MULTIPLE SCLEROSIS ▪ Complement activation further drives

demyelination
General Information
o Mechanism of Immune System Activation
- Autoimmune disease of the central nervous system (Additional notes from Copilot)
characterized by chronic inflammation, ▪ Peripheral activation: T cells are first
demyelination, gliosis, and neuronal loss activated outside the CNS, in the
- The course can be progressive or relapsing peripheral lymphoid organs, by APC
presenting CNS-related antigens – possibly
Epidemiology myelin proteins like MBP or MOG
- Women > Men (3:1) ▪ Differentiation into inflammatory subsets:
- Age of onset is between 20 and 40 years these activated T cells become Th1 and
o Unimodal distribution Th17 cells, which secrete cytokines (IFN-y,
o Peak between 28 – 31 years old IL-17) that:
- Risk factors • Promote macrophage activation
o Genetic predisposition • Increase expression of adhesion
▪ DR locus on chromosome 6 molecules on CNS endothelium
▪ HLA-DR2, HLA-DR3, HLA-B7, HLA-A3 ▪ CNS entry and perivascular accumulation:
▪ IL-2Ra once inside the CNS, these T cells and
▪ IL-7Ra macrophages accumulate around small
o Vitamin D deficiency veins (perivenular spaces), drawn by
o Epstein-Barr virus exposure after early chemokine and local antigen presentation
childhood o Macrophage activation: macrophages adopt an
o Cigarette smoking intermediate activation state, releasing pro-
inflammatory mediators that contribute to
Pathogenesis demyelination and lesion formation
- Demyelination and Axonal impact
Pathology
o Hallmark feature: sharply demarcated areas of
Demyelination demyelination are the classic pathological
signature
- MS lesion formation and immune involvement
o Early damage: Myeline degeneration is evident
o Initial inflammation: lesions begin with
from the earlies stages
perivenular cuffing – T cells and macrophages
o Axonal involvement:
cluster around the small veins and infiltrate
▪ Axons are relatively spared, but partial or
nearby white matter
complete destruction can occur in severe
o BBB Disruption: the blood-brain barrier
inflammation
becomes leaky/compromised at inflammation
▪ Axonal loss contributes to irreversible
sites, but unlike vasculitis, the vessel wall
neurological deficits
remains intact
▪ Due to tight junction breakdown (copilot): Neurodegeneration
inflammatory chemokines (IFN-y, TNG-a,
- Axonal and Neuronal Loss: core driver of disability
IL-1B) and chemokines case:
o Primary cause of irreversible symptoms:
• Disorganization of tight junction
cumulative axonal and neuronal loss is the
proteins (occluding, claudin-5)
main contributor to progressive neurologic
• Impaired adherens junctions (VE-
decline
cadherin)
o Motor tract damage: up to 70% of axons in
• Resulting to impaired permeability
the lateral corticospinal tract may be lost in
without tearing or necrosis of the
MS-related paraplegia
vessel wall
o Consequences of demyelination
o CD8+ Cytotoxic T cells: found in large
▪ Reduced trophic support for axons
numbers at the lesion’s leading edge,
▪ Redistribution of ion channels
contributing to tissue damage
▪ Destabilization of action potential
o Humoral Immunity:
conduction
▪ B cells infiltrate in small numbers
o Axonal adaptation and degeneration
▪ Myelin-specific autoantibodies bind to
▪ Initial compensation is possible
degenerating myelin
 ▪ Eventually leads to dying-back axonopathy Disease course
(distal and retrograde degeneration)
Relapsing/Remitting or bout onset MS (RRMS)
- Chronic Lesions and Progressive Pathology
o Chronic active plaques: - Accounts for 90% of MS cases
▪ Persistently inflamed white matter lesions - Discrete attacks of neurologic dysfunction that
▪ Show progressive axonal loss and generally evolve over days to weeks
concentric expansion - Evidence of substantial or complete recovery
▪ Microglia cluster at lesion edges, but BBB is observed every after attacks
remains intact - Patient is often observed to be mentally stable
o Cortical involvement: in between attacks
▪ Cortical plaques are common but poorly
visualized on MRI Secondary Progressive MS (SPMS)
▪ May extend from white matter or lie within - Always begins as RMS
cortex/subpial regions - Clinical course changes leading to the patient
▪ Associated with direct neuronal loss and experiencing progressive deterioration in function
demyelination unassociated with acute attacks
o Ectopic lymphoid follicles: - For patients with RMS, the risk of developing SPMS
▪ Aggregates of B, T, and plasma cells in was approximately 3% each year in the pre-
superficial meninges and perivascular treatment era
spaces
▪ Found especially over deep cortical sulci Primary Progressive MS (PPMS)
▪ Release diffusible factors that drive subpial
- Accounts for 10% of MS cases
cortical damage
- Patients do not experience attacks but rather
Histologic Appearance decline in function from disease onset
- Even sex distribution
- Recent lesion
o Partial or complete destruction and loss of
myelin
Clinical Manifestations of MS
o Axons are spared or less affected
o Variable but slight degeneration of Optic neuritis
oligodendroglia
- Involvement of the optic nerve
o Perivascular and para-adventitial
- Clinically identified when there is visual loss
infiltration of mononuclear cells and
o Visual loss is preceded by pain:
lymphocytes
▪ Pain on eye movements
- Later (lesion > 2 weeks)
▪ Pain on palpation of the eye
o Macrophages infiltrate the lesions
- Examination:
o Astrocytes in and around the lesions
o Reduced visual acuity
increase in size and number
o Papillitis (edema of the optic nerve head) in
- Old lesion
fundoscopic exam
o Relatively acellular glial tissue
▪ Always associated with visual impairment
o Bare axons are surrounded by astrocytes
- Marcus Gunn pupil
o Partial remyelination
o Relative afferent pupillary defect (RAPD)
o Cavitation
o Examination in optic neuritis
Histologic subgroups ▪ Normal: shine light in the right (normal
eye) → both pupils constrict
- Pattern I: inflammatory lesions made up of T-
▪ Abnormal: swing light quickly to the left
cells and macrophages
affected eye → pupils dilate instead of
- Pattern II: immunoglobulin and complement
constricting
- Pattern III: apoptosis of oligodendrocytes and
o Indicates a defect in the afferent limb of the
partial remyelination
pupillary light reflex arc (CN II, optic nerve)
- Pattern IV: oligodendrocyte dystrophy and no
- Optic neuritis can be the initial manifestation and
remyelination
increase the possibility of developing MS
 Weakness Lhermitte

- Distribution could be unilateral (hemiparesis) or - Not a sign but a symptom to indicate lesion in the
bilateral (paraparesis) cervical spinal cord
- Upper motor neuron weakness (spine and - Electric shock-like sensation radiating from
brain involvement) the shoulders down the back and into the thighs,
o Spastic weakness triggered by neck anteflexion
o Hyperreflexia (increased deep tendon reflexes)
Other Manifestations
o Presence of pathologic reflexes
▪ Babinski sign - Vertigo
▪ Grasp reflex - Dementia
▪ Ankle clonus - Facial palsy
▪ Hoffman’s reflex - Ataxia
- Paroxysmal attacks
Paresthesia
- Bladder dysfunction
- Abnormal sensations vs. loss of sensation
Variants of MS
- Characteristics
o Allodynia: non-painful stimulus perceived as Acute and Tumor-like MS (Marburg Variant)
painful
o Tingling sensation - Severe onset which can lead to stupor or coma in
o Electric-like sensation a matter of weeks
o Crawling insect-like sensation - MRI findings
- Trigeminal neuralgia (tic douloureux) o Large MS clot that enhances with gadolinium
o Chronic pain condition characterized by and resembles a tumor, with massive
recurrent brief episodes of electric shock-like surrounding edema
pains affecting the structures innervated by Concentric Sclerosis of Balo (Balo’s disease)
the CN V
o Early manifestation in young females - Common in Asians
o Indicate involvement of intramedullary - Diagnosis: biopsy showing alternating bands of
trigeminal root myelinating and demyelinating fibers in white
matter
Diplopia - Classic “onion-skin” concentric pattern
- Double vision or seeing double - Monophasic, non-remitting
- CN III, IV, VI → innervate EOM Diffuse Sclerosis (Schilder Disease)
o Allows conjugate movement (simultaneous
and coordinated movement of both eyes in the - Clots that located on both sides of the cerebral
same direction) hemisphere, that no other parts are affected
- Pathophysiology - Common in children and young adults
o Dysfunction of EOM → disconjugate eye
Diagnostic criteria for MS
movements → diplopia
- Medial longitudinal fasciculus (MLF) Diagnostic Test
o White matter tract connecting CN III, IV, VI
Magnetic Resonance Imaging
nuclei
o Coordinates conjugate gaze - More sensitive; not specific for white matter
o Commonly affected in diplopia disease
(internuclear ophthalmoplegia) - T2W images: patchy areas of abnormal white
▪ One eye can’t move inward when looking matter are found most commonly in the cerebral
to the side, while the other eye moves hemisphere in paraventricular areas
outward but has nystagmus o Lesions often present in the cerebellum,
brainstem, and/or thoracic spinal cord
o Periventricular lesions
▪ Seen as fence-like lesions or filiform
pattern, known as Dawson’s size

Evoked potentials
- Assesses function in afferent or efferent CNS Disease-Modifying Agents
pathways
Interferon-B
- Visual EP
o Optic nerve: delayed latency and reduced - Helps in prevention of antibody production
amplitude of large positive wave - Used for maintenance to avoid repeated attacks
- Somatosensory EP - Immunomodulatory properties
o Detect central sensory pathway lesion o Downregulating expression of MHC molecules
- Brainstem auditory EP on antigen-presenting cells
o May detect brainstem lesion o Inhibiting proinflammatory and increasing
regulatory cytokine levels
CSF examination
o Inhibition of T cell proliferation
- Mild pleocytosis (mainly lymphocytes) o Limiting the trafficking of inflammatory cells in
o Increased WBC count in the CSF the CNS
- Total protein may be elevated
Glatiramer acetate
- Elevated gamma globulin in 50%
- Electrophoresis of CSF using agar: shows discrete - Synthetic, random polypeptide composed of 4
bands which are not present in serum amino acids
o L-glutamic acid
o L-lysine
Treatment o L-alanine
o L-tyrosine
Treatment for Acute Attack
- Immunosuppressant that prevents antibody
Glucocorticoid formation
- MOA:
- IV methylprednisolone: 500 – 1000mg/d for 3-5 o Induction of antigen-specific suppressor T cells
days o Binding to MHC molecules, thereby displacing
- Oral prednisone: beginning at 60-80 mg/d and bound MBP
gradually tapered over 2 weeks o Altering balance between proinflammatory and
- Side effects; watch out for: regulatory cytokines
o Gastric disturbance
o Acne Natalizumab
o Fluid retention
- Humanized monoclonal antibody → alpha-4
o Emotional lability and psychosis
subunit of alpha-4-beta-1 integrin
o Potassium loss
- Prevents lymphocytes from binding to endothelial
o Weight gain
cells
o Elevated sugar levels
o Prevent penetration into BBB and CNS
Plasma exchange entry

- If high-dose glucocorticoid fails to produce Ocrelizumab

adequate recovery
- Targets CD20-positive B cells
- 7 exchanges (40-60ml/kg/exchange, every other
- Indicated for primary progressive MS
day for 14 days)
Rituximab
Intravenous Immunoglobulin
- Murine B cell depleting monoclonal antibody that
- 0.2g/kg once a day for 5 days in ACUTE
targets CD20 lymphocytes
ATTACKS
- Effective in reducing relapses and accumulation of
- 0.2g/kg x 5 days monthly for 2 years to
MRI lesions
PREVENT RELAPSES
- Be cautious of anaphylactic shock or allergic Mitoxantrone Hydrochloride
reactions
- Anthracenedione that exerts antineoplastic action
- MOA:
o Intercalating into DNA and producing both
strand breaks and interstrand cross-links
o Interfering with RNA synthesis
 o Inhibiting topoisomerase II (DNA repair) o Diazepam, 2-40mg/d
o Tizanidine, 8-32mg/d
Oral Medications
o Dantrolene, 25-100mg/d
- Fingolimod: prevents WBC from entering the CNS o Cyclobenzaprine hydrochloride, 10-60mg/d
- Dalfampridine: oral potassium channel blocker - Pain
o Shown to improve walking in patient with MS o Anticonvulsants
o Seizure and kidney disease ▪ Carbamazepine
- Teriflunomide: lowers number of WBC in the CNS ▪ Phenytoin
- Dimethyl Fumarate: activates a chemical pathway ▪ Gabapentin
in the body that helps protect nerve cells from ▪ Pregabalin
damage and inflammation o Antidepressants
▪ Amitriptyline
Off-label Treatment options for RRMS and SPMS ▪ Nortriptyline
Azathioprine ▪ Desipramine
▪ Venlafaxine
- 2-3mg/kg/day o Antiarrhythmic
- Used primarily in SPMS ▪ Mexiletine
- Marginally effective at lowering relapse rates - Bladder dysfunction
o Advice evening fluid restriction or frequent
Methotrexate
voluntary voiding
- 7.5-20mg/week o Medications:
- Slows progression of upper extremity dysfunction ▪ Propantheline bromide, 10-15 mg/d
in SPMS ▪ Oxybutynin, 5-15mg/d
- Irreversible liver damage ▪ Hyocyamine sulfate, 0.5-0.75mg/d
▪ Tolterodine tartrate 2-4mg/d
Cyclophosphamide
▪ Solifenacin 5-10mg/d
- 700mg/m2, every month - Urinary Tract Infections
- For refractory patients who are: o Large post-void residual urine volumes are
o Otherwise in good health predisposed to infections
o Ambulatory o Prevention by urine acidification
o <40 years of age - Constipation – high fiber diets
- Fecal incontinence – reduction in dietary fiber
IViG - Depression
- 1k/kg, monthly impulses o SSRIs
- Reduce annual exacerbation rates ▪ Fluoxetine
▪ Sertraline
Methylprednisone o TCAs
▪ Amitriptyline
- Monthly high doses intravenous pulses
▪ Nortriptyline
- Reduced disability progression
▪ Despiramine
o Nontricyclic antidepressants
▪ Venlafaxine
Symptomatic Therapy - Fatigue
- Weakness o Amantadine 200mg/d
o Potassium channel blockers o Methylphenidate, 5-25mg/d
▪ 4-aminopyridine, 10-40mg/d o Modalinil 100-400 mg/d
▪ 3,4 di-aminopyridine, 40-80 mg/d - Cognitive problems
▪ High dose → seizures o Cholinesterase inhibitor – donepezil
- Ataxia/tremor hydrochloride 10mg/d
o Clonazepam, 1.5 – 20mg/d - Paroxysmal symptoms – acetazolamide 200-600
o Mysoline, 50-250mg/d mg/d
o Propranolol, 40-200mg/d
o Ondansetron 8-16 mg/d
- Spasticity and spasm
o Lioresal 20-120mg/d (Baclofen)
 Neuromyelitis Optica or Devic’s Disease - Glial scars are less frequent and usually only
partial in contras to typical MS lesions
NMO Criteria
Pathogenesis of NMO
- Transverse myelitis and optic neuritis
o At least 2 of the following features: - Humoral immunity
▪ MR brain negative/nondiagnostic of MS o Main difference with MS
▪ MRI spinal cord lesion extending over 3 o B-cells/humoral
vertebral segments (LETM) o IgG and complement-mediated (vs MS, T-cell
▪ Presence of NMO-IgG seropositivity mediated)
(Aquaporin 4 motor channel) - Target antigen is AQP4
- NMOSD with AQP4-IgG o Dominant water channel in CNS
o At least 1 core clinical characteristics
Treatment of NMO
▪ Optic neuritis
▪ Acute myelitis Acute Attacks
▪ Area postrema syndrome
• Nausea - Steroid
• Vomiting o Mainstay treatment
• Hiccups o Methylprednisolone 1g/day for 5 days
▪ Brainstem syndrome - Immunoadsorption
• Diplopia o Best treatment; eliminate or remove IgG
• Vertigo antibodies
• Ataxia - Therapeutic plasma exchange for 5-7 days
▪ Symptomatic narcolepsy or acute - IViG
diencephalic syndrome with MRI lesion(s) Long Term Treatment (preventing relapse)
• Sudden LOC due to hypothalamic
involvement - Azathioprine
▪ Symptomatic cerebral syndrome with MRI o Immunosuppressant
lesion(s) o 2.5-3 mg/kg/day orally with monitoring of
o Positive test for AQP4-IgG hematologic parameters and liver enzymes
- NMOSD without AQP4-IgG (or unavailable) - Rituximab
o At least 2 core clinical characteristics all o 375mg/m2 BSA every 2-4 weeks, IV infusion;
satisfying: 1 of optic neuritis, myelitis, or area given until monitoring of the levels of
postrema syndrome antibodies are negative
▪ Dissemination in space o MOA: B-cell depletion
• Isolated recurrent on or recurrent o Monitor: CD20
TM do not qualify - IViG
• Not qualifying with MS o 2g/kg divided in 5 days every 4 weeks for
▪ Additional MRI requirements at least up to 2 years
• AP syndrome: dorsal medulla lesion
Acute Disseminated Encephalomyelitis
▪ Myelitis: LETM
▪ ON: normal brain MRI or >1/2 ON or - Mainly affects children
chiasm lesion - Acute or subacute onset
o Negative results for AQP4-IgG - Commonly appear 4-13 days after infection or
vaccination
Optic Neuritis
- Encephalopathy: characteristic feature
- Refer to above discussion on ON o Diffuse involvement of the cortex
o Changes in mental state of the patient
Pathological features of NMO (vs. MS) o Confusion, delirium, stupor
- Demyelination with necrosis - Lethargy, irritability, coma
- Prominent vascular fibrosis and hyalinization - Polysymptomatic presentation
within the lesions o Acute hemiparesis
- Perivascular deposition of IgG and complement o Cerebellar ataxia
- Perivascular infiltrates of PMNs, leukocytes, o Cranial neuropathies (ON)
plasma cells, eosinophils
 ▪ Vision loss, pain with eye movement and Central Pontine Myelinolysis (CPM)
palpation, afferent pupillary defect
- Demyelination without inflammation in the base of
(Marcus Gunn pupil)
the pons, with relative sparing of axons and nerve
Diagnostics cells
- “Locked-in” syndrome
- MRI:T2W images
- Irreversible and permanent
o Large (>1 to 2cm in size)
- Uncommon consequence of certain metabolic
o Multifocal
derangements
o Hyperintense
o Rapid correction of hyponatremia,
o Bilaterally asymmetric lesions
hyperosmolar conditions, such as
o Located in the supratentorial or infratentorial
hyperglycemia
white matter
- Microscopic findings
- CSF analysis
o Loss of myelin with sparing of axons, without
o Lymphocytic pleocytosis >= 50WBC/mm
evidence of inflammation
o Increase protein; normal glucose
- Clinical findings
Acute Necrotizing Encephalomyelitis o Devastating fashion as quadriplegia and
pseudobulbar palsy
- Acute hemorrhagic leukoencephalitis of Weston
Hurst Progressive Multifocal Leukoencephalopathy
- Affects children and young adult
- Caused by Polyoma Virus (JC virus)
- Severe end of the spectrum of ADEM
o Preferentially infects oligodendrocytes →
- Preceding respiratory infection
demyelination in CNS
- Evolves more slowly over a period of 2-3 weeks
- Immunosuppressed patients and AIDS patients are
- MS plaque + hemorrhagic necrosis inside CNS
at risk
Diagnostics - Relentlessly progressive
o Irreversible
- CSF o No PMN cells are seen
o Increased opening pressure - Main manifestation: Dementia
o Pleocytosis greater than or equal to 3,000
cells/mm3, lymphocytes, and PMN cells
o Increase protein levels
METABOLIC CAUSES OF ALTERED CONSCIOUSNESS
o Normal glucose
AND BRAIN DEATH
- MRI
o Bilateral Definition of Terms (concerned with consciousness)
o Asymmetrical
- Coma: a deep sleep-like state from which the
o Confluent edematous lesions
patient cannot be aroused
o Cerebral white matter area
o No amount of stimulation might awaken the
o Punctate hemorrhages in the gray and
patient
white matter
- Stupor: a higher degree of arousability in which
Pathologic Findings the patient can be transiently awakened only
vigorous stimuli, accompanied by motor behavior
- Almost liquefied white matter of one or both
that leads to avoidance of uncomfortable or
hemisphere
aggravating stimuli
- Tissue is pink or yellow-gray and flecked with
o Requires a higher degree of stimulation
multiple petechial hemorrhages
- Drowsiness: stimulates light sleep and is
Treatment characterized by easy arousal and the persistence
of alertness for brief periods
- High-dose steroids o A little tap or nudge can awaken the patient
- Plasma exchange - Locked-in State
- IViG o Patient is awake but has no means of
producing speech or volitional movement
o Retains voluntary vertical eye movements and
lid elevation
o Brainstem involvement
- Vegetative state o The brain does not store and metabolize
o Awake but nonresponsive state in a patient glycogen in the event of decreased blood
who has emerged from a coma sugar levels
o Intellectual capacity are absent due to damage o <20mg/dL or 10mg/dL glucose supplies
to the bilateral cerebral hemisphere → possible coma
- Akinetic Mutism o Clinical pearls: hyperglycemia has better
o Partially awake or fully awake state prognosis than hypoglycemia
o Patient is able to form impressions and think
Release of Circulating Substances by Systemic Disease
o Patient is able to recount events
which crosses the BBB and cause diffuse function
o Virtually immobile
- Abulia - Organ Failure
o Milder form of akinetic mutism o Hepatic failure
o Characterized by mental and physical slowness ▪ High ammonia level
and diminished ability to initiate activity • Interferes with cerebral energy
o Fontal area involvement metabolism → metabolic insult due to
o Lost of interest, stimulus, and/or initiative decreased ATP production
- Catatonia • Increase the number and size of
o Curious hypomobile and mute syndrome astrocytes
o Occurs as part of a major psychosis • Affect NTs
(schizophrenia/major depression) ▪ Renal failure
• Increased permeability of the BBB to
Anatomy and Physiology
toxic substances
- Principal causes of coma • Increase in brain calcium
o Lesions that damage the RAS in the upper • Increase in CSF phosphate content
midbrain or its projections • Renal failure → decrease excretion of
▪ Due to stroke, trauma, tumor toxic substance → accumulates in the
o Destructions of large portions of cerebral blood → increase concentration in the
hemispheres brain (phosphatase)
o Suppression of reticulocerebral function
Alteration of Neuronal Excitability
Metabolic Encephalopathy
- Drug and alcohol intoxication
- Alteration of consciousness caused by diffuse or o Low levels → excitatory
global brain dysfunction from impaired cerebral o High levels → depressant
metabolism - Epilepsy
- Changes in osmolality
Mechanisms
o Increased serum osmolality (>350 mOsm/kg)
Interruption of delivery of energy substrate → brain shrinkage
o Decreased serum osmolality (<280 mOsm/kg)
- Hypoxia → brain swelling
o Mechanism: ↓BP → ↓Blood flow → ischemia → - Changes in CNS biochemistry, membrane
↓Cerebral blood flow function and NTs
o Possible causes o Hypercalcemia
▪ Cardiopulmonary arrest – most o Hypercapnia
common cause of metabolic coma ▪ ↑CO2 in the blood → acidosis → neuron
• Causes ischemic-hypoxic damage and LOF → swelling due and
encephalopathy inviting calcium into the neurons
▪ Severe dehydration o Hyperthyroidism
▪ Massive blood loss o Hypothermia
▪ GI bleeding o Vit B12 deficiency (Korsakoff syndrome)
▪ Gun shot wounds o Atropinic agents
- Ischemia o Opiates and Barbiturates → cause a reduction
- Hypoglycemia in wakefulness and consciousness due to
o Brain is highly dependent on the blood flow for changes in the neuronal activity
the source of glucose o Subclinical seizures and postictal state
 Approach to the Patient with Coma - Caloric testing
o Prelim tests: check otoscopic findings to make
History
sure tympanic membranes are intact
- Identify cause of metabolic insult o Normal brainstem reflex (intact): eyes move
o Possible organ system toward the ear irrigated with cold water
▪ Diabetes
Corneal Reflex
▪ Renal problem*
▪ Hepatitis - CN V → afferent; CN VII → efferent
▪ Liver failure* - Stimulation on the sclera
• * Facial facies and/or characteristic - Intact response: patient will immediately close the
smell eyelids

General Physical Examination Gag Reflex

- Initial inspection - CN IX, X: medullary reactions; tests for brainstem

o Check for:
Ocular Movements
▪ Characteristic smell
▪ Skin - Brisk downward movement
▪ Myoclonus jerking and slow upward movement of
▪ Tremors the eyes
- Always check for ABC OCULAR - Associated with loss of
- Quickly measure VS BOBBING horizontal eye movements
- Diagnostic of bilateral pontine
Neurologic Examination damage from basilar artery insults
- Present in PONTINE LESIONS
- Determine if the insult is caused by structural or - Slower arrhythmic downward
metabolic causes movement followed by a faster
o Once ID’ed as metabolic, prognosis is great as OCULAR movement
it is reversible DIPPING - Normal reflex horizontal gaze
- Indicates diffuse CORTICAL
Examination of Brainstem Reflexes ANOXIC DAMAGE

Pupillary signs and reflexes

Respiratory Pattern
- Pupils are equal, normal size, normal reaction →
brainstem is not involved - MEDULLARY in localization
o Midbrain involvement → dilated pupils
- Cyclic form ending with brief apneic
o Pontine involvement → pinpoint and
period
nonreactive pupils - Signifies bihemispheric damage or
CHEYNE-
- CN II → afferent; CN III → efferent metabolic suppression and commonly
STOKES
- Atropine overdose → pupillary dilation accompanies coma
- Metabolic encephalopathy affecting the
associated with tachycardia and dry skin
bilateral hemispheres
- Opiates, barbiturates, benzodiazepine - Rapid, deep breathing
overdose KUSSMAUL - Implies metabolic acidosis
o Causes pupillary constriction BREATHING - May also occur with
pontomesencephalic lesions
o Vs pontine lesions which is pinpoint and
- Pause of 2-3 seconds in full respiration
NONREACTIVE APNEUSTIC - Short cycles of rapid breaths followed by
BREATHING apneic cycles
Extraocular Movement - Due to low pontine lesions
- Chaotic breathing being irregularly
- CN III, IV, VI (midbrain and pontine) interrupted
- In coma patients, do Doll’s eyes (due to inability BIOT/ATAXIC
- Each breath varies in depth and rate
BREATHING
to follow commands) - Due to dorsomedial part of the
o Normal response (intact brainstem) medulla

▪ Turn head to the right → eyes move in

opposite direction
o Abnormal response → eyes move to the
direction of the head turning → do caloric
testing
Motor Examination Treatment

- ID handedness of the patient - Goal: prevent further neurologic damage

- Application of stimuli → movement of - Early dx and management
nondominant hand (left) over dominant hand o Immediate removal of insulting elements →
(right) may suggest lesion on the contralateral side reverse insults → good prognosis
(right)
Brain Death
- If patient can move dominant hand → metabolic is
less likely - State of cessation of cerebral function with
preservation of cardiac activity and maintenance of
Pathologic Reflexes
somatic function by artificial means
- (+) Babinski sign in adults or ankle clonus - Exclude first metabolic causes → can be reversed
o May signify focal neurological deficits - Hypoxic-ischemic encephalopathy
▪ (+) Babinski + weakness o Only metabolic cause that can lead to
structural damage
Posturing
Neurologic criteria
- Done with application of painful stimuli
- Decorticate → UE flexes; LE extends - Rule out reversible causes of unconsciousness
- Decerebrate → both UE and LE extends o Check/observe for:
o Loss of other functions, leaving only the ▪ Sedative medications
brainstem intact ▪ Neuromuscular blocking agents
▪ Hypothermia
Neck Examination for Meningeal Irritation
• =< 31˚C → deep coma
- Kernig: pain or resistance when a patient’s knee • 35˚C → management of ↑ICP in
cannot be fully extended after the hip and stroke patient
knee are flexed to 90 degrees • <35˚C → lead to arrhythmia
- Brudzinski: positive if reflex flexion of the hips - Rule out the presence of cortical activity and
and knees are observed upon passive flexion of brainstem reflexes using clinical tests
the patient’s neck o No spontaneous movement and no movement
in response to painful stimuli
Laboratory Imaging o No seizures, decerebrate or decorticate
- Routine laboratory exams posturing, or dyskinetic movement
o CBC ▪ Seizures indicate functional cortex
o CBG o Absent CN reflexes (i.e. corneal, pupillary
o Electrolytes reflexes)
o Creatinine - Absence of central respiratory drive
o Thyroid functions Adjunctive Confirmatory Tests
o Blood typing
- Other tests: ABG, alcohol or drug level tests - Electroencephalogram
- CT scan/MRI: if structural involvement is - Transcranial doppler
suspected - Somatosensory evoked potentials
- EEG: if subclinical status of epilepticus or a - ICP
subclinical seizure is suspected - CT/conventional angiography
o May also be used to support impression of a
Apnea Testing
metabolic problem
▪ Metabolic encephalopathy: slowness of the - Tests for medullary respiratory center
brain waves and presence of triphasic - Patient is given oxygen (100%) through T-piece →
waves observe and monitor CO2
- Lumbar Puncture - (+) apnea test is noted if no breathing
o CNS infection movement is observed and PaCO2 rises to a
predetermined level
ABNORMALITIES OF MOVEMENT AND POSTURE motivation-driven behaviors; reward,
CAUSED BY DISEASES OF THE BASAL GANGLIA reinforcement, and goal-directed movement
o OLFACTORY TUBERCLE – integrates
Major Cortical and Subcortical neural structures in
olfactory input with limbic and reward circuits;
movement
minor role in motor but contributes to
- Corticospinal tract motivated behaviors
- Cerebrocerebellar pathways
Motor Function
- Corticostriate pathways
- Dentothalamic pathways - Automatic execution of learned motor plan and in
- Striatothalamic pathways the preparation for movement
- Thalamocortical pathways
Gating Function
- Dopaminergic pathways
- Benefit of external sensory cues in Parkinson’s
Corticospinal Tract vs. Extrapyramidal Syndromes
disease and sensory tick in dystonia
Corticospinal Extrapyramidal - In normal subjects:
Character of Clasp-knife effect Plastic, equal throughout o Dopamine (inhibitory) and cortical
the alteration (spastic) passive movement
of muscle (rigidity), or intermittent
sensorimotor (excitatory) inputs to the
tone (cogwheel rigidity) striatum are in physiologic balance
Distribution of Flexors of arms, Generalized, ▪ The inhibitory output of the pallidum,
hypertonus extensors of legs predominates in flexors of thus, regulates sensorimotor access
limbs and of trunk
- In PD patients
Involuntary Absent Presence of tumor,
movements chorea, athetosis, o Loss of dopamine (inhibitory) will allow cortical
dystonia facilitation of a free hand to stimulate the
Tendon Increased Normal or slightly inhibitory basal ganglia output
reflexes (hyperreflexia) increased
▪ This limits access of sensory
Babinski Present Absent
Paralysis of Present Absent or slight
information to the motor system and
voluntary decreases motor activity, hence the
movement hypokinesia
- In Huntington’s Chorea
o Loss of basal ganglia neurons → decrease in
Basal Ganglia
inhibitory output of the basal ganglia
- Group of interconnected nuclei involved in motor ▪ Increase in the access of sensory
and non-motor functions information of the motor system and
- Refers to the following nuclei increased activity (hyperkinetic movement)
o CAUDATE – involved in cognitive aspects
Other Functions
of motor control, especially goal directed
movement and motor planning - Dorsolateral prefrontal circuit (loop)
▪ Integrates frontal lobe input (executive o Lesions result in cognitive deficits and
function, attention) with motor circuits deficits on tasks that require spatial memory
o PUTAMEN – primary input nucleus for o Lesions are linked to cognitive disturbances in
motor control – receives signals from motor Schizophrenia, Huntington’s chorea, and PD
cortex - Lateral orbitofrontal circuit
▪ Works with caudate as part of the o Lesions are linked to OCD
striatum, modulating voluntary - Decreased in size has been linked to bipolar
movements disorders
O GLOBUS PALLIDUS (INTERNA AND - Spatial neglect
EXTERNA) o Involves the putamen with right-sided basal
▪ Interna – major output nucleus; exerts ganglia lesions
tonic inhibition on thalamocortical o Both nuclei are directly connected with the
circuits – acts as a brake on movement superior temporal gyrus
▪ Externa – part of the indirect pathway, ▪ Agnosia
modulating subthalamic nucleus activity; ▪ Neglect syndrome
helps suppress unwanted movements
o NUCLEUS ACCUMBENS SEPTI – interface
between limbic and motor systems – regulates
 Basal Ganglia Nomenclature Neostriatal Input

- Corpus striatum: Caudate + Putamen + Globus - Projections from the cerebral cortex to the
pallidum striatum are both direct and indirect
- Striatum, dorsal striatum, neostriatum: o Direct: reach the neostriatum (caudate +
Caudate + Putamen putamen) via the internal and external
- Ventral striatum: Caudate + Putamen + Nucleus capsules and subcallosal fasciculus
accumbens + olfactory tubercle o Indirect pathways include:
- Pallidum, paleostriatum: Globus pallidum ▪ Corticothalamostriate pathway
- Lentiform nucleus: Putamen + Globus pallidum ▪ Collaterals of the cortico-olivary pathway
▪ Collaterals of the corticopontine pathway
Anatomic Circuits Projecting to the Frontal Lobe
Direct Striatomedial Pallidonigral Pathway
- Prototypical motor circuit
- Oculomotor circuit - Activated by glutaminergic projections from
- Two prefrontal circuits the sensorimotor cortex and by dopaminergic
- Limbic circuit nigral (pars compacta; DOPAMINE) – striatal
projections
Globus Pallidus and Substantia Nigra Pars Reticulata
- Activation inhibits the medial pallidum (GPi) →
- Globus Pallidus disinhibition (activates) of the ventrolateral and
o Wedge-shaped nuclear mass between the ventroanterior nuclei of the thalamus →
putamen and internal capsule enhanced thalamocortical drive → facilitates
▪ External pallidal lamina (GPe): cortical initiated movements
separates the globus pallidus from the o Medial pallidum (interna)
putamen ▪ Acts as major output station of the basal
• Receives input from the striatum ganglia
• Sends inhibitory signals to the ▪ Sends inhibitory signals (GABA) to the
subthalamic nucleus ventroanterior and ventrolateral nuclei of
• Indirect pathway → suppresses the thalamus
unwanted movements ▪ Inhibited in direct pathway → reduced
▪ Internal pallidal lamina (GPi; medial movement modulation → promotes
pallidum): divides the globus pallidus movement
into a larger lateral (outer) and smaller o Ventrolateral
medial segment ▪ Receives input from the cerebellum
• Major output station of the basal (dentate nucleus)
ganglia ▪ Sends signals to the primary motor
• Sends inhibitory signals (GABA) to cortex (precentral gyrus)
the VA and VL nuclei of the ▪ Helps fine-tune and coordinate voluntary
thalamus movements
- Substantia nigra o Ventroanterior
o Occupies the ventral zone of the substantia ▪ Receives input from the basal ganglia
nigra and contains iron compounds (globus pallidus and substantia nigra)
o Functions: ▪ Projects to the motor premotor cortex and
▪ Pars compacta: makes dopamine – helps supplementary motor area
start and smooth movements ▪ Helps with planning, initiating, and
▪ Parts reticulata: sends signals to control sequencing movements
eye and body movement - Clinical pearls: enhanced conduction through the
• Uses GABA as the inhibitory NT direct pathway results in HYPERKINESIA (think
of HD) by reducing pallidothalamic inhibition
 o Striatum – highest concentration of ACh and
enzymes needed for its synthesis and
Indirect Circuit
metabolism
- Arise from the putaminal neurons that contain o Synthesized and released by non-spiny striatal
GABA and smaller amounts of enkephalin neurons
- Have inhibitory effect on the lateral pallidum o Mixed but mainly excitatory effect
(Gpe) → disinhibition (activates) of the - Dopamine
subthalamic nucleus through GABA o Excitatory or inhibitory depending on the site
o Provides subthalamic drive to the medial of action
pallidum and substantia nigra pars reticulata o Areas of rich dopamine reserves
o Net effect: thalamic inhibition → reduced ▪ Substantia nigra – synthesized in the
thalamocortical input to the precentral motor nerve cell bodies of the pars compacta
fields → impedes voluntary movement
Diseases of the Basal Ganglia
- Clinical pearls: insults resulting to enhanced
conduction through the indirect pathway leads Symptoms of Basal Ganglia Disorders
to HYPOKINESIA (think of PD)
- Functional deficits (negative symptoms)
Neostriatal Output o Bradykinesia
o Hypokinesia
Direct Pathways
o Loss of normal postural reflexes
- Direct projection is from the neostriatum to the - Excessive motor activity (positive symptoms):
GPi and the substantia nigra pars reticulata attributed to the release or disinhibition of the
(output nuclei) activity of undamaged parts of the motor system
- Activation → net disinhibitory (facilitatory) o Tremors
effect on the thalamus and an increase in o Rigidity
motor behavior o Chorea
- Clinical pearls: enhanced activity in the direct o Athetosis
pathway → excessive activity (hyperkinesia) of o Ballismus
some basal ganglia disorders (Huntington’s o Dystonia
chorea) - Anatomic loci for pathology
o Substantia nigra for PD
Indirect Pathway o Caudate nucleus in chorea
- Projection from the neostriatum to GPe and via ▪ Behavioral and cognitive manifestations
the subthalamic nucleus to the GPi and the ▪ Abulia
substantia nigra pars reticulata o Subthalamic nucleus in Ballismus
- Activation → increased inhibition of the thalamus Hypokinesia
and decreased motor activity
- Clinical pearls: enhanced activity of the indirect - Reduction in spontaneous movement
pathway → poverty of movement (hypokinesia) - Expressed more clearly in parkinsonian patient
of diseases like PD - Absent or greatly reduced frequent automatic,
habitual movements
Important NT form the POV of Basal Ganglionic - Underactivity or “poverty” of movement
Nucleus
Bradykinesia
- Glutamate
o Excitatory projections from the cortex to the - Slowness rather than lack of movement
striatum - Parkinsonian patient displaying “slow off the mark”
o Excitatory neurons of the subthalamic nucleus o Longer-than-normal interval between a
- GABA command and the first muscle contraction
o Inhibitory NT of the ff projection neurons: - Cause: process or drug that interrupts some
▪ Striatal component of the cortico-striato-pallidothalamic
▪ Pallidal circuit
▪ Substantia nigra pars reticulata - Clinical pearls
- Acetylcholine o Reduced dopaminergic input from the
o Found at the NMJ and the autonomic ganglia substantia nigra to the striatum – PD
o Dopamine blockade by neuroleptic drugs
 o Extensive degradation of striatal neurons, as in Hypokinetic Disorders: Parkinsonism
striatonigral degeneration and the rigid form of
- Paralysis agitans
Huntington chorea
- Characterized by:
o Destruction of the medial pallidum (GPi)
o Tremor
o Rigidity
o Hypokinesia or akinesia
Disorders of Postural Fixation, Equilibrium and Righting
- Other manifestations:
- Demonstrated most clearly in the parkinsonian o Decreased blinking rate
patient o Expressionless mask facies
- Prevailing posture: involuntary flexion of the trunk o Dysphagia
and limbs and of the neck o Speech disorders
- Not attributable to weakness or to defects in o Gait disturbances
proprioceptive, labyrinthine, or visual function o Fatigue
o Postural instability
Rigidity and Alterations in Muscle Tone
Parkinson’s Disease
Rigidity
- Epidemiology
- Muscles are continuously or intermittently firm and o Begins between 45 – 70 years of age
tense o Peak age: 6th decade
- Extrapyramidal disorder rigidity is not velocity- - Tetrad of:
dependent o Hypo- and bradykinesia
- Greater in the large muscle groups o Resting tremor – most prominent symptom
o Muscle in the face and tongue and the larynx o Postural instability
can also be affected o Rigidity
- Cogwheel Phenomenon - Initial symptoms
o Rhythmically interrupted, “ratchet-like” o Tremor
resistance felt/observed when the hypertonic o Gait disturbances
muscle is passively stretched o Stiffness
- Observed in: o Slowness
o PD o Muscle aches
o Wilson disease o Loss of dexterity
o Striatonigral degeneration o Handwriting disturbance
o Progressive supranuclear palsy o Depression, nervousness, other psychiatric
o Dystonia disturbance
o Exposure to neuroleptic drugs o Speech disturbance
o Fahr disease
Pathology and Pathogenesis
Spasticity
- Loss of pigmented cells in substantia nigra and
- Increased resistance on passive movement that other nuclei:
characterizes rigidity o Locus coeruleus
- Velocity-dependent o Dorsal motor nucleus of the vagus
Dyskinesia - In idiopathic PD
o Pigmented nuclei contain eosinophilic
- Encompasses all the active movement phenomena cytoplasmic inclusions surrounded by a faint
that are a consequence of disease of the basal halo – LEWY BODIES
ganglia - Affects dopaminergic neurons in the substantia
- Tardive dyskinesias – numerous dystonic and nigra pars compacta
athetotic movements that may follow the use of
neuroleptic drugs
 Major Feedback Loops involving the Basal Ganglia Clinical Presentation

- Cortical direct pathway - Epidemiology

o Cerebral cortex (glutaminergic) → striatum o Age of onset: 4th – 5th decades
(GABAergic) → medial globus pallidus, GPi - Limbs are often slack or hypotonic and because
(GABAergic) → thalamus (glutaminergic) → of this, the knee jerks tend to be pendular
cortex - Choreic patients often presents with:
- Cortical indirect pathway o Milkmaid’s grip: Unable to sustain a tight
o Cerebral cortex → striatum → lateral globus hand grip
pallidus, GPe → subthalamus → medial o Trombone tongue: Cannot maintain a
globus pallidus (GPi) → thalamus → cerebral protruded tongue, which tends to dart in and
cortex out irregularly
- Cortical-nigral
o Cerebral cortex → striatum → substantia nigra
→ thalamus → cortex Varieties of Chorea
- Midbrain
o Pedunculopontine nuclei → subthalamus → Sydenham’s
globus pallidus and substantia nigra → - Benign, reversible
pedunculopontine nuclei - Occur in children as complication of RF
- Internal striatal - Appendicular musculature is predominantly
o Striatum → globus pallidum → thalamus → involved
striatum
Huntington’s
Treatment
- Malignant
- L-dopa - Hereditary (autosomal dominant)
o Carbidopa-L-dopa o Defect in chromosome 4
o Controlled release carbidopa-L-dopa o Associated with progressive mental and
- Dopamine agonists cognitive deterioration
o Ropinirole o HDL2 (Huntington’ disease-like-2)
o Pramipexole ▪ Associated with CATCG repeat expansion
- Glutamate antagonist of juntophilin-3 gene
o Amantadine - Truncal musculature is predominantly involved
- Anticholinergics - Triad:
o Benztropine o Dominant inheritance
o Trihexyphenidyl o Choreoathetosis
Surgical Measures o Dementia
- Clinical Features
- Deep brain stimulation o Mental disorder
o Electrodes are placed in the posterior and o Abnormality of movement
ventral parts of the subthalamic nucleus or in o Mental deterioration observed in childhood
GPi may be accompanied with:
▪ Cerebellar ataxia
Hyperkinetic Disorders
▪ Behavior problems
Chorea ▪ Seizures
▪ Bradykinesia
- Involuntary arrhythmic movements of a
▪ Rigidity
forcible, rapid, jerky type
▪ Dystonia
- Movements are purposeless
- Pathology and Pathogenesis
o Characteristic abnormality: gross atrophy
bilaterally of the head of the caudate
nucleus and putamen
▪ Accompanied usually by moderate gyral
atrophy in the frontal and temporal
regions
 o Expansion of the polyglutamine region of
Huntingtin

Treatment

- Haloperidol
o Daily doses of 2-10 mg – control seizures
o Dopamine antagonist

Athetosis

- Characterized by an inability to sustain the fingers

and toes, tongue, or any other part of the body in
one position
- Maintained posture is interrupted by relatively
slow, sinuous, purposeless movement
- Characteristic movements
o Eversion-inversion of the foot
o Retraction and pursing of the lips
o Twisting of the neck and torso
o Alternate wrinkling and relaxation of the
forehead
o Forceful opening and closing of the eyelids

Choreoathetosis

- Chorea + athetosis
- Cardinal feature of:
o Huntington Disease
o Double athetosis
- Location of the lesion: Putamen

Ballismus

- Uncontrollable, poorly patterned flinging

movement of an entire limb
- Location of the lesion: Subthalamic nucleus