Neuroimmunology + Movement Disorders Flashcards
Characteristics of transverse myelitis and causes
- Monophasic inflammatory and demyelinating myelopathy affecting a portion of the spinal cord.
- Subacute onset of weakness, sensory changes, bowel/bladder dysfunction
Causes:
Causes of transverse myelitis
- viral infections: varicella-zoster, herpes simplex, cytomegalovirus, Epstein-Barr, influenza, echovirus, human immunodeficiency virus
- bacterial infections: syphilis, Lyme disease
post-infectious (immune mediated)
- first symptom of multiple sclerosis (MS) or neuromyelitis optica (NMO)
Diagnostic criteria
- clinical features
- evidence of inflammation (leukocytosis in the CSF or contrast enhancement on MRI)
- CSF: elevated leukocytes, lack of oligoclonal bands, elevated IgG in CSF
The radiographical features are descriptive of transverse myelitis -inflammation across most of the spinal cord - Hyperintense T2 signal extending across the spinal cord, between the levels of T9 and T12.
Tx:
- First line: high dose steroids
- Plasma exchange in those who are unresponsive to corticosteroids
Effect of severe vitamin B 12 deficiency
Causes subacute combined degeneration - dysfunction of corticospinal and dorsal columns
- Spastic paresis with reduced vibration, proprioception and ataxia
- Low vitamin b12, elevated methylmalonic acid, elevated homocysteine
Other causes of subacute combined degeneration
- copper deficiency
- malabsorption
- Zinc toxicity
Characteristics of optic neuritis
- Subacute onset
- PAIN ON EYE MOVEMENT
- decreased visual acuity
- decreased colour vision
- Photopsia (sparkles of light)
- Abnormal visual fields - central of cecocentral scotoma (central scotoma that joints up with the blind spot)
- relative afferent pupillary defect
- May or may not have disc swelling depending on the location of the inflammation
Retrobulbar (no swelling) vs anterior neuropathy (swelling)
Progresses to optic nerve disc pallor
Pathophysiology of parkinsons disease
Aggregation of a-synuclein protein and formation of lewy body inclusions in the substantia nigra
Genes including autosomal dominant LRRK2 and autosomal recessive PARK2
Clinical features of parkinsons
- Pre-symptomatic Stage
- Anosmia
- Constipation
- REM sleep behavioural disorder
- Mood changes, increased fatigue - MOTOR Symptoms (symptomatic stage)
TRAP
- Tremor - usually unilateral at onset and remains asymmetric
- Rigidity
- Bradykinesia (most important diagnostic feature)
- Postural instability - Non motor syptoms: autonomic dysfuncion
hyposmia
constipation
rapid eye movement sleep behaviour disorder - acting out of dreams secondary to loss of normal muscle paralysis during the dream phase of sleep
Non motor may precede onset of motor symptoms by years - Late Stage: cognitive and psychiatric manifestations
depression is the most common feature (affects about 40%); dementia, psychosis and sleep disturbances may also occur
- RBD is a marker of worse outcome for dementia
- Reducing or withdrawing antidepressants alleviate RBD
- Tx: Melatonin and clonazepam
What are the cognitive impairments in PD?
Cognitive impairments in PD are subcortical which implies they primarily involve slow processing speed, impaired short term memory and attention deficits with relative sparing of cortical functions such as language and declarative memory.
Levodopa
MOA
Indication
SE
L dopa/Carbidopa (Sinemet/Kinson)
L dopa/Benserazide (Madopar)
- L dopa is the main precursor in doapmine synthesis
- 1st line treatment for motor impairment
- usually combined with a decarboxylase inhibitor (e.g. carbidopa or benserazide) to prevent peripheral metabolism of levodopa to dopamine
- reduced effectiveness with time (usually by 2 years)
SE
- Sedation, N+V
- Dyskinesia (involuntary writhing movements)
- Motor fluctuations ‘on-off’ effect
- Punding: involves repetitive, often purposeless, stereotyped behaviours, such as sorting or diassembling that can be disruptive
- Dopamine dysregulation syndrome is a form of addictive behaviour that occurs in up to 4% of patients and is characterised by compulsive overuse of dopaminergic medications, which are typically short acting (eg: levodopa and apomorphine), impairing physical, social and occupational functioning
dyskinesia 'on-off' effect postural hypotension cardiac arrhythmias nausea & vomiting psychosis reddish discolouration of urine upon standing
What are motor fluctuations and risk factors
Motor fluctuations present as periods of ‘on’ and ‘off’. During ‘on’ phase patients show a positive response to levodopa while during ‘off’ phase they show symptoms of Parkinson’s
- Wearing off classically associated with the later stages of PD
RF Higher risk if: - Longer disease duration - Higher levels of levodopa used - Younger onset PD - NOT the duration of L dopa therapy
Tx
- Divide dose into increased frequency
- Addition of COMT inhibitor (eg: entacapone, tolcapone) or MAO inhibitor (selegiline, rasagline)
- New Medication: Safinamide - MOA B inhibitor + glutamate release inhibitor
Increased “on” time without troublesome dyskinesias
Dyskinesia in PD and treatment
- Dyskinesia (involuntary writhing movements)
- More strongly associated to the AMOUNT of L dopa and disease duration
Tx
- Minimise doses of dopaminergic medications
- Amantadine: weak antagonist of the NMDA glutamate receptor, increase dopamine release, block dopamine reuptake
- Break doses into higher frequency.
Dopamine agonists in PD
- Stimulate dopamine by binding directly to post synaptic dopamine receptors in the striatum
Non ergot dopamine agonists
- Pramipexole, ropinirole (D2/3)
- Transdermal rotigotine (D3)
Ergot derived dopamine agonists
- Cabergoline, bromocriptine, pergolide (D1/2)
- Complications of heart valve and retroperitoneal fibrosis
Not as effective as levodopa
Long acting, single dosing
Consider for night time for early morning off periods
Can be used as patch (rotigotine) when unable to give oral
Can be used for young patients
SE
- Nauses, somnolence, oedema, dizziness, vomiting, hallucinations (more risk), hypotension
- Worsens delirium
- Impulse control disorders, punding (more specific to dopamine agonists)
- Can still get motor fluctuations and dyskinesia but not as severe
Impulse control disorder:
- Prior addictive personalities at greatest risk
- Increase addictive behaviour based on prior personality
- Hypersexuality, pathological gambling, excessive shopping/eating
MOA B inhibitors - rasgline, selagiline
MOA:
MAO-B inhibitor: inhibits the breakdown of dopamine secreted by the dopaminergic neurons
- As effective as dopamine agonist if not slightly better
- Used in mild/early symptoms or young patients
- Can cause hepatic dysfunction
- Most common SE - insomnia
Tyramine (found in cheese/wine) hypertensive crisis: tyramine release noradrenaline, ordinarily MAO-A would break down excess noradrenaline. Therefore excess in MOAI - adrenergic crisis
- Can still get motor fluctuations + dyskinesia
Best medication for PD
In terms of mobility and quality of life
L dopa > MAOI > DA
DA and MAOI had slightly better dyskinesia but no difference in motor fluctuations
Hallucinations and Parkinsons
Medications in order of potency
- Anticholinergic medications
- Amantadine
- Dopamine agonist
- Monamine oxidase inhibitors
- COMT
- L dopa
Summary of PD medications
- If young and mild: MAOI
- Most patients: L dopa
- If too parkinsonia: increase the dose
- If motor fluctuations: break up the dose into increased frequency, COMT
- If impairing dyskinesia: reduce dose and increase frequency if required
- Never stop medications abruptly as this can lead to a parkinsonian crisis (neuroleptic malignant syndrome)
What medications can be given for REM sleep?
Clonazepam
Melatonin
What medications can be given for postural hypotension?
High salt diet
Domperidone
Fludrocortisone
What medications can be given for hallucinations?
For psychosis
- Reduce dopaminergic medication
- Clozapine
D1/2 and noradrenergic antagonist
Anticholinergic, antihistaminergic, antiserotonergic
- Quetiapine (5HT2 and D1/2 antagonist)
- Pimavanserin
Advanced therapy for parkinsons disease
- Deep brain stimulation
- Apomorphine infusion: dopamine agonist and it is administered as a continuous subcutaneous infusion or intermittent as needed. Apomorphine use decreases the off time and dyskinesia in PD patients
- Intraduodenal levodopa: Continuous infusion through percutaneous gastrojejunostomy tube by an externally carried pump. - levodopa/carbidopa (duodopa) intestinal gel
- Focused US sub-thalamotomy
Where does DBS work the best for:
Motor fluctuations
Tremor
Gait freezing and postural instability
- Motor fluctuations
Subthalamic nucleus and globus pallidus - Tremor
Subthalamic nucleus, thalamic
Gait freezing and postural instability
- Possibly helped by pedunculopontine nucleus
Indications and complications for DBS
Choice of candidates for DBS
- Response to dopaminergic therapy is most important while deciding DBS.
- Presence of on–off fluctuations
- Age < 70 years, although can be considered for higher age groups
- Severe Dyskinesias impairing quality of life
- Tremor that cannot be controlled with medication alone
- Reasonable cognitive function
Complications of DBS
- Neuropsychiatric, surgical complications, behavioural issues and mechanical malfunction related to the device can occur.
- Higher risk of suicide may occur with STN targeted DBS
