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Flashcards in CN LANGE - Motor Disorders III Deck (111):

Spinal cord infarction - Causes:

1. Trauma.
2. Dissecting aortic aneurysm.
3. Aortography.
4. PAN.
5. Hypotensive crisis.


Spinal cord infarctions - Why are the infarcts more common caudally?

Because the ASA is particularly well supplied in the CERVICAL REGION, infarcts almost always occur more caudally.


Spinal cord infarction - Clinical findings - The acute onset of a flaccid, areflexic paraparesis is followed by ...?

By spastic paraparesis (as spinal shock wears off after a few days or weeks) with brisk tendon reflexes + extensor plantar responses.


Spinal cord infarction - In addition, there is ...?

DISSOCIATED impairment - pain and temp appreciation are lost, but vibration and position sense are spared because the posterior columns are supplied by posterior spinal arteries.


Spinal cord infarction - Prognosis:

Survivors may show improvement; most remain chair-bound, however, and only a minority regain the ability to walk unaided.


Spinal cord infarction - DDx:

1. A subacute, asymmetric myelopathy sometimes develops as a consequence of a vasculitic process.
2. An even more insidious, asymmetric ischemic myelopathy may result from compression of the ASA or its major feeder, as by degenerative disease of the spine --> The resulting disorder may simulate ALS, when there is a combined UMN + LMN deficit, without sensory changes.



Hemorrhage into the spinal cord is rare.
--> Caused by trauma, a vascular anomaly, a bleeding disorder, or anticoagulant therapy.


Spinal epidural or subdural hemorrhage - May occur ...?

Spontaneously or in relation to trauma or tumor and as a complication of:
1. Anticoagulation.
2. Aspirin therapy.
3. Coagulopathy.
4. Epidural catheters.
5. LP.


Hemorrhage after LP:

Usually EPIDURAL in location - More likely when a disorder of coagulation is present.


Patients with how may platelets should undergo platelet transfusion before LP?


Spinal epidural hemorrhage usually presents with ...?

Back pain that may radiate in the distribution of one or more spinal nerve roots.
--> It is occasionally painless.


Spinal epidural hemorrhage - What may develop rapidly, necessitating urgent CT or MRI + surgical evaluation of the hematoma?

1. Paraparesis or quadriparesis.
2. Sensory disturbances in the lower limbs.
3. Bowel + Bladder dysfunction.


AVM or fistula - May present with:

Spinal SAH or with myelopathy.
--> Most of these lesions involve the LOWER spinal cord.


AVM or fistula - Symptoms include:

1. Motor and sensory disturbances in the LEGS.
2. Disorders of sphincter function.
3. Leg or back pain is often, conspicuous.


AVM or fistula - On exam:

1. There may be an UMN or LMN, or mixed fixed deficit in the legs, and sensory deficits are usually extensive but occasionally radicular.
2. The signs indicate an extensive lesion in the longitudinal axis of the cord.
3. In patients with cervical lesions, symptoms and signs may also be present in the ARMS.
4. A BRUIT is sometimes audible over the spine, and there may be a cutaneous angioma.


AVM or fistula - Spinal MRI shows ...?

Multiple flow voids, but can rarely be normal.


AVM or fistula - Myelography reveals ...?

Serpiginous filling defects caused by enlarged vessels.
--> The diagnosis is confirmed by selective spinal arteriography.


What nutritional myelopathy can mimic B12 def.?

1. NO toxicity.
2. Copper deficiency.


Cervical spondylosis - Characterized by any or all of the following:

1. Pain and stiffness in the neck.
2. Pain in the arms, +/- a segmental motor or sensory deficit.
3. UMN deficit in legs.


Cervical spondylosis - Pathogenesis:

Chronic cervical disk degeneration, with herniation of disk material, 2o calcification, and associated osteophytic outgrowths.
--> It can lead to impingement on one or more nerve roots on either or both sides + to myelopathy related to compression, vascular insufficiency, or recurrent minor trauma to the cord.


Cervical spondylosis - Clinical findings:

Patients often present with neck pain + limitation of head movement or with occipital headache.
--> In some cases: Radicular pain + other sensory disturbances occur in the arms, and there may be weakness of the arms or legs.


Cervical spondylosis - Exam commonly reveals:

Restricted lateral flexion + rotation of the neck.
--> There may be a segmental patter of weakness or dermatomal sensory loss in one or both arms, along with depression of those tendon reflexes mediated by the affected root(s).


Cervical spondylosis tends to affect particularly ...?

C5-C6 nerve roots.


Cervical spondylosis - If there is an associated myelopathy ...?

UMN weakness develops in one or both legs, with concomitant changes in tone and reflexes.
--> There may also be posterior column or spinothalamic sensory deficits.


Cervical spondylosis - DDx:

Spondylotic myelopathy may resemble myelopathy caused by such disorders as:
1. MS.
2. MND.
3. Subacute combined degeneration.
4. Cord tumor.
5. Syringomyelia.
6. Hereditary spastic paraplegia.
--> Degenerative changes in the spine are common in the middle-aged + elderly and may coincide with one of these other disorders.


Congenital spinal anomalies - Platybasia or basilar invagination:

A combination of corticospinal + cerebellar signs may occur in the limbs of patients with congenital skeletal abnormalities, such as platybasia or basilar invagination.



Flattening of the base of the skull.


Basilar invagination:

Upward bulging of the margins of the foramen magnum.



Cavitation of the cord - Can be congenital or acquired, may lead to:
1. LMN deficit.
2. A dissociated sensory loss in the arms.
3. UMN signs in the LEGS.


Spinal cord tumors - 2 groups:

1. Intramedullary (10%).
2. Extramedullary (90%).


MC type of intramedullary tumor:

(the various types of gliomas make up the remainder).


Extramedullary tumors can be either ... or ... in location.

Extradural or intradural.


Among the primary extramedullary tumors, which are relatively common?

1. Neurofibromas.
2. Meningiomas.
--> Benign.


Spinal cord tumors - Metastases are usually ... in location.



Spinal cord tumors - Metastases from ...?

1. Lung.
2. Breast.
3. Prostate.
4. Lymphomatous or leukemic deposits.


Spinal cord tumors - Pathogenesis of myelopathy:

May occur in patients with malignant neoplasms because of:
1. Spinal cord compression or direct involvement by the primary tumor or by metastases.
2. Ischemic or hemorrhagic complications of the neoplasm or its treatment.
3. Complications of radiation or chemo.
4. 2o infection (immunocompromised).
5. Paraneoplastic disorder.


In paraneoplastic necrotizing myelopathy, the MC antibody is ...?



Paraneoplastic myelopathy - The underlying tumor is commonly a cancer of ...?

1. Lung.
2. Breast.
3. Lymphoma/leukemia.


Paraneoplastic myelopathy - Patients present with ...?

Rapidly ascending flaccid paraplegia.


Paraneoplastic myelopathy - Often accompanied by ...?

Encephalopathy and neuropathy --> Paraneoplastic encephalomyelitis.


Clinical features of spinal cord compression by extradural metastasis - Initial feature:

96% --> Pain.
2% --> Weakness.
0% --> Sensory disturbance.
0% --> Sphincter dysfunction.


Clinical features of spinal cord compression by extradural metastasis - Present at diagnosis:

96% --> Pain.
76% --> Weakness.
57% --> Sphincter dysfunction.
51% --> Sensory disturbance.


Spinal cord tumors - Investigative studies - The CSF is often ...?

Xanthocromic, due to a greatly increased PROTEIN CONCENTRATION rather than hemorrhage.
--> Normal or elevated WBC count + N or depressed glucose.


Spinal cord tumors - The prognosis:

Depends on the cause and severity of the cord compression BEFORE it is relieved.


Anterior horn cell disorder - Disorders that predominantly affect the anterior horn cells are characterized clinically by:

Wasting + weakness of the affected muscles without accompanying sensory changes.


Anterior horn cell disorders - Electromyography shows changes that are characteristic of:

1. Chronic partial denervation.
2. With abnormal spontaneous activity in resting muscle + a reduction in the number of motor units under voluntary control.
3. Signs of reinnervation may also be present.
4. Motor conduction velocity is usually normal but may be slightly reduced.
5. Sensory conduction studies are normal.


Anterior horn cell disorders - The idiopathic disorders depend in part on the ...?

Patient's age at onset.


MND in children:

3 forms of spinal muscular atrophy (SMA-I, II, and III) occur in infants and children.


SMA-I,II,III - Mutations in 95% of cases:

In the survival of motor neuron 1 (SMN1) gene.


A nearby gene, coding for neuronal apoptosis inhibitory protein (NAIP), is also affected in ...% of SMA-I and ...% of SMA-II and III.

45% of SMA-I.
18% of SMA-II, III.


NAIP may ...?

Modify disease severity!


Another disease modifier of SMA, improving survival?

Survival of motor neuron 2 (SMN2) gene, a homolog of SMN1 gene.


Infantile SMA (Werdnig-Hoffmann disease or SMA-I).

AR disorder that manifests itself within 3 MONTHS of life.
--> The infant is floppy and may have difficulty with sucking, swallowing, or ventilation.


Infantile SMA - Exam reveals:

1. Impaired shallowing or sucking.
2. Atrophy and fasciculation of the tongue, and muscle wasting in the limbs that is sometimes obscured by subcutaneous fat.
3. Tendon reflexes are normal or depressed.
4. Plantar responses may be absent.
5. No sensory deficit.


Infantile SMA (SMA-I) - Prognosis:

Rapidly progressive, generally leading to death from respiratory complications by approx. 3 years of age.


Intermediate SMA (Chronic Werdnig-Hoffmann or SMA-II):

AR disorder that usually begins clinically in the LATTER HALF of the 1st year of life.


SMA-II - Exam:

1. Extremities become wasted and weak.
2. Bulbar weakness is less common.


SMA-II - Prognosis:

Progression occurs slowly, ultimately leading to severe disability with kyphoscoliosis and contractures, but the course is more benign that in the infantile variety.


Juvenile SMA (Kugelberg-Welander of SMA-III):

Develops in childhoor or early adolescence, on a sporadic or hereditary (usually AR) basis.
--> It particularly affects the proximal limb muscles, with generally little involvement of the bulbar musculature.


Juvenile SMA (SMA-III) - Prognosis:

Follows a gradually progressive course, leading to disability in early adult life.


SMA-III - The proximal weakness may lead to a mistaken diagnosis of ...?

Muscular dystrophy, BUT ...
1. Serum CK.
2. Electromyography.
3. Muscle biopsy.
--> Will differentiate the disorders.


MND in adults - Characterized by degeneration of:

1. Anterior horn cells in the spinal cord.
2. Motor nuclei of the lower CN in the brainstem.
3. Corticospinal and corticobulbar pathways.


MND in adults - Epidemiology:

1. Between the ages 30-60.
2. Annual incidence of 2 per 100.000.
3. Male predominance (except in familial cases - 5% to 10% of cases).


MND - Occasional familial cases have a ...?

Juvenile onset.


MND - Pathogenesis - Genetics:

Approx. 90-95% of cases are sporadic and of unknown cause.
--> No robust environmental risk factors have emerged.


MND - Genetics - Approx. ...% of familial cases show AD inheritance related to SOD1 mutations.



MND - Genetics - Other AD forms are associated with mutations in ...?

1. Senataxin (SETX).
2. Fused in sarcoma (FUS).
3. Vesicle-associated membrane protein-associated protein B (VAPB).
4. Angiogenin (ANG).
5. TAR DNA-binding protein (TARDP).
6. Homolog of S.cerevisiae FIG4 (FIG4).
7. Ataxin 2 (ATXN2).
8. Profilin 1 (PFN1).
9. Valosin-containing protein (VCP).


MND - Genetics - AR MND is linked in some cases to ...?

Alsin (ALSN).


MND - Genetics - Both AD and AR inheritance have been seen with mutations in ...?

Optineurin (OPTN).


MND - Genetics - An X-linked mutation occurs in ...?

Ubiquilin 2 (UBQLN2).


MND - Genetics - VEGF polymorphisms may ...?

Increase the risk of MND.


MND - Genetics - Other susceptibility genes include:

1. Heavy neurofilament subunit (NEFH).
2. Peripherin (PRPH).
3. Dynactin (DCTN1).


MND - Genetics - A GGGGCC hexanucleotide repeat ...?

Present within the non-coding region of the C9ORF72 gene on 9q21 --> Accounts for many familial and some sporadic cases.
--> C9ORF72 is an RNA-binding protein and provides a new target for therapy.


MND - Mechanisms - General picture:

The pathophysiologic basis of MND is UNCERTAIN, but several mechanisms have been proposed, based largely on studies in animal models with SOD1 mutations.
--> Because there are gain-of-function mutations, the mechanisms inferred generally involve a toxic effect of the mutated protein.


MND - Cellular mechanisms:

1. Although motor neurons are the primary cellular target, studies in which mutant SOD1 is expressed selectively in different cell types indicate that NON-neuronal cells also contribute to the pathogenesis of MND.
2. Involvement of neurons appears to determine the age at onset + early course of disease.
3. Involvement of microglia + astrocytes influence the subsequent rate of progression.


MND - Molecular mechanisms - With SOD1 mutations:

An early pathogenetic step is ABNORMAL FOLDING + AGGREGATION of the mutant protein, as in other neurodegenerative proteinopathies.


MND - Molecular mechanisms - Excitotoxicity:

1. The principal excitatory neurotransmitter, glutamate, is toxic to neurons when present in excessive amounts.
2. In MND, spinal cord astrocytes express REDUCED levels of the EAAT2 excitatory amino acid (glutamate) transporter, which is the major site through which extracellular glutamate is cleared.
3. This could expose motor neurons to toxic concentrations of glutamate.


MND - Molecular mechanisms - Endoplasmic reticulum stress:

Mutant SOD1 accumulation in the ER, where it may interfere with the degradation of misfolded proteins or the synthesis of normal proteins.


MND - Molecular mechanisms - Proteasome inhibition:

Production of large amounts of mutant SOD1 may overwhelm the ability of the proteasome to perform its normal function.


MND - Molecular mechanisms - Mitochondrial damage:

Mutant SOD1 associated with the outer mt membrane, which might inhibit the production of ATP or the ability of mt to regulate intracellular calcium levels.


MND - Molecular mechanisms - Secretion of mutant SOD1:

SOD1 released into the extracellular space may activate microglio, resulting in immune-mediated injury of motor neurons.


MND - Molecular mechanisms - Increased production of superoxide:

Mutant SOD1 may stimulate increased production of toxic superoxide radicals by glial cell NADPH oxidase.


MND - Molecular mechanisms - Impaired axonal transport:

Anterograde and retrograde axonal transport may be disrupted by the accumulation of misfolded SOD1 or other proteins.


MND - Molecular mechanisms - Microvascular dysfunction:

Loss of tight junctions between the capillary endothelial cells could cause microhemorrhages that allow toxins such as iron to escape into the extravascular compartment and damage motor neurons.


MND - Molecular mechanisms - Summary:

1. Excitotoxicity.
2. Endoplasmic reticulum stress.
3. Proteasome inhibition.
4. Mitochondrial damage.
5. Secretion of mutant SOD1.
6. Incr. production of superoxide.
7. Impaired axonal transport.
8. Microvascular dysfunction.


MND - Classification:

5 varieties of adult-onset MND can be distinguished clinically by their predominant distribution (limb or bulbar musculature) and whether deficits are from UMN or LMN involvement.
1. Progressive bulbar palsy.
2. Pseudobulbar palsy.
3. Progressive spinal muscular atrophy.
4. Primary lateral sclerosis.
5. Amyotrophic lateral sclerosis.


Progressive bulbar palsy:

Predominant bulbar (brainstem) involvement from lesions affecting the motor nuclei of CNs (ie LMNs) in the brainstem.


Pseudobulbar palsy:

Predominant bulbar involvement due primarily to UMN disease (ie bilateral involvement of corticobulbar pathways).
--> A pseudobulbar palsy can occur in any disorder that causes BILATERAL CORTICOBULBAR disease (eg vascular dementia or progressive supranuclear palsy).


Progressive spinal muscular atrophy:

There is primarily a LMN deficit in the limbs, caused by anterior horn cell degeneration in the spinal cord.
--> Familial forms have been recognized.


Primary lateral sclerosis:

A purely UMN (corticospinal) deficit is found in the limbs.


Amyotrophic lateral sclerosis:

1. A mixed UMN + LMN deficit is present in the limbs.
2. Bulbar involvement of the UMN+LMN may also occur.


Which disorders are considered to be variant of ALS?

Both primary lateral sclerosis + progressive spinal muscular atrophy --> At autopsy, abnormalities of BOTH UMN+LMN are likely.
--> Cognitive and behavioral changes also occur in some patients.


ALS - Clinical findings - In approx. ...% of ALS, the initial symptoms are related to weakness of the bulbar muscles.



ALS - Bulbar involvement is somewhat more common in ...?

Familial cases and is generally characterized by difficulty in shallowing, chewing, coughing, breathing, and speaking (dysarthria).


In progressive bulbar palsy, exam reveals:

1. Drooping of the palate.
2. Depressed gag reflex.
3. Pool of saliva in the pharynx.
4. Weak cough.
5. Wasted + fasciculated tongue.


In pseudobulbar palsy, the tongue is ...?

Contracted + spastic.
--> Cannot be moved rapidly from side to side.
--> The extraocular muscles are not involved.


ALS - Clinical findings - Limb muscles:

40% --> Weakness of the upper extremities (initial presentation)
40% --> Weakness of the lower extremities (initial presentation).


ALS - Limb involvement is characterized by ...?

1. Easy fatiguability.
2. Weakness.
3. Stiffness.
4. Twitching.
5. Wasting.
6. Muscle cramps.
7. May be vague sensory complaints and weight loss.


ALS and which disorder overlap clinically, pathologically, and genetically?

Frontotemporal dementia.


Genetic overlap of ALS + FTD:

The GGGGCC repeat in the non-coding region of the C9orf72 GENE ON 9q21 occurs in at least:
40% of familial cases of ALS.
25% of familial cases of FTD.
5-10% of apparently sporadic cases of these disorders.


ALS - Cognitive and behavioral alterations are common in patients with ALS including:

1. Personality changes.
2. Irritability.
3. Lack of insight.
4. Deficits in executive function.
5. In other instances, parkinsonism or dysautonomic features may be present.
6. Sensory and sphincteric functions are characteristically spared.


ALS - Clinical diagnosis - El Escorial criteria of the World Federation of Neurology - Definite:

UMN and LMN signs in the bulbar + 2 spinal regions or in 3 spinal regions (cervical, thoracic, lumbosacral).


ALS - Clinical diagnosis - El Escorial criteria of the World Federation of Neurology - Probable:

1. UMN + LMN signs in 2 or more regions.
2. The regions may differ, but some UMN SIGNS must be rostral to the LMN deficit.


ALS - Clinical diagnosis - El Escorial criteria of the World Federation of Neurology - Possible:

1. UMN + LMN signs in only one region or
2. UMN signs alone in 2 or more regions or
3. LMN signs rostral to UMN signs.


ALS - Clinical diagnosis - El Escorial criteria of the World Federation of Neurology - Suspected:

LMN (but not UMN) signs in at least 2 regions.


ALS - DDx:

1. Other noninfective disorders of anterior horn cells must be excluded.
2. Multifocal motor neuropathy is also an important consideration.
3. Cervical spondylosis can mimic ALS when it produces LMN signs in the arms and UMN signs in the legs --> Can be distinguished by the ABSENCE of clinical and electromyographic evidence of LMN involvement in the legs.


ALS - Prognosis:

MND is progressive and usually has a fatal outcome within 3-5yrs, MC from respiratory failure.


ALS - Prognosis of familial cases:

Some progress more slowly.


ALS - In general, which patients have a poorer prognosis?

Patients with bulbar involvement than those in whom dysfunction is limited to the extremities.


Patients with primary lateral sclerosis - Prognosis:

Often survive longer despite severe quadriparesis + spasticity.


Vascular myelopathies - Spinal cord infarction - MC involves ...?

--> Supplies the anterior 2/3 of the cord, is itself supplied by only a limited number of feeding vessels, whereas the paired posterior spinal arteries receive numerous feeders at many different levels.