Neurology Flashcards
Antibody associated with Miller Fisher syndrome
GQ1B antibodies - present in 90-95% of MFS cases
Antibodies associated with Acute Motor Axonal neuropathy
GD1a, GM1
Antibodies associated with sensory GBS
GD1b
Poor prognostic factors for GBS
Rapid onset prior to presentation (<7 dayys)
High disability nadir
Mechanical ventilation
Severely reduced CMAPs
Older than 40 yrs
Preceding diarrhoea illness - Campylobacter jejui
Preceding infection with CMV
Inexcitable nerves
Definition of epilepsy
- At least two unprovoked (or reflex) seizures occurring > 24 hours apart
- One unprovoked seizure and probability of further seizures similar to general recurrence risk after two unprovoked seizures, occurring over next 10 yrs
- Diagnosis of epilepsy syndrome
Classification of seizures
Focal onset
- Aware vs impaired awareness
- Motor or non motor onset
- Focal to bilateral tonic-clonic
Generalised onset
- Motor - tonic clonic vs other motor
- Non-motor - absence
Unknown onset
Focal seizure semiology
Temporal - deja vu, olfactory aura, epigastric rising feeling, oral automatisms
Occipital - simple visual hallucinationrs
Primary auditory - buzzing/ringing
Primary motor - focal clonic activity
Frontal - complex motor behaviour
Management of focal seizures
1st line - Carbamazepine
Other agents - lamotrigine, topiramate, levetiracetam, gabapentin
Surgical procedures - temporal lobectomy, lesionectomy, cortisectomy, implanted devices
Childhood absence epilepsy
Onset between age 4-10
Dominant seizure type absence seizures (rare GTCS)
Juvenile absence epilepsy
Onset over age 10
Commonly absence, but more likely GTCS and may have myoclonus
Juvenile myoclonic epilepsy
Onset over age of 10
Myoclonus common - occurring early morning or shortly after walking
GTCS common and absence can occur
Lennox Gastaut syndrome
Occurring in early childhood
Multiple seizures types
Associated with developmental disability
Management of generalised epilepsy
Sodium valproate
Levetiracetam
Lamotrigine
Topiramate
Management of absence seizures
Ethosuximide
Structural lesions for epilepsy
Hippocampal sclerosis
- defined by increased T2 signal and reduced size
Benign tumours
- dysembryoplastic neuro-ectodermal tumour
- ganglioglioma
- cortical dysplasia
Vascular malformations
- cavernoma
- arterio-venous malformation
Malignant lesions
- metastatic
- primary
AEDs in pregnancy
Lamotrigine
- 2-3 fold increase in metabolism during pregnancy
- metabolism enhanced by oestrogen
Levetiracetam
- increased renal clearance in 2nd-3rd TM
HLA association between SJS and carbamazepine
HLA B*1502
Associated greatest in Asian ancestry
Treatment of status epilepticus
1st line - IV/IM benzodiazepine (midaz, loraz)
2nd line - Levetiracetam, phenytoin, sodium valproate
Indication of cannabidiol in management of epilepsy
Dravet syndrome
Lennox Gastaut syndrome
Dravet syndrome
Severe epilepsy syndrome due to Na+ gene mutation (SCN1A) treatment refractory seizures of multiple types
Risk factors for SUDEP
Male gender
Young age
Non-compliance
Poorly controlled epilepsy
Prone sleeping
Sleeping alone
Risk and protective factors for Parkinson’s disorder
Risk factors:
- Age
- Pesticide/solvent exposure
- Farmers
- High levels of education
- History of TBI
- Low sunlight/vitamin D
- Melanoma
- Genetics
Protective:
- Smoking
- Artistic occupation
Genetic markers for PD
PARK 1-15
Pathogenesis of PD
a-synuclein key protein in pathogenesis of PD
- prone to mutate and form insoluble species which aggregate in neurons through genetic or environmental factors
- spread in prion-like fashion through CNS
Lewy body
- pathological hallmark of PD
- composed of alpha synuclein
Clinical features of PD
In order of progression:
Change in bowel habits/constipation
RBD
EDS
Hyposmia
Depression
Motor symptoms
Urinary symptoms, postural hypotension
Hallucinations, psychosis, dementia
Non-motor features of PD
REM sleep disorder
Hyposmia
Depression
Urinary symptoms
Psychosis
Reduced libido
ED
Motor features of PD
Presence of bradykinesia
Rigidity
Resting tremor
Postural instability
Unilateral onset
Progressive disorder
Persistent asymmetry
Responsive to levodopa
MRI sign of MSA
Hot cross bun sign
T2 hyperintense cruciform appearance of pons
Increased signal in transverse pontocerebellar fibers
MSA-C (cerebellar types)
MRI sign of PSP
Hummingbird sign
Midbrain strophy
Preserved pontine volume
Mickey mouse appearance
Reduction in AP diameter of midbrain
MRI sign of Wilson’s disease
Giant panda sign
Relative hyperintensity of basal ganglia and mid brain
Treatment of early PD
Exercise
Maintaining and improving mobility, flexibility, range of motion, speed of movement
Easing secondary symptoms i.e. depression and constipation
Commence treatment when functionally disabled - L-dopa, dopamine agonist, MAOI-B
Considerations with levodopa
Higher risk of dyskinesias over other PD treatments
Honeymoon period - beneficial effect in early phase of treatment
Consideration of dopamine agonist use
Initial therapy in patients < 60 yrs
In combination with L-dopa, motor fluctuations and dyskinesias reduced
Side effects of dopamine agonists
Sleepiness
Peripheral oedema
Neuropsychiatric SEs particularly in pts > 70 yrs
Impulse control disorders
Dopamine agonist examples
Pramipexole
Apomorphine
MAO B inhibitors indications and considerations
Selegiline
Trial as initial therapy for mild disease in pts with bradykinesia or postural instability
May improve end of dose akinesias
May worsen dyskinesias
Indications and considerations of NMDA antagonist
Amantadine
Short term treatment of mild symptoms
Levodopa induced dyskinesia
Akinetic crisis
May cause adverse CNS effect
Indications for functional neurosurgery
Motor complications not managed by medical treatment
Types of functional neurosurgeryy
Thalamic stimulation (DBS) - tremor
Pallidal stimulation - dyskinesias
Subthalamic stimulation - motor fluctuations
Advanced therapies for PD
Duodopa L-dopa gel
SC apomorphine
Pathophysiology of cognition impairment in PD
Lewy bodies spread in involve cortex
Pathophysiology of PD
- Progressive dopaminergic neuron degeneration in the substantia nigra (part of the basal ganglia) and the locus coeruleus → dopamine deficiency at the respective receptors of the striatum with interrupted transmission to the thalamus and motor cortex → motor symptoms of PD
- Indirect pathway of the basal ganglia is affected
- Serotonin and noradrenaline depletion (in the raphe nuclei): likely cause of depressive symptoms
- Acetylcholine surplus (in the nucleus basalis of Meynert): likely cause of dyskinesia
Pathophysiology of Lewy Body dementia
If motor symptoms precede by < 1 year + dementia
Clinical features of LBD
Visual hallucinations
Fluctuations in GCS
PD motor symptoms
Neuroleptic sensitivity (cog and motor)
Paranoia
Friederich’s ataxia features
Trinucleotide repeat expansion (of the nucleotide triplet GAA) in the FXN gene on chromosome 9
Progressive ataxia
Spastic paralysis
Nystagmus
Dysarthria
HOCM
DM
Scoliosis
Fragile X associated tremor ataxia syndrome features
X-linked dominant disease caused by a CGG trinucleotide repeat expansion in the FMR1 gene (fragile X mental retardation 1 gene)
Late onset ataxia
Postural tremor
Executive deficits
Parkinsonism
Neuropathy
Increased T2 signal in cerebellar peduncles
Huntington disease features
Autosomal dominant
Increased number of CAG repeats (trinucleotide or triplet repeat expansion) in the huntingtin gene on chromosome 4
Mean age onset 45 yrs, median survival 18 yrs
CAG repeats in Huntington disease and interpretation
Normal: < 26
Intermediate: 27-35 –> no development of symptoms, but children at risk
Reduced penetrance: 36-39 –> may or may not develop symptoms at any age
Full penetrance: > 40 –> have disease
Imaging for Huntington disease
Neuronal loss and atrophy of caudate putamen
Clinical features of Huntington disease
Motor - chorea, motor impersistence, dysarthria, ataxia, trouble walking, dystonia
Psych - depression, anxiety, apathy, paranoia
Dementia - Impulsive, personality change, social withdrawal, cognitive slowing, weight loss
Findings of demyelinating lesions in NCS
Slowed conduction velocity
Conduction block
Temporal dispersion
Lower amplitudes due to distal dispersion or conduction block
Delayed or absent F-waves
Findings of axonal lesions in NCS
Low amplitudes
Recovery of neurapraxia/demyelination
Remyelination of local Schwann cells
Weeks to months
Recovery of axonal loss/axonotmesis/neurotmesis
Axonal regrowth -1mm/day, 1 inch/month
Distal branch sprouting
Carpal tunnel syndrome clinical features
Sensory disturbances (pain, tingling, and numbness) and motor symptoms (weakened thenar muscles leading to weakened pinch and grip of the thumb) in the area innervated by the median nerve distal to the carpal tunnel
Radial neuropathy clinical features
Sudden painless wrist and finger drop
Compression at spiral grooves, triceps spared
Sensory loss of dorsum of hand, especially thumb and index
EMG findings in acute denervation
Prominent fibrillation/positive sharp waves
Reduced recruitment in proportion to number of motor units lost
EMG findings of chronic denervation
No fibrillation potentials
Increased duration
Increased amplitude
Reduced recruiment
EMG findings of myopathy
Minimal fibrillations, may be present in some myopathies
Decreased duration
Decreased amplitude
Small amplitude, recruited early
Clinical manifestations of anterior horn cell disease
Progressive, asymmetric motor disorder with mixed proximal/distal, UMN and LMN signs
One of four body segments (cranial/bulbar, cervical, thoracic, and lumbosacral)
- Sparing eye movements, bowel and ladder
- Tongue fasciculations
- Painless
- Region spread within and to adjacent regions
- “Split hand syndrome”
MND epidemiology
Sporadic - 5% dominantly inherited
Mean age of onset 55 yrs
Median survival from diagnosis 3-5 yrs
Variants of MND
Amyotrophic lateral sclerosis - mixed UMN and LMN
Spinal muscular atrophy - predominant LMN
Primary lateral sclerosis - predominant UMN, better prognosis
Progressive bulbar palsy
MND EMG findings
Findings of acute and chronic denervation and reinnervation
- Fasciculations in muscles with chronic denervation
- Fibrillations and positive sharp waves with acute denervation
MND NCS findings
No conduction block
Normal or near normal motor conduction velocities
Normal sensory studies
Gold coast criteria for ALS
- Progressive motor impairment documented by history of repeated clinical assessment, preceded by normal motor function
AND - Presence of UMN and LMN dysfunction in at least 1 body region with
- UMN and LMN dysfunction noted in same body region OR LMN in at least 2 body regions
AND - Investigations excluding other disease processes
Clinical features of multifocal motor neuropathy with conduction block
Progressive, asymmetrical, predominantly distal, pure motor, LMN pattern with some atrophy
Upper limbs > lower
Cramps and fasciculations common
CN involvement rare
Absent sensory symptoms
Clues to diagnosis of MMCB
Age
Weakness > atrophy
Peripheral nerve pattern of weakness
Absence of CN or UMN signs
Depressed or absent tendon reflexes
Unusual sites of focal demyelination
Investigation findings of multifocal motor neuropathy w/ conduction block
NCS - partial conduction block in one or more nerves, sensory nerves normal
IgM anti-GM1 antibodies
Management of MMCB
IVIg
IV cyclophosphamide
Plasma exchange
Rituximab
Prednisone can worsen it
MMN clinical features
Stepwise, multifocal, asymmetric, can be distal or proximal
Eventually becomes symmetrical
MMN causes
Diabetes
Infectious - leprosy, HIV
Arteritis - CTD, vasculitis
Trauma
Hereditary liability to pressure palsies
Sarcoidosis
Malignancy
Causes of peripheral neuropathy
Metabolic - diabetes, uraemia, porphyria, hypothyroidism, acromegaly, EtOH, B1/B6/B12/niacin deficiency
Infections - HIV, lyme, leprosy
Toxic - drugs, poisons
Inherited - CMT, Frederich’s ataxia
CTD - RA, PAN, SLE, Sjogren’s, Wegener’s, Churg-Strass
Paraproteinaemias - MM, MGUS, POEMS, amyloid
Immune mediated - GBS, CIDP, MMCB, POEMS, Amyloid
Charcot Marie Tooth disease subtypes
CMT I - demyelinating (AD/X linked)
- Due to duplication of PMP 22 gene: CMT1A
Hereditary neuropathy with pressure palsies
- PMP 22 deletion/point mutation
CMT IX - X linked dominant
CMT II- axonal
CMT genetics
PMP22
GJB1 - CMT1X
MFN2 - CMT 2A
MPZ - CMT1B
Types of diabetic neuropathies
Symmetric polyneuropathies
- sensory
- sensorimotor
–> distal, length dependent
–> sensory > motor. axonal > demyelinating
- autonomic
Focal and multifocal
- CN palsies
- Radiculopathies
- Mononeuritis
- Asymmetric proximal neuropathy (amyotrophy)
- Treatment induced
Investigations of peripheral neuropathy
NCS
Metabolic screens
Autoimmune and paraprotein screens
ESR, CRP
Toxic screen
LP
Consider cancer screen, HIV, sural nerve biopsy
What feature on NCS most sensitive in detection of early diabetic polyneuropathy?
F wave latency
GBS features
Acute, demyelinating, autoimmune neuropathy
Asymmetric, patchy and global
Weakness, sensory features and autonomic disturbance developing over days
Triggers for GBS
URTI, GIT infection, immunisation, surgery, trauma
Specific agents: campylobacter jejuni, EBV, CMV, mycoplasma, viral hepatitis, HIV, seroconversion
Clinical variants of GBS
Miller Fisher syndrome
- External ophthalmoplegia, ataxia, areflexia
- GQ1B
Polyneuritis cranialis
Pure sensory variant
Acute autonomic neuropahty
Acute axonal variant
- Acute motor axonal neuropathy (AMAN) (AMSAN)
- Pharyngeal-cervical-brachial variant
Investigations of GBS
CSF
- Elevated protein
NCS
- conduction slowing, block, long latencies and delayed F waves
EMG
- may shown denervation changes 2-4 weeks
Treatment of GBS
IVIg
Plasma exchange
Clinical criteria for typical CIDP
Chronically progressive, stepwise or recurrent
Symmetric proximal and distal weakness
Less prominent sensory dysfunction
Absent or reduced reflexes
Minimal autonomic involvement
Clinical criteria for atypical CIDP
Predominantly distal (DADS)
Asymmetric (MADSAM)
Focal
Pure motor
Pure sensory
Clinical features of CIDP
Progress or relapse/remit over > 8 weeks
Symmetric weakness of both proximal and distal muscles
↓ Deep tendon reflexes in both upper and lower extremities
Sensory involvement (e.g., paresthesias)
Autonomic dysfunction and cranial nerve involvement are rare.
CIDP variants can manifest with asymmetric symptoms and/or purely sensory or motor symptoms.
Investigation findings of CIDP
LP
- Increased protein, low cell count
NCS
- slow CV, conduction block or temporal dispersion, prolonged DML, absent/prolonged F-waves
Treatment of CIDP
Prednisone
Plasma exchange
IVIg
Azathioprine
Features of distal acquired demyelinating symmetric neuropathy (DADS-M)
Elderly males
Predominant distal sensory loss
Mild distal weakness - foot drop, ataxia
Associated unsteadiness/falls/tremor
Investigation findings of DADS-M
Prolongation of distal latencies on NCS
IgM paraproteinaemia in 2/3
Anti MAG
Features of myasthenia gravis
Fatiguable weakness
90% of cases involve extraocular muscles
80% involve facial and bublar muscles
50% involve purely ocular disease
50% progress to generalised myasthenia
Myasthenia and thymoma
Almost all thymoma associated with MG
Thymic lymphoid hyperplasia in 70%
Thyrotoxicosis in 5%
Diagnosis of MG
Repetitive stimulation - decremental response at low frequency
ACh receptor antibodies
- 85% of pts with generalised MG, 60% with ocular MG
Anti-MuSK
- high frequency in bulbar involvement and respiratory crises
Tensilon test
- Positive in 80%
Features of LEMS
Antibody to presynaptic voltage gated calcium channel, reducing number of vesicles released
Proximal muscle weakness; muscle strength improves with repetitive or ongoing use
Reduced or absent reflexes
Autonomic symptoms
Causes of LEMS
Paraneoplastic - SCLC
AI disorder
Diagnosis of LEMS
EMG: Repetitive nerve stimulation results in incremental responses.
NCS: Small initial CMAP, increases after voluntary contraction or high frequency stimulation
Confirmatory test: anti-VGCC antibodies in serum
Other: CT chest, abdomen, and pelvis to screen for underlying malignancy
Treatment of LEMS
Plasma exchange
Prednisone
Azathioprine
Guanidine
Diaminopyridine
Features of statin myopathy
Symptom onset at any time - 25% after > 12 month usage
Mild myalgias –> severe rhabdomyolosis
Self-limiting, lasting ~2-3 months
Elevated CK levels
Myalgias common symptom
General principles of stroke anatomy
ACA - leg weakness
MCA - hemiplegia, hemiparesis with cortical signs. if dominant side, can have speech deficits.
PCA - visual field deficits
Penetrating vessels in subcortical - hemiplegia or hemiparesis without cortical signs
Causes of ICH
Idiopathic
Hypertensive
Amyloid angiopathy –> microhaemorrhage, SAH, cortical calcification
Vascular abnormality
Secondary to ischaemic stroke
Trauma
Underlying bleeding disorder
Anticoagulation related
Drug related
Management of cerebral haemorrhage
Surgery for significant compression
Aim SBP < 140mmHg
Reversing agents for anticoagulation
Fibrinolytics beneficial in first 24 hours from onset
Risk factor screening for stroke
HTN
Hypercholesterolaemia
Diabetes
Precoagulant states/IE
AF or other source of cardio-embolic source
Collagen disorders, vascular dissection, rare genetic causes
Risk of stroke in TIA
In 48 hours - 6%
In 1 week - 10%
In 6 months - 17%
Stroke prevention strategies
Early carotid surgery for symptomatic stenosis after TIA and mild stroke
Antiplatelet agents
Anticoagulation for non valvular AF
Antihypertensives aiming BP < 130/85
High dose cholesterol lowering agents
Lifestyle advice
DAPT duration
Usual DAPT for 3 weeks and then stepdown to SAPT
If high risk intracranial atherosclerosis, consider longer duration of 90 days
Time windows for acute stroke therapy
IV thrombolysis up to 9 hours if evidence of salvageable tissue
Endovascular therapy up to 24 hours
DOACs for embolic stroke
ARISTOPHANES study
Apixaban - less stroke/embolic events, less major bleeds
Rivaroxiban - higher bleeding risk
Most likely location for thrombus in AF
Left atrial appendage
Device for AF if DOAC not appropriate
Left atrial appendage oclusion
Evidence re: LAAO compared to DOACs
Prague 17 study
Left atrial appendage occlusion non-inferior to DOAC at preventing embolic events/bleeding
Risk stratification of PFO and stroke
Characteristics
- Large shunt
- septal aneurysm
Clinical
- age
- stroke features
- ROPE score
- hypercoagulopathy
- Concomitant VTE
- competing risks
COVID-19 and stroke
Associated with hypercoagulable state +/- direct infection/inflammation of blood vessels
Mostly causing large vessel occlusion
More likely to develop:
- AKI
- Hepatic failure
- Respiratory failure
Stroke mimics
Focal seizures
Migraines
Tumour
SDH
Hypotension/syncope
Peripheral vestibular conditions
Panic attacks
Conversion disorders/FND
Tenectoplase vs alteplase for acute stroke therapy
Alteplase = tenectoplaste - equally more effective up to 4.5 hours
Hypertension in stroke population
Up to 70%
Definition of MS
Chronic inflammatory autoimmune disease of CNS characterised by inflammation, demyelination and axonal loss
Braak staging
Lower brainstem and olfactory system (dorsal motor nucleus of vagus nerve, anterior olfactory nucleus) > medulla oblongata > pontine tegmentum > basal mid- and forebrain, hypothalamus, thalamus > mesocortex, allocortex > neocortex
Risk factors for MS
Caucasian
Female
If affected sibling
High latitude of residence
Low vitamin D levels
Smoking
Obese
Inadequate sleep in adolescence
Genetic risks of MS
HLA-DRB1+15:01 confers greatest risk
EBV and MS
Increased risk of MS linked to antibody response to EBV nuclear antigen
Role of myelin and oligodendrocytes
Oligodendrocytes responsible for myelinating axons in CNS
Myelin increases speed of electrical conduction
Oligodendrocyte provides trophic support to neurons
Immunopathogenesis of MS
- Peripheral activated autoreactive T cells (especially Th17) migrate across blood brain barrier
- Reactivation by local antigen presenting cells
- Clonal expansion
- Secretion of proinflammatory cytokines
- Stimulation of microglia and astrocytes
- Destruction of myelin, oligodendrocyte loss, and axonal loss
Acute vs chronic demyelinated plaque
Acute plaque
- indistinct margin
- inflammatory cells centred around vessels in ‘perivascular cuff’
- oedema and demyelination throughout plaque
- oligodendrocyte and axonal loss varialbe
Chronic plaque
- more distinct borders
- hypocellular core with thickened vessels and enlarged perivascular spaces
- loss of myelin and glial scarring prominent
Clinical phenotypes of MS
Relapsing remitting MS (85-90%)
Primary progressive (10%)
Secondary progressive MS
Primary relapsing MS
Definition of relapse
Any new or worsening neuro symptoms that last longer than 24 hours, or shorter than 24 hours but recurs repeatedly over days
Definition of pseudorelapse
Previous neuro symptoms may temporarily worsen if body temperature is elevated –> reflects conduction block in previously demyelinated axons
Typical MRI lesions in MS
Corpus callosal
Periventricular “Dawson fingers”
Infratentorial
Role of oligoclonal bands
Represents immunoglobulins to specific antigens within CNS
Found in CNS
Role of VEP
Measures time taken for visual stimulus to be recorded over occiput
Normal VEP virtually excludes a lesion of optic nerve or along visual pathways in anterior brain
Diagnostic criteria for RRMS
> /2 clinical attacks + MRI findings or good historical evidence
1 clinical attack with typical MRI + follow up MRI with new lesion and/or OCB present in CSF
Diagnostic criteria for PPMS
1 year of disability progression independent of clinical relapse + two of following criteria
- >1 T2 hyperintensive lesion characteristic of MS in one or more following brain regions (periventricular, cortical or juxtacortical or infratentorial)
- >2 T2 hyperintense lesions in spinal cord
- Presence of CSF specific oligoclonal bands
Definition of neuromyelitis optica spectrum disorder (NMOSD)
Immune mediated disease causing demyelination and axonal damage or optic nerves and spinal cord
Pathology of NMOSD
Necrosis and cavitation involving both gray and white matter
Majority of patients have aquaporin-4 antibodies
- crosses BBB and binds to water channels on astrocytes
- activates complement system/MAC causing complement dependent cytotoxicity
- stimulates Ab-dep cellular toxicity
- death to astrocytes followed by oligodendrocytes and neurons
- oligodendrocytes loss leads to demyelination
Neuroimaging in NMOSD
Longitudinally extensive spinal cord lesion (LETM)
Long optic nerve lesion, often involving posterior aspects of nerve or optic chiasm
Lesions involving dorsal medulla
Lesions involving hypothalamus/thalamus
Clinical characteristics of NMOSD
- Optic neuritis
- Acute myelitis
- Area postrema syndrome (intractable hiccups, N+V)
- Acute brainstem syndrome
- Symptomatic cerebral syndrome with NMOSD-typical brain lesions
Treatment of NMOSD
IV methylpred + oral corticosteroids
+/- PLEX
Steroid sparing agents (MMF, azathioprine)
B cell depleting therapy
Pathophysiology of MOGAD
Myelin oligodendrocyte glycoprotein exclusively expressed on oligodendrocytes and myelin. inCNS
Anti-MOG Ab –> demyelination
Presentation of MOGAD
Bilateral (consecutive) optic neuritis
Typically very severe
Steroid responsive with good recovery of vision
Poor prognostic factors in MS
Frequent relapses within first 2 years of diagnosis
Short interval between first 2 relapses
Rapid early disability progression
High lesion load (especially spinal cord or infratentorial)
Cerebral atrophy
Male gender
Later age of onset
MOA of natalizumab
alpha 4 integrin monoclonal Ab (found on monocytes and lymphocytes)
Natalizumab SEs
Increased risk of herpes virus reactivation
Risk of progressive multifocal leukoencephalopathy, caused by JC virus
Higher risk of PML if
JCV serology positive and:
- Any prior immunosuppression
- >2 yrs on natalizumab
- JCV index (level of positivity)
MOA of alemtuzumab
Anti-CD52 (found on differentiated lymphocytes and monocytes) –> eliminates pathogenic T cells
Alemtuzumab SEs
Infusion reactions common
Increased infection risk
Risk of secondary autoimmunity (thyroid disease, ITP)
MOA of ocrelizumab
Anti-CD20 fully humanised monoclonal Ab
Ocrelizumab SEs
Infusion reactions common
Increased infection risk
Risk of PML
Increased risk of malignancies (though not significant)
MOA of ofatumumab
Fully humanised monoclonal antibody against CD20+ B cells
MOA of cladribine
Selective immune reconstitution therapy
Deoxyadenosine analogue prodrug selectively targets lymphocytes due to preferential intracellular activation
Cladribine SEs
Lymphopenia
Increased risk of infections (whilst lymphopenic)
MOA of fingolimod
Binds to S-1-P receptors on lymphocytes and blocking their egress from lymph nodes
Fingolimod SEs
First dose bradycardia - requires cardiac monitoring when first given
LFT derangement
Lymphopenia
Increased infection risk especially herpes virus
Increased risk of non-melanomatous skin cancers
PML risk
Ozanimod MOA
Sphingosine-1-phosphate inhibitor
Slightly different receptor specificity and lower risk of cardiac complications
Dimethyl fumarate MOA
Modulates antioxidative pathways via activation of Nrf2
Dimethyl fumarate SEs
Flushing
GIT upset
Lymphopenia
Rare LFT deranagements
Risk of PML
MOA of teriflunomide
Inhibits dihydroorotate dehydrogenase and interferes with pyrimidine synthesis
SEs of teriflunomide
Hepatotoxicity
Hair thinning
HTN
GI upset
Teratogenic
MOA of glatiramer acetate
Synthetic polypeptide antigenically similar to myelin basic protein
MOA of interferon beta 1a and 1b
Diverts immune system away from proinflammatory Th1 and Th17 pathways to more anti-inflammatory Th2 pathway
Also effects T-reg, NK cells, B-cells and lymphocyte migration into BBB
Washout periods for MS drugs prior to conception
None
- Glatiramer acetate
- Interferon beta
- Dimethyl fumarate
- Natalizumab
2 months
- Fingolimod
4 months
- Alemtuzumab
6 months
- Cladribine
- Ocrelizumab/Ofatumumab
Accelerated elimination
- Teriflunomide
Prognosis of MS
Untreated MS, ~50% of pts develop SPMS after 10-20 yrs of RRMS diagnosis
Cortical signs of frontal lobe
Personality
Primitive reflexes
Dysphasia expressive
Anosmia
Optic nerve compression
Gait apraxia
Cortical signs of parietal lobe
Gerstmann syndrome - acalculia, agraphia, L-R disorientation, fingeragnosia
Sensory, visual and spatial inattention
Construction and dressing apraxia
Lower quandrantanopia
Signs of Gerstmann syndrome
Dominant, angular gyrus
Acalculia
Agraphia
L-R disorientation
Fingeragnosia
Cortical signs of temproal lobe
Receptive dysphasia (dominant)
Memory loss
Upper quandrantanopia
Cortical signs of occipital lobe
Homonymous hemianopia
Anton’s syndrome
Alexia without agraphia
Signs of Anton’s syndrome
Cortical blindness with confabulation
Types of aphasia
Non-fluent, Expressive, Broca’s, transcortical motor
- Able to comprehend, paucity of word
- Usually frustrated
- Dominant frontal lobe
Fluent, receptive, Wernicke’s, transcortical sensory
- Unable to comprehend, fluent but incomprehensible speech
- Not frustrated
- Dominant temporal lobe
Conduction aphasia
- Mix between the two
- Able to comprehend elements of fluent aphasia and poor repetition
Thalamus sign and functions
Terminal for all sensory nerves
Arterial supply from PCA
Anterior nuclei - language and memory function
Lateral nuclei - motor and sensory function
Medial nuclei - maintaining arousal and memory
Posterior nuclei - visual function
Peripheral cerebellum signs
Ipsilateral limb ataxia
Past pointing
Dysmetria
Intention tremor
Dysdiadochokinesia
Nystagmus
Vermis cerebellum signs
Truncal ataxia
Nystagmus (flocculonodular lobe)
4 rules of brainstem
- 4 cranial nerves in medulla, 4 in pons, 4 above pons
- 4 structures in midline beginning with M
- 4 structures to side beginning with S
- 4 motor nuclei in midline
4 medial structures
Motor pathway
Medial lemniscus
Medial longitudinal fasciculus
Motor nucleus
4 side structures
Spinocerebellar pathways
Spinothalamic pathways
Sensory nucleus of 5th CN
Sympathetic tract
CN location in brainstem
Midbrain - III, IV
Pons - V, VI, VII, VIII
Medulla - IX, X, XI, XII
Brown-Sequard syndrome
Ipsilateral UMN weakness below level of lesion
Ipsilateral impairment of vibration and position sense below level of lesion
Contralateral pain and temperature sensation from one to two segments below lesion
Ipsilateral LMN weakness and complete sensory loss at level of lesion
Central cord syndrome
Loss of pain and temperature in one or more adjacent dermatomes bilaterally at level of lesion
Sensory classically seen in “cape” or “vest” distribution across neck and shoulders or trunk
Further expansion affects lateral corticospinal tracts causing UMN weakness and temperature and sensation loss below lesion
Anterior cord syndrome
Dorsal columns preserved
Proprioception and vibration preserved
Usually ischaemic with occlusion on anterior spinal artery
Posterior cord syndrome
Just loss of dorsal column
Rarely ischaemic given bilateral blood supply
Demyelination, nutritional, genetic
