NEUROMUSCULAR JUNCTION AND INFECTIOUS DISORDERS

Dayna Ryan, PT, DPT

Winter 2012

NEUROMUSCULAR JUNCTION DISEASES

• Botulism• Myasthenia Gravis• Lambert-Eaton Syndrome

Latin: “botulus,” meaning sausage

• Etiology- Neurotoxin produced by Clostridium Botulinum- Anaerobic, Gram-positive rods- Found in improperly preserved or canned foods

& contaminated wounds

• Classification (mode of acquisition)- Food-borne (ingested)- Wound- Unclassified

BOTULISM

• Lesion- Pre-synatic terminals

• Mechanism1.Botulinum toxin enters presynaptic terminals2.Blocks the fusion of ACh vesicles with

presynaptic membrane 3.Inhibit ACh release into neuromuscular junction4.Nerve impulse fails to transmit across the

neuromuscular junction5.Muscle paralysis

• Progression- Typically get full recovery in both adult & infant

MECHANISM OF ACTION OF BOTULINUM TOXIN

INCIDENCE

10 adult & 100 infant cases in US each year

Infant botulismAge 3 wk - 9 month

Signs and symptomsDevelop within 12-36 hours following ingestion of contaminated

food

Mortality rate from 1990 – 1996 in US Type A (6.7%), type E (6.5%), type B (0%)

Gradual recovery over weeks - 12 months

SIGNS & SYMPTOMS Develops within 12-36 hours following

ingestion of contaminated foodFlaccid symmetrical paralysisBlurred & double vision, photophobiaDry mouth, nausea, & vomitingDifficulty in swallowing & speechRespiratory failure can occur in 6-8

hours

TREATMENT

ABE serum antitoxin (antibodies of type A, B, E toxin)

Debridement & antibiotics for wound Removal of toxin from GI (gastric

lavage)Supportive measures, e.g. IV,

mechanical vent

MYASTHENIA GRAVIS

• Fluctuating weakness & fatigability

• Autoimmune disorder– Abnormal Thymus function in 75% of

cases

• Classifications of MG– Ocular myasthenia (~10-15%) – Generalized weakness (~85%)– Myasthenic crisis: respiratory failure

MECHANISM OF MG

ACh receptors # reduced; Decreased efficiency of neuromuscular transmission

Nerve impulse fails to pass across the neuromuscular junction to cause muscle contraction

Antibodies block & damage ACh receptors

MYASTHENIA GRAVIS Prevalence: 14/100,000 Ratio of women-to-men= 3:2

Factors that exacerbate MG: hyper- or hypothyroidism, menstrual cycle

Disease Progression:Slowly, progressive weakness (maximal

weakness occurs in first year in 2/3 of all cases)

After 15-20 years, weakness becomes fixed Remissions occur in about 25% of

cases

SIGNS & SYMPTOMS

Generalized weakness: proximal muscles more affected

Fatigability of skeletal musclesprogressive muscular weakness on exertion, followed by recovery of strength after rest

Respiratory impairments

SIGNS & SYMPTOMS

Muscle weakness varies day to day and over long periods of time

Cranial muscles are the first to show weakness

Patients compensate for weak muscles (e.g. use of thumb to close jaw)

Eyelids fatigue with sustained upward gaze

DIAGNOSISTest anti-Ach receptor antibodies

if +, then MG

Tensilon test Repetitive movements or holding a position Compare performance following giving Tensilon

(anticholinesterase) vs. Placebo (saline) If strength/endurance is improved, then MG

EMG Reduced amplitudes over repetitive stimulation

TreatmentAnticholinesterase drugsThymectomy ImmunosuppressantsPlasmaphoresis

Blood is routed to a machine that separates the plasma & cells

Plasma, which contains antibodies, dissolved proteins, glucose, clotting factors, etc., is discarded while cells are returned to the body

Temporarily (4-6 weeks) reducing anti-ACh receptors antibodies

Used to get a patient more stable for surgery or to get them out of crisis

Intravenous immunoglobulin (IVIG)

LAMBERT-EATON SYNDROME

Rare but still the most frequent presynaptic neuromuscular transmission disorders in adults

Etiology~50% of cases associated with cancer,

especially small cell carcinoma of the lungOthers primarily from autoimmune disorders

e.g. RA, thyroid disease, MS

Mechanism

1. Antibodies destroy voltage-gated Ca++ channel

2. Block of Ca++ into presynaptic terminal

3. Reduced release of presynaptic ACh vesicles

4. Reduced probability of reaching depolarization threshold of a muscle fiber

SIGNS & SYMPTOMS– Muscle weakness and fatigue

• At proximal limbs & torso (LE > UE)

• Difficulties climbing stairs, lifting objects

– Early symptoms: aching of thighs and difficulty walking

– Decreased or absent DTRs– Cranial nerves usually spared

Lambert-Eaton Syndrome

DIAGNOSIS– EMG

• Will see a low amplitude response to a single stimulation

– Voltage-gated calcium channel antibody

• If +, then LEMS– MRI or CT scan for

lung cancer

INFECTIOUS DISORDERS OF THE NS

• Meningitis • Encephalitis • Lyme Disease • West Nile Virus

MENINGITIS

= meninges of the brain and SC become inflamed

All 3 layers can be involved, but usually pia and arachnoid

Etiology: bacterial or viral infection Viral (Aseptic) – most common Tuberculous – enter by inhalation Bacterial – EMERGENCY!!

Incidence: 2-6/1,000,000 adults

MENINGITIS

• SIGNS & SYMPTOMS Fever & chills Severe headache Stiff & painful neck!

(cardinal sign) Mental status changes Sensitivity to light

(photophobia) Confusion Vomiting

Pain in lumbar area and posterior thigh Positive Kernig sign

SIGNS & SYMPTOMS - PROGRESSION Positive Brudzinski

sign as it progresses when neck is flexed,

patient flexes leg to decreased stretch on meninges

Seizures or coma if untreated

Focal neurologic signs, e.g. CN palsies or deafness

Edema, which causes increased ICP and can lead to lethargy and confusion

BACTERIAL MENINGITIS IN A BABY Fever Poor feeding Vomiting Bulging Fontanels

Soft spots Seizures High-pitched cry

• DIAGNOSIS Lumbar puncture: CSF analysis & culture Blood culture CT, MRI: brain abscess or infarction

Bacterial type Isolation for 3 days Bed rest Antibiotics ASAP Meds for seizure Corticosteroids for cerebral edema

or vasculitis Viral type

Meds to control headache and nausea

• Treatment

ENCEPHALITIS Lesion Site: gray matter of the CNS Etiology: viral or bacterial infection

Most often from viral infection In US, Herpes simplex encephalitis most

common; 1/250,000 – 1/500,000

ENCEPHALITIS Most cases: only mild symptoms or

asymptomatic

Serious cases cause: Fever & chills Headache Nausea & vomiting Mental status changes; irritability Lethargy, fatigue Seizures Stiff neck (if meninges are involved) Bulging fontanels (soft spot in skull) in infants Focal neurological signs, e.g. ataxia,

hemiparesis, aphasia

ENCEPHALITIS Prognosis depends on type

Mortality rate varies from <1% to 50-70% Permanent neural damage is more likely in

infants

Diagnose with spinal tap, EEG, CT scan, or MRI

LYME DISEASELyme disease was first reported in the

US in the town of Old Lyme, Connecticut, in 1975.

Most cases (90%) in mid-Atlantic, northeast, & north central regions.

• Lesion Sites:– CNS and PNS

• Incidence on the rise– 23,763 cases in 2002

EtiologyBitten by an

infected tick carrying the bacterium Borrelia burgdorferi

Risk FactorsHaving a petOutdoor activities Walking in high

grasses

Signs & Symptoms – Early StageThe initial sign is rash

Bull's-eye appearances (i.e. erythema migrans) at the site of tick bite

Present in ~80% of patientsGradually expands to ~ 12” across

Flu-like symptoms: chills, fever, headache, lethargy, muscle pain

Chronic RA is the most commonly recognized symptom

Some neurologic and psychiatric symptoms

LYME DISEASE

PROGRESSION OF LYME DISEASE

Stage 1Flu-like symptoms and rash (7-14 days after

tick bite) Stage 2

Generalized fatigue, loss of appetite, vomiting

Neurologic or cardiac abnormalities develop weeks to months later

Stage 3 (weeks to year later)RA develops in >50% of people who did not

receive earlier treatment Affects knees mostly Often unilateral presentation of joint involved

SIGNS & SYMPTOMS – LATER STAGES

Swollen knee from chronic rheumatoid arthritis is most commonly recognized symptom

TREATMENT OF LYME DISEASE

Oral antibiotics Removal of tick Joint surgeries

**15% of those who received early treatments still get complications involving heart, joints, and nervous system

MOST people have complete recovery within weeks or months of antibiotic treatment

PREVENTION IS KEY

Wear long pants Walk on cleared paths Wear high socks and appropriate shoes Wear light-colored clothing to make ticks

easier to see

WEST NILE VIRUSIt was first discovered in the United States in the summer of 1999 in New York. Since then, the virus has spread throughout the United States

• Lesion: CNS, PNS, Multi-systems

(depends on where bitten)

WEST NILE VIRUS

2009 West Nile Virus Activity in US(Reported to CDC as of December 2009)

WEST NILE VIRUS Etiology:

Single-stranded RNA virus from mosquitos primarily

Flavivirus No treatment available – only supportive care Risk factors: age, hypertension, diabetes,

CAD, immunosuppression

SIGNS & SYMPTOMS ~80% of individuals are asymptomatic

~20% of individuals affected by the virus develop systemic symptoms< 1% develop neurological manifestations

Those that do develop nervous system involvement usually evolve a severe illnessMortality rates 12%-14%

PRESENTING SIGNS AND SYMPTOMS Fever Headache Muscle Ache Joint Pain Fatigue Rash (with

swollen lymph nodes)

Nausea/vomiting Periocular pain

Muscle weakness Altered mental

status Backache Photophobia GI/Respiratory

Symptoms

NEUROLOGIC SIGNS & SYMPTOMS Encephalitis Meningitis Meningoencephalitis Anterior myelitis

Acute flaccid paralysis Proximal muscles

affected more than distal

From damage to anterior horn cells

Painless, asymmetric weakness

No sensory abnormalities

SERIOUS SIGNS & SYMPTOMS

High fever Severe headache Stiff neck Disorientation Coma Tremors Convulsions Muscle weakness Ataxia and

extrapyramidal signs

CN abnormalities Optic neuritis/vision

loss Polyradiculitis Seizures Myelitis Photophobia Numbness Paralysis