Neurodegenerative diseases Flashcards
A 28 year old Norwegian woman presents to A&E after she was unable to feel 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?
A Multiple lesions on MRI that all enhanced with gadolinium
B The patient’s symptoms reoccur 1 year later
C The patient develops blurry vision in one eye a year later
D The patient reports blurry vision currently
E A 1 year follow up finds oligoclonal bands matched with the serum
C The patient develops blurry vision in one eye a year later
Define multiple sclerosis
A chronic inflammatory multifocal, demyelinating disease of the central nervous system of unknown cause, resulting in loss of myelin and oligodendroglial and axonal pathology
What are the symptoms of multiple sclerosis
- Plaques on optic nerve - optic neuritis - vision loss and pain
- Charot’s neurological triad - dysarthria, nystagmus, intention tremour
- Plaques on sensory neurones - numbness, parasthesia, pins and needles
- Plaques in the ANS - bladder (urinary incontinence/urgency) sexual dysfunction
- plaques on motor neurones - weakness of the limbs with spasticity and hyper-reflexia
- Disturbances in higher order activities- poor concentration + critical thinking, depression + anxiety
- Lhermitte’s sign - electric shock radiating down patients neck triggered by neck flexion
What are the clinical signs of multiple sclerosis
- Fundoscopy - inflamed optic disc
- CN exam - internuclear ophthalmoplegia: for example when R eye glare to the left. R eye cannot look past the midline
- Lhermitte’s sign - electric shock radiating down patients neck triggered by neck flexion
- Charot’s neurological triad - dysarthria, nystagmus, intention tremour
What are the risk factors of multiple sclerosis
- Female
- Vitamin D deficiency (pts with Scandinavian origin)
- HLA DLR B1*15
- Other autoimmune conditions such as SLE
What can be found on a MRI of a patient with multiple sclerosis
White matter plaques
These are pathological substrate of relapses
What is the most common type of multiple sclerosis
Relapsing remitting (RR) MS
To make a clinical diagnosis of multiple sclerosis, what should be present
- absence of an alternative diagnosis
- Dissemination in time
- Dissemination in space
What stain is used in MRI to diagnose multiple sclerosis
Gadolinium contract (GAD)
How can GAD be used in the diagnosis of multiple sclerosis
- acute inflammation
- breakdown of BBB
- GAD penetrates CNS
- GAD enhances active lesions
(older lesions remain darker, so looking at older lesions in different parts of the brain can diagnose MS)
What can be said about the oligoclonal bands in multiple sclerosis
- Oligoclonal bands were present in the CSF but not the serum
Must only be in the CSF otherwise IgG could have been from an infection at the periphery.
CSF bands are 95% sensitive for MS, but not specific as could also be infection of the CNS
How can visual evoked potentials be used in the diagnosis of multiple sclerosis
These look for subtle abnormalities in the visual pathways (commonly affected in MS) which may help clinicians to pick up subclinical features even the patient was not aware of
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?
A Iron Deficiency Anaemia
B Myasthenia Gravis
C Lambert Eaton Myasthenic Syndrome
D Carcinoma
E Horner’s Syndrome
B Myasthenia Gravis
What are the symptoms of myasthenia gravis
- Muscles fatigue with use (symptoms at the end of the day)
- Ptosis
- Diplopia
- Dysarthria
- Dysphagia
+/- SOB
What are the clinical signs of myasthenia gravis
- Fatigable muscles
2. Normal reflexes
What are the antibodies that can be produced in myasthenia gravis
- anti-AChR antibody
2. MuSK (Muscle-Specific Kinase) protein
What conditions is myasthenia gravis associated with
- Thymic hyperplasia (70%)
2. Thymoma (10%)
What investigations can be done to diagnose myasthenia gravis
- Bloods - anti-AChR and anti-MuSK
- EMG (can demonstrate muscle weakness, action potentials will gradually decreased)
- CT/MRI (CT chest can detect thymoma)
What are the symptoms of Lambert Eaton Myasthenic Syndrome
- Weakness where muscles improve with use (symptoms in the morning)
- Difficulty walking
- weakness in upper arm and shoulders
- similar symptoms to myasthenia gravis
- Autonomic symptoms include dry mouth, constipation and incontinence
What are the clinical signs of Lamber Eaton Myasthenic syndrome
- Muscle function better following use
2. hyporeflexia
What is Lambert Eaton Myasthenic Syndrome
The immune system attacks calcium channels on nerve endings
What conditions is Lambert Eaton Myasthenic syndrome associated with
- Small cell lung cancer
2. Autoimmune disease
What are the investigations to diagnose Lambert Eaton Myasthenic syndrome
- Bloods - anti-VGCC
- EMG
- CT/MRI (for cancer detection)
What are the symptoms of motor neurone disease
- progressive muscle weakness
- Dysphagia
- Shortness of breath
What neurones does motor neurone disease spare
- Occulomotor
- sensory function
- autonomic function
What are upper motor signs
- increased weakness
- increased reflexes
- No fasciculations
- increased tone
- Extensor response present
What are lower motor signs
- increased weakness
- atrophy - wasting of the tongue and thenar muscles in the hand and
- reduced reflexes
- fasciculations present
- Tone decreased
- Extensor response absent (babinski’s sign)
What condition has both upper and lower motor neurone signs
Motor Neurone Disease
Which muscles undergo wasting in motor neurone disease
- wasting of the thenar hand muscles (base of the thumb)
2. Wasting of the tongue muscle (bulbar onset)
What is the pathophysiology behind motor neurone disease
Normally proteins that need degradation are marked with ubiquitin.
This malfunctions in in MND
These proteins build up which eventually kill the motor neurones.
Upper and lower motor neurones killed.
This leads to death of the corticospinal tract
What genetic risk factor increases the chances of developing motor neurone disease
97% of MND patients have ubiquitin inclusions positive for TDP-43
Normally TDP-43 is found in the nucleus where it is involved with normal DNA and RNA function.
In MND, the TDP-43 protein is found in the cytoplasm where it is tagged with ubiquitin. However, it is not degraded and builds up and leads to cell death.
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?
A Ataxic
B Hemiplegic
C Shuffling
D Scissor
E Choreiform
C Shuffling
What is the classical Parkinsonism triad
- Bradykinesia
- Rigidity
- Resting tremur
What are the 6Ms that help describe Parkinson’s symptoms
- Monotonous
- Micrographia (small handwriting)
- HypomiMesis (expressionless face)
- March a petit pas (gait with little steps)
- Misery (depression)
- Memory loss (dementia)
What are the symptoms of Parkinson’s disease
- Pill-rolling tremor (resting)
- Cog-wheeling rigidity
- Stooped posture
- expressionless face
- Bradykinesia, hypokinesia, akenesia (due to difficulty initialting movement)
- Late feature: postural instability which can lead to falls
- Depression
- Dementia
- Sleep disturbances
- difficulty smelling
How can Parkinson’s disease be differentiated from cerebellar disease
Parkinson’s disease manifests itself as a pin rolling resting tremor whereas cerebellar disease has an action tremor
What is not a symptom of Parkinson’s disease
weakness
How can Parkinson’s disease be differentiated from motor neurone disease
Parkinson’s disease does not affect the corticospinal tract or the motor cortex like motor neurone disease does. Therefore Parkinson’s does not lead to weakness
What are 3 causes of Parkinsonism (symptoms)
- Parkinson’s disease
- Drug induced
- Atypical Parkinsonism
What drugs may cause Parkinsonism
- anti-psychotics
2. anti-emetics
What is the aetiology of Parkinson’s disease
Death of doperminergic neurones in the substanita nigra.
Before neurones die, they have eosinophilic, alpha-synuclein Lewy body’s
What is the first pathway affected in Parkinson’s disease
nigrostriatal pathway
What are the Risk factors for Parkinson’s disease
- Ageing
- Pesticides
- 10% of cases are said to be genetic with mutations in the Parkin, PINK, alpha synuclein gene
What is lewy body dementia
Early dementia with visual hallucinations
What is vascular Parkinson’s
Legs are particularly affected
Gait is worse than tremor
What is the difference between lewy body dementia and Parkinson’s disease dementia
PDD develops many years after the onset of motor symptoms.
Whereas lewy body dementia, these symptoms develop without the presence of motor symptoms. If motor symptoms do develop, they develop a year before or a year after the onset of dementia symptoms
What are the 5 As of Alzheimer’s
Amnesia
Anomia (unable to recall names of everyday objects)
Apraxia (dysfunction in motor planning - unable to do actions on command)
Agnosia (unable to recognise)
Aphasia
What are the MRI brain findings of an individual with Alzheimers
Global cortical atrophy
Atrophy of medial temporal lobes
Gyri get narrower
Sulci get wider
What is the aetiology of Alzheimer’s disease
- beta and gamma secretase breakdown amyloid precursor protein (APP) into insoluble protein (normally done by alpha and gamma sectrase).
Beta amyloid plaques accumulate outside the neurone. - These beta amyloid plaques cause intracellular signalling in neurone. Tau protein normally support microtubules. When they are phosphorylated, they detach and form plaques within the neurone.
Intracellular signally cannot occur due to unsupported microtubules. - This leads to cellular apoptosis
What are the histological findings in Alzheimer’s disease
- Beta amyloid plaques
- neurofibrillary tangles
- Neuronal and synaptic loss
What causes neurofibrillary tangles
Hyperphosphorylated Tau protein
What genetic condition increases the likelihood of developing Alzheimer’s
Down’s syndrome
What is the greatest risk factor for Alzheimer’s
Age
Which gene mutations are risk factors for developing Alzheimer’s disease
APOE (cholesterol transport protein involved in Abeta clearance)
Autosomal dominant
Amyloid precursor protein
Presenilin 1
Presenilin 2
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?
A Pick’s disease
B Lewy body dementia
C Vascular dementia
D Alzheimer’s dementia
E Wernicke-Korsakoff
syndrome
A Pick’s disease
What is protective against Alzhiemer’s disease
- Educational/professional attainment
2. Exercise
What is the Gold Standard for Alzheimer’s disease
Brain biopsy
What are the investigations for Alzheimer’s
- CSF: Tau and beta amyloid
- Imaging: CT, MRI, PET, SPECT (Single-photon emission computed tomography)
- Cognitive assessment: MMSE, MOCA
Name 3 cognitive assessments
- Mini-mental state examination (MMSE)
- Montreal cognitive assessment (MOCA)
- Addenbrooke’s Cogniive assessment
What are the buzzwords for vascular dementia
- Sudden onset
2. Stepwise deterioration
What are the symptoms of vascular dementia
- location-specific deficits
- emotional and personality changes
- focal neurology
What is vascular dementia
multi-infarct dementia
Either atherosclerosis in arteries leading to brain causing long-term poor blood flow to the brain. or parts of the atherosclerotic plaque break off and cause mini strokes
What are the risk factors for vascular dementia
- Effects men more than women
- increasing age
- CVD risk factors
What is fronto-temporal dementia also known as
Pick’s disease
What is the aetiology of fronto-temporal dementia
Tauopathology
Hyperphosphorylated 3R Tau proteins. Which leads to a collection of Pick’s bodies in the neurone. Eventually leading to apoptosis
What is the age of onset of fronto-temporal dementia
40-60 y/o
What are the symptoms od fronto-temporal dementia
- Personality changes
- Disinhibition
- Overeating (prederence for sweet foods)
- emotional blunting
- relative preservation of memory
What is Lewy body dementia
Dopaminergic neurones in the substantia nigra develop Lewy bodies which causes neuronal death
What are Lewy bodies
misfolded alpha synuclein which aggregates to form Lewy bodies.
They appear as dark, eosinophilic inclusions inside neurones
What are the early symptoms of lewy body dementia
Likened with Alzheimer’s
- difficulty focusing
- poor memory
- visual hallucinations 4. disorganised speech
What are the late symptoms of lewy body dementia
Likened with Parkinson’s disease
- resting tremur
- stiff and slow movements
- reduced facial expressions
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?
A Multiple Sclerosis
B Motor Neuron Disease
C Korsakoff’s syndrome
D Wernicke’s Encephalopathy
E Head trauma
D Wernicke’s Encephalopathy
What is the classic triad which leads to Wernicke’s encephalopathy
- Ataxia
- confusion
- eye signs
Deficiency in what causes Wernicke’s encephalopathy
Vitamin B1 (thiamine)
What are causes of Wernicke’s encephalopathy
- alcoholism
- malnourishment
- Absorption restriction: gastric bypass, stomach cancer and IBD
- patients on dialysis
What protein is the biggest indicator of liver function
albumin
What investigations are done in Wernicke’s encephalopathy
- Blood - serum albumin and vitamin b1
- ECG
- CT
- Neuropsychology
What is the difference between Wernickes’s encephalopathy and Korsakoff syndrome
W: acute
K: chronic
W: confusion
K: Alert
W: cerebellar and eye signs
K: amnesia and confabulation
W: reversible
K: irrevisible
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?
A FBC
B Karyotyping
C Whole genome sequencing
D CAG repeat testing
E MRI head
D CAG repeat testing
What are the cognitive symptoms of Huntington disease
- Lack of concentration
- Depression
- Dementia
- personality changes as aggression
On a cranial nerve exam, what will a Huntington patient not be able to do
protrude their tongue
What parts of the brain are affected by Huntington disease
- caudate
- putamen
which together make the dorsal striatum
cell death causes increased size of lateral ventricles
What does a brain MRI show in a patient with Huntington disease
- global atrophy
2. increased size of lateral ventricles
What is the aetiology of Huntington disease
- mutation of the Huntingtin gene (HTT)
- Expansion of CAG trinucleotide
- autosomal dominant
What is the role of the normal Huntingtin protein in the neurone
It stabilises neurones preventing apoptosis an d prolonging cell life
What is the Gold Standard investigation for Huntington disease
CAG repeat testing
How many CAG repeats will lead an individual to develop Huntington disease
40 or more
The more CAG repeats, the earlier onset of illness (earlier death)
What is the prognosis for Huntington disease
10-15 years after the onset of symptoms
