Neuro - Neuronal Disease

Question 1

Multiple Sclerosis

Pathophysiology 
Risk Factors/Causes
Clinical Features
Diagnosis 
Investigations

Answer 1

1. ) Pathophysiology - progressive demyelination of the neurones in the CNS (affects oligodendrocytes)
   - due to the inflammatory process activating immune cells that infiltrate and damage the myelin
   - hallmarks: demyelination plaques and axonal loss
   - often many lesions in CNS which don’t cause any sx
   - lesions are ‘disseminated in time and space’
2. ) Risk Factors/Causes
   - smoking, obesity, low vitamin D, genetics, EBV
   - mean onset 30s (<50), more common in women
   - sx improve in pregnancy and post-partum period
3. ) Clinical Features - UMN signs
   - sx usually progresses >24hrs, at first presentation, sx last days to weeks and then improve
   - in early disease, sx resolve due to re-myelination but in later disease, re-myelination is incomplete
   - presentations: optic neuritis, ophthalmoplegia, focal sensory sx, focal weakness, ataxia,
   - lethargy is a very common early symptom
4. ) Diagnosis - using the McDonald criteria
   - multiple lesions ‘disseminated in time and space’
   - lesions consistent with an inflammatory process
   - no alternative diagnosis: must exclude other causes
   - PPMS: sx have to be progressive for > 1yr period
5. ) Investigations
   - MRI w/ contrast of the brain and spinal cord: plaques of demyelination (periventricular white matter lesions)
   - LP for immunoelectrophoresis of the CSF: shows oligoclonal bands of IgG

Question 2

Presentations in Multiple Sclerosis

Optic Neuritis
Ophthalmoplegia 
Focal Sensory Symptoms
Focal Weakness
Ataxia

Answer 2

1.) Optic Neuritis - most common presentation in MS

2. ) Ophthalmoplegia - patient presents w/ double vision
   - lesion in the medial longitudinal fasciculus
   - CN VI palsy causes internuclear ophthalmoplegia causing a conjugate lateral gaze disorder
3. ) Focal Sensory Symptoms
   - sensory disturbance: numbness, paraesthesia
   - neuropathic pain: trigeminal neuralgia
   - spastic paraparesis due to transverse myelitis
   - Lhermitte’s sign: shooting pain down the spine, into limbs when flexing the neck due to stretching the demyelinated dorsal column in the cervical spinal cord
4. ) Focal Weakness - due to UMN involvement
   - limb paralysis, incontinence
   - Bell’s palsy, Horner’s syndrome
5. ) Ataxia - can be either sensory or cerebellar
   - sensory: loss of proprioception, +ve Romberg’s test, can cause pseudoathetosis
   - cerebellar: -ve Romberg’s

Question 3

Disease Patterns in Multiple Sclerosis

Clinically Isolated Syndrome
Relapsing-Remitting (RRMS)
Secondary Progressive
Primary-Progressive (PPMS)

Answer 3

1. ) Clinically Isolated Syndrome - first episode of demyelination and neurological signs and sx
   - cannot diagnose MS as the lesions have not been “disseminated in time and space”.
   - may never have another episode or develop MS.
2. ) Relapsing-Remitting (RRMS) - most common (80%)
   - episodes of disease/neuro sx followed by recovery
   - sx occur in different areas with different episodes
   - active (or non-active): new sx or new lesions on MRI
   - worsening: overall worsening of disability over time
3. ) Secondary Progressive
   - RRMS –> progressive worsening of sx w/ incomplete remissions with sx becoming more permanent
   - active (or non-active): new sx or new lesions on MRI
   - progressing: overall worsening of disease over time
4. ) Primary-Progressive (PPMS) - < 10%
   - worsening of disease/neuro sx from the point of diagnosis without initial relapses and remissions
   - also classified into active and/or progressing

Question 4

Management of Multiple Sclerosis

Disease Modification
Treating Relapses
Symptomatic Treatments

Answer 4

1. ) Disease Modification - aim of treatment is to induce long term remission w/o evidence of disease activity
   - treat w/ disease-modifying drugs and biologics
   - target interleukins, cytokines, various immune cells
   - monoclonal antibodies: natalizumab
   - IV infusions: beta-interferon and glatiramer
   - oral: dimethyl fumarate, teriflunomide and fingolimod
2. ) Treating Relapses - treat w/ methylprednisolone, must exclude infection before treating
   - 1°: PO methylprednisolone 500mg OD for 5 days
   - 2°: IV methylprednisolone 1g OD for 3-5 days
   - 3°: plasma exchange
3. ) Symptomatic Treatments
   - spasticity: baclofen, gabapentin, physio, botox,
   - neuropathic pain: amitriptyline or gabapentin
   - urge incontinence: oxybutynin or tolterodine
   - depression: SSRIs
   - tremor: clonazepam
   - fatigue: modafinil, exercise

Question 5

Optic Neuritis

Pathophysiology
Clinical Features
Management

Answer 5

1. ) Pathophysiology - damage to the optic nerve
   - most common cause is MS, other causes include:
   - diabetes, SLE, sarcoidosis
   - syphilis, lyme disease, measles, mumps
2. ) Clinical Features
   - unilateral reduced vision over hours to days
   - periocular pain: pain on eye movement
   - dyschromatopsia: deficiency in colour perception
   - central scotoma (enlarged blind spot)
   - RAPD due to optic neuropathy
3. ) Management
   - IV high-dose methylprednisolone
   - contrast sensitivity, colour vision and visual fields can remain impaired even after recovery of visual acuity.
   - 50% of patients with a single episode of optic neuritis will go on to develop MS over the next 15 years

Question 6

Motor Neurone Disease

Pathophysiology 
Clinical Features
Clinical Variants
Investigations
Management

Answer 6

1. ) Pathophysiology - progressive degeneration of both UMN + LMN, sensory neurones are spared
   - after motor cell death follows retrograde axonal degeneration, with subsequent denervation and reinnervation in corresponding muscles
   - risk factors: genetics/FH, smoking, exposure to heavy metals and certain pesticides
   - mean onset is 50-60, more common in men
   - associated with frontotemporal dementia
2. ) Clinical Features
   - insidious, progressive weakness of the muscles affecting the limbs (esp upper), trunk, face and speech
   - mix of UMN (lower limb) and LMN (upper limb) signs
   - spares extraocular muscles and no sensory sx
   - dyspnoea, dysphagia, dysarthria
   - fasciculations and wasting of the small hand muscles/tibialis anterior is common
   - UMN involvement is associated with pseudobulbar affect or emotional lability
3. ) Clinical Variants
   - amyotrophic lateral sclerosis (ALS): most common and classic presentation, affects both UMN and LMN
   - progressive bulbar palsy: early tongue and bulbar involvement causing speech and swallowing problems (liquids worse than solids), worst prognosis
   - progressive muscular atrophy: only affects LMNs, has the best prognosis
   - primary lateral sclerosis: only affects UMNs
4. ) Investigations - clinical diagnosis but can do:
   - nerve conduction studies to exclude neuropathy
   - electromyography (EMG): ↓no. of APs with ↑amplitude
   - MRI: exclude cervical cord compression and myelopathy
5. ) Management - no cure or effective treatment
   - Riluzole: can extend survival by a few months
   - NIV (Bi-PAP): for patients w/ T2 respiratory failure (main cause of death, with pneumonia)
   - palliative care: MDT, median survival 3-5 years

Question 7

Guillain-Barré Syndrome

Pathophysiology 
Clinical Features
Investigations
Definitive Investigations
Management

Answer 7

1. ) Pathophysiology - acute ascending inflammatory demyelinating polyneuropathy affecting the PNS
   - typically 1-3wks after an infection (campylobacter, EBV, CMV) but 40% of cases are idiopathic
   - B cells create antibodies against the antigens of the infection that also target proteins on nerve cells
   - may target the myelin sheath or the nerve axon

2.) Clinical Features
- progressive ascending symmetrical limb weakness
in a ‘glove and stocking’ distribution (lower limbs first)
- paraesthesia may precede the onset of motor sx
- peripheral loss of sensation or neuropathic pain
- LMN signs: e.g. hypotonia, flaccid paralysis, areflexia
- can affect CNs: diplopia, facial palsy, bulbar palsy
- many experience back/leg pain in the early stages
- respiratory muscles affected in severe cases causing T2 respiratory failure (CO2 flap, bounding pulse)

3. ) Investigations
   - bloods: exclude peripheral neuropathy (TFTs, B12, BM, ESR), include antiganglioside antibodies (GBS)
   - brain/spinal imaging to exclude other causes
   - exclude respiratory weakness: spirometry (↓FVC), ABG (T2 respiratory failure)
4. ) Definitive Investigations - diagnosis is based on the Brighton criteria which include:
   - LP: ↑protein with a normal cell count and glucose
   - nerve conduction studies: ↓ motor nerve conduction velocity due to demyelination
5. ) Management
   - IVIG or plasma exchange
   - common SE of plasma exchange is hypocalcaemia
   - VTE prophylaxis (PE is a leading cause of death)
   - monitor ventilation: serial spirometry and ABGs
   - respiratory failure: intubation and ventilation, ICU
   - sx peak after 2-4wks then recovery lasting mths-yrs
   - 80% recover, 15% left w/ neuro disability, 5% die

Question 8

Myasthenia Gravis

Pathophysiology (85%)
Pathophysiology (15%)
Risk Factors/Demographic
Clinical Features
Examination

Answer 8

1.) Pathophysiology (85%) - AChR autoimmune Abs made by the immune system blocks NMJ receptors
- prevents ACh stimulation –> ↓muscle contraction
- ↑muscle activity –> ↑receptor blockage meaning increased muscle usage –> ↑muscle weakness
- improves with rest as more receptors are freed up
- Abs also activate the complement system –> cell damage at postsynaptic membrane –> worsening sx

2. ) Pathophysiology (15%) - antibodies against muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4)
   - MuSK and LRP4 are important for the production of AChR and destruction leads to inadequate AChRs
3. ) Risk Factors/Demographic
   - thymoma: thymus gland tumour (can cause SVCO)
   - age/gender: women <40yrs or men >60yrs
   - exacerbating drugs: beta-blockers, lithium, phenytoin, Abx (gentamicin, macrolides, quinolones, tetracyclines), penicillamine, quinidine, procainamide
4. ) Clinical Features - varying severity between patients from mild and subtle to life-threateningly severe
   - ↑↑weakness w/ muscle use which improves w/ rest, minimal sx in the morning, worst at the end of the day
   - affects proximal muscles + small muscles of H+N:
   - diplopia and ptosis: extraocular and eyelid muscles
   - myasthenic snarl: due to facial movement weakness
   - difficulty swallowing, jaw fatigue, slurred speech
   - progressive weakness with repetitive movements
   - signs of SVCO caused by a thymoma (rare)
   - important differential is acute bulbar palsy (MG spares the ocular muscles)
5. ) Examination - ways to elicit fatigability in muscles:
   - ptosis: repeated blinking will exacerbate ptosis
   - diplopia: prolonged upward gazing
   - weakness: abduction of one arm 20 times will result in unilateral weakness when comparing both sides
   - spirometry to test forced vital capacity (FVC)
   - check for a thymectomy scar

Question 9

Management of Myasthenia Gravis

Diagnosis
Treatment
Myasthenic Crisis

Answer 9

1. ) Diagnosis
   - antibody tests: ACh-R (85%), MuSK (10%), LRP4 (<5%)
   - CT/MRI of thymus: thymic hyperplasia, thymoma
   - edrophonium (neostigmine) test: patients given IV neostigmine which blocks AChE so ↑ACh at NMJ, if it relieves the weakness, diagnosis of MG is confirmed
   - repetitive nerve stimulation:↓muscle action potential
2. ) Treatment
   - pyridostigmine or neostigmine: reversible AChEi
   - immunosuppression: ↓production of antibodies (e.g. prednisolone or azathioprine)
   - thymectomy: can improve sx even w/o a thymoma
   - consider mechanical ventilation: if FVC <15mL/kg, can be worsened with beta-blockers (e.g. bisoprolol)
   - MABs: rituximab (↓antibody production) last-line eculizumab (↓complement activation)
3. ) Myasthenic Crisis - a life-threatening complication
   - often triggered by another illness e.g. U/LRTI
   - acute worsening of sx can lead to respiratory failure as a result of weakness in the muscle of respiration
   - may require BiPAP or full intubation/ventilation
   - treat with IVIG or plasma exchange

Question 10

Lambert-Eaton (Myasthenic) Syndrome

What is it?
Pathophysiology 
Clinical Features
Investigations
Management

Answer 10

1. ) What is it? - syndrome which produces a similar set of features to myasthenia gravis
   - most common cause (60%) is SCLC (lung cancer)
   - can be idiopathic in younger patients where it is presumed to be autoimmune in origin
2. ) Pathophysiology - ↓release of ACh into the NMJ synapse due to damage to VGCa channels in NMJ
   - immune system produces antibodies against VGCa-channels in SCLC cells which also targets VGCa-channels in the presynaptic terminals of the NMJ
3. ) Clinical Features - symptoms tend to develop slowly
   - proximal (limb-girdle) muscle weakness: often presents in legs and manifests as a waddling gait
   - hyporeflexia because it affects LMNs
   - improves with exercise: ‘post-tetanic potentiation’ (tendon reflexes temporarily improve after a period of strong muscle contraction)
   - autonomic dysfunction: dry mouth, blurred vision, impotence and dizziness
   - ophthalmoplegia and ptosis (more common in MG)
   - slurred speech + dysphagia: oropharyngeal muscles
4. ) Investigations
   - diagnosed via bloods: ↑anti-VGCC antibodies
   - EMG: ↑in muscle action potentials after exercise
   - assess for underlying malignancy (SCLC): esp in older smokers with sx of Lambert-Eaton syndrome
5. ) Management
   - management of underlying cancer
   - immunosuppression: prednisolone or azathioprine
   - amifampridine: ↑ release of ACh into the NMJ by blocking VG-K channels in pre-synaptic cells which prolongs depolarization, which helps Ca channels
   - other: IVIG or plasmapheresis may be beneficial