Multiple Sclerosis
General information
- Main cells involved are oligodendrocytes, with inflammation, demyelination and axonal loss.
- T Cell problem, bias towards Th1, Th17, loss of Treg function. Upregulation of adhesion molecules into CNS à T cells into CNS
- Clinically isolated syndrome:
- Single attack of demyelination.
- If MRI done and lesions in other areas that are clinically effected, there is risk of progression to MS 50% in 2 yrs.
- If the brain MRI is abnormal with other lesions, then therapy is recommended.
- Use human interferon Beta 1a or glatiramer acetate (random mixture of polymers of four amino acids antigenically similar to myelin basic protein).
- No treatment if there is just radiological isolated syndrome (Just MRI lesions of demyelination).
- Mean time to death 30y, relapses decreases in pregnancy but increases significantly in the pueperium.
- Presenting symptoms:
- Spastic parapersis/ hemiparesis/tetraparesis
- Transverse myelitis
- Limb paraesthesiae (posterior column, medial lemniscus or internal capsule)
- Visual disturbances - Optic neuritis or INO (Optic neuritis = loss of acuity, pain on movement, loss of central visual field
- Fatigue
- Cerebellar ataxia
- Bowel/ bladder and sexual dysfunction
- Current disability – mobility, sexual dysfunction, ADLs and work
- Duration of symptoms
- Complete versus partial resolution of Sx
- Clinical course
- Relapsing-remitting - most common
- Secondary progressive
- Primary progressive – 10% of Pts
- Progressive relapsing – gradual worsening with episodes of deterioration
- Precipitating factors:
- Uhthoff’s phenomenon - heat worsens Sx
- Infection, fever, pregnancy & exercise
- Family history: 8x more common in immediate relatives
- Place of birth: 10x more common if childhood spent in temperate latitudes (? Vit D related)
- Treatment:
- What has been tried and which was successful?
- Side effects of treatment
- Based on McDonalds criterion.
- Main thing to discern is dissemination in time and dissemination in space.
- Two or more clinical events with (a) objective clinical evidence of both lesions or objective clinical evidence of one lesion with historical evidence of another (b) two or more events with objective clinical evidence of one event and >=1 T2 lesion in >=2/4 MS typical regions [periventricular, juxtacortical, infratentorial, spinal cord].
- Evoked potnetials can be used to assess the optic system especially optic nerves which may be hard to assess on MRI. Abnormal VERs occur in 50 – 90% of MS pts.
- Oligoclonal bands are present in 90% of patients with MS.
- CN exam:
- Visual acuity, optic atrophy, papillitis and scotoma (usually central)
- INO: weakness of adduction in one eye due to damage to ipsilateral MLF with nystagmus in the abducting eye; often bilateral
- Charcot’s triad: nystagmus, intention tremor, scanning speech; occurs in only 10%
- Lhermitte’s sign: electric shock-like sensation in the limbs or trunk following neck flexion
- UL/LL
- Signs of spastic paraparesis and posterior column sensory loss
- Cerebellar signs
- General:
- Home and social supports
- Physiotherapy and OT
- Depression
- Education and management of flares
- Acute flair:
- bed rest; oral prednisone; IV methylprednisone; plasmapharesis
- Immunomodulators for reduction in relapses:
- Beta interferons - reduce frequency of exacerbations by one third when used in early stage of disease. Risk of hepatotoxicity and leucopenia
- Fingolimod = first tablet PBS listed for MS in aus. Retains circulating lymphocytes in lymphoid organs. SE fingolimod – 2:1 heart block
- Glatiramer = copaxone, reduce new episodes of RR MS by about 30% for 2-3y
- Mitoxantrone (antineoplastic drug), more efficacious but more toxic, limited to aggressive disease with freq relapses, but not much effect on progressive non relapsing disease.
- Natalizumab – Antibody to alpha4beta1 integrin on surface of lymphocyte, reduces relapse rate in 1y by 68%. Because of risk of PML (dependent on exposure and previous use of immunosuppression), only liscenced in NHS for severe relapsing remitting multiple sclerosis
- Alemtuzumab – CD52, but cannot be used in progressive disease
- BMTx – remains an option
- Progressive multifocal leukoencephalopathy
- Risk for matiluzimab --> opportunistic infection of JC virus causing an oligodendropathy.
- PML when compared to MS is subacute, progressive, mainly has cortical signs
- Dx PML: MRI Brain --> often subcortical U fibers, contrast enhance in early PML. Serology – 55% of normal adults have JC virus antibody, can do JC Virus PCR on CSF, often need biopsy.
- Rx PML: Stop immunosuppressant, consider immune restoration, plasmapharesis to remove natiluzimab Abs, watch out for IRIS, give methylpred at first sign of IRIS. IRIS can cause cerebral oedema.
Myasthenia Gravis
History
- Sx at presentation - diplopia, drooping eyelids, choking, difficulty with speaking, difficulty with chewing or swallowing, problems using limb, with prompt resolution after rest
- Difficulty with anaesthesia, previous episodes of pneumonia
- Fatigability, most cases ocular involvement without pupillary involvement, facial and bulbar muscles affected 80% of cases
- Resp muscles may be involved
- Smooth muscle and cardiac muscle not involved
- Pure ocular myasthenia --> good prognosis, others are generalised
- Anti-MUSK --> usually all generalizable cf purely occular, bulbar and resp weakness severe
- Hx of thymectomy
- Hx of treatment
- Other organ specific autoimmune disease associations
- Muscle fatigue:
- Elevators of the eyelids and the occulomotor muscles (sustained upward gaze)
- Bulbar muscles – counting or reading aloud --> develop nasal speech
- Proximal limb girdles – hold arms above the head
- Neck flexion weakness
- Peek sign: orbicularis occuli weakness – close the eyelids: within 30secs they begin to separate and you will see the lower sclera
- Speech: dysarthric or nasal because of weakness of the palate
- Reflexes are preserved
- No sensory loss
- Muscle atrophy is usually minimal
- Thymectomy scar
- Serology – AchR antibody, MuSK antibody, anti-PRP4
- Single fibre EMG shows increased jitter and blocking
- Repetitive stimulation à decrement in AP
- Tensilon test --> trial of acetylcholinesterase inhibitor
- CT chest for thymoma
- Respiratory function tests
- Non-pharmacological
- Support groups
- Depression
- Mobility
- Avoid drugs that interfere with neuromuscular transmission e.g. aminoglycoside Abx (streptomycin, gentamicin)
- Aggressive treatment of infection (infection can precipitate myasthenia crisis; avoid aminoglycosides)
- Pharmacological
- Anticholinesterases: pyridostigmine
- Intensive respiratory support for myasthenia crisis (respiratory failure)
- May require mechanical ventilation and course of plasmapharesis
- Monitor respiratory function tests
- Steroids: indicated for generalised severe disease when anticholinesterases are inadequate
- Initially aggravate disease in first ~week to 10 days à Pts need close monitoring when steroids commenced
- Usually required long term
- Immunosuppressive Rx: Azathioprine, cyclosporin, mycophenolate
- Failed steroid treatment in severe dx
- Rituximab
- Thymectomy if ACh-Ab positive
- Thymomas occur in 10% of cases (and 25% are malignant); thymic hyperplasia in 65%
- 70% of Pts show improvement after resection; 25% remission
- Plasmapharesis: useful in acute situations such as myasthenia crisis, preparation for surgery, or in the peripartum period
- IVIG: Fc2R in IVIG can mop up Abs, rapid onset of action, as effective as plasma exchange
- For MUSK --> immunosuppression tends not to work, plasma exchange > IVIG, significant chance of resp failure
- Epidemiology
- M>F [5:1], associated with paraneoplastic syndrome but 40% no tumour is found
- Clinical
- Limb weakness, no significant bulbar or ophthalmoplegic weakness, autonomic instability
- Diagnosis
- NCS/ EMG à small CMAP then increment on repetitive firing
- Abs à VGCa [80-90% positive]
- Rx:
- No response to acetylcholinesterase inhibitors
- Di-aminopyridine [blocks channel] can be useful
- Apheresis, pred
Epilepsy
General
- Definition
- Epilepsy = chronic disorder with tendency for recurrent unprovoked sz, need 2 sz >24h apart OR 1 sz + >60% prob of recurrence [eg if fit into clear clinical syndrome]
- Sz = transient manifestation of co-ordinated epileptic neuronal activity
- Misdiagnosis = 25%, and when misdiagnosed usually 90% psychogenic non-epileptic events, misinterpretation of EEG common factor!
- Mx of psychogenic = containment à reassure, education, psych Mx of co-morbidities
- SUDEP - Sudden Unexplained Death in Epilepsy Patient
- Uncontrolled sz is major RF for mortality
- Unexpected sudden death of which there is no other attributable cause and exclusion of status. Most often at night. Causes (1) central hypoventilation > (2) cardiac arrhythmias + (3) sz induced asystole/ autonomic processes
- Seizure - define the type, precipitant, prodrome, postictal phase, complications such as injuries
- Risk factors
- febrile convulsion from age – 6/12 – 5yo, head trauma, cerebral infection, FHx, intellectual impairment, cerebral palsy, stroke, tumour, but mainly idiopathic [62%] > CVD [14%]
- Investigations including CT, MRI, EEG, sleep deprived EEG
- Pregnancy planning for the purpose of choosing anti-epileptic medications
- Medication history including adverse effect and careful exploration into adherence of therapy
- Social/ work complications:
- Driving
- Operating machinery
- Planning pregnancy?
- Blood tests including drug levels
- EEG looking for epileptiform activity, interictal EEG abnormalities can also be helpful
- MRI brain looking for structural lesion:
- Messial temporal sclerosis causing temporal lobe epilepsy
- Tumours
- Vascular malformations
- Anticonvulsant therapy
- Multiple considerations: patient factors always, note drug interactions, co-morbidities, Sz type. Try make Sz Dx, then find drug that best fits that one
- Focal = carbamazepine + phenytoin + valproate
- New = lamotrigine, levitaracetim, lacosamide [any sz type]
- Generalised = valproate, lamotrigine, topiramate, levetiracetam
- Absence = ethosuximide
- Aim: monotherapy, response 47%, add on second --> response additional 13%, add on third --> response add on 4%.
- Who to treat:
- Any patient with recurrent seizures of unknown etiology or a known cause that cannot be reversed
- After first seizure, only if there are risk factors for recurrent seizures
- Monitor compliance with drug levels
- Start with monotherapy. If one agent fails trial another monotherapy
- Driving
- After a first seizure a patient cannot drive for 6 months (12 months if they had a car crash as a result of seizure)
- If patient has active epilepsy they have to be seizure free for 12 months before driving again
- Family/ partner education on seizure management
- Pregnancy management - All antiepileptic drugs are teratogenic and there is no 'drug of choice' in pregnancy. However, the first priority is to avoid seizures, which may have catastrophic consequences for the patient, the unborn child and others
- Epilepsy Sx
- Resective epilepsy surgery is an excellent treatment for some patients with drug-resistant focal epilepsy
- Pre-operative evaluation is designed to identify the epileptogenic zone and its relationship to eloquent cortex
- For the maximal choice of success the resection aims to excise as much as possible of the epileptogenic zone while sparing as much as possible eloquent cortex
Stroke
Epidemiology
- 1 in 6 lifetime prevalence, number 2 cause of death worldwide, number 1 disability adults
- Haemorrhagic stroke 15% [75% ICH, 25% SAH]
- Lobar haemorrhage [near cortex] --> amyloid angiopathy, MRI usually shows multiple microhaemorrhages, elderly pts
- Hypertensive --> basal ganglia + mid brain + pons
- AVM --> anywhere
- Rx:
- CTA --> esp if haemorrhage around the anterior cranial vault or sylvian fissure, but everyone gets it
- Control BP: <140 [INTERACT trial, p = 0.06], although recently no advantage compared to maintaining SBP 140 - 180 - ATACH 2 trial DOI: 10.1056/NEJMoa1603460
- Control bleeding: reversal. Although platelet transfusion associated with worse outcome in ICH
- Control complications: if mass effect --> Sx, ventricular shunt if hydrocephalus
- Coiling vs clipping for SAH --> coiling preferred [lower death but greater rebleeding]. Note CT Dx 95% sensitivity first 12-24h, if neg MRI. If neg do LP for xanthochromia 12h after event
- Ischaemic stroke 85% [cardio embolic > undetermined > large artery athero > small artery athero > other ie vasculitis]
- Most common = seizure 23%
- Look for acute onset
- Note new stroke definition which includes symptoms <24h + brain imaging evidence of stroke
- TACI --> proximal MCA [note ICA much worse clinically, NIHSS worse] = contralateral hemiplegia [upper > lower limbs] + hemi sensory loss + global dysphasia
- PACI
- MCA superior branch --> contralateral hemiplegia + hemisensory + conjugate gaze parasesis with forced gaze towards side of lesion + broccas if left side;
- MCA inferior branch --> contralateral hemianopia + visuo-spatial innatention + receptive dysphasia
- Proximal ACA --> contralateral lower limb > upper limb + primitive reflexes + frontal signs
- LACI --> perforator lenticulostriate arteries
- Pure motor, pure sensory, pure sensory-motor, hemiparesis, homolateral ataxia, dysarthria/ clumsy hand
- NO cortical signs [aphasia/ agnosia/ apraxia/ neglect]
- POCI --> homonymous visual defect +/- contralateral sensory defects +/- anterograde amnesia [mesial temporal lobe]
- TIA Mx (all TIAs go home in C-A-B)
- Rx as medical emergency [high risk stroke recurrence 10%], Sx last <10m, Ix looking for cause (carotids, heart, ECG, CTB).
- If AF + CHADS-VASC = >2 then anticoagulate [NOACS if CrCl>30, dabigatrin 150 superior, 110mg BD noninferior, less ICH, more GIB REMEMBER only for non valvular {no MS, no vegetation, no valve replacement}]
- No AF then antiplatelet + BP control + statin
- C = cholesterol lowering
- A = antithrombotic [aspirin vs clopidogrel vs assasantin]
- In Chinese pts USE aspirin and clopidogrel for 3 weeks followed by clopidogrel monotherapy, ARR = 3.5% wrt recurrent stroke]
- B = Blood pressure lowering,
- No driving 2/52 (they go home in a CAB)
- Educate on Mediterranean diet with mixed nuts --> biggest benefit in stroke reduction
- Carotid endarterectomy:
- Symptomatic 70 – 99% need revascularisation with CEA, some evidence for stent if younger
- Asymptomatic --> medical management [statin + antiplatelet + BP control]
- TPA [provided no contra-indications and from symptom onset <=4.5h] --> outcome [better functional outcome, no mortality benefit]
- Contra-indications include past ICH, GI, UT bleeding last 21/7, active bleeding, BP >185, INR <1.7, plts <100, CT hypodensity not >1/3 hemisphere
- Endovascular clot retrieval
- Carefully selected pts with imaging after TpA and within 6hrs, anterior circulation only, new age devices [functional outcomes better 3/12 and mortality benefit]
- Hemicraniectomy for malignant MCA stroke
- < 60y --> shifts mortality towards disability
- 60 – 80 --> NEJM 2014: mortality benefit, but lots left with significant disability, no one had rankin score 0-2!
- NO steroids for oedema
- Blood Pressure:
- Ischaemic stroke, reduce cautiously no more 10 – 20% if BP >220/120
- ICH: Craig Anderson RPA --> Reduce BP <140, Stroke guidelines say <180. ATACH-2 says no role for intensive blood pressure management DOI: 10.1056/NEJMoa1603460
- Anti-platelet
- Aspirin first 150 – 300mg dose, then can reduce later, to be given within 48h
- Assasantin or clopidogrel > aspirin, but aspirin alone can be used, evidence as mentioned above for DAPT in chinese
- Anti-coagulation:
- Initiate, but delay 1/ 3/6/9 day based on size of stroke. This is expert opinion
- Stroke guidelines Aus say that the decision can wait 2 weeks
- If warfarin then do not need heparin bridging [different to DVT/PE]
- Stroke Unit Care:
- All patients admitted for MDT care [grade 1 evidence]
- Includes glycaemic care and pyrexia Mx
- DVT prophylaxis
- Enoxaparin > SC heparin Re DVT prophylaxis, no haemorrhage difference
- Driving
- No driving for at least 1/12 post discharge