of segmental demyelination?
1. Remyelinated segments may not conduct as efficiently as normal segments (shorter internodal segments)
2. Onion bulb formations -> concentric proliferation of Schwann cells and collagen around nerve fiber leads to enlargement of nerve fascicle called "hypertrophic neuropathy"
110
Give a couple other causes of endocrine myopathies than thyroid hormone and cortisol?
1. Acromegaly - increased GH leads to abnormal muscle growth
| 2. Hypoparathyroidism - hypocalcemia -> tetany -> muscle breakdown
111
What drugs are associated with toxic myopathy? Include drugs causing myopathy with neuropathy, and drugs causing cardiomyopathy?
Myopathy with neuropathy - statins, fibrates, organophosphates, vincristine
Cardiomyopathy: doxorubicin, metronidazole (high dose in Crohn's)
Grand trio: COLCICHINE, doxorubicin, chloroquine / hydroxychloroquine, fibrates, ethanol
112
What will EMG (electromyography) show at rest vs. slight contraction vs maximal contraction in denervated muscle (neurogenic atrophy)?
Rest - fibrillation - denervated muscles produce extrajunctional ACh receptors and begin to fire randomly
Slight contraction - giant unit waves with high amplitude -> motor units are much larger on small firing due to "fiber type grouping"
Maximal contraction - reduced interference pattern -> fewer motor units fire
113
What will EMG (electromyography) show at rest vs. slight contraction vs maximal contraction in myopathy?
Rest - Fibrillation - fibers are still sick so they fire randomly
Slight contraction - small amplitude units - motor units innervate fewer fibers (muscle disease / atrophy)
Maximal contraction - full interference pattern, but lower amplitude than normal, due to loss of muscle fibers
114
Give viral, bacterial, and parasitic causes of infectious myositis.
Viral - influenza / parainfluenza, coxsackievirus
Bacterial - S. aureus or S. pyogenes
Parasitic - T. spiralis, cysticercosis, toxoplasmosis
115
Which inflammatory myositis presents more acutely and is associated with systemic symptoms? What are its symptoms?
Dermatomyositis
- erythematous dermatitis over upper trunk, neck, and extensor surfaces of fingers, elbows, and knees
- heliotrope rash - purple discolatoration with periorbital edema
- rash on fingers gives look of calloused 'mechanics hands' with nailbed infarcts
116
What is the most typical treatment regimen for DM/PM?
Prednisone, which should be gradually tapered as symptoms improve.
- > Add azathioprine, MTX, cyclosporin as needed
- > rituximab if refractory
117
What are the clinical features of Duchenne? Are there any CNS symptoms?
Patients present by age 5 with waddling gait due to pelvic girdle muscle weakness -> lordosis. Calf muscles shorten with pseudohypertrophy. Become wheelchair dependent by age 12. Cognitive impairment is common as dystrophin is needed for neuronal maintenance.
Death occurs due to respiratory compromise / infection / dilated cardiomyopathy
118
What are the relevant symptoms of myotonic dystrophy type 1?
Most common muscular dystrophy of adults, due to CTG repeat in DMPK gene
CTG - cataracts, toupee (frontal balding), gonadal atrophy
Myotonia - inability to relax muscles after vigorous effort - i.e. handshake
Muscular dystrophy
EKG changes - heart block leads to arrhythmias
119
What is Charcot-Marie-Tooth disease also known as? Is the myelin or axon defected?
Hereditary motor and sensory neuropathy (HMSN)
-> myelin or axon could be affected, depending on the subtype -> need to do nerve conduction studies or biopsy to confirm
120
What will lab testing of small fiber neuropathies show? How is it diagnosed?
Normal reflexes, strength, and EMG assuming it is only small fiber involvement (A-delta fibers are needed for reflex pathway)
-> skin biopsy is widely accepted technique for diagnosis, with special stains to quantify nerve fiber density
121
Prior to EMG and more invasive studies, what clinical workup should be done for evaluating neuropathy?
Genetic testing if family history is positive, and examine family members if possible
Ask about alcohol and inhalant use / exposures
Chemistry panel with tests for syphilis, lyme disease, diabetes, and autoimmune causes of axonal neuropathy
122
How do patients present with ALS? Is bowel / bladder dysfunction common?
Any combination of UMN and LMN weakness involving limbs / bulbar innervated muscles -> can cause swallowing / voice problems
It is asymmetrical.
Bowel / bladder dysfunction is relatively rare until late in the disease -> sphincters are spared
123
What is the most common familial ALS mutation, and what is the most common cause overall?
Familial ALS - superoxide dismutase 1 (SOD1) -> leads to free radical injury of neurons
-> overall, usually idiopathic
124
How is SMA categorized? Which one is most severe?
Based on age of onset and severity
Most severe: infantile form (SMA I) called Werdnig-Hoffmann disease, presents a floppy baby with fasciculations
Least severe form is SMA III: Kugelberg-Welander, adolescent onset
Most common lethal AR condition in Caucasians behind CF
125
What does dense artery sign + loss of gray/white distinction + gyral swelling and sulcal effacement mean and what do these indicate when taken together?
Dense artery sign - intraluminal thrombus -> area enhances on CT due to thrombous
Gray-weight distinction loss -> increased water content of cortex making it more hypodense -> seen in first few hours of infarct
Gyral swelling / sulcal effacement - late manifestations of acute infarct (12-24 hours) from brain swelling
126
Will T2 MRI become positive very quickly in acute infarct?
No -> there is no significant net increase in water content following infarction, and thus normal T2 will appear unchanged until about 6-8 hours post infarct when enough water has actually gotten into the brain to make it appear bright
Visible by early T2 DWI: Early restricted diffusion makes cells swell as water enters them from the interstitium, but there is no major increase in brain water
127
What is the radiologic hallmark of multiple sclerosis?
Periventricular plaques which are areas of oligodendrocyte loss and reactive gliosis. Lesions may also exist in corpus callosum. Will appear hypointense on T1 and hyperintense on T2
Dawson's fingers are plaques reaching from corpus callosum
Many white matter lesions disseminated in time and space
128
Where in the brain does metastatic cancer typically spread to, and what are the most common types of cancer to spread there?
80% will spread to gray / white junction of cerebrum
15% will spread to cerebellum
Lung, breast, and melanoma are most common cancers to spread there
129
What is the role of the cortex to suppress pain and how can neurotransmitter imbalance affect this?
Cortex sends down descending pathways which release NE, 5-HT, and GABA to facilitate the inhibition of excitatory pain impulses
- > pain loop should shut off overtime
- > GABA and NE release is decreased in central sensitization, while glutamate is increased (works through exciting nerve thru Ca+2 channels, the target of pregabalin and gabapentin)
130
How does peripheral sensitization occur?
1. Inflammation damages or destroys peripheral nerves
2. Threshold for firing is lowered, as regeneration of nerve triggers development of excess Na+ and adrenergic channels.
3. Peripheral neurons fire impulses spontaneously leading to pain
Common in conditions such as diabetic neuropathy, post-herpetic neuralgia, and trigeminal neuralgia
131
What type of pain is neuropathic pain usually described as? What other symptoms often go with it?
Shooting or stabbing pain, or "Shock-like" electric pain.
Orthostatic hypotension - autonomic neuropathy
Bowel dysmotility - autonomic neuropathy
Stocking and glove pattern -> distal sensory polyneuropathy
132
What drug classes are most closely associated with neuropathic pain?
Anti-retrovirals & HIV itself
Cancer chemotherapy** - cisplatin, vincristine, paclitaxel, thalidomide
Antibiotics - isoniazid
133
What are the agents for neuropathic pain?
1st line: Lidocaine, pregabalin, gabapentin, duloxetine,
2nd line: Opioids (avoid), tramadol, TCA's, venlafaxine
3rd line / adjunct: Valproic acid, topiramate, lamotrigine, capsaicin (depletes substance P)
134
What is a concussion? What are the possible sequellae?
A type of closed head injury where there is instant onset transient neurological dysfunction, with or without loss of consciousness
Possible sequellae include post-concussive syndrome.
-> prolonged symptoms of concussion lasting 7-10 days:
headache, dizziness, nausea, memory disturbance, depression, sleep problems, difficulty concentration, mental fog
Repetitive concussions may cause chronic traumatic encephalopathy
-> progressive degeneration in football players and boxers, with plaques and tangles, hydrocephalus ex vacuo, and degradation of substantia nigra + locus coeruleus
135
What is diffusion axonal injury (DAI) caused by and what will happen to axons?
Rotational / acceleration injuries with whiplash - axons get torn at nodes of Ranvier due to shearing forces.
There will be perivascular microhemorrhages and formation of swollen axons which accumulate beta-amyloid.
136
# Define the following skull fracture types:
1. Linear
2. Basal
3. Depressed
4. Diastatic
5. Comminuted
1. Linear - fracture lines radiate from site of impact
2. Basal - fracture of basal skull
3. Depressed - Skull is depressed into cranial cavity, like a pingpong ball (often in children)
4. Diastatic - Separation along suture lines
5. Comminuted - fragmented bone into pieces
Displaced -> when bone enters cranial cravity at depth greater than thickness of skull
Compound -> also causes laceration in overlying scalp
137
What clinical signs and symptoms are associated with basilar skull fracture?
Raccoon eyes - orbital hematomas
Battle's sign - bruising near mastoid process
Lower cranial nerve involvement
138
What are the possible complications of open skull fracture?
Standard:
1. Intracranial hematoma
2. Damage to cranial nerves
Unique to the fact that it's open:
3. CSF leak -> through ear or nose
4. Pneumocephalus - ingress of air
5. Meningitis - easy entry of infectious agents
139
What pathology can be seen on CT secondary to diffuse axonal injury?
"Shearing hemorrhages" - small little contusions due to shearing forces on blood vessels
-> remember the perivascular microhemorrhages
140
What are the causes of vertebral and carotid artery dissection?
Carotid artery - hyperextension and rotation of neck (i.e. chiropractor) or direct blow to anterolateral aspect of head
Vertebral - cervical spinal cord fracture
Tears vessel intima and leads to bloodflow into vessel wall.
Can lead to superimposed thrombosis and stroke
141
What is ASIA-A vs ASIA-B?
ASIA - A = complete, no preservation in S4-S5
ASIA - B = sensory incomplete - S4/S5 preserved (LT, PP, or DAP) + no motor function preserved more than 3 levels below the NLI on either side
(deep anal pressure)
142
What are the Kock-Witebsky Postulates of autoimmune disease?
1. Circulating antibodies are present and titers are related to disease activity
2. Passive transfer of antibodies should reproduce all major pathogenic effects (reproduce in animal models)
3. Immunization with putative antigen should produce the disease in healthy animals
143
Give three tests which can be used in the bedside diagnosis of MG?
1. Arm abduction time - patient holds arms out as long as possible, MG holds usually <2 min
2. Edrophonium test -> better if testing diplopia, make sure to have atropine ready to reverse bradycardia
3. Ice pack test - cooling inhibits AChE, will improve ptosis if present
144
What is the most sensitive EMG test for neuromuscular junction disease in general and how does it work?
Single fiber electromyography (SFEMG)
- hook up electrodes to a single motor unit with two fibers coming from it.
- healthy individuals will have a normal delay based on the distance apart between two motor fibers
- diseased individuals will have varying delay times between firing of 1 & 2 because the response is unpredictable
- > "jitter pattern" on EMG
145
How do the clinical symptoms of LEMS (aside from EMG studies and reflexes) differ from MG?
1. Bulbar and respiratory muscles are less frequently affected than MG, and gait is more affected
2. Associated with more autonomic dysfunction (not purely neuromuscular ACh release that's inhibited)
- > loss of PANS = dry mouth, impotence
146
How does treatment of LEMS differ from MG?
LEMS - less responsive to pyridostigmine
Add: Fampridine (3,4-diaminopyridine) -> enhances calcium entry by inhibiting K+ channels, prolonging repolarization
-> may be CNS-toxic and cause seizures
147
What is the most common subtype of Guillain-Barre syndrome? What nerve types are affected and where are they affected most?
Acute inflammatory demyelinating polyneuropathy (AIDP)
Autoimmune destruction of peripheral myelin (Schwann cells) -> affects both sensory and motor nerves -> especially proximally / distally where the blood-nerve barrier is the weakest
148
What is the treatment of choice for AIDP? Are there circulating antibodies which are pathogenic? Should you use prednisone?
Plasmapheresis and IVIg
-> Pathogenic circulating antibodies have never been demonstrated, but intraneural injection of patient serum has produced conduction block in rats
Note: Steroid therapy is NOT helpful!!
149
How is MMN told apart from ALS and what antibody is associated? Does it respond to plasmapheresis?
MMN has no UMN symptoms, only lower motor neuron
Associated with anti-GM1 ganglioside antibodies
Responds well to IVIg but not plasmapheresis
150
What paraneoplastic syndrome has been associated with the development of ataxia, and what antibodies are the culprit?
Paraneoplastic Cerebellar Degeneration
Antibodies against Purkinje cells of cerebellum
-> i.e. anti-Yo antibodies
Associated with breast and gynecologic malignancies
-> ay-Yo baby girl how u doin, you making me swoon and fall over (cerebellar ataxia)
151
What paraneoplastic syndrome is associated with neuroblastoma in children and what are the symptoms?
Opsoclonus-Myoclonus
"Dancing eyes, dancing feet" -> multidirectional rapid eye movements with myoclonus
152
What antibodies are isolated in paraneoplastic encephalitis and sensory neuronopathy?
Anti-Hu antibodies, especially in small cell lung cancer patients
-> small Hu-man
153
What is PANDAS and what is it associated with?
Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection
- > analogous to Sydenham's chorea following Strept infection
- > Associated with child onset tic disorders and obsessive-compulsive disorder
154
What is the disease modifying medication in MS which is an analog of myelin basic protein which distracts the immune system?
Glatiramer
155
What is mitoxantrone's mechanism and why is it rarely used anymore?
Antibiotic-class antineoplastic
Rarely used now because it is cardiotoxic (anthracycline)
Finglomid -> prevents lymphocytes from leaving LN
Teriflunomide -> inhibits dihydroorotate reductase
Dimethyl fumarate -> inhibits B cells
156
What is the new IV medication for treatment of MS which is a large step following natalizumab? What other drug is it similar to?
Ocrelizumab
- > think "okra" (ocrelizumab)
- > anti-CD20, so it is active against B cells, causing antibdoy-depending cellular cytolysis
-> like rituximab, but more humanized so fewer serum sickness reactions
157
What is neuromyelitis optica?
A severe inflammatory demyelinating disease selectively affecting optic nerves and spinal cord
- > considered a severe variant of MS
- > anti-aquaporin 4 antibody to astrocyte foot processes, treat with plasmapheresis and rituximab
Fisher syndrome is to AIDP as neuromyelitis optica is to MS
158
What are the first and second line suggestions for migraine prophylaxis?
First line: Beta blockers or topiramate
-Tricyclics like amitryptyline if h/o depression
Second line: Verapamil, if beta blockers not tolerated.
Valproic acid also an option
159
What is used for acute treatment and prophylaxis in cluster headache?
Acute - 100% oxygen therapy and sumatriptan
Prophylaxis - Verapamil preferred > lithium
160
What is the neurovascular hypothesis for how migraine is generated?
Trigeminovascular system is a network of nerve fibers innervating cranial vessels in meninges
Sensitization of vessels occurs when nerves release substance P, calcitonin gene-related peptide (CGRP), and vasoactive peptides, causing irritative vasodilation
5HT1B - Blood vessel vasoconstriction
5HT1D - Inhibits release of vasoactive peptides
161
What can be used as prophylaxis for menstrual migraine?
1. Birth control pills - keeps estrogen more level and constant
2. Standard prophylaxis
3. "Miniprophylaxis" - taking triptans right before you think a migraine is likely to happen during your menstrual cycle (only time triptans are used prophylactically)
162
What should be used and avoided in patients with migraines during pregnancy? Is it common to have migraines in pregnancy?
Less common -> estrogen levels stable
Tylenol and caffeine are probably the best
Avoid:
NSAIDs - prevent PGE2, especially in third trimester is important
Ergots - cause vasoconstriction which can cause intrauterine contraction
Triptans - uterine vasospasm
163
What is the most commonly used ergot alkaloid and what should be given with it?
Dihydroergotamine
-> may cause gangrene due to sympathomimetic properies. Avoid in hepatic disease due to CYP interactions
Commonly used with metoclopramide (antiemetic)
164
What are the most serious adverse events of triptans and hence contraindications?
Coronary vasospasm -> MI, arrhythmias, and strokes
Contraindicated in Prinzmetal angina, coronary artery disease, and uncontrolled HTN
Avoid in hepatic disease. Also has CYP interactions. Don't use with a MAO-A inhibitor within 2 weeks -> serotonin syndrome
