Week 5

Question 1

Describe the complex role of basal ganglia in movement control

Answer 1

Group of grey matter nuclei located deep within the cerebral hemisphere; no projections to spinal cord.

Exert indirect control via projections to brain stem and cortical areas; essential for motor function

Ganglia help plan and control complex patterns of muscle movement and control relative intensities of the sequential movements for achieving specific motor goals

Question 2

Anatomy of the basal ganglia: 4 basic structures

Answer 2

Dorsal striatum: the caudate nucleus and putamen
- caudate nucleus - curved structure involved in motor control and learning
- putamen - lenticular nucleus assisting in motor coordination

Globus pallidus: pale spherical structure structure modulating motor functions

Substantial nigra - dark pigmented area regulating motor functions

Subthalamic nucleus - Beneath the thalamus, contributes to motor control

Question 3

Discuss dorsal striatum

Answer 3

Contains caudate nucleus and putamen

Caudate nucleus consists of a head, body and tail giving it its characteristic C shape.

Head of the caudate nucleus protrudes into the lateral ventricle —> easily identifiable.

Putamen is separated from caudate by fibres of anterior limb of internal capsule. Some connections via cellular bridges give striped (striated) appearance.

Question 4

Describe the globus pallidus

Answer 4

Roughly translates to pale globe. Describes high number of myelinated fibres.

Lies medial to the putamen, when these 2 are combined it is known as the lentiform nucleus.

2 divisions: internal segment (GPi) and external segment (GPe):

• GPi = output nucleus of globus pallidus involved in motor inhibition
• GPe = input nucleus of the globus pallidus, modulating movement via connections with subthalamic nucleus

Question 5

Describe the subthalamic nucleus

Answer 5

Cigar shaped structure located under the thalamus

Question 6

Describe the substantia nigra

Answer 6

Located at level of the midbrain

Divided into 2 components: pars compacta (SNc) and pars reticularis (SNr)

• pars compacta (SNc) = region of substantia nigra involved in dopamine production
• pars reticular (SNr) = portion of the substantia nigra serving as an output nucleus for basal ganglia circuits

Question 7

Inputs and outputs to the basal ganglia

Answer 7

Inputs:
From cerebral cortex (regulated by glutamate) and the SNc (regulated by dopamine) —> sent to the striatum —> sent to MSNs (inhibitory GABAergic neruons w/ little spontaneous activity. Dependent on excitatory input to discharge) —> MSNs project to the globus pallidus and pars reticularis via indirect or direct pathways.

Outputs:
Inhibitory outputs from globus pallidus and pars reticularis relayed to thalamus (VA and anterior VL) as well as other brain stem areas. GPi are in high tonic firing state because they are inhibitory GABAergic on the thalamus. High tonic activity maintains thalamus in suppressed state resulting in low levels of firing in thalamic nuclei such as VA and VL nuclei at rest. Movement modulation occurs through transient release of this inhibition allowing physic decreases in firing rates that temporality disinhibition the thalamus and facilitate movement initiation and coordination.

Flow chart:
Inputs cerebral cortex —> medium spiny neurons (MSNs) of striatum —> pars reticularis of the substantia nigra (SNr) OR internal segment of the globus pallidus (GPi).

SNr —> brain stem (superior colliculus)
GPi —> thalamus (VA/VL complex) —> frontal lobe
—> motor loop/limbic loop/oculomotor loop/ prefrontal loop

Question 8

Distinguish between direct and indirect pathways of the basal ganglia disorders

Answer 8

Basal ganglia pathways consist of 2 parallel loops originating from striatum which are modulated by dopamine.

Direct:
- Dopamine promotes execution of a planned motor function by exciting cortex.
- Involves GABAergic MSNs projecting directly to GPi and SNr leading to disinhibition of thalamocortical projections

Indirect:
- indirect pathway inhibits execution of planned motor function by inhibiting the cortex
- MSNs projecting to GPe, leading to increased inhibition of the GPi/SNr and reduced activation of thalamocortical projections

Question 9

What is dopamine

Answer 9

Neurotransmitter associated with regulating movement, cognition, reward and mood in the brain.

Produced by neurons located in substantia nigra and lays a crucial role in function of basal ganglia.

Dopamines function involves modulating neural pathways within basal ganglia, influencing motor coordination, decision making and emotional responses.

Question 10

Discuss dopamine receptors

Answer 10

2 main family’s: D1 (1 and 5) and D2 (2, 3, 4)

D1 receptors are Gs-coupled that stimulate adenylate cyclase, leading to an increase in cyclic adenosine monophosphate (cAMP) levels when dopamine binds exciting the cell.
- D1 = stimulate adenylate cyclase, increasing cAMP

Conversely when receptors in D2 family are Gi-coupled receptors that inhibit adenylate cyclase resulting in a decrease in cAMP levels upon dopamine binding inhibiting cell.
- D2 = inhibit adenylate cyclase, decreasing cAMP

Question 11

The direct pathway

Answer 11

Facilitates movement by enhancing cortical motor output.

Excitatory input (glutamate) from motor cortex —> striatum —> glutamatergic neurons activate GABAergic MSNs —> MSNs inhibit GPi which normally exerts inhibitory control on thalamus —> by inhibiting GPi, striatum reduces iinhibitory influence on the thalamus —> disinhibition of thalamic neurons —> excites motor cortex promoting initiation.

Dopaminergic input from SNr further modulates pathway via D1 receptors enhancing striatum’s excitatory influence on GPi:

Question 12

The indirect pathway

Answer 12

Primarily involved in inhibiting movement.

Excitatory input from cerebral cortex (glutamate) —> striatum excites D2 receptor sends GABAergic neurons to GPe —> GPe is inhibited —> GPe goes to subthalamic nucleus (STN) where it is disinhibted due to lack of GABA from GPe —> therefore, STN sends excitatory glutaminergic input to GPi activitng it —> stronger inhibition signal to the thalamus —> reduces thalamic excitation of cortex.

Reduction in cortical input to the motor areas limits motor activity, facilitating the inhibition of movement.

Question 13

Discuss Parkinson’s disease

Answer 13

Neurodegenerative disorder characterised by loss of dopaminergic neurons in the substantia nigra of the brain.

Leads to symptoms such as tremors, rigidity, bradykinesia, postural instability.

Primarily affects motor function but can also involve cognitive impairment and mood disturbances.

Can affect all systems of the body however most known for altering motor function, cognitive, neuropsychiatric, autonomic and gastrointestinal function.

Question 14

Motor and non-motor clinical features of PD

Answer 14

Motor clinical features (must have 2 for diagnosis):
- Tremor- involuntary shaking of limbs or extremities
- rigidity - stiffness and resistance to passive movement in muscles
- akinesia - difficultly initiating voluntary movements or sudden freezing during movement
- postural instability - impaired balance, leading to difficulty maintaining upright posture
- bradykinesia - slow movement

Non motor clinical features:
- personality changes - depression, fear, anxiety, dependence, passivity, loss of motivation
- cognitive deficits - Bradyphrenia, dementia, altered sleep patterns
- autonomic changes - hypotension, bladder problems, sexual dysfunction, sweating
- sensory changes - pain, parasthesisa, numbness, burning, akathisia, restless leg syndrome

Question 15

Aetiology of PD

Answer 15

Complex interplay of genetic and environmental factors.

Age largest risk factor, gender (more common in men till menopause) and familial history (5-10% clear link) contribute to its development.

Familial PD - 5-10% of cases clear link, 20% family with symptoms

Idiopathic PD - 90-95% of cases; no genetic link; often attributed to environmental factors

Question 16

Pathophysiology of Parkinson’s disease (typed)

Answer 16

Aeitiology —> Loss of dopaminergic neruons in substantial nigra pars compacta (SNc) —> severe depletion of dopamine in striatum —> neuronal death of striatum —> Imbalance between direct and indirect pathways caused by dopamine deficiency —> hypoexceution of movements due to reduced activity in the direct and increased activity in indirect.

Consequently, output nuclei become overactive leading to excessive inhibition of the thalamus which normally relays excitatory signals to cerebral cortex.

Understimulation of cortical activity results in loss of motor function, accompanied by oscillatory neuronal discharge leading to tremor and altered output to the brain stem contributing to rigidity.

Question 17

Pathophysiology of PD flow chart

Answer 17

Aetiology -> loss of dopaminergic neruons in SNc -> compensatory responses (upregulation of dopamine receptors, production in surviving neruons etc.) ->
Compensatory mechanisms fail -> decreased activation of direct pathway + decreased inhibition of indirect = decreased movement initiation and increased movement inhibition.

Question 18

Pharmacological management of PD

Answer 18

Typically medications aimed at increasing dopamine levels in brain or mimicking its effects.

• dopamine agonists (levodopa) which is converted to dopamine in the brain and dopamine receptor agonists like pramipexole and ropinirole
• medications that inhibit breakdown of dopamine such as MAO-B inhibitors and COMT inhibitors can prolong its effect.
• anticholinergic drugs may also be used to help manage tremors and some other symptoms.
• In advanced cases deep brain stimulation surgery may be considered to alleviate symptoms
• treatment plans often individualised

Question 20

List the indications, mechanisms, contraindications and side effects of medications used in PD

Answer 20

Dopamine agonist:
- bradykinesia (+++)
- side affects: nausea, hypotension, confusion

MAO inhibitor:
- bradykinesia (++)
- side effects: confusion, compulsive behaviour

Anticholinergic:
- bradykinesia (++)
- side effects: nausea, anorexia, postural hypotension

L dopa (+decarboxylase inhibitor):
- tremor (++)
- side effects: hallucinations, xerostomia

Question 21

Discuss hyperkinetic disorders

Answer 21

Characterised by excessive and involuntary movements.

These movements can manifest as tremors, tics, cornea, dystopia and are often associated with dysfunction in the basal ganglia-thalamocortical circuits which regulate motor control.

Examples:
- HD: neruodegenerative, involuntary movements, cognitive decline, psychiatric symptoms
- Dystonia: movement disorder characterised by sustained or intermittent muscle contractions causing abnormal postures or repetitive movements.
- tardive kyskinesia: involuntary, respective movements of face, limbs, torso. Often caused by long term use of meds (antipsychotics)
- DOPA-induced dyskinesia: abnormal involuntary movements from prolonged use of L-DOPA for PD
- hemiballismus: violent, flinging movements of one side of the body often caused by damage to STN
- Tourette’s: neurodevelopmental, involuntary motor or vocal tics, accompanied by other behavioural symptoms such as OCD or ADHD

Question 22

Choreatic symptoms

Answer 22

Chorea - dance like movements
Athetosis - changeable or writhing moving
Dystonia - torsion spas

Question 23

Discuss huntingtons disease

Answer 23

Neruodegenerative disorder most common among individuals of Western European descent.

Prevalence - 4-5 in one million people

Affects men and women equally between ages 30-50

People w/ HD experience progressive decline in neural function leading to death typically 15-20 years after onset of symptoms.

Question 24

Clinical features of HD

Answer 24

Features worsen over time.
Motor and cognitive decline.
Earliest sign is dystonia, rigidity, and bradykinesia.
With decline may experience severe disabilities.
Typically cognitive symptoms preceded motor

Symptoms:
Chorea
Dysphasia
Loss of coordination
Continual muscle contractions
Slurred speech
Memory decline
Delusions/hallucinations
Hostility/irritability

Question 25

Outline genetic basis of HD

Answer 25

Primarily caused by a mutation in the HTT gene located on chromosome 4 which encodes the hungtingtin protein. Mutation involves heterozygous expansion of a CAG trinucelotide repeat sequence within the gene leading to an abnormal elongation of the polygutamine tract in the Huntingtin protein. Mutated hungtingtin undergoes abnormal aggregation in neurons leading to dysfunction, cell death and progressive neurodegeneration Size of CAG repeat expansion correlates with age and onset of symptoms. - larger expansions associated with earlier onset and more severe progression - 26 or fewer CAG repeats = no risk of HD - 27-35 CAG repeats = no risk to you, can have kid w/ - 36 or more CAG repeats = risk of HD —> 36-39: risk of HD but some never symptoms —> 40-more: will get HD symptoms - interrupted CAG repeat >95% of alleles: —> ((CAG)n-CAA-CAG) penultimate CAA interruption increases stability of repeat - uninterrupted CAG repeats (1% of alleles): —> ((CAG)n) increase instability of repeat.

Question 26

What is juvenile HD

Answer 26

Get it before 20 years of age. 5-10% of people with huntingtons Decline in school performance, clumsiness frequent falling all signs. Seizures in 30-50% when onset <10 years Progress more quickly than the adult onset form

Question 27

What is HDs inheritance pattern

Answer 27

Autosomal dominance. Vertical pedigree patterns with multiple generations affected. Each effected normally has an effected parent. Each child of affected person has 50% chance of getting HD.

Question 28

What do you need to diagnose HD

Answer 28

Clinical features Family history Heterozygous expansion of 36 or more CAG trinucelotide repeats in gene HTT of chromosome 4

Question 29

Reproductive options for those with HD

Answer 29

take the risk IVF with preimplantation genetic diagnosis Prenatal diagnosis Donor gamete No biological children Adoption

Question 30

Discuss what the cerebellum is and role.

Answer 30

Essential for motor function No direct projects to spinal cord Exerts control via projections to brain stem and cortical areas. Plays major role in planning and timing of motor activities and in sensory motor coordination. Helps control intensity of muscle contraction as well as controlling agonist and antagonist muscle groups Also receives unconscious info about position sense e.g. from muscle spindles. Compared to motor plan (received from motor areas of cortex) allowing for adjustments of movement. Feedback is sent from cerebellum back to motor areas

Question 32

Functions of the cerebellum

Answer 32

Motor coordination - integration of sensory and motor info to coordinate smooth movements Balance and posture - regulation of body position and stability during static and dynamic activities Motor learning - facilitation of skill aquisition and refinement of motor movements Cognitive function - attention, language, memory and emotional regulation Timing and rhythm - control of temporal aspects of movements and coordination of motor sequences

Question 33

Gross anatomy of the cerebellum

Answer 33

Located in posterior cranial fossa as part of the metencephalon supplied by the fourth ear ventricle. Consists of internal white matter (arbour vitae) and external grey matter (cerebellar cortex). Cerebellum Serpentes from cerebral cortex by tentorium cerebelli. Consists of midline vermis, 2 large hemispheres separated by falx cerebelli. Structures: - tentorium cerebelli - dural fold seperating from lobe - vermis - midline structure within cerebellum, involved in coordinating axial and proximal limb movements. - falx cerebrelli - dural reflection that separates the 2 cerebellar hemispheres along the midline - Arbor vitae - white matter in cerebellum - Cerebellar cortex - outer layer of cerebellum, contains densely packed neuronal cell bodies and dendrites

Question 34

List Cerebellar peduncles, lobes of the cerebellum and cerebellar fissures and their functions

Answer 34

Peduncles: Superior - supplies midbrain (efferent); AKA brachial Conjunctivum Middle - supplies pons (afferent); AKA brachium pons Inferior - supplies the medulla (afferent); AKA restiform body Lobes of cerebellum: Anterior - regulation of muscle tone and coordination of voluntary movements Posterior - integration of sensory input and coordination of fine motor movements Flocculonodular - control of balance, spatial orientation and eye movements. Cerebellar fissures: Primary - separates anterior and posterior lobes Posterolateral - separates posterior from flocculonodular lobes

Question 36

Explain microscopic circuitry of the cerebellum including major cell types and layers.

Answer 36

3 layers: - molecular; outermost contains parallel fibres and Perkinje cell dendrites - perkinje cell layer; middle layer, contains cell bodies of perkinje neurons, man output neruons of cerebellar cortex - granular; innermost, densely packed granule cells, most numerous neuron in cerebellum Cell types: - stellate; inhibitory interneurons, molecular layer - basket; inhibitory interneurons, basket like structures around perkinje cell bodies - perkinje; principle out put neurons, extensive dendritic trees - granule; small excitatory neruons in granular layer - golgi; inhibitory interneurons with short axons that synapse with granule cells

Question 37

Compare and contrast major input and output pathways of the cerebellum

Answer 37

Output - mossy fibres: Mossy fibres ascend through cerebellar white matter —> excitatory synapses on dendrites of granule cells —> granule cell axons to molecular layer —> bifurcate and form parallel fibres to the folia, perpendicular to dendritic trees of purkinje cells —> parallel fibres excitatory contacts with multiple purkinje cells —> purkinje cell axons carry inhibitory output to deep cerebellar and vestibular nuclei, and outputs from cerebellum are carried by nuclei into other regions of the brain. Input - climbing fibres Climbing fibres excitatory input to cerebellum. Originate inferior olive in brainstem —> direct excitatory synapses onto dendrites of perkinje cells —> powerful and capable of inducing complex spikes in perkinje cells influencing firing patterns —> climbing fibres play crucial role in motor learning and coordination by providing error signals that can modify and refine output of purkinje fibres.

Question 38

White matter nuclei of the cerebellum

Answer 38

“Dont eat greasy foods” = dentate, emboliform, globose, fastigal Denate - receives projections from lateral cerebellum Emboliform - receives projections from intermediate cerebellum Globose - receives projections from the intermediate cerebellum Fastigal - receives projections from the vermis and flocculonodular node

Question 39

3 functional divisions of the cerebellum and their functions

Answer 39

3 functional distinct divisions with different roles associated with subconscious control of motor activity - vestibulocerebellar consists of flocculonodular node important for maintaining balance and eye movements - spinocerebellum consists of the anterior lobe, vermis and medial posterior lobe; it is responsible for enhancing muscle tone, coordinating skilled, voluntary movements - cerebrocerebellum consists of lateral parts of posterior lobe; responsible for planning and initiating voluntary movements by input from the motor cortical areas.

Question 40

Localise cerebellar lesions based on clinical features

Answer 40

Mnemonic DANISH can be used to remember cerebellar deficits. Dysdiadochokinesia - inability to perform rapid alternating movements —> cerebellar vermis Ataxia - lack of coordination and balance —> vestibulocerebellum Nystagmus - involuntary rhythmic eye movements —> vestibulocerebellum Intention tremor - tremor w/ voluntary movements —> cerebellar hemisphere Slurred speech - impaired articulation and fluency —> cerebrocerebellum Hypotonia - reduced muscle tone —> cerebellar nuclei

Question 41

Describe components of a peripheral nerve

Answer 41

Network of nerves located outside CNS Transmit sensory and motor signals between CNS and the rest of the body, allowing for voluntary movements, reflexes and sensory perceptions. Peripheral nerve components: - epineurium - dense outer layer surrounding a peripheral nerve - perineurium - protective sheath around a bundle of nerve fibres - endoneurium - fine connective tissue surrounding individual nerve fibres - Schwann cell - myelin producing cell in the peripheral NS - axon - long, slender projection of a nerve cell conducting electrical impulses

Question 42

Discuss peripheral neuropathy

Answer 42

Condition resulting from damage to peripheral nerves leading to sensory, motor and autonomic dysfunction Commonly affects extremities in a glove and stocking distribution causing (positive symptoms) tingling, burning, pins and needles due to hyperexcitability and negative symptoms of weakness, loss of reflexes, sensory deficits due to impaired nerve function. Various aetiologies of neuropathy: diabetes, infections, toxins, and autoimmune disorders. Acronym ABCD for most common causes - alcohol overuse, B12 deficiency, cancer, diabetes

Question 43

Classification of peripheral neuropathy

Answer 43

Mononeuropathy - affects singalong nerve; specific deficits depending on affected nerve (e.g. trauma, entrapment) Polyneuropathy - multiple nerves; usually distal nerves; distal deficits, usually symmetrical (e.g. glove and stocking distribution) Mononeuritis multiplex - individual nerves; haphazard fashion; specific deficits, usually asymmetrical (e.g. right arm and left leg) Polyradiculoneuropathy - multiple nerves AND nerve roots; diffuse deficits in proximal and distal parts of the body, usually symmetric symptoms.

Question 44

Disease classification of PNS disorders based on location (primary site of pathology)

Answer 44

Neuronal disorders - degeneration of the soma as seen in MNDs, like spinal muscular atrophy, leading to progressive weakness and atrophy. Axonal neuropathies - primarily affect axons and their myelin sheaths resulting in slowed conjunction velocity and distal sensory-motor deficits. Neuromuscular junction disorders - primarily impair synaptic transmission as seen in myasthenia gravis where acetylcholine receptor dysfunction leads to fatigable weakness.

Question 45

Compare and contrast proximal vs distal changes during peripheral nerve degeneration

Answer 45

Proximal changes: - cell body swells - nucleus moves to the periphery - chromatolysis (break down of Nissl bodies/rER) Distal changes: - synaptic/neuromuscular junction stripping “denervation” - wallerian degeneration of distal axon “dying back phenomenon” - myelin breakdown - macrophages clearing debris

Question 46

Describe how a peripheral nerve regenerates

Answer 46

Formation of proximal axon sprouts following injury. Which are guided by the surrounding endoneurium tube. Shwann cells play a critical role in this process by providing structural guidance and promoting axonal growth. They also secrete growth factors. Regeneration occurs within confines of the endoneurium tube acting as condit to direct axon toward the distal nerve stump. Regenerating axons re-establish connections with target tissues they restore function and full motor/sensory function recovery is possible. Influenced by distance between injury and target, extent of damage and presence of supportive tissues like Schwann cells.

Question 47

Factors that affect peripheral nerve regeneration

Answer 47

Proximity - distance between nerve ends Restoring contact - ensuring proper alignment enhances nerve repair Type of injury - severity and nature determine regrowth potential

Question 48

Outline 3 main types of traumatic peripheral nerve injuries

Answer 48

Neurapraxia (mild) - temporary nerve conduction block without structural damage leading to rapid and complete recovery —> e.g. cold, ischaemia, honeymooners palsy Axonotmesis - axonal and myelin damage with preservation of nerve sheath, requiring axonal regeneration to restore function often over weeks to months. —> e.g. nerve crush, stretch injury Neurotmesis - most severe form, entails complete disruption of the axon, myelin and surrounding connective tissue. Results in irreversivle loss of function unless surgical intervention facilitates nerve repair. —> e.g. sharp injuries, exposure to neurotoxic substances

Question 49

Lost common causes of peripheral neuropathy

Question 50

Discuss dopamine receptors

Question 52

List common causes of peripheral neuropathy

Answer 52

Common causes: ABCD - alcohol; toxic effect on nerve cells - B12 deficiency; impaired myelin sythesis - cancer; tumour infiltration/treatment induced - diabetes; elevated blood sugar Other causes: - Autoimmune/inflammatory conditions: Gillian barre, CIDP etc. - traumatic; incision, compression, stretching - Metabolic; diabetes, renal failure, hypothyroidism - malignancy; especially smell cell carcinoma of lung - drugs; isoniazid, phenytoin, nitrofurantoin - toxins; lead, alcohol - infections; leprosy, Lyme disease, HIV - inflammatory; Gillian barre, sarcoid - vascular; prolonged ischaemia, rheumatoid disease - genetic; Charcot-Marie-tooth disease, porphyria - vitamin deficiencies; B1, B6, B12, nicotinic acid

Question 53

Outline the pathophysiology and current theories around the underlying cause of Motor Neuron Disease

Answer 53

Neruodegenerative disorder characterised by progressive loss of upper and lower motor neurons. Mechanisms: Mutation - genetic mutations in SOD1, C9orf72, TARDBP, and FUS lead to protein misfolding, RNS dyes regulation and toxic aggregate formation, driving MN degeneration Glutamate excitotoxicity - impaired astrocytic glutamate clearance via reduced EAAT2 transporter function results in excessive glutamate accumulation, leading to intracellular calcium overload and neuronal apoptosis. Oxidative stress - dysfunction and increased reactive oxygen species (ROS) production cause lipid peroxidation, DNA damage, and impaired cellular homeostasis, accelerating neuronal death Neuroinflammation - activated microglia and dysfunctional astrocytes release pro-inflammatory cytokines and neurotoxic mediators, exacerbating motor neuron injury and synaptic dysfunction Axonal transport - Disruptions in cytoskeletal components and molecular motor proteins impair bidirectional axonal transport, leading to intracellular trafficking defects and neuronal degeneration

Question 54

Clinical subtypes of MND

Answer 54

Amyotrophic lateral sclerosis (ALS) - most common form; characterised by simultaneous UMN and LMN degeneration; muscle weakness, spasticity, atrophy Progressive muscular atrophy (PMA) - primarily affects LMNs; flaccid weakness, muscle wasting, absent reflexes, subset of cases evolving into ALS Primary lateral sclerosis (PLS) - rare variant exclusively involves UMNs; progressive spasticity, hyperreflexia, muscle stiffness w/o significant muscle atrophy. Progressive bulbar palsy (PBP) - predominantly affects MNs in brainstem; dysarthria, dysphagia, severe speech and swallowing difficulties, progresses rapidly. Spinal muscle atrophy (SMA) - genetic form of MND caused by SMN1 mutations and leads to LMN degeneration with early-onset muscle weakness and atrophy.

Question 55

Clinical features of MND

Answer 55

Varying clinical features depending on underlying cause. Can be characterised by loss of UMN or LMN function. Can also present with both UMN and LMN lesion symptoms: - atrophy - flaccid paralysis - hyporeflexia - hyperreflexia - hypotonia - hypertonia - spastic paralysis - pathophysiological fasiculations

Question 56

Outline the investigations of MND

Answer 56

EMG - measures muscle electrical activity for signs of denervation and reinnervation Nerve conduction study (NCS) - assesses peripheral nerve function and conduction speed MRI - rules out other neurological conditions affecting brain and spinal cord Lumbar puncture - analyse CSF for abnormalities or infections Blood tests - check for metabolic, inflammatory and other conditions that mimic MND —> note: LP and blood tests to rule out other similar conditions such as infections and metabolic pathologies

Question 57

Management of MND

Answer 57

Primarily supportive, aimed at prolonging survival and maintaining quality of life. No curative treatment. - riluzole; glutamate-release inhibitor, modestly extends survival by reducing excitotoxicity. - edaravone (an antioxidant); may slow functional decline in select ALS patients (low evidence) - non invasive ventilation (NIV); most effective intervention for resp insufficiency, significantly improving survival and reducing symptom burden - multidisciplinary care; includes physio, speech therapy, nutritional support, optimising function and managing complications - emerging therapies targeting genetic mutations (SOD1, C9orf72) and neuroinflammatory pathways being investigated.

Question 58

Describe Pathophysiology of Gillian barre syndrome

Answer 58

Autoimmune disorder where immune system mistakenly attacks the PNS Initial trigger often follows bacterial or viral infection which leads to immune response that damages myelin sheath of peripheral nerves or even nerve axons themselves. Demyelination or axonal damage disrupts signal transmission causing muscle weakness, numbness, tingling starting in legs spreading upwards. Body can repair this damage and can lead to gradural recovery in many cases although some may experience residual weakness or other neural deficits

Question 59

Clinical features of GBS

Answer 59

Ascending weakness - muscle weakness starts in feet and moves upwards Back pain - often present as an initial symptom or alongside weakness Autonomic changes - dysregulation of involuntary bodily functions LMN signs - like muscle atrophy and hyporeflexia

Question 60

Investigions for GBS

Answer 60

Nerve conduction studies - assess peripheral nerve function and conduction speed LP - analyse CSF for protein levels and cell count EMG - detects abnormal muscle electrical activity. Blood tests - rule out infections and other potential triggers

Question 61

Describe Pathophysiology of myasthenia gravis

Answer 61

Autoimmune disorder characterised by impaired neuromuscular transmission due to antibodies targeting ACh receptors at postsynaptic junctions Antibodies primarily IgG are directed against ACh receptor leading to reduction in receptor density inhibting ACh binding impairing transmission. Results in weakened skeletal muscle contraction and variable muscle fatigue. Chronic inflammation and complement activation contribute to destruction of postsynaptic membrane worsening neuromuscular dysfunction. Clinical manifestation of MG involves proximal muscle weakness worsening with exertion and improves with rest. Hence progressive neuromuscular dysfunction as more receptors are compromised.

Question 62

Clinical features of Myasthenia gravis

Answer 62

Muscle weakness and fatigability. Primarily affects ocular, bulbar and proximal limb muscles. Extraocular - diplopia due to extraocular muscle weakness and ptosis Limb/axial - symmetrical proximal limb weakness and decreased power Respiratory - dysphagia, dysarthria, dystonia, decreased vocal volume. symptoms worsening with prolonged use and improving with rest. generalised MG can cause limb weakness and resp failure (myasthenic crisis) Reflexes and sensation remain intact; can be used to clinically distinguish MG from other neuromuscular disorders. Typically worsens later in day.

Question 63

Investigations of Myasthenia gravis

Answer 63

ACh receptor antibody test - detects antibodies against acetylcholine receptors on muscle cells Tension test - short acting acetylcholinesterase inhibitor to temporarily improve muscle strength Repetitive nerve stimulation test - measures decremental response of muscle action potentials to repetitive nerve stimulation EMG - detects abnormal jitter and blocking in individual muscle fibres