Transverse myelitis

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Transverse Myelitis

Definition

Transverse myelitis (TM) is an acute or subacute inflammatory-demyelinating lesion of the spinal cord, presumed to be autoimmune in origin, that interrupts ascending and descending pathways at a given cord level. The term "transverse" implies involvement of the full cross-sectional area - though in practice this is often incomplete, particularly in MS-associated cases. It is rare, affecting approximately 1 in 100,000 people, and is usually monophasic. - Goldman-Cecil Medicine, p. 3995

Etiology and Associations

TM is heterogeneous - it can be:

Category	Examples
Idiopathic	No cause found in ~30% of cases
Post-infectious	Follows viral illness in ~30%; termed postinfectious myelitis
Demyelinating disease	Multiple sclerosis (MS), Neuromyelitis Optica Spectrum Disorder (NMOSD)
Autoimmune / CTD	SLE, Sjögren syndrome, antiphospholipid antibody syndrome, vasculitis
Infectious	Direct viral/bacterial cord invasion
Vascular	Dural AV fistula, spinal cord infarction
Post-vaccination	Rare, described after various vaccines

Key antibody associations: anti-AQP4 (aquaporin-4) antibodies are strongly associated with NMOSD-related TM, and anti-MOG (myelin oligodendrocyte glycoprotein) antibodies are seen in MOG antibody disorder. - Rosen's Emergency Medicine, p. 1508 | Goldman-Cecil, p. 3995

Pathophysiology

The cord lesion involves inflammatory cell infiltration and demyelination, disrupting both ascending sensory pathways (spinothalamic tract, posterior columns) and descending motor pathways (corticospinal tract), as well as autonomic fibers.
When the lesion spans 3 or more vertebral body segments rostrocaudally, it is called Longitudinally Extensive Transverse Myelitis (LETM) - a hallmark of NMOSD.
The thoracic cord is affected in 60-70% of cases; cervical cord involvement is less common.
Progression is rapid: 66% reach maximal deficit within 24 hours, though progression can occur over days to weeks. - Rosen's Emergency Medicine, p. 1508

Clinical Features

Classic triad:

Motor - bilateral weakness progressing to paraparesis/paraplegia; hypertonia, hyperreflexia, clonus, and Babinski signs once spinal shock resolves
Sensory - distinct sensory level on the trunk; ascending paresthesias; loss of deep sensation (vibration, proprioception) in the feet
Autonomic - bladder/bowel dysfunction (urinary and fecal retention or incontinence); sexual dysfunction; in cervical/high thoracic lesions: hyper- or hypotension, tachy- or bradycardia

Additional features:

Back or neck pain is common at onset
Low-grade fever may be present
In MS-associated TM, deficits are often asymmetrical and incomplete (partial TM) - full paraplegia and complete sensory loss are unusual
In NMOSD-associated TM, the picture is typically fulminant and complete
Adams and Victor's Neurology, p. 925 | Rosen's Emergency Medicine, p. 1508 | Tintinalli's Emergency Medicine, p. 1929

Diagnosis

MRI (Investigation of Choice)

MRI with gadolinium enhancement is the gold standard. Findings include:

T2 hyperintensity in the spinal cord at the level of involvement
Cord swelling/expansion in acute phase
Gadolinium enhancement (patchy or ring)
LETM (>3 vertebral segments) favors NMOSD over MS

In MS, the cord lesion tends to be short (< 2 vertebral segments), asymmetric, and peripheral.

The MRI image below shows MS findings including periventricular white matter plaques and cervical cord lesions for comparison:

MRI in multiple sclerosis: periventricular plaques, optic neuritis, Dawson fingers, and cervical spinal cord demyelinating lesions

Adams and Victor's Neurology, Fig. 35-1: MRI in MS showing periventricular T2 plaques (top left), acute right optic neuritis with gadolinium enhancement (top right, arrow), Dawson fingers (bottom left), and cervical cord lesions at C3 (acute, with swelling) and T1 (chronic, with atrophy) (bottom right).

CSF

Normal in 40% of cases
Remaining 60%: mild lymphocytosis and elevated protein
Oligoclonal bands favor MS
Note: CSF findings may lag the clinical presentation

Serology

Anti-AQP4-IgG (NMO-IgG): specific for NMOSD
Anti-MOG-IgG: MOG antibody disorder
ANA, anti-dsDNA, antiphospholipid antibodies: for CTD work-up
Infectious serologies as clinically indicated
Rosen's Emergency Medicine, p. 1508 | Bradley and Daroff's Neurology, p. 472

Differential Diagnosis

Condition	Key distinguishing features
Spinal epidural abscess	Fever + severe back pain + focal tenderness; prior procedure/IVDU
Spinal cord compression	Disk, tumor, hematoma; gradual onset; MRI shows extrinsic compression
MS	Short, asymmetric, incomplete cord lesion; brain MRI shows additional plaques
NMOSD	LETM, bilateral optic neuritis, AQP4-Ab positive
Spinal cord infarction	Sudden onset, vascular risk factors; anterior cord syndrome pattern
Spinal epidural hematoma	Anticoagulation history; acute-onset back pain
Vitamin B12 deficiency	Subacute combined degeneration; posterior column + corticospinal tracts
Dural AV fistula	Progressive myelopathy; T2 changes + flow voids on MRI

Rosen's Emergency Medicine, p. 1508 | Bradley and Daroff's Neurology, p. 472

Treatment

First-line: IV Corticosteroids

Methylprednisolone 1000 mg IV daily for 3-5 days is the standard approach
Note: Evidence base is limited; most benefit is inferred from MS trials

Steroid-refractory or severe cases:

Plasma exchange (PLEX) - particularly effective in NMOSD and aggressive post-infectious TM
IVIG - an alternative, especially in post-infectious cases
Cyclophosphamide - for refractory cases

NMOSD-specific preventive therapy (to reduce relapses):

Eculizumab (terminal complement inhibitor, 900 mg IV weekly x4, then 1200 mg q2 weeks)
Satralizumab (anti-IL-6R, 120 mg SC at 0, 2, 4 weeks, then q4 weeks)
Tocilizumab (anti-IL-6R, 8 mg/kg IV q4 weeks)
Older options: Rituximab (1000 mg IV x2, 2 weeks apart, q6 months) or Azathioprine (3 mg/kg/day)

All patients require neurologic consultation and hospitalization.

Goldman-Cecil Medicine, p. 3995

Prognosis

Outcome varies widely from complete recovery to permanent paralysis
Recovery typically begins within 1-3 months; maximal improvement by 3-6 months
Outcomes (Goldman-Cecil / Rosen's):
- ~30% "good" recovery
- ~25% "fair" recovery
- ~30% "poor" outcome (remain significantly disabled)
- ~15% mortality at 5 years
Prognosis is worse than in MS - significant recovery in fewer than 50%
Risk of developing MS: fewer than half develop evidence of additional demyelinating disease within 5 years; cumulative risk is similar after TM vs. optic neuritis (Beck et al., 2002)
Adams and Victor's Neurology, p. 926 | Rosen's Emergency Medicine, p. 1508 | Goldman-Cecil Medicine, p. 3995

Key Distinction: Partial vs. Complete TM

Feature	Partial (incomplete) TM	Complete TM
Motor	Asymmetric weakness	Bilateral paraplegia
Sensory	Incomplete level	Complete sensory level
Association	More often MS	More often NMOSD or idiopathic
Lesion length	Short (<2 segments)	LETM (≥3 segments)
Prognosis	Better	Worse

Summary

Transverse myelitis presents with the triad of motor weakness, sensory level, and autonomic dysfunction. The primary workup is MRI with gadolinium to exclude compressive lesions and characterize cord signal change. Serology for AQP4 and MOG antibodies is essential to identify NMOSD/MOGAD. Treatment is IV methylprednisolone, with PLEX or IVIG for refractory cases. Long-term immunosuppression is required in NMOSD to prevent relapses.

Bells palsy

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Bell's Palsy

Definition

Bell's palsy is an acute, idiopathic, unilateral lower motor neuron (LMN) facial paralysis - a diagnosis of exclusion. It is the most common cause of facial paralysis, affecting ~23-25 per 100,000 people annually, which translates to approximately 1 in 60 persons over a lifetime. - Harrison's, p. 3597 | Adams and Victor's, p. 1371

Anatomy Recap: Why LMN Matters

The facial nerve (CN VII) has a long intratemporal course through the facial canal. Key landmarks:

Greater petrosal nerve (preganglionic parasympathetics to lacrimal gland) branches off at the geniculate ganglion
Nerve to stapedius - controls the stapedius muscle (sound dampening)
Chorda tympani - taste to anterior 2/3 of tongue + parasympathetics to submandibular/sublingual glands

The level of the lesion in Bell's palsy is proximal to the chorda tympani in most cases, explaining taste loss and hyperacusis.

UMN vs. LMN facial palsy:

UMN (e.g., stroke): lower face only affected; forehead spared (bilateral cortical representation of frontalis)
LMN (Bell's palsy): entire ipsilateral face involved, including forehead and orbicularis oculi
Goldman-Cecil Medicine, p. 2962

Etiology and Pathophysiology

The cause is reactivation of latent Herpes Simplex Virus type 1 (HSV-1) in the geniculate ganglion - this is well-established by PCR evidence (Murakami et al., 1996, finding HSV-1 DNA in endoneurial fluid in 11/14 cases). The virus was also able to reproduce facial palsy when inoculated into mice.

Varicella-zoster virus (VZV) is the second most frequent viral cause (up to one-third of cases)
SARS-CoV-2 and HIV seroconversion have also been implicated
Pathologically: mononuclear cell infiltration of the facial nerve, edema, swelling - the nerve becomes compressed within the tight bony facial canal

Risk factors:

Pregnancy (especially third trimester and first 2 weeks postpartum - up to 3-fold increased risk)
Diabetes mellitus
Hypertension (possible)
Recurrence in ~7-8% of cases; mean interval between episodes ~10 years
Harrison's, p. 3597 | Adams and Victor's, pp. 1371-1372

Clinical Features

Onset

Abrupt - maximal weakness by 48 hours as a rule (practically all within 3-4 days)
Patient often notices on inspection in the mirror in the morning

Symptoms and Signs

Feature	Mechanism
Unilateral facial weakness (all divisions)	LMN CN VII palsy
Inability to close eye (lagophthalmos)	Orbicularis oculi paralysis
Bell's phenomenon	Upward rolling of the eye on attempted lid closure (protective reflex)
Drooping of corner of mouth, drooling	Orbicularis oris / buccinator paralysis
Loss of nasolabial fold	Ipsilateral
Pain behind the ear	Precedes palsy by 1-2 days (mastoid pain)
Loss of taste (anterior 2/3 tongue)	Chorda tympani involvement
Hyperacusis	Stapedius muscle paralysis
Mild facial numbness/fullness	(Uncommon; trigeminal overlap)
Mild CSF lymphocytosis	Occasional finding

Harrison's, p. 3597 | Adams and Victor's, p. 1371

MRI Findings

MRI with gadolinium (fat-suppressed T1) shows diffuse, smooth linear enhancement of the facial nerve - involving the geniculate ganglion, tympanic, and mastoid segments within the temporal bone - without a mass lesion.

MRI Bell's palsy: gadolinium-enhanced T1 images (coronal left, axial right) showing linear enhancement of the left facial nerve at the geniculate, tympanic, and mastoid segments (arrows), consistent with Bell's palsy

Harrison's, Fig. 452-4: T1 post-gadolinium with fat suppression showing diffuse smooth linear enhancement of the left facial nerve (arrows). Note: similar enhancement can be seen in Lyme disease, sarcoidosis, and perineural malignant spread.

More pronounced enhancement correlates with a worse prognosis. - Harrison's, p. 3598 | Adams and Victor's, p. 1371

Differential Diagnosis

Bell's palsy is a diagnosis of exclusion. Always consider:

Condition	Key distinguishing features
Ramsay Hunt Syndrome (VZV reactivation)	Vesicular rash in external auditory canal, pinna, palate; CN VIII involvement; more severe palsy; worse prognosis
Lyme disease	Endemic area; erythema migrans; can be bilateral; CSF pleocytosis; treat with antibiotics
Otitis media / mastoiditis	Abnormal otoscopy; hearing loss; fever
Parotid tumor	Slowly progressive; palpable mass; no taste loss
Facial nerve neuroma	Recurrent or slowly progressive palsy
Sarcoidosis	Often bilateral palsy; hilar lymphadenopathy; elevated ACE
Guillain-Barré syndrome	Bilateral facial palsy; ascending weakness; areflexia
HIV seroconversion	CSF pleocytosis
Carcinomatous meningitis	Multiple cranial nerve palsies; abnormal CSF cytology
Melkersson-Rosenthal syndrome	Recurrent facial palsy + facial edema + fissured tongue
Stroke / UMN lesion	Forehead spared; contralateral body weakness
Leprosy	Endemic area; skin lesions; sensory loss
Diabetes mellitus	Background; mononeuropathy

Harrison's, p. 3598 | Goldman-Cecil, p. 2962 | Adams and Victor's, p. 1372

Investigations

In straightforward Bell's palsy, investigations are not always required. However:

MRI - not routine; useful if atypical features, slow progression, or suspected central cause
Serology - consider Borrelia (Lyme), HIV, VZV in appropriate clinical context
EMG/nerve conduction - prognostic value:
- Evidence of denervation after 10 days = axonal degeneration = expect long recovery (months to years), potentially incomplete
- Early motor recovery (days 5-7) = most favorable prognostic sign
- Recovery of taste in first week = good prognostic sign
Harrison's, p. 3597 | Adams and Victor's, p. 1371

Treatment

1. Corticosteroids (First-line)

Prednisolone 25 mg twice daily (50 mg/day) for 10 days, started early
Evidence: Large RCTs (Sullivan et al., Engstrom et al.) show steroids increase return of facial function from 63% to 83% at 3 months
Mechanism: reduces nerve swelling and edema within the bony facial canal
Goldman-Cecil, p. 2973 | Adams and Victor's, p. 1372

2. Antiviral Agents

Acyclovir alone - no independent benefit over placebo
Valacyclovir + prednisolone - additive benefit shown in severe/complete palsy (Hato et al.) vs. prednisolone alone; particularly for complete facial palsy
Acyclovir 400 mg 5x/day for 7 days; double dose for VZV-suspected cases
Note: Ramsay Hunt syndrome should receive antivirals (valacyclovir/acyclovir) + steroids
Goldman-Cecil, p. 2973 | Adams and Victor's, p. 1372

3. Eye Care (Essential)

Corneal protection is mandatory - inability to close the eye leads to corneal exposure, dryness, and risk of ulceration
Lubricating eye drops during the day; eye ointment + eye patch/tape at night

4. Physical Therapy

Facial exercises may help maintain muscle tone and promote neuromuscular retraining
A 2025 systematic review (Varelas et al., Am J Otolaryngol, 2025) supports a role for physical therapy in idiopathic facial paralysis

5. Surgical Decompression

No evidence of benefit; may be harmful. Not recommended. - Adams and Victor's, p. 1372

Children

Recovery rate is very high (~90%) regardless of treatment; steroid use is not mandatory in children - Scott-Brown's Otorhinolaryngology

Prognosis

~70-80% recover completely within 1-2 months
~85% achieve near-normal function overall
~10% have little or no recovery
Unfavorable signs: complete palsy, denervation on EMG after 10 days
Favorable signs: incomplete palsy in first week, early taste recovery, early motor recovery (days 5-7)

Complications of Incomplete Recovery

Synkinesis - aberrant nerve regeneration causing involuntary co-contractions:
- "Jaw winking" (eye closes when mouth opens)
- Crocodile tears (lacrimation accompanying salivation) - from aberrant regeneration of parasympathetic fibers
Facial contracture
Hemifacial spasm (rare, late)
Goldman-Cecil, p. 2978 | Adams and Victor's, p. 1372

Summary Table

Feature	Detail
Incidence	~25/100,000/year; 1 in 60 lifetime
Cause	HSV-1 reactivation in geniculate ganglion; VZV 2nd most common
Onset	Abrupt; max weakness by 48h
Pattern	Unilateral LMN (all face including forehead)
Key symptoms	Facial weakness, lagophthalmos, post-auricular pain, taste loss, hyperacusis
MRI	Linear gadolinium enhancement of facial nerve in temporal bone
Treatment	Prednisolone 50 mg/day x10 days ± valacyclovir; eye care
Prognosis	85% near-complete recovery; ~10% poor outcome
Recurrence	~7-8%

Dementia

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Dementia

Definition

Dementia is an acquired, persistent deterioration in cognitive abilities that impairs the successful performance of activities of daily living (ADLs). It affects over 6 million people in the United States, with a total annual healthcare cost exceeding $300 billion. Prevalence rises sharply with age: 10% of persons >70 years and 20-40% of individuals >85 years have clinically identifiable memory loss.

Key points:

Episodic memory (recall of time/place-specific events) is the most commonly lost cognitive function
Other domains affected: language, visuospatial function, praxis, calculation, judgment, executive function
Neuropsychiatric symptoms are common: depression, apathy, anxiety, hallucinations, delusions, agitation, disinhibition
A preclinical stage (brain pathology present, no symptoms) and a prodromal stage - Mild Cognitive Impairment (MCI) (cognitive decline but ADLs preserved) precede overt dementia in neurodegenerative disease
Harrison's 22E, p. (Ch. 31)

Functional Anatomy

Different dementia syndromes begin in distinct brain regions:

Region Initially Affected	Dementia Type	Early Presentation
Entorhinal cortex → hippocampus → limbic → parietal cortex	Alzheimer's disease (AD)	Episodic memory loss
Frontal/prefrontal cortex, anterior temporal	Frontotemporal dementia (FTD)	Behavioral change, language, executive dysfunction
Cortical + subcortical (patchwork)	Vascular dementia	Executive dysfunction, psychomotor slowing
Posterior cortical (parietal/occipital)	Dementia with Lewy bodies (DLB)	Visuospatial, hallucinations
Subcortical (striatum, basal ganglia)	Huntington's disease	Movement, executive, mood

Ascending cholinergic pathways are critical for attention and memory (hence cholinesterase inhibitors as therapy). Noradrenergic, serotonergic, and dopaminergic pathways modulate behavior and mood. - Harrison's 22E

Causes of Dementia

A. Neurodegenerative (Progressive, Irreversible)

Disease	Key Pathology	Key Features
Alzheimer's disease (AD)	Amyloid-β plaques + tau neurofibrillary tangles	Most common (~60-70%); episodic memory first
Dementia with Lewy bodies (DLB)	α-synuclein (Lewy bodies) in cortex	Visual hallucinations, parkinsonism, REM sleep behavior disorder, cognitive fluctuation
Frontotemporal Dementia (FTD)	Tau or TDP-43 aggregates	Behavioral disinhibition/apathy OR progressive aphasia; spares memory early
Parkinson's disease dementia (PDD)	α-synuclein (subcortical)	Motor Parkinson's precedes dementia by ≥1 year
LATE (Limbic-predominant Age-related TDP-43 Encephalopathy)	TDP-43 aggregates	Mimics AD; increasingly common >90 years; >50% of dementia at age >90
Huntington's disease	CAG repeat expansion in HTT gene	Chorea, executive dysfunction, psychiatric
Progressive supranuclear palsy (PSP)	Tau; subcortical	Vertical gaze palsy, axial rigidity, early falls
Prion disease (CJD)	Misfolded PrP	Rapid progression; myoclonus; MRI cortical ribboning

B. Vascular

Cortical/subcortical infarctions (multi-infarct dementia)
Confluent white matter disease (leukoaraiosis), CADASIL
Small vessel disease

C. Reversible / Treatable Causes (Critical to identify)

Cause	Treatment
Hypothyroidism	Thyroid replacement
Vitamin B12 deficiency	Parenteral B12
Thiamine (B1) deficiency (Wernicke's)	IV thiamine
Neurosyphilis	Penicillin
HIV-associated dementia	Antiretrovirals
Normal pressure hydrocephalus (NPH)	Ventriculoperitoneal shunting
CNS neoplasm	Surgery, radiation, chemotherapy
Chronic subdural hematoma	Surgical drainage
Drug/medication toxicity	Remove offending agent
Depression ("pseudodementia")	Antidepressants
Hypercalcemia, hyponatremia	Correct metabolic disturbance
Chronic CNS infections (TB meningitis, fungal)	Antimicrobials
Autoimmune/paraneoplastic encephalitis (anti-NMDAR, LGI1, etc.)	Immunotherapy

Harrison's 22E

Differential Diagnosis: Key Features Side-by-Side

Disease	First Symptom	Mental Status	Neuropsychiatry	Neurology	Imaging
AD	Memory loss	Episodic memory loss; executive, language, visuospatial	Irritability, anxiety, depression	Initially normal	Entorhinal/hippocampal atrophy; posterior-predominant
Vascular	Often sudden; variable; apathy, falls	Frontal/executive; cognitive slowing; can spare memory	Apathy, delusions, anxiety	Motor slowing, spasticity	Cortical/subcortical infarctions; white matter disease
DLB	Visual hallucinations, REM sleep behavior disorder, Capgras syndrome, parkinsonism	Drawing/frontal-executive; spares memory; delirium-prone	Visual hallucinations, depression, sleep disorder	Parkinsonism	Posterior parietal atrophy; hippocampi larger than AD
LATE	Memory loss	Episodic memory; mild semantic deficits	None described	Normal	Medial temporal/hippocampal atrophy (anterior predominant)
FTD	Apathy, poor judgment/insight, speech/language, hyperorality	Frontal/executive and/or language; spares drawing	Apathy, disinhibition, overeating, compulsivity	May have vertical gaze palsy, MND	Frontal, insular, anterior temporal atrophy; spares posterior parietal
CJD	Dementia, mood, anxiety, movement	Variable; frontal/executive; focal cortical	Depression, anxiety, psychosis	Myoclonus, rigidity, parkinsonism	Cortical ribboning + basal ganglia/thalamic hyperintensity on DWI/FLAIR

From Harrison's 22E, Table 31 (Ch. 31)

Alzheimer's Disease - Key Details

Epidemiology: Most common dementia (~60-70%). Most are sporadic late-onset (age >65). Early-onset familial AD (<65 years) accounts for ~5%.

Genetics:

APOE ε4 allele: major genetic risk factor for late-onset sporadic AD
APP, PSEN1, PSEN2 mutations: autosomal dominant early-onset AD
Down syndrome (Trisomy 21): virtually all develop AD pathology by age 40-50 (APP gene on chromosome 21)

Pathology (amyloid cascade hypothesis):

Senile plaques: extracellular deposits of amyloid-β (Aβ) peptide (from cleavage of APP)
Neurofibrillary tangles (NFTs): intracellular aggregates of hyperphosphorylated tau protein
Neuronal loss and synapse loss - particularly cholinergic neurons of the nucleus basalis of Meynert
Spreads in a predictable Braak staging pattern: entorhinal cortex → hippocampus → association cortex → diffuse

Biomarkers (amyloid-tau-neurodegeneration [ATN] framework):

CSF: low Aβ42, elevated total tau and phospho-tau
Amyloid PET: positive for Aβ plaques
Tau PET: elevated tau tangles
MRI: hippocampal and entorhinal atrophy, posterior cortical predominance
FDG-PET: hypometabolism in temporal-parietal regions

Frontotemporal Dementia - Key Details

FTD encompasses three core clinical syndromes:

Behavioral variant (bvFTD) - most common; apathy, disinhibition, compulsivity, loss of empathy, hyperorality
Semantic variant PPA - loss of word/object/person meaning; fluent but empty speech
Nonfluent/agrammatic PPA - effortful, halting speech; motor speech impairment

Genetics: Autosomal dominant in 10-20%; mutations in C9orf72 (hexanucleotide GGGGCC expansion), GRN (granulin), MAPT (tau) on chromosome 17. FTD-MND (with motor neuron disease) is a serious overlap syndrome. - Harrison's 22E

Dementia with Lewy Bodies - Key Features

Core clinical features:

Fluctuating cognition (variable attention and alertness)
Recurrent visual hallucinations (well-formed, detailed)
REM sleep behavior disorder (RBD) - often precedes dementia by years
Parkinsonism (bradykinesia, rigidity, tremor)

Important caveat: DLB patients are exquisitely sensitive to antipsychotics (neuroleptic sensitivity) - typical antipsychotics can cause irreversible worsening or death. Avoid haloperidol and other D2 blockers. Memantine also used with great caution. - Harrison's 22E

Diagnosis

History: Onset, progression (insidious vs. stepwise), first domain affected, neuropsychiatric features, family history, medications, vascular risk factors

Cognitive testing: MMSE, MoCA (better for MCI), MOCA-Blind; formal neuropsychological testing

Investigations:

Essential bloods: TSH, B12, folate, CBC, CMP, LFTs, glucose, calcium, VDRL/RPR, HIV in appropriate cases
Brain MRI (preferred over CT) - structural atrophy pattern, vascular disease, NPH
Lumbar puncture: if CNS infection, inflammatory/autoimmune dementia, or paraneoplastic suspected; CSF biomarkers (Aβ42, tau) for AD
EEG: useful in CJD (periodic sharp wave complexes), and to exclude seizure-related cognitive decline
PET: FDG-PET (hypometabolism pattern), amyloid PET, tau PET - increasingly used to confirm AD diagnosis
Genetic testing: APOE genotyping (risk), familial AD gene panel in early-onset cases

Treatment

1. Treat Reversible Causes

See the reversible causes table above - always exclude before accepting a neurodegenerative diagnosis.

2. Cholinesterase Inhibitors (AChEIs)

Mechanism: inhibit acetylcholinesterase → increase synaptic acetylcholine
Agents: Donepezil (AD), Rivastigmine (AD, PDD), Galantamine (AD)
Modest symptomatic benefit in mild-moderate AD and PDD
Side effects: GI (nausea, diarrhea), bradycardia, vivid dreams

3. Memantine

Mechanism: NMDA glutamate receptor antagonist; reduces excitotoxic neuronal damage
Indicated for moderate to severe AD
Combination with a cholinesterase inhibitor delayed nursing home placement in some studies
Use with great caution in DLB (risk of worsening agitation)

4. Anti-Amyloid Monoclonal Antibodies (new, disease-modifying)

Lecanemab (Leqembi) - FDA approved for early AD (MCI/mild dementia with confirmed amyloid); reduces amyloid burden and slows clinical decline (van Dyck et al., NEJM 2023 [PMID referenced in Harrison's])
Donanemab - FDA approved 2024; similar mechanism; significant slowing of decline in TRAILBLAZER-ALZ 2 trial (Sims et al., JAMA 2023)
Key risk: ARIA (Amyloid-Related Imaging Abnormalities) - brain edema/microhemorrhages on MRI; APOE ε4 homozygotes at highest risk

5. Behavioral/Neuropsychiatric Symptoms

First: identify and correct reversible triggers (pain, infection, constipation, UTI, electrolyte disturbance, drug toxicity, hunger)
Depression: SSRIs (escitalopram 5-10 mg/day starting) or SNRIs - few cognitive side effects; preferred
Agitation/aggression/psychosis: second-generation antipsychotics (e.g., quetiapine 12.5-25 mg starting) - significant risk including increased mortality in elderly with dementia; use cautiously; brexpiprazole is now first FDA-approved drug specifically for AD-related agitation
Apathy, visual hallucinations in DLB: cholinesterase inhibitors often help, avoiding need for antipsychotics
Avoid in DLB: typical antipsychotics, memantine (high doses), anticholinergics, benzodiazepines

6. Anticonvulsants

Levetiracetam or lamotrigine preferred if seizures develop (favorable cognitive profile, and animal model evidence of possible cognitive benefit in AD)

7. Non-Pharmacological

Cognitive stimulation, physical exercise, sleep hygiene
Mediterranean diet - associated with reduced risk of cognitive impairment and AD in a 2025 meta-analysis (Fekete et al., Geroscience, 2025)
Caregiver education and support; advance care planning
Harrison's 22E (Ch. 31 + Ch. 442)

Prognosis

Dementia Type	Course	Mean Survival from Diagnosis
AD	Slow progressive (8-10 years average)	8-10 years
DLB	Progressive with fluctuations	Shorter than AD; ~5-7 years
FTD	Variable; 6-8 years	6-8 years; shorter with MND overlap
Vascular	Stepwise or gradual	Depends on vascular events
CJD	Rapid (months)	<1 year from symptom onset
NPH	Reversible with shunting	Good if treated early

Late-onset dementia is rarely "pure" pathology - at autopsy, most patients with dementia have 3-4 concurrent pathologies. In one large cohort (mean age at death 89.7 years), AD neuropathology explained ~39% of attributable dementia risk, vascular pathology ~25%, with the rest from LATE, DLB, and mixed pathology. - Harrison's 22E

Summary: DEMENTIA Mnemonic for Reversible Causes

Letter	Cause
D	Drugs/Deficiencies (B12, thiamine, folate)
E	Endocrine (hypothyroidism, Cushing's, hypercalcemia)
M	Metabolic (hyponatremia, hepatic/renal failure)
E	Emotional/psychiatric (depression = pseudodementia)
N	Neoplasm (CNS tumor, paraneoplastic)
T	Trauma (chronic subdural hematoma)
I	Infections (neurosyphilis, HIV, TB meningitis, viral encephalitis)
A	Autoimmune/vascular (anti-NMDAR encephalitis, NPH, vasculitis)

Ataxia

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Ataxia

Definition

Ataxia refers to a disturbance in the smooth, coordinated performance of voluntary motor acts - causing incoordination or impaired balance. Movements are flawed in rate, range, timing, direction, and force. In the absence of cerebellar inhibitory and modulating influences, skilled movements become inaccurate and poorly controlled. Ataxia may affect the limbs, trunk, or gait. - Localization in Clinical Neurology, 8e

Types of Ataxia

There are three main types based on the underlying mechanism:

1. Cerebellar Ataxia

Caused by dysfunction of the cerebellum or its connections (spinocerebellar tracts, cerebellar peduncles).

Clinical features:

Wide-based, lurching, irregular gait
Dysmetria - overshooting/undershooting targets (finger-nose, heel-shin tests abnormal)
Dysdiadochokinesia - inability to perform rapid alternating movements
Intention tremor - tremor that worsens on approaching a target
Nystagmus - often horizontal or gaze-evoked
Dysarthria - scanning (staccato) speech
Truncal titubation - rhythmic oscillation of the trunk/head
Hypotonia - decreased muscle tone ipsilateral to cerebellar lesion
Rebound phenomenon (failure of check)
Romberg test: may be positive but less dramatically than sensory ataxia

2. Sensory Ataxia

Due to loss of proprioception (large fibre afferents) from peripheral nerves, dorsal root ganglia, or posterior columns of spinal cord.

Clinical features:

Wide-based gait; patient looks down at feet when walking ("stamping gait")
Feet thrust forward with slapping sound ("slapping gait")
Worsens dramatically in the dark and on uneven surfaces
Romberg sign positive - falls when eyes closed (critically distinguishes from cerebellar ataxia)
Loss of joint position sense and vibration in lower limbs
Heel-shin test: relatively preserved compared to cerebellar

3. Vestibular Ataxia

Due to vestibular organ or pathway dysfunction.

Clinical features:

Veering/leaning toward the side of the lesion
Severe vertigo, nausea, nystagmus
Unsteadiness unmasked during head rotation while walking
Less severe when running vs. walking (in acute vestibular disease)

Comparison Table: The Three Ataxias

Feature	Cerebellar Ataxia	Sensory Ataxia	Frontal Gait Disorder
Base of support	Wide	Wide; looks down	Wide
Velocity	Variable	Slow	Very slow
Stride	Irregular, lurching	Regular with path deviation	Short, shuffling
Romberg test	+/-	Unsteady, falls (positive)	+/-
Heel-shin test	Abnormal	+/-	Normal
Initiation	Normal	Normal	Hesitant
Turns	Unsteady	+/-	Hesitant, multistep
Falls	Late event	Frequent	Frequent

From Harrison's 22E, Table 26-3

Cerebellar Anatomy and Localization

Cerebellar Region	Function	Lesion Effect
Vermis (midline)	Truncal/axial coordination, gait	Truncal ataxia, gait ataxia, titubation
Hemispheres (lateral)	Limb coordination (ipsilateral)	Limb ataxia, dysmetria, dysdiadochokinesia
Flocculonodular lobe	Vestibular-ocular coordination	Nystagmus, vertigo, gait imbalance
Deep nuclei (dentate)	Output to thalamus/cortex	Intention tremor

Causes of Ataxia by Time Course

Acute Ataxia (Hours to Days)

Category	Examples
Toxic/Drug	Alcohol intoxication, phenytoin, lithium, barbiturates, carbamazepine
Metabolic	Hypoglycemia, hyponatremia, hyperammonemia, Wernicke's encephalopathy (thiamine B1 deficiency)
Vascular	Cerebellar infarction, cerebellar hemorrhage
Infectious	Bacterial/viral meningitis; acute postinfectious cerebellar ataxia (varicella - especially in children)
Immune	Fisher variant of GBS (anti-GQ1b; ataxia + ophthalmoplegia + areflexia), Bickerstaff brainstem encephalitis
Biotinidase deficiency	Treatable metabolic disease
Trauma	Posterior fossa hemorrhage

Subacute Ataxia (Weeks to Months)

Category	Examples
Paraneoplastic	Anti-Yo (breast, ovarian Ca), anti-Hu (small-cell lung Ca), anti-Tr (Hodgkin's)
Autoimmune	Anti-GAD65 antibodies (most common autoimmune cerebellar ataxia); anti-gliadin/anti-tissue transglutaminase (gluten ataxia)
Alcohol + malnutrition	Cerebellar vermis degeneration (B vitamins deficiency)
Prion disease	CJD - rapidly progressive ataxia with myoclonus, dementia
Toxic	Heavy metals (mercury), toluene (glue/solvent sniffing), chemotherapy (5-FU, paclitaxel)

Chronic Progressive Ataxia (Months to Years)

Category	Examples
Hereditary	SCAs (autosomal dominant), Friedreich's ataxia (AR), ataxia-telangiectasia
Multiple system atrophy - cerebellar (MSA-C)	Progressive with autonomic failure
Hypothyroidism	Reversible; always check TFTs
Vascular	Chronic white matter disease, CADASIL
Paraneoplastic	Slow-growing tumor, long latency
Infectious	Meningovascular syphilis, tabes dorsalis (posterior column degeneration)

Inherited Ataxias

Autosomal Dominant: Spinocerebellar Ataxias (SCAs)

SCAs include SCA1 through SCA50+, caused by mutations in different genes. The most common are:

SCA Type	Gene/Mechanism	Distinguishing Features
SCA1	CAG repeat ↑ in ATXN1 (chr 6)	Progressive cerebellar ataxia, nystagmus, dysarthria, pyramidal signs, extrapyramidal features
SCA2	CAG repeat ↑ in ATXN2 (chr 12)	Slow saccades (very characteristic), hyporeflexia, peripheral neuropathy
SCA3 (Machado-Joseph disease)	CAG repeat ↑ in ATXN3 (chr 14) - most common SCA worldwide	Ataxia + parkinsonism/dystonia/pyramidal signs; "bulging eyes" (eyelid retraction)
SCA6	CAG repeat ↑ in CACNA1A (chr 19) - calcium channel	Pure cerebellar ataxia; late onset; relatively mild
SCA7	CAG repeat ↑ in ATXN7	Ataxia + progressive retinal degeneration (pigmentary macular dystrophy → blindness)
SCA17	CAG repeat ↑ in TBP (TATA-binding protein)	Ataxia + dementia + psychiatric symptoms

Mechanism common to CAG-repeat SCAs: CAG encodes glutamine → expanded polyglutamine proteins (ataxins) → toxic gain of function, protein aggregation, neuronal apoptosis. Anticipation occurs (earlier onset in successive generations with increasing CAG repeat number).

Episodic Ataxia (EA):

EA-1: KCNA1 potassium channel mutation (chr 12p); brief episodes (minutes); myokymia between episodes; triggered by startle/posture change
EA-2: CACNA1A calcium channel mutation (chr 19p); longer episodes (hours-days); gaze-evoked nystagmus between episodes; stress/exercise triggers; treat with acetazolamide

DRPLA (Dentatorubropallidoluysian Atrophy): CAG repeat in ATROPHIN gene (chr 12p); ataxia + chorea + myoclonus + seizures + dementia; common in Japan

Autosomal Recessive Ataxias

Friedreich's Ataxia - Most Common Inherited Ataxia (~50% of all hereditary ataxias)

Genetics: GAA trinucleotide repeat expansion in intron 1 of the frataxin (FXN) gene on chromosome 9q → deficiency of frataxin protein → mitochondrial iron accumulation → oxidative stress → neurodegeneration

Clinical features (onset <25 years - most present in adolescence):

Progressive gait ataxia and frequent falls; lower limbs more affected than upper
Dysarthria (scanning speech)
Absent deep tendon reflexes (areflexia) - lost early
Extensor plantar responses (Babinski sign) - UMN involvement
Loss of vibration and proprioception (posterior column degeneration)
Nystagmus, loss of fast saccades
Pes cavus (high-arched feet) and scoliosis - characteristic deformities
Cardiomyopathy (90%) - hypertrophic cardiomyopathy, conduction defects; leading cause of death
Diabetes mellitus (20%)
Median age of death: 35 years; women have better prognosis than men

Pathology: Degeneration of spinocerebellar tracts, posterior columns, lateral corticospinal tracts, dorsal root ganglia; slight cerebellar/cerebral atrophy

Treatment: Omaveloxolone (Skyclarys) - FDA-approved (2023) for Friedreich's ataxia in patients ≥16 years; activates Nrf2 pathway, reduces oxidative damage; slows neurological progression. Symptomatic: physical therapy, cardiac management, orthopedic care for scoliosis/foot deformities.

Ataxia-Telangiectasia (AT)

Gene: ATM (chr 11q22-23) - DNA repair kinase; autosomal recessive
Features: Progressive cerebellar ataxia from infancy, oculocutaneous telangiectasias (conjunctiva, ears, skin), immune deficiency (IgA, IgE deficiency; T-cell dysfunction), increased cancer risk (lymphomas, leukemias), sinopulmonary infections, elevated AFP
Radiosensitivity - avoid radiation exposure (increased DNA damage); cancer risk with radiotherapy

Investigations

Test	Indication
MRI brain + spine	Structural cause, cerebellar/spinal atrophy pattern; infarction, hemorrhage, tumor
TFTs (TSH)	Hypothyroid ataxia (reversible)
Vitamin B12, B1 (thiamine)	Nutritional/malabsorptive
Glucose, electrolytes (Na, Ca)	Metabolic ataxia
Toxicology screen	Drug/alcohol intoxication
Anti-gliadin, tTG antibodies	Gluten ataxia
Paraneoplastic panel	Anti-Yo, Anti-Hu, Anti-Tr, anti-GAD65
CSF analysis	Prion disease (14-3-3 protein, RT-QuIC), immune-mediated ataxia
Genetic testing	SCA panel (CAG repeat sizing), Friedreich's (GAA repeat), AT (ATM mutation)
EMG/NCS	Peripheral neuropathy (sensory ataxia), Friedreich's (absent sensory potentials)
Echocardiogram	Friedreich's ataxia (cardiomyopathy screening)
VDRL/RPR	Tabes dorsalis
Karyotype	If clinical features of chromosomal disease
FDG-PET / DAT scan	MSA-C vs. Parkinson-plus

Treatment

Specific/Curative

Cause	Treatment
Episodic ataxia EA-1/EA-2	Acetazolamide (EA-2 especially); anticonvulsants (EA-1)
Hypothyroidism	Thyroid hormone replacement
Gluten ataxia	Strict gluten-free diet
Vitamin deficiency	Thiamine (Wernicke's), B12, vitamin E
Autoimmune/paraneoplastic	IV methylprednisolone, IVIG, plasma exchange; treat underlying cancer
Friedreich's ataxia	Omaveloxolone (FDA-approved 2023); antioxidants; cardiac management
Drug toxicity	Remove offending agent
Cerebellar hemorrhage/infarct	Surgical decompression if mass effect; stroke risk factor management

Symptomatic/Supportive

Physiotherapy and occupational therapy - gait rehabilitation, walking aids, fall prevention
Non-invasive brain stimulation (rTMS/tDCS) - emerging evidence; recent meta-analyses (Matsugi et al., Mov Disord Clin Pract, 2024) suggest modest benefit for degenerative cerebellar ataxia
Speech therapy for dysarthria and dysphagia
Baclofen or clonazepam for tremor
Scoliosis/foot deformity - orthotics, surgical correction in Friedreich's ataxia
Genetic counselling for hereditary ataxias

Summary: Approach to a Patient with Ataxia

Ataxia
├── Acute (<days)      → Toxic (alcohol, drugs), metabolic, stroke, Fisher GBS
├── Subacute (weeks)   → Paraneoplastic, autoimmune (anti-GAD65, gluten), Wernicke's
├── Chronic/hereditary → SCA (AD), Friedreich's (AR), MSA-C, AT
│
├── Cerebellar signs dominant → Cerebellum or its pathways
├── Sensory loss + positive Romberg → Posterior columns / large-fibre neuropathy
└── Vestibular features → Labyrinth / CN VIII / brainstem

Always exclude reversible causes first: hypothyroidism, vitamin deficiencies, alcohol/drug toxicity, gluten ataxia, and autoimmune/paraneoplastic disease before diagnosing a hereditary or degenerative condition.

Epilepsy

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Epilepsy

Definition

Epilepsy is defined as two or more unprovoked seizures occurring more than 24 hours apart. A seizure is a paroxysmal event caused by abnormal, excessive, hypersynchronous neuronal discharges from the cerebral cortex.

Incidence: ~0.3-0.5% of the population worldwide
Prevalence: 5-30 persons per 1000
About 30% of patients fail to respond to standard antiseizure medications (drug-resistant epilepsy)

Classification of Seizures (ILAE 2017)

The International League Against Epilepsy (ILAE) updated classification in 2017 divides seizures into three main categories:

1. Focal Onset Seizures

Originate within networks limited to one cerebral hemisphere (the older term "partial seizures" is no longer used). Further classified by:

Awareness: intact (formerly "simple partial") or impaired (formerly "complex partial")
Onset type: motor or nonmotor
Evolution: may progress to focal to bilateral tonic-clonic seizures (formerly "secondary generalization")

Common focal seizure types by region of onset:

Lobe	Typical Semiology
Temporal (most common)	Aura (déjà vu, rising epigastric sensation, fear), oral/manual automatisms, impaired awareness, postictal confusion
Frontal	Motor activity (tonic, clonic, hypermotor), brief, nocturnal, often no postictal state
Parietal	Contralateral sensory aura (tingling, numbness), body image distortion
Occipital	Visual aura (flashing lights, colored patterns), eye deviation, ictal blindness

2. Generalized Onset Seizures

Arise within and rapidly engage networks distributed across both cerebral hemispheres.

Type	Description
Tonic-clonic (GTC)	Tonic phase (stiffening, apnoea, cyanosis) → clonic phase (rhythmic jerking) → postictal drowsiness/confusion
Absence (typical)	Brief (5-30 sec) staring spell, sudden onset and offset, no postictal state; 3 Hz spike-wave on EEG
Absence (atypical)	Slower onset/offset; associated with cognitive impairment; part of Lennox-Gastaut syndrome
Myoclonic	Sudden, brief (<100 ms) muscle jerks, often bilateral; consciousness usually preserved
Tonic	Sustained muscle contraction; often nocturnal; risk of falls
Atonic ("drop attacks")	Sudden loss of muscle tone; fall to ground; risk of injury
Clonic	Rhythmic jerking without preceding tonic phase

3. Unknown Onset

When the onset cannot be determined.

Harrison's 22E, Ch. 436 (ILAE 2017 classification)

Causes of Epilepsy

The ILAE 2017 also classifies epilepsy by etiology:

Structural

Hippocampal sclerosis (mesial temporal lobe epilepsy - most common form in adults)
Cortical dysplasia / malformations of cortical development
Tumors (primary or metastatic)
Prior stroke/vascular malformation (AVM, cavernoma)
Traumatic brain injury
Periventricular leukomalacia (perinatal injury)

Genetic

Ion channel mutations: SCN1A (Dravet syndrome), KCNQ2, CACNA1A
Trinucleotide repeat disorders: fragile X, Huntington's (rarely)
Chromosomal: Down syndrome, Angelman syndrome, ring chromosome 20
Neurocutaneous syndromes: tuberous sclerosis (TSC1/TSC2), neurofibromatosis, Sturge-Weber

Infectious

Neurocysticercosis (most common worldwide cause of acquired epilepsy)
HSV encephalitis, HIV, tuberculoma, cerebral abscess
Cerebral malaria

Metabolic

Hypoglycemia, hyponatremia, hypocalcemia, hypomagnesemia
Pyridoxine (B6) deficiency (neonates)
Uraemia, hepatic encephalopathy
Mitochondrial disorders

Immune / Autoimmune

Anti-NMDAR encephalitis (most common autoimmune encephalitis)
LGI1, CASPR2, GABA-B, AMPA receptor antibodies
Rasmussen encephalitis

Drugs that Lower Seizure Threshold

Bupropion, clozapine, lithium
Beta-lactam antibiotics, quinolones, isoniazid
Cocaine, amphetamine, phencyclidine
Alcohol/benzodiazepine/barbiturate withdrawal
Tramadol, meperidine, fentanyl
Antimalarials (chloroquine, mefloquine)
Cyclosporine, tacrolimus

Unknown (Idiopathic)

Large proportion, especially in children with genetic epilepsy syndromes.

Epilepsy Syndromes

Key recognizable syndromes by age of onset:

Syndrome	Age of Onset	Seizure Types	EEG	Outcome
Benign neonatal seizures	Neonatal	Focal clonic	Variable	Good
West syndrome (infantile spasms)	3-12 months	Epileptic spasms + developmental regression	Hypsarrhythmia	Poor if untreated
Dravet syndrome	<1 year	Febrile + afebrile; drug-resistant	Abnormal	Poor; SCN1A mutation
Lennox-Gastaut syndrome	1-7 years	Multiple types (tonic, atonic, atypical absence)	Slow spike-wave (<2.5 Hz)	Poor; intellectual disability
Childhood absence epilepsy	4-10 years	Typical absence	3 Hz spike-wave	Good; often remits
Juvenile absence epilepsy	Adolescence	Absence + occasional GTC	3-4 Hz spike-wave	Moderate; lifelong in many
Juvenile myoclonic epilepsy (JME)	12-18 years	Morning myoclonic jerks + GTC + absence	3.5-4 Hz polyspike-wave	Good with medication; but lifelong
Mesial temporal lobe epilepsy (MTLE)	Any (often adolescence)	Focal with impaired awareness; oral automatisms	Temporal sharp waves	Often drug-resistant; surgical candidate

JME is particularly important: seizures triggered by sleep deprivation and alcohol; EEG shows bilateral polyspike-wave at 3.5-4 Hz; responds to valproate; requires lifelong treatment.

Pathophysiology

Two key mechanisms of seizure generation:

Increased excitation: enhanced glutamatergic transmission (NMDA, AMPA receptors); mutation in Na+/Ca2+ channels causing increased neuronal firing
Decreased inhibition: reduced GABA-ergic inhibition (GABA-A receptor dysfunction); loss of inhibitory interneurons

The ictal discharge begins with paroxysmal depolarization shifts (PDS) in neurons - large depolarizations driven by NMDA receptor activation - causing a burst of action potentials. Hypersynchronisation of neuronal populations within a focus then spreads.

Diagnosis

History

Detailed seizure description from patient AND witness (onset, duration, postictal state, aura)
Risk factors: prior febrile seizures, family history, head trauma, stroke, CNS infection
Precipitating factors: sleep deprivation, alcohol, drugs
Developmental history (children)

Investigations

Test	Purpose
EEG	Primary test; epileptiform discharges in ~90% of epilepsy; 3 Hz spike-wave in absence; temporal sharp waves in TLE; normal EEG does not exclude epilepsy
MRI brain	Structural cause; hippocampal sclerosis, dysplasia, tumor, AVM; preferred over CT
Blood tests	Glucose, electrolytes (Na, Ca, Mg), LFTs, urea, FBC; toxicology screen
Lumbar puncture	Suspected CNS infection/encephalitis; mandatory in HIV
Autoantibody panel	Anti-NMDAR, LGI1, CASPR2, GABA-B - serum and CSF
Genetic testing	Suspected genetic epilepsy; SCN1A (Dravet), KCNQ2, chromosomal microarray
Video-EEG monitoring	Gold standard for seizure classification and pre-surgical evaluation
FDG-PET / SPECT	Pre-surgical evaluation for drug-resistant focal epilepsy (interictal hypometabolism / ictal hyperperfusion)
Neuropsychological testing	Cognitive profiling; lateralisation pre-surgery

EEG pearls:

Only ~2% of people without epilepsy have epileptiform discharges
~90% of epilepsy patients show epileptiform activity, depending on recording circumstances
3 Hz spike-wave: absence epilepsy
Hypsarrhythmia: West syndrome (infantile spasms)
Periodic sharp wave complexes: CJD
Normal EEG does not exclude epilepsy (especially temporal lobe or frontal lobe)

Antiseizure Drug Therapy

When to Start

After two or more unprovoked seizures
After one unprovoked seizure if high risk of recurrence (structural lesion, abnormal EEG, nocturnal seizure, neurological deficit)

Principles

Monotherapy is the goal; start low, go slow
Choice based on: seizure type/syndrome, age, sex (especially women of childbearing age), comorbidities, drug interactions, side effects

Drug Selection by Seizure Type

Seizure Type	First-Line	Second-Line / Alternatives
Focal seizures	Lamotrigine, levetiracetam, carbamazepine, oxcarbazepine	Valproate, lacosamide, zonisamide, eslicarbazepine, perampanel
GTC (generalized)	Valproate, lamotrigine, levetiracetam	Topiramate, perampanel, zonisamide
Absence	Ethosuximide (drug of choice), valproate, lamotrigine	Clonazepam
Juvenile Myoclonic Epilepsy	Valproate (most effective), levetiracetam, lamotrigine	Topiramate, clonazepam; avoid carbamazepine/oxcarbazepine (worsen myoclonus)
Myoclonic seizures	Valproate, levetiracetam, clonazepam	Zonisamide, piracetam
Atonic / tonic (LGS)	Valproate, lamotrigine, rufinamide	Fenfluramine, clobazam, topiramate, ACTH
Infantile spasms (West)	ACTH / vigabatrin (tuberous sclerosis)	Prednisolone, pyridoxine
Dravet syndrome	Clobazam, valproate, stiripentol	Fenfluramine, cannabidiol (CBD); avoid carbamazepine/phenytoin

Key Drug Details

Drug	Mechanism	Key Features / Side Effects
Valproate	Na+ channel, GABA ↑, Ca2+ channel	Broad spectrum; teratogenic (neural tube defects, cognitive); weight gain, tremor, hepatotoxicity; avoid in women of childbearing age
Lamotrigine	Na+ channel	Broad spectrum; skin rash (Stevens-Johnson if titrated too fast); titrate slowly; relatively safe in pregnancy
Levetiracetam	SV2A synaptic vesicle protein	Broad spectrum; minimal drug interactions; behavioral side effects (irritability, depression)
Carbamazepine	Na+ channel	Focal seizures; enzyme inducer; hyponatremia; rash; teratogenic; worsen absence/myoclonus
Phenytoin	Na+ channel	Acute: IV for SE; chronic: gingival hyperplasia, ataxia, hirsutism, folate deficiency; zero-order kinetics
Ethosuximide	T-type Ca2+ channel (thalamus)	Absence only; GI side effects
Topiramate	Na+ channel, GABA, AMPA	Weight loss; cognitive impairment ("topiramate fog"); nephrolithiasis; teratogenic
Lacosamide	Slow inactivation of Na+ channel	Focal seizures; IV available; cardiac conduction
Zonisamide	Na+ + T-type Ca2+ channels	Broad spectrum; weight loss; nephrolithiasis
Perampanel	AMPA receptor antagonist	Focal and GTC; behavioral side effects
Cenobamate	Na+ channel + GABA-A	Drug-resistant focal epilepsy; Cochrane review 2024 confirms add-on efficacy
Fenfluramine	Serotonin/sigma-1 receptor	Dravet syndrome and LGS; FDA-approved
Cannabidiol (CBD, Epidiolex)	Multiple; unclear	Dravet, LGS, tuberous sclerosis complex

Women and Epilepsy

Valproate is contraindicated in women of childbearing potential where alternatives exist (teratogenic, cognitive effects on offspring)
Lamotrigine is preferred in pregnancy (relative safety, but doses need adjustment as levels fall in pregnancy)
All women with epilepsy taking antiseizure medications should take high-dose folic acid (5 mg/day)

Status Epilepticus (SE)

Definition

Seizure lasting ≥5 minutes OR two or more seizures without return to baseline consciousness.

Convulsive SE is a medical emergency with 10-20% mortality and risk of permanent neurological damage.

Management (Time-based Protocol)

Time	Phase	Treatment
0-5 min	Stabilisation	ABC, IV access, O2, glucose check, cardiac monitor
5-20 min	Initial (benzodiazepine)	Lorazepam 0.1 mg/kg IV (or diazepam IV/rectal, or midazolam IM/buccal if no IV access)
20-40 min	Second-line (if seizure continues)	Levetiracetam 60 mg/kg IV, or fosphenytoin 20 mg PE/kg IV, or valproate 40 mg/kg IV
40-60 min	Third-line (refractory SE)	Anaesthetic doses: propofol, midazolam infusion, thiopental (ICU, intubation, continuous EEG monitoring)

Always investigate for and treat the underlying cause (hypoglycemia, CNS infection, metabolic derangement, drug toxicity, structural lesion).

Drug-Resistant Epilepsy

Defined as failure of adequate trials of two tolerated, appropriately chosen antiseizure drugs. Affects ~30% of patients.

Surgical Options

Temporal lobectomy / selective amygdalohippocampectomy: best results for MTLE with hippocampal sclerosis; 60-80% seizure-free
Lesionectomy: resection of dysplasia, tumor, AVM
Corpus callosotomy: palliative for atonic/tonic/GTC in LGS
Hemispherotomy/hemispherectomy: for hemispheric epilepsy syndromes in children

Pre-surgical evaluation: Video-EEG, MRI, neuropsychology, FDG-PET, ictal SPECT (SISCOM), +/- intracranial EEG (stereo-EEG or subdural grids)

Neuromodulation

Vagus nerve stimulation (VNS): reduces seizure frequency by ~50% in ~50% of patients; not curative
Responsive neurostimulation (RNS): closed-loop cortical stimulation detecting and aborting seizure onset
Deep brain stimulation (DBS of anterior nucleus of thalamus): effective for refractory focal epilepsy

Dietary Therapy

Ketogenic diet (KD): high fat, very low carbohydrate; effective for drug-resistant epilepsy especially in children, Dravet syndrome, glucose transporter deficiency (GLUT1); mechanism: ketone bodies reduce neuronal excitability

Differential Diagnosis of Seizures

Condition	Key distinguishing features
Syncope	Prodrome (light-headedness, nausea, visual grey-out); brief (<30 sec); triggered (standing, pain); no prolonged postictal
TIA	Negative symptoms (weakness, sensory loss); not convulsive; brief
Psychogenic non-epileptic seizures (PNES)	Emotional trigger; eyes closed; pelvic thrusting; long duration; no postictal; normal ictal EEG (video-EEG confirms)
Migraine with aura	Slow march of visual/sensory aura over minutes; followed by headache
Hypoglycemia	Check blood glucose; tremor, sweating, confusion
Transient global amnesia	Sudden amnesia; repetitive questioning; no motor features
Breath-holding spell	Children; triggered by crying/frustration; cyanotic vs. pallid type
Sleep disorders	REM behavior disorder, night terrors, parasomnias

Cognitive and Psychiatric Comorbidities

Epilepsy is associated with significant cognitive and psychiatric comorbidity - not merely epiphenomena but a bidirectional relationship:

Memory deficits are the most common, particularly in temporal lobe epilepsy; left TLE causes verbal memory impairment
Executive dysfunction and visuoconstructional deficits occur in both left and right TLE
Depression (affects ~30-40%); anxiety; psychosis (particularly postictal or interictal)
SUDEP (Sudden Unexpected Death in Epilepsy) - major cause of premature mortality; risk increased with uncontrolled seizures, nocturnal GTC, young men
Social impact: driving restrictions, employment limitations, stigma
Harrison's 22E, Ch. 436 | Bradley & Daroff's Neurology

Meningitis

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Meningitis

Definition

Meningitis is inflammation of the arachnoid membrane, pia mater, and the intervening cerebrospinal fluid (CSF), extending throughout the subarachnoid space around the brain, spinal cord, and into the ventricles.

Bacterial (pyogenic) meningitis: acute, polymorphonuclear (PMN) CSF response; a medical emergency
Viral (aseptic) meningitis: usually self-limiting; lymphocytic CSF; most common form
Tuberculous/fungal/carcinomatous: subacute to chronic course

Epidemiology

Bacterial meningitis incidence: ~1.4 cases/100,000/year in the US
Community-acquired causes:
- Streptococcus pneumoniae ~50%
- Neisseria meningitidis ~25%
- Group B Streptococcus ~15%
- Listeria monocytogenes ~10%
- Haemophilus influenzae type b: <10% (markedly reduced post-vaccination)
Mortality: ~15-20% despite antibiotic therapy
N. meningitidis causes recurring epidemics every 8-12 years
Harrison's 22E | Goldman-Cecil Medicine

Etiology by Age/Risk Group

Patient Group	Common Organisms
Neonates (<1 month)	Group B Streptococcus, E. coli, Listeria monocytogenes, Klebsiella
Infants 1-3 months	Above + S. pneumoniae, N. meningitidis
Children >3 months - adults <55	S. pneumoniae, N. meningitidis
Adults >55, alcoholism, chronic illness	S. pneumoniae, Listeria, gram-negative bacilli
Immunocompromised	Listeria, gram-negative bacilli, Cryptococcus neoformans, CMV
Post-neurosurgery/VP shunt	Staphylococci (S. aureus, coagulase-negative), gram-negatives (Pseudomonas)
Otitis/sinusitis/mastoiditis	Streptococcus spp., Haemophilus, gram-negative anaerobes
Endocarditis	Viridans streptococci, S. aureus, HACEK organisms
Complement deficiency/properdin	N. meningitidis (recurrent)

Listeria is acquired through contaminated food (coleslaw, soft cheeses, deli meats, hot dogs). - Harrison's 22E

Pathophysiology

Nasopharyngeal colonization → S. pneumoniae and N. meningitidis attach to and invade nasopharyngeal epithelium
Bacteremia → polysaccharide capsule resists phagocytosis and complement-mediated killing
CNS invasion → bacteria enter via choroid plexus or cerebral capillary endothelium → replicate freely in CSF (normal CSF has very few WBCs, little complement or immunoglobulin)
Inflammatory cascade → bacterial components (LPS from gram-negatives, teichoic acid/peptidoglycan from gram-positives) trigger cytokines (TNF-α, IL-1β, IL-6) → blood-brain barrier disruption → cerebral edema, vasculitis, thrombosis, raised ICP

Clinical Features

Classic Triad (present in only ~44% of patients on presentation)

Fever
Neck stiffness (nuchal rigidity)
Altered consciousness / headache

Full Spectrum of Symptoms

Severe headache (most constant symptom)
Fever, rigors
Photophobia and phonophobia
Neck stiffness - resist passive neck flexion
Nausea, vomiting
Seizures (~20-40%)
Altered consciousness - confusion → stupor → coma
Focal neurological deficits (cranial nerve palsies, hemiparesis) in ~20%

Meningeal Signs

Kernig's sign: With hip flexed at 90°, inability to extend the knee beyond 135° without pain
Brudzinski's sign: Passive neck flexion causes involuntary flexion of the hips and knees
Jolt accentuation: Worsening of headache with rapid horizontal head rotation (sensitive but not specific)

Specific Features by Organism

Organism	Distinguishing Features
N. meningitidis	Petechial/purpuric rash (non-blanching); fulminant course; Waterhouse-Friderichsen syndrome (bilateral adrenal hemorrhage); DIC
S. pneumoniae	Often with pneumonia, sinusitis, otitis; alcoholism/splenectomy; highest mortality
Listeria	Brainstem involvement (rhombencephalitis); elderly/immunocompromised; pregnancy
Herpes simplex	Encephalitic features (temporal lobe involvement); behavioral change; seizures
Tuberculosis	Subacute onset; cranial nerve palsies; basal exudates; hydrocephalus
Cryptococcus	Immunocompromised (HIV); subacute/chronic; positive India ink; elevated opening pressure

CSF Analysis - The Key Investigation

Lumbar puncture (LP) is the definitive diagnostic test. Perform CT head first if: focal neurological deficit, papilloedema, new seizure, reduced consciousness, or immunocompromised.

CSF Findings Comparison

Parameter	Normal	Bacterial	Viral	TB/Fungal
Appearance	Clear	Turbid/cloudy	Clear	Clear/xanthochromic
Opening pressure	<180 mmH₂O	↑↑ (>180 in 90%)	Normal/mildly ↑	↑
WBC	<5/μL	PMN >100/μL (90%)	Lymphocytes 25-500/μL	Lymphocytes (early PMN)
Glucose	2.8-4.4 mmol/L	↓↓ <2.2 mmol/L (60%)	Normal/slightly ↓	↓↓
CSF:serum glucose	>0.6	<0.4 (highly suggestive)	>0.6	<0.4
Protein	<0.45 g/L	↑ >0.45 g/L (90%)	Normal/slightly ↑	↑↑
Gram stain	Negative	Positive >60%	Negative	Negative (AFB positive in ~10-40%)
Culture	Negative	Positive >70%	Negative	Positive in weeks

Additional CSF Tests

CSF multiplex PCR (BioFire FilmArray panel): detects S. pneumoniae, N. meningitidis, L. monocytogenes, HSV-1/2, CMV, EBV, enterovirus, cryptococcus - rapid result
Cryptococcal antigen: for immunocompromised patients
India ink preparation: Cryptococcus (positive in ~50%)
AFB smear and culture: TB meningitis
Adenosine deaminase (ADA): elevated in TB meningitis
Cytology and flow cytometry: carcinomatous/lymphomatous meningitis
Lactate: >3.5 mmol/L favors bacterial meningitis

Serum Biomarkers

Procalcitonin: elevated in bacterial; helps distinguish from viral
Blood cultures: positive in ~50-80% of bacterial meningitis
CBC, CRP, ESR

Investigations Summary

Test	Purpose
CT head (before LP if indicated)	Exclude mass lesion, cerebral herniation risk
LP + CSF analysis	Definitive diagnosis (opening pressure, cell count, differential, glucose, protein, culture, PCR, Gram stain)
Blood cultures (x2)	Before antibiotics; positive in majority
Bloods: FBC, CMP, coagulation, LFTs, glucose	Assess severity, metabolic status
Procalcitonin / CRP	Bacterial vs. viral discrimination
Meningococcal PCR (blood/CSF)	N. meningitidis in rash with purpura
Chest X-ray / CT chest	Source (pneumonia, TB)
MRI brain	Complications: cerebral edema, infarction, abscess, empyema, hydrocephalus

Treatment

Step 1: Immediate Empirical Antibiotics

Bacterial meningitis is a medical emergency. Target antibiotic administration within 60 minutes of arrival.

Do NOT delay antibiotics for CT or LP if there is clinical suspicion. Draw blood cultures first, then give antibiotics.

Empirical Antibiotic Regimens by Age/Risk

Patient Group	Empirical Regimen
Preterm/neonates <1 month	Ampicillin + cefotaxime
Infants 1-3 months	Ampicillin + cefotaxime or ceftriaxone
Immunocompetent children >3 months and adults <55	Cefotaxime or ceftriaxone + vancomycin
Adults >55 / alcoholism / debilitating illness	Ampicillin + cefotaxime or ceftriaxone + vancomycin (adds Listeria coverage)
Hospital-acquired / post-neurosurgery / neutropenic / immunocompromised	Ampicillin + ceftazidime or meropenem + vancomycin

Add:

Acyclovir (empirically) - HSV encephalitis is the leading differential
Doxycycline during tick season (rickettsial / Ehrlichia)
Metronidazole if source is otitis/sinusitis/mastoiditis (gram-negative anaerobes)

Why vancomycin? Due to emergence of penicillin- and cephalosporin-resistant S. pneumoniae

Drug Doses (Adults)

Drug	Adult Dose
Ampicillin	12 g/day IV, q4h
Cefotaxime	12 g/day IV, q4h
Ceftriaxone	4 g/day IV, q12h
Vancomycin	45-60 mg/kg/day IV, q8-12h (target AUC 400-600)
Acyclovir	10 mg/kg IV, q8h

Step 2: Dexamethasone (Adjunctive Therapy)

Dexamethasone 0.15 mg/kg q6h for 4 days, given 10-20 minutes BEFORE or with the first dose of antibiotics
Mechanism: reduces cytokine-mediated inflammation; decreases BBB disruption
Benefit: reduces hearing loss and neurological complications, especially in S. pneumoniae meningitis
Evidence: landmark trial (de Gans and van de Beek, NEJM 2002) showed reduced mortality and morbidity for pneumococcal meningitis in adults
Caveat: may reduce vancomycin penetration into CSF - ensure adequate doses; if penicillin-sensitive pneumococcus confirmed, stop vancomycin

Step 3: Targeted Therapy (Once Organism Identified)

Organism	Drug of Choice	Alternative
S. pneumoniae (penicillin-sensitive, MIC <0.1)	Penicillin G 24 million U/day	Ceftriaxone
S. pneumoniae (resistant)	Ceftriaxone + vancomycin	Meropenem
N. meningitidis	Penicillin G or ceftriaxone	Chloramphenicol
L. monocytogenes	Ampicillin (+ gentamicin in severe cases)	TMP-SMX
H. influenzae	Ceftriaxone	Chloramphenicol
S. aureus (MSSA)	Nafcillin/flucloxacillin	Vancomycin
S. aureus (MRSA)	Vancomycin ± rifampicin	Linezolid
Gram-negative bacilli / Pseudomonas	Ceftazidime or meropenem	Cefepime
Cryptococcus neoformans	Liposomal amphotericin B + flucytosine (induction x2 weeks), then fluconazole
TB meningitis	RIPE (Rifampicin + Isoniazid + Pyrazinamide + Ethambutol) + dexamethasone

Duration of Antibiotics

N. meningitidis: 7 days
H. influenzae: 7-10 days
S. pneumoniae: 10-14 days
L. monocytogenes: ≥21 days
Gram-negative bacilli: 21 days

Viral Meningitis (Aseptic Meningitis)

Etiology (most common to less common):

Enteroviruses (coxsackieviruses, echoviruses) - most common; seasonal (summer/fall)
HSV-2 > HSV-1
Varicella-zoster virus (VZV)
EBV, CMV, HHV-6
Arboviruses (West Nile virus, others) - note: WNV can cause PMN pleocytosis (45%)
HIV (seroconversion illness)
Mumps (in unvaccinated populations)

CSF: Lymphocytic pleocytosis (25-500/μL); normal glucose; normal to mildly elevated protein; negative Gram stain; identify by PCR

Treatment:

Mostly supportive (rest, analgesia, antipyretics, hydration)
Acyclovir for HSV or VZV meningitis (IV acyclovir 10 mg/kg q8h for moderate-severe; oral for mild VZV)
Antiretrovirals for HIV seroconversion meningitis
Enteroviruses: Pleconaril (investigational; not widely available); generally self-limiting

Prognosis: Excellent; full recovery in the vast majority within 1-2 weeks.

Complications of Bacterial Meningitis

Complication	Mechanism	Features
Raised ICP	Cerebral edema, hydrocephalus	Headache, vomiting, papilloedema, Cushing's triad, herniation
Cerebral infarction	Vasculitis, thrombosis, vasospasm	Focal deficit, hemiplegia
Seizures	Cortical irritation, infarction	20-40% of cases
Hydrocephalus	CSF obstruction by exudates	Worsening consciousness
Subdural empyema / brain abscess	Extension of infection	Focal signs, worsening despite antibiotics
Cranial nerve palsies	Basal exudates	CN III, IV, VI, VII, VIII most common
Sensorineural hearing loss	Most common neurological sequel; pneumococcal > others	Up to 30% with S. pneumoniae - reduced by dexamethasone
DIC / Waterhouse-Friderichsen	N. meningitidis; endotoxin-mediated	Purpura, adrenal hemorrhage, shock
SIADH	Inappropriate ADH secretion	Hyponatraemia; fluid restrict
Septic shock	Bacteraemia	Haemodynamic instability

Chemoprophylaxis for Close Contacts

Indicated for close contacts of N. meningitidis cases:

Rifampicin 600 mg q12h for 2 days (adults); or
Ciprofloxacin 500 mg single dose (adults); or
Ceftriaxone 250 mg IM single dose

Not indicated for S. pneumoniae meningitis contacts.

Vaccination: Meningococcal conjugate vaccine (serogroups A, C, W-135, Y) + serogroup B vaccine for close contacts and high-risk groups (complement deficiency, asplenia, complement inhibitor therapy).

Differential Diagnosis of Meningitis

Condition	Key distinguishing features
Subarachnoid haemorrhage	"Thunderclap" headache; xanthochromic CSF; CT shows blood
Brain abscess	Focal deficit; less meningism; ring-enhancing lesion on MRI
Encephalitis	Prominent psychiatric/cognitive features; seizures; focal signs > meningism
Neurosarcoidosis	Chronic; cranial nerve palsies; hilar lymphadenopathy; CSF ACE
Carcinomatous meningitis	Malignancy history; multiple cranial nerve palsies; positive CSF cytology
Drug-induced aseptic meningitis	NSAIDs, TMP-SMX, IVIG; takes weeks-months
Migraine	No fever; normal CSF; recurrent; responds to triptans

Summary: Approach to Suspected Meningitis

Suspected meningitis
├── Stabilise: ABC, IV access, O2, blood cultures
├── Any contraindication to LP? (focal deficit, papilloedema, new seizure, coma, immunocompromised)
│   ├── YES → CT head first → LP when safe
│   └── NO → LP immediately
├── Give antibiotics within 60 min regardless of LP result
├── Dexamethasone BEFORE or WITH first antibiotic dose
├── Add acyclovir (exclude HSV encephalitis)
└── Adjust therapy when CSF/culture results available

Neuroimaging

Finding Sources

Reading File

Finding Sources

Reading File

Finding Sources

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