17. Chronic Neurology Flashcards
MS Definition
A chronic inflammatory multifocal, demyelinating disease of the central nervous system of unknown cause, resulting in loss of myelin, and oligodendroglial and axonal pathology
MS Common Symptoms and Signs
Symptoms depend on where in the CNS damage is
Optic neuritis
Motor weakness (with spasticity and hyper-reflexia), pyramidal signs
Sensory disturbances (Paraesthesiae, pain or sensory loss in limbs or trunk)
Fatigue
Lhermitte’s sign (electric shock radiating down back and triggered by neck flexion)
MS other symptoms
Urinary urgency and incontinence
Sexual dysfunction
Dysarthria
Paraesthesiae, pain (incl.trigeminal neuralgia) or numbness of face or tongue
Visual field defect - unilateral, Conjugate eye movement disorders: diplopia, nystagmus
Seizures
Psychiatric disturbances
Vertigo and nystagmus
Impairment of concentration or memory
Hemiparesis
Hemi sensory loss
Ataxic and spastic gait
Impaired coordination, action and intention tremor
Dysmetria
MS Invx
Fundoscopy - eye signs e.g. papillitis. Diplopia, nystagmus, internuclear ophthalmoplegia
Retro-bulbar optic neuritis (2/3)
Optic neuritis with papillitis (1/3)
Multiple Sclerosis Epidemiology
Around 2.5 millions worldwide
Higher prevalence among white people of Nordic origin - ‘Latitude effect’
Highest in UK, Sweden, Denmark
Multiple Sclerosis RF
AI PMHx
HLA-DLRB1*15
VItamin D levels (more sunlight)
Latitude
Multiple Sclerosis MRI
The demyelinated plaques in the white matter of the CNS are the pathological substrate of relapses
Areas of inflammation, with loss of myelin are scattered around the CNS.
The location and size of plaques determine the type and severity of symptoms (given rise to such varied symptoms)
Often plaques are silent, as may be in area of white matter that is of little importance. Or could appear in area of importance like the brainstem, possible leading to respiratory failure.
MS Pathophysiology
During an acute relapse, there is inflammation in response to myelin basic protein. The inflammation leads to demyelination, which causes delay of the nerve impulse and eventually the neurological symptoms. At first these completely resolve (treatment can speed up process- give steroids), but as disease progresses can often be left with residual symptoms.
3 types of MS phenotypes
Relapsing-remitting (RR) - 85%
Patients mostly fine, but suffer from relapses (acute symptoms) which then resolve; for most of these patients this eventually converts to SPMS (mean 10-15 years)
Secondary Progressive MS: gradually more and more disabled, may have more relapses superimposed on this, but often with incomplete recovery.
Primary progressive MS – progressing immediately, without the initial relapsing remitting stage
MS Dx
Clinical - Absence of alternative diagnosis
Dissemination in time (DIT)
Dissemination in space (DIS)
Based off: Clinical history and examination Radiological evidence – MRI Laboratory evidence – CSF Electrophysiology – VEPs
How can we differentiate old and new lesions?
MRI with gadolinium contrast
During an acute attack, inflammation makes the BBB leaky (for 2-6 weeks) to allow immune cells into the CNS (normally brain is immune privileged). GAD also crosses the barrier = lights up any active lesions, and old lesions remain darker
Anything that lights up is at most 6 weeks old.
What is diagnostic of MS in the CSF?
Oligoclonal bands (95% sensitive) present in the CSF but not the serum (B cells release IgG Ab targeting myelin)
NB if present in serum = infection/inflammation systemically
What are VEPs and what are they used for?
Visual evoked potentials (VEPs) – these look for subtle abnormalities in the visual pathways (commonly affected in MS) which may help clinical to pick up subclinical features even the patient was not aware of
A 28 year old Norwegian woman presents to A&E after she was unable to fell the hot water on her left leg whilst taking a bath. CSF analysis demonstrated oligoclonal bands that were unmatched with the serum. Which of the following would most likely confirm a diagnosis of Multiple Sclerosis?
Multiple lesions on MRI that all enhanced with gadolinium
The patient’s symptoms reoccur 1 year later
The patient develops blurry vision in one eye a year later
The patient reports blurry vision currently
A 1 year follow up finds oligoclonal bands matched with the serum
Risk factors of being young, Nordic woman. Also demyelination can be precipitated by a hot bath
DIT
DIS
A 40 year old woman visits her GP complaining of tiredness. On questioning, she reports getting tired when climbing the stairs or during a conversation. She often has to stop what she is doing to regain her energy. The GP asks her to look upwards, and after a few seconds she begins to develop ptosis. What is the most likely diagnosis?
Iron Deficiency Anaemia Myasthenia Gravis Lambert Eaton Myasthenic Syndrome Carcinoma Horner’s Syndrome
This question demonstrates the classical presentation of myasthenia gravis – muscles fatiguing after use. Also a 40 year old woman which is typical group of people affected.
If it were not for the final sentence then IDA would be most likely statistically, but it wouldn’t produce the stereotypical ptosis on upwards gaze.
LEMS would be tiring at first and improve with use, so wrong way around for this question.
Carcinoma can obviously lead to tiredness, but firstly it is a little vague and secondly wouldn’t give the ptosis after a few seconds, likely provide some other symptoms too.
Horner’s syndrome is characterised by ptosis, but that is at rest.
Myasthenia Gravis Symptoms and signs
Symptoms - Muscles fatigue with use Ptosis Diplopia Dysarthria Dysphagia ±SOB
Signs
Fatigable muscles
Normal reflexes
Who does MG normally affect
It most commonly impacts young adult women (under 40) and older men (over 60) – as it is an autoimmune condition
What muscles does MG usually implicate
Those that control eye and eyelid movement, facial expression, chewing, talking, and swallowing
Muscles that control breathing and neck and limb movements may also be affected.
MG Aetiology
Antibodies block, alter, or destroy nAChR or MuSK
May also have seronegative myasthenia
Muscles will fatigue with repeated use as more and more ACh is required to maintain contraction; in MG this happens quicker compared to normal person
MG Associations
Thymic hyperplasia (70%) Thymoma (10%)
Mg Investigations
Bloods – anti-AChR or anti-MuSK
EMG -demonstrate muscle weakness, action potentials will gradually decrease over time
CT/MRI - for thymomas
Lambert Eaton Myasthenic Syndrome Symptoms
Symptoms – weakness where muscles improve with use
Difficulty walking (upper legs and hips)
Weakness in upper arms and shoulders
Similar symptoms to myasthenia gravis - mild weakness in eye, talking + chewing muscles etc
Autonomic: Dry mouth, constipation, incontinence
Signs
Muscles function better following use
Hyporeflexia
Lambert Eaton Myasthenic Syndrome Aetiology
Anti voltage gated calcium channels on nerve endings that are required to trigger exocytosis of Ach –> less Ach cannot cause normal contractions
Improves with repeated use as incoming stimulus leads to cumulative opening of the few calcium channels not blocked by antibodies
Lambert Eaton Myasthenic Syndrome Associations
Small cell lung cancer (paraneoplastic - producing Ab); older age of onset (averaging 60 years) and is caused by an accidental attack of the nerve terminal by the immune system as it attempts to fight the cancer. Tx of cancer removes LEMS
Autoimmune disease (onset = 35)
Lambert Eaton Myasthenic Syndrome Investigations
Bloods - Antibodies to voltage-gated calcium channels (VGCCs) have been reported in 75-100% of LEMS patients who have small cell lung cancer (SCLC) and in 50-90% of LEMS patients who do not have underlying cancer.
EMG
CT/MRI - lung cancer?
A 50 year old man visits his GP complaining of weakness in his right arm. He reports the weakness has gradually developed over the last 2 months. On inspection, the GP notices wasting of his tongue and hyperreflexia. His right arm is rigid. What is the most likely diagnosis?
Stroke Multiple Sclerosis Parkinson’s disease Motor Neuron Disease Carpel Tunnel Syndrome
Motor Neuron Disease
The key thing is spotting the mixture of UMN (hyperreflexia and rigidity) and LMN signs (wasting).
Men are more likely to get MND
Stroke would be an acute onset, not progressive. MS would not really give wasting as it involved UMN’s, would also most likely be an acute attack.
Parkinson’s does have motor signs, but doesn’t give wasting as again it’s CNS not PNS. Also missing the classic triad.
Carpel tunnel syndrome can give arm/hand weakness, but no signs/symptoms outside of this.
MND Definition and Incidence
5-8/100,000
(AML/Charcot’s Disease)
Chronic neurodegenerative condition (hardening of the lateral corticospinal tracts) causing progressive muscle wasting, paralysis and death usually within 3-5 years due to respiratory failure
Progressive denervation and secondary muscle weakness of limbs, trunk, tongue and respiratory(Intercostal) muscles. Onset usually occurs in distal muscles of a single limb or may be bulbar, followed by widespread progression
MND Symptoms
Bulbar symptoms - dysphagia, impaired speech
Spastic weakness/paralysis of all skeletal musc –> respiratory failure
SOB
Changed cognitive function (15%)
Sparing of oculomotor, sensory and autonomic function (bladder, bowel, sexual function preserved)
Signs of MND
Wasting of:
- Thenar hand muscles (base of the thumb
- Tongue (bulbar onset)
What does bulbar mean?
Relating to the medulla oblongata (it’s shaped like a bulb)
What causes MND?
Unclear: sporatic + familial
Ubiquinated proteins in cytoplasm (normally marked for degradation by proteasome) but not destroyed –> builds up –> CS tract death.
97% of MND patients have ubiquitin inclusions positive for TDP-43 (protein in DNA/RNA processing normally in nucleus, but ends up in cytoplasm)
MND Invx
Clinical Dx
- EMG: fibrillation and fasciculations; motor units are polyphasic and have high amplitude and long duration.
- Nerve conduction studies should show normal motor and sensory conduction in MND.
- CT/MRI/blood tests to exclude other causes
A 70 year man is referred to a neurologist by his GP. The referral letter notes that the man has slowly been struggling to get around and carry out basic activities like cooking dinner, finding he struggles to initiate movement. The letter also notes that the patient has a resting tremor and rigid upper arms. When the neurologist calls the patient into the room, what gait does he expect the patient to most likely have?
Ataxic Hemiplegic Shuffling Scissor Choreiform
Shuffling
Patient has classical triad of bradykinesia, rigidity and tremor, telling us it is likely Parkinson’s. Therefore answer is shuffling gait (shuffle as otherwise can lose balance) Patient obviously wouldn’t say “I’m struggling to initiate movement” that is the words of the GP, patient more likely to say “struggle to get going”
Ataxic gait is cerebellar sign, seen in Wernicke’s encephalopathy.
Hemiplegic is typically following a stroke
Scissor gait characteristic of cerebral palsy
Choreiform (dance like) typical of Huntington’s
Parkinsons - 6M’s
Monotonous, hypotonic speech Micrographia HypomiMesis (expressionless face) March a petit pas (chasing one's gravity) Misery → depression Memory loss → dementia
Later: ANS e.g. dysphagia and drooling, anosmia etc, REM sleep disorder
Tremor is absent in % of Parkinsons patients
30%
How to test postural instability?
Push them –> fall
What is Parkinson’s syndrome and what causes it?
Triad of bradykinesia, resting tremor and rigidity
- Parkinson’s disease
- Antipsychotics or antiemetics (Lower DA)
- Atypical Parkinsonisms (multi-infarct/vascular - strokes in striatum)
Full name of site of pathology in Parkinson’s
Substantia nigra pars compacta (midbrain)
Compare Parkinson’s brain with normal - colour
Normal is darker, neurons produce Neuromelanin
How much neurons to lose before symptoms in parkinson’s?
80%
Pathophysiology of Parkinson’s
Alpha synuclein misfold –> accumulate in Lewy bodies and lewy dendrites –> neuron death in:
1. Nigrostriatal pathway - motor symptoms (striatum required for smooth, functional movement; inhibits oppositional movements).
Later:
2. Mesolimbic and mesocortical pathways –> cognitive symptoms.
RF for Parkinsons
Age: 50% of those >80 have two or more clinical signs of Parkinsonism
Male
Countryside (pesticides?)
10% genetic
Parkinson’s disease dementia vs Lewy Body disease
P’s D: Dementia develops many years after the onset of motor symptoms
Lewy body dementia vs. Alzheimer’s
Hallucination (little people + animals)
Visuospatial dysfunction
aren’t as common in Alzheimer’s dementia
A 55 year old gentleman is accompanied to the GP by his daughter. She is distressed that ‘something’s happened to Dad, he’s changed …’. It transpires that he has started swearing at people in the street and flirting with all the women he meets. He is able to chat to you about current events and his favourite sport team’s latest match. What is the most likely diagnosis?
Pick’s disease Lewy body dementia Vascular dementia Alzheimer’s dementia Wernicke-Korsakoff syndrome
The factors that point to pick’s disease over the other options is that this patient is relatively young to have the other forms of dementia. They also have the classical symptoms of Pick’s – disinhibition and personality change. The fact he can chat to you about recent events and his sports team (effective way to test memory) tells us it not likely Alzheimer’s – as normally memory of recent events is the first thing to go
There’s no motor signs or symptoms of reduced thiamine – pointing us away from LBD and Wernicke’s
What does dementia typically affect
Cognition and memory
- Affect
- Motivation and attention
- Personality and behaviour
The 5 As of Alzheimer’s dementia:
Amnesia (Episodic memory) Anomia Apraxia Agnosia Aphasia
± Depression
± Paranoid delusions
Alzheimer’s symptoms
Memory: Poor day-to-day memory, repetitive, can get lost
Language: Word-finding problems, People’s names
Attention: Following conversations, especially in groups
Calculation: Partner/family take over accounts and bills
Executive Function: Household tasks, preparing meals
Praxis: Problems with dressing, manual tasks
What is loss of memory in Alzheimer’s due to?
Atrophy of medial temporal lobes, where we normally have hippocampus
Later: global cortical atrophy
Alzheimer’s pathophysiology
Amyloid precursor protein [APP] = transmembrane protein
Normal = a and γ secretase → normal degradation product
AD = b and γ secretase → abnormal product resistant to degradation → Ab
Ab accumulates outside the cell to form amyloid plaques
Interferes with neuronal communication (+ inflammation
Tau Tangles
What else does Ab do?
(Tau = protein that supports microfilaments)
Ab triggers phosphorylation of tau, causing it to disassociate from the MF and accumulate into neurofibrillary tangles
Tangles + weakened microfilaments → ↓neuronal function and apoptosis → atrophy
→ degeneration of cholinergic nuclei → ↓ cortical ACh
Key things for SBA (Alzheimers)
β Amyloid → extracellular plaques
Hyperphosphorylated tau → neurofibrillary tangles
Neuronal and synaptic loss
Alzheimer RFs
Ages Female Trauma APOE (biggest genetic cause, involved in Ab clearance)/AD familial alzheimer's Down's Exercise and education is protective
How does Trauma cause Alzheimer’s?
Chronic traumatic encelopathy (Punch-drunk syndrome) -> THI
–> chronic inflam, increase amyloid levels (Ab deposits in 30% of HI pts)
Alzheimer’s Invx
Very few effective laboratory tests
Clinical diagnosis
CSF: tau (low) & beta amyloid (high)
Imaging: CT, MRI, (atrophy) PET, SPECT
Brain Tissue required for definitive diagnosis
Vascular dementia symptoms
Location-specific deficits
Emotional and personality changes
Focal neurology
(sudden onset, step wise)
Vascular dementia RF and pathophys
Infarction damaging the small and medium sized vessels
Vasculopaths, age, male, CVD
Vascular dementia MRI
Hemosiderin deposits from previous infarcts
Pick’s disease and pick bodies
Most common form of fronto-temporal dementia
Pick bodies: Hyperphosphyorlated tau protein
Pick’s symptoms
Personality change Disinhibition Overeating, preference for sweet foods Emotional blunting Relative preservation of memory
RF for pick’s, prognosis
Typically affects people younger than in other dementias
±FHx (although most are sporadic)
Death within 5-10yrs
RF for pick’s, prognosis
Typically affects people younger than in other dementias
±FHx (although most are sporadic)
Death within 5-10yrs
How to DDx dementias
Alzheimer’s
Insidious amnesia, language impairment
Lewy Body Dementia
Fluctuation, agitation, hallucinations, visuospatial dysfunction, Parkinsonism
Vascular Dementia
Stepwise decline, focal/motor/gait signs
Frontotemporal dementia
Lack of hygiene, personality change, poor comportment & planning
You are called to see a 40 year old man in A&E. You try to take a history but the man in confused and unable to tell you much. On examination he has numerous spider naevi on his chest, an ataxic gait and nystagmus. What is the most likely diagnosis?
Multiple Sclerosis Motor Neuron Disease Korsakoff’s syndrome Wernicke’s Encephalopathy Head trauma
Wernicke’s Encephalopathy
Patient has classic triad ACE: ataxia, confusion and eye signs – pointing us towards Wernicke’s encephalopathy. The spider naevi suggest patient may be alcoholic, which is likely a causative factor.
If untreated this could progress to Korsakoff’s, which is not the answer as they would not be confused and would be chronic, not acute
Head trauma can give ataxic gait and confusion, less likely to give eye signs. But probably second most likely on the list
MND and MS would rarely give confusion.
Wernicke’s Encephalopathy signs
Ataxia (cerebellar dmg)
Confusion
Eye signs - ophthalmoplegia, nystagmus, diplopia, ptosis
10% has triad
Why is ETOH so bad for W’s E
Poor diet
Prevents vitamin B-1 absorption and storage
What is Thiamine used for?
- Metabolism of carbohydrates, releasing energy.
- Production of neurotransmitters including glutamic acid and GABA.
- Lipid metabolism, necessary formyelin production.
- Amino acid modification - production of taurine, of great cardiac importance.
Why is ETOH so toxic?
Brain atrophy
Can Exacerbate Cognitive function in other dementias
Invx for W’s E
Bloods Pabrinex LFT ECG before and after Tx CT - lesions Neuropsychological test to determine the severity of any mental deficiencies.
W’s E prognosis
12% no cognitice sequelae, with LT Pabrinex
68% Karsakoff’s
20% Death
Karsakoff’s features
Chronic
Alert
Amnesia and confabulation
Irreversible?
A 40 year old man starts to make random jerky movements at points throughout the day. Worried about this, he visits his GP. Upon questioning, he informs the GP that his father died in his 40s, but he was too young to remember why, although he did have similar symptoms. What test should be arranged?
FBC Karyotyping Whole genome sequencing CAG repeat testing MRI head
CAG repeat testing
This man has symptoms suggestive of Huntington’s, the jerky movements one of the first symptoms to develop. The fact is father died young and had similar symptoms supports this. The typical genetic test for suspected Huntington’s is CAG repeat testing, if they have 40 or more repeats then Huntington’s is confirmed.
FBC wouldn’t explain these symptoms, Karyotyping is normally for aneuploidy like Down’s or translocation disorders.
Whole genome sequencing is for de novo mutations, where you can compare to the parents. Currently only used in research setting as very expensive.
MRI head might show atrophy of caudate but it is non-specific.
Huntington’s symptoms
Motor: (hands and face first) Chorea (jerky) Athetosis (writhing hands) Ataxia Dysphagia
Cognitive Lack of concentration Depression Dementia Personality changes, aggression Difficulty eating, swallowing, can't protrude tongue
Pathology of Hungtintons
Atrophy of medium spiny GABAergic neurons of mainly the caudate, but also putamen; (collectively = striatum) –> can’t inhibit movements –> chorea
Progression = global atrophy
Genetic basis of Huntington’s
AD: Mutation of the HTT gene on short arm of chromosome 4, CAG
Sporadic: new genetic mutation-an alteration in the gene that occurs during sperm development and that brings the number of CAG repeats into the range that causes disease.
Normal (<35 codons) huntingtin protein is thought to stabilize neurons, preventing apoptosis from occurring and prolonging cell life.
> 40 codons = toxic (large glutamine blocks) - induces apoptosis in neurones (bc metab change sensed by mitochondria)
CAG repeats significance
≤28: Normal range; individual will not develop Huntington’s disease
29-34: Individual will not develop Huntington’s disease but the next generation is at risk
35-39: Some, but not all, individuals in this range will develop Huntington’s disease; next generation is at risk
≥ 40: Individual will develop Huntington’s disease
