Module 6 Neuroanatomy

Multiple sclerosis (MS)

- demyelinating disorder that affects CNS myelin

- rate of degeneration of myelin varies greatly, along with the first symptoms that are reported

- different types of MS, such as relapsing/remitting, secondary progressive, primary progressive, and progressive relapsing

- can affect motor, sensory, and autonomic white matter

- impulse of action potential can't pass = conduction block

What are some chief complaints experienced in the first attack in MS?

- any system can be affected, and this varies between each person. no case of MS looks the same

- limb weakness, sensory symptoms, optic neuritis, brain stem symptoms and signs

What are the motor related neurological manifestations associated with MS?

fatigue, paresis, paralysis, gait disturbances, spasticity, tremors, slurred speech

What are the sensory related neurological manifestations associated with MS?

pain, numbness, tingling

What are the autonomic related neurological manifestations associated with MS?

bladder and bowel dysfunction, sexual dysfunction

What are the major motor impairments in the visual system commonly associated with MS?

internuclear ophthamoplegia - eyes turned to left, right eye lags; eyes turned to right, left eye lags to a lesser degree; convergence is unimpaired

What are the major sensory impairments in the visual system commonly associated with MS?

sudden unilateral blindness that is self-limited, realization that the other eye is partially or totally blind, visual fields have center scotoma due to acute retrobulbar neuritis

What are the major brainstem and/or cerebellar manifestations commonly associated with MS?

- wide-based gait (patient teeters back and forth and sideways)

- exaggerated, repetitive knee jerk (hyper-reflexia)

- finger-to-nose test (patient cannot direct finger accurately with eye closed)

- intention tremor (hand is unsteady with attempting to hold glass, write)

What are the major spinal cord manifestations commonly associated with MS?

- spastic gait

- Lhermitte's sign

- neurogenic bladder with urinary urgency and dribbling

- loss of position sense

- paraplegia, partial or complete

What are the four different patterns of progression and rates of attacks in MS?

- relapsing/remitting: unpredictable attacks which may or may not leave permanent deficits followed by periods of remission

- secondary progressive: initial relapsing-remitting MS that begins to have decline without periods of remission

- primary progressive: steady increase in disability without attacks

- progressive relapsing: steady decline since onset with super-imposed attacks

What is the pathophysiology of an acute attack in MS?

a focal area of inflammation develops, causing a disruption of the BBB and edema. there will be lytic dissolution of myelin sheath. after this, macrophages with come in and perform phagocytosis of myelin debris. due to loss of myelin, loss of saltatory conduction of impulses. the axon is generally sparred. more difficult to re-myelinate, but if there is some re-myelination, this is better than nothing.

Describe the immunopathology theory of MS.

abnormal activation of the person's immune system in which t-lymphocytes somehow become sensitized to proteins (MBP) in the CNS myelin. once the t-lymphocyte makes its way inside of the BBB, they will communicate via cytokines to promote increased activity against tissue. there will be a direct attack on the CNS for the immune system to destroy myelin

What are integrins?

- alpha4-beta1

- on the outside of WBC

- help WBCs bind to other cells, specifically the wall of the blood vessel by grabbing onto VCAM1

What are VCAMs?

located on the inside (lumen) of blood vessels, and they bind to the integrin molecules that are on the outside of the WBCs

Is an oligodendrocyte capable of re-myelinating a demyelinated region of an axon in the CNS of someone with MS?

yes. there isn't much that occurs, but it is better than nothing

Is a lesioned axon located in the CNS capable of re-growing in a person with MS?

no, it isn't. remember, axon regeneration has been unsuccessful in the CNS compared to the PNS

What is the clinical utility of used MRI to diagnose MS?

can look at small lesions in the white matter, and can allow for detection of new lesions where there is breakdown of the BBB during acute inflammation

What is the clinical utility of employing evoked potential studies to diagnose MS?

- repetitive stimulation of a sensory pathway while measuring the speed and amplitude of the response as it arrives at the cortex

- patients will sit in front of a monitor that flashes on and off, which stimulates the visual system. arrival of the cortical evoked peak is measured through the occipital EEG leads and summed over time.

- with previous optic neuritis, there is prolonged latency of the cortical peak compared with normative data and uninvolved eye.

What is the clinical utility of using CSF analysis to diagnose MS?

elevated levels of immunogobulin G and the presence of oligoclonal bands on gel electrophoresis can be used to help indicate presence of an immune or infectious condition

What is the MOA of Tysabri (natulizumab)?

antibodies against alpha4-beta1 integrins on the outside of WBC; blocks lymphocyte adhesion and migration through the BBB

What is the MOA of corticosteroids?

speeds recovery from acute attacks; inhibit inflammation and suppress the immune system by stopping the production of inflammatory mediators of inflammation and also inhibiting cytokines

What is the MOA of interferon-B?

inhibits mediators of inflammation (suppresses the immune system)

What is the MOA of Copaxone?

blocks antigen-binding site on Th cells - acts as a decoy so that the immune cells see it in the blood stream and bind to it here rather than in the CNS

What is Guillain-Barre syndrome?

- acute demyelinating inflammatory prolyradiculoneuropathy

- arises from an autoimmune response against PNS myeling and/or PNS axons several weeks following a viral illness or vaccine

What are the major motor symptoms associated with Guillain-Barre?

- "ascending" symmetric weakness of the lower limbs

- loss of the deep tendon reflexes

- progressive onset of paralysis

What are the major sensory symptoms associated with Guillain-Barre?

- tingling

- numbness becoming very painful

- diminished sensation.

What are the major autonomic symptoms associated with Guillain-Barre?

- cardiovascular instability with cardiac dysrhythmias and severe hyper- or hypotension

- bladder and bowel dysfunction

Can a lesioned axon in the PNS re-grow in a person after an episode of Guillain-Barre?

yes --> successful in the PNS!

What is Charcot-Marie-Tooth disease?

- CMT1A and B due to mutations in PMP22 and P0

- affects peripheral Schwann cell myelin proteins

- symmetric weakness and wasting of the foot and calf muscle

-may complain of difficulty running or of abnormal appearing feet rather than weakness

- slow progression

What are the two types of genetic mutations associated with Charcot-Marie-Tooth disease?

- CMT1A = duplication of the PMP22 gene, which plays a part in compaction of peripheral myelin

- CMT1B = point mutation of P0 gene, which also plays a part in compaction of peripheral myelin

Describe the progression of CMT1A.

- initially develop normal peripheral nerves and myelin

- an increased myelin sheath thickness is noted as the disease progresses slowly

- more advanced stages of the disease reveal loss of myelin proteins, demyelination, axonal atrophy, and axonal loss coinciding with a worsening of clinical symptoms

- schwann cell proliferation to demonstrate the onion bulb growths (schwann cells are accumulated around an axon)

Describe the clinical utility of a nerve conduction velocity test focusing on how changes in speed and amplitude reflect extent of demyelination and loss of axons.

speed = reflection of myelination. a longer latency period (period between stimulation and response) will show that there is slower speed of an axon

amplitude = reflection of the number of units that are activated synchronously. decreased shows a decreased number of axons involved

What are the major clinical manifestations of Charcot-Marie-Tooth disease?

- distal muscular atrophy and weakness

- minor sensory symptoms

- usually starts in late childhood (about 9-12)

- progresses very slowly

- thin myelin sheets but also onion bulb presentations due to an increase in the number of Schwann cells

What is x-linked adrenoleukodystrophy?

- adrenal insufficiency and the destruction of CNS myelin

- affects boys

- slowly progressing phase that is followed by rapid progression and the later onset form, AMN, affects mostly the spinal cord and progresses more slowly

- due to an accumulation of very long chain fatty acids (VLCFA) that become toxic and causes demyelination

What are the clinical manifestations during the progression of adrenoleukodystrophy?

- loss of communication

- cortical blindness

- tube feeding

- total incontinence

- wheelchair dependence

- complete loss of voluntary movement

What are some promising treatments for adrenoleukodystrophy?

gene therapy - normal gene is introduced into bone marrow stem cells. these cells are isolated ad introduced to normal gene through viral vector, and then the transduced stem cell will be put back into the bone marrow where then it carries the normal gene