Anterior Horn Cell Dz

 and Dz of the actual Motor Neuron

In these conditions, the muscle fibers are not directly affected however both the motor axons and the fibers they innervate are secondarily affected.

True

Dz of peripheral nerves (peripheral neuropathies) can affect various types of fibers/axons (incl pain, proprioceptive and autonomic fibers) producing sensory symptoms.

Note that it is possible to have a peripheral neuropathy (typically focal) which affects only motor neurons and this would not have sensory symptoms.

Weakness!

Myopathies= Proximal weakness and atrophy+Gower's sign, difficulty rising from the floor.

Polyneuropathies=Distal weakness and atrophy, often with ↓ sensation (unless only motor neurons are involved) and arefexia.

FALSE

Polyneuropathy pts do have distal weakness/atrophy but are often Areflexic having severely ↓ or abscent muscle reflexes in affected areas.

A pt presents with what appears to be a polyneuropathy of the distal L lower extremity but has no deficits and has noticed no changes in pain sensation.

How is this possible?

It is possible that a polyneuropathy manifests with only effects on motor neurons.

In this case there are no sensory deficits.

Still have distal weakness/wasting and depressed reflexes.

Occurs often with focal/mononeuropathies

(ex: damage to the peroneal nerve can make a pt unable to dorsiflex the toes of that foot OR a focal neuropathy of the long thoracic nerve causes weakness of serratus anterior and unilateral winged scapula).

Myasthenia gravis

A dz of the NMJ (disorder of neuromuscular transmission)

FALSE

Neuropathies are typically asymmetrical with distal muscle weakness/wasting and possible sensory loss.

Myopathies are typically symmetrical whith proximal atrophy/wasting and no sensory loss.

Motor Neuron Dz (ant horn cell or motor neuron itself) can begin (are) asymmetrical but have no sensory loss*

Motor Neuron Dz

(Ant horn cell or motor neuron)

Fasciculations are not seen in polyneuropathies, dz of the NMJ or myopathies.

Remember that fasciculations are not aways pathologic.

The Myopathies

Damaged muscle fibers become leaky and release CK into the blood stream.

Motor Neuron Dz and Polyneuropathies

Reflexes can decrease in the late stages of some myopathies and are decreased in presynatpic dz of the NMJ (Lambert-Eaton myasthenic syndrome and botulism)

Type II

This gross anatomical appearence is due to the poor capillary supply.

In 'Dark' or type I fibers, there is an abundance of capillary supply whcih gives this meat its dark appearnece (among other compositional differences).

Type I fibers stain pale (despite being darker on gross exam)

Type II fibers stain dark (despite being grossly lighter)

Checkerboard distribution of normal muscle fibers.

Type I

(Red meat, slow twich)

Have high oxidative enzyme and lipid content as well as a rich capillary supply.

Low threshold to activation.

Low glycolytic acitivty and low myofibrillar ATPase content (hence light staining on alkaline ATPase stain)

Type II (white meat, fast twich)

Low oxidative enzyme and lipid content, poor capillary supply.

High myofibrillary ATPase content (stain dark),

High threshold to activation,

High glycolytic acitivty

FALSE

Histological charactaristics are determined by the type of motor neuron innervating it/by the motor neuron firing pattern and can be altered (as in reinnervation).

As such, all motor fibers innervated by a given motor neuron are of the same type.

Motor Unit Action Potential

The resut of depolarization of a motor neuron which causes all muscle fibers of the motor unit to depolarize.

Their action potentials summate and this generates the MUAP.

MUAPs are recorded during EMG.

Each spike represents the depolarization of a single motor unit.

At rest there are no spikes, with minimal exertion there are a few and at max exertion all motor units are recruited and there are many spikes, each representing a MUAP.

Note that a few phases are norma in a given MUAP owning to the fact that contraction of all muscle fibers within a given motor unit are not exactly synchronized, however, significant polyphasia is pathological.

Denervation (caused by injury, neropathy or motor neuron damage) produces atrophic muscle fibers.

Stain: nonspecific esterase

Atrophic fibers appear dark and angulated (like flattened beachballs).

Stain: ACh receptor stain

Shows that there has been dispursal of the ACh receptors (as opposed to the normal condition where they are concentrated at the NMJ).

This results in fibers that do not depolarize when a nerve impulse arives at the NMJ however amy spontaneously depolarize (are sensitive to ACh) producing fibrillations.

Spontaneous depolarizations that occur in cases of peripheral nerve injury/motor neuron dz in which there are atrophic muscle fibers.

Show up on EMG as biphasic potentials.

Sharp waves may also be present.

Not the same as Fasciculations*

Spontaneous depolarizations of an entire motor unit!

Do not always indicate denervation/damage

Not a fibrillation (which is a spontaneous depolarization of individual muscle fibers, indicate denervation).

When there has been damage to a motor axon.

Typically in peripheral neuropathy or motor neuron dz.

Axons sprout from nearby intact axons to take over and reinnervate previosuly denervated fibers.

Abolishes the checkerboard pattern of fibers and produces clumps of like-type fibers.

FALSE

Fiber type grouping as a result of reinnervation produces large motor units (more muscle fibers per motor neuron) but fewer total motor units (because you lost a motor neuron) which means fewer APs.

*Peripheral nerve injuery with dnervationa nd reinnervation → fewer but larger motor unit APs on EMG*

(Fewer spikes[MUs] but each spike is taller [more fibers summating to generate the spike])

Motor neuron or axonal injury

Denervation (atrphic, angular m. fibers)

Reinnervation by healthy motor neurons generates large motor units that produce large but asynchronous (polyphasic) APs.

What are some of the findings in a neuropathy/motor neuron disorder pt at rest.

Fibrillations, positive sharp waves and possibly fascicullations.

During activities there are large polyphasic MUAPs but the number of motor unit potentials is reduced (less spikes but individual spikes are taller and polyphasic).

FALSE

Myopathic fibers have different histological charactaristics than do denervated fibers and do not have one histological appearance but rather several, dependign on the cause of the myopathy.

They can become nectotic due to autoimmune processes (which can be seen with a trichrome stain).

Inflammation, glycogen storage, and deficiencys in dystrophin may also be detected on biopsy.

TRUE

In myopathy (unlike in neuropathy and motor neuron dz) there is no reduction int he number of motor neurons (and therefore no dec in the number of motor units).

However, because individual motor units have fewer viable fibers, the MUAPs are smaller and often polyphasic (desynchronous depol of damaged fibers) prodiucing a weak contractiond espite a normal number of MUAPs.

Serum CK or CPK*

Myopathy causes necrosis/damage of muscle fiber cells causing them to become leaky and release their enzymes into the blood.

EMG may also be useful but is secondary to serum enzyme levels/blood test.

Normal MUAP: baseline size/height of AP and a normal, intermediate number of motor units recruited with minimal and moderate effort. All motor units recruited with maximal effort. All amplitudes are the same, despite effort level.

Neurogenic MUAP: Increasd amplitude but fewer spikes (fewer motor units), fewer in number with increased effort (you've lost some, not as many to recruit).

Myogenic MUAP: THe number of motor units recruited is baseline but the amplitude of each is reduced (loss of muscle fibers of each individual motor unit.

Motor units are smaller but not reduced in number.

Polyneuropaties show decreased nerve conduction velocity.

Particularily slowed if it is a demyelinating neuropathy.

Anterior horn cell dz can show some mild reduction in nerve conduction but not a major finding.

Subtract the distal and proximal latencies.

Nerve conduction velocity is calculatied by dividing the distance between the electrodes (cm) by the difference in latnency (ms) [?] and converted to m/s for reporting.

Miniature End Plate Potential

Spontaneous releases of Ach from presynaptic vesicles (Voltage and Ca2+-mediated process) and binding of Ach to their receptors on the mucle endplates opening its ion channel and triggering end plate depolarization.

In a MEPP the depolarization does not reach threshold and there is no opening of Na+ channels/depolarization that follows (MEPPs don't trigger AP in the muscle).

Compound Muscle Action Potentials

Normally, CMAPs do not change in amplitude during stimulation (there are just more of them at high exertion).

However, if there is a disorder of the NMJ (as in myasthenia) the amplitude of the CMAPs becomes smaller during slow, repetitive  stimulation.

In Presynaptic neuromusuclar transmission disorders the amplitude becomes larger during fast stimulation (more Ach liberated and no problems with the endplate).

An AP must occur within the presynaptic neuron which reaches the nerve terminal.

V-gated Ca2+ channels must be activated to trigger the process of ACh release into the NMJ.

When ACh binds to its receptors on the postsynaptic neurons it triggers the opening of Nicotinic, ligand-gated ion channels → let Na+ out and K+ in→ End Plate Potential, EPP (depol of post-synaptic neuron) →if EPP is of sufficent magnitude it triggers the opening of V-gated Na+ channels→ AP → muscle contraction.

Compound Muscle Action Potential

Normally: does not change in amplitude despite varied stimuli.

In Postsynatpic disorders of the NMJ: (MG) the amplitude of CMAPs becomes smaller during slow, repetitive stimulation.

In Presynaptic disorders of the NMJ: (EL syndrome) CMAP becomes larger during fast stimulation.

Unique Signs/Symptoms: Fluctuating muscle weakness made worse on exertion.

Ptosis which worses on sustained upward gaze.

Diplopia.

Reflexes (depressed?)

Other Signs/Symptoms: proximal limb weakness,

difficulty swallowing or breathing.

=Neostigmine

A reversible anti-acetylcholinesterase (AChase Inhbitor)

used to tx myasthenia gravis.

Improves muscle strength by increasing the amount of ACh in the NMJ to compete at ACh receptors.

ALS: Progressive, does not fluctuate and does not affect the eye muscles.

Brain Tumors: may affect EOM but have other stroke-like symptoms (affect level of consciousness and the corticospinal tracts).

Poliomyelitis: Fever! Does not fluctuate and does not affect the eye muscles.

Hyperthyroidism: Exopthalmos. This one is a little different as many pt have both MG and hyperthyroid.

Diptheria: Fever! Paralasis

GBS/Miller-Fischer: Paralysis is acute and non-fluctuating, Negative Tensilon Test, areflexia.

Polymyositis: Inflammatory and does not affect the eye.

Botulism: Acute paralysis, areflexia, and dilation of pupils (no pupillary involvement in MG).

Muscular dystrophy: herediatry component, progressive and non-fluctuating.

Used to dx MG and to diffirentiate a worsened case of MG (not enough ACh) from cholinergic crisis (overstimulation at the NMJ by ACh)

Give a pt suspected of having MG a dose of Endorphonium (a short-acting AChase Inhibitor).

Shows rapid improvement of MG-induced ptosis and no change or worsening of cholinergic crisis.

Baseline: diminish slightly in magnitude at baseline but are always over threshold to initiate an AP.

After tetanic contraction: are all large because ACh molecules have been mobilized.

2 min post-contraction: Become smaller than baseline even but still over the threshold.

Baseline EPPs: are reduced from normal individuals but typically still generate an AP.

Post tetanic contraction: EPPs still increase in magnitude but do not remain high like they do in normal individuals.

2 mins post-stimuation: Afer contraciton or exercise EPPs are so small they often don't generate an AP/contraction.

Normally the magnitude of CMAPs do not change in amplitude or shape in slow or in fast stimulation.

In MG (post synaptic) CMAP amplitudes get smaller at both slow and fast stimulations.

In Myasthenic syndrome/EL syndrome (post-synaptic) Potentials are small with slow stimulation and large imcrement in amplitude during fast stimulation (?)

Single Fiber Electromyography

Microelectrode is placed between 2 fibers of the same motor unit and observe individual and composite fiber potentials.

Normally little variaiblity is recorded between fibers and potentials are always generated by stimulation.

In MG: there are increased 'jitters' or variations in fiber potentials and some fibers my not even generate potentials.

1) Thyroid issues (Hyper or hyp thyroidis, thyroiditis)

2) Thymic issues (hyperplasia, high incidence of thymomas)

3) Other Autoimmunes (RA, SLE, anemia, Scleroderma, Sjogrens, ulcerative colitis).

4) Cancers (Leukemia, Lymphoma, thymoma)

5) Multiple sclerosis

and more...

TRUE...sorta

Not fully contraindicated but often cause the patients to develop weakness (unknown cause).

Anti-arrhythmics (quinidine, procanamide, lidocaine)

NM blockers (Vercuronium, pancuronium)

Aminoglycoside and peptide ABx

Ampicillin

Erythromycin

Ciproflloacin

Beta Blockers

Thyroid Hormones

Diuretics (cause kypokalemia)

Penicillamide (causes development of more antibodes)

Pyridostigmine (and other anticholinesterase drugs for symptomatic relief from weakness).

Corticosterioids, Immunosuppressants and chemothereputic agents to decrease Ab production.

Thymectomy

Plasma exchange

Ig infusions

FALSE

MG and EL have different causes but similar manifestations.

Eaton Lambert Syndrome is often seen as a paraneoplastic syndrome of lung tumors and is caused by Abs that block the release of ACh by blocking the presynaptic V-gated Ca2+ channels which impairs the release of ACh.

Impairs both Nicotinic transmission in the NMJ and autonomic (muscarinic) transmission*

MG only affects Nicotinics*

EL has sympathetic manifestations.

Often present with difficulty climbing stairs, decreased slavation/dry mouth, pinpoint pupils that are poorly reactive and depressed reflexes.

Symptoms improve with exercise (unlike in MG)

No ptosis in EL and diplopia is rare.

Removal of the offending neoplasm.

Boost NM transmission with AChase inhibitors and 3,4 diamniopyridine which prolongs depolarization and improves signal transmission.

Immunosuppresive drugs (high dose corticosteriods and Azathioprine) + plasmapheresis are also used.

Hereditary (AD)

Caused by mutations that prolong the attachment of ACh to its receptor prolonging the opening of its ion channel (excessive Na+ entering prolongs depolarization).

Seen as a second or more AP after the main compound AP with a decrease in muslce APs on repeated stimulation.

MEEP in these pt have slow decay because the channels do not close.

Excess ions destroy the end plate.

Pt present with limitation of lateral gaze and ptosis with weakness of the finger extensor muscles. Muscle fatigue fluctuates like MG but these pt have no response to Endorphonium challenge.

No benefit form AChase inhbitors.

Tx with Quinidine (which makes MG worse as an antiarrhythmic) and Prozac.

They are both Anterior Horn Cell Diseases, a group of conditions which primarily affect motor neurons in the spinal cord.

Note that ALS is also lumped with this category although it also has upper motor neuron affects.

Anterior Horn Cell Dz Charactaristics:

Cause weakness and muscle atrophy, often with signs of denervation on EMG/biopsy.

Usually accompanied by fasciculations and depressed reflexes*

No sensory deficits (remember is a group of dz of the motor neurons in the spinal cord).

Most are uncurable.

Can be hereditary or sporatic.

Secondary effects on the motor neurons/motor axons/muscle fibers.

aka Infantile spinal muscular atrophy

An anterior horn cell disease.

AR (defect in the "Survival Motor Neuron Gene" on 5q

Fatal (early from respirtory failure)

Arguably the most severe motor neuron dz.

Manifests at birth

Charactarized by hypotonicity (Floppy Baby, frog-leg posture), hyporeflexia, tounge fasciculations, a poor suck reflex (general areflexia), muscular atrophy, and abdominal respirations/difficulty breathing.

Muscle biopsy shows fiber type grouping and atrophy.

EMG shows signs of denervation and fasiculations.

aka Juvenile Proximal Chronic Spinal Muscular Atrophy (there is an adult-onset version)

Anterior Horn Cell Dz

AR (mutation in Survival Motor Neuron Gene. SMN1 is abscent and SMN2 determines if the pt has a neonatal or juvenile form: juvenile form has more of SMN2 gene)

Slowly progressive.

Manifests in childhood

Charactarized by proximal weakness (pectoralis and thigh muscles), atrophy (causing hyperpronation of the arm) and fasiculations.

Can clinically resemble musuclar dystrophy or myopathy.

Unlike myopathies, EMG and byopsy show dnervation changes and serum CK is normal*

Adult couterpart to Wolfart-Kugelberg-Welander

Sporatic (note not AR like juvenile form)

Charactarized by proximal and distal wekaness, hypotonicity, and hyporeflexia.

Anterior Horn Cell Dz

Adult-onset, sporatic

Rapidly progressive with possibility of pt developing ALS later in the dz course.

Charactarized by weakness of the bulbar muscles (those innervated by the medulla) resulting in weakness/atrophy of the tounge and palate with fasciculations.

Caused by degeneration of Upper and Lower motor neuron involvement + bulbar symptoms

(but often clumped w/ anterior horn cell dz).

Typically adult-onset and sporatic (10% familial)

Rapidly progressive and Fatal

Charactarized by weakness, Hyperreflexia (UMN invovlement), spasticity, atrophy/wasting (often of the tounge, Distal bf proximal wasting in the extremities*), and fasciculations.

Pt develop difficulty swallowing/breathing, distal weakness becomes generalized atrophy/weakness.

Bilateral Babinski

Upper motor neuron disease

Therefore shows little signs of atrophy or dnervation.

Charactarized by a relatively benign corse but invovling spasticity, hyperreflexia, and the possible development of a slowly-progressing form of ALS.

aka Anterior Horn Cell Dz

Weakness (symmetrical or asymmetrical)

Atrophy

Reflexes (typically diminished but hyper in ALS/when the corticopinal tract is invoved).

Fasciculations

Normal sensation and normal nerve conduction velocities (distinguishes from a neuropathy)

Denervation findings on EMG

Decreased number of motor units.

Biopsy shows atrophic fibers and fiber type grouping.

What are some dx that should also be considered in a pt presenting with the symptoms of ALS?

What about these other DDx makes ALS a better fit?

Multisystem Atrophy: has much slower progression.

Spinocerebellar Degeneration: pt also have ataxia

Craniocervical junction disorders: MRI confirms presence of an impinging tumor.

Cervical Spondylosis: MRI shows compresion of the spinal cord.

Polyglucosan Body Dz: biopsy shows polyglucoson inclusions.

Hexoamindase A Deficiency: pt also have ataxia and mental deterioration.

Hyperparathyrodism: elevated serum Ca2+ and PTH

Lead Intoxication: serum lead levels

Late-onset degenerative dz that can affect LMN, autonomic and cerebellar neurons.

It can therefore be considered in the ddx for ALS, however, it progresses much more slowly than ALS.

Hereditary degenerative disorder.

Can present with difficulty swallowing.

It can therefore be considered in the ddx for ALS, however, it involves ataxia which ALS does not.

Tumors in the Craniocervical junction often present with arm weakness and dysphagia.

It can therefore be considered in the ddx for ALS, however, an MRI can show tumor compression.

A cervical canal dz where degenerative disc dz can cause compression of the pyrmidal tracts producing arm and hand atrophy/weakness/spasticity.

May also present with LMN signs secondary to nerve root compression.

MRI here also rules out ALS.

Pt who have had polio commonly develop progressive LMN dz (exact cause unknown)

Hx is key in making this dx.

A glycogen storage disorder.

Presents in younger individuals with LMN weakness.

Biopsy of muscle/nerve shows polyglucosan inclusions charactaristic of this dz.

ex: Tay Sachs

Mild phenotypes of this dz present like ALS in younger individuals but typically have accompanying intellectual deterioration and ataxia.

Presents with progressive muscle weakness (like ALS)

Endocrine Myopathy

Elevated serum Calcium and PTH are diagnostic.

aka Bulbo-spinal muscular atrophy

A relatively benign disorder that often presents w/o FmHx

Caused by mutations in the androgen receptor gene ont he X chromosome.

Presents with gynecomastia, testicular atrophy, possible elevation of serum CPK and LMN syndrome (atropy, fasiculations, signs of denervation), mild neuropathy.

DNA testing=diagnostic

Lack of myelin staining in the corticospinal tracts and in the anterior horn representing los sof those neurons.

Bunina Bodies: eosinophilic inclusions of ubiquitin seen in the cytoplasm of anterior horn cell neurons in ALS pt.

Ubiquitin inclsions that are found in the cytoplasm of the cell bodies of anterior horn cells.

Charactaristic of ALS.

FALSE....mostly

90%+ of pt with ALS have no family history and no known genetic predisposition for the dz.

There have been genes isolated that may contribute.

The SOD gene is mutated in AD familial ALS

Some mutations in juvinile forms have associations.

It's been suggested that glutimate-mediated excitotoxicity may be the cause of htis neurodegeneration.

Disease Treatment:

Glutamate Antagonists (Riluzole and Gabapentin) are currently the standard.

Several experimental agents have been tried including antioxiants, minocycline, and creatine.

Symptomatic Tx:

Anticholonergics for excesive slavation (sialorrhea), stool softeners, antispastic drugs (botox, botulinum) anti depressants, GI tube, respiratory assistance.

Physical therapy and bracing (for foot drop) can help preserve some quality of life.

Wekaness in myopathies is (distal/proximal) and is typically (asymmetrical/symmetrical).

Small/brief motor unit potentials on EMG

(same # of spikes b/c the # of motor units is the same but there are fewer functional muscle fibers per unit)

Normal or ↑ recruitment on maximal effort (more units required to do the same job since each is weaker)

Often Polyphasic

1) Congenital myopathies (Central Core, Myotubular, Nemaline, Congenital MD)

2) Muscular Dystrophies (Duchenne's, Becker, limb girdle, fascioscapulohumeral, oculopharyngeal)

3) Myotonic Dystrophies

What is a NADH-TR stain and what is it used to diagnose?

A stain used in muscle biopsy to dx Central Core Dz

A congenital myopathy that presents at birth, is hereditary and whose initial symptom is 'Floppy Baby'

Central core refers to the NADH-TR staining pattern where there are central pale areas within the muscle fibers that fail to stain.

This pattern is charactaristic of/diagnostic for Central Core Dz.

Congenital Myopathy

Pt have small muscle fibers with centrally located nuclei.

these fibers resemble myotubules (fetal muscle fibers).

Floppy at birth, later develop scoliosis and ptosis.

Congenital Myopathy

Floppy baby at birth.

Trichrome stain on muscle biopsy shows red incusions within the cells which contain Z line material and are diagnostic for this congenital myopathy.

False

Congenital muscular dystrophies, though more rare, present at birth.

The majority of muscular dystrophies present in childhood though some more mild forms don't present until early adulthood.

They are geneatically-determined (X, AD, or AR)

Typically progressive, degenerative diseases of muscles.

Produce weakness and atrophy.

A myopathic disorder caused by the lack of production of the dystrophin protein responsible for membrane integrity.

X-linked (male boys, 1/3500)

Presents in Childhood

Lethal

Presentation: Winged scapulae, lordosis, large (but weak) calf muscles.

Progresive weakness, psudohypertorphy, cardiac problems and possible lowered IQ.

Muscle biopsy shows necrosis, atrophy, fiber over-contraction and CT proliferation.

Serum CK is elevated (necrosis)

Muscle fiber necrosis/atrophy

H&E stain shows prominant CT between fibers, necrotic fivers undergoing phagocytosis and prominant nuclei in fibers attempting to regenerate.

Immunoperoxidase Stain (for dystrophin) is abmormal with no dystrophin present in the atrophic fibers.

Dystropahties are are group of disorders in which there is abnormal production or failure of production of dystrophin (and other proteins) causing unstable muscle membranes.

There are classical dystropathies=Becker and Duchenne's.

There are also symptoms of these myopathies which are charactaristic of other genetic disorders (Turner and Klinfelter's).

Female carriers can also manifest symptoms of Duchenne's (weakness).

Dystrophinopathies charactaristically show weakness, elevated CK, cardiomyopathy and muscle cramps.

A mild/moderate muscular dystrophy-type myopathy.

Caused by defects in (but not total loss of) the dystrophin protein.

Age of onset, phenotype and prognosis are variable depending on the severity of the dystrophin mutation.

Typically presents later than Duchennes with lordosis quadriceps myopathy, calf hypertorphy, cardiomyopathy.

Elevated CK.

Muscle biopsy with Immuno stain for Dystrophin shows reduced levels but it is still present in the muscle fibers.

Antisense oligonucleoties (Morpholine) which restore the reading frame in prematurely terminated dystrophin genes (nonsense mutated).

Restores some dystrophin gene function.

Wokrs in mice and now being tested in humans.

Myopathy/Muscular Dystrophy

Autosomal dominant*

Charactarized by facial and scapular muscle weakness and atrophy as well as atrophy of the pectoralis and biceps muscles. Pelvic girdle can be involved later.

Scapula is unfixed and protrudes upward resembing a large trap muscle.

CK is only mildly elevated (unlike in DMD and BMD)

Muscle biopsy shows nonspecific or dystrophic changes with lobulated fibers and often mild inflammation.

Tx is often to simply fix the scapula to restore some range of motion.

Muscular Dystrophy/Myopathy

Can be AD or AR

Variable age of onset.

Cause is largely unknown and many protieins can be mutated to produce the phenotype (often sarcoglycan)

Normal Face*

Weakness of the limb girdle. Prominent winged scapula*

Biopsy shows dystrophic fibers and possible lobulations.

A muscular dsytrophy/myopathy

Autosomal Dominant with anticipation (CGT repeats)

Percussion and grip myotonia.

Charactaristic long faces with distal facial and neck weakness, cataracts, balding, DM, megaesophagus/colon.

*Note there is a Proximal myotonic dystrophy (different genotype, proximal instead of distal weakness).

Dermatomyositis

An autoimmune inflammatory myopathy

Aquired, autoimmune inflammatory myopahty

Aquired but may be assoc w CT dz and/or cancers

Presents with proximal weakness and uscle pain.

If accompanied by heliotrope rash/dermatitis=Dermatomyositis.

Elevated CK and ESR

EMG shows fibrillation potentials (like in neropathy) and small, polyphsic MUAPs.

Muscle biopsy: Inflammation (Perivascular in derm; interstital/muscular in poly***), necrosis, & atrophy.

Tx: Corticosteroids, Immunosuppresants, Ig infusion

False

Dermatomyositis shows perivascular inflammation (with lymphocytic infiltration and atrophy of the fibers n the boarder perifascicular atrophy) characteristic of this dz.

In Polymyositis Abs are to the muscles themselves and not to the muscle vasculature=muscular inflammation.

Inclusion Body Myositis

A common inflammatory myopathy in older people (males 50+yo)

Presents with proximal weakness but distal weakness and wasting of the forearm is also a prominant feature.

Quadraceps wasting/weakness. Dysphagia.

Biopsy w/ H&E stain shows blue-rimmed vacuoles, atrophic and split fibers and inflammation*

Inflammation, necrosis, angular atrophic and ragged red muscle fibers are also key biopsy findings*

Large filamentous, congophilic incusion bodies (myeloid or amyloid incusions) are charactaristic.

POOR RESPONSE TO TX (steroids, immunosuppresants, chemo). This is often diagnostic as the other inflammatory myopathies respond well to steroids.

Incusion Body Myositis*

This is unusual as most inflammatory/autoimmune myopathies respond well to corticosteroids and immunosuppresants.

Weakness/stiffness is episodic and often precipitated by temperature or activity.

Episodic muscle problems are caused by either a lack of repol or recurrent muscle depol.

Cl-, Na+ and Ca2+ channels may be defective.

Autosomal Dominant Channelopathy caused by an abnormailty in the Na+ Channel.

Charactarized by weakness after exercise and fasting made worse with cold temps, myotonia also common.

Tx with diuretics and carbonic anhydrase inhbitors.

Autosomal Dominant channelopahty caused by defects in the DHP V-gated Ca2+ channel (sometimes by Na+ defects as well)

Late onset (early adulthood)

Attachs of paralysis in the morning, after rest, after exercise, following high carb meals.

Perminant weakness may develop later.

On EMG: evidence of ↓ depol with unexcitable muscle membranes and ↓ resting membrane potentials during attacks (harder to excite). ↓ CMAP amplitude and ↓ motor unit duration of action and amplitude.

Vacuolar myopathy present on biopsy.

Looks a lot like Thyrotoxicosis*

Check TSH levels to distinguish the two.

Hereditary channelopathy producing myopathy.

AD form:Thomsen's Myotonia Congenita,

AR form: Becker's Myotonia Congenita.

Caused by disorders of Cl- channels

Cl- channel loss of function means that with repetitive depol of muscle fibers pt have difficulty relaxing the muscle (myotonia) which is aggrivated by cold.

Muscle Hypertrophy (Herculean appearence) due to frequent spontaneous depolarization and contraction of muscles.

EMG shows ↓ MUAP response to nerve stimulation (caused by abnormal Cl- conductance) with waxing and waining spontaneous potentials.

Dive bomber sound on EMG.

Pt are generally not weak and have a CC of myotonia*

Myotonia Congenita

Due to waxing and waning spontaneous potentials occuring in muscles at rest.

Metabolic Myopathy

Caused by a deficiency in muscle phosphorylase which prevents the breakdown of glycogen for use during anaerobic metabolism.

Pt present w muscle pains on exertion.

Serum lactate on exertion is normal.

Biopsy shows a lack of phosphorylase staining in muscle fibers (seen in vessels but not muscles)

Metabolic Myopathy

Caused by alpha-glycosidase deficiency.

Causes weakness and respiratory failure (iron lung use)

Biopsy is charactaristic: Shows PAS+ Vacuoles (glycogen-rich) and acid-phosphatase staining of lysozomes (red bubbles near the nucleus).

Tx: synthetic alpha glycosidase enzyme

Metabolic Myopathy

Manifests with glycogen accumulation and the involvement of several organs.

Glossomegaly, hypotonia (floppy baby), hepatomegly, and cardiomegly.

Enzyme replacement (alpha glycosidase) helps here too

Metabolic Myopathy

Caused by carnitine deficiency.

Impairs entrance of LCFA into the mitochondria as a source of fuel.

Presents as weakness and/or muscle pain on exercise or when fasting. Rhabdomyolysis (muscle breakdown) and progressive weakness.

Muscle biopsy shows small vacuoles on H&E that satin positive for fat on an oil red O stain. Lipid droplets are also seen on EM.

Often due to defects in the respiratory chain.

Presents with opthalmoplegia, ptosis, exercise intolorance, weakness, and cardiac arrhythmia.

Deafness and seizures are also possible.

Ragged Red Fibers on trichome stain*

Due to mitochondrial accumulations.

Trichrome stain

In mitochondrial myopathy (mitochondrial accumulations) and IBM (Inclusion body Myotonia)

Can cause endocrine myopathy

Severe weakness resembling ALS

Can cause endocrine myopathy

Muscle spasms but less severe weakness than hyperthyroidism.

Atrophy of Type II muscle fibers only.

Stain dark with ATPase stain and pale with oxidative stain (NADH-TR)

Anesthetics

Cholesterol-lowering drugs (Statins*)

Glucocorticoids (dexamethasone)

Insecicides

Organophasphates

Lead

Botulism

The average person sleeps ____ hours per night

7.5 +/- 2 Hours

This ↓ with age (as does the percentage of sleep time spent in REM)

Ambient Light

Clock Time

Appetitie

Personal Schedule/habits

If there are no physical clues, they body reverts to a 26 hour evolutionary cycle.

What part of the brain is considered the "Master Clock"?

The Suprachiasmatic Nucleus

A hypothalamic nucleus located just dorsal and superior to the optic chiasm.

Receives input from retinal ganglion cells and sends output to the paraventricular nucleus of the hypothalamus.

No light → ↑ firing of the retinal ganglion cells → signal travels to the mater clock (suprachiasmatic nucleus of the hypothalamus) → leads to activation of the Paraventricular nucleus (PVN) of the hypothalamus → sympathetic activation of the upper spinal cord → modulation of the neurons in the superior cervical ganglion → pineal gland activation → melatonin synthesis and release → sleep

READER'S DIGEST VERSION

No light→retinal ganglion cell firing→suprachiasmatic nucleus→ PVN→interomedolateral grey horn neurons → superior cervical ganglion → pineal gland → melatonin synth/release → sleepy

Paraventricular Nucleus

A hypothalamic nucleus which lies directly adjacent to the third ventricle (hence its name).

Plays key regulatory roles in oxytocin and ADH release from the posterior pituitary.

Also serves as the relay center for ambient lighting signaling from the suprachiasmatic nucleus, relaying this signal to sympathetic neurons which will lead to increased melatonin production by the pineal gland.

Beta and Alpha waves are the high frequency low amplitude EEG tracings typical of an awake or of a REM sleep state.

Note that Beta has higher frequency and lower amplitude than Alpha but that otherwise there was no distinction made bw the two.

EEG tracings typical of Stages I and II of sleep (relatively light sleep stages)

Are of intermediate frequency and amplitude (lower frequency and higher amplitude than Beta/Alpha but higher frequency/lower amplitude than Delta waves).

Lowest freqeuncy highest amplitude EEG tracings.

Seen in Stage III (deep) sleep.

~90 mins

Note that the duration of REM increases towards the waking/morning hours.

The duration of stages III and IV decreases over the period of time one is asleep.

NREM= Stages I-IV

Theta and Delta waves on EEG

Few eye movements (slow and rolling)

↓ muscle tone but movement still can and does occur

↓ HR, BP, RR, T, and metabolic rate*

Low emotional content dreams.

Sleep walking & night terrors occur during NREM sleep*

These changes are at their max during stage IV

Sleep Spindles (high activity periods)

and

K-complexes (large EEG spikes)

Alpha and Beta EEG waves

Rapid, ballistic eye movements

Muscles are paralyzed with some twiching possible (note that the diaphragm is spared)

 HR, BP, RR, T and metabolic rate are near waking levels.

Dreems are vivid and bizarre with strong emotional content.

Erection occurs during REM (useful for distinguishing physiological from psychological impotence).

Amygdala

Parahippocampal Gyrus

Anterior Cingulated Cortex

Likely account for the emotional content of dreams during REM sleep.

Frontal Cortex

Posterior Cingulated Cortex

May add to the bizarre nature of REM dreams (loss of rational thought and inhibition)

Pedunculopontine (PPT), Lateral Dorsal Tegmentum (LDT) [Cholinergic Neurons]

Locus ceruleus [Noradrenergic Neurons]

Substantia Nigra [Dopaminergic Neurons]

Raphe Nuclei [Serotonergic Neurons]

Tuberomammillary Nucleus [Histaminergic Neurons]

Lateral Hypothalamus [Orexin/Hypcrein Neurons]

PPT and LDT (cholinergic brainstem nuclei) project to the thalamus.

Activation of PPT and LDT results in thalamic signaling eliciting High Freq, Low Amp BETA waves (wake/REM)

This pathway is inhbited during NREM and the deactivated thalamic-cortical path results in slow wave sleep (Theta/Delta waves)

A cholinergic neuron group located inferior to globus palldus with cholinergic projections to the neocortex.

It is depressed during NREM (and activated during wake/REM)

Where do the dopaminergic pathways that regulate wakefulness originate?

Where do these pathways project?

Substantia nigra

Mesostriatal (Nigrostriatal) → Striatum (Putamen/Caudate)

Mesocortical → Prefrontal cortex

Mesolimbic neurons → Cortical Structures

(Amygdala, hippocampus, nucleus accumbuns, medial orbital frontal cortex, cingulate cortex)

FALSE

DA pathways are vital to acheive full wakefullness.

The serotonergic nuclei are called _Tuberomammillary nuclei_.

They have  High activity during wakefulness, Low activity during NREM sleep and Very low activity during REM Sleep.

Lateral hypothalmic nucleus

The lateral/posterior hypothalamic nuclei produce orexin and use it as an excitatory NT with diffuse forebrain projections that heavily innervate brainstem nuclei involved in wakefulness.

Lateral hypothalamic nuclei (Orexin Pathway)

Heavy innervation and exitatory input into brainstem nuclei involved in wakefulness.

VLPO=Ventrolateral Preoptic Nucleus of the hypothalamus

GABAnergic and Galanin

+ SLEEP!

Primarily active during sleep (NREM and REM). Acts to inhbit the nuclei that are invovled in wakefulness (locus coeruleus, raphe, tuberomamillary nuclei)

VLPO is activated by sominogens (serotonin, adenosine, PGD2) and inhbited by the arousal NT (NE and Ach)

PPT and LDT (cholinergic, Ach, brainstem nuclei)

Activated in the transition from NREM to REM (leads to increased ACh-mediated activation of the thalamus and several higher cortical areas.

PPT/LDT are activated in REM leading to increased Ach signaling to the thalamus and higher cortical areas.

This results in glycine-mediated inhbition of anterior horn cells and the paralysis associated with REM sleep*

Locus coeruleus (brainstem NE nucleus)

Terminates REM by inhbiting the REM ON nuclei (PPT/LDT)

Adenosine (accumulates in the CNS during waking)

Cytokines IL-1-beta and TNF

Melatonin (levels increase with darkness)

Name that mnemonic...

OHS (Pickwick)

RLS

PLMD

OSA

PLMS

OHS/Pickwick: Obesity Hypoventilation Syndrome

RLS: Restless Leg Syndrome

PLMD: Periodic Limb Movement Disorder

OSA: Obstructive Sleep Apnea

PLMS: Periodic Limb Movement Syndrome

9 or higher

Scale is a self-report measure of ones tendancy to fall asleep in 8 different situations with differing soporific natures.

The time from the start of a nap to the first signs of sleep on EEG.

MSLT is 20 mins in normal adults but can go down to 5 min after a sleepless night.

Obstructive Sleep Apnea

2:1 Men:Women, 30-60 yo

Defined as repetitive blockage of repsiratory pathways during sleep causing apneic periods lasting longer that 10 seconds and causing oxyHgb desaturation of >4%

Increased incidience with obesity (larger collar size), heart dz, acromegly, hypothyroidism and HTN.

Causes daytime fatigue, snoring, heartburn, depression, headaches, dyspnea, nocturea, and impotence.

Delayed sleep phase in adolescents: have trouble functioning in the morning.

Advanced sleep phase in the elderly: wakeing in the middle of the night.

Sleep attacks

Cataplexy (abrupt loss of muscle tone)

Sleep paralysis (persistent REM atonia after waking)

Hypnagogic hallucinations (dreams persistant after waking)

A loss of the hypocretin/orexin secreting neurons in the lateral hypothalamic nucleus*

Can be secondary to MS, pititary tumors or stroke.

Remember that these are normally active in while awake and their activity is depressed during sleep.

All pt have early-onset of sleep (EOS), 75% have cataplexy, 70% have hallucinations and over 50% have sleep paralysis.

How would one treat the following symptoms of narcolepsy?

Excessive daytime sleepiness

Cataplexy

Excessive daytime sleepiness can be tx with Methylphenidate (psychostimulant, ↑ levels of NE & DA)

Modafinil (a wakefulness promoting agent with an unknown mechanism of action)

GHB (GHB receptor agonist, promotes wakefulness)

Cataplexy (abrupt loss of muscle tone) can be tx with

TCAs and/or SSRIs

Aging, sedative wearing off, depression, REM disorder, effects of medications, CN degeneration.

In insomnia there is a failure to be able to fall asleep and/or a failure to stay asleep.

Can be transient or chronic (>6 weeks) and is very common (50% of adults) with females slightly more affected.

Strong correlation with depression.

Pt on an antidepressant, given Demerol and restrained = Serotonin Syndrome induction, high fever, death.

Lead to more strict regulation of physician work schedules (interns were on that night and had been on for many hours at the time of the mistake).

A loss of atonia during REM leading to physical acting out of dream states (verbilazation, punching , kicking, jumping etc...) Can lead to injury to self and others.

MC in Males >50 yo

Primary is idopathic (assoc w alpha-synucleinopathies such as PD, lewy body dementia, supranuclear palsy)

Can be secondary to Alcohol withdrwal, TCA/SSRI use.

75% of drugs used to tx insomnia are antidepressants used on or off label to tx insomnia.

Typically lower doses are used to tx insomnia vs the primary indication of the drug.

Trazadone (SSRI)

Amtryptyline (TCA)

Mirtazepine (TCA)

These are not scheduled drugs which may make them more attractive for use than BNZ etc...

Gabapentin

MoA unknown

Causes fatigue, weight gain, dizziness, ataxia, and nystagmus

Quietapine

MoA=sedation via action on H1 receptors

Prolong the QT interval, cause orthostatic hypoT, weight gain, constipation and xerostoma.

Drugs that enhance the effect of GABA inducing sleep, acting as an anxolytic, and an anticonvulsant.

Approved tx of insomnia.

Withdrawl is possible, taper dose.

Zolpidem

What is it, what is it used to tx, and where does it act?

Benzo Receptor Agonist

Approved to tx insomnia.

Bindst to the BZ-1 Receptor responsible for sedation and amnesia.

Does not bind to the BZ-2 receptor (responsible for anxiolysis) or the BZ-3 receptor (responsible for relaxation and anticonvulsion)

Melatonin receptor agonist

Approved tx for insomnia

Not scheduled, minimal residual effects.

Still undergoes hepatic metabolism with the potential for drug interactions but does not accumulate.

Differ from herbal melatonin in receptor specificity (do not bind MT3 so they have longer half life and greater effects in sleep induction.

OTC tx for insomnia

1st generation antihistamine

Cross the BBB=Extensive CNS effects

MoA is via H1 receptor antagonism with minor anticholinergic effects (cause blurred vision, xerostomia, and inc IOP).

Rapid tolorance develops to their sedative effects*

CI/use caution in the elderly and those with narrow-angle glaucoma.

Lethal at high doses (act like GABA itself, CNS depression)

Withdrawl effects,

Schedule IV drugs

Extensive hepatic metabolism (porphyria, drug interactions), caution req with COPD and other CNS depressants.

Their use has largely been replaced by the use of Benzos.

Barbituates are drugs whose names end in -barbital (ex:amobarbital, phenobarbital etc...)

Though commonly used, there are many downsides:

Shcedule IV drugs with CYP interactions that can accumulate metabolically and cause liver dz.

Extensive hepatic metabolism with metabolites that have their own effects (overall effect is that of drug+metabolites) which leads to morning after effects.

Class X, CI in pregnancy

Can cause impaired driving and depression

CI in pt with COPD, closed angle glaucoma, or are on other CNS drugs.

Ambien

A short-acting non-benzo hypnotic used to tx insomnia

Still schedule IV with CYP interactions and caution used when pt have hepatic dz.

Class C, acceptible for some PG women.

Still need to take caution with pts who have COPD, depression or are on other CNS drugs.

MT1 and MT2 are GPCRs with wide CNS distribution.

MT1 attenuates the activity of the suprachisamatic nucleus and therefore induces sleep.

MT2 maintains circadian rhythms

There is an MT3 but it is not involved in sleep/wake cycles.

BNZ and BzRA antagonist (the anti-benzo)

Reversal of sedation or BNZ overdose.

Short-acting, IV adminstration.

Causes abrupt wakening with agitation and dhsphoria. Seizures in withdrawl in chronic BNZ pt.

Does not reverse the actions of barbituates, opiates or TCAs.

A psychotropic agent with TCA and anxiolytic properties.

Used to tx insomnia off label (at lower doses 6 mg bs 25-50 mg in depresion)

Causes sedation, M-Block, blocks NE and 5-HT reuptake.

SE: Fatigue, confusion, agitation, tachycardia, sweating, orthostatic hypotension.

CYP metabolized, drug interactions.

CI wiht alcohol and other drugs that are CNS depressants.

Heterocyclic antidepressants used off label to tx insomnia.

CAUTION: Black box warning for suicidal ideation

Indirect endocrine effects with DM pt

CYP metabolism, drug interactions.

TCAs, MAOIs, SSRIs, Beta blockers, decongestants, antibiotics, asthma meds, other stimulants.

While reducing these meds may help in insomnia, sometimes good pain management is the best way to let a pt sleep.

Parkinson's Disease (PD)

"Parkinson's Plus" syndromes=

Progressive Supranuclear Palsy and

Multiple System Atrophy

Huntington's Disease (HD)

Tourette's Syndrome

Dystonia (Primary Focal and Primary Generalized)

The Basal Ganglia

(Fxn is to facilitate intedned movement and suppress unwanted movement. Modulation not initiation)

True

In PD (but not in some PD+ dz) the onset of motor features (tremor, bradykinesia, instability, rigidity) is typically asymmetical at onset but will become bilateral as the dz progresses.

PD

Lewy bodies are cytoplasmic inclusion bodies present in the surviving pigmented neurons of the substantia nigra and some non-pigmented neurons of the enteric nervous system.

Have a distinctive fried-egg appearence.

Dopamine Deficincy*

Within the substantia nigra of the midbrain and the striatum within the cerebellum.

DA deficiency can also be present in the mesolimbic, hypothalamic and retinal areas.

Is the second most common neurodegenerative dz behind Alzheimer's.

Incidence increases with age.

Young onset is typically more genetically determined but more operative than late onset.

Late onset is the majority of cases (55-65 yo)

Life expectancy is typically near normal.

Primary: Resting tremor, rigidty, bradykinesia, postural instability.

Secondary: Reduced facial expression (masking), diminished blink frequency, stooped posture, shuffling gate, hypokinetic dysarthia (soft, slured speech), micrographia (diminshed size of writing from L to R)

You have a 48 yo pt exhibiting signs of PD (bradykinesia, emotional liability instability).

Symptoms are relatively new and have been accompanied by progressive cognitive impairment with the pt having difficulty making plans with friends and following through with plans that have been made.

What do these features indicate?

Early onset (PD is typically 55 yrs or older), early onset of cognitive impairment (executive dysfunction) makes you think of a Parkinson Plus dz and not PD.

Think Progressive Supranuclear Palsy or

Multiple System Atrophy

FALSE

All aspects of the ANS can be affected by PD

Constapation, dysphagia, bladder over-activity, erectile dysfunction, impaired BP regulation (orthostatic hypoT) and profuse sweating can all occur.

Degeneration of the dopaminergic, pigmented nuerons that have their cell bodies in the substantia nigra pars compacta of the midbrain.

Neurons of the brainstem nuclei (locus ceruleus and dorsal motor nucleus of X) are also affected.

Lewy bodies are charactaristic.

Parkinsonism (rigidity, bradykinesia, fixed facial expression)

+

Early onset of disarthia, gait disturbance and instability.

Symptoms are often symmetrical at onset and tremor is not typically present*

Opthalmologic features are prominant

Babinski sign and sleep disturbances may also be present.

Supranuclear Glaze palsy is a key feature of PSP but not of PD*

Pt have impaired voluntary downgaze (wheras in PD problems are with upgaze).

As PSP progresses, pt develop problems with up and lateral gaze as well.

Note that these gaze problems are not due to dysfunction of the EOM but rhater due to damage of brainstem nuclei involved.

Perform the Oculocephalic Maneuver

Pt is asked to fix their gaze on a stationary point while the head is moved passively.

The eyes are able to remain fixed through the full range of motion of the head indicating that the EOM are functional but the brainstem nuclei controlling their movement is impaired.

Progressive Supranuclear Palsy

They are of the globose type.

Unpaired straight filamnets with highly phosphorylated Tau protein are also charactaristic of this disorder.

Midbrain and Cerebral cortial atrophy with neuronal loss and gliosis.

Substantia nigra, pedunculopontine nucleus in the rostral midbrain and blobus pallidus are all typically involved.

Multiple System Atrophy

Charactarized by urinary system dysfunction, orthostatic hypoT, impotence, GI dysfunction and thermoregulatory dysfunction.

Compared to PD these symptoms appear earlier and are more severe.

What are the key features of Multiple System Atrophy?

A Parkinson's Plus syndrome

Sporatic, earlier age of onset (50-55 yo) with a life expectancy after dx of 5-10 yrs.

Begins with one of three clinical patterns and progresses to involve all 3:

1) Parkinsonism

(rigidity, bradykinesia, instability)

2) Progressive Autonmic Failure

(urinary and GI dysfunction)

3) Cerebellar Syndrome (ataxia, dysarthia)

True

Though there is cognitive dysfunction, depression and personality changes there is no dementia in this disorder.

Cell loss and gliosis in multiple areas of the brain and brainstem (but the cortex is spared, hence no dementia)

Substantia nigra and posterior putamen are most prominantly involved.

Glial cytoplasmic incusion bodies are present as in PD but these stain for alpha synuclein.

Autosomal Dominant

Trinucleotide (CAG) repeat sequence with the number of repeats being related to the severity and age of onset of the dz.

Life expectancy after onset: 15-20 yrs.

Chorea

which lessens as the dz progresses.

Behavioral changes!

Impulsiveness, iritability, obsessive behavior, agression, depression, dementia (executive dysfunction).

This is followed by chorea (which is replaced by dystonia in late dz), dysarthria, oculomotor diturbances and cachexia.

Involvement of the Striatum (esp caudate and putamen) and the Cortex with

atrophy, neuronal loss, gliosis.

Onset before age 21 (typically 2-25 yrs w male predominance)

Multiple motor tics and at least one phonic tic must have been present.

Tics must occur multiple times per day, nearly every day or intermittantly for a year.

The complexity or severity of the tics must change over time*** HALLMARK of Tourette's

Must be unexplainable by any other condition and witnessed by a reliable observer.

Tourette's pt typically respond to drugs that block DA*

Define:

Echopraxia

Copropraxia

Echolalia

Palilalia

Coprolalia

These terms all describe motor and phonic tics seen in Tourette's Syndrome pt.

Echopraxia is involuntary immitation of another person's movements

Copropraxia is involuntary performance of inappropriate or obscene gestures.

Echolalia involuntary repetition of vocalizations of another person.

Palilalia is the rapid repetition of ones own words.

Coprolalia is involuntary swearing or utterance of obscene words (rare)

ADHD and OCD commonly co-occur with Tourette's

Obsessions about symmetry, sex, counting, violence and Compulsions about counting, touching or checking things.

Dystonia

Onset 7-10 yrs

Primary due to mutation (GAG deletion) of the DYT1 gene producing an altered Toursin A protein.

Prevelant in Ashkenzi jews.

False

Autosomal Dominant with only ~35% penetrance*

Caused (primary form) by mutaiton of the DYT-1 gene (altered Torsin A protein)

Onset is focal with action dystonia (sustained contraction initatied by motion) and typically begins in the lower extremeiteis (ankle infersion or plantar flexion of the toes).

Spreads proximally.

Eventually resuts in gait and posture abnormalities with neck extension, hip flexion and exaggerated hip abduction and hyperexension of the knee.

Postures eventually become fixed.

False

In Pt with dystonia, Cognition, Strength, and Sensation are all normal*

Adult onset (compared to kids in other)

No genetic basis

More common* than primary generalized

Typically affects muscles above the waist, may be only task-specific, pt may have sensory tricks that can be used to control the contractions.

Cervical dystonias are common.

These are all cranial dystonias associated with adult-onset Primary Focal Dystonia.

Blephoarosmasm: the muscles around the eye,

Ormandibular the muscles of the jaw and mouth,

cervical (spasmotdic torticollis) the neck muscles,

and laryngeal the vocal cords.

Rare

Autosomal Recessive, caued by mutaiton of the ATP7B gene which results in deffective copper transport to Ceruloplasmin which meas that coper acumulates and deposits around the body causing damage.

Onset ages 10-20, typically with hepatic symptoms (but neurolgical and psych presentations are also possible)

What are the lab values that would be expected in a Wilson's Dz pt?

Which lab value is the most sensitive/accurate for dx Wilson's Dz?

↓ serum ceruloplasmin, ↓ serum total copper

↑ serum free copper, ↑ urinary copper, ↑ hepatic copper.

↑ hepatic copper is the most sensitive/accurate dx tool for Wilson's Dz*

Acute transient hepatitis,

chronic active hepatitis,

progressive cirrhosis,

acute fulimant hepatitis (bad prognosis).

Lots of extrapyramidal features (caused by basal ganglia dysfunction caused by Cu deposition).

Parkinsonism

Chorea

Dystonia

Intention tremor * frequent

Dysarthria

Lack of coordination

Wilson's Dz

Brown pigment around the outer rim of the cornea produced by Cu depostion in Descement's membrane in the cornea.

Always present in Wilson's pt who have neuro and psych signs along with the hepatic signs.

Wilson's Dz

Can only be seen with a slit lamp.

Caused by Cu deposition in the lens

Wilson's Dz

Distinctive cells originating from altered glial cells in the basal ganglia (often degenerating astrocytes)

Personality changes

Depression

Mania

Psychosis

Opthamalogic

also hepatic.

[Damage caused by Cu deposition]

Hepatic fibrosis and cirrhosis

Neuronal loss and gliosis

(in the putamen, thalamus, cerebral cortex etc...)