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1

Weakness 

Considered disorders of nerve conduction

Autoimmune, Lymphocytes?

Common to what two disorders?

Multiple Sclerosis and Myasthenia Gravis 

2

Autoimmune disease which causes inflammatory demylnation of CNS

Reduces nerurons ability to function

Multiple Sclerosis 

3

Found primarily in young adults, usually under age of 55 at onset (typically mid-20's to 30)-if older onset, may be more severe

Women>men (may be more severe in men)

Epidemiology of which condition?

Multiple sclerosis 

4

CIS

RRMS

primary progessive

secondary progressive

progressive relapsing

Different forms of which condition?

MS

5

Likely autoimmine- higher risk with other autoimmune diseases

High risk: Northern Europe, Southern Canada, Northern US

Low risk: Asian, African, American Indian

MS

6

  • Patients of Western European lineage (genetics) who live in temperate zones (environmental)
  • If patients move from one “zone” to another before age 15, he/she appears to adopt that zone’s risk
  • Less risk closer to equator—is sunlight or Vitamin D protective?
  • HLA-DR2 ?, HLA-DRB1 association
  • Exposure to viral infections—EBV? Varicella?
  • Genetic predisposition? Increased risk if (+) FHX
  • Exposure to vaccines?
  • Smoking? Alcohol?
  • Month of birth? May>November 

Risk factors for which condition?

 

MS

7

Inflammation --> demyelination --> axonal degeneration

Still an area of research

Pathogenesis of what condition?

MS

8

Shows response to treatment with immunomodulating rx

Disruption of BBB= rx that blocks T cell movement into CSF improve MS sx

MS

9

Signs/Sx: 

Weakness, fatigue, numbness, tingling, unsteadiness in a limb, spastic paraparesis, retobulbar neuritis/optic neuritis (blurred or dimmed vision, blind spots (central vision), pain w. eye movement, HA, sudden color blindness, imparied night vision, impaired contrast sensitivity, diplopia), disequilibrium/vertigo, pain, sphincter disturbance (urinary urgency or hesitancy)

MS

10

Relapse/remission

Onset between 15-50

Optic neuritis

Lhermitte's sign

Internuclear opthalmoplegia

Fatigue

Uhtoff's phenomenon

These are suggestive or not suggestive of MS?

SUGGESTIVE 

11

Steady progression

Onset before age 10 or after 50

Cortical deficits-aphasia, apraxia, alexia, neglect

Rigidity, sustained dystonia

Convulsions

Early dementia

Deficity developing in minutes

Suggestive/Not suggestive of MS?

NOT suggestive 

12

TIA/CVA

B12 deficiency

HIV

Lyme Neuroborreliosis

Neurosyohilis

Acute disseminated encephalomyelitis

Acute hemorrhagic leukoencephalitis

Acute/subacute transverse myelitis 

DDX with which condition?

MS 

13

Certain criteria must be met (McDonald)

Must show two or more different areas in central areas of white matter affected to different times 

Only one area may be clinically affected—but a “probable” diagnosis can be made in patients with multi-focal disease on imaging but with only one clinical attack or with a history of at least two clinical attacks but signs of only one lesion 

Dx for which condition?

MS 

14

Imaging test of choice to diagnosis clinically suspected MS?

MRI 

15

Lesion is the cerebral or spinal plaque - descrete region of demyelination with initially preserved axon

Found in the periventricular, juxtacortical, infratentorial and/or spinal cord

MRI results of which condition?

MS 

16

Increased Gadolinium enhancement may indicate ______ lesion?

Acute or chronic 

Acute 

17

Is an acute lesion symptomatic/asymptomatic in MS?

Asymptomatic!

18

What other lab should be performed for MS?

Lumbar puncture 

Also useful to rule out other dx: B12, Lyme, etc 

19

May have mild lymphocytosis, may have IgG in CSF

Probably normal opening pressure

Albumin in CSF indicates disruption in BBB

Lumbar puncture results in which condition?

MS

20

Presense of ________ on lumbar puncture is highly suggestive of MS

oligoclonal bands 

21

What is the most common form of MS?

Relapsing-remitting MS 

22

How many forms of MS are recognized?

4!

23

Initial episode then months or years before new sx emerge or previous sx return

Can lead to incomplete remissions and progressive disability with weakness, spatsticity, ataxia of limbs, impaired vision, and urinary inconinence

PE: optic atrophy, nystagmus, dysarthria, pyramidal/sensory/cerebellar deficits in one or multiple limbs 

What form of MS?

RRMS 

24

Acute exacerbation of sx lasting says to weeks, at minimum 24 hours 

Defintion of what?

Relapse 

25

Can be previous sx or new sx

Relapse triggers/infection/trauma/stress/pregnancy?

Frequency of relapse is variable --> more common in early dx

Uhthoff's phenomenon

What form of MS?

RRMS

26

In some patients, clinical course changes to secondary progressive (SPMS). Some studies indicate that most patients will progress to SPMS

Primary progressive (PPMS)—less common (~10%), Symptoms are steadily progressive from onset.

Progressive relapsing MS (PRMS)—a subset of MS which has some remissions, but steady decline still dominates disease course.

Other forms of what dx?

MS

27

Fully functional in all neurological systems 15 years after disease onset

What severity of MS?

Benign

28

Rapidly progressive course leading to significant disability

What severity of  MS?

Malignant 

29

No cure

Tx aimed at improving quality of life and limiting disability

Strong support network- family, therapists, social services 

Tx for what?

MS 

30

What are acute attacks of MS most commonly treated with?

Glucocorticoids

(methylprednisolone 1g IV x 3-7 days)

31

Aimed at reducing relapses and slowing progression  of MS?

Disease Modifying Therapy 

32

Historically SC or IM (IV for certain patients)

Now 3 oral options

What type of therapy for MS?

Disease Modifying Therapy 

33

  • Interferon-b-- cytokine that modulates immune responsiveness
  • Betaseron / Extavia(Interferon-b1b)
    • 250mcg SC administered QOD
  • Rebif (Interferon-b1a)
    • 44mcg SC administered 3x/week
  • Avonex (Interferon-b1a)
    • 30mcg IM administered weekly
  • Plegridy (Pegylated Interferon-b1a)
    • 125mcg SC every other week

Tx for which condition?

MS 

34

Injection site reactions

Flu-like sx

Depression

Elevated LFTs

Leukopenia/anemia

S/E of which type of drugs for MS therapy?

Interferons 

35

What can develop and limit the effectiveness of IFNB treatment in MS?

Neutralizing antibody formation 

36

Mixture of amino acids antigenically similar to myelin protein. Works by competing for T cells - but process not entirely understood

Daily 20mg SC admin

No routine bloodwork neeed

What tx for MS?

Glatiramer (Copaxone | Teva) 

37

Injection site reactions (MC)

Transient flushing/anxiety/chest pains

S/E of which drug for MS?

Glatiramer (Copaxone)

38

First oral agent approved for MS

Sphingosine 1-phosphate receptor modulator on T-cells

Results in down-regulation of receptors and T-cell sequestration in lymphoid tissue

Generally well tolerated

What drug tx for MS?

Fingolimod (Gilenya | Novartis) 

39

Elevated LFT's

bradycardia (transient)

macular edema

skin cancers

varicella infections

S/E of which drug for MS?

Fignolimod

40

Underlying cardiac conditions including those on rate-controlling medications

Diabetics 

Exclusion criteria for which drug tx of MS?

Fingolimod 

41

2nd oral med for MS

Inhibits a mitochondrial enzyme involved in DNA replication

Reduces T- and B-cell proliferation and response to autoantigens

Well tolerated 

Which drug tx for MS?

Teriflunomide (Aubagio | Genzyme)

42

Diarrhea

Abnormal LFTs

Nausea 

hair loss

birth defects (PG X)

increased infections

peripheral neuropathy

renal failure

hyperkalemia

HTN

S/E of which drug for MS?
 

Teriflunomide (Aubagio | Genzyme

43

How long can Teriflunomide (Aubagio | Genzyme) remain in your system?

Up to 2 years! 

44

3rd oral MS medication

Once used as a psoriasis medication

Formerly called BG-12

Exact mechanism of action is not known

Thought to inhibit immune cells and molecules, and may have anti-oxidant properties that could be protective against damage to the brain and spinal cord

Generally well tolerated

Dimethyl Fumarate (Tecfidera | Biogen IDEC)

45

First line treatment for MS?

Glatiramer with or without Interferon B 

46

Autoimmune disease -- Uncommon

10-20: 1,000,000 new cases in US

MC disease of neuromuscular transmission 

 

Myasthemia Gravis 

47

Ab against nicotinic AchR at NMJ (Ab vs nAchR @ NMJ)

nSome Ab impair ability of Ach to bind to AchR, other Ab destroy AchR

Also, Ab against MuSK (Muscle-specific receptor tyrosine kinase)

MuSK proteins mediate clustering of AchR during NMJ formation and associated with AchR maintenance—research ongoing to explain pathogenetic role of MuSK

MG

48

Ocular: limited to lids, EOM

Generalized

Two primary manifestations of what disorder?

MG

49

About ___% of those wtih ocular progress to generazlied in 2 years

50%

50

Common in men and women (slight predisposition for women)

Occurs at all ages (women most likely in child bearing years, and later in life, 6-7th decade, in men)

Genetic predisposition (HLA DR3), also, commonly found in patients with other auto-immune disorders

May be transient in neonates—placental transmission of maternal Ab

 

MG

51

Up to __% of patients with MG have thymic abnormalities

75%!

52

MG: mind to ground (descending)

Facial sx: ptosis (unilateral/bilateral), diplopia, bulbar muscle weakness (chewing, swallowing, speech), expressionless face, neck muscles (head drop)

May progress DOWN to respiratory muscles, limb weakness that is focal or generalized and may fluctuate through the day (may be worse at night or after exercise)

Signs/Sx of MG 

53

Weakness may remit and relapse (can last for weeks)

Sx usually progress to become more frequent 

Fluctuations of sx helpful to distinguish from myopathy and motor neuron disease 

Signs/Sx of MG 

54

FATIGABILITY of muscles- normal sensation, normal reflexes

Frank ptosis on exam, slack jaw

Simpson test

Cogan lid twitch sign

MG crisis: respiratory failure

 

MG

55

Short acting AchE inhibitor

Administered incrementally

May produce increased salvation or abdominal cramping 

May produce symptomatic bradycardia or bronchospasm—need Atropine at bedside as well

May see response at lower dose before onset of S/E - may not see response at all 

Not really used much anymore

Test used to dx MG?

Tensilon test (edrophonium) 

56

Brainstem or motor cranial nerve pathology

Kearns-Sayre Syndrome

Generalized fatigue

Motor neuron disease (ALS)

Lambert-Eaton Myasthenic Syndrome (LEMS)

Botulism

GBS

OPMD

Diff Dx with what condition?

MG 

57

Neuromuscular transmission improved at cooler temperatures

Ice pack test not helpful for testing weak muscles that can’t be cooled (EOM)

Eyelid muscles easily cooled (ice pack for two minutes)

Ptosis may immediately improve after removal of ice pack

About 80% sensitive but may have many false positives 

Test to dx MG?

Ice pack test 

58

80-90% OF PTS WITH GENERALIZED MG HAVE CIRCULATING AB AGAINST NACHR

THREE TYPES: BINDING, BLOCKING, MODULATING—MOST GO WITH BINDING

HIGHLY SPECIFIC WITH VIRTUALLY NO FALSE-POSITIVES

3-7% HAVE CIRCULATING AB AGAINST MUSK (MUSCARINIC TYROSINE KINASE)

SEROPOSITIVE (ABOUT 50% OF THOSE WITH OCULAR MG, ABOUT 90% WITH GENERALIZED)

LEVELS OF CIRCULATING AB DO NOT CORRELATE WITH SEVERITY OF DISEASE

SERONEGATIVE—NO AB AGAINST ACHR OR MUSK, BUT SIMILAR RESPONSE TO TREATMENT (DISCUSSED BELOW), SIMILAR FINDINGS ON ELECTROPYSIOLOGIC TESTING

Blood test for diagnosis of what disorder?

MG

59

More commonly performed

Easier to do

Faily good sensitivity and specificity

Checking nerve condiction: speed and amplitude at certain muscle 

Distinct "U" shaped pattern

What test for MG?

Repetitive nerve stimulation studies 

60

More complex specialized procedure

Reserved for patients w/ suspected MG that have not been adequately dx'd through other tests

Needles directly on nerves

Last test used 

What test for MG?

Single fiber EMG 

61

Acetylcholinesterase inhibitors

Immunomodulation

Surgery (especially if thymoma)

IV-Ig

Plasmapheresis (plasma-exchange)

Tx options for what disorder?

MG 

62

Inhibits the enzymes that breakdown Ach=more Ach=more muscle stimulation

Pyridostigmine

Neostigmine

What drug tx for MG?

Anticholinesterase inhibitors 

63

Often leads to symptomatic relief and may lead to remission

Consider risk factors (age-usually recommended for younfer patients)

Can take up to 10 years to lead up to ultimate remission

What type of tx for MG?

Thymectomy 

64

Respiratory weakness may lead to respiratory failure

Can occur spontaneously during active phase of disease or be precipitated by surgery, infection, medications (memorize list) or tapering of immunosuppresion.

Worsening generalized weakness may precede MG Crisis, but variable time course

Must monitor VC, up to q2hrs, MIP (NIF)

Accessory muscle weakness may mask underlying respiratory distress

MG crisis 

65

Admit to ICU

Monitor FVC MIP (NIF)

Electively intubate if FVC <15mL/kg or serial decline approaching 15mL/kg or clinical signs of respiratory distress

Withdraw acetylcholinesterase inhibitors

Begin IVIg or plasmapheresis

Begin high dose immunomodulating therapy

Wean off mechanical ventilation as FVC improves 

Tx for what type of MG?

MG crisis

66

Useful for acute decline or MG crisis

2/3 of patients will improve with treatment about 7-10 days after starting

Monitor for side effects: volume overload, rash, fever and flu-like symptoms, headaches, chest and abdominal pain, anaphylaxis, renal failure, transaminitis, aseptic meningitis 

What type of tx for MG?

IVIg 

67

useful for acute decline or MG crisis

2/3 of patients will improve in 2-3 days

Equally efficacious as IVIg but more adverse effects

Reduces AChR titers by 50-70%

What type of tx for MG?

Plasma Exhange (PLEX)

68

Inherited disorders causing progressive muscle weakness and atrophy due to genetic defect 

Multiple types

Some forms can cause cardiac dysfunction and cognitive defects 

Muscular Dystrophies 

69

What is the common theme with the different types of MD?

Muscle weakness 

70

Nerve sends the signal to the muscle, but the muscle is unable to respond normally 

Myopathies 

71

Defectie gene on X chromosone responsible for producing dystrophin (a protein that protects muscles)

Dystrophin deficits --> enzymatic muscle breakdown

What type of MD?

Duchenne Musclar Dystrophy (DMD)

72

Disease occurs in males

Age of onset 2-3 y/o

May be wheelchair bound by 12

Survival into late teens/20s 

What type of MD?

DMD

73

Sx likely start centrally (trunk) and spread to legs first

Will likely see elevations in CK

May cause: cardiomyopathy, scoliosis, fractures (from falls), and some cognitive impairment

What type of MD?

DMD 

74

Corticosteroids can increase strength, will not change prognosis

Tx for what types of MD?

DMD

Beckers MD 

75

Patients affected make some dystrophin 

Defectie gene on X chromosome responsoible for producing dystrophin --> enzymatic muscle breakdown

What type of MD?

Becker Muscular Dystrophy 

76

Disease occurs in males

Age of onset is later than DMD

Comorbid cardiomyopathies less common but can be more severe than DMD, survival into 40s

what type of MD?

Becker MD

77

Sx milder than that of DMD

Likely elevations in CK

Sx start centrally (trunk) and spread to legs first

What type of MD?

Becker MD 

78

Exam: weakness

Family history

CK, AST, ALT

Genetic testing

EMG

Muscle biopsy

Dx of what types of MD?

DMD and BMD 

79

Steroids

Ca++/Vit. D

ACEI

B-blockers

Pacer/Defib

Pulm support

Immunizations

Tx for what types of MD?

DMD and BMD 

80

Muscle weakness that usually begins in arms in teen years then progresses to legs and face 

Uncommon but distinctive 

Caused by a number of different inheritance patterns 

Occurs in males and females 

What type of MD?

Emery-Dreifuss MD 

81

Contractures of elbows, ankle platar flexors, and spine early

Later onset of humeroperoneal weakness

Cardiac abnormalities (arrhythmias, cardiomyopathies-can lead to malignant arrhythemias)

Classic Triad for what type of MD?

Emery-Dreifuss MD 

82

CK normal or slightly elevated

EMG

Genetic testing

Often still ambulatory after 20 years

Dx for what type of MD?

Emery-Dreifuss MD

83

What is the most common inheritance pattern in Emery-Dreifuss MD?

X linked 

84

What is the most common form of MD?

Myotonic dystrophy 

85

Affects males and females

Two genetic types:

Type 1: Classic adult onset, congenital, child onset, late onset oligosymptomatic

Type 2

What type of MD?

Myotonic Dystrophy 

86

Muscle stiffness, inability to relax muscles after contraction

Affects different body systems causing muscle loss in weakness - facial muscles, arms, legs 

Cardiac complications

Cataracts

Abnormal intellectual functioning

Excessive daytime somnolence 

Signs/Sx of what type of MD?

Myotonic dystrophy

87

Clinical findings

normal to slightly elevated CK

Variable EMG patterns

Genetic testing

Bx 

Dx for what type of MD?

Myotonic dystrophy 

88

Multiple subtypes (>20)

Characterized by:

Age of onset

Muscle weakness patterns

Cardiac involvement

Contractures

Bx features

Inheritance patterns

What type of MD?

Limb-Girdle MD 

89

Affects shoulder girdle and/or hip girdle

May see elevations in CK

Dx prgression slow and comorbid conditions (cardiac, cognitive) are rare

What type of MD?

Limb-girdle MD

90

Subtypes 1b, 1e, 2g, and 2m are more prone to what involvement?

Cardiac 

91

Treatment focused on stretching to prevent contractures

What type of MD?

Limb-girdle MD 

92

Affects males and females

May progress slowly

Extremely variable age of onset and severity of onset

Has 3 different forms: Autosomal dominant, Infant form, and Classical form

What type of MD?

Facioscapulohumeral MD (FMD)

93

Parent with disease has 50% chance of passing disease to offspring 

What type of FMD?

Autosomal dominant 

94

Sx early in life

profound facial weakness (inability to close eyes, etc)

Progresses to include shoulders, hip, etc

Most wheelchair bound by 9-10 y/o

May have seizures, cognitive deficits, hearing loss

What type of FMD?

Infant form 

95

Sx between 20-30 y/o

Slow progression with milder weakness of facial muscles (pouting appearance)

shoulders and arms usualy involved eventually

What type of FMD?

Classical form 

96

Try to push up, sit up, reversal of anterior axillary folds, scapular winging, decresed hearing

Slightly elevated CK

Myotonic EMG pattern

Genetic testing

Dx of what type of MD?

FMD 

97

Ptosis and dysphagia

Present in 4-5th decade

Most develop leg weakness eventually

Tongue atrophy and facial muscle weakness 

Dx based on clinical findings and exclusion of other causes

Normal to slightly elevated CK

Genetic testing

What type of MD?

Oculopharyngeal MD 

98

Sx apparent at birth

"floppy baby"

No treatments available

What type of MD?

Congential MD