Neurology Flashcards
first sign myasthenia gravis
diplopia and ptosis
often worse at the end of the day
Mobius syndrome
Congenital palsy of multiple cranial nerves, most often the 6th (abducens) and 7th (facial) nerves.
Normal intelligence
what does floppy weak vs floppy strong refer to ?
when assessing a baby with hyptonia,
floppy strong= low tone but no weakness: central cause, chromosomal, syndromic, metabolic
floppy weak= weak, poor antigravity movements: peripheral cause, neuromuscular disease
which part of the motor unit is affected in spinal muscular atrophy
anterior horn cell
creatinine kinase is raised in …
peripheral causes of neuromuscular disease
There are many peripheral neuromuscular conditions where the CK is always elevated from birth (e.g., in Duchenne and Becker muscular dystrophies, and in some of the congenital muscular dystrophies, and some limb girdle muscular dystrophies) and other conditions where CK is mildly elevated or normal (e,g., spinal muscular atrophy, neuropathies, and congenital myopathies)
also see elevated transaminases in DMD and BMD
SMA genetics
autosomal recessive
Carrier frequency in population 1/50
deletion of exon 7 of the SMN1 gene (chromosome 5)
SMN2- nearly identical to SMN1 but differs at a single nucleotide, which modulates splicing, resulting in a lack of exon 7 from 90% of mRNA transcripts - however does make some functional protein
thus, those with mild disease tend to have more copies, those with severe disease have less copies (eg SMA1 have 2 x SMN2 copies, thoese with SMA4 have >4 copies SMN2)
Subtypes SMA
tongue fasiculations occur in …
SMA (anterior horn cell pathology)
basics of SMA presentation
floppy weak baby with bright alert face
SMA1- present in neonatal period –> hypotonia, poor antigravity movement, weak cry, bulbar dysfunction/feeding difficulties, tongue fascinations, areflexia, respiratory insufficiency, death by 2 years
SMA2- present 6-12 months, sit but dont walk, progressive muscle weakness, orthopaedic complications (scolitosis, contractures, resp weakness (frequent chest infections, nocturnal resp support needed), normal IQ
SMA3- onset 18-24 months, walk unaided but maybe late, can later lose walking ability. Progressive PROXIMAL muscle weakness, especially shoulder girdle, reduced reflexes, tremor
Ix: newborn screening, SMN1 single gene testing or multigene panel (not microarray- deletion is too small to detect)
CK is mildly elevated
SMA treatment
Modulation of the low functioning SMN2 gene
- Nusinersen - intrathecal
-Risdiplam - oral
Nusinrsen
“antisense oligonucleotide therapy”
modifies splicing of SMN2 gene allowing incorporation of exon 7 into SMN2 –> increasing production of full length SMN2 mRNA
needs to be used every 4 months forever
has clear survival advantages and improved gross motor milestones
best outcomes if treatment started early prior to irreversible loss of motor neurons
Gene therapy
- replacement or correction of the faulty SMN1 gene
“Zolgensma” - single dose
AAV9 vector carries the replacement gene into the body
Dystrophy vs Myopathy
Dystrophy
- degenerative loss and destruction of previously normal muscle “breakdown of muscle
- progressive clinical course
- often abnormal extracellular proteins
- high CK
Myopathy “muscle disease”
- abnormality in intracellular protein architecture
- usually stable muscle weakness
- mild increase in CK
Duchenne Muscular Dystrophy
X linked recessive
Out of frame mutation in DMD gene - encodes dystrophin (usually large insertion or deletion causing frameshift)–> premature stop codon, so bridge function of dystrophin lost
No dystrophin production
Progressive degeneration, fibrosis, muscle fibre death
More common than BMD
Symptoms start at 3-5 years- delayed gross motor milestones, frequent falls, difficulty climbing stairs, toe walking, low mean IQ (may present with learning difficulties or ASD prior to weakness so always do a CK level if any kind of delay!!)
Sleep study then FVC to monitor progression of restrictive lung disease
Steroids can slow progression
Most will need bipap
Becker Muscular Dystrophy
X linked recessive
In frame DMD mutation - residual dystrophin production
Can occasionally affect girls (eg Turners, skewed X lyonisation)
Onset usually teen years
Muscle cramps and pain more prominant
CK usually <5000
Role of dystrophin is to …
bridge actin cytoskeleton to extracellular matrix
DMD complications
achilies tightening
contractures
loss of ambulaiton
resp weakness, nocturnal hypoventialation requiring BIPAP
scoliosis
Dilated cardiomyopathy (100% by 20 years)
examination DMD
Proximal “limb girdle” weakness
Positive Gowers sign
Scapular winging (weakness of thoracoscapular muscles)
Calf pseudohypertrophy
No facial weakness
CK usually >5000
Toe walking
Often present with diffiulty climbing stairs, funny gait developmental delays
Investigations of DMD/BMD
Genetics: dystrophin MLPA, or dystrphin sequencing
Muscle biopsy
Neuroimaging
EMG
- all not usually done
Treatment DMD/BMD
STEROIDS
- slow decline in musce strength and function
stabilise lung function
delay need for NIV and wheelchair
Limb girdle muscular dystrophy
Predominant weakness around shoulder and hip girdle
Onset >2 years, childhood
Variable progression
Present with progressive gait difficulties and scapular winging, positive Gower
No facial weakness
CK usually >5000
Ix: gene panel
Congenital myotonic dystrophy
-CTG Triplet repeat - DMPK gene
-autosomal dominant
- phenotype depends on number of repeats. Normal = 3-37, premutation 37-50, affected >50 , congenital >1000 (less repeats lead to presentation in childhood or adulthood)
- anticipation; number of repeats more likely to increase with female transmission
- often diagnose mother after infant
- progressive weakness, hypotonia, facial weakness, tent mouth, bulbar dysfunction, may require respiratory support, gross motor and cognitive developmental delays ( facial weakness NOT a feature of SMA unless extremely severe)
** Need to examine parents for myotonia
but babies have hypotonia
Mildly elevated CK
Facio-scapular humeral dystrophy
3rd most common muscular dystrophy after myotonic dystrophy and DMD/BMD
- AD inheritance
- present in adolescence
- arm weakness, difficulty raising arms, prominent scapular winging and highly mobile scapula
-facial weakness
- can sometimes progress and cause loss of ambulation
Myotonic dystrophy
50->800 CTG repeats present in childhood or adulhood
progressive muscle weakness
Myotonia
Low IQ
slow gastric emptying, constipation
hypothyroidism
testicular atrophy, male infertility
low IgG
cataracts “ christmas light cataracts”
Arrythmias
fatigue and hypersomnolence
Congenital myopathy
-Non dystrophic muscle disease- non progressive or slowly progressive
-Structural abmormality of muscle - mutation in sarcomeric proteins/contractile apparatus
- Can be evident from birth or early childhood
- generalised weakness, myopathic (tent) facies, bulbar dysfunction, aspiraiton, resp weakness, arthrogyposis, scoliosis, contractures, normal cognition
- may have hx of polyhydramnios and reduced fetal movements
examples: nemaline myopathy, central core disease, centronuclear myopathy
best diagnosed with a gene panel
normal or only mildly elevated CK
Central core myopathy associated with malignant hyperthermia
Charcot Marie Tooth
progressive peripheral neuropahty
- motor and sensory
distal > proximal
reduced distal reflexes- eg absent ankle jerk (distal)
- demyelinating and axonal types
- often present in late childhood/adulthood 5-25 years
- tibeal and peroneal nerves are earliest and most severely affected eg toe walking, progressive weakness of dorsifexion –> foot drop
–> distal weakness, distal wasting, pes cavus, reduced distal reflexes, pain on prolonged ambulation,
palpably enlarged nerves
- <5% become wheelchair dependant, but normal life expectancy
Sensation may be spared until later on in disease
Sensory loss to pinprick and proprioception in a length-dependent manner (glove and stocking)
Demonstrate length-dependent loss by running sharp object up the limb
Gait: high steppage, may have sensory ataxia
Positive Rhomberg’s sign as disease progresses
CMT1A: demyelinating
- damage to myelin sheath –> slowed motor nerve conduction
- PMP22 gene duplication - can be detected on microaray, AD
CMT2: axonal
- axon itself is damaged, low amplitude action potential, but conduction velocity is maintained
Ix: nerve conduction studies (motor and sensory velocities reduced), CK normal, sural nerve biopsy diagnostic, geentics
Rx: pain management, support
transient myosthenia gravis
10-20% of infants born to myasthenic mothers due to transfer of maternal AChR antibodies
- present with feeding and respiratory difficulties by 72 hours of life - hypotonia, weakness, weak cry, stridor, recurrent choking/apnoeic episodes
- may present with reduced feta movements, arthrogyposis if severe
Diagnosis:
neostigmine (inhibits acetylcholyesterase)
Rx: support with feeding and breathing
Neostygmine
Symptoms resolve by 2 months
When to think about myasthenia gravis?
fatigable weakness
ptosis
opthalmoplegia
dysarthria
dysphagia
symptoms worse at end of day or after repeated activity
Myotonia congenita
Muscle channelopathy —> muscle membrane hyperexcitability
impaired relaxation
warm up phenomenon- usualy worse after period of rest and improved with continuing exercise
worse in cold
muscle hypertrophy
can present with difficulty opening eyes
Symptoms include delayed relaxation of the muscles after voluntary contraction (myotonia), and may also include stiffness, generalised hypertrophy (children resembling body builders), sluggishness of movement, transient weakness in some mutations, pain, and cramping. Myotonia is prominent and may develop at 2-3 years of age. The disease may appear clinically stable and non-progressive for many years. Routine histochemical preparations of muscle biopsy are non-diagnostic and show minimal pathologic changes.
Incidence of epilepsy
Epilepsy affects 1% Australians
benign familial neonatal seizures
Channelopathy- mutation in voltage-gated K+ channels – KCNQ2 and KCNQ3
AD inheritance
Clonic seizures, onset first few days of life, usually resolve in weeks
Normal development
Exclude other causes and use anti seizure meds to treat acutely, but no long term medications - usually very good prognosis
***rare severe outcome with KCNQ2 epileptic encephalopathy
West syndrome
Triad: Infantile spasms, hypsarrhythmia, developmental arrest
Epileptic encephalopathy
Clusters of brief contractions especially on waking
Peak onset 3-7 months, almost all in first year
most common cause is focal cortical dysplasia
Poor prognosis
Rx: steroids/ACTH, vigabatrin for tuberus sclerosis
Mutations: ARX, SPTAN1, STXBP1, CDKL5
Aicardi syndrome
absence of corpus collosum
infantile spasms
chorioretinal lacunae –> vision impairment
microcephaly
Lennox-Gastaut syndrome
Childhood onset
Usually 2-8 years
May evolve from West syndrome, or be previously normal
Clasically multiple seizure types, periods of non convulsive status
Multiple (hundreds) seizures/day - including drop attacks (helmet)
EEG: slow spike wave <2.5hx
Profound retardation
Dravet syndrome
severe myoclonic epilepsy of infancy
presents in 1st year of life
prolonged, febrile or afebtrile , hemiclonic GTC seizures - but not limited to one side
Related to fever, hyperthermia- hot baths, illness, vaccination
Main mutations: SCN1A (less commonly-SCN2A)
Can also lead to gefs +
Genetic epilepsy with febrile seizures plus
Spectrum includes Dravet syndrome, up to 75% SCN1A positive
AD inheritance
Mutation itself doesnt predict phenotype
Febrile siezures continue >6 years
GTC in adolescence then remission
May have other seizure types
Self limited epilepsy with centro temporal spikes
onset 4-10 years
focal sensorimotor seisures from sleep involve face and tongue, may progress to GTC
Normal exam, development may be mildly affected
Most have infrequent seizures, 20% single seizure
Rx: nil or carbomazepine (low dose)
Interpreting EEG
Odd numbers = left
Even numbers = right
F= frontal
C= central
T= temporal
O= occipital
hz= number of waves between green markers (per 1 second)
Childhood absence epilepsy
Staring spells ~10 seconds
Abrupt cessation of activity, motionless blank stare, ends abruptly, not aware of event
Peak 5-6 years
Normal IQ and development, but may have social and learning difficulties
EEG: 3Hx spike wave
**provoked by hyperventilation **
Rx: ethosuxamide, valproate
Second line: lamotrigine
AVOID carbamazepine
Some patients go on to have JME
Most remit in adolescence
Juvenile absence epilepsy
Absence seizures, multiple/day <5
Onset 8-20 years, peak ~10 years c. Long duration of absences
May have non convulsive status
More likely to have GTC (80%)
Investigations
a. EEG similar to CAE; polyspikes more common
Rx: females: lamotrigine
males: valproate
NOT ethosuxamide as more GTC seizures here
less likely to remit than CAE
Juvenile Myoclonic epilepsy (JME)
Age onset 8-26, peak 12-16 years
Lifelong epilepsy
Early morning myoclonic jerks, (eg drop breakfast, hairbrush, toothbrush)
90% have GTC, up to 30% absence
EEG: 4-6Hzz polyspike wave - provoked by photic stimulation
1st line- vaproate, lamotrigine
Again, avoid carbamazepine which aggrevates absence and myoclonic seizures
Temporal lobe seizures
1.focal , no change in awareness
Often aura
2.focal with change in awareness
- behavioral arrest, unresponsiveness
- automatisms- mouth and hand
- more prolonged absence than absence seizures , longer post ictal peirod
- usually amnesic for seizure, may recall aura
most common type of focal epilepsy
most commonly caused by hippocampal sclerosis (prev long febrile seizure), also trauma, infection, hamrtoma, glial tumor
Must do MRI- check for hippocampal sclerosis or another cause
Ammenable to surgery- cut out affected badness
Frontal lobe epilepsy
Clusters of motor seizures often nocturnal - bizzare complex motor activity
Brief <30 sec
Minmal post ictal confusion
often bicycling automatisms
facial swollowing, chewing, hypersalivation
prominant vocalisation common
clue- stereotyped for each patient
DDX- night terror (but much older kids), occurs most nights and brief compared to night terrors
Landau-Kleffner
Acquired epileptic aphasia
Regression in expressive language, seizures
change in personality/behavior
EEG: continuous status epilepticus in sleep
Difficult to treat
Benign sleep myoclonus
babies
only in sleep
multifocal - not just one limb
stops with gentle pressure
Tics
Stereotypes, brief, repetitive, sudden movements
Motor or vocal
Many /day
Able to suppress for variable periods
May change over time
M»F
Median onset 6-7 years
Wax and wane, most reduce by adulthood
Rx: reassurance, clonidine if QOL affected
CACNA1A gene mutation
Mutations in ion channel genes, in particular CACNA1A, have been implicated in familial hemiplegic migraine (FHM) and in the development of concussion-related symptoms in response to trivial head trauma.
Moyamoya disease
progressive cerebrovascular occlusive disease of the bilateral internal carotid arteries that leads to a compensatory abnormal vascular network at the base of the brain.
presents as ischemic stroke, TIA, headaches, aphasia, cognitive decline
Malignant hypothermia
Malignant hyperthermia is a syndrome which is usually inherited as an autosomal dominant trait. It occurs in all patients with central core disease but is not limited to that particular myopathy.
Acute episodes are precipitated by exposure to general anaesthetics and occasionally to local anaesthetic drugs.
Patients suddenly develop extreme fever, rigidity of muscles, and metabolic and respiratory acidosis; the serum CK level rises to as high as 35,000 IU/L. Myoglobinuria may result in tubular necrosis and acute renal failure.
Neuroleptic malignant syndrome
MRI findings in white matter diseases
Metachromatic leukodystrophy- white matter hyperintensities around both front and back of lateral horns
Adrenoleukodystrophy- bilateral parieto-occipital periventricular white matter hyperintensities (back of lateral horns)
Leigh sryndrome- bilateral symmetric areas of T2 hyperintensite in basal ganglia and brainstem
when is valproate contraindicated
children <2 years (hepatotoxicity if there is an underlying metabolic syndrome) or in girls of child bearing age
can be used for both focal and generalised seizures
when is carbamazapine contraindicated
Dravet syndrome
absence epilepsy
juvenile myoclonic epilepsy
children of Han Chinese descent- SJS
In general, dont use for any generalised epilepsy. Only use for focal epilepsies
posterior reversible encephalopathy syndrome
vasogenic oedema
headache
seizures
confusion/altered mental status
vision loss (cortical blindness)
hypertension
usually subacute presentation
RISK FACTORS:
severe hypertension
renal failure
immunosuppressive medications such as tacrolimus and cyclosporin
chemotherapy
hypomagnesemia
post-transplant
MRI: hyperintensity in occipital (posterior) lobes
non convulsive status epilepticus
persistent change in mental status from baseline lasting more than 5 minutes, generally with epileptiform activity seen on EEG monitoring and subtle or no motor abnormalities
neurotoxicity secondary to asparaginase
Acute encephalopathy
Hyperammonianemia
cerebral venous thrombosis and cavernous sinus thrombosis
thrombus in the dural venous/cavernous sinuses
Presentation: severe headaches, weakness, seizures, raised ICP (headache, vomiting, papilloedema)
CNS defects due to the intracranial nerves that pass through the cavernous sinus - III, IV, V (V1 and V2), VI
can lead to haemrrhagic stroke
most often caused by head and neck infections and sepsis
thrombophilia, chronic inflammatory disease, sickle cell anemia, cocp, etc
Cavernous sinus thrombosis:
Eye findings are nearly universal (90%). These include periorbital edema, lid erythema, chemosis, ptosis, proptosis (due to impaired venous drainage of the orbit), restricted or painful eye movement, and less commonly papilledema. Can lead to blindness
Most common CN palsy- CN 6
resulting in partial ophthalmoplegia with limited eye abduction. Most cases, however, progress rapidly to complete external ophthalmoplegia from third, fourth and sixth cranial neuropathy.
Internal ophthalmoplegia results in a nonreactive pupil, from paralysis of the iris and ciliary body, either constricted (miosis) from loss of sympathetic fibers from the short ciliary nerves or dilated (mydriasis) from loss of parasympathetic fibers from cranial nerve III.
Cerebral venous thrombosis: adache, seizures, decreased level of consciousness, and focal neurologic deficits.
Adverse effects all AEDs
fatigue, impaired cognition, altered mood and behavior, suicide risk
Vagibatran and keppra can cause depresion and psuchosis
lamotrigine and gabapentin can stabilise mood’
Na channel- headache, nausea, dissiness, fatigue, ataxia
Rash
AED most associated with rash
Lamotrigine most associated with SJS
- need to titrate slowly
Carbamazepine most associated with SJS in Han Chinease- need to test for HLA B1502 (as phenytoin)
Which AED has best safety profile in pregnancy?
Lamotrigine
VPA most associated with neural tube defects, congenital heart disease, cleft palate
Which AEDs are renally excreted?
Levetiracetam
Gabapentin
Vabigatrin
Topiramate
Which AEDs are metabolised in the liver?
Carbamazepine
Valproate
Lamotrigine
Diazepam
Phenytoin
Phenobarb
What is the AED of choice for MOST childhood epilepsy
valproate
good for all types including absence
**keppra ineffective for absence
Which AEDs are associated with weight gain ?
VALPROATE, Carbamazepine, gabapentin, vigabatrin, clobazam
Weight neutral: lamotrigine, keppra, phenytoin
Which AEDs are associated with weight loss
Topiramate
Which AEDs are sodium channel blockers?
Carbamazepine
Phenytoin
Lamotrigine
Topiramate
Valproate
Which AEDs are calcium channel blockers
Ethosuximide
Gabapentin and pregabalin to lesser degree
Which AEDs are GABA ergic?
Phenobarbitone
Valprotate
BZD
Clobazam
Vigabitran
What is the mechanism of action of levetiracetam
Unknown
Binds to synaptic vesicle protein SV2A
Main side effects are neuropsychiatric
Bell’s palsy
Bell’s palsy is a form of facial paralysis resulting from a dysfunction of the cranial nerve VII (the facial nerve) that results in the inability to control facial muscles on the affected side.
It is thought that an inflammatory condition leads to swelling of the facial nerve
The facial nerves control a number of functions, such as blinking and closing the eyes, smiling, frowning, lacrimation, salivation, flaring nostrils and raising eyebrows
They also innervate the stapedial (stapes) muscles of the middle ear and carry taste sensations from the anterior two thirds of the tongue.
The glossopharyngeal nerve is associated with taste sensation to the posterior third of tongue.
Layers of cerebral cortex
