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135 Cards in this Set
- Front
- Back
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What does the basal ganglia do?
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Output of motor loops is primarily to frontal and prefrontal motor cortex
-There are lesser brainstem and cerebellar projections as well Cognitive sequencing of actions -Dorsolateral prefrontal cortex Motor habit formation (learning) -Dorsolateral prefrontal cortex Setting the stage for (context) & planning movement sequences -Supplementary Motor Cortex -Premotor Cortex Creating motor commands -Premotor and motor cortex Here is a review of the BG restraint of thalamic input to different cortical regions. -Motor functions – BG restrains thalamic projections to premotor, and motor association cortex (premotor and SMA) -Oculomotor – BG restrains thalamic projections to eye fields (frontal eye fields and supplementary eye fields) -Cognitive – BG restrains thalamic projections to large areas of prefrontal cortex -Motivation / Reward Systems – BG restrains thalamic projections to limbic cortex (orbitofrontal cortex) -Emotional - BG restrains thalamic projections to limbic cortex (anterior cingulate gyrus) |
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BG motor circuit
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-Originates in all somatosensory & motor areas
-The putamen is the BG input region receiving cortical and (intralaminar) thalamic inputs -The output is via the ventral anterior and ventral lateral thalamic nuclei -The cortical targets are primarily the supplementary and premotor areas -Lesser targets are dorsolateral prefrontal cortex and primary motor cortex |
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Frontal lobe targets of the BG
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For Motor Processing Tasks: The GPi projects GABAergic fibers that inhibit targets in the motor regions of the thalamus (VA and VL). These regions of the thalamus excite regions of the frontal lobe important for motor planning and programming and movement execution (Premotor, Supplementary Motor Area (SMA) and Primary Motor Cortex). Connections between the thalamus and cortex are reciprocal.
For Oculomotor Processing Tasks: BG inhibitory output to the VA nucleus and the medial nuclei of the thalamus modulate the thalamic output to the frontal eye fields and supplementary eye fields. Connections between the thalamus and cortex are reciprocal. For Cognitive Processing Tasks: BG inhibitory output to the VA and medial nuclei of the thalamus modulate the thalamic output to a vast area of the prefrontal cortex. Connections between the thalamus and cortex are reciprocal. |
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BG Core processing loop
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Sensory motor cortex has positive input to striatum
Striatum has negative input to output nuclei (GP) -Sometimes has positive input Output nuclei has negative input to thalamus Thalamus has positive input to pre-frontal cortex |
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BG main input nucleus
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The striatum (caudate and putamen) receives cortical input so it is the entrance door to the basal ganglia.
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Striatum functional domains
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Divided by its cortical input
Caudate -Cognitive Putamen -Motor Nucleus accumbens -Emotional/motivational |
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Globus Pallidus projections
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GPi: Thalamus
GPe: Subthalamic nucleus |
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Sumthalamic nucleus
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Input from GPe
Projects to GPi and SNr Only BG nucleus with excitatory output |
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Substantia nigra
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Floor of midbrain
The Substantia nigra is divided into a pars compacta (SNc) and pars reticulata (SNr). Neurons in the SNc contain the pigment melanin giving the SN its descriptive name (black substance). The SNc is connected to the striatum and provides the neurotransmitter dopamine to striatal neurons. The neurons in the SNc selectively die in Parkinson’s Disease. The SNr (red) is one of the exit doors of the BG that provide a constant stream of inhibitory output of the BG to the thalamic nuclei. |
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BG main output nuclei
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The outlet of BG computational activity is the GPi and the SNr. Both of these nuclei contain inhibitory neurons connected to the thalamus that release GABA as their neurotransmitter. Functionally these two regions are the same.
In general, the GPi deals largely with information processing output for problem solving tasks related to movements in the body and the SNr deals with information processing output for problem solving tasks related to movements in the head and eyes. |
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Direct pathway from striatum
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Striatal projections all arise from Medium Spiny neurons
They are all GABAergic But, they contain different peptides And receptors Direct pathway - Cortex to striatum -GABA/SP containing output directly inhibits GPi -Reduced GPi activity disinhibits thalamic neurons -Increased thalamic activity favors movement -Direct Path Projections to the GPi & SNr contain: -Substance P & dynorphin -They express D1 dopamine receptors -Inhibition of GPi Disinhibits the Thalamus |
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Indirect pathway from striatum
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Indirect
- Cortex to striatum -GABA/enk containing output inhibits GPe -Reduced GPe activity disinhibits STN -Glutamate-containing STN output excites GPi -Increased GPi activity inhibits the thalamus -Decreased thalamic activity inhibits movement -Indirect Path Projections to the Gpe contain: -enkephalin -They express D2 dopamine receptors |
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Hyperdirect pathway from striatum
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Directly from cerebral cortex
In parallel with projection to striatum It is the first influence on Gpi/SNr -Excites them, leading to increased thalamic inhibtion This effect can be quickly overridden by the; input from the direct path, which follows Finally, the input from the indirect pathway can override Direct path influences and again shut down movement We will not focus on this because specific BG pathologies are easily explained without it |
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How whole BG circuit works
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Thalamic activity excites the cortex
-Favors movement -Thalamus is not spontaneously active GPi inhibits the thalamus, blocking movement -GPi is spontaneously active, so there is always inhibitory tone on the thalamus Striatum inhibits GPi via the direct pathway -This favors movement by disinhibiting the thalamus The indirect pathway excites GPi via STN -This inhibits movement -GPe is spontaneously active, inhibiting STN -Inhibition of GPe by the striatum releases STN from inhibition, allowing it to excite Gpi This inhibits movement Dopamine favors movement by exciting direct path neurons in striatum & inhibiting the indirect path neurons |
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Cortical Input to the Striatum Drives the Direct Pathway to Release Movement
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Without Cortical input to the Putamen Direct Pathway (SP neurons) the baseline uninhibited spontaneous activity of GPi restrains the thalamus (VA / VL) and there is no thalamic stimulation of motor planning or movement.
With Cortical input to the Putamen Direct Pathway the spontaneous out of GPi is inhibited and the thalamic stimulation of movement is favored. |
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Cortical Input to the Striatum Drives the Indirect Pathway to Inhibit Movement
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Without Cortical input to the Putamen Indirect Pathway (Enk neurons) the spontaneous activity of GPe inhibits the STN and without normal STN activity driving an increase in GPi activity the influence of the direct pathway to inhibit GPi is unopposed and the net effect is a reduction in GPi firing. This release of the thalamic brake favors movement.
With Cortical input to the Putamen Indirect Pathway (Enk neurons) the GPe neurons are inhibited and the STN provides a very robust stimulation of GPi which shuts down the thalamic stimulation of the cortex and slows or stops movement. |
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The role of dopamine
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Dopamine favors movement
-Dopamine excites the Direct pathway via D1 (drives movement) -Dopamine inhibits the Indirect pathway via D2 inhibits the inhibition of Enk spiny neurons D1 receptors are excitatory -They are found on striatal neurons of the direct pathway D2 receptors are inhibitory -They reside on striatal neurons of the indirect pathway |
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The role of acetylcholine
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Cholinergic interneurons synapse on Med Spiny Neurons
They are excitatory Predominant effect is on the indirect pathway -Net inhibition of movement -This balances the excitatory effect of dopamine -Anticholinergics can amerlioate akinesia of PD |
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Basal Ganglia
Activity During Hyperkinetic Disorders |
Lesions in indirect pathway leading to direct pathway to dominate
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How the loss of Dopamine leads to
Parkinson’s Disease |
Decreased activity in the direct pathway:
-loss of SP spiny cell inhibition of GPi due to loss of D1 receptor activation of SP neurons -Gpi is disinhibited Increased activity in the indirect path -increased ENK spiny cell inhibition of GPe due to loss of D2 receptor inhibition of Enk neurons -STN is disinhibited Both of these effects tend to inhibit movement -Increase in Bradykinesia, Rigidity -Treatment with L-Dopa (to restore normal inhibition of Enk cells in the indirect pathway) and with anticholinergics to inhibit aspiny interneuron stimulation of Enk cells. |
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Normal vs abnormal dopaminergic input to striatum
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Direct:
With SNc dopaminergic input to the Putamen Direct Pathway (via D1 on SP neurons) the SP neurons are fire more frequently and inhibit the spontaneous activity of GPi releasing the thalamic stimulation of movement. Without SNc Dopaminergic input to the Putamen Direct Pathway (SNc death and dopamine depletion in Parkinson’s Disease) SP neurons are not stimulated so they fire less frequently and the spontaneous activity of GPi restrains the thalamus so there is a slowing or reduction of movement. Indirect With SNc dopaminergic input to the Putamen Indirect Pathway (via D2 receptor on Enk neurons) the Enk neurons are inhibited so they fire less frequently and the normal inhibition of GPe is released which in turn fully inhibits STN so that the GPi neurons fire less frequently releasing the thalamus to stimulate movement. Without SNc Dopaminergic input to the Putamen Indirect Pathway (SNc death and dopamine depletion in Parkinson’s Disease) Enk neurons are not inhibited so they fire more frequently and the STN is released from inhibition to strongly stimulate GPi firing so the thalamic nuclei are inhibited and there is a slowing or reduction of movement. |
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Hyperkinetic basal ganglia disorders
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Huntington’s Disease – section 16.6.5, KCC 16.3
-Cell Death in Striatum (severe Caudate degeneration) -Decreased activity and initial death of Enk-containing neurons Therefore, loss of indirect pathway -Progressive loss of all BG and Forebrain Functions -Chorea, dementia, psychiatric disorders, death -Autosomal dominant neurodegenerative disease :mutation associated with trinucleotide repeat in the Huntington gene (HD) on chromosome 4p. Hemiballism section 16.6.6 -Unilateral Subthalamic Nucleus Lesion -Loss of GPi output to thalamus decrease in thalamic inhibition |
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Athetosis, chorea, ballismus, tic, myoclonus, asterixis: Positive motor signs
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Athetosis
restless twisting movements of limbs, face or trunk (athetos – without position or place) Choreoathetosis (athetosis merged with chorea) Chorea continuous involuntary fluid or jerky movements that vary in quality and complexity (chorea – dance as in choreograph) Ballismus -large amplitude flinging or rotating movements of proximal limb joints - Hemiballismus is unilateral ballism Tic – sudden brief motor activity preceded by an urge and followed by relief Motor - face or neck tics Vocal – grunts, coughs, barks, coprolalia (speaking obscenities) Myoclonus sudden very rapid muscle jerk (many mechanisms)fastest type of movement disorder, focal, may be unilateral or bilateral contractions (many possible mechanisms) Palatal Myoclonus – unusual because persists during sleep Asterixis (lack of fixed position) “negative myoclonus” – toxicity “liver flap” tested by interrupted wrist extension with arms and wrist extended – hands fall while “stopping traffic” |
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Dystonia
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Is literally abnormal muscle tone, resulting in distorted positions of limbs, trunk or facial expressions.
Dystonia may arise from a variety of lesions including BG lesions and a variety of multisystem lesions seen with long term drug use or metal toxicity. Dystonias may be focal (isolated to muscles in one region of the body) or global or generalized. 1) Focal Dystonias -Torticollis – neck muscles (tortus - twisted collum - neck) -Blepharospasm – facial muscles (blepharon - eyelid) -Spasmodic Dysphonia – laryngeal muscles 2) Global or Generalized Dystonia -Primary idiopathic torsion dystonia -Multiple sites of twisted muscle distortion – hereditary disorder (idiopathic is sometimes described as essential means of unknown origin) |
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Tremor
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Resting Tremor – observed when limbs are at rest, decreases with intentional movement of limbs
-Parkinsonian tremor – “pill rolling” tremor Postural Tremor – observed when limbs are held in position – test with arms extended and held out Essential Tremor (postural tremor of unknown origin) – “idiopathic” -often early in life (familial), problems holding a full glass, fast tremor increases with stress, tremor improves with propranolol (b-adrenergic antagonist) or alcohol Intention Tremor -Cerebellar appendicular ataxia Irregular oscillating trajectory (ataxia) when moving toward a target Tremor Look Alikes (mistaken for tremors) -Clonus – vibrating reflex with UMN injury (hyperreflexia) -Myoclonus / Asterixis – sudden jerk or brief fall off -Fasciculations (fibrillations) – independent random firing of denervated muscle following LMN injury |
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Rigidity
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Increase limb resistance to passive movement
BG Lesion -“Lead pipe” (“plastic”) rigidity -Constant Resistance throughout attempts to move limb (bending) -“Cogwheel rigidity” Parkinsonian – ratchet-like interruptions in tone throughout limb bending Frontal Lobe Lesion -“Gegenhalten” (paratonia) – seems like “voluntary or active” resistance |
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Fucntions of the cerebellum
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Plan and help to initiate movement
Coordinate & refine movements - revise & correct ongoing movement Modulate vestibular reflexes - maintaining balance Modulate the control of eye Movements - crucial for controlling reflex eye movements including the vestibulo-ocular reflex (VOR) Motor learning & memory – participates in learning and remembering of repetitive procedures & skills The first four functions are related to specific regions of the cerebellum. The last is a global ability of all regions. The cerebellum can only influence movement by modifying the activity of Executive motor regions -No direct connection to lower motor neurons -Functions unconsciously (involuntary) -Major output motor cortex via thalamus -Additional projections to reticulo- and vestibulospinal -tracts |
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Classic cerebellar deficits
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Delay in the onset of initiation of movements
Ataxia Intention tremor Disdiadochokinesa -Can’t perform rapid alternating movements -E.g., pronation & supination of the hand Loss of muscle tone -Loss of tonic excitation of γ motor neurons There may also be vertigo, nausea, vomiting, and nystagmus. |
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Cerebellar cognitive affective disorder
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Deficits in:
-Cogniton -Executive function -visuospatial behavior -Emotional blunting, depression, psychosis Autism is characterized by cerebellar abnormalities |
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Cerebellum anatomy
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Primary fissure divides anterior and posterior lobe
Convolutions called folia Ant lobe + post vermis = spinocerebellum Most of hemisphere (post lobe) = Cerebrocerebellum Flocculonodular lobe = vestibulocerebellum Also have vermis, paravermis, and hemispheres |
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Phylogenetic subdivisions
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Archicerebellum/vestibulocerebellum
-Flocculonodular lobe -vestibular system Paleocerebellum/spinocerebellum -vermis of anterior lobe + inferior part of posterior vermis -spinal cord Neocerebellum/cerebrocerebellum/pontocerebellum -hemispheres and middle part of vermis -cerebral cortex via ventral pons |
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Deep cerebellar nuclea
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Deep cerebellar nuclei from lateral to medial: Dentate, Emboliform, Globose and Fastigial (Don’t Eat Greasy Food)
The emboliform and globose nuclei collectively called the “interposed” nuclei (i.e., between the dentate and the fastigial). Although the Vestibular nuclei are physically outside of the cerebellum, they function as deep cerebellar nuclei, receiving the output of the flocculonodular lobes, and to a lesser extent, the fastigial nuclei. These coordinate movement of the eyes and body in relation to gravity and head movement |
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Cerebellar peduncles
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Superior = output to thalamus, red nucleus & brainstem
-The superior cerebellar peduncles form a bridge that connects the cerebellum to the midbrain and thalamus for the ascending outputs of cerebellar deep nuclei Middle = input from pons -The axons of the pontocerebellar tracts cross the middle line in the pons and enter the cerebellum via the middle cerebellar peduncle. Thus, input from the right cerebral hemisphere goes to the left cerebellar hemisphere and input from the left cerebral hemisphere goes to the right cerebellar hemisphere. Inferior = input from spinal cord and brainstem -The inferior cerebellar peduncle is made up of a large lateral part, the restiform body, which carries the input from the spinal cord, and a small medial part, the juxtarestiform body, which carries the axons connecting the vestibular nuclei and the flocculonodular lobe of the cerebellum. The connections with the vestibular nuclei run both ways (input to and output from cerebellum) -Vestibular n -Olivary complex -Output to vestibular n reticular formation |
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Microanatomy of cerebellar cortex
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Three layers:
-Molecular Layer -Purkinje Cell Layer -Granule Cell Layer The external granule cell layer is only present in the developing cerebellum, up to about 1 year of age Thought to be a common source of childhood medullobastomas |
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Afferents and efferents of cerebellum
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Mossy fibers synapse on granule cells
-Regular cerebellar processing -From spinal cord and brainstem Climbing fibers synapse on Purkinje cells -Motor learning -From Inferior Olive All cortical output is via Purkinje cell axons Synapse in the deep nuclei Deep nuclei project out of cerebellum Afferents: -cortex (via pons) -vestibular and cochlear nuclei -inferior olive -spinocerebellar |
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Climbing fibers
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Involved in motor learning
Enter the cerebellum via the contralateral inferior peduncle Olivary inputs from -Cerebral cortex -Red nucleus -Brainstem & spinal cord |
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Spinocerebellar inputs to cerebellum
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Vermis:
Movement of trunk and proximal limbs muscles -Stability -Muscle tone Paravermis: Refines movement of distal muscles -Speeds initiation of movement -Stops unwanted and promotes wanted oscillations -Stabilizes holds |
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Vestibular inputs to cerebellum
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Originate in:
-Vestibular nuclear complex -Vestibular ganglia without synapsing in vestibular nuclei Travel in the inferior cerebellar peduncle (juxtarestiform body) Project to flocculonodular lobe and inferior vermis Concerned with -Posture -Equilibrium -Vestibulo-ocular reflexes Some flocculonodular lobe Purkinje cells project directly to vestibular nuclei |
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Pontine inputs to cerebellum
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Projections from almost all of the cerebral cortex
-Also from Basala Ganglia Decussate in pons before entering middle peduncle Largely project to lateral hemisphere |
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Cerebellar outputs
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Dentate nucleus to:
-parvocellular red n. to inferior olive -Caudal ventrolateral thalamus To primary motor cortex Interposed nuclei to: -magno cellular red nucleus (to spinal cord) -reticular formation -VLc thalamus Fastigial nuclei to: -reticular formation -vestibular nuclei -Hypothalamus |
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Regions function and nuclei in cerebellum
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Lateral hemisphere
-motor planning -dentate n. Intermediate (paravermis) -distal limb coordiation -interposed n. Vermis -proximal limb and trunck coordination -fastigial n. FN lobe and inferior vermis -equilibrium, balance, VOR -fastigial and vestibular n. |
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Cerebellar dysfunctions
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Ataxia
-Abnormalities in rate, range, and force of movement -Slowing of speed of initiating movement -Irregularity and slowing of movement, both on acceleration and deceleration --AKA intention tremor Abnormal involuntary movements -wing-beating tremor -Titubation -myoclonus Dysarthria: scanning or explosive speech Eye movement abnormalities -nystagmus -ocular dysmetria -slow saccades -impaired suppression of VOR Disorders of gait and equilibrium Loss of check reflex Diminished muscle tone (with acute lesions) |
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Three cerebellar arteries
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PICA
-Lateral Medullary Syndrome -Wallenberg syndrome AICA -Lateral Pontine syndrome -Marie-Foix syndrome SCA -Similar to PICA or AICA |
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Lesions of vermis and anterior lobe
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affect medial motor systems
-Wide-based, unsteady, gait resembling drunkenness -Difficulty performing tandem gait -Inability to stand with feet together -May have difficulty sitting without support -Titubation: rhythmic (3-4 Hz) tremor of head and upper trunk mainly in anteroposterior plane |
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Lesions of paravermis and lateral hemisphere
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affect lateral motor systems
-Ataxia in limbs --Abnormalities of rate, range, and force of movement --Dysmetria --dysrhythmia, --dysdiadochokinesia -Loss of check -Intention tremor, postural tremor |
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Pan-cerebellar syndrome
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Bilateral signs of cerebellar dysfunction affecting trunk, limbs, and cranial musculature
Usual causes: -Infection -Immune-mediated --Paraneoplastic cerebellar degeneration --Parainfectious -Toxic-metabolic |
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Extra-cerebellar causes of ataxia
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Locations of lesions outside the cerebellum that may cause ataxia
Cerebellar peduncles -Lateral medulla -Lateral pons -Midbrain -Ventral pons Frontopontine pathways -Hydrocephalus -Prefrontal cortex Spinal cord |
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Sensory ataxia
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Loss of proprioception: sensory ataxia
Sensory loss -Loss of proprioception +/- loss of vibration -Hypo- or areflexia -Due to abnormality of afferent limb of reflex arc -Positive Romberg sign |
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Vestibular inputs sent to:
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The medial & inferior vestibular nuclei
The thalamus and cortex for perception of movement and position of head in space The spinal cord for balance and posture The cranial nerve nuclei III, IV & VI for the control of extraocular eye muscles The cerebellum to assure muscular coordination and for motor learning -Some direct projections to FL lobe |
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Vestibulo-ocular reflex
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Signals from semicircular canals (head position) control activity of motor neurons projecting to extraocular eye muscles.
Flocculonodular lobe and vestibular nuclei coordinate this reflex. Vestibular system drives the eyes in the opposite direction of the head movement so that they move together and with the same velocity as the head. Head turning -Increases the rate of firing in the vestibular nucleus on the side toward which the head is turning -Decreases the rate of firing in the contralateral vestibular nucleus. Excitation of vestibular nucleus induces conjugate eye movement in the opposite direction. Vestibular nucleus projects to contralateral abducens nucleus -Abducens α motor neurons project to ipsilateral lateral rectus muscle Abducens interneurons project to contralateral oculomotor nucleus -Axons of these interneurons cross to opposite side of the brainstem and ascend in medial longitudinal fasciculus (MLF) to synapse in the oculomotor nucleus. -Oculomotor α motor neurons project to medial rectus |
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Effects of semicircular canals on eye muscles
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Horizontal
-excites: Ipsi med rectus Contra lat rectus -inhibits: Ipsi lat rectus Contra med rectus Posterior -excites: Ipsi sup Oblique Contra inf rectus -inhibits: Contra inf oblique Contra sup rectus Anterior -excites: Ipsi sup rectus Contra inf oblique -inhibits: Ipsi inf rectus Contra sup oblique |
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Oculocephalic reflexes
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Turning head makes eyes move in opposite direction
Usually performed in comatose person -Make sure the neck is not fractured or dislocated! Normal response is when both eyes to move conjugately in the opposite direction This response is usually inhibited by the cortex in a conscious person Assesses integrity of the entire pathway This is also called “doll’s eyes”, a very confusing term to be avoided. Describe the responses observed. |
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Oculovestibular testing (calorics)
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Caloric stimulation is a stronger stimulus of the vestibulo-ocular reflex than head turning and should be used if oculocephalic testing is contraindicated (due to neck instability) or if it fails to illicit a response
The usual caloric stimulus is cold water injected into the external auditory canal Before doing this, examine the ears to make sure the tympanic membranes are intact Irrigate the external auditory canal with cold water Creates currents in the endolymph Inhibits vestibular nucleus Eyes deviate toward the side where cold water was injected. In an alert patient, see corrective saccadic jerks in the opposite direction. -This is the basis of the mnemonic “COWS” = “Cold Opposite, Warm Same” In comatose patient, no corrective saccades are seen (saccades are voluntary movements) -Therefore, COWS mnemonic does not apply in this situation. -Deviation of eyes lasts about 10-25 seconds -Wait 5-10 minutes and test the other side |
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Muscle fiber types
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Are determined by motor neuron innervating the fiber
Type 1 -Sustained force, weight bearing -Slow twitch -Red -Many mitochondria -NADH-TR dark staining -ATPase pH 4.2 dark staining -ATPase pH 9.4 light staining -Abundant lipids -Scant glycogen Type 2 -Sudden movements, purposeful motion -Fast twitch -White -Few mitochondria -NADH-TR light staining -ATPase pH 4.2 light staining -ATPase pH 9.4 dark staining -scant lipids -abundant glycogen |
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Neurogenic atrophy and reinnervation
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The first thing that happens in denervation is that the denervated muscle fibers become atrophy…..The contours of the muscle fiber when seen in cross section look angular rather than round with denervation. If there is a viable axon, it can sprout and reinnervate the previously denervated muscle. If the neuron is a different type, the muscle fiber type will change. This results fiber type grouping….large groups of muscle fibers that are all the same type. There should be groups of both types of muscle fibers in fiber type grouping. If there is around episode of denervation, or ongoing denervation, atrophy of groups of muscle fibers that are the same type is seen. This is called group atrophy
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Pyknotic nuclear clumps
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The muscle fibers are so atrophic they have been reduced to clump of nuclei. This finding is seen in denervation atrophy.
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Myopathies
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Muscular dystrophies
Ion-channel myopathies -Myotonia and paramyotonia -Dyskalemic episodic weakness -Malignant hyperthermia Congenital myopathies Metabolic myopathies -Mitochondrial diseases -Lipid storage diseases -Glycogen storage diseases Myopathies associated with endocrine diseases Inflammatory myopathies -Infection-related: viral myositis, trichinosis -Immune-mediated Toxic myopathies -Drugs --HMG CoA reductase inhibitors (statins) necrotizing myopathy --Steroid myopathy proximal muscle weakness with type 2 fiber atrophy -Chemical toxins -Critical illness myopathy |
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Myopathic changes
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Non-specific changes associated with primary muscle diseases include segmental necrosis of muscle fibers (see upper picture), phagocytosis of necrotic areas, loss of fibers, rounded atrophy of some fibers, hypertrophy of others which may result in fiber splitting (see lower picture), fibrosis, and infiltration of muscle by fat in the end stages.
In some conditions, there is an increase in the number of myofibers exhibiting internal nuclei. This is a non-specific finding. In some primary muscle disease changes in the structural proteins or organelles can occur. This is a ring fiber seen in a cross-section of a muscle fiber where the myofilaments should be oriented perpendicular to the plane of the slide. |
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Some of the molecules affected in muscular dystrophies
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Cytoskeletal proteins form a link between extracellular matrix and actin
Stabilize sarcolemma against mechanical stress of cycles of contraction and relaxation May also have a role in signal transduction |
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Muscular dystrophy classifications
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X-linked: Duchenne, Becker, Emery-Dreifuss MD
Pattern: Limb-Girdle MD (numerous subtypes now recognized), Facioscapulohumeral MD, Oculopharyngeal MD Myotonia: Myotonic MD vs non-dystrophic hereditary myotonias (now known to be ion-channel myopathies) “Congenital muscular dystrophies” not to be confused with “congenital myopathies” |
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Duchenne muscular dystrophy overview
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X-linked recessive; gene at Xp21.
-Girls and women may be manifesting carriers --Weakness, calf hypertrophy, increased serum CK -Symptoms usually detected at 3-5 years -Walking may be delayed (never run normally) toe-walking and waddling gait overt difficulty walking, climbing stairs, rising from chairs Increased lumbar lordosis, falling, Gowers’ sign WC by age 9-12 years (scoliosis and contractures) Respiratory difficulty and mechanical ventilation needed by age 20 --Hands and arms affected late --Speech, swallowing, ocular movements spared --May have cardiomyopathy with CHF Becker’s Muscular Dystrophy, another dystrophinopathy -Age of onset usually after 12 years -Still walking by age 20 years |
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Duchenne muscular dystrophy pathology
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Pathologic changes include variation in fiber size, rounded atrophy of fibers, scattered hypertrophic opaque (dark-looking) fibers, muscle fiber necrosis, regenerating fibers, fibrosis and fat infiltration.
Becker muscular dystrophy is also related to abnormalities of dystrophin and has a more protracted clinical course. Pathologic changes are similar. |
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Duchenne muscular dystrophy physiology
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Serum CK usually ≥ 20 times normal
-Risk for myoglobinuria after general anesthesia Dystrophin is a normal protein -Associated with membrane glycoproteins that link it to laminin on external surface of muscle fiber --Dystrophin is absent in DMD --Dystrophin is abnormal in BMB (decreased in amount and abnormal in size) -Not clear why abnormalities in dystrophin result in clinical syndrome or high CK levels. DNA analysis -60-70% of patients have deletion or duplication at Xp21 -Remainder have point mutations (difficult to identify) |
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Myotonic MD overview
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Genetics:
-Autosomal dominant -Almost complete penetrance -Gene at 19q13.2 --CTG repeat --Dystrophia myotonica protein kinase (DMPK) gene --Direct DNA diagnosis possible Prevalence: 5 per 100,000 Incidence: 13.5 per 100,000 live births Multisystem disease: myotonia, cardiomyopathy, ocular cataracts, endocrinopathy Variation in age of onset and severity Most common MD of adults |
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Myotonic MD clinical signs
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Cranial muscle involvement
-Ptosis -Facial weakness -Dysarthria and dysphagia -Wasting of temporalis muscles and SCMs Distal > proximal weakness -Hand and feet affected equally -Weakness of finger flexors -Foot drop: steppage gait Weakness of muscle of respiration: hypersomnia Rate of progress is usually slow |
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Myotonia
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Impaired relaxation
-Most evident in hands: difficulty letting go -May elicit (percussion) myotonia by tapping on thenar eminence, forearm, or finger extensors -Myotonia persists after curare given (i.e., after neuromuscular transmission is blocked) EMG: waxing and waning high-frequency discharge that continues after relaxation begins (essential for diagnosis of myotonia) |
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Congenital myopathies
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These usually present early in life, as a ”floppy baby” and are slowly progressive. Some are associated with skeletal abnormalities. Several different patterns of inheritance have been described for each. In the lower figure the dark reddish blobs are nemaline rods (made of Z-band material). The pictures to the left show centronuclear myopathy. (Recall the muscle fiber nuclei should be at the periphery in mature muscle).
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Mitochondrial myopathies
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Can be the results of mutations in nuclear or mitochondrial genes. Mitochondrial myopathy is often a feature of a more generalized mitochondrial disease.
Irregular aggregates of mitochondria are seen with the modified Gomori trichrome stain, often in a subsarcolemmal location (see upper picture). These are called “ragged red fibers”. With electron microscopy, the mitochondria are increased in number and exhibit abnormalities in size and shape. Some have paracrystalline inclusions (see lower figure). |
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Lipid storage myopathies
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Lipid is demonstrated with Oil red O (seen here) or Sudan black stains. Deposition occurs predominantly in type 1 fibers.
Due to deficiencies in carnitine, acyl-CoA dehydrogenase, or carnitine palmitoyltransferase (CPT). Carnitine deficiency occurs as a myopathy alone (weakness) or part of a systemic illness. CPT deficiency often presents as recurrent myoglobinuria. |
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Glycogenoses
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Defects in enzymes glycogen metabolic pathway
Examples: -Myophosphorylase deficiency (McArdle’s disease) -Phosphofructokinase deficiency -Acid maltase deficiency Usually associated with: -Exercise intolerance -Cramps -Myoglobinuria Can occur as systemic disease or as disease of muscle alone. Periodic acid-Schiff (PAS) stain shows glycogen accumulation as magenta blobs (see right side; normal muscle on left for comparison.) |
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Polymyositis overview
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Subacute (usually) onset of weakness
-Nadir in months rather than weeks or years -Onset usually after age 35 years Proximal muscle weakness (including neck) Eyelids and EOM not involved Dysphagia may be present but dysarthria not usually seen Arthralgias (without arthritis), myalgias, Raynaud symptoms may occur May occur as isolated problem or as part of systemic disease (usually collagen-vascular) in about half of cases No rash No family history of similar problem Serum CK levels usually ≥ 10-times normal Muscle biopsy important for diagnosis Responds to steroids and immunosuppressive therapy |
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Polymyositis pathology
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Biopsy shows a mononuclear cell infiltrate consisting of CD8+ cytotoxic T-cells and macrophages.
The inflammation is endomysial and perimysial. No vasculitis is present. Muscle fiber necrosis is also seen. Absence of inflammation on biopsy does not rule out this diagnosis. Inflammation is not continuous and its absence may be due to sampling error. |
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Dermatomyositis overview
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Differences compared to polymyositis
-Rash -DM occurs at all ages (including children) -Weakness often more severe in DM -Rarely associated with collagen vascular diseases, except scleroderma -About 10% of cases starting after age 40 years are associated with cancer, especially lung and breast carcinomas. -Muscle biopsy is usually performed; skin may be biopsied as well. -It is possible to have dermatomyositis sine myositis |
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Dermatomyositis pathophysiology
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Skin changes: lilac (heliotrope) discoloration of eyelids, periorbital edema, and scaly red patches over knuckles, knees, and elbows (Grotton lesions).
In addition to inflammation, perifascicular atrophy is seen on biopsies. Lymphocytes are B-cells and CD4+ T-cells. Capillaries are attacked by antibodies and complement inducing necrosis in muscle. |
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Inclusion body myositis similarities and differences with polymyositis
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Similarities:
-Inflammatory myopathy -No rash -Rarely affects children -Dysphagia may be present -Not a paraneoplastic disease Differences: -IBM more likely to affect distal muscles -Long finger flexors commonly involved -IBM usually seen in men > 50 years old -IBM may show mixed neurogenic and myopathic features -IBM less often associated with collagen vascular or other autoimmune disease -IBM does not respond to steroids -IBM muscle biospy rimmed vacuoles and inclusion bodies This disease does not respond to corticosteroids, so the distinction between IBM and polymyositis is important. |
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Inclusion body myositis pathogenesis
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Often involves quadriceps, wrist and finger flexors, and ankle dorsiflexors early; weakness may be asymmetric.
The pathogenesis of this illness is unknown. Biopsy shows “rimmed vacuoles”, called that because of the granular basophilic material at the periphery of the vacuoles, and nuclear and cytoplasmic inclusion bodies consisting of tubular and filamentous material (seen with EM). |
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Type 2 fiber atrophy
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This is a non-specific finding associated with disuse, corticosteroid therapy, endocrinopathies, collagen vascular diseases, uremia, pregnancy, myasthenia gravis, paraneoplastic syndromes, and some CNS problems.
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Myasthenia gravis epidemiology
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Prevalence about 14 per 100,000
Before age 40: 3 times more common in women; after 40, F= M. Familial cases rare, but first-degree relatives have increased incidence of other autoimmune diseases Thymus pathology -65%: lymphoid hyperplasia -15%: thymoma |
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Myasthenia gravis clinical features
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Weakness:
-Fluctuates --During a single day --Over longer period: exacerbations and remissions --Crisis: weakness associated with inadequate ventilation -Distribution of weakness --Ocular muscle affected first in about 40% of cases --Ultimately involved in 85% of cases --If restricted to ocular muscles for 2-3 years, likely to remain restricted --Facial weakness, dysarthria, dysphagia common --Limb and neck weakness may be present, but almost never without cranial weakness -Clinical improvement with cholinergic drugs |
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Myasthenia gravis diagnosis
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Electrophysiologic diagnosis:
-Progressive decrement in amplitude of muscle action potential with repetitive nerve stimulation seen in 90% of cases Antibodies to acetylcholine receptors -85-90% of patients with generalized MG -50% of patients with ocular MG |
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Myasthenia gravis pathophysiology
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Antibodies to acetylcholine receptors increase the degradation of the receptors.
Muscle biopsy is usually not needed to make this diagnosis, but if done, it shows type 2 fiber atrophy in more advanced cases. Fixation of complement by antibodies results in injury to the post-synaptic membrane causing “simplification” or loss of folds and thus decreased surface area |
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Lambert-Eaton myasthenic syndrome overview
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Weakness and difficulty walking that improves with effort
Hypoactive reflexes May have autonomic insufficiency Paraneoplastic syndrome: 60-70% with LEMS have cancer, usually small cell lung cancer Antibodies to pre-synaptic calcium channels: decreased release of acetylcholine Usually responds to immunosuppression or plasmapheresis |
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Axonal degeneration
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longest fibers first
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Wallerian degeneration
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Transection of an axon results in breakdown of the myelin, and later of the axon, distal to the site of injury and in the distal 2-3 internodes proximal to the injury. Phagocytosis of debris by Schwann cells macrophages occurs. The neuron cell body becomes rounded, the nucleus moves to the periphery, and the ribosomes in the Nissl substance disperse (hence, the term “central chromatolysis”). Schwann cell proliferate within the tubes of basal laminae left over from the original Schwann cells. This results in the formation of tubes of cells which help guide the sprouting axon back to the muscle during nerve regeneration (rate = about 1mm/day).
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Nerve biopsy
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Usual nerve biopsied: sural nerve.
Goal of biopsy: look for specific causes of neuropathy, some of which may be treatable. Only a few specific problems can be diagnosed with biopsy. Vasculitis Sarcoidosis Leprosy Amyloidosis Inflammatory neuropathies Hypertrophic neuropathies Biopsy is not needed in most cases of neuropathy. |
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Vasculitis
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These sections are stained with a trichrome stain so that collagen appears blue. The lighter blue areas are the nerve fascicles. The red circular structure is a blood vessel exhibiting fibrinoid necrosis (which accounts for the red stain) and inflammation.
The possibility of vascultis is one of the major indications for a nerve biopsy, because it is treatable and requires urgent medical intervention. |
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Leprosy
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In the lepromatous form of the disease, patients are anergic to lepromin (an antigen extracted from the organisms). These patients have more diffuse lesions containing macrophages stuffed with organisms (multibacillary leprosy). In the nerves, Schwann cell involvement results in demyelination, but axons are also lost. The nerves are not usually enlarged in this form of the disease. Anesthesia of the extremities contributes to injury.
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Amyloidosis
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Familial amyloidosis, which is an autosomal dominant disease, results in amyloid deposits in vessel walls and connective tissue in nerves causing axonal degeneration and sensory and autonomic neuropathies.
Amyloid is demonstrated with the Congo red stain (see left), which stains amyloid deposits a salmon color. With polarization, the deposits have an apple-green birefringence (see right). |
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Guillain Barre Syndrome overview
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AKA acute inflammatory demyelinating polyradiculopathy (AIDP)
-Most frequent acquired demyelinating neuropathy Acute-to-subacute onset of peripheral and cranial nerve dysfunction -Symmetrical weakness -Facial diplegia occurs in about 50% of cases -Weakness may initially be worsen in proximal muscles (unlike most neuropathies); but may start distally and ascend rapidly -Mechanical ventilation may be needed Sensory changes -Muscle pain and paresthesias common -Objective sensory loss is highly variable Reflexes are lost after the first few days Autonomic dysfunction is common |
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Guillan Barre epidemiology and prognosis
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Incidence about 2 per 100,000 people
Predisposing factors: viral respiratory or GI infection, immunization, general surgery precede neurological symptoms by 5 days to 3 weeks. Nadir of symptoms by 3 weeks Prognosis: majority have good recovery with no or mild neurological deficit -Early plasmapheresis and IVIG (intravenous immunoglobulin) therapy are beneficial; glucocorticoids are not. -Death occurs in about 2-5% of patients due to: --Aspiration pneumonia --Pulmonary embolism --Infection --Autonomic dysfunction |
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Guillan Barre pathophysiology
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CSF findings
-Normal pressure -Acellular or contains few lymphocytes (< 50 mm3) -Protein initially normal but rises, peaking at 4-6 weeks Electrophysiologic findings reflect presence of demyelination -Slowed nerve conduction velocity or conduction block -Prolonged distal latencies -Prolonged or absent F-reflexes |
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Onion bulb formations
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Layers of Schwann cells and collagen surrounding axons due to repeated episodes of demyelination and remyelination
Short list of causes: -Diabetes mellitus -Chronic inflammatory demyelinating polyneuropathy (CIDP), -Inherited neuropathies --Charcot-Marie-Tooth (HSMN type I) --Dejerine-Sottas (HSMN type III) --Refsum (a defect in phytanic acid metabolism) |
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Hereditary neuropathies
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Hereditary motor and sensory neuropathies (HMSN)
-Type 1 = Charcot-Marie-Tooth, hypertrophic form -Type 2 = CMT, not associated with hypertrophy -Type 3 = Dejerine-Sottas Hereditary sensory and autonomic neuropathies (HSAN) Inherited enzyme defects -Leukodystrophies (see lecture on Myelin) -Amyloidoses -Porphyrias -Refsum’s disease |
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Diabetic neuropathy pattern
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Most common cause of neuropathy
Patterns: 1) Distal symmetric polyneuropathy; 2) Mononeuropathy cranial nerve palsies, e.g., CN-III 3) Mononeuropathy multiplex 4) Autonomic neuropathy Distal symmetric sensory or sensorimotor neuropathy is predominantly an axonal degeneration (a “dying back” neuropathy affecting distal most areas first). In addition to loss of axons, biopsies show hyalinization of arterioles and reduplication of basement membranes. Most common form of diabetic neuropathy is diffuse distal symmetric polyneuropathy -Sensory > motor (weakness is minor) May be accompanied by autonomic neuropathy -Associated with increased risk of mortality compared to general diabetic population --RR intervals on EKG at rest, deep breathing, standing --Changes in BP supine and standing Develops slowly; related to duration of DM Small fibers affected first -Pain & temperature before proprioception and vibration |
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Diabetic neuropathy transient neuropathies
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Acute painful neuropathy
-Burning pain in stocking distribution -Recovery of severe pain usually complete in 1 year Mononeuropathies -Nerve prone to compression or entrapment -Cranial nerves, especially oculomotor and abducens Diabetic amyotrophy -Pain, asymmetric weakness and atrophy of iliopsoas, quadriceps, and adductor muscles --Loss of patellar reflex -Older non-insulin dependent diabetics -Severe weight loss and cachexia -Resolves spontaneously but may last 1-3 years |
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Excitotoxicity
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Excessive glutaminergic stimulation: neuronal death
-Stimulation causes excessive calcium entry into cell -Stimulation triggers second messenger systems Expression of different types of glutamate receptors may account for selective vulnerability of certain neurons to this kind of damage |
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Protein aggregates
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Form inclusion bodies in cells that are diagnostic hallmarks of disease
Inclusions may be a: -Marker of the underlying primary disease process. --Protein aggregates toxic to cells: cell death via apoptosis --Protein aggregation could also reflect sequestration of toxic proteins: protection of cell from toxic effects of proteinopathy -Non-specific secondary marker of cell injury. |
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Clinical manifestations of ALS
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Both UMN and LMN signs are present
Combination of hyperreflexia and Hoffmann sign with weak, wasted, fasciculating muscles is highly characteristic Dysarthria, tongue wasting and fasciculation, impaired movement of uvula Pseudobulbar palsy: dysarthria, dysphagia, uvula does not more well or phonation but vigorously in testing gag reflex, emotional lability (frontal release) Weakness: limbs, oropharynx Asymmetric weakness of hand is a common presentation Impaired gait: -Foot drop -Spasticity Muscle cramps -Due to denervation hypersensitivity Weight loss (muscle wasting and dysphagia) Respiration usually effected late Sensation intact, unless there is a complicating disease Bladder function is spared Eye movements usually spared |
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Course of ALS
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Relentless and progressive without remission or plateaus
Death from respiratory failure, aspiration pneumonia, pulmonary embolism (due to immobility) 80% die in 3-5 years after onset of symptoms 10% have associated dementia Accuracy of clinical diagnosis is thought to be > 95%. |
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Epidemiology of ALS
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Onset
-Middle to late life -Only 10% before 40 yrs Men > women 5-10% familial -Of these, 20% are related to autosomal dominant mutation in superoxide dismutase 1 (SOD1) --Thought to be a toxic gain of function and not loss of antioxidant function, possibly due to abnormal folding of mutant SOD1 protein and protein aggregation. |
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Pathogenesis of ALS
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No known environmental factor identified, even in Guam which has a high incidence of:
-Parkinson-ALS-Dementia complex; -ALS alone. Lead and mercury intoxication can cause similar syndrome, but heavy metals have not been showns to cause ALS. Excitotoxicity: -Riluzole (Rilutek), glutamate antagonist, prolongs life 3-6 months but does not affect quality of life or function. Autoimmunity: -Increased incidence of monoclonal gammopathy or lymphoproliferative diseases (but these are found in < 10% of cases) -Paraneoplastic forms of MND exist -However, immunotherapy is not effective against ALS. Infection (association, but causation not proven): -MND as been reported in patients with: --HIV --Human T-cell lymphotrophic virus, type 1 -Prion diseases (e.g., Creutzfeldt-Jakob disease) may exhibit lower motor neuron signs Angular atrophy of both type 1 and type 2 fibers. |
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Microscopic pathology of ALS
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Loss of motor neurons and gliosis in spinal cord, brainstem, motor cortex
Neurogenic atrophy of skeletal muscle (see next slide) Inclusion bodies in motor neurons -Bunina bodies, stain for cystatin, lysosomal cysteine proteinase inhibitor -Hyaline inclusions -Ubiquitinated skein-like inclusions Spinal motor neurons may be ballooned due to accumulation of phosphorylated neurofilaments Degeneration of myelinated fibers in corticospinal tracts Clinically silent involvement of non-motor-neuron regions also seen. |
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ALS Differential diagnosis
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Cervical spondylosis
-Degenerative changes in cervical vertebral column form fibrous and calcified osteophytes compressing spinal nerve roots and spinal cord Cervical spondylosis versus ALS: -LMN signs in hand without sensory involvement favor ALS -Fasciculations in legs or tongue favor ALS -Neck pain, paresthesias, sensory loss favor spondylosis Multifocal motor neuropathy with conduction block -Conduction block in > 1 nerve (not due to entrapment) -Asymmetric hand involvement in men -50% have active reflexes in limbs with LMN signs -Progresses more slowly than ALS; little disability after 5 years of symptoms -Treatment with immunosuppressive drugs or IVIG -Autopsy shows involvement of motor neurons as well as peripheral nerves |
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Kennedy's disease
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X-linked spinobulbar muscular atrophy
-Slowly progressive LMN weakness of facial, bulbar, proximal limb muscles -Onset in adolescence or later Differs from ALS: -No UMN signs -Subtle sensory loss in some patients Increased CAG repeats in first exon of androgen receptor gene -Androgen insensitivity: gynecomastia, testicular atrophy, oligospermia (infertility) -Nuclear inclusions: aggregated androgen receptor |
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Secondary motor neuron diseases
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Infections
Metabolic -thyroid Immune Environmental -heavy metals Paraneoplastic -lymphoma |
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Spinal muscular atrophies
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Lower motor neurons only
Locus on chromosome 5 (autosomal recessive) -Survival motor neuron (SMN) gene involved -Usually a deletion, which may also involve the neuronal apoptosis inhibitory protein (NAIP) gene. Types (related to age of onset): -SMA-type 1: Severe infantile form (Werdnig-Hoffman) --80% of cases of SMA -SMA-type 2: Chronic childhood form -SMA-type 3: Juvenile (Kugelberg-Welander) --Proximal muscle weakness resembling a primary myopathy --Electrophysiological testing and muscle biopsy show evidence of denervation -SMA-type 4: Adult --Onset > 25 year old --Mild |
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Werdnig Hoffman Disease overview
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Onset between birth and 6 months old
Can be cause of fetal hypokinesia in 3rd trimester Alert with normal intelligence but weak and floppy -Flaccid quadriplegia (hypotonia) -Frog-leg position, i.e. hips abducted & knee flexed -Swallowing and feeding difficulties -Tongue fasciculations -Weakness of muscles of respiration: mechanical ventilation -Areflexia Most die before age 2 years |
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Werdnig hoffman diagnosis
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Unlike ALS, these patients often have muscle biopsies to confirm the diagnosis of this fatal disease.
-Rounded atrophic fibers often involving entire fascicles; -Scattered hypertrophic fibers, usually type 1. |
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Synuclein
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Protein found in synaptic terminals and nuclear envelope; functions not well understood.
Ubiquitously expressed in all brain regions Three types: α, β, γ; only α-synuclein associated with filamentous inclusions Missense mutations in α-synuclein gene (chromosome 4): rare cause of familial Parkinson’s disease Lewy bodies, Lewy neurites, and glial cytoplasmic inclusions are immunoreactive for α-synuclein |
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Causes of parkinsonism
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Drugs: dopamine antagonists, calcium channel blockers, lithium
Toxins: manganese, iron, carbon monoxide, cyanide, methanol, pesticides, -MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) Infections: AIDS, CJD, fungus. post-encephalitis Trauma: head trauma increases risk Vascular Metabolic: Wilson’s disease, hypoparathyroidism Paraneoplastic Neurodegenerative diseases (partial list): -Parkinson’s Disease, described in 1817 by James Parkinson -Dementia with Lewy bodies (Diffuse Lewy Body Disease) -Multiple system atrophy |
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Parkinson's disease epidemiology
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Idiopathic, sporadic PD = 75% of cases of parkinsonism
-About 5% of cases are familial Interaction between genetic vulnerability and environmental factors -Risk factors: family history, male gender, head injury, pesticides, well water, rural living. -Reduced risk: caffeine, nicotine, NSAID use, estrogen replacement in post-menopausal women. |
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Parkinson's disease pathology
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Loss of pigmentation in substantia nigra
Lewy bodies |
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Lewy body components
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Functional proteins
-Neurofilament proteins (NFP) -Ubiquitin – involved in cytosolic proteolysis -α-synuclein – neurofilament chaperone -Kinases – phosphorylation Incorporated proteins -Tubulin and microtubule-associated proteins -β-amyloid precursor protein -Synaptic proteins Classical (upper figure): -Roughly spherical with eosinophilic core and surrounded by paler ‘halo’ -More than one may be present in one cell Cortical (lower figure): -Small neurons in cortical layers V & VI -Less clearly defined than classical LB -Lack halo |
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Multiple system atrophy overview
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Sporadic
Progressive -Median survival = 6-10 years after onset of symptoms Reported in all races Males > females -May be diagnosed more readily in males exhibiting impotence Etiology unknown |
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MSA syndromes
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Striatonigral degeneration (parkinsonism predominates); now called MSA-P.
Shy-Drager syndrome (autonomic failure predominates) Olivopontocerebellar atrophy (cerebellar ataxia predominates); now called MSA-C. -Not the same as the hereditary OPCAs -Hereditary OPCAs are now classified with spinocerebellar ataxias (SCAs). |
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Features suggesting MSA over parkinson's
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Poor response to levodopa
Rapid progression to disability Prominent autonomic features Rigidity and bradykinesia out of proportion to tremor Falls occur early in disease Speech severely affected Abnormal aspiration, inspiratory gasps, stridor Absence of dementia (i.e., dementia is more common with PD) Diagnosis of definite MSA requires neuropathological confirmation -About 10% of patients thought to have PD are found to have MSA at autopsy. |
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MSA Gross pathology
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Atrophy of involved areas
Pallor of substantia nigra and locus ceruleus Discoloration of putamen (see next slide) May have mild cortical atrophy Spinal cord grossly normal even if autonomic failure is present; but neuronal loss in intermediolateral column is present on microscopic examination. In addition to pallor of SN and LC, atrophy and slate-gray discoloration of putamen is seen. Color is due to accumulation of lipofuscin-like pigment. Involvement of striatum is basis of poor response to levodopa. |
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MSA microscopic pathology
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Neuronal loss and gliosis of affected regions
Loss of myelinated fibers Cytologic abnormalities -Glial cytoplasmic inclusions (see next slide) -Loss of neurons and oligodendroglia -Neuronal cytoplasmic inclusions -Nuclear inclusions -Neuropil threads Eponym = Papp-Lantos inclusions GCI occur in oligodendroglia -Hypothesis: impaired trophic function between oligos and neurons secondary neuronal damage -Myelin degeneration also present and may play role in pathogenesis of MSA. α-synuclein & ubiquitin positive |
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Tau
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Microtubule-associated protein active primarily in distal axons
Stabilizes microtubules to promote microtubule assembly Microtubules are made of repeating αβ-tubulin heterodimers that are labile unless stabilized by other molecules. Process controlled by phosphorylation and isoforms Phosphorylation -Phosphorylation (by kinases) disrupts microtubule assembly -Hyperphosphorylation of tau (seen in disease states) can result in self-assembly of tangles of paired helical filaments and straight filaments Isoforms have either 3 or 4 microtubular binding domains, called 3-repeat-tau or 4-repeat-tau. -Two types are normally expressed about equally; -Altered ratios of these two types in disease states. |
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Progressive supranuclear palsy
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Progressive akinetic-rigid syndrome starting after age 40 years
-Axial rigidity > appendicular rigidity --Retrocollis -Symmetric onset of symptoms (compared to PD) -Cogwheel rigidity is present, but tremor is uncommon. -Relative lack of response to levodopa Progressive supranuclear gaze palsy -Down gaze affected before up gaze -Lateral eye movements usually preserved Slowing of vertical saccades Progressive and prominent postural instability -Falls begin in first year (more rapidly progressive than PD) Neurobehavioral: apathy, slowness of thinking and responding, impaired attention, difficulty shifting cognitive set, impairment of memory, concept formation, planning, and execution. -Disconnection between basal ganglia and frontal lobes -Cognitive decline more rapid that in PD or MSA |
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PSP epidemiology
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2nd most common cause parkinsonism after PD
-Prevalence is about 10% of that of PD Peak onset: 63 years old Median survival: 6 years after symptom onset Few familial cases Environmental factors -Tropical fruits and herbal teas containing tetrahydroisoquinolones -Inhibition of mitochondrial complex I |
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PSP pathology
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Gross
-Loss of pigment from SN and LC -Atrophy of rostral midbrain, superior cerebellar peduncles, and pons Microscopic -Neuronal loss and gliosis -Fibrillary tau pathology --Neurofibrillary tangles --Round to globose --Straight filaments and filaments with long periodicity --Neuropil threads --Tau immunoreactivity in astrocytes and oligodendroglia |
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Corticobasal degeneration overview and clinical features
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Average age of onset about 60 years
Early phase (years 1-3): asymmetric clumsiness, stiffness, or myoclonus Middle phase (years 3-5): dystonic rigidity and akinesia of limbs, ‘alien limb’, lower limb apraxia, pyramidal signs, cortical sensory loss; findings progress to become bilateral Late phase (years 5-8): cognitive dysfunction and frontotemporal behavioral deficits (dementia and aphasia) |
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Corticobasal degeneration pathology
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Gross
-Depigmentation of substantia nigra and locus ceruleus -Asymmetric frontoparietal atrophy, especially in pre- and post-central regions Microscopic -Neuronal loss and gliosis -Spongiosis (microvacuolation) of superficial cortical layers -Neuronal achromasia (swollen neurons, balloon cells) -Glial and neuronal intracytoplasmic filamentous inclusions (tau-positive, ubiquitin-negative) -Paired helical filaments and straight filaments |
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Post-encephalitic parkinsonism overview
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Pandemic of encephalitis lethargica between 1915-1925
-Described by Constantin von Economo in 1915 -Non-infectious, non-transmissible disease of unknown cause -Contemporaneous with influenza pandemic --Recent PCR studies on archival tissue failed to identify H1N1 influenza viral DNA (or any other causative agent). PEP cases between 1925-1938 accounted for almost 50% of cases of parkinsonism diagnosed at that time. -This deceased to about 6% in an autopsy series from 1957-1970. -Now has virtually disappeared -Condition portrayed in the movie, Awakenings |
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Friedreich's ataxia pathology
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Spinal cord is thin
-Loss of axons in posterior columns, corticospinal tracts, spinocerebellar tracts -Loss of neurons in Clarke’s column Loss of neurons in dorsal root ganglia thin posterior nerve roots, especially lumbosacral Loss of neurons in nuclei of CN 8, 10, 12 Cerebellum -Loss of neurons in dentate, Purkinje cell of cerebellar vermis, and inferior olivary nuclei -Loss of axons in middle and superior cerebellar peduncles |
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Post-encephalitic parkinsonism pathology
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Gross:
-Reduced pigment in SN > LC; more than in PD. -May be mild generalized cortical atrophy Microscopic: -Neuronal loss and gliosis -Neurofibrillary tangles (NFT) -Paired helical filaments -Tau-positive cytoplasmic inclusions in astrocytes -Fragmented and swollen axons with neurofilament staining |
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Wilson's disease
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Autosomal recessive disease due to copper
accumulation in tissues (brain, eye, liver). Decreased serum copper and ceruloplasmin, increased urinary copper excretion Presents as liver disease. Then extrapyramidal movement disorder and dementia occurs. Neurologic problems can be prevented by early institution of chelation therapy. Kayser-Fleischer ring (eye) Necrosis and discoloration of basal ganglia |
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HD clinical features
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Movement disorder: chorea, hypokinesia, dystonia, tics, myoclonus
-Initially chorea; over time hypokinesia and dystonia develops. Dementia Psychiatric disturbances -Personality changes, irritability, aggressiveness, mood changes -Depression with increased risk of suicide Cachexia -Movement disorder burns energy -Difficulties with eating and swallowing -Loss of interest in food -Changes in hypothalamic function Initial symptoms are usually subtle chorea and behavioral changes |
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HD Genetics
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Autosomal dominant;
Locus of gene is chromosome 4p16.3 5'-end (N-terminus) of the gene has CAG trinucleotide repeats polyglutamine (poly Q) amino acid tail in protein -More than 35 copies unstable DNA replication increase in number of repeats -Asymptomatic parents with repeat count near 36 may have affected child with repeat-length in symptomatic range (“de novo” onset seen in up to 10% of cases) -Juvenile onset associated with paternal inheritance --High number of cell division during spermatogenesis paternal repeat instability. |
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Huntingtin (Htt)
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Widely distributed protein of unknown function
-Critical in early embryonic development -Absence is lethal in mice Selective vulnerability of striatum thought to be due to altered interaction of Htt with other proteins enriched in striatum due to the presence of polyglutamine repeat in mutant huntingtin (mHtt) Effect of mutant Htt (mHtt) thought to be due to a toxic gain in function. Fragments of mHtt, when present in nucleus, interfere with transcription proteins. -Nuclear localization appears to be necessary for mHtt toxicity. Aggregates of these mHtt fragments are seen in nucleus in HD. -Not clear if aggregates are toxic, harmless, or protective. |
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HD Gross pathology
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Atrophy of neostriatum: region most affected in HD
May have frontotemporal cortical atrophy |
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HD micropathology
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Loss of medium-sized, inhibitory spiny neurons in striatum increased inhibition of subthalamic nucleus
Encephalin containing neurons affected first (see red arrow). “Spiny” neurons are those with many dendritic spines (see next slide) that project out of the striatum. Aspiny neurons are interneurons. Neuronal loss is accompanied by gliosis. |
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Friedreich's ataxia
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Most common form of progressive spinocerebellar ataxia
-Accounts of about 50% of cases of SCA AR, chromosome 9q13, GAA repeat Protein = frataxin -Frataxin inner mitochondrial membrane, regulation of iron levels, used in complexes involved in oxidative phosphorylation -Mutation iron accumulates free radical damage mitochondrial dysfunction |
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Friedreich's ataxia clinical symptoms
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Onset of symptoms usually first decade
Progressive wheel chair bound in 5 years Ataxia (both sensory and cerebellar) is initial symptom Involvement of posterior columns and cerebellum Clumsiness of hands Incoordination of speaking, breathing, and swallowing Areflexia, due to involvement of dorsal root ganglia Weakness, extensor plantar response (Babinski sign) and flexor spasms due to corticospinal tract involvement Pes cavus (high-arched feet) and hammertoes (retraction at MRP joint and flexion at IP joints), due to early onset peripheral neuropathy Kyphoscoliosis Cardiomyopathy congestive heart failure and arrhythmia |
