Neuromuscular disorders Flashcards
Myasthenia Gravis
Upper extremity weakness
● Ocular muscle weakness
● Diploplia and/or ptosis
● Pt improve with rest
hallmark sign of myasthenia gravis
● Hallmark is fluctuating or fatigable weakness that is worse at end of day and during/after
exercise
myasthenia gravis etiology
Postsynaptic neuromuscular junction (NMJ) autoimmune disease
ACh antibodies disrupt NMJ in 3 ways
Complement-mediated activation leading to destruction of postsynaptic membrane
Endocytosis of AChR
Direct blockage of ACh binding site
○ Thymus gland
Thymoma= tumor of thymus gland
Removal= rapid relief
how to treat myasthenia gravis
● Tx with ACh esterase inhibitors
Lambert-Eaton Myasthenic Syndrome (LEMS)
50% will have underlying malignancy→ small cell lung cancer (SCLC)
- This type is called paraneoplastic
- Type without malignancy is called non-paraneoplastic
- Both paraneoplastic and non-paraneoplastic forms are associated with P/Q type voltage-gated CA channel (VGCC) antibodies
- Paraneoplastic onset at age 60
- Difficulty climbing stairs or rising out of chair
- Lack of muscle reflex
LEMS often precede tumor detection in the paraneoplastic form
what disease is associated with small cell lung cancer
lambert eaton myasthenic syndrome
Lambert-Eaton Myasthenic Syndrome (LEMS) paraneoplastic onset vs non-paraneoplastic onset
- Paraneoplastic onset at age 60
Non-paraneoplastic has 2 peaks
- First peak at 35 years
- Second peak at 60 years
Botulism
■ Type A or B toxin
○ Hypotonia, dysphagia, loose stool ○ Most numerous cases in Alaska
■ Old canned food
INFANTILE
○ Etiology
where is botulism common?
alaska
Neurofibromatosis Type I (NF1)
Aka von Recklinghausen Disease
- Genetic mutation in NF1 gene encoding neurofibromin
- Neurofibromin
- tumor suppressor
- downregulates p21-RAS oncoprotein
Neurofibroma: benign tumor of schwann cell
what diesease is from a genetic mutation in NF1 gene
neurofibromatosis type 1
what does neurofibromin downregulate?
NF1
it is a tumor suppressor that downregulates p21-RAS oncoprotein
what are cafe au lai spots
Neurofibromatosis Type I (NF1)
- Cafe-au-lai-spots: well demarcated cutaneous hyperpigmentations
what is iris hamartoma
Neurofibromatosis Type I (NF1)
Iris hamartoma (Lisch nodule): pigmented aggregate of dendritic melanocytes affecting
the eye
complications of neurofibromatosis type 1
Glioma (tumor) of optic nerve, increased risk for meningioma
- Most severe is neurofibrosarcoma
- The fibrosarcomas go from benign growths to malignant
- Ex: plexiform neurofibroma
- Affects cervical nerve root and brachial plexus - Ex: MPNST (malignant peripheral sheath tumor)
- Large mass originating in flank region
Neurofibromatosis Type 2 (NF2)
Aka central neurofibromatosis
- Autosomal dominant
- Bilateral tumors of CN8 (acoustic)
- Most vestibular schwannomas are unilateral and not associated with NF
- **bilateral vestibular schwannomas are pathognomonic of NF2
- Unilateral acoustic neuromas are also characteristic of NF2
what is disease is called central neurofibromatosis
Neurofibromatosis Type 2 (NF2)
what CN is associated with Neurofibromatosis Type 2 (NF2)
CN8 acoustic
what is Neurofibromatosis Type 2 (NF2) etiology
Mutation in NF2 gene at 22a12
- Problem with encoded protein Merlin (schwannomin)
- Fxns as tumor suppressor
Neurofibromatosis Type 2 (NF2) mutation causes
Mutation in NF2 gene at 22a12
- Problem with encoded protein Merlin (schwannomin)
- Fxns as tumor suppressor
Vestibular Schwannoma
Benign and slow growing
- Unilateral
- Not associated with NF!
- Originate from vestibular branch of CN8
- Hearing loss, tinnitus, headache
- Hydrocephalus
- Increased intracranial pressure
Spinal and Peripheral Schwannoma
schwannoma→ mass arising from nerve sheath of schwann cell
Spinal
- Originate from dorsal spine root
- Radicular pain
- Spinal cord compression
Peripheral
- Originate on nerves of head, neck, extremities
○ Down syndrome (Trisomy 21)
Nondisjunction in 1st meiotic division
T21
Myeloid proliferations
Epicanthic fold (eyelid)
Small nasal bridge
Transverse (Simian) crease - palm of hands
○ Edwards Syndrome (Trisomy 18 aka Patau Syndrome)
Mental retardation
Congenital heart disease
Die in 3 months
Rocker bottom foot
Spine anomalies
Hand clenched with overlapping fingers
○ Patau Syndrome (Trisomy 13)
Cardiac defects
Hallmark: Holoprosencephaly
● Alobar
● Facial abnormalities
● Hypotelorism or cyclopia
● Midline or bilateral cleft lip/palate
what disease has holoprosencephaly
patau syndrome trisomy 13
5P-Syndrome (Cri Du Chat):
Baby cries - sounds like a kitten (high pitched)
● Microcephaly
● Facial Dysmorphology
○ Hypertelorism (separation between organs or body parts):
Low set ears
Small jaw
Rounded face
● Deleted gene CTNND2 (chromosome 5)
○ Intellectual disability
Types of imprinting
● Genomic - some genes get inactivated
● Maternal - transcriptional silencing of maternal allele
● Paternal - paternal allele inactived
● “Imprinting” - methylation of gene to turn it off
Multifactorial inheritance
● Polydactyly - extra digits
● Syndactyly - fusion of digits
● Cleft lip and palate
Errors/Morphogenesis
● Malformations - primary errors of morphogenesis
● Teratogens - chemicals that cause developmental anomalies
● Polytopic effect - when noxious stimulus affects several organs in critical stages of
development
● Monotopic effects - single localized anomaly that results in cascade of pathogenetic
effects
● Potter complex - developmental sequence anomaly
● TORCH Complex
Maternal infections
○ Toxoplasma, Others, Rubella, Cytomegalovirus, Herpes simplex virus
neural tube defects
● Meningocele - only CSF
● Myelomeningoceles - Neural elements
● Myeloschisis - spinal cord + nerve roots
● Anencephaly - brain is missing
vestibular schwannoma/acoustic schwannoma
origin is vesticular branch of CN 8
at cerebellopontine angle tumor
unilateral
most vestibular schwannomas are unilateral and not associated with neurofibromatosis
meiningocels vs myelomeningoceles
Meningoceles (white solid arrow) contain only cerebrospinal fluid, while myelomeningoceles (white curved arrow) also contain neural elements
typical location of a myelomeningocele
within the lumbosacral region
The most common location for spina bifida
lumbar, followed by sacrum
Maternal infections- TORCH Complex
CMV infection is associated with abnormal erythropoiesis and hemolytic anemia
numerous periventricular (black solid arrow) and basal ganglia (black curved arrow) calcifications
Anencephaly
- Dysraphic defect of neural tube closure
- Congenital absence of cranial vault
- Cerebral hemispheres completely missing or reduced to small masses attached to the base of the skull
Essential information for Primary Central Nervous System (CNS) Tumors
Patient age and gender
Anatomic location and compartment of the lesion
Neuroimaging (computed tomography, magnetic resonance imaging) features
Nature and time course of presenting signs and symptoms
Relevant clinical history
two most common brain tumors of childhood are
medulloblastoma and Pilocytic Astrocytoma
•Anatomic localization of brain lesions includes two components:
- Region of the CNS involved
- Cerebrum, Cerebellum or Spinal cord
- Compartment(s)
- Intraparenchymal (e.g., within the brain substance), intraventricular or intradural–extra-axial (within the spinal subarachnoid space)
Most Common Central Nervous System Tumors
Meningiomas
Meningioma definition
•Neoplasm arising from meningothelial (arachnoid) cells, that form the outer boundary of the Subarachnoid space
where do meningiomas arise
•Can arise at any CNS site where arachnoid cells are present
meningioma arises in what 3 settings
- Most Sporadic
- Partial deletion or mutation of the NF2 locus (22q12)
- Iatrogenic
- Generally, involves a latent period of a decade or more and is directly related to radiation dosage
- With higher radiation doses, such as are used for head and neck cancers, the interval may be as short as 5 year
- Tumor predisposition syndromes
- Neurofibromatosis 2 (NF2)
- Multiple, potentially innumerable
- Early onset, childhood
- Schwannomatosis
- 5% of patients
- SMARCB1 germline mutation
Most Common Primary Brain Tumors
Astrocytomas
how are astrocytomas divided
on how diffusely they infiltrate the brain parenchyma
diffuse vse non-infliltrating astrocytomas
- Diffuse Astrocytomas
- Low-grade fibrillary astrocytoma
- Anaplastic astrocytoma
•Glioblastoma (Most malignant astrocytic tumor)
•Non-infiltrating/Diffuse Astrocytomas
•Pilocytic astrocytoma
- Pleomorphic xanthoastrocytoma
- Subependymal giant cell astrocytomas
Most malignant astrocytic tumor
Glioblastoma
Diffuse Astrocytomas – Clinicopathologic Features
- Ability of individual tumor cells to infiltrate widely through brain and spinal cord parenchyma
- This property reaches its extreme in gliomatosis cerebri (WHO grade III)
Glioblastoma – Clinicopathologic Features
- Terminology
- Highly malignant (grade IV) Astrocytic neoplasm
- Synonyms
- Glioblastoma (spongioblastoma) Multiforme (GBM)
- High-grade (malignant) astrocytoma (WHO grade IV)
- Etiology/Pathogenesis
- Primary GBM (90%): No evidence of precursor lesion
- Short history; older patients; EGFR amplification
- Secondary GBM: From lower grade astrocytoma
- In 4-5 years; women, children; TP53 mutation
primary vs secondary GBM
Primary GBM (90%): No evidence of precursor lesion
- Short history; older patients; EGFR amplification
- Secondary GBM: From lower grade astrocytoma
- In 4-5 years; women, children; TP53 mutation
age group that glioblastomas affect
•Older patients; represents most GBMs (90%)
characteristic signs of glioblastomas
Central necrosis (white open arrow) surrounded by hemorrhage, edema, and infiltrating tumor
what is a common gliobastoma mtation
- Pediatric High-Grade Astrocytomas
- Common TP53 mutation, rare EGFR amplification
- Especially brainstem lesions: Diffuse Pontine Astrocytoma
Diffuse Pontine Astrocytoma
Diffuse astrocytomas of childhood, diffuse pontine astrocytomas infiltrate and expand the brainstem pons, often to the point of encircling the basilar artery.
