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Definition: Strength of muscles about a joint
- Procedure: Assess strength of movement
- Grading: 0 to 5 (5= normal, 1-4= paresis, 0= plegia)
- FIRST: Perform Passive ROM to assess function of joint
- Compare/contrast with other side

Grading (MRC scale)
5: Against gravity and significant external resistance
4: Against gravity and minimal external resistance (4-, 4, 4+)
3: Against gravity
2: Incomplete, needs assistance against gravity
1: Twitch
0: No movement= plegia

Fasiculations= LMN damage

Atrophy: disuse or LMN damage

Pseudohypertrophy= usually of gastrocnemius; flaccid enlargement, muscular dystrophy


Assessment of power

Passive ROM, inspection, then active ROM for:
- Abduction at shoulder
- Flexion at elbow
- Forward flexion at hip
- Extension at knee


Abduction at shoulder

Position: Neutral; scapular plane
Joints: Glenohumeral, scapulothoracic, acromioclavicular, sternoclavicular
Muscles: 0 to 100 degrees: Supraspinatus and deltoid
Nerves: C5: axillary and suprascapular nerve


Elbow flexion

Position: Neutral; handshake position
Joints: Humeral-ulnar
Muscles: 0 to 130 degrees: Biceps brachii
Nerves: C5 and 6: musculocutaneous


Hip forward flexion

Position: standing, sitting or supine
Muscles: 0 to 130 degrees:iliopsoas
Nerves: Branches of L1 and 2


Knee extension

Position: Knee at 90 degrees of flexion
Muscles: Quadriceps muscle
Nerves: L3 and L4, femoral nerve


Testing for reflexes

Note clonus, look and feel for contraction of muscle

Jendrassik's maneuver:
- Have patient hook hands together and pull to distract from reflex testing

4+: Clonus and/or cross-over
3+: Brisk; without clonus/cross-over
2+: Normal
1+: hyporeflexia; present only with Jendrassik’s manuever
0: Absent

3+/4+ = Hypereflexia
1+= Hyporeflexia
0= Areflexia
Clonus= Rhythmic beats
** 1,2,3= normal until proven otherwise
** 0,4= abnormal until proven otherwise


Plexors (reflex testing)

Queen Square
Flexed digit


Biceps reflex

Hand and forearm in neutral handshake position
Place thumb over biceps tendon
Strike thumb with plexor
Observe/feel contraction of biceps
Root: C5, C6


Quadriceps reflex

Stabilize knee in 20 degrees flexion
Tap over the patellar ligament
Observe/feel quadriceps muscle contraction
L4 root


Plantar reflex

Gently stretch tendons by passively extending toes and dorsiflexing foot
Tap over mid plantar foot
Observe/feel contraction of posterior compartment muscles-plantar flex/toe flexion
S1 root


Cranial nerve exam: eyes

1. Cranial nerve 3: Superior rectus, inferior rectus, Inferior oblique, medial rectus; levator palpebrae
- Damage: multiple deficits and a marked ptosis
2. Cranial nerve 4: Superior oblique
3. Cranial nerve 6: Lateral rectus


Cranial nerve exam: face

Cranial nerve 5:
1. Sensory
- V1: Skin of forehead, periorbital skin, conjunctiva, cornea, tip of nose
- V2: Skin of maxilla
- V3: Skin of mandible: Cotton-tipped swab
2. Motor
- Masseter: Gentle bite down on a tongue blade

Cranial Nerve 7:
1. Motor:
- Puff out cheeks-buccinator
- Growl-orbicularis oris
- Protrude lower lip-mentalis
- Close eyes-orbicularis oculis
- Wrinkle forehead-frontalis

** Central 7 damage:
- Unable to growl, protrude lower lip, smile
- Able to close eyes and wrinkle forehead
- Contralateral UMN lesion

** Peripheral 7 damage:
- Unable to growl, protrude lower lip, smile, close eye, wrinkle forehead
- Ipsilateral LMN lesion
- Trauma
- Lyme
- Multiple sclerosis


Cranial nerve exam: swallowing

Cranial Nerve 9 and 10:
- Swallowing dysfunction
- Abnormal uvular movement with AHHH
- Hoarseness, esp. when stating "AHH"
- NEVER perform gag reflex

Cranial Nerve 12:
- Tongue muscles
- Dysarthria
- Protrusion of the tongue; repeat thrice
1. Normal: Tngue prtruded and midline
2. Paralysis: Unable to protrude
3. Paresis: protrudes but deviates from midline


Cranial nerve exam: shoulders

Cranial nerve 11:
- Push hands forward as if one were doing a “push-up” against resistance applied by clinician; look for scapular winging
- Serratus anterior
- Trapezius-Cranial nerve 11
- Shrug shoulders against resistance


Normal gait

Normal based: Feet placed beneath the anterior superior iliac spines (ASIS)
Complementary arm swinging-left arm with right leg; right arm with left leg


Spastic hemiparetic gait

Arm adducted, elbow flexed, forearm supinated
Leg adducted, plantar flexed, increased arch
- Increased reflexes
- Spastic tone
- Upgoing and flared toes with noxious stimulus applied to foot


Ataxic gait

Minimal arm swinging
Cerebellar or sensory deficit
Very high falls risk

1. Stance
- Patient stands in anatomic position; then is instructed to place feet together
- Note any deviation of body from midline
2. Romberg
- Stance position, then patient instructed to close eyes; then to forward flex arms to horizontal plane; then apply stress to arms
- Note any deviation of body from midline



Procedure: Finger-to-finger-to-finger
- Perform in X, Y and Z axes
- Perform on both sides of midline; on both the left and then the right hand
- Better than old, “Finger to nose”

- Dysmetria: Unable to judge distances and move to site; past-pointing present. Indicates cerebellar disease



Procedure: Ability to perform rapidly alternating actions
- Supinate/pronate forearm…
- Thumb to tip of digit 2 then 3, then 2, then 3…

- Diadochokinesis: normal
- Dysdiadochokinesis: unable to perform this; indicates cerebellar disease



Measurement of graceful, gliding smooth actions
Procedure: Swing a bat, heel to shin, write a note using elegant handwriting, state the word “kentucky”

Asynergy: unable to perform; fragmented actions; indicates cerebellar disease


Thrombosis and ischemic stroke

An localized occlusive process within one or more blood vessels.
- The lumen of the vessel is narrowed by superimposed clot formation.
- Most common type of vascular pathology: atherosclerosis

Platelets adhere to the plaque crevice --> form clumps --> serve as nidus --> deposition of fibrin, thrombin and clot.


Causes of cerebrovascular disease

1. Ischemic stroke (80%)
- Atherosclerotic CVD (#1): larger intra- and extra-cranial arteries
- Embolism
- Lacunar
- Cryptogenic

2. Hemorrhagic stroke (20%)
- Intracerebral hemorrhage
- Subarachnoid hemorrhage


Embolism and ischemic stroke

Unlike thrombosis, embolic blockage is not caused by a localized process originating within the blocked vessel.

Most common sources: heart, aorta, carotid and vertebral arteries


Decreased systemic perfusion and stroke

Diminished flow to brain tissue is caused by low systemic perfusion pressure

Most common causes:
- Pump failure – due to myocardial infarction
- Systemic hypotension – due to blood loss


Biochemical changes and ischemic stroke

Neurons become ischemic --> K+ moves into the extracellular space --> Ca moves into the cell.

Decreased O2 availability --> production of oxygen-free radicals --> peroxidation of fatty acids in cell organelles and plasma dysfunction --> severe cell dysfunction

Excitatory neurotransmitters (glutamate, aspartate, kainic acid) --> significantly increased in regions of brain ischemia.

Hypoxia, hypoglycemia, and ischemia --> energy depletion --> increase in glutamate release --> decrease in glutamate uptake --> cell death


Stroke warning signs

Sudden weakness of the face, arm or leg, especially on one side of the body
Sudden confusion, trouble speaking or understanding
Sudden trouble seeing in one or both eyes
Sudden trouble walking, dizziness, loss of balance or coordination
Sudden severe headache with no known cause


Transient ischemic attack (TIA)

a temporary focal neurologic deficit, related to ischemia of the brain and/or the retina, lasting less than 24 hours, with a negative imaging study.
“Amarausis Fugax” – temporary loss of vision to one eye

** Same risk factors as strokes
** Same symptoms of a stroke


Major stroke syndromes: Left Middle Cerebral Artery

- Right hemiparesis
- Right sensory loss
- Right homonymous hemianopia

- Aphasia
1. global (Mute= can't speak at all)
2. Broca’s (frustrated, unable to say what they want to say)
3. Wernicke’s (no awareness of nonsensical speech)

- Dysarthria= cannot articulate

- Alexia= "word blindness", can't read

- Acalculia= Difficulty performing math tasks


Major stroke syndromes: Right Middle cerebral artery

- Left hemiparesis
- Left sensory loss
- Left visual field cut
- Dysarthria
- Neglect of left side
- Anosognosia= no knowledge of what's wrong
- Flat affect= lose prosidy in voice
- Aprosody - loss of prosody of speech
- Extinction= can only feel right side
- Apraxia= inability to do common tasks (dressing apraxia, constructional apraxia)
- Topographic memory deficit (get lost in familiar surroundings)


Major stroke syndromes: posterior cerebral artery strokes

R/L homonymous hemianopia
Hemi- ataxia
Color anomia


Brainstem strokes

Decreased level of consciousness
Contralateral paresis
**Nausea, vomiting
**Hearing loss


Risk factors for stroke

- Hypertension
- Diabetes
- Cardiac disease
- Atrial fibrillation
- TIA/prior stroke
- Dyslipidemia
- Cigarette smoking
- Alcohol abuse
- Obesity
- Physical inactivity
- Carotid stenosis

- Age
- Gender
- Race/ethnicity
- Heredity


Screening/diagnosis for stroke

1. CT scan:
- First test ordered for determination of hemorrhage (don't use contrast!)

2. CT angiography: large vessels in neck and 1st/2nd order vessels in brain

3. CT perfusion: cerebral blood flow, cerebral blood volume, mean transit time maps (blue= bad)

4. MRI

5. Echocardiography

6. Arteriography


Causes for ischemic stroke

1. Large Vessel Disease
- Atherosclerosis
- Carotid artery disease
- Fibromuscular dysplasia
- Carotid/vertebral artery dissection

2. Small Vessel disease
- Hypertension
- Diabetes mellitus
- Hypercholesterolemia
- Infective arteritis

3. Hematologic Disorders
- Polycythemia
- Thrombocythemia
- Sickle Cell Disease
- Factor V Leiden mutation
- Anticardiolipin antibody


Treatment for stroke: Medical

1. tPA
- Initially, had a 3 hour time window; not given to those who are rapidly improving, or those at risk for converting into a hemorrhage; strict inclusion/exclusion criteria
- At present, window is extended to 4.5 hours, with some restrictions:
1) Intake of coumadin
2) history of previous strokes and diabetes
3) Age > 80
- 6 hour window= if large clot is seen by imaging

Thrombus formation --> stimulates an endogenous fibrinolytic mechanism for thrombolysis --> release of tissue plasminogen activator, and other substances --> promote conversion of plasminogen to plasmin, the active fibrinolytic enzyme

2. Aspirin: if given within 48 hours (325 mg)


Surgical treatment for Stroke

Medical retrievers:
1. MERCI: groin catheter, push corkscrew around clot and pull out
2. Penumbra: catheter to clot, suctions out clot
3. Solitaire device: basket weave device prevents clot from moving distally

4. Hemicraniotomy: after day 5-7, hemorrhage begins to impinge on brain (pushes down--> herniation--> RAS killed)
- Drill hole into skull to allow blood to move out of skull
- Wear helmet for 2-3 months
5. Carotid endarterectomy
- Clamp above and below clot, excise and remove clot
- Done while patient is awake to ensure that brain continues to function


Stroke prevention: medications

Anti-platelet agents:
- Aspirin
- Clopidogrel (Plavix)
- ASA/Dipyridamole (Aggrenox)

- Atrial fibrillation
- Hypercoagulable state
- Mechanical valves


Intracranial Hemorrhage (ICH): definition

Supra-tentorial Intra-parenchymal hemorrhage (IPH)
- Infratenorial hemorrhage= named by location, ICH not usually applied
- NOT used for subdural, epidural or subarachnoid bleed

Accounts for 10% of all cerebrovascular events


Risk for ICH

1) HTN!!
2) Cerebral amyloid angiopathy: beta-amyloid deposition in cerebral arteries
3) binge drinking
4) Vascular anomalies: AVMs, AV fistulae, Cavernomas
5) Tumors
- Thyroid, RCC, coriocarcinoma, melanoma
6) Coagulopathy
- Liver failure, uremia, antiplatelet agents, anticoagulation
- Look for fluid level


Locations for Hypertensive ICH

1) Basal ganglia (putamen)
2) Subcortical white matter
3) Thalamus
4) Pons

Occur in areas of distribution of small perforating arteries due to:
- Medial lipohyalinosis
- Microaneurysms
- Microdissections


Cerebral amyloid angiopathy

Cortically located lobar hemorrhage

Pts older than 60 with majority (88%) > 70

Beta amyloid accumulates in media (replaces smooth muscle)

Overlap with Alzheimer’s disease
- Both associated with Apolipoprotein e4
- CAA common in alzheimer’s dz, however, only 20-40% of CAA pts have clinical dementia

** Common cause of frontal lobe intraparenchymal bleeds in elderly (risk for intracerebral hemorrhage)

Diagnosis: Boston Criteria
- Definite: postmortem examination
- Probable with supporting pathology: Bx or evacuated hematoma c/w CAA
- Probable: MRI / CT with ≥ 2 lobar hemorrhages (microhemorrhages) in pt ≥ 55 (no other cause)
- Possible: MRI / CT with 1 lobar hemorrhage in pt ≥ 55 (no other cause)
* Microhemorrhages in deeper structure (basal ganglia)= hypertensive hemorrhage


Presentation of intraparenchymal hemorrhage

- head pain: 30%
- Nausea/vomiting: 30%
- Altered consciousness: 60%.
- Focal deficits: 100% (Specific deficit depends on the location)
- High Blood Pressure: 90%

** More common in Asians

Prognosis based on blood in hemorrhage:
- 0 – 30 cc: good outcome
- 31 – 60 cc: intermediate prognosis
- > 60 cc: poor prognosis
- Intraventricular rupture worsens the prognosis at any hematoma volume
- Posterior Fossa: 15-30cc is LETHAL


Treatment of intraparenchymal hemorrhage

1. Control HTN: target mean arterial pressure < 120 (1st 24hrs) then < 100 (SLOW)

2. Correct Coagulopathy
- FFP, Factor 9 complex (for anticoagulation)
- Limits hematoma expansion (usually within 6 -24hrs)

3. Control Cerebral Edema (maximal @ 72hrs)
- Osmotherapy (mannitol, 3% NaCl)
- Theraputic hypothermia
- Sedation
- Pentobarbital Coma (decrease blood demands to head)

4. External ventrical drain
- Reduce ICP, hydrocephalus

5. Decompressive Hemicraniectomy +/- hematoma evacuation
- Decrease ICP / mass effect / MLS
- MUST consider for posterior fossa ICH


Cerebral aneurysm: incidence

Sub-arachnoid hemorrhage
- 10% of all Cerebrovascular events
- 80% attributed to aneurysm rupture
- 50% die within 30 days
- 25% survivors have significant deficits

Aneurysm incidence:
- 3-5% of population harbor cerebral aneurysms
- 20% of pts have multiple aneurysms
- Most commonly appear at branch points
- Represents out-pouching of intima & adventitia without intervening internal elastic membrane and media

85% seen in anterior location. Common locations:
1) Anterior communicating artery (34%)
2) ICA-Posterior comm. junction (23%)
3) Middle Cerebral artery, M2 segment at branch of inferior/superior division (19%)


Cerebral aneurysm: presentation

Sudden severe HA generally described as “Worst headache of my life” or WHOL if you're a neurosurgeon

Brief LOC (loss of conciousness)= Upon aneurysmal rupture, ICP approaches MAP, hence CPP falls toward zero!

Seizure occurs with ictus in 15-20%

Other associated Sx:
- MS Change
- Nausea
- Vomiting
- Nucal rigidity
- Cranial nerve palsies (ex. CN III with p-com rupture)

Prodromal headache:
- > 15% have prodromal HA within 1-3 mo prior to SAH due to sentinal bleed or aneurysm expansion


Cerebral aneurysm: evaluation

ABCs as always !!

Detailed History and Physical
- PE can give clues such as CN palsies, subhyaloid hemorrhage

Non-contrast head CT
- Positive in 95% of cases if done within 24 hrs
- 50% positive after day 7

Lumbar Puncture:
- useful if CT scan does not clearly demonstrate SAH
- Traumatic VS. SAH blood in CSF
** XANTOCHROMIA, present from 12 hours post ictus to ~ 2 weeks
- Demonstrated by spinning down CSF, blood break-down products remain in supernatant (yellow-tinged CSF)


Grading subarachnoid hemorrhage

Grade I= asymptomatic, mild HA, nucal rigidity
Grade II= CN palsy, severe HA, nuchal rigidity
Grade III= lethargy, confusion
Grade IV= Stuporous, moderate to severe hemiparesis
Grade V= comatose, decerebrate


Risks from Subarachnoid hemorrhage

- Occurs in 15 – 20% of aneurysmal SAH
- Casting in the ventricles or mass effect from a parenchymal clot yield elevated ICP

- 10% re-bleed within hours of ictus
- 50 % mortality with re-bleed

- detectable in ~ 70% of aneurysmal SAH @ 1wk by angiogram (changes in function)
- Symptomatic in 20 – 30% of patients (DCI)
- Vasospasm peaks @ day 5 -10, abates by day 14 - 21
- Irritation from blood breakdown products
- Causes delayed cerebral ischemia
- Highest risk in young women (tendency to vasospasm)


Treatment for subarachnoid hemorrhage

External Ventricular Drain (EVD)
- Direct drainage of CSF (remember Monroe-Kellie)
- ICP monitoring (mmHg, NOT cm H2O)

Medical Management
- Mannitol 1gm per Kg, follow serum osm (max = 320)
- 3 % Saline (Target Na 150)
- Sedation / Paralytics (propofol, nimbex)
- Pentobarbital Coma (decrease metabolic demands)

In case of re-bleeding:
1. Keep MAP < 90
- Labetalol, hydralazine, nicardipine
2. Emergent angiography to identify aneurysm
- Secure aneurysms: Coil (endovascular) or Clip (craniotomy)

Prevention of vasospasm:
- Prediction: Fischer Scale, gauges likelyhood of vasospasm by clot thickness & location of hemorrhage (SAH, IPH, IVH) based on blood seen on CT (1= minimal SAH, no IVH; 2= minimal SAH and bilateral IVH; 3= Thick SAH without bilateral IVH, 4= thick SAH with bilateral IVH)
- Prevention: Ca2+ channel blockers: prevents Ca+2 influx into smooth muscle
- Detection: Transcranial Doppler (TCD), measures changes in arterial flow velocities (detect increased velocity due to spasm)- may increase in fever/sepsis (Lindegaard ratio can help distinguish; MCA:ICA velocity)
- Treatment: Triple H therapy (Hypertension, Hypervolemia, Hemodilution)


Triple H therapy for SAH

Theory: Hypertension & Hypervolemia maintain Cranial perfusion pressure in setting of vasospasm, hemodilution decreases blood viscosity

Induced Hypertnsion: Usually 20 -30 mmHg > baseline MAP
- Typical MAP Goal: 100-110
- Pressors: Neo, dopamine, levophed

Hypervolemia: CVP goal 10-14 mmHg, or PCWP 14-16 (nl 8-10)
- Normal saline maintenance fluid

Hemodilution: target HCT 33%


Other issues associated with SAH

1. CHF, Pulm Edema secondary to Triple H
2. Elevated troponins, (Voodoo Death) occurs with catacholemine discharge, esp. with SAH in sylvian fissure
3. Stunned Myocardium (Tako-Tsubo Cardiomyopathy): base of heart contracts while apex balloons out, can't contract
4. SIADH (hypervolemic hyponatremia)
5. Cerebral Salt Wasting (hypovolemic hyponatremia)


Subdural hematoma: background

- bleeding between the dura and the arachnoid membranes
- most commonly from a venous source (bridging veins)
Not limited by Sutures

- Head trauma: motor vehicle accidents, Falls, assaults
- complicates ~11 % of mild to moderate head injury requiring hospitalization
- Complicates ~20 % of severe TBI

- Tearing of bridging veins
- Rarely rupture of cortical arteries of < 1mm in diameter
- Low CSF Pressure: Loss of buoyancy yields seperation of dura and arachnoid with traction placed upon veins

Risk factors:
- Cerebral atrophy: advanced age, EtOH, prior head trauma


Subdural Hematoma: presentation

- Headache / nausea / vomiting
- Loss of consciousness / change in Mental status (MS)
- Focal neurologic deficits referable to area underlying SDH

Chronic (insiduous onset):
- light-headedness
- cognitive impairment
- Apathy
- Somnolence
- Rare seizures
** Blood breaks down, takes on color of CSF

- Urgent surgical evaluation with: SDH >= 10mm in thickness, or midline shift >= 5mm


Epidural Hematoma

Bleeding between the dura mater and the inner table of the skull
- Limited by sutures
- Arterial laceration caused by traumatic head injury
- Most common in adolescents and young adults with the mean age between 20 and 30.

- 85% due to arterial injury: tearing of the middle meningeal artery as it courses through the foramen spinosum
- Skull fractures are present in 75 to 95 of cases
- Head trauma: motor vehicle accidents, falls, Assaults

- Headache / nausea / vomiting
- Loss of consciousness / change in MS
- Focal neurologic deficits- Referable to area underlying EDH
- "lucid interval“: recovery of consciousness, followed by deterioration over hours
--> continued arterial bleeding and hematoma expansion

Prognosis: related to level of consciousness on presentation; Mortality:
- Awake: 0 %
- Obtunded: 9%
- Comatose: 20%
- Bilateral hematomas: 15-20%
- posterior fossa hematomas: 26%.


Survival rates and diagnosis of common primary CNS tumors

Glioblastoma= 15%
Astrocytoma= 34%
Oligodendroglioma= 65% (chemo/radiation responsive)
Medulloblastoma= 60%
Ependymoma= 60%

MRI= MANDATORY (w/ and w/o contrast)

CT= more useful for bony structure evaluation, cerebral hemorrhage, calcification

CSF cytology: needed for:
- Medulloblastomas, anaplastic ependymomas
- Both invade meninges


Symptoms and management of symptoms of brain tumors

Symptoms by site:
1. Cortex:
- Aphasia- expressive or sensory (speech cortex)
- Memory impairment and dementia
- Seizures
- Local weakness or hemiparesis (motor cortex)
- Visual field deficits (including blindness) (occipital cortex)
- Personality changes, including mood/mentation/concentration (frontal lobes)

2. Pituitary:
- Visual field deficits (including blindness)

3. Midbrain:
- Visual field deficits (including blindness)

4. Cerebellum:
- Dysarthria
- Ataxia

5. Brainstem:
- Ataxia
- Diplopia (cranial nerves 3-6)
- Facial drooping (cranial nerve 7)
- Deafness (cranial nerve 8)
- Facial numbness or pain (cranial nerve 5)

5. Any site:
- Headache (any site, if edema and mass present; common in posterior fossa tumors)
- Nausea and vomiting (increased intracranial pressure, particularly in posterior fossa)

6. Spinal cord:
Back pain (including neck pain)

Headache, weakness: Decadron
Increased ICP/Herniation: Decadron, Mannitol
Seizures: Anticonvulsants (Dilantin, Keppra
Hydrocephalus (mental status change,gait difficulty,incontinence): LP, VP shunt
Leptomeningeal disease: RT, CTx
Neoplastic meningitis: IT chemotherapy
Lymphomatous meningitis: IT CTx/HDMTX


Low-grade astrocytomas/ gliomas

Mean age at presentation= 37 years.

The most common symptom is seizure, but most patients do not have any signs of their disease (i.e., they are neurologically “intact”).

** Age is the most powerful clinical prognostic factor that affects survival. Children and younger adults have a significantly better outcome than older adults.

** Seen with increased frequency in patients with type 1 and 2 neurofibromatosis.

- Maximum surgical resection is associated with a more favorable outcome.
- After gross total resection in children, observation is recommended. 
- After subtotal resection or biopsy, treatment (radiation therapy, chemotherapy) is either given upfront or deferred until the time of symptomatic or imaging progression. It is a controversial issue.
- Recommended dose is 54 Gy in 30 fractions treating the MRI-defined tumor volume with a 2- to 3-cm margin.
** Chemotherapy does not have a defined role in the management of adult low-grade glioma.


High-grade astrocytoma/ gliomas

Glioblastoma multiforme (GBM)is most common in adults; anaplastic astrocytoma (AA) second most common.

Location is primarily supratentorial in adults and infratentorial in children. 

Multiple chromosomal abnormalities are found in astrocytomas, including deletions, gene amplifications, rearrangement of chromosomes, and overexpression of oncogenes.

 The most important prognostic factors are age of patient, performance score, and extent of surgical resection and MGMT methylation.

- Cure is not feasible at present;
- 2-year survival for grade 4 gliomas is still only around 25% (improved from <10%). 
- Surgical resection= improved outcomes in younger patients with lower grade tumors.
- Radiation therapy (RT) given after surgery/biopsy significantly prolongs survival (from 2-4 months without RT to 10-12 months with RT).


Treatment of recurrent gliomas

Target angiogenesis:
1. Bevacizumab= Avastin:
- Glioblastoma cells express high levels of VEGF in situ
- Inhibit VEGF--> impede growth of glioma xenographs
- Significant in colorectal and NSCLC



- Most radiation and chemotherapy sensitive brain tumors

Codeletion of 1p, 19q confers better treatment response and prognosis

Pure oligodendroglioma (grade II)
- Benign, survival time > 9 years (surg and xrt only)
- Complete resection: no tx
- Partial resection/recurrence: temodar or xrt
- Chemo: CR with 100% survival at 2 years

Anaplastic oligodendrioma (grade III):
- Survival time 2 yrs (Surg & XRT only), highly chemosensitive, >90% RR with 50% SR at 2 yrs
- PCV as pre/post XRT, Temodar
- Recurrence-ChemoTx


Oligoastrocytoma (mixed tumor)

Various proportions of oligodendroglial and astrocytic cells within tumor
- Unless tumor has > 20% oligodendroglial/astrocytic components--> neuropath will read as pure oligodendroglioma/ pure astrocytoma



Medulloblastoma= PNET (primitive neuroectodermal tumor)
- occurs in children and young adults.

- associated with obstruction of CSF flow (hydrocephalus) and include headache, nausea, vomiting, ataxia.

- Standard treatment is very intense and includes maximal surgical resection, craniospinal radiation therapy (=irradiation of the entire spine and brain), as well as several months of chemotherapy.
- Cure rates are 75% at 5 years.


Primary CNS lymphoma

Incidence : rare; increasing in both immunocompromized and non-IC
- concommitant EBV, HHV-6, Autoimmune, immunosuppressant drugs

Location: intraparenchymal, periventricular or callosal (butterfly lesions),
- appears homogeneous and hyperintense on T1-GD
- Screening not necessary except Opthal/ CSF study.
* Recent small study suggested the role of systemic PET to rule out systemic and indolent Lymphoma

- High dose methotrexate (HDMTX)= more durable response over 3-4+ years


Brain metastases

20-40% of all cancer patients
- Frequency rising due to better imaging, longer survival
- 60-85% of autopsy of patients who died of cancer have multiple brain mets
- May be synchronous (diagnosed with primary cancer) or metachronous (later)

Clinical presentation:
- 2/3 have neurologic symptoms during cancer
- Most common= Headache, more often in morning or night (posterior fossa lesions)
- Focal weakness (secondary to HA)
- Seizures (10%)
- Cognitive abnormalities (aphasia)
- Cranial nerve involvement= meningeal carcinomatosis

** 30% die due to progression of old or development of new brain lesions
- Remainder die due to systemic disease

- Untreated= 1 month
- Steroids= 2 months
- Whole brain radiation therapy= 2-7 months

1. Whole brain radiation therapy
- based on hypothesis that entire brain parenchyma is seeded)
--> reduces tumor recurrence, risk of neurologic death
2. Surgery:
- does not eliminate microscopic disease
- best for patients with controlled systemic disease, functional independence
- OR patients with large masses, cerebral herniation possible, or increased intracranial pressure (cerebellar masses)
3. Focused radiotherapy (radiosurgery)
- best for recurrent brain mets
4. Chemo (radiosensitizer)


Spinal cord compression

Oncologic emergency:
- Breast, lung, prostate, lymphoma, myeloma, kidney

- Pain (local, radicular)
- Motor weakness
- Sensory loss
- Paresthesia,
- Incontinence
- Paralysis

- X-ray
- Myelogram/CT
- MRI= standard

- Chance of restoring and preserving neurological function
1. Steroid= decrease swelling
2. Radiation tx= reduce tumor burden, pain
3. Surgery= total, partial


Glial Cells

Oligodendrocytes= produce CNS myelin

Astrocytes= Maintain proper environment for neurons

Ependyma= Lining of ventricles, central canal of spinal cord and filum terminale. Some production of CSF

Microglia= Resident immune cells of the CNS. Undergo activation in response to a variety of CNS injury processes
- Most prominent in viral encephalitis


Epidural hematoma

Accumulation of blood between cavarium and dura
- Creates high-pressure system within the skull
- Usually results from trauma to side of head

Ex: Fracture of temporal bone--> transection of middle meningeal artery


Cerebral herniation

Final common pathway in multiple fatal CHS processes (trauma, tumors, cerebral hemorrhage)

Supratentorial intracranial pressure increase:
- Due to intracerebral hemorrhage, tumor, liver failure (hepatic encephalopathy), encephalitis
- Transtentorial herniation--> CN3 palsy
- Rostrocaudal displacement of brainstem--> intraparenchymal (Duret) hemorrhages in brainstem
- Loss of brainstem--> DEATH


Subdural hematoma

Accumulation of blood in subdural space due to torn bridging veins
- Death= 74%
- Recovery= 8%
- Large, clinically significant= almost always traumatic
- Subdural blood--> does NOT enter subarachnoid space (can't see on spinal tap)

Ex: elderly have cerebral atrophy--> bridging veins span greater distance--> more susceptible to damage


Subarachnoid hemorrhage (SAH)

Bleeding into subarachnoid space

Due to:
- Trauma
- Rupture of saccular aneurysm (66%)
- Rupture of AV malformation (10-15%)
- Infection
- Vasculitis
- Tumor

Subarachnoid blood--> reactive vasospasm--> secondary ischemic brain injury


Impact-associated cerebral injury

Intraparenchymal hemorrhage due to severe impacts
- rupture of intracerebral blood vessels

Cerebral contusions


Cerebral contusions

Head impact related cerebral contusions results from the brain forcefully hitting the interior surface of the overlying skull.
- Contusions usually occur in areas of prominence of the cerebral hemispheres including the tips of frontal, temporal and occipital lobes

Contusion= Bruise on the cortical surface
- Necrosis followed by phagocytosis of damaged cortex and white matter
- Coup lesions: at site of impact
- Countercoup lesion: Located at site distant from impact. Brain moves within skull due to impact to head and slams into skull at site remote from traumatic impact on head.


Diffuse axonal injury

Results from rotational acceleration of the brain within the head. (can occur in absence of impact)

Three characteristic features of the pathology of DAI in its most severe form include:
1) diffuse damage to axons
2) a focal lesion in the corpus callosum
3) focal lesions in the dorsolateral sector of the rostral brain stem adjacent to the superior cerebellar peduncles.

Can result in formation of numerous axonal spheroids
- Blocks axonal flow--> buildup in one space (indicates axonal transection)


Chronic Traumatic Encephalopathy

= progressive neurologic deterioration related to repeated traumatic brain as can occur in number of athletic activities.
- CTE is a slowly progressive tauopathy with a trauma associated etiology

Tauopathy= increased expression of Tau, neurofibrillary tangles


Circulatory disorders for brain

Vascular malformations
Cerebral hemorrhage
Ischemia and infarction


AV malformation in brain

Disorganized mass of abnormal arteries and veins
- Direct connection between arterial and venous circulations
- Congenital cases result from lack of development of local capillary network
- Rate of bleeding is 2-4 % per year (with high mortality due to herniation)

See disorganized arrray of abnormal blod vessels--> abnormal communication between arteries and veins--> seizures, SAH, intraparenchymal hemorrhage


Cavernous hemangioma

- Venous vascular malformation
- Dilated vascular channels
- Large vascular spaces with fibrous walls and little or no intervening brain parenchyma
- Seizures, headaches or neurologic deficits
- Most are asymptomatic
- May rarely result in intraparenchymal bleed


Cerebral telangiectasias

Telangiectasias consist of an aggregate of small thin-walled blood vessels with intervening parenchyma.
They may cause seizures but rarely rupture.


Saccular aneurysms

Acquired lesions; loss of internal elastic lamina, muscularis at junction of artery with aneurysm
- Aneurysm has thinned fibrous wall vs normal muscular, elastic lamina
- Thin, dilated structure--> risk for rupture

** Rupture of saccular (berry) aneurysm--> life-threatening, 35% mortality during initial hemorrhage
- 2/3 of Subarachnoid hemorrhage are secondary to aneurysm rupture
- 10-15% due to AV malformations
- Blood in subarachnoid space--> vasospasm of cerebral blood vessels--> secondary cerebral ischemia


Atherosclerotic brain aneurysms

Fusiform dilitations of basilar and vertebral arteries due to severe atherosclerosis
- Major complication= thrombosis


Mycotic aneurysms

Infections of arterial walls from septic emboli give rise to mycotic aneurysm.
- The septic emboli are usually derived from an infected heart valve or pulmonary vein.
- Most common organisms include Streptococcus viridans and Staphylococcus aureus.
- Mycotic aneurysms may rupture and present as intracerebral hemorrhage or subarachnoid hemorrhage.



Sudden, rhythmic change in electrical activity in cerebral cortex
- Almost always accompanied by change in behavior
- Rarely, occur without behavior changes

Seizures come from:
- Abnormal, synchronous firing of neurons (not supposed to do that)
- Cortical phenomenon (don't arise from basal ganglia, cerebellar, brain stem, spinal cord)

Brain has built-in seizure-termination mechanisms
- Failure--> Status Epilepticus (medical emergency)


Types of generalized seizures

Generalized seizure: starts in both hemispheres simultaneously
– How can your whole cortex be hyperexcitable at the same time?
– Diffuse thalamo-cortical interactions

- Generalized tonic-clonic (“grand mal”)- lasts 1-2 minutes
- Clonic (back-and-forth shaking)
- Tonic (stiffening)
- Myoclonic (lightning-like single jerk)
- Absence (“petit mal”)- lasts few seconds
- Atypical absence
- Atonic- lasts few seconds


Types of focal seizures

Focal or partial seizure: starts in one hemisphere and then spreads
– Might start anywhere in the cortex

Simple partial: no change in level of awareness
– Aura (subjective symptoms only)
– Focal motor seizure (unilateral clonic or tonic)

Complex partial: alteration of awareness
– Often preceded by an aura
– May secondarily generalize
– Post-ictal confusion/lethargy
– Doesn’t have to be complete LOC to be considered complex partial



A predisposition to spontaneous seizures
- Seizures (plural)
- Spontaneous, NOT provoked by an acute disturbance of the brain (not within 1 week):
– Cerebral injury (stroke, trauma, infection) – Drug or toxin – Major metabolic disturbance (↓ gluc, Na+)
- Predisposition: potential is there, even if seizures are controlled

1. Generalized: predisposed to generalized seizures
- idiopathic (primary) generalized epilepsy= nothing else wrong with brain
- symptomatic (secondary) generalized epilepsy= due to trauma, deranged brain activity (mentally retarded, brain waves abnormal)
- EEG: sharp waves

2. Focal epilepsy: predisposed to focal epilepsy
- Focal can appear generalized (spreads from focus)
- If patient has focal and generalized tonic-clonic seizures, it's focal epilepsy
- EEG: increased activity



Neurophysiologic basis
- APs too brief to summate
- Due to post-synaptic potentials (EPSPs and IPSPs)--> longer in duration adding together, produces change in scalp potentials
- Spikes due to rapid synchronous firing--> rapid return to baseline

Thalamocortical interactions:
- Focal EEG activity due to events occurring locally in cortex
- Activity of whole cortex= sculpted, regulated by diffuse projections of thalamus (reticular nucleus)


Childhood Absence Epilepsy

Onset around 4-8 years of age
- May have dozens in a day
- May have rare GTC seizures
- Normal intellectur functions
- Responds easily to meds
- Resolve by puberty

EEG: 3 Hz "Spike and wave" pattern

- Characteristic 3/sec spike and wave appearing in entire cortex
- Interplay of cortical and diffusely- projecting thalamic relay neurons
- Excitatory connections with each other
- Reticular nucleus of the thalamus (NRT)
has inhibitory connections onto both – GABA mediated

Sequence of events:
1. GABA-mediated hyperpolarization
2. T-type Ca+2 channel opening--> depolarization
3. Cycle takes 300 msec to complete (3/sec)

Treatment: Drugs that block T-type Ca+2 channels= Ethosuximide


Juvenile myoclonic epilepsy

Onset 12-18 years of age
- Seizures occur upon awakening
- On "bad days"--> cluster of myoclonic seizures culminating in GTC
- 10-20% have absence seizures

Respond easily to meds, probably lifelong


Benign Rolandic Epilepsy

- Onset of focal motor sz (unilateral facial twitching) age 5 - 9
- GTC occur only at night
- Normal cognitive fxn; normal MRI
- Seizures always resolve by puberty
- Doesn’t require treatment
- An idiopathic partial epilepsy (few of these)


Mesial Temporal Lobe Epilepsy

- Onset of sz typically in childhood or adolescence

Often a history of a predisposing “hit”:
- Complex febrile sz
- CNS infection
- serious head injury

Often a few GTC early on, followed by typical focal seizures

Mesial Temporal Lobe Aura: most seizures preceded by characteristic aura:
– Rising epigastric sensation (or nausea)
– Déjà vu
– Olfactory hallucinations (foul)
– Perceptual distortions= things look different in size (micropsia/macropsia)
– Autonomic (flushing, tachycardia)

Isolated auras are frequent, but at times also proceed into complex partial sz


Temporal lobe complex partial seizure

After aura, loss of awareness with automatisms
– Automatic, quasi-purposeful movements – Oro-alimentary: lip-smacking, swallowing – Manual: fumbling, picking at clothes

May also have dystonic posturing
Secondary generalization is rare


Frontal lobe epilepsy

Seizures mostly nocturnal
- Often no aura, no post-ictal confusion
- Strange noises, weird postures, bizarre & complex automatisms
- Supplementary motor area --> “fencer’s posture”
– Head turning, extension of one arm, flexion of the other
- Pt may remain responsive, but still be amnestic for the event


Causes of idiopathic epilepsy

Nothing else accompanying seizures (essential epilepsy)
Presumed genetic
- Family history common
- Few genes recognized with incomplete penetrance


Causes of symptomatic epilepsy

Caused by diffuse brain lesions:
– Global hypoxia, perinatal ischemia
– Meningitis/encephalitis in infancy
– Pan-cerebral malformations (lissencephaly, microcephaly)
– Tuberous sclerosis or any other congenital multifocal cerebral disease
– Metabolic derangements
– Chromosomal abnormalities

Focal epilepsy:
- Neoplasms – Can be very indolent (or completely benign)
- Cortical dysplasias – Abnormal (but not neoplastic) neurons
- Heterotopias/hamartomas – Normal neurons in the wrong place
- Vascular malformations – Arteriovenous malformations – Cavernous angiomas
- Stroke
- Intracerebral hemorrhage
- Trauma
- Gliosis
- Cysticercosis – Probably the #1 cause in the developing
- Genetically-inherited focal lesions= Autosomal dominant nocturnal frontal lobe epilepsy found due to a mutation in the ACh receptor
- Cryptogenic


Hippocampal sclerosis

Unique lesion causing mesial temporal lobe epilepsy
– The most common cause of medically refractory epilepsy
- Hippocampus appears atrophic (small) and sclerotic (abnormal signal on MRI)
– May occur unilaterally or bilaterally

Caused by:
- Many pts with HS have a history of a presumed precipitating event in infancy
– Meningitis
– Head trauma
– Complex or prolonged febrile seizure
- Families w/HS have been documented
- Reigning theory is “two hit” hypothesis: genetic susceptibility + precipitating insult (often the prolonged febrile sz)


Consequences of epilepsy

– Falls, lacerations, intracerebral bleeds
– Automobile accidents
– Drowning

Memory impairment
– Focal epilepsy only
– Almost certainly due to progressive hippocampal cell loss with seizures

Status epilepticus
– Cognitive impairment, death

Psychosocial maladjustment
- Employment discrimination

Sudden unexplained death (SUDEP)
– Unclear if this is seizure-related
– Cardiac? Respiratory?
– Thankfully, rare -- but not that rare


Multiple Sclerosis

Disease of oligodendrocyte and myelin loss plus severe axonal loss and grey matter injury (degenerative process)

Dawson's finger= areas of slow blood flow around neurons

CIS= clinically isolated syndrome (first attack, demyelinating in nature)
- Can be optic neuritis, brainstem sydrome,

RRMS= relapsing, remitting MS

SPMS= Secondary progressive MS; Starts with attacks, progression of disability without clear attacks

PPMS= primary progressive MS; starts out with just progressive disability, no attacks

RIS= radiographically isolated syndrome
- Find "MS" lesions (asymptomatic) at time of MRI (or autopsy)


Etiology of MS

Genetic factors: complex level of genetic involvement
- May carry some genes (25-35% concordance among twins)
- HLA-DR2, IL-2Ra, IL-7Ra, GWAS ( > 100 alleles)

Environmental factors: EBV (live in B cells- enhances B-cell survival), hygeine hypothesis, smoking
- Geographic factors (Northern= higher rates, southern= lower rates); could correlate with Vit D (receptor next to MHC), GI infections

Immunologic pathogenesis


Characteristic MS lesions

Infratentorial (cerebellar)
Gadolinium + lesion

** Significant small vessel involvement, rich in periventricular and juxtacortical areas

Also see lesions in cortex- not visible in conventional imaging (need post-processing)
- Axons in cortex have small amount of myelination--> gray matter can still be demyelinated

Neuroaxonal injury persists for life
- After first attack, significant chance of repeat attacks--> must start immunomodulatory therapy quickly


Diagnosis of MS

Primary diagnosis based on dissemination in space:
1. First attack or progression of > 6 months
2. Two or more lesions in appropriate locations:
- periventricular,
- juxtacortical (inferior, posterior fossa)
- cord lesion or asymptomatic infratentorial lesion

Lesions over time:
1. Presence of asymptomatic enhancing and nonenhancing lesions at any time
2. >= 1 new T2 or enhancing lesion
* Can now diagnose patient at first attack

** risk of having another attack increases based on location of lesions (in diagnostic areas, risk is ~90%)
** Fewer lesions, less likely to have disability at 5 years (10%)

Biomarkers: NONE detected thus far


Pathogenesis of neurologic dysfunction in MS

Demyelination--> if it stops, axon will re-myelinate

In progression of MS:
Axonal transection and degeneration
- Axon is cut in half before it can regenerate the myelin sheath


Treatment for MS

Reduce likelihood of another attack after precipitating event by administering:
- IFN-beta-1b: reduced risk of new lesion formation
- S1P receptor antagonists
- Anti-VLA4
- Anti-metabolites
- Anti-neoplastic agents


Acute disseminated encephalomyelitis

Monophasic illness, lasting ~2 to 4 weeks
- Affects predominantly children and young adults
- Usually follows an infection, also immunizations
- Immune mediated complication

Acute onset of multifocal neurologic disturbances
- Many patients recover (early recognition and steroid treatment)

- Perivenous inflammation and demyelination,
- Punctate to confluent, contemperaneous


Dysmyelinating diseases

Disorder leading to abnormal myelin formation:
- Metachromatic Leukodystrophy
- Globoid Cell Leukodystrophy (Krabbe disease)
- Adrenoleukodystrophy


Metachromatic leukodystrophy

Deficiency of the lysosomal enzyme arylsulfatase A; autosomal recessive
- Late infantile form most common, onset 1-2 years; progressive motor disability, intellectual decline, rapid demise

- “Metachromatic” deposits of sulfatide in CNS, PNS, and kidney
- Diagnosis made by measurement of enzyme activity, urinary sulfatide excretion; prenatal diagnosis is possible


Globoid cell leukodystrophy

AKA Krabbe disease
Deficiency of the lysosomal enzyme beta galactocerebrosidase;
- autosomal recessive

Onset and symptoms:
- Late infancy most common (80%), usually before 6 months
- developmental arrest
- extreme irritability and crying followed by rigidity and spasms;
- frequent episodes of pyrexia
- death by 1-2 years with continued seizures and opisthotonus

CNS pathology due to accumulation of psychosine--> loss of oligodendrocytes, myelin
- May also affect the peripheral nervous system

- numerous globoid cells, paucity of intact myelin and oligodendrocytes and variable loss of axons.



- X-linked recessive (Xq28)

- Disturbances in affective behavior
- Neurologic deficits
- Adrenal insufficiency

- Peroxisomal disorder
- Accumulation of VLCFA (>C22:0) due to defective beta-oxidation
- Mutations in ALDP gene, an ABC transp.

Childhood cerebral (peak age of onset 4-8 years)
- Age of onset and extent of lesions at presentation (by MRI scans) are predictive of clinical course

Adrenomyeloneuropathy (peak age of onset 20-30 years)
- slowly progressive (over decades) spastic paraparesis,
- sphincter disturbance due to spinal cord involvement;
- variable cerebral involvement

Adult cerebral
- Cerebral symptoms after age 21, no spinal involvement

Adrenal insufficiency only (“Addison disease” in men)

Symptomatic ALD Heterozygotes (women age 25-55 years)
- 61% with “neurologic abnormality”, widely varying severity


Hypomyelinating disease

Pelizaeus-Merzbacher Disease
Alexander Disease
CACH (Vanishing White Matter)


Alexander disease

Occurs sporadically (usually)
- More common in males
- autosomal recessive

- Most often presents in infancy with increased head size,
- psychomotor retardation, spasticity; rapidly progressive

- widespread demyelination in CNS with Rosenthal fibers in astrocytic processes
usually sporadic;
- majority of patients have mutations in glial fibrillary acidic protein, an intermediate filament protein of astrocytes


Myelinolytic disease

Central Pontine Myelinolysis
Marchiafava-Bignami Disease
Spongy Degeneration of Infancy (Canavan)
Vacuolating Leukoencephalopathy
Hexachlorophene Toxicity
Heroin toxicity (“chasing the dragon”)


Central pontine myelinolysis

Noninflammatory, demyelinating condition commonly associated with the rapid correction of hypo- or natremia. However, it was originally described in those with chronic alcoholism and in malnourished persons.


Canavan's disease

Deficiency of the lysosomal enzyme aspartoacylase;
- N-acetyl-aspartic acid accumulates in brain

Autosomal recessive; most common in Ashkenazi Jews

Presents at 2-6 months of age with psychomotor retardation, hypotonia; blindness, megalencephaly, seizures occur

Vacuolar change (“spongy”) in CNS due to intramyelinic edema in white matter of cerebrum and cerebellum


Neuromuscular symptoms

Motor symptoms;
- Weakness
- Fatigability
- Muscle cramps
- Muscle twitching

Sensory symptoms:
- Numbness
- Tingling and other paresthesias
- Pain


Neuromuscular signs

Motor signs:
- Weakness
- Atrophy
- Fasciculations

Sensory signs:
- Abnormal sensation to touch, pin, temperature, vibration, and joint position
- Romberg test – does not distinguish central from peripheral
- Skin changes: hair loss, skin color and temperature changes
- Dysautonomia: orthostatic hypotension, cardiac arrhythmias, abnormal peristalsis, erectile/ejaculatory dysfunction


Motor Unit

Four parts:
1. Anterior horn cell (lower motor neuron in the spinal cord)
2. Motor nerves (motor axons originating from AHC)
3. Neuromuscular junctions (synapses between motor axons and the muscle membranes)
4. Muscles (myofibers innervated by motor axons)

Death and repair of the Motor Unit:
- If an anterior horn cell dies (AHC1), muscle may receive collateral sprouts from a neighbor (AHC2)
- If AHC2 allows collateral sprouts, its motor unit will increase in size, by providing additional innervation to all muscle fibers previously connected to AHC1
- Analogously, the same may occur with peripheral motor nerve injury, increasing size of the motor unit by collateral sprouting

** Neuromuscular junction disease and muscle disease do not result in increase size of the motor unit (no collateral sprouting)


Electrodiagnostic Tests for NM disease

Nerve conduction studies: CMA (conduction mass action potential)

Needle Electromyography


Motor Neuron Diseases

- Amyotrophic lateral sclerosis (ALS)
- Primary Lateral Sclerosis (PLS): motor tract affected
- Hereditary forms of progressive spinal muscular atrophy (SMA)
- Spinobulbar muscular atrophy (SBMA, Kennedy disease)
- Hereditary Spastic Paraparesis (HSP)= paraplegia
- Poliomyelitis, MND associated with West Nile infection


ALS (Amyotrophic Lateral sclerosis)

Familial Variants (< 10%): Cu Zn SOD 1 gene

Linked to Frontotemporal dementia (FTLD)

Sporadic (> 90%); 1.5-2 per 100,000
- Man > woman
- Onset 40-60 years
- Survival 2-6 years

Etiology unclear; pathological inclusions (ubiquitin, Bunina bodies, TDP-43) in motor neurons
- Muscle fibers are disconnected from dying nerve cells in brain and cord
- TDP-43= link betweeen sporadic and familial ALS

Signs and Symptoms:
- Progressive degeneration of motor neurons in anterior horn of spinal cord, brainstem and motor cortex
- ALS= Upper and Lower motor neuron signs in same segment; asymmetric weakness and atrophy (amyotrophy) with corticospinal tract signs (hyperreflexia)
- Starts as hand/foot muscle weakness
- Normal extraocular movements, sensory and sphincter function; normal mentation
- Cognitive impairment in 40%
- Dysphagia, dysarthria, resp. muscle involvement
- Hyperreflexia, Babinski sign, pseudobulbar affect- emotional lability

No effective therapy: Riluzole and supportive care, ventilatory support


Hereditary Motor Neuron Diseases

Progressive Motor Neuron Diseases:
- SMA I (Werdnig-Hoffman)
- SMA III (Kugelberg-Welander)

Spino-bulbar muscular disease (Kennedy's disease)


Spinal Muscular Atrophy

Type I (Werdnig-Hoffman)=
"Floppy infant"
- birth to 6 months
- Arreflexia
- Isolated Tongue fasciculations

Presentation of SMA:
May have childhood, juvenile and adult onset
- Autosomal recessive; affects lower motor neurons
- Normal intellect
- No sensory loss

Path: One of the 2 copies of the Survival Motor Neuron 1 (SMN1) is deleted

Treatment: symptomatic and supportive

Prognosis depends on ventilatory status


Kennedy's disease (spinobulbar muscular atrophy)

Motor neuron loss in anterior horn of spinal cord and brainstem motor nuclei

Hereditary neurodegenerative disease; expansion of trinucleotide CAG repeat in androgen receptor gene on X chromosome- toxic gain of function in the disease gene product
- Anticipation phenomenon

- Proximal symmetric weakness; arms & legs; face- upper & lower; slowly progressive (over decades)
- Bulbar dysfunction: dysphagia, masseter weakness, dysarthria
- Tongue weakness, atrophy, fasciculations
- Muscle cramps; fatigue; contractures
- Tendon reflexes: Absent or reduced
- Sensory neuropathy, often subclinical; reduced vibration LE>UE; small SNAPs
- Hand tremor: postural & action
- Androgen insensitivity: gynecomastia, reduced fertility, testicular atrophy


Peripheral neuropathy: Symptoms

Motor, sensory, and sensorimotor
- Tendon reflexes - reduced or absent
- Distal > proximal muscle weakness
- Atrophy of weak muscles, typically distal muscles before proximal muscles (intrinsic foot and hand muscles)

1. Reduced sensation to small and large nerve fiber modalities
- Small fiber: touch, pinprick, and temperature
- Large fibers: vibratory and joint position sense

2. Length-dependent gradient
- Stocking and glove patterns
- When neuropathy reaches up to knees -> sensory deficits in fingertips/ hands
- Shield and mask patterns


Peripheral neuropathy: patterns

1. Distal symmetric polyneuropathy
- Length-dependent sensory loss
- Most common cause: diabetes mellitus
- Other causes: hypothyroidism, alcohol, chemotherapy, vitamin deficiencies (B12, B1, B6), toxicity from too much vitamin B6, etc

2. Mononeuropathy
- Single nerve
- E.g.: entrapment neuropathies (CTS, UNE, PNF)

3. Multiple Mononeuropathies (Mononeuritis multiplex)
- >1 nerve, asymmetric
- Nerve infarction/ inflammation (vasculitis)
- E.g.: lupus and polyarteritis nodosa)

4. Autonomic Neuropathies
- Postural hypotension, abnormal heart rate variability, gastrointestinal dysmotility, erectile dysfunction, and urinary retention (bladder detrusor m. dysfunction).
- E.g.: amyloid and diabetic neuropathy

5. Small Fiber Sensory Neuropathy
- Numbness, paresthesias, burning/ electric-like pain
- Length-dependent (feet or hands first)
- Neurological examination may be normal
- Normal EMG/NCS (test only for large nerve fibers)
- Epidermal nerve fiber density assessment (skin biopsy) may help confirm diagnosis


Causes of Peripheral Neuropathy

Diabetes – most common cause worldwide
Environmental Toxins
Systemic Disease


Immune-Mediated Neuropathies

- Multifocal motor neuropathy (MMN)
- Paraproteinemia-associated neuropathy (MGUS)
- Vasculitic neuropathy (PA, Wegener granulomatosis)
- Autoimmune plexitis (Parsonage-Turner syndrome)
- PN associated with systemic disease (Sjögren's, SLE, scleroderma, RA, sarcoidosis, celiac disease etc.)
- Paraneoplastic neuronopathy- sensory ganglionopathy (anti-Hu syndrome)
- Primary amyloidosis-related neuropathy
- Immune neuropathies associated with lymphoma


Diabetic neuropathy

60-70% of diabetes patients experience complications involving nerves
- Distal limb numbness with tingling sensation, prominent pain, gait imbalance, muscle weakness and wasting, falls and other complications

Early recognition and optimal management of diabetes delays disability and prevents complications

Symptomatic therapy for pain, Physical therapy


Charcot-Marie-Tooth Disease

Most common inherited neurological disorder (1:2,500)
- Hereditary Motor and Sensory Neuropathy (HMSN)
- Distal > proximal weakness, atrophy, and numbness
- Autosomal dominant common (autosomal recessive and X-linked forms also exist)

1. Most common type CMT1A is caused by duplication or mutation of PMP22, CMT1B mutation of MPZ gene
- Uniform demyelination and slowing on NCS
2. Axonal variants (CMT2)
3. Severe infantile forms (Dejerine-Sottas) CMT3
4. CMT4 with childhood onset, multiple genes recognized (PMP22, myelin protein zero, EGR2)


Peripheral nerve injury

Neuronal damage - neuron dies along with its axons and dendrites
- ALS (motor neurons and axons die)
- Sjogren’s disease and anti-Hu paraneoplastic syndrome – sensory cell bodies (DRG) die
- Axonal injury - traumatic nerve injury, progressive death of the axon distal to the injury (Wallerian degeneration)
- Demyelinating injury (segmental demyelination) - Guillain-Barre syndrome and CIDP - immune-mediated process against peripheral nerve myelin


Acute inflammatory demyelinating polyneuropathy (Guillain-Barre Syndrome)

Annual incidence is 1-4 per 100,000 population;
- younger patients;
- can be preceded by URI or GI infection,
- acquired autoimmune neuropathy

- Ascending weakness of lower and upper limbs < 4 weeks
- Initial distal limb tingling and numbness; may be associated with back or radicular pain
- Subjective sensory disturbance, often without sensory deficit on physical examination and electrodiagnostic test
- Progressive weakness- most frequently distal LE; ascending and symmetric
- Mild paresis to complete paralysis
- Can lead to respiratory compromise requiring intubation
- Generalized hypo or areflexia

Diagnostic testing:
- EMG/ NCS can be normal early on; prolonged F-waves, decreased conduction velocities, CMAP temporal dispersion
- Supportive test: elevated CSF protein with normal cell count (cytoalbuminic dissociation)
- Elevated cell count suggests infection
(Lyme, HIV among others)
- Autonomic dysfunction: arrhythmias, labile blood pressure, urinary retention; requires CARDIAC MONITORING

1. IVIg 2 grams/kg over 2-5 days (more commonly used because of availability); check IgA level before
- Risks: headache, hypotension, rash, aseptic meningitis, thrombosis- stroke, nephrotic syndrome, serum sickness
2. Plasmapheresis 200-250 ml/Kg in 4-6 treatments
- Requires central line
- Risks: hypotension, bleeding and arrhythmias
3. Corticosteroids not beneficial for AIDP
** Clinical response in 2-3 weeks- IVIg/ PE improve neurological deficit and time of recovery (time on ventilator, to walk unaided, % of patients improved 1 and 6 months after onset)


Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

- > 8 weeks, proximal and distal weakness
- Elevated CSF protein
- Acquired demyelinating features on EMG/NCS (conduction block and temporal dispersion)

Treatment : IVIg, plasma exchange, and steroids as adjunct therapy
- Other immunomodulating and suppressive tx: Cellcept, azathioprine, MTX, Rituximab, cyclophosphamide


Parsonage-Turner Syndrome (Brachial plexus neuritis, amyotrophic neuralgia)

"Focal" Guillian-Barre
- Acute onset of arm pain associated with patchy weakness and numbness
- Often associated with diabetes mellitus
- Described also in association with lupus and vasculitis

- May have preceding history of viral infection or vaccination
- Anterior interosseous nerve involvement is common (patients cannot form a circle with the tips of the thumb and index finger)


Myasthenic Syndromes

- Myasthenia gravis, Neonatal myasthenia gravis
- MG is the prototypic autoimmune disease
- Incidence between 1 and 9 per million; slightly greater in women than men
- Age of onset is bimodal (20-25 and 70-75 years)
- Distinctive fluctuating features derived from dynamic pathophysiology of impaired NMT, including relative ease of NMJ repair

Toxic/ Metabolic:
- Botulism, organophosphates, venom poisoning

Congenital myasthenic syndromes:
1. Presynaptic: Choline acetyltransferase deficiency, paucity of synaptic vesicles/ reduced quantal release
- Lambert-Eaton myasthenic syndrome (LEMS)
- Botulism and botulinum toxin
- Tick paralysis
- Congenital MG (choline acetyltransferase deficiency)
- Drugs and toxins (hypermagnesemia, snake toxins, aminoglycosides, calcium channel blockers (minor), corticosteroids, aminopyridines etc.

2. Synaptic: End-plate AChE deficiency
- Congenital myasthenic syndromes (end plate acetylcholinesterase deficiency)
- Drugs and toxins (organophosphates)

3. Postsynaptic: Primary kinetic defect +/- AChR deficiency ( ‘slow channel syndrome’ ), Rapsyn deficiency, Plectin deficiency, MuSK mutations, Dok-7 myasthenia
Autoimmune MG including transient neonatal myasthenia
- Drug-induced myasthenia: penicillamine, alpha-interferon
- Congenital myasthenic syndromes (slow and fast channel syndromes, primary AChR deficiency, Rapsyn deficiency, sodium channel myasthenia, Plectin deficiency, MuSK mutations, Dok-7
- Toxins: d-tubocurarine, vecuronium and other nondepolarizing and depolarizing blocking agents, tetracyclines


Myasthenia gravis

Acquired, autoimmune

Fatigability (improves with rest)
1. ocular (binocular diplopia, ptosis)
- fluctuating symptoms (alternating vertical/ horizontal diplopia, variable weakness of extra-ocular muscles)
- normal pupillary responses
2. bulbar symptoms (difficulty chewing, swallowing, speaking)
3. limb involvement (proximal > distal)
4. no sensory symptoms

1. Ultrastructural alterations of motor end-plate:
- simplification of postsynaptic region of nerve terminal,
- widening of synaptic cleft,
- marked reduction in number of AChRs on postsynaptic membrane
2. Antibodies:
- ACh-Receptor antibodies
- MuSK (muscle-specific tyrosine kinase) antibodies

** Risk of severe respiratory failure requiring intensive care with intubation and mechanical ventilation
** Ocular MG – only ptosis/ diplopia

1. Painless fatigable weakness (worse with activity)
- May fluctuate and alternate in different muscle groups
- Eyelid ptosis, jaw weakness, dysphagia, dysphonia
- Weakness of extraocular muscles, proximal limbs
2. Ice pack test
3. Edrophonium (Tensilon) test
4. Laboratory tests: antibodies against the alpha subunit of the acetylcholine receptor (AChR) or against muscle specific kinase (MuSK)
5. Electrophysiological studies (NCS):
- Repetitive nerve stimulation: decremental responses
- Single fiber EMG: increased jitter


Changes in Neuromuscular Junction: MG vs LEMS

- there are fewer folds with overall simplification of postsynaptic membranes (antibodies against Ach receptor)
- Number of synaptic vesicles same
- Quantal release mechanism: only complete vesicles can be released
- Normal Achesterase function

LEMS: Lambert-Eaton myasthenic syndrome
- autoimmune reaction, where antibodies are formed against presynaptic voltage-gated calcium channels in the neuromuscular junction
- postsynaptic membrane is more complex
- Number of synaptic vesicles same
- Normal Achesterase function


Disorders associated with MG

1. Tumors:
- Thymoma (10-15%)= benign 90%, malignant 10%
- Thymic hyperplasia (50-65%)
- Thymic tumors resection: videothoracoscopy vs standard sternotomy
- Thymectomy is believed to confer long-term improvement of symptoms and treatment response

2. Other autoimmune diseases
- Thyrotoxicosis
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Sjögren syndrome
- Mixed connective tissue disease
- Aplastic anemia

3. Multiple sclerosis

4. Familial cases

5. Neonatal myasthenia – transient placental Ab transfer

6. Congenital myasthenic syndromes
- Hereditary myasthenic syndromes
- Not autoimmune in etiology


Treatment of MG

Symptomatic treatment - AchE inhibitors: pyrdostigmine (Mestinon) and neostigmine

Thymectomy for generalized and seropositive MG

Immunomodulatory therapy:
1. Plasma exchange
- Requires central line
- Risks: hypotension, bleeding and arrhythmias

2. Intravenous immunoglobulin (IVIg)
- Risks: headache, hypotension, rash, aseptic meningitis, thrombosis- stroke, nephrotic syndrome, serum sickness

3. Corticosteroids
- Used cautiously for severe exacerbation, easier if patient intubated

4. Immunosuppressive agents:
- Azathioprine, mycophenolate mofetil (Cellcept), Tacrolimus
- Rituximab, B-cell depleting therapy used for refractory MG


Neonatal MG

Babies born to myasthenic mothers (20%), transient hypotonia (‘floppy infant’), weak cry and suck, no correlation with maternal symptoms and antibody titers

Transient disease (< 12 weeks), recovery complete, no relapse

Due to passive transplacental transfer of anti-AChR antibodies

Usually no therapy is needed


Congenital MG

Infants born to non-myasthenic mothers show ptosis, bulbar/ resp. weakness; later fluctuating ocular palsies, delayed motor milestones, fatigue

Negative anti-AChR antibodies; autosomal recessive

A) Presynaptic defect of synthesis/ packaging of ACh
B) Synaptic deficiency of end-plate ACh esterase
C) Postsynaptic (kinetic) abnormality of AChR channels with or without AChR deficiency


Lambert-Eaton Myasthenic Syndrome (LEMS)

Pre-synaptic disorder
- Acquired and autoimmune (frequently paraneoplastic)
- Antibodies against pre-synaptic VGCC (voltage-gated Ca+2 channels)

Associated diseases
- Cancer (especially small lung carcinoma)
- Lymphomas

Apparent fatigability, but strength and reflexes improve with exercise

- Older man
- Limb weakness, LE > UE
- Dry mouth and dry eyes, may not have fluctuating ptosis and diplopia
- Impotence, ANS involvement
- Incremental response on fast repetitive nerve stimulation
- 3,4 diaminopyridine (DAP) improves strength in LEMS, contraindicated in patients with epilepsy and arrhythmia



Pre-synaptic disorder

- Neurotoxin from Clostridium botulinum
- Impaired acetylcholine vesicle docking, fusion, and release from the pre-synaptic side

- Constipation, generalized and extraocular muscle weakness with difficulty swallowing and breathing, at times requiring mechanical ventilation
- Progressing over 12-36 hours: dysphagia, xerostomia, diplopia, dysarthria; weakness affecting first UE than LE including resp. muscles, ANS disturbances, pupils poorly reactive to light
- GI: nausea, vomiting, diarrhea followed by constipation, excessive drooling
- BTX A tend to cause more severe disease than BTX B
- Require assisted mechanical ventilation
- CMAP amplitude reduction as in other presynaptic disorders

"Floppy baby"= foodborn illness in infants (vs wound infection in adults)


Hereditary Myopathies

Muscular dystrophies
Congenital myopathies
Metabolic myopathies
Mitochondrial myopathies
Myotonic dystrophies
Nondystrophic myotonias, periodic paralysis


Acquired myopathies

- Polymyositis
- Dermatomyositis
- Inclusion Body myositic
Myopathies associated with illness:
- Infectious, endocrine, drug-induced, toxic


Muscular dystrophies

Inherited, progressive weakness due to gene mutation--> muscle protein defect
- Multi-system involvement (heart, smooth m. affected)

1. EMG
- myopathic motor unit potentials
- early recruitment

2. NCS - normal

3. Serum muscle enzymes
- elevated CK (may also be due to trauma, exercise, increased muscle mass, age/gender variations)
- lactate may be elevated
- serum “liver” enzymes may be elevated (AST, ALT)
- Abnormal GGT is specific for primary liver disease

4. Muscle biopsy – findings dependent on etiology
- metabolic deposits (glycogen, lipids)
- presence of inflammatory cells
- aggregation of mitochondria
- absence of protein products essential for muscle cell membrane stability


Sex-linked muscular dystrophies

Duchenne (DMD): dystrophyn

Becker (BMD): Dystrophyn, milder form

Limb-Girdle (LGMD): AD or AR


Toxic myopathies

Lipid lowering agents may trigger immune-mediated necrotizing myopathy
- HMG-CoA reductase inhibitors (statins)
Often high CK values, EMG can be normal or abnormal
- fibric acid derivatives (fibrates)

Antiretroviral therapy (zidovudine - AZT) can induce mitochondrial dysfunction

Alcohol, cocaine


Metabolic myopathies

Abnormal energy use by muscle cells

Exercise-induced weakness, stiffness, cramps, pain Myoglobinuria (dark, tea-like)

Endocrine: Thyrotoxicosis induced myopathy

Glycogen Storage Myopathies:
- Acid-maltase deficiency or Pompe’s disease
- Myophosphorilase deficiency or McArdle’s disease
- Phosphofructokinase deficiency

Lipid Storage Myopathies:
- Carnitine deficiency (CPT1 and CPT2)


Mitochondrial Myopathies

Progressive or static weakness

Extra-ocular muscle involvement:
1. ptosis or ophthalmoplegia
2. Medical history or family history of:
- diabetes mellitus
- short stature
- Seizures
- Deafness

Myoclonic epilepsy with ragged red fibers (MERRF)

Mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome (MELAS)

Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE)


Channelopathies: Periodic Paralyses

Episodic attacks
Sudden transient weakness

Associated with:
- rigorous exercise
- large carbohydrate meals
- emotional stress
- changes in serum potassium levels

Hypokalemic periodic paralysis
- Attacks last from hours to days
- Calcium channel abnormality

Hyperkalemic periodic paralysis
- Attacks last for minutes to hours
- Sodium channelopathy


EEG (Electroencephalography)

Common test performed to assess brain waves

Brain waves are micro-volts in amplitude

• Delta 0-4 Hz
• Theta 5-7 Hz
• Alpha 8-13 Hz
• Beta >13 Hz

Different Types:
• Routine EEG: 20 minute recording
• Ambulatory EEG: Home recording
• Continuous EEG: Typically bedside in the hospital
• Video/EEG: Utilized to capture and define spells

Why order an EEG:
• Seizure events
• Encephalopathy (Confusion)
• Brain death (very difficult to qualify)


EMG (Electromyography)

Common test performed to assess muscle and nerve function

The amplitudes of the activity range from micro-volt to milli-volt

Two main components:
• Nerve conduction studies (NCS)
• Needle electromyography

Ordered to diagnose:
• Peripheral neuropathy
• Motor neuron disease
• Myositis
• Muscular Dystrophy


Nerve conduction study

Involves stimulating a nerve and monitoring for a response either over a sensory nerve or muscle.

Sensory nerve recording results in a sensory nerve action potential

Muscle recording results in a compound muscle action potential.


Needle Electromyography

Nerve inserted into muscle-
- Muscle activity can be visualized and heard

Testing occurs at:
- Rest
- Minimal Activation
- Maximal activation


Evoked potentials

Assess peripheral and CNS at same time
- Test sensory pathways

4 main types:

1 and 2. Somatosensory (Median and Posterior tibial): Used to assess for lesion in long tract sensory pathways (demyelinating disease, tumor, trauma)
- Can localize damage in spinal cord (upper vs lower extremity deficit)

3. Visual: used in disease assessment of MS= optic neuritis (decreased acuity, vision loss--> assess for lesion)

4. Auditory: used to test for auditory nerve tumors, demyelinating disease, vertigo, brain death
- Signal from 8th nerve to inferior colliculus is monitored
- 5 key waves: I= auditory nerve, II= cochlear nucleus, III= Superior Olive, IV= Lateral lemniscus, V= inferior colliculus

Provide peripheral stimulus then measure AP as it reaches CNS

* Very sensitive to artifact--> overcome with averaging



Utilizes ionizing radiation

A contrast agent (is denser then brain on the images) is injected into the blood vessels

Serial images are acquired to track the bolus of contrast

These images can then be reviewed and abnormalities can be identified

Ordered to:
- assess for arterial problems (aneurysms, Arterio-venous malformations, Atherosclerosis)
- assess tumors: Some tumors are highly vascularized and may require
embolization prior to removal
- assess for venous problems: Dural venous thrombosis

Invasive procedure
• Risk of hemorrhage, ischemic stroke, or
hemorrhagic stroke, and allergic reaction

Since it is invasive, why not fix something
• coil (occlude) aneursyms, embolize tumors, stent atherosclerosis, break up clots
** This is known as the field of endovascular treatment


CAT scans

Radiation, Fast imaging

Typically preferred emergent scan
- Great for acute blood
- Required for acute stroke treatment
- Widely available
- Newer angiogram and 3D capabilities very promising

• Faster then MRI (10 versus 45 minutes)
• Widely available
• Ideal for detecting acute blood (shows up bright)

• Radiation
• Poor grey/white matter differentiation



• Superior tissue contrast
• No radiation
• Non-iodinated dye (Gadolinium)
• Many different techniques to highlight different pathology

• Long scan time
• Claustrophobia
• Availability

Superior technology for most pathology
- Able to manipulate scan technique
- CAT – scans better at visualizing bone for some spinal conditions


Clinical features of PD

Four cardinal features:
- Tremor (3-6 Hz rest tremor);
- Bradykinesia;
- Rigidity (cogwheeling);
- Postural instability.

Supportive features:
- Hypomimia and hypophonia,
- micrographia
- stooped-flexed posture
- shuffling gait and festination
- constipation, anosmia, mood and sleep disorders


Pathology of PD

Loss of pigmented dopaminergic cell in the substantia nigra pars compacta and the formation of Lewy bodies in the brainstem.

Lewy bodies are cytoplasmic inclusion bodies that contain alpha-synuclein.
- Synucleinopathy?


Treatment of PD

The goal of treatment is to keep the patient functional for as long as possible.

Nonpharmacological treatment such as physical and speech therapy.

Pharmacological treatment aims at replacing or increasing dopamine levels in the brain. Drugs include Carbidopa/Levodopa, dopamine agonists, COMT inhibitors (that increase serum levodopa levels), and MAO-B inhibitors (that inhibit the breakdown of dopamine).

Complications of levodopa therapy include motor fluctuations and dyskinesias.

Deep brain stimulation is an option for select PD patients who have developed motor complications and medically refractory PD.


Secondary Parkinsonism

Drug Induced (neuroleptics)
Toxic (MPTP/Lytico-Bodig)
Dementia Pugilistica


Progressive Supranuclear Palsy (PSP)

Gaze palsy, nuchal rigidity, early gait disorder with falls, and speech disorder, dementia


Dementia with Lewy Bodies

Early dementia, hallucinations, cognitive fluctuations


Multiple System Atrophy (MSA-A, C, P)

Autonomic insufficiency, early incontinence, cerebellar ataxia


Corticobasal Degeneration

Asymmetric limb apraxia, rigidity, dementia


Restless Leg Syndrome

RLS is a subjective disorder where the patient experiences a restless sensation in their legs at night that improves with moving around.

Affects 5-10% of the population usually in 40’s or 50’s.

The majority of RLS cases are idiopathic but there are several secondary causes including iron deficiency, pregnancy, and end-stage renal disease.

Diagnosis questions:
1. Do you have an urge to move your legs and is this urge usually accompanied or caused by uncomfortable and unpleasant sensations in your legs?
2. Are your symptoms worse, or exclusively present, during periods of rest or inactivity such as lying or sitting?
3. Are your symptoms partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues?
4. Are your symptoms worse at night, rather than during the day, or do they only occur in the evening or the night?

- dopamine agonists such as ropinorole or pramipexole in the majority of cases.



Tremor is the involuntary rhythmic oscillations produced by alternating contractions of agonist and antagonist muscles. The amplitude and frequency are regular. The location and symmetry may vary depending on the type of tremor.

Common tremors include:
- Enhanced physiologic (caffeine, stress, sleep deprivation)
- Drug induced (lithium, depakote, beta-agonists)
- Resting tremor (PD)
- Postural Tremor (Essential Tremor)


Essential Tremor

ET is the most common movement disorder.

It is inherited in an autosomal dominant pattern in more than 50% of patients.

The tremor is typically
- a 4-12 Hz postural tremor and kinetic tremor
- generally bilateral and symmetric.
- generally affects the hands and arms but - may also involve the voice, head and lips.
- The remainder of the neurological exam is normal.
- ET typically improves with alcohol and worsens with stress and stimulants such as caffeine.

- beta-blockers, typically propranolol, or an anticonvulsant Primidone.


Comparison of Essential Tremor of Parkinson's Disease

- 4-12 Hz postural and kinetic tremor
- Family History Generally present
- Distribution: Begins bilateral and symmetric
- Resonse to EtOH: Usually decreases tremor
- Other neuro signs: none

- Tremor: 3-6 Hz rest
- Family History: Generally absent
- Anatomic Distribution: Usually unilateral and asymmetric
- Response to EtOH: Usually no effect
- Other neuro signs: Rigidity, bradykinesia, postural instability



Tics are brief, involuntary, repetitive, rapid and non-rhythmic movements (motor tics) or sounds (vocal tics).

They are classified as either simple or complex:
- A simple motor tic involves a non-purposeful isolated movement (eye blink, shoulder shrug).
- A simple vocal tic is usually a sound (sniff, grunt, squeak, bark).
- A complex motor tic involves stereotyped coordinated movements (such as touching oneself or others, imitating the movements of others, or making obscene gestures).
- A complex vocal tic involves saying words or phrases out of context and may include echolalia (repeating other’s words), or coprolalia (obscenities).

- Preceded by an overwhelming urge to perform the tic activity.
- Exacerbated by stress and relieved by concentration and can often be briefly suppressed.
- Up to 15% of children will experience transient tics and often are misdiagnosed with habits or allergies.
- Tics often migrate to different body parts and tend to relapse and remit.


Gilles de la Tourette's Syndrome

Most severe form of tic disorder

Diagnostic criteria:
- Multiple motor tics and one or more vocal tics occurring for at least one year without a period of at least 3 months in which tics are absent;
- Onset before age 21;
- No other medical etiology (infection including strep or HIV or drugs such as amphetamines) causing tics.

- Treatment depends on whether the tics are interfering with the patient’s life.
- If not, generally education and support are enough.
- If the tics are debilitating, then dopamine antagonists such as fluphenazine, pimozide or haloperidol.
- OCD issues are generally treated with selective serotonin uptake inhibitors such as fluoxetine.
- Isolated reports of patients with GTS being successfully with deep brain stimulation.



"Dance" (Greek word)
- Chorea describes rapid, unpredictable, non-rhythmic movements that tend to flow from joint to joint.
- Will often appear as fidgety movements.
- Patients try to incorporate the movement into a purposeful movement.
- The gait is dance-like.
- Accompanied by motor impersistence (the inability to continue an ongoing movement). “Flycatcher Tongue” “Milkmaid’s Grip”

Differential diagnosis:
- drug-induced such as tardive dyskinesia (TD)
- vascular disorders such as strokes
- post-infectious (Sydenham’s Chorea- after Strep infection) and
- neurodegenerative such as Huntington’s disease (HD).
- Metabolic causes (rare)


Tardive dyskinesia

Choreatic movements that occur in the setting of:
- chronic dopamine blockade,
- typical antipsychotic medications
- atypical antipsychotic
- anti-emetic medications.

It usually occurs after three months but some reports of TD following a single dose.

Unlike most chorea, the movements in TD are usually very stereotyped and typically involve orobuccolingual movements resembling chewing and tongue thrusting.

Difficult to treat and generally involves stopping the offending medication. Try switching to an atypical antipsychotic medication.


Huntington's Disease

HD is an autosomal dominant disorder characterized by:
- chorea,
- problems with personality and affect
- dementia.

Trinucleotide disease involving a CAG repeat in the Huntingtin gene on Chromosome 4.
- Greater than 35 repeats is diagnostic.
- The prevalence is 4-8 in 100,000.

- Typically presents in the 40’s-50’s but may present at any age.
- Insidious, beginning with subtle motor signs and depression and apathy and progressing to total loss of motor function and dementia.

- Loss of neurons in caudate, putamen, globus pallidus

Treatment= supportive.
- There are no effective treatments to stop or slow the disease.
- Antidepressants are used for mood issues
- Dopamine depleting agents, including tetrabenazine, may be tried to ameliorate the chorea.

** Patients are at a marked risk for suicide, accounting for up to 10% of deaths of patients with HD.



Fast jerk-like movements due to muscle contractions.
- Random and irregular but generally it is more abrupt than chorea.
- May resemble tics but it is not suppressible and no urge.
- The origin of myoclonus may be cortical or subcortical (brainstem or spinal).
- Myoclonus may be focal, segmental or generalized.
** Seen in normal individuals during sleep or when stressed (physiologic myoclonus)

Primary= idiopathic essential myoclonus
Secondary= drugs, anoxia (The Lance-Adams syndrome), tumor, infection, or metabolic derangement

Treatment= GABAnergic medications such as clonazepam or valproic acid.



Characterized by involuntary sustained muscle contractions causing abnormal repetitive twisting postures, frequently accompanied by pain.

These contractions may occur and rest but often are exacerbated by voluntary motion.

Genetics are thought to play an important role, especially in some primary generalized dystonias.

Primary (idiopathic)
Secondary (symptomatic resulting from trauma, stroke, drugs or other neurological conditions such as Parkinsonism).

Dystonia can also be characterized by what part of the body it affects:
1. generalized (affecting the entire body),
2. segmental (affecting contiguous body parts) or
3. focal (affecting one body part).

Examples of primary focal dystonia include:
1. Writer’s cramp (action induced muscle spasms of the hand only while writing);
2. Blepharospasm (involuntary forced eyelid closure);
3. Cervical dystonia or Torticollis (involuntary twisting of neck muscle).

A distinctive feature of dystonia is that it can often be relieved by a sensory trick or “geste antagoniste.”

- Symptomatic.
- Drug therapy, usually involving benzodiazepines or anticholinergics, is only mildly successful.
- Botulinum toxin is very successful for treating focal dystonias and is the treatment of choice.



Lack of coordination with voluntary movement.

Movement is fragmented and disordered with respect to velocity, timing and acceleration.

Generally the result of damage to the cerebellum (cerebellar ataxia) or the afferent proprioceptive system (sensory ataxia).

- Most often affects the arms, legs, voice and eyes.
- The speech is dysarthric and “scanning”
- Eye movements are often affected
- High amplitude proximal intention tremor
- Past-pointing on finger nose finger testing.
- Gait is wide-based with hyper extended legs to offset the instability. The patient may appear drunk.

* Many types are hereditary, over 20 different AD forms of spinocerebella ataxia (SCA)

- drugs (anti-epileptics)
- ETOH (both acute and chronic use)
- thyroid disease (hypothyroidism)
- vitamin deficiency (B12, B6 and thiamine)
- lesions (stroke, tumor, or demyelinating disease) and
- paraneoplastic syndromes (antibodies secreted by distant tumors attacking the cerebellum).

- Largely supportive, determine if there's an underlying disease


Cerebral blood flow (CBF) in migraines

Without Aura: No change in CBF

With Aura: Wave of oligemia begins in occipital cortex and spreads forward at rate of 2-3mm/min
- Begins with aura and persists for hours after headache
- CBF changes not in distribution of any cerebral artery
- Consistent with primary neuronal event producing secondary vascular changes


Migraine Aura

Secondary to neuronal dysfunction
- Ischemia rarely, if ever, occurs
- Symptoms resemble those due to direct brain stimulation
- May be due to spreading depression or its human homolog


Migraine Headache

Migraine is a neurovascular pain syndrome
- Referred pain from dura mater and blood vessels

Peripheral mechanisms:
- Neurogenic inflammation (below): Plasma protein extravasation (PPE)
- Peripheral sensitization

Central neural processing
- Pain modulation
- Central sensitization

Neurogenic Inflammation:
- Cerebral blood vessels and meninges innervated by trigeminal nerve
- Sensory C fibers contain SP, CGRP, and NKA
- Depolarization results in neuropeptide release producing NI
- C fibers have inhibitory 5-HT1D preterminal heteroreceptors

** For a headache to qualify as a migraine:
- Photophobia + Phonophobia OR
- N/V


CGRP Receptor Antagonists in Migraine

CGRP infusions triggers migraine

CGRP levels increase during migraine attacks and decrease with headache relief

Triptans and ergots inhibit CGRP release

CGRP receptor antagonists:
- Block CGRP in CNS and inhibit pain transmission
- Not direct vasoconstrictors


Initiation of Migraine Headache

Central Facilitation:

1. Prodrome: Hypothalamic activation

2. Aura: Cortical spreading depression (CSD) triggered in hypersensitive cortex

3. Headache: Referred pain from dura mater and blood vessels
- Aura activates meningeal nociceptors
- Direct nociceptor activation via parasympathetics?

4. Meningeal nociceptor activation associated with:
- Neurogenic inflammation (NI)
- Peripheral sensitization


Migraine Triggers

Diet: MSG, caffeine withdrawal, alcohol
Sleep deprivation or excess
Hormonal changes
Environmental factors
Physical exertion
Stress and anxiety
Head trauma


Vasculitis in Cerebral Blood Vessels

Secondary vasculitis of the CNS (more common) can be part of a variety of systemic illnesses including generalized
autoimmune disease such as:
- Sjogren’s syndrome
a variety of systemic vasculitides such as:
- Wegener’s Granulomatosis
- Polyarteritis nodosa

Primary CNS vasculitis (primary angiitis of CNS):
- No other disease or condition causing vessel damage
- Often granulomatous


Hypertensive Hemorrhage

Rupture of a cerebral blood vessel as a consequence of long standing hypertension

The most common locations for hypertensive cerebral hemorrhages are:
- the basal ganglia and thalamus (65%),
- the pons (15%)
- the cerebellum (8%).

May be related to lipohyalinosis of small vessel walls--> formation of microscopic Charcot-Bouchard aneurysms


Watershed infarct

Reduced blood flow to the brain -->
produce areas of ischemic injury in the watershed areas between:
- the circulations of the anterior and middle cerebral arteries
- the circulations of the middle and posterior cerebral arteries.


Global ischemia

Produces damage in areas of the brain most sensitive to anoxic/hypoxic injury. These include:
1) Sommer’s sector (CA 1) of the hippocampus
2) Purkinje cells of the cerebellum
3) Layers IV to VI of the cerebral cortex

- Neuronal death seen in cell populations sensitive to anoxic/hypoxic injury


Cerebral infarction

Cerebrovascular occlusive disease (thrombotic and embolic) remains a major cause of morbidity and mortality in the United States and worldwide.

- Atherosclerosis predisposes to vascular thrombosis and embolic events.
- Geographic location of occluded vessel defines area of infarction and clinical symptoms.

- Occlusion of the trifurcation of the MCA results in cortical infarction with motor and sensory loss and often aphasia.
- Striate branch occlusion causes damage to the internal capsule with subsequent motor defects.

HTN--> Narrowing (arteriosclerosis) of brain parenchymal arteries and arterioles-->
small cystic ischemic infarcts referred to as lacunar infarcts.

Severe disease with numerous lacunar infarcts can result in the clinical entity multi-infarct dementia.

- Coagulative necrosis with acute inflammation
- Phagocytosis of cellular debris by macrophage
- Eventual cyst formation and surrounding reactive astrocytosis.


Saggital sinus thrombosis

The Sagittal sinus receives the venous drainage from the superior portions of the cerebral hemispheres. Venous infarcts of the brain result from thrombosis of the dural sinuses and cerebral veins.

Primary aseptic thromboses of the sagittal sinus usually are associated with hypercoagulable states or circulatory slowing. Underlying conditions include:
- dehydration
- pregnancy,
- oral contraceptives
- hemolytic anemias
- postoperative period

Secondary or septic venous thrombosis is
seen with pyogenic infection of the face
or sinuses, subdural abscesses and meningitis.


Polymorphonuclear Leptomeningitis

Infections of the leptomeninges may be caused by many bacterial species as well as some viruses, fungi and amebas

Acute bacterial meningitis is an infection of the meningeal spaces.

Bacterial organisms are the most common cause of acute leptomeningitis:
- E. coli
- H. influenzae
- Streptococcus pneumoniae
- Neisseria meningitidis

Frequent causes in newborn:
- Streptococcus agalactiae (Lancefield's group B)
- Escherichia coli K1
- Citrobacter
- Klebsiella species
- Listeria monocytogenes.

Histo: see PMNs in CSF of subarachnoid space


Lymphocytic Meningitis

Caused by viral or bacterial antigens

Viral meningitis is frequently a benign, short-lived illness characterized by:
- Meningitic symptoms and signs (head ache, photophobia and neck stiffness)
- CSF pleocytosis consisting predominantly of lymphocytes. Meningitis is the most common viral disease of the CNS.
Viruses causing meningitis:
- Most commonly caused by enteroviruses.
- Mumps virus
- Herpes simplex
- Lymphocytic Choriomeningitis Virus (rodents)
* 50-75,000 cases/year

Other infectious causes of aseptic meningitis (lymphocytic) other than viruses include:
- Borellia burgdorferi
- Mycobacterium tuberculosis,
- Cryptococcus neoformans
- Treponema pallidum.


Tuberculous meningitis

Tuberculous meningitis is the most common form of TB of the CNS.

TB meningitis frequently involves the leptomeninges at the base of the brain. Arteritis associated with the tuberculous meningitis may lead to parenchymal infarcts.

Rare cases M. tuberculosis organisms can infect the brain parenchyma with the formation of a tuberculoma.
- Tuberculomas = spherical masses with central areas of caseous necrosis surrounded by granulomatous tissue.
- Pott's disease= destructive lesions in vertebral column--> spinal cord compression


Cryptococcal meningitis

Most commonly seen as opportunistic infection in immunocompromised hosts.

Cryptococcus neoformans= fungus usually harbored in soil and manure of some birds.

- Organisms gain entry to the CSF --> disseminate in leptomeninges and in the Virchow-Robin spaces.
- Sparse host tissue response is characteristic compared to other infections

- Cryptococcus are encapsulated organisms that reproduce by budding.
- Carbohydrate-rich capsule (india-ink positive, PAS, mucicarmine stains)


Syphillis meningitis

In approximately 25% of patients with Syphilis, blood-borne spirochetes, Treponema pallidum, transiently reside in the leptomeninges during secondary syphilis.

Years later some of the patients display tertiary neurologic manifestations including meningovascular syphilis, general paresis and tabes dorsalis.

Meningovascular syphilis = subacute or chronic meningitis characterized by spirochetes in the meninges.
- Subsequent invasion of the brain parenchyma by the spirochetes can produce chronic meningoencephalitis designated general paresis

Tabes dorsalis= myelopathy thought to result from meningeal fibrosis secondary to spirochete infection with involvement of the dorsal roots followed by degeneration of the posterior columns.


Cerebral Abscess

Blood-borne bacteria can lodge in capillaries in the brain and elicit an acute inflammatory reaction termed cerebritis.

Further development of the lesion with multiplication of organisms and inflammatory response--> focus of acute inflammation and necrosis consistent with an abscess.
- Fibroblasts from around blood vessels proliferate and deposit collagen with eventual development of a fibrous capsule around the abscess.
- Growth factors secreted by immune response--> fibrotic tissue formation

Cerebral abscesses can follow sinus or dental infections or otitis media.



Infection by this protozoan is frequent cause of CNS symptoms in AIDS patients
- Responds to therapy

* Usually due to reactivation of previously acquired infection of Toxoplasma gondii rather than a newly acquired infection

Definitive host: cats
- Infection is acquired from undercooked meat or from cat feces.

Prevalence of antibodies ranges from 20-40% in US.
- Most primary infections in immunocompetent humans are asympsomatic



Most common parasitic disease of the CNS worldwide

Humans serve as intermediate host for pork tapeworm= Taenia solium

Usually results from ingestion of ova in fecally contaminated food or water
- Larvae of pork tapeworm


Viral Encephalitis

More severe than viral meningitis since the infection and resultant inflammation involves the brain parenchyma and not just the subarachnoid space.

Typical symptoms include:
- seizures
- focal neurologic deficits
- impaired consciousness

- Perivascular, parenchymal lymphocytic infiltrates
- Microglial nodules

* Arbovirus= epidemic encephalitis
West Nile virus (flavivirus, ssRNA):
- IgM antibody in serum/CSF
- can invade brainstem--> neuronophagia (immune system attacks neurons)
Histo: reactive gliosis, microglial nodules, PMN inflammation

Herpes virus= sporadic encephalitis
- hemorrhagic necrotizing encephalitis and
- most important sporadic viral infection of the human nervous system in immunocompetent individuals.
- focus of the necrotizing pathology in the temporal lobes.

- features of encephalitis and focal neurologic signs due to involvement of temporal and frontal lobes
- Fever, headache and confusion are common



Infection during 1st trimester--> congenital CMV encephalitis
- See areas of calcification
- Hydrocephalus

Adults (HIV/AIDS):
- Periventricular encephalitis (smoldering)
- "Owl's eye" nucleus



non-enveloped ssRNA virus
- Drinking contaiminated water
- Infects neurons--> spinal cord/brainstem
- 5-25% mortality (respiratory failure)


Rabies Virus

Enveloped RNA virus
- Transmitted to humans through bite
- Bat strains

Variable incubation
- "flu-like" symptoms
- The incubation period for rabies virus is variable (about 3 months)
- 70-90% of patients go on to develop "furious (encephalitic) rabies characterized by:
- insomnia, episodes of agitation and aggressive behavior, autonomic dysfunction, hallucinations, hydrophobia, dysphagia, dysarthria and nystagmus.

- 20-30% of patients can have "dumb" or paralytic rabies characterized by paralysis of one or more limbs

Negri bodies are eosinophilic cytoplasmic inclusions identified in cerebellar Purkinje cells, brainstem neurons and pyramidal neurons of the hippocampus in Rabies.



Chronic and progressive decline in the cognitive ability of a patient that leads to a decline in their activities of daily living.

Only if cognitive problems have a direct impact on a patient’s daily life (especially if they lead to loss of independence) can a diagnosis of dementia be made



An acute change in a patient’s mental state usually secondary to some sort of a metabolic condition.

Typical findings include:
- acute onset of confusion,
- poor attention,
- disturbances in sleep-wake cycle,
- hallucinations,
- waxing and waning of symptoms.

* Frequently, patients with pre-existing dementia develop delirium.

Onset of delirium can be within a few hours and resolves quickly after the problem is diagnosed and treated.


Causes of dementia

The most frequent cause of dementia is a neurodegenerative process.
This process can affect different neurons in the brain with different severity which leads to different clinical presentations of dementia.

Alzheimer's disease is the leading cause of dementia among older people
Other causes of dementia include
- multiple strokes
- vitamin deficiencies (B1, B12)
- chronic alcohol abuse
- chronic infections (syphilis, HIV, JCV)
- recent or remote head trauma
- paraneoplastic syndromes
- hydrocephalus
- prion diseases


Alzheimer's disease: clinical feature

Memory impairment plus:
- Aphasia= paucity of speech
- Apraxia
- Agnosia= simultagnosia, eye movement changes, predominant parietal atrophy

Other symptoms:
- Difficulty planning
- Paranoia
- Hallucinations
- Nocturnal wandering
- Myoclonus in up to 20% in late stages

Continued gradual cognitive and functional decline, interfere significantly with social/occupational functioning (decline from past functioning)
- Accounts for 60-70% of cases of progressive cognitive impairment in elderly


Amyloid hypothesis

Cause of AD remains unknown

Hallmarks on microscopic exam:
- Loss of neurons/synapses in neocortex, hippocampus
- loss of pyramidal cells
- Extracellular amyloid plaques
- Intracellular neurofibrillary tangles

Amyloid protein: APP
- Protective in plasma membrane
- Pathogenic (amyloidogenic) when full-length protein internalized

Plaques form first--> Neurofibrillary tangles

Amyloid plaques:
- Extracellular accumulation of A-beta (fragment of the amyloid precursor protein)
- Abnormal processing of APP critical to pathophysiology of Alzheimer’s disease

Neurofibrillary tangles:
- Intracellular, paired helical structures composed of hyperphosphorylated tau.
- Correlate well with disease severity and neuronal death.



Presenilin 1 (PS1) and presenilin 2 (PS2) are highly homologous 43-50 kD proteins with eight transmembrane domains

Presenilins make crucial contributions to neurodegeneration in AD

Presenilin’s are crucial components of the enzymes that work to cleave amyloid precursor protein (APP), and mutations in presenilins cause the production of A-beta42 and A-beta43 peptides (insoluble forms of A-beta amyloid)


A-beta42 protein in AD

Aβ42 is thought to polymerize as oligomers and trigger an inflammatory / oxidative response
- Soluble monomers ok, oligomers are toxic, and salt-linked polymer plaques are thought not to be intrinsically toxic so much as indication of dysfunction

This in turn results in hyperphosphorylation of tau, a microtubule-associated protein
- Phosphorylation of tau renders it insoluble and causes it to precipitate in the form of paired helical filaments called neurofibrillary tangles (NFTs).

This cascade and polymerization is toxic to neurons resulting in the death of neurons that produce neurotransmitters.

** Inheritance of apoE4 polymorphism enhances Beta-amyloid stability--> accumulation of beta-amyloid


Genetics of AD

95% of cases are considered sporadic

2 to 5% of cases are autosomal dominant
- Onset usually before 60 and often significantly earlier
- Mutations of the amyloid precursor protein on chromosome 21
- Presenilin 1 protein on chromosome 14
- Presenilin 2 protein on chromosome 1
* Presenilin proteins are likely involved in the cleavage of APP

Epsilon-4 allele of the apolipoprotein E gene (chromosome 19)


Pathophys of AD

Granulovacuolar degeneration - small intracytoplasmic vacuoles within the pyramidal cells of the hippocampus

Hirano bodies are highly eosinophilic inclusions located primarily in the cells of the subiculum and the CA1 region of the hippocampus.

- Widespread cortical atrophy
- Generalized atrophy, hippocampal atrophy, hydrocephalus ex vacuo


Treatment of AD

1. Enhancing cholinergic transmission
- Cholinergic neurons degenerate in AD: found in basal forebrain nuclei
- Increase Ach using Ach-esterase inhibitors: donepezil, rivastigmine, galantamine

2. Blocking excitotoxicity:
- Excitatory molecules toxic in neurodegeneration
- Memantine= NMDA receptor antagonist

3. Supportive treatment for pt and family

4. In the pipeline:
- Drugs clearing amyloid plaques (bapineuzemab vaccine)
- Drugs stabilizing tau (Davunetide)
- Drugs stablizing SORL1
- Basal forebrain DBS, hippocampal prosthetic, entorhinal cortex DBS


Vascular dementia

2nd most common cause of dementia
- After stroke, 20-25% of patients are demented

- Dementia
- cerebrovascular disease
- temoporal relation between vascular changes in dementia

Scoring: Hachinski Ischemic score to differentiate from VaD to AD

- should focus on treating underlying vascular disease and modifying vascular risk factors
- AChEIs have been shown efficacious.
- Neurostimulants such as methylphenidate, bromocriptine, and modafinil


Dementia with Lewy Bodies

DLB is a common neurodegenerative syndrome similar to Parkinson’s disease.
- DLB presents with progressive cognitive decline accompanied by features of Parkinson’s disease.
- In Parkinson’s disease, the movement disorder is profound with relative sparing of cognition.
- In DLB, cognition is severely affected and the movement disturbance is milder.

Two distinct clinical features of DLB are:
1. fluctuations of cognition and alertness
- At times the patient will be alert and relatively cognitively intact and then suddenly have acute episodes of confusion.
These periods may last hours or days

2. Recurrent complex visual hallucinations

Lewy bodies.
-Parkinson disease, Lewy bodies are found in the substantia nigra of the midbrain.
- In DLB, there are Lewy bodies in the cortex.

Lewy bodies= spherical, intraneuronal, cytoplasmic, eosinophilic inclusions
- aggregates of alpha-synuclein and ubiquitin.

- Dopaminergic medications may improve parkinsonism but will often worsen the hallucinations.
- Neuroleptics may help the hallucinations (by blocking dopamine) but markedly worsen the Parkinson’s symptoms.
- In general, AChEIs have been shown to be of benefit for cognitive aspects of the disease. (basal forebrain cholinergic neurons degenerate - patients also benefit from having their Ach levels revved up)


Frontotemporal degeneration

Frontotemporal degeneration is a group of neurodegenerative diseases which are distinct from AD and which predominantly involve the frontal lobes of the brain.

The disease was first recognized clinically in 1892 and called Pick’s disease.

The three subtypes are:
- frontotemporal dementia (FTD) or behavioral-variant (bvFTD)
- agrammatic or non-fluent primary progressive aphasia (PPA)
- semantic dementia (SD) or semantic PPA (sPPA)

- Onset typically between 45-65 years of age
- Usually starts in the late 50’s, a younger age than in Alzheimer’s disease.
- 60% are hereditary, linked to tau gene on chromosome 17q21-22
- Often relative sparing of memory
- Characterized by personality change and impaired social conduct.
- Patients may also have emotional blunting and loss of insight.
- Other common features are disinhibition, neglect of personal hygiene, mental rigidity, perseverative behaviors, voracious appetite (especially for sweets) and hypersexuality.

- Focal degeneration of the frontal and temporal lobes, with corresponding cognitive and behavioral disturbances.

-Atrophy of frontal and temporal lobes, varyingly severe neuron loss and fibrous gliosis in corpus straitum, substantia nigra and medial thalamus
- Spongy vacuolization primary affecting cortical layer 2

- Very limited, treat symptomatically (behavioral changes)
- AchEIs= contraindicated
- No treatments to alter course


Primary Progressive Aphasia/ Semantic Dementia

Patients with aPPA will have effortful non-fluent agrammatic speech with preserved understanding of language.
- Patients with SD will have difficulty understanding individual word meaning. Their speech is often empty of any meaningful content.
- With time however, the dementia becomes more general.

*In some patients, artistic creativity develops as other systems degenerates.
- Underlying mechanism: Release frontal-inhibition, break structured reasoning and release creativity
- Possibly related balance between parietal cortical circuits involved in multisensory integration and those turned offline frontal circuits

- Loss of concepts
- Poor comprehension
- Anomia (nouns>verbs)
- Associative agnosia, eventually prosopagnosia
- Surface dyslexia (read words like first grader)

- "Knife-edge” gyral atrophy in frontal / temporal lobes
- Pick bodies (tau-positive spherical cytoplasmic neuronal inclusions, composed of straight filaments; also ubiquitin)
- swollen, achromatic neurons (a.k.a. ballooned neurons or “Pick cells”)


Prion Disease

- Creutzfeld-Jacob Disease (CJD)
- new variant Creutzfeld-Jacob disease (nvCJD)
- Gerstmann-Straussler-Scheinker disease (GSS)
- Fatal Familial Insomnia (FFI)
- Kuru


Creutzfeld-Jacob disease

Rapidly progressive dementia with startle myoclonus.
- The duration of illness is typically 4 months and median age at death is 68 years old.

85% of CJD is sporadic.
- Familial CJD associated with various mutations in human prion protein (PrPC, chr 20p) and accounts for only 15% of cases.
- A small number of cases of CJD occur iatrogenically (corneal transplants, neurosurgical EEG electrodes, pooled human growth hormone, dura mater transplants, organ transplants).


New Variant Creutzfeld-Jacob Disease (nvCJD)

Early neuropsychiatric symptoms and ataxia with pyramidal symptoms before dementia.
- The duration of illness is typically 14 months and the median age at death is 28.
- nvCJD is thought to result from the consumption of beef suffering from bovine spongiform encephalopathy (BSE, or 'mad cow' disease).

* There have been 3 cases of nvCJD in the US


Gerstmann-Straussler-Scheinker Disease (GSS)

GSS features prominent ataxia with later onset of dementia.
- The duration of illness usually 5 years and typically occurs in the 3rd or 4th decade of life.
- It is inherited in an autosomal dominant fashion.

FFI features:
- progressive insomnia
- neuropsychiatric symptoms
- dysautonomia
- weight loss,
- total insomnia and dementia.

Most severe involvement in the anterior ventral and mediodorsal thalamic nuclei, the cingulate gyrus, and the orbitofrontal cortex

Duration of illness is typically 18 months.



Rare and fatal brain disorder that occurred at epidemic levels during the 1950s-60s among the Fore people in New Guinea.
- The disease was caused by ritualistic cannibalism among the Fore.

Kuru mainly affected the cerebellum and is manifested by an unsteady gait, tremors, and slurred speech.
- Dementia was either minimal or absent.
- Mood changes were often present and patients would often laugh uncontrollably.

After cannablism fell out of favor among the Fore, Kuru has largely disappeared.


Normal Pressure Hydrocephalus

Normal-pressure hydrocephalus is thought to be a form of communicating hydrocephalus resulting from impaired CSF reabsorption at the arachnoid villi.
- Manifested clinically by the triad of gait disturbance, dementia and urinary incontinence. (wet, wacky, wobbly)

The gait disturbance is often the first symptom and is described as a “magnetic” gait where the feet appear stuck and the patient shuffles.

The dementia in NPH is characterized by subcortical cognitive deficits including forgetfulness, decreased attention, inertia, and bradyphrenia.

Urinary incontinence is typically the last symptom

CT or MRI off the brain demonstrates:
- ventricular enlargement out of proportion to sulcal atrophy,
- prominent periventricular hyperintensity consistent with transependymal flow of CSF,
- thinning and elevation of corpus callosum on sagittal images and rounding of frontal horns.

Patient should have a large volume lumbar tap or lumbar drain placement to see if the patient improves with removal of CSF.

Treatment: Surgical CSF shunting


Malignant Hyperthermia

Life threatening hyper metabolic disorder
- Incidence 1:100,000 anesthetics, exposure to inhalation agents
- Autosomal inheritance

Mutation in calcium channel receptor, ryanidine receptor 1 (RyR1)
- Uncontrolled release of calcium into the sarcoplasmmic reticulum

Effects: Tachycardia, hyperthermia, hypercarbia, muscle rigidity, severe metabolic acidosis, death

Treatment: dantrolene sodium (muscle relaxant)


Subacute sclerosing panencephalitis

Encephalitis of insidious onset following measles virus infection
- Occurs in children
- Caused by measles virus defective in terms of M protein (can't bud) or abnormal immune response

characterized by astrogliosis of gray and white matter, myelin loss, perivascular lymphocytes and a protracted course


Progressive Multifocal Leukoencephalopathy

- demyelination secondary to viral destruction of oligodendroglia by JC virus.

JC virus is a polyoma virus that causes a lytic infection of oligodendrocytes in immunocompromised persons.

70-80% of adults worldwide are seropositive for JC virus.
- Patients with compromised immune status especially AIDS patients are at risk for PML.

- macrophage infiltration of white matter
- breakdown and phagocytosis of myelin
- loss of oligodendrocytes
- enlarged oligodendrocytes with intranuclear inclusions
- “Bizarre” astrocytes.


HIV dementia

Dementia associated with HIV may be related to actions of cytokines released by macrophages cells in response to HIV virus infection of these cells.
- HIV in the brain is characterized histologically by the presence of perivascular multinucleated giant cells that have been shown to contain HIV.

Also associated with a vacuolar myelopathy.
- The pathogenesis of the vacuolar myelopathy may also be cytotoxic cytokine release.
- The posterior and lateral columns of the spinal cord show marked vacuolization.
- Clinically patients with vacuolar myelopathy demonstrate ataxia and spastic paraparesis.
- The immunosuppression caused by HIV predisposes the CNS to infection by numerous infectious agents and to the development of CNS B cell lymphomas


Post-infectious encephalomyelitis

- Foci of perivascular demyelination and a conspicuous mononuclear cell infiltrate around small to medium sized venules in the white matter.
- Immune mediated attack against the CNS.


Central pontine myelinolysis

CPM= selective demyelination of discrete areas in the pons and at times in extra-pontine locations

May be related to damage of oligodendrocytes by electrolyte imbalances in areas of close association of gray and white matter tracts
- Hyponatremia--> rapid correction--> neuronal cells lose water--> demyelination
- Symptoms: confusion, delirium, hallucinations, difficulty with swallowing, lethargy, coma

- Macrophages breakdown myelin
- Preservation of axons/neurons


Wernicke's encephalopathy

Petechial hemorrhages present in the mamillary bodies and walls of the third ventricle.
- Due to thiamine deficiency.
- Thiamine in the form of thiamine pyrophosphate is a cofactor for various enzyme systems such as the pyruvate dehydrogenase complex and transketolase.
- Areas affected in Wernicke’s encephalopathy have highest activity of transketolase.

- Conjugate gaze and lateral rectus palsies, nystagmus, ataxia and mental confusion are classic features.


Sequence of cough reflex

1. Irritation of the trachea, larynx, pharnyx or bronchi stimulates sensory "stretch receptors”
cough center -- localized near the vomiting center in the medulla.

2. Epiglottis and larynx close

3. Expiration occurs.

4. Epiglottis and larynx open suddenly so that air under pressure explodes outward, expelling the irritant.

- Irritating substances
- Chemicals/ Medications
- Infection
- Congestive heart failure
- Psychogenic factors

Drug therapy approaches:
1. Reduce excitability of “cough center” in the medulla.
- These drugs act centrally.
2. Reduce input to “cough center”.
- These drugs act peripherally. (and reduce afferent input to the cough center)


Chemoreceptor trigger zone (CTZ) for emesis

Located in the area postrema (AP) at the base of the 4th ventricle.

It has a minimal blood brain barrier and

is accessible to chemical stimuli present either in blood or in cerebrospinal fluid
(“smoke detector” for the body-- danger)


Stimuli for Nausea/Vomiting

Apomorphine (D2 agonist):
- alcohol, salicylates, nicotine, digoxin, L-dopa, hydergine, and opiate alkaloids

Antineoplastic agents and radiation:
- cause cell damage in the GI tract to liberate serotonin from the enterochromaffin cells.
- Serotonin acts on receptors (5-HT3 subtype) to:
1. activate vagal afferents--> emetic center
2. greater splanchnic nerves to the CTZ, respectively.

Afferent input:
- Emetogenic stimuli in blood or CSF
- Vestibular system- vertigo
- Irritation of the pharynx (gag reflex)
- Gastrointestinal irritation and inflammation
- Excessive vagal and spinal afferent inputs (severe pain)
- CNS- Psychic and sensory stimuli


Trigeminal neuralgia in Migraines

Primary trigeminal neuralgia= normal neuro exam
- Vascular loop impinges in CNV

Secondary trigeminal neuralgia= loss of sensitivity to touch (due to tumor)


Headaches of concern


Systemic symptoms
- (fever, weight loss, fatigue)
Secondary risk factors
- HIV, immune suppression, cancer
Neurologic symptoms/signs
- Altered consciousness, focal defecits
- Split second, thunderclap
- new after age 50
Prior history
- Different from usual
- Dramatic change (upright vs recumbent)
- Visual obscurations
- Dramatic, consistent triggering by valsalva


Tension headache

Episodic tension-type headache with variable duration

IHS diagnostic criteria:
1. Headache lasting 30 min to 7 days
2. Two or more of following:
- Bilateral
- Pressing/tightening (non-pulsating quality)
- Mild/moderate intensity
- Not aggravated by activity
3. Both: NO N/V, no photo/phonophobia
4. NOT attributed to another disorder


Migraine prodrome

Seen in 60% of patients
- Aura in 20%

Prodrome symptoms:
- irritability
- elation
- physical hyperactivity
- yawning
- food craving
- photophobia
- Phonophobia
- Increased bowel/bladder activity
- mental/physical slowing
- poor concentration
- word-finding difficulty
- weakness/fatigue
- chill
- anorexia
- constipation
- abdominal bloating


Migraine Aura

Seen in 20% of cases
- Scintillating scotoma (spreading)
- May occur without headache- more common in elderly (migraine equivalents of elderly)
- Most commonly visual then sensory
- Aphasia, Hemiplegia, olfactory, depersonalization, deja vu may occcur
- Brief flashes of light= phosphenes (common in headache attack)


IHS diagnostic criteria for migraine without aura

Headache lasts 4-72 hours (with or without treatment)
1. Headache has 2+:
- Unilateral location
- Pulsating quality
- Moderate/severe pain intensity
- Aggravation by or causing avoidance of routine physical activity
2. During headache:
- N/V
- Photophobia and phonophobia
3. Not attributed to another disorder

Other symptoms:
- Neck pain
- Nasal congestion
- Allodynia
- postdrome (tired, mood changes, depression, elation)


Cluster headache

3x more common in Males
Risk factor= smoking
ALWAYS unilateral, centered around eye,
- Pain in occiput, forehead, temple, face
- Attacks at least 1 hour
- 1-6 times per day on diurnal schedule
- Awaken patient at same time each night

Accompanied by:
- Unilateral autonomic symptoms: rhinorrhea, tearing, conjunctival redness/tearing, lid edema, physical activity

Cluster daily (6-8 weeks) then remits
Cycles 1-2 times per year
Chronic= "suicide headache"


Pathophysiology of migraine


Hyperexcitable brain
- Throbbing pain due to trigeminal nerve inflammation to meninges

1. Interictal brain hyperexcitability
2. Aura= neuronal excitation, depression spreading at 2-3 mm/min over cortex
3. Throbbing pain due to sterile trigeminal nerve inflammation
4. Allodynia common (1-2 hours after pain starts)
5. Increased blood flow in rostral pons and midbrain tegmentum= neuronal activation

Familial types:
FHM1= disorder of Ca+2 channel
FHM2/FHM3= less common, due to extracellular glutamate


Risk factors for daily headache/migraine

High headache frequency (4+ times a month)
High caffeine consumption
Acute mediation overuse


Changes in Down syndrome

Moderately reduced size
Flattened occipital pole
Possible abnormal gyral patterns (slender superior temporal gyri)
Alzheimer’s disease like changes


Changes in Trisomy 13/15 (Patau)

Decreased brain size


Changes in Trisomy 18 (Edwards)

Gyral abnormalities
Dysplasias of the hippocampus and inferior olive
Neural tube defects
Cerebellar heterotopias
Absence of corpus callosum


Periventricular-intraventricular hemorrhage

Prevalence is 35%-45% in newborns less than 35 week gestation.

Usually occurs in first 72 hours of life

Infant usually has respiratory distress.

Most often results from hemorrhage in subependymal germinal matrix

May occur at any site along the ventricular borders with germinal matrix

• Matrix blood vessels may be fragile and germinal matrix may be vulnerable to hypoxic injury.


Hypoxic-ischemic injury

May occur antepartum, intrapartum or postpartum

• Can result in periventricular leukomalacia with necrosis, phagocytosis, gliosis and cavitation of white matter

• Gray matter necrosis is seen in perinatal asphyxia in full-term infants


Cavitary encephalopathies

Characterized by formation of cavitary lesions involving the cerebral hemispheres

• Lesions have been associated with intrauterine infection, toxin exposure and genetic factors.

• Porencephaly is a circumscribed cavity involving one or both hemispheres.

Most or all of the cerebral cortex and white matter are replaced by a CSF fluid filled sac in hydranencephaly.