Neuro disorders and MS Flashcards
Define Multiple sclerosis
an immune mediated inflammatory disease of the CNS characterised by demyelination (destruction of normal myelin)
Where are myelinated axons most commonly located?
White matter - thus diseases of myelin are indicative of white matter disorders
How is myelin formed and what is its function?
In CNS - formed by oligodendrocytes
In peripheral nerves- formed by Schwann cells
Function: insulates axons and increases conductance(transmission of action potential) along axon
Cause of MS?
Caused by a combo of environmental and genetic factors that result in a loss of tolerance of self proteins aka myelin antigens
Risk factors include EBV smoking low serum Vit D Genetics- HLA DR2
Pathogenesis of MS
characterised by an imbalance between immunoregulatory and proinflammatory immune cells.
The abnormalities in multiple sclerosis are confined to the
CNS; the peripheral nervous system is not involved. Patients with multiple sclerosis have numerous demyelinated plaques in the brain and spinal cord , often closely related to veins.
Acute plaques are soft and pink with ill-defined boundaries. Histologically, there is myelin breakdown and
phagocytosis by macrophages. Perivascular cuffing with
inflammatory cells (plasma cells and T lymphocytes) is
widespread in the acute plaque. * Essentially perivascular and parenchymal inflam involve macrophages and lymphocytes *
The plasma cells synthesise immunoglobulins, which can be detected in the CSF. B lymphocytes have also been identified at the edges
of acute plaques.
As myelin breakdown eventually subsides, reactive gliosis is established, giving rise to a chronic plaque. These appear as sharply defined, grey, lucent areas of demyelination in
which oligodendrocytes are scarce or absent. The inflammatory infiltrate subsides, leaving small numbers of perivascular lymphocytes at the edge of chronic plaques aka hypocellular.
Although oligodendrocytes can proliferate in an attempt
to repair myelin, successful remyelination of established
plaques probably never occurs. Axonal damage also occurs
in multiple sclerosis and correlates with the inflammatory activity in the white matter, contributing to progressive neurological
debility. Remaining axons have reduced caliber
Describe the macroscopic vs microscopic findings in MS
Macroscopic
essentially well demarcated white matter plaques
-cavitating when old plaque
-yellow when more acute
Can affect brainstem(midbrain,pons and medulla), cerebellum, spinal cord and cerebral hemispheres
Microscopic
Preservation of axons
Macrophages and lymphocytes
Diagnosis of MS?
Primarily is a clinical diagnosis McDonald Criteria:
-Objective demonstration of dissemination of CNS lesions in both space and time based on either clinical findings alone or a combination of clinical and MRI findings
CSF analysis(via lumbar puncture) and SPEP(serum protein electrophoresis)
-Oligoclonal bands (OCBs) support a diagnosis of MS via SPEP
-increased lymphocytes and Igs
-myelin basic protein
Bloods : ENA, ANCA, ANA, Lyme, HIV, VDRL, anti aquaporin-4 antibodies, anti MOG antibodies
Optical coherence tomography/ Visual evoked potentials
-Delayed P100 potentials supportive of MS diagnosis using electroencephalography (P100 assesses conduction along optic nerve- usually slowed in pts with MS)
What are the presenting symptoms of MS?
Fatigue++ Visual loss, optic neuritis Acute transverse myelitis Trigeminal neuralgia Diplopia Gait/balance disturbance Vertigo Bladder dysfunction Lhermitte’s sign -Neck flexion results in rapid tingling or electric shock-like feeling that passes down the spine and into the limbs Uhtoff’s phenomenon -Raised body temperature can result in an exacerbation of symptoms
Typical Clinical course of MS
The course of MS is variable, but commonly there are multiple relapses followed by episodes of remission; typically,
recovery during remissions is not complete. As a consequence, over time there is usually a gradual, often stepwise, accumulation of neurologic deficits
What are the subtypes of MS?
Clinically isolated syndrome-
-used to describe a first episode of neurologic symptoms that lasts at least 24 hours and is caused by inflammation and demyelination in one or more sites in the central nervous system (CNS)
-A single clinical syndrome suggestive of demyelination with accompanying physical signs on examination
-May include: optic neuritis, brain stem syndrome or partial myelitis; can be multifocal (more than one sign/symptom) or monofocal (one sign/symptom)
-A risk for developing MS but not all cases of CIS develop MS
-increased risk of conversion to MS; Abnormal baseline brain MRI
Asymptomatic spinal cord lesions
Presence of unmatched oligoclonal bands in the CSF i.e. present in CSF but not in serum
Relapsing-remitting MS
-Majority of cases are relapsing-remitting at onset
-this is a clinical diagnosis
-Diagnosis based on the concepts of dissemination in time and dissemination in space
-History of relapses suggestive of demyelination with periods of remission and must have accompanying physical signs on exam
-‘Active’ or ‘inactive’
Based on relapses (diagnosed by history and exam) and MRI activity
Secondary progressive MS
-A progressive myelopathy
Onset begins when walking distance is restricted to approximately 500m
-Symptoms include: ambulatory dysfunction (stick/wheelchair), urinary dysfunction (catheter), pain, depression, fatigue
-May experience relapses
-A clinical diagnosis – no confirmatory tests for diagnosis of SPMS
-‘Active’ with or without progression
-‘Inactive’ with or without progression
-Based on relapses and MRI activity
Primary progressive MS (10-20%pts) Accounts for 15% of cases of MS
-Progressive myelopathy
-Begins later in life – mean age onset in 50s
-Disability accumulates quicker
-Approximately 10% of cases may have superimposed relapses
-Male: female ratio closer to 1:1
-‘Active’ with or without progression
-‘Inactive’ with or without progression
-Based on relapses and MRI activity
Diagnosis of PPMS
One year of disease progression (retrospectively or prospectively confirmed)
Plus 2 of 3 of the following:
-Evidence of DIS on brain MRI
-Evidence of DIS in the cord based on ≥2 T2 lesions in the cord
-Positive unmatched OCBs in the CSF
What is the MRI contrast media used for diagnosis of MS?
GADOLINIUM
MRI+contrast (Gadolinium) -MS
If gadolinium enhanced- active plaque
Describe the Mc Donald Criteria
- MRI criteria
- Essentially when MS has been diagnosed clinically based on dissemination in time and space: the diagnosis may be confirmed using MRI
- If person has two or more attacks and there is objective clinical evidence for two or more lesions w a historical evidence of a prior attack- no additional data needed as clinical evidence is sufficient(however MRI can be done if so desired but must be consistent w MS)
- Two or more attacks w/ object clinical evidence of 1 lesion; additional data via MRI to show dissemination in space OR by further awaiting clinical attack compromising a different site
- One attack with 2 or more lesions; additional data via MRI showing dissemination in TIME OR await second clinical attack
Define dissemination in time
onset of two CNS disorders separated by at least one month in time
Demonstrated by either:
- A new T2 and/or Gd enhancing lesion(s) on follow up MRI, with reference to baseline MRI
- Simultaneous presence of asymptomatic Gd-enhancing and non-enhancing lesions at any time
- Dissemination in space and unmatched oligoclonal bands in the CSF
Define dissemination in space
Lesions in two separate places in the central nervous system e.g. Optic nerve and brain stem or spinal cord and cortex
more than/equal to 1 T2 lesion in 2 of 4 areas in CNS: Periventricular Juxtacortical Infratentorial Spinal cord Cortical/juxtacortical
The MS lesions on a T2-weight MRI show up as hyperintense lesions, or “bright spots” and are often referred to as plaques
Describe how MS related demyelination might clinically manifest according to neuroanatomical location
Optic neuritis
- Unilateral visual loss
- Red vision affected first
- Pain on eye movement
- Pain typically does not last more than two weeks
- Signs of optic neuritis
- Rapid Afferent Pupillary Defect ; pts pupils constrict less when a bright light is swung from the unaffected eye to the affected eye
- optic disc swelling (Acute)
- optic disc pallor (chronic)
Brain stem/cerebellar symptoms -Facial palsy -Ataxia -Diploplia -Trigeminal neuralgia: trigeminal neuralgia, even mild stimulation of your face — such as from brushing your teeth or putting on makeup — may trigger a jolt of excruciating pain Signs in brain stem syndrome *Nyastagmus *one and a half syndrome-affecting both eyes, in which one cannot move laterally at all, and the other can move in only one lateral direction (inward or outward)
Spinal cord symptoms: Lhermitte’s symptom Numbness Urinary urgency Faecal incontinence Sexual dysfunction Spastic paraplegia
Signs a/w spinal cord damage : Weakness Increased tone +/- clonus Brisk reflexes Upgoing plantar response Brown Sequard syndrome -loss of pain, temp, light touch on opp side -loss of motor function, vibration, position, deep touch sensation on same side as cord damage
Cerebral hemisphere symptoms Cognitive impairement Hemiparesis Seizures Encephalopathy Signs: -brain damage -paralysis -spatial/perceptual deficits or speech/language defcits -behavioral style: quick, impulsive/ slow, cautious -memory deficits (performance/language)
What are the differential diagnoses for MS?
Ischaemia – small vessel ischaemic abnormalities on brain scan or migraine
Functional disorder (psychogenic)
Inflammatory – sarcoid, lupus
Infection – syphilis, listeria, lyme
Nutritional – B12, zinc/copper
Metabolic – central pontine myelinolysis, mitochondrial
Genetic – eg Fabry’s disease ( lysosomal storage)
How do you take an adequate history for MS
Determine disease activity i.e. History of new/recent relapses
Determine symptoms related to prior relapses:
Fatigue
Bladder dysfunction
Pain
Spasticity
Social History is extremely important*: adaptations to bathroom, transfers from chair, home help etc.
Who is involved in the management of a MS pt
Management involves multidisciplinary approach: neurologist, MS nurse, physio, OT, SLT, social work, neuropsychiatry, neuropsychology
Pharm treatment for MS pt
Spasticity: botulinum, gabapentin
Pain: cannabinoids, pregabalin, gabapentin
Bladder dysfunction: oxybutinin
Sexual dysfunction: sildenafil
Depression/anxiety: citalopram, venlfaxine
Fatigue: amantidine. modafinil
Other pharm treatment for long term management
Disease modifying therapy (DMT) is recommended in patients with a diagnosis of definite relapsing remitting MS
- To reduce the relapse rate and slow disability progression
- Earlier the better in RRMS
- No role at present in SPMS/PPMS
1st line disease modifying drugs :
interferon
dimethyl fumarate
2nd line disease modifying:
rituximab, natalizumab
How do you acutely treat someone with MS?
Glucocorticoids
-IV Methylprednisolone 1g for 3-5 days
-Oral Prednisolone considered as an alternative
Plasma exchange
-May be beneficial in those not responding to glucocorticoid therapy with a severe relapse
Natural history of relapse- onset MS
Clinically isolated syndrome then to relapsing remitting MS in approx 2.5 years. This can be then followed by secondary progressive MS for approx 50% by 15 years, 85% by 40 years
What is the prognosis for MS?
50% chance of walking unaided 15 years after diagnosis
Epidemiology of MS?
commonest demyelinating disease in CNS
Peak age 20-40s
F>M
common in Europe
Define and classify neurodegenerative disorders
Disease characterised by progressive dysfunction and death of neurons
Pathogenesis characterised by: -neuronal loss -gliosis -intracellular accumulation -selective neuronal vulnerability
Classification
Movement disorders
Dementia Syndromes
Describe the pathogenesis a/w intracellular accumulation
abnormal protein production
abnormal protein folding
failure to remove protein
defective neuronal/glial functioning and cell death (Due to oxidative stress,cytokine mediated, excitotoxicity, programmed cell death)
What are the known proteins a/w intracellular pathogenesis
TAU AMYLOID(Extracellular) ALPHA SYNUCLEIN TDP-43 FUS HUNTINGTIN UBIQUITIN(removal of protein)
What are the functions of the main proteins?
TAU : to stabilise microtubules in neurons. Microtubules for part of the cytoskeleton.
Alpha synuclein: not fully understood, abundant in brain, thought to play a role in maintaining supply of synaptic vesicles in axonal terminal of neurons
Amyloid precursor protein: many hypotheses; role not fully understood.
What is another type of pathogensis a/w neurodegenerative disorders?
Selective neuronal vulnerability
Phenomenon whereby specific groups of neurons/ systems are targeted by disease process
This is what determines the clinical phenotype
Considerable clinical and pathologic overlap i.e.
-Distinct clinical phenotypes are associated with several different types of pathology
-The same neurodegenerative disease process can have several different clinical phenotypes
Describe the two main classifications/clinical groups of neurodegenerative disorders
Movement disorders
Akinetic & rigid eg Parkinson’s disease
Hyperkinetic eg Huntington’s chorea
Ataxic eg Spinocerebellar ataxia
Motor neuron disorders eg Motor neuron disease
Dementia syndromes
Temporo-parietal degeneration eg Alzheimer’s disease
Frontotemporal degeneration FTLD
Multifocal degeneration
Cause of neurodegenerative diseases
Majority are sporadic diseases
Some have multiple susceptibility factors eg. Alzheimer disease at least 10 genes with environmental factors (eg head injury) implicated
Those with hereditary basis (minority) have lead to major understanding in pathogenesis
Single mutation eg MAPT
Trinucleotide repeat (polyglutamine disorders) eg HD
Describe Prion disease
Unique TRANSMISSIBLE PROTEIN (within one brain and from one brain to another, via neurosurgery, cannibalism), not DNA/ RNA
Exact function unknown; highly concentrated in neurons
-SPONGIFORM ENCEPHALOPATHY
-Creutzfeldt Jacob disease
-Gerstmann Straussler Scheinker
-Fatal familial insomnia
-Kuru
(Same neuro disease but diff phenotypes)
Rapidly progressive dementia often with behavioural symptoms, hallucinations, myoclonus.
Differentiate delerium and dementia
Delirium is an acute disorder of attention and global cognition, reversible, by treating underlying cause.
Dementia is progressive decline in at least 2 cognitive areas, irreversible.
What investigations are carried out for neurodegenerative disorders?
- Exclude acute cause of cognitive decline eg. infection
- Detailed history & cognitive assessment to identify affected cognitive domains eg. MMSE, Montreal Cognitive assessment +/- psychological evaluation
- Exclude metabolic cause of cognitive decline – thyroid function tests, vitamin B12 levels, U&E, LFTs
- Autoantibody work up (vasculitis)
- Brain imaging (CT, MRI +/- PET) – exclude other causes such as stroke and assess distribution of any atrophy
- Rarely brain biopsy to identify treatable cause eg. vasculitis, lymphoma
Alzheimer/s symptoms
memory loss for recent events
confusion in familiar places
difficulty in finding words
change in mood and behavior
difficulty solving problems or doing puzzles
loss of interest- hobbies pasttime, lack of initiative to go somewhere or do something
repeating a question several times or parts of a story without noticing
What are the macroscopic and microscopic findings for Alzheimer’s disease
Macro
medial temporal lobe(hippocampus)
cortex
Micro
AMYLOID and TAU protein deposits - amyloid plaques and neurofibrillary tangles
Parkinson/s disease symptoms/signs
Cardinal signs
Bradykinesia
Resting tremor
Rigidity
- autonomic dysfunction
- cognitive decline
- dysphagia
What are the macro and micro features of Parkinson’s disease
Macro: pale substantia nigra (plays a role in reward and movement)
Micro: Lewy Body (alpha synuclein)
Define motor neuron disease
Neurodegeneration of upper and lower motor neurons (brain, spinal cord, nerve)
Clinical features of motor neuron disease
Mix of both
UMN - spasticity, hyperrelexia
LMN- fasciculations, bulbar palsy (9-12 damage a/ signs and symptoms)
What is the mean age and prognosis of motor neuron disease?
60 years
Progressive motor failure to include resp failure which is the cause of death
Med survival 3-5 years
Microscopic and Macroscopic findings of motor neuron disease
Macro:
corticospinal tract degeneration
anterior nerve root atrophy in spinal cord
Micro
anterior horn cell
Protein : TDP43
Other name for motor neuron disease
amyotrophic lateral sclerosis
