Neurological and Neuromuscular Disorders Flashcards
What is Parkinson’s disease?
Neurodegenerative disorder of the extrapyramidal system associated with the disruption of NT in the striatum
• Causes unwanted movements (tremors/shakes), increased muscle tone (rigidity), slow initiation of motor behaviours
• Onset usually after 40 years (incidence greater after 60); prevalence increases with age
*In Australia 294 per 100,000 people
What is primary and secondary Parkinsonism?
- Parkinsonism: clinical syndrome due to dopamine deficiency in the putamen portion of the striatum
- Primary (idiopathic-most common, genetic): loss of DA neurons in the substantia nigra,noradrenergic neurons and gliosis (production of a dense fibrous network)
- Secondary: usually caused by drugs, head trauma, infection, MS, neoplasms. Drug-induced parkinsonism typical antipsychotics, Lithium and antiemetics
What is the aetiology of PD?
exact cause of primary PD is still poorly explained:
• Could be environmental & genetic factors, ageing
• Oxidative stress = auto-oxidation of DA during melanin synthesis = injury to DA neurons in the SN
• Exposure to endogenous/exogenous toxins = degeneration
• Age-related nigrostriatal pathway damage = loss of SN-DA neurons
• Mutation in the gene expressed in the SN (α-synuclein) is linked to inherited PD
• Mutations in a second gene that encodes the protein parkin is linked to an early-onset form of PD (MJF)
What is the pathophysiology of PD?
*Anatomical changes are demonstrated by degeneration of dopaminergic neurons and atrophy
*There needs to be a dopamine and acetylcholine (ACh) balance for normal motor function
• Biochemical changes show a DA depletion in the putamen portion of the striatum
*DA is an inhibitory NT responsible for behaviour, motor control, hormone release (PRL)
Acetylcholine (ACh) = an excitatory specific action = cognition, motor control & memory formation
• ACh excess and DA loss which leads to tremor & rigidity
What are the cardinal signs of PD? (5)
appear after a 70-80% loss of nigral neurons and 60-70% of striatal dopamine
• Resting Tremors (shakes): usually the first manifestation to appear (usually unilateral)
○ More pronounced in arm than the leg
○ Can be intensified by stress & anxiety and disappears during voluntary movement & sleep
○ Usually progresses to involve both sides of the body
• Muscle Stiffness (rigidity): caused by increase resting muscle tone = excess ACh activity
○ 1st symptoms usually painful muscle cramps hands and/or toes
○ Commonly limbs feel heavy, stiff, painful
• Akinesia:
○ Bradykinesia (slowness of voluntary movements) - seen as difficulties in initiation, continuation and synchronisation of movements. Patients often feel ‘wooden’ & severely fatigued
○ Hypokinesia (decreased frequency or absence of associated movements)
• Postural Abnormalities: occur due to a loss of normal postural reflexes
○ Causes a postural fixation (involuntary flexion of the head/neck; cannot maintain an upright position of the trunk while walking/standing, problems with equilibrium = loss of ability to make a postural adjustment to falling/tilting (fall like a post)
○ Problems with righting or the inability to right themselves when changing positions
• Weakness and difficulty walking
What are other manifestations of PD?
autonomic abnormalities, Orthostatic hypotension, Urinary retention & constipation, Endocrine abnormalities, (Seborrhea) Cognitive-affective symptoms (Sleep disturbances, Depression (~ 50%), and Dementia (~ 30%))
What is the diagnosis of PD?
based on patient history and clinical manifestations of resting tremor, rigidity, bradykinesia, postural abnormalities
- Causes of secondary parkinsonism first excluded
What are the pharmacological treatments to PD?
Levodopa (L-dopa): aimed at
· Increasing brain DA levels
· Inhibit levodopa conversion in peripheral tissues (Benserazide, carbidopa, entacapone)
· Stimulate DA release (Amantadine)
· Inhibit the breakdown of DA (Selegiline)
· L-dopa (precursor of DA) = crosses BBB = replenish depleted striatal DA · Converted to DA in the periphery = given with peripheral inhibitors to reduce peripheral DA production & adverse effects · Inhibitors of decarboxylase that can’t cross BBB are benserazide and carbidopa (fixed-dose combinations). Adverse effects: nausea, vomiting (CTZ), Orthostatic hypotension, involuntary movements (head, lips, tongue), agitation & confusion (due to disease itself) and depression (may require antidepressants) Entacapone: COMT inhibitor - does not cross BBB, mainly affects the peripheral COMT, prolongs the clinical response to levodopa Adverse effects: N & V, diarrhoea, Dyskinesia and Drug-drug interactions
*COMT (catechol-O-methyltransferase): enzyme responsible for the metabolism of catecholamines (DA) and levodopa
Amantadine: · Antiviral activity used against some strains of influenza A · Increases DA release; blocks cholinergic receptors · Acts as an NMDA antagonist in the glutamatergic pathway from the subthalamic nucleus to Globus pallidus Adverse effects: Nightmares, insomnia, hallucinations, Dizziness, Orthostatic hypotension and Ankle oedema Selegiline: · MAO (monoamine oxidase) inhibitor (MAO-B): enzyme responsible for the degradation of DA, particularly in the SN = ↑ dopamine levels and may also block DA re-uptake · Smaller doses of L-dopa are used Adverse effects: Dry mouth and transient increase in liver enzymes
What is Deep Brain Stimulation (DBS)?
implantation of electrodes into the subthalamic nuclei (USA) + RMH Stereotaxic frame, drilling hole (brain surgery). Electrodes connected to an impulse generator that delivers electrical stim to block abnormal nerve activity
What is multiple sclerosis (MS)?
demyelinating autoimmune disorder of the CNS
· Characterised by inflammation & selective destruction of CNS myelin (PNS spared), scarring and axonal loss
· Age of onset is between 20 & 40 years with an M/F ratio is 1:3; men more severe progressive course
· In Australia – 2.4 per 100,000 people, particularly in eastern parts
· Exact aetiology is unknown - displays atypical inheritance pattern (15% MS sufferers have affected relative)
· Common in individuals of European background with greater than 50 susceptibility genes identified
What is the pathophysiology of MS?
· Autoimmunity component of MS occurs in genetically susceptible individuals; can be triggered by an Epstein-Barr virus infection, smoking, vitamin D deficiency
· Genetic susceptibility is linked to MHC (set of recognition glycoproteins)
· A Viral insult in the genetically susceptible individual = altered immune response: auto-reactivity of T and B cells = cascades to Myelin-specific antibodies being produced triggering inflammatory de-myelination
· Damage causes a loss of oligodendrocytes and myelin sheath and resulting in scar formation
· Most progressive forms – neuronal death and brain atrophy
· Demyelinating lesions (plaques) cause slowing of the conduction of impulses; leading to a conduction block
What is the acute stage of plaque formation? What is chronic stage?
· Early (acute) stage of plaque formation: partial de-myelination and inflammatory oedema in and around the plaque = neurological deficits
· Chronic stage: gliosis/scarring—common pathological findings in progressive cases
What are the 4 main classifications of MS?
- Relapsing/remitting (most common course – women): relapses/flares with full or partial recovery
- Primary progressive (uncommon course): steady progression from the onset and affects men & women equally affected
- Secondary progressive: follows relapsing/remitting with continued worsening
- Progressive relapsing: steadily worsening symptom from the onset with acute attacks and more severe symptoms
What is the diagnosis of MS?
No single test available to diagnose or rule out MS
• Clinical examination with Magnetic imaging scan is the most sensitive: MRI detects demyelinating plaques, i.e. brainstem, optic nerve, spinal cord and quantifies macrophages infiltration and abnormal iron deposition
• EP (evoked potential) testing aids diagnosis
What are the clinical manifestations of MS?
• Multifocal Symptoms - face/trunk/limbs paraesthesia, weakness, impaired gait, visual disturbances (inflammation & CNS de-myelination – diffuse)
• Monofocal Symptoms - due to a single lesion
○ Optic neuritis (blurred vision in one eye – progressive and pain with eye movement)
○ Brainstem syndromes (vertigo, double vision, facial sensory loss or weakness)
○ Spinal cord syndrome (motor and sensory tracks) - unilateral at the start then bilateral (weakness/numbness in one or more limbs, stiffness, slowness)
○ Cerebellar syndromes (tremor, ataxia, gait instability)
○ Lesions in the cerebrum (hemifacial weakness, pain, motor impairment)
○ Cognitive deficits (decreased memory, concentration and attention, word-finding problems later in the disease)
○ Psychiatric disorders (dementia, depression)
*As the disease progresses, grey matter also gets affected. Males are a greater risk factor for a severe cognitive decline affecting daily life (meal preparation, financial management, sexual activities, employment)
What is the treatment for MS?
purely palliative and to prevent exacerbations, manage acute relapses, minimise disease progression or decrease MRI lesion burden
• Medications to control symptoms: depression (antidepressants), spasticity (diazepam) • Management of acute relapses: corticosteroids (PO and IV) ○ Methylprednisolone IV - shorten duration of acute relapse - inhibits inflammatory mediator synthesis, mast cell de-granulation, increase WBC, fibroblasts = improves nerve conduction • Minimise disease progression, reduce the frequency of relapses, promote remyelination, prevent de-myelination, prevent disability: ○ Interferon β: immunoregulatory action = decrease cytokine release & augmentation of suppressor T cell function and increases the activity of macrophages & cytotoxic T cells Adverse effects: influenza-type signs & symptoms that decrease with continued therapy, fever, joint, muscle pain, headache, injection site reaction ○ Glatiramer: (pharmacodynamics poorly understood) blocks presentation of myelin antigens to T cells and induces suppressor T cells Adverse effects: local effects = redness, pain, itching; systemic effects = chest pain, palpitations, flushing ○ Fampridine: K+ channel blocker (SR, BD); restores conduction in demyelinated axons = reduce current leakage from demyelinated neurons = improves walking speed Contraindicated: history of seizures and renal insufficiency Adverse effects: insomnia, dizziness, headaches and UTI
What is Myasthenia Gravis (MG)?
disorder of the neuromuscular junction (NMJ); defect in nerve impulse transmission
• Autoimmune disorder: Ab-mediated loss of nACh receptors at the NMJ causing fatigue & weakness
• Linked to other autoimmune diseases: Rheumatoid arthritis; thyrotoxicosis
• 70-80% related to pathologic changes in thymus: thymoma, thymic hyperplasia—however, the aetiology IS unknown: genetic susceptibility
• Can occur at any age - peak incidence occurs 20-30 years; 3x more common in women than men; not very common in Australia
What is the pathophysiology of MG?
- Defect in nerve impulse transmission: AChR not recognised due to autoantibodies (IgG) and MuSK (muscle-specific kinase Ab) produced
- IgG binds to the receptor sites = receptor destruction
- Block ACh binding & decreasing the number of nAChR = diminished transmission across NMJ
- 10-15% have no IgG but have MuSK causing fatigue and weakness
What are the subtypes of MG?
- Subdivision on age, gender and thymus involvement (early, late, both sexes)
- Involves proximal musculature throughout the body
- Neonatal MG occurs in 10-15% of infants born to mothers with MG: onset of signs 1-3 days after birth but may be days/weeks - weakness of the eye muscles & eyelids, swallowing difficulties and slurred speech
What are the clinical manifestations of MG?
- All have an insidious onset: muscular fatigue & weakness - eyes, face, throat, mouth are first affected = ocular palsies, diplopia, ptosis
- Problems with chewing, swallowing, speech and facial expression
- Muscle fatigue is most common after exercise; can be a progressive weakness requires periods of rest, head position altered, impaired ventilation, congestion
What is myasthenia crisis?
severe muscle weakness causing quadriplegia, SOB & difficulty in swallowing; can occur after 3-4 hours after administration of inadequate or XS doses of drugs, stress (infection), pregnancy, cold exposure, surgery; can lead to respiratory arrest
What is cholinergic crisis?
Secondary to anticholinesterase overdose an occurs 30-60 min after taking medication; causes increased GI motility, salivation, and sweating; can lead to respiratory arrest
What is the Diagnosis for MG?
- Anticholinesterase test, nerve stimulation test & an assay for AChR & MuSK Abs
- Drug ‘edrophonium chloride’ Tensilon its IV administration improves muscle strength
- Electromyography: determine how nerve impulses are functioning
What is the treatment for MG?
• Anticholinesterases: Neostigmine (SC/IM) & Pyridostigmine (PO) = reduce degradation of ACh = inhibit cholinesterase and enhance NMJ transmission = more ACh available = action prolonged
Adverse effects: increased salivation, nausea, vomiting, diarrhoea
• Corticosteroids: decrease inflammation; immunosuppressant drugs:
○ Ciclosporin (calcineurin inhibitor): blocks action of calcineurin in activated T cells = prevent production of IL-2 and other cytokines which normally stimulate T cell proliferation & differentiation
Adverse effects: GI disturbances and Hirsutism
○ Azathioprine: impairs lymphocyte proliferation, cellular immunity and antibody response
Adverse effects: thrombocytopenia, anaemia, leucopenia, susceptibility to infection , liver & kidney dysfunction in higher doses
• Other approaches: Plasmapheresis removal of Ab’s from the plasma – short term clinical improvement
