Neuro 4😊

Duchene Muscular Dystrophy

Q. A 4-year-old boy presents with difficulty in climbing stairs. There is a family history of similar illness in the child's maternal uncle. The Child's CPK levels are 12,400 units/L. What is the probable diagnosis?

• X-linked Recessive disorder

• Mainly affects boys

• Gene affected:
• Dystrophin gene;
• Largest genes found in humans +
• it is present on ChrXp21.
• Leads to ⛔ of calcium uniport in mitochondria

• Mode of inheritance:
• X-linked recessive inheritance.

• If Dystrophin protein is
• less or reduced
• Called Becker's muscular dystrophy (milder variant)
• totally absent
• Duchenne muscular dystrophy
• Progressive increase in muscle weakness
• Dystrophy → progressive weakness

Clinical features of DMD

• Progressive proximal muscle weakness i.e.,
• weakness involving thigh muscles
• arm muscles

Clinical signs in DMD

• On examination:
• Pseudohypertrophy of calf muscles is seen,
• inverted bottle appearance
• Hour glass appearance
• brachioradialis

• Valley sign positive:
• It is a groove-like depressed area
• in between pseudo hypertrophied deltoid and infraspinatus muscles.

• Gower sign positive:



• Due to weakness in hip joint muscles
• If a child with DMD is asked to get up from a sitting position,
• he will first take the help of a hand
• put them on the ground
• take support of his legs
• slowly taking help from himself,
• the child will get up.

• Floppy muscles

• Most children become Wheelchair bound at 10-12 years

• Subsequently leads to death
• M/c: Congestive Heart Failure

Investigations findings in muscular dystrophy

• Serum CPK levels
• (Normal - <160 U/L):
• 10,000 U/L.
• This is often used as screening and first-line investigation.

• Definitive diagnosis:
• PCR for dystrophin gene
• It can be done by multiplex PCR or MLPA
• (Multiplex Ligation-dependent Probe Amplification).

• Muscle biopsy is not done to diagnose, but if done

• Chest X-ray:
• Cardiomegaly.

Others not used:

• EMG

• CPK MM:
• Elevated initially
• Falsely normal once wheel chair bound

NOTE: Gower sign in 25 year old female

• Dermatomyositis

Treatment of muscular dystrophy

• Supportive care including
• physiotherapy,
• taking care of cardio-respiratory issues.

• Corticosteroids:
• They decrease the progression of the disease but
• it can not cure the disease.
• It will improve muscle strength and
• prolong the ambulation.
• Prednisolone or Deflazacort can be used.

• Newer drugs of muscular dystrophy:
• Anti-sense oligonucleotides.

• Eteplirsen (51 exon-skipping drug).
• Get up Lirsen

Tensilon test:

• Edrophonium injection
• ↓↓ ptosis

• Not done now
• Trigger cholingeric crisis, hypersalivation
• Patient may not be able to swallow → aspiration

• Mnemonic: Edada phone → tension kuraykan

ICE PACK test

• Now used

• Put ice pack over eyes → Ptosis ↓↓

• Sensitivity of tensilon and ice pack tests equal

Revise Epilepsy

SSLC / SCENE Genes

Motor Neurone Disease

• Disorder of Hexanucleotide repeats

Three main types:

1. Lower motor neuron type

• Flaccid weakness

• Absent reflex

• Site: Anterior horn cells of spinal cord
• Lesion → current will not flow → LMN lesion

• Progressive muscular atrophy
• Limb weakness
• Areflexia

• Progressive bulbar palsy

---

• Ipsilateral Bulbar Palsy
• Injury to Nucleus Ambiguus (LMN Lesion)
• Features
• (tongue spared)
• Dysphagia
• Dysarthria
• Nasal speech
• Loss of GAG reflex
• High risk of aspiration
• Wasting & fasciculations of palate/pharynx

Region	Location	Structures	Nucleus
Vision	Midbrain	Oculomotor Nerve, Superior Colliculus	Edinger–Westphal (EW) nucleus
Pharynx & Larynx	Medulla	Cranial nerves 9, 10, 11	Nucleus Ambiguus

---

2. Upper motor neuron type

• Spasticity

• Brisk reflex

• Primary lateral sclerosis
• Involves corticospinal pathway

• Pseudobulbar palsy is a sign B/L UMN lesion

• Hoffman’s sign
• Can be present in normal individuals
• UMN lesion above C5–C6 level
• Patient relaxes hand.
• Examiner holds middle finger and flicks the distal phalanx downward.
• Observe thumb and/or index finger:
• Flexion or adduction of the thumb → Positive

3. Both LMN + UMN involvement

Amyotrophic lateral sclerosis

• UMN + LMN.

• M/c: Autosomal Dominant

• Lou Gehrig's disease.

• Mnemonic: Stephan hawking was in love (lou Gehrig. like to eat Banana (Bonina) and drink SODA (SOD1), edavazhiyil (Edavarone) Mulli (Riluzole)

• Gradual onset weakness over years

• Asymmetrical pattern
• Example
• Knee/ankle jerk (left):
• Brisk
• Biceps jerk (right):
• Absent

• Onset Types:
• Limb-onset ALS → Starts in the hands or feet.
• Bulbar-onset ALS → Initial symptoms are difficulty speaking and swallowing.

• Sensory, sexual, and cognitive functions remain intact.

• Clinical Sign: 
• Hoffman's sign positive → Indicates Upper Motor Neuron Lesion (UMNL).

Microscopic Finding: 

• Shows Bonina bodies.

Death due to

• Respiratory failure (Pneumonia)

Management of ALS:

• Increase longevity
• Riluzole
• Edaravone

• New drugs
• Tofersen
• Turursodiol

• Mnemonic:
• ALS padikkan poyapo edavazhiyil (edavarone) Banana (Bonina) and toffee (toferson) turi (riluzole, turursodiol)

UMN + LMN
(absent ankle jerk, extensor plantars):

• B12 deficiency
• posterior columns Sensory loss present → think B12 deficiency

• Friedreich ataxia
• Most common inherited ataxia
• Onset in childhood/adolescence (<15 years)
• Autosomal recessive
• Genetic testing: GAA repeat expansion in FXN gene
• Combination of: ataxia + absent reflexes + cardiomyopathy + scoliosis
• Friedreich = “feet first” mnemonic: gait ataxia, pes cavus

• Amyotrophic lateral sclerosis
• Fasciculations + mixed UMN & LMN signs → think ALS

• SNc → Substantia Nigra

• Norepinephrine locked in ICU → Locus ceruleus

• ↑↑ Dopamine activity → Madly (Schizophrenia) hunting ()

• ↓↓ GABA → ↓↓ inhibitions → during anxiety () and hunting ()

• Norad → patients becomes anxious ()

• ↓↓ AcH → Alzheimer's, Huntintons (↑↑ in Park)

Condition	NT	Location
Alzheimer's disease	↓↓ Acetyl choline	Nucleus basalis of Meynert
Parkinson's disease	Dopamine ↓↓ ↳ bradykinesia ↑↑ Acetyl choline	Nigrostriatal Mnemonic: Mayil (Meynert) Basil (Basalis) nu Achingum (Acetylcholine) Alzheimersum vannu
Addiction	Dopamine	Nucleus accumbens Mesolimbic Location ↳ Medial Frontal area ↳ Ventral tegmental area
ALS	Glutamate Amy → Glue	Hippocampus, Subthalamic nucleus → Memory A-delta fibres → Fast pain
Huntington's chorea	Dopamine ↑↑ GABA ↓↓ AcH ↓↓	Loss of GABA in striatum
Tetanospasmin ↳ spastic paralysis ↳ Presynaptic	GABA	Inhibits release of GABA
Strychnine ↳ spastic paralysis ↳ Postsynaptic	Glycine Stry → Gly	Inhibits release of glycine.
Mesocortical	ㅤ	Prefrontal cortex ↳ Motivation ↳ Emotional regulation ↳ Decision making ↳ Memory
Tuberoinfundibular	Dopamine	• Hypothalamus • Physiologic inhibition of prolactin

Parkinson's Disease

• Reason: Decrease in dopaminergic neurons.

Gross Finding: 

• Substantia nigra appears pale 
  (normally brown due to melanin, which decreases with dopamine).

Microscopic Finding: 

• Presence of Lewy bodies.
• Description: Round bodies, darker in center, whiter at periphery.
• Composition: Made of alpha-synuclein.
• Park (Parkinson's) is synonymous (Synuclein) with lawn (Lewy bodies

Lewy Body Disease (Dementia due to Lewy bodies)

• Second most common overall cause of dementia.

• Subcortex > cortex

Three core features:

1. Fluctuating cognitive impairment (variations in attention/alertness)

2. Visual hallucinations.

3. Motor features of parkinsonism (tremors, rigidity, bradykinesia)

Suggestive features:

• REM sleep behavior disorder.

• Severe neuroleptic sensitivity.

Supportive features:

• Repetitive falls, syncope, transient loss of consciousness.

• Severe autonomic dysfunction.

• Systematized delusions
• e.g., delusion of persecution
• Capgras syndrome.

• Other delusions or hallucinations (auditory, tactile).

Microscopic findings:

• Lewy bodies
• eosinophilic inclusions of alpha-synuclein
• Also found in Parkinsons and MSA
• Lewy Parkin Shy

Differential diagnosis with Parkinson's disease dementia:

• Parkinson's disease dementia:
• Motor symptoms develop first.
• Cognitive symptoms follow (at least 1 year later).
• It is a subcortical dementia.

• Lewy body disease:
• Cognitive symptoms present from the beginning.
• Motor symptoms may be present initially or occur later.

Assessment of Dementia

• Tool: Mini Mental State Examination (MMSE).

• A screening tool for cognitive symptoms.

• Score < 24 out of 30 is suggestive of dementia.

• Developed by Folstein et al.

Progressive Supranuclear Gaze Palsy

 

• Mnemonic: Square frame wave cheythu → Humming bird ullil kude mukalilot parannu poi

• Seen in Atypical Parkinsonism.
• unresponsive to levodopa

• Tauopathy

• a type of Parkinson's plus syndrome.

Multisystem Atrophy (MSA) / shy dragger

• Parkinson's plus syndromes
• α synuclein accumulate in Oligodendrocyte

• Autonomic symptoms (Erectile dysfunction) ++
• recurrent urinary infections

• cerebellar signs

• "bent-over" posture
• (stooped posture observed in idiopathic PD)

• Types
• MSA P → Parkinsonian → Putaminal ring
• MSA C → Cerebellar → Hot cross bun sign

• Lewy Parkin Shy

• Cross cut Bun with a dagger

Corticobasal degeneration

• Alien limb phenomenen

• Parkinson's plus syndromes

Alzheimer's Disease (AD)

• Most common type of dementia.

• Cortical dementia.

• Seen in senile old age (after 70 years).

• Gradual and insidious onset.

• Temporal → Parietal → Frontal

• Slightly more common in females.

• Most common presentation:
• memory deficit.
• Language disturbance and other domains (agnosia, apraxia) affected gradually.

• Genetic Factors:

Genetic Factor	Chr.	Associated Effect
Amyloid Precursor Protein (APP)	21	• Premature Alzheimer's by 30 years in Down Syndrome • due to increased APP • APP → Premature
Presenilin 1 (PS1)	14	ㅤ
Presenilin 2 (PS2)	1	ㅤ
APOE E4 mutations	19	• Results in late onset Alzheimer's • Bad Prognosis • APO E → Early • 4 bad people
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)	6	• late onset Alzheimer's
APO E2	ㅤ	• Good Prognosis • too (2) good

• Mnemonic (PS): 
• PlayStationil (PS → Presenilin) Game (gamma secretase activity) → from 14 years old (chromosome 14)
• At 21 → Alzheimers () vannu → aappilaayi (APP)

• Diagnosis: 4A
• Amnesia
• Apraxia
• Agnosia
• Aphasia
• → Apraxia/Aphasia:
• Parietal and temporal lobe involvement

Clock face test:

• Hemineglect

• Finds cognition defect > Apraxia

Microscopic Findings:

Neurotransmitters implicated:

• Acetylcholine is reduced.

• Glutamate is increased (can cause excitatory damage).

Screening test:

• MMSE (mini-mental state examination)
• MMSE <24/30 suggestive of Dementia
• MMSE may be false positive in depression

Investigation of choice:

• Functional MRI
• Detects hypometabolism in parietal & temporal lobe

Treatment:

• Cholinesterase Inhibitors:
• Mechanism: Increase acetylcholine levels.
• Drugs: Donepezil, Rivastigmine, Galantamine.
• Rivastigmine and Donepezil
• transdermal patch
• Tacrine not used much (hepatotoxicity).
• Can cause severe GI side effects.

• Memantine:
• Mechanism:
• Non-competitive NMDA antagonist
• decreases glutamate levels
• Used in moderate to severe Alzheimer's disease.
• Can be used as monotherapy or with Donepezil.

• Monoclonal Antibodies for Alzheimer's Disease
• Mechanism:
• Human IgG1 monoclonal antibodies that clear A beta deposits.
• Given as IV infusion.
• Approved for mild cognitive impairment or mild dementia stage of AD.
• Mnemonic (AL D):
• Alzheimer patient says
  “Le i can (Lecanemab) still Adukaam (Aducanumab) → Do None (Donenumab) ”
• Aducanumab.
• Lecanemab (Approved 2023).
• Side effects:
• headache,
• infusion reactions,
• ARIA (Amyloid Related Imaging Abnormalities).
• Donanemab (Approved July 2024).

Normal Pressure Hydrocephalus (NPH):

• Wet-Wacky-Wobbly Grandpa

• Presents with Hakim's triad (Adam's triad):
1. Cognitive impairment.
2. Gait abnormality (magnetic gait).
• Shuffling gait with preserved arm swing
3. Urinary incontinence.

• Treated by shunting.

HIV associated Neurocognitive disorder (HAND)

• HIV + Subcortical dysfunction

• Microglial nodule + Giant cell

• Cause: Blockade of D2 receptors in Nigrostriatal Pathway

• More common in Typical > Atypical Antipsychotics.

• Mnemonic: ADAPT
• AD - Acute Dystonia
• A - Akathisia
• P - Drug-induced Parkinsonism
• T - Tardive Dyskinesia
• Night - Neuroleptic Malignant Syndrome

• VMAT ⛔ →Also used in chorea