Stroke Update

Acute ischemic stroke has been the focus of intense research in which the landscape has changed dramatically. From the previous paradigm of no acute treatment with heavy emphasis of antiplatlets and statins for thrombic or thromboembolic strokes and/or anticoagulation for cardioembolic strokes, to the introduction of intravenous alteplase in 1996 when given within 3 hours, to an extension of intravenous alteplase to 4.5 hours in 2010.

In most stroke programs including our growing endovascular and stroke program at Lutheran GEneral Hospital, the outcomes of endovascular thrombectomy that neurologists have seen have suggested an overall positive trend in selected patients whom have a proximal artery occlusion and either small or no ischemic stroke changes on CT (based on ASPECTS) in regards to functional independence. However, the data has not shown this observation to be valid until now.

I will touch on two of the more recent studies: the ESCAPE trial and EXTEND-IA trial.

ESCAPE trial -

Eligibility - Acute ischemic stroke (AIS) within 12 hrs, >/= 18 yrs of age, NIHSS > 6, functionally independent before stroke, CTA showing proximal vessel occlusion in anterior circulation, no large infarct core on initial head CT and had good collateral flow. Controls received IV tPA only.

Main objective - mRS score @ 90 days

Outcomes - after 90 days - odds ratio of improving by 1 point on mRS was 2.6 for endovascular treatment (EVT) patients, achieving mRS score of functional independence of 0-2 @ 90 days was 53% in EVT and 29% in control. Mortality @ 90 days - 10.4% EVT, 19% control. Symptomatic hemorrhage in 3.6% of EVT patients, 2.7% control. Cerebral ischemia TIMI scores of 2b or 3 (excellent reperfusion) noted in 72.4% of EVT patients.

EXTEND-IA trial -
Eligibility - Acute ischemic stroke (AIS) within 6 hrs, >/= 18 yrs of age, CTA showing proximal vessel occlusion in anterior circulation, no large no large infarct core on perfusion imaging, mismatch between infarct and perfusion volume. Controls received IV tPA only.

Main objectives - % reduction in perfusion lesion volume between initial imaging and imaging at 24 hrs (reperfusion), early neurological recovery, mRS score @ 90 days, death due to any cause

Outcomes - Significant increase in successful reperfusion - median 100% in EVT patients versus 37% in controls. mRS score @ 90 days have odds ratio of 2 of reducing mRS score by 1. 71% had acheived functional independence (mRS score 0-2) in EVT patients vs 40% in controls. TIMI cerebral ischemia scores of 2b and 3 achieved in 86% of patients. Finally and interestingly, 0% of EVT group suffered symptomatic ICH vs 6% in controls.

These studies show that individuals with an acute ischemic strokes with proximal anterior circulation occlusion (in my institution within 6 hours) would benefit from endovascular treatment. There is an important caveat however, both studies had different inclusion criteria. EXTEND-IA covered perfusion, ESCAPE was based on perusal of initial CT brain. Some aspects of the studies may not be relevant to your practice, especially if you do not have perfusion imaging available. Also, angiography results also play a role, patients with poor collateral flow will not have such rosy outcomes as noted in EXTEND-IA, ESCAPE and even the MR CLEAN trial which was published in 2014. These trials were based on highly selected patients and thus, should be considered when evaluating whether a patient would be a good candidate for endovascular thrombectomy.

Pearls in evaluation of headache in an clinical setting.

The most important part of the headache history is to differentiate between primary headaches and secondary headaches! The fine details of the description of a migraine headache for example has low priority. 

Primary headache disorders include migraine headaches with and without aura, trigeminal autonomic cephalgia spectrum headaches including cluster headaches, paroxysmal hemicrania, SUNCT, SUNA, hemicrania continua. Secondary headache disorders are headaches derived from structural or secondary cause in which the differential diagnosis is extensive. 

The best way to break secondary headaches is by category:

Vascular (Anuersymal or non-anuerymsal ubarachnoid hemorrhage - SAH, cerebral venous thrombosis, cavernous sinus thrombosis, reversible vasoconstriction syndrome, posterior reversible leukoencephalopathy, extra-cranial or intra-cranial dissection), structural (neoplasm, colloid cyst, Chiari I malformation, arteriovenous malformation), inflammatory or infectious (HIV associated immunocompromise, CNS vasculitis or systemic vasculitis, CNS meningitis, encephalitis), ICP related (intracranial hypotension, intracranial hypertension) or pregnancy related (pre-eclampsia spectrum). 

Key elements of the headache description include:

Age of onset

Frequency

Duration

Time of onset

Time of maximum intensity

Characteristics - location, quality and severity

Associated symptoms

Precipitating and alleviating factors

Knowing a basic understanding of the secondary etiologies of headache, we can now apply the questions that we ask to help formulate a differential diagnosis. 

1) Age of onset - 50 years old or greater?

This question is obviously important because there is an increased risk of cancer as well as the consideration of giant cell arteritis, which affects medium sized arteries and can cause monocular or binocular blindness if not treated promptly with steroids.

2) Frequency - increasing frequency?

3) Duration - how long does the headache last? is the duration different from previous or established headaches that you have had?

4) TIME OF ONSET AND TIME OF MAXIMUM INTENSITY- what is the onset of headache? how fast does it reach its maximum intensity?

This is important because a "thunderclap headache" in which you need to immediately consider secondary etiologies of headache such as SAH, sentinel bleed from aneurysm, pituitary apoplexy or reversible cerebrovasconstriction syndrome is defined as a headache that REACHES MAXIMUM INTENSITY WITHIN 60 SECONDS. The initial start of the headache occurs within a few seconds. Patients differ in description, but asking if the patient didn't have a headache one moment and then with a snap of the fingers, the patient had a headache, typically brings out this history.  

5) Characteristics - location? quality? severity? 

Watch out for the description of a new headache or a headache that has changed in location, quality or severity or a headache that is unilateral, especially in a patient that has established headache history (migraine headaches can be unilateral or bilateral as an example). Beware of the temptation to write off a "new headache" in a patient with established primary headache history.

Ask if the headache wakes the patient at night. This can be classically associated with headaches with elevated ICP due to the relative hypercarbic status of the patient when sleeping. Think neoplasm or space occupying lesion and pseudo tumor cerebri. 

6) Associated symptoms - unilateral motor or sensory symptoms? Diplopia, facial sensory deficits or other cranial nerve signs? Altered level of consciousness? Fever? Neck stiffness? Loss of consciousness? Seizures?

For psuedotumor cerebri if suspected, then ask about transient visual obscurations (ask with neck flexion, do they lose binocular vision briefly?), pusatile tinnitus (ask if the patient hears rhythmic whooshing in their ears) and binocular diplopia.

And of course we cannot forget the patient whom is pregnant in their 3rd trimester with a new onset headache. As clinicians, we can never miss the spectrum of pre-eclampsia or eclampsia! This is a life threatening situation for the fetus and the mother. Always check a patient's blood pressure and do a urine dipstick to evaluate for proteinuria. Only determine if it is a primary headache as a diagnosis of exclusion. 

7) Precipitating and allevating factors. Now you have to know what to ask.

Ask if the patient has a headache that changes dramatically with position, in which this easy to ask question can differentiate between intracranial hypotension (worse when standing, improved with supine position) and intracranial hypertension (worse in supine position, improved when standing).

Ask if the headache occurred during or after physical exertion, especially sexual intercourse. Consider SAH, dissection, RCVS, 3rd ventricle colloid cyst if you hear this history.

Ask if the headache is triggered by any Valsalva maneuver including coughing, sneezing or straining, which could indicate posterior fossa mass, Chiari I malformation, intracranial hypotension or presence of an aneurysm. 

NEUROLOGICAL AND PHYSICAL EXAMINATION:

Of course, we can never discount the importance of a neurological and physical examination. An abnormal neurological examination is tantamount to a secondary cause of headache (with exception of trigeminal autonomic cephalgias, which has an obvious pattern discussed in another lecture). Look in the fundus for papilledema, test for Kernig or Bruzinski's sign with the neurological examination. In the physical examination, palpate the temporal arteries, auscultate the carotid arteries (some neurologists that I used to rotate through in medical school state auscultation of the vertebral arteries are possible by placing the stethoscope in the nape of the neck). 

Neuromyelitis Optica Review

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Neuromyelitis optica review

Excellent Overview in Chart Form

	MS	Devic’s disease
Definition	CNS s/s involving WM tracts Evidence of dissemination of space and time on MRI findings and/or clinical hx No better explanation	Transverse myelitis + optic neuritis At least 2 of the following: - Negative MRI - SC lesion spanning 3 or more vertebral segments - + NMO IgG Ab
Clinical course	85% RR 15% 1 progressive	80-90% relapsing course 10-20% monophasic course
Median age	29	39
Sex (F:M)	2:1	9:1
MRI SC	Short segment peripheral lesions	3 or more vertebral segment central lesions
CSF WBC and diff count	Mild pleocytosis Mononuclear cells	Occ prominent pleocytosis PMN and mononuclear cells
CSF oligoclonal bands	85%	15%

Entire spectrum of NMO IgG Ab entities include:

1)   Devic’s disease

2)   Asian optic-spinal MS

3)   Idiopathic single or recurrent events of longitudinally extensive myelitis

4)   Optic neuritis, recurrent or simultaneous bilateral

5)   Optic neuritis/myelitis associated with brain lesions (hypothalamus, CC, periventricular, brainstem)

Clinical Features

First described in 1894 by Devic and Gault

Can cause nausea, hiccups, acute neurogenic respiratory failure from cervical myelitis extending into the lower brainstem

Can also see paroxysmal tonic spasms (recurrent, stereotypic painful spasms of limbs and trunk lasting 20-45 seconds) and Lhmermitte’s sign (spinal or limb dysesthesias on neck flexion) with extensive cervical myelitis

Brain lesions can be seen later in the disease course (60% after 5 yrs), but lesions are clinically silent

Brain areas with large amounts of aquaporin 4 include: hypothalamus and periaqudectal gray region in brainstem

Epidemiology

9:1 F:M ratio

Onset 39 yrs of age vs MS which is 29 yrs of age

Large proportion affected are non white including east Asians, Brazilians, however the majority of neuromyelitis optica still are white

? familial cases of neuromyelitis optica

Disease Course and Prognosis

80-90% relapsing remitting, 10% monophasic

Relapse occurs 60% within 1 year, 90% within 3 years

Relapses worsen over several days, slowly improve in weeks and months

Recovery usually incomplete

Number of relapses over 2 years, severity of first attack, and superimposed SLE are predictive of poor prognosis

Within 5 years, 50% blind in 1 or both eyes

Immunopathology

NMO IgG Antibody attacks aquaporin 4 which controls water homostasis in the CNS, it is 73% sensitive, 91% specific for neuromyelitis optica and 10-25% of clinical neuromyelitis optica cases are seronegative

MS and neuromyelitis optica pathophysiology is distinctly different:

MS

Peripherally activated T-cells  à interaction with endothelium via integrins, proteinases, and selectins à T-cell extravasation and penetration into CNS parenchyma à T cells penetrating into CNS interacts with APC à CD 8 T-cell mediated attack + recruitment of peripheral B-cells,complement with CNS clonal expansion results in demyelination and axonal attack à CD4 + T-cells + OLIGOCLONAL BANDS in CSF

Neuromyelitis Optica

Unknown insult à peripheral IgG pool has NMO IgG à limited penetration into CNS parenchyma via endocytosis or through BBB injury à IgG attack on aquaporin 4 channels lead to massive complement attack, massive infiltration of leukocytes à limited clonal B-cell expansion (mainly complement induced destruction) à vascular hyalinization _ demyelination, axonal injury and necrosis, and relative large amounts of PMN, eosinophils in CSF

Neuromyelitis optica and systemic autoimmune disease

Neuromyelitis optica are likely to occur in patients with SLE or Sjogren’s syndrome. In patients that test positive for NMO IgG with SLE and/or Sjogren’s syndrome, in the context of transverse myelitis or optic neuritis, there is a coexistance of TWO autoimmune diseases NOT one.

Treatment

1^st line – IV corticosteroids

2^nd line – 7 plasma exchanges over 14 days, earlier plasma exchange if there is severe cervical myelitis who are at high risk for neurogenic respiratory failure and/or severe visual loss

Maintanence treatments include, but not proven with RCT:

1)   2-3 mg/kg azathioprine + 1 mg/kg oral prednisone

2)   Mitoxantrone

3)   IV Immunoglobulin

4)   Rituximab

Diff Diagnosis List #2

Diff Diagnosis List #2

VI - Diff dx of Dementia
VII - Diff dx of ataxia and ophthalmoplegia
VIII - Diff dx of altered mental status, fever, headache
 IX - Diff dx of gradual onset hemiparesis
X - Workup of Multiple Sclerosis
XI - Brain death criteria
 
Diff dx of dementia

Vascular – Strokes, diffuse ischemic injuries
Infectious – Syphilis, chronic meningitis (TB, fungal), HIV dementia, PML, CJD
Trauma – SDH, dementia pugilistica
Autoimmune – CNS vasculitis, MS
Metabolic/toxic – hypothyroidism, vitamin B12, hepatic, renal failure, hypercalcemia, Korsakoff syndrome, heavy metal intoxication (lead, arsenic, bismuth), prolonged hypoglycemia, hypoxia
Idiopathic – Alzheimer’s disease, Parkinson’s dementia, dementia with Lewy bodies, PSP, MSA, ALS-Parkinson dementia of Guam, frontotemporal dementias, Wilson’s disease, primary progressive aphasia
Neoplastic – brain tumor, CNS lymphoma, paraneoplastic limbic encephalitis, postradiation effects
Miscellaneous – psuedodementia secondary to depression, complex partial seizures, NPH

Workup
Labs – CBC, BMP, LFT, vitamin B12, VDRL, TSH, ESR, HIV (if applicable), toxicology screen (if applicable)
Imaging – MRI brain
Lumbar puncture – therapeutic large volume tap, 14-3-3 protein assay (if applicable)
Depression screening
Head trauma screening

Diff dx of subacute presentation of ataxia and ophthalmoplegia

Miller Fisher variant of GBS
Wernicke’s encephalopathy
Toxins – botulism (ileus + fixed pupils), marine toxins, tick paralysis
Posterior circulation stroke
Myasthenia gravis
Hypothyroidism (peripheral neuropathy + cerebellar degeneration)
Paraneoplastic cerebellar degeneration

Workup:
Labs – CBC, BMP, LFT, TSH, Lyme titer (if applicable)
Imaging – MRI/MRA
Tx – thiamine + glucose
Lumbar puncture
EMG (if Miller Fisher, myasthenia gravis suspected)






Diff dx of altered mental status, fever, meningismus, headache

Vascular – SAH, ICH (BG, thalamus, cerebellar if HTN), SDH, epidural hematoma, bilateral thalamic CVA
Infectious – bacterial meningitis, tuberculous meningitis, viral encephalitis
Metabolic-toxic – HTN encephalopathy (if HTN present), DKA induced coma, hepatic, renal encephalopathy, hypothyroid (asterixis +)
Tumor – hemorrhage into tumor
Autoimmune – CNS vasculitis

Workup:
Labs: CBC, BMP, LFT, TSH, ESR
Imaging: CT or MRI brain
Lumbar puncture

Diff dx of gradual onset hemiparesis

Neoplastic – 1 neoplasm including astrocytoma, oligodendroglioma, 1 CNS lymphoma), metastasis
Infectious – Abscess (bacterial, parasitic such as echinococcus, toxoplasmosis, fungal such as aspergilloma, mucoymycosis)
Vascular – CVA, ICH, complicated migraine, hemorrhage from AVM or aneurysm
Traumatic – SDH, epidural hematoma, contusion
Autoimmune – CNS vasculitis, MS
Metabolic – Hypoglycemia
Psychiatric – Conversion disorder

Workup:
Labs: CBC, BMP, LFT, ESR
Imaging: CT or MRI brain with contrast
Lumbar puncture

Immunocompromised:
Includes HIV, CD4 titers, CXR, blood cultures

Common organisms in brain abscesses:

1. Bacterial – strep, staph aureus, pseudomonas, enterobacteria, anaerobes
2. Immunocompromised – Cryptococcus, toxoplasmosis

Workup for MS

Basic Labs – CBC, BMP, LFT, TSH
MS masqueraders – ESR, ANA, ACE, CXR, vitamin B12, VDRL, Lyme titer, if indicated HIV, HTLV-1
Imaging – MRI brain with contrast, if MRI brain suspicious or exam demonstrates myelopathy, MRI C, T-spine with contrast
Lumbar puncture – IgG synthesis index, oligoclonal bands
Evoked potentials – VEP (1st choice, esp with optic neuritis presentation), BAER, SSEP

Brain death criteria

Prerequisites to determine brain death
Cause known and irreversible
No confounding medical condition
NL metabolic (electrolytes, acid base status, endocrine)
No drugs or poison
T > 32 C

Exam
Coma
No motor response
Corneal reflexes absent
Caloric testing negative aftger 1 min after irrigation
Gag reflex absent
No response to suction
No sucking/rooting reflex
No respiratory drive on apnea test

Apnea test
T > 36.5, BP > 90, + fluid balance
Preoxygenate with 100% O2 for 10 mins
Start pulse ox/D/C ventilator
100% O2 6L via cannula
After 8 mins obtain ABG
If desaturation or hypotension occurs, draw ABG
+ if no respiratory drive with PCO2 > 60 mm Hg or > 20 mm Hg above baseline

Confirmatory tests
Angiogram – no filling
EEG – 8 electrodes, impedance < 10 KU, 2 uV sensitivity, 10 cm between electrodes, 30 minute recording, NONREACTIVE rhythm
TCD – lack of diastolic flow
SPECT: hollow skull 30, 60 mins, 2 hrs after injection
SSEP: absent responses

Diff Diagnosis List

Diff Diagnosis List Part I

I - Differential Diagnosis of Stupor
II - Cerebral Vasculitis
III - Horner's Syndrome Review
IV - Subacute etiologies of Headache
V - Review of Nystagmus

Differential Diagnosis of Stupor

Vascular	CVA (brainstem, thalamic, large hemispheric) ICH SAH Epidural/subdural hematoma
Metabolic	Thyroid disturbance Adrenal insufficiency DKA, hyper, hypoglycemia Hepatic Renal Medication induced Toxin induced Wernicke’s encephalopathy
Infectious	Meningitis Encephalitis Brain abscess Sepsis
Neoplastic	1 brain tumor, metastasis Limbic encephalitis
Inflammatory	ADEM CNS vasculitis
Hypertensive encephalopathy
Seizures	Non convulsive status epilepticus Post icital
Hydrocephalus
Psychogenic coma

Workup

Labs – CBC, BMP, LFT, TSH, urine tox, ammonia, ABG, EKG, if infection suspected – CXR, U/A, blood, urine cultures
Tx – 100 mg IV thiamine then glucose
Imaging – CT or MRI brain, if no mass lesion or focal neuro deficit, LP, EEG











Causes of cerebral vasculitis

Primary angiitis of the CNS
Infectious – HIV, VZV
Meningitis – fungal, viral, treponemal, parasitic
Drug induced – amphetamines, cocaine
Lymphoma
GCA – high ESR, older age, EXTRADURAL

Systemic Vasculitis
Behcet’s – genital/oral ulcers, ocular signs
PAN – fever, arthralgias, myalgias, mononeuropathies
Churg Strauss – asthma, eosinophilia, neuropathy
Wegner’s - +ANCA, neuropathy
SLE – fever, rash, pleuritis, encephalopathy

Vasculitis workup:
Labs: ESR, CRP, ANA, CBC c diff, BMP
Imaging: CXR, MRI brain, MRA, CTA or angiogram of head and neck

Review of Horner’s syndrome

Horner’s syndrome – ptosis, anhidrosis, miosis

1 order sympathetic fibers: hypothalamus → brainstem → descend to interomediolateral cell column of spinal cord at C8-T2
2 order sympathetic fibers: exit spinal cord at T1 → ascend cervical sympathetic chain → synapse at superior cervical ganglion at carotid artery bifurication
3 order/postganglionic sympathetic fibers: travel along ICA → 1) sudomotor fibers travel along EXTERNAL carotid artery 2) pupillomotor fibers enter cavernous sinus → superior orbital fissure via long cillary nerve → iris dilator and Muller muscle

Agents to localize Horner syndrome
4% cocaine – inhibits NE reuptake, will lead to POOR papillary dilatation in sympathetic lesion at any order
1% hydroxyamphetamine – stimulates release of NE from presynaptic postganglionic nerve terminals, 1st, 2nd order fibers will result in papillary dilation, 3rd order will NOT dilate









Basic diff dx for subacute onset of severe HA

Vascular – ICH, SAH, CVT
Infectious – meningitis, encephalitis, brain abscess
Neoplastic – 1 neoplasm or metastatic
Idiopathic intracranial hypertension
Vasculitis – CNS or systemic
Metabolic – thyroid, electrolyte, toxin
Hydrocephalus

Labs – CBC, BMP, LFT, TSH, coags, ESR
Imaging – CT/MRI, CTV/MRV
Lumbar puncture







Characterization of Nystagmus

	Peripheral	Central
Vertigo	Intense	Mild
N/V	Intense	Less common
Duration	Short	Persitent
Fatigability	Yes	None with multiple trials
Direction	Fixed, horizontal or diagonal, rotatory or torsional	Multidirectional, can include vertical
Latency	Several seconds	None

Horizontal nystagmus if caused by labyrinth or vestibular nerve – the fast phase of nystagmus is opposite the affected side ie fast phase to L signals R vestibular dysfunction