Activation of trigeminal vascular system and cortical spreading depression

Affects people in their peak productive years. Second most disabling condition, second only to low back pain

More common in females, strong family history present

5 or more attacks

Lasting 4hrs to 3 days

With 2 of the following: unilateral, pulsating/throbbing quality, moderate to severe intensity, worse with activity

With 1 of: photo/phonophobia or nausea/vomiting

Aura lasting 5 to 60min before headache onset, accompanied or followed by headache within 60min. Symptoms of aura are fully reversible and can present as sensory (e.g. numbness/parasthesias), visual, speech and/or language, motor, or brainstem (rare) features

Unusual, prolonged, or persistent aura

Increasing frequency, severity, or change in migraine clinical features unless change in pattern (i.e. medication overuse headache)

First or worst migraine

Migraine with brainstem aura

Confusional migraine

Hemiplegic migraine

Late-life migrainous accompaniments - acephalgic migraine

Migraine aura without headache

Side-locked migraine

Post-traumatic migraine

Abortive therapy: NSAIDs (e.g. Ibuprofen, Naproxen 250-500mg p.o. with PPI, Cambia 1 sachet p.o.), Tylenol, triptans, Mg can be taken with aura to try and reduce its duration and severity, Ubrogepant (CGRP antagonist) - 50-100 mg daily is a new approved medication for an abortive agent (side effects: nausea, drowsiness)

Acute therapy in the ED: normal saline 2-3L IV bolus (ensure no CHF), metoclopramide 10mg IV (check QTc interval), Mg 1g IV, Ketorolac 15-30mg IV, DHE 0.5mg IV with metoclopramide and if tolerated can receive 1mg as next dose (contraindicated if triptan use within 24 hours; check QTc interval)

Preventative therapy: started when >4 headache days/month and/or no response to acute therapy, and the choice depends on comorbidities and symptoms

CGRP antagonists can be considered in outpatient follow-up as a preventative therapy

Lidocaine nerve block (+/- methylprednisone) acts as both acute and preventative therapies

Nutraceuticals: Mg 300-600mg qhs, vitamin D 1000-2000IU, riboflavin 400mg, coenzyme Q10 300mg daily

Non-pharmacological therapy: reduce lifestyle triggers, relaxation/meditation, massage, exercise, reduce caffeine intake, increase hydration, protein-rich diet (especially breakfast), Cephaly device, mindfulness

Medication overuse headache (>15 days/month of NSAID/Tylenol use and/or >10 days/month of triptan use) therapy: discontinue NSAIDs/Tylenol, attempt to break the headache cycle with a longer acting NSAID (e.g. Anaprox 550mg BID or Naproxen 250-500mg BID) x1-2 weeks

MAO inhibitor within 2 weeks

CAD, vasculopathy, PVD

Cardiac arrhythmia

Recent stroke

Uncontrolled HTN

Renal disease

Anaphylaxis to triptans previously

Hemiplegic migraine

Migraine with brainstem aura

Intake of ergots or triptans within 24 hours

CGRP antagonists (erenumab, fremanezumab, galcanezumab) are options for treating migraines as well - although currently, indicated for patients who have headaches ≥ 8 headache days/months and have failed or are intolerant to ≥ 2 preventative agents. Side effects of CGRP antagonists include constipation, injection site reaction, and hypertension (erenumab).

Encourage patients to keep track of the frequency and intensity of their migraines (Migraine Tracker app)

Patients should be taking abortive therapies EARLY (as soon as they feel like they are getting their migraine) to prevent central sensitization

If their migraines continue to persist - they can take another NSAID or triptan in another 2 hours

Not all triptans are effective for everyone; just because one triptan is not effective does not mean another will not be for the patient

If a patient still experiences high intensity of migraine after taking a triptan, a second dose can be taken 2 hours after the first dose (maximum 2 doses in 24 hours)

Preventative therapy can take 2-3 months to see benefits and often can be up-titrated as tolerated

Treatment of comorbid conditions (e.g. depression) is important

Can last hours to days

With 2 of the following: bilateral, pressing/tightening (non-pulsatile), mild or moderate intensity, not worse with activity

No more than 1 of photophobia, phonophobia, or mild nausea

Considered a chronic tension type headache if it occurs < 15 days a month or > 3 months

If a patient presents to the physician/hospital with TTH, re-think the diagnosis

Raised ICP without the presence of a space-occupying lesion

Thought to be related to reduced CSF absorption

More common in females of child-bearing age

Headache

Transient visual obscurations - unilateral or bilateral greying of vision or dark spots that are worse when bending over or Valsalva

Blurry vision

Horizontal diplopia - CN6 palsy

Reduced visual acuity in some (less common)

Pulsatile tinnitus

Back and/or neck pain

Radicular pain

Cognitive disturbance

New headache or significant worsening of pre-existing headache

Both of: IIH diagnosis, and CSF opening pressure >25 cmH2O

Either of: headache developed or significantly worsened in relation to IIH or led to its diagnosis; headache accompanied by either or both of pulsatile tinnitus, papilledema

Not better accounted for by other ICHD-3 criteria

CVST

Medications: antibiotics (tetracyclines, fluoroquinolones), vitamin A derivatives, lithium, thyroxine in children, corticosteroids

SVC obstruction (very rare)

Endocrine: PCOS, Cushing’s, Addison’s, hypoparathyroidism, hypothyroidism

Polycythemia, anemia

Uremia and/or renal failure

OSA

SLE

Down’s syndrome, Turner’s syndrome

CBC

MRI/MRV brain or acutely CT/CTV brain if MRI unavailable

Consult/refer to Ophthalmology

Lumbar puncture with opening pressure in supine position

Blood pressure

Optic nerve tortuosity

Enlarged optic nerve sheath

Flattened posterior globe

Intraocular protrusion of optic nerve head

Empty sella

Bilateral transverse sinus stenosis

Slit-like ventricles

Acquired tonsillar ectopia

Weight loss; consider referral to bariatric clinic

Low sodium diet

Acetazolamide 500mg p.o. BID (up to 4000mg/day) - titrated by Ophthalmology based on degree of papilledema and visual function

Topiramate

Discontinue offending agent if present; treat underlying cause if present

Management of comorbidities (i.e. OSA)

Surgery in fulminant cases: VP shunting, optic nerve sheath fenestration, sinus stenting

Treatment is aimed at visual sparing and persistence of headache should not be considered treatment failure

Patients should be counseled on the importance of weight loss, as it is the most common risk factor and the only disease modifying treatment available

The importance of adequate follow up should be emphasized, as untreated IIH can cause permanent vision loss

Up to 40% of patients may have recurrence

Caused by CSF leakage, diagnosis requires presence of low CSF pressure and/or evidence of CSF leak on imaging

Female predominance (2:1) and in patients in their 30-50's

Orthostatic headaches (develops when upright and improves with lying supine) - orthostatic features may disappear if SIH has been longstanding

Other symptoms include: nausea/vomiting, hypoacusis, neck stiffness/pain, tinnitus, other neurological symptoms if due to downward displacement of the brain (e.g. diplopia, gait changes)

Can also be seen in unexplained coma

Headache fulfilling criteria for 7.2 Headache attributed to low cerebrospinal fluid (CSF) pressure (see below)

Absence of a procedure or trauma known to be able to cause CSF leakage (Cannot be diagnosed within 30 days of a spinal tap)

Headache has developed in temporal relation to occurrence of low CSF pressure or CSF leakage, or has led to its discovery

Not better accounted for by another ICHD-3 diagnosis

Either or both of the following:

Low CSF pressure (<60 mm CSF)

Evidence of CSF leakage on imaging

MRI/MRV brain and spine

Consider CT Myelogram or Digital Subtraction Myelography - helpful to localize CSF leak

Lumbar puncture with opening pressure in supine position (may not be necessary if enough clinical suspicion)

Subdural collections

Enhancement of pachymeninges

Engorgement of venous structure

Pituitary enlargement

Sagging of brain (can ask radiology to look specifically for mammilopontine distance)

Subdural collection and hematomas

Conservative: Bed rest, hydration, NSAIDs, caffeine

Epidural blood patch or fibrin glue patch (intrathecal infusion of 20 - 130 cc of blood) - will need to consult anesthesiology - however only 1/3 patients respond to first patch

Surgical referral if three failed blood patches

Male to female predominance (3:1) only in cluster headaches

Unclear pathophysiology - thought to be related to trigeminal autonomic reflex (trigeminovascular system, occipital nerves, thalamus and hypothalamus)

Most causes are primary but important to rule out secondary causes of cluster headaches including vascular & masses (carotid artery dissections, cavernous meningioma, pituitary adenomas)

More pituitary lesions seen in people with cluster headaches

Often side-locked headaches with unilateral autonomic symptoms (lacrimation, red eye, ptosis/eye edema, nasal congestion, sweating/flushing)

Associated with restlessness/agitation (banging head on wall, rocking), not able to sit still during an attack

Four common TACS:

MRI brain with sella views +/- vascular imaging (MRA)

Hormonal testing - testosterone

Sleep study

Cluster Headache treatment classified as abortive, transitional, and preventative treatment

Paroxysmal Hemicrania and Hemicrania Continua: Indomethacin (up to 75 mg TID) and/or Melatonin

Indomethacin trial: Start with 25 mg TID for 1 week, then increase by 25 mg TID per week until final dose of 75 mg TID. If headaches are eliminated, then slowly remove one tablet per week until you reach the lowest effective dose for headache improvement. PPI is also recommended.

SUNCT: Lamotrigine is 1st line, then topiramate, gabapentin/pregabalin, verapamil, methylprednisolone

Secondary causes of cluster headaches: Medical or surgical treatment of lesion can improve headaches

Must rule out post-herpetic neuralgia

Usually middle age, females affected more

May be secondary to MS lesions (especially if bilteral)

Greater than or equal to 3 attacks

Recurrent sudden onset paroxysmal attacks lasting <2min that are severe, described as electrical shocks, shooting, sharp pain

Affecting the greater than or equal to 1 trigeminal nerve distribution unilaterally (V2 and V3 are more common than V1)

Pain with innocuous stimuli (eating, brushing teeth, shaving, wind blowing on face)

Refractory period: period of time where repetitive innocuous stimuli do not aggravate the attack; not a feature in TACs

Can consider MRI brain with trigeminal nerve protocol to visualize is there is any vascular compression of the nerve

Acute treatment in the ED: Phenytoin 15 mg/kg IV over 30 minutes or Lacosamide 100 mg IV

Carbamazepine 200-1200 mg/day

Gabapentin or Pregabalin

Gamma knife radiosurgery (if refractory to medical treatment)

Surgical decompression of nerve if evident pathology

Chronic inflammatory disease of the CNS with evidence of demyelination and axonal damage

Mean age of onset 30 years (40 years with PPMS), affecting female : male 3:1

Latitude - further from equator, greater risk; when a patient immigrates from their country of origin after 15 years old, they maintain the MS risk from the country of origin.

Low vitamin D levels and sunlight exposure

Genetics - HLA DRB1

Smoking

Adolescent obesity

Vitral triggers - EBV

NOT meant for patient with incidental MRI findings

Imperative that alternative diagnoses are considered and excluded (particularly NMO/MOG in the right contexts)

An attack/relapse/exacerbation: symptoms or signs typical of an acute inflammatory demyelinating event (current or historical) with duration at least 24 hours, in absence of fever or infection

Dissemination in Space (DIS): 1 or more T2 lesions in at least 2 of 4 areas (periventricular, juxtacortical, infratentorial, spinal cord)

Dissemination in Time (DIT): A new T2 and/or gadolinium enhancing lesion on follow up MRI (at least 30 days after presentation) OR simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions at any time

History of 2 or more attacks and objective clinical evidence of 2 or more lesions (or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack)

2 or more attacks but only objective clinical evidence of 1 lesion: demonstrate DIS as above or await further attack involving a different CNS site

1 attack and objective clinical evidence of 2 or more lesions: demonstrate DIT as above or await second clinical attack

1 attack and objective clinical evidence of 1 lesion (CIS): must demonstrate DIS and DIT as above or await second attack

CSF studies positive for OCBs can be used as a surrogate for DIT if the DIS criteria are met to make a diagnosis

Clinically isolated syndrome (CIS): one clinical attack with corresponding MRI finding, but does not fit dissemination in time or space criteria

Relapsing remitting MS (RRMS): most common (80%); discrete clinical relapses with resolution of symptoms back to baseline in-between attacks

Primary progressive MS (PPMS): progression of disease from onset with variable degree of recovery; stable between episodes of PPMS

Secondary progressive MS (SPMS): initially beginning as RRMS, patients continue to have clinical attacks with less and less baseline recovery in-between attacks

Optic neuritis - reduced visual and color acuity, blurry vision, and pain with extraocular eye movements

Internuclear ophthalmoplegia - inability to adduct one eye due to lesion in MLF but with compensatory abduction Video Example

Transverse myelitis - defined sensory level loss, weakness in upper or lower extremities, autonomic dysfunction (e.g. bladder/bowel or respiratory)

Brainstem syndrome presenting with ataxia, vertigo, or dysarthria

Upper cervical cord lesions can have L'hermitte's sign (electric-like shock radiating down the back with flexion of the neck)

MS relapse usually lasts for a minimum of 24 hours without an alternative explanation. However, patients with MS can also have fluctuations in their symptoms due to concurrent infection (e.g. UTI), fevers, or heat which represent pseudo-relapses and need additional work-up

MRI brain and spine with GAD - (important to include GAD to look for enhancing, active lesions)

Lumbar puncture - send for oligoclonobands (CSF and serum)

Bloodwork - Consider serum NMO/MOG in appropriate context

CBC, lytes, extended lytes, Cr, LFTs, TSH

Hep B core antibody, Hep C

TB skin test prior to certain immunotherapies

Strongyloides testing if from endemic region

Chest x-ray, urinalysis and urine culture, blood cultures x2

Indications: Acute disabling MS relapse

Dosage & Duration: IV methylprednisolone 1g OR PO prednisone 1250mg for 3-5 days

Contraindication: Sepsis or severe infection

Precautions: Administer in AM to minimize nighttime insomnia

Short-term: GI upset, psychiatric symptoms (insomnia, depression, mania, hallucinations), hyperglycemia, susceptibility to infections

Long-term: Hypertension, weight gain, osteoporosis and avascular necrosis of the hip (rare)

No clear evidence for PLEX in people with MS, though sometimes used in an off-label fashion if severe relapse with poor recovery

Indications: Acute, severe MS relapses poorly responsive to glucocorticosteroids

Dosage & Duration: 1 PV exchange x7 over 14 days

Contraindications: Prior anaphylactic reaction

Precautions: Central line insertion may be required

Mild: Citrate toxicity, hypotension, fever/chills/rigor, urticaria, pruritis

Severe: Arrythmia, thromboembolism, pulmonary edema, seizures, coagulopathy, angioedema, bronchospasm, anaphylaxis

Indications: Acute, severe MS relapses poorly responsive to glucocorticosteroids or PLEX; MS relapses in pregnancy

Dosage & Duration: 2 g/kg over 2-5 days

Contraindication: Prior anaphylactic reaction

NMOSD is an inflammatory disease of CNS characterized by episodes of optic neuritis, transverse myelitis, and other focal neurological symptoms

AQP4 (Aquaporin-4) IgG is the most common antibody found in patients with NMOSD (80% of cases)

Consider MOG (myelin oligodendrocyte glycoprotein) IgG in seronegative patients

Less common in predominantly Caucasian countries

One core clinical feature: optic neuritis, acute myelitis, area postrema syndrome, other brainstem syndrome, symptomatic narcolepsy or acute diencephalic syndrome with with MRI lesion(s), symptomatic cerebral syndrome with MRI lesion(s)

No better explanation

2+ core clinical features including 1 of optic neuritis, acute myelitis, or area postrema syndrome

Meets MRI requirements for clinical features (see below)

Dissemination in space met with two or more different core clinical characteristics

No better explanation for the clinical syndrome

Negative testing for AQP4 IgG (ideally with cell-based testing)

Optic neuritis with either normal MRI or optic nerve lesion (T2/FLAIR or T1-GAD) involving more than half of the optic nerve or chiasm

Acute myelitis with MRI cord lesions extending over 3 + continuous segments (or atrophy in patients with remote history of myelitis)

Acute area postrema syndrome: Dorsal medulla lesion

Acute brainstem syndrome: Periependymal brainstem lesions

(See #7 in requisitions for serum NMOSD panel)

Serum anti-aquaporin-4 IgG - greater specificity than in CSF and with cell based assays

Serum MOG antibodies - greater specificity than in CSF

Do not test MOG in all patients with MS; only send off antibodies in appropriate clinical scenarios

MRI brain +/- spine (depending on symptomatology)

Lumbar puncture if indicated to rule out other causes of optic neuritis/transverse myelitis as indicated

Acute therapy: pulse steroids, early PLEX if disabling symptoms (see MS section)

Maintenance: MMF, Rituximab, Azathioprine

New agents that can be used: Eculizumab, Satralizumab, Inebilizumab for AQP4+ NMOSD

MOG+ disease may require longterm immunosuppression with agents such as MMF, Azathioprine, Rituximab, or monthly IVIG

Pediatric patients with ADEM have a 10-15% risk of developing or initially presenting with MOG

Many cases of MOG are monophasic

AQP4+ NMO can be paraneoplastic so consider screening for malignancy in elderly individuals

MOG and MS have typically better functional recovery than NMO

Transverse myelitis: heterogeneous group of disorders with acute to subacute inflammatory spinal cord syndrome

“Complete” cord lesion: relatively symmetric moderate or severe sensory-motor loss. Suggestive of a monophasic disorder (i.e., infectious) or relapsing NMO

“Partial” cord lesion: incomplete or patchy involvement of at least one spinal segment with mild to moderate weakness and asymmetric or dissociated sensory symptoms. More likely secondary to MS with high risk for relapses in the future

Development of sensory, motor, or autonomic dysfunction due to spinal cord etiology

Clearly defined sensory level

MRI-confirmed exclusion of extra-axial compressive etiology

Inflammation within the spinal cord - CSF pleocytosis, elevated IgG index, or gadolinium enhancement

Progression to nadir between 4 hours and 21 days following symptom onset

Bowel/bladder dysfunction - constipation, urinary retention, urinary/fecal incontinence

Weakness - upper and/or lower limb involvement depending on spinal level

Hypotonia in affected limbs

Numbness, paraesthesias - upper and/or lower limb involvement depending on spinal level

Pain or tightness - often occurring around stomach or chest

+/- Lhermitte sign

Paroxysmal tonic spasms

CT lumbar spine if bowel/bladder symptoms - first rule out cauda equina and indication for surgery!

MRI spine with contrast (level depends on limb involvement)

Serum NMOSD antibodies (see NMOSD section)

LP including infectious work-up

Rheumatological work-up: ANA, anti-dsDNA, ENA, RF, ANCA, C3/C4, APLA

HIV, VDRL, Lyme serology

Vitamin B12, vitamin E

Serum copper

Solumedrol 1g IV daily x5 days then maintenance Prednisone 1 mg/kg with slow taper

IVIG 2 g/kg IV over 2 days if no response to steroids

PLEX

Prophylaxis while on high dose steroids: calcium, vitamin D, PPI, PJP prophylaxis

Management of comorbid symptoms (i.e., neuropathic pain, bowel regimen, spasticity, spasms)

Seizure: A transient occurrence of signs and/or symptoms (e.g. sensory, motor, speech, consciousness) due to abnormal excessive or synchronous neuronal activity in the brain

Epilepsy: disorder of the brain with an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition; in a patient who has any of the following:

1) at least 2 unprovoked seizures occurring >24 hours apart;

2) one unprovoked (or reflex) seizure and a probability of further seizures (similar to the general recurrence risk after two unprovoked seizures (at least 60%) occurring over the next 10 years (e.g. abnormal imaging with a potential seizure focus or EEG with epileptiform activity);

3) diagnosis of epilepsy syndrome (e.g. West, Dravet, Lennox-Gastaut)

Provoked seizure: occur with an identifiable proximate cause (metabolic, toxic, structural, infectious, inflammatory) and are not expected to recur in the absence of that particular cause/trigger (e.g., hypoglycemia, alcohol withdrawal, etc.)

Unprovoked seizure: occur without an identifiable cause or in the context of a remote symptomatic cause (i.e., pre-existing brain lesions, such as a remote stroke). Recurrent unprovoked seizures are more likely to be associated epilepsy

Focal onset (“partial”) seizure: abnormal synchronous neuronal activity originating from one location (within limited to one hemisphere) of the brain, more concerning to be associated with elevated future recurrence risk

Generalized onset seizure: abnormal synchronous neuronal activity arising within and rapidly engaging bilaterally distributed networks

Stroke/TIA

Syncope: cardiac arrhythmia, orthostatic syncope, vasovagal syncope

Migraine

Encephalopathy: drug-induced, metabolic disturbance

Psychiatric: anxiety/panic attack, PNES

Involuntary events in response to internal or external triggers that have similar features to those seen in epileptic seizures, but without corresponding electrophysiological features (i.e., epileptiform discharges)

Patients with epilepsy can also have PNES

Associated with adverse events and trauma

Triggers for PNES may include positional change, physical exertion, emotional/stressful situations, dehydration, or heat

Treatment may involve education and support (see Functional Neurological Disorders section)

Traumatic brain injury

Abnormalities in childhood development and birth history

Febrile seizures

Meningitis and/or untreated meningitis

Intracranial structural lesion: (gliosis, encephalomalacia, mass lesion, developmental malformations, cavernomas)

Previous seizure/epilepsy history

Family history

Neurodegenerative disorders

Sleep deprivation

Substance use/withdrawal

Infection

Trauma

Menstruation and ovulation

Non-adherence to treatment

Metabolic abnormalities: hypoglycemia, hyponatremia >hypernatremia, hypocalcemia > hypercalcemia, hypomagnesium

Preceding aura: somatosensory, experiential (i.e., deja vu, jamais vu, epigastric rising sensation), motor, speech/language, autonomic, olfactory/gustatory, and/or visual perceptual disturbance experienced prior to the seizure with positive phenomenology

Event: level of awareness, circumstances leading up to the event (i.e., sleeping, awake), duration, movements (i.e., facial movements, head deviation, eye movements and deviation, rhythmic vs. arrhythmic limb movements, tonic clonic, posturing), urinary/fecal incontinence, tongue biting

Post-ictal period: confusion, drowsiness/altered level of consciousness, Todd’s paresis (hemiparesis), duration to return to baseline; important to complete neurological examination following event and assess for lateralizing signs

Stat CT head to rule out acute intracranial abnormality (i.e., hemorrhage, stroke, mass lesion)

CBC

Lytes, extended lytes (Mg, Ca, PO4), creatinine

Blood glucose

CK

Prolactin (When considering PNES, should be drawn within 10-20 minutes, should be ~2x versus baseline)

Liver enzymes

Toxicology screen if indicated

Blood, urine, CSF cultures if indicated

MRI brain with contrast (seizure protocol) when clinically stable: may see some T2/FLAIR hyperintensity, diffusion restriction (ADC drop >10% is associated with permanent damage)

EEG

AED levels if prescribed to patient

LP with cell count and differential, protein, glucose, bacterial/viral/fungal cultures, cytology/flow cytometry, autoimmune/paraneoplastic panels as indicated

Serum autoimmune/paraneoplastic panels if indicated

Autoimmune work-up: ANA, anti-dsDNA, ENA, RF, C3/C4, cryoglobulins as indicated

If there is suspicion for PNES - prolonged video EEG or EMU is helpful for the diagnosis

ABCs (airway, breathing, circulation) and consultation of ICU if the patient may require intubation with prolonged seizure

First-line Benzodiazepines - Midazolam 10mg IM x1 (if patient is >40kg) or Lorazepam 2mg IV q2min (max 8mg)

AED load after acute management if indicated

Patients with a single provoked seizure do not typically require maintenance AED

Maintenance AED: predominantly used if unprovoked seizure with high risk of recurrence or multiple unprovoked seizures or abnormal EEG/MRI or nocturnal seizures

If suspicious of infectious cause, antimicrobials based on suspected organism/etiology should be initiated after the collection of cultures (if possible)

Correction of metabolic abnormalities

Seizure type (focal vs. generalized onset, specific seizure syndrome)

Comorbidities

Side effects and tolerance

Dosing frequency

Drug coverage/affordability

VPA

Carbamazepine

Topiramate

Phenytoin

Phenobarbital

High Topiramate levels

Enzyme inducers: Phenytoin, Carbamazepine

Phenobarbital, primidone, oxcarbazepine

Driving: reporting to MTO is a mandatory obligation in Ontario and instruct the patient not to drive until driving privileges are reinstated by the MTO

Precautions to counsel patients surrounding baths alone, swimming alone, heights/dangerous activities (e.g. climbing ladders)

A single seizure lasting more than 5 minutes or multiple seizures with incomplete recovery of level of consciousness to baseline between the seizures

May present as generalized tonic clonic (GTC) seizures or non-convulsive seizures

Defined by 2 time-points: T1 (time beyond which seizures will likely prolong >5 minutes GTC) and T2 (GTC 30 minutes with higher risk for long-term consequences)

Mortality is 20% - most important determinant of mortality is underlying cause

Evidence supporting early treatment of seizures stems from studies showing increasing pharmaco-resistance (especially to benzos) and neuronal injury with longer seizure durations

Neuroleptic Malignant Syndrome

Serotonin Syndrome

Substance use/withdrawal

Autoimmune encephalitis - suspect if no response to AEDs

GTC seizure with head and gaze deviation, +/- urinary/fecal incontinence

Non-convulsive seizure - nystagmus, sustained eye deviation, facial/periorbital twitching, abnormalities in vital signs

Post-ictal phenomenon - confusion/agitation, dysarthria/aphasia, altered level of consciousness, Todd’s paresis (unilateral hemiparesis)

Stat CT head to rule out acute intracranial abnormality (i.e., hemorrhage, stroke, mass lesion)

CBC

Lytes, extended lytes (Mg, Ca, PO4), creatinine

Blood glucose

Liver enzymes

Toxicology screen if indicated

Blood, urine, CSF cultures if indicated

MRI brain with contrast (seizure protocol) when clinically stable: may see some T2/FLAIR hyperintensity, diffusion restriction (involving cortex, hippocampi/mesial temporal lobes, thalamus, and cerebellum)

EEG

AED levels if prescribed to patient

LP with cell count and differential, protein, glucose, bacterial/viral/fungal cultures, cytology/flow cytometry, oligoclonal bands/IgG index, autoimmune/paraneoplastic panels as indicated

Serum autoimmune/paraneoplastic panels if indicated (see requistions)

ABCs (airway, breathing, circulation) and consultation of ICU as the patient may require intubation with prolonged seizure

First-line Benzodiazepines - Midazolam 10mg IM x1 (if patient is >40kg) or Lorazepam 2mg IV q2min (max 8mg)

AED load after acute management

Consider giving thiamine 500 mg IV followed by 50 ml of D50

Intubated patients may require burst suppression (target 40-60%) and ICU monitoring with titration of sedatives including propofol and barbiturates

If suspicious of infectious cause, antimicrobials based on suspected organism/etiology should be initiated after the collection of cultures (if possible)

Correction of metabolic abnormalities

* Max dose of Levetiracetam is 4.5 g for status epilepticus

** In an average-size (70 kg) individual, consider 1500 mg load of

phenytoin if unable to obtain weight quickly

For patients with known seizure disorders, compliance to AEDs is important to reduce risk of status epilepticus

Second most common neurodegenerative disorder following Alzheimer's disease

Due to dopamine deficiency secondary to degradation of dopaminergic neurons in the substantia nigra

Can be genetic (10%) or idiopathic (90%)

Average age of onset in 60’s

Pathologically characterized as an alpha synuclein proteinopathy with presence of Lewy bodies

Cardinal features of Parkinsonism are: 4-6 Hz Rest tremor, Rigidity, Akinesia/Bradykinesia, and Postural instability not due to visual, vestibular, or cerebellar or proprioceptive dysfunction (TRAP)

Non-motor features of PD: Rapid eye movement (REM) sleep disorders, anosmia, autonomic dysfunction (constipation, orthostatic hypotension), mood changes, cognitive changes

Constipation, REM sleep disorders, and anosmia can precede motor symptoms of PD by over a decade

At present there are no confirmatory diagnostic tests for PD, it is a clinical diagnosis

Drug induced: Antipsychotic use (especially first generation like haloperidol) and dopamine antagonists (e.g. metoclopramide) - can often have tardive dyskinesia and akathsias

Toxins: Manganese, MPTP

Vascular parkinsonism: concomitant vascular risk factors, may be more symmetric and have lower body predominance

Parkinson’s Plus Syndromes (see below)

Rigidity

4-6 Hz rest tremor

Postural instability “not caused by primary, visual, vestibular, cerebellar or proprioceptive dysfunction

History of repeated strokes with stepwise progression of parkinsonism

History of repeated injury

History of definitive encephalitis

Neuroleptic treatment at onset of symptoms

MPTP exposure

Negative response to large doses of levodopa

>1 relative affected (this criteria is usually no longer applied)

Sustained remission

Strictly unilateral features after 3 years

Early severe autonomic involvement

Early severe dementia with disturbances of memory, language and praxis

Oculogyric crises

Supranuclear gaze palsy

Babinski sign

Cerebellar signs

Presence of cerebral tumor or communicating hydrocephalus on CT or MRI

Unilateral onset

Rest tremor

Progressive disorder

Persistent asymmetry affecting the side of onset most

Excellent response (70-100%) to levodopa

Severe levodopa-induced chorea

Levodopa response for 5 years or more

Clinical course of 10 years or more

Inspection: Decreased facial expression (hypomimia), softer voice (hypophonia), decreased blink rate

Eye movements: Difficulties with extraocular eye movements (e.g. PSP - slowed or impaired vertical saccades), hypometric saccades (Can be tested with OKN strips, in PSP - decreased vertical saccades)

Tremor: Parkinson’s tremor typically occurs at rest and is asymmetrical, but can re-emerge with sustained posture, often described to have a “pill-rolling” quality and can worsen with distraction (“Count months of the years backwards”)

Bradykinesia: Finger tapping, hand open-close, supination-pronation, foot and heel tapping will demonstrate not just slowness but decrement in amplitude or freezing of movements

Tone: Testing for both appendicular rigidity (usually Parkinson’s Disease) and axial rigidity (often seen in PSP)

Gait: Slow, shuffling gait with often stooped posture. Arm swing can be diminished with emergence of tremor. Difficulty with turns, requiring multiple steps to move (en-bloc turning). Patients can walk slowly but then accelerate with small steps (festination). Advanced PD can demonstrate freezing of gait at times which are overcome by visual stimuli (e.g. stepping over a line)

Postural instability: Pull test to look for retropulsion (will require several >3 steps to regain balance)

Other signs: Micrographia or tremor in writing

Atypical symptoms may benefit from MRI brain to rule out Parkinson’s Plus syndromes

Depression: Dopamine agonist (Pramipexole), Serotonin reuptake inhibitor (Citalopram, Fluoxetine), Serotonin and Norepinephrine Reuptake Inhibitor (Venlafaxine), Tricyclic antidepressant (Desipramine, Nortriptyline),

Psychosis: Atypical antipsychotic (Clozapine, Quetiapine), acetylcholinesterase inhibitor (Rivastigmine)

REM Sleep behaviour disorder: Hormone (Melatonin), Benzodiazepine (Clonazepam)

Constipation : Osmotic laxative (PEG)

Gastrointestinal motility : Peripheral dopamine antagonist (Domperidone)

Orthostatic hypotension: peripheral dopamine antagonist (Domperidone), Mineralocorticoid (Fludrocortisone), Vasopressor (Midodrine)

Common, can be both familial (about 50% will have a family history although no single causative gene yet identified) or idiopathic

Two peaks of onset at 20s and 60s

Usually an isolated tremor syndrome of the bilateral upper limb presenting as a posture or kinetic tremor, with or without head tremor or tremor in other locations

Benign, but tremors can become progressively worse which may warrant symptomatic treatment

Tremors may improve with small amounts of alcohol

Isolated tremor syndrome of bilateral upper limb action tremor

At least 3 years’ duration

With or without tremor in other locations (e.g. head, voice or lower limbs)

Absence of other neurological signs, such as dystonia, ataxia, or parkinsonism

Isolated focal tremors (voice, head)

Orthostatic tremor with a frequency > 12 Hz

Task- and position-specific tremors

Sudden onset and step-wise deterioriation

Enhanced physiological tremor: common bilateral upper limb action tremor (8-12 hz), caused by anxiety, fatigue, hyperthyroidism, other drugs. It is often reversible if the cause of the tremor is removed

Parkinson’s disease and other forms of Parkinsonism: classic parkinsonian tremor is typically a 4-7 Hz rest tremor. It can involve the upper or lower extremities, jaw or tongue. See section on Parkinson’s disease. See section on Parkinson’s disease

Cervical dystonia: common cause of isolated head tremor.

Task- and position-specific tremors: focal tremor that typically occur during a specific task or posture

Primary orthostatic tremor: a generalized high frequency (13-18 hz) isolated tremor syndrome that occurs upon standing up. Often, confirmation of the tremor frequency is done using electromyography

Functional tremor: characterized by distractibility, frequency entrainment or antagonistic muscle coactivation

Generally no investigations are needed unless there are atypical findings

Initial dose: 60 - 80 mg/day (divided into two or three doses per day, e.g. 40 mg BID) and gradually titrate up to efficacy (may start at lower dose in elderly)

Maintenance dose : 120 to 320 mg/day (Lower dose is better for elderly individuals)

Side Effects: Lightheadedness, bradycardia, fatigue

Contraindications: Patients with heart block/heart failure, asthma, and type 1 diabetes

Initial dose: 25 mg/day (at bedtime) and increase by 25 mg every 3-7 days

Maintenance dose : 250 mg - 500 mg/day

Side Effects: Sedation, drowsiness, fatigue, nausea and vomiting, ataxia

Propranolol + Primidone

Gabapentin 100-300mg p.o. TID (max 1200mg daily)

Topiramate 25mg p.o. daily-BID (max 400mg daily)

MRI-guided focused ultrasound thalamotomy

Deep brain stimulation to thalamus

The clinical course of ET is typically slow, progressive over years

Younger age of onset usually correlates with slower progression

Sudden, brief involuntary muscle jerks that occur occur at rest, movement, or provoked by stimuli (e.g. touch, sound)

Positive myoclonus: Caused by abrupt muscle contraction

Negative myoclonus: Caused by loss of tone (e.g. asterixis)

Cortical myoclonus: Usually affecting the face and hands and with voluntary action. stimulus sensitive and triggered by action or touch, can also be seen in certain epilepsy syndromes

Subcortical/Brainstem myoclonus: Generalized jerks in axial and bilateral proximal extremities, stimulus sensitive to auditory triggers - startle response (e.g. loud clap)

Spinal myoclonus (Propriospinal myoclonus and segmental spinal myoclonus): Usually arrhythmic jerks in the arm/trunk but in propriospinal myoclonus, you can see abdominal myoclonus (torso flexion)

Secondary myoclonus is the most common form of myoclonus - due to an underlying neurological or non-neurological cause → important to differentiate whether onset of myoclonus is acute vs gradual

Diffuse myoclonus is often seen post-anoxic brain injury (associated with poor prognosis) - e.g. Lance-Adams Syndrome

CBC, lytes, extended lytes, LFTs, TSH

MRI brain in appropriate clinic context to evaluate for anoxic injury, brainstem pathology, neurodegenerative conditions

EEG and EMG may be helpful but generally not required for diagnosis

If reversible cause of myoclonus is found (e.g. due to metabolic cause or drug-induced) - need to treat

Symptomatic treatment for myoclonus:

Ischemic stroke: hypoperfusion of brain tissue due to thrombus/embolus within the intracranial vasculature

TIA*: transient episode of neurological dysfunction due to focal ischemia without infarction; should see resolution of symptoms without neuroimaging correlate if symptoms resolve within 24hrs and typically do not see neuroimaging correlate if symptoms resolve within 2hrs

High risk TIA: high risk for occurrence of an ischemic stroke within the first 48hrs in a patient with transient unilateral motor and/or speech/language symptoms lasting >5 minutes

Increasingly, there is recognition that TIA is not the best terminology and we expect the field to revolve to potentially remove this term; but for now it remains

Cardioembolic - secondary to atrial fibrillation

Large vessel atherosclerosis

Small vessel/lacunar strokes - secondary to HTN

Other (more common in young patients <50) - PFO, carotid/vertebral dissections

Cryptogenic/unknown

HTN

Dyslipidemia

Diabetes

Smoking

Atrial fibrillation

Cardiac disease/PVD

Obesity/reduced physical activity

EtOH misuse

Pro-thrombotic/hypercoagulable state - OCP/hormone replacement use, SLE, APLA, Factor V Leiden, protein C and/or S deficiency, anti-thrombin III deficiency, malignancy

Stat CT/CTA/CTP - assess for ischemic changes, hemorrhage, arterial occlusion, perfusion mismatch

NIHSS clinical examination

Vital signs including heart rate and BP

ECG

CBC

Lytes, extended lytes (Mg, Ca, PO4), creatinine

Blood glucose

24 hours after tPA and/or EVT: CT head

MRI brain when clinically stable

Lipid profile

HbA1c

Transthoracic +/- transesophageal echo with bubble study/definity contrast to look for vegetations, intracardiac thrombus, and/or PFO; TEE is for valves/PFO

In appropriate situations, consider cardiac CT for LAA clot

Blood and urine cultures - especially if patient is febrile and has risk factors for endocarditis (i.e., younger age, IVDU

Holter monitor

Stroke in the young work-up

Hyperdense vessel

Loss of grey-white differentiation

Sulcal effacement

Loss of insular ribbon

Hypoattenuation of deep grey matter nuclei - highly specific for ischemia within 6hrs

Swelling/mass effect

Assess the core and the penumbra (brain at risk)

Core features: increased MTT, markedly decreased CBF and CBV

Penumbra features: increased MTT, moderately reduced CBF, normal/increased CBV

More likely to have favourable outcome with mismatch ratio >/= 1.8, volume >/= 15mL

Assess patient for stability and call for help from the emergency department/ICU as needed

Thrombolysis (TPA/TNK) and/or EVT (see below)

Thrombolysis-angioedema: Solumedrol 125mg IV or Hydrocortisone 200mg IV + Famotidine 20mg IV IV or Diphenhydramine 50mg IV

If clinically stable with stable CT head 24hrs post-intervention (tPA, EVT), can start single anti-platelet and DVT prophylaxis

If NIHSS </= 3 can start dual anti-platelets for 21 days, then monotherapy life-long thereafter (CHANCE, POINT trials)

Starting anti-coagulation post-ischemic stroke (i.e., for AFib): initiation on day 3 (small stroke), 6-7 (medium), or 12-14 (large stroke) but depends on staff and presence of any hemorrhage Reference: Secondary Stroke Prevention Guidelines 7.2

BP: target <140/90 or <130/80 (diabetic patients/small vessel disease)

Dyslipidemia: target LDL <1.8 for those with small vessel disease

Carotid endarterectomy versus stenting in patients with symptomatic large vessel atherosclerosis

Diabetes: target HbA1c <7% (some leniency in patients >80 based on Canadian Diabetes Association)

Must address driving based on residual function as an inpatient!

Lifestyle: cessation of smoking, physical activity, reduced salt intake/DASH diet/Mediterranean diet, reduced EtOH intake

Etiology characterized based on location - lobar (CAA, ischemic stroke with hemorrhagic transformation), deep (HTN, tumor/metastasis), intraventricular (extension from HTN hemorrhage in basal ganglia, aneurysmal rupture, intraventricular AVM/tumor)

Less common stroke type (10-15%) - more common in individuals with hypertension and older adults (presence of CAA)

HTN

Age - > 65

Trauma & Head Injuries

Vascular anomalies - arterial dissection, CVST, AVM, aneurysmal rupture

Tumors/metastasis

Sympathomimetic drugs (e.g. cocaine, amphetamines)

Smoking

EtOH misuse

Family history

Headache - often described as sudden onset & worst headache (thunderclap)

Altered level of consciousness

Nausea/vomiting

Dizziness/vertigo

Focal neurological deficits

Seizure

Stat CT/CTA/CTP - assess for ischemic changes, hemorrhage, arterial occlusion, perfusion mismatch

NIHSS clinical examination

ICH score

Vital signs including heart rate and BP

ECG

CBC

Lytes, extended lytes (Mg, Ca, PO4), creatinine

Blood glucose

Blood and urine cultures - especially if patient is febrile and has risk factors for endocarditis (i.e., younger age, IVDU) and subsequent mycotic aneurysms/emboli with hemorrhagic transformation

CT head 6-24 hours after initial presentation

MRI brain when clinically stable with SWI/GRE sequence

Ventricular effacement

Midline shift

Hyperdense blood with surrounding hypodensity (edema)

Spot sign - active bleeding

Acute BP control: SBP <140 (if spot sign present indicating active bleeding) versus SBP <160 (if initial SBP >220 and/or renal dysfunction, absence of active bleeding)

Eventually target BP <140/90 or <130/80 (diabetics)

If patient uses Warfarin, can give Octaplex 1000IU (for patients 50-90kg with INR 1.5-4) and vitamin K 10mg IV push, TXA 1g IV push

Consult Neurosurgery - consideration of EVD and/or decompressive hemicraniectomy if indicated

Avoid secondary brain injury: treat Hb <70, avoid fever, correct coagulopathy

Patients do not require anti-platelets!

Risk factors for poor prognosis: ICH score - older age, initial GCS 3-4, intraventricular hemorrhage, hemorrhage volume >30mL

Typically considered a “stroke in the young” in an individual <50 years old

Systemic disease associated with prothrombotic state and infarct/hemorrhage: SLE, APLA, vasculitis, Behcet’s, Susac syndrome

See ischemic stroke and hemorrhagic stroke for full description of focal neurological deficits

See ischemic stroke section for basic blood work, neuroimaging, and standard stroke investigations

Autoimmune work-up: ESR/CRP, ANA, anti-dsDNA, ENA, RF, C3/C4, cryoglobulins

Pro-thrombotic/hypercoagulable state work-up: APLA (anti-cardiolipin, B2-glycoprotein-1, lupus anticoagulant), Factor V Leiden, protein C and/or S deficiency, anti-thrombin III deficiency, testicular U/S in males, CT chest/abdo/pelvis for malignancy work-up

Infectious work-up: VDRL, HIV serology

Depends on etiology (see table above for examples)

Caused by build-up of CSF

Idiopathic NPH (iNPH): Unknown etiology

Secondary NPH (sNPH): Due to conditions impairing CSF absorption (e.g. SAH, brain tumors)

Insidious onset of changes starting with gait, then urinary and/or cognitive changes

Initially develops non-specific gait difficulties (slowing of gait, feeling imbalanced) before developing difficulties with initiating of gait (previously known as magnetic gait) or increased falls due to postural instability

May start with increased urinary frequency, than urgency, and finally incontinence

Cognitive impairment includes difficulties in executive dysfunction (e.g. multitasking, judgement)

Ventriculomegaly present

DESH (disproprotionately enlarged subarachnoid hydrocephalus)

Crowding present

Transependymal flow present

Significant ischemic white matter changes present

Evans index >0.3

Callosal angle between 40º and 90º

Are there secondary causes of NPH? (e.g. Head trauma, meningitis, SAH, ICH, tumors)

Does the patient have arthritis, spinal disease, pain/sensory symptoms, or other causes (e.g. poor vision, hearing, parkinsonism) that also explains gait difficulties?

Are there other confounders to diagnosis? (e.g. Sleep apnea, fecal incontinence, headaches, REM sleep disorders, orthostatic hypotension, anosmia)

Was gait difficulty before or after cognitive decline? - Gait onset before or at same time as cognitive changes has a good prognosis of shunting, not true if cognitive decline occurred prior to gait changes

How long have they had cognitive changes and do they have other comorbid cognitive dysfunction? - 2+ years of cognitive decline indicates poor prognosis with shunting

UHN NPH protocol developed by Dr. Tang-Wai and Dr. Fasano - for use at UHN but can be used as a reference guide at other sites (i.e. but should not be printed and placed in patient's chart)

Physical exam to assess for orthostatic hypotension, extraocular eye movements, parkinsonism, UMN presence, and peripheral neuropathy

MRI Brain with sagittal FIESTA sequence

Need high clinical suspicion of NPH before proceeding with the NPH assessment

Pre and post- MOCA with semantic fluency (e.g. animals), and naming (BNT-15)

Pre- video recording of gait (stand up from chair, walk towards camera for at least 10 meters, turn, walk back to chair, repeat)

Large volume lumbar puncture (30-40 cc)

1 hour post-LP - Video record of walk

3 hour post-LP - Video record of walk

** Note: Gait is best performed at a Gait Lab to determine if gait is improved/changed

If patient demonstrates improvement of gait post large-volume LP, they should be referred and assessed by Neurosurgery for possible shunt

Unfortunately, prognosis can still be poor without guarantee for improvement post-surgery and there can significant complications including infections and shunt malfunctions post-operatively

VP shunt’s main purpose is improvement in gait and urinary incontinence but NOT cognitive impairment

Rapidly progressive dementia due to prion disease (conformational change of proteins)

Sporadic CJD: age 55-70 years, mean 64 years

Variant CJD: mean 26 years, longer duration of symptoms >6 months

Iatrogenic CJD: rare, due to dura mater transplantation

Heidenhain variant CJD: targeting of prions to occipital lobe

Fatal Familial Insomnia: 50's, progressive sleep and autonomic disturbances (hypertension, tachycardia, hyperhidrosis), ataxia

Gerstmann-Straussler-Scheniker: 40-50's, progressive cerebellar ataxia, dysarthria, nystagmus and then with cognitive and UMN symptoms

Altered level of consciousness/mental status

Psychosis - delusions, hallucinations

Progressive cognitive impairment

Myoclonus

Seizures

Cortical visual disturbances (especially in Heidenhain variant CJD) - disturbed perception of colours or structures, optical distortions, hallucinations

Cerebellar ataxia

Extrapyramidal symptoms

MRI brain - diffusion restriction in striatum and cortex (cortical ribboning), pulvinar sign, Hockey stick sign

LP - RT-QuIC assay with elevated 14-3-3 tau

EEG - periodic sharp wave complexes and triphasic components

Acute severe hepatic encephalopathy

Autoimmune encephalitis

Hypoglycemic brain injury

Hypoxic ischemic encephalopathy

Mitochondrial disease

Post-ictal state

Extrapontine osmotic demyelination

EBV encephalitis

Supportive care

Management of comorbidities and symptoms (i.e., anti-epileptic medication)

Patient and family counseling

Average survival 6-7 months from diagnosis for most cases of CJD, although GSS can be longer (years)

Early involvement of the thalamus is a poor prognostic sign

AIDP - Acute or subacute onset autoimmune demyelinating polyradiculoneuropathy - often thought to be preceded by respiratory or GI infection

Numbness/paresthesias and weakness beginning in the legs, progressing proximally, commonly involving the face, eyes, and respiratory muscles (sensory symptoms are less pronounced than weakness)

Onset is over the course of days with rapid progression to possible quadriplegia in a few days, with maximum weakness achieved in 2-4 weeks

Hyporeflexia or areflexia

Neuropathic pain in lower back and thighs

Autonomic involvement, such as tachy/bradycardia, hyper/hypotension, gastric hypomotility, and urinary retention

70% of cases are preceded by respiratory or gastrointestinal infection. Less common precipitants are pregnancy, vaccination (controversial), surgery, or cancer

Acute motor axonal neuropathy (AMAN)

Acute motor-sensory axonal neuropathy (AMSAN)

Miller-Fisher syndrome (Triad of ophthalmoparesis, ataxia, and hyporeflexia)

Paraplegic variant

Pharyngeal-cervical-brachial variant

HIV

Rash

Severe pain

Pupillary involvement

If concern for severe weakness, dyspnea, autonomic involvement - telemetry, VBG, consult RT, SLP, PT +/- ICU

ANA

SPEP with immunofixation and free light chains

HBA1c

ESR/CRP

Lumbar puncture (Cell count, Protein & Glucose, Cultures, Cytology & Flow Cytometry) - CSF analysis may show albuminocytologic dissociation (increased total protein without an increase in WBC)

MRI Spine with GAD (may see nerve root enhancement)

EMG/NCS (may show prolonged/absent F waves, temporal dispersion prolonged distal latencies, sural nerve sparing)

Consider: Lyme, HIV, CMV, ACE for other infectious/inflammatory causes

For severe exacerbation or prior to surgery if preo-operative bulbar/respiratory symptoms (Onset 3- 10 days, benefits weeks to months)

Dosing: 2g/kg IV over 2-5 days

Side effects: Infusion reactions, allergic reaction, aseptic meningitis, thromboembolic events, hemolytic transfusion reactions

For severe exacerbation or prior to surgery if preo-operative bulbar/respiratory symptoms (Onset 1 - 5 days, benefits 1 - 3 months)

Dosing: 4-6 exchanges

Side effects: Hypocalcemia, hypotension, febrile/allergy, immunosuppression (if septic, give IVIg instead if indicated)

AVOID PLEX AFTER IVIg - otherwise you will be removing IVIg from patient’s system

Chronic inflammatory demyelinating polyradiculoneuropathy - similar to AIDP (e.g. GBS) except duration of symptoms can be over months or relapsing-remitting

Can initially present as GBS with severe weakness but progression is longer ( > 4 weeks)

Can be associated with HIV, paraprotein, inflammatory disease, malignancies

Similar symptoms to that of AIDP/GBS with ascending sensory and motor symptoms (proximal and distal weakness) as well as areflexia Symptom progression beyond the 4 weeks seen in GBS (thus; important to change differential if GBS is persistent and worsening > 1 month)

Often have other features such as tremors, cranial nerve/bulbar findings, increased ICP

The differential for diseases like CIDP can also include the following:

If concern for severe weakness, dyspnea, autonomic involvement - telemetry, VBG, consult RT, SLP, PT +/- ICU

ANA

SPEP with immunofixation and free light chains *

HBA1c

ESR/CRP

Lumbar puncture (Cell count, Protein & Glucose, Cultures, Cytology & Flow Cytometry) - CSF analysis may show albuminocytologic dissociation (increased total protein without an increase in WBC)

MRI Spine with GAD (may see nerve root enhancement)

EMG/NCS (may show prolonged/absent F waves, temporal dispersion prolonged distal latencies, sural nerve sparing)

Consider: Lyme, HIV, CMV, ACE if concern for another process

CIDP panel - download requisition - Contactin-1, Neurofascin-155, CASPR1

** If + for IgG or IGA lambda monoclonal gammopathy - consider skeletal survey and VEGF for possible POEMs*

First line treatment include IVIG and PLEX (see GBS section)

Corticosteroids also considered depending on response to IVIG/PLEX - can consider steroid pulse x 5-7 days and then start prednisone 1mg/kg for 1-2 months before tapering

"Treatment resistant" - can consider cyclophosphamide but patients with antibodies to contactin-1 and neurofascin can benefit better from PLEX/B-cell depleting therapies (Rituximab)

POEMS - treatment is with targeted radiation (limited disease) or chemotherapy/stem cell transplant

Autoimmune disease affecting post-synaptic proteins at neuromuscular junction - impairs binding of acetylcholine to receptor

Common Myasthenia Gravis antibodies include: Anti-ACHr (80-85%) and MuSK (8%)

More often seen in younger females and older males

Patients with MG may also have a thyoma

Classic presentation is fatigable weakness of muscles - patients may endorse that symptoms worsen with activity (e.g. diplopia worse with reading, dysarthria if they talk for a long period of time)

Most common presenting symptoms:

Patients may have ocular myasthenia gravis but this can “generalize” to affect elsewhere

Myasthenia Gravis can be exacerbated by: stress, illnesses, fever, hypothyroidism/hyperthyroidism, menstruation, drugs

Clinical signs of an impending crisis include - prominent bulbar involvement, neck and deltoids weakness, changes in respiration

Need urgent evaluation and measurement of respiratory parameters (FVCs)

Indications for intubation include: FVC < 15 ml/Kg, PEmax < 20 cmH2O, Pmax less than -20 cmH2)

Frontalis activation to compensate for ptosis

If asymmetric ptosis, lifting the obviously ptotic eyelid may bring out ptosis on the other side as the frontalis activation relaxes

Sustained upgaze for 1 minute with worsening of ptosis (diplopia will worsen at 15-30 seconds)

Ice-pack test: Hold ice against ptotic eye for 2-5 minutes. Improvement of ptosis is expected

Inability to bury the eyelashes upon eye closure with subsequent “peek sign” (sclera becomes visible as eye closure weakens)

Ability of examiner to open jaw against resistance (jaw closure is weaker than jaw opening)

Testing power for neck flexion and extension

Binocular diplopia with any combination of extraocular movement abnormalities (though downgaze typically spared)

Count to 20 at 2 Hz on one breath. If able to do so, respiratory weakness is unlikely. Also listen for nasal dysarthria

Repeatedly test power in deltoids, triceps, or hip flexors, assessing for fatigability

CBC, LFTs, HbA1c

Repetitive nerve stimulation and single-fiber EMG

CXR → CT Chest to rule out thyoma

AChR and MuSK antibody testing (Mitogen requisition forms or BC Neuro requisition forms)

If concern for respiratory weakness - VBG and consult RT +/- ICU , FVCS daily - TID (see above for indications for intubation for myasthenic crisis)

Refer for thymectomy if thymoma present (although can consider trhymectomy for non-thymomatous myasthenia gravis - see below in treatment)

Temporary symptomatic improvement of symptoms (onset of action: 20-30 minutes)

Starting dose: 30 mg PO q4-6 hours (can increase by 30-60 mg every 1-2 weeks up to a maximum of 480 mg/day)

Side effects: Nausea, vomiting, diarrhea, secretions

May worsen symptoms in patients with anti-MuSK antibody-positive MG

Can increase secretions in patients in MG crisis - often held in the ICU setting

For severe exacerbation or MG crisis (onset of action: 3-10 days, benefits last weeks to months)

Dosing: 2g/kg IV over 2-5 days

Side effects: Infusion reactions, allergic reaction, aseptic meningitis, thromboembolic events, hemolytic transfusion reactions

For severe exacerbation or MG crisis (preferred to IVIg in anti-MuSK antibody-positive MG) (onset of action: 1-5 days, benefits last 1-3 months)

Dosing: 4-6 exchanges

Side effects: Hypocalcemia, hypotension, febrile/allergy, immunosuppression

AVOID PLEX AFTER IVIg - otherwise you will be removing IVIg from patient’s system

First line disease modifying therapy for intolerable symptoms or risk of deterioating respiratory/bulbar function

Starting dose for ocular - mild generalized MG: 10-20 mg PO daily

Starting dose for moderate-severe generalized MG: 0.5 - 0.75 mg/kg/day (start at 10 mg PO and increase by 10 mg every 3-5 days)

Starting dose for intubated patients: 100 mg PO daily

There can be a phenomenon of transient prednisone associated weakness that patients experience when first starting prednisone

Adverse effects: Sleep disturbance, mood changes, weight gain, GI irritation, avascular necrosis

Patient should also be on Vitamin D and Calcium

Patients may require PJP prophylaxis and should have TB, hepatitis B, and strongyloides testing prior to initiation of prednisone

Azathioprine

Mycophenolate mofetil

Cyclosporine

Tacrolimus

Rituximab

NEW TREATMENTS - Eculizumab, Ravulizumab, Efgartigimod

Should be considered in patients who are found to have a thymoma and ACHr +

Can also be considered in patients < 55 who have moderate-severe generalized MG for < 2 years who may not be adequately controlled with symptomatic management

Counsel patients on medications to avoid that can exacerbate MG

Absolutely contraindicated - Alpha-interferon, botulinum toxin, D-penicillamine, telithromycin

Relatively contraindicated:

Autoimmune disease affecting pre-synaptic voltage gated calcium channels (VGCC) - impairs release of acetylcholine into synaptic cleft

Can be either primary autoimmune or paraneoplastic (almost always associated with small cell lung cancer in adults)

Common antibodies: anti-VGCC found in 90% of patients

Age of onset - bimodal peak at ~35 and 60

Prominent proximal weakness that progresses distally

Areflexia (but reflexes improve with sustained voluntary contraction)

Autonomic dysfunction: Dry mouth & eyes, constipation, erectile dysfunction, orthostatic hypotension, pupillary abnormalities

anti-VGCC antibody testing (Mitogen requisition forms)

NCS and EMG

CT Chest to assess for SCLC

Refer to oncology for management of underlying SCLC if paraneoplastic

Increases pre-synaptic release of Ach by blocking K+ channel, onset of action 30-90 minutes

If patient improves, no need for another treatment

Starting dose: 5-10 mg PO TID or QID (can increase to max 100 mg/day)

Side effects: Risk of seizures with > 100 mg/day, paraesthesia, nausea, palpitations

Consider IVIG, PLEX, immunotherapy

** For paraneoplastic LEMS - immunosuppression not recommended given risk of tumor progression **

Thought to be virally mediated by reactivation of HSV1 infection of the facial nerve

Spontaneous, acute (can occur within hours), isolated unilateral facial palsy - since it’s lower motor neuron pattern of weakness, there should be weakness in BOTH upper and lower part of the face (e.g unlike a stroke where a facial droop is ‘forehead sparing’)

Patients may endorse a slight ear pain behind the ear during the onset

Patients may endorse difficulties closing eye, smiling, difficulty eating, decreased taste

Symptoms occur over 72 hours and gradually recover over months

As symptoms improve, synkinesis can occur due to aberrant regeneration of facial nerve (e.g. eye closing when smiling)

Gradual onset (slowly progressive over weeks and other cranial nerve involvement) - consider neoplastic cause

Vertigo, hearing loss, tinnitus - consider CPA angle mass/lesion

Bilateral facial nerve palsy - consider other infectious causes e.g. Lyme

Vesicles in external auditory canal, tympanic membrane, orophyrynx - Ramsay Hunt

Sensory symptoms - usually Bell's Palsy have more weakness than sensation difficulties

Extraocular eye movement abnormalities

Usually a clinical diagnosis but if red flags are present, consider MRI brain +/- GAD

If suspicious for Lyme disease - can send for serological testing

Eye care: given poor eyelid closure/tearing from facial palsy - consider artificial tears applied regularly, ointment, patches

Corticosteroids: given within 72 hours of symptom onset - 60-80 mg/day for 1 week

Adverse effects: Sleep disturbance, mood changes, weight gain, GI irritation, avascular necrosis

Patient should also be on Vitamin D and Calcium

Antiretrovirals: no clear evidence to be used with steroids but can consider: valcyclovir 1000 mg TID for 1 week - use with caution in patients with renal failure

Prognosis is good, 85% of patients recover within 3 weeks and if facial function does not return within 3-4 months, consider another diagnosis

Even after the disease is treated, there may still be asymmetry of the face and synkinesis with facial movements

Can be divided into two categories - focal neuropathy (one nerve/root involvement) vs multifocal neuropathy (subdivided even further into three sections - see below)

Can be focal mononeuropathy (affecting one nerve, e.g. carpal tunnel syndrome) or radiculopathy (affecting one nerve root e.g Disc herniation) or plexopathy (affecting plexus - e.g. Parsonage Turner)

Symptoms include numbness, paraesthesia, pain, and weakness that follows the distribution of the nerve or root

Usually due to a compressive or traumatic etiology

Sensory symptoms (paraesthesia then numbness, usually vibration/proprioception affected first) with motor symptoms later in onset, length-dependent pattern (glove and stocking), reflexes diminish in ascending pattern

Often have autonomic dysfunction (e.g. decreased sweating in the feet, orthostatic hypotension, erectile dysfunction)

DDx: Toxic/metabolic causes (Diabetes, EtOH), Genetics (CMT)

Presentation similar to multiple focal neuropathies

Often has a patchy pattern of sensory and motor symptoms, asymmetrical, nerves affected at different times, and subacute in onset

Unlike polyneuropathy, often have motor symptoms > sensory symptoms, asymmetrical reflexes, and occasionally cranial nerve involvement

DDx: Vasculitis (polyarteritis nodosa, eGPA, Sjogren's), Sarcoidosis

** Similar to polyneuropathy but more acute /subacute in onset with possible involvement of cranial nerves

DDx: GBS, CIDP

Nerve roots supplying brachial plexus are C5-T1

Common entrapment of the median nerve in the carpal tunnel of the wrist

Often affect women more than men

Can be idiopathic but other mechanisms include repetitive stress injury (wrist usage), edema, inflammation, or trauma to the wrist

Risk factors include obesity, pregnancy, aromatase inhibitors, acromegaly, and other medical conditions (e.g. diabetes, arthritis, hypothyroidism, infiltrative disorders, connective tissue disorders)

Sensory symptoms: Can have pain, numbness, or paraesthesia of the hands (often noted in textbooks that it involves the distal thumb and 2nd + 3rd digits but spares the palmar aspect of the thumb since palmar sensory branch does not pass through carpal tunnel - however, patients may not always state that)

Some patients may endorse tingling radiates up to the shoulder at night when symptoms are severe

Motor symptoms: Difficulties holding objects if severe, thumb abduction weakness - if severe, will appreciate thenar atrophy

Key symptom is whether patients may complain of pain and paraesthesia waking them up at night or in the morning and improved with shaking/wringing of the hands

Provocative maneuvers for CTS: Phalen and Tinel

EMG/NCS

Individualize treatment based on how severe nerve compression is as determined by electrodiagnostic findings

If mild-moderate - consider wrist splints at night and NSAID treatment for pain

If severe with significant motor deficits - carpal tunnel release surgery for those of whom nonsurgical therapies have failed

Entrapment of the ulnar nerve at the elbow is second most common compressive neuropathy (compression at wrist (Guyon’s canal) is less common)

Usually due to compression or stretch at the groove of the elbow or cubital tunnel

Other etiologies include trauma and masses at the site (e.g. tumors, ganglias)

Motor symptoms: Weak grip, dexterity, pinch strength and there may be atrophy of hypothenar and thenar (but thumb abduction will be spared)

Sensory symptoms: Pain, numbness and paraesthesia along the pinky and 4th digit of fingers

Provocative maneuvers: Tinel’s test on elbow

EMG/NCS

Individualize treatment based on how severe nerve compression is as determined by electrodiagnostic findings

If mild-moderate - consider wrist splints at night and NSAID treatment for pain, avoid leaning on elbow

If severe with significant motor deficits - could consider surgery for cubital tunnel release

Radial neuropathies are divided into three lesions: at the axilla, spiral groove, or below the elbow (posterior interosseous neuropathy)

Most common neuropathy is a lesion at the spiral groove due to compression or prolonged immobilization (e.g. Saturday night palsy)

Radial neuropathies at the axilla are due to prolonged compression (e.g. crutches)

Posterior interosseous neuropathy (PIN) may be due to entrapment

Wrist drop is often the presenting chief concern

Radial neuropathy at spiral groove: wrist drop and finger drop, weakness in supination, sensory loss in lateral dorsum of hand and fingers

Radial neuropathy at the axilla: Motor weakness as above WITH arm extension weakness and sensory loss extending to posterior forearm and arm

Posterior interosseous neuropathy demonstrates reduction in wrist extension with radial deviation and NO SENSORY LOSS

If symptom onset of wrist drop is acute and if there are UMN findings, consider stroke/lesion in hand-knob region of the brain

EMG/NCS

+/- CT Head/CTA to rule out stroke for acute wrist drop

Symptoms generally resolve in weeks to months

Consider NSAIDs for pain management and wrist splinting to assist with hand function

Nerve roots supplying lumbosacral plexus are L1 - S3

Commonly due to nerve root compression from disc herniation/spondylosis (e.g. degenerative arthritis)

Less common can be due to inflammation, neoplasm, vascular disease

Most common nerve roots affected are L5 and S1

Lower back pain that is radicular (sharp, burning, needle pain that radiates down leg) with sensory symptoms of numbness, tingling, burning, electric shock

Can also have associated weakness with walking up and down stairs

May have UMN signs

Common tests include straight leg raise (patient supine while examiner raises leg on the affected side with knee extended. Test is positive and suggestive of L5 or S1 nerve root compression if radicular symptoms are reproduced or worsened between 30-70 degrees)

MRI lumbar spine +/- GAD

NCS/EMG

Improvement over months - a year

Symptomatic treatment with neuropathic pain medications (e.g. pregabalin, gabapentin)

If no improvement or significant pain component - consider referral to pain specialist for epidural injections

If symptoms are significant with motor deficits - referral to surgery

Most common lower extremity mononeuropathy

Commonly due to compression against fibular head (leg crossing, trauma, kneeling, surgery, weight loss)

Motor symptoms include foot drop (due to tibialis anterior) and impairment in foot eversion

Sensory symptoms include numbness along lateral calf and dorsum of foot

NCS/EMG

Individualize treatment based on how severe nerve compression is as determined by electrodiagnostic findings

May require orthotics/foot brace to help provide support to the foot with dorsiflexion weakness

Physiotherapy/Occupational therapy to help retrain mobility

Affecting multiple nerves - can be classified into polyneuropathy, mononeuropathy multiplex, or generalized neuropathy

Any process affecting the peripheral nervous system that causes pain, paraesthesia, numbness, or weakness

Can affect the nerve roots to the peripheral nerves

What modality is affected? Patients may have numbness, paraesthesia, pain, sensory ataxia, weakness, and autonomic symptoms (e.g. impaired sweating) which may point to one diagnosis more than another

How long has the patient had symptoms? A slower, chronic progression suggests a metabolic, toxic, or genetic (CMT) disease vs an acute onset may be more inflammatory

Length dependent or non-length dependent? Length-dependent patterns are typically axonal and non-length independent are often demyelinating (HOWEVER, demyelination can be associated with axonal loss)

Demyelinating neuropathies are special because acquired demyelinating neuropathies are often treatable

CBC, ESR, CR, HbA1c, TSH, ANA, B12, SPEP

NCS/EMG

MRI of cauda equina MRI with contrast to assess for root enhancement

+/- LP to send for CSF if concerned for GBS or other immune/malignancy causes

** Gabapentin**(Starting dose: 300 mg BID/TID - can increase up to 1800 - 3600 mg max per day), Side effects: Drowsiness, ankle edema, weight gain, and caution in use with patients with renal failure

Pregabalin (Starting dose: 75 mg BID and increase up to 150 - 600 mg max daily) Side effects: Drowsiness

Amitriptyline (Starting dose: 10 mg QHS and increase up to 25 - 50 mg max daily) Side effects: Anticholinergic effects (Drowsiness, constipation, dizziness, dry mouth)

Duloxetine (Starting dose of 60 mg daily and increase to 60 mg BID) Side effects: Nausea, drowsiness, mental fogginess

** GBS/CIDP** - See GBS for further information

Importance of foot care, weight loss, management of metabolic and other conditions that is contributing to peripheral neuropathy

Counseling patients that for the majority of peripheral neuropathy (especially metabolic conditions like diabetes), symptoms may not improve or disappear completely even with treatment (success in treating neuropathic pain is 50% reduction in pain in 50% of patients)

Goal of treatment is to help patients live better and help maintain function & mobility (e.g. avoid falling, being able to walk)

Diffuse or focal inflammation of the parenchyma due to infection (more commonly viral over bacterial, fungal, etc), autoimmune, and other processes

HSV1 accounts for up to 20% of identified viral encephalitis and has a mortality of 70% if untreated

More than 50% of presumed viral encephalitis remains undiagnosed

Travel (e.g., Zika virus, rabies in Africa)

Season (e.g., rabies, WNV, Powssan, Zika, EBV in the summer)

Immunocompromised host

Animal/insect/tick bites

Hiking, camping, fresh water exposures

Lethargy

Altered mental status/level of consciousness

Headache

Seizures

Focal neurological deficits: aphasia, hemiparesis or flaccid paralysis, paraesthesias

Maculopapular pruritic rash (WNV) or Dermatoma rash (VZV)

Stat CT head to rule out acute intracranial abnormality (i.e., hemorrhage, stroke, mass lesion)

CBC

Lytes, extended lytes (Mg, Ca, PO4), creatinine

Blood glucose

Liver enzymes

Toxicology screen if indicated

Blood and urine cultures

HIV serology

LP: cell count and differential, protein, glucose, bacterial/viral (HSV, VZV, WNV, CMV)/fungal cultures and Gram stain (HSV PCR sensitivity 96%, specificity 99%), cytology/flow cytometry - commonly find leukocytosis (lymphocytic), normal glucose, normal/elevated protein

Ask the Micro Lab to hold extra CSF for additional testing

MRI brain with contrast when clinically stable - HSV preferentially causes T2/FLAIR hyperintensities the medial temporal lobes or hemorrhagic necrosis; VZV may be associated with unilateral infarcts and vasculopathy; WNV preferentially causes T2/FLAIR hyperintensities in the basal ganglia/thalamus and leptomeningeal/periventricular enhancement

Prudent to cover for bacterial meningitis until cultures are available: CTX 2g IV BID or Cefotaxime 2g IV q4-6h + Vancomycin 1-2g IV q12h + Dexamethasone 10mg IV q6h (for 4 days) administered before or with first dose of antibiotics

Consider adding Ampicillin 2g IV q4h if patient is less than 2, older than 50, immunosuppressed, or chronically ill for Listeria coverage

If AIDS and low CD4 (less than 100< consider gancyclovir for CMV (Check with Infectious Disease)

Acyclovir 10mg/kg IV q8h x14-21 days for encephalitis, x10-14 days for meningitis (HSV/VZV)

Supportive care for other viruses

IV hydration to avoid renal failure

Viral encephalitis, unlike meningitis, is life-threatening and results in permanent neurologic damage

Often self-limiting, but the host inflammatory response contributes to neurologic damage

Post-infectious acute demyelinating encephalomyelitis (ADEM)

Up to 50% have permanent neurologic sequelae

20% of patients with HSV encephalitis may go on to develop an autoimmune encephalitis, occurring 2-6 weeks after the viral encephalitis

Patients at risk should receive shingles vaccinations to reduce the risk of HSV/VZV encephalitis

Inflammation of meninges - most commonly caused by infection (but can also be caused by chemical irritation, neoplastic causes)

Common pathogens: Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Listeria monocytogenes (immunocompromised, EtOH misuse), Escheria coli

Fever

Headache

Neck stiffness - may be masked by analgesia or corticosteroids; Kernig and Brudzinski signs (limited sensitivity and specificity)

Altered mental status/level of consciousness

Cranial neuropathies (common with basiliar meningitis)

Seizures

Petechial rash (N. meningitidis)

Infants/children: nausea/vomiting, irritability, lethargy, anorexia, hypotonia, seizures (up to 34%), bulging anterior fontanelle, hydrocephalus

Immunocompromised hosts may not show classic signs!

Stat CT head to rule out acute intracranial abnormality (i.e., hemorrhage, stroke, mass lesion) - consider CT with contrast to increase sensitivity for meningeal and parenchymal involvement

CBC

Lytes, extended lytes (Mg, Ca, PO4), creatinine

Blood glucose

Liver enzymes

Toxicology screen if indicated

Blood and urine cultures - bacteremia is common in up to 70% (always do cultures before starting antibiotics)

LP: cell count and differential, protein, glucose, bacterial/viral/fungal cultures and Gram stain, Cryptococcal, VDRL- commonly find leukocytosis (80-90% neutrophils), low glucose, elevated protein in bacteria meningitis

MRI brain with contrast when clinically stable

Consult ID to guide longterm management of antimicrobial agents

Empiric treatment: CTX 2g IV BID or Cefotaxime 2g IV q4-6h + Vancomycin 1-2g IV q12h + Dexamethasone 10mg IV q6h (x 4 days) (administered before or with first dose of antibiotics + Acyclovir 10mg/kg IV q8h (as it is difficult to exclude viral encephalitis)

Consider adding Ampicillin 2g IV q4h if patient is less than 2, older than 50, immunosuppressed, or chronically ill for Listeria coverage

Steroids are associated with reduced risk of hearing loss in children, and reduced morbidity/mortality with S. pneumoniae

Antimicrobial therapy can be adjusted depending on cultures

There are increased risks of hearing loss, cognitive impairment, hemiparesis, epilepsy, vasospasm, ischemic and hemorrhagic stroke, and cerebral venous thrombosis

Patients at risk should receive Prevnar vaccinations to reduce the risk of bacterial meningitis due to S. pneumoniae

Chancre: painless, non-pruritic, genital or oral

Lymphadenopathy

Rash: diffuse, symmetric, macular including palms/soles, condyloma lata in intertriginous regions and mucous patches

Neurological features: meningitis/encephalitis, meningovascular syphilis causing stroke (10%), cranial nerve palsies (especially II, III, VI, VII), uveitis/iritis with decreased visual acuity, otosyphilis with hearing loss and tinnitus, behavioural/cognitive changes

Other organ involvement: hepatitis, nephropathy, adenopathy, fever, sore throat, headache, generalized painless lymphadenopathy

Cardiac involvement: aortitis, aortic aneurysms, saccular aneurysms

Gummatous lesions: affect long bones, upper respiratory tract

Neurological features: Symptoms of early neurosyphilis, PARESIS (see table below), and tabes dorsalis (33% - affects dorsal roots and dorsal columns of spinal cord)

Penicillin G 4 million units IV q4h x14 days.

Jarisch-Herxheimer reaction: result of release of endotoxin-like products within a few hours of the first dose of antibiotic; fever, chills, hypotension, hyperventilation, flushing.

If Penicillin allergy: Ceftriaxone 2g IV daily x14 days.

If severe Penicillin allergy: Doxycycline 200mg p.o. BID x28 days.

Pregnancy: screening (e.g. CIA) should be performed at the time pregnancy is confirmed.

Serologic and CSF titres of VDRL can be checked and fall with treatment of syphilis.

If untreated, syphilis can lead to tabes dorsalis or general paresis of the insane (frontotemporal dementia), which have declined in the antibiotic era.

Head Impulse: Testing vestibulo-ocular reflex (VOR) by having the patient maintain focus on the examiner’s nose while the examiner quickly turns the patient’s head sharply to left or right (caution: avoid if patient has a cervical spine injury or vessel dissections) - abnormal head impulse is characterized by a re-fixation saccade (eyes will look away and then back at examiner's nose) and is suggestive of peripheral vertigo - Video demonstration of abnormal head impulse test

Nystagmus: Assessing if patient has nystagmus in primary gaze or looking in different directions, what kind of nystagmus it is (horizontal, vertical, torsional, direction-changing) - any nystagmus that is NOT unilateral or dominantly horizontal is concerning for a central lesion - Video demonstration of vertical nystagmus

Skew deviation: Misalignment of eyes - alternate-cover test while patient fixates on a distant target and see whether there is vertical movement of the eyes; presence of skew deviation suggests central lesion - Video demonstration of skew deviation

Irritation of semicircular canals due to otoliths - usually induced by sudden change in head position (e.g. turning over in bed)

Most commonly affected semicircular canal is posterior (followed by anterior and horizontal)

Acute onset vertigo (“the room is spinning”, “I’m on a rocking boat”) provoked by head movements and can be associated with nausea/vomiting

Can have multiple episodes that are short-lasting (< 1 minute) but due to periods of feeling unwell in between, patients often report that their symptoms are constant

Diagnosis is made with a positive Dix-Hallpike test (DHT): Bring patient from upright to supine with head turned 45 degrees to one side and neck extended 20 degrees and look for vertigo and upbeating and torsional nystagmus. Repeat this with the head turned towards the opposite direction, if no nystagmus is elicited - Video demonstration of Dix-Hallpike

CAUTION: If downbeat nystagmus appears → consider central etiology

Monitor - At least 30-50% of cases will resolve spontaneously without any treatment

Epley maneuver - Video demonstration of Epley

Vestibular rehab especially if there is a heightened risk of falls

Pharmacotherapy generally not effective but helpful for symptomatic management/prophylaxis prior to repositioning maneuvers but not for resolution of symptoms (e.g. antihistamines (diphenhydramine), betahistine, ondansetron)

Recurrence of symptoms is common (up to 30%) so important to counsel patients that symptoms may return/reoccur

Patients can access www.vestibular.org for resources

The oculomotor (CN III) nuclear complex is in the midbrain at the level of the superior colliculus. It is ventral to the sylvian aqueduct, and dorsal to the medial longitudinal fasciculi

Innervates superior rectus, medial rectus, inferior rectus, and inferior oblique - Elevation, depression, and adduction of the eye

Innervates levator palpabrae - Eyelid elevation

Edinger-westphal nucleus is posterior to CN III - supplies parasympathetic fibers for pupil constriction

Complete palsy: Ptosis, large unreactive and dilated pupil, paralysis of eye adduction, elevation, and depression

**Partial palsy: **Variably affect pupil, eyelid, and involves extraocular muscles

**Pupil-sparing CN III : **Pupillary fibers run on the medial exterior part of the nerve while the oculomotor fibers are inside the nerve. Thus, most compressive lesions will affect the pupillary fibers (causing impaired pupillary constriction) compared to ischemic lesions that affect the innermost fibers and often spares the pupil

Aberrant Regeneration: Indicative of chronic CN III palsy, with regeneration of axons that results in unintended ocular findings with attempted movement - may be suggestive of tumor, aneurysm, or trauma (can be seen by elevation of eyelid with downward gaze or adduction of the eye)

Majority of patients >50 with isolated CN III palsy have microvascular cause

BUT MUST RULE OUT aneurysmal etiology

Trauma - most common cause in young people and can occur post-neurosurgical procedure

Compression due to malignancy, sellar masses (e.g. pituitary apoplexy, pituitary adenoma)

GCA - may present as cranial neuropathy, do ESR/CRP

Neuromuscular (Myasthenia Gravis, Miller-Fisher)

Congenital

Testing for extraocular movements, pupils, and convergence

Misalignment can be comitant (deviation similar to all position of gazes), or incomitant (deviation differs depending on gaze position).- childhood strabismus is comitant

Blood pressure, glucose, HbA1c, ESR, CRP, platelets

CT/CTA (for all patients to rule out aneurysms)

If pupil is normal: Observe, no MRI in the beginning

If pupil is abnormal: URGENT MRI Brain with Orbits with GAD to rule out aneurysm or compressive lesion

Aneurysm - Should be assessed by neurosurgery for consideration of endovascular coiling or surgical clipping (63% of patients with PCOM aneurysms operated on within 2 weeks of onset made complete recovery, compared to 30% 2-4 weeks, and 17% >1 month)

Ischemic/Microvascular cause - Usually conservative treatment including patching, prisms. Ocular surgery may be helpful to restore primary position alignment if CN III palsy persists

Microvascular palsy: A vast majority of patients with microvascular third nerve palsy have complete recovery. Complete recovery is less common in post-neurosurgery (36%), aneurysmal (33%) and neoplastic (19%) compressive, and traumatic (22%).

Aneurysmal palsy: with successful aneurysm treatment a majority of patients have complete or partial recovery, which can take up to a year

The trochlear nerve (CN IV nerve) is caudal to CN III, dorsal to MLF at the level of the inferior colliculus

The only nerve that runs dorsally from the brainstem

Innervates the superior oblique muscle - eye depression

CN IV Palsy causes hypertropia and excyclotorsion of the affected eye and patients may complain of vertical or horizontal diplopia

Hypotropia seen in the normal eye when the affected eye is fixating

Hypertropia is seen in the affected eye when the unaffected eye is fixating

Presence of excyclotropia

Patients may develop head tilt to compensate for hypertropia and cyclotropia (usually away from affected side)

Step 1: Identify hypertropic eye (the eye that looks higher up)

Step 2: Identify gaze direction which worsens hypertropia. Adduction of hypertropic eye should increase hypertropia if there is a CN IV palsy.

Step 3: Identify direction of head tilt that increases hypertropia

Blood pressure, glucose, HbA1c, CBC

If > 50 - ESR/CRP

If other CN involvement and not congenital/traumatic - Consider MRI brain and orbits with contrast

Non-pharmacological: Prisms and occasionally occluding one eye for symptomatic relief

Strabismus surgery: Indicated if lack of spontaneous improvement in 6 months

Spontaneous improvement in 44% of patients from traumatic CN IV palsy (few days - months)

Majority of patients with microvascular CN IV palsy improves by 4-6 months

If no improvement after 6 months, consider corrective surgery

The abducens (CN VI) nucleus is located in the dorsal lower pons, separated from the floor of the 4th ventricle by the facial nerve fascicle (facial colliculus)

Innervates the lateral rectus - Abducts the eye

Coordinates horizontal eye movements (Looking to the right - right eye ABDUCTS and left eye ADDUCTS) - CN VI motor neurons are mixed with internuclear neurons through the medial longitudinal fasciculus (MLF), ascending through the pons and midbrain, terminating in the oculomotor (CN III) nucleus - Internuclear Opthalmoplegia (INO) can be a result if MLF is damaged

CN VI Palsy causes impaired abduction of the eye, horizontal diplopia and eso-deviation of the eye that is worse upon attempted abduction of the affected eye

Other causes can include trauma, demyelination, inflammatory (neurosarcoid), or idiopathic

If papilledema present - urgent MRI with contrast

Bloodwork: Blood pressure, glucose, HbA1c, ESR, CRP

Patients with isolated CN VI palsy that are >50 years of age, with microvascular risk factors (diabetes, hypertension) may not require neuroimaging

If patients do not improve in 3-4 months, consider MRI Brain with Orbits with GAD

First 6 months: Patching and botulinium toxin injections may improve diplopia. Many CN VI palsies resolve within several months, and symptomatic management is warranted

>6 months: If CN VI palsy does not improve by 6 months, surgery is indicated

Microvascular: 62% of patients recover over 6 months

Traumatic: Traumatic CN VI palsies recovery in almost all cases if partial, and in 1/3 of cases if complete

Idiopathic: A majority of patients with undetermined cause recover CN VI function

Typically in people in their 30’s, 77% female

Most commonly seen in demyelinating diseases - e.g. multiple sclerosis, NMOSD/MOG

Must have RAPD (unless bilateral involvement)

Acute or subacute eye pain (or pain with eye movements)

Vision loss or blurry vision - typically peaks in 1-2 weeks

Dyschromatopsia and contrast sensitivity loss - abnormal color vision

Absent or mild disc edema

Age >50

Painless vision loss

Retinal abnormalities

Severe vision loss without early recovery

History of cancer

Worsening visual function after reducing or stopping steroids or immunosuppressants

Patients should have a visual acuity measurement, retinal exam, clinical and formal visual field testing including red desaturation, pupil examination looking for RAPD.

Bloodwork: CBC, ESR/CRP, VDRL, ACE, ANA

NMO/MOG serum antibodies

MRI Brain and Orbits with GAD

Consider additional work-up including a lumbar puncture (CSF: Cytology, protein, glucose, oligoclonal bands)

ONTT study found IV methylprednisolone accelerates visual recovery but no benefit in visual acuity at 2 years

Dose and Duration: Methylprednisolone 1000 mg IV or Prednisone 1250 mg PO for 5 days

For atypical cases that do not improve after initial treatment: consider prednisone 1 mg/kg pulse

Adverse effects: Sleep disturbance, mood changes, weight gain, GI irritation, avascular necrosis

Patient should also be on Vitamin D and Calcium

Idiopathic, vascular insult due to transient hypoperfusion of the optic nerve head

Does not involve embolic infarction

Common in middle aged individuals; more common in Caucasians due to smaller cup-to-disc ratios

Vascular risk factors: HTN, dyslipidemia, type II diabetes, ischemic heart disease, OSA, tobacco use, nocturnal hypotension, coagulopathies

PDE5 inhibitors (e.g., Viagra, Tadalafil)

Renal failure on dialysis

Optic disc drusen

Acute, painless, monocular vision loss

Ocular pain (present in 10%)

Disc-at-risk (unaffected optic disc is at risk of optic disc edema) - essential for the diagnosis

Fundoscopy: disc edema (may persist for 6-11 weeks), pallor, may see peripapillary wrinkles caused by displacement of the retina by the disc edema

Diagnosis is made when the disc edema resolves within the appropriate time course

CBC

ESR/CRP

Monitor BP and avoid hypoperfusion which can exacerbate

Referral to Ophthalmology/Neuro-ophthalmology

None - may have mild to no improvement in vision

Treatment of vascular risk factors in an attempt to preserve visual function in the other eye

Management of vascular risk factors (compliance with medications, CPAP if OSA present) is important to protect the unaffected eye

15% of patients risk development of NAION in the other eye at 5 years

Inflammatory condition of the optic disc vasculature resulting in disc edema

Infections: VDRL, TB, Lyme, WNV, Toxoplasmosis, Bartonella (most common; “cat scratch disease”)

Parainfectious: MMR, HSV/VZV, EBV, CMV, coxsackie B

Inflammatory: sarcoidosis, IBD, polyarteritis nodosa, tubulointerstitial nephritis and uveitis

Acute, painless, monocular vision loss

RAPD if unilateral

Fundoscopy: disc edema, macular edema, macular exudates (“macular star”; late finding), subretinal fluid, loss of architecture under the fovea

Referral to Ophthalmology/Neuro-ophthalmology

CBC

ESR/CRP

Infectious work-up: VDRL, Bartonella serology, Toxoplasmosis serology, and additional serology if indicated depending on clinical history

CXR

MRI brain with orbits (typically normal)

None - most patients have gradual resolution without treatment

Antimicrobials depending on etiology (i.e., Azithromycin for cat scratch disease, Penicillin G for VDRL)

Vascular insult due to transient hypoperfusion of the optic nerve head typically due to vasculitic or embolic cause

CRAO is less common than BRAO

Common in middle aged individuals

Vascular risk factors: carotid artery atherosclerosis, HTN, dyslipidemia, type II diabetes, ischemic heart disease, OSA, tobacco use, nocturnal hypotension, coagulopathies

Cardioembolic risk factors (more common in patients <40-years-old): infective endocarditis, IVDU, rheumatic heart disease, cardiac tumor

Other vascular disease: fibromuscular dysplasia, carotid artery dissection, Moyamoya disease, Fabry disease

Inflammatory disease: GCA, vasculitis, Susac syndrome, sarcoidosis

Acute, painless, monocular vision loss

CRAO typically has more severe vision loss, rarely can count fingers but can identify hand motions

BRAO has less severe vision loss usually restricted to part of the visual field

Associated symptoms depending on etiology: headache, jaw claudication, unilateral sensory-motor loss, neck pain

Fundoscopy: ischemic retinal whitening, cherry red spot, retinal emboli (up to 40% of patients with CRAO)

Fluorescein angiography: slowed or absent filling of the central retinal artery with sparing of the choroid in the acute phase; if the choroid is also affected, consider GCA

Can be seen as a Code Stroke - CONSULT OPHTHALMOLOGY STAT IF NOT ALREADY INVOLVED

CBC

ESR/CRP

Stroke work-up: HbA1c, Lipids, Echocardiogram, Holter monitor 48hrs, Referral to TIA/Rapid Stroke Clinic or ED (if patient seen in peripheral site/clinic)

Ophthalmology/Neuro-ophthalmology consultation/referral ASAP for fundoscopy and visual field testing

MRI/MRA brain and neck vasculature (or CT/CTA to obtain images quicker)

Antiplatelet agent if no contraindications (i.e., already fully anticoagulated for another reason)

Treatment of vascular risk factors in an attempt to prevent recurrence and preserve visual function

Requires Ophthalmology to follow after the initial presentation to monitor for neovascular complications

Management of vascular risk factors (compliance with medications, CPAP if OSA present) is important to protect visual function

BRAO has a much better prognosis than CRAO, with up to 80% of patients recovering visual function; CRAO has a poor prognosis for spontaneous visual recovery

For those > 50, must consider Giant Cell Arteritis (GCA) in the differential diagnosis

Most common in females and Caucasians of Scandanavian descent

GCA can be associated with Polymyalgia Rheumatica (proximal muscle pain and stiffness that is worse in morning)

Giant Cell Arteritis

ANCA-associated vasculitis

Infection

Neoplastic

Sudden, profound visual loss that can become bilateral in hours to days

Diplopia - Transient or persistent

Majority of patients have systemic symptoms: (Headache, scalp tenderness, jaw claudication, muscle aches/stiffness in the morning, malaise, fever)

Superficial temporal artery pulse: Cord-like feel with reduced pulses

Fundoscopy: optic disc may appear swollen, pale “chalky white” optic nerve head with nerve fiber layer hemorrhage and cotton wool spots

Age at onset ≥ 50 years

New headache

Temporal artery abnormality: tenderness or reduced pulsation

ESR ≥ 50 mm/hour

Abnormal artery biopsy demonstrating vasculitis, with mononuclear cell or granulomatous inflammation

CBC

MUST DO ESR AND CRP

Referral to Ophthalmology/Neuro-ophthalmology and Rheumatology

MRI brain and orbits with GAD

If high pre-test probability of GCA: Consider temporal artery biopsy

Confirmed GCA - Steroid pulse (do not delay for temporal artery biopsy because it can lead to permanent vision loss)

Methylprednisolone 1g IV pulse for 3-5 days with subsequent taper of with PO prednisone; in some cases of GCA, can treat with Prednisone 1 mg/kg dosing

Adverse effects: Sleep disturbance, mood changes, weight gain, GI irritation, avascular necrosis

Patients should also be on Vitamin D and Calcium

Vision loss at time of presentation may be irreversible but steroids can prevent further progression

Airway - Threatened airway, stridor, excessive secretions (with vital sign changes)

Breathing - Respiratory rate > 30 or < 8, Oxygen saturations < 90% on 6L/min, or respiratory distress

Circulation - sBP < 90 mmHg or > 200 mmHg (if patient symptomatic) or changes of sBP > 60 mmHg

Disability - Altered Mental Status

You should ALWAYS call CCRT if you have concerns about a patient

Always call your staff if a patient becomes sick (e.g. status epilepticus, blown pupil)

or if you need to administer emergency medications

Investigations: STAT CBC, lytes, extended

lytes, Cr, blood glucose, lactate, troponin,

VBG

+/- STAT blood cultures x 2 and urine

cultures

+/- STAT CXR and/or ECG

+/- STAT Imaging based on context

+ Check for good IV access

Call CCRT and staff if concerned

New stroke (re-infarction, new territory infarct,

hemorrhagic conversion)

Medications/drugs (check medication history for opioids, benzos)

Metabolic derangements (lytes, extended lytes, glucose, lactate)

Infection

Structural causes (hematoma expansion, edema, bleed)

Post-ictal

Hypertonic saline: 150-300 cc bolus over 15 - 30 min (Useful if patient needs volume expansion, Avoid if Na > 160)

20% mannitol (1 – 1.5 g/kg BOLUS over 10-15 mins) * Rough calculation: patient wt in kg x 5 = amount of mannitol in mL to infuse (Useful if patient needs diuresis, Avoid mannitol in hypotension, poor renal function, or serum osmolality > 320 + Ensure patient has a foley in situ)

**Ischemic stroke not eligible for tPA/EVT ** – Permissive hypertension if sBP < 220 mmHg (If sBP > 220 mmHg or dBP > 120 mmHg, then reduce blood pressure by 15-25% over the first 24 hours

Ischemic stroke pre-tPA – BP < 180/105 mmHg (For stroke at UHN, otherwise 185/110)

**Ischemic stroke post-tPA ** – BP < 180/105 mmHg

Ischemic stroke post-EVT – sBP < 180/105 mmHg (Please check with stroke and INR staff for targets

Intracerebral hemorrhage – sBP < 140 -160 mmHg (Aim to reach sBP < 140 mmHg in 1-2 hours especially if spot sign positive, Factors that favor sBP <140 mmHg: LSN < 6 hours, initial sBP < 220 mmHg, anticoagulants, no renal dysfunction, spot sign positive on CTA)

Alert: normal state of arousal

Obtunded: loss of responsiveness to some stimuli but still able to communicate

Stupor: only arousable to vigorous, repetitive stimuli with inability to communicate

Coma: unarousable, unresponsive individual with reflexes present

Brain death: comatose patient without intact reflexes

Uncal: inner portion of the temporal lobe is pushed down causing lateral deviation and pressure onto the midbrain; commonly compresses CN3 and motor tracts resulting in a unilateral dilated pupil and ipsilateral hemiparesis (Kernohan’s phenomenon)

Central: due to lesions higher up in the brain causing downward pressure and deviation through a notch in the tentorium; causes small, equal pupils (early) to mid-position fixed pupils (late), bilateral Babinski response, and decorticate posturing

Subfalcine: subfalcine compression under the falx; often presenting with contralateral leg weakness and frontal behavioural changes, or asymptomatic in the majority

External: common in cases of malignant MCA syndrome/edema

Upward: due to infratentorial ischemic/hemorrhagic events or mass lesions with edema resulting in cerebellar (i.e., nystagmus, ataxia) and brainstem signs (i.e., respiratory changes, obtunded state)

Tonsillar: compression of the medulla due to cerebellar tonsil herniation through the foramen magnum; often presenting with medullary signs (i.e., Cheyne-Stokes respiration to respiratory arrest) and Cushing’s reflex (widened pulse pressure, bradycardia, hypertension)

Stat CT head to rule out intracranial cause (i.e., stroke, hemorrhage, mass lesion)

CBC

Lytes, extended lytes (Mg, Ca, PO4), creatinine

Blood glucose

Liver enzymes

Toxicology screen if indicated

Blood, urine, CSF cultures if indicated

LP with cell count and differential, protein, glucose, bacterial/viral/fungal cultures, cytology/flow cytometry, autoimmune/paraneoplastic panels as indicated

EEG

MRI brain with contrast depending on the clinical scenario and when the patient is clinically stable

ABCs (airway, breathing, circulation) and consultation of ICU if the patient may require intubation and/or pressor support

Correction of metabolic derangements

Reduction of elevated ICP - raise head of the bed to 30 degrees, hyperventilation (if possible) to PCO2 35-40 mmHg, avoid hypotension, hypertonic saline 150-300 cc over 15-30 min (avoid in patients with serum Na+ >160) or mannitol 1-1.5 g/kg bolus q4-6h PRN (avoid in patients with disrupted blood brain barrier or renal dysfunction)

CIWA protocol for suspected alcohol withdrawal

Consultation of Neurosurgery or other specialties if indicated

Consultation of Poison Control depending on investigations and clinical scenario

For more information in managing specific acute level 2/ICU scenarios, please see the Level 2 Guide

Components of the brain death exam cannot be completed because of the underlying medical condition

Uncertainty about the reliability of parts of the neurologic examination

Apnea test cannot be performed

CTA Head & CT Perfusion

Transcranial Dopplers

Radionuclide brain perfusion scan

Unresponsive to voice or touch

Changes in breathing, increased apnea, Cheyne-stokes breathing pattern

Mottling in the skin and cooler extremities

Anuria

Decreased/no oral intake

Discontinue vitals, bloodwork, telemetry , POCTs

Monitor patient q1h for comfort (e.g. pain, dyspnea)

Insert subcutaneous butterfly

Oxygen via Nasal Prongs as needed, titrate to patient comfort NOT SpO2

Diet as tolerated

Artificial saliva Q1H PRN

Discontinue all medications except the following: *

For pain: Hydromorphone 0.25 - 0.5 mg SC q1h PRN for pain (can increase up to 0.5 - 1 mg, also used for breathlessness)

For agitation/delirium: Haldol 1 mg SC q4h PRN for agitation or Methotrimeprazine 6.5 - 12.5 mg SC q4h PRN for agitation (very sedating, only use in cases where comfort is the focus)

For breathlessness: Lorazapam 0.5 mg SC q4h PRN for breathlessness or anxiety

For secretion management: Glycopyrrolate or Scopolamine 0.2 - 0.4 mg SC q4h PRN for secretions

For dry mouth: Artificial saliva spray or gel q2h for dry mouth

Syndrome of subacute onset of neurological and/or psychiatric dysfunction affecting one or more brain systems and associated with an immune-response compromising function

Peak incidence <40 years

Female predominance

60-75% of patients have a preceding infectious prodrome

Malignancy is common in up to 50% of females between 20-50 years old

Several antibodies have been identified with variable clinical presentations: anti-NMDA, anti-LGI1, anti-DPPX, anti-Caspr2, anti-GABA, anti-AMPA, anti-IgLON5, thyroid antibodies among others

Altered level of consciousness/mental status

Psychosis - delusions, hallucinations

Seizures

Agitation, aggression

Catatonia

Disinhibition

Short-term memory impairment

Dysautonomia

Abnormal movements - dystonia, myoclonus, chorea, rigidity

Language dysfunction - mutism, echolalia, aphasia

Sleeping disorders - insomnia at onset, hypersomnia later

Stat CT head to rule out acute intracranial abnormality (i.e., hemorrhage, stroke, mass lesion)

CBC

Lytes, extended lytes (Mg, Ca, PO4), creatinine

Blood glucose

Liver enzymes

TSH, free T3 and T4, and thyroid antibodies

MRI brain with contrast: may be normal or show T2/FLAIR hyperintensities or contrast uptake depending on associated antibody

LP: may see pleocytosis, normal glucose, normal to high protein

Serum and CSF autoimmune/paraneoplastic panels (see Requisition Forms section)

Autoimmune blood work: ESR, CRP, ANA, anti-dsDNA, ENA, RF, ANCA, C3/C4

HIV, VDRL [Remember to send CSF Oligoclonal bands with Serum SPEP test]

EEG if there is concern of altered mental status and/or seizures

CT chest/abdo/pelvis to assess for malignancy

Transvaginal U/S in female, testicular U/S in males to assess for malignancy

In preparation for high dose steroids: Hepatitis B and C serology, TBST, strongyloides serology

Pulse steroids x5 days with maintenance Prednisone 1 mg/kg thereafter

IVIG 2 g/kg over 2-4 days (4 days if patient has cardiac comorbidities)

PLEX - can vary from 5-7 sessions

Second-line therapy: Rituximab, Cyclophosphamide

Management of comorbid symptoms (i.e., seizures, pain, psychosis)

Prophylaxis while on high dose steroids: calcium, vitamin D, PPI, PJP prophylaxis

Granulomatous, multisystem disease (commonly in the lungs, lymph nodes, but can also affect other organs including the brain)

Pathophysiology not well understood

Genetic predisposition - 5-fold higher risk with first- or second-degree relatives

High risk occupations - agriculture, healthcare, animal laboratories

Smoking

Panhypopituitarism

Pulmonary involvement - dyspnea, persistent dry cough

Painless lymphadenopathy

Cardiac involvement - cardiomyopathy, chest pain, palpitations/arrhythmia, syncope

Neurological involvement - cranial nerve palsies, radiculopathy, confusion, myelopathy

Orbital involvement - dry eyes, blurry vision, visual loss, uveitis

Rashes, erythema nodosum

Arthralgias

Hepatosplenomegaly

Amenorrhea

Elevated serum ACE level (not specific)

Elevated IgG subclasses (not specific)

Hypercalcemia

MRI brain with contrast: may have meningeal or parenchymal enhancement, involvement of cranial nerves or spinal nerve roots, spinal cord or cauda equina edema

LP: may have elevated opening pressure, may have pleocytosis, normal to low glucose, normal to high protein, elevated ACE and IgG index and increased CD4/CD8 ratio (on cytology)

CXR: hilar lymphadenopathy

Cardiac investigations: TTE, ECG, cardiac MRI

Biopsy: non-caseating granuloma

EMG/NCS if component of neuropathy

In preparation for high dose steroids: Hepatitis B and C serology, TBST, strongyloides serology

Solumedrol 1g IV x3-5 days followed by maintenance Prednisone 1 mg/kg daily with taper

Steroid sparing agents: MTX, Azathioprine, Cyclophosphamide

Prophylaxis while on high dose steroids: calcium, vitamin D, PPI, PJP prophylaxis

3 main classes of immune checkpoint inhibitors: anti-CTLA4, anti-PD1, and anti-PDL1

Checkpoint inhibitors were initially developed for treatment of melanoma but now are used as targeted therapies against T-cell activation in many types of malignancy

Exact pathophysiology in relation to the neurological complications is unknown

Neurological involvement is rare (1-3%) but has the highest fatality alongside cardiac involvement

Symptom onset within 1-4 weeks of therapy

Myasthenia gravis - fatigable proximal muscle weakness, bulbar weakness (i.e., dysphagia, diplopia, respiratory difficulties) occurring more commonly in men of older ages unlike typical bimodal distribution in idiopathic MG

Myositis - second most common complication

Polyneuropathy

Mononeuritis multiplex

Cranial nerve palsies - most commonly VI and VII

Encephalitis

Aseptic meningitis

CK - often normal or elevated depending on presence of myopathy and/or myocarditis

Serum mitogen myositis panel

EMG/NCS - results depend on clinical presentation but may identify sensorimotor polyneuropathy, active myopathy

If there are features of myasthenia gravis: serum anti-AChR antibody and anti-MuSK antibody, single fiber EMG identifying increased jitter response

MRI brain and/or full spine depending on clinical presentation

Consider LP and assess for autoimmune/paraneoplastic antibodies depending on patient profile and clinical presentation

If there is cardiac involvement: elevated troponin, ECG, TTE, cardiac MRI

Discontinue the offending agent and supportive care

Pulse steroids Solumedrol 1g IV daily x5 days followed by maintenance steroids of Prednisone 1 mg/kg dosing with slow taper

IVIG 2 g/kg over 2 days (4 days if cardiac comorbidities) or PLEX in patients with incomplete benefit from steroids or those with severe bulbar weakness and/or respiratory difficulties

If myasthenia gravis: trial of Mestinon 30mg p.o. TID

Some of the side-effects from checkpoint inhibitors are not completely reversible even with discontinuation of the inhibitor and treatment as outlined above

There is mortality benefit with early initiation of pulse steroids in those with myocardial involvement

Neurological symptoms due to a “functional” disruption of brain networks than a recognized “structural” disorder of the nervous system

Etiology is incompletely understood, multiple aspects of biopsychosocial model involved in the disease (e.g. genetics, childhood adverse events, acute stressors such as trauma)

A diagnosis made by positive findings from physical examination and semiology

Patients do not necessarily need a psychosocial stressor or psychological trigger in making the diagnosis

Based on DMS-5 Criteria for Conversion Disorder (Functional Neurological Disorder) - patient must have altered sensory/motor symptom that is incompatible with a recognized medical/neurological condition and causes clinically significant distress or impairment in areas of functioning

To learn more about FND, visit this module created by Dr. Jane Liao and Dr. Sarah Lidstone - Functional Neurological Disorders: Let's talk about it

For a full detailed list of possible clinical features: consider reading Diagnosis and Management of Functional neurological disorder by Aybek and Perez 2022

Functional neurological disorder is a diagnosis made on the basis of positive signs as outlined above, however can consider investigations including bloodwork, imaging, +/- EEG/EMG if there is uncertainty about the diagnosis

Communicating the diagnosis to the patient- critical for the patient's understanding and demonstrating positive symptoms can be helpful. Communicating the diagnosis does not mean telling the patient what diseases they don’t have or that their symptoms are “medically unexplained”

Important to validate patients’ experiences and provide education regarding the disease

Multidisciplinary approach to treatment depending on presentation e.g. some patients with motor-related FND can benefit from FND-informed physiotherapy or patients with PNES can benefit from Cognitive-behavioral therapy

Patients with co-morbid anxiety and depression (which can worsen FND) can benefit from psychotherapy and antidepressants

One aspect that can benefit patients is to provide them with resources to learn more about FND and speak to other people living with it - these include www.fndhope.org or www.neurosymptoms.org