17. Chronic Neurology

Question 1

MS Definition

Answer 1

A chronic inflammatory multifocal, demyelinating disease of the central nervous system of unknown cause, resulting in loss of myelin, and oligodendroglial and axonal pathology

Question 2

MS Common Symptoms and Signs

Answer 2

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)

Question 3

MS other symptoms

Answer 3

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

Question 4

MS Invx

Answer 4

Fundoscopy - eye signs e.g. papillitis. Diplopia, nystagmus, internuclear ophthalmoplegia

Retro-bulbar optic neuritis (2/3)
Optic neuritis with papillitis (1/3)

Question 5

Multiple Sclerosis Epidemiology

Answer 5

Around 2.5 millions worldwide
Higher prevalence among white people of Nordic origin - ‘Latitude effect’
Highest in UK, Sweden, Denmark

Question 6

Multiple Sclerosis RF

Answer 6

AI PMHx
HLA-DLRB1*15
VItamin D levels (more sunlight)
Latitude

Question 7

Multiple Sclerosis MRI

Answer 7

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.

Question 8

MS Pathophysiology

Answer 8

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.

Question 9

3 types of MS phenotypes

Answer 9

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

Question 10

MS Dx

Answer 10

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

Question 11

How can we differentiate old and new lesions?

Answer 11

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.

Question 12

What is diagnostic of MS in the CSF?

Answer 12

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

Question 13

What are VEPs and what are they used for?

Answer 13

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

Question 14

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

Answer 14

Risk factors of being young, Nordic woman. Also demyelination can be precipitated by a hot bath

DIT
DIS

Question 15

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

Answer 15

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.

Question 16

Myasthenia Gravis Symptoms and signs

Answer 16

Symptoms - Muscles fatigue with use
Ptosis
Diplopia
Dysarthria
Dysphagia
±SOB

Signs
Fatigable muscles
Normal reflexes

Question 17

Who does MG normally affect

Answer 17

It most commonly impacts young adult women (under 40) and older men (over 60) – as it is an autoimmune condition

Question 18

What muscles does MG usually implicate

Answer 18

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.

Question 19

MG Aetiology

Answer 19

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

Question 20

MG Associations

Answer 20

Thymic hyperplasia (70%)
Thymoma (10%)

Question 21

Mg Investigations

Answer 21

Bloods – anti-AChR or anti-MuSK
EMG -demonstrate muscle weakness, action potentials will gradually decrease over time
CT/MRI - for thymomas

Question 22

Lambert Eaton Myasthenic Syndrome Symptoms

Answer 22

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

Question 23

Lambert Eaton Myasthenic Syndrome Aetiology

Answer 23

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

Question 24

Lambert Eaton Myasthenic Syndrome Associations

Answer 24

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)

Question 25

Lambert Eaton Myasthenic Syndrome Investigations

Answer 25

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?

Question 26

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 ```

Answer 26

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.

Question 27

MND Definition and Incidence

Answer 27

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

Question 28

MND Symptoms

Answer 28

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)

Question 29

Signs of MND

Answer 29

Wasting of: - Thenar hand muscles (base of the thumb - Tongue (bulbar onset)

Question 30

What does bulbar mean?

Answer 30

Relating to the medulla oblongata (it’s shaped like a bulb)

Question 31

What causes MND?

Answer 31

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)

Question 32

MND Invx

Answer 32

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

Question 33

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 ```

Answer 33

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

Question 34

Parkinsons - 6M's

Answer 34

``` 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

Question 35

Tremor is absent in % of Parkinsons patients

Answer 35

30%

Question 36

How to test postural instability?

Answer 36

Push them --> fall

Question 37

What is Parkinson's syndrome and what causes it?

Answer 37

Triad of bradykinesia, resting tremor and rigidity - Parkinson’s disease - Antipsychotics or antiemetics (Lower DA) - Atypical Parkinsonisms (multi-infarct/vascular - strokes in striatum)

Question 38

Full name of site of pathology in Parkinson's

Answer 38

Substantia nigra pars compacta (midbrain)

Question 39

Compare Parkinson's brain with normal - colour

Answer 39

Normal is darker, neurons produce Neuromelanin

Question 40

How much neurons to lose before symptoms in parkinson's?

Answer 40

80%

Question 41

Pathophysiology of Parkinson's

Answer 41

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.

Question 42

RF for Parkinsons

Answer 42

Age: 50% of those >80 have two or more clinical signs of Parkinsonism Male Countryside (pesticides?) 10% genetic

Question 43

Parkinson’s disease dementia vs Lewy Body disease

Answer 43

P's D: Dementia develops many years after the onset of motor symptoms

Question 44

Lewy body dementia vs. Alzheimer's

Answer 44

Hallucination (little people + animals) Visuospatial dysfunction aren’t as common in Alzheimer’s dementia

Question 45

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 ```

Answer 45

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

Question 46

What does dementia typically affect

Answer 46

Cognition and memory - Affect - Motivation and attention - Personality and behaviour

Question 47

The 5 As of Alzheimer’s dementia:

Answer 47

``` Amnesia (Episodic memory) Anomia Apraxia Agnosia Aphasia ``` ± Depression ± Paranoid delusions

Question 48

Alzheimer’s symptoms

Answer 48

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

Question 49

What is loss of memory in Alzheimer's due to?

Answer 49

Atrophy of medial temporal lobes, where we normally have hippocampus Later: global cortical atrophy

Question 50

Alzheimer’s pathophysiology

Answer 50

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

Question 51

What else does Ab do?

Answer 51

(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

Question 52

Key things for SBA (Alzheimers)

Answer 52

β Amyloid → extracellular plaques Hyperphosphorylated tau → neurofibrillary tangles Neuronal and synaptic loss

Question 53

Alzheimer RFs

Answer 53

``` Ages Female Trauma APOE (biggest genetic cause, involved in Ab clearance)/AD familial alzheimer's Down's Exercise and education is protective ```

Question 54

How does Trauma cause Alzheimer's?

Answer 54

Chronic traumatic encelopathy (Punch-drunk syndrome) -> THI | --> chronic inflam, increase amyloid levels (Ab deposits in 30% of HI pts)

Question 55

Alzheimer's Invx

Answer 55

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

Question 56

Vascular dementia symptoms

Answer 56

Location-specific deficits Emotional and personality changes Focal neurology (sudden onset, step wise)

Question 57

Vascular dementia RF and pathophys

Answer 57

Infarction damaging the small and medium sized vessels Vasculopaths, age, male, CVD

Question 58

Vascular dementia MRI

Answer 58

Hemosiderin deposits from previous infarcts

Question 59

Pick’s disease and pick bodies

Answer 59

Most common form of fronto-temporal dementia Pick bodies: Hyperphosphyorlated tau protein

Question 60

Pick's symptoms

Answer 60

``` Personality change Disinhibition Overeating, preference for sweet foods Emotional blunting Relative preservation of memory ```

Question 61

RF for pick's, prognosis

Answer 61

Typically affects people younger than in other dementias ±FHx (although most are sporadic) Death within 5-10yrs

Question 62

RF for pick's, prognosis

Answer 62

Typically affects people younger than in other dementias ±FHx (although most are sporadic) Death within 5-10yrs

Question 63

How to DDx dementias

Answer 63

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

Question 64

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 ```

Answer 64

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.

Question 65

Wernicke’s Encephalopathy signs

Answer 65

Ataxia (cerebellar dmg) Confusion Eye signs - ophthalmoplegia, nystagmus, diplopia, ptosis 10% has triad

Question 66

Why is ETOH so bad for W's E

Answer 66

Poor diet | Prevents vitamin B-1 absorption and storage

Question 67

What is Thiamine used for?

Answer 67

- Metabolism of carbohydrates, releasing energy. - Production of neurotransmitters including glutamic acid and GABA. - Lipid metabolism, necessary for myelin production. - Amino acid modification - production of taurine, of great cardiac importance.

Question 68

Why is ETOH so toxic?

Answer 68

Brain atrophy | Can Exacerbate Cognitive function in other dementias

Question 69

Invx for W's E

Answer 69

``` Bloods Pabrinex LFT ECG before and after Tx CT - lesions Neuropsychological test to determine the severity of any mental deficiencies. ```

Question 70

W's E prognosis

Answer 70

12% no cognitice sequelae, with LT Pabrinex 68% Karsakoff's 20% Death

Question 71

Karsakoff's features

Answer 71

Chronic Alert Amnesia and confabulation Irreversible?

Question 72

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 ```

Answer 72

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.

Question 73

Huntington’s symptoms

Answer 73

``` 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 ```

Question 74

Pathology of Hungtintons

Answer 74

Atrophy of medium spiny GABAergic neurons of mainly the caudate, but also putamen; (collectively = striatum) --> can't inhibit movements --> chorea Progression = global atrophy

Question 75

Genetic basis of Huntington's

Answer 75

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)

Question 76

CAG repeats significance

Answer 76

≤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